Diagnostic Approach to Interstitial Lung Diseases Associated with Connective Tissue Diseases.

Interstitial lung disorders are a group of respiratory diseases characterized by interstitial compartment infiltration, varying degrees of infiltration, and fibrosis, with or without small airway involvement. Although some are idiopathic (e.g., idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, and sarcoidosis), the great majority have an underlying etiology, such as systemic autoimmune rheumatic disease (SARD, also called Connective Tissue Diseases or CTD), inhalational exposure to organic matter, medications, and rarely, genetic disorders. This review focuses on diagnostic approaches in interstitial lung diseases associated with SARDs. To make an accurate diagnosis, a multidisciplinary, personalized approach is required, with input from various specialties, including pulmonary, rheumatology, radiology, and pathology, to reach a consensus. In a minority of patients, a definitive diagnosis cannot be established. Their clinical presentations and prognosis can be variable even within subsets of SARDs.

COVID-19 pneumonia in a patient with granulomatosis with polyangiitis on rituximab: case-based review.

A 77-year-old man with past medical history of granulomatosis with polyangiitis (GPA) on rituximab and prednisone, presented to the hospital with worsening cough and shortness of breath. He had tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by nasal swab polymerase chain reaction (PCR) while asymptomatic, 6 weeks earlier. He started with cough and shortness of breath 2 weeks after his initial positive test. After developing symptoms, he tested negative twice by nasal swab PCR, but the PCR of his bronchioloalveolar lavage was positive for SARS-CoV-2. He did not develop antibodies against coronavirus. Prednisone 15 mg daily was continued, and he received remdesivir, and convalescent plasma with quick recovery. We reviewed the literature to search for similar cases. Our case suggests that SARS-CoV-2 infection in patients on rituximab may have an atypical presentation and the diagnosis may be delayed due to negative PCR testing in the nasal swab. Patients may benefit from treatment with convalescent plasma.

Individuals With Scleroderma May Have Increased Risk of Sleep-Disordered Breathing.

STUDY OBJECTIVES: Scleroderma is associated with abnormal skin thickening, interstitial lung disease, pulmonary hypertension, and abnormalities of the upper airway. These changes can cause cardiopulmonary complications, potentially including sleep-disordered breathing. The objective of this study is to examine the risk of sleep-disordered breathing in patients with scleroderma. METHODS: We retrospectively identified patients with documented scleroderma. We abstracted data from their electronic health records, including findings from antibody tests, serial pulmonary function tests, transthoracic echocardiography, high-resolution computed tomography, and overnight forehead oximetry. RESULTS: We identified 171 patients with scleroderma. Mean age at the time of initial consult was 56.5 years (range, 18-96 years), and 150 (86.7%) were women. Scleroderma was categorized as limited disease for 108 (62.4%), diffuse disease for 59 (34.1%), and mixed connective tissue disease for 6 (3.5%). Fifty-four patients (31.2%) had abnormal overnight forehead oximetry results, defined as an oxygen desaturation index greater than 5 or a baseline mean arterial oxygen saturation level less than 90%. CONCLUSIONS: Cardiopulmonary complications are common in patients with scleroderma, one of which may be sleep-disordered breathing. In our cohort, approximately one-third of individuals with scleroderma had evidence of sleep-disordered breathing. Moreover, the rate of sleep-disordered breathing in our population of scleroderma patients was twice the rate of pulmonary hypertension and was approximately the same as the rate of interstitial lung disease. Future prospective studies are needed to further assess the role of sleep-disordered breathing in scleroderma clinical outcomes.

Microbiologic yield of bronchoalveolar lavage specimens from stem cell transplant recipients.

PURPOSE: Stem cell transplant (SCT) recipients commonly undergo bronchoalveolar lavage (BAL) collection as an infectious pulmonary work-up. Previous studies report the utility and overall diagnostic yield of fiberoptic bronchoscopy with BAL in this vulnerable population, though none focused purely on microbiologic yield or made comparisons with less invasive means of pathogen detection. We sought to determine and elaborate on the microbiologic yield of BAL in SCT recipients, assess a correlation between BAL studies and less invasive means of pathogen detection, and assess the utility of repeating a BAL within 30 days. METHODS: Between January 1, 2009, and July 31, 2013, we reviewed medical records of 125 SCT recipients who underwent 179 BALs. In addition to demographic information and details pertaining to their SCT, a comprehensive review of their microbiologic data was performed and recorded. RESULTS: Our study showed an overall BAL microbiologic yield of 40%, despite 92% of patients receiving broad-spectrum antimicrobial therapy at the time of the BAL procedure. CONCLUSIONS: Although an initial BAL sample in this population provides crucial microbiologic information, repeating the procedure within 30 days may have minimal additional microbiologic yield. BAL continues to be an essential diagnostic tool in SCT recipients undergoing an infectious pulmonary work-up.

Diagnosis of Usual Interstitial Pneumonitis in the Absence of Honeycombing: Evaluation of Specific CT Criteria With Clinical Follow-Up in 38 Patients.

