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Community Respiratory Viruses: Organ Transplant Recipients
Community Respiratory Viruses: Organ Transplant Recipients Christine H. Wendt, MD, Minneapolis, Minnesota
Respiratory infections are common after solid organ transplantation, but the significance of community respiratory viral infections in this patient population has not been determined. Review of the literature indicates that infection of organ transplant recipients by community respiratory viruses can result in significant morbidity with some associated mortality. These viruses include respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus, and adenovirus. As in normal hosts, infection of organ transplant recipients by these viruses can result in limited upper respiratory tract symptoms, such as rhinorrhea, cough, and fever. Immunocompromised patients can also have lower respiratory tract infection, resulting in bronchiolitis, pneumonitis, respiratory failure, and death. The highest incidence of infection with these viruses is reported in lung transplant recipients, with an incidence up to 21%. In addition to the effects of the usual immunosuppressant regimen, lung transplant recipients have altered lung immunity due to impaired ciliary clearance, poor cough reflex, and abnormal lymphatic drainage, predisposing these patients to lower respiratory tract infections. Of additional importance to organ transplant recipients is the correlation of organ rejection to recent viral infections with these agents. Influenza A and B, PIV, and adenovirus have been reported to be associated with acute rejection in renal transplant recipients. Diagnosis of these infections is often made by positive respiratory cultures, often with a delay between symptom onset and diagnosis. Clinical trials of antiviral agents in this patient population have not been carried out, and treatment has often been limited to severe, life-threatening cases. Am J Med. 1997;102(3A):31–36. Q 1997 by Excerpta Medica, Inc.
From the Department of Medicine, Pulmonary and Critical Care Medicine, University of Minnesota, Minneapolis, Minnesota. Requests for reprints should be addressed to Christine H. Wendt, MD, Department of Medicine, Pulmonary and Critical Care Medicine, University of Minnesota, Box 276 UMHC, 420 Delaware Street SE, Minneapolis, Minnesota 55455.
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rgan transplantation is effective therapy for many end-stage organ disorders. However, infection, especially respiratory tract infection, is a significant cause of morbidity and mortality after transplantation, and there have been numerous reports emphasizing the significance of respiratory tract virus infection in organ transplant recipients. Bacterial pneumonias are the most common infections, although viral infections occur as well. Cytomegalovirus (CMV) is the most common viral infection reported. The respiratory tract viruses, including parainfluenza virus (PIV), respiratory syncytial virus (RSV), influenza, and adenovirus, are a major cause of respiratory tract infection in the general population. Infection in children with normal immune function ranges from mild upper respiratory tract infection to croup, bronchiolitis, and pneumonia. Immunity is transient, and infection in the adult with normal immune function usually causes a mild, self-limiting illness confined to the upper respiratory tract. In the immunocompromised organ transplant recipient, however, lower respiratory tract infection occurs in both the pediatric and the adult population. In addition, disease can be severe, causing significant morbidity and mortality.
PARAINFLUENZA AND RESPIRATORY SYNCYTIAL VIRUS Epidemiology and Characteristics PIV and RSV are common respiratory viruses that belong to the Paramyxoviridea family.1 PIV is characterized by nucleocapsids, which develop in the cytoplasm of infected cells, with hemagglutinin present in the virion envelope. PIV can be separated into four serotypes (type 1 to 4) based on complement fixation and hemagglutinating antigens. RSVs are mediumsized viruses with only one serotype. The viruses contain two surface proteins (F and G), which appear to be important factors in their infectivity and pathogenicity. The F protein can promote the spread of RSV by fusing infected cells to adjacent uninfected cells. This process results in the formation of protoplasmic masses called syncytia. PIV and RSV are common community respiratory viruses that infect most people during childhood.1 Serologic surveys reveal that by the age of 5, 90 – 100% of children have antibodies to RSV and PIV type 3. PIV infection occurs throughout the year,
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Figure 1. Timing of paramyxovirus infection. Shown is the month of the first positive culture for respiratory syncytial virus (RSV) or parainfluenza virus (PIV) for each patient. (Reprinted with permission from Wendt CH, Fox JMK, Hertz MI. Paramyxovirus in lung transplant recipients. J Heart Lung Transplant 1995;14:479–485.13)
whereas RSV infection occurs during epidemics in the winter and spring. RSV is highly contagious, and the nosocomial spread of RSV has been recognized. Immunity is transient for both viruses, with reinfection occurring in older children and adults, usually as mild upper respiratory tract infection. In 1987, Breinig et al2 reported a case of RSV and adenovirus infection in a liver transplant recipient. Since then, scattered case reports have appeared, suggesting that RSV may be an important pathogen in this patient population.3 – 11 The most comprehensive report of RSV infection in organ transplant recipients was published by Pohl et al,12 who reported 17 cases of RSV infection in pediatric liver transplant recipients between 1985 and 1991. This represented 3.4% of their transplant recipients. Similar to RSV infection in normal hosts, these infections occurred during the peak epidemic months, and 13 of the 17 cases were considered to be nosocomial. In 1995, Wendt et al13 reported 19 cases of paramyxovirus infection in lung transplant recipients (10 PIV and 9 RSV infections). These 19 cases of paramyxovirus infection represented 21% of all lung transplant recipients at the University of Minnesota between 1986 and 1993. Similar to Pohl’s report, RSV in this lung transplant population occurred during the peak epidemics in winter and spring. PIV was primarily by serotype 3 (eight cases), with two cases 32
of serotype 1, and occurred throughout the year (Figure 1). Unlike in Pohl’s study, however, infection occurred in both adults and children, although age õ18 years was the strongest predictor of infection. There may be several reasons for the high incidence of infection in lung transplant recipients. First, lung transplant recipients may have an increased risk of respiratory infection because of (1) suppressed cough due to denervation of the transplanted lung; (2) abnormal lymphatic drainage due to severing of lymphatics at the time of transplantation; and (3) impaired mucociliary clearance in the transplanted lung. Second, rejection in the lung transplant recipient manifests as bronchiolitis obliterans, which is an inflammatory lesion in the respiratory bronchioles that leads to fibrosis and obliteration of these airways. These respiratory bronchioles are also the site of lower respiratory tract infection by the paramyxoviruses. The combination of immunosuppression with abnormal pulmonary host defenses and the potential injury of the airways by rejection may predispose the lung transplant recipient to infection with the paramyxoviruses. In Pohl’s study12 of pediatric liver transplant recipients the median time of diagnosis was 24 days, compared with 260 days in the lung transplant group reported by Wendt et al.13 Although organ
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transplant recipients are believed to be more susceptible to viral infections in the first few months after transplantation, lung transplant recipients may have increased susceptibility late in the posttransplantation period, owing to persistent abnormal lung defenses. With any decline in pulmonary function, lung transplant recipients often undergo bronchoscopy to screen for rejection or infection. Therefore, more lung transplant recipients may be screened for respiratory viral infections compared with other organ transplant recipients. Consequently, the infection rate in other organ transplant recipients is likely to be underestimated, owing to low surveillance for these viruses.
