Noninfectious Granulomatous Diseases Research Articles

Clinical and Histopathological Evaluation of Forty-one Cases of Pediatric Granuloma Annulare.

Granuloma annulare (GA) is a non-infectious granulomatous disease that can affect children and adults. Although many studies have been conducted in adult GA patients, the literature on pediatric GA cases is limited. Therefore, this study aimed to examine the demographic, clinical, and pathological features of pediatric GA cases. This study was performed retrospectively in a single-center tertiary dermatology hospital. Demographic characteristics and clinical and histopathological features were recorded. Forty-one participants were included in this study, of which 66% were females. The mean age was 3.8 ± 2.6 years, and the mean lesion duration was 7.5 ± 10.3 months. The involvement of 78% of the patients was localized, and the remaining 22% was generalized. Asthma (30%) was the most common comorbid disease. Histopathological examination was performed on 21 patients, and the infiltrate pattern was interstitial in 71% of the cases and palisadic in 29%. Generalized distribution, trunk involvement, and concomitant disease tended to be higher in patients with an interstitial pattern than in those with a palisadic pattern. Atopy and asthma should be questioned in pediatric GA cases. There are differences between involvement, distribution, concomitant disease, and histopathological patterns, which may indicate differences in pathogenesis.

A case of idiopathic granulomatous vasculitis with phlebitis and underlying subcutaneous necrotizing venulitis

Granulