key: cord-0684964-6musyeez authors: Manuel, Oriol; Estabrook, Michele title: RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice date: 2019-03-22 journal: Clin Transplant DOI: 10.1111/ctr.13511 sha: 8b1b13ba17dad6c461b61063b7d4d55abfc89dbc doc_id: 684964 cord_uid: 6musyeez These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of RNA respiratory viral infections in the pre‐ and post‐transplant period. Viruses reviewed include influenza, respiratory syncytial virus (RSV), parainfluenza, rhinovirus, human metapneumovirus (hMPV), and coronavirus. Diagnosis is by nucleic acid testing due to improved sensitivity, specificity, broad range of detection of viral pathogens, automatization, and turnaround time. Respiratory viral infections may be associated with acute rejection and chronic lung allograft dysfunction in lung transplant recipients. The cornerstone of influenza prevention is annual vaccination and in some cases antiviral prophylaxis. Treatment with neuraminidase inhibitors and other antivirals is reviewed. Prevention of RSV is limited to prophylaxis with palivizumab in select children. Therapy of RSV upper or lower tract disease is controversial but may include oral or aerosolized ribavirin in some populations. There are no approved vaccines or licensed antivirals for parainfluenza, rhinovirus, hMPV, and coronavirus. Potential management strategies for these viruses are given. Future studies should include prospective trials using contemporary molecular diagnostics to understand the true epidemiology, clinical spectrum, and long‐term consequences of respiratory viruses as well as to define preventative and therapeutic measures. for all recognized viruses 3, 4 with particular emphasis on ones that might be amenable to therapy. toms and fever may be absent. Lung transplant recipients, for example, may initially only have subjective symptoms of short ness of breath or subtle changes in pulmonary function testing without more typical symptoms. 5 4. Viral shedding is usually prolonged among transplant recipients. Prolonged shedding is seen even with the use of antivirals and therefore may contribute to the increased risk of resistant variant emergence. 1, 6, 7 5. Transplant recipients are at higher risk of infectious complica tions compared to immunocompetent hosts. Respiratory viral infections are a significant risk factor for subsequent develop ment of fungal and bacterial pneumonia. 1, 8 6. Respiratory viral infections appear to be a risk factor for both acute and chronic rejection with the greatest risk in lung trans plant recipients, 5, 911 although data on this topic in the litera ture are conflicting. 12, 13 The pathogenesis of the link between respiratory viral infections and rejection is not clearly understood. A wide range of PCRbased assays to detect respiratory viruses are commercially available, and many centers have locally developed assays that detect select viruses. Nucleic acid amplification assays appear to be the most sensitive diagnostic tools available and most allow for simultaneous detection of a broad range of respiratory pathogens from a single sample and are therefore the preferred diagnostic testing method for immunocompromised patients. 14 Multiplex PCR assays provide the advantage of identification of viruses not routinely found by conventional methods, including rhinovirus and hMPV, 1720 although multiplexing can affect the sen sitivity of the assay. Commercially available multiplex assays differ in sensitivity and specificity for different viruses most notably ade novirus, 17, 2123 and the clinician should be aware of the performance characteristics of the assay used. For influenza, PCR assays can dis tinguish among viral subtypes and can quantify viral load. Although not available at all centers, rapid PCRbased assays allow rapid re sults (within 34 hours), particularly for influenza and RSV, although their sensitivity may vary among virus types. 24, 25 Rapid antigen detection is available for influenza and RSV and has the advantage of rapid result testing (within 15'), but suboptimal sensitivity (between 50% and 60%) and low predictive value. 26, 27 Several studies of direct fluorescent antibody (DFA) testing of primary patient specimens have documented sensitivity that approached that of PCR for certain viruses. 28 Patients with known or suspected influenza should be isolated from other patients with standard and droplet precautions. Influenza vaccination is the key measure to prevent influenza. 36 • Patients with influenza infection in a healthcare setting need to be isolated with standard and droplet measures (Strong, moderate). • Inactivated influenza vaccine should be administered to all SOT recipients and household members (strong, high). • In patients whom influenza vaccine is contraindicated or may have insufficient response (eg, therapy for acute rejection, early after transplantation), antiviral prophylaxis with oseltamivir 75 mg once daily for a duration of 12 weeks (renally adjusted if needed) starting at the beginning of the influenza season may be proposed (weak, high). • In SOT recipients that are close contacts of a patient with docu mented influenza (in particular in cases of nosocomial influenza and in patients with enhanced immunosuppression), we suggest admin istering postexposure prophylaxis with oseltamivir (strong, low). Two families of drugs are approved for the treatment of influenza, namely M2 inhibitors and neuraminidase inhibitors. 46 M2 inhibitors (amantadine and rimantadine) are not active against influenza B, and because of the high incidence of antiviral resistance to influenza A/ H1N1 and A/H3N2, these drugs are no longer recommended for treatment of influenza. 46 Neuraminidase inhibitors include oral os eltamivir, inhaled zanamivir, and intravenous peramivir ( Table 2) . Laninamivir is a longacting inhaled neuraminidase inhibitor that is approved in Japan for prophylaxis and treatment of influenza. 