Community-acquired Respiratory Viral Infections Research Articles

Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation.

Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD). We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients. Higher IL-23 (p=.048) and IL-31 (p=.035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p=.041) and eotaxin (EOX) (p=.017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p<.001), pro-inflammatory cytokine IL-23 (p=.02), and sTNFRI (p=.01) below cutoff levels as associated with BOS-free survival. Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.

Community-Acquired Respiratory Viruses Post–Lung Transplant

Survival in lung transplant recipients (LTRs) lags behind heart, liver, and kidney transplant, in part due to the direct and indirect effects of infection. LTRs have increased susceptibility to infection due to the combination of a graft continually exposed to the outside world, multiple mechanisms for impaired mucus clearance, and immunosuppression. Community-acquired respiratory viral infections (CARVs) are common in LTRs. Picornaviruses have roughly 40% cumulative incidence followed by respiratory syncytial virus and coronaviruses. Although single-center retrospective and prospective series implicate CARV in rejection and mortality, conclusive evidence for and well-defined mechanistic links to long-term outcome are lacking. Treatment of viral infections can be challenging except for influenza. Future studies are needed to develop better treatments and clarify the links between CARV and long-term outcomes.

COVID-19 in lung transplant recipients: A multicenter study.

This study describes the clinical presentation, treatment, and outcomes of SARS-CoV-2 infection in lung transplant recipients (LTRs). This is a multicenter, retrospective study of all adult LTRs with confirmed SARS-CoV-2 infection from March 4 until April 28, 2020 in six Spanish reference hospitals for lung transplantation. Clinical and radiological data, treatment characteristics, and outcomes were reviewed. Forty-four cases were identified in that period. The median time from transplantation was 4.2 (interquartile range: 1.11-7.3) years. Chest radiography showed acute parenchymal abnormalities in 32 (73%) cases. Hydroxychloroquine was prescribed in 41 (93%), lopinavir/ritonavir (LPV/r) in 14 (32%), and tocilizumab in 19 (43%) patients. There was a strong interaction between tacrolimus and LPV/r in all cases. Thirty-seven (84%) patients required some degree of respiratory support and/or oxygen therapy, and 13 (30%) were admitted to intermediate or intensive critical care units. Seventeen (39%) patients had died and 20 (45%) had been discharged at the time of the last follow-up. Deceased patients had a worse respiratory status and chest X-ray on admission and presented with higher D-dimer, interleukin-6, and lactate dehydrogenase levels. In this multicenter LTR cohort, SARS-CoV-2 presented with high mortality. Additionally, the severity of disease on presentation predicted subsequent mortality.

ALL-045: Community-Acquired Viral Infections in Hospitalized Egyptian Children with Malignancy

Context Children with cancer comprise an important immunocompromised population who are more vulnerable and at high-risk to a variety of infectious pathogens, including respiratory viruses that are widespread in the community. Objective Studying the role of these viruses is important especially in countries with high population density, increasing chances of community-acquired infections. This prospective study aimed to assess the annual prevalence of community-acquired respiratory viral infections among children with cancer presenting with clinical picture suggestive of lower respiratory tract infections (LRTIs), and evaluate its risk factors and prognosis. Design Patients who presented either to the out-patient clinic or to the emergency department, had clinical evidence and/or radiological criteria suggestive of LRTIs, and were fulfilling the criteria of community-acquired infection were recruited, subjected to clinical assessment, investigated through hematology panel, blood culture, chest X-ray, CT chest, and PCR for influenza A and B, parainfluenza (PIV) types 1 and 3 viruses, and respiratory syncytial virus (RSV), and prospectively followed up for the clinical outcome. Results Over a year, 90 eligible children were recruited; 48 patients had ALL, 9 had AML, and 33 had solid tumors; 54.4% of them were in the induction phase. Annual prevalence of viral infections was 37.7%, with a seasonal peak from April to May. The most frequently detected virus was influenza virus [type A (47%), type B (12%)] followed by parainfluenza virus [PIV1 (26%), PIV3 (15%)], and none had RSV. Bacteria were identified in 26 patients, fungi in four, mixed infections (bacterial/viral and bacterial/fungal) in 13, and 36 cases had unidentified etiology. The majority of patients with influenza and parainfluenza infections had haematological malignancy, presented with fever, and had mild self-limited respiratory illness. Five patients with mixed viral and bacterial infection had severe symptoms, necessitating ICU admission. Six patients died from infection-related sequelae; two had mixed PIV and staphylococcal infections. Conclusions Community-acquired influenza and parainfluenza infections are common in pediatrics children with malignancy, either as isolated or mixed viral/bacterial infections. Clinical suspicion is essential as radiological manifestations are non-specific and mandate rapid diagnosis and management to improve patients' outcome.

