Severe adenovirus infection: an under- recognised disease with limited treatment options Case reports
Transcription
Severe adenovirus infection: an under- recognised disease with limited treatment options Case reports
Case reports © The Intensive Care Society 2012 Severe adenovirus infection: an underrecognised disease with limited treatment options 3A13 C Houlihan, M Valappil, S Waugh, K Cantlay, DA Price Severe adenovirus infections can occur in both immunocompromised and immunocompetent patients. New serotypes are emerging in the UK, and should be considered in patients who present with respiratory tract symptoms and no other obvious pathogen. The difficulties of diagnosis and treatment of severe adenovirus infection are discussed. Keywords: Adenoviridae; pneumonia, viral; infection; immunocompromise; lymphopenia Introduction Adenovirus (AdV) infections occur worldwide and are associated with sporadic as well as institutional and community outbreaks and epidemics. Most infections occur in children and are mild or asymptomatic. Typically AdV infections result in self-limiting respiratory, gastrointestinal or ocular infections,1 however, AdV can cause severe disseminated disease in immunocompromised patients.2,3 Severe or fatal infections have been reported in immunocompetent adults4 and were previously thought to be extremely rare. However, serotypes with previously limited circulation and geographical distribution are emerging as significant pathogens,5-7 including in the UK.8 Several reports now exist of new serotypes,9 variants10 and novel recombinant serotypes. These reports describe altered tissue specificities and clinical presentations.11- 15 AdV infections may well be easily overlooked if not clinically suspected.16 We contribute to the growing literature on these infections by presenting a case of severe AdV pneumonitis in a patient with no underlying comorbidity, underlining the need to consider and investigate the possibility of viral pathogens including AdV in patients admitted to the intensive care unit (ICU) with severe respiratory infection. Further, we briefly mention two fatal cases seen in our hospital, where the clinical significance of AdV detection remains unclear. These cases highlight the importance of awareness about severe AdV infection and the challenges of interpretation of AdV tests in the severely ill. Emergence and spread of recombinant and novel AdV variants warrants the creation of systems for molecular surveillance of AdV infections. Finally, in this review we summarise treatment options for severe AdV infection, highlighting the need for further research in this area. history. He presented with a two-week history of fever, myalgia, dyspnoea with a productive cough and clear sputum. Initial presentation to his GP led to referral to hospital because of worsening dyspnoea on exertion. On admission to the emergency department, he was febrile (39°C), tachycardic (112 bpm), tachypnoeic (28 breaths/min) and hypoxic (SpO2 90% on room air) but normotensive (119/55 mmHg). His initial chest radiograph (CXR) is illustrated in Figure 1. Abnormalities of his initial blood tests included lymphopenia 1.14 × 109/L with a normal total white cell count, a C-reactive protein (CRP) of 390 mg/L, alanine transaminase (ALT) 1,49U/L and pO2 7.2 kPa on 2 L/min oxygen flow. Urinary legionella antigen and both serum and urine pneumococcal antigens were negative, as were HIV antibody, mycoplasma serology and blood and sputum bacterial cultures. After 48 hours, hypoxaemia persisted and worsened such that he required non-invasive respiratory support with continuous Case descriptions The first patient was a 26-year-old man who had had an adenoidectomy as a child. He had no other past medical JICS Volume 13, Number 4, October 2012 Figure 1 CXR with left lower zone infiltrates in patient 1. 337 Case reports positive airway pressure (CPAP). High dependency care was required for five days. Broad-spectrum antibiotics (cefuroxime and clarithromycin) were administered, with the addition of linezolid on admission to the high dependency unit to cover resistant staphylococcus and pneumococcus. These were rationalised after negative serology results and identification of AdV DNA (serotype 3) from a throat swab. This viral throat swab was negative for other respiratory viruses including influenza and parainfluenza viruses. Venous blood was tested at this time (day 4 of admission), revealing high level of AdV viraemia (viral load 3.0 × 106 IU/mL). Cidofovir was considered in light of this result; however at day 4 (day 3 HDU), although the ALT had risen to 584 U/L, the CRP had dropped to 144 mg/L, the patient’s