TABLE I Signs and Symptoms Present at the Time of Paramyxovirus Isolation (n Å 19) Clinical Findings Cough Shortness of breath Fever Coryza Wheezing Radiographic Findings Pulmonary infiltrate Sinus opacification
16 10 9 9 7 10/18 chest radiographs obtained 1/2 sinus films obtained
Reprinted with permission from Wendt CH, Fox JMK, Hertz MI. Paramyxovirus in lung transplant recipients. J Heart Lung Transplant 1995;14:479– 485.13
tively); in one case, the viral culture became positive only after the patient had died. Concurrent pulmonary infections, which were present in a significant percentage (59%) of the liver transplant group and in 21% of the lung transplant group, can lead to the lack of recognition of the significance of infections with community respiratory viruses.
Clinical Manifestations Infection with paramyxoviruses in organ transplant recipients can be severe. In Pohl’s report of RSV infection in pediatric liver transplant recipients, the majority of patients (71%) had lower respiratory tract involvement.12 Similarly, in Wendt’s report of lung transplant recipients, all patients had evidence of lower respiratory tract involvement, defined as dyspnea, wheezing, new hypoxemia, and/or abnormalities on the chest radiograph (Table I).13 Not all patients with significant lower respiratory tract involvement had abnormalities on their chest radiographs, however. Paramyxovirus infection may cause only subtle interstitial changes that can be difficult to detect on chest radiographs, particularly in lung transplant patients whose baseline chest radiographs often showed abnormalities. In addition, bronchiolitis, a common condition caused by these viruses, can result in obstruction with hyperinflation, and increased lung volumes can obscure subtle infiltrates. Therefore, severe infection can occur in the absence of significant infiltrates.
Treatment and Outcome In the normal immune host, most cases of RSV and PIV resolve fully; however, the immunocompromised organ transplant recipient is at risk for both increased morbidity and mortality. A significant percentage of organ transplant recipients infected with RSV and PIV have lower respiratory tract involvement. In Pohl’s study, lower respiratory tract involvement was associated with respiratory failure in 12% of the liver transplant group, with a mortality rate of 12%.12 Although the mortality rate in the lung transplant group in Wendt’s study was lower (5%), there was significant morbidity.13 In addition to symptoms of infection, spirometry readings declined significantly in six lung transplant patients. In four patients, spirometric values returned to normal (range Å 14–177 days, median Å 23 days), but in two patients they never returned to baseline. These two patients had a persistent reduction in their forced expiratory volume in 1 second of 28% and 58%, respectively. Ribavirin (1-b-D-ribofuranosyl-1H-1,2,4-triazole3-carboxamide) is an antiviral agent that is active against several viruses, including RSV and PIV. Numerous trials have shown ribavirin to be effective in the treatment of RSV, and ribavirin has antiviral effects against PIV in vitro. Aerosolized ribavirin was administered to 14 of the lung transplant recipients (74%) in Wendt’s study,13 whereas none of the liver transplant patients in Pohl’s study received ribavirin, which may explain the higher mortality in the latter group.12 The only patient in the lung transplant group who died had not re-
Diagnosis In all cases in Pohl’s and Wendt’s studies, RSV and PIV infections were diagnosed by sampling respiratory tract secretions.12,13 In Pohl’s study, culture specimens that tested positive were obtained from the nasopharynx, whereas in the lung transplant study, the majority (79%) of culture specimens that tested positive were obtained from bronchoalveolar lavage. Antigen detection with the RSV enzymelinked immunosorbent assay (ELISA) is a quick and powerful tool for the diagnosis of RSV. Results of the RSV ELISA are available within 24 hours after the specimen is acquired, whereas viral cultures require several days to become positive. In Wendt’s study, results of the RSV ELISA were positive within 24 hours in 75% of the cases, whereas RSV cultures took 3 – 14 days and PIV cultures took 3–15 days to become positive (median of 6 and 5 days, respec-
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ceived ribavirin. In the lung transplant group, no side effects of ribavirin therapy were reported, and most patients reported improvements in symptoms during therapy.
TABLE II Signs and Symptoms Present at the Time of Influenza Isolation (n Å 12) Fever Respiratory URI LRI Gastrointestinal Neurologic
INFLUENZA Epidemiology and Characteristics Influenza viruses are common respiratory viruses belonging to the Orthomyxoviridae family, all of which are medium-sized RNA viruses. Influenza viruses are unique among the respiratory viruses in that they have continuing antigenic variation. The appearance of new strains, for which most of the world population lacks immunity, can cause worldwide outbreaks or pandemics. These pandemic strains are associated with worldwide spread over a 6 – 9-month period, with high attack rates. Influenza is grouped into subtypes A, B, and C, and antigenic variation occurs in each subtype. Infectivity rates of influenza in the general population are high, and mortality is highest in infants, the elderly, and patients with underlying cardiopulmonary disease. Although effective vaccination and prophylactic antiviral agents exist, they are generally underutilized. Organ transplant recipients may be at high risk for infection and significant morbidity from influenza, owing to their immunosuppression. In addition, single-lung transplant recipients and lung transplant recipients with rejection have coexisting pathology in either their native lung or their transplanted lung with rejection that can predispose them to infection. There have been many reports of influenza infection in organ transplant recipients.14 – 16 Mauch et al17 reported 12 cases of infection with influenza B in pediatric organ transplant recipients between 1989 and 1992. None of these patients had been vaccinated against influenza. The interval between transplantation ranged from 6 weeks to 4 years (average, 26.7 months), and 5 of these 12 infections were nosocomial. Ljungman et al18 and Aschan et al14 also reported infection with both influenza A and B in renal allograft recipients.1 Clinical Manifestations Infection with influenza virus in organ transplant recipients can be a self-limiting mild illness or associated with significant morbidity and mortality. Ljungman et al18 and Aschan et al14 reported 12 cases of influenza A and 5 cases of influenza B in renal transplant recipients.1 However, in Mauch’s report of 12 pediatric organ transplant recipients, symptoms were more severe and consisted of fever (12 patients), respiratory complaints (11 patients), and gastrointestinal complaints (8 patients).17 All 11 patients with respiratory tract symptoms had upper respira34
LRI Å lower respiratory tract involvement; URI Å upper respiratory tract involvement. Adapted with permission from Pediatrics Vol. 94, pp. 225–229, copyright 1994.17
tory tract involvement, with lower respiratory tract involvement occurring in 5 of the 12 patients (Table II). Surprisingly, 5 of the 12 patients had neurologic involvement, and one patient died of cerebral herniation. In addition to symptoms of infection, leukopenia developed in five patients, requiring discontinuation of their immunosuppressant, azathioprine. Both the discontinuation of azathioprine and the viral syndrome can predispose transplant patients to rejection.
Diagnosis Influenza infection was diagnosed by positive cultures of specimens obtained from the respiratory tract of all patients in Mauch’s study. Many previous studies relied on more insensitive measures, such as complement fixation, as a means of diagnosis.17 In Mauch’s study, most patients had virus isolated from the upper respiratory tract, with the virus isolated from the trachea of one patient and from bronchoalveolar lavage fluid of two patients. In one case, viral shedding persisted for 24 days. Treatment and Outcome Management of influenza is geared mainly toward prevention, with yearly vaccination and prophylactic antiviral therapy with amantadine or rimantadine in patients with known exposure to influenza. In Mauch’s group of pediatric transplant recipients, none of the patients had been vaccinated against influenza.17 Mauch’s cases consisted of influenza B, and one patient with respiratory failure was empirically treated with ribavirin. Subsequent studies by Mauch showed that vaccination of this population resulted in an antibody response similar to that in normal immune populations.19 Although most cases of influenza in the normal immune host are self limiting, significant mortality can occur in certain at-risk populations. Most of Mauch’s pediatric patients (10/12) required hospitalization. Two patients with acute lung injury required mechanical ventilation, and three children experi-
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enced allograft rejection. There was a high incidence of neurologic involvement, and one patient died of cerebral herniation.
vates the airway damage in rat lung allografts with chronic rejection. In Wendt’s study, there was no association between the existence of chronic rejection and PIV or RSV infection; however, the reverse, that is, PIV or RSV causing or exacerbating rejection, has not been determined in this population.13
ADENOVIRUS Adenovirus is a medium-sized DNA virus consisting of multiple serotypes. Adenovirus infection of the general population occurs mainly during the summer months, in association with outbreaks of febrile pharyngitis or bronchitis, and accounts for no more than 5% of the total acute respiratory infections. This is not true for military recruits, however, among whom outbreaks of acute respiratory disease have been observed to occur throughout the year. There are very few reports of adenoviral respiratory infection in organ transplant recipients. Although Breinig et al2 reported four cases of adenoviral infection in liver transplant recipients, concurrent viral and bacterial infections in all these patients made positive cultures difficult to interpret. Two specific populations are at risk for nonrespiratory tract adenoviral infections. In the early 1980s, several cases of hemorrhagic cystitis due to adenoviral infection with serotype 11 were reported.20 – 23 This condition is often associated with acute graft rejection. Successful therapy has ranged from treatment for rejection with increased steroids and antilymphocyte preparations to antiviral therapy with ganciclovir. Adenovirus-induced hepatitis in liver transplant recipients is a more malignant infection that is associated with significant mortality.24,25 This infection, which can strike up to 2% of liver transplant recipients, leads to massive hepatic necrosis, with a reported mortality of 40–50%. Treatment is geared toward minimizing immunosuppression; no effective antiviral therapy has been developed to date.
SUMMARY The respiratory tract viruses are a common cause of respiratory tract infection in the general population and a cause of serious infection in both adult and pediatric organ transplant recipients. Seasonal variations in infection of immunocompromised organ transplant recipients are similar to those in the general population. Lung transplant recipients may be at a higher risk of respiratory infection, owing to abnormal lung defenses after transplantation. In addition, studies suggest that rejection may be associated with infection with respiratory viruses. Because these infections are associated with rejection, significant morbidity, and mortality, and are potentially treatable, they should be actively sought and accurately diagnosed in transplant recipients.
