key: cord-0775643-vei3czm2
authors: Lee, Ingi; Barton, Todd D.
title: Viral Respiratory Tract Infections in Transplant Patients: Epidemiology, Recognition and Management
date: 2012-09-14
journal: Drugs
DOI: 10.2165/00003495-200767100-00004
sha: 6fd431caa05459425a6cdfe9b198e0e5314d525b
doc_id: 775643
cord_uid: vei3czm2

Viral respiratory tract infections (RTIs) are common causes of mild illness in immunocompetent children and adults, with occasional significant morbidity or mortality in the very young, very old or infirm. However, recipients of solid organ transplants (SOT) or haematopoietic stem cell transplants (HSCT) are at markedly increased risk for significant morbidity or mortality from these infections. The infections are generally acquired by transmission of large respiratory droplets and can be nosocomial in origin with many documented outbreaks on specialised transplant units. Typically, the infections begin as upper RTIs, with cough or rhinorrhoea predominating. Many will resolve at this stage, but more immunocompromised patients, typically closer in time to their SOT or HSCT, may develop progressive infection to lower RTI or pneumonia. The most common RTI pathogens are influenza viruses, parainfluenza viruses and respiratory syncytial viruses. Newer polymerase chain reaction-based diagnostic strategies are more sensitive than previous assays, and allow rapid and accurate diagnoses of these infections. These newer assays may also detect emerging pathogens of significance, one of which is human metapneumovirus. While diagnostic techniques have advanced significantly in the past decade, well established and effective specific treatments for these infections remain elusive. The epidemiology, clinical presentation, diagnosis and treatment of the common viral RTIs in SOT or HSCT recipients are reviewed, and recommendations presented based on a thorough review of recent literature.

Viral respiratory tract infections (RTIs) are common causes of mild illness in Abstract immunocompetent children and adults, with occasional significant morbidity or mortality in the very young, very old or infirm. However, recipients of solid organ transplants (SOT) or haematopoietic stem cell transplants (HSCT) are at markedly increased risk for significant morbidity or mortality from these infections. The infections are generally acquired by transmission of large respiratory droplets and can be nosocomial in origin with many documented outbreaks on specialised transplant units. Typically, the infections begin as upper RTIs, with cough or rhinorrhoea predominating. Many will resolve at this stage, but more immunocompromised patients, typically closer in time to their SOT or HSCT, may develop progressive infection to lower RTI or pneumonia. The most common RTI pathogens are influenza viruses, parainfluenza viruses and respiratory syncytial viruses. Newer polymerase chain reaction-based diagnostic strategies are more sensitive than previous assays, and allow rapid and accurate diagnoses of these infections. These newer assays may also detect emerging pathogens of significance, one of which is human metapneumovirus. While diagnostic techniques have advanced significantly in the past decade, well established and effective specific treatments for these infections remain elusive. The epidemiology, clinical presentation, diagnosis and treatment of the common viral RTIs in SOT or HSCT recipients are reviewed, and recommendations presented based on a thorough review of recent literature.

Respiratory viruses are common causes of mild, tality rates. [1, 2] Incidence rates have ranged from self-limited, upper respiratory tract infections (UR-11-65% in surveillance studies of HSCT recipients TIs) in immunocompetent individuals. They vary in to 4-27% in retrospective studies of HSCT recipitheir seasonality and frequency, and tend to infect ents and 8-21% in lung transplant recipients with children more often than adults. While symptomatic symptomatic disease. [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] A surveillance study of disease may persist for days to weeks in healthy hospitalised patients with leukaemia and hospitaloutpatients, significant morbidity or mortality is unised or clinic patients with recent HSCT at the MD common.

