key: cord-0866392-c3blj4t9 authors: Bodey, MD Gerald P title: Community Respiratory Viral Infections in the Immunocompromised Host: Past, Present, and Future Directions date: 1997-03-17 journal: The American Journal of Medicine DOI: 10.1016/s0002-9343(97)80017-4 sha: ddbc5c8061f5b5f978be98867142c548bec94c9d doc_id: 866392 cord_uid: c3blj4t9 nan Gerald P. Bodey, MD, Houston, Texas C linicians first became interested in infectious complications in immunocompromised hosts in the late 1950s and early 1960s. Three major medical advances stimulated this interest: successes in renal transplantation, effective chemotherapeutic regimens with curative potential against a few malignant diseases, and the availability of antimicrobial agents with activity against gram-negative bacilli. Bacterial infections were the major cause of mortality in those early years, so much attention centered on management of these infections. 1 Fungal infections were also recognized as a complication in some immunocompromised hosts, such as those with acute leukemia. Most of these infections occurred in leukemia patients who were not responding to chemotherapy, and progress in this area was thwarted by difficulties in diagnosis and limited therapeutic options. A few viral infections were recognized as potential problems in these early years, but they were mainly caused by DNA viruses. Micro-epidemics of chicken pox were reported in children with acute leukemia, some of whom died as a result of serious complications. 2 In some cancer patients, herpes zoster infection was recognized as a potential complication that could progress to cutaneous or even visceral dissemination. Occasional cases of giant cell pneumonia due to measles virus were reported in children with acute leukemia. Early experience with renal transplantation emphasized the importance of cytomegalovirus (CMV) as a cause of serious infection in immunocompromised patients. 3 Sporadic cases of CMV infections were also reported in cancer patients, especially those with acute leukemia. Indeed, a small epidemic occurred on the leukemia service at the National Cancer Institute. 4 As CMV has caused increasing numbers of infections among certain groups of immunocompromised hosts, such as bone marrow transplant recipients and patients with acquired immune deficiency syndrome (AIDS), a large body of knowledge on the pathogenesis, natural history, diagnosis, therapy, and prevention of these infections has been compiled. One other viral infection deserves mention in this review, and that is hepatitis B. Hepatitis was recognized as a complication in patients with acute leukemia. This was not surprising, since no routine screening procedures were available during the early 1960s, and these patients often received blood cell transfusions. Several papers were published on the frequent identification of the hepatitis-associated antigen in patients with acute leukemia. 5 After empiric antibiotic therapy for fever in neutropenic patients became accepted practice, it became apparent that a bacterial pathogen could not be identified as the cause of many of these fevers. Hence, in the early 1970s, a few physicians considered the possibility that some febrile episodes in these patients might be due to community-acquired viral infections. Several surveys were conducted to detect these viruses, but they were unsuccessful, and the effort was essentially abandoned. Pneumonia in the immunocompromised host has always been a difficult management problem. This is exemplified by the experience in neutropenic patients, in whom response rates with various antibacterial regimens have usually only been in the range of 30-50%. 6, 7 Although response rates for other infections have improved substantially during the past two decades, this has not been true for pneumonias. Routine sputum cultures have identified the causative agent in only about 20% of cases and bronchoscopy with bronchoalveolar lavage frequently has failed to establish a diagnosis. Open lung biopsy is often a risky procedure, owing to the possibility of hemorrhage secondary to the patient's thrombocytopenia, and frequently shows only nonspecific acute and chronic inflammation. Many clinicians have recognized that the high failure rate has been due in part to the fact that some of these pneumonias were not caused by bacteria. In retrospect, it is somewhat surprising that those of us caring for immunocompromised patients did not give much consideration to community respiratory viruses as a possible cause of some of these infections. In the past, there were some legitimate reasons for ignoring these viruses as a possible cause of infection in immunocompromised hosts. Diagnosis depended upon viral cultures or serologic tests. Both of these required excessive time, and the patient usually recovered or died before the results were known. Furthermore, immunocompromised hosts usually could not mount adequate antibody responses, so the results of serologic tests were unreliable. Most important, however, was the lack of effective antiviral therapy. We have now entered an exciting era in which the role of community respiratory viruses as important pathogens in immunocompromised hosts has been recognized. Even more exciting is the fact that therapies are available that appear to be effective against several of these infections and may prevent some deaths. Some of the earliest studies appeared in the late 1970s and reported surveys in children with malignancies, many of whom had mild-to-moderate infections while in remission from their underlying disease. 