Are Community Acquired Respiratory Viral Infections an Underestimated Burden in Hematology Patients?

Despite a plethora of studies demonstrating significant morbidity and mortality due to community-acquired respiratory viral (CRV) infections in intensively treated hematology patients, and despite the availability of evidence-based guidelines for the diagnosis and management of respiratory viral infections in this setting, there is no uniform inclusion of respiratory viral infection management in the clinical hematology routine. Nevertheless, timely diagnosis and systematic management of CRV infections in intensively treated hematology patients has a demonstrated potential to significantly improve outcome. We have briefly summarized the recently published data on CRV infection epidemiology, as well as guidelines on the diagnosis and management of CRV infections in patients intensively treated for hematological malignancies. We have also assessed available treatment options, as well as mentioned novel agents currently in development.

Absence of evidence that respiratory viral infections influence pediatric lung transplantation outcomes: Results of the CTOTC-03 study.

Based on reports in adult lung transplant recipients, we hypothesized that community-acquired respiratory viral infections (CARVs) would be a risk factor for poor outcome after pediatric lung transplant. We followed 61 pediatric lung transplant recipients for 2+years or until they met a composite primary endpoint including bronchiolitis obliterans syndrome/obliterative bronchiolitis, retransplant, or death. Blood, bronchoalveolar lavage, and nasopharyngeal specimens were obtained with standard of care visits. Nasopharyngeal specimens were obtained from recipients with respiratory viral symptoms. Respiratory specimens were interrogated for respiratory viruses by using multiplex polymerase chain reaction. Donor-specific HLA antibodies, self-antigens, and ELISPOT reactivity were also evaluated. Survival was 84% (1year) and 68% (3years). Bronchiolitis obliterans syndrome incidence was 20% (1year) and 38% (3years). The primary endpoint was met in 46% of patients. CARV was detected in 156 patient visits (74% enterovirus/rhinovirus). We did not find a relationship between CARV recovery from respiratory specimens and the primary endpoint (hazard ratio 0.64 [95% confidence interval: 0.25-1.59], P=.335) or between CARV and the development of alloimmune or autoimmune humoral or cellular responses. These findings raise the possibility that the immunologic impact of CARV following pediatric lung transplant is different than that observed in adults.

A Pilot Randomized Placebo Controlled Trial of Inhaled Beclomethasone after Community-Acquired Respiratory Viral (CARV) Infection in Lung Transplant Recipients (LTR)

Purpose CARV infections are associated with an increased risk of CLAD development and progression. Inhaled corticosteroids are used to treat airway inflammation , but there is a dearth of data regarding their use in lung transplantation . This study aimed to examine the effect of inhaled beclomethasone on the development and progression of CLAD after CARV. Methods Single-center, double blind, pilot, randomized, placebo controlled trial of inhaled beclomethasone in adult LTR diagnosed with a CARV between Jan 2017 and Dec 2017. Patients were randomized in a 1:1 ratio stratified by BOS stage (BOS 0/0p vs 1/2) within 7 days of CARV. Study drug was continued for 6 months. The primary endpoint was freedom from new or progressive CLAD (defined as a 15% decline in pre CARV FEV1). Secondary endpoints included all-cause mortality and development of new DSA post-CARV. Results 7 patients were randomized to inhaled beclomethasone and 8 to placebo. Baseline demographics were well matched between groups including gender, age at LTR, time from LTR to CARV, upper vs lower CARV, BOS stage, and DSA at the time of study enrollment (Table 1). There was no difference in freedom from CLAD or CLAD progression between the 2 groups (Figure 1). No patients died or developed new DSA during the study period. Conclusion Inhaled beclomethasone was not associated with a lower incidence of new or progressive CLAD after CARV when compared to placebo. However, this study had limited power and sample size. Additional studies are necessary to assess the potential benefit of inhaled corticosteroids in LTR after CARV.

