Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination.

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

Utility of Transbronchial Biopsy in the Immunocompromised Host With New Pulmonary Radiographic Abnormalities.

OBJECTIVE: To assess how often transbronchial biopsy (TBBx) added unique positive findings apart from other synchronous bronchoscopic sampling techniques including the bronchoalveolar lavage-immunocompromised host (BAL-ICH) panel that justified changes in management in an array of immunocompromised patients with new pulmonary radiographic abnormalities. METHODS: We retrospectively reviewed all bronchoscopies performed at Mayo Clinic Rochester between January 2012 and December 2017; on the basis of the physician's selection of a BAL-ICH panel, we identified 192 immunocompromised patients who underwent bronchoscopy with both a BAL-ICH panel and TBBx. The results of the BAL-ICH panel and TBBx were compared and subsequent management decisions analyzed from clinical notes. We identified changes in immunosuppressive agents, antibiotics, chemotherapy, goals of care, and decisions on further evaluation and procedures. We assessed whether the TBBx findings added information not identified on the BAL-ICH panel and other bronchoscopic sampling methods performed during the same procedure that justified subsequent management changes. RESULTS: Of 192 bronchoscopic procedures performed on immunocompromised patients with acute and subacute pulmonary radiographic abnormalities, management changes justified by the unique positive results of the TBBx occurred 28% (51/192) of the time. Those immunocompromised by solid malignant neoplasms and receiving active immunosuppressive therapy had management changes justified 62.1% (18/29) of the time by the TBBx results. No additional fungal organisms were identified on TBBx that were accounted for on the BAL-ICH panel. CONCLUSION: Transbronchial biopsy may add information to other bronchoscopic findings in immunocompromised patients, especially those with solid malignant neoplasms receiving active immunosuppressive treatment. These potential benefits must be weighed against the risks inherent to the procedure.

Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.

RATIONALE: An efficacious medical therapy for idiopathic pulmonary fibrosis (IPF) remains elusive. OBJECTIVES: To explore the efficacy and safety of etanercept in the treatment of IPF. METHODS: This was a randomized, prospective, double-blind, placebo-controlled, multicenter exploratory trial in subjects with clinically progressive IPF. Primary endpoints included changes in the percentage of predicted FVC and lung diffusing capacity for carbon monoxide corrected for hemoglobin (Dl(CO(Hb))) and change in the alveolar to arterial oxygen pressure difference P(a-a)(O(2)) at rest from baseline over 48 weeks. MEASUREMENTS AND MAIN RESULTS: Eighty-eight subjects received subcutaneous etanercept (25 mg) or placebo twice weekly as their sole treatment for IPF. No differences in baseline demographics and disease status were detected between treatment groups; the mean time from first diagnosis was 13.6 months and mean FVC was 63.9% of predicted. At 48 weeks, no significant differences in efficacy endpoints were observed between the groups. A nonsignificant reduction in disease progression was seen in several physiologic, functional, and quality-of-life endpoints among subjects receiving etanercept. There was no difference in adverse events between treatment groups. CONCLUSIONS: In this exploratory study in patients with clinically progressive IPF, etanercept was well tolerated. Although there were no differences in the predefined endpoints, a decreased rate of disease progression was observed on several measures. Further evaluation of TNF antagonists in the treatment of IPF may be warranted. Clinical trial registered with www.clinicaltrials.gov (NCT 00063869).

A 52-Year-Old Woman With an Abdominal Mass, Bilateral Pulmonary Nodules, and Mediastinal and Hilar Lymphadenopathy.

CASE PRESENTATION: A 52-year-old, nonsmoking, African-American woman with a history of obesity, hypertension, and rheumatoid arthritis was referred for workup of multiple bilateral pulmonary nodules. The pulmonary nodules were discovered incidentally while undergoing a CT scan for an abdominal mass that was radiographically diagnosed as a uterine leiomyoma. She was asymptomatic from a pulmonary standpoint without unintentional weight loss, fevers, or night sweats. Her mother and sister had a history of lung cancer. She was diagnosed with rheumatoid arthritis 5 years earlier that was controlled with adalimumab for approximately 3 years when she stopped being seen by her rheumatologist and discontinued adalimumab. During evaluation for the abdominal mass, she re-established care with a rheumatologist and was started on 40 mg prednisone daily with plans to restart adalimumab once the workup for the abdominal mass and pulmonary nodules was completed. She had undergone bariatric surgery with cholecystectomy approximately 5 years earlier, after which she experienced intentional postsurgical weight loss.