Anderson Cancer Center reported that >60% of pa-In immunocompromised patients, including tients had progression of viral URTIs to pneumohaematopoietic stem cell transplant (HSCT) and nia. [2] Mortality rates associated with respiratory solid organ transplant (SOT) recipients, respiratory viruses have varied in the literature. Earlier case viruses may be either community acquired or hospi-series of hospitalised HSCT or SOT recipients with tal acquired. They are associated with longer periods LRTIs reported high mortality rates (≥50%). [8] More of infection, increased progression to lower respira-recent studies of HSCT recipients with URTIs, tory tract infections (LRTIs), as well as higher mor-including those treated as outpatients, reported low-er mortality rates of 2-18%. [4, 11, 12] In addition to ents, starting with the most commonly reported reincreased disease severity, certain viral infections -spiratory viruses including RSV, PIV, influenza A including those caused by influenza virus A and B, and B, and adenovirus, and concluding with less parainfluenza virus (PIV) and adenovirus -have reported or newly recognised viral infections includalso been associated with an increased risk for rejec-ing rhinovirus, coronavirus, herpesviruses excluding tion in SOT recipients. [13] [14] [15] cytomegalovirus (CMV), and human metapneumovirus (table I provides a synopsis of the key Early diagnosis of respiratory viruses in immupoints). nocompromised patients is crucial to the consideration of therapies and to efforts to limit the spread of 1. Respiratory Syncytial Virus disease among patient populations. Several testing options are available. A combination of direct 1.1 Epidemiology (DFA) or indirect (IFA) fluorescent antibody testing with viral culture has been the standard used at many RSV is a single-stranded RNA virus and a meminstitutions. However, in recent years, polymerase ber of the paramyxovirus family. The seasonality of chain reaction (PCR) has gained popularity, given RSV outbreaks varies according to latitude. In temits increased sensitivity and fast processing time, perate areas, RSV occurs seasonally from winter to and is being used more often in the diagnosis of early spring. In tropical and subtropical areas, there respiratory syncytial virus (RSV), influenza A and is less seasonal variation, and RSV outbreaks in the B, PIV and adenovirus. [6] Serological assays are not tropics may be associated with the rainy season. [19] routinely helpful in detecting acute infection. Of RSV is a common cause of community-acquired note, bacterial or fungal infection is often found as a respiratory tract infections with a tendency to infect co-pathogen along with viral infections, and this children more often than adults. Almost all children may be more common with PIV. [16, 17] have had primary infection by the age of 2 years, Treatment and prevention of respiratory tract inwith more severe disease seen in higher risk groups, fections can vary depending on the pathogen. In including very-low-birth-weight infants, as well as 2000, the Centers for Disease Control and Prevenchildren with bronchopulmonary dysplasia, congention, Infectious Disease Society of America and the ital heart disease and immune deficiencies. [20] RSV American Society of Blood and Marrow Transplanis highly contagious and reinfection can occur at any tation established guidelines for preventing opportupoint later in life as a result of incomplete immunity. nistic infections in HSCT recipients. [18] General pre-RSV is an important pathogen in immunocomventative guidelines include instituting infectionpromised patients, with many observational studies control measures such as appropriate hand hygiene, finding that it is the most commonly identified viral early isolation of patients with suspected respiratory RTI in HSCT and SOT recipients. Studies have tract infections and avoidance of sick contacts. shown a cumulative incidence ranging across These measures aim to limit the exposure of HSCT 3.5-8.8% in allogenic HSCT recipients, [21] [22] [23] recipients to viral infections. Other preventative 0.4-1.5% in autologous HSCT recipients, [22, 23] and measures include vaccination or antiviral prophy-3.4-10% in paediatric liver and adult lung transplant laxis. Treatment options are limited but should be recipients. [24, 25] considered when available.

Although RSV is often considered a community-This article reviews the current literature on re-acquired infection, nosocomial transmission is also spiratory tract infections in HSCT and SOT recipi-common. Hospital-acquired infection may occur for several reasons. HSCT and SOT recipients with HSCT patients with RSV developed LRTIs, and only one of those patients died (6.6%). RSV infection may have difficulty clearing the virus because of their immunosuppressed states, and

In patients with haematological malignancies or therefore have prolonged periods of shedding. [26, 27] HSCT recipients with RSV infection, progression to These patients should be isolated but are often LRTIs may be associated with increased age and placed in close proximity to each other on dedicat-lack of RSV treatment. [34] In HSCT recipients, prognosis is also associated with timing of the disease in ed wards. Therefore, they have opportunities to inrelation to the transplantation. Patients infected prefect multiple other immunocompromised patients engraftment or ≤1 month post-transplant tend to through environmental contamination or by inhave higher complications rates of pneumonia and fecting staff members who are then exposed to other death. [35] Peck and colleagues [36] performed a retropatients. Taylor and colleagues [26] reported that durspective study following 37 HSCT candidates who ing the 1995-6 season, there were ten cases of RSV were diagnosed with RSV URTIs pre-transplantaat an HSCT unit in Bristol, UK. Of the nine RSV tion (n = 31) or early during their conditioning specimens that could be amplified, restriction enregimen (n = 6). The six patients diagnosed early in zyme analysis demonstrated that eight sequences their conditioning regimen all had symptoms prior were identical -the patients had become infected to treatment but had delayed virological confirmawith the same strain of virus. This strain also diftion. Of the 34 patients who had their HSCT fered from those found in patients hospitalised from delayed, only one progressed to proven RSV pneuthe community, suggesting that RSV had been monia, compared with two of three patients in the nosocomially acquired within this HSCT unit. In group who did not delay HSCT. Given their findaddition, during an RSV season, 15-20% of healthings, the authors recommended that physicians care providers may shed RSV, with this figure inshould strongly consider delaying transplantation in creasing to 50% during community outbreaks. [28] those patients with RSV infection and perhaps also Because of these factors, nosocomial transmission in those patients with URTI symptoms (even prior to may be responsible for approximately 50% of all virological confirmation). cases. [29] [30] [31] 

