key: cord-017227-66dx2dkv
authors: Humphreys, Hilary; Winter, Bob; Paul, Mical
title: Immunocompromised Patients
date: 2012-08-21
journal: Infections in the Adult Intensive Care Unit
DOI: 10.1007/978-1-4471-4318-5_10
sha: 
doc_id: 17227
cord_uid: 66dx2dkv

The ominous prognosis of cancer patients with or without neutropenia in need of critical care has led to reservations with regard to admission of cancer patients to the ICU. However, significant improvements in ICU and in-hospital survival of cancer patients in ICU have been demonstrated in studies in recent years [1–4]. Risk factors for mortality have shifted from those related to the underlying condition to those related to the severity of acute illness similar to other critically-ill patients. Neutropenia per se and the underlying malignancy (solid and hematological) do not have an impact on the outcome of patients in ICU. Recent chemotherapy is associated rather with improved survival [3, 5–7], while organ dysfunction, severity of disease scores, need for vasopressor treatment, need for mechanical ventilation immediately or after noninvasive ventilation, no definite diagnosis and a non-infectious diagnosis are associated with mortality [1–3, 8]. Invasive aspergillosis is also associated with very high mortality rates in ICU (see below). In several studies, admission to ICU in the early stages of sepsis or other acute event was associated with better survival than admission later, after development of organ dysfunction. Performance status is perhaps the most important and only variable relating to the underlying condition that is correlated with ICU death. The prognosis remains guarded for certain cancer patients, including patients after allogeneic hematopoietic stem cell transplantation (HSCT) with active uncontrolled graft versus host disease, those with relapse of the primary disease after allogeneic HSCT and special cases of solid cancer including pulmonary carcinomatous lymphangitis and carcinomatous meningitis with coma [9].

associated rather with improved survival [ 3, [5] [6] [7] , while organ dysfunction, severity of disease scores, need for vasopressor treatment, need for mechanical ventilation immediately or after noninvasive ventilation, no de fi nite diagnosis and a noninfectious diagnosis are associated with mortality [1] [2] [3] 8 ] . Invasive aspergillosis is also associated with very high mortality rates in ICU (see below). In several studies, admission to ICU in the early stages of sepsis or other acute event was associated with better survival than admission later, after development of organ dysfunction. Performance status is perhaps the most important and only variable relating to the underlying condition that is correlated with ICU death. The prognosis remains guarded for certain cancer patients, including patients after allogeneic hematopoietic stem cell transplantation (HSCT) with active uncontrolled graft versus host disease, those with relapse of the primary disease after allogeneic HSCT and special cases of solid cancer including pulmonary carcinomatous lymphangitis and carcinomatous meningitis with coma [ 9 ] . An "ICU trial" consisting of patient admission and re-assessment after 3-5 days has been suggested for cancer patients [ 9 ] . Outcomes were better associated with the hemodynamic and respiratory status after the fi rst stabilization phase than at the time of admission. Another study supporting this concept showed that organ failure scores predicted survival more accurate on day six than at admission [ 7 ] . All patients who required initiation of mechanical ventilation, vasopressors, or dialysis after 3 days in the ICU died.

An early invasive diagnostic strategy should be pursued in immune compromised patients, since the differential diagnosis is broad including infectious and noninfectious etiologies and the spectrum of infectious agents is large. This includes bronchoalveolar lavage (BAL) with or without lung biopsy for pulmonary disease, functional endoscopic sinus surgery (FESS) for sinusitis/ rhinocerebral disease, endoscopy for colitis, biopsies from liver nodules, etc. Some infectious conditions by organ system to be considered in immune compromised patients are provided in Table 10 .1 . In additions, patients presenting with respiratory insuf fi ciency should be evaluated for community-acquired respiratory viruses using PCR, direct antigen tests and cultures of respiratory samples. These include in fl uenza, parain fl uenza, adenovirus, respiratory syncytial virus (RSV), and human metapneumovirus.