REFERENCES 1. Wendt CH, Hertz MI. Respiratory syncytial virus and parainfluenza virus infections in the immunocompromised host. Sem Resp Infect. 1995;10:224– 231. 2. Breinig MK, Zitelli B, Starzl TE, Ho M. Epstein-Barr virus, cytomegalovirus, and other infections in children after liver transplantation. J Infect Dis. 1987;156:273–279. 3. Berbari N, Johnson DH, Cunha BA. Respiratory syncytial virus pneumonia in a heart transplant recipient presenting as fever of unknown origin diagnosed by gallium scan. Heart Lung. 1995;24:257–259. 4. Doud JR, Hinkamp T, Garrity ER Jr. Respiratory syncytial virus pneumonia in a lung transplant recipient: case report. J Heart Lung Transplant. 1995;11:479–485. 5. Englund JA, Anderson LJ, Rhame FS. Nosocomial transmission of respiratory syncytial virus in immunocompromised adults. J Clin Microbiology. 1991;29:115–119. 6. Englund JA, Sullivan CJ, Jordan MC, et al. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med. 1988;109:203– 208. 7. Murrin-Espin M, Didier A, Carre P, et al. Continuous aerosolized ribavirin for respiratory syncytial virus infection in lung transplant recipients. Lancet. 1993;341:897. 8. Panuska JR, Hertz MI, Taraf H, et al. Respiratory syncytial virus infection of alveolar macrophages in adult transplant patients. Am Rev Respir Dis. 1992;145:934–939. 9. Peigue-Lafeuille H, Gazuy N, Mignot P, et al. Severe respiratory syncytial virus pneumonia in an adult renal transplant recipient: successful treatment with ribavirin. Scand J Infect Dis. 1990;22:87–89. 10. Salt A, Sutehall G, Sargaison M, et al. Viral and toxoplasma gondii infections in children after liver transplantation. J Clin Pathol. 1990;43:63–67. 11. Sinnott JT, Cullison JP, Sweeney MS, et al. Respiratory syncytial virus pneumonia in a cardiac transplant recipient. J Infect Dis. 1988;158:650– 651. 12. Pohl C, Green M, Wald ER, Ledesma-Medina J. Respiratory syncytial virus infections in pediatric liver transplant recipients. J Infect Dis. 1992;165:166– 169.
INFECTION AND REJECTION Viral infections, especially with the herpesviruses, have been associated with increased allograft rejection. Early reports of patients exposed to PIV, as determined by increases in complement fixation antibody titers, suggest that respiratory viruses may also predispose patients to rejection.26 In addition, influenza A and B and adenovirus have been reported to be associated with acute rejection in renal transplant recipients.27 Viral infections may alter host immunity or cause allograft dysfunction, resulting in an increased risk of rejection. Infection of an allograft may lead to organ damage with an increase in antigen presentation, which can result in an increase in acute or chronic rejection. This may be particularly true in lung transplants, in which infection with respiratory viruses and chronic rejection are common. Winter et al28 demonstrated that PIV infection aggra-
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SYMPOSIUM ON RESPIRATORY VIRAL INFECTIONS/WENDT 13. Wendt CH, Fox JMK, Hertz MI. Paramyxovirus infection in lung transplant recipients. J Heart Lung Transplant. 1995;14:479–485. 14. Aschan J, Ringden O, Ljungman P, et al. Influenza B in transplant patients. Scand J Infect Dis. 1989;21:349–350. 15. Beyer WEP, Diepersloot RJA, Masurel N, et al. Double failure on influenza vaccination in a heart transplant patient. Transplantation. 1987;43: 319. 16. Briggs KD, Timbury MC, Paton AM, Bell PRF. Viral infection and renal transplant rejection. Br Med J. 1972;4:520–522. 17. Mauch TJ, Bratton S, Myers T, et al. Influenza B virus infection in pediatric solid organ transplant recipients. Pediatrics. 1994;994:225–229. 18. Ljungman P, Andersson J, Aschan J, et al. Influenza A in immunocompromised patients. Clin Infect Dis. 1993;17:244–247. 19. Mauch TJ, Crouch NA, Freese DK, et al. Antibody response of pediatric solid organ transplant recipients to immunization against influenza virus. J Pediatr. 1995;127:957–960. 20. Blohme I, Nyberg G, Jeansson S, Svalander C. Adenovirus infection in a renal transplant patient. Transplantation Proceedings . 1992;24: 295.
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21. Harnett GB, Bucens MR, Clay SJ, Saker BM. Acute haemorrhagic cystitis caused by adenovirus type 11 in a recipient of a transplanted kidney. Med J Australia. 1982;1:565–567. 22. Shindo K, Kitayama T, Ura T, et al. Acute hemorrhagic cystitis caused by adenovirus type 11 after renal transplantation. Urol Int. 1986;41:152–155. 23. Yagisawa T, Takahashi K, Yamaguchi Y, et al. Adenovirus induced nephropathy in kidney transplant recipients. Transplantation Proceedings. 1989;21:2097–2099. 24. Carnes B, Rahier J, Burtomboy G, et al. Acute adenovirus hepatitis in liver transplant recipients. J Pediatr. 1992;120:33–37. 25. Koneru B, Atchison R, Jaffe R, et al. Serological studies of adenoviral hepatitis following pediatric liver transplantation. Transplantation Proceedings. 1990;22:1547–1548. 26. DeFabritus AM, Riggio RR, David DS, et al. Parainfluenza type 3 in a transplant unit. JAMA. 1979;241:384–386. 27. Gabriel R, Selwyn S, Brown D, et al. Virus infections and acute renal transplant rejection. Nephron. 1976;16:282–286. 28. Winter JB, Gouw ASH, Groen M, et al. Respiratory viral infections aggravate airway damage caused by chronic rejection in rat lung allografts. Transplantation. 1994;57:418–422.