RSV antibody titres tend to be low in adults, RSV typically begins as a URTI, with a majority particularly those who are immunosuppressed. of patients experiencing cough. Other symptoms Therefore, a combination of fluorescent antibody may be present, including fever, rhinorrhoea, sinus testing (DFA and IFA) with viral culture has tradicongestion and wheezing. Prognosis in transplant tionally been used to make the diagnosis of RSV. recipients has been associated with disease severity, Processing time varies between these two tests; rewith those developing LRTIs experiencing worse sults from fluorescent antibody tests are available outcomes. Early series described mortality rates of within hours to days in contrast to viral culture in cell lines such as human epithelial (Hep-2), human 30-80% in patients progressing to pneumonia, with lung fibroblast (WI-38 or MRC-5) or rhesus monkey perhaps 60% progressing to pneumonia. [32] Howevkidney cells, which may take up to several weeks. [37] er, more recent studies have reported lower mortality rates. A study by Machado and colleagues [33] Over the past few years, PCR has become more found that during the 2001-2 season, 55.5% of commonly used. PCR can identify RSV in patients with lower viral levels, and therefore may be more insufficient data in humans, with only case reports in sensitive than traditionally used viral cultures. Van the literature of pregnant women who were treated Elden and colleagues [38] compared the TaqMan ® with ribavirin in the latter half of their pregnancy PCR versus viral culture or shell vial culture in and did not experience adverse fetal outcomes. [42] diagnosing RSV in HSCT recipients. TaqMan ® 1 However, given this concern, pregnant women PCR was positive for RSV in 13 samples. Conven-should try to avoid entering a patient's room during tional culture detected only four of these cases, treatment with the aerosolised product. while none were detected using shell vial culture. A Although there are no definitive trials evaluating study by Weinberg and colleagues [39] found that the therapeutic role of ribavirin in immunocommultiplex PCR was more sensitive in detecting repromised patients with RSV, trials of various doses spiratory tract infections, particularly RSV B and and treatment durations have been reported in the PIV 1, in lung transplant recipients compared with literature. In HSCT recipients with RSV pneumonia viral culture, enzyme immunoassays and rapid shell or LRTI, aerosolised ribavirin alone has not shown vial detection tests. PCR was also associated with significant benefit, with mortality rates as high as the fastest processing time of 6-8 hours. Other rapid 70% reported in the literature. [43] Boeckh and coldetection tests include enzyme-linked immuleagues designed a randomised multicentre trial to nosorbent assay and immunofluorescence. study the effects of aerosolised ribavirin in HSCT recipients with RSV URTIs. [44] The authors reported that patients randomised to receive aerosolised 1.4 Treatment ribavirin had a nonsignificant decrease in the rate of Antiviral treatment for RSV is controversial, progression to pneumonia (one of nine patients in with conflicting study results found in the literature. the ribavirin group vs two of five patients in the Ribavirin, a guanosine analogue, is the main ancontrol group; p = 0.51) and lower 10-day viral tiviral agent that has been studied in immunocomloads (0.75 log10 copies/mL reduction versus 1.26 promised patients, particularly HSCT recipients.

