Viral Infections in Immunocompromised Patients (2010)

Viruses that cause acute respiratory illness in the general population and are responsible for hospitalizations in persons of all ages with underlying medical conditions are also a common cause of respiratory disease in transplant recipients. With the widespread availability of sensitive and reliable molecular detection methods, common respiratory viruses including respiratory syncytial virus (RSV), influenza and parainfluenza viruses (PIVs), adenoviruses, rhinoviruses (RhV), and coronaviruses have been detected worldwide in transplant recipients. More recently, newly identified viruses such as human metapneumoviruses (HMPV) [1Peret T.C. Boivin G. Li Y. et al.Characterization of human metapneumoviruses isolated from patients in North America.J Infect Dis. 2002; 185: 1660-1663Crossref PubMed Scopus (334) Google Scholar, 2Boivin G. Abed Y. Pelletier G. et al.Virological features and clinical manifestations associated with human metapneumovirus: a new paramyxovirus responsible for acute respiratory-tract infections in all age groups.J Infect Dis. 2002; 186: 1330-1334Crossref PubMed Scopus (487) Google Scholar], new strains of coronaviruses [3Milano F. Campbell A.P. Guthrie K.A. Kuypers J. et al.Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients.Blood. 2010; 115: 2088-2094Crossref PubMed Scopus (144) Google Scholar], and bocavirus have also been detected in symptomatic transplant recipients [4Schenk T. Strahm B. Kontny U. Hufnagel M. Neumann-Haefelin D. Falcone V. Disseminated bocavirus infection after stem cell transplant.Emerg Infect Dis. 2007; 13: 1425-1427Crossref PubMed Scopus (64) Google Scholar]. Community-acquired respiratory viruses (CRV) have a significant impact on the morbidity and mortality of the transplant recipient, causing a variety of diseases ranging from self-limited upper respiratory tract illnesses (URIs) to life-threatening lower respiratory tract infection (LRTI) and occasionally disseminated disease. Disease manifestations are dependent on the specific virus, the type of transplant, and the type, degree, and duration of immune deficiency. Pneumonia following infection with these viruses may be primarily viral, bacterial, fungal, or mixed in origin. Some respiratory viruses, such as parainfluenza viruses, may also have higher associated rates of copathogens. Nosocomial transmission of CRVs is common, and widespread hospital outbreaks of CRVs have occurred with sometimes devastating sequelae [5Harrington R.D. Hooton T.M. Hackman R.C. et al.An outbreak of respiratory syncytial virus in a bone marrow transplant center.J Infect Dis. 1992; 165: 987-993Crossref PubMed Scopus (319) Google Scholar, 6Raad I. Abbas J. Whimbey E. Infection control of nosocomial respiratory viral disease in the immunocompromised host.Am J Med. 1997; 102 (discussion 3-4): 48-52Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Because these viruses are so easily transmitted from person to person in both inpatient and outpatient settings, infection control measures and enforcement of these measures are critical in controlling the spread of these infections [5Harrington R.D. Hooton T.M. Hackman R.C. et al.An outbreak of respiratory syncytial virus in a bone marrow transplant center.J Infect Dis. 1992; 165: 987-993Crossref PubMed Scopus (319) Google Scholar, 6Raad I. Abbas J. Whimbey E. Infection control of nosocomial respiratory viral disease in the immunocompromised host.Am J Med. 1997; 102 (discussion 3-4): 48-52Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 7Bowden R. Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience.Am J Med. 1997; 102: 27-30Abstract Full Text Full Text PDF PubMed Google Scholar]. Community outbreaks of RSV infections typically occur during the late fall, winter, and early spring, frequently followed by outbreaks of human metapneumovirus. Influenza outbreaks typically occur during the winter in temperate climates, but may occur throughout the year in more tropical areas. Parainfluenza virus infections occur throughout the year, with outbreaks occurring primarily in the spring, summer, and fall. Other viruses, such as rhinoviruses, coronaviruses, and adenoviruses, tend to take place throughout the year, although