key: cord-0040433-8xmi0sd4
authors: KARP, CHRISTOPHER L.; COLEBUNDERS, ROBERT
title: Approach to the Patient with HIV and Coinfecting Tropical Infectious Diseases
date: 2009-05-15
journal: Tropical Infectious Diseases
DOI: 10.1016/b978-0-443-06668-9.50138-1
sha: 250543d2df3a87e7d92cdd481b0fcb8afe0da206
doc_id: 40433
cord_uid: 8xmi0sd4

nan

The morbidity, mortality, and social disruption due to the global acquired immunodeficiency syndrome (AIDS) pandemic weigh disproportionately upon resource-poor areas of the tropics. 2 Because these are the very areas where "tropical" infectious diseases continue to hold greatest sway, the potential for interactions between human immunodeficiency virus (HIV) infection and other tropical infectious diseases is great.

Such interactions are marked by epidemiologic complexity. The AIDS pandemic is best described as the sum of discontinuous and overlapping epidemics of disease among populations of variable and varying risk (see Chapter 76) . The predominant modes of transmission of HIV (perinatal, sexual, and parenteral) result in a bimodal distribution of disease, with peaks among young children and young adults. The risk of infection or disease due to tropical pathogens varies widely with differences in ecological, political, and socioeconomic conditions (including access to medical care); related specific host factors such as age of exposure, pregnancy, behavior, and nutrition; and host genetics. Disease due to a coinfecting pathogen may be due to primary infection, recurrent infection, or the reactivation of latent infection. For some pathogens, the risk factor responsible for the acquisition of HIV may also be the risk factor responsible for the acquisition of the coinfecting pathogen. As a consequence of this epidemiologic complexity, both the prevalence and the expression of coinfection are likely to be variable across ecological, economic, political, behavioral, and cultural divides.

There is also, of course, considerable biologic and clinical complexity in the interaction of agents of tropical diseases with HIV. Either pathogen has the potential for altering the natural history, immune response, or response to therapy of the other. 3, 4 

Infection with HIV has the ability to influence the natural history of infection with other pathogens through (1) facilitating infection, (2) altering the incidence of disease by increasing the ratio of disease to infection, (3) changing the presentation of disease, or (4) exacerbating the course of disease. 4 Such effects are presumed to be primarily the result of the immunosuppression associated with HIV infection.

Abnormalities of immune function are found in essentially every cellular and functional compartment of the immune system in AIDS, although profound defects in cell-mediated immunity (CMI) appear to be of greatest clinical importance. 5 In vitro correlates include functional abnormalities of • CD4+ T cells, with progressive failure of proliferation, interleukin (IL)-2 and interferon-γ (IFN-γ) production, 6 ,7 dysregulated expression of molecules essential for T-cell/antigen presenting cell interactions, 8 abnormal activation-induced apoptosis, 9, 10 and expansion of a subset of CD4+ T cells (CD4+CD25+ regulatory T cells) that are potent inhibitors of immune responses both to self and to pathogens 11, 12 • Monocyte/macrophages, with decreased chemotaxis and intracellular microbicidal activity and abnormal cytokine production 5,6 • Dendritic cells, with reduced ability to present antigen and activate T cells (along with efficient transfer of HIV infection to CD4+ T cells) 13 • CD8+ T cells, with decreased cytotoxic T-lymphocyte (CTL) function 5 and abnormal activation-induced apoptosis 10 • Natural killer (NK) cells, with decreased proliferation and IFN-γ production 14 Dysregulation of humoral immunity, marked by polyclonal B-cell activation, is also seen. 5 Functionally, abnormalities of CD4+ T cell, monocyte/macrophage, and dendritic cell function have been thought to be paramount to the suppression of CMI and the opportunistic infections seen in patients with AIDS. In addition to the direct effects of HIV infection, the immune system of HIV-seropositive people may also be compromised in clinically significant ways by profound nutritional and metabolic derangements (e.g., wasting or "slim disease"), therapeutic interventions (e.g., corticosteroids used for the treatment of Pneumocystis pneumonia), and the immune abnormalities associated with secondary infections (e.g., the suppression of CMI seen in visceral leishmaniasis).

The list of infectious diseases that are exacerbated by HIV coinfection 5 includes many that are predictable from data demonstrating the important role of CMI in protection from the etiologic agent. Several pathogens for which immunity has been presumed to depend on CMI do not appear to be exacerbated by HIV coinfection, however. The HIV "experiment of nature" has caused a reexamination of the immunology of such "missing infections" in AIDS. 15 HIV infection can also influence the therapeutic response of patients with presumed tropical infection. The ability to diagnose and monitor coinfection may be compromised by aberrant serologic responses, including false positives due to polyclonal B-cell activation, false negatives due to blunted antigen-specific antibody responses to newly acquired pathogens in late HIV disease, and false serologic reversion after treatment in late HIV disease. 5 Diagnosis may also be hindered by unusual presentations of disease with coinfecting pathogens. Finally, a plethora of intercurrent pathologic conditions may lead to a dulling of Ockham' s razor during the evaluation of disease in AIDS patients. A single pathogen, multiple pathogens, HIV infection, side effects of therapeutic drugs, or a combination of these may be responsible for the presenting complaints. Given the suboptimal response to the chemotherapy of many infections in the presence of profound immunosuppression, drugs may need to be given in greater numbers or for a longer duration. With many pathogens, in the absence of immune reconstitution resulting from highly active antiretroviral therapy (HAART), lifelong suppressive therapy is necessary. Drug therapy in the HIV-infected patient may be complicated further by increased rates of drug allergy as well as by untoward drug interactions in the setting of polypharmacy. 16 Prophylaxis against coinfections may be compromised by substandard vaccination responses. [17] [18] [19] Finally, the presence of HIV coinfection can complicate the public health consequences of tropical diseases. AIDS may increase the transmissibility of secondary infections and provide fertile soil for the development of drug resistance. Public health resources devoted to the AIDS pandemic may divert resources away from the control and prevention of other infectious diseases.

The presence of HIV coinfection can lead to disease of markedly greater incidence or severity [the standard definition of an opportunistic infection (OI)] 20 with some tropical infectious diseases, such as leishmaniasis and American trypanosomiasis (Chagas' disease). Coinfection has also been demonstrated to have subtle effects on the course of disease with other tropical agents, such as Schistosoma mansoni. No identified alteration has been found in the natural history of many tropical infections, including most nematodes.

With organisms in the latter groups, the current absence of evidence of significant effects of HIV on the expression of disease or the response to treatment should not be construed as strong evidence for the absence of such effects. Most research resources have been spent on understanding the clinical and epidemiologic manifestations of the HIV pandemic in industrialized countries, where tropical infectious diseases are obviously underrepresented. 4, 21 Where coinfections with HIV and endemic tropical diseases are marked by low prevalence, subtlety of interaction, diagnostic difficulty, or low research priority, the presence and significance of any interaction are likely to be missed. For example, despite the research priority among tropical infections accorded to malaria, a significant interaction with HIV infection-the lack of a benefit of increasing parity in the control of malaria in pregnant women-was only discovered 15 years after the AIDS epidemic was recognized. 22 With less heavily studied pathogens, comparatively subtle interactions will likely emerge over time as research resources are appropriately directed.

Focusing on OIs may help to highlight some of the clearest data on the clinical expression of AIDS in the tropics. Of the more than 100 agents known to cause OIs in AIDS patients, several are classic tropical pathogens. 20 These are mostly found among the intracellular protozoans, bacteria, and endemic fungi; there is a marked absence of metazoans. Overall, the clinical expression of AIDS in many resource-poor areas of the tropics appears to involve a different spectrum of OIs than those common in North America and Europe. In place of the high incidences of Pneumocystis carinii pneumonia (PCP), disseminated Mycobacterium avium, and cytomegalovirus (CMV) found in the resource-rich north, the clinical expression of AIDS in much of the tropics has been marked by frequent tuberculosis (the most common serious AIDS OI in the world), chronic diarrhea, wasting, chronic fever without an obvious localizing source, and pulmonary disease. 23 The contribution of predominantly tropical pathogens to these latter common syndromes is unclear, which illuminates the problems with much of the available data on HIV disease in the tropics. Understanding the spectrum of AIDS-associated OIs in any given area depends on the presence of adequate surveillance systems, which are often lacking in resource-poor regions of the tropics. In the presence of inadequate infrastructures, limited financial resources, and difficult access to medical care on the part of the socially disadvantaged, surveillance is likely to be sporadic and to involve mainly the sampling of subgroups of AIDS patients at late stages of disease. 21 Where resources are limited, diagnostic reporting is likely to be biased in favor of OIs that are inexpensive to diagnose (or misdiagnose). 21 Even the common impression that the progression of AIDS is more rapid in sub-Saharan Africa than in industrialized countries 24-27 rests on data that are less than robust. 28 A more rapid observed course (presumed due to a higher frequency and virulence of coinfection and problems of nutrition and access to medical care) may represent in large part a systematic bias in favor of later initial diagnosis of HIV infection and AIDS. 21, 23 Conversely, it has been suggested that the burden of illness and mortality in early HIV disease (often unrecognized as such) due to high-grade pathogens, such as Streptococcus pneumoniae, Mycobacterium tuberculosis, and the salmonellae, may rival that due to the OIs of late-stage AIDS in the tropics. 29, 30 HIV has shed light on many previously obscure human pathogens. Some, such as the enteric microsporidians, were unknown as agents of human disease prior to the AIDS epidemic. Others, such as Cryptosporidium parvum, were underappreciated as causes of disease in normal hosts until their prevalence in AIDS patients led to systematic study in normal hosts. The list of agents causing OIs in AIDS patients is bound to expand. It is reasonable to expect that tropical regions will be prime locations for the identification of further such agents.

There are theoretical and experimental reasons to believe that coinfection can significantly alter the course of HIV pathogenesis. The central role of ongoing viral replication in HIV pathogenesis is firmly established, and the set point concentration of plasma viremia correlates well with long-term clinical outcome. 31 It is presumed that any increases in viral replication have the potential for accelerating the course of disease. Efficient replication of HIV in CD4+ T cells is dependent on cellular activation. Similarly, activation of monocyte/ macrophages and dendritic cells can stimulate HIV replication by increasing transcription factor binding to the HIV long terminal repeat region (LTR), enhancing LTR-directed transcription. Coinfecting pathogens can stimulate such immune cell activation either directly (e.g., stimulating signaling through pathogen recognition receptors such as Toll-like receptors 32 or upregulating transcription factor transactivation in coinfected immune cells) or indirectly (e.g., promoting the generation of proinflammatory cytokines such as tumor necrosis factor-α [TNF-α] or activating CD4+ T cells as part of the adaptive immune response). Immune activation can also lead to upregulation of the expression of HIV coreceptors, 33 thereby facilitating the infection of fresh cells.

Immunologic responses to pathogens, as well as to purified vaccine antigens, clearly have the potential for enhancing the dynamic burden of HIV replication. In vitro studies with diverse pathogens have provided mechanistic support for this idea. [34] [35] [36] Experimental evidence has also suggested that immune activation-driven augmentation of the HIV viral burden can occur in vivo. [37] [38] [39] [40] [41] [42] [43] [44] There is also circumstantial evidence that such immune activation may enhance HIV pathogenesis. 45, 46 Both points remain somewhat controversial, however. 47 Whether immune activation-related increases in viral load actually accelerate the pathogenesis of HIV may depend on whether the changes are transient (as with immunization or with treated acute infection) or chronic (as with untreated or untreatable infection, or through a resetting of the set point of plasma viremia by a particular coinfection). 48 Direct equation of immune activation with upregulation of HIV replication is simplistic, however. With CD4+ T cells, the mechanism of activation appears to be critical to whether viral replication is induced or suppressed. 49,50 Furthermore, activation of proinflammatory cytokine production with positive effects on HIV replication goes hand in hand with activation of anti-inflammatory cytokine production that can inhibit HIV replication. 51 More generally, proinflammatory responses reliably induce counterregulatory responses that suppress subsequent immune activation. 52 It thus should not be surprising that in vitro studies have provided mechanistic support for the ability of coinfecting pathogens to suppress HIV replication. 53-56 Indeed, the overall effect of acute coinfection with some pathogens, including measles virus, dengue virus, and Orientia tsutsugamushi, may be a decrease in HIV viral load. [57] [58] [59] In addition to the viral sequelae of generalized immunologic activation, induction of specific alterations in the immunoregulatory environment of the host by ubiquitous tropical pathogens has been postulated to accelerate the course of HIV. Cross-regulating subsets of CD4+ T cells have been distinguished by their cytokine profiles and functional activities: Th1 cells (producing IFN-γ and IL-2, among other cytokines) are important in classical macrophage activation, the development of CMI, and the generation of humoral responses involving complement-fixing antibody isotypes; Th2 cells (producing IL-4, IL-5, and IL-13, among other cytokines) are important in alternative macrophage activation, the generation of immunoglobulin E (IgE ) responses, eosinophilia, mast cell responses, and atopy. The immunologic response to most helminthic parasites is dominated by the production of Th2 cytokines. Evidence from murine systems shows that helminth-driven Th2 polarization can shift the immunologic response to heterologous antigens and pathogens from a Th1-to a Th2-dominant pattern, as well as significantly suppress CD8-mediated viral clearance. 60,61 Such responses have also been found to impair antigen-specific Th1 immune responses in both mice and humans. 60,62 Helminthic infection is chronic and widespread in the tropics. The resultant Th2 "priming" of the immune system may favor progression of HIV disease. 63 Several mechanisms have been postulated. First, a Th2-polarized immune system may directly suppress CD8 T cell-mediated anti-HIV responses. 61 Second, HIV may preferentially replicate in Th2 cells. 64 Third, T cells from HIVseropositive people undergo abnormal activation-induced apoptosis, 9, 10 which is thought to play a role in the depletion of both CD4+ and CD8+ T cells over time. Th2 cytokines can amplify such activation-induced apoptosis. 65 Fourth, Th2 cytokines can upregulate HIV coreceptor expression by CD4+ T cells and monocyte/macrophages. 66, 67 Of note, it has been demonstrated that peripheral blood cells from patients with intestinal helminth infection are more susceptible to in vitro infection with HIV than are cells from helminth-uninfected patients. 68, 69 Although intriguing, the hypothesis that endemic helminth coinfection leads to acceleration of the disease course of HIV remains unproven. A study in Ethiopia indicated that HIV viral load was significantly higher in individuals with various helminthic infections than in individuals without helminths, correlating positively with the parasite load as well as decreasing after elimination of the worms by antiparasitic treatment. 70 However, similar studies performed in Uganda and examining larger numbers of patients convincingly failed to replicate these findings. 71, 72 These latter studies strongly suggest that helminth coinfection is not associated with faster progression of HIV disease.

Other effects of coinfection are perhaps more concrete. Tropical diseases may lead directly to an increased risk of infection with HIV. Treatment of the severe anemia induced by malaria has led to the HIV infection of countless children by transfusion. 73 Genital schistosomiasis, like other genital inflammatory conditions, may increase the efficiency of HIV transmission. 74 

Lewis Thomas wrote that infectious disease "usually results from inconclusive negotiations for symbiosis." 75 In this light, most tropical pathogens lead to high infection:disease ratios. Whether disease is present or not, sterile immunity is not thought to be achieved after infection with most intracellular protozoans. This is as much the case with the tropical and subtropical agents of leishmaniasis and Chagas' disease as it is with the ubiquitous agent of toxoplasmosis. These are thus lifelong infections, with serious disease often resulting when an HIV-infected host defaults on his or her side of these immunologic "negotiations." From the point of view of the clinician in a nonendemic area, this necessitates obtaining a lifetime travel history for all HIV-infected patients. From the perspective of the clinician from either endemic or nonendemic areas, it is equally necessary to have an appropriate index of suspicion for HIV coinfection when contemplating the possibility of a tropical infectious disease. In the process of giving this important virus its diagnostic due, however, it is critical to avoid letting the presence or suspicion of HIV infection distract from the careful consideration of etiologic agents that present and respond similarly in HIV-seronegative and HIV-seropositive people.

The basic biology of HIV; the progression, diagnosis, and treatment of HIV disease; and the epidemiology of HIV/AIDS in the tropics are discussed in Chapter 76. This chapter focuses on the natural history, diagnosis, treatment, and prevention of tropical diseases and OIs in the HIV patient. Distinguishing tropical from other pathogens has its artificial side. Measles, not usually thought of as a tropical disease, causes significant mortality only in the tropics today. Tuberculosis, a pandemic infection, is the principal AIDS-related OI in the tropics. Given the historical preoccupation of the field of tropical medicine with parasitic infections, such infections receive close attention here. For practical reasons, OIs that are common in the industrialized world are not discussed in depth unless there are compelling clinical or epidemiologic reasons for doing so. Multiple references are available via the Internet that discuss these cosmopolitan OIs in detail. [76] [77] [78] [79] Further information on all of the specific organisms discussed here can also be found in the relevant chapters of this book.

The diagnostic, prophylactic, and therapeutic recommendations discussed here describe an approach to the HIV patient that is not limited by scarce medical resources. As such, like many strategies for dealing with HIV disease that have evolved in affluent industrialized countries (including HAART, high-technology diagnostics, and multidrug chemoprophylaxis), many of these recommendations may not easily be translated to resource-poor areas of the tropics.

Malaria (see chapter 90) remains one of the most important infectious diseases in the world today, causing 100 to 200 million new cases and 1 to 2 million deaths each year. Evidence from both murine and human studies suggests an important role for CD4+ T cells in protective immunity to blood-stage malaria. With large areas of shared endemnicity and prevalence, a medically significant interaction between HIV and malaria was thus expected and feared. 80 Initial studies were negative; falciparum malaria did not appear be an OI or to accelerate the progression of HIV disease. [80] [81] [82] [83] [84] [85] However, follow-up studies have revealed significant bidirectional interactions between Plasmodium falciparum and HIV.

HIV replication in peripheral blood cells is enhanced by exposure to P. falciparum antigens in vitro, in part through induction of TNF-α. 86 Increased HIV replication in dendritic cells has also been seen after the in vivo infection with Plasmodium chabaudi of mice transgenic for the HIV genome in a process that appears to be dependent on CD4+ T-cell activation. 87 The production of TNF-α during malarial paroxysms, 88 along with the antigenic exposure of parasitemia, might thus reasonably be expected to increase HIV viral load. Indeed, clinical studies from Malawi have shown that P. falciparum infection is associated with increased HIV viral burden in peripheral as well as placental blood. 89, 90 Treatment was associated with a reduction in viral load, although it remained elevated compared to controls for the 4-week duration of the study. 89 Whether or not malaria-mediated increases in HIV replication accelerate the course of HIV disease remains to be determined.

The first significant clinical effect of HIV on malaria was found in the setting of pregnancy. In areas of high malarial endemnicity, the high degree of immunity that women of childbearing age have developed to severe malaria is compromised by pregnancy. The placental vasculature shields parasitized erythrocytes from the systemic immune response, allowing localized erythrocytic replication of the parasite. Placental parasitemia has been associated with low birth weight and, hence, increased infant mortality. Local uteroplacental immune responses do restrict parasite replication, however, and the effectiveness of these local responses increases in subsequent pregnancies under pressure of recurrent malarial exposure. In 1996, a study performed in rural Malawi demonstrated that the beneficial effects (maternal, placental, and neonatal) of parity in the control of parasitemia during pregnancy were markedly attenuated in the face of HIV coinfection. 22 Since then, multiple studies performed in sub-Saharan Africa have probed the effects of coinfection on the outcome of pregnancy. [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] Such studies have shown that (1) HIV infection is associated with increased rates and levels of peripheral and placental parasitemia, clinical malaria, and maternal anemia in pregnant women, and (2) coinfection is associated with a higher risk of low birth weight, preterm birth, intrauterine growth retardation, and postnatal infant mortality. 101 Although placental parasitemia is associated with increased placental HIV viral loads in coinfected patients, 90 it remains unclear as to whether malaria infection increases the risk of mother-to-child transmission of HIV. Conflicting results (enhancement, protection, and no effect) have been published. 96, 97, 100 A World Health Organization (WHO) technical consultation has recommended that HIV-infected pregnant women who are at risk for malaria should always have protection with insecticide-treated bed nets, along with (according to HIV stage) either intermittent preventive treatment with sulfadoxine/pyrimethamine or daily trimethoprimsulfamethoxazole (cotrimoxazole; TMP-SMX) prophylaxis. 102 HIV infection is associated with an increased incidence of parasitemia, the risk of clinical malaria is significantly higher in HIV-infected adults, and this risk increases with decreasing CD4 cell count. [103] [104] [105] Notably, HIV infection has also been found to be a risk factor for severe malaria in nonimmune populations (in an area of unstable transmission). 106 Finally, although early studies found no evidence that the treatment or prophylaxis of malaria was altered by HIV coinfection, 81, 83 the risk of malaria treatment failure has recently been found to be higher in CD4-depleted HIV positive individuals. 107, 108 HIV protease inhibitors currently used for HAART have understudied interactions with a variety of drugs used for malaria prophylaxis and treatment. A variety of protease inhibitors, as well as the nonnucleoside reverse transcriptase inhibitors delaviradine and efavirenz, inhibit hepatic cytochrome P-450 enzymes. Principal effects are on the CYP3A4 isoform (with ritonavir being the most potent inhibitor), although the CYP2D6 isoform may also be affected. 109, 110 Nevirapine and efavirenz cause secondary induction of CYP3A4, an effect of ritonavir and nelfinavir as well. 109, 110 Most antimalarial agents are largely metabolized via P-450 enzymes. Mefloquine appears to be no exception, although the details remain poorly understood. 111 Proguanil and chloroquine metabolism appears to be largely by the CYP2C19 and CYP2D6 isoforms, respectively. [112] [113] [114] [115] Chloroquine also undergoes appreciable renal excretion, whereas doxycycline largely avoids these pathways in vivo. A detailed understanding of atovaquone metabolism appears to be lacking.

Actual published pharmacokinetic data suggest that (1) there are no significant drug-drug interactions between nelfinavir or indinavir and mefloquine 116 ; (2) ritonavir has minimal effects on mefloquine pharmacokinetics, whereas mefloquine suppresses ritonavir plasma levels 117 ; and (3) atovaquone increases serum zidovudine (AZT) levels by approximately 30%, although AZT has no effect on the pharmacokinetics of atovaquone. 118 In summary, the actual pharmacokinetics are not easily predictable from theoretical considerations, and there is a paucity of data. Based on the current data, mefloquine, doxycycline, chloroquine, and malarone (atovaquone + proguanil) are likely to be safe and to retain efficacy for prophylaxis of sensitive strains of malaria.

Among other malaria treatment options, quinidine, quinine, and β-artemether are all predominantly metabolized through CYP3A4 isoforms. 110 Large (more than threefold) increases in the area under the curve (AUC) for quinidine are expected for ritonavir. 119 As a result, quinidine has been considered to be contraindicated for those on ritonavir, 119 and this likely applies to quinine as well. There are no actual data, however. Whether there are clinically relevant effects of these protease inhibitors on the metabolism of artemisinin compounds (dependent at least in part on CYP3A4) remains unknown. Uncomplicated malaria can probably be safely treated with chloroquine (if sensitive), pyrimethamine/sulfadoxine, or mefloquine. Use of quinine, quinidine, or artemisinin compounds remains essential for the parenteral therapy of severe chloroquine-resistant malaria. For those on ritonavir (and/or other protease inhibitors, delaviridine, or efavirenz), the normal loading dose of quinine or quinidine should probably be given, along with some reduction of the maintenance infusion dose. Obviously, careful monitoring needs to be done for the potentially fatal arrhythmic consequences of quinine/quinidine overdosage in this setting. Given the lack of data, however, underdosing may also be a potential problem. The "washout" period for the metabolic effects of ritonavir is thought to be 24 to 48 hours.

A higher incidence of allergic responses to sulfonamides makes pyrimethamine-sulfadoxine (Fansidar) less attractive as a malaria therapy in HIV-seropositive patients, at least in North American populations. 120 Furthermore, Stevens-Johnson syndrome and related adverse mucocutaneous reactions to the long-acting sulfa compound, sulfadoxine, have contraindicated its benefits for use in malaria prophylaxis in developed countries. 121 The presence of HIV infection alters the predictive value of fever in the empirical diagnosis of malaria. In areas with a high prevalence of both HIV and malaria, the common practice of empirically treating febrile adults for malaria leads to gross overestimation and overtreatment of malaria. 103 Finally, treatment of severe anemia due to malaria is one of the most common reasons for blood transfusion in sub-Saharan Africa. Malaria thus provides an indirect but very important risk factor for the acquisition of HIV infection by children where the blood supply is not well screened. 73 

The genus Babesia contains more than 70 known species of tick-borne intraerythrocytic protozoans that parasitize wild and domestic vertebrates, predominantly in tropical and subtropical areas. Human babesial disease has been reported mostly from temperate climates (see Chapter 91) . A significant clinical interaction with HIV infection has been suggested for Babesia microti, raising the possibility that disease with tropical babesial species may be a risk for AIDS patients and providing the rationale for the current discussion. There are five reported cases of babesiosis due to B. microti in HIV-infected people. [122] [123] [124] [125] [126] Two cases occurred in splenectomized patients; in one, chronic low-level hemolysis due to Babesia prior to splenectomy was likely. Patients with intact spleens presented with fevers of unknown origin (FUOs) in the face of CD4 counts less than 200/μL. In one, the FUO lasted for months and was associated with night sweats, dry cough, weight loss, and dyspnea on exertion. Persistent parasitemia after clinically successful chemotherapy led to the need for chronic suppressive therapy. In another patient, recurrent disease led to retreatment 8 months after initial therapy. Quinine plus clindamycin and atovaquone plus azithromycin both have therapeutic efficacy in acute disease. 127 In HIV-infected patients, chronic suppressive therapy appears to be indicated. As with all vector-borne diseases, vector avoidance is the most efficient way to prevent disease. Significant interactions with HIV infection remain to be described for European bovine Babesia species (Babesia bovis and Babesia divergens) and the emerging agents of human babesiosis (WA 1 , CA 1 , MO 1 ) in North America.