temperature had normalised and oxygen dependency decreased. Plasma AdV viral load was re-tested on day 6 and had dropped to <2 × 103 IU/mL. He was discharged 16 days after admission with no respiratory sequelae. Two further patients were, firstly, a 60-year-old unemployed male who was a 20-pack-year smoker with scoliosis and osteoarthritis but no other medical history. He presented with a six-day history of dyspnoea and non-productive cough, and on admission was febrile, tachycardic and hypoxaemic. Admission blood tests revealed lymphopenia of 1.35 × 109/L, CRP 106 mg/L, with normal liver and renal function. He was transferred immediately to ICU but had progressive respiratory, cardiovascular and renal failure in the 24 hours following admission, requiring escalating ventilatory and inotropic support and renal replacement therapy. Broncho-alveolar lavage (BAL) fluid was positive for AdV and serotyping indicated either type 21 or 50. Cidofovir was commenced on day 3. Unfortunately, he died from multiple organ failure six days after admission. The final patient was a 38-year-old HIVpositive male with asthma and Addison’s disease, for which he used a steroid inhaler and took hydrocortisone. He had a CD4 count of 332 cells/µL (18%) prior to admission and was not on antiretroviral medication. He presented with a five-day history of fever, dyspnoea and a non-productive cough, and on admission was febrile, tachycardic and hypoxaemic. Abnormal bloods on admission included lymphopenia, 0.41 x 109/L, and elevated CRP of 334 mg/L. He was admitted directly to ICU where he was intubated and mechanically ventilated. BAL specimens were again positive for AdV serotype 3. Cidofovir was initiated but progressive multi-organ failure ensued and death occurred three days after admission. Both patients had normal liver function tests prior to developing elevated transaminases, both were lymphopenic on admission with normal total white cell count, and both had negative screening for alternative pathogens (as with the first patient). Discussion Currently, six species of AdV (A-G) with 51 distinct serotypes, have been identified.17 These serotypes demonstrate organ tropism; for example, serotypes 8,19 and 37 from species D are associated with epidemic kerato-conjunctivitis, and serotypes 7,14, and 21 from species B, with acute respiratory disease.2 AdV infection can lead to several other clinical syndromes, including meningoencephalitis, acute haemorrhagic cystitis, 338 hepatitis, acute febrile pharyngitis and gastroenteritis. Transmission of the virus is through direct contact with an infected person, faecal-oral or aerosol transmission, and from fomites. AdV is usually, but not always, included in the panel of respiratory viruses tested from throat swabs, nasopharyngeal aspirates and broncheo-alveolar lavage fluid in hospital laboratories with capabilities to perform polymerasechain reactions (PCR). The development of real-time multiplex PCR and the investment in laboratory capacity due to pandemic 2009 influenza A (H1N1) has allowed increased availability of same-day results. Although there are a variety of commercial kits available, development of in-house assays is common in NHS hospitals. In-house validation and participation in regional and national quality assurance schemes ensures the standardisation of results, although not the panel of viruses tested. Recent reports indicate that the virus genome has altered through recombination11-15 and epidemics and outbreaks of virulent AdV have been described.5,6,18 In analysis of AdV positive samples from Ireland collected between 2009 and 2010, AdV 14 was identified in nine patients (31%), three of whom died.8 As in the cases described in this report, severe illness and death from AdV infection is usually associated with some degree of immunocompromise and an intact immune system is key to clearance of the virus. The first patient reported here had no immunocompromise at presentation and no factors have been identified during subsequent clinical follow-up. He was a smoker; however, his only risk factor for severe AdV infection was being male.19 No other pathogen was identified to explain his severe community-acquired pneumonia (CAP). AdV displays the potential for viral latency/low level persistence; virus has been detected in the blood of asymptomatic HIV-infected children20 and in tonsillar tissue from children and adults.21,22 The mechanism through which the virus evades immune clearance is mediated in part through avoiding recognition by T-cells and partly by preventing activation of natural killer cells.23 Differentiating latency from active infection can therefore be a clinical