Coronavirus and Chronic Lung Allograft Dysfunction: Hiding in Plain Sight?

Coronavirus and Chronic Lung Allograft Dysfunction: Hiding in Plain Sight?

One-Year Prospective Study of Community Acquired Influenza and Parainfluenza Viral Infections in Hospitalized Egyptian Children with Malignancy: Single Center Experience

Background: Respiratory viruses are widespread in the community and easily transmitted to immunocompromised patients. Aims: Assess the prevalence of community-acquired respiratory viral infections among children with cancer presenting with clinical picture suggestive of lower respiratory tract infections (LRTIs), and evaluate its risk factors and prognosis. Methods: Over a year, 90 hospitalized children with malignancy and LRTIs recruited, subjected to clinical assessment, investigated through hematology panel, blood culture, chest x-ray, CT chest and PCR for influenza A and B, parainfluenza (PIV) types 1 and 3 viruses, and respiratory syncytial virus (RSV), and prospectively followed up for the clinical outcome. Results: Viral pathogens were identified in 34 patients (37.7%), with a seasonal peak from April to May. The most frequently detected virus was influenza virus [type A (16 cases; 47%), type B (4 cases; 12%)] followed by parainfluenza virus [PIV1 (9 cases; 26%), PIV3 (3 cases; 15%)], and none had RSV. Bacteria were identified in 26 patients, fungi in four, mixed infections [bacterial/viral and bacterial/fungal] in 13, and 36 cases had unidentified etiology. The majority of patients with influenza and parainfluenza infections had hematological malignancy, presented with fever, and had mild self-limited respiratory illness. Five patients with mixed viral and bacterial infection had severe symptoms necessitating ICU admission. Six patients died from infection-related sequelae; two had mixed PIV and Staphylococcal infections. Conclusions: Community acquired influenza and parainfluenza infections are common in pediatrics patients with malignancy, either as isolated or mixed viral/bacterial infections. Clinical suspicion is essential as hematological and radiological manifestations are nonspecific. Rapid diagnosis and management are mandatory to improve patients’ outcome.

(491) - Community Acquired Respiratory Viral Infection after Lung Transplantation: BOS Risk and Risks of Specific Viruses

Community acquired respiratory viral (CARV) infections are a reported risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx) but the risk of specific viral infections is unknown. We assessed the risk of specific CARV for BOS and death after LTx. Retrospective, single-centre analysis of 380 LTx recipients 01/2003- 01/2013, (BLTx 318, SLTx 18, HLTx 11),(CF 81, IPF 61, COPD 107, A1AT 29, PAH 12, CHD 9, ILD 21, B 21, OB 6). 33 were excluded for insufficient data, survival < 90 days, or retransplantation. Data were collected through 07/2013 with a mean +/- SD (range) follow up of 1473±1029 (107-3776) days. 225/347 had 487 symptomatic CARV infections confirmed by direct fluorescence antigen, PCR or viral culture of nasopharyngeal swabs and/or bronchoalveolar lavage. Standard therapeutic protocols were followed for specific viruses. Univariate and multivariate time-dependent Cox models were used. CARV included 76 Parainfluenza virus (PIV), 82 Respiratory Syncytial virus (RSV), 5 Adenovirus (AV), 25 Human metapneumovirus (HMPV), 46 Influenza A (FluA), 12 Influenza B (FluB), and 241 Picornavirus (PRNA). Analysed as a time dependent variable initial CARV (PIV =37, RSV=47, AV=3, HMPV=6, FluA=24, FluB=7,PRNA=101) were a significant risk factor for BOS (HR 1.46 95%CI 1.06-2.01, p=0.02) but not death (HR 1.39 95%CI 0.94-2.03, p=0.10). Risk was not dependent on type of CARV (p=0.56, log rank) or stratification by antecedent rejection history (p=0.16, log rank). Biopsy proven rejection remained a significant independent risk factor for BOS (HR 1.23 95%CI 1.03-1.48, p=0.02) and BOS was the major risk for death (HR 7.73 95%CI 5.05-11.84, p<0.001). Symptomatic CARV infection is a significant risk factor for BOS but not death and the risk is independent of viral species or prior rejection episodes. Modification of natural history by antiviral therapy may explain in part the similarity of outcomes shown for specific viruses.

