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.

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.

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.

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.

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.

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.

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.

Idiopathic pulmonary fibrosis: evolving concepts.

Idiopathic pulmonary fibrosis (IPF) occurs predominantly in middle-aged and older adults and accounts for 20% to 30% of interstitial lung diseases. It is usually progressive, resulting in respiratory failure and death. Diagnostic criteria for IPF have evolved over the years, and IPF is currently defined as a disease characterized by the histopathologic pattern of usual interstitial pneumonia occurring in the absence of an identifiable cause of lung injury. Understanding of the pathogenesis of IPF has shifted away from chronic inflammation and toward dysregulated fibroproliferative repair in response to alveolar epithelial injury. Idiopathic pulmonary fibrosis is likely a heterogeneous disorder caused by various interactions between genetic components and environmental exposures. High-resolution computed tomography can be diagnostic in the presence of typical findings such as bilateral reticular opacities associated with traction bronchiectasis/bronchiolectasis in a predominantly basal and subpleural distribution, along with subpleural honeycombing. In other circumstances, a surgical lung biopsy may be needed. The clinical course of IPF can be unpredictable and may be punctuated by acute deteriorations (acute exacerbation). Although progress continues in unraveling the mechanisms of IPF, effective therapy has remained elusive. Thus, clinicians and patients need to reach informed decisions regarding management options including lung transplant. The findings in this review were based on a literature search of PubMed using the search terms idiopathic pulmonary fibrosis and usual interstitial pneumonia, limited to human studies in the English language published from January 1, 2000, through December 31, 2013, and supplemented by key references published before the year 2000.

Sarcoidosis with major airway, vascular and nerve compromise.

The present report describes a 60-year-old Caucasian woman who presented with progressive dyspnea, cough and wheeze. A computed tomography scan of the chest showed innumerable bilateral inflammatory pulmonary nodules with bronchovascular distribution and a mediastinal and hilar infiltrative process with calcified lymphadenopathy leading to narrowing of lobar bronchi and pulmonary arteries. An echocardiogram revealed pulmonary hypertension. Bronchoscopy showed left vocal cord paralysis and significant narrowing of the bilateral bronchi with mucosal thickening and multiple nodules. Transbronchial biopsy was compatible with sarcoidosis. Despite balloon angioplasty of the left lower lobe and pulmonary artery, and medical therapy with oral corticosteroids, her symptoms did not significantly improve. To the authors' knowledge, the present report describes the first case of pulmonary sarcoidosis resulting in major airway, vascular and nerve compromise due to compressive lymphadenopathy and suspected concurrent granulomatous infiltration. Its presentation mimicked idiopathic mediastinal fibrosis.

IgG4-related systemic disease presenting with lung entrapment and constrictive pericarditis.

We describe a 29-year-old woman who presented with chronic pleuropericarditis complicated by lung entrapment and constrictive pericarditis. Pleural biopsy performed during the decortication procedure revealed fibrinous pleuritis with lymphoplasmacytic inflammation including IgG4-positive plasma cells. The patient responded favorably to corticosteroid therapy with resolution of pleural effusion and constrictive physiology. To our knowledge, this is the first reported case of IgG4-related systemic disease manifesting as lung entrapment and constrictive pericarditis.

Mediastinoscopy in patients with lung cancer and negative endobronchial ultrasound guided needle aspiration.

BACKGROUND: Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) has been proposed as a safe, less-invasive alternative to mediastinoscopy to stage mediastinal lymph nodes in patients with lung cancer. We evaluated the negative predictive value of EBUS-TBNA in lung cancer patients suspected of having N2 nodal metastases. METHODS: This study is a single-institution retrospective review of cases with suspected or confirmed lung cancer undergoing mediastinoscopy after a negative EBUS-TBNA between June 2006 and February 2008. RESULTS: A total of 494 patients underwent EBUS-TBNA during the study period. Twenty-nine patients with suspected or confirmed lung cancer had a negative EBUS-TBNA and underwent subsequent mediastinoscopy. Mediastinoscopy was performed for findings suspicious of N2 disease based on noninvasive imaging. Mediastinoscopy found metastatic nodes in eight of 29 patients (28%) for a patient-specific negative predictive value of EBUS-TBNA of 72% (95% CI, 56% to 89%). Mediastinal lymph node dissection found four further patients with positive N2 nodes (19%). The EBUS-TBNA and mediastinoscopy sampled the same lymph node station on 36 occasions in the 29 patients. The average lymph node size was 10 mm. Mediastinoscopy was positive in 5 of 36 stations, for a nodal-specific negative predictive value of EBUS-TBNA of 86% (95% CI, 75% to 97%). CONCLUSIONS: Endobronchial ultrasound with transbronchial needle aspiration can effectively sample mediastinal lymph node stations in patients with lung cancer. However, in this early experience, 28% of patients with high clinical suspicion of nodal disease had N2 mediastinal nodal metastases confirmed by mediastinoscopy despite negative EBUS-TBNA.