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Respiratory infections are common after solid organ transplantation, but the significance of community respiratory viral infections in this patient population has not been determined. Review of the literature indicates that infection of organ transplant recipients by community respiratory viruses can result in significant morbidity with some associated mortality. These viruses include respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus, and adenovirus. As in normal hosts, infection of organ transplant recipients by these viruses can result in limited upper respiratory tract symptoms, such as rhinorrhea, cough, and fever. Immunocompromised patients can also have lower respiratory tract infection, resulting in bronchiolitis, pneumonitis, respiratory failure, and death. The highest incidence of infection with these viruses is reported in lung transplant recipients, with an incidence up to 21%. In addition to the effects of the usual immunosuppressant regimen, lung transplant recipients have altered lung immunity due to impaired ciliary clearance, poor cough reflex, and abnormal lymphatic drainage, predisposing these patients to lower respiratory tract infections. Of additional importance to organ transplant recipients is the correlation of organ rejection to recent viral infections with these agents. Influenza A and B, PIV, and adenovirus have been reported to be associated with acute rejection in renal transplant recipients. Diagnosis of these infections is often made by positive respiratory cultures, often with a delay between symptom onset and diagnosis. Clinical trials of antiviral agents in this patient population have not been carried out, and treatment has often been limited to severe, life-threatening cases. Am J Med. 1997;102(3A):31–36. Q 1997 by Excerpta Medica, Inc.
From the Department of Medicine, Pulmonary and Critical Care Medicine, University of Minnesota, Minneapolis, Minnesota. Requests for reprints should be addressed to Christine H. Wendt, MD, Department of Medicine, Pulmonary and Critical Care Medicine, University of Minnesota, Box 276 UMHC, 420 Delaware Street SE, Minneapolis, Minnesota 55455.
O
rgan transplantation is effective therapy for many end-stage organ disorders. However, infection, especially respiratory tract infection, is a significant cause of morbidity and mortality after transplantation, and there have been numerous reports emphasizing the significance of respiratory tract virus infection in organ transplant recipients. Bacterial pneumonias are the most common infections, although viral infections occur as well. Cytomegalovirus (CMV) is the most common viral infection reported. The respiratory tract viruses, including parainfluenza virus (PIV), respiratory syncytial virus (RSV), influenza, and adenovirus, are a major cause of respiratory tract infection in the general population. Infection in children with normal immune function ranges from mild upper respiratory tract infection to croup, bronchiolitis, and pneumonia. Immunity is transient, and infection in the adult with normal immune function usually causes a mild, self-limiting illness confined to the upper respiratory tract. In the immunocompromised organ transplant recipient, however, lower respiratory tract infection occurs in both the pediatric and the adult population. In addition, disease can be severe, causing significant morbidity and mortality.
PARAINFLUENZA AND RESPIRATORY SYNCYTIAL VIRUS Epidemiology and Characteristics PIV and RSV are common respiratory viruses that belong to the Paramyxoviridea family.1 PIV is characterized by nucleocapsids, which develop in the cytoplasm of infected cells, with hemagglutinin present in the virion envelope. PIV can be separated into four serotypes (type 1 to 4) based on complement fixation and hemagglutinating antigens. RSVs are mediumsized viruses with only one serotype. The viruses contain two surface proteins (F and G), which appear to be important factors in their infectivity and pathogenicity. The F protein can promote the spread of RSV by fusing infected cells to adjacent uninfected cells. This process results in the formation of protoplasmic masses called syncytia. PIV and RSV are common community respiratory viruses that infect most people during childhood.1 Serologic surveys reveal that by the age of 5, 90 – 100% of children have antibodies to RSV and PIV type 3. PIV infection occurs throughout the year,
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Figure 1. Timing of paramyxovirus infection. Shown is the month of the first positive culture for respiratory syncytial virus (RSV) or parainfluenza virus (PIV) for each patient. (Reprinted with permission from Wendt CH, Fox JMK, Hertz MI. Paramyxovirus in lung transplant recipients. J Heart Lung Transplant 1995;14:479–485.13)
whereas RSV infection occurs during epidemics in the winter and spring. RSV is highly contagious, and the nosocomial spread of RSV has been recognized. Immunity is transient for both viruses, with reinfection occurring in older children and adults, usually as mild upper respiratory tract infection. In 1987, Breinig et al2 reported a case of RSV and adenovirus infection in a liver transplant recipient. Since then, scattered case reports have appeared, suggesting that RSV may be an important pathogen in this patient population.3 – 11 The most comprehensive report of RSV infection in organ transplant recipients was published by Pohl et al,12 who reported 17 cases of RSV infection in pediatric liver transplant recipients between 1985 and 1991. This represented 3.4% of their transplant recipients. Similar to RSV infection in normal hosts, these infections occurred during the peak epidemic months, and 13 of the 17 cases were considered to be nosocomial. In 1995, Wendt et al13 reported 19 cases of paramyxovirus infection in lung transplant recipients (10 PIV and 9 RSV infections). These 19 cases of paramyxovirus infection represented 21% of all lung transplant recipients at the University of Minnesota between 1986 and 1993. Similar to Pohl’s report, RSV in this lung transplant population occurred during the peak epidemics in winter and spring. PIV was primarily by serotype 3 (eight cases), with two cases 32
of serotype 1, and occurred throughout the year (Figure 1). Unlike in Pohl’s study, however, infection occurred in both adults and children, although age õ18 years was the strongest predictor of infection. There may be several reasons for the high incidence of infection in lung transplant recipients. First, lung transplant recipients may have an increased risk of respiratory infection because of (1) suppressed cough due to denervation of the transplanted lung; (2) abnormal lymphatic drainage due to severing of lymphatics at the time of transplantation; and (3) impaired mucociliary clearance in the transplanted lung. Second, rejection in the lung transplant recipient manifests as bronchiolitis obliterans, which is an inflammatory lesion in the respiratory bronchioles that leads to fibrosis and obliteration of these airways. These respiratory bronchioles are also the site of lower respiratory tract infection by the paramyxoviruses. The combination of immunosuppression with abnormal pulmonary host defenses and the potential injury of the airways by rejection may predispose the lung transplant recipient to infection with the paramyxoviruses. In Pohl’s study12 of pediatric liver transplant recipients the median time of diagnosis was 24 days, compared with 260 days in the lung transplant group reported by Wendt et al.13 Although organ
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transplant recipients are believed to be more susceptible to viral infections in the first few months after transplantation, lung transplant recipients may have increased susceptibility late in the posttransplantation period, owing to persistent abnormal lung defenses. With any decline in pulmonary function, lung transplant recipients often undergo bronchoscopy to screen for rejection or infection. Therefore, more lung transplant recipients may be screened for respiratory viral infections compared with other organ transplant recipients. Consequently, the infection rate in other organ transplant recipients is likely to be underestimated, owing to low surveillance for these viruses.
