Thoracic manifestations of tularaemia: a case series.

BACKGROUND: Tularaemia is a zoonotic disease caused by Francisella tularensis, a highly virulent bacterium that affects humans and small wild animals. It is transmitted through direct contact with infected animals or indirectly through contaminated soil, water or arthropod bites (e.g. ticks). Primary thoracic manifestations of tularaemia are infrequent and, therefore, a diagnostic challenge for clinicians. METHODS: We report six tularaemia cases with exclusively thoracic involvement diagnosed in a clinic for pulmonary diseases in Bavaria between 10/2020 and 02/2022. RESULTS: All patients lived or were active in rural areas, four reported a recent tick bite. All patients presented with thoracic lymphadenopathy and pulmonary tumours or consolidations; all underwent bronchoscopy with EBUS-TBNA of lymph nodes, three lung biopsies as well. Five patients showed inflammatory changes in the endobronchial mucosa. The main histological findings were necrotic epithelioid granulomas with remarkable granulocyte infiltration. All cases were identified by positive serology, five by PCR (here identification of F.t. ssp. Holarctica) from biopsy as well. As first-line therapy, oral ciprofloxacin was given (5/6); in 2/6 cases, a combination of quinolone-rifampicin was given. CONCLUSIONS: Pulmonary tularaemia may occur after tick bites and without extrathoracic manifestations. In patients who present with thoracic lymphadenopathy and pulmonary consolidations and who are exposed to increased outdoor activities, tularaemia should be included in the diagnostic pathway. Histologically, the presence of neutrophil-granulocyte infiltrations might help to distinguish tularaemia from other granulomatous infections, e.g. tuberculosis. The combination of quinolone-rifampicin rather than i.v. gentamicin reduced length of hospital stay in two patients.

IL23R on myeloid cells is involved in murine pulmonary granuloma formation.

PURPOSE OF THE STUDY: The involvement of the IL-23/IL23R pathway is well known in the disease pathogenesis of sarcoidosis and other inflammatory diseases. To date, the pathogenic mechanism of IL-23 is most notably described on CD4+ Th17 lymphocytes. However, the function of the IL23R on myeloid cells in sarcoidosis is poorly understood. Thus, the aim of the study is to investigate the role of the IL23R on myeloid cell in pulmonary granuloma formation. Methods: We generated IL23RLysMCre mice lacking the IL23R gene in myeloid cells. The importance of IL23R in myeloid cells for the development of sarcoidosis was studied in a mouse model of inflammatory lung granuloma formation through embolization of PPD from Mycobacterium bovis-coated Sepharose beads into previously PPD-immunized mice. In addition the function of IL23R on myeloid cells was studied in LPS or IFNγ stimulated BMDMs and BMDCs. The mRNA and protein expression levels of relevant cytokines were analyzed by RT-PCR (TaqMan) and ELISA. The composition of immune cells in BALF was quantified by flow cytometry and alteration in granuloma sizes were observed by H&E stained lung sections. Results: Mycobacterium Ag-elicted pulmonary granulomas tend to be smaller in IL23RLysMCre mice and NF-κB dependent Th1 cytokines in the murine lungs are reduced compared to wildtype mice. In line, we observed that IL23R-deficient bone marrow-derived macrophages show a reduced production of Th1 cytokines after LPS stimulation. Conclusion: We here for the first time demonstrate a role for IL23R on myeloid cells in pulmonary inflammation and granuloma formation. Our findings provide essential insights in the pathogenesis of inflammatory lung diseases like sarcoidosis, which might be useful for the development of novel therapeutics targeting distinct immunological pathways like IL-23/IL23R.

Granulomatous lung disease in two workers making light bulbs.

BACKGROUND: Associations between sarcoidosis or sarcoid-like granulomatous lung disease and exposure to silica and other inorganic agents have been suggested in several studies. CASES: We describe granulomatous lung disease in two workers of a small production unit making metal-halide lamps. Initially, both were diagnosed with sarcoidosis. However, in both men, birefringent particles were observed in the lung or mediastinal lymph node biopsies. Clipping of glass tubes led to moderate exposure to dust, consisting mainly of amorphous fused silica, with some cristobalite. After removal from exposure, both subjects improved clinically, radiologically, and functionally. CONCLUSION: The present cases support the hypothesis that silica might be a trigger for sarcoid-like granulomatous lung disease. Sarcoidosis should be considered a diagnosis of exclusion and clinicians should carefully collect occupational and environmental exposure histories to identify workplace triggers.

Pathology of pulmonary tuberculosis and non-tuberculous mycobacterial lung disease: Facts, misconceptions, and practical tips for pathologists.