8, 9 Most of the studies indicating the potential serious and even fatal consequences of these infections in both children and adults were prompted by experience with transplant recipients, especially bone marrow transplant recipients. 10 With additional studies, other groups of immunocompromised hosts at risk of these infections have been identified. The many excellent reports presented in this Supplement document the great advances in our understanding of the role that community respiratory viruses play in causing infection in the immunocompromised host. Most attention has centered on influenza A and B, parainfluenza, respiratory syncytial virus (RSV), and adenoviruses. Other viruses, such as picornaviruses and enteroviruses, also may cause significant infections in these patients, but less attention has been focused on them. Among the immunocompromised patients at risk of community respiratory virus infections are those with severe combined immunodeficiency syndrome, agammaglobulinemia, cancer, leukemias, lymphoma, aplastic anemia, and AIDS, and recipients of bone marrow and solid organ transplants. Bone marrow transplant recipients and patients with acute leukemia are at especially high risk of serious and potentially fatal infections. Community respiratory virus infections also develop in renal transplant recipients, but they are often less serious and may resolve without therapy. Age plays a role in susceptibility to some of these infections. For example, adenovirus infection is reported to be twice as common in children receiving bone marrow transplants as in adults. 11 Some infections, such as those caused by influenza virus and RSV, are seasonal; others, such as those caused by parainfluenza, are not. There is also geographic diversity in the frequency of these infections. All these viruses have the potential to cause serious and fatal pneumonia in the immunocompromised host. Concomitant infections or superinfections due to other organisms are not uncommon. Of special concern is the recognition that these viruses can be transmitted nosocomially, not only by infected patients and visitors but also by hospital personnel. This problem is further compounded by the fact that immunocompromised hosts may shed the virus for protracted periods, even while receiving therapy. Consequently, infection control measures are an extremely important component of management strategies. It has become apparent that community respiratory viruses are responsible for a substantial proportion of pneumonias in some populations of immunocompromised hosts. Their frequency has not been well defined and obviously varies from season to season and from year to year, depending on the prevalence of these infections in the community. At the present time, RSV is probably the most frequently recognized cause of community respiratory viral infection in the immunocompromised host. There have been RSV outbreaks on bone marrow transplant units in which 15-20% of patients have been infected. 12 Similarly, during influenza epidemics, as many as 25% of bone marrow transplant recipients in whom acute respiratory symptoms develop are infected with these viruses. 13 Undoubtedly, as more effort is directed toward detecting these viruses, it will become apparent that they are a common cause of pneumonia in immunocompromised patients. Although the number of therapeutic options are limited, several antiviral agents hold promise for the treatment of community respiratory virus infections in immunocompromised patients. If administered early, ribavirin with or without intravenous immunoglobulin (IV Ig) has reduced the mortality from RSV pneumonia. 14 Ribavirin also appears to be effective against pneumonia caused by influenza A and B and parainfluenza, although information is limited. Amantadine and rimantadine may also be effective therapy for pneumonia caused by influenza A. Unfortunately, no effective therapy for adenovirus infections has been identified. Recent investigations have provided important information that has opened the door to many new pursuits. There is an urgent need to transmit this information to oncologists, hematologists, and transplant and infectious disease physicians. Although in- creasing numbers of hospitals are providing bone marrow transplantation and intensive cancer chemotherapy, the number of patients treated at any one institution may be small, so sporadic cases of community respiratory infections may go unrecognized and untreated. Also, microbiology laboratories at these institutions may not be equipped to perform the necessary diagnostic procedures. To offer optimal care to all infected patients, therefore, additional education of physicians and microbiologists is required. Many areas of investigation need to be pursued. Although we know that immunocompromised hosts are susceptible to pneumonia caused by these viruses, we do not know much about the specific deficiencies in host defenses that place them at risk. Studies in animal models and humans are needed to define better the immunopathogenesis