Empirical antibiotic treatment is recommended for neutropenic cancer patients (neutrophil count <500/mm 3 or <1,000/mm 3 and expected to decline to <500/mm 3 ) with fever, diarrhoea or suspected infection [ 10 ] . Intravenous empirical treatment for high-risk patients should provide broad coverage against Gram-negative (including Pseudomonas aeruginosa ) and Gram-positive bacteria. Vancomycin should not be administered routinely, but is reserved for patients with hypotension or other hemodynamic compromise, those with a source of infection likely to be caused by Staphylococci (skin/ soft tissue, catheter-related and pneumonia). Antibiotic treatment should not be automatically discontinued with neutrophil recovery, even if infection has not been con fi rmed during neutropenia. Rather repeated patient examination, imaging and microbiological evaluation for suspected sources of infection should be performed after neutrophil recovery to exclude new or exacerbations of pre-existing infections.

Among patients with documented infections during neutropenia, neutrophil recovery may be associated with "deterioration" in the status of the patient. Local signs and symptoms of infection are frequently exacerbated. Thus, pulmonary in fi ltrates may increase with new onset respiratory compromise (see Figs. 10.1 and 10.2 ), an abscess may appear or enlarge or local signs of catheter-related infection may become manifest. In this case, treatment should not necessarily be changed or expanded. This is the normal response to neutrophil recovery.

An immune reconstitution in fl ammatory response (IRIS), originally described among patients with HIV following treatment initiation (see below), has also been described among cancer patients following neutrophil recovery [ 11 ] . This syndrome represents an overly robust and dysregulated in fl ammatory response resulting in re-appearance or deterioration in clinical signs and symptoms of infection. It occurs usually later than the initial worsening following neutrophil recovery, days to weeks after immune reconstitution. Diagnosis is dif fi cult and is based mostly on negative cultures and biomarkers for the initial infection and treatment is with corticosteroids. A speci fi c syndrome of adult respiratory distress syndrome (ARDS) has been described following neutrophil recovery in hematological cancer patients [ 12 ] . The only independent risk factor for ARDS is pneumonia during neutropenia.

The importance of administering chemotherapy, if needed, cannot be overemphasized, even during an acute infection. While inducing immune suppression during an acute infection is counter intuitive, it is the underlying malignancy that is most commonly responsible for infection among cancer patients. Without control of the underlying malignancy the long term outcomes of most or all infections remain ominous. Close liaison with hematologists/ oncologists is recommended for oncological patients admitted to the ICU [ 9 ] .

Cancer patients, especially hematological cancer patients are frequently thrombocytopenic as part of their underlying illness or as a result of chemotherapy. While randomized controlled trials have not shown an advantage to a threshold higher than 10 × 10 9 /l for thrombocyte transfusions, these studies did not include critically ill patients [ 13 ] . A higher threshold should probably be used (20-30 × 10 9 /l) in critically ill hematological cancer patients, especially with sepsis or with pulmonary involvement. Pulmonary and intracerebral hemorrhage are frequent terminal events in these patients and prophylactic transfusions may prevent mortality. Neutrophil transfusions have not been shown to improve survival for patients with severe neutropenia as part of the management of acute infections. However, when sub-grouped according to the dose of neutrophils transfused, survival was improved with average neutrophil doses of 1 × 10 10 . This dose can be obtained by pre-treating donors with granulocyte growth stimulating factors (G-CSF) [ 14 ] . Neutrophil transfusions should be reserved for severely neutropenic patients (<100/ ml 3 ) for whom the neutrophil count is expected to increase in a few days, as a bridge until bone marrow reconstitution. Neutrophil transfusion is probably futile when there is no expectation that the natural neutrophil count will increase.