TABLE I Signs and Symptoms Present at the Time of Paramyxovirus Isolation (n Å 19) Clinical Findings Cough Shortness of breath Fever Coryza Wheezing Radiographic Findings Pulmonary infiltrate Sinus opacification
16 10 9 9 7 10/18 chest radiographs obtained 1/2 sinus films obtained
Reprinted with permission from Wendt CH, Fox JMK, Hertz MI. Paramyxovirus in lung transplant recipients. J Heart Lung Transplant 1995;14:479– 485.13
tively); in one case, the viral culture became positive only after the patient had died. Concurrent pulmonary infections, which were present in a significant percentage (59%) of the liver transplant group and in 21% of the lung transplant group, can lead to the lack of recognition of the significance of infections with community respiratory viruses.
Clinical Manifestations Infection with paramyxoviruses in organ transplant recipients can be severe. In Pohl’s report of RSV infection in pediatric liver transplant recipients, the majority of patients (71%) had lower respiratory tract involvement.12 Similarly, in Wendt’s report of lung transplant recipients, all patients had evidence of lower respiratory tract involvement, defined as dyspnea, wheezing, new hypoxemia, and/or abnormalities on the chest radiograph (Table I).13 Not all patients with significant lower respiratory tract involvement had abnormalities on their chest radiographs, however. Paramyxovirus infection may cause only subtle interstitial changes that can be difficult to detect on chest radiographs, particularly in lung transplant patients whose baseline chest radiographs often showed abnormalities. In addition, bronchiolitis, a common condition caused by these viruses, can result in obstruction with hyperinflation, and increased lung volumes can obscure subtle infiltrates. Therefore, severe infection can occur in the absence of significant infiltrates.
Treatment and Outcome In the normal immune host, most cases of RSV and PIV resolve fully; however, the immunocompromised organ transplant recipient is at risk for both increased morbidity and mortality. A significant percentage of organ transplant recipients infected with RSV and PIV have lower respiratory tract involvement. In Pohl’s study, lower respiratory tract involvement was associated with respiratory failure in 12% of the liver transplant group, with a mortality rate of 12%.12 Although the mortality rate in the lung transplant group in Wendt’s study was lower (5%), there was significant morbidity.13 In addition to symptoms of infection, spirometry readings declined significantly in six lung transplant patients. In four patients, spirometric values returned to normal (range Å 14–177 days, median Å 23 days), but in two patients they never returned to baseline. These two patients had a persistent reduction in their forced expiratory volume in 1 second of 28% and 58%, respectively. Ribavirin (1-b-D-ribofuranosyl-1H-1,2,4-triazole3-carboxamide) is an antiviral agent that is active against several viruses, including RSV and PIV. Numerous trials have shown ribavirin to be effective in the treatment of RSV, and ribavirin has antiviral effects against PIV in vitro. Aerosolized ribavirin was administered to 14 of the lung transplant recipients (74%) in Wendt’s study,13 whereas none of the liver transplant patients in Pohl’s study received ribavirin, which may explain the higher mortality in the latter group.12 The only patient in the lung transplant group who died had not re-
Diagnosis In all cases in Pohl’s and Wendt’s studies, RSV and PIV infections were diagnosed by sampling respiratory tract secretions.12,13 In Pohl’s study, culture specimens that tested positive were obtained from the nasopharynx, whereas in the lung transplant study, the majority (79%) of culture specimens that tested positive were obtained from bronchoalveolar lavage. Antigen detection with the RSV enzymelinked immunosorbent assay (ELISA) is a quick and powerful tool for the diagnosis of RSV. Results of the RSV ELISA are available within 24 hours after the specimen is acquired, whereas viral cultures require several days to become positive. In Wendt’s study, results of the RSV ELISA were positive within 24 hours in 75% of the cases, whereas RSV cultures took 3 – 14 days and PIV cultures took 3–15 days to become positive (median of 6 and 5 days, respec-
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ceived ribavirin. In the lung transplant group, no side effects of ribavirin therapy were reported, and most patients reported improvements in symptoms during therapy.