With the exception of Toxoplasma gondii, Leishmania is the most common tissue protozoan causing OI in patients with AIDS (see Chapter 94). This is not surprising because cellular immune responses (in particular, Th1-mediated immune responses) are critical for protection from Leishmania. The competence of the Th1 axis of cellular response becomes increasingly compromised during the progression of HIVrelated immunosuppression, providing a favorable environment for disease due to Leishmania species. Furthermore, in vitro evidence suggests that coinfection of macrophages with HIV and Leishmania can directly upregulate parasite replication. 128 In vivo, the overall loss of immunological control of parasite infection is reflected by often aberrant manifestations of visceral leishmaniasis (VL) in AIDS, including peripheral parasitemia (found in more than 50% of coinfected people) and parasite dissemination to unusual body compartments. 129 An AIDS-related OI occurring at low CD4+ T-cell counts, leishmaniasis may be due either to primary Leishmania infection or to the reactivation of clinically latent infection. 130, 131 Although the published data on the interaction of HIV and Leishmania focus largely on the effects of HIV on leishmanial infection and disease, it should be noted that there is also both in vitro and in vivo evidence that Leishmania can augment HIV replication. [132] [133] [134] [135] Although leishmaniasis has a worldwide distribution in the tropics and subtropics, it normally requires an arthropod vector, the sandfly, to move the organism from its sylvatic (zoonotic) cycle to the human host. With certain species of Leishmania (Leishmania tropica and Leishmania donovani) and in some locations (e.g., Syria and India, respectively), an anthroponotic human-to-human cycle via the sandfly can exist. In situations in which intravenous drug use is practiced, transmission is simplified even further by direct person-to-person transfer via contaminated needles and syringes. Generally, however, leishmaniasis is a rural or periurban zoonosis.

The experience with VL complicating HIV/AIDS in Mediterranean countries indicates that many, perhaps most, of the leishmanial infections are acquired with HIV or after HIV infection has already occurred. The transmission of both agents that occurs by sharing of needles and syringes by intravenous drug users could theoretically be reduced by an aggressive program of education and provision of clean needles and syringes. An effective program of sandfly vector control will interrupt transmission from heavily infected human reservoirs to other humans as well as the more usual cycle of infected dogs to humans. Vector control is also the only way to prevent coinfection with Leishmania in those who acquire HIV sexually.

From the relatively high prevalence of latent leishmanial infections, it would appear that reactivation of latent infections could account for the increasing numbers of HIV-Leishmania coinfections; however, this concept is not always supported by epidemiologic evidence. A greater variability in zymodemes (enzyme markers) has been found in parasite isolates from HIV-infected than -uninfected patients. In one series, five isolates were recovered from HIV-infected patients that had previously not been encountered in immunocompetent people with either VL or cutaneous leishmaniasis (CL). 136 The finding that certain strains of Leishmania typically causing cutaneous disease are being recovered from the bone marrow of coinfected patients could support either the primary or the reactivation hypothesis. 137 Normally, the age distribution of VL caused by L. donovani includes adults as well as children. In contrast, VL due to Leishmania infantum affects children predominantly, often age 5 years or younger. In Spain, where intravenous drug use accounts for the majority of HIV-Leishmania coinfections, the age distribution of VL has been reversed, with most cases occurring in young adult males. 138 The fact that 50% of coinfected patients have demonstrable organisms in peripheral blood smears 139 and the fact that sandflies can readily be infected by feeding on coinfected patients 140 provide evidence for an additional anthroponotic cycle of transmission in this setting. 137 In summary, although reactivation of latent leishmanial infection is difficult to exclude, increasing evidence-in southern Europe, at least-favors primary infection by certain strains of Leishmania as the main mechanism for coinfection with HIV/AIDS.

With the spread of the HIV pandemic, there is increasing epidemiological overlap of areas in which HIV and leishmania occur, particularly in eastern Africa, India, Brazil, and Europe. Cases have been reported from approximately 40 countries, although the bulk of cases have been reported from southern Europe. [129] [130] [131] 137, 141, 142 Of note, relatively few cases of American mucocutaneous leishmaniasis have been recognized in HIVinfected subjects. 143, 144 The propensity for disseminated disease in the presence of HIV appears to be limited to certain species of Leishmania. The bulk of the information on VL complicating HIV infection involves L. infantum in the Mediterranean region. Presumably, the ability to visceralize under the influence of HIV also applies to L. donovani in southern Asia and Africa and to L. chagasi in Latin America; however, documentation for this is still somewhat meager, one of the possible reasons being the poor overlap between geographic distribution of leishmaniasis caused by these species and the distribution, as well as prevalence, of HIV infection. The species of Leishmania that cause CL have been implicated only rarely as OIs in HIV/AIDS. In one instance, L. braziliensis was recovered from the bone marrow of a patient with a CD4+ T-cell count of less than 10/μL, 145 but the main clinical picture in this case, as well as in others, [146] [147] [148] including a patient infected with Leishmania major, 149 has been one of multiple cutaneous lesions resembling diffuse CL.

A febrile illness of longer than 2 weeks' duration in an HIVinfected person with a lifetime history of travel to Leishmaniaendemic regions of the world should certainly raise suspicion of leishmaniasis complicating HIV infection. If the patient is an intravenous drug user, travel to southern Europe, especially Spain, France, and Italy, would be particularly pertinent. Clinical diagnosis of VL in leishmania-HIV coinfected people may be difficult. Only 75% of HIV-infected patients, as opposed to 95% of non-HIV-infected patients, exhibit the characteristic clinical pattern, namely fever, splenomegaly, and hepatomegaly. 130, 131, 137, 142, 150 With increasing immunosuppression, clinically evident ectopic localization of parasites becomes common. 151 Gastrointestinal, laryngeal, pulmonary, and peritoneal involvement has been reported. [151] [152] [153] [154] [155] [156] [157] [158] Single and multiple cutaneous forms and/or mucosal and mucocutaneous lesions have also been described in AIDS patients worldwide. 148, 153, 159 In immunocompetent people, tests for antileishmanial antibodies have been very useful in the diagnosis of VL because B cell activation is prominent, with large amounts of both specific and nonspecific antibody being produced. In contrast, approximately 50% of coinfected patients lack detectable antibody levels. 130, 131, 150, 160 The situation may be different in instances in which leishmanial infection has preceded HIV infection and the impaired immune response that ensues. Gradoni and associates 161 suggested that this type of serologic data could be used as an indicator of the sequence of acquisition of the two infections. Support for this concept is provided by a report from Ethiopia of seven cases of VL with HIV coinfection, all with highly elevated antileishmanial antibody titers. 162 All patients had lived for many years in a leishmaniasis-endemic area of Ethiopia. 162 The recombinant antigen rK-39 appears to be highly sensitive and specific for immunodiagnosis of VL due to L. donovani and L. chagasi in patients without complicating HIV infection; however, the sensitivity of rK-39 for immunodiagnosis of cutaneous cases from Turkey was greatly reduced compared with most cases of VL. 163 The utility of rK-39-based diagnostics is not clear in HIV-seropositive people. The peripheral parasitemia displayed by many HIV coinfected individuals allows the detection of parasites from the blood in approximately 50% of cases. Cultures and polymerase chain reaction (PCR) of buffy-coat preparations are positive in 70% and up to 100%, respectively. 130, 131, 164 There is abundant evidence that successful treatment of leishmanial disease, regardless of the drugs used, ultimately requires intact CMI. The coinfected patient is the victim of a double insult to the immune system. VL is associated with antigen-specific T-cell unresponsiveness 165 and dysfunctional cytokine responses. 166 This situation is further compounded by the immunologic abnormalities associated with HIV infection.

Therapy for VL in the face of HIV coinfection remains controversial, largely due to a lack of firm data. The same drugs used for treatment of VL in normal hosts (including pentavalent antimonials and amphotericin B preparations) have utility in the treatment of HIV coinfected patients, albeit with significantly less efficacy. 150 Amphotericin B is a conventional drug for all forms of leishmaniasis, including visceral disease. Liposomally encapsulated amphotericin has the theoretical advantage of being targeted to monocyte/macrophages, host cells for leishmanial parasites. Between 40% and 65% of coinfected patients have initial parasitological cure after treatment with pentavalent antimonials, amphotericin B deoxycholate, or amphotericin B lipid complex. 150, 167, 168 Among these options, treatment with lipid formulations of amphotericin B appears to have similar efficacy, but less severe toxicity, than the other drugs. However, the experience with lipid formulations of amphotericin B in coinfected patients remains meager. 168 These lipid formulations are also quite expensive. Trials aimed at optimizing the therapy of VL in AIDS are clearly needed. 168 Even with initial cure, relapse is predictable over time, occurring in up to 80% of coinfected individuals within 1 year. 150, 167, 169 The optimal drug for secondary prophylaxis remains unclear. Pentamidine given once every 3 or 4 weeks 170 and liposomeencapsulated amphotericin every 2 weeks 171 or 3 weeks 169 have been used for secondary prophylaxis.

Miltefosine, an oral agent that is safe and effective for the treatment of Indian patients with VL, 172 has shown some promise in early compassionate-use treatments for VL in HIVinfected subjects. 173 Further optimization of treatment and suppressive regimens of miltefosine in HIV patients may establish roles for this new antileishmanial agent for therapy and suppressive prophylaxis of VL in HIV-infected patients.

The fact that significant reductions in the incidence of AIDS-related VL have been seen in southern Europe after the advent of HAART, 174, 175 along with the fact that HAART-related immune reconstitution has allowed the discontinuance of secondary prophylaxis for other OIs, has raised hope that HAART will allow for safe discontinuance of secondary prophylaxis for VL. Details of the levels of immunological and virological responses needed for termination of such secondary prophylaxis remain to be determined. [176] [177] [178] American Trypanosomiasis (Chagas' Disease) American trypanosomiasis, or Chagas' disease (see Chapter 93) , is a well-recognized OI in AIDS. 179 The causative organism, Trypanosoma cruzi, and the blood-sucking vector (triatomine) bugs that transmit this protozoan are restricted to the Western Hemisphere but are widely distributed from the United States to Chile and Argentina. Because the HIV-related Chagas' disease reported to date largely represents reactivation of chronic infection during the course of HIV-induced immunosuppression and not primary infection in the face of AIDS (which is not surprising given the differing patterns of epidemiological risk for these infections: largely rural for T. cruzi and largely urban for HIV), this OI can be expected to appear outside these geographic bounds. It should be noted that activation of latent T. cruzi infection, as well as exacerbated primary infection (transmitted by blood transfusion), is also well described in the face of the iatrogenic immunosuppression used for solid organ transplantation and therapy for hematological malignancies.

Available data suggest that clinical T. cruzi reactivation in the face of HIV coinfection occurs largely in those with CD4+ T-cell counts less than 200/μL. Clinically, such reactivation most commonly involves the central nervous system. 179, 180 Trypanosoma cruzi was probably late in being recognized as an opportunistic pathogen in those with HIV infection because the most prominent features of central nervous system disease are similar to those of toxoplasmic meningoencephalitis. Enlargement of hemorrhagic foci can produce mass effects simulating brain tumors. Lesions are often multiple, with computed tomographic (CT) scans and magnetic resonance imaging (MRI) showing ring enhancement and preferential involvement of the white matter. Toxoplasmic encephalitis may also be present in the same patient. 181 The cerebrospinal fluid (CSF) findings include a slight pleocytosis, increased protein, slightly decreased glucose in some patients, and the presence of trypanosomes. Histologically, the brain lesions show necrotic foci with hemorrhage and infiltration of inflammatory cells. Amastigote forms of the parasite are abundant in glial cells and macrophages and only occasionally in neuronal cells. Myocarditis is a common autopsy finding in those dying of AIDS-related T. cruzi meningoencephalitis. 178 Such myocarditis is often clinically silent. Clinical manifestations, when present, involve arrhythmias and congestive heart failure. 179, 182, 183 Correct diagnosis of reactivated T. cruzi infection depends, first, on considering the possibility based on the geographic origin of the patient and on an appreciation of the clinical picture. If neurologic signs are present, performing a CT scan or MRI is key. 184 The imaging pattern of central nervous system (CNS) T. cruzi infection is indistinguishable from that of toxoplasmic encephalitis. Direct microscopic examination of centrifuged sediment of CSF will often show motile trypanosomes. If fever and other systemic signs are present, direct examination of the buffy coat from the microhematocrit tube may also show motile trypanosomes. Since serum antibodies to T. cruzi indicate previous infection with the parasite, this test is only useful for ruling out reactivated infection if it is negative. If other tests are inconclusive, biopsy of a brain lesion to demonstrate characteristic organisms can be done. PCR on blood or CSF requires research laboratory facilities.

Clinically, differentiating HIV-related reactivation of Chagas' disease reactivation from chronic chagasic disease may be difficult. HIV-related reactivation is associated with high parasitemia, however, whereas the parasitemia of chronic disease is very low. 185 Indeed, even in the absence of overt, clinical reactivation, chronic Chagas' disease is associated with a higher percentage and level of parasitemia in those coinfected with HIV (independent of CD4 count) than in HIV seronegatives. 186 The effects of coinfection appear to be bidirectional. HIV viral load was carefully documented to increase simultaneously with an asymptomatic increase in T. cruzi parasitemia, subsequently returning to baseline in the face of successful antiparasitic treatment. 187 Nifurtimox and benznidazole, both of which have moderate antitrypanosomal activity, are the standard drugs recommended for treatment of Chagas' disease. There simply is not enough experience to evaluate the effectiveness of these drugs in the treatment of T. cruzi infections complicating HIV or AIDS, especially in cases with meningoencephalitis. No information is available on the penetration of these drugs into the CNS, and the survival time of reported cases of coinfection has been short. A patient reported by Nishioka and coworkers 188 survived for 92 days, with disappearance of trypanosomes from the blood and CSF as well as clearance of a brain lesion while being treated with benznidazole at a dose of 8 mg/kg/day for 80 days. Clinical improvement and reduction in size of a brain lesion were attributed to treatment with benznidazole plus, later, itraconazole and fluconazole in another patient with coinfection who survived for at least 6 months. 189 Although there is no other reported experience with the use of itraconazole or fluconazole in the treatment of American trypanosomiasis in humans, itraconazole was reported to be very effective in experimental infections. 190 Infected mice given as little as 15 mg/kg/day were protected against death, and concentrations of itraconazole as low as 0.001 μg/mL inhibited replication of the parasites in macrophages. It has been recommended that treatment of T. cruzi infection in HIV-positive individuals be started early in the reactivation process, when parasitemia is detectable, but before irreversible end-organ damage has occurred. 187 Such a strategy would hinge on serological identification of those at risk, something indicated in all HIV-infected individuals with appreciable risk of T. cruzi infection. Although data are lacking, it should be noted that immunological reconstitution through HAART therapy is likely to provide considerable prophylactic and therapeutic benefit in this disease.

No significant interactions between the agents of African trypanosomiasis (see Chapter 92) and HIV have been delineated. Although T cell and macrophage responses are not thought to be important in the protective host response to trypanosomiasis, trypanosomiasis can suppress cellular immune responses, so a biologic interaction between the two is plausible. No significant epidemiologic association between Trypansoma brucei gambiense and HIV has been found. [191] [192] [193] [194] Whether HIV alters the clinical course of either West or East African trypanosomiasis is unclear. 193 There is anecdotal evidence that HIV may complicate the therapy of West African trypanosomiasis, however. Of 18 patients treated with melarsoprol in a rural hospital in the Congo, all 14 HIVnegative patients recovered, whereas 3 of 4 HIV-positive patients died during treatment (likely due to treatmentrelated encephalopathy) and the fourth failed to respond to therapy. 195 Other Trypanosomatids

In addition to the two genera, Leishmania and Trypanosoma, known to cause disease in humans, the Trypanosomatidae family includes other genera of protozoa that parasitize other vertebrates, insects, and plants. There have been three reports of HIV-infected individuals presenting with symptoms typical of visceral leishmaniasis in which ultrastructural, isoenzyme, and/or kinetoplast DNA analyses of the isolated lesional parasites have indicated that the responsible organism actually belongs to one of these latter genera. 196 The strong implication is that HIV-related immunosuppression can render humans vulnerable to normally nonpathogenic lower trypanosomatids.

Toxoplasma gondii is a ubiquitous parasite of mammals throughout the world (see Chapter 97) . Latent infection lasts for the lifetime of the host. Maintenance of latency is dependent on CMI responses. Reactivation of latent infection is common with increasing immunosuppression in AIDS. The principal manifestation of such reactivation, toxoplasmic encephalitis (TE), is thus a common OI in AIDS patients throughout the world.

The incidence of TE is proportional to the prevalence of latent infection in the population at risk of or with AIDS. 197 In the United States, the rate of latent infection varies between 10% and 40%; in Paris, the rate is 90%. 197 Acquisition of Toxoplasma infection is age dependent, but there is wide variation in infection rates even over narrow geographic areas. 198, 199 Prevalence rates in the tropics vary from 0% to 90%, with most measured communities falling in a broad middle range. [200] [201] [202] [203] [204] [205] [206] In the United States, prior to the advent of HAART, onethird of Toxoplasma-seropositive AIDS patients developed TE in the absence of prophylaxis, 207 90% of such cases were in patients with less than 200 CD4+ T cells/μL and 70% in those with less than 100 CD4 T cells/μL. 208 The prevalence of TE in AIDS patients in the tropics is unclear, but the burden is thought to be immense and underdiagnosed. Autopsy series that have included examination of the brain have suggested disease prevalence rates in late-stage AIDS patients of 15% in Abidjan, Côte d'Ivoire, 209 25% in Mexico City, 210 and 36% in Kampala, Uganda. 211 The presumptive diagnosis of TE is based on clinical presentation, positive Toxoplasma serologies, and characteristic neuroradiologic features. 212 A final clinical diagnosis is made based on the clinical and radiographic response to specific chemotherapy. Less common manifestations of toxoplasmosis in AIDS include pneumonia, retinochoroiditis, myocarditis, orchitis, and gastrointestinal involvement. The reader is referred to one of many excellent reviews on Toxoplasma in AIDS for information on the clinical management of this cosmopolitan OI. [76] [77] [78] [79] Five percent of TE occurs not as reactivation but as an acute infection. 207 Preventing the transmission of T. gondii to Toxoplasma-seronegative, HIV-infected people has two facets: (1) avoiding the ingestion of tissue cysts of other intermediate mammalian hosts (i.e., cooking meat well) and (2) avoiding the oocysts of the definitive host, the cat. Avoiding cat feces in and around dwellings is probably not sufficient because the oocysts are viable for up to 18 months in moist soil. Contamination of fresh vegetables may be a common method of human infection, and such foodstuffs should probably be washed well or cooked or both.

Primary prophylaxis (TMP-SMX is preferred) 213 should be taken by all Toxoplasma-seropositive HIV patients with a CD4+ T-cell count less than 100/μL. It is safe to discontinue both primary and secondary prophylaxis after HAART-related immune reconstitution (sustained CD4+ T-cell counts >200/μL). [76] [77] [78] [79] Free-Living Amebae Free-living amebae of the Acanthamoeba and Balamuthia genera (see Chapter 95) are rare causes of opportunistic encephalitis and cutaneous disease in late-stage AIDS. Most case reports have been from the United States, but the worldwide environmental distribution of these ubiquitous protozoans and the fact that diagnosis is often postmortem suggest that underdiagnosis is widespread in the tropics and elsewhere.

Granulomatous amebic encephalitis (GAE), a subacute to chronic disease of compromised hosts caused by multiple species of Acanthamoeba as well as Balamuthi mandrillaris, generally causes death in weeks to months. Clinical and pathologic data, as well as animal models, suggest that the pathogenesis of GAE involves hematogenous dissemination to the brain from initial upper or lower respiratory (or perhaps cutaneous) sites of infection. 214 Pathologic changes, in the form of necrotizing granulomatous inflammation, are found predominantly in the posterior neuraxis.

Acanthamoeba and Balamuthia have been isolated from soil, water (including tap water, bottled water, chlorinated pools, and natural sources of fresh-and seawater), and air throughout the world. 215 The isolation of Acanthamoeba from the nasopharynx of healthy adults indicates that these organisms may be a common constituent of normal flora. 216 Cellular immunity, along with antibody and complement, appears to be critical to protective immunity to Acanthamoebae. 217 Invasive disease occurs in the immunocompromised and debilitated. 214 Occasionally, encephalitis with Balamuthia mandrillaris has occurred in apparently normal hosts. 218, 219 More than 20 cases of GAE have been reported in AIDS patients. 214,220-229 Implicated Acanthamoeba organisms include Acanthamoeba castellani, Acanthamoeba culbertsoni, Acanthamoeba polyphaga, Acanthamoeba rhysodes, and Acanthamoeba divionensis. Disseminated cutaneous disease [subacute granulomatous dermatitis (SGD)] has been a feature of many of these cases and has preceded clinical cerebral involvement by weeks or months in some. SGD has been the sole manifestation of invasive disease in some patients. [230] [231] [232] [233] [234] Reported CD4+ T-cell counts have been less than 250/μL (median, 24/μL) at the time of presentation. Where CD4 counts have not been reported, the histories reveal clinical evidence of late-stage AIDS. 214, 234 GAE in AIDS patients is marked by a more rapid course (with death in 3 to 40 days) 214 and a paucity of well-formed granulomas in comparison to other hosts with the disease. 214, 233 Symptomatic involvement of the nasopharynx, paranasal sinuses, or the skin prior to development of GAE is common in AIDS patients. 214 Cutaneous lesions are usually nodular, with subsequent enlargement, ulceration, and metastatic spread. Such lesions can be quite pleomorphic (pustules, plaques, eschars, and cellulitis), however, and have been confused with cat-scratch disease, cryptococcosis, sporotrichosis, bacillary angiomatosis, mycobacterial infections, and vasculitis. 214 The most common presentation of cerebral disease is that of fever and headache. 214, 232 Focal neurologic deficits and profound changes in mental status are also frequent. Neuroradiologic findings mimic those of toxoplasmic encephalitis, with multiple enhancing mass lesions and surrounding edema. CSF findings are quite variable. 214, 232 A high index of suspicion and tissue or microbiologic diagnosis is key to the antemortem identification of disseminated Acanthamoeba infection. Wet mounts of CSF are occasionally useful. Both trophozoites and cysts can be found in tissue biopsies. Cysts have been mistaken for the sporangia of Rhinosporium or Prototheca or for cryptococci; trophozoites have been mistaken for tissue macrophages. 214 Acanthamoebae can be isolated by culture on Escherichia coli-seeded nonnutrient agar or in tissue culture medium. 214, 232 Identification of species (and even differentiation of Acanthamoeba from Balamuthia) is not possible morphologically. Immunofluorescence techniques can differentiate Acanthamoeba to the group level in tissue section or with cultured organisms. Treatment of disseminated disease due to these organisms is difficult. No chemotherapeutic regimen is clearly efficacious. Agents with possible clinical utility in combination therapy include pentamidine, 5-fluorocytosine, sulfamethazine, sulfadiazine, fluconazole, itraconazole, ketoconazole, macrolides, phenothiazines, and rifampin. 214, 228, 229, 231 There may be value in testing clinical isolates for drug sensitivities. With isolated cerebral lesions, there may be a role for surgical excision. 229 In a possible foreshadowing of a newly emerging OI, a case of primary amebic meningoencephalitis due to an apparently newly recognized ameba and not associated with thermally polluted water was reported in a patient with late-stage AIDS in Spain. 235, 236 Enteric Coccidiosis (Isospora, Cryptosporidium, and Cyclospora)

A trio of coccidian protozoa-Isospora belli, Cryptosporidium spp., and Cyclospora (Eimeria) cayetanensis-are all prominent causes of self-limited, small bowel diarrhea in immunologically normal hosts as well as causes of chronic, severe disease in the face of HIV coinfection. All are cosmopolitan infections. Infection with a fourth organism, Sarcocystis hominis, responsible for both enteric and disseminated coccidioisis in humans, does not appear to have been reported in HIV-infected individuals.

Cryptosporidium spp. (see Chapter 88) . In addition to the most common human pathogen Cryptosporidium hominis (previously Cryptosporidium parvum human genotype, or genotype 1), a variety of zoonotic species also infect humans, including Cryptosporidium parvum (previously bovine genotype, or genotype 2), Cryptosporidium canis, Cryptosporidium felis, Cryptosporidium meleagridis, and Cryptosporidium muris. [237] [238] [239] Zoonotic species may cause more severe human disease and may occur more commonly in immunocompromised people. Because of the high prevalence of disease and the lack of effective specific treatment, cryptosporidiosis is a particularly common and severe problem as an OI throughout the world. Chronic infection and disease are most frequent with CD4+ T cell counts less than 180/mL 240 and are associated with increased mortality. [241] [242] [243] The use of HAART therapy has led to a decreasing prevalence of cryptosporidial disease in HIVinfected individuals. 244, 245 Four clinical syndromes of cryptosporidial diarrheal disease in patients with AIDS have been limned: chronic diarrhea (36%), cholera-like disease (33%), transient diarrhea (15%), and relapsing illness (15%). The severe end of the spectrum is seen largely in those with CD4+ T-cell counts less than 180/μL. 246, 247 Less commonly, extraintestinal sites are secondarily involved, including biliary tract, stomach, pancreas, lung, paranasal sinuses, and middle ear. [246] [247] [248] [249] Of these, biliary tract involvement (presenting with right upper quadrant pain, nausea, vomiting, and fever) represents the most common, clinically important site, being found in up to one-fourth of patients with AIDS-related intestinal disease prior to the use of HAART. 250 Individuals with CD4+ T-cell counts less than 50/μL are at a particular risk for development of symptomatic biliary disease. 250 No antimicrobial agent has demonstrable, consistent efficacy in HIV-related cryptosporidiosis. Immune reconstitution with HAART should be pursued. 251, 252 If HAART fails or is not available, a variety of antimicrobial agents (including nitazoxanide, azithromycin, paromomycin, and atovaquone) may be tried. Supportive treatment with fluids, nutrition, and antimotility agents plays an obvious therapeutic role. [76] [77] [78] [79] Isospora belli (see Chapter 88) . Disease due to Isospora is less cosmopolitan than that due to Cryptosporidia, being most common in tropical and subtropical areas. 253 Isosporiasis usually presents with chronic watery diarrhea and weight loss, with or without vomiting, abdominal pain, and fever. 254 Invasion of gallbladder tissue, similar to that described with Cryptosporidium, has been described, along with disseminated involvement of mesenteric and tracheobronchial lymph nodes, in the setting of HIV coinfection. 254, 255 Prominent tissue eosinophilia of the involved lamina propria is often present. 253 Diagnostic and therapeutic issues are covered in Chapter 88. TMP-SMX provides effective therapy. 256 Pyrimethamine (with leucovorin) provides a second option. 257 Clinical response is usually rapid, but relapses are common. In the absence of immune reconstitution, suppressive therapy is indicated. [76] [77] [78] [79] Cyclospora (Eimeria) cayetanensis (see Chapter 89) . The clinical picture of enteric infection with C. cayetanensis in AIDS appears to be similar to that due to other coccidia. 258 It is of interest that biliary tract involvement-as evidenced by right upper quadrant pain, elevated alkaline phosphatase, and thickened gallbladder by ultrasound-has also been described in Cyclospora infection. 259 Thus, all three of the enteric coccidia of humans are capable of invading the gallbladder. Diagnostic and therapeutic issues are covered in Chapter 89. As with isosporiasis, cyclosporiasis in AIDS is treatable with TMP/SMX. 258 Subsequent suppressive therapy is indicated. [76] [77] [78] [79] Microsporidiosis Microsporidia are intracellular protozoans that, due to HIV and AIDS, have emerged from their relative obscurity as pathogens of insects, fish, and laboratory animals to occupy a new role as important OIs of humans. These cosmopolitan emerging pathogens of the immunosuppressed (including Enterocytozoon bienusi, Enterocytozoon [Septata] intestinalis, Enterocytozoon cuniculi, Enterocytozoon hellem, as well as pathogens from several other genera) are considered in Chapter 96.