OBJECTIVE: We sought to evaluate specific CT criteria for the diagnosis of usual interstitial pneumonitis (UIP) in the absence of honeycombing. These criteria included peripheral reticulation and lobular distortion; some upper lobe involvement, but a lower zone predominance; a heterogeneous appearance with areas of normal lung, minimal reticulation, and substantial distortion alternating throughout the study and often on an individual image; a nonsegmental distribution; and traction bronchiectasis. MATERIALS AND METHODS: We searched reports of CT studies performed between January 1, 2009, and January 1, 2012, to identify patients for whom UIP was a likely or probable diagnosis and reviewed the CT study for each case (n = 106). There were 38 patients who met all CT criteria and who also had a clinical diagnosis of idiopathic UIP (also known as idiopathic pulmonary fibrosis [IPF]) and follow-up of at least 6 months, as determined from the electronic medical record. We reviewed prior and subsequent CT examinations in this cohort. RESULTS: The median age of our patients was 80 years, and the duration of clinical follow-up was 6-104 months (mean, 38 months; median, 37 months). For all patients, a pulmonary medicine physician made a working diagnosis of IPF. Fifteen patients died from pulmonary complications, and 16 of the surviving patients had clinical or functional progression of disease. There were no instances in which the initial diagnosis was revised or reversed. CONCLUSION: Strict application of specific CT criteria may allow a specific diagnosis of UIP in the proper clinical setting in the absence of honeycombing.

Wheezes and desert breezes: when asthma and valley fever collide.

OBJECTIVE: To evaluate interactive effects of pulmonary coccidioidomycosis and asthma. METHODS: We identified three groups of 33 age- and sex-matched patients: Group 1 (both asthma and coccidioidomycosis), Group 2 (asthma only), and Group 3 (pulmonary coccidioidomycosis only). Predetermined end points included: rate of disseminated coccidioidomycosis, duration of symptoms and antifungal therapy, hospitalization, death, and escalation of asthma therapies. RESULTS: Baseline characteristics were similar across groups. Group 1 patients had worsening asthma outcomes (except forced expiratory volume in 1 s) with coccidioidomycosis. They required more asthma medications (median, 2.0 vs 0.0; p < 0.001), more corticosteroids (mean [SD], 0.9 [4.2] vs 0.3 [0.6]; p < 0.001), and more healthcare visits (mean [SD], 0.2 [0.4] vs 0.1 [0.3]; p = 0.03). Groups 1 and 3 had no differences in coccidioidal end points, including rates of dissemination (1 vs 0; p > 0.99), symptom duration (mean, 15.2 vs 23.6 weeks; p = 0.24), antifungal treatment (n = 21 [63.6%] vs n = 24 [72.7%]; p = 0.60), and treatment duration (median, 26.5 vs 11 weeks; p = 0.09). Ten patients in Group 1 versus none in Group 3 required systemic corticosteroids for coccidioidomycosis (p < 0.001). CONCLUSIONS: Active pulmonary coccidioidomycosis significantly worsens asthma outcomes. Asthma (or its treatment) does not worsen coccidioidal outcomes, despite increasing the likelihood of treatment with systemic corticosteroids.

Pulmonary pyoderma gangrenosum without cutaneous manifestations.

Pyoderma gangrenosum is a chronic sterile skin disorder that is frequently seen in association with systemic disorders such as inflammatory bowel disease. Extracutaneous pyoderma gangrenosum is rare and most commonly occurs in the lungs. It is particularly unusual for extracutaneous pyoderma gangrenosum to manifest prior to skin findings and without an associated systemic disorder. A 19-year-old white man presented with shortness of breath and a productive cough. His skin exam was normal. Unenhanced chest computed tomography showed peripheral consolidations, areas of cavitation, nodules and bilateral pleural effusions. A bronchoalveolar lavage and an autoimmune panel were unremarkable. Right lung wedge biopsies via thoracostomy was performed and showed pulmonary pyoderma gangrenosum. He was treated with corticosteroids and has returned back to his baseline. This is the first case of pulmonary pyoderma gangrenosum without any associated underlying systemic disorder and without any cutaneous manifestations to date. Serial follow-ups are necessary to assess for the development of an associated systemic disorder or skin lesions.

Serious Pulmonary Toxicity Secondary to Novel Hepatitis C Antiviral Therapy in a Liver Transplant Recipient.

Historically, the treatment of hepatitis C virus infection has been difficult, but therapeutic options have improved markedly recently because of the development of novel antiviral therapies. These therapies have been well tolerated. We describe a patient who was receiving such therapy and had development of temporally related and histologically confirmed severe pulmonary toxicity. Pulmonary toxicity should be considered a potential serious complication of novel antiviral therapy for hepatitis C virus infection.

Pseudomembranous tracheobronchitis caused by Rhizopus sp. After allogeneic stem cell transplantation.

Invasive fungal infections are a major cause of morbidity and mortality in allogeneic stem cell transplant recipients. They can occasionally involve the tracheobronchial tree with serious clinical consequences. Tracheobronchial involvement is often an unexpected finding during diagnostic bronchoscopy. Herein, we report a case of pseudomembranous tracheobronchitis caused by Rhizopus sp. in an allogeneic stem cell transplant recipient.