log10 copies/mL increase; p = 0.07) compared with Although it can be given orally, intravenously or patients receiving best supportive care. Although the via inhalation, only aerosolised ribavirin is approved findings are intriguing, it is difficult to make further by the US FDA for the treatment of RSV. Aer-conclusions given that the study was insufficiently osolised ribavirin is difficult to administer. It re-powered as a result of slow patient accrual. In a quires a small particle nebuliser machine, which phase 1 study by Lewinsohn and colleagues, [32] inmay not be available at some institutions. Adverse travenous ribavirin had similar efficacy to aereffects -including psychological distress for the osolised ribavirin. However, it was also associated patient due to isolation during treatments, rash, with adverse effects, including haemolysis, signifiheadache and conjunctivitis -may occur in anyone cant enough to require drug cessation in two of ten exposed to aerosolised ribavirin. There is also con-patients. In contrast, Glanville and colleagues recern that ribavirin may be teratogenic, and that ported that lung transplant recipients with RSV who patients, visitors and staff may be at risk from aer-were treated with a combination of intravenous osolised ribavirin. Animal studies have noted an ribavirin and corticosteroids had excellent progincrease in skeletal malformations in pregnant rats noses (0% mortality) and only experienced mild and hamsters treated with ribavirin. [40, 41] There are adverse effect profiles. [45] Combination treatment with ribavirin and RSV tate this process. Another important intervention intravenous immunoglobulin (IVIg) has yielded po-involves quickly implementing droplet and contact tentially encouraging results (mortality rates of isolation measures when RSV infection is first sus-14-42%), particularly if given earlier in the course pected, particularly given the potential for a 24-to of respiratory illness. [46, 47] In a study by Ghosh and 48-hour delay before confirmation of infection colleagues, [46] aerosolised ribavirin and RSV IVIg through diagnostic testing. Raad and colleagues [30] were administered to 14 bone marrow transplant reported that instituting isolation precautions de-(BMT) recipients with RSV URTIs. Four patients creased the rates of RSV in a HSCT ward by 81%. (29%) developed pneumonia and two died. RSV There is no currently available RSV vaccination. IVIg has subsequently been discontinued world-2. Parainfluenza Virus wide and replaced by the monoclonal antibody formulation palivizumab. Two phase 1 studies by Boeckh and colleagues [48] reported long half-lives 2.1 Epidemiology (10.7-22.4 days), mild adverse-effect profiles, and PIV, like RSV, is a single-stranded RNA virus high survival rates in HSCT recipients treated with and a member of the paramyxovirus family. Howevaerosolised ribavirin and palivizumab. An abstract er, PIV has four different serotypes that vary in from Zamora and colleagues [49] found that combinaprevalence, seasonality and clinical disease. PIV1 tion treatment with aerosolised ribavirin and either and 2 are common causes of childhood croup, result-RSV IVIg or palivizumab and IVIg decreased rates ing in outbreaks during autumn (fall) and winter. of acute rejection, bronchiolitis obliterans and mor-PIV3, which is more often associated with adult tality in lung transplant recipients with pneumonia. disease, is found year-round with an increased inci-Given the available information, the Swedish dence during spring and summer. PIV4 is the least Consensus Group proposed that aerosolised commonly isolated serotype and has not as been ribavirin and RSV IVIg be considered in allogenic well characterised. HSCT or SOT recipients with >1 episode of rejec-There are a limited number of studies evaluating tion with mild or moderate RSV pneumonia. [50] The PIV infections in transplant recipients. Nichols and American Society of Transplantation (AST) guidecolleagues [16] reported that 7.1% of HSCT recipients lines state that "for patients with upper respiratory acquired PIV infection (90% PIV3, 6% PIV1 and tract disease and the presence of risk factors and for 4% PIV2) at the Fred Hutchinson Cancer Research those organ transplant recipients with lower respira-Center over a 9-year period. Unlike RSV, the rates tory tract disease the use of aerosolised ribavirin in of PIV infection were similar between autologous combination with RSV immune globulin or and allogenic HSCT recipients. Studies have also palivizumab should be considered". [51] reported that 1.6-11.9% of lung transplant recipients become infected with PIV (63% PIV3, 29%

PIV1 and 8% PIV2). [52, 53] Infection control methods are crucial in the pre-A study by Nichols and colleagues reported durvention of respiratory viral infections including ing the 1998-9 season, 93 HSCT recipients at the RSV. Because RSV is transmitted via aerosolised Fred Hutchinson Cancer Research Center acquired droplets or fomites, hand hygiene is an important PIV. [54] Approximately 71% cases occurred in paand effective preventive measure. Many hospitals tients seen in outpatient clinics. An increased numoffer alcohol-based hand-washing products to facili-ber of cases were identified at this hospital during September and October, suggesting an outbreak, (DFA or IFA), viral culture using primary monkey even though there was no increase in PIV infections kidney tissue and PCR. Because adults tend to shed in the community. Molecular analysis demonstrated low titres of PIV, there has been an emphasis on that many of the isolates were related and fell into finding more sensitive detection methods, namely distinctive clusters, suggesting that many of the PIV PCR. A study by Weinberg and colleagues [39] found cases occurred via nosocomial transmission in the that PCR was in fact more sensitive in detecting PIV outpatient setting. serotype 1.

PIV is a common cause of community-acquired Although in vitro studies have shown that respiratory illness in children, and progresses to ribavirin has activity against PIV, clinical studies LRTIs 15% of the time. [52] In immunocompetent have yielded mixed results. Smaller studies in adults, who have often developed incomplete immu-HSCT recipients seemed to suggest that aerosolised nity, infections are restricted to the upper respiratory and intravenous ribavirin resulted in decreased mortract and tend to be mild.

tality rates compared with historical controls. [12, 56] Over the past several years, studies have demon-Larger series using ribavirin with or without IVIg, strated that PIV is associated with significant morhowever, have not shown the same efficacy. [16, 17] bidity and mortality in transplant recipients. In im-Nichols and colleagues [16] also reported that munocompromised patients, PIV may initially preribavirin did not affect the duration of viral shedsent as a URTI, with 70% of patients having a ding. After reviewing the available information, the cough. [52] Other symptoms -including rhinorrhoea, AST guidelines state that "because no other therawheezing, coryza and fever -are less common.