Entamoeba histolytica. This intestinal parasite (see Chapter 86) was initially associated with HIV because of its high prevalence in men who have sex with men (MSM). Despite considerable evidence that immunity in amebiasis requires the participation of CMI, there is no evidence that patients with HIV infection or AIDS are more likely to develop invasive disease.

Giardia lamblia. As with E. histolytica, a high prevalence of infection with G. lamblia (see Chapter 87) was found in the 1980s among MSM. 260 A study of MSM performed at that time revealed no increased prevalence or severity of giardiasis in patients with AIDS. 261 Since then, no evidence has been found of a significant effect of HIV coinfection. Although some studies have indicated a higher prevalence of giardiasis in HIV seropositives, this has not been a consistent finding. Therapy of giardiasis in people with AIDS is usually successful. Some patients, immunocompromised as well as immunocompetent, are refractory to standard therapeutic regimens for giardiasis. It may well be that such refractoriness to standard therapy is found more commonly in the face of HIV coinfection. 262 Blastocystis hominis. Controversy continues to exist as to the role of this organism as a cause of diarrheal disease in either immunocompetent patients or HIV-infected people. 263 Blastocystis hominis has a cosmopolitan distribution; there is no association with the tropics.

Balantidium coli. No information is available as to whether this organism can serve as an OI in HIV-infected people.

There is no evidence that any trematode infection is more severe or difficult to treat in HIV-infected people. More subtle interactions have been explored in schistosomiasis (see Chapter 116) . Study of car washers working on the shores of Lake Victoria in Kenya, a population with a high intensity of exposure to S. mansoni and an HIV seroprevalence of approximately 30%, has provided insights into the bidirectional effects of coinfection. 264 The CD4+ T cell-dependent granulomatous response to schistosome eggs has been shown to be important in egg migration from venules to the lumen of the intestine in mouse models of disease. 264 As might thereby be expected, a significant suppression of egg excretion efficiency, controlled for the degree of infection, was found in S. mansoni-infected patients in the presence of HIV coinfection and low CD4+ T-cell counts. 265 Although successful therapy of S. mansoni infection with praziquantel may depend on the host antibody response, praziquantel was efficacious in treating schistosomiasis in this HIV-infected cohort. 266 Given that schistosome infection likely preceded HIV infection in these individuals, whether praziquantel will have equal efficacy in individuals infected with HIV first remains an open question. Notably, despite similar responses to therapy, individuals with HIV coinfection and low CD4+ T cell counts showed increased susceptibility to reinfection after therapy, 267 a response that appears to correlate with blunted immunological responses to successful drug therapy (and the resultant release of parasite antigen) in such individuals. 268 A study of HIV/S. haematobium coinfection in Zambia led to findings that mirror these findings with S. mansoni: (1) Coinfected individuals had lower egg excretion, and (2) praziquantel retained efficacy in the face of HIV coinfection. 269 No alteration in resistance to reinfection with S. haemotobium was seen in the face of HIV infection, but CD4+ T-cell counts were not performed in this cohort lacking evident HIV-related disease. It thus remains possible that, as with S. mansoni infection, resistance to reinfection with S. haematobium is decreased with progression of HIV/AIDS.

As for effects of schistosomiasis on HIV, there is evidence suggesting that genital schistosomiasis due to S. haematobium infection is a risk factor for HIV transmission. [269] [270] [271] As with a variety of sexually transmitted diseases, the mucosal (vulval, vaginal, and cervical) inflammatory lesions associated with female genital schistosomiasis are likely to compromise the antiviral barrier of the mucosa, provide a cellular milieu that allows for efficient viral transmission and replication, and enhance viral shedding. 270, 271 Correspondingly, male genital schistosomiasis is also likely to be associated with an increased risk of HIV transmission. In Madagascar, S. haematobium caused inflammation of the prostate and of the seminal vesicles in most adolescent and adult male patients. 272 By analogy to bacterial urethritis, such chronic inflammation is likely to be associated with increased viral shedding in the semen in HIV-coinfected individuals.

Schistosomiasis is a prime example of a chronic tropical infection that has been postulated to enhance the pathogenesis of HIV. Schistosoma mansoni infections act as powerful inducers of Th2 polarization in both murine models and humans. 60-62 The type 2 cytokine environment induced by S. mansoni eggs can significantly suppress CD8 T cell-mediated viral clearance in experimental models 61 and has been found to impair antigenspecific Th1 immune responses in both mice and humans. 61,66 Type 2-dominant immunologic responses have also been postulated to favor HIV progression due to preferential replication of HIV in Th2 cells, 64 amplification of activation-induced apoptosis in lymphocytes by type 2 cytokines, 9, 10 and upregulation of expression of the HIV coreceptors CCR5 and CXCR4 by CD4+ T cells and monocyte/macrophages. 66,67 Finally, the antigenic exposure of schistosomiasis may lead to sustained upregulation of HIV replication via the effects of chronic immune activation. 60 These considerations remain theoretical. Indeed, treatment of S. mansoni infection does not appear to reduce plasma HIV load in coinfected individuals. 273, 274 Cestodes A few unusual manifestations of cestode infection have been reported in AIDS patients. A rapidly expanding, invasive, and ultimately lethal abdominal mass in a patient with a CD4+ T-cell count less than 100/μL was found by ribosomal DNA amplification and sequencing to be due to an as yet uncharacterized cestode. 275 Whether this represents merely the fortuitous concurrence of an unusual pathologic finding with dramatic improvements in diagnostic technology (previous rare cases in normal hosts having occurred in the absence of diagnosis) or the recognition of a new disease because its expression is facilitated or dependent on immunosuppression (AIDS patients serving as "sentinel chickens" for the population at large) is unclear. The latter interpretation is favored by a previous similar case report of presumably disseminated cestode infection in the face of immunosuppression due to Hodgkin' s disease and its therapy. 276 Four cases of exuberant subcutaneous disease due to the larval form of Taenia crassiceps have been reported in AIDS patients. [277] [278] [279] [280] As this bests by one the previous number of case reports of human infection with T. crassiseps, the suggestion is that HIV infection is a risk for disease with this cestode. A case of hepatic alveolar echinococcal disease in a 6-year-old child with AIDS has been described. 281 Uncommon features of this case include the remarkably young age and hence short incubation period for disease and the complete lack of demonstrable parasite-specific humoral or cellular immune responses.

Finally, 10 cases of neurocysticercosis have been reported in HIV-infected patients, 282-286 a number that is sure to increase given the increasing rates of HIV infection in endemic areas. The frequency of giant cysts and racemose forms of disease is remarkably elevated in these reported cases, again perhaps a reflection of the role of CD4+ T cells in tissue immunity to T. solium. Further clinical data on the interaction between HIV and cestode infections are awaited.

Strongyloides stercoralis. The only nematode implicated as a cause of an OI in the presence of HIV coinfection is the intestinal parasite, Strongyloides stercoralis (see Chapter 111) .

S. Stercoralis appeared to qualify as an OI because it is one of the few nematodes capable of actually multiplying in, especially immunocompromised, human hosts. Capillaria philippinensis, for which humans are not the natural host, can also multiply internally, but C. philippinensis is rare, quite limited in its geographic distribution, and has not been reported as a coinfection in HIV-seropositive people (see Chapter 106) .

One way in which immunosuppression enhances Strongyloides infection is by permitting or stimulating an increased degree of the normal process of autoinfection. 287 In this process, first-stage rhabditiform larvae (L1) produced by the adult female worm in the upper small bowel are transformed into infective filariform larvae (L3) that can reinvade the intestinal wall of the colon or the perianal or perineal areas. Massive upregulation of the autoinfective process results in the hyperinfection syndrome, with the development of many more adult worms, and the production of large numbers of larvae that disseminate to all organs. The clinical picture is dominated by gram-negative bacterial sepsis, meningitis, or pneumonia.

Hyperinfection is usually associated with immunosuppression, particularly the administration of corticosteroids. In fact, the list of immunosuppressive diseases, both malignant and benign, associated with hyperinfection is unified by having corticosteroids as a common denominator of treatment, 287 but steroids do much more than alter T-cell function, both in the host and in the organism. The defense mechanisms necessary for control of S. stercoralis in humans have not been identified. Even direct effects of steroids on the female worms' reproductive efficiency have been postulated. 287, 288 The data are meager.

Strongyloides was initially designated as an AIDS OI on its past record of causing hyperinfection in the immunosuppressed. 289 Five years later, when it became apparent that hyperinfection syndrome was not being encountered frequently in patients with AIDS, it was removed from the list of OIs indicative of AIDS. 290 Given the low but appreciable rate (3.9%) of strongyloidiasis among men attending a venereal disease clinic in New York City in 1981, 291 the AIDS epidemic in the United States that developed in the 1980s should have provided some clinical evidence of any predisposition of AIDS patients to hyperinfection. This did not occur. The available evidence makes it extremely unlikely that misdiagnosis or underreporting are the relevant factors here; severe strongyloidiasis or hyperinfection syndrome has prominent clinical features and is often fatal if untreated, and it is not likely that the association would escape notice. Few cases of hyperinfection syndrome have been reported in the English-language literature. [292] [293] [294] [295] [296] [297] [298] [299] [300] [301] Even among these cases, the presence of hyperinfection is poorly documented in many.

Diagnosis of (as opposed to suspicion of) hyperinfection syndrome depends on the demonstration of markedly increased numbers of filariform larvae in the stool or multiple such larvae in the sputum. The mere presence of filariform larvae in the sputum only indicates the existence of autoinfection. (It should also be noted that the presence of rhabditiform larvae in the sputum points to neither autoinfection nor hyperinfection but to the presence of adult female worms in the lung.) Unfortunately, confusion of gastrointestinal disease with hyperinfection syndrome is embedded in the literature.

It is possible that the frequency of severe strongyloidiasis complicating HIV infection is much higher in certain areas of the tropics where both infections are prevalent and medical facilities are lacking; however, an absence of such an association has been noted from just such areas. 15 Petithory and Derouin 302 pointed out that clinical studies of AIDS patients in central Africa, where the prevalence of strongyloidiasis varies from 26% to 48%, did not mention extraintestinal strongyloidiasis. Similarly, a report from Brazil estimated a 1% or 2% prevalence of Strongyloides infection in the population of São Paulo, finding the parasite in 10% of 100 AIDS patients, who showed no evidence of systemic strongyloidiasis. 303 Similar results have been found in Zambia. 304, 305 A survey of urban adults in Kinshasa (Congo, formerly Zaire) detected S. stercoralis in 20% by intensive fecal examinations of single specimens, and it estimated a 50% infection rate in the same population on the basis of positive serologies. There were no significant differences in infection rates in those seropositive or seronegative for HIV (F. Neva, unpublished observations).

Taken together, these data suggest that the presence and severity of clinical disease due to S. stercoralis are not significantly increased in patients with HIV infection or AIDS alone. A recent study has shed light on the subject. 306 Careful quantitation of the numbers and proportions of free-living adult worms and directly developing L3 larvae in stool cultures revealed a surprising negative correlation between CD4+ T-cell count and the proportions of adult worms in individuals infected with HIV. Thus, advancing immunosuppression due to HIV is associated, paradoxically, with suppression of the direct development of L3 larvae. 306 More subtle interactions, such as an increased mean gastrointestinal parasite burden or slower response to therapy, may have been missed. Also, some conditions that cosegregate with HIV/AIDS are known to predispose to the hyperinfection syndrome, including the use of steroids (given for pneumocystis pneumonia and lymphoma in AIDS), inanition (seen in patients with chronic diarrhea, untreated oropharyngeal or esophageal candidiasis, and slim disease), and coinfection with human T-cell lymphotropic virus type I (HTLV-I; see Chapter 76) . Strongyloidiasis is an important OI in individuals infected with HTLV-1, and Strongyloides infection has been suspected to be a cofactor in the development of acute T-cell leukemia and tropical spastic paraparesis in asymptomatic carriers of HTLV-I. 307, 308 Notably, intravenous drug use is a risk factor for infection with both HTLV-I and HIV.

Intestinal helminthiasis. Intestinal helminth infection is ubiquitous in low-income tropical countries. Although such helminths do not appear to act as OIs in AIDS, it has been hypothesized that the immune dysregulation associated with geohelminthic infections may alter the natural history of HIV infection in an unfavorable manner. Such hypotheses are founded on the presence of chronic immune activation and Th2 polarization during chronic helminthic infection. Indeed, it has been demonstrated that peripheral blood cells from patients with intestinal helminth infection 68 (and filarial infection 69 ) are more susceptible to in vitro infection with HIV than are cells from helminth-uninfected patients. The overall hypothesis remains unproven, however. An initial study from Ethiopia indicated that HIV viral load was significantly higher in individuals with various helminthic infections than in individuals without helminths, correlating positively with the parasite load as well as decreasing after elimination of the worms by antiparasitic treatment. 70 However, similar studies performed in Uganda and examining far larger numbers of patients have convincingly failed to replicate these findings. 71, 72 These latter studies strongly suggest that helminth coinfection is not associated with faster progression of HIV disease.

Onchocerca volvulus. Among the filaria, the effect of HIV coinfection has been studied in a large cohort of patients with Onchocerca volvulus infection. No significant epidemiological association was found between the two infections, nor was there any difference in the efficacy of ivermectin treatment in HIV-infected compared with -uninfected patients. 309 Arthropods Sarcoptes scabiei var. hominis stands alone among the arthropod and crustacean infestations of humans as a cause of exacerbated disease in the presence of HIV infection. In normal hosts, scabies is usually manifest as a markedly pruritic, papular, and vesicular dermatitis, with pathognomonic burrows harboring gravid females. Excoriations, nodules, and eczematous or impetiginized plaques may also be found. Relatively few adult mites are normally present.

Norwegian or crusted scabies is seen in neurologically impaired or immunosuppressed patients. Pruritus is often absent or mild. Lesions consist of widespread hyperkeratotic, crusted, scaling, fissured plaques. The nails are frequently involved. Patients tend to be heavily infested, with thousands of adult mites (see Chapter 118) . Crusted scabies has been reported as a complication of HIV infection. CD4+ T-cell counts in reported cases have been less than 500/μL. [310] [311] [312] Both typical and atypical presentations are seen, the latter including the "pruritus of AIDS," crusting with pruritus, pruritic papular dermatitis, and mimics of Darier' s disease and psoriasis. 311 Secondary sepsis and death have been reported. 313 In the face of this clinical variability, the diagnosis of crusted scabies in HIV-seropositive people rests on appropriate clinical suspicion and the demonstration of heavy infestation by microscopic examination of skin scrapings. With such extraordinary mite loads, these patients are remarkably contagious. 314, 315 Combination therapy with ivermectin 200 μg/kg and topical benzyl benzoate (or perhaps permethrin) appears be the treatment of choice. 312 Single-dose ivermectin is also effective at preventing transmission in close contacts. Despite speculation early in the AIDS pandemic, there is no evidence of transmission of HIV by arthropod vectors.

Pruritic papular eruptions associated with HIV infection are common in sub-Saharan Africa. The etiology of these intensely pruritic lesions has been attributed to exaggerated immune responses to arthropod bites in HIV-infected individuals. 316

Disseminated infection with P. marneffei, a dimorphic fungus endemic to Southeast Asia and southern China (see Chapter 82) , has emerged as an important OI in AIDS patients. It is the third most common OI in HIV disease in northern Thailand, after extrapulmonary tuberculosis and cryptococcal meningitis. 316 First isolated in 1956, infection with P. marneffei was a rare event before the arrival of the AIDS pandemic in Southeast Asia. 316 Since then, thousands of cases have been diagnosed, primarily in southern China, northern Thailand, Hong Kong, Taiwan, Malaysia, Vietnam, Singapore, Indonesia, and Myanmar. [316] [317] [318] [319] [320] The overwhelming majority of cases have been in AIDS patients, although normal hosts are also known to develop systemic disease with this fungus. 316, 318, 321 There is a pronounced intracountry variation in infection rates. In northern Thailand, up to one-fourth of AIDS patients suffer disease with it, whereas in southern Thailand the prevalence is 10-fold less. 320 The environmental reservoir for P. marneffei is unknown, but the organism has been isolated from the organs, feces, and burrows of three species of bamboo rats. The geographic range of these rodents overlaps the previously mentioned known areas of endemicity for disease with P. marneffei [317] [318] [319] and suggests the likelihood that this fungus is also endemic in Laos, Cambodia, and Malaysia. 316 Whether bamboo rats are important reservoirs for human infection or just another natural host is unclear. There is no evidence of transmission between rats and humans. The seasonal distribution of the diagnosis of disseminated disease in AIDS patients suggests that the reservoir for P. marneffei expands during the rainy season. 317 Exposure to soil appears to be a key factor. 322 The pathogenesis of disease due to P. marneffei is presumed by analogy with other endemic systemic mycoses to involve transmission by inhalation, with secondary systemic dissemination. Like Histoplasma capsulatum, P. marneffei is an intracellular parasite of monocyte/macrophages. 318 A murine model of pulmonary and disseminated infection shows that T cells play a central role in controlling infection. 323 In AIDS patients, disseminated disease is associated with CD4+ T-cell counts less than 100/μL. 316, 324 The largest clinical series reported to date of AIDS patients with disseminated P. marneffei infection provided detailed information on 80 patients. 316 The onset of symptoms was generally sudden and intense. The most common presenting symptoms and signs were fever (92%), anemia (77%), weight loss (76%), and skin lesions (71%). Other frequent signs and symptoms included cough (49%), generalized lymphadenopathy (58%), hepatomegaly (51%), and diarrhea (31%). The most common cutaneous manifestation (87%) was a generalized papular rash with central umbilication that resembled the lesions of molluscum contagiosum. These were predominantly found on the face, scalp, and upper extremities but occurred throughout the body, including the palate. Other cutaneous lesions included papules without umbilication, a maculopapular rash, subcutaneous nodules, acne-like lesions, and folliculitis. Chest films were frequently abnormal, with diffuse reticulonodular or localized alveolar infiltrates the most common.

The mean duration of illness prior to presentation in this study was 4 weeks. The incubation period for disseminated disease is unclear, as is the percentage of patients whose disease is a result of reactivation of latent infection, as opposed to new infection or reinfection. The fact that reactivation with increasing immunosuppression occurs is supported by the several cases of disseminated disease reported from nonendemic areas in AIDS patients who had a distant history of travel to endemic areas. 324, 325 Many such patients had spent little time in endemic areas, indicating that infection with P. marneffei can occur rapidly. The development of clinically active disease within weeks of exposure in endemic areas 326 and the reports of children with vertically transmitted HIV infection developing disease in the first months and years of life 327 demonstrate that primary infection can quickly lead to disseminated disease. Finally, the pronounced seasonal variation in disease incidence implies an important role for exogenous reinfection in the expression of disease with P. marneffei in AIDS patients in endemic areas. 317 The mortality rate of patients with disseminated P. marneffei infection is very high in the absence of prompt treatment. Diagnosis depends on a high index of suspicion, including a careful history to assess possible residence or travel in an endemic area. The differential diagnosis includes tuberculosis, other endemic fungi, and cryptococcosis. Cutaneous lesions may mimic those of AIDS-related molluscum contagiosum, Histoplasma capsulatum and Cryptococcus neoformans. An absence of cutaneous lesions may retard diagnosis. In this regard, a characteristic syndrome of hepatic disease in the absence of skin lesions (fever, hepatomegaly, and markedly elevated serum alkaline phosphatase levels) should be noted. 328 A presumptive diagnosis can be made by the examination of a Wright' s-stained bone marrow aspirate, lymph node aspirate, or touch preparations of skin biopsy specimens. 316, 318, 329 Intracellular and extracellular basophilic elliptic yeast-like organisms with central septation (as opposed to the budding of H. capsulatum) are characteristic. Indirect fluorescent antibody reagents have been developed that may prove useful for differentiating P. marneffei from H. capsulatum and C. neoformans in tissue. 330 Characteristic intracellular organisms have been detected on routine blood smears. 331 In the previously discussed series, definitive diagnosis was performed by culture of P. marneffei from blood (76%, even in the absence of routine lysis-centrifugation culture), skin biopsy (90%), bone marrow (100%), and sputum (34%). Diagnostic antigenemia tests that may prove valuable for rapid diagnosis have been developed. 332, 333 Quantitation of urinary antigen by enzyme immunoassay (employing rabbit hyperimmune IgG) is especially promising: High sensitivity and specificity were demonstrated in an area of high endemnicity. 334 Of note, P. marneffei infection is a known cause of false-positive reactions in the H. capsulatum polysaccharide antigen immunoassay. 335 Current serologic assays are unlikely to be helpful in the diagnosis of AIDS patients but, with improved sensitivity, may provide a useful index of infection. 330, 336 Amphotericin B, 0.6 mg/kg/day for 2 weeks, followed by itraconazole, 200 mg twice a day for 10 weeks, is safe and effective. 337 In mild to moderately ill patients, primary therapy with itraconazole may be reasonable. Secondary prophylaxis is mandatory, given relapse rates of 50% within 6 months in its absence. 338 A placebo-controlled, double-blind randomized trial showed that secondary prophylaxis with itraconazole (200 mg once daily) is safe and effective. 78, 339 With immune reconstitution as a result of a successful response to HAART, discontinuation of secondary prophylaxis is probably safe. 340 A controlled, double-blind trial of primary prophylaxis with itraconazole (200 mg once daily) in Thai patients with AIDS and CD4+ T-cell counts less than 200/μL showed that the regimen was well tolerated and effective at preventing both cryptococcosis and penicilliosis. 341 No survival benefit was found, but the study was not powered to detect a survival advantage. 341 

The dimorphic fungus P. brasiliensis is the cause of the most common systemic mycosis in Latin America (see Chapter 81) . Two clinical forms are distinguished in normal hosts: an acute or subacute "juvenile" form and a chronic "adult" form. Acute, juvenile disease, occurring in children and young adults and accounting for a small minority of cases (3% to 5%), is marked by a rapid course, disseminated involvement of monocyte/ macrophages and lymphoid tissue, and severe suppression of CMI. Chronic, adult disease, accounting for the vast majority of cases, is a slowly progressive disease, predominantly of older men. In most patients, the primary clinical and pathologic manifestations are pulmonary, with nodular, infiltrative, or cavitary lesions progressing to fibrosis. Other frequent manifestations of adult disease include infiltrative and ulcerative mucosal lesions of the oro-and nasopharynx, polymorphic cutaneous lesions, lymphadenopathy, and adrenal infiltration. Most infections are subclinical. Long latency has clearly been demonstrated, with a mean of 15 years between leaving an endemic area and presentation. 342 It is thought that CMI responses are critical to the host defense from disease with P. brasiliensis. 342, 343 Clinical and experimental evidence indicates that paracoccidioidomycosis is associated with marked abnormalities of immune function, with suppression of CMI responses, polyclonal B-cell activation, and elevation of plasma IgE levels. [342] [343] [344] These immunologic perturbations are more common and severe in juvenile disease and are reversed with successful therapy. 342 Given the immunology of paracoccidioidomycosis, one might expect it to be a prominent OI in South America and among HIV patients with a history of travel there. In fact, fewer than 100 cases have been reported, despite the presumed wide prevalence of infection or coinfection in areas such as urban Brazil. [345] [346] [347] [348] Possible reasons for the low number of cases in HIV-seropositive patients include (1) prophylaxis with TMP-SMX, which has activity against P. brasiliensis; (2) the use of ketoconazole for oropharyngeal candidiasis; (3) misdiagnosis as PCP, with a therapeutic response to TMP-SMX; (4) lack of diagnosis; and (5) the presence of a particularly subtle interaction between HIV and P. brasiliensis. 345, 348 Paracoccidioidomycosis in HIV-seropositive people has been primarily of the "acute" form, with prominent involvement of the reticuloendothelial system. However, pulmonary and oral mucosal involvement, more typical of the "chronic" form, often coexists. 346 Although published reports have suggested that this disseminated disease may occur across a broad range of HIV-associated immunosuppression, CD4+ T-cell counts less than 200/μL have been the reported norm. 346, 347 More than one-third of patients with paracoccidioidomycosis have presented with another opportunistic coinfection, most frequently oral/esophageal candidiasis or tuberculosis. 346 Reported clinical presentations span a wide spectrum, from relatively indolent to rapidly progressive disease. Clinical manifestations have included prolonged fever, weight loss, cough, dyspnea, generalized lymphadenopathy, hepatosplenomegaly, skin lesions (localized or disseminated maculopapular, nodular, or ulcerative), oral lesions (ulcerative and/or nodular), osteoarticular lesions, and meningitis. 345, 346 Diagnosis in these patients was made by direct examination or culture of clinical specimens, including skin biopsies, lymph node aspirates or biopsies, bone marrow aspirates, CSF, or blood. 345, 346 Sputum should also be examined using potassium hydroxide preparations, calcofluor stains, or immunofluorescence. The "pilot wheel" cell, consisting of numerous small buds surrounding the mother cell, is characteristic. Serologies have not been diagnostically helpful.

Mortality in the reported cases of disease in HIV-seropositive people was 30%. 345 No randomized clinical trials have been performed with any of the drugs commonly used for the treatment of P. brasiliensis infection (sulfonamides, amphotericin B, ketoconazole, and itraconazole), even in normal hosts. Treatment recommendations are based on data from case series and comparison with historical controls. 348 However, the data are fairly compelling that itraconazole (100 mg/day) is the drug of choice in normal hosts. 342 Published reports of itraconazole treatment in the face of HIV coinfection are scant. 346, 347 Although amphotericin B and intraconazole may both have therapeutic roles to play, amphotericin B should probably be used for initial treatment in HIV coinfected patients. Lifelong suppressive therapy is necessary; itraconazole seems to be a reasonable choice.

The endemic dimorphic fungus H. capsulatum var. duboisii is localized to western and central Africa and Madagascar (see Chapter 88) . In normal hosts, it tends to cause chronic necrotizing cutaneous and skeletal infections. Disseminated disease is unusual. It may be an emerging OI in AIDS patients. No increases in the incidence of African histoplasmosis were reported in a study from the People' s Republic of the Congo (now Congo Republic) in the 1980s, despite a rapid increase in the AIDS-related incidence of cryptococcal disease. 349 Disease manifestations reported in the handful of HIV-H. capsulatum var. duboisii coinfections described in the literature, however, suggest that AIDS patients are at risk of more severe, disseminated disease. [350] [351] [352] [353] [354] [355] Diagnosis is by direct examination of clinical specimens and culture. The yeast form is larger and has a thicker wall than H. capsulatum var. capsulatum. Amphotericin B and itraconazole have therapeutic efficacy.

The dimorphic fungus S. schenckii has a worldwide distribution, although most reports have been from tropical and subtropical areas of the Americas (see Chapter 84). The highest incidence of disease is thought to be in the highlands of Mexico and in southern Brazil. Cutaneous and lymphocutaneous disease is most common. Extracutaneous involvement, including osteoarticular disease, pneumonia, and meningitis, has been described in both normal and immunosuppressed hosts. A handful of cases of severe, disseminated sporotrichosis in late-stage AIDS have been described. [356] [357] [358] Diffuse cutaneous involvement is the norm. Some patients have also presented with CNS, ocular, osteoarticular, splenic, bone marrow, and/ or mucosal involvement. It appears likely that disseminated Sporothrix will become a more prominent OI in heavily endemic areas. The response to therapy (with amphotericin B, potassium iodide, itraconazole, ketoconazole, and 5-fluorocytosine) has been variable and problematic. Amphotericin B should probably be used for initial treatment, followed by lifelong suppressive therapy with itraconazole. 359 

Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis are systemic mycoses endemic to the United States that cause OIs in AIDS patients. As such, they are obviously not distinctly tropical diseases and have been covered in-depth elsewhere. [76] [77] [78] [79] [360] [361] [362] The tropical extent of their respective areas of endemicity deserves brief mention, however.

Histoplasma capsulatum var. capsulatum (see Chapter 80) is found in distinct river basin systems worldwide between 45°N and 30°S of the equator. 360 Progressive disseminated histoplasmosis is common in AIDS patients in endemic areas. 360 In addition to the most prominent worldwide focus (the Ohio and Mississippi River valleys of the United States), cases have been reported from Central and South America, the Caribbean, Africa, Southeast Asia, and Europe. 363, 364 Disease caused by B. dermatitidis was originally named North American blastomycosis. It is now clear, however, that the distribution of this fungus is far more cosmopolitan (see Chapter 80) . Blastomycosis has been reported in all the major regions of Africa, with a concentration in southern Africa. It is likely underreported. 365 Occasional cases have been reported from Central and South America, the Middle East, and India. 366 African strains of B. dermatitidis appear to be antigenically distinct from North American strains. The clinical spectrum likewise appears to be different in African cases, with prominent involvement of bone and chronic draining sinuses. Disseminated blastomycosis is an uncommon, late, frequently fatal OI in patients with AIDS in the United States. 367, 368 Cases in Africa are to be expected in the future.

Coccidioides immitis is endemic to lower Sonoran life zones in the United States, Mexico, Guatemala, Honduras, Colombia, Venezuela, Bolivia, Paraguay, and Argentina (see Chapter 80) . Coccidioidomycosis is a severe, often fatal disease in patients with AIDS and low CD4+ T-cell counts. 362, 369, 370 Most have presented with diffuse or focal pulmonary disease; extrapulmonary dissemination is not uncommon. In some endemic areas, it is the third most common OI in AIDS patients. 362, 369, 370 Cryptococcus neoformans Cryptococcosis (see Chapter 80) is a common lifethreatening fungal infection in AIDS patients. 371 Although the dissemination of C. neoformans can affect almost any organ system in HIV-infected people, meningitis is the most frequent manifestation. Other relatively common manifestations include pneumonia and cutaneous lesions. Occurring most commonly when CD4 counts fall well below 200/μL, cryptococcosis is a frequent presenting diagnosis in AIDS. 371 Excellent reviews on cryptococcosis in AIDS are available for detailed information on the clinical approach to this ubiquitous OI. [76] [77] [78] [79] 372 Cryptococcus neoformans is distributed globally. The distribution of cryptococcus as an OI in AIDS is global as well. Regional differences exist in the prevalence of disease as defined by clinical or autopsy series. The prevalence of cryptococcosis in AIDS patients in the United States was estimated to be 7% or 8% in the 1980s. 373 In Thailand, it is the second most common OI (after tuberculosis), with a prevalence of 13% to 44% in different clinical series. 21, 374, 375 In Africa, the case series prevalence has been variable, from 1% in Soweto, South Africa, 376 to 6% to 13% in Kinshasa (the former Zaire). [377] [378] [379] The prevalence in autopsy series has similarly varied from 3% in Abidjan (Côte d'Ivoire) 209 to 29% in Uganda. 211 Overall, the rates of disease in Africa appear to be higher than those in North America or Europe. Interestingly, a large retrospective case study in London found a significantly higher rate of extrapulmonary cryptococcal disease in Africans attending an HIV clinic than in non-Africans attending the same clinic. 380 Data from case series estimated the prevalence of cryptococcosis in Mexico to be 8% to 12% 381 and in Haiti 13%. 382 In Brazil, from 1980 to 2002, 6% of patients had cryptococcus as an AIDS-defining diagnosis. 383 Cryptococcus neoformans exists in two varieties: C. neoformans var. neoformans and C. neoformans var. gatti. They inhabit different ecological niches, with C. neoformans var. neoformans being associated with soil contaminated with bird excrement and C. neoformans var. gatti having a unique, if poorly understood, association with the tree Eucalyptus camaldulensis. 384, 385 Whereas C. neoformans var. gatti has a predominantly tropical and subtropical distribution, C. neoformans var. neoformans occurs worldwide. 384, 385 Of note, although cryptococcosis due to C. neoformans var. gatti occurs with some regularity in normal hosts in regions where this variety is endemic, cases of cryptococcosis in AIDS patients have been almost exclusively due to C. neoformans var. neoformans. 385, 386 Pneumocystis jiroveci (Previously P. carinii f. spp.

Throughout the world, there is almost universal serologic evidence of exposure by the age of 2 years to P. jiroveci, a ubiquitous fungus 387 (see Chapter 85) . The prevalence of antibodies to specific P. jiroveci antigens varies, however, suggesting exposure to antigenically different strains in different areas of the world, 388 which is mirrored by genetic studies revealing strain differences in this organism. 389 PCP (Pneumocystis carinii pneumonia, based on the prior terminology) remains the most frequent serious OI in the United States and Europe, despite dramatic decreases in incidence due to the introduction of HAART. 390, 391 Prior to HAART, it occurred in 40% to 50% of patients with a CD4 count less than 100/μL per year, and in 60% to 80% of patients overall, in the absence of prophylaxis.

HAART is far from widely available in much of the tropics, and PCP prevalence appears to be high, as expected, among AIDS patients in Central and South America and in Asia. 391 Interestingly, however, the incidence of PCP in adult AIDS patients in Africa is thought to be far lower than was seen in the pre-HAART era in industrialized countries. 391 Adult clinical series in Africa have shown prevalence rates of 0% to 22%. 376, 382, [392] [393] [394] [395] Studies including bronchoscopy for diagnosis have described rates of 0% to 39% (the highest figures being obtained as a percentage of acid-fast bacillus-negative pneumonias). 382, 392, [396] [397] [398] Autopsy series have had rates of 0% to 11%. 210, 394, 399 The reasons for these lower rates of PCP in Africa are unclear. Possible explanations include less environmental exposure to P. jiroveci, exposure to differing strains of P. jiroveci, differences in host susceptibility, earlier deaths in tropical patients with AIDS due to exposure to more virulent organisms, diagnostic difficulties, and host-specific differences in susceptibility. 382, 400 Exposure to P. jiroveci appears to be similar worldwide. 387, 388 As noted previously, the existence of genetically and antigenically distinct human strains is likely; however, pediatric PCP rates in AIDS patients in Africa are quite similar to those in the industrial north. 391, 401 Indeed, approximately one-third of HIV-infected infants in Africa die during the first year of life, and PCP is thought to be responsible for 30% to 50% of such deaths. 402, 403 Demise from more virulent pathogens prior to clinical PCP may well occur in adults (and PCP does tend to occur early in the course of HIV disease in North American infants, 404 perhaps with initial exposure 79 ). The high prevalence of cryptococcal disease in these same series, which is thought to occur at similar levels of immunosuppression, suggests that this is not the complete answer. 382 Diagnostic difficulties may also play a role, but these have been well addressed in several of the cited studies.

The clinical presentation of PCP in the tropics appears to be similar to that in the industrial north. 398 Frequent coinfection with tuberculosis may obscure the diagnosis. Multiple reviews of the clinical approach to PCP in AIDS are available. [76] [77] [78] [79] 405 Other Fungi

Other predominantly tropical fungi, such as the agents of maduromycosis, lobomycosis, rhinosporidiosis, and subcutaneous zygomycosis, may prove to cause opportunistic infection in AIDS patients but have not been reported as such. Isolated case reports of infection due to a variety of unusual fungi in AIDS patients have been published (reviewed in Kaplan and colleagues, 20 Vartivarian and associates, 406 and Perfect and Schell 407 ). Some may indeed prove to be OIs, even predominantly tropical OIs, but firm data are lacking. The common occurrence of superficial and invasive infections with Candida and the growing problem of Aspergillus infection in neutropenic long-term survivors of late-stage AIDS are beyond the scope of this chapter.

Although tuberculosis (see Chapter 36) is not usually perceived as a tropical disease, the prevalence and mortality of the disease in the tropics far surpass those in the industrial countries of the temperate zones. Approximately one-third of the 39.4 million people living with HIV worldwide are coinfected with M. tuberculosis, 70% of whom live in sub-Saharan Africa. 2 In developing countries, 50% of patients with HIV infection will develop active tuberculosis; in contrast, in the United States, only 4% of patients with AIDS have had tuberculosis. 2, 408 In some countries in sub-Saharan Africa, more than 70% of tuberculosis patients are HIV-seropositive. Tuberculosis is the leading cause of death among people with HIV infection, accounting for one-third of AIDS deaths worldwide. 409 The introduction of HAART has decreased death and OIs such as tuberculosis by 60% to 90% among people living with HIV worldwide in affluent countries 410 ; in developing countries, however, HAART remains available only to a small minority of those who need it.

Tuberculosis was one of the earliest OIs to be linked to HIV infection and in many developing countries is the most common serious OI associated with HIV. 408 Tuberculosis is a relatively early complication of HIV, occurring before other AIDS-defining illnesses in 50% to 67% of HIV-infected patients. 411 Several relevant CMI functions, including lymphocyte proliferation and cytolytic T-cell activity, have been shown to be significantly suppressed in HIV-infected patients with tuberculosis. Additional host responses that may be impaired include the elaboration of cytokines such as IFN-γ and IL-2. CD4+ T-cell counts are suppressed in tuberculosis patients, both with and without HIV coinfection, and rise with therapy for tuberculosis. 412 Although the consequences of coinfection appear to adversely affect the tuberculous process mainly, there is also evidence, albeit somewhat controversial, of a deleterious effect of tuberculosis on the course of HIV disease. Several studies have shown that in vitro HIV replication is enhanced in blood monocytes from patients with active pulmonary tuberculosis and in lymph node mononuclear cells and CD4+ T cells from HIV-infected, purified protein derivative (PPD) skin test-positive patients after stimulation with PPD. 413 On the other hand, both enhancement and suppression 55 of HIV replication in monocytes have been reported after in vitro infection with M. tuberculosis. In vivo, plasma viral load has been shown to be higher in HIV-infected patients with active tuberculosis than in HIV-infected people without active tuberculosis, remaining high throughout the course of treatment. [413] [414] [415] [416] [417] However, whether tuberculosis increases HIV load, or whether higher HIV load is really a marker of increased risk for tuberculosis in coinfected patients, remains unclear. 47 Similarly, although tuberculosis has been associated with reduced survival in HIV-infected patients, 46,418-420 direct and indirect lines of evidence have suggested the relation may well not be a directly causal one. 28, 421, 422 The prophylaxis, diagnosis, and treatment of tuberculosis in the presence of HIV coinfection have been dealt with in depth elsewhere. [76] [77] [78] [79] Certain issues of particular relevance to the tropics are explored further here.

Primary preventive therapy against tuberculosis with isoniazid has been shown be effective in HIV-infected individuals, regardless of tuberculin status. 423, 424 Meta-analyses have suggested a reduction in tuberculosis incidence of 60% to 68% in those with a positive tuberculin test and a reduction of approximately 42% among all treated individuals. 423, 424 WHO/UNAIDS recommendations are for primary preventive therapy to be given to PPD-positive, HIV-infected individuals who do not have active tuberculosis. 425 In settings where it may not be feasible to do PPD testing, WHO/UNAIDS recommendations are for primary preventive therapy to be considered for those living in populations with a prevalence of tuberculous infection estimated to be more than 30%, health-care workers, household contacts of tuberculosis patients, prisoners, miners, and other groups at high risk of acquisition or transmission of tuberculosis. Although studies have shown that "short-course" therapy with rifampin plus pyrazinamide for 2 months is as efficacious as 6 to 12 months of isoniazid in preventing active tuberculosis in HIV-infected adults with positive tuberculin skin tests, 426-428 the side effects associated with this regimen (in the general population and not, apparently, in the HIV-infected population) have left isoniazid the prophylactic agent of choice. 429, 430 Treatment of active, susceptible tuberculosis with first-line drugs is as effective for curing tuberculosis in HIV-infected as in HIV-uninfected individuals. In the absence of HAART, however, the death rate for those under treatment for tuberculosis is higher for people with HIV infection alone, mainly due to other OIs. Conflicting reports on increased rates of tuberculosis recurrence in the face of HIV coinfection 431 have not provided sufficient evidence for increasing the duration of treatment. Combining HAART with tuberculosis treatment is difficult for several reasons: overlapping toxicity profiles of some antituberculosis and antiretroviral drugs, drug interactions, and nonadherence with complicated treatment regimens. 432 An important problem is the possibility of paradoxical reactions. Such reactions include the transient worsening or appearance of new signs, symptoms, or radiographic manifestations of tuberculosis within days to weeks after initiating antiretroviral treatment. These reactions, likely due to immune reconstitution, may be particularly severe when HAART is started soon after initiating treatment for active tuberculosis. The Centers for Disease Control and Prevention (CDC)/ American Thoracic Society recommendations for tuberculosis treatment are to (1) continue previously started HAART; (2) avoid initiating HAART and tuberculosis therapy at the same time; and (3) always start tuberculosis therapy first, delaying HAART initiation until the first 1 or 2 months of tuberculosis therapy have been completed. 432 Many of the world' s children are vaccinated with bacille Calmette-Guérin (BCG). The risk:benefit ratio of vaccination is surely altered by the presence of HIV infection. On the risk side, there are a few case reports of localized or disseminated disease due to BCG in children and adults. 433-436 Disseminated disease in most hosts is a devastating event, with an overall mortality of 70%, and usually occurs in the immunosuppressed patient. Whether local or disseminated disease was due to HIV coinfection in the cited cases remains unclear, however. 433-439 On the side of potential benefit, the efficacy of BCG in HIV-infected populations is unclear. Data supporting both a lack of benefit of vaccination in HIV-seropositive children and a benefit of childhood vaccination in HIV-seropositive adults in protection from disease due to M. tuberculosis have been published. 440, 441 Any such benefit would likely be multiplied by the much higher risk of tuberculosis in the face of concurrent HIV infection. Furthermore, data suggesting a beneficial effect of early BCG vaccination on mortality from all causes in HIV-uninfected children suggest that measures of benefit in HIV-seropositive patients need to be broader than mere prevention of tuberculosis. 442 BCG vaccination remains in the WHO Expanded Programme on Immunization (EPI). 443 WHO recommendations are that BCG be given to children with asymptomatic HIV infection in areas with a high risk of tuberculosis infection. BCG is not recommended for those with symptomatic HIV infection (defined as AIDS). In areas where the risk of tuberculosis is minimal, BCG is not recommended for people known or suspected of being infected with HIV. 443 The use of BCG in HIV-seropositive patients is considered to be contraindicated under U.S. Public Health Service-Infectious Disease Society of America (USPHS-IDSA) guidelines 213 and by the Advisory Committee on Immunization Practices (ACIP). 444

The M. avium complex (MAC) (see Chapter 36) consists of 28 serovars of two Mycobacterium species, Mycobacterium avium and Mycobacterium intracellulare. MAC bacteria are ubiquitous, with organisms commonly being isolated from soils, natural sources of water, tap water, and domestic and wild animals worldwide. 445, 446 Most MAC isolates from AIDS patients are M. avium; more than 90% are of serovars 1, 4, and 8. 447, 448 Disseminated disease due to M. avium is the most common systemic bacterial infection in AIDS patients in the industrial north, occurring in up to 43% of AIDS patients in the United States. 449, 450 Disease occurs almost exclusively in those with CD4+ T-cell counts less than 100/μL, most frequently in those with CD4+ T-cell counts less than 50/μL. 450 The pathogenesis of disseminated M. avium infection in AIDS is thought to involve primary infection (or reinfection) as opposed to reactivation, with initial colonization of the respiratory or gastrointestinal tracts followed by widespread dissemination. [451] [452] [453] Systemic disease is marked by high-grade mycobacteremia (almost exclusively in monocytes) and impressive tissue burdens of bacteria. 454 The remarkable feature of M. avium in the tropics is the apparent virtual absence of disseminated disease in AIDS patients in many areas, predominantly in sub-Saharan Africa. None of 95 blood cultures from severely ill patients with advanced AIDS in Uganda were positive for M. avium, nor were any of 165 mycobacterial sputum cultures from HIVseropositive and -seronegative patients at the same hospital found to be positive for M. avium. 455, 456 None of 202 blood cultures from HIV-positive adult inpatients in Côte d'Ivoire grew M. avium (whereas 4% grew M. tuberculosis). 457 None of more than 200 diagnostic lymph node biopsies in HIVseropositive African patients had histology characteristic of disseminated M. avium infection. 211 The reasons for the apparent absence of disseminated disease due to M. avium in areas of the tropics are unclear. As with the decreased prevalence of PCP, many explanations have been proposed, including less exposure to M. avium, exposure to different (less pathogenic) variants of M. avium, differences in host susceptibility, greater acquired immunity to mycobacteria, earlier death by more virulent pathogens, and diagnostic difficulties. Overall exposure to MAC organisms is likely to be similar. Environmental isolation of MAC occurs with similar or greater frequency in Congo and Uganda than in the United States, 446, 456 and skin test surveys suggest a similar frequency of exposure to MAC in economically developed and developing countries. 463 Piped water systems in the United States and Europe have a higher frequency of MAC isolation, however, and economic conditions may lead to greater exposure to MAC-containing droplets via showerheads in economically developed countries 445, 446, 464 ; such differences, however, are unlikely to lead to an essentially total absence of disease in countries such as Uganda. Exposure to different M. avium serovars or strains may well be important. Data on serotyping of African clinical strains are scarce. Preliminary data suggest that African clinical isolates are distinguishable from European and American isolates by restriction fragment length polymorphism analysis. 465 The possibility of underlying genetic differences in host susceptibility is belied by the similar rates of disseminated M. avium infection as a presenting diagnosis in African and non-African AIDS patients in a London clinic. 380 Greater acquired immunity to mycobacterial disease through BCG vaccination 441 or prior infection with M. tuberculosis may exist, but the reported BCG coverage (50%) and PPD reactivity (82%) in Uganda seem unlikely to explain the lack of any disseminated MAC disease. 456 Earlier death due to a greater environmental presence of, or greater latent infection with, more virulent pathogens may occur. This is unlikely to be the entire explanation because patients in many of the previously mentioned studies had clinical late-stage AIDS. Finally, the design of several of the previous studies makes the assertion that the central problem is one of a lack of diagnostic sophistication untenable. Further data are awaited.

Mycobacterium leprae, the causative agent of leprosy (see Chapter 38), is an incredibly slow-growing parasite of monocyte/macrophages. For comparative purposes, it may be useful to recall that Leishmania, which infects similar cells, is a prominent opportunistic pathogen for patients with HIV infection. The importance of CMI in leprosy and leishmaniasis was emphasized by Turk and Bryceson 466 in their detailed comparison of skin lesions and histopathology of both diseases. Moreover, the immunopathology of both infections is very similar. In view of the widespread prevalence of leprosy in the tropics and subtropics, the immunosuppressive effects of HIV or AIDS on leprosy would be expected to become readily apparent, but there is little or no evidence of this interaction. In fact, in a comprehensive analysis of the possible interaction between HIV/AIDS and leprosy, Lucas concluded that leprosy appears to be another "missing infection in AIDS." 15 There is no quantitative measure of immune unresponsiveness in leprosy, such as the CD4 count in AIDS, as an indicator of clinical progression; however, there is general agreement that the tuberculoid form of disease is characterized by a well-organized granuloma on biopsy of a skin lesion or the lepromin reaction, with very few or no organisms (paucibacillary). Patients with lepromatous leprosy have a negative lepromin skin test, and biopsies of their skin lesions lack a granulomatous response and show large numbers of organisms (multibacillary). Some of the ways in which the adverse effects of HIV infection on leprosy could be manifested include an increase in the disease:infection ratio, a shift toward multibacillary disease, or an altered response to antileprosy chemotherapy. Of course, the presence of leprosy may also enhance HIV infection.

Several studies have examined positive serology for HIV in newly diagnosed leprosy cases. One report from a rural hospital in Zambia found a higher prevalence of reactors compared with blood donors and surgical patients (6 of 18 vs. 9 of 105), but the numbers were small and the controls were not adequately matched. 467 A larger study of HIV seroprevalence in northwest Tanzania of 93 new leprosy cases compared with more than 4000 controls found that the presence of HIV antibody was significantly associated with multibacillary disease. 468 The fact that this association was based on only five HIV-positive cases with multibacillary disease illustrates the complexity of epidemiologic analysis in a disease such as leprosy. Another comparison of seropositivity for HIV was carried out among 189 new cases of leprosy matched for age, sex, and district of residence with 481 controls in Uganda. No significant difference in overall positive rates was found (12% in cases vs. 18% in controls), but again, positive HIV reactions were more frequent among multibacillary cases. 469 A different clinical association was noted in Zambia in leprosy patients with active neuritis, which suggested that HIVpositive cases had poorer recovery of nerve function than controls after treatment with steroids. 470 A factor that should be considered in evaluating reports of HIV/AIDS in leprosy patients is the greater likelihood of false-positive serologic reactions. One or more positive bands to HIV antigens in Western blots were commonly found in several hundred sera from northern India in the absence of positive enzyme-linked immunosorbent assays (ELISAs). 471 Another report claimed that 3 of 75 (4%) sera from Indonesia and 6 of 100 (6%) sera from Somalia gave positive HIV ELISAs but negative Western blots. 472 These were attributed to leprosy.

There appears to be no striking evidence that HIV infection has an adverse effect on the course of leprosy. There is a suggestion from several of the reports cited previously that multibacillary disease may develop under the influence of HIV infection; however, there are several features of leprosy that may tend to obscure an interaction with HIV infection. Both infections are chronic and slow in their progression, so it may simply take more time to recognize an influence of one on the other. Leprosy is predominantly a rural infection involving people not yet caught up with the ravages of HIV and AIDS. Patients with AIDS in the tropics may not survive long enough to display interactions with leprosy. Finally, patients in the early stages of leprosy have relatively subtle clinical manifestations with which physicians in the urban environment may not be familiar. Therefore, there may be more going on out there than we realize. It has been noted that HAART-associated immune reconstitution may trigger injurious inflammatory reactions in treated patients coinfected with leprosy. [473] [474] [475] Other Nontuberculous Mycobacteria Disease due to Mycobacterium genavense (see Chapter 36) mimics that due to M. avium, causing disseminated disease in AIDS patients with very low CD4+ T-cell counts (mean, <50/μL). The pathogenesis appears to involve initial gastrointestinal colonization followed by dissemination. 476, 477 The important environmental reservoirs are unclear, but pet birds can have extensive gastrointestinal tract involvement.

The organism may also be present in tap water. 478 The geographic range of disease is only beginning to be defined. Cases have been reported from North America, Europe, and Australia. 476 The most common presenting symptoms and signs are fever, weight loss, abdominal pain, chronic diarrhea, lymphadenopathy, hepatosplenomegaly, "pseudo-Whipple' s disease," and anemia. 476, 479, 480 Imaging of the spleen may suggest splenic abscesses 481 ; diffuse nodular infiltrates may be seen in the lung. 482 Pathologically, involved organs are filled with histiocytes that are packed with acid-fast bacilli. The diagnosis can be established by the isolation of M. genavense from normally sterile sites (blood, bone marrow, lymph node, and spleen). Specific diagnosis is confounded by the fastidious growth requirements of the organism. Primary isolation on solid media is difficult, and growth in liquid broth may have only 50% sensitivity. Definitive identification demands PCR techniques. 476 The clear implication is that a significant percentage of cases ascribed to disseminated M. avium are likely due to M. genavense. 479 Data on treatment are all retrospective, but therapy appears to be associated both with improvement in symptoms and with survival. Multidrug regimens that include clarithromycin appear to be associated with the best clinical responses. 483, 484 Before the AIDS pandemic, Mycobacterium kansasii was known primarily as a cause of chronic pulmonary disease, resembling tuberculosis in lungs with underlying damage. Mycobacterium kansasii is second to MAC among nontuberculous mycobacteria as a cause of disease in HIV-infected patients in the United States. 485 Although M. kansasii has been reported as a cause of pulmonary disease in most areas of the world, most case reports of HIV coinfection are from North America and Europe. However, coinfection may be especially prevalent in the gold mines of the Transvaal in South Africa. 486 In HIV-infected individuals, disease due to M. kansasii and M. tuberculosis has very similar clinical and radiological characteristics. 487 A major difference (with epidemiological and prognostic implications) is that M. kansasii disease tends to occur later in the course of HIV infection. The mean CD4+ T-cell count at the time of presentation is approximately 50 to 60/μL [487] [488] [489] ; 60% to 90% present with pulmonary disease alone and 20% to 35% with disseminated disease. 489, 490 The incidence in industrialized countries has plummeted in the HAART era. 491 With all nontuberculous mycobacteria, differentiation between colonization, contamination, and disease can be problematic. Mere colonization of the respiratory tract with M. kansasii appears to be infrequent in AIDS patients, however. All pulmonary isolates should be taken seriously. 488, 490 Despite relative in vitro resistance to isoniazid, 491 the recommended therapy is isoniazid, rifampin, and ethambutol. Therapy clearly alters survival in patients with pulmonary disease. 489, 490, 492 Disseminated disease has a particularly poor prognosis.