Genetic determinants of emphysema distribution in the national emphysema treatment trial.

RATIONALE: Computed tomography (CT) scanning of the lung may reduce phenotypic heterogeneity in defining subjects with chronic obstructive pulmonary disease (COPD), and allow identification of genetic determinants of emphysema severity and distribution. OBJECTIVES: We sought to identify genes associated with CT scan distribution of emphysema in individuals without alpha1-antitrypsin deficiency but with severe COPD. METHODS: We evaluated baseline CT densitometry phenotypes in 282 individuals with emphysema enrolled in the Genetics Ancillary Study of the National Emphysema Treatment Trial, and used regression models to identify genetic variants associated with emphysema distribution. MEASUREMENTS AND MAIN RESULTS: Emphysema distribution was assessed by two methods--assessment by radiologists and by computerized density mask quantitation, using a threshold of -950 Hounsfield units. A total of 77 polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. GSTP1, EPHX1, and MMP1 polymorphisms were associated with the densitometric, apical-predominant distribution of emphysema (p value range = 0.001-0.050). When an apical-predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 single-nucleotide polymorphisms were found to be significantly associated. In a case-control analysis of COPD susceptibility limited to cases with densitometric upper-lobe-predominant cases, the EPHX1 His139Arg single-nucleotide polymorphism was associated with COPD (p = 0.005). CONCLUSIONS: Apical and basal emphysematous destruction appears to be influenced by different genes. Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution, and these findings may lead to further insight into genetic determinants of emphysema.

Extracellular matrix fistula plug for repair of bronchopleural fistula.

INTRODUCTION: Bronchopleural fistula (BPF) is a feared complication of pulmonary resection. Fistula plugs (FP) have been described as an adequate treatment in anorectal disease. We describe our early experience placing an FP in the treatment of BPF. MATERIALS AND METHODS: We retrospectively reviewed 5 patients for whom a FP was placed for BPF at our institution. Demographic data, initial perioperative information, method and technique of FP placement, and success is reported. RESULTS: Five patients (4 male, 1 female) with a median age of 63 years (range, 57-76 years) underwent 6 FP placements for BPF. Two patients were post-pneumonectomy and 3 patients post-lobectomy. The median time to presentation following surgery was 118 days (range 22-218). Upon bronchoscopic or operative re-evaluation, 3 patients had successful cessation of their air leak at 0, 1 and 4 days. Two of three patients subsequently underwent a thoracic muscle flap placement to augment healing. One patient had a persistent air leak despite 2 separate FP placements. The air leak stopped with endobronchial valves (EBV) which were deployed proximal to the FP, 9 days after placement of the FP. Another patient had a successful muscle flap placed 80 days after FP placement. There were no complications associated with the FP. Three of five patients were deemed successfully treated with FP placement alone. CONCLUSION: In patients with a postoperative BPF and pleural window, placement of a FP had a modest success rate and can be considered as a treatment modality option for BPF.

Management and outcomes of cardiac sarcoidosis: a 20-year experience in two tertiary care centres.

AIMS: Cardiac sarcoidosis (CS) often presents with ventricular arrhythmias, heart block, and cardiomyopathy. The prognosis of CS with contemporary management is uncertain. We estimated the impact of baseline and treatment variables on left ventricular ejection fraction (LVEF), ventricular assist device placement, heart transplant, and death. METHODS AND RESULTS: We identified patients with CS seen from 1994-2014 at two large academic medical centres. All met the 2014 Heart Rhythm Society expert consensus criteria for diagnosis. From the 574 patients identified, 91 met inclusion criteria. Twenty-two (24.2%) were diagnosed by endomyocardial biopsy. Cardiomyopathy was the primary presentation in 47 patients (51.6%). Within 90 days of diagnosis, 41 patients (45.0%) received prednisone alone, 29 (31.9%) received alternative immunosuppression with or without prednisone, and 21 (23.1%) received no immunosuppression. During follow-up, 31 of 47 cardiomyopathy patients experienced improvement in LVEF, while 23 experienced decline in LVEF or clinical exacerbation, and 15 of 22 patients presenting with ventricular arrhythmia had recurrence. These results did not differ by treatment group. During a median follow-up of 44 months for our cohort, 14 patients reached the composite endpoint of ventricular assist device placement, heart transplant, or death. Survival without the composite outcome did not differ by treatment group, but was worse among patients presenting with cardiomyopathy (log-rank = 0.005). CONCLUSION: In a large series of CS subjects, rates of ventricular arrhythmia and heart failure events remain high with no treatment regimen clearly associated with better outcome. Patients with cardiomyopathy at diagnosis were more likely to reach the composite endpoint.