peutic options are currently available, consideration Approximately one-third of HSCT recipients with can be given to the use of aerosolised ribavirin for PIV then progress to LRTIs, and of those who do, high-risk patients with PIV-associated severe lower the literature cites a mortality rate in the range of tract disease". [51] Careful attention to diagnosis and 0-73%. [3, 8, 11, 14, 16, 17, 55] Corticosteroid administration treatment of bacterial or fungal co-infections is also for graft-versus-host disease is believed to be a risk important. factor for pneumonia. [16] In lung transplant recipients, 10-66% of PIV infections involve the lower 2.5 Prevention respiratory tract. [52] PIV infection predisposes transplant recipients to As with RSV, infection control measures are co-infection with other bacterial or fungal pathoimportant in preventing the spread of PIV among gens. Studies have reported that 50% of HSCT transplant recipients. Because inoculation occurs recipients with PIV have superimposed bacterial or through direct contact with fomites or other infected fungal pneumonias. [16, 17] PIV has also been associatobjects, proper hand hygiene is again essential. Coned with higher rates of bronchiolitis obliterans and tact and droplet precautions should also be instituted allograft rejection in lung transplant recipients. [52] early when viral infection is first suspected. It is important to note that immunocompromised patients 2.3 Diagnosis may have prolonged shedding durations, as demon-Diagnostic methods for PIV are similar to those strated by one report in which two HSCT recipients for RSV and include fluorescent antibody tests shed PIV for >100 days. [17] A formalin-inactivated PIV vaccination is availa-study conducted over a 10-year period reported that ble. While this vaccination results in antibody rethere was anywhere from 2.8 cases of influenza/ sponse, it has not been shown to prevent infec-1000 person-years in liver transplant recipients to tion. [57] Studies are currently underway to evaluate 41.8 cases/1000 person-years in lung transplant rethe efficacy of intranasal PIV vaccination in immucipients. [15] Viral shedding occurs for 5-10 days in nocompetent patients. immunocompetent patients, with longer durations of shedding occasionally noted in immunocompromis-3. Influenza ed patients. Nichols and colleagues [61] reported that the mean duration of influenza virus shedding in 3.1 Epidemiology allogenic HSCT recipients was 7 days (range 2-37 days) and that patients who did not receive treatment Influenza virus is a single-stranded, negative shed for longer periods (average 11 days). Other sense RNA virus and a member of the orthomyxovirus family. There are three types -influenza A, B case reports have noted shedding of influenza virus and C -based on antigenic differences. Influenza is for >1 year, [62] but more research is needed to deterhighly infectious, spreads through respiratory dropmine the frequency and significance of prolonged lets, and epidemics typically occur during winter shedding in transplant recipients. months resulting in significant morbidity and mortality. Machado and colleagues [58] reported that 12%

of influenza cases occurred during summer months in a tropical climate, although given the known Most patients infected with influenza develop potential for prolonged shedding and the limited typical symptoms such as fever, headache and myalability to detect other viruses in their study, it is not gias. These symptoms may be less common in some completely clear that these represented true incident transplant patient populations, [62] although few pacases of influenza. Within a single influenza season, most cases will be of the same (major) strain, alpers report a methodical gathering of detailed sympthough other (minor) strains may also cause disease. toms prospectively. Some patients from whom in-However, antigenic changes in the virus, vaccine fluenza virus is recovered are asymptomatic (e.g. contents and population vaccine penetration, and lung transplant patients undergoing routine bronantiviral use and resistance, lead to different circuchoscopy), but the significance of this finding is lating influenza strains each year. Several articles unclear. In general, influenza should be suspected in have noted infections in transplant patients with any patient who presents with a constellation of either influenza A or B, [58] [59] [60] but it is unclear in these fever, rhinorrhoea, cough, malaise, myalgias and/or small series whether there are substantive differheadache during the winter season. Progression ences in clinical presentation or outcomes. Although from URTI to pneumonia is rare in immunocominfluenza is commonly considered a communitypetent patients, and may be underestimated in imacquired respiratory illness, nosocomial spread also munocompromised patients. [63] Certain complicaoccurs. Hospitalised HSCT or SOT recipients may tions are more common in BMT or SOT recipients. become infected soon after transplantation, resulting These include bacterial superinfection, CNS inin severe disease and worse prognosis. volvement, myocarditis, and graft dysfunction or The incidence of influenza in SOT recipients rejection. [15, 25, 64] varies, depending on the type of transplantation. A

duration as is prescribed for immunocompetent individuals. [51] Although infrequent, resistance to Nasopharyngeal and throat specimens, bronoseltamivir has been reported in the literature. choalveolar lavage and endotracheal aspirates can Machado and colleagues [58] have reported a systembe used in the diagnosis of influenza. The gold atic approach using oseltamivir to treat early influstandard is viral culture, which has a processing time enza infection in BMT recipients. Progression to of 3-7 days. Other tests including fluorescent antipneumonia was observed in 5% of patients, similar body techniques (DFA or IFA) are also available. to other series, although notable for the fact that Because viral load is highest during the first few many patients in this series were at especially high days of illness and then quickly decreases afterrisk in the early post-BMT period, and therefore not wards, diagnosis is easier earlier on in the course of vaccinated. illness. PCR testing is available and becoming more Ribavirin is another antiviral agent that has been commonly used at most institutions for diagnosing mentioned in the literature. Small studies have respiratory viruses, including influenza A and B.