First described in 1977, Mycobacterium malmoense is an uncommon cause of pulmonary disease resembling tuberculosis. The environmental reservoir is unknown. Personto-person transmission has never been documented. Multisystem disease with bacteremia has rarely occurred in the presence of profound immunosuppression, including several patients with AIDS and low CD4+ T-cell counts. Pulmonary and gastrointestinal disease, along with bacteremia, is usual. 493, 494 In vitro susceptibility testing does not correlate well with clinical response. 495 The best regimen for pulmonary disease in the nonimmunosuppressed patient appears to be isoniazid, rifampin, and ethambutol. 495 Optimal therapy in AIDS patients is unclear.

Mycobacterium haemophilum causes localized lymphadenitis in immunologically healthy children and cutaneous, osteoarticular, and, more rarely, pulmonary or disseminated disease in immunocompromised patients. Several cases have been reported in AIDS patients. [496] [497] [498] [499] [500] Cutaneous lesions include furuncles, abscesses, papules, vesicles, and deep ulcers. Such lesions are usually diffuse, most often on the extremities. Culture (at 30°to 32°C) demands supplementation of media with an iron source. In vitro susceptibility data and scattered clinical reports suggest that rifampin plus ciprofloxacin is reasonable empirical therapy. Other agents with good activity include amikacin, ciprofloxacin, and clarithromycin. 498 The environmental source and mode of infection are unclear.

Several other mycobacteria have been demonstrated or suspected to cause opportunistic disease in AIDS patients, including Mycobacterium fortuitum (primary pulmonary disease, 501 disseminated disease, 502 cervical lymphadenitis, 502 and meningitis 503 ), Mycobacterium marinum (disseminated cutaneous and systemically disseminated disease 504, 505 ) , Mycobacterium celatum (pulmonary and disseminated disease 506, 507 ) , Mycobacterium xenopi (disseminated disease, pulmonary disease, and pulmonary colonization 508-510 ), Mycobacterium gordonae (pulmonary, cutaneous, and disseminated disease [511] [512] [513] , Mycobacterium scrofulaceum (disseminated disease 514 ), Mycobacterium bovis (disseminated disease), and Mycobacterium simiae (disseminated disease 515, 516 

Along with other genital inflammatory or ulcerative diseases, syphilis (see Chapter 44) has been implicated as a cofactor in HIV transmission. Many case reports have suggested that HIV infection can alter the course of disease with Treponema pallidum. In the presence of concurrent HIV infection, syphilis has been thought to (1) progress more frequently and rapidly to neurosyphilis, 519, 520 (2) lead to an increased incidence of meningitic manifestations of neurosyphilis, 521 (3) lead to an increased frequency of "malignant secondary syphilis" with ulcerating lesions and prominent systemic symptoms, 522 and (4) be less amenable to successful therapy with standard regimens as assessed by clinical or serologic measures (including a lack of appropriate nontreponemal titer reduction or a serologic relapse). [523] [524] [525] [526] [527] Such concerns, based largely on case reports and retrospective studies, were amplified by the disconcerting finding of T. pallidum invasion of the CNS in early syphilis in HIV-infected patients. Such early invasion of the CNS occurs equally frequently in HIV-seropositive and -seronegative people, however, 528 and the "atypical" courses of syphilis described previously were well-known in the pre-AIDS era. Knowledge of the actual frequency and relative significance of such events has awaited well-designed prospective studies. Three studies now provide evidence that the clinical presentation and clinical and serologic responses to treatment of syphilis may not be appreciably altered by HIV coinfection. [529] [530] [531] A major caveat of these studies is that the mean level of immunosuppression in the patients in these studies, as assessed by CD4+ T-cell counts, was not severe. Furthermore, the number of patients involved was relatively small. Thus, the clinical course of syphilis in the face of severe HIV-induced immunosuppression may in fact be exacerbated, and the response to conventional therapy may lead to the infrequent occurrence of serious adverse treatment outcomes. 531 The clinical approach to the HIV patient infected with this cosmopolitan sexually transmitted disease (STD) has been thoroughly discussed elsewhere [76] [77] [78] [79] 532, 533 and will likely continue to evolve.

Whether HIV infection has a deleterious effect on the course of the nonvenereal, endemic treponematoses (see Chapter 44) is unknown, but such an effect has been postulated by analogy with syphilis. 534 No effects of HIV on concurrent infection with the Borrelia species that cause relapsing fever have been reported (see Chapter 45). Whether Lyme disease follows an unusual course in HIV-infected people is unclear. 535, 536 Finally, initial observations suggest that leptospirosis (see Chapter 46) runs a similar course in patients coinfected with HIV. 537, 538 

Among the rickettsiae and related organisms, only Coxiella burnetii and Ehrlichia organisms have been suspected of being exacerbated by concurrent HIV infection. Notably, these pathogens are obligate intracellular parasites of monocyte/ macrophages. Q fever (see Chapter 54) has a worldwide distribution. The responsible pathogen, C. burnetii, lives and multiplies in the phagolysosomes of monocyte/macrophages. As with other such parasites, host defense against infection appears to depend on specific T-cell activation of the microbicidal effector functions of infected cells. 539 Radiation, cyclophosphamide, corticosteroids, and pregnancy have led to reactivation of disease in animal models. 539 Case series have suggested that patients with immunocompromise due to a variety of causes (including leukemia, Hodgkin' s disease, bone marrow and renal transplantation, and alcoholism) are more susceptible to both symptomatic acute and relapsing or chronic disease with C. burnetii. [540] [541] [542] The rationale for expecting more frequent or serious disease in the HIV-infected patient is clear. The data are less so. A study from southern France demonstrated a threefold higher prevalence of antibodies to C. burnetii in HIVseropositive people. 543 This suggestion of an increased rate of transmission in HIV-infected people has not been found in other seroprevalence studies from Paris, Spain, or the Central African Republic. [544] [545] [546] Given the differential prevalence of risk factors for the acquisition of HIV infection between the studies, the contradictory data strongly suggest that C. burnetii can be blood-borne and that intravenous drug use is a risk for its transmission. Two studies from southern Europe have further suggested that HIV infection leads to a higher disease-infection ratio with C. burnetii. 543, 547 A retrospective serologic study of 520 patients with acute Q fever from an area of Spain with a high incidence of both HIV and C. burnetii infection revealed no overrepresentation of HIV-infected people, however. 546 The clinical features of Q fever do not appear to vary between HIV-infected and -uninfected hosts. 543, [545] [546] [547] However, definitive statements await prospective studies in severely immunosuppressed AIDS patients.

Human monocytic ehrlichiosis (HME), caused by the tick-borne Rickettsia-like agent E. chaffeensis, is an acute febrile illness associated with leukopenia, thrombocytopenia, and hepatic enzyme abnormalities. Most case reports of infection with E. chaffeensis (see Chapter 53) have been from the United States. A report of infection in Mali supports a much wider distribution of disease, however. 548 HME appears to be an AIDS-related OI. 549 Reported hospitalized cases have had a high rate of complications and a mortality of approximately 30% 549 (compared with an estimated case fatality rate for HME in the absence of HIV of <3% 550 ). Patients with fatal disease had CD4+ T-cell counts less than 200/μL; in patients with less than 100/μL, the mortality rate was more than 50%. Of eight reported cases of disease caused by E. ewingii, a related tick-borne agent, seven occurred in patients with immune deficiencies, including four with HIV infection. 549, 550 The suspicion is thus strong that E. ewingii is an opportunistic pathogen in the setting of HIV infection. 551 No cases of infection with the tickborne agent of human granulocytic ehrlichiosis 552 in the face of HIV infection appear to have been reported.

There is no evidence implicating any of the spotted fever or typhus group of rickettsiae as having a clinically significant interaction with HIV. Although neither the mortality nor the morbidity of Rocky Mountain spotted fever are changed by HIV coinfection, this infection should not be overlooked in favor of defined OIs in the differential diagnosis of febrile illness in HIV-seropositive patients. A prospective study on scrub typhus [due to Orientia (formerly Rickettsia) tsutsugamushi] revealed no increase in clinical severity at time of presentation in HIV-infected patients with a median CD4+ T-cell count of 70/μL. 553 Interestingly, rickettsemia occurred significantly less often in the HIV-seropositive patients. Neither the relative prevalence of infection nor the response to treatment was addressed in this study.

Brucella A cause of systemic disease worldwide, Brucella species are facultative intracellular parasites that infect and multiply in macrophages (see Chapter 41). CMI responses, particularly the activation of monocyte/macrophages by antigen-specific T cells, are important in host resistance. Despite this, the meager published data on coinfection do not support a significant effect of HIV on infection with Brucella and, in fact, prior to the AIDS pandemic, only two cases of brucellosis in immunocompromised hosts (hairy cell leukemia and IgM deficiency) had been reported. 554, 555 A retrospective seroprevalence study found no significant association between Brucella serology and HIV serology in a cohort of female sex workers in Kenya. 556 The prevalence of antibodies to each pathogen was high (HIV, 65%; Brucella, 35%). The clinical course of brucellosis in the 18 reported cases with concurrent HIV infection was not outside the spectrum of disease seen in normal hosts. [556] [557] [558] [559] [560] Definitive data on the interaction between these two pathogens await careful prospective studies.

Melioidosis (see Chapter 34) does not appear to behave as an AIDS-related OI. The disease is endemic in Southeast Asia, particularly in northern Thailand, where the prevalence of AIDS is high. Only one case of fatal, recrudescent, bacteremic disease in an HIV-seropositive person has been reported, however. 561 Clinical series from Thailand are silent with regard to the presence of melioidosis in AIDS patients, 374,375,561-563 and a 10-year study of bloodstream infections in a hospital in northern Thailand reported a similar proportion of B. pseudomallei isolates in HIV-infected and -uninfected patients. 564 

Several enteric bacterial infections have been reported to cause disease of greater severity, invasiveness, chronicity, or recurrence in the presence of HIV coinfection. Enterotoxigenic E. coli has not been described as causing more severe disease in HIV-seropositive patients, but Shigella species, Salmonellae, Campylobacter, and Listeria monocytogenes have all been implicated as causes of more severe or relapsing disease in the presence of HIV. Data from the tropics on enteric bacterial pathogens are scant. Studies of slim disease (enteropathic AIDS) have not revealed an enteric bacterial cause in most cases. 304, 458, 459 The prevalence of certain enteric pathogens such as Campylobacter, vibrios, and enteropathogenic E. coli in the tropics has not been accurately assessed because their detection requires the use of special media and experienced laboratory personnel. In the case of less fastidious organisms that are easier to detect, such as Salmonella spp., the phenomenon of bacteremia with nontyphoid organisms has been noted in tropical Africa. 29 Since bacteremia with Shigella spp. probably occurs more commonly in patients with HIV disease, 565 this association may be expected to occur in the tropics as well. There is no reported evidence to suggest that cholera is altered in the presence of HIV, although the gastric secretory failure that occurs commonly in AIDS may lead to a greater susceptibility to infection to Vibrio cholerae. 566, 567 It should be noted that although the live oral cholera vaccine is considered to be contraindicated in people with HIV infection by the USPHS-IDSA working group, 213 it has been shown to be safe and immunogenic in HIV-infected adults in Mali. 568 Further details on the association of HIV and enteric bacterial infections, including therapy, are presented in Chapters 16 through 21 and in reviews elsewhere. 76, 77 Other Bacteria

Although the data on HIV infection and epidemic meningococcal meningitis have not provided evidence for a significant interaction, 569 studies suggest that HIV infection may be a risk factor for sporadic meningococcal disease. 570, 571 Interactions between HIV and Bacillus anthracis or Yersinia pestis have not been reported. The globally endemic Bartonella species, Bartonella henselae and Bartonella quintana (see Chapter 40), cause acute and persistent bacteremia as well as localized tissue infection (including bacillary angiomatosis, bacillary peliosis, microscopic abscess formation, and lymphadenitis), primarily in AIDS patients and other immunocompromised people. 572 The closely related species Bartonella bacilliformis, which is geographically restricted to Andean river valleys, causes a similar spectrum of disease (including acute and persistent bacteremia and hemangiomatous nodules resembling those seen in bacillary angiomatosis) in immunologically normal hosts (see Chapter 40). Cases of coinfection with HIV and B. bacilliformis do not appear to have been reported.

None of the viruses that, along with parasites, have formed the traditional focus of the Anglo-American specialty of tropical medicine have been reported to cause uniquely prevalent, severe, or unusual disease in people infected with HIV. No significant interactions have been well documented between HIV and bunyaviruses, hantaviruses, phleboviruses, arenaviruses, alphaviruses, or filoviruses. In part, of course, this may be a function of a lack of sufficient experience with coinfection with these agents. Among the flaviviruses, (1) two uncontrolled series of patients with St. Louis encephalitis in Texas have suggested the possibility that the ratio of disease to infection, but not the course of symptomatic disease, is worsened in the presence of HIV infection, 573, 574 and (2) there are insufficient data to determine whether HIV alters the course of yellow fever (no case reports; 20% to 50% mortality in the absence of coinfection 575 ), West Nile virus infection (single case report 576 ), or dengue infection (single case report 577 ). Interestingly, the case report of dengue coinfection suggests that dengue fever, like acute measles and scrub typhus, may lead to a reversible suppression of HIV replication. 577 Should the live-attenuated yellow fever vaccine be given to those infected with HIV? There are theoretical risks of vaccineinduced encephalitis and/or hepatic damage due to prolonged viremia in the immunodeficient. 575 A handful of cases of postvaccinial encephalitis or multiple organ failure (yellow fever vaccine-associated viscerotropic disease [YEL-AVD]) have been reported in presumably immunocompetent patients (against a denominator of approximately 400 million people vaccinated). 575 Of note, 4 of 23 vaccinees who developed YEL-AVD had undergone thymectomy for thymomas, raising the concern that deficient thymic function may permit fatal vaccineinduced viral infections. 578 A single case has also been reported of fatal myeloencephalitis after vaccination in a Thai man with asymptomatic HIV infection, albeit a low CD4+ T-cell count and a high viral load. 579 Approximately 100 asymptomatic HIV-seropositive U.S. military personnel received yellow fever vaccination prior to the introduction of routine HIV screening; no adverse effects were detected (R. Redfield, personal communication, 1997). Small published series of travelers have suggested safety and variable efficacy of the 17D yellow fever vaccine in HIV seropositives without severe immunosuppression. [580] [581] [582] The immunogenicity of yellow fever vaccination has been noted to be severely reduced, again in the absence of significant adverse events, in HIV-infected children in Côte d'Ivoire 583 (T. Tsai, personal communication, 1997). WHO recommendations are to use yellow fever vaccine in HIV-seropositive patients who are asymptomatic. It remains a part of the WHO EPI. 443 Pending further studies, yellow fever vaccine is not recommended for symptomatic HIV-infected patients by WHO. 443 The ACIP recommends that HIV-infected people without AIDS or other symptomatic manifestations of HIV infection, who have laboratory-established verification of adequate immune function, and who cannot avoid potential exposure to yellow fever be offered the choice of vaccination. 584 Given apparent reduced vaccination efficiency, neutralizing antibody titers should probably be measured prior to travel. If travel requirements (as opposed to actual risk of infection) are the only reason for vaccination of an asymptomatic HIV-infected person, a vaccination waiver letter (which may not be accepted at some borders) should be obtained. 584 For all travelers, avoidance of areas of transmission and, if travel to such areas is essential, conscientiously avoiding mosquito exposure is prudent.

Measles virus (see Chapter 55) causes an annual mortality in the tropics far in excess of that due to the "traditional" tropical disease viruses. In fact, the worldwide yearly mortality due to measles is rivaled among single pathogens only by falciparum malaria, tuberculosis, and AIDS. This mortality is predominantly in sub-Saharan Africa. Similar to AIDS, infection with measles virus is accompanied by marked abnormalities of CMI that contribute to the increased susceptibility to secondary infections that account for much of the morbidity and mortality of the disease. [585] [586] [587] [588] [589] Measles is exacerbated in the presence of HIV coinfection. [590] [591] [592] [593] [594] [595] [596] [597] [598] [599] [600] [601] [602] The mortality rate in North American case series and reports of measles in HIV-positive children and adults has been 40%, far higher than the usual 0.1% case fatality rate seen in the United States. Although the presentation of disease has been normal in many, up to 40% have had no rash. In these reports, giant cell pneumonitis has been the principal complication and the prime cause of death, although fatal subacute measles encephalitis has also been described. CD4+ T-cell counts have not been reported in many of these cases, but where they have been reported they have generally been less than 500/μL. Such case reports and series are obviously likely to be biased toward the severe end of the spectrum of disease, however. Three substantial studies have investigated HIV-measles coinfection in sub-Saharan Africa. [600] [601] [602] A study of children hospitalized with measles in Kinshasa showed similar mortality rates among HIV-seropositive (31.3%) and -seronegative (28%) children. 600 The fact that only severely ill patients, with complications, were hospitalized likely obviated the ability to detect differential mortality in this study. An initial study of children with measles in Lusaka revealed a significantly higher mortality rate in HIV seropositives (28%) than seronegatives (8.3%). 601 A second prospective study in hospitalized children in Lusaka that distinguished between HIV infection and HIV seropositivity found few differences in the clinical presentation, complications, or mortality of HIV-infected compared to -uninfected children with measles. 602 However, enrollment was based on a clinical diagnosis of measles, which would be expected to minimize the ability to detect differences in clinical presentation; there was a bias against enrollment of critically ill children and those dying soon after admission; and there was significantly greater mortality among HIV-infected compared with -uninfected children among those with clinically diagnosed as opposed to confirmed measles. 602 Early death prior to mounting diagnostic measles IgM titers in the face of severe immunosuppression was suspected to be confounding. Other positive findings in this study included a higher proportion of HIV infection among children hospitalized with measles than expected from (maternal) population prevalence rates, a greater proportion of coinfected patients hospitalized with measles younger than the age of 9 months, and a longer duration of illness before hospitalization and longer hospitalization in coinfected children. 602 Follow-up studies have shown that coinfected patients have a higher risk (90.9% vs. 52.8%) for prolonged (30 to 61 days after rash onset) shedding of measles virus 603 ; and that in vivo HIV replication appears to be suppressed during acute measles. 604 No therapies have been rigorously studied. Vitamin A, which has been shown to be protective in severe measles in malnourished children, 605 may be of benefit, especially given the marginal nutritional status of many with HIV infection. Ribavirin has been shown to reduce the severity of measles in normal hosts. 606 Reports of its use in HIV-positive patients with measles pneumonitis have suggested some efficacy, although rigorous data are lacking. 591, 592, 594, 595, 598 Intravenous use is probably most effective. Intravenous immune globulin (IVIG) may also be of benefit. 592 Given the severity of measles in HIV patients, prevention is key. Postexposure prophylaxis with intramuscular immune globulin attenuates disease in normal hosts. It is recommended by the ACIP 607 in symptomatic HIV patients (and in those with CD4+ T-cell counts <200/μL) regardless of measles serostatus, but it may have limited efficacy in these and other immunosuppressed patients. 595, 608 The recommended dose is 0.5 mL/kg (15 mL maximum), given intramuscularly within 6 (or, better, 3) days. Such postexposure prophylaxis is also recommended by the American Academy of Pediatrics (AAP) for all HIV-infected children and adolescents, and for all children of unclear infection status born to HIV-infected women, regardless of measles immunization status or degree of immunosuppression. 609 Preexposure prophylaxis with monthly IVIG has been advocated for HIV-positive children with documented measles vaccine nonresponsiveness during community outbreaks of measles, 595 but this is not likely to be an economically viable option in the resource-poor areas of the tropics where measles is heavily endemic.

Vaccination remains the principal strategy for preventing measles in HIV-infected people. In normal hosts, the protective efficacy of measles vaccination is greater than 95%. 610 Vaccination efficacy data in HIV-seropositive people is lacking, but seroconversion data are available. This is a less than ideal surrogate. In general, there is a strong correlation between levels of neutralizing antibody and protection, but the failure of postexposure prophylaxis with immune serum globulin in preventing fatal giant cell pneumonia in patients with the cellular immunodeficiencies noted previously provides compelling evidence that CMI mechanisms, whether specific or nonspecific, are important even in protection from initial infection. In adults with HIV infection, there appears to be no waning of measles antibody titers with increasing immunosuppression. [611] [612] [613] Unfortunately, there are no clear data on the response to vaccination in those adults who lack antibodies to measles. 614 In children, the situation is different. HIV-infected infants have a markedly lower rate of seroconversion after measles vaccination, generate lower titers of antibody on seroconversion, and have a high rate of secondary vaccine failure, with antibody titers that decrease with time and with increasing immunosuppression. 615 Variable, but generally poor, responses to second doses of vaccine have been reported. 615 There may be a benefit to vaccinating early (at 6 to 9 months of age) to take advantage of the fact that there is less HIV-related immunosuppression at this early age. Early vaccination may also be valuable because both HIV-positive and HIV-negative infants born to HIV-infected mothers have lower titers of maternal antimeasles antibody. 616 In a study in Kenya, the risk of acquiring measles before vaccination at 9 months of age (the standard age of vaccination in Africa at the time) was 3.8 times higher (95% confidence interval, 1.2 to 13.2) in infants born to HIV-seropositive mothers. 616 High-titer measles vaccines may be more immunogenic in HIV-infected children 617, 618 but have been discontinued for safety reasons in all children.

Safety concerns have obviously been of great importance in the use of this live-attenuated vaccine in HIV patients. Although the use of measles vaccine had appeared to be quite safe in HIVinfected children and adults, 619 two reports have emphasized the need for some caution. A 20-year-old man with no HIVrelated symptoms but a CD4+ T-cell count "too few to enumerate" received a second dose of measles vaccine prior to entry into college. One year after vaccination, he developed progressive, vaccine-associated measles pneumonitis. 620 A study of the effect of HIV on measles mortality in 356 children hospitalized with measles in Lusaka, Zambia, is also troubling. 601 Previous studies have suggested that when prior measles vaccination does not prevent disease, it can reduce the severity of infection. 600 In HIV-seronegative boys hospitalized for measles, prior measles vaccination did lead to a significantly lower case fatality rate. 601 Although case fatality rates were not significantly lower in vaccinated HIV-seropositive boys or HIV-seronegative girls than in their unvaccinated controls, there was a trend toward a lower case fatality rate in the vaccinees. Surprisingly, however, the case fatality rate was higher in measles-vaccinated than in unvaccinated HIVseropositive girls. Although this did not reach statistical significance, it is reminiscent of the experience with the hightitered Edmonston-Zagreb (EZ) vaccine. Use of high-titered EZ vaccine at less than 9 months of age was associated with a delayed excess mortality in several study sites. [621] [622] [623] This occurred exclusively in female infants for reasons that remain unclear. It is notable that in the Zambian study noted previously, the highest mortality was seen in the youngest, vaccinated HIV-seropositive girls. However, in regions where there is measles transmission, risk-benefit analysis clearly favors measles immunization of all children regardless of HIV status. 615 In regions where measles transmission does not occur and where immune status can be monitored, withholding of measles vaccine from HIV-infected children with severe immune compromise is wise. 615 WHO recommends measles vaccination for all children in developing countries regardless of HIV infection or symptom status because of the high risk and severity of measles in general in such countries. 443, 624 In the United States, the USPHS-IDSA working group and the ACIP recommend measles vaccination for HIV-infected people according to the schedule and conditions for normal hosts if they are not severely immunocompromised. 213, 610 In addition, the risks and benefits of vaccination or immune globulin prophylaxis should be weighed in severely immunocompromised patients who are at increased risk due to travel or outbreaks. 213,607 AAP recommendations for HIV-infected infants to young adults in the United States include

• No immunization in the face of severe immunosuppression • Use of the measles-mumps-rubella (MMR) vaccine at 12 months of age, with a second dose given as soon as 28 days after the first dose • With measles transmission in the community, vaccination of infants as young as 6 months old with MMR or monovalent measles vaccine, and revaccination with MMR at 12 months • Vaccination of all measles-susceptible household members of an HIV-infected person • Use of immune globulin prophylaxis as noted previously 609 Few data are available on other paramyxoviruses in AIDS. With respiratory syncytial virus infection, pneumonia may be more common than bronchiolitis with wheezing, and viral carriage may also be prolonged. [625] [626] [627] [628] Copathogens may occur more frequently than in normal hosts. 626 Ribavirin appears to be efficacious in both children and adults.