Hematological cancer patients may be hypoglobulinemic as part of the underlying hematological malignancy or following chemotherapy. There is no evidence from high-quality studies that intravenous immuneglobulins (IVIG) reduces mortality in sepsis in general and in cancer patients speci fi cally [ 15 ] . In one randomized controlled trial speci fi cally assessing patients with hematological malignancies, there was no survival advantage with IVIG [ 16 ] . IVIG is used in some centers for infection prevention among patients with multiple myeloma or chronic lymphocytic leukemia, known hypogammaglobulinemia and recurrent respiratory infections [ 17 ] .

Patients with HIV may be seen in the ICU as the fi rst presentation of their disease or following an infectious complication after diagnosis. Highly active antiretroviral therapy (HAART) has changed the epidemiology of HIV such that the latter group of patients is rare nowadays in locations where treatment is available (and depending on patient's compliance). Clearly, the change in prognosis of HIV with HAART has led to a shift in management such that HIV patients are offered maximal treatment, including full ICU support, organ transplantation in the appropriate circumstances, or chemotherapy if needed. The impact of HAART availability on mortality has been shown also in ICU, where predictors of mortality in the HAART era are no longer HIV-related [ 18 ] . A thorough discussion of the management of HIV patients is beyond the scope of this book. However, we will address a few critical decisions in the management of infections with suspected or known HIV.

Administering antiretroviral therapy in the ICU is dif fi cult [ 19 ] . All antiretrovirals except zidovudine are available only as oral preparations, most only as tablets.

Beyond the poor bioavailability of orally administered drugs in the critically-ill patient, absorption and side effects of speci fi c antiretrovirals frequently depend on the provision of concurrent oral feeding. Drug interactions are common; for example proton-pump inhibitors and histamine-2 blockers are contraindicated with protease inhibitors (PIs). All nucleoside reverse-transcriptase inhibitors (NRTIs), except for abacavir, require dose adjustment for renal failure. Several PIs require dose adjustment for hepatic impairment [ 19 ] . Thus, fi xed drug combination usually cannot be used in patients with renal and hepatic impairment; individual drugs must be dose-adjusted and administered separately. Drug-related adverse effects are common, although few may be relevant in the critical care setting. NRTIs (mainly stavudine, didanosine, and zidovudine) may induce lactic acidosis. Abacavir-related hypersensitivity is a serious adverse event and this drug should be administered only after genetic testing for HLA-B*5701.

The most common infectious scenario encountered in the ICU will be the recently diagnosed patient presenting with an opportunistic infection. The question in this scenario is whether to initiate antiretroviral therapy early while treating the acute infection or after its successful management. Aside from the practical dif fi culties in the administration of HAART in ICU, there is the fear of IRIS with worsening of the underlying infectious process during immune reconstitution. IRIS can occur between days to weeks after initiation of HAART [ 19 ] . Although logically predicted by rising CD4 counts, it can occur before signi fi cant CD4 cell count increase or viral load suppression [ 20 ] .

There are few randomized trials to guide the strategic decision of early vs. deferred HAART initiation during infection (Table 10 .2 ). Three trials have shown a clinical bene fi t for early, but not immediate antiretroviral drug initiation (e.g. within 2 weeks of starting anti-infective treatment), for patients mostly with pulmonary tuberculosis and PCP [21] [22] [23] . One study showed no difference in outcomes for patients with pulmonary and extrapulmonary tuberculoisis [ 24 ] . In contrast two trials assessing HIV patients with meningitis showed no bene fi t or increased harm with early initiation of HAART initiation [ 25, 26 ] (Table 10 .2 ) . There is no direct evidence on timing of HAART initiation in the critical care setting. Summarizing the evidence from existing trials, it seems that the initiation HAART about 2 weeks after anti-infective therapy directed at the opportunistic infection is reasonable for patients with pulmonary infections, including tuberculosis. This allows the time for patient stabilization, HIV drug resistance testing and involving an HIV specialist in the management and all treatment decisions. With tuberculosis or cryptococcal meningitis, the start of HAART should probably be deferred for longer.