Immunodetection of occult eosinophils in lung tissue biopsies may help predict survival in acute lung injury.

BACKGROUND: Acute lung injury (ALI) is a serious respiratory disorder for which therapy is primarily supportive once infection is excluded. Surgical lung biopsy may rule out other diagnoses, but has not been generally useful for therapy decisions or prognosis in this setting. Importantly, tissue and peripheral blood eosinophilia, the hallmarks of steroid-responsive acute eosinophilic pneumonia, are not commonly linked with ALI. We hypothesized that occult eosinophilic pneumonia may explain better outcomes for some patients with ALI. METHODS: Immunohistochemistry using a novel monoclonal antibody recognizing eosinophil peroxidase (EPX-mAb) was used to assess intrapulmonary eosinophil accumulation/degranulation. Lung biopsies from ALI patients (n = 20) were identified following review of a pathology database; 45% of which (i.e., 9/20) displayed classical diffuse alveolar damage (ALI-DAD). Controls were obtained from uninvolved tissue in patients undergoing lobectomy for lung cancer (n = 10). Serial biopsy sections were stained with hematoxylin and eosin (H&E) and subjected to EPX-mAb immunohistochemistry. RESULTS: EPX-mAb immunohistochemistry provided a >40-fold increased sensitivity to detect eosinophils in the lung relative to H&E stained sections. This increased sensitivity led to the identification of higher numbers of eosinophils in ALI patients compared with controls; differences using H&E staining alone were not significant. Clinical assessments showed that lung infiltrating eosinophil numbers were higher in ALI patients that survived hospitalization compared with non-survivors. A similar conclusion was reached quantifying eosinophil degranulation in each biopsy. CONCLUSION: The enhanced sensitivity of EPX-mAb immunohistochemistry uniquely identified eosinophil accumulation/degranulation in patients with ALI relative to controls. More importantly, this method was a prognostic indicator of patient survival. These observations suggest that EPX-mAb immunohistochemistry may represent a diagnostic biomarker identifying a subset of ALI patients with improved clinical outcomes.

Cadmium accumulation and detoxification by alveolar macrophages of cigarette smokers.

STUDY OBJECTIVES: Cadmium (Cd) is a toxic metal associated with emphysema and lung cancer, which is present in both air pollution and cigarette smoke. Metallothionein (MT) is an inducible protein that binds and detoxifies cellular Cd. The goals of this study were to determine whether increased concentrations of Cd are present in alveolar macrophages (AMs) of cigarette smokers (CSMs) and to determine whether MT accumulated in response to the presence of Cd. DESIGN: AMs were recovered by BAL from 10 healthy nonsmokers (NSMs) and 10 CSMs. The Cd content of the AMs was determined by inductively coupled plasma-mass spectrometry, and the MT content was determined using a Cd/hemoglobin radioassay (with (109)Cd). MEASUREMENTS: Cd was detected in AMs recovered from all subjects, with higher mean (+/- SEM) concentrations in CSMs compared with those in NSMs (3.4 +/- 0.5 vs 1.3 +/- 0.2 ng/10(6) cells; p < 0.005). There was a correlation between current smoking history (cigarettes per day) and the AM content of Cd (r = 0.74; p < 0.05). The mean AM content of MT was similar in NSMs (1.2 +/- 0.2 microg/10(7) cells) and CSMs (1.0 +/- 0.2 microg/10(7) cells). CONCLUSIONS: AMs in CSMs accumulate significant amounts of Cd without a concurrent increase in MT content, indicating greater saturation of MT. Increased Cd burden in alveolar cells could contribute to the development of lung diseases in CSMs.

Effects of hypoxia and nitric oxide on ferritin content of alveolar cells.

Concentrations of ferritin in alveolar cells and on the alveolar surface are increased in patients with a variety of respiratory disorders. Ferritin synthesis by cells is modulated by iron content but is also influenced by stimuli other than iron. In this study we sought to determine whether in vitro exposure to hypoxia- or nitric oxide (NO)-induced ferritin accumulation or release by human alveolar macrophages (AMs) or a lung cancer-derived epithelial cell line (A549). Changes in cell content of iron and ferritin (L- and H-types), as well as ferritin content of cell supernatants, were determined after in vitro exposure to hypoxia (1% or 10% O(2), 18 hours) or the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 0.01-1.0 mmol/L, 18 hours). Exposure to 1% O(2) increased ferritin content in both cell types (>fourfold increase; P <.005) without changing iron content. Treatment with SNAP increased ferritin content of A549 cells in a dose-dependent manner, whereas treatment of AMs decreased cellular iron and ferritin content and increased supernate ferritin content. Pretreatment of cells with N-acetylcysteine (500 micromol/L) reduced hypoxia-induced ferritin accumulation in alveolar cells and completely inhibited NO-induced ferritin accumulation in A549 cells. These findings indicate that exposure to 1% O(2)can increase ferritin content in alveolar cells, whereas NO can increase ferritin content (A549 cells) or decrease ferritin content (AMs).