US Pharm. 2013;38(11)(Oncology suppl):8-10.

ABSTRACT: Immunosuppression is an independent risk factor for severe respiratory syncytial virus (RSV) infection, which can cause significant morbidity and mortality in the immunocompromised host. The risk of mortality increases as the infection progresses from the upper respiratory tract to the lower respiratory tract. Prompt identification of the underlying disease and timely initiation of treatment are prudent. Although the optimal treatment for RSV infection in the immunocompromised patient has not been clearly defined, a combination of aerosolized ribavirin with an immunomodulator should be considered. Preventive measures are critical to avoid transmission of RSV to the household or hospital ward.

Respiratory viral infection has become one of the leading causes of morbidity and mortality in immunocompromised patients. Among the respiratory viruses most often implicated in patients who are immunocompromised, respiratory syncytial virus (RSV) is the leading cause of severe infections in this population, with mortality rates as high as 80%.1 Depending upon the degree to which the patient is immunocompromised, RSV can elicit varied immune-response mechanisms. T cell–mediated responses usually assist in RSV viral clearance, but altered immune regulation limits these responses in immunocompromised patients, increasing the risk of an exaggerated inflammatory response.

Although RSV infection most commonly manifests as upper respiratory tract symptoms in children and adults, its recognition in immunocompromised patients may be challenging. Prompt identification of the underlying pathogen and timely initiation of antimicrobial therapy are critical, owing to the significant mortality associated with RSV infection in this population. RSV infection in an immunocompromised patient can rapidly progress from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI), and subsequently to RSV pneumonia. Progression to LRTI occurs in up to 50% of patients undergoing hematopoietic stem cell transplantation (HSCT) or receiving chemotherapy.2 Studies evaluating RSV infection in the immunocompromised host have found a prolonged length of hospitalization, an increase in transfers to the ICU, and a reduction in overall outcomes.3 Case reports and studies have enumerated the burdens that RSV infection places on the immunocompromised host; however, there is still a paucity of information on the risks specific to this patient population and on prevention and management strategies.4

Risk of Severe RSV Disease

Although being in an immunocompromised state is an independent risk factor for severe RSV infection, the stratification of factors that increase risk across different groups of immunocompromised patients is important for prevention and management. HSCT patients, solid organ transplantation (SOT) patients, and patients receiving cancer chemotherapy are at highest risk for mortality from RSV infection.5 Additional risk factors for the development of severe RSV infection vary depending upon the cause of immunosuppression, lymphopenia, time to RSV diagnosis, history of lung disease, age (younger patients are at higher risk), and use of IV immune globulin (IVIG) for viral prophylaxis.4,6

Level of immunosuppression has been evaluated to determine its bearing on the clinical outcome of RSV infection. In the immunocompromised population, HSCT recipients are at highest risk for mortality within 100 days after transplantation.4 Although a comparison of clinical outcomes between RSV infections in matched allogeneic and autologous HSCT patients has not been described, allogeneic HSCT is thought to be an independent risk factor for the development of severe RSV disease.3 Other key risk factors for severe RSV disease in HSCT patients include graft-versus-host disease (GVHD), time to engraftment, myeloablative chemotherapy, cytomegalovirus seropositivity, and preengraftment status.7

Risk factors for severe disease in RSV-infected patients receiving SOT or undergoing cancer chemotherapy have been described. Risk depends upon the type of organ transplanted, as well as the patient’s age and gender. Fatality can occur within 30 to 100 days after SOT unless the RSV infection was diagnosed prior to transplantation.4,6 Younger patients, males, and RSV-infected patients receiving a lung or heart transplant are at higher risk for severe disease and worse outcomes compared with liver and kidney transplant recipients.6 For chemotherapy, the induction phase appears to be when the patient is most vulnerable to morbidity and mortality secondary to RSV infection.6 Additional risk factors include prolonged bacterial or fungal infections and concomitant influenza infections, as well as prolonged hospitalizations beyond scheduled chemotherapy sessions.