In previously treated HIV patients, the question is whether to continue or stop HAART in ICU. Discontinuation could result in the selection of anti-viral resistance because of the different half-lives of the drugs included in the combination and functional monotherapy with the long-acting antiretrovirals. An expert recommendation is to try and continue HAART for patients with virological suppression (plasma HIV RNA below the limit of detection) [ 19 ] . In other patients, HAART can probably be discontinued after consultation with an HIV expert. HIV/ hepatitis B co-infected patients require special consideration. Antiretroviral treatment active against hepatitis B (lamivudine, emtricitabine, and tenofovir) should not be discontinued for fear of exacerabations of hepatitis B after discontinuation.

Adrenal insuf fi ciency is common among HIV patients and should be evaluated in all patients admitted to the ICU. Testing of stress cortisol concentration and lowdose adrenocorticotropic hormone (ACTH) corticotropin stimulation test (1-microg of ACTH) is recommended [ 27 ] .

Solid organ transplant (SOT) recipients require life long immune suppression to prevent rejection. This immune suppression affects mainly the T-cell lymphocyte function. Consequently, opportunist infections seen most frequently among SOT recipients include herpesvirus infections, mainly CMV, pneumocystis pneumonia and more rarely fungal infections. EBV-associated post-transplantation lymphoproliferative disease (PTLD) is a special entity. In the fi rst month after transplantation, most infections will be healthcareassociated, related to the surgical site, catheter or post-operative mechanical ventilation. Lung transplant recipients are frequently colonized before transplantation by bacteria and pneumonia is very common in the fi rst year after transplantation (mostly in the fi rst month) and is associated with a high relative risk of death [ 28 ] . Donors may also be colonized with antibiotic resistant bacteria [ 29 ] . Prophylaxis for a more prolonged period (i.e. days) compared with non-transplant surgery (i.e. 1-2 doses of antibiotics) should be guided by the presence of pre-existing antibiotic-resistant bacteria in the recipient or the donor. All antibiotics continued after transplantation should be reviewed early with a view to discontinuation if the recipient is clinically well and there is no other evidence to suggest infection. Antibiotics can be discontinued 48-72 h after transplantation if culture of donor and recipient samples is negative and the patient is stable.

Antibiotic prophylaxis in liver transplantation should provide a therapeutic concentration in the wound and within the biliary tract. In a European survey, all liver transplant centres administered antibiotic prophylaxis for liver transplantation, using a variety of different antibiotic regimens for a median of 3 days after transplantation [ 30 ] .

Given the shortage of organs, transplant centers are increasingly using marginal donors, sometimes with documented infections at the time of death, which might have been previously treated or not. Studies describe non-inferior outcomes for recipients receiving organs from donors with clinical infections, including bloodstream infection and meningitis [31] [32] [33] [34] . Treatment directed against the donor's isolate/s was given to recipients. Procurement of organs from previously untreated patients with meningitis has not been described.

Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii most commonly affects patients with cellular immune de fi ciency, including lymphopenia or qualitative defects in lymphocyte activity, rather than patients with neutropenia or neutrophil dysfunction. Susceptible patients therefore include patients with: multiple myeloma • chronic lymphocytic leukemia • following HSCT with graft versus host disease (GVHD hematological cancer • patients receiving anti-lymphocyte antibodies such as rituximab and alemtuzumab (mainly lymphoma) SOT recipients mainly during periods of high-corticosteroid therapy or anti-• lymphocyte antibody treatment for rejection non-immune-reconstituted HIV patients. • HAART has changed the epidemiology of PCP such that most patients are now not HIV-positive. PCP is more severe and is associated with higher mortality in non-HIV patients. Prophylaxis with trimethoprim-suphamethoxazole (TMP-SMX) given daily or thrice weekly is highly effective in PCP prevention and patients who are receiving TMP-SMX prophylaxis presenting with a clinical picture suspected of PCP probably do not have PCP. Compliance with prophylaxis in the period before admission should be ensured by history taking, since discontinuation of PCP prophylaxis for adverse events is common and protection from PCP is reliable only while this drug is taken. Less is known about the ef fi cacy of other prophylaxis agents, including dapsone or pentamidine, and their administration should not rule out the possibility of PCP in the appropriate clinical setting.