sporadic outbreaks of all these respiratory viruses may occur. Prompt and accurate identification of the respiratory viral pathogen is critically important in the transplant recipient because it enables specific infection control precautions to be instituted, the initiation of specific antiviral therapy, and the potential delay of immunosuppressive therapy or transplantation. The appropriate collection of specimens is critically important for the successful identification of viruses in clinical samples. Different diagnostic methods have been used, but during recent years, the use of multiplex PCR techniques has gained popularity because this method may detect multiple respiratory viruses from a single, readily obtained specimen [8Fan J. Henrickson K.J. Savatski L.L. Rapid simultaneous diagnosis of infections with respiratory syncytial viruses A and B, influenza viruses A and B, and human parainfluenza virus types 1, 2, and 3 by multiplex quantitative reverse transcription-polymerase chain reaction-enzyme hybridization assay (Hexaplex).Clin Infect Dis. 1998; 26: 1397-1402Crossref PubMed Scopus (180) Google Scholar, 9Templeton K.E. Scheltinga S.A. van den Eeden W.C. Graffelman A.W. van den Broek P.J. Claas E.C. Improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction.Clin Infect Dis. 2005; 41: 345-351Crossref PubMed Scopus (266) Google Scholar]. Management of CRV infections has been controversial. With the exception of influenza infections for which neuramidase inhibitors have been shown to be effective, there are no established treatments. Several uncontrolled studies have been performed with ribavirin, suggesting some efficacy at least in preventing progression to lower tract disease [10Khanna N. Widmer A.F. Decker M. Steffen I. Halter J. Heim D. et al.Respiratory syncytial virus infection in patients with hematological diseases: single-center study and review of the literature.Clin Infect Dis. 2008; 46: 402-412Crossref PubMed Scopus (211) Google Scholar]. Although there is no licensed or proven therapy for parainfluenza virus infections, ribavirin has antiviral effects against parainfluenza virus in cell culture and has been used for the treatment of lower respiratory tract disease in immunocompromised hosts [11Sparrelid E. Ljungman P. Ekelof-Andstrom E. et al.Ribavirin therapy in bone marrow transplant recipients with viral respiratory tract infections.Bone Marrow Transplant. 1997; 19: 905-908Crossref PubMed Scopus (114) Google Scholar]. Case reports have documented decreased viral load and clinical improvement in several children with severe combined immunodeficiency and parainfluenza virus infection following multiple treatments with aerosolized ribavirin [12Frank Jr., J.A. Warren R.W. Tucker J.A. Zeller J. Wilfert C.M. Disseminated parainfluenza infection in a child with severe combined immunodeficiency.Am J Dis Child. 1983; 137: 1172-1174PubMed Google Scholar, 13Piedra P. Englund J. Glezen P. Respiratory synctal virus and parainfluenza viruses.in: Hayden F.W.R. Clinical Virology. Churchill Livingstone, New York1997: 718-819Google Scholar]. There is no laboratory data supporting antiviral activity of oseltamivir against parainfluenza viruses, although new parainfluenza-specific antiviral agents with activity against the neuraminidase of parainfluenza virsues are under development. Preliminary data indicates that infections from human bocavirus, human coronavirus, and other newly identified viruses such as WU/KI viruses are less likely to cause severe problems in transplant patients compared with the well-described viral pathogens above. Adenoviruses (ADV) are nonenveloped lytic DNA viruses. Fifty-two different human serotypes have been identified divided into 7 subgroups or species. In immunocompromised patients, ADV can cause lethal disease, with damage occurring in many different organs. During the last decade ADV infection in the context of allogeneic hematopoietic stem cell transplantation (HSCT) has been increasingly recognized as a cause of transplant-related mortality (TRM), especially in children and the most severely immunocompromised adults, such as those undergoing haploidentical or T cell-depleted transplants. Runde et al. reported a significantly higher incidence of ADV-infection in patients receiving antithymocyte globulin (ATG), and a study by van Tol et al. [14van Tol M.J. Kroes A.C. Schinkel J. et al.Adenovirus infection in paediatric stem cell transplant recipients: increased risk in young children with a delayed immune recovery.Bone Marrow Transplant. 2005; 36: 39-50Crossref PubMed Scopus (93) Google Scholar] found the risks of ADV infection and disease were increased in patients with more intensive T cell depletion. They also demonstrated that patients with delayed T cell recovery have a significantly higher risk of ADV infection and disease. Other studies found a strong correlation between the presence of ADV-specific T cells and the clearance of ADV infection. Feuchtinger et al. showed that patients with ADV-specific T cells could be found in higher numbers in patients who cleared ADV infection compared to those who did not. Myers et al. found that a delayed recovery of ADV-specific T cells in recipients of unrelated or haploidentical grafts correlated with an increased risk for ADV disease. The observation that the outcome of ADV disease is related to specific immune reconstitution suggests that the recovery of ADV-specific immunity is a critical process that can be improved by decreasing the intensity of immunosuppression. In addition, the transfer of virus-specific T cells has been shown to be effective in controlling cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) infections in HSCT recipients. Although the different ADV subtypes are to some extent antigenically distinct, these same subtypes share T cell epitopes on the hexon protein. Furthermore, crossreactivity has been shown ex vivo. Early in vitro experiments showed that ADV-specific T cells can be generated by ADV pulsed dendritic cells, and that these can lyse adenoinfected cells. Chatziandreou et al. [15Chatziandreou I. Gilmour K.C. McNicol A.M. et al.Capture and generation of adenovirus specific T cells for adoptive immunotherapy.Br J Haematol. 2007; 136: 117-126Crossref PubMed Scopus (37) Google Scholar] and Feuchtinger et al. [16Feuchtinger T. Richard C. Joachim S. et al.Clinical grade generation of hexon-specific T cells for adoptive T-cell transfer as a treatment of adenovirus infection after allogeneic stem cell transplantation.J Immunother. 2008; 31: 199-206Crossref PubMed Scopus (86) Google Scholar] isolated ADV-specific T cells through an interferon (INF)-γ-secretion and capture assay and could show specific antigen responses of both CD4+ and CD8+ T cells upon restimulation with different ADV strains. Another promising approach is the adoptive immunotherapy with allodepleted donor T cells to improve immune reconstitution concerning all common viruses. In a pilot study, Feuchtinger et al. [17Feuchtinger 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: 64-76Crossref PubMed Scopus (343) Google Scholar] treated 6 patients with ADV-viremia with virus-specific donor T cells generated by INF-γ secretion assays. In 3 of 4 evaluable patients receiving this adoptive T cell transfer, the infused T cells underwent an in vivo expansion and the viral load decreased in peripheral blood. In vivo expansion of specific T cells was dose-independent, suggesting that even very low numbers of ADV-specific donor T cells expand easily in vivo in the presence of viremia. The mortality rate following influenza infections in HSCT recipients was previously reported to be around 15% [18Whimbey E. Elting L.S. Couch R.B. et al.Influenza A virus infections among hospitalized adult bone marrow transplant recipients.Bone Marrow Transplant. 1994; 13: 437-440PubMed Google Scholar, 19Ljungman P. Ward K.N. Crooks B.N. et al.Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.Bone Marrow Transplant. 2001; 28: 479-484Crossref PubMed Scopus (265) Google Scholar], although recent data reporting outcome after more widespread utilization of neuramidase inhibitors suggest a somewhat lower risk for fatal outcome [20Machado C.M. Boas L.S. Mendes A.V. et al.Use of Oseltamivir to control influenza complications after bone marrow transplantation.Bone Marrow Transplant. 2004; 34: 111-114Crossref PubMed Scopus (87) Google Scholar, 21Nichols W.G. Guthrie K.A. Corey L. Boeckh M. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy.Clin Infect Dis. 2004; 39: 1300-1306Crossref PubMed Scopus (322) Google Scholar]. The recent outbreak of new pandemic strain A/H1N1 stressed the importance of having strategies in place for management of these patients. Influenza infection is controlled by different parts of the immune system including both the innate and adaptive immune systems. After vaccination, both T cell and B cell responses are activated. Clearance of the primary infection depends on CD8 cells. These cells recognize epitopes from both the hemagglutinin (HA) and internal proteins of the influenza virus. Following recovery from influenza, antigen-specific T cells maintain long-lasting immunologic memory that responds quickly to restimulation. The B cells produce antibodies to the influenza proteins and HA-specific antibodies appear within 2 weeks of the infection. In contrast to antibodies directed to HA, antibodies directed to NA do not neutralize virus but reduces the release of virus from infected cells. A problem specific for influenza viruses is the antigenic shifts and drifts of circulating influenza virus that regularly occur, requiring adaptation of the seasonal tri-valent influenza vaccines that must be administered to provide protection. Two main types of influenza vaccine exist: inactivated, and live, cold-adapted vaccine for intranasal administration. Safety and efficacy of the intranasal, live vaccine has not been evaluated in HSCT recipients but is safe in HIV-infected adults and children. Because influenza infection occurring early after HSCT might result in severe disease, it would be logical to immunize candidates before HSCT. However, most studies show that adult patients with hematologic malignancies respond poorly to vaccination. In addition, the likelihood that whatever immunity that does exist will be lost is very high. The time after HSCT is important for vaccine responses. Engelhard et al. [22Engelhard D. Nagler A. Hardan I. et al.Antibody response to a two-dose regimen of influenza vaccine in allogeneic T cell-depleted and autologous BMT recipients.Bone Marrow Transplant. 1993; 11: 1-5PubMed Google Scholar] studied the antibody response to 2 doses of influenza virus vaccine given 2 to 82 months after HSCT to allogeneic BMT recipients (adults and children) who had received a T cell-depleted transplant, and showed a significant association between the serologic response and the interval between bone marrow transplant (BMT) and vaccination. The second vaccine dose had only a marginal effect. Pauksen et al. [23Pauksen K. Linde A. Hammarstrom V. et al.Granulocyte-macrophage colony-stimulating factor as immunomodulating factor together with influenza vaccination in stem cell transplant patients.Clin Infect Dis. 2000; 30: 342-348Crossref PubMed Scopus (83) Google Scholar] found response rates in allogeneic SCT patients vaccinated 4 to 12 months after HCT of 11/35 (31%) for H1N1, 3/35 (9%) for H3N2, and 7/35 (20%) for influenza B. However, despite suboptimal serologic responses, clinical effectiveness of vaccination could potentially exist. Machado et al. [24Machado C.M. Cardoso M.R. da Rocha I.F. Boas L.S. Dulley F.L. Pannuti C.S. The benefit of influenza vaccination after bone marrow transplantation.Bone Marrow Transplant. 2005; 36: 897-900Crossref PubMed Scopus (103) Google Scholar] found that influenza vaccination performed at least 6 months after SCT had an efficacy in preventing influenza of 80%. It is possible that protection is mediated also by T cells. Avetisyan et al. [25Avetisyan G. Aschan J. Hassan M. Ljungman P. Evaluation of immune responses to seasonal influenza vaccination in healthy volunteers and in patients after stem cell transplantation.Transplantation. 2008; 86: 257-263Crossref PubMed Scopus (78) Google Scholar] analyzed the T cell response in adult patients and found a significant increase in the number of IFN-γ producing T cells both in patients vaccinated between 3 and 6 months after HCT and in those vaccinated later, although the response in the late group was stronger. Furthermore, it has been shown in the elderly that the risk for influenza disease is comparable in individuals demonstrating a cell-mediated response alone, an antibody response alone, or both types of responses [26Murasko D.M. Bernstein E.D. Gardner E.M. et al.Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly.Exp Gerontol. 2002; 37: 427-439Crossref PubMed Scopus (212) Google Scholar]. The response to vaccination is suboptimal early after transplantation also in autologous HSCT recipients [22Engelhard D. Nagler A. Hardan I. et al.Antibody response to a two-dose regimen of influenza vaccine in allogeneic T cell-depleted and autologous BMT recipients.Bone Marrow Transplant. 1993; 11: 1-5PubMed Google Scholar, 23Pauksen K. Linde A. Hammarstrom V. et al.Granulocyte-macrophage colony-stimulating factor as immunomodulating factor together with influenza vaccination in stem cell transplant patients.Clin Infect Dis. 2000; 30: 342-348Crossref PubMed Scopus (83) Google Scholar]. No specific data exist regarding vaccine efficacy in patients receiving rituximab in close proximity to transplantation either during pretransplant chemotherapy, as part of the conditioning regimen, or after HSCT. However, in nontransplant patients the immune response within 6 months of receiving monoclonal antibodies is very poor [27Ljungman P. Nahi H. Linde A. Vaccination of patients with haematological malignancies with one or two doses of influenza vaccine: a randomised study.Br J Haematol. 2005; 130: 96-98Crossref PubMed Scopus (89) Google Scholar], and it is therefore likely that this will be the case also after autologous HSCT. When the new pandemic H1N1 strain spread rapidly around the world, new vaccines were rapidly developed. There were uncertainties regarding efficacy and of these especially those including new Preliminary data suggest that 2 doses of vaccine were safe and to immune responses. In addition, the of antiviral to neuraminidase inhibitors has been demonstrated in immunocompromised although no of virus was seasonal influenza vaccination with influenza vaccine is for all HSCT recipients P. C. H. et of hematopoietic cell transplant recipients.Bone Marrow Transplant. PubMed Scopus Google Scholar]. It is early vaccination after HCT is Because influenza vaccination is are to 4 months after HSCT P. C. H. et of hematopoietic cell transplant recipients.Bone Marrow Transplant. PubMed Scopus Google Scholar]. Influenza vaccination of and is during influenza to risks for influenza in HCT candidates or recipients. influenza vaccination is also for with HCT recipients. Although severe and fatal has been reported in HSCT recipients T. Y. K. et al.Clinical features of in immunocompromised PubMed Scopus Google Scholar, L. R. M. C. in immunocompromised 1992; PubMed Scopus Google Scholar], the risk for infection after allogeneic HSCT is likely to be However, with more patients undergoing transplantation after intensity conditioning the potential for patients is likely to increase and the risk of The vaccines are live, and are not for use in immunocompromised patients. can be in allogeneic HSCT patients disease or immunosuppression. indicates that vaccine can be given to such patients severe effects at 2 after SCT P. E. B. et and of vaccination of marrow transplant recipients with a live and Infect Dis. PubMed Scopus Google Scholar]. During an in patients were year after SCT C.M. Pannuti C.S. Dulley F.L. in bone marrow transplant recipients during an outbreak in 2002; PubMed Scopus (64) Google Scholar]. Although data are vaccine might be for HCT recipients who the for live virus vaccination for The vaccine not be Two new vaccines are under development. There are no data regarding vaccination of HSCT recipients with the licensed vaccines against human virus, and vaccination be A new vaccine is under with data promising infections in an immunocompromised have the to cause severe disease at higher rates in the healthy to viral and viral outbreaks in the diagnostic of symptomatic patients with the of new respiratory and the use of infection control methods that are in both the outpatient and inpatient are important in viral spread to these risk patients. The use of antiviral therapy to the of respiratory may also be of benefit in these patients. The efficacy of or monoclonal antibody to the spread of infection within patients is frequently but has not been proven in in this clinical studies of agents to both and these important viral infections are