Elucidating allergic reaction mechanisms in response to SARS-CoV-2 mRNA vaccination in adults.

BACKGROUND: During the COVID-19 pandemic, novel nanoparticle-based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined. METHODS: To understand COVID-19 vaccine-mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors. Using standard hemolysis assays, we demonstrated that sera from allergic participants induced stronger complement activation compared to nonallergic subjects following ex vivo vaccine exposure. RESULTS: Vaccine-mediated complement activation correlated with anti-polyethelyne glycol (PEG) IgG (but not IgM) levels while anti-PEG IgE was undetectable in all subjects. Depletion of total IgG suppressed complement activation in select individuals. To investigate the effects of vaccine excipients on basophil function, we employed a validated indirect basophil activation test that stratified the allergic populations into high and low responders. Complement C3a and C5a receptor blockade in this system suppressed basophil response, providing strong evidence for complement involvement in vaccine-mediated basophil activation. Single-cell multiome analysis revealed differential expression of genes encoding the cytokine response and Toll-like receptor (TLR) pathways within the monocyte compartment. Differential chromatin accessibility for IL-13 and IL-1B genes was found in allergic and nonallergic participants, suggesting that in vivo, epigenetic modulation of mononuclear phagocyte immunophenotypes determines their subsequent functional responsiveness, contributing to the overall physiologic manifestation of vaccine reactions. CONCLUSION: These findings provide insights into the mechanisms underlying allergic reactions to COVID-19 mRNA vaccines, which may be used for future vaccine strategies in individuals with prior history of allergies or reactions and reduce vaccine hesitancy.

Routine Collection of Patient-Reported Outcomes in Thoracic Surgery: A Quality Improvement Study.

BACKGROUND: Patient-reported outcomes are critical for delivering high-quality surgical care, yet they are seldom collected in routine clinical practice. The objective of this quality improvement study was to improve routine patient-reported outcomes collection in a thoracic surgery clinic. METHODS: Thoracic surgery patients at a single academic institution were prospectively monitored from April 2019 to March 2020. The National Institutes of Health-validated Patient-Reported Outcomes Measurement Information System (PROMIS) was used. Using a Model for Improvement design and through multidisciplinary participant observation, we performed multiple plan-do-study-act cycles, an iterative, 4-stage model for rapidly testing interventions, to improve routine collection reliability. RESULTS: During the study period, 2315 patient visits occurred. The baseline PROMIS assessment collection rate was 53%. After convening a multidisciplinary stakeholder team, the key drivers for PROMIS collection were having engaged staff, engaged patients, adequate technological capacity, and adequate time for survey completion, including when to complete the survey during the patient visits. Regular meetings between stakeholders were initiated to promote these key drivers. Several plan-do-study-act cycles were then used to test different interventions, resulting in several positive system shifts, as demonstrated on a statistical process control chart. Adherence to survey collection reached 91% of office visits by approximately 7 months, a 72% relative improvement, which was sustained. CONCLUSIONS: Routine collection of patient-reported outcomes, such as PROMIS, are critical for improving thoracic surgical care. Our study shows that reliably collecting these data is possible in a clinical setting with minimal additional hospital resources.

Donor management using a specialized donor care facility is associated with higher organ utilization from drug overdose donors.

Drug overdoses have tripled in the United States over the last two decades. With the increasing demand for donor organs, one potential consequence of the opioid epidemic may be an increase in suitable donor organs. Unfortunately, organs from donors dying of drug overdose have poorer utilization rates than other groups of brain-dead donors, largely due to physician and recipient concerns about viral disease transmission. During the study period of 2011 to 2016, drug overdose donors (DODs) account for an increasingly greater proportion of the national donor pool. We show that a novel model of donor care, known as specialized donor care facility (SDCF), is associated with an increase in organ utilization from DODs compared to the conventional model of hospital-based donor care. This is likely related to the close relationship of the SDCF with the transplant centers, leading to improved communication and highly efficient donor care.

Comparison of outcomes in lung and heart transplant recipients from the same multiorgan donor.