PCP presents with dyspnea, tachypnea and hypoxia. Lung imaging shows bilateral interstitial or ground glass in fi ltrates. Initially the chest X ray may appear near normal but a high-resolution CT scan will show these opacities better. With more severe disease bilateral diffuse in fi ltrates can be seen also on the chest X-ray. The radiological picture is similar to than seen with CMV pneumonitis and actually coinfection of PCP and CMV is not uncommon. A diagnosis of one does not rule out the existence of the other and a search for CMV infection should be performed when PCP is diagnosed, especially in hematological cancer and SOT patients.

The interval from symptom onset to diagnosis of PCP was 3-14 days in one study [ 35 ] . Diagnosis is established most commonly by examination of BAL fl uid, but it is possible also with induced sputum (Table 10 .1 ). Giemza stain or immuno fl uorescence stain with human monoclonal anti-Pneumocystis cyst antibodies will demonstrate P. jirovecii trophozoites or cysts. PCR is more sensitive but less speci fi c; P. jirovecii was identi fi ed by nested PCR in 68 % of people dying suddenly of non-infectious reasons, representing low-level colonization [ 36 ] . In the appropriate clinical scenario a positive PCR probably mandates treatment, but in other cases PCR results may represent colonization.

TMP-SMX is considered the most effective therapy for PCP [ 37 ] . It is administered using high doses of 15-20 mg/kg/day of the trimethoprim component and 75-100 mg/kg/day of the sulphamethoxazole component, divided in four daily doses. Clinical response may be delayed until day 7 or later and treatment should be continued for 21 days. Adverse effects are common and include mainly rash and TMP-SMX-induced leucopenia. Hematologists or oncologists may be reluctant to use TMP-SMX in patients with neutropenia for fear of delaying neutrophil recovery. Leucovorin (folinic acid) can attenuate the hematologic adverse effects of TMP-SMX, but should probably not be used during active PCP infection since it has been shown to increase death and failure rates in HIV patients [ 38 ] . Alternative agents include the combination of primaquine 30 mg/ day and clindamycin 600 mg thrice daily, a combination of dapsone with trimethoprim, atovaquone alone or intravenous pentamidine alone. Each medication has its own adverse effect pro fi le which should be considered on a patient-by-patient basis before treatment and monitored for during treatment.

Adjunctive corticosteroid treatment for patients with hypoxemia (room air PaO 2 <70 mmHg) is based on evidence of improved survival in HIV patients, but it is recommended in other immune compromised patients with severe PCP [ 37 ] .

The dose recommended is 40 mg prednisone twice daily for 5 days, 40 mg/day for the next 5 days and 20 mg/day until day 21.

The classical risk factors for invasive aspergillosis include severe prolonged neutropenia, the immune de fi ciency state following allogeneic hematopoietic stem cell transplantation, particularly in the fi rst year after transplantation and with GVHD and more rarely following SOT, mainly lung transplantation. However, currently, invasive aspergillosis is also reported among other patient populations in the ICU not "classically" considered as immune compromised. These include patients with chronic lung disease, cirrhosis, burns and others [ 39 ] . Post-mortem studies show that invasive aspergillosis is under-diagnosed in the ICU. Therefore, in this setting, positive respiratory cultures for Aspergillus sp . should not be automatically disregarded.

Aspergillus sp . may cause infectious, saprophytic and allergic syndromes. Herein, we will address three of the more important infectious syndromes seen in ICU: invasive aspergillosis, aspergillus tracheobronchitis and chronic necrotizing aspergillosis.