challenge. In the first patient described in this report, a high level of viraemia with clinical pneumonitis and hepatitis suggested a disseminated viral illness. Other authors have highlighted AdV’s unique propensity to cause focal or lobar changes on chest X-ray.16 Focal changes were seen on X-ray in the illustrated case, further supporting our conclusion that AdV was responsible for the patient’s illness. Both this patient, and the last patient described had extremely high CRPs (390 and 334 mg/L), which has been thought to indicate bacterial rather than viral pathogens. The association has been supported in some studies; however, a systematic review of the diagnostic value of CRP in lower respiratory tract infections in 12 studies concluded that ‘testing for CRP is neither sufficiently sensitive to rule out nor sufficiently specific to rule in…. bacterial aetiology of lower respiratory infection.’24 In patients with severe disseminated viral illness, the use of CRP or even lymphopenia (which all three patients also had) in differentiating viral and bacterial illness is not a reliable indicator. This presentation and clinical findings of the first case highlight the message that AdV should be tested for in patients with severe respiratory Volume 13, Number 4, October 2012 JICS Case reports illness, with or without competent immune systems. In the two further cases described, the challenge of differentiating reactivated latent AdV from disseminated severe primary AdV infection is clear. Neither patient had peripheral blood tested for AdV; suspicion was raised by the presence of AdV in BAL samples. Both patients had an acute severe illness and in this type of presentation, it is not unusual for there to be a lack of identification of the responsible pathogen.25 Reactivation of virus in those with pre-existing immunocompromise, and perhaps an inability to fully clear less pathogenic viruses, may be an explanation for the detection of AdV-DNA. Similarly, the presence of viral remnants after an initial viral infection prior to superadded, overwhelming unidentified bacterial infection cannot be ruled out. Legionella and mycoplasma present with similar symptoms and signs and tests for these lack sensitivity.16 The challenge in correctly attributing illness to an identified pathogen should not prevent testing however, especially when treatments, although limited, are available. Both ribavirin and cidofovir have been used in immunocompromised patients with AdV infection; however, convincing evidence of efficacy in vivo is lacking.26 Ribavirin is a purine nucleoside analogue with anti-adenoviral activity in vitro. Although there have been a number of case reports and case series of its use for AdV infections,27,28 evidence to date is unconvincing. In the immunocompromised patient, IV cidofovir, a monophosphate nucleotide analogue, is now more commonly used for disseminated AdV infection. Limited evidence, again based on small studies, suggests cidofovir may be of some value.27,29,30 Despite this, mortality remains high in this patient group31 and ultimate resolution of infection often occurs only with the generation of effective specific T-cell responses. The use of cidofovir for AdV infection in the immunocompetent individual has not been studied but it is doubtful whether it would offer significant advantage in a patient with an intact immune system. Importantly, side effects of cidofovir are common and significantly limit use; most often, these involve renal toxicity. It was for these reasons that the first patient was not treated, ultimately allowing time for recovery without antiviral treatment. In the other two patients, with more severe and ultimately fatal disease, cidofovir treatment was initiated. Renal failure in these two patients preceded the initiation of cidofovir, although further deterioration with its use cannot be ruled out. Other treatment modalities which have been used include IV immunoglobulins in combination with antiviral treatments, but there is little evidence to suggest efficacy.32 T-cell immunotherapy has been successfully used to treat EpsteinBarr virus (EBV) related post-transplant lung disease in transplant patients. Limited data suggest that this approach may also be successful for controlling established AdV disease.33 A new orally active lipid-ester derivative of cidofovir is currently under investigation, which may prove less toxic than the IV drug.34 Effective, safe antivirals are clearly lacking for adenoviral disease. Further research in this area is urgently needed. Viral pneumonitis is an important cause of severe respirJICS Volume 13, Number 4, October 2012 atory infection