Most human rabies (see Chapter 75) occurs in tropical countries where canine rabies is still endemic. The presentation of rabies does not appear to be altered by HIV infection. 629 HIV-infected children and adults clearly have substandard responses to rabies vaccination, however. 630 

Great strides have been made in worldwide polio eradication (see Chapter 60). Most of the remaining burden of poliomyelitis is in the tropics outside the Western Hemisphere. There is no evidence that HIV infection alters the outcome of infection with poliovirus. It has been estimated that more 500,000 HIV-infected children have received live oral polio vaccine (OPV). 615 Only two cases of vaccine-associated paralytic poliomyelitis in HIV-infected children have been reported. 615 If there is greater risk of vaccine-associated disease in the face of HIV infection, the attributable risk is thought to be very low. 615 OPV remains part of the WHO EPI for all children. 443 In the United States, the OPV is supported by the ACIP as the only vaccine recommended for polio eradication where there still is transmission of wild-type polio. 634 ACIP recommendations have replaced OPV with inactivated polio vaccine for all vaccinees in the United States. 634 

Chronic diarrhea is a common problem in AIDS patients throughout the world. Although no definite pathogenic role has been ascribed to enteric viruses (small round structured viruses, enteric adenoviruses, and coronaviruses) in AIDSrelated diarrhea in either North America or Africa, 635, 636 there are some preliminary data suggesting greater disease severity in children coinfected with HIV and astroviruses 637 and an association of picobirnaviruses with diarrhea in HIV-coinfected patients. 638 In non-cholera-endemic areas of the tropics, rotavirus is probably the principal cause of diarrheal deaths in HIV-uninfected infants. 639 Rotavirus diarrhea does not appear to be an opportunistic pathogen in children with HIV coinfection. In a large study in Malawi, no differences in the severity of rotavirus gastroenteritis were found between HIV-infected and -uninfected children. 640 Interestingly, rotavirus was less frequently detected in HIV-infected children with gastroenteritis. Despite equal resolution of clinical disease, however, the frequency of death after hospital discharge was significantly greater in coinfected children. 640 

Infection with hepatitis A virus (HAV) (see Chapter 64) occurs worldwide. In resource-poor countries, especially in the tropics, HAV is hyperendemic, and exposure to the virus (usually subclinical) is essentially universal by the age of 10 years. Virtually all adults are immune. HIV/HAV coinfection appears to be associated with a higher HAV serum viral load, a longer duration of viremia, and lower elevations in serum alanine aminotransferase levels 641 but a similar disease course. [641] [642] [643] Vaccination against HAV is safe in HIV-infected patients. [644] [645] [646] Efficacy wanes with increasing immunosuppression. 645, 646 Some recommend vaccination for all those at risk (defined by a negative serology). 76 Infection with hepatitis E virus (HEV) (see Chapter 64) is more localized, with sporadic and epidemic disease being reported in Mexico; North and West Africa; the Middle East; and South, Southeast, and East Asia. Clinical disease occurs in both adults and children. HEV has not been implicated as having any significant interaction with HIV.

With the cosmopolitan hepatitis viruses that are capable of causing chronic disease, however, several potentially important interactions with HIV have been described. The prevalence of coinfection is furthered by the fact that these viruses share routes of transmission with HIV. For hepatitis B virus (HBV) (see Chapter 64), CMI responses are thought to be important both for the resolution of acute disease and for the production of hepatic inflammation in chronic disease. HIV infection has been reported to lead to • At least a threefold increase in risk of the development of a chronic HBV carrier state (with an inverse correlation with the CD4 count), without a significant change in the severity of acute disease 647,648 • Potential reactivation of quiescent HBV infection 649, 650 • Increased HBV replication and decreased inflammation in those with 647, 649 or without 651 chronic hepatitis • A decreased response to HBV vaccination 652 • Loss of HBV antibody over time 652, 653 • A 15-fold increase in liver-related mortality in HBVinfected individuals 654 Vaccination against HBV has reasonable efficacy in HIVseropositive populations. Interestingly, however, the highest reported rate of development of the chronic carrier state in adults (56% to 80%) occurred in HIV-infected people who were vaccinated at the same time that they developed HBV infection. 648 HBV does not appear to have a significant effect on the clinical course of HIV infection. 655 With hepatitis C virus (HCV) infection (see Chapter 64), HIV coinfection is associated with an increased risk of progression to chronic infection. 656 Documented interactions between the two viruses 657 include (1) an increase in HCV viral load 658,659 ; (2) an increase in vertical 660 and male-to-female sexual transmission 659 of HCV, probably due to higher viral load; (3) a more severe clinical and histopathologic course 661, 662 ; and (4) a high percentage of indeterminate HCV immunoblot assays, with frequent HCV seroreversion. 656 Whether HCV infection has a significant effect on the natural history of HIV infection or the response to HAART therapy remains controversial. [663] [664] [665] [666] [667] Maternal HCV infection appears to be associated with an increased risk of HIV vertical transmission. 668 Treatment of both HIV/HCV and HIV/HBV infection has been reviewed recently. 657 The data on hepatitis D virus (HDV) are more meager. HDV replication may be prolonged or reactivated in the presence of HIV coinfection. 669, 670 Herpesviruses As in the industrial world, herpes zoster is quite common in adult AIDS patients in the tropics. A history of shingles is reported by more than 10% of AIDS patients in Africa. 671 In areas of Africa with a high seroprevalence for HIV, the positive predictive value of a history of shingles for HIV infection is greater than 90%. 671 As elsewhere, zoster tends to develop early in HIV disease, and recurrence is common. 671, 672 Chronic genital herpes simplex lesions are common throughout the world in patients with sexually transmitted HIV infection. CMV infection is ubiquitous in most of the tropics. 673 The reported incidence of severe disease due to CMV in AIDS in Africa and Asia (although not Latin America and the Caribbean) has lagged behind that of the industrial north, however, likely because of greater mortality at earlier stages of disease. 674, 675 The natural history, diagnosis, and therapy of disease due to coinfection with these cosmopolitan herpesviruses have been discussed elsewhere. [76] [77] [78] [79] Endemic (central Africa), AIDS-related, "classic," and post-transplant Kaposi' s sarcoma are all closely associated with human herpesvirus 8 (HHV8) (see Chapter 57). 676 In the AIDS era, Kaposi' s sarcoma has become one of the leading malignancies in areas of sub-Saharan Africa. 677 The epidemiology, clinical manifestations, and therapy of HHV8 infection and Kaposi' s sarcoma (a disease that the industrialized world had considerable experience with early in HIV pandemic) have been reviewed elsewhere. 76, 77, 678, 679 Other Viruses

Although data remain somewhat limited, the cosmopolitan influenza virus appears to cause more severe disease in HIV coinfected patients, with prolongation of symptoms and a higher risk for complications, hospitalization, and death. 680 Influenza vaccination is safe and recommended by the ACIP for HIV-infected patients. 680 Such vaccination has been shown to have good efficacy in a study in individuals with a mean CD4+ T-cell count of 200/μL. 681 With advanced HIV, vaccination may not generate protective antibody titers. 682 The single case report of severe acute respiratory syndrome (SARS) coronavirus infection in the face of HIV coinfection was within the described clinical spectrum of this newly emerging virus. 683

The association of blood (or tissue) eosinophilia with tissue exposure to helminthic parasites can be of considerable diagnostic utility in non-HIV-infected populations (see Chapter 125) . Data suggest that this utility may be lessened by the presence of HIV infection. Both relative and absolute eosinophilia occur for nonparasitic reasons with considerable frequency in HIV-infected populations. A relative eosinophilia commonly occurs with progressive HIV disease, at least in North American adult AIDS patients, 684, 685 due to a sparing of absolute blood eosinophil concentrations in the face of decreasing concentrations of all other granulocytic and mononuclear leukocyte populations. 685 This effect becomes marked with CD4+ T-cell counts less than 200/μL. 685 Nonhelminth-related absolute eosinophilia also occurs with regularity with advancing HIV disease. Absolute eosinophilia in North American HIV-seropositive adults has most frequently been associated with pruritic cutaneous disease, particularly the diagnoses of eosinophilic pustular folliculitis, atopic dermatitis, and prurigo nodularis. 686 Most such patients have CD4 counts less than 100/μL. 686 It remains unclear in these patients whether the eosinophilia is primary with secondary cutaneous manifestations or an allergic response to a predominantly cutaneous antigen. A few AIDS patients have presented with what appears to be a variant of the hypereosinophilic syndrome with prominent cutaneous manifestations 687, 688 or a hyper-IgE-like syndrome. 689 Rare causes of tissue or blood eosinophilia in AIDS patients have included acute eosinophilic pneumonia 690 and high-grade B-cell lymphomas. 691 Adverse reactions to various prophylactic and therapeutic agents may also elicit eosinophilia in AIDS patients. Other causes of secondary blood eosinophilia appear to be quite uncommon in North American AIDS patients. 691 This includes adrenal insufficiency, despite the high prevalence of adrenalitis at autopsy in AIDS patients. 692 The upshot of these reports is that the diagnostic specificity of blood eosinophilia for tissue helminthic infection is probably poorer in HIVinfected than in HIV-free adult patients in the industrial north (a conclusion somewhat undermined by the low population prevalence of helminthic disease in the studies cited previously). It is probably reasonable, however, to avoid an extensive workup for parasitic and other causes of eosinophilia in adult eosinophilic AIDS patients with cutaneous disease from the industrial world; however, in populations at higher risk of helminthiasis, such a conclusion is unwarranted in the absence of prospective studies of eosinophil levels in AIDS patients with tissue helminthiasis. 693 Such eosinophilia with advancing HIV disease has not been noted in children in the industrial world. 694, 695 The data from the tropics are dramatically at variance with the reports from the industrial world. A study of patients with tuberculosis in Burkina Faso reported lower eosinophil levels in HIV-seropositive people compared with seronegative people, with a strong correlation between CD4+ T-cell and eosinophil counts. 696 A follow-up study in Faso reported that in helminth noninfected HIV patients, eosinophil counts were higher in CDC stage B patients than in controls but were severely decreased in CDC stage C patients. 697 Mean eosinophil counts in a cohort of 611 HIV-infected patients in Cote d'Ivoire, with a mean CD4+ T-cell count of 115 cells/μL, were in the normal range for HIV-uninfected populations in areas of the world with a low prevalence of helminth infection. 698 Finally, a case report from England of HAART-related immune reconstitution in a schistosome-infected woman from southeast Africa is intriguing. 699 The patient presented with a CD4+ T-cell count less than 200/μL and an eosinophil count of 300/μL. Immune reconstitution was accompanied by the development of robust eosinophila (1500/μL) that decreased with praziquantel treatment. Taken together, these findings suggest that late HIV disease in the tropics, as opposed to the industrial world, is associated with a suppression of blood eosinophil levels. The mechanism(s) responsible for these divergent findings remains unclear.

The USPHS-IDSA working group has updated guidelines for preventing OIs in HIV-infected people in industrialized countries. 213 The data on 19 OIs frequent in North American HIV-infected populations were reviewed. Factors considered in these evaluations were

• Disease incidence • Disease severity in terms of morbidity and mortality • The level of immunosuppression at which disease is most likely to occur • The feasibility, efficacy, and cost of preventive measures • The impact of intervention on quality of life • Toxicities, drug interactions, and the potential for drug resistance • The quality of the evidence supporting each recommendation 213 The prevention of each OI was evaluated from the standpoint of prevention of exposure, prevention of the first episode of disease by immuno-or chemoprophylaxis (primary prophylaxis), prevention of disease recurrence (secondary prophylaxis), and discontinuance of prophylaxis in those whose CD4+ T-cell counts had risen in response to HAART. 213 Specific recommendations for prevention of exposure were made for several agents, including T. gondii, C. parvum, M. tuberculosis, bacterial enteric agents, Bartonella, herpes simplex virus (HSV), varicella zoster virus (VZV), CMV, HHV8, human papillomavirus, and HCV. 213 For adults and adolescents, prophylaxis to prevent the first episode of opportunistic disease was strongly recommended as a standard of care for P. carinii, M. tuberculosis (in the face of tuberculin skin test reactivity or contact with a case of active tuberculosis), T. gondii, M. avium complex, and VZV (with exposure to chickenpox or shingles in patients without a history of such, or with negative serologies for VZV [varicella Zoster immunoglobulin (VZIG)]. Primary prophylaxis against HBV, HAV, influenza virus, and S. pneumoniae was generally recommended. Although evidence exists for efficacy, primary prophylaxis against C. neoformans, H. capsulatum, CMV, and bacterial infection (in the face of neutropenia) was not routinely recommended. For two of these agents (P. carinii and M. avium), primary prophylaxis has been shown to confer a survival benefit. 700, 701 Secondary prophylaxis to prevent recurrent disease was strongly recommended as the standard of care for P. carinii, T. gondii, M. avium complex, CMV, C. neoformans, H. capsulatum, C. immitis, and nontyphi Salmonella species. Such prophylaxis was recommended for HSV and Candida only if subsequent episodes are frequent or severe. 213 For children, primary prophylaxis was strongly recommended as a standard of care for P. carinii, M. tuberculosis, M. avium complex, and VZV (VZIG); generally recommended for T. gondii, VZV (immunization in the absence of immunosuppression), and influenza virus; and recommended only in unusual circumstances for invasive bacterial infection (hypogammaglobulinemia, IVIG), C. neoformans (severe immunosuppression), H. capsulatum (severe immunosuppression, endemic geographic area), and CMV (CMV antibody positivity and severe immunosuppression). Primary prophylaxis was also addressed through review of the recommendations for routine immunization schedules in HIV-infected children. In addition to standard schedules for immunization against HBV, HAV, polio, H. influenzae type b, diphtheria, tetanus, and pertusis, altered schedules for vaccination against S . pneumoniae (use of the heptavalent pneumococcal conjugate vaccine beginning at 2 months, followed by 23-valent pneumococcal polysaccharide vaccine at 2 years), influenza (yearly dose recommended), MMR (no administration to severely immunosuppressed children), and VZV (administration only to asymptomatic, nonimmunosuppressed children) were reviewed. Recommendations for secondary prophylaxis were similar to recommendations for adults, with the addition of a recommendation for use of TMP-SMX or IVIG to prevent invasive bacterial infection in the presence of more than two such infections in a 1-year period. 213 These recommendations are likely to find broad applicability in the industrial world, where the OI spectrum, healthcare priorities, and available prevention options are similar. The applicability to much of the tropics is less clear, however, given differing spectra of OIs, differences in antibiotic resistance patterns, and differences in sociocultural acceptability or feasibility of preventive measures. Limits in the availability of health-care resources (including not just an inability to support the cost of many prevention regimens but also an inability to diagnose HIV disease early enough for preventive measures to be effective, to reliably stage the degree of HIVassociated immunosuppression, and to definitively diagnose OIs) also directly influence the range of prevention options and priorities. It should also be noted that compared with HAART therapy (or prevention of HIV infection), the benefit of OI prevention in reducing HIV-related morbidity and mortality may be somewhat modest. 702 Adequate global provision of HAART represents an ongoing, immense challenge, however, and wide implementation of simple, cheap, effective OI prevention strategies provides an opportunity to rapidly and widely reduce morbidity and mortality. 675 The wide availability of affordable and effective regimens may also encourage people to seek HIV testing. 675 In 1996, Kaplan and colleagues argued that effective research on OI prevention strategies in the tropics will require an integrated approach, including the area-specific determination of OI spectra, determination of environmental reservoirs of opportunistic pathogens and feasible ways to reduce exposure, assessment of immuno-and chemoprophylaxis against such pathogens, and improvement in the ability to identify and inexpensively stage HIV infection. 20 Since then, data on the efficacy of some OI prevention strategies in resource-poor countries of the tropics have accrued.

First, as noted previously, primary preventive therapy against tuberculosis (TB) with isoniazid has been shown be effective in HIV-infected individuals, regardless of tuberculin status. 423,424,675 WHO and UNAIDS recommendations are for primary preventive therapy to be given to PPD-positive, HIVinfected individuals who do not have active TB. 425 In settings where it may not be feasible to do PPD testing, the recommendations are for primary preventive therapy to be considered for those living in populations with a prevalence of tuberculous infection estimated to be more than 30%, healthcare workers, household contacts of TB patients, prisoners, miners, and other groups at high risk of acquisition or transmission of TB. 425 Second, TMP-SMX-a cheap, widely available antibiotic with activity against a plethora of OIs (including PCP, nontyphoid salmonellosis, pneumococcal disease, and toxoplasmosis) and malaria-has been shown to reduce morbidity and mortality in HIV-infected adults 675,702-705 and children. 401, 706 WHO/UNAIDS recommendations are that TMP-SMX should be used for prophylaxis in adults and children living with HIV/AIDS in Africa as a minimum package of care. 707 For adults in Africa (defined as those older than the age of 13 years), such prophylaxis should be offered to all people with symptomatic HIV disease, those who are asymptomatic with a CD4 count of 500/μL or less (or total lymphocyte equivalent), and pregnant women after the first trimester. 707 WHO/UNAIDS/UNICEF recommendations are that all HIVexposed children (born to HIV-infected mothers) should get TMP-SMX from the age of 4 to 6 weeks, as should any child identified as HIV infected with any clinical signs or symptoms suggestive of HIV, regardless of age or CD4+ T-cell count. 708 It is further recommended that TMP-SMX should be discontinued (1) in HIV-exposed children only once HIV infection has confidently been excluded (and the mother is no longer breastfeeding); (2) in HIV-infected children on antiretroviral therapy only when evidence of immune restoration has occurred; and (3) in those with severe cutaneous, renal, hepatic, or hematological toxicity. 708 It has been noted that such mass prophylaxis strategies entail some as yet to be quantified risks, principally of increasing rates of drug-resistant bacteria and malaria. 709 Studies to examine such risks should be performed.

Third, a large, randomized, double-blind, placebocontrolled trial of the 23-valent pneumococcal polysaccharide vaccine in HIV-infected Ugandan adults showed no protective effect (with invasive pneumococcal disease as the primary endpoint). 710 Surprisingly, increased rates of pneumococcal disease were seen in vaccine recipients. The potential mechanism(s) remains unclear; not surprisingly, the study remains controversial.

Fourth, among the specifically tropical OIs, a controlled, double-blind trial of primary prophylaxis with itraconazole in Thailand showed efficacy in preventing penicilliosis (and cryptococcosis). 340 There are little or no data available on the prophylaxis of other tropical OIs, such as leishmaniasis and American trypanosomiasis, although the utility of avoiding exposures to the vectors of the agents of these diseases should be clear.

More generally, certain options for preventing or reducing exposure to opportunistic pathogens are likely to be broadly useful, including avoiding unboiled water, raw or undercooked foods, and unpasteurized milk to prevent enteric bacterial and protozoan infections as well as T. gondii exposure and also avoiding contact with patients with TB, for example, in patient-care settings. Avoidance of exposure to the opportunistic agents of disseminated fungal disease is likely to be impractical in most settings.

It is clear that for many people, HIV infection is more an inducement than a hindrance to travel. 711 For HIV-infected patients from the industrial world, travel to the tropics leads to an increased risk of exposure to a variety of ubiquitous as well as geographically focal infectious diseases (see Chapter 120) . The principal concerns are enteric, respiratory, and vector-borne infections. STDs deserve special mention, however. Despite the AIDS pandemic, studies continue to document a high frequency of unprotected sexual encounters among travelers to the tropics. 712, 713 For the HIV-infected traveler, it bears remembering that spread of the AIDS pandemic has been along the routes of human travel and migration. 712 HIV-infected travelers should notify sexual partners of their HIV status, observe safe sex practices, refrain from donating fluids or tissue, inform health-care providers of the need for blood precautions, and avoid the sharing or recreational use of needles. For travelers who are not infected with HIV, pretravel counseling should be given on strategies to minimize the risk of HIV acquisition during travel, including

• Avoiding sex with new partners • Using latex condoms if having sex (remembering that condom quality varies throughout the world) • Taking a supply of sterile needles and syringes if routine or frequent injections are required (e.g., for insulindependent diabetes) or if a prolonged stay in remote areas is planned • Avoiding all skin-piercing procedures (e.g., tattooing, acupuncture, and shaving by barbers) and avoiding invasive medical and dental procedures if possible • Being cognizant of the risks of motor vehicle travel because motor vehicle injuries are not just among the greatest health threats to travelers in the tropics but also provide a major risk factor for needing emergency blood transfusion in countries where HIV screening of the blood supply is not routine These are also important educational points for HIV-infected travelers.

There are recent reviews of medical issues in the HIVinfected tropical traveler from the industrial world 714,715 and information is available from www.cdc.gov/travel/hiv. trav.htm. Careful, timely pretravel advice and planning can help HIVinfected patients minimize the unavoidable risks of travel to the tropics. Issues to cover include

• Providing an adequate supply of currently used medications • Identifying optimal sources of medical care in planned destinations (and obtaining adequate medical insurance to cover such care) • Discussing potential legal restrictions on travel • Providing education on avoiding food-, water-, and vector-borne disease • Providing vaccination, chemoprophylaxis, and antimicrobial agents as appropriate reviewing the medical geography of the route and planned activities to identify any special risks

• Providing for adequate medical follow-up on return from travel Prior to travel, those at risk of HIV infection should be screened for infection as part of the routine pretravel evaluation. Those known or found to be HIV infected should have their disease staged by CD4 count and viral load because the level of immunosuppression will influence the travel medical recommendations given. Therapy with HAART can complicate tropical travel. 715 For those already on HAART, concerns include

• The problem of appropriate clinical and laboratory monitoring-for those planning extended residence in places lacking appropriate clinical or laboratory services, it would be prudent to schedule two or three trips per year for medical follow-up to a country where such services are available • Difficulties with compliance with complicated HAART regimens during the dislocations and changing daily schedules of travel • The fact that approximately 50 countries currently restrict the entry of those infected with HIV, especially long-term visitors such as students and workers, despite compelling arguments against the utility and for the counterproductive nature of such policies An unofficial listing of country requirements is available at http://travel.state.gov/trvel/HIVtestingregs.html. Because possession of HAART medications may reveal the traveler' s HIV infection, a potential solution is to remove or cover drug labels. Clearly, this is not without its own risks, which demand that careful records (medication names, dosages, frequencies, and physical appearance) be kept in more than one safe place by the traveler. Finally, there is the problem of untoward drug interactions with protease inhibitors. When initial HIV infection diagnosis and/or staging occurs during pretravel evaluation, the traveler may be newly recognized to fall into a group for whom HAART therapy is recommended. For those planning short-term travel, initiation of HAART just prior to departure is probably unwise due to the risk of developing significant side effects-many of which tend to be worse with initiation of therapy and some of which are intensified by stress-in the absence of close contact with a knowledgeable provider. For those in this situation who are planning long-term residence in the tropics, departure should probably be postponed until the traveler is stably on HAART therapy, unless close, timely follow-up can be achieved in the destination country. A critical variable, as ever in the rapidly changing field of HIV clinical care, is adequate, ongoing experience. Travel physicians without extensive, current experience in the care of those with HIV/AIDS should be in close consultative contact with physicians who possess this expertise: Today' s verities rapidly become out of date. Textbooks of HIV care with frequent Web-based updates are also valuable resources. 76, 77 Sufficient quantities of currently used medications, along with replacement prescriptions, are essential. Patients should be counseled to seek medical attention promptly when ill. Although the current communication revolution allows a growing number of traveling patients to stay in close contact with their HIV and travel medicine physicians at home via e-mail, the prior identification of physicians with significant HIV experience in countries of planned travel is prudent. Obtaining medical insurance to cover such care is wise.

Another basic consideration, especially for those with advancing HIV-related disease, is the buying of trip cancellation and/ or repatriation insurance.

Enteric pathogens are a major threat to the HIV-infected traveler to the tropics. In addition to the fact that many tropical travel-associated enteric bacterial infections are more severe in the presence of HIV coinfection, the achlorhydria that occurs in AIDS may markedly lower the amount of inoculum needed for the establishment of infection. 566, 567 Precautions recommended for all travelers should be followed assiduously. Foods and beverages may be contaminated, particularly raw, unpeeled fruits and vegetables; raw or undercooked eggs; meats; seafood; tap water; ice; unpasteurized dairy products (beware of soft cheeses); and food purchased from street vendors. 213 Steaming hot foods, meat cooked until brown throughout, water brought to a boil for 1 minute, bottled (especially carbonated) beverages, very hot beverages, beer and wine, and fruits and vegetables peeled by the traveler are generally safe. 213 In addition to preventing enteric disease, following these precautions will also lower the risk of infection with T. gondii. Treating water with iodine or chlorine may be done, preferably in conjunction with filtration, when boiling is not practical. Filtration of water, using reverse osmosis or sub 1 micron filters, is efficacious in removing Cryptosporidia from water. 716 All tap water should be avoided, even small amounts used for brushing teeth. Recreational water exposure also carries a risk.

Obviously, fecally contaminated water should be avoided altogether. Swallowing water while swimming should be avoided. 213 Direct contact with soil and sand should be avoided in places where fecal contamination is likely; hands should be washed frequently. Antimicrobial prophylaxis for enteric pathogens is not routinely recommended for HIV-uninfected Three doses (one each at 0, 1, and 3-6 mo), with boost at 1 or 2 yr Rabies See text Avoid giving HDCV given intradermally, given potentially weaker response Japanese encephalitis Three doses, one each on days 0, 7, and 30; boost, based on antibody levels, at 1-3 yr *Routine primary series of immunization for diphtheria-tetanus, MMR, and polio is assumed. † Absolutely or relatively contraindicated in some circumstances.

travelers. For HIV-infected travelers, such prophylaxis may be considered, however, depending on the level of immunosuppression, the risk of infection, and the duration of travel. 213 Fluoroquinolones are probably the drugs of choice. All HIVinfected travelers should carry antimicrobials (with or without antimotility agents) for an empirical treatment course in case diarrhea develops. Ciprofloxacin 500 mg twice a day for 3 to 7 days is a reasonable choice. Alternatives such as TMP-SMX or azithromycin should be used for children and pregnant women. Medical attention should quickly be sought if empirical therapy fails, if shaking chills or hematochezia occur, or if dehydration develops. 213 Contact with arthropod vectors should be reduced through the careful use of insect repellents, wearing clothes that cover the arms and legs when outdoors, sleeping in wellscreened areas or under a bed net, and avoiding outdoor exposure between dusk and dawn (see Chapter 120) . The threat of sandfly transmission of visceral leishmaniasis (see Chapter 94) deserves special mention and education.

Malarial chemoprophylaxis is essential, where indicated, for all travelers. The HIV protease inhibitors currently used for HAART have understudied interactions with a variety of drugs used for malaria prophylaxis and treatment. Based on current data, mefloquine, doxycycline, chloroquine, and malarone (atovaquone + proguanil) are likely to be safe and to retain efficacy for malaria prophylaxis. The provision of empiric, standby treatment doses (e.g., of malarone) seems prudent.

Recommendations for the immunization of HIV-seropositive travelers to the tropics are summarized in Table 133 -1. Preparation for travel should include a careful review of routine vaccinations in addition to both routine and special travel vaccinations. Vaccine response rates, as measured by antibody titers, tend to decline with increasing HIV-related immunosuppression. This gives impetus, especially for "routine" vaccinations, to early identification of the need for vaccination. Essentially all live bacterial and viral vaccines are considered to be contraindicated in the presence of HIV infection, 213 including oral polio vaccine, oral typhoid vaccine (Ty21a), and BCG. The special cases of measles and yellow fever vaccines are considered in the "pathogen-centered" discussions earlier in the chapter and in Table 133 -1.