of these diseases and to identify the role of cellular and humoral mechanisms and cytokines in the development and prevention of these infections. It is possible that other, thus-far-overlooked viruses, such as rhinoviruses, enteroviruses, and coronaviruses, are causing serious infections in immunocompromised patients. Also, other populations of immunocompromised hosts not yet identified may be at risk. Improved diagnostic capabilities are needed. It takes time to identify viruses from cultures, but therapy must be initiated promptly for optimum efficacy. Antigen detection and other rapid diagnostic techniques must be made generally available so that infection can be diagnosed quickly. Progress has been made in rapidly identifying some RSV infections, but further improvements are needed, especially enhancing the sensitivity of rapid diagnostic tests. 15 Greater efforts must be made to overcome current therapeutic limitations. For example, the role of amantadine against influenza A and of ribavirin against influenza A and B and parainfluenza needs to be definitively determined, and therapy for adenovirus infection needs to be developed. Ribavirin has been effective against RSV pneumonia, if given promptly, in uncontrolled studies. However, the optimum method of administration has not been determined. Existing evidence suggests that inhalation therapy is superior to intravenous therapy, but should we be administering the drug by both routes? Is ribavirin plus IV Ig superior to ribavirin alone? What is the most effective therapy for influenza A pneumonia? Is combination therapy with amantadine plus ribavirin more effective than single-agent therapy? Since no individual institution has a sufficient number of cases of community respiratory viruses in immunocompromised hosts, comparative trials would be difficult to conduct. Perhaps a multiinstitutional effort could address some of these issues. Even with existing therapy, there is room for improvement. The excretion of resistant influenza A virus by patients receiving amantadine or rimantadine therapy is potentially worrisome. 16 Individuals who acquire infections caused by these resistant strains will not respond to amantadine or rimantadine therapy. Although ribavirin appears to be effective against RSV infection in immunocompromised hosts, inhalation therapy is cumbersome, and some patients have been unable to complete therapy because of restrictions imposed by the method of administration. Prophylaxis represents an even more difficult challenge. Immunizations are unlikely to be effective, since many immunocompromised patients do not produce an antibody response. Two doses of influenza vaccine have been more effective than single doses in lymphoma patients receiving chemotherapy, but this approach has not been successful in the 6-month period following bone marrow transplantation. 17, 18 Immunization of donors before their bone marrow is transplanted may be effective. Results of studies in children at high risk of RSV infection suggest that passive immunization with hyperimmune serum may prove effective, but this approach to prophylaxis will be expensive. Furthermore, this is unlikely to be a feasible means of preventing some infections, such as those caused by adenoviruses, because of the great diversity of serotypes. It is likely that only an effective antiviral agent, or perhaps a cytokine, will prove to be useful for prophylaxis. The recognition that community respiratory viruses are capable of causing serious infections in immunocompromised hosts has been an important discovery. Patients are now surviving who would otherwise have died. Despite the substantial progress that has been made, much work remains to be done. It is hoped that, with a concerted effort toward further research, the potential lethal threat of these viral infections will be greatly diminished or eliminated in the future. Causes of death in acute leukemia. A ten year study of 414 patients from 1954-1963 The clinical significance of cytomegalovirus infection in renal transplant recipients Cytomegalic inclusion disease in patients with acute leukemia Hepatitis and leukemia: their relations to Australia antigen Antibiotic combinations for infections in neutropenic patients. Evaluation of carbenicillin plus either cephalothin or kanamycin Beta-lactam regimens for the febrile neutropenic patient Virus infections in children with acute lymphoblastic leukemia Influenza in children and young adults with cancer Viral pneumonia in the immunocompromised adult with neoplastic disease: the role of common community respiratory viruses Molecular epidemiology of adenovirus type 35 infections in immunocompromised hosts An outbreak of respiratory syncytial virus in a bone marrow transplant center Influenza A virus infections among hospitalized adult bone marrow transplant recipients Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients Rapid diagnosis of respiratory syncytial virus infections in immunocompromised adults Emergence and apparent transmission of rimantadine-resistant influenza A virus in families Antibody response to a two-dose influenza vaccine regimen in adult lymphoma patients on chemotherapy Antibody response to a two-dose regimen of influenza vaccine in allogeneic T cell-depleted and autologous BMT recipients