shown in vitro activity against influenza and anecdotal reports suggest possible activity in immuno-3.4 Treatment competent patients.

[51] Some experts suggest adding aerosolised ribavirin to neuraminidase inhibitor Two classes of antiviral medications exist for therapy in transplant recipients with severe influenprevention and treatment of influenza infections: za infection. [51] M2 inhibitors or adamantanes (amantadine and rimantadine), which have activity against influenza

A, and neuraminidase inhibitors (oseltamivir and zanamivir), which have activity against both influ-Careful hand hygiene, avoidance of sick contacts enza A and B. Over the past several years, there has and yearly vaccination are the main preventative been a worldwide increase in adamantane-resistant measures against influenza. Transplant recipients, influenza A virus. In the US, up to 92% of influenza close contacts and healthcare workers should all A (H3N2) virus was adamantane resistant, resulting receive the standard inactivated vaccination intrain guideline changes. [65] In 2006, the Advisory Commuscularly; the live attenuated intranasal vaccine is mittee on Immunisation Practices stated that not recommended in this patient population. Transamantadine and rimantadine should not be used for plant recipients may develop weaker antibody retreatment or chemoprophylaxis of influenza A in the sponses to vaccination compared with immunocom-US. [65] petent individuals. [66] The frequency of protective Oseltamivir and zanamivir are the two neu-responses has ranged widely from 15-100% in varaminidase inhibitors that are currently available for ried transplant populations, [67] [68] [69] [70] and probably also treatment. Oseltamivir, which is administered oral-depends both on individual factors (e.g. type and ly, and zanamivir, which is inhaled, are able to intensity of immunosuppression, time from transshorten the duration of illness by 1 day in immu-plant) and vaccine factors (e.g. immunogenicity of nocompetent patients when given within 48 hours of the particular vaccine strains, correlation of the vacsymptom development. Although there is a paucity cine strain with epidemic strain). Given that many of data in transplant recipients, most experts includ-patients will achieve protective antibody responses ing the AST recommend treating HSCT and SOT and that the annual variability in response rates is recipients with influenza using the same dose and not predictable, yearly vaccination should be en-couraged. Currently, there are no recommendations plant recipients may be more susceptible to to monitor vaccine titres. It is also unclear whether pandemic influenza, given their immunocomthere is a role for higher dose or repeated vaccina-promised state as well as their frequent exposure to tions in HSCT or SOT recipients to increase protec-the healthcare system. Once infected, transplant pative immunity.

tients may be prone to more severe disease with higher rates of complications. These patients may Preventative antiviral medications may be conalso have difficulty clearing the virus and could sidered in those patients who do not respond or have become 'super-spreaders', as was the concern with not had a chance to respond to vaccination, and in severe acute respiratory syndrome (SARS). [71, 75] those who are unable to receive the vaccination. It is Pandemic influenza would also be likely to affect unclear whether such a strategy should be employed transplant centres. Similar to the SARS outbreak, during the full course of an influenza season or in a pandemic influenza may lead to closing of transpost-exposure manner.

plant centres for periods of time, and prompt consideration for at least a temporary revision of transplan-3.6 Pandemic Influenza tation guidelines (e.g. donor and recipient screen-Influenza has resulted in three 20th century ing). pandemics, in 1918, 1957 and 1968 ; the highest Avian influenza is inherently resistant to adamortality was associated with the 1918 Spanish flu mantanes. Neuraminidase inhibitors have been used pandemic which resulted in 40 million deaths. [71] in patients with H5N1 avian influenza and have Currently, there is concern that avian influenza demonstrated some efficacy when started early. (H5N1) could progress to become the next pandem-However, there are oseltamivir-resistant viruses that ic. The first case of avian influenza was reported in have been identified in patients who did not improve 1997 during a poultry outbreak in Hong Kong and with treatment. [76] No vaccinations are currently was followed by 18 human cases. [ 