The risk of acquisition of tuberculosis is much higher in most tropical countries than in the United States, although the risk of becoming infected during short-term travel is low. As noted previously, the ACIP and the USPHS-IDSA working group consider the administration of BCG to be contraindicated because of the risk of dissemination, although it is recommended by WHO for those with asymptomatic HIV infection in areas with a high prevalence of TB infection. All HIV-infected people should receive PPD testing. Follow-up testing after return from the tropics (or during travel or residence in the tropics, if extended) should be performed. With a positive PPD (>5 mm induration) or a known high-risk exposure, HIV-infected people with no evidence of active TB, or history of treatment for latent or active TB, should be treated for latent TB. 213 Whether primary chemoprophylaxis should be recommended for travel in areas with a high population prevalence of TB is unclear.

The endemic systemic fungi carry considerable risk for HIV-infected travelers. Where the environmental sources are known, the risk of infection may be reduced somewhat by attempting to minimize exposure. Such measures include avoiding soil exposure, especially during the rainy season, in southern China and Southeast Asia (P. marneffei); avoiding exposure to disturbed soil and dust in lower Sonoran life zones of the Americas (C. immitis); and avoiding caves and soil and dust exposure in areas with heavy avian and bat excrement (H. capsulatum). Most often, the reservoirs are either unknown or too widespread to allow for avoidance. Primary prophylaxis with itraconazole (200 mg daily) may have merit for short-term prophylaxis during travel in areas with a high incidence of systemic fungal infection. 340, 717 Finally, it may be wise to avoid some areas of high potential risk by changing the planned travel itinerary or activities, especially for those people with advanced HIV disease. In this regard, it should be noted that many of the tropical infectious diseases of special concern here, such as yellow fever, have a fairly focal pattern of risk within endemic countries. 

Travel and HIV infection

UNAIDS: AIDS epidemic update

Investigating interactions between HIV infection and tropical diseases

Interactions of HIV infection with endemic tropical diseases

Immunology of HIV infection

Impaired interleukin-12 production in human immunodeficiency virus-infected patients

T cell function in vitro is an independent progression marker for AIDS in HIV-infected asymptomatic subjects

CD40 ligand dysregulation in HIV-associated dysfunction of antigen-presenting cells

Activation-induced death by apoptosis in CD4 + T cells from human immunodeficiency virusinfected asymptomatic individuals

Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV + donors by cysteine protease inhibitors

Human CD4+CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus

Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV patients

Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells

Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus-infected patients

Missing infections in AIDS

Problems of chemotherapy in multiply-infected AIDS patients

Antibody response to diphtheria, tetanus, and poliomyelitis vaccines in relation to the number of CD4 + lymphocytes in adults infected with human immunodeficiency virus

Increased density of human immunodeficiency virus type 1 coreceptors CCR5 and CXCR4 on the surfaces of CD4+ T cells and monocytes of patients with Schistosoma mansoni infection

Increased susceptibility to HIV-1 infection of peripheral blood mononuclear cells from chronically immune-activated individuals

Filarial infection increases susceptibility to human immunodeficiency virus infection in peripheral blood mononuclear cells in vitro

Treatment of intestinal worms is associated with decreased HIV plasma viral load

Associations between helminth infection and CD4+ T cell count, viral load and cytokine responses in HIV-1-infected Ugandan adults

Helminth infection is not associated with faster progression HIV disease in co-infected adults in Uganda

The association between malaria, blood transfusions, and HIV seropositivity in a pediatric population in Kinshasa

Female genital schistosomiasis as a risk factor for the transmission of HIV

The Lives of a Cell: Notes of a Biology Watcher

Medical Management of HIV Infection

The HIV inSite Knowledge Base

Centers for Disease Control and Prevention: Treating opportunistic infections among HIV-infected adults and adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America

Centers for Disease Control and Prevention: Treating opportunistic infections among HIV-infected children: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/ Infectious Diseases Society of America

HIV and malaria: A lesson in immunology?

Incidence of malaria and efficacy of oral quinine in patients recently infected with human immunodeficiency virus in Kinshasa

The clinical and parasitological presentation of Plasmodium falciparum: Malaria in Uganda is unaffected by HIV-1 infection

Plasmodium falciparum malaria and perinatally acquired human immunodeficiency virus type 1 infection in Kinshasa, Zaire

Childhood malaria parasitaemia and human immunodeficiency virus infection in Malawi

Effects of malaria infection in human immunodeficiency virus type 1-infected Ugandan children

Plasmodium falciparum antigeninduced human immunodeficiency virus type 1 replication is mediated through induction of tumor necrosis factor-a

Malaria infection induces virus expression in human immunodeficiency transgenic mice by CD4 T cell-dependent immune activation

Tumour necrosis factor production in falciparum malaria and its association with schizont rupture

The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration

The effect of Plasmodium falciparum malaria on peripheral and placental HIV-1 RNA concentrations in pregnant Malawian women

Maternal HIV infection and infant mortality in Malawi: Evidence for increased mortality due to placental malaria infection

Efficacy of sulfadoxinepyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection

Increased prevalence of malaria in HIV-infected pregnant women and its implications for malaria control

Human immunodeficiency virus seropositivity and malaria as risk factors for third-trimester anemia in asymptomatic pregnant women in western Kenya

HIV infection, malaria, and pregnancy: A prospective cohort study in Kigali, Rwanda

The effects of placental malaria on mother-to-child HIV transmission in Rakai

Placental malaria and perinatal transmission of human immunodeficiency virus type 1

Effect of maternal HIV and malaria infection on pregnancy and perinatal outcome in Zimbabwe

The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya

Maternal malaria and perinatal HIV transmission, western Kenya

The burden of coinfection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-Saharan Africa

Effect of HIV-1 and increasing immunosuppression on malaria parasitemia and clinical episodes in adults in rural Uganda: A cohort study

HIV, malaria parasites, and acute febrile episodes in Ugandan adults: A case-control study

Increasing rates of malarial fever with deteriorating immune status in HIV-1-infected Ugandan adults

HIV infection as a cofactor for sever falciparum malaria in adults living in a region of unstable malaria transmission in South Africa

Higher risk of antimalarial treatment in HIV positive than HIV negative individuals with clinical malaria

HIV infection may adversely affect clinical response to chloroquine therapy for uncomplicated malaria in children

JJ: Drug interactions of HIV protease inhibitors

Cytochrome p450 Drug Interaction Database

Mefloquine metabolism by human liver microsomes. Effect of other antimalarial drugs

Chloroquine modulation of specific metabolizing enzymes activities: Investigation with selective five drug cocktail

Johansson, I: Inhibitory effects of antiparasitic drugs on cytochrome P450 2D6

Comparison of (S)-mephenytoin and proguanil oxidation in vitro: Contribution of several CYP isoforms

In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase

No drug-drug interaction between nelfinavir or indinavir and mefloquine in HIV-1-infected patients

Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers

Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine

Norvir package insert

Current trends: Adverse reaction to Fansidar and updated recommendations for its use in the prevention of malaria

Babesiosis and infection with human immunodeficiency virus (HIV)

Babesiosis, asplenia, and AIDS (letter)

Treatment of babesiosis by red blood cell exchange in an HIV-positive splenectomized patient

Babesiosis in patients with AIDS: A chronic infection presenting as fever of unknown origin

Babesiosis and HIV

Atovaquone and azithromycin for the treatment of babesiosis

Leishmania-HIV interaction: Immunopathogenic mechanisms

Clinical manifestations of visceral leishmaniasis associated with HIV infection: A retrospective study of 91 French cases

The lipophosphoglycan of Lesihmani donovani up-regulates HIV-1 transcription in T cells through the nuclear factor-kB elements

Role of Leishmania donovani and its lipophosphoglycan in CD4+ T-cell activation-induced human immunodeficiency virus replication

HIV viral load and response to antileishmanial chemotherapy in co-infected patients

Leishmania infantum promotes replication of HIV type 1 in human lymphoid tissue cultured ex vivo by inducing secretion of the proinflammatory cytokines TNF-α and IL-1α

Heterogeneity among zymodemes of Leishmania infantum from HIV-positive patients with visceral leishmaniasis in South Italy

Leishmania and human immunodeficiency virus co-infection: The first 10 years

Leishmaniasis and AIDS co-infection. The Spanish example

An easy and quick method for the diagnosis of visceral leishmaniasis in HIV-1-infected individuals

Indirect xenodiagnosis of visceral leishmaniasis in ten patients with HIV infection using colonized Phlebotomus perniciosus

Ethiopian visceral leishmaniasis patients co-infected with human immunodeficiency virus

Global control and leishmania HIV co-infection

Leismania/HIV co-infection in Brazil: An appraisal

American cutaneous leishmaniasis associated with HIV infection: Report of four cases

Visceral leishmaniasis with cutaneous and rectal dissemination due to L. braziliensis in acquired immunodeficiency syndrome (AIDS)

Disseminated American muco-cutaneous leishmaniasis caused by Leishmania braziliensis braziliensis in a patient with AIDS: A case report

Unusual association of American cutaneous leishmaniasis and acquired immunodeficiency syndrome

American cutaneous leishmaniasis associated with HIV infection: Report of four cases

Diffusely disseminated cutaneous Leishmania major

Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study

HIV and Leishmania coinfection: A review of 91 cases with focus on atypical locations of Leishmania

Gastrointestinal leishmaniasis in human immunodeficiency virus-infected patients: Report of five cases and review

Pancreatic involvement in co-infection of visceral leishmaniasis and HIV: Histological and ultrastructural aspects

Two cases of laryngeal leishmaniasis in patients infected with HIV

Pulmonary site of visceral leishmaniasis in HIV infection

Pleural and peritoneal leishmaniasis in an AIDS patient

Leishmaniasis presenting as a dermatomyositis-like eruption in AIDS

Unusual cutaneous lesions in two patients with visceral leishmaniasis and HIV infection

Nasal leishmaniasis in an HIVpositive patient

The role of serology in the diagnosis and prognosis of visceral leishmaniasis in patients co-infected with human immunodeficiency virus type-1

HIV-Leishmania co-infections in Italy: Serological data as an indication of the sequence of the two infections

Ethiopian visceral leishmaniasis patients co-infected with human immunodeficiency virus

Serodiagnosis of Asian leishmaniasis with a recombinant antigen from the repetitive domain of a Leishmania kinesin

Haemoculture as a tool for diagnosing visceral leishmaniasis in HIV-negative and HIV-positive patients: Interest for parasite identification

An analysis of T cell responsiveness in Indian kala azar

In vivo cytokine profiles in patients with kala azar. Marked elevation of both IL-10 and IFN-γ

Treatment of visceral leishmaniasis in HIV-infected patients: A randomized trial comparing meglumine antimoniate with amphotericin B

Amphotericin B lipid complex versus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV: A randomized pilot study

Amphotericin B lipid complex versus no treatment in the secondary prophylaxis of visceral leishmaniasis in HIV-infected patients

Pentamidine isethionate as secondary prophylaxis against visceral leishmaniasis in HIV-positive patients

Efficacy of liposomal amphotericin B in the treatment and secondary prophylaxis of visceral leishmaniasis in HIV-infected patients: Report of two cases

Oral miltefosine for Indian visceral leishmaniasis

Oral miltefosine for leishmaniasis in immunocompromised patients: Compassionate use in 39 patients with HIV infection

The impact of highly active antiretroviral therapy (HAART) on visceral leishmaniasis in Spanish patients who are co-infected with HIV

Relapsing visceral leishmaniasis in HIV-infected patients undergoing successful protease inhibitor therapy

Impact of highly active antiretroviral therapy on the incidence of visceral leishmaniasis in a French cohort of patients infected with human immunodeficiency virus

Discontinuation of secondary anti-Leishmania prophylaxis in HIV-infected patients who have responded to highly active antiretroviral therapy

Frequency of visceral leishmaniasis relapses in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy

Reactivation of Chagas' disease in patients with AIDS: Report of 3 new cases and review of the literature

Trypanosoma cruzi menignoencephalitis in HIV-infected patients

Concurrent cerebral American trypanosomiasis and toxoplasmosis in a patient with AIDS

Follow-up of 18 patients with human immunodeficiency virus infection and chronic Chagas' disease, with reactivation of Chagas' disease causing cardiac disease in three patients

Reactivation of Chagas' disease in a human immunodeficiency virus-infected patient leading to severe heart disease with a late positive direct microscopic examination of the blood

Chagas' granulomatous encephalitis in immunosuppressed patients. Computed tomography and magnetic resonance imaging findings

Clinical analysis and parasite genetic diversity in human immunodeficiency virus/Chagas' disease co-infections in Brazil

Trypanosoma cruzi parasitemia in chronic Chagas' disease: Comparison between human immunodeficiency virus (HIV)-positive and HIV-negative patients

Exacerbation of HIV viral load simultaneous with asymptomatic reactivation of chronic Chagas' disease

Reactivation of Chagas' disease successfully treated with benznidazole in a patient with AIDS

Successful treatment of Trypanosoma cruzi encephalitis in a patient with hemophilia and AIDS

In vitro and in vivo effects of itraconazole against Trypanosoma cruzi

Absence of relationship between human immunodeficiency virus 1 and sleeping sickness

Absence of epidemiological inter-relations between HIV infection and African human trypanosomiasis in Central Africa

The impact of human immunodeficiency virus infection on the epidemiology and treatment of Trypanosoma brucei gambiense sleeping sickness in Nioki, Zaire

Human immunodeficiency virus infection and human African trypanosomiasis: A case-control study in Côte d'Ivoire

Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis

Lower trypanosomatids in HIV/AIDS patients

Toxoplasmic encephalitis in AIDS

Toxoplasmosis in Panama: A 10-year study

Human Toxoplasma infection in Kuna and Embera children in the Bayano and San Blas, eastern Panama

Prevalence of Toxoplasma antibodies in Chiang Mai population

Toxoplasma serology in Zambian and Ugandan patients infected with the human immunodeficiency virus

Prevalence of infections affecting the child among pregnant women in Yaounde, Cameroon

Regional variation in toxoplasmosis seronegativity in the São Paulo metropolitan region

OM: Prevalence of antibodies to Toxoplasma gondii among blood donors in Abha, Asir Region, southwestern Saudi Arabia

Toxoplasma gondii antibodies in pregnant women and their newborns in Dar es Salaam, Tanzania

A study of Toxoplasma and cytomegalovirus serology in tuberculosis and in HIV-infected patients in Burkina Faso

Toxoplasmic encephalitis

Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome

The mortality and pathology HIV infection in a West African city

The spectrum of clinical and pathological manifestations of AIDS in a consecutive series of autopsied patients in Mexico

The pathology of severe morbidity and mortality caused by HIV infection in Africa

Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome

CDC: Guidelines for preventing opportunistic infections among HIV-infected persons-2002

Disseminated Acanthamoeba infection in patients with AIDS: Case reports and review

Free-living amebas of the genera Acanthamoeba and Naegleria: An overview and basic microbiologic correlates

Isolation of Hartmannella species from human throats

Immunity to pathogenic freeliving amoebae: Role of cell-mediated immunity

Granulomatous amebic encephalitis due to Balamuthia mandrillaris (leptomyxiidae): Report of four cases from Mexico

Successful treatment of Balamuthia amebic encephalitis: Presentation of 2 cases

Acanthamoeba meningoencephalitis: Diagnosis by squash preparation of brain biopsy specimen

Acquired immunodeficiency syndrome associated with Acanthamoeba infection and other opportunistic organisms

Acanthamoeba meningoencephalitis in a patient with AIDS

Amebic meningoencephalitis in a patient with AIDS caused by a newly recognized opportunistic pathogen. Leptomyxid ameba

Acanthamoeba meningoencephalitis in a patient with acquired immunodeficiency syndrome

Disseminated Acanthamoeba infection in a child with symptomatic human immunodeficiency virus infection

Culture isolation of Acanthamoeba species and leptomyxid amebas from patients with amebic meningoencephalitis, including two patients with AIDS

Acanthamoeba infection presenting as skin lesions in patients with the acquired immunodeficiency syndrome

Granulomatous amebic encephalitis in a patient with AIDS: Isolation of Acanthamoeba sp. group II from brain tissues and successful treatment with sulfadiazine and fluconazole

Diagnosis of Acanthamoeba infection by cutaneous manifestations in a man seropositive to HIV

Cutaneous Acanthamoeba infection associated with leukocytoclastic vasculitis in an AIDS patient

Cutaneous Acanthamoeba infection associated with acquired immunodeficiency syndrome

Cutaneous Acanthamoeba infection in the acquired immunodeficiency syndrome: Response to multidrug therapy

Disseminated acanthamebiasis in patients with AIDS

Primary amebic meningoencephalitis in a patient with AIDS: Unusual protozoological findings

Primary amebic meningoencephalitis in a patient with AIDS: Unusual protozoological findings

Cryptosporidium systematics and implications for public health

Molecular analysis of the 18S rRNA gene of Cryptosporidium parasites from patients with or without human immunodeficiency virus infections living in Kenya, Malawi, Brazil, the United Kingdom, and Vietnam

Cryptosporidium species and genotype in HIV-positive patients in Lima, Peru

Cryptosporidium infection and CD4 counts

Cryptosporidiosis in patients with AIDS: Correlates of disease and survival

Impact of opportunistic disease on survival in patients with HIV infection

Cryptosporidiosis among patients infected with human immunodeficiency virus. Factors related to symptomatic infection and survival

Decreased prevalence of intestinal cryptosporidiosis in HIV-infected patients concomitant to the widespread use of protease inhibitors

Declining prevalence of cryptosporidiosis in San Francisco

New insights into human cryptosporidiosis

Parasitic sinusitis and otitis in patients infected with human immunodeficiency virus: Report of five cases and review

Cholecystectomny in patients with AIDS: Clinicopathologic correlations in 107 cases

Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of cryptosporidiosis in Milwaukee

Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy

Treatment of HIV-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy

Biology of Isospora spp. from humans, nonhuman primates, and domestic animals

Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome

Isospora belli infection associated with acalculous cholecystitis in a patient with AIDS

Treatment and prophylaxis of Isospora belli infection in patients with the acquired immunodeficiency syndrome

Isospora belli infection: Treatment with pyrimethamine

Cyclospora infection in adults infected with HIV. Clinical manifestations, treatment, and prophylaxis

Cyclospora cayetanensis infection in patients with and without AIDS: Biliary disease as another clinical manifestation

The polymicrobial origin of intestinal infections in homosexual men

Prevalence of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome

Treatment of patients with refractory giardiasis

Intestinal parasitic infections in HIV/AIDS and HIV seronegative individuals in a teaching hospital

Interactions between schistosomiasis and human immunodeficiency virus in western Kenya

Studies on schistosomiasis in western Kenya. I. Evidence for immune-facilitated excretion of schistosome eggs from patients with Schistosoma mansoni and HIV co-infections

Studies on schistosomiasis in western Kenya: II. Efficacy of praziquantel for treatment of schistosomiasis in persons co-infected with human immunodeficiency virus-1

Resistance to reinfection with Schistosoma mansoni in occupationally exposed adults and effect of HIV-1 co-infection on susceptibility to schistosomiasis: A longitudinal study

Impairment of the Schistosoma mansoni-specific immune responses elicited by treatment with praziquantel in Ugandans with HIV-1 co-infection

Interactions between Schistosoma haematobium and human immunodeficiency virus type 1: The effects of co-infection on treatment outcomes in rural Zambia

Schistosomiasis of the female genital tract: Public health aspects

Female genital schistosomiasis of the lower genital tract: Prevalence and disease-associated morbidity in northern Tanzania

Sexual behavior and sexually transmitted infections in men living in rural Madagascar

The effect of treatment of schistosomiasis on blood plasma HIV-1 RNA concentration in co-infected individuals

Associations between helminth infection and CD4 + T cell count, viral load and cytokine responses HIV-1-infected Ugandan adults

Lethal infection by a previously unrecognized metazoan parasite

Disseminated parasitosis in an immunosuppressed patient

Taenia-crassiceps-Infektion bei AIDS

Cysticercose envahissante à Taenia crassiceps chez un patient atteint de sida

Taenia crassiceps invasive cysticercosis: A new human pathogen in acquired immunodeficiency syndrome?

Alveolar echinococcosis of the liver in a six-year-old girl with AIDS

Unusual form of neurocysticercosis associated with HIV infection

Neurocysticercosis and HIV infection: Report of two cases and review

Asymptomatic neurocysticercosis in a patient with AIDS and cryptococcal meningitis

Neurocysticercosis and human immunodeficiency virus infection

The neuropathology of acquired immune deficiency syndrome

Strongyloides stercoralis in the immunocompromised population

Anonymous: Update: Acquired immunodeficiency syndrome (AIDS) in the United States

Anonymous: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome

Sexual transmission of enteric protozoa and helminths in a venereal disease clinic population

Strongyloides stercoralis hyperinfection in a patient with the acquired immunodeficiency syndrome

Strongyloides stercoralis hyperinfection and the acquired immunodeficiency syndrome

Disseminated strongyloidiasis with central nervous system involvement diagnosed antemortem in a patient with acquired immunodeficiency syndrome and Burkitt' s lymphoma

Disseminated strongyloidiasis in AIDS and non-AIDS immunocompromised hosts: Diagnosis by sputum and bronchoalveolar lavage

Strongyloides stercoralis hyperinfection in an HIV-positive patient

Disseminated Strongyloides stercoralis in human immunodeficiency virus-infected patients: Treatment failure and a review of the literature

Efficacy of ivermectin in the treatment of strongyloidiasis complicating AIDS

Systemic strongyloidiasis in patients infected with the human immunodeficiency virus: A report of 3 cases and review of the literature

Fulminant, systemic strongyloidiasis in AIDS

Strongyloides stercoralis hyperinfection in the acquired immunodeficiency syndrome

HIV-related enteropathy in Zambia: A clinical, microbiological, and histological study

Intestinal parasites in Zambian patients with AIDS

Why does HIV infection not lead to disseminated strongyloidiasis?

Concurrent infections with Strongyloides and T cell leukemia virus and their possible effect on the immune response of the host

Infectious complications of human T cell leukemia/ lymphoma virus type I infection

Onchocerciasis and human immunodeficiency virus in western Uganda: Prevalences and treatment with ivermectin

Crusted (Norwegian) scabies in patients with AIDS: The range of clinical presentations

The treatment of scabies with ivermectin

Hyperkeratotic (Norwegian) scabies with gram-negative bacteremia as the initial presentation of AIDS

Norwegian") scabies in a specialist HIV unit: Successful use of ivermectim and failure to prevent nosocomial transmission

Atypical scabies in HIVpositive patients

Disseminated Penicillium marneffei infection in southeast Asia

Seasonal variation of disseminated Penicillium marneffei infections in northern Thailand: A clue to the reservoir?

Infection due to Penicillium marneffei, an emerging pathogen: Review of 155 reported cases

Penicillium marneffei: Part of southeast Asian AIDS

Invasive infection caused by Penicillium marneffei: An emerging pathogen in Taiwan

Penicillium marneffei infection in patients infected with human immunodeficiency virus

Case-control study of risk factors for Penicillium marneffei infection in HIV-infected patients in northern Thailand

Cell-mediated immunity in host resistance against infection caused by Penicillium marneffei

Disseminated Penicillium marneffei infection as an imported disease in HIV-1 infected patients

Die HIV-assoziierte Penicilliummarneffei-infektion

Systemic mycosis due to Penicillium marneffei in a patient with antibody to human immunodeficiency virus

Penicillium marneffei infection in children infected with human immunodeficiency virus

Hepatic penicilliosis in patients without skin lesions

Lymphadenopathy due to Penicillium marneffei infection: Diagnosis by fine needle aspiration cytology

Development of specific fluorescent antibody test for tissue form of Penicillium marneffei

Disseminated Penicillium marneffei infection diagnosed on examination of a peripheral blood smear of a patient with human immunodeficiency virus infection

Diagnostic antigenemia tests for penicilliosis marneffei

Differences in clinical and laboratory diagnostic characteristics of Penicilliosis marneffei in human immunodeficiency virus (HIV)-and no-HIV-infected patients

Diagnosis of Penicilliosis marneffei infection by quantitation of urinary antigen by using an enzyme immunoassay

Cross-reactivity in Histoplasma capsulatum variety capsulatum antigen assays of urine samples from patients with endemic mycoses

Serodiagnosis of Penicillium marneffei infection

Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficiency virus-infected patients

Response to antifungal therapy by human immunodeficiency virus-infected patients with disseminated Penicillium marneffei infections and in vitro susceptibilities of isolates from clinical specimens

A controlled trial of itraconazole to prevent relapse of Penicillium marneffei infection in patients infected with human immunodeficiency virus

A controlled trial of itraconozaole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand

Discontinuation of secondary prophylaxis for Penicilliosis marneffei in AIDS patients responding to highly active anti-retroviral therapy

Paracoccidioidomycosis: An update

Correlation between cell-mediated immunity and clinical forms of paracoccidioidomycosis

Lymphocyte subpopulations and cytokine production in paracoccidioidomycosis patients

Paracoccidioidomycosis and AIDS: An overview

Paracoccidioidomycosis: A model for evaluation of the effects of human immunodeficiency virus infection on the natural history of endemic tropical diseases

Paracoccidioidomycosis associated with human immunodeficiency virus infection

Nishioka Sde A: Paracoccidioidomycosis and AIDS

Is African histoplasmosis an opportunistic fungal infection in AIDS?