Invasive aspergillosis, the classical condition described in immunocompromised patients, involves the lungs, sinuses with or without cerebral extension and skin mostly. Both contiguous extension disregarding normal anatomical barriers (as in the extension from the respiratory sinuses to the brain) and hematogenous dissemination (causing lung infarction) may occur. Chest and sinus x-rays are notoriously insensitive for the diagnosis of invasive aspergillosis and CT is the imaging of choice. During neutropenia fi ndings are usually lacking or minimal, but after neutrophil recovery lesions frequently increase in size even with adequate treatment and control of systemic infection (Fig. 10.3 ) . Respiratory deterioration should also be expected at the time of neutrophil recovery. The classical signs of cavitation and crescent formation are usually observed at later stages of the disease (Fig. 10.4 ) . Lung hemorrhage is a feared complication, especially after biopsy, and thus attention should be given to correcting thrombocytopenia during invasive aspergillosis (see above).

Criteria for the diagnosis of invasive Aspergillosis have been suggested [ 40 ] . These consist of at least one host risk factor and one clinical fi nding (Table 10. 3 ). To diagnose probable invasive aspergillosis laboratory con fi rmation is needed in addition to host and clinical criteria (Table 10 .4 ) and for proven disease histological con fi rmation is necessary. Aspergillus spp . appear as narrow, non-septate, acutebranching hyphae.

Given the dif fi culties in obtaining histological specimens in cancer patients that are severely thrombocytopenic, diagnosis usually relies on culture, direct stains, PCR and galactommanan (GM, a cell wall component of Aspergillus spp. and Penicillium spp ). PCR and GM can be tested in serum or in BAL fl uid. As can be seen in Table 10 .5 , the sensitivity and speci fi city are slightly higher in BAL, favoring the performance of BAL for patients with suspected invasive aspergillosis.

Aspergillus tracheobronchitis represents infection of the major airways, with erythema, ulceration, nodules and pseudomembrane formation [ 39 ] . It has been described mostly among lung transplant recipients, but also among patients with COPD and Chronic necrotizing aspergillosis (or "semi-invasive aspergillosis") consists of a more chronic and diffuse form of lung infection, resembling pulmonary coccidioidomycosis or histoplasmosis [ 37 ] . It has been described among patients with chronic lung disease, diabetes mellitus, AIDS and with chronic corticosteroid therapy. The existence of the syndrome is important to recognize for patients presenting severe respiratory diseases and positive respiratory culture of Aspergillus sp ., without the classical features of invasive aspergillosis.

The primary recommended therapy for the infectious syndromes described herein is voriconazole [ 37, 45 ] . Voriconazole is available both in oral and intravenous formulations. Blood level concentrations should be monitored, since currently recommended dosing frequently results in subtherapeutic concentrations [ 46 ] . Many other antifungals are active and recommended for the treatment of invasive aspergillus infections; [ 37, 45 ] fl uconazole is the only azole inactive against Aspergillus sp . (see Chap. 4 on antifungals). Treatment failure and mortality rates are very high, especially with ongoing immune suppression. Because of the ominous prognosis combinations of antifungals have been suggested as primary or salvage therapy. In one small randomized controlled trial, the combination of liposomal amphotericin B with caspofungin resulted in a higher rate of favorable response than liposomal amphotericin B, with no deaths in the combination arm (0/15 vs. 3/15 with monotherapy [ 47 ] . The most common combination reported in observational studies was voriconazole and caspofungin, but at this time no conclusions can be drawn on the effects of this combination over monotherapy [ 48 ] .