47 can be considered in cases of lifethreatening infection or concerns with oral absorption, although, as mentioned, experience with these drugs in SOT recipients is lacking. 50, 51 The use of amantadine and rimantadine for treatment of influ enza is no longer recommended due to the high rate of resistance to these drugs (>95%). Rates of oseltamivir resistance were high for prepandemic influenza A/H1N1 virus, but antiviral resistance has been only occasionally described for the new influenza A/H1N1 strain. 58 Immunosuppression and exposure to oseltamivir are risk factors for development of antiviral resistance. 59 Most resistance in A/H1N1 viruses in patients exposed to oseltamivir is caused by the H275Y mutation, which results in an increased IC50 for peramivir, but retains zanamivir activity, 58 • Transplant recipients should receive antiviral therapy with a neur aminidase inhibitor (either oseltamivir or inhaled zanamivir) when influenza is suspected (strong, moderate). • Although early (<48 hours) administration of antivirals is associ ated with better outcomes, all symptomatic patients should re ceive antiviral therapy, irrespective of duration of symptom onset (strong, low). • Duration of antiviral therapy should be at least 5 days. Antiviral therapy may be prolonged in cases of persistent clinical symptoms (weak, low). • Double dosing of oseltamivir may be considered in severe cases or in cases of insufficient response to therapy (weak, low). • IV drugs (peramivir or zanamivir) can be also used in selected cases (intubated patients, concerns with oral absorption) (weak, low). • Resistance testing should be considered when clinical symptoms and/or viral shedding are present despite antiviral therapy. RSV is a paramyxovirus in the genus pneumovirus that causes sea sonal annual epidemics worldwide; yearround disease is seen in some tropical locations. 60 Patients with known or suspected RSV should be isolated from other patients using standard contact precautions. 68 Prophylaxis with the RSVspecific humanized monoclonal antibody palivizumab has been shown to be effective for highrisk infants and children <24 months with specific underlying conditions 6972 and updated recommenda tions regarding its use were published by the American Academy of Pediatrics in 2014. 73 No specific recommendations were given for immunocompromised individuals except that children younger than 24 months who will be profoundly immunocompromised during the RSV season may be considered for prophylaxis. Survey data suggest that antibodybased prophylaxis is commonly used among pediatric transplant centers. 74, 75 However, no studies have been conducted to evaluate its use in the solid organ transplant setting, and the cost in adults is significant. There are no approved vaccines for prevention of RSV, although various vaccine formulations are under development. Ribavirin is a nucleoside analog with activity against RSV and the aero 5, 14, 85 Although all respiratory viruses are associated with an in creased risk of progression to obliterative bronchiolitis in lung trans plant recipients, the association appears to be clearest and strongest with PIV lower tract disease. 5, 9, 10 Patients with known or suspected PIV should be isolated from other patients using standard and contact precautions. 68, 86 There are no ap proved vaccines nor are there recognized preventative antiviral agents. Although the use of IVIG and ribavirin is not associated with ben efit in the management of PIV infections in stem cell transplant re cipients, ribavirin has in vitro activity and the inhaled form has been used to treat lung transplant recipients with lower tract disease; some experts also consider the use of IVIG and corticosteroids as well. 66, 67, 82, 85 Inhaled DAS181 is a recombinant fusion protein that is undergoing investigation for treatment of PIV lower respiratory tract infection. 87 • Treatment of lung transplant recipients with PIV lower tract infec tion with ribavirin can be considered (weak, very low). • Adjunctive therapies to ribavirin, including IVIG and corticosteroids may be considered in lung transplant recipients (weak, very low) With the use of molecular diagnostics, a wider range of respiratory viruses have been isolated. Many of these viruses, such as newly recognized variants of coronavirus (HKU1, NL63), the polyomavi ruses (WU, KI viruses), and bocavirus have not been widely studied in transplant recipients and so their clinical impact has not been fully assessed. 14 Severe and sometimes fatal cases of all of these viruses in immunocompromised patients have been recognized, so they should be considered in the differential diagnosis of patients pre senting with severe lower respiratory tract disease. Newly identified viruses are more challenging to diagnose since they are not included in the routine, clinically available diagnostic tests. In addition, opti mal management of these pathogens has not been defined. Although respiratory viruses are increasingly recognized as causes of morbidity and mortality in transplant recipients, there is still much to be learned about the impact of these viruses. Prospective stud ies using molecular diagnostics are needed to understand the true epidemiology and clinical spectrum of respiratory viral diseases. In particular, studies of the longterm consequences of infection, even when mild or asymptomatic, are needed. This is particularly are under investigation. 84, 96, 97 Inhaled DAS181 is a recombinant fu sion protein that has shown promise in inhibiting PIV replication. 87 In addition, adoptive Tcell therapy including the generation of PIV specific 98 and hMPV 99 Tcells in healthy donors is an emerging therapeutic modality. Prospective trials are needed to define the optimal timing, duration, and treatment regimen for each of the viruses. This manuscript was modified from a previous guideline written AST Infectious Diseases Community of Practice. 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RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice