key: cord-0802032-cixyw3bn authors: de Zwart, Auke E. S.; Riezebos‐Brilman, Annelies; Alffenaar, Jan‐Willem C.; van den Heuvel, Edwin R.; Gan, Christiaan Tji; van der Bij, Wim; Kerstjens, Huib A. M.; Verschuuren, Erik A. M. title: Evaluation of 10 years of parainfluenza virus, human metapneumovirus, and respiratory syncytial virus infections in lung transplant recipients date: 2020-06-17 journal: Am J Transplant DOI: 10.1111/ajt.16073 sha: 2139498ca6a022f44749845e06e4a78c6f54daf8 doc_id: 802032 cord_uid: cixyw3bn Respiratory tract infection with pneumoviruses (PVs) and paramyxoviruses (PMVs) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). Ribavirin may be a treatment option but its effectiveness is unclear, especially with respect to infection severity. We retrospectively analyzed 10 years of PV/PMV infections in LTRs. The main end points were forced expiratory volume in 1 second (FEV(1)) at 3 and 6 months postinfection, expressed as a percentage of pre‐infection FEV(1) and incidence of new or progressed CLAD 6 months postinfection. A total of 139 infections were included: 88 severe infections (63%) (defined as >10% FEV(1) loss at infection) and 51 mild infections (37%) (≤10% FEV(1) loss). Overall postinfection CLAD incidence was 20%. Associations were estimated on postinfection FEV(1) for ribavirin vs no ribavirin (+13.2% [95% CI: 7.79; 18.67]) and severe vs mild infection (−11.1% [95% CI: −14.76; −7.37]). Factors associated with CLAD incidence at 6 months were ribavirin treatment (odds ratio (OR [95% CI]) 0.24 [0.10; 0.59]), severe infection (OR [95% CI] 4.63 [1.66; 12.88]), and mycophenolate mofetil use (OR [95% CI] 0.38 [0.14; 0.97]). These data provide valuable information about the outcomes of lung transplant recipients with these infections and suggests possible associations of ribavirin use and infection severity with long‐term outcomes. Well‐designed prospective trials are needed to confirm these findings. are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). Ribavirin may be a treatment option but its effectiveness is unclear, especially with respect to infection severity. We retrospectively analyzed Well-designed prospective trials are needed to confirm these findings. This morbidity is especially pronounced in lung transplant recipients (LTRs), where an acute mortality due to these infections has been reported in up to 6%-20% of cases for individual viruses. [2] [3] [4] [5] In addition, PV/PMV infections are associated increasingly with the development of chronic lung allograft dysfunction (CLAD). 3,6-10 CLAD is the primary factor limiting long-term survival after lung transplantation. It has a poor prognosis and is difficult to treat, which makes prevention paramount. 11, 12 Unfortunately, CLAD incidence ranging from 25%-67% have been described after untreated PV/PMV infections in LTR. 5, 6, 8, 9, 13 Although, these virus infections do not seem to increase the risk of acute rejection, 14, 15 the severity of infection may be related to allograft dysfunction. 7, 16 Thus far the treatment options for these infections are limited, with some transplant centers currently using augmented steroids in combination with ribavirin. 17 Ribavirin is a nucleoside analogue antiviral that is currently only registered as inhalation therapy for severe RSV infection and is used off label (increasingly in oral form) based on its in vitro activity against hMPV and PIV 1-4. [18] [19] [20] Thus far, a limited number of small cohort studies have reported successful outcomes with ribavirin treatment for PV/PMV infections in LTR. 2, [21] [22] [23] [24] However, the effectiveness remains a matter of debate, as data from randomized studies are lacking. In this retrospective cohort study we aim to evaluate the course of lung function and incidence of new-onset or progression of CLAD in LTR with a PV/PMV infection, with or without ribavirin treatment. This is a retrospective cohort study. All adult patients with a single-, double-, or heart-lung transplantation who were at least 6 months posttransplant and were diagnosed with an RSV, hMPV, or PIV1-4 infection between 2008 and 2018 at the University Medical Centre Groningen were eligible for inclusion. If a patient had had multiple PV/ PMV infections over the years, only the first 2 cases were included (which had to be at least 1 year apart, else only the first case was included). As part of regular care, chest x-ray and bacterial and fungal sputum cultures were performed in all patients to exclude other causes of lung function decline. Patients with factors that could interfere with reliable spirometry (eg, airway stenosis, chest wall pathology, pain), or who had a concomitant fungal infection, or had an episode of acute rejection within 3 months prior to PV/PMV infection were excluded. The primary end point was the change in forced expiratory volume in 1 second (FEV 1 ) at 6months postinfection, as a percentage of preinfection FEV 1 . Secondary end points were FEV 1 at 3 months postinfection (as a percentage of preinfection FEV 1 ), new-onset or progression of CLAD at 6 months postinfection, and change in hemoglobin level as a side-effect of ribavirin therapy. All patients had provided written informed consent for transplant-related research and the study was approved by the local ethics committee (METc 2015.452). The manuscript was prepared in accordance with the Strenghtening Reporting of Observational studies in Epidemiology statement. 25 Spirometry was performed according to American Thoracic Society/ European Respiratory Society guidelines. 26 Treatment in case of PV/PMV infection consisted of oral prednisolone in combination with ribavirin or oral prednisolone only, and was up to the discretion of the attending physician. Prednisolone was increased to 0.5 mg/kg/day in all patients for 7-10 days. 5, 21, 29 Suspected bacterial co-infection (indicated by purulent sputum production and/or infiltrate on chest x-ray without positive sputum culture) was treated up to the discretion of the attending physician. Medians were compared using the nonparametric Mann-Whitney U test Figure S1 ). 12, 31 First, the most appropriate covariance structure was selected using restricted maximum likelihood and Akaike's information criterion. This was followed by variable selection using backward elimination, and lastly the final model was analyzed with restricted maximum likelihood to provide proper estimates of the associations of the variables with FEV 1 and their P-value. CLAD incidences were analyzed using multiple logistic regression with backward selection using the same independent variables. Variables are reported as unadjusted odds ratios (uORs) and adjusted odds ratios (aORs). Material (Table S1-S4). Patient demographics and detected PV/PMV are shown in Table 1 . Median FEV 1 at the different time points for the subgroups is illustrated in Figure 2 . FEV 1 dropped notably during infection, with a median acute loss compared to preinfection FEV 1 of 14% (IQR 22), 15% (IQR 14) , and 16% (IQR 20) for RSV, hMPV, and PIV, respectively. In total, 23 patients (17%) did not return to >90% of their preinfection FEV 1 value at 6 months postinfection (7 RSV, 6 hMPV, 10 PIV). For the multivariate analysis of long-term FEV 1 at 3 and 6 months postinfection, the variable selection approach identified ribavirin treatment (independent of time point), time since transplantation, their interaction, and severe infection as significant factors associated with long-term FEV 1 ( Table 3 ). The other independent variables did not reach statistical significance or improved model fit and were omitted during the backward selection process (Table S1 ). Figure S3 ). Hemoglobin levels during treatment were available in 64 patients treated with ribavirin (94%) and 28 patients in the non-ribavirin subgroup (39%) and are reported in Table 5 . Five patients treated with oral ribavirin developed de novo or progressive anemia during infection (9%), 2 of whom required blood transfusion and therapy cessation. This study showed that PV/PMV infection was associated with a high CLAD incidence for all studied viruses, and the severity of The yearly incidence of PV/PMV infections in our study was approximately 5%, which is comparable with earlier studies. 5, 9 Because patients in our center are only tested on clinical indication instead of routine screening, the real incidence may be higher especially for mild or asymptomatic PV/PMV infection. 9, 10, 21 The impact of these asymptomatic or mild infections is unclear, however, which is underscored by the outcome in our mild infection cohort. Outcome in these patients was better than in patients with a severe infection, regardless of antiviral treatment. This is analogous to other reports of mild infection. 13 loss. An acute FEV 1 loss may be indicative of infection of the lower respiratory tract with activation of the immune response causing inflammation of the small airways yielding swelling and limiting airflow, thereby forming a risk factor for worse outcome. [33] [34] [35] [36] Moreover, because PV/PMV infections often do not show radiographic abnormalities, the amount of acute FEV 1 loss may be a useful clinical marker for severe or mild infection and could guide treatment decisions. The impact of PIV infections is described far less in LTR compared to hMPV and RSV. We found here that PV/PMV type was not a significant factor in our multivariate models and that severe infections Furthermore, although successful treatment of hMPV and PIV has been described, 5, 6, 21, 24, 38 no consensus exists whether to treat these infections with ribavirin. Our study had several strengths to address these questions and assess the impact of PV/PMV infections and to make an estimation of associations of ribavirin treatment with outcome. The large sample size of the cohort and regularly scheduled follow-up at our center resulted in detailed clinical data that allowed a multivariate analysis, taking into account multiple infectious and non-infectious factors that could influence outcome, thereby minimizing confounding. 7, 12, 31 Using this strategy our study showed that ribavirin treatment, in- CLAD incidence of untreated severe PIV infection in our study of 66% is comparable with two small studies reporting incidences of 57% and 66% of untreated PIV cases. 8, 9 Given the possible detrimental effects of PV/PMV infection in LTR, and the in vitro susceptibility to ribavirin of PV/PMV, we believe ribavirin treatment for RSV, hMPV, and PIV may be considered an option until evidence from randomized controlled trials about its effectiveness or other treatment options are available. Interestingly, we found a protective effect of mycophenolate mofetil as standard immunosuppression for the CLAD end point, but not for the FEV 1 end point. Mycophenolate mofetil is the prodrug for mycophenolic acid, which has shown intrinsic antiviral potential against, amongst others, hepatitis C and E viruses, and PIV-3, through a similar antiviral mechanism as ribavirin. [39] [40] [41] Having ambiguous results for the two different end points and a broad confidence interval, we cannot be certain there was a true influence of mycophenolate mofetil on graft function. However, this finding certainly warrants further investigation into the antiviral properties of mycophenolic acid, its interplay with ribavirin and the balance with immunosuppression. We do note certain limitations exist inherent to the study design such as a selection bias for patients who were more critically ill and the lack of randomization, thereby limiting causal inference. In addition, different ribavirin treatment regimens have been used in our study; however, several studies showed comparable results using different treatment regimens for RSV. 22, 23, 37, 42, 43 Finally, although