1. The patient in the case vignette underwent bronchoalveolar lavage (BAL) with lung biopsy. CMV was isolated in cultures of the BAL fl uid. CMV antigenemia was tested after neutropil recovery (the pp65 antigen is present in neutrophils which are required for CMV antigenemia assessment) and was negative. Direct immuno fl uorescence and PCR for P. jirovecii in BAL fl uid were negative. Lung biopsy demonstrated diffuse alveolar damage with eosinophlic alveolar foam compatible with PCP. A methamine-silver and immunohistochemical stains for PCP were negative, as was the immunohistochemical stain for CMV. The patient was diagnosed with PCP based on the clinical presentation and histological Sensitivity and speci fi city values refer to the diagnosis of probable or proven IA GM galactomannan, CI con fi dence interval a Values refer to a GM cut-off of 0.5 optical density index fi ndings. CMV co-infection could not be ruled out. The positive CMV culture in BAL fl uid could re fl ect CMV reactivation and infection in the presence of immune suppression, without disease. 2. The patient was empirically treated with high-dose trimethoprim-sulfamethoxazole and intravenous gancyclovir with no adverse events and these were continued after the results of the tests discussed above. 3. The dose of prednisone was increased and tapered down following the recommendations for severe PCP. 4. Respiratory insuf fi ciency improved gradually until the patient was discharged with normal saturation on room air. Notable was the appearance of pulmonary in fi ltrates and respiratory distress only after neutrophil recovery, although fever started during neutropenia and probably re fl ected the same infection. This exacerbation after neutrophil recovery is similar to the immune reconstitution syndrome seen with HIV patients after start of HAART.

The prognosis of acute respiratory failure in critically ill cancer patients

Survival in neutropenic patients with severe sepsis or septic shock

ICU and 6-month outcome of oncology patients in the intensive care unit

Prognosis of patients with acute myeloid leukaemia admitted to intensive care

Impact of neutropenia on the outcomes of critically ill patients with cancer: a matched case-control study

Impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies

The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation

Characteristics and outcomes of patients with cancer requiring admission to intensive care units: a prospective multicenter study

Intensive care of the cancer patient: recent achievements and remaining challenges

Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America

The impact of the host on fungal infections

Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies

Prophylactic platelet transfusion for haemorrhage after chemotherapy and stem cell transplantation

Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction

Intravenous immunoglobulin for treating sepsis and septic shock

IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial

Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis

Short-and long-term outcome of HIV-infected patients admitted to the intensive care unit

Intensive care of patients with HIV infection

Clinical features and serum biomarkers in HIV immune reconstitution in fl ammatory syndrome after cryptococcal meningitis: a prospective cohort study

Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial

Timing of antiretroviral therapy for HIV-1 infection and tuberculosis

Timing of initiation of antiretroviral drugs during tuberculosis therapy

Time to initiation of antiretroviral therapy between 4 weeks and 12 weeks of tuberculosis treatment in HIV-1 infected patients. Results from the TIME Study. In: Paper presented at the 22nd European Congress of clinical microbiology and infectious diseases

Timing of initiation of antiretroviral therapy in human immunode fi ciency virus (HIV)-associated tuberculous meningitis

Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa

Adrenal insuf fi ciency in critically ill patients with human immunode fi ciency virus

Pneumonia after lung transplantation in the RESITRA Cohort: a multicenter prospective study

Impact of bacterial and fungal donor organ contamination in lung, heart-lung, heart and liver transplantation

Antimicrobial prophylaxis in liver transplant patients-a multicenter survey endorsed by the European Liver and Intestine Transplant Association

The use of liver grafts from donors with bacterial meningitis

Intrathoracic organ transplantation from donors with meningitis: a single-center 20-year experience

Donors with positive blood culture: could they transmit infections to the recipients?

Clinical signi fi cance of donor-unrecognized bacteremia in the outcome of solid-organ transplant recipients

Clinical picture of P. jirovecii pneumonia in cancer patients

Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population

An of fi cial American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients

Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death

Aspergillus infections in the critically ill

Revised de fi nitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group

Use of PCR for diagnosis of invasive aspergillosis: systematic review and meta-analysis

Evaluation of PCR on bronchoalveolar lavage fl uid for diagnosis of invasive aspergillosis: a bivariate metaanalysis and systematic review

Galactomannan detection for invasive aspergillosis in immunocompromized patients

Accuracy of BAL galactomannan in diagnosing invasive aspergillosis: a bivariate metaanalysis and systematic review

Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America

Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients

Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial)

The role of combination antifungal therapy in the treatment of invasive aspergillosis: a systematic review