Most human cases have occurred via bird-to-human transmission, although there is speculation that there Adenovirus may be acquired by person-to-person may have been limited human-to-human transmis-transmission as a primary RTI. However, some adesion. Human cases of avian influenza have been novirus disease in immunocompromised patients associated with high mortality rates (54%), particu-may represent reactivation of latent infection. In larly in younger patients who are able to mount addition, adenovirus infection can produce a variety significant immunological responses. [74] of clinical syndromes in addition to respiratory tract illness, and these patterns of illness may vary by To date, there have not been any cases of avian host, transplant type and adenovirus serotype. [77] influenza in transplant recipients. However, given the heightened concern, experts have extrapolated Adenovirus infections account for 0-21% of viral the information known about other respiratory vi-RTIs in recent large case series, [3] [4] [5] [8] [9] [10] 78, 79] and are ruses in transplant recipients to address the implica-more common in children. [80] While adenovirus is tions of possible pandemic influenza in this popula-the least commonly reported of the common respiration. On the patient level, it is possible that trans-tory viruses, most of these series tested patients with symptomatic URTI -the true incidence of ade-gold standard for identification of adenovirus infecnovirus infection would probably be higher if pa-tion. tients with other clinical manifestations were tested should be used with caution in transplant recipients or positive testing from lower respiratory tract samwho are at increased risk for renal impairment. ples. [11, 81] In these patients, mortality may result Finally, two recent articles have questioned the need from involvement of the digestive system, kidneys for treatment in all patients with documented adeor CNS. Outcomes from adenovirus RTI after novirus infections, making watchful waiting a rea-HSCT have been poor, with a cumulative mortality sonable option for minimally symptomatic paof 56% (30 of 54 cases). [8, 9, 11, 81] One-third of these tients. [6, 84] deaths occurred in patients with adenovirus URTI without evidence of pneumonia. Only a few studies have addressed the potential overall incidence of 5.8%. [82] Several longitudinal role of rhinoviruses -ubiquitous common cold studies have reviewed the potential significance of pathogens -as respiratory pathogens in SOT and adenovirus infection in lung transplant patients, HSCT recipients, but in aggregate they suggest that demonstrating a 1-3% incidence. [83] It is hyrhinovirus infection may be underdiagnosed. Four pothesised that adenovirus and other RTIs may prerecent studies [5, 6, 81, 85] of prospective active surveildispose to acute or chronic rejection in lung translance with newer diagnostic techniques noted rhiplant recipients, but the data to support this hypothenovirus infection in their cohorts, and in two, [6, 85] 55] Progression to LRTI was observed in but the test is insensitive, missing up to 50% of 17% of cases and two deaths from rhinovirus pneucases. While emerging PCR assays may provide monia were noted. Children may be particularly easier and faster diagnosis, viral culture remains the susceptible to rhinovirus, as one series noted 18% mortality in post-BMT patients with rhinovirus. [86] tine antiviral prophylaxis, these are especially rare These patients underwent BMT for primary immu-pathogens in the first several post-transplant nodeficiencies and therefore may represent a months. VZV may occur at any time post-transplant uniquely susceptible population. Many older DFA and dormant virus is ubiquitous in the population. or IFA panels did not include rhinovirus in routine Since most cases of VZV pneumonia in HSCT or testing, so as newer diagnostic technologies (i.e. SOT recipients are preceded by the characteristic PCR) become more widely used, the true epidemiol-vesicular skin rash, [88] and since VZV pneumonia is ogy and impact of rhinovirus infections in HSCT or very rare, it is presumed that prompt antiviral ther-SOT recipients will become clearer. At present, apy with aciclovir can halt the progression of reactithere is no specific antiviral therapy available for the vation disease to pneumonia. Patients with antecetreatment of rhinovirus infections. dent herpes zoster followed by pneumonia should also be empirically treated for bacterial superinfec-

tion, given the high rates of superinfection and the aggressive nature of some of the more common Coronaviruses, like rhinoviruses, are frequent pathogens like Staphylococcus aureus. causes of benign URTIs occurring in annual winter-

The roles of human herpesvirus 6 (HHV)-6 and time community outbreaks. No systematic study of HHV-7 as pulmonary pathogens remain poorly untheir possible role in LRTIs in HSCT or SOT recipiderstood. [89] [90] [91] While active replication with either ents has been undertaken, but recent experience with virus may be detected in some transplant recipients SARS coronaviruses, the causative agent of SARS, (particularly HSCT patients), no consistent pattern is noteworthy. A study of tissue obtained at autopsy of pulmonary disease has been associated with eifrom a liver transplant recipient revealed extremely ther virus. Proposed associations include pneumonia high numbers of viral copies, [87] suggesting both a or bronchiolitis obliterans with or without organisreason for the fatal course as well as the possible ing pneumonia. [92] No commonly accepted treatrole of immunosuppressed patients as 'superments are available for either virus, though some spreaders' of this and other epidemics. [75] With the agents with activity against other herpesviruses (e.g. more widespread availability of PCR diagnostics for ganciclovir, cidofovir) have some in vitro activity coronaviruses, more research is needed to clarify the against these viruses. frequency and incidence of these infections in transplant recipients.