we considered alternative factors explaining the outcomes in the ribavirin group, we did not identify associations for these factors. Nevertheless, we cannot exclude some degree of residual confounding even with careful covariate selection based on previous literature and use of multivariate techniques. It is unlikely, however, that this will be of such magnitude that it would invalidate the main associations. Considering the increased recognition of the importance of these non-influenza viral infections and the current state of evidence, a multicenter randomized controlled trial would be the next step to evaluate the true value of ribavirin for PV/PMV infections in LTRs. This is also important in light of upcoming new therapeutic options which should be compared to currently available options. In conclusion, our data provide valuable information about the outcomes of LTRs with PV/PMV infections and suggests possible associations for ribavirin use and infection severity with long-term outcomes. However, well-designed prospective trials are needed to confirm these findings. We are grateful to N. Nawar for assistance in the data collection process. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. The data that support the findings of this study are available from the corresponding author upon reasonable request. Note: Hb is reported as g/dL, data reported as: mean (standard deviation), P value is from the paired samples t-test. Abbreviation: Hb, hemoglobin. Disease severity and clinical outcomes of community-acquired pneumonia caused by non-influenza respiratory viruses in adults: a multicentre prospective registry study from the CAP-China Network Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection Clinical features and outcomes of paramyxoviral infection in lung transplant recipients treated with ribavirin Human metapneumovirus in lung transplant recipients and comparison to respiratory syncytial virus Single-centre experience with oral ribavirin in lung transplant recipients with paramyxovirus infections The epidemiology of parainfluenza virus infection in lung transplant recipients Graft loss and CLADonset is hastened by viral pneumonia after lung transplantation Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death Community-acquired respiratory viral infections in lung transplant recipients: a single season cohort study Human metapneumovirus infection in lung transplant recipients: clinical presentation and epidemiology Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients An international ISHLT/ATS/ ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome Low incidence of severe respiratory syncytial virus infections in lung transplant recipients despite the absence of specific therapy Transplanting the pulmonary virome: dynamics of transient populations Incidence and outcomes of respiratory viral infections in lung transplant recipients: a prospective study Community-acquired respiratory viruses are a risk factor for chronic lung allograft dysfunction Current practices for treatment of respiratory syncytial virus and other non-influenza respiratory viruses in high-risk patient populations: a survey of institutions in the Midwestern Respiratory Virus Collaborative Comparison of the inhibition of human metapneumovirus and respiratory syncytial virus by ribavirin and immune serum globulin in vitro Ribavirin inhibits human parainfluenza virus type 2 replication in vitro In vitro sensitivity of human parainfluenza 3 clinical isolates to ribavirin, favipiravir and zanamivir Human metapneumovirus in lung transplant recipients: characteristics and outcomes Oral ribavirin for respiratory syncytial virus infection after lung transplantation: efficacy and cost-efficiency Intravenous ribavirin is a safe and cost-effective treatment for respiratory syncytial virus infection after lung transplantation Clinical outcomes of paramyxovirus infections in lung transplant recipients treated with oral ribavirin: a two-center case series Annals of Internal Medicine Academia and Clinic The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting Standardisation of spirometry Chronic lung allograft dysfunction: definition, diagnostic criteria, and approaches to treatment-a consensus report from the Pulmonary Council of the ISHLT The emergence of enterovirus D68 in a Dutch University Medical Center and the necessity for routinely screening for respiratory viruses RNA respiratory viral infections in solid organ transplant recipients: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System Symptomatic respiratory virus infection and chronic lung allograft dysfunction Epidemiology and immediate indirect effects of respiratory viruses in lung transplant recipients: a 5-year prospective study CXCR3 chemokine ligands during respiratory viral infections predict lung allograft dysfunction The host immune response in respiratory virus infection: balancing virus clearance and immunopathology Pro-and anti-inflammatory responses in respiratory syncytial virus bronchiolitis RSV infection modulates IL-15 production and MICA levels in respiratory epithelial cells Oral versus inhaled ribavirin therapy for respiratory syncytial virus infection after lung transplantation Incidence and morbidity of human metapneumovirus and other community-acquired respiratory viruses in lung transplant recipients Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis e virus Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C Virus infection in vitro and in vivo The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase Comparative effectiveness of aerosolized versus oral ribavirin for the treatment of respiratory syncytial virus infections: a single-center retrospective cohort study and review of the literature Oral versus aerosolized ribavirin for the treatment of respiratory syncytial virus infections in hematopoietic cell transplant recipients