TABLE II Signs and Symptoms Present at the Time of Influenza Isolation (n Å 12) Fever Respiratory URI LRI Gastrointestinal Neurologic
INFLUENZA Epidemiology and Characteristics Influenza viruses are common respiratory viruses belonging to the Orthomyxoviridae family, all of which are medium-sized RNA viruses. Influenza viruses are unique among the respiratory viruses in that they have continuing antigenic variation. The appearance of new strains, for which most of the world population lacks immunity, can cause worldwide outbreaks or pandemics. These pandemic strains are associated with worldwide spread over a 6 – 9-month period, with high attack rates. Influenza is grouped into subtypes A, B, and C, and antigenic variation occurs in each subtype. Infectivity rates of influenza in the general population are high, and mortality is highest in infants, the elderly, and patients with underlying cardiopulmonary disease. Although effective vaccination and prophylactic antiviral agents exist, they are generally underutilized. Organ transplant recipients may be at high risk for infection and significant morbidity from influenza, owing to their immunosuppression. In addition, single-lung transplant recipients and lung transplant recipients with rejection have coexisting pathology in either their native lung or their transplanted lung with rejection that can predispose them to infection. There have been many reports of influenza infection in organ transplant recipients.14 – 16 Mauch et al17 reported 12 cases of infection with influenza B in pediatric organ transplant recipients between 1989 and 1992. None of these patients had been vaccinated against influenza. The interval between transplantation ranged from 6 weeks to 4 years (average, 26.7 months), and 5 of these 12 infections were nosocomial. Ljungman et al18 and Aschan et al14 also reported infection with both influenza A and B in renal allograft recipients.1 Clinical Manifestations Infection with influenza virus in organ transplant recipients can be a self-limiting mild illness or associated with significant morbidity and mortality. Ljungman et al18 and Aschan et al14 reported 12 cases of influenza A and 5 cases of influenza B in renal transplant recipients.1 However, in Mauch’s report of 12 pediatric organ transplant recipients, symptoms were more severe and consisted of fever (12 patients), respiratory complaints (11 patients), and gastrointestinal complaints (8 patients).17 All 11 patients with respiratory tract symptoms had upper respira34
LRI Å lower respiratory tract involvement; URI Å upper respiratory tract involvement. Adapted with permission from Pediatrics Vol. 94, pp. 225–229, copyright 1994.17
tory tract involvement, with lower respiratory tract involvement occurring in 5 of the 12 patients (Table II). Surprisingly, 5 of the 12 patients had neurologic involvement, and one patient died of cerebral herniation. In addition to symptoms of infection, leukopenia developed in five patients, requiring discontinuation of their immunosuppressant, azathioprine. Both the discontinuation of azathioprine and the viral syndrome can predispose transplant patients to rejection.
Diagnosis Influenza infection was diagnosed by positive cultures of specimens obtained from the respiratory tract of all patients in Mauch’s study. Many previous studies relied on more insensitive measures, such as complement fixation, as a means of diagnosis.17 In Mauch’s study, most patients had virus isolated from the upper respiratory tract, with the virus isolated from the trachea of one patient and from bronchoalveolar lavage fluid of two patients. In one case, viral shedding persisted for 24 days. Treatment and Outcome Management of influenza is geared mainly toward prevention, with yearly vaccination and prophylactic antiviral therapy with amantadine or rimantadine in patients with known exposure to influenza. In Mauch’s group of pediatric transplant recipients, none of the patients had been vaccinated against influenza.17 Mauch’s cases consisted of influenza B, and one patient with respiratory failure was empirically treated with ribavirin. Subsequent studies by Mauch showed that vaccination of this population resulted in an antibody response similar to that in normal immune populations.19 Although most cases of influenza in the normal immune host are self limiting, significant mortality can occur in certain at-risk populations. Most of Mauch’s pediatric patients (10/12) required hospitalization. Two patients with acute lung injury required mechanical ventilation, and three children experi-
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enced allograft rejection. There was a high incidence of neurologic involvement, and one patient died of cerebral herniation.
vates the airway damage in rat lung allografts with chronic rejection. In Wendt’s study, there was no association between the existence of chronic rejection and PIV or RSV infection; however, the reverse, that is, PIV or RSV causing or exacerbating rejection, has not been determined in this population.13
ADENOVIRUS Adenovirus is a medium-sized DNA virus consisting of multiple serotypes. Adenovirus infection of the general population occurs mainly during the summer months, in association with outbreaks of febrile pharyngitis or bronchitis, and accounts for no more than 5% of the total acute respiratory infections. This is not true for military recruits, however, among whom outbreaks of acute respiratory disease have been observed to occur throughout the year. There are very few reports of adenoviral respiratory infection in organ transplant recipients. Although Breinig et al2 reported four cases of adenoviral infection in liver transplant recipients, concurrent viral and bacterial infections in all these patients made positive cultures difficult to interpret. Two specific populations are at risk for nonrespiratory tract adenoviral infections. In the early 1980s, several cases of hemorrhagic cystitis due to adenoviral infection with serotype 11 were reported.20 – 23 This condition is often associated with acute graft rejection. Successful therapy has ranged from treatment for rejection with increased steroids and antilymphocyte preparations to antiviral therapy with ganciclovir. Adenovirus-induced hepatitis in liver transplant recipients is a more malignant infection that is associated with significant mortality.24,25 This infection, which can strike up to 2% of liver transplant recipients, leads to massive hepatic necrosis, with a reported mortality of 40–50%. Treatment is geared toward minimizing immunosuppression; no effective antiviral therapy has been developed to date.
SUMMARY The respiratory tract viruses are a common cause of respiratory tract infection in the general population and a cause of serious infection in both adult and pediatric organ transplant recipients. Seasonal variations in infection of immunocompromised organ transplant recipients are similar to those in the general population. Lung transplant recipients may be at a higher risk of respiratory infection, owing to abnormal lung defenses after transplantation. In addition, studies suggest that rejection may be associated with infection with respiratory viruses. Because these infections are associated with rejection, significant morbidity, and mortality, and are potentially treatable, they should be actively sought and accurately diagnosed in transplant recipients.