Treatment

The treatment of RSV-associated LRTI is generally supportive, involving supplemental oxygen for hypoxemia, management of respiratory secretions, and mechanical ventilation for respiratory failure. The availability of pharmacologic agents indicated for the treatment of RSV infections is limited, and definitive evidence of these agents’ efficacy in immunocompromised patients is lacking. Most clinical trials examining the treatment of RSV infections in the immunocompromised population have assessed combination regimens pairing an antiviral with an immunomodulator, thus making it difficult to determine the efficacy of an individual agent.

Ribavirin: Ribavirin, the broad-spectrum antiviral agent most widely studied in hospitalized children with severe LRTIs, is currently the only drug FDA-approved to treat RSV infections.8,9 To date, there is a paucity of randomized, placebo-controlled studies evaluating the safety and efficacy of ribavirin in immunocompromised patients. The largest of these, a retrospective study of 280 allogeneic HSCT patients, found that aerosolized ribavirin was the single most significant factor in reducing the risk of LRTIs, all-cause mortality, and RSV-associated mortality.10 Despite the lack of well-designed studies, current evidence suggests that aerosolized ribavirin can potentially prevent RSV-associated LRTI and reduce overall mortality in allogeneic HSCT patients.

Aerosolized ribavirin is preferred in order to minimize systemic adverse effects (AEs) such as hepatotoxicity and nephrotoxicity. Utilization of ribavirin is limited by administration challenges related to its teratogenic effects and its potential for environmental spread. To minimize secondary exposure to neighboring patients and healthcare personnel, ribavirin should be administered in a well-ventilated room with at least six air exchanges per hour or in a negative-pressure room. Healthcare workers who provide direct care to patients receiving aerosolized ribavirin should be aware of the teratogenic effects noted in animal studies. Although no reports of teratogenesis in offspring of mothers exposed to aerosolized ribavirin during pregnancy have been confirmed, there have been no controlled studies in pregnant women.8

Aerosolized ribavirin must be administered via the Small Particle Aerosol Generator (SPAG-2) to ensure delivery of drug particles into the lower respiratory tract.8 Ribavirin is traditionally administered as 6 g of a 20 mg/mL solution continuously delivered over 12 to 18 hours for 3 to 7 days. However, the prolonged patient isolation required for administration has been associated with psychological distress, often reported as loneliness or anxiety.11 In studies comparing intermittent versus continuous dosing strategies for aerosolized ribavirin in immunocompetent patients, both regimens were equally efficacious and there was no significant difference in reported AEs.12 Thus, an intermittent regimen of 2 g of a 60 mg/mL solution over 2 hours given three times daily is preferred because of the favorable administration time, lessened environmental spread, and risk of exposure.

Immunomodulators: The use of immmunomodulators as part of a multidrug regimen for the treatment of RSV in SOT and HSCT recipients is promising.2,11,13,14 Combination therapy using aerosolized ribavirin with an immunomodulator (e.g., immune globulin, monoclonal antibodies [Mabs], or corticosteroids) can significantly reduce the mortality rate in immunocompromised patients being treated for an RSV LRTI.7 In animal models, concomitant therapy using ribavirin with RSV immune globulin or palivizumab can boost the clearance of pulmonary viral loads, whereas the use of corticosteroids reduces the progression of obliterative bronchiolitis associated with RSV in the immunocompromised host.15-17

Palivizumab is a humanized Mab successfully used for prophylaxis of severe RSV disease in children at high risk. Although IV palivizumab has been shown to be a viable option in immunocompetent patients,18 there is a lack of definitive evidence of its efficacy in immunocompromised patients. Palivizumab monotherapy in allogeneic HSCT recipients failed to yield an additional benefit, as it did not prevent progression to LRTI or improve overall survival.19