Community-acquired respiratory viral infections in lung transplant recipients

Community-acquired respiratory virus (CARV) infections are a significant cause of morbidity and sometimes mortality in lung transplant recipients (LTRs); this review will focus on the most recent advances in this field. Recent advancements in molecular diagnostics have resulted in the detection of higher rates of CARVs in LTRs. Persistence of rhinovirus has been implicated in the development of acute and chronic rejection, whereas the role of bocavirus remains uncertain. The data on the association of CARV infections with acute or chronic rejection remain less. A recent systematic review failed to show an association between CARV infections and acute or chronic rejection. Different routes of administration of antiviral medications, vaccines and newer promising antiviral medications are being evaluated to assess efficacy and safety. Similarly, newer strategies of vaccination may potentiate the immune response in these patients. With current advanced investigating tools, the full impact of CARV infections in LTR is increasingly coming to realization. Research for novel effective treatments and improved responses to current and new vaccines is ongoing; they would provide great benefit in solving this complex and ever-evolving problem.

Effect of Hypogammaglobulinemia on the Incidence of Community-Acquired Respiratory Viral Infections After Lung Transplantation

BackgroundHypogammaglobulinemia (HGG) has been associated with an increased risk of infectious complications in lung transplant recipients, but its effect specifically on community-acquired respiratory viruses (CARVs) remains unknown. This study aimed to determine if lung transplant recipients with HGG are at an increased risk of developing CARV infection. Secondary endpoints included the effect of HGG on lung function, incidence of rejection, and mortality. MethodsA retrospective review of all lung transplant recipients from 2008 to 2011 was performed. Patients were stratified as either having HGG after transplantation or having normal IgG titers according to their nadir IgG level. HGG was defined a serum IgG level of <700 mg/dL. CARVs included human metapneumovirus, influenza A/B, respiratory syncytial virus A/B, parainfluenza 1/2/3, rhinovirus, and adenovirus isolated from bronchoalveolar lavage/wash, sputum, or nasal swab. ResultsThe cohort consisted of 263 patients with a mean follow-up time of 612 ± 356 days. The incidence of CARV infection was 27% in patients with normal IgG titers and 23.4% in patients with HGG (P = .62). No difference in rejection, mortality, or lung function was found between the groups. As expected, patients who ever had a CARV infection had a significantly lower 1-second forced expiratory volume % reference on their most recent spirometry than those who had not had a CARV infection (81.6% vs 86.9%; P = .027). ConclusionsAlthough CARV infection has been shown to affect lung graft function, these data suggests that HGG is not associated with the incidence of CARV infection.

Bronchiolitis obliterans syndrome, hypogammaglobulinemia, and infectious complications of lung transplantation

Because infection has been associated with the development of bronchiolitis obliterans syndrome (BOS), we hypothesized that post-transplant hypogammaglobulinemia would be associated with infection and BOS. Cross-sectional levels of serum immunoglobulins were measured on 2 occasions in our transplant cohort and models developed to explain serum immunoglobulin levels and BOS-free survival. A total of 139 patients (median age, 46.6 years) were evaluated at 47 months (range, 15-74 months) after transplant, and 87 were re-evaluated at 72 months (40-107 months). Of this cohort, 44% were immunoglobulin (Ig) G deficient and levels remained stable across the study period, and 27% were IgA deficient and levels fell slightly over time (p = 0.003). Both immunoglobulin classes were lower in patients with a history of invasive fungal infection, whereas IgA levels were lower in patients with a history of community-acquired respiratory viral infection. Low IgG was independently associated with shorter BOS-free survival (hazard ratio, 0.79; 95% confidence interval, 0.71-0.88; p<0.001). Serum immunoglobulin deficiency is common after lung transplantation and is associated with community-acquired respiratory viral infection, invasive fungal infection, and BOS.