and can easily be overlooked without appropriate investigation. Viruses account for around 15% of all patients admitted with pneumonia25 and specific treatments may be required. It is therefore important that patients admitted with severe respiratory infections should be screened for respiratory viruses including AdV by sensitive techniques as part of their initial investigation. Further, surveillance for emerging pathogenic AdV sub-types must be instituted and finally, there is an urgent need for additional studies to clarify the efficacy of emerging therapies for AdV infections in various settings. Conflict of interest None declared. References 1. Lenaerts L, De Clercq E, Naesens L. Clinical features and treatment of adenovirus infections. Rev Med Virol 2008;18:357-74. 2. Echavarria M. Adenoviruses in immunocompromised hosts. Clin Microbiol Rev 2008;21:704-15. 3. Pham TT, Burchette JL, Jr., Hale LP. Fatal disseminated adenovirus infections in immunocompromised patients. Am J Clin Pathol 2003;120:575-83. 4. Lewis PF, Schmidt MA, Lu X et al. A community-based outbreak of severe respiratory illness caused by human adenovirus serotype 14. J Infect Dis 2009;199:1427-34. 5. Centers for Disease Control and Prevention. Acute respiratory disease associated with adenovirus serotype 14--four states, 2006-2007. MMWR Morb Mortal Wkly Rep 2007;56:1181-84. 6. Kajon AE, Lu X, Erdman DD et al. Molecular epidemiology and brief history of emerging adenovirus 14-associated respiratory disease in the United States. J Infect Dis 2010;202:93-103. 7. O’Flanagan D, O’Donnell J, Domegan L et al. First reported cases of human adenovirus serotype 14p1 infection, Ireland, October 2009 to July 2010. Euro Surveill 2011;16:pii=19801. 8. Carr MJ, Kajon AE, Lu X et al. Deaths associated with human adenovirus-14p1 infections, Europe, 2009-2010. Emerg Infect Dis 2011;17: 1402-08. 9. Jones MS, Harrach B, Ganac RD et al. New adenovirus species found in a patient presenting with gastroenteritis. J Virol 2007;81:5978-84. 10.Landry ML, Lebeck MG, Capuano AW, McCarthy T, Gray GC. Adenovirus type 3 outbreak in connecticut associated with a novel variant. J Med Virol 2009;81:1380-84. 11.Walsh MP, Chintakuntlawar A, Robinson CM et al. Evidence of molecular evolution driven by recombination events influencing tropism in a novel human adenovirus that causes epidemic keratoconjunctivitis. PLoS One 2009;4:e5635. 12.Robinson CM, Rajaiya J, Walsh MP et al. Computational analysis of human adenovirus type 22 provides evidence for recombination among species D human adenoviruses in the penton base gene. J Virol 2009;83:8980-85. 13.Kaneko H, Suzutani T, Aoki K et al. Epidemiological and virological features of epidemic keratoconjunctivitis due to new human adenovirus type 54 in Japan. Br J Ophthalmol 2010;95:32-36. 14.Rebelo-de-Andrade H, Pereira C, Giria M et al. Outbreak of acute respiratory infection among infants in Lisbon, Portugal, caused by human adenovirus serotype 3 and a new 7/3 recombinant strain. J Clin Microbiol 2010;48:1391-96. 15.Yang Z, Zhu Z, Tang L et al. Genomic analyses of recombinant adenovirus type 11a in China. J Clin Microbiol 2009;47:3082-90. 16.Cunha BA. Severe adenovirus community-acquired pneumonia mimicking Legionella. Eur J Clin Microbiol Infect Dis 2009;28:313-15. 17.Fields BN, Knipe DM, Howley PM, editors. Fields Virology. 5th ed. Philadelphia: Lippincott-Raven;2007. 339 Case reports 18.Louie JK, Kajon AE, Holodniy M et al. Severe pneumonia due to adenovirus serotype 14: a new respiratory threat? Clin Infect Dis 2008;46:421-25. 19.Tate JE, Bunning ML, Lott L et al. Outbreak of severe respiratory disease associated with emergent human adenovirus serotype 14 at a US air force training facility in 2007. J Infect Dis 2009;199:1419-26. 20.Ferdman RM, Ross L, Inderlied C, Church JA. Adenovirus viremia in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1997;16:413-15. 21.Garnett CT, Talekar G, Mahr JA et al. Latent species C adenoviruses in human tonsil tissues. J Virol 2009;83:2417-28. 22.Neumann R, Genersch E, Eggers HJ. Detection of adenovirus nucleic acid sequences in human tonsils in the absence of infectious virus. Virus Res 1987;7:93-97. 23.McSharry BP, Burgert HG, Owen DP et al. Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B. J Virol 2008;82:4585-94. 24.van der Meer V, Neven AK, van den Broek PJ, Assendelft WJ. Diagnostic value of C reactive protein in infections of the lower respiratory tract: systematic review. BMJ 2005;331:26. 25.Johnstone J, Majumdar SR, Fox JD, Marrie TJ. Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation. Chest 2008;134:1141-48. 26.Lenaerts L, Naesens L. Antiviral therapy for adenovirus infections. Antiviral Res 2006;71:172-80. 