BACKGROUND: Primary graft dysfunction (PGD) and acute cellular rejection (ACR) are important causes of early morbidity and mortality following lung and heart transplantation. While many studies have elucidated donor-related risk factors of PGD and ACR, these complications often occur even with "ideal" donors. Therefore, we investigated potential associations of PGD and ACR between bilateral lung and heart transplant recipients from the same multiorgan donor, respectively. METHODS: Between 2011 and 2017, 100 donors contributed 100 bilateral lung transplants and 100 heart transplants performed. Logistic regression analysis for PGD and Cox proportional hazards regression analysis for ACR were used to estimate the relationship of heart and lung transplants. RESULTS: The incidence of PGD was 33% among lung and 17% among heart transplant recipients. Similarly, the incidence of ACR grade ≥ A2 for lung recipients was 38% (30/80), and the incidence of ACR grade ≥ 2R for heart recipients was 19% (15/80). There was no association between the development of PGD and ACR in lung and heart transplant recipients from the same donor, respectively. CONCLUSIONS: These findings suggest that inherent donor factors are not critical to the development of PGD and ACR after lung and heart transplantation.

The impact of pre-transplant allosensitization on outcomes after lung transplantation.

BACKGROUND: Allosensitization can be a significant barrier to transplantation for some patients, and previous studies suggested that pre-transplant allosensitization was associated with worse outcomes after lung transplantation. However, human leukocyte antigen (HLA) antibody testing has evolved significantly over the past 10 years, and current assays are highly sensitive and specific. METHODS: We examined the impact of pre-transplant allosensitization on post-transplant outcomes in the era of solid-phase multiplex HLA antibody detection assays in this retrospective, single-center study of 304 adult transplant recipients between January 1, 2006, and December 31, 2012. We accepted donor organs for allosensitized patients if a virtual crossmatch was compatible with all previously identified antibodies. RESULTS: In univariate and multivariate Cox proportional hazards models, pre-transplant allosensitization, the calculated panel reactive antibody, and the number of pre-transplant HLA antibodies were not associated with the development of acute cellular rejection, lymphocytic bronchiolitis, donor-specific HLA antibodies, chronic lung allograft dysfunction, or graft failure. CONCLUSIONS: Pre-transplant allosensitization does not adversely affect outcomes after lung transplantation when the potentially reactive HLAs are avoided in the donor by a virtual crossmatch with the recipient.

Attaining proficiency with endobronchial ultrasound-guided transbronchial needle aspiration.

OBJECTIVES: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is becoming the preferred method of mediastinal staging for lung cancer. We investigated the learning curve for EBUS-TBNA using risk-adjusted cumulative sum (Cusum). METHODS: A retrospective study of EBUS-TBNA was performed at a single academic institution for patients with mediastinal or hilar lymphadenopathy in the setting of proven or suspected lung cancer. A sampling pass was defined as a full retraction and repositioning of the aspiration needle. Rapid on-site evaluation was not available. To track proficiency, risk-adjusted Cusum analysis was performed using acceptable and unacceptable failure rates of 10% and 20%, respectively. Failure was defined as false negative or nondiagnostic results. RESULTS: During the study period, 231 patients underwent EBUS-TBNA. Prevalence of mediastinal or hilar malignancy was 66.7% (154 out of 231). Sensitivity was 92.2% (142 out of 154), and negative predictive value was 87.9% (58 out of 66). Node size was identified as a significant predictor of EBUS-TBNA success by multiple regression. Risk-adjusted Cusum analysis demonstrated that the first and only unacceptable decision interval was crossed at 22 cases. Individual practitioner learning curves were highly variable, and the operator with the highest volume was the most consistently proficient. CONCLUSIONS: In our experience, attainment of an acceptable failure rate for EBUS-TBNA required 22 cases. Node size is a predictor of EBUS-TBNA success. Risk-adjusted Cusum proved a powerful evaluative tool to monitor the training process of this new procedure.

Pre-transplant antibodies to Kα1 tubulin and collagen-V in lung transplantation: clinical correlations.