A Prospective Molecular Surveillance Study Evaluating the Clinical Impact of Community-Acquired Respiratory Viruses in Lung Transplant Recipients

Community-acquired respiratory viral infections (RVIs) are common in lung transplant patients and may be associated with acute rejection and bronchiolitis obliterans syndrome (BOS). The use of sensitive molecular methods that can simultaneously detect a large panel of respiratory viruses may help better define their effects. Lung transplant recipients undergoing serial surveillance and diagnostic bronchoalveolar lavages (BALs) during a period of 3 years were enrolled. BAL samples underwent multiplex testing for a panel of 19 respiratory viral types/subtypes using the Luminex xTAG respiratory virus panel assay. Demographics, symptoms, and forced expiratory volume in 1 sec were prospectively collected for 93 lung transplant recipients enrolled. Mean number of BAL samples was 6.2+/-3.1 per patient. A respiratory virus was isolated in 48 of 93 (51.6%) patients on at least one BAL sample. Of 81 positive samples, the viruses isolated included rhinovirus (n=46), parainfluenza 1 to 4 (n=17), coronavirus (n=11), influenza (n=4), metapneumovirus (n=4), and respiratory syncytial virus (n=2). Biopsy-proven acute rejection (> or =grade 2) or decline in forced expiratory volume in 1 sec > or =20% occurred in 16 of 48 (33.3%) patients within 3 months of RVI when compared with 3 of 45 (6.7%) RVI-negative patients within a comparable time frame (P=0.001). No significant difference was seen in incidence of acute rejection between symptomatic and asymptomatic patients. Biopsy-proven obliterative bronchiolitis or BOS was diagnosed in 10 of 16 (62.5%) patients within 1 year of infection. Community-acquired RVIs are frequently detected in BAL samples from lung transplant patients. In a significant percentage of patients, symptomatic or asymptomatic viral infection is a trigger for acute rejection and obliterative bronchiolitis/BOS.

Chest CT Features of Community-acquired Respiratory Viral Infections in Adult Inpatients With Lower Respiratory Tract Infections

The appearance of respiratory virus infection on thoracic computed tomography (CT) has been described only to a limited extent in the current literature, and viral pneumonias may be under-recognized by radiologists. Our objective was to describe thoracic CT findings in a broad range of adult inpatients with respiratory virus infections. A retrospective analysis of chest CTs was performed on symptomatic adult inpatients presenting with positive nucleic acid-based assays for 1 of 4 common community-acquired respiratory viruses. Forty-two patients with viral respiratory tract infections who underwent chest CT imaging were evaluated. The reviewer was blinded to virus type and patient information. CT findings were compared with CT reports produced at the time of the original study and correlated with clinical outcome measures. Influenza (n=21), adenovirus (n=9), respiratory syncytial virus (n=8), and parainfluenza (n=4) were represented among the cohort. Three patterns of the disease were seen with viral infection: (1) limited infection with normal imaging (21%), (2) bronchitis/bronchiolitis characterized by bronchial wall thickening and tree-in bud opacities (31%), and (3) pneumonia characterized by multifocal consolidation or ground-glass opacities (36%). Viral infection was suggested in only 4/42 (10%) of the original radiology reports, all of which had evidence of bronchitis/bronchiolitis on chest CT. Viral pneumonia, characterized by multifocal ground-glass opacities or multifocal consolidations, was interpreted as aspiration pneumonia or bacterial pneumonia in 15/16 (94%) of the original CT reports. CT scans of the inpatients with community-acquired viral infections most commonly show 1 of 2 patterns: consolidation and ground-glass opacities or bronchial wall thickening and tree-in-bud opacities. It is important that physicians interpreting CTs with multifocal consolidations and/or multifocal ground-glass opacities consider viral pneumonia when these findings are observed and recommend appropriate diagnostic testing when clinically warranted.