27.Bordigoni P, Carret AS, Venard V et al. Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2001;32:1290-97. 28.Lankester AC, Heemskerk B, Claas EC et al. Effect of ribavirin on the plasma viral DNA load in patients with disseminating adenovirus infection. Clin Infect Dis 2004;38:1521-25. 29.Ribaud P, Scieux C, Freymuth F et al. Successful treatment of adenovirus disease with intravenous in an unrelated stem-cell transplant recipient. Clin Infect Dis 1999;28:690-91. 30.Legrand F, Berrebi D, Houhou N et al. Early diagnosis of adenovirus infection and treatment with cidofovir after bone marrow transplantation in children. Bone Marrow Transplant 2001;27:621-26. 31.Symeonidis N, Jakubowski A, Pierre-Louis S et al. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis 2007;9:108-13. 32.Emovon OE, Lin A, Howell DN et al. Refractory adenovirus infection after simultaneous kidney-pancreas transplantation: successful treatment with intravenous ribavirin and pooled human intravenous immunoglobulin. Nephrol Dial Transplant 2003;18:2436-38. 33.Feuchtinger T, Matthes-Martin S, Richard C et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol 2006;134:64-76. 34.Paolino K, Sande J, Perez E et al. Eradication of disseminated adenovirus infection in a pediatric hematopoietic stem cell transplantation recipient using the novel antiviral agent CMX001. J Clin Virol 2011;50:167-70. Catherine Houlihan Department of Infectious Disease and Tropical Medicine, Royal Victoria Hospital, Newcastle upon Tyne [email protected] Manoj Valappil Health Protection Agency North East, Newcastle General Hospital, Newcastle upon Tyne Sheila Waugh Department of Microbiology, Newcastle upon Tyne Hospitals NHS Trust Kaye Cantlay Department of Anaesthetics and Critical Care, Royal Victoria Hospital, Newcastle upon Tyne D Ashley Price Department of Infectious Disease and Tropical Medicine, Royal Victoria Infirmary, University of Newcastle upon Tyne Commentary: A of each of these infections can occur; they can be difficult to control and pose a significant infection control challenge. Less frequent syndromes include meningo-encephalitis, hepatitis, myocarditis, pancreatitis, genital infections and haemorrhagic cystitis.2 Most children are infected with at least one respiratory serotype early on in life. If symptomatic, the usual signs are of an upper respiratory tract infection and are usually mild and self-limiting. Lower respiratory infections can be more severe and may require hospitalisation. Severe pneumonia in children (those under two years of age are more susceptible) can have a fatality rate of 16%.3 Serotype 7 (species B) is particularly associated with serious infection. AdV was primarily recognised as a respiratory pathogen in military recruits.4 In the 1950s and ’60s, AdV was one of the most important causes of illness within the American military population. Hospitalisation reached 50%5 and fatalities were reported in previously healthy individuals.6 These numbers declined with the advent of the oral vaccine, which will be discussed below. AdVs are one of the commonest causes of acute gastroenteritis; long-term sequelae are not seen. Ocular 340 Volume 13, Number 4, October 2012 JICS denoviruses (AdVs) are large non-enveloped dsDNA viruses that are found ubiquitously in nature. The Adenoviridae family is split into four genera: Mastadenovirus, Aviadenovirus, Atadenovirus and Siadenovirus. Of these, it’s the Mastadenoviridae that infect humans.1 Infections with AdV are common globally and predominantly affect children, when they tend to be endemic, minor and self-limiting. Epidemics and severe disease usually occurs in neonates and in adulthood; these viruses are increasingly implicated in high morbidity and mortality in immunocompromised adults. Modalities of transmission include direct contact, faecaloral route (particularly in children), aerosols and fomite contamination. To date there are six species (A-G) and 53 serotypes identified. Different species demonstrate organ tropism; for example species B and C are commonly associated with respiratory tract infection in children, whereas species F (especially types 40 and 41, also known as the ‘enteric adenoviruses’) is linked to gastrointestinal disease. The major clinical manifestations of AdV infection are respiratory, gastrointestinal and ocular infections. Outbreaks Case reports infections such as pharnygo-conjunctival fever (PCF) and kerato-conjunctivitis (KC) are seen, again mostly in children, and outbreaks can occur.7 In most cases, severe AdV disease is seen in immunocompromised patients. Here, it tends to run a more prolonged course