BACKGROUND: Immune responses to lung-associated self-antigens (SAgs) have been implicated in chronic lung allograft rejection. The goals of this study were to determine the prevalence of pre-existing antibodies (Abs) to the SAgs in pulmonary diseases and the association between pre-existing Abs to SAgs and the development of primary graft dysfunction (PGD), donor-specific antibodies (DSA), and chronic rejection. METHODS: Pre- and post-transplant sera were analyzed from 317 lung transplant (LTx) recipients between 2000 and 2011 with diagnosis of chronic obstructive disease (n = 161), idiopathic pulmonary fibrosis (IPF; n = 50), cystic fibrosis (CF; n = 55), and others (n = 51). Samples were analyzed for Abs to SAgs by enzyme-linked immunosorbent assay, and DSA and cytokines by Luminex. The clinical diagnosis of PGD and bronchiolitis obliterans syndrome (BOS) was based on International Society for Heart and Lung Transplantation guidelines. RESULTS: The overall prevalence of Abs to SAgs was 22.71%, including 18% in chronic obstructive pulmonary disease (p = 0.033), 34% in IPF (p = 0.0006), 29% in CF (p = 0.0023), and 19.6% in other diagnoses (p = 0.044). The incidence of PGD (88% vs 54%, p < 0.05), DSA (70% vs 45%, p < 0.01), and BOS (90% vs 38% (p < 0.001) after LTx was significantly higher in patients with pre-LTx Abs to SAgs than without. Pro-inflammatory cytokines (interleukin-1ß, interleukin-17, and interferon-γ) were elevated in patients who had pre-LTx Abs to SAgs, along with a reduction in anti-inflammatory interleukin-10. CONCLUSIONS: Patients with IPF and CF have the highest prevalence of Abs to SAgs. Patients with pre-existing Abs to SAgs are at increased risk for development of PGD, DSA, and BOS. Strategies to remove pre-existing Abs to SAgs should be considered to improve lung allograft outcome.

Vulnerability to somatic symptoms of depression during interferon-alpha therapy for hepatitis C: a 16-week prospective study.

OBJECTIVE: This study evaluated the distinctive clinical and biological manifestations of depressive symptom subtypes (i.e., cognitive-affective and somatic) in Veterans with hepatitis C viral infection (HCV) before and during interferon-alpha (IFN) based antiviral therapy. METHODS: Thirty-two Veterans with HCV and no prior history of IFN therapy were followed prospectively during the first 16weeks of therapy to evaluate depressive symptoms and to determine if baseline cytokine and serotonin levels predicted subsequent changes in depressive scores. RESULTS: IFN therapy resulted in a significant increase in total depressive symptoms from baseline (week 0) to week 16, with neurovegetative and somatic symptoms of depression including loss of appetite, fatigue and irritability increasing within the first two weeks of therapy and continuing to increase throughout IFN therapy. When depressive symptoms were evaluated using a two-factor (i.e., Cognitive-Affective and Somatic) model, the Cognitive-Affective factor score did not change significantly following IFN therapy initiation, while the Somatic factor score showed a significant increase from week 0 to week 16. Veterans with the largest increases in somatic symptoms from week 0 to week 2 had significantly higher levels of tumor necrosis factor-alpha (TNF-α) and lower levels of serotonin at baseline, as compared to Veterans with minimal or no increase in somatic symptoms. CONCLUSION: Somatic symptoms of depression can be significantly exacerbated during IFN therapy and may be predicted by higher TNF-α levels and lower serotonin levels at baseline.

Antibodies to MHC class II molecules induce autoimmunity: critical role for macrophages in the immunopathogenesis of obliterative airway disease.

Previous studies have shown that intrabronchial administration of antibodies (Abs) to MHC class I resulted in development of obliterative airway disease (OAD), a correlate of chronic human lung allograft rejection. Since development of Abs specific to mismatched donor HLA class II have also been associated with chronic human lung allograft rejection, we analyzed the role of Abs to MHC class II in inducing OAD. Administration of MHC class II Abs (M5/114) to C57BL/6 mice induced the classical features of OAD even though MHC class II expression is absent de novo on murine lung epithelial and endothelial cells. The induction of OAD was accompanied by enhanced cellular and humoral immune responses to self-antigens (Collagen V and K- α1Tubulin). Further, lung-infiltrating macrophages demonstrated a switch in their phenotype predominance from MΦ1 (F4/80(+)CD11c(+)) to MΦ2 (F4/80(+)CD206(+)) following administration of Abs and prior to development of OAD. Passive administration of macrophages harvested from animals with OAD but not from naïve animals induced OAD lesions. We conclude that MHC class II Abs induces a phenotype switch of lung infiltrating macrophages from MΦ1 (F4/80(+)CD11c(+)) to MΦ2 (F4/80(+)CD206(+)) resulting in the breakdown of self-tolerance along with an increase in autoimmune Th17 response leading to OAD.