Prospective evaluation of a novel multiplex real-time PCR assay for detection of fifteen respiratory pathogens—Duration of symptoms significantly affects detection rate

Background Nucleic acid amplification techniques have improved the diagnostic possibilities in respiratory tract infections, although their clinical applicability is not yet fully defined. We have evaluated a multiplex real-time PCR method for the detection of 13 respiratory viruses and 2 bacteria ( Mycoplasma and Chlamydophila) in a clinical setting. Objectives The aim of the present study was to evaluate the diagnostic performance and clinical use of a novel multiplex PCR method in adults with community-acquired respiratory viral infection, and the impact of duration of symptoms on detection rates. Study design Nasopharyngeal swab samples were prospectively collected from 209 adult outpatients with respiratory infections and 100 asymptomatic controls. Results An infectious agent was identified in 43% of samples from patients and 2% of asymptomatic controls. The detection rate was significantly higher in samples from patients with a duration of symptoms of 6 days or less (51%) than in samples from patients with a duration of symptoms of 7 days or more (30%, p < 0.01). For human corona viruses, and influenza virus A and B there was a correlation between the amount of virus in each patient sample as measured Ct values and duration of symptoms. Conclusions Duration of symptoms significantly affects the detection rate of respiratory pathogens by multiplex real-time PCR in nasopharyngeal swab samples from adult patients with respiratory infections. Our finding should be taken into account when using these tests in clinical practise.

Infections in Patients With Aplastic Anemia

Infection is a major cause of death in patients with aplastic anemia (AA). There are differences between the immunocompromised state of a patient with AA and the patient who is neutropenic due to chemotherapy and this leads to a difference in the infections that they incur. Prolonged neutropenia is one of the largest risk factors for the development of infections with the invasive mycoses and bacteria. Recovery from neutropenia is directly related to survival, and supportive care plays a large role in protection while the patient is in a neutropenic state. The most common invasive mycoses include the Aspergillus species, Zygomycetes, Candida spp., and Fusarium spp. Bacterial infections that are seen in patients with AA include gram-positive coagulase-negative Staphylococcus species, Enterococcus, Staphylococus aureus, Clostridium spp., Micrococcus, alpha-hemolytic streptococci, Listeria monocytogenes, and Bacillus cereus. Gram-negative infections including gram-negative bacilli, Escherichia coli, Salmonella, Bacteroides fragilis, Klebsiella oxytoca, Klebsiella pneumonia, Aeromonas hydrophilia, Pseudomonas aeruginosa, and Vibrio vulnificus. Viral infections are much less common but include those that belong to the Herpesviridae family, community-acquired respiratory viral infection, and the viral hepatitides A, B, and C. Evidence of the parasite Strongyloides stercoralis has also been documented. This review discusses the major invasive fungal infections, bacterial pathogens, parasites, and viral infections that are found in patients with AA who are treated with immunosuppressive therapy. The specific immune impairment and current treatment parameters for each of these classes of infection will also be discussed.

Community-Acquired Respiratory Viral Infections in Lung Transplant Recipients: A Single Season Cohort Study

The impact of community-acquired respiratory virus (CARV) infections on bronchiolitis obliterans syndrome (BOS) and outcome after lung transplantation (LTx) and diagnostic techniques were prospectively evaluated. A single-center prospective cohort study was performed in LTx-outpatients between October 31, 2005 and April 30, 2006. Symptoms of respiratory tract infections were recorded and nasopharyngeal and oropharyngeal swabs were obtained. Lower respiratory sampling was performed when indicated. Immunofluorescence testing, cultures, and polymerase chain reaction for 12 different CARV were applied. Patients were followed up until December 31, 2007. New onset and BOS-stage was recorded 1 year after presentation. Three hundred eighty-eight LTx-recipients were screened. Fifty-one percent reported of symptoms of respiratory tract infection. Seven hundred seventy upper and 180 lower respiratory samples were obtained. Thirty-four CARV were detected in 30 patients (7.7%): 12 parainfluenza, 7 respiratory syncytial virus, 6 metapneumovirus, 5 coronavirus, 3 rhinovirus, and 1 influenza virus. At 1 year, 43 new cases of BOS developed. One-year incidence of BOS was 25.0% in CARV-positive versus 9.0% in CARV-negative patients (log-rank P=0.01). Symptomatic CARV-infection proved to be a significant covariate for 1-year BOS-free survival in multivariate analysis (P=0.002, adjusted hazard ratio 4.13). CARV-infection did not influence BOS progression in 88 patients with prior BOS (P 0.45). After paramyxovirus infection, 8 of 24 patients developed new-onset BOS, whereas no case was recorded after rhinovirus and coronavirus infection. Surveillance detected CARV in LTx outpatients infrequently. Symptomatic CARV-infection increases the risk for new onset of BOS, but not progression. Risk to develop BOS was especially increased after paramyxovirus infection.