Disseminated African histoplasmosis in a white heterosexual male patient with the acquired immune deficiency syndrome

African histoplasmosis in a Belgian AIDS patient

Disseminated African histoplasmosis in a Congolese patient with AIDS

Histoplasmose africaine: Aspects cliniques et thérapeutiques-relations avec le SIDA

Histoplasmosis capsulati and duboisii in Europe: The impact of the HIV pandemic, travel and immigration

African histoplasmosis due to Histoplasma capsulatum var. duboisii: Relationship with AIDS in recent Congolese cases (in French)

Disseminated sporotrichosis and Sporothrix schenkii fungemia as the initial presentation of human immunodeficiency virus infection

Sporotrichosis in patient with AIDS: Report of a case and review

Practice guidelines for the management of patients with sporotrichosis. For the Mycoses Study Group. Infectious Diseases Society of America

Blastomycosis in the immunocompromised patient

Endemic mycoses in AIDS: A clinical review

Disseminated histoplasmosis in the acquired immune deficiency syndrome: Clinical findings, diagnosis and treatment, and review of the literature

Blastomycosis in Africa: Clinical features, diagnosis, and treatment

The ecology of Blastomyces dermatitidis

Blastomycosis in patients with the acquired immunodeficiency syndrome

Disseminated atypical blastomycosis in two patients with AIDS

Coccidioidomycosis in the acquired immunodeficiency syndrome

Coccidioidomycosis in patients infected with human immunodeficiency virus: Review of 91 cases at a single institution

Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome

Current approach to the acute management of cryptococcal infections

The growing problem of mycoses in patients infected with the human immunodeficiency virus

Opportunistic infections in AIDS/HIV infected patients in Thailand

Clinical study of HIV disease in the lower area of northern Thailand in 1994

AIDS-The Baragwanath experience. III. HIV infection in adults at Baragwanath Hospital

Acquired immunodeficiency syndrome in a heterosexual population in Zaire

Le syndrome d'immunodéficience acquise (SIDA) à Kinshasa, Zaire: Observations cliniques et épidémiologiques

The value of cryptococcal serum antigen screening among HIV-positive/AIDS patients in Kinshasa

Spectrum of disease in Africans with AIDS in London

Transfusion associated AIDS in Mexico. Clinical spectrum, conditional latency distribution, and survival

Pulmonary infections in the tropics: Impact of HIV infection

Ministerio da Saude do Brasil: Dados e pesquisa em DST e AIDS. Coordenacao do programa nacional de DTS/AIDS. Brasilia

Natural habitat of Cryptococcus neoformans var. gatti

The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis

Cryptococcus neoformans var. gatti among patients with cryptococcal meningitis in Mexico. First observations

Serologic responses to Pneumocystis carinii antigens in health and disease

Geographic variation in the humoral response to Pneumocystis carinii

Nucleotide sequence variation in Pneumocystis carinii strains that infect humans

Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy

Current epidemiology of Pneumocystis pneumonia

Pneumocystis carinii pneumonia in patients with AIDS in Central Africa

Pneumocystoses observées au Congo chez les malades atteints de SIDA

An uncommon cause of death in African patients with acquired immunodeficiency syndrome

Occurrence of Pneumocystis carinii in HIV-positive patients with suspected pulmonary tuberculosis in Ethiopia

Pneumocystis carinii is rare in AIDS in Central Africa

Pulmonary disease associated with the human immunodeficiency virus in Kigali, Rwanda

Pneumocystis carinii pneumonia in Zimbabwe

Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana, 1997-1998

Predictors of Pneumocystis carinii pneumonia in HIV-infected persons. Pulmonary complications of HIV infection study group

Ineffectiveness of trimethoprimsulfamethoxazole prophylaxis and the importance of bacterial and viral co-infections in African children with Pneumocystis carinii pneumonia

Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: A pooled analysis

HIV and respiratory infections in children

Prophylaxis against Pneumocystis carinii pneumonia among children with perinatally acquired human immunodeficiency virus infection in the United States

Pneumocystis pneumonia

Emerging fungal pathogens in immunocompromised patients: Classification, diagnosis, and management

The new fungal opportunists are coming

HIV-associated tuberculosis in developing countries: Epidemiology and strategies for prevention

Deaths from tuberculosis in sub-Saharan African countries with a high prevalence of HIV-1

Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group

Tuberculosis in the time of AIDS-The facts and the message

CD4+ lymphocyte count in African patients co-infected with HIV and tuberculosis

Effect of Mycobacterium tuberculosis on HIV replication

Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients

Human immunodeficiency virus-1 RNA levels and CD4 lymphocyte counts, during treatment for active tuberculosis, in South African patients

Sustained plasma TNF-α and HIV-1 load despite resolution of other parameters of immune activation during treatment of tuberculosis in Africans

Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive Ethiopians

A prospective study of tuberculosis and human immunodeficiency virus infection: Clinical manifestations and factors associated with survival

Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area

Does the onset of tuberculosis in AIDS predict shorter survival? Results of a cohort study in 17 European countries over 13 years

Impact of tuberculosis on HIV disease progression in persons with well-documented time of HIV seroconversion

Long-term follow-up of HIVpositive and HIV-negative individuals in rural Malawi

Effect of preventive treatment for tuberculosis in adults infected with HIV: Systematic review of randomised placebo controlled trials

Isoniazid prophylaxis for tuberculosis in HIV infection: A meta-analysis of randomized controlled trials

Anonymous: Preventive therapy against tuberculosis in people living with HIV

Rifampin and pyrazinamide vs. isoniazid for prevention of tuberculosis in HIV-infected persons

Randomised trial of isoniazid versus rifampin and pyrazinamide for prevention of tuberculosis in HIV-1 infection

Anonymous: Update: Fatal and severe liver injuries associated with rifampicin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations-United States

Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIVinfected persons: Is it different than in HIV-uninfected persons?

Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy

Anonymous: Disseminated Mycobacterium bovis infection from BCG vaccination of a patient with acquired immunodeficiency syndrome

Disseminated BCG in HIV infection

The safety of bacille Calmette-Guérin vaccination in HIV infection and AIDS

Disseminated bacille Calmette-Guérin disease after vaccination: Case report and review

BCG vaccine abscesses are unrelated to HIV infection (letter)

Bacillus Calmette-Guérin immunization in infants born to HIV-1-seropositive mothers

Bacillus Calmette-Guérin complications in children both to HIV-1-infected women with a review of the literature

HIV, BCG and TB in children: A case control study in Lusaka, Zambia

The risks and benefits of childhood bacille Calmette-Guérin immunization among adults with AIDS

BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific bacterial effect of BCG? Vaccine 21:2782

Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices: The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices

The Mycobacterium avium complex

Isolation of Mycobacterium avium complex from water in the United States

Mycobacterium avium-M. intracellulare isolates from patients with or without AIDS

Clinical and epidemiological importance of typing of Mycobacterium avium complex isolates

Mycobacterium avium infection and AIDS: A therapeutic dilemma in rapid evolution

Incidence of Mycobacterium avium-intracellulare complex bacteremia in HIVpositive patients

Natural history of disseminated Mycobacterium avium complex infection in AIDS

A prospective evaluation of Mycobacterium avium complex colonization of the respiratory and gastrointestinal tracts of persons with HIV infection

Mycobacterium avium complex in the respiratory or gastrointestinal tract and the risk of M. avium complex bacteremia in patients with HIV infection

Continuous high-grade Mycobacterium avium-intracellulare bacteremia in patients with AIDS

Absence of bacteremia with Mycobacterium avium-intracellulare in Ugandan patients with AIDS

Absence of Mycobacterium avium complex disease in patients with AIDS in Uganda

Pathogens and predictors of fatal septicemia associated with human immunodeficiency virus infection in Ivory Coast, West Africa

Enteropathic AIDS in Uganda. An endoscopic, histological and microbiological study

Persistent diarrhoea in Zairian AIDS patients: An endoscopic and histological study

Disseminated Mycobacterium avium infection among HIV-infected patients in Kenya

Comparative demographic and autopsy findings in acquired immune deficiency syndrome in two Mexican populations

Isolation of Mycobacterium avium complex from bone marrow aspirates of AIDS patients in Brazil

Evidence of previous infection with Mycobacterium avium-Mycobacterium intracellulare complex among healthy subjects: An international study of dominant mycobacterial skin test reactions

Concentration of Mycobacterium avium by hospital hot water systems

Epidemiological and genetic markers, virulence factors and intracellular growth of Mycobacterium avium in

Immunological phenomena in leprosy and related diseases

Prevalence of HIV infection among patients with leprosy and tuberculosis in rural Zambia

HIV-1 infection as a risk factor for leprosy: A case-control study in Tanzania

Leprosy and infection with the human immunodeficiency virus in Uganda: A case control study

Clinical observations on leprosy patients with HIV-1 infection in Zambia

Antibodies to HIV-1 in sera from patients with mycobacterial infections

False HIV positivity in leprosy (abstract)

Human immunodeficiency virus type 1 (HIV-1) and Mycobacterium lepra co-infection: HIV-1 subtypes and clinical, immunologic, and histopathologic profiles in a Brazilian cohort

Immune reconstitution inflammatory syndrome associated with HIV and leprosy

Leprosy and AIDS: Two cases of increasing inflammatory reactions at the start of highly active antiretroviral therapy

Mycobacterium genavense: An emerging pathogen

Species-specific Mycobacterium genavense DNA in intestinal tissues of individuals not infected with HIV

Generalized Mycobacterium genavense infection in HIV-infected patients: Detection of the mycobacterium in hospital tap water

Clinical and epidemiologic features of infection with Mycobacterium genavense

Disseminated Mycobacterium genavense infection as a cause of pseudo-Whipple' s disease and sclerosing cholangitis

Disseminated Mycobacterium genavense infection in two patients with AIDS

Mycobacterium genavense infection in AIDS: Imaging findings in eight patients

Disseminated Mycobacterium genavense infection: Clinical and microbiological features and response to therapy

Mycobacterium genavense infection in a patient with AIDS who was successfully treated with clarithromycin

The epidemiology of disseminated nontuberculous Mycobacterium infection in AIDS

Nontuberculous mycobacteria: Defining disease in a prospective cohort of South African miners

Epidemiological, clinical, and prognostic differences between the diseases caused by Mycobacterium kansasii and Mycobacterium tuberculosis in patients infected with human immunodeficiency virus: A multicenter study

Mycobacterium kansasii: A cause of treatable pulmonary disease associated with advanced HIV infection

Mycobacterium kansasii disease in patients infected with

Clinical manifestations and implications of co-infection with Mycobacterium kansasii and HIV type 1

Epidemiological, clinical and therapeutic features of AIDS-related Mycobacterium kansasii infection during the HIV pandemic: An 11-year follow-up study

Mycobacterium kansasii infections in patients positive for HIV

Extrapulmonary and disseminated infections due to Mycobacterium malmoense: Case report and review

Mycobacterium malmoense bacteremia in two AIDS patients

Pulmonary infection with Mycobacterium malmoense-A review of treatment and response

Mycobacterium haemophilum: Microbiology and expanding clinical and geographic spectra of disease in humans

Mycobacterium haemophilum infection in immunocompromised patients: Case report and review of the literature

Mycobacterium haemophilum: An emerging pathogen

Successful treatment of disseminated Mycobacterium haemophilum infection in a patient with AIDS (letter)

Remission of cutaneous Mycobacterium haemophilum infection as a result of antiretroviral therapy in a human immunodeficiency virus-infected patient

Right middle lobe syndrome caused by Mycobacterium fortuitum in a patient with HIV infection

Clinical and pathologic features of Mycobacterium fortuitum infections: An emerging pathogen in patients with AIDS

Fatal Mycobacterium fortuitum meningitis in a patient with AIDS

Mycobacterium marinum infection in a patient with cryptosporidiosis and AIDS

Fatal disseminated Mycobacterium marinum infection

Isolation of the newly described species Mycobacterium celatum from AIDS patients

Isolation of Mycobacterium celatum from patients infected with HIV

Mycobacterium xenopi: Innocent bystander or emerging pathogen?

Human immunodeficiency virus type 1-related pulmonary Mycobacterium xenopi infection: A need to treat?

Clinical and therapeutic management of pulmonary Mycobacterium xenopi infection in HIV-positive patients

Mycobacterium gordonae: A possible opportunistic respiratory tract pathogen in patients with advanced HIV, type 1 infection

Disseminated infection with Mycobacterium gordonae: Report of a case and critical review of the literature

Cutaneous infection caused by Mycobacterium gordonae in a human immunodeficiency virus-infected patient receiving antimycobacterial treatment

Disseminated Mycobacterium scrofulaceum infection: A potentially treatable complication of AIDS

Anonymous: Disseminated infection with simiae-avium group mycobacteria in persons with AIDS-Thailand and Malawi

Buruli ulcer and HIV infection

Disseminated Mycobacterium ulcerans disease in an HIV-positive patient: A case study

Musher DM: Syphilis, neurosyphilis, penicillin, and AIDS

The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with HIV infection

Neurosyphilis. A comparative study of the effects of infection with HIV

Active syphilis in HIV infection: A multicentre retrospective survey

Alteration in the natural history of neurosyphilis by concurrent infection with HIV

Effect of HIV infection on the course of syphilis and on the response to treatment

Syphilis treatment response in HIV-infected individuals

Syphilis and neurosyphilis in a HIV type-1 seropositive population: Evidence for frequent serologic relapse after therapy

Serologic response to treatment of syphilis in patients with HIV infection

Invasion of the central nervous system by Treponema pallidum: Implications for diagnosis and treatment

Effects of HIV infection on the serologic manifestations and response to treatment of syphilis in intravenous drug users

Similar serologic response to conventional therapy for syphilis among HIV-positive and HIVnegative women

A randomized trial of enhanced therapy for early syphilis in patients with and without HIV infection

Syphilis and HIV: A dangerous combination

Sexually transmitted diseases treatment guidelines-2002

Yaws, an endemic treponematosis reconsidered in the HIV era

Lyme disease concurrent with HIV infection

Atypical Lyme borreliosis in an HIV-infected man

Leptospirosis in patients with anti-HIV antibodies: Report of 2 cases

Leptospirosis patient with AIDS: The first case reported

Immunity in Q fever

Coxiella burnetii infection in immunocompromised patients

Acute and chronic Q fever in patients with cancer

Chronic Q fever. Ninetytwo cases from France, including 27 cases without endocarditis

Q fever and HIV infection

Coxiella burnetii infection among HIV-1-infected people living in Paris, France (letter)

Coxiella burnetii infection among subjects infected with HIV type 1 in the Central African Republic

Coxiella burnetii infection in subjects with HIV infection and HIV infection in patients with Q fever

Consecutive epidemics of Q fever in a residential facility for drug abusers: Impact on persons with human immunodeficiency virus infection

A case of human ehrlichiosis acquired in Mali: Clinical and laboratory findings

Infections with Ehrlichia chaffeensis and Ehrlichia ewingii in persons co-infected with human immunodeficiency virus

Fatal seronegative ehrlichiosis in a patient with HIV infection

Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis

Human granulocytic ehrlichiosis in the upper Midwest United States: A new species emerging

Infection with human immunodeficiency virus does not influence the clinical severity of scrub typhus

Brucellosis in hairy cell leukaemia

Transient T cell abnormality in a selective IgM-immunodeficient patient with Brucella infection

Serological responses to brucellosis in HIV-seropositive patients

Brucellosis and HIV infection: A casual association? (letter)

Brucella melitensis osteitis following craniotomy in a patient with AIDS

Brucellosis in patients infected with the human immunodeficiency virus

Relapsing brucellosis in a patient infected with the human immunodeficiency virus (HIV)

Tropical disease in the immunocompromised host: Melioidosis and pythiosis

A preliminary survey for human immunodeficiency virus (HIV) infections and melioidosis patients in Ubon Tatchathani, Thailand

Survival of AIDS patients in the emerging epidemic in

The changing pattern of bloodstream infection associated with the rise in HIV prevalence in northern Thailand

Bacterial enteric infections in persons infected with human immunodeficiency virus

Influence of gastric acidity on bacterial and parasitic enteric infections. A perspective

Gastric secretory failure in patients with the acquired immunodeficiency syndrome (AIDS)

A single dose of live oral cholera vaccine CVD 103-HgR is safe and immunogenic in HIVinfected and HIV-noninfected adults in Mali

Meningococcal meningitis and HIV infection: Results from a case-control study in western Uganda

Sporadic meningococcal disease in adults: Results of a 5-year population-based study

Invasive meningococcal disease and HIV co-infection

Infections associated with Bartonella species in persons infected with human immunodeficiency virus

Louis encephalitis in patients with human immunodeficiency virus infection

encephalitis: A review of 11 cases in a 1995 Dallas, Texas epidemic

Prevention of yellow fever in persons traveling to the tropics

West Nile viral encephalitis in an HIV-positive woman in New York

Decrease in human immunodeficiency virus type 1 load during acute dengue fever

Eidex RS for the Yellow Fever Vaccine Safety Working Group: History of thymoma and yellow fever vaccination

Fatal myeloencephalitis following yellow fever vaccination in a case with HIV infection

Yellow fever vaccine is safe and effective in HIV-infected patients

Yellow fever vaccination of human immunodeficiency virus-infected patients: Report of 2 cases

Good tolerance and efficacy of yellow fever vaccination among carriers of human immunodeficiency virus

Poor antibody response to yellow fever vaccination in children

Advisory Committee on Immunization Practices: Yellow fever vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Mechanism of suppression of cell-mediated immunity by measles virus

Natural measles causes prolonged suppression of interleukin-12 production

Interaction of measles virus glycoproteins with the surface of uninfected peripheral blood lymphocytes induces immunosuppression in vitro

Mechanism of measles virus-induced suppression of inflammatory immune responses

Measles virus infection results in suppression of both innate and adaptive immune responses to secondary bacterial infection

Fatal measles pneumonia without rash in a child with AIDS

Measles and measles immunity in children infected with HIV

Successful treatment of disseminated measles in a patient with AIDS: Consideration of antiviral and passive immunotherapy (letter)

Measles giant cell pneumonia in a child with HIV infection

Severe measles in immunocompromised patients

Population-based study of measles and measles immunization in HIV-infected children

Subacute measles encephalitis in the young immunocompromised host: Report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature

Ribavirin and intravenous immune globulin therapy for measles pneumonia in HIV infection

Severe measles pneumonitis in adults: Evaluation of clinical characteristics and therapy with intravenous ribavirin

Acute necrotizing measles encephalitis in a child with AIDS

Measles in hospitalized African children with HIV (letter)

Measles case fatality by sex, vaccination status, and HIV-1 antibody in Zambian children (letter)

Prospective study of measles in hospitalized human immunodeficiency virus (HIV)-infected and HIVuninfected children in Zambia

Prolonged measles virus shedding in human immunodeficiency virus-infected children, detected by reverse transcriptase-polymerase chain reaction

Suppression of human immunodeficiency virus replication during acute measles

A randomized, controlled trial of vitamin A in children with severe measles

Clinical use of ribavirin in measles: A summarized review

Advisory Committee on Immunization Practices: Update: Vaccine side effects, adverse reactions, contraindications, and precautions. Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Immunoglobulin prophylaxis of measles in acute lymphoblastic leukaemia

Committee on Infectious Diseases and Committee of Pediatric AIDS

Prevention: Measles, mumps, and rubella-Vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Prevalence of measles antibodies in asymptomatic HIV-infected adults

Prevalence of measles antibodies in adults with HIV infection: Possible risk factors of measles seronegativity

Progressive immunodeficiency due to infection with HIV does not lead to waning immunity to measles in a cohort of homosexual men

Response of HIVinfected adults to measles-rubella vaccination

Immunization of children at risk of infection with human immunodeficiency virus

Increased risk of early measles in infants of HIV type 1-seropositive mothers

Safety and immunogenicity of highdose Edmonston-Zagreb measles vaccine in children with HIV-1 infection. A cohort study in Kigali, Rwanda

Immunogenicity of high-titer Edmonston-Zagreb measles vaccine in HIV-infected children in Kinshasa

Implications of the human immunodeficiency virus epidemic for control and eradication of measles

Anonymous: Measles pneumonitis following measles-mumps-rubella vaccination of a patient with HIV infection

Child mortality after high-titre measles vaccines: Prospective study in Senegal

Long-term survival after Edmonston Zagreb measles vaccination in Guinea-Bissau: Increased female mortality rate

Differential mortality by measles vaccine titer and sex

World Health Organization: HIV-infected children should be immunized against measles

Respiratory syncytial virus pneumonia in a HIV-infected man (letter)

Respiratory syncytial virus infection in HIV-infected children

Respiratory syncytial virus infection in an adult with AIDS (letter)

Respiratory syncytial virus illnesses in human immunodeficiency virus-infected and -noninfected children

Rabies encephalitis in a patient with AIDS: A clinicopathological study

Postexposure rabies vaccination in patients infected with human immunodeficiency virus

Safety and immunogenicity of postexposure rabies vaccination in children infected with human immunodeficiency virus type 1

Failure of multiplesite intradermal postexposure rabies vaccination in patients infected with human immunodeficiency virus with low CD4+ lymphocyte counts

Updated recommendations of the Advisory Committee on Immunization Practice (ACIP)

Enteric viruses and diarrhea in HIV-infected patients

Prevalence of enteric viruses among hospital patients with AIDS in Kinshasa

Detection and characterization of human astroviruses in children with acute gastroenteritis in Blatyre, Malawi

Detection of picobirnavirus in HIV-infected patients with diarrhea in Argentina

Detection of enteropathogens in fatal and potentially fatal diarrhea in Cairo

Effect of concomitant HIV infection on presentation and outcome of rotavirus gastroenteritis in Malawian children

Influence of human immunodeficiency virus type 1 infection on acute hepatitis A virus infection

Occurrence of acute hepatitis A in patients infected with human immunodeficiency virus

Rate of subclinical hepatitis A virus infection in adult HIV-1-infected patients

The effect of immunization with inactivated hepatitis A vaccine on the clinical course of HIV-1 infection: 1-year follow-up

Safety and immunogenicity of an inactivated hepatitis A vaccine among HIV-infected subjects

Safety and immunogenicity of hepatitis A vaccine in human immunodeficiency virus-infected patients: A double-blind, randomized, placebo-controlled trial

The influence of HIV type 1 infection on the development of the hepatitis B virus carrier state

Outcome of hepatitis B virus infection in homosexual men and its relationship to prior HIV infection

The influence of HTLV-III infection on the natural history of hepatitis B virus infection in male homosexual HBsAg carriers

Reappearance of hepatitis B virus in immune patients infected with HIV type 1

Interactions between human immunodeficiency virus and hepatitis B virus infections in 260 chronic carriers of hepatitis B virus

Antibody to HIV and suboptimal response to hepatitis B vaccination

Accelerated loss of antibody to hepatitis B surface antigen among immunodeficient homosexual men infected with HIV (letter)

HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS)

Hepatitis B in patients with HIV infection: Relationship to AIDS and patient survival

The natural history of hepatitis C virus infection: Host, viral, and environmental factors

Hepatitis C in the HIV-infected person

Increasing hepatitis C virus RNA levels in hemophiliacs: Relationship to HIV infection and liver disease

Effect of HIV on hepatitis C virus infection among injecting drug users

Mother-to-infant transmission of hepatitis C virus

Natural history of hepatitis C virus infection in multitransfused hemophiliacs: Effect of co-infection with HIV

HIV infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis

Does hepatitis C co-infection accelerate clinical and immunological evolution of HIV-infected patients?

Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus co-infection: The Swiss HIV Cohort Study

Hepatitis C and progression of HIV disease

Hepatitis C in the HIV Atlanta VA Cohort Study: The effect of co-infection on survival

Immune recovery is associated with persistent rise in hepatitis C virus RNA, infrequent liver test flares, and is not impaired by hepatitis C virus in co-infected subjects

Increased vertical transmission of HIV from hepatitis C virus-co-infected mothers

Possible reactivation of hepatitis D with chronic antigenaemia by HIV

Hepatitis delta virus RNA detection in chronic HBsAg carriers with and without HIV infection

Herpes zoster in African patients: A clinical predictor of human immunodeficiency virus infection

Herpes zoster in African patients: An early manifestation of HIV infection

Complement-fixing antibodies against cytomegalovirus in different parts of the world

The epidemiology of CMV retinitis in Africa

Preventing opportunistic infections among human immunodeficiency virus-infected adults in African countries

Kaposi' s sarcoma-associated herpesvirus (KHHV)/human herpesvirus 8 (HHV-8) as a tumour virus

Review of the distribution of Kaposi' s sarcoma-associated herpesvirus (KHSV) in Africa in relation to the incidence of Kaposi' s sarcoma

Update of Kaposi' s sarcoma and other HHV8 associated diseases. Part 1: Epidemiology, environmental predispositions, clinical manifestations, and therapy

Transmission and disease association of Kaposi' s sarcoma-associated herpesvirus: Recent developments

Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Effects of influenza vaccination in HIV-infected adults: A double-blind, placebo-controlled trial

Antibody response after influenza vaccination in HIV-infected individuals: A consecutive 3-year study

Coronavirus infection in an AIDS patient

Hypereosinophilia secondary to immunodysregulation in patients with HIV-1 disease

Eosinophilia in patients infected with human immunodeficiency virus

Clinical significance of eosinophilia in HIVinfected individuals

Hypereosinophilic syndrome with unusual cutaneous manifestations in two men with HIV infection

Hypereosinophilic syndrome associated with HIV infection

Immunologic aspects of hyperimmunoglobulinemia E-like syndrome in patients with AIDS

Acute eosinophilic pneumonia in a patient infected with the human immunodeficiency virus

Epstein-Barr virus and interleukin-5 mRNA in acquired immunodeficiency syndrome-related lymphomas with eosinophilia

Endocrine abnormalities associated with HIV infection and AIDS

Eosinophilia in patients infected with human immunodeficiency virus

Objective measures of allergic disease in children with human immunodeficiency virus infection

Eosinophil involvement and serum IgE level in HIV-1-infected children

Eosinophils: A putative marker of immunodepression in HIV-infected African patients with tuberculosis?

Relationship between interleukin-5 production and variations in eosinophil counts during HIV infection in West Africa: Influence of Mycobacterium tuberculosis infection

Assessing eosinophil count as a marker of immune activation among human immunodeficiency virusinfected persons in sub-Saharan Africa

Immune reconstitution eosinophilia due to schistosomiasis

Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia in AIDS

A randomized trial of clarithryomycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome

Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group

Cotrimoxazole prophylaxis for opportunistic infections in adults with HIV

Global strategies to prevent bacterial pneumonia in adults with HIV disease

Cotrimoxazole prophylaxis reduces mortality in human immunodeficiency virus-positive tuberculosis patients in Karonga District

Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): A double-blind randomised placebo-controlled trial

Provisional WHO/UNAIDS Secretariat recommendations on the use of cotrimoxazole prophylaxis in adults and children living with HIV/AIDS in Africa

Joint WHO/UNAIDS/UNICEF statement on use of cotrimoxazole as prophylaxis in HIV exposed and HIV infected children

Reconsidering empirical cotrimoxazole prophylaxis for infants exposed to HIV infection

23-Valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: Doubleblind, randomised and placebo controlled trial

Travels with HIV: The compliance and health of HIV-infected adults who travel

Sex and travel: Studies of sexual behaviour, disease and health promotion in international travellers-A global review

Sexually transmitted diseases in travelers

Preparation of the HIV-infected traveler to the tropics

Centers for Disease Control and Prevention: Preventing cryptosporidiosis: A guide to water filters and bottled water

Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: Randomized, placebo-controlled, double-blind study