REFERENCES 1. Wendt CH, Hertz MI. Respiratory syncytial virus and parainfluenza virus infections in the immunocompromised host. Sem Resp Infect. 1995;10:224– 231. 2. Breinig MK, Zitelli B, Starzl TE, Ho M. Epstein-Barr virus, cytomegalovirus, and other infections in children after liver transplantation. J Infect Dis. 1987;156:273–279. 3. Berbari N, Johnson DH, Cunha BA. Respiratory syncytial virus pneumonia in a heart transplant recipient presenting as fever of unknown origin diagnosed by gallium scan. Heart Lung. 1995;24:257–259. 4. Doud JR, Hinkamp T, Garrity ER Jr. Respiratory syncytial virus pneumonia in a lung transplant recipient: case report. J Heart Lung Transplant. 1995;11:479–485. 5. Englund JA, Anderson LJ, Rhame FS. Nosocomial transmission of respiratory syncytial virus in immunocompromised adults. J Clin Microbiology. 1991;29:115–119. 6. Englund JA, Sullivan CJ, Jordan MC, et al. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med. 1988;109:203– 208. 7. Murrin-Espin M, Didier A, Carre P, et al. Continuous aerosolized ribavirin for respiratory syncytial virus infection in lung transplant recipients. Lancet. 1993;341:897. 8. Panuska JR, Hertz MI, Taraf H, et al. Respiratory syncytial virus infection of alveolar macrophages in adult transplant patients. Am Rev Respir Dis. 1992;145:934–939. 9. Peigue-Lafeuille H, Gazuy N, Mignot P, et al. Severe respiratory syncytial virus pneumonia in an adult renal transplant recipient: successful treatment with ribavirin. Scand J Infect Dis. 1990;22:87–89. 10. Salt A, Sutehall G, Sargaison M, et al. Viral and toxoplasma gondii infections in children after liver transplantation. J Clin Pathol. 1990;43:63–67. 11. Sinnott JT, Cullison JP, Sweeney MS, et al. Respiratory syncytial virus pneumonia in a cardiac transplant recipient. J Infect Dis. 1988;158:650– 651. 12. Pohl C, Green M, Wald ER, Ledesma-Medina J. Respiratory syncytial virus infections in pediatric liver transplant recipients. J Infect Dis. 1992;165:166– 169.
INFECTION AND REJECTION Viral infections, especially with the herpesviruses, have been associated with increased allograft rejection. Early reports of patients exposed to PIV, as determined by increases in complement fixation antibody titers, suggest that respiratory viruses may also predispose patients to rejection.26 In addition, influenza A and B and adenovirus have been reported to be associated with acute rejection in renal transplant recipients.27 Viral infections may alter host immunity or cause allograft dysfunction, resulting in an increased risk of rejection. Infection of an allograft may lead to organ damage with an increase in antigen presentation, which can result in an increase in acute or chronic rejection. This may be particularly true in lung transplants, in which infection with respiratory viruses and chronic rejection are common. Winter et al28 demonstrated that PIV infection aggra-
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SYMPOSIUM ON RESPIRATORY VIRAL INFECTIONS/WENDT 13. Wendt CH, Fox JMK, Hertz MI. Paramyxovirus infection in lung transplant recipients. J Heart Lung Transplant. 1995;14:479–485. 14. Aschan J, Ringden O, Ljungman P, et al. Influenza B in transplant patients. Scand J Infect Dis. 1989;21:349–350. 15. Beyer WEP, Diepersloot RJA, Masurel N, et al. Double failure on influenza vaccination in a heart transplant patient. Transplantation. 1987;43: 319. 16. Briggs KD, Timbury MC, Paton AM, Bell PRF. Viral infection and renal transplant rejection. Br Med J. 1972;4:520–522. 17. Mauch TJ, Bratton S, Myers T, et al. Influenza B virus infection in pediatric solid organ transplant recipients. Pediatrics. 1994;994:225–229. 18. Ljungman P, Andersson J, Aschan J, et al. Influenza A in immunocompromised patients. Clin Infect Dis. 1993;17:244–247. 19. Mauch TJ, Crouch NA, Freese DK, et al. Antibody response of pediatric solid organ transplant recipients to immunization against influenza virus. J Pediatr. 1995;127:957–960. 20. Blohme I, Nyberg G, Jeansson S, Svalander C. Adenovirus infection in a renal transplant patient. Transplantation Proceedings . 1992;24: 295.
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21. Harnett GB, Bucens MR, Clay SJ, Saker BM. Acute haemorrhagic cystitis caused by adenovirus type 11 in a recipient of a transplanted kidney. Med J Australia. 1982;1:565–567. 22. Shindo K, Kitayama T, Ura T, et al. Acute hemorrhagic cystitis caused by adenovirus type 11 after renal transplantation. Urol Int. 1986;41:152–155. 23. Yagisawa T, Takahashi K, Yamaguchi Y, et al. Adenovirus induced nephropathy in kidney transplant recipients. Transplantation Proceedings. 1989;21:2097–2099. 24. Carnes B, Rahier J, Burtomboy G, et al. Acute adenovirus hepatitis in liver transplant recipients. J Pediatr. 1992;120:33–37. 25. Koneru B, Atchison R, Jaffe R, et al. Serological studies of adenoviral hepatitis following pediatric liver transplantation. Transplantation Proceedings. 1990;22:1547–1548. 26. DeFabritus AM, Riggio RR, David DS, et al. Parainfluenza type 3 in a transplant unit. JAMA. 1979;241:384–386. 27. Gabriel R, Selwyn S, Brown D, et al. Virus infections and acute renal transplant rejection. Nephron. 1976;16:282–286. 28. Winter JB, Gouw ASH, Groen M, et al. Respiratory viral infections aggravate airway damage caused by chronic rejection in rat lung allografts. Transplantation. 1994;57:418–422.
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