Clinical Correlates and Treatment Outcomes for Patients With Short Telomere Syndromes.

Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.

Organizing pneumonia in patients with hematologic malignancies: a steroid-responsive lesion.

BACKGROUND: Organizing pneumonia (OP) is a distinct histopathologic lesion that occurs in a variety of clinical contexts. There have been occasional reports of OP occurring in patients with hematologic malignancies. STUDY OBJECTIVES: To examine the association of OP with hematologic malignancies and to assess the clinical course of affected patients. DESIGN: A retrospective review of our institutional experience of unexplained OP developing in patients with hematologic malignancies. SETTING: Tertiary care, referral medical center. PATIENTS: We identified 6 patients with a verified histopathologic diagnosis of OP and antecedent or concomitant diagnosis of a hematologic malignancy from the Mayo Clinic database (1995-2003). Clinical, radiologic, and outcome data were abstracted from records. RESULTS: Underlying hematologic disorders included lymphoma (2), acute leukemia (2), cutaneous T-cell lymphoma (1), and myelodysplastic syndrome (1). OP was diagnosed by surgical lung biopsy in 4 and bronchoscopic biopsy in 2. Four of the 6 patients had previously been exposed to chemotherapeutic agents, two had not. Three of the 6 patients had bone marrow transplantation prior to development of OP. Five patients were treated with prednisone and all experienced symptomatic improvement with documented radiologic resolution in 4. One patient experienced symptomatic and radiologic resolution with observation alone. Three patients ultimately died from complications of their underlying hematologic disorder and 1 patient died of unknown causes. Two patients were alive without respiratory complaints more than 1 year after lung biopsy. CONCLUSIONS: OP occurs in patients with underlying hematologic malignancies who may or may not have been treated with chemotherapy and responds favorably to corticosteroid therapy.

Mediastinal Solitary Fibrous Tumor Diagnosed by Endobronchial Ultrasound-Directed Biopsy.

BACKGROUND Solitary fibrous tumors of the middle mediastinal space are uncommon and often not discovered until symptoms secondary to compression of adjacent structures occur. Diagnosis requires surgical biopsy and histological tissue analysis. We describe the ECHO appearance of the solitary fibrous tumor and successful non-invasive EBUS diagnosis. This method of diagnosis allowed for surgical planning for resection and allowed us to exclude non-surgical diseases, such as small cell carcinoma. CASE REPORT A 32-year-old man presented to his primary care physician with worsening intermittent chronic chest pain with recent progressive dysphagia, cough, and dyspnea. Physical examination and routine laboratory work-up were unrevealing. Chest radiograph and computed tomography (CT) of the chest revealed a middle mediastinal mass. Flexible bronchoscopy confirmed extrinsic compression of right and left bronchial trees. Endobronchial ultrasound (EBUS) was used to biopsy the mass and the diagnosis of solitary fibrous tumor was confirmed. The patient underwent successful tumor resection and was discharged home after an uneventful postoperative period. CONCLUSIONS Endobronchial ultrasound-directed tissue biopsy is an appropriate modality for suspected solitary fibrous tumors of the mediastinum. To our knowledge, this is only the second reported case of SFT diagnosed by EBUS-TBNA. Our case uniquely demonstrates the advantages of pre-surgical diagnosis of mediastinal masses with EBUS-TBNA when the diagnosis SFT is suggested on CT and US imaging.

Nontraumatic disruption of the fibrocartilaginous trachea: causes and clinical outcomes.