Smoking cigarettes as a coping strategy for chronic pain is associated with greater pain intensity and poorer pain-related function.

UNLABELLED: Smoking cigarettes is prevalent among individuals with chronic pain. Some studies indicate nicotine reduces pain and others suggest it may cause or exacerbate pain. Participants in this cross-sectional study were 151 chronic pain patients from a large, urban VA medical center. Patients were divided into 3 groups: 1) nonsmokers; 2) smokers who deny using cigarettes to cope with pain; and 3) smokers who report using cigarettes to cope with pain. Patients who reported smoking as a coping strategy for chronic pain scored significantly worse compared with the other 2 groups on the majority of measures of pain-related outcome. Nonsmokers and smokers who denied smoking to cope did not differ on any variable examined. After controlling for the effects of demographic and clinical factors, smoking cigarettes as a coping strategy for pain was significantly and positively associated with pain intensity (P = .04), pain interference (P = .005), and fear of pain (P = .04). In addition to assessing general smoking status, a more specific assessment of the chronic pain patient's reasons for smoking may be an important consideration as part of interdisciplinary pain treatment. PERSPECTIVE: This paper describes the relationship between smoking cigarettes as a mechanism to cope with chronic pain and pain-related outcome. Understanding this relationship may illuminate the broader relationship between smoking and chronic pain and provide new directions for effective interdisciplinary pain treatment.

Screening for depression in patients with hepatitis C using the Beck Depression Inventory-II: do somatic symptoms compromise validity?

OBJECTIVE: The objective of the study was to evaluate the validity of the Beck Depression Inventory-II (BDI-II) when used to measure depression in patients with hepatitis C virus (HCV). METHOD: Factor analysis was utilized to validate the BDI-II in a sample of 671 patients with HCV recruited from a large Veterans Affairs medical center. The data were split randomly: the first half was subjected to exploratory factor analysis, and confirmatory factor analysis was used with the second half to confirm the model. Diagnostic data were retrieved from the electronic medical records. RESULTS: Subjects were 97.0% male, average age was 52.8 years, 16.1% had a cirrhosis diagnosis, 62.9% had a current major depressive disorder diagnosis, and 42.3% endorsed significant depressive symptoms on the BDI-II. A two-factor model was an excellent fit for the data; the factors were labeled Cognitive-Affective and Somatic. Patients scored significantly higher on the Somatic factor than on the Cognitive-Affective factor (P<.001), and this discrepancy increased when comparing patients based on whether they had a diagnosis of cirrhosis. CONCLUSIONS: When screening for depression in HCV patients, questions targeting cognitive and affective symptoms of depression may provide a more valid measurement of depression than questions targeting somatic symptoms of depression, particularly for patients with more advanced liver disease.

Synergistic effect of antibodies to human leukocyte antigens and defensins in pathogenesis of bronchiolitis obliterans syndrome after human lung transplantation.

BACKGROUND: This study aims to determine the role of antibodies to donor-mismatched human leukocyte antigen (HLA) developed during the post-transplant period in inducing defensins and their synergistic role in the pathogenesis of chronic rejection, bronchiolitis obliterans syndrome (BOS), after human lung transplantation (LTx). METHODS: Bronchoalveolar lavage (BAL) and serum from 21 BOS+ LTx patients were assayed for ß-defensins human neutrophil peptides (HNP) 1-3 (enzyme-linked immunosorbent assay [ELISA]) and anti-HLA antibodies (Luminex, Luminex Corp, Austin, TX). Human airway epithelial cells (AEC) were treated with anti-HLA antibodies, HNP-1/2, or both, and the levels of ß-defensin were measured by ELISA. Using a mouse model of obliterative airway disease induced by anti-major histocompatibility (MHC) class-I antibodies, we quantitatively and qualitatively determined neutrophil infiltration by myeloperoxidase (MPO) staining and activity by MPO assay, and defensin levels in the BAL. RESULTS: In human LTx patients, higher defensin levels correlated with presence of circulating anti-HLA antibodies (p < 0.05). AEC treated with anti-HLA antibodies or HNP-1/2, produced ß-defensin with synergistic effects in combination (612 ± 06 vs 520 ± 23 pg/ml anti-HLA antibody, or 590 ± 10 pg/ml for HNP treatment; p < 0.05). Neutrophil numbers (6-fold) and activity (5.5-fold) were higher in the lungs of mice treated with anti-MHC antibodies vs control. A 2-fold increase in α-defensin and ß-defensin levels was also present in BAL on Day 5 after anti-MHC administrations. CONCLUSIONS: Anti-HLA antibodies developed during the post-transplant period and α-defensins stimulated ß-defensin production by epithelial cells, leading to increased cellular infiltration and inflammation. Chronic stimulation of epithelium by antibodies to MHC and resulting increased levels of defensins induce growth factor production and epithelial proliferation contributing to the development of chronic rejection after LTx.