Most pathologists are familiar with the microscopic features of tuberculosis and the need to examine special stains for acid-fast bacteria (AFB) in cases of granulomatous lung disease. However, misconceptions do exist, including the concept that finding AFB in "caseating granulomas" confirms the diagnosis of tuberculosis. This dogma is attributable to the high prevalence of tuberculosis in many countries, as well as unfamiliarity with the microscopic spectrum of non-tuberculous mycobacterial lung disease. This review aims to provide surgical pathologists with practical tips to identify AFB, illustrate the histologic overlap between pulmonary tuberculosis and non-tuberculous mycobacterial lung disease, and highlight the importance of cultures in this setting. M. tuberculosis and non-tuberculous mycobacteria cannot be reliably differentiated either on the basis of the tissue reaction or by bacterial morphology on acid-fast stains. Although a presumptive clinical diagnosis of tuberculosis can be made without culture-confirmation, the only definitive means to determine the true identity of AFB is by cultures or molecular methods. Making this distinction is most critical when AFB are found in incidentally detected lung nodules in geographic locations where the incidence of tuberculosis is low, because in such settings AFB in necrotizing granulomas of the lung are more likely to be non-tuberculous mycobacteria than M. tuberculosis.

Role of Bronchoscopy in Diagnosis of Sarcoidosis.

Sarcoidosis is a multisystem inflammatory disorder with unclear etiology and can often pose a diagnostic challenge. A tissue diagnosis is often necessary to illustrate the non-caseating granulomas on histopathology. This review aims to synthesize current evidence related to tissue diagnosis of sarcoidosis using various bronchoscopic techniques. We start by discussing standard bronchoscopic techniques which have remained the cornerstone of diagnostic workup such as bronchoalveolar lavage (BAL), endobronchial biopsy (EBB), conventional transbronchial needle aspiration (cTBNA) and transbronchial lung biopsy (TBLB) followed by newer modalities that incorporate real-time image guidance using endobronchial and endoscopic ultrasound. Although BAL, EBB, and TBLB have been employed as a diagnostic tool for several decades, their sensitivity and diagnostic yield is inferior to ultrasound-based endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). More recently, convincing evidence has also emerged to support the diagnostic accuracy and tissue yield of transbronchial lung cryobiopsy which will also be discussed in this review. These advances in bronchoscopic equipment and techniques over the last 2 decades have made it possible to obtain tissue samples using minimally invasive techniques thus avoiding invasive open lung biopsy and the risks that inherently follow. Up-to-date knowledge of these modalities is imperative for ensuring evidence-based medicine and improving patient-centric outcomes.

Sarcoid-like Granulomatous Lung Disease with Subacute Progression in Silicosis.

A 67-year-old man was admitted to our hospital with cough and fatigue. He had had long-term exposure to silica due to cement processing. Chest computed tomography showed bilateral centrilobular nodules, and hilar and mediastinal lymphadenopathy with calcification, suggesting chronic silicosis. Within a few months, these nodules enlarged, and bilateral patchy consolidations appeared. A lung biopsy revealed sarcoid-like granulomas with birefringent particles under polarized light without malignancy or infection. He was diagnosed with silicosis-associated sarcoid-like granulomatous lung disease, rather than sarcoidosis, according to the clinicopathological findings. His pulmonary manifestations improved after the discontinuation of silica exposure and combination therapy of corticosteroid and azathioprine.

Occupational and environmental exposures in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study.

INTRODUCTION: Sarcoidosis is a granulomatous disorder thought to be caused by exposures in genetically susceptible individuals. This study investigated whether specific exposures were associated with different sarcoidosis phenotypes. METHODS: Extensive demographic, occupational and environmental exposure data was analyzed from subjects enrolled in the NHLBI Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. RESULTS: In patients with sarcoidosis, radiation exposure was significantly associated with an increased risk of cardiac sarcoidosis versus non-cardiac sarcoidosis. No exposures were significantly associated with pulmonary only disease versus extrapulmonary disease with or without pulmonary involvement, Scadding Stage II/III/IV versus Scadding Stage 0/I, acute or remitting disease versus non-acute or non-remitting disease, nor chronic versus non-chronic disease. Although not reaching statistically significance after adjustment for multiple comparisons, there were a number of exposures associated with specific disease phenotypes, including exposures where relationships to sarcoidosis have previously been described such as rural exposures and pesticide exposures. CONCLUSIONS: Radiation exposure may be a risk factor for cardiac sarcoidosis. Other exposures may also be associated with specific phenotypes and should be further explored. The study was limited by small groups of exposed subjects for individual exposures and multiple comparisons. The development of novel and innovative exposure assessment tools is needed.

Genomic biomarkers in chronic beryllium disease and sarcoidosis.