and can result in a fatal outcome. Mortality rates approach up to 60% in suppressed patients with pneumonia, compared with 15% in immunocompetent people.8 Clinical syndromes seen in this cohort of patients include pneumonia, hepatitis, colitis, pancreatitis and disseminated disease. The manifestation depends on the patient’s age, the serotype of virus and the underlying disease, with bone marrow transplant and haematopoietic stem-cell transplantation recipients most at risk of AdV infection. Recent advancements in diagnostics have greatly aided AdV recognition. Multiplex polymerase chain reaction (PCR) is highly sensitive, specific and rapid, with real-time PCR allowing quantification of the virus. This is of great value in terms of treatment and follow-up of infected patients.9 With regards to antiviral treatment, there is no specific therapeutic agent for AdV. Of all the current options, cidofovir has the most clinical evidence-base, primarily for immunocompromised patients.10 Ribavirin and ganciclovir have also been mooted as possible agents.11 The cornerstone of treatment is reducing the level of immunosuppression. If this is not possible, antiviral medication should be considered. Other non-antiviral therapeutic options (less widely used) include donor lymphocyte infusion12 and intravenous immunoglobulin. An oral vaccine was developed in the 1960s to prevent acute respiratory disease in military personnel. The vaccine was active against serotypes 4 and 7, and was highly successful in preventing illness. However, manufacturing issues led to the cessation of the vaccine and a rise in respiratory illness has occurred in this cohort.13 The vaccine was never considered in the paediatric populations or for civilians. AdVs have been studied as vectors for gene therapy to combat genetic disorders such as cystic fibrosis and myotonic dystrophy. AdV has also been used as an anti-oncogenetic agent (with p53 insertion) and as a variety of recombinant vaccine, with studies investigating possible efficacy against infectious diseases like HIV and rabies. Although initial generations of vectors have been unsuccessful, third-generation vectors are now being investigated; this is a highly active and exciting area of research.14 JICS Volume 13, Number 4, October 2012 References 1. Benko M, Harrach B, Both GW. Family Adenoviridae. In: Fauquet CM, Mayo MA, Maniloff J et al, eds. Virus Taxonomy. VIIIth report of the International Committee on Taxonomy of Viruses. New York: Elsevier; 2005:213-228. 2. Munoz FM, Piedra PA, Demmler GJ. Disseminated adenovirus disease in immunocompromised and immunocompetent children. Clin Infect Dis 1998;27:1194-200. 3. Murtagh P, Cerqueiro C, Halac A et al. Adenovirus type 7h respiratory infections: a report of 29 cases of lower respiratory disease. Acta Paediatr 1993;82:557-61. 4. Hilleman MR, Werner J. Recovery of new agent from patients with acute respiratory illness. Proc Soc Expl Biol Med 1954;85:183-88. 5. Top FH. Control of adenovirus acute respiratory disease in US Army trainees. Yale J Biol Med 1975;48:185-95. 6. Dudding BA, Wagner SC, Zeller JA et al. Fatal pneumonia associated with adenovirus type 7 in three military trainees. N Engl J Med 1972;286:1289-92. 7. Turner M, Istre GR, Beauchamp H et al. Community outbreak of adenovirus type 7a infections associated with a swimming pool. South Med J 1987;80:712-15. 8. Hierholzer JC. Adenoviruses in the immunocompromised host. Clin Microbiol Rev 1992;5:262-74. 9. Lankester AC, van Tol M, Claas E et al. Quantification of adenovirus DNA in plasma for management of infection in stem cell graft recipients. Clin Infect Dis 2002;34:864-67. 10.Bordigoni P, Carret AS, Venard V et al. Treatment of adenovirus infections in patients undergoing allogenic haemopoietic stem cell transplantation. Clin Infect Dis 2001;32:1290-97. 11.Arav-Boger R, Echavarria M, Forman M et al. Clearance of adenoviral hepatitis with ribavirin therapy in a pediatric liver transplant recipient. Pediatr Infect Dis J 2000;19:1097-100. 12.Chakrabarti S, Collingham KE, Fegan CD et al. Adenovirus infections following haemopoietic cell transplantation: is there a role for adoptive immunotherapy? Bone Marrow Transpl 2000;26:305-07. 13.Kolavic-Gray SA, Binn LN, Sanchez JL et al. Large epidemic of adenovirus type 4 infection among military trainees; epidemiological, clinical and laboratory studies. Clin Infect Dis 2002;35:808-18. 14.Russell WC. Update on adenovirus and its vectors. J Gen Virol 2000;81:2573-04. Rishi H-P Dhillon Specialist Registrar in Microbiology, Department of Infection and Immunity, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London [email protected] 341