The newly recognised pathogen human metap-Nearly all viruses in the herpesvirus family have neumovirus (hMPV) was first recovered in 2001 been reported as occasional causes of pneumonia in from a cohort of Dutch children with RTIs. [93] In the HSCT and SOT recipients. Cytomegalovirus short time since this report, a number of important (CMV) is perhaps the most important post-trans-surveys have demonstrated both the commonness plant pathogen and an occasional cause of respirato-and potential significance of this pathogen in transry infection, but its pathophysiology, epidemiology plant patients. Three studies examining the frequenand treatment are beyond the scope of this review. cy of hMPV recovery from stored bronchoalveolar Herpes simplex virus type 1 (HSV-1) and varicella lavage specimens documented a positivity rate of zoster virus (VZV) are both rarely reported but 3-9% among transplant recipients with symptomatpotential pulmonary pathogens. [85] In the era of rou-ic RTI; while this rate may seem low, it is compara-ble to the observed rates for RSV, PIV and influen-

Phase I study of infections after hematopoietic stem cell transplantation: risk intravenous ribavirin treatment of respiratory syncytial virus factors, response to antiviral therapy, and effect on transplant pneumonia after marrow transplantation. Antimicrob Agents outcome

Low mortality infection after stem cell transplant: relevance to outcome of rates related to respiratory virus infections after bone marrow rapid diagnosis and ribavirin treatment

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syncytial virus infection: impact of a strategy to delay trans

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Community respiratory virus

The outcome of 26 infections following lung transplantation

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Respiratory syncytial respiratory syncytial virus infection in immunocompromised virus infection following hematopoietic stem cell transplantaadults

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Respiratory virus chain reaction for the diagnosis of viral respiratory tract infecinfections after stem cell transplantation: a prospective study tions in lung transplant recipients

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Teratogenic effects of ribavirin

olitis obliterans: the respiratory viruses connection: myth or 42

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An outbreak of outbreak of respiratory syncytial virus within bone marrow respiratory syncytial virus in a bone marrow transplant center. transplant unit

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on behalf of the Advisory of the respiratory syncytial virus-specific monoclonal antibody Committee on Immunization Practices. Prevention and control palivizumab in recipients of hematopoietic stem cell transof influenza

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The epidemiology of response to influenza vaccination in lung transplant recipients. parainfluenza virus infection in lung transplant recipients

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Prolonged outbreak of influenza vaccination in renal allograft recipients. Transplant human parainfluenza virus 3 infection in a stem cell transplant

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Clinical features and 73. World Health Organization. Cumulative number of confirmed outcomes of paramyxoviral infection in lung transplant recipihuman cases of avian influenza A/(H5N1) reported to WHO ents treated with ribavirin

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Influenza and parain-75. Centers for Disease Control an Prevention. Severe acute respirafluenza respiratory viral infection requiring admission in adult tory syndrome

Oseltamivir resistance 1075-8 during treatment of influenza A (H5N1) infection

in adult solid organ transplant recipients

Low mortality

Influenza infections rates related to respiratory virus infections after bone marrow after hematopoietic stem cell transplantation: risk factors, mortransplantation

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of multidrug-resistant influenza A virus in an immunocom-181-7 promised patient

Viral pneumonia in the immunocomtions in hematopoietic stem cell transplant recipients. Clin promised adult with neoplastic disease: the role of common Infect Dis

Viral infections in immunocompromised study of respiratory viral infections in pediatric hemopoietic patients: what's new with respiratory viruses? Curr Opin Infect stem cell transplantation patients

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adenovirus infection in adult solid organ transplant recipients

tion after pediatric bone marrow transplantation: is treatment always necessary?

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A prospective study

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Fatal human syndrome (SARS) in a liver transplant recipient and guidelines metapneumovirus infection in stem-cell transplant recipients. for donor screening

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Human herpesvirus-6 and -7 infections in transplantation

Human Correspondence: Dr Ingi Lee

Silverstein Building, Suite E, Philadel

Human herpesvirus phia, PA 19104, USA. 6: infection and disease following autologous and allogeneic E-mail: ingi.lee@uphs.upenn.edu bone marrow transplantation

Acknowledgements za. [94] [95] [96] Although it is difficult to calculate an accu-No sources of funding were used to assist in the prepararate frequency of progression to pneumonia or tion of this review. The authors have no conflicts of interest death, these outcomes have been observed. [96] Furthat are directly relevant to the content of this review. thermore, studies demonstrate that cases are clustered in epidemic fashion -whether these are community-based epidemics or nosocomial epidemics References

nosis is likely to be difficult because hMPV is not