Risk of recurrence of resected stage I non-small cell lung cancer in elderly patients as compared with younger patients.

PURPOSE: Half of all patients with non-small cell lung cancer (NSCLC) are 70 years or older at the time of diagnosis. Surgery is an option for fit elderly patients with early stage disease, but rates of disease recurrence after surgical resection are not well described. We report the outcomes in elderly patients (70 years or older) with stage I NSCLC after surgical resection. PATIENTS AND METHODS: We conducted a retrospective study of patients diagnosed with stage I NSCLC after surgical resection at Washington University School of Medicine-Alvin J. Siteman Cancer Center from 1990 to 2000. Demographic, pathologic, treatment, and follow-up data were collected. Recurrence rates and overall survival were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were used to detect associations between potential prognostic factors and survival and recurrence. RESULTS: Of the 715 patients with stage I NSCLC, 286 were 70 years or older at diagnosis. In this elderly cohort, the median age was 74 years (range, 70-89 years) and 140 of them were women (49%). Lobectomy was performed in 237 patients (83%) whereas 43 patients (15%) had a wedge or segmental resection, and six patients (2%) underwent pneumonectomy. Clinical and pathologic characteristics were not statistically different between the elderly and younger cohorts, with the exception that older patients were more likely to be white (90% versus 80%, p = 0.0003) and less likely to be smokers (88% versus 95%, p = 0.019) compared with the younger cohort. With a median follow-up of 4.6 years, the overall 5-year survival rate was 52% with a 5-year recurrence rate of 24%. In comparison, the patients younger than 70 years had a 5-year survival rate of 67% (p < 0.001) and a 5-year recurrence rate of 24%. CONCLUSIONS: Although overall survival was worse in elderly patients, estimated disease recurrence rates after resection were identical.

Esophageal carcinoma with celiac nodal metastases; curative or palliative?

INTRODUCTION: To determine the prognostic value of celiac lymphadenopathy for patients with esophageal or gastroesophageal junction carcinomas treated with neoadjuvant or definitive chemoradiotherapy. METHODS: The records of patients undergoing chemoradiation therapy for esophageal cancer, who received a dose of at least 45 Gy, were retrospectively reviewed. RESULTS: One hundred forty-four patients were eligible for this retrospective analysis; 99 had M0 and 45 M1a disease. The median radiation dose was 50.4 Gy for patients receiving both neoadjuvant and definitive chemoradiotherapy. After a median follow-up of 15 months, the 2-year overall survival for the entire cohort was 45% and 20% in M0 and M1a groups, respectively (p < 0.001). On multivariate analysis, the most significant factors for overall survival were performance status (p < 0.001) and M1a status (p < 0.001). The patients who underwent definitive concomitant chemoradiation had a 2-year overall survival of 36% and 15% in M0 and M1a, respectively (p = 0.03). For patients who underwent neoadjuvant chemoradiation followed by surgery, the 2-year overall survival was 63% and 37% in M0 and M1a, respectively (p = 0.07). CONCLUSIONS: M1a status is a strong predictor of poor outcome for patients with cancers of the esophagus or gastroesophageal junction. For patients receiving concurrent chemotherapy and radiation therapy for M1a esophageal cancer, treatment is largely palliative.

A clinical model to estimate recurrence risk in resected stage I non-small cell lung cancer.

OBJECTIVE: There are no reliable markers to predict recurrence in resected Stage I non-small cell lung cancer (NSCLC). A validated clinical model to estimate the risk of recurrence would help select patients for adjuvant therapy. METHODS: We reviewed the medical records of 715 patients who had a potentially curative resection for Stage I NSCLC at our institution from 1990 to 2000. Recurrence rates were estimated by the Kaplan-Meier method. A model to estimate risk of recurrence was developed by combining independent risk factors. RESULTS: With a median follow-up of 4.7 years, the 5-year survival rates for Stages IA and IB were 66% and 55% respectively, and 5-year recurrence rates were 19% and 30%, respectively. Four factors were independently associated with tumor recurrence: tumor size >3 cm (hazard ratio [HR] = 2.4), surgery other than lobectomy (HR = 2.0), nonsquamous histology (HR = 1.4), and high-grade cellular differentiation (HR = 1.4). A scoring system for recurrence was developed by assigning 2 points for each major risk factor (tumor size and surgery) and 1 point for each minor risk factor (histologic subtype and cellular grade). Scores were grouped as low (0-1), intermediate (2-3), and high (>3), yielding 5-year estimates of risk of recurrence of 14%, 27%, and 43%, respectively. CONCLUSION: This model, based upon readily available clinicopathologic characteristics, can estimate the risk of recurrence in Stage I NSCLC, independent of T classification. This model could be used to select patients for adjuvant therapy if validated in independent data sets.

Prognostic value of preoperative positron emission tomography in resected stage I non-small cell lung cancer.

PURPOSE: Approximately 20 to 40% of patients with surgically resected stage I non-small cell lung cancer (NSCLC) will develop recurrent disease. Positron emission tomography (PET) with 2-[18F] fluoro-2-deoxy-D-glucose (FDG) is used often in staging NSCLC. We conducted this study to determine whether the preoperative maximum tumor standardized uptake value (SUVmax) was associated with recurrence in patients with resected stage I NSCLC. PATIENTS AND METHODS: We identified consecutive patients who underwent curative surgical resection for stage I NSCLC between 1999 and 2003 who had preoperative FDG-PET imaging. Patients were divided into two cohorts based on SUVmax above or below the median for the group. Recurrence rates were estimated by the Kaplan-Meier method and overall survival was analyzed as a secondary end point. RESULTS: Of 136 patients who met inclusion criteria, 77 (57%) had T1 and 59 (43%) had T2 tumors. The median follow-up time was 46 months and 32 patients had a disease recurrence. The median SUVmax was 5.5. The 5-year estimates of recurrence rates for patients with low and high SUVmax were 14% and 37%, respectively (p = 0.002), with 5-year overall survivals of 74% and 53%, respectively (p = 0.006). In multivariate analyses based on SUVmax, T-classification, age, and histology, high SUVmax was independently associated with recurrence (p = 0.002) and mortality (p = 0.041). CONCLUSION: High SUVmax (>or=5.5) on preoperative FDG-PET is an independent predictor of relapse and death in resected stage I NSCLC. Prospective trials of adjuvant chemotherapy in patients with stage I NSCLC and high SUVmax should be considered.

Soluble CD30 levels as a diagnostic marker for bronchiolitis obliterans syndrome following human lung transplantation.

The long term survival of human lung allograft is hampered by the occurrence of chronic rejection, Bronchiolitis Obliterans Syndrome (BOS). This end-stage disease is normally diagnosed clinically by using the pulmonary function tests. This results in delay of BOS diagnosis and consequently prevents early intervention. It is generally accepted that alloimmunity plays an important role in chronic rejection of the allograft. In this study we analyzed serial serum samples from BOS+ and BOS- patients for sCD30 levels to determine the role of sCD30 to predict the onset of BOS. In contrast to BOS negative patients and normal subjects, 6 out of 9 BOS+ patients (p<0.05) studied had an increase in the sCD30 levels. Significantly, the rise was noted 7.57+/-2.63 months before the clinical diagnosis was evident. Therefore, we propose that the rise in serum sCD30 levels can be used as a marker for the detection of patients who are at risk of development of BOS.

Respiratory viral infection in obliterative airway disease after orthotopic tracheal transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.