Impact of Immediate Primary Lung Allograft Dysfunction on Bronchiolitis Obliterans Syndrome

Primary graft dysfunction is a common complication after lung transplantation and a significant risk factor for short- and long-term mortality. We examined the impact of primary graft dysfunction on bronchiolitis obliterans syndrome. We performed a retrospective cohort study of 334 adult lung transplant recipients at our program and graded the severity of primary graft dysfunction according to the International Society for Heart and Lung Transplantation definition. We evaluated the impact of primary graft dysfunction on acute rejection, lymphocytic bronchitis, and bronchiolitis obliterans syndrome stage 1, using univariable and multivariable Cox proportional hazards models. Among the 334 recipients, 65 did not have primary graft dysfunction (grade 0), 130 had grade 1, 69 had grade 2, and 70 had grade 3. In the univariable analysis, all grades of primary graft dysfunction were associated with a significantly increased risk of bronchiolitis obliterans syndrome stage 1 (grade 1: relative risk [RR] = 1.73; grade 2: RR = 2.13; and grade 3: RR = 2.53, compared with grade 0). The multivariable model demonstrated that the increased risk of bronchiolitis obliterans syndrome associated with primary graft dysfunction was independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections. However, there was no association between primary graft dysfunction and acute rejection or lymphocytic bronchitis. Primary graft dysfunction is associated with an increased risk of bronchiolitis obliterans syndrome independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections, and this risk is directly related to the severity of primary graft dysfunction.

Respiratory Viral Infection in Obliterative Airway Disease After Orthotopic Tracheal Transplantation

The long-term survival after human lung transplantation is limited by bronchiolitis obliterans syndrome (BOS). Clinically, community-acquired respiratory viral infections have been correlated with an increased incidence of BOS. The goal of this study was to investigate the role of respiratory viral infections in chronic lung allograft rejection using the murine orthotopic tracheal transplantation model. Eighty orthotopic tracheal transplants were performed using BALB/c and C57BL/6 mice. Recipient mice were infected intranasally with Sendai virus (SdV), a murine parainfluenza type I virus. Experiments altering the infectious dose, infection time, harvest time, allogeneic response, and viral response were performed. Tracheal allograft rejection was monitored using percent fibrosis and lamina propria to cartilage ratio measurements. Interferon-gamma ELISPOT analysis against irradiated donor (BALB/c) splenocytes was used as immunologic indicator of alloreactivity after transplantation. Sendai virus infection revealed a dose-dependent transient suppression of alloreactivity with a decrease in tracheal allograft fibrosis and frequency of alloreactive T cells at 30 days. This immunosuppression was reversed by day 60, leading to increased tracheal allograft fibrosis with a concomitant increase in the frequency of interferon-gamma producing alloreactive T cells. Pretransplant sensitization with donor antigens prevented the initial suppression of alloreactivity due to SdV infection. Furthermore, pretransplant immunization against SdV infection resulted in rapid clearing of the infection and reduced the immunopathology of rejection. Respiratory viral infections can cause enhanced tracheal allograft rejection despite the initial phase of transient immunosuppression. Early treatment or vaccination against the respiratory infections may represent a viable intervention to reduce the risk of chronic rejection.