BACKGROUND: Nontraumatic disruption of the fibrocartilaginous trachea is rare, and the appropriate management of this condition is not well-characterized. METHODS: Retrospective analysis of the clinical features, causes, and outcomes with surgical and nonsurgical management in nine adult patients with nontraumatic fibrocartilaginous tracheal disruption identified by bronchoscopy from January 1, 1975, to December 31, 2004, at a single institution. RESULTS: The most common cause was external beam radiotherapy (RT) in five patients. Other causes included postoperative complications of cervical and superior mediastinal operations in three patients and Aspergillus fumigatus-induced ulcerative tracheobronchitis in one patient post-lung transplantation. Four patients were treated surgically; three because of significant pneumomediastinum and one because the size of the tracheal defect made spontaneous healing seem unlikely. A silicone stent was placed in one patient for concomitant tracheal narrowing, and one patient was treated medically with antifungal agents. The remaining three patients were followed up serially without any intervention. With these treatments, only one patient died as a consequence of tracheal disruption. Repeat bronchoscopies were performed in seven of the remaining eight patients and confirmed healing of the necrotic defect in all. CONCLUSION: Nontraumatic disruption of the fibrocartilaginous trachea occurs most commonly as a consequence of external beam RT. It can also occur as a complication of cervical and superior mediastinal operations or from A fumigatus-induced ulcerative tracheobronchitis post-lung transplantation. Although surgical treatment has been generally recommended for patients with this condition, patients with contained disruptions without evidence of pneumomediastinum may be managed nonoperatively.

Epidemiology of Sarcoidosis 1946-2013: A Population-Based Study.

OBJECTIVE: To characterize the epidemiology of sarcoidosis from 1946 through 2013. PATIENTS AND METHODS: An inception cohort of patients with incident sarcoidosis from January 1, 1976, through December 31, 2013, in Olmsted County, Minnesota, was identified based on comprehensive individual medical record review. Inclusion required physician diagnosis supported by histopathologic confirmation, radiologic features of intrathoracic sarcoidosis, and a compatible clinical presentation. Data were collected on demographic characteristics, clinical presentation, laboratory investigations, and mortality. The data were augmented with a previously identified cohort of Olmsted County residents diagnosed as having sarcoidosis in 1946-1975. Incidence rates were age and sex adjusted to the 2010 US white population. RESULTS: A total of 448 incident cases of sarcoidosis were identified (mean age, 44.2 years; 52% women). The annual incidence of sarcoidosis was 10.0 per 100,000 population. The incidence of sarcoidosis increased in women from 1950 to 1960, but otherwise there were no significant calendar year trends. However, the peak age at incidence for women shifted from 40 to 59 years in 1950 to 50 to 69 years in 2010. Similarly, the peak age at incidence for men shifted from 30 to 49 years in 1950 to 40 to 59 years in 2010. Ninety-seven percent of patients had intrathoracic involvement, but only 43% had respiratory symptoms. The overall mortality of patients with sarcoidosis was not different from that of the general population (standardized mortality ratio=0.90; 95% CI, 0.74-1.08). CONCLUSION: Sarcoidosis occurred in approximately 10 persons per 100,000 per year. Most of the patients had intrathoracic involvement, although less than half had respiratory symptoms. Overall mortality was not different from that of the general population.

Usual interstitial pneumonia complicating dyskeratosis congenita.

Dyskeratosis congenita (DC) is a rare disorder characterized by skin hyperpigmentation, nail dystrophy, and leukoplakia of mucous membranes. Pulmonary complications occur in approximately 20% of patients, although the specific histopathologic features, the temporal relationship between the diagnosis of DC and the development of pulmonary fibrosis, and the response to specific treatment are largely undefined. We describe 2 patients with DC who developed usual interstitial pneumonia. Pulmonary fibrosis developed 18 and 38 years after the original manifestations of DC. Both patients died of respiratory failure, 4 and 6 months after lung biopsy. Pulmonary fibrosis in patients with DC may be linked to underlying abnormalities of fibroblast function.

Alkaptonuria diagnosed by flexible bronchoscopy.

A 68-year-old white man was evaluated for failure to wean from mechanical ventilation after cardiac surgery. Bronchoscopy performed prior to percutaneous dilatational tracheotomy revealed circumferential strikingly dark-colored airways, most prominent in the trachea and mainstem bronchi, extending distally into all airways with overlying desiccated black secretions. Histologic examination of bronchial mucosal biopsy samples and the desiccated secretions showed acute bronchitis and necrotic debris, respectively. This finding and the patient's history led to testing for plasma homogentisic acid, which was found to be elevated at 12.6 mug/mL, establishing the first diagnosis of alkaptonuria made using flexible bronchoscopy.