Background Previous gene expression studies have identified genes IFNγ, TNFα, RNase 3, CXCL9, and CD55 as potential biomarkers for sarcoidosis and/or chronic beryllium disease (CBD). We hypothesized that differential expression of these genes could function as diagnostic biomarkers for sarcoidosis and CBD, and prognostic biomarkers for sarcoidosis. Study Design/Methods We performed RT-qPCR on whole blood samples from CBD (n = 132), beryllium sensitized (BeS) (n = 109), and sarcoidosis (n = 99) cases and non-diseased controls (n = 97) to determine differential expression of target genes. We then performed logistic regression modeling and generated ROC curves to determine which genes could most accurately differentiate: 1) CBD versus sarcoidosis 2) CBD versus BeS 3) sarcoidosis versus controls 4) non-progressive versus progressive sarcoidosis. Results CD55 and TNFα were significantly upregulated, while CXCL9 was significantly downregulated in CBD compared to sarcoidosis (p < 0.05). The ROC curve from the logistic regression model demonstrated high discriminatory ability of the combination of CD55, TNFα, and CXCL9 to distinguish between CBD and sarcoidosis with an AUC of 0.98. CD55 and TNFα were significantly downregulated in sarcoidosis compared to controls (p < 0.05). The ROC curve from the model showed a reasonable discriminatory ability of CD55 and TNFα to distinguish between sarcoidosis and controls with an AUC of 0.86. There was no combination of genes that could accurately differentiate between CBD and BeS or sarcoidosis phenotypes. Interpretation CD55, TNFα and CXCL9 expression levels can accurately differentiate between CBD and sarcoidosis, while CD55 and TNFα expression levels can accurately differentiate sarcoidosis and controls.

Non-Infectious Granulomatous Lung Disease: Imaging Findings with Pathologic Correlation.

Non-infectious granulomatous lung disease represents a diverse group of disorders characterized by pulmonary opacities associated with granulomatous inflammation, a relatively nonspecific finding commonly encountered by pathologists. Some lesions may present a diagnostic challenge because of nonspecific imaging features; however, recognition of the various imaging manifestations of these disorders in conjunction with patients' clinical history, such as age, symptom onset and duration, immune status, and presence of asthma or cutaneous lesions, is imperative for narrowing the differential diagnosis and determining appropriate management of this rare group of disorders. In this pictorial review, we describe the pathologic findings of various non-infectious granulomatous lung diseases as well as the radiologic features and high-resolution computed tomography imaging features.

Granulomatous lung disease: clinical aspects.

INTRODUCTION: Granulomatous lung diseases (GLD) are heterogeneous group of diseases that can be broadly categorized as infectious or noninfectious. This distinction is extremely important, as the misdiagnosis of a GLD can have serious consequences. In this manuscript, we describe the clinical manifestations, histopathology, and diagnostic approach to GLD. We propose an algorithm to distinguish infectious from noninfectious GLD. AREAS COVERED: We have searched PubMed and Medline database from 1950 to December 2019, using multiple keywords as described below. Major GLDs covered include those caused by mycobacteria and fungi, sarcoidosis, hypersensitivity pneumonitis, and vasculidities. EXPERT OPINION: The cause of infectious GLD is usually identified through microbiological culture and molecular techniques. Most noninfectious GLD are diagnosed by clinical and laboratory criteria, often with exclusion of infectious pathogens. Further understanding of the immunopathogenesis of the granulomatous response may allow improved diagnosis and treatment of GLD.

Sarcoidosis-Like Granulomatous Lymphadenopathy Mistaken for Neoplastic Disease on Positron Emission Tomography.

This is a rare case of sarcoidosis-like granulomatous lymphadenopathy that was initially mistaken for a neoplastic process due to the degree of hypermetabolic changes observed on positron emission tomography (PET) scan. Sarcoid-like granulomatous pulmonary disease is a disorder that has been described in WTC (World Trade Center) Rescue Workers, and also known as post 9/11 sarcoidosis. We present an interesting case of a man who presented with several months of progressive dyspnea and was later discovered to have significant bilateral hilar adenopathy, which was PET avid. Even more interesting, this patient's symptoms completely resolved without the use of systemic steroids or immune suppressants. This is a condition that requires awareness in order to avoid repeating unnecessary tests of performing interventions on a benign condition that may resolve on its own.

Interstitial lung disease preceding primary biliary cirrhosis in a male patient.

A 47-year-old male was admitted with subacute onset of dry cough and fever. Chest tomography demonstrated multifocal areas of consolidation and ground glass attenuation. Cytological analysis of bronchoalveolar lavage revealed lymphocytosis and eosinophilia and anatomopathological exam of transbronchial cryobiopsy showed poorly formed non-caseous granulomas associated to interstitial lympho-plasmocitary infiltrate. The diagnosis of idiopathic granulomatous lung disease (GLD) was assumed and the patient started oral prednisolone, presenting clinical, functional and radiological improvement. Two years later, the patient was diagnosed with primary biliary cirrhosis (PBC). At this time, it was possible to associate GLD with the autoimmune hepatobiliary disease. Clinical, epidemiological and pathological aspects of this uncommon case of interstitial lung disease as first presentation of PBC in a male patient are discussed.