Immune globulin and corticosteroids have been studied in combination with ribavirin or palivizumab. In a retrospective study of treatment of RSV infection with combinations of ribavirin, IVIG, and palivizumab in patients with hematologic diseases, Khanna and colleagues found that outcomes are more highly associated with the underlying disease than with treatment of the RSV infection.2 Moreover, a systematic literature review of adult HSCT recipients detected a trend toward improved outcomes for progression to LRTI and for mortality in patients receiving aerosolized ribavirin combined with an immunomodulator versus patients receiving aerosolized ribavirin alone.20 Current evidence suggests that immunomodulators should not be used alone for the treatment of RSV infection in the immunocompromised host; rather, they should be given in combination with other treatment modalities, such as aerosolized ribavirin.

Prevention

Although specific recommendations for immunocompromised patients cannot be made, patients with severe immunodeficiencies (e.g., severe combined immunodeficiency or advanced AIDS) may benefit from immunoprophylaxis.21 Antibodies mediate immune responses and play a critical role in defending against viral infection by eliminating RSV from the patient’s circulation. The natural immune response to RSV from pooled human plasma was used to develop a prophylactic polyclonal RSV hyperimmune globulin (RSV-IGIV) that validated the role of immunoprophylaxis as an effective approach to RSV prevention, leading to the development of RSV-specific Mabs.

Palivizumab, a humanized Mab that is 50-fold more potent than RSV-IGIV, is currently the only FDA-indicated product available to reduce the risk of RSV infection.22 Palivizumab is administered intramuscularly at a dosage of 15 mg/kg once a month during the RSV season.23 The efficacy and safety of palivizumab for RSV prophylaxis have not been investigated in randomized, controlled trials of immunocompromised patients. During a nosocomial RSV outbreak in adult HSCT patients, Kassis and colleagues implemented infection-control procedures and administered a single 15 mg/kg palivizumab dose to high-risk patients, which circumvented further spread of RSV infection.24 A high-risk patient was defined as one who had received an allogeneic transplant, was preengraftment, or had GVHD; had received high-dose steroids; or was neutropenic, with an absolute neutrophil count less than 500 cells/mL.

Although the importance of RSV as a respiratory pathogen has been recognized for decades, a vaccine is not yet available because of several problems inherent in RSV vaccine development. Moreover, infants and immunocompromised patients may not respond adequately to vaccinations because of their relative immunologic immaturity and suppression, respectively. In studies of human RSV vaccine, history of inactivated RSV vaccine administration potentiated a naturally occurring RSV disease, which could be devastating in an immunocompromised patient.25,26 Motavizumab, a second-generation humanized Mab, is currently in phase III clinical trials; it has been studied for the prevention of RSV infection in high-risk immunocompetent children but appears to be noninferior to palivizumab, with a higher incidence of AEs.27

Finally, good hygiene and infection-control practices are critical in protecting immunocompromised patients from severe RSV disease. RSV transmission can occur through direct and indirect contact of nasal and oral secretions, as well as via inhalation of aerosolized droplets from infected individuals. RSV is often introduced into the household by school-age RSV-infected children with URTI. In hospital units that house immunocompromised patients, RSV is generally introduced by the medical staff or by visitors who have mild or unrecognized symptoms of a community-acquired RSV infection.2 In RSV patients with a URTI requiring HSCT, delayed transplantation has been suggested as a means of preventing the morbidity and mortality associated with progression to RSV pneumonia. It is important that healthcare professionals proceed with caution when caring for immunocompromised patients; they must also practice good hand hygiene to minimize the spread of disease and infection.20

Conclusion

RSV infection is most commonly considered a viral illness in pediatric patients, but it can cause significant morbidity and mortality in immunocompromised patients. The management of RSV infection in the immunocompromised patient requires prompt diagnosis and treatment initiation to prevent progression to LRTI. Treatment of RSV infection should consist of a combination of aerosolized ribavirin with an immunomodulator. Effective pharmacologic agents to prevent RSV disease are lacking; therefore, infection-control efforts to prevent transmission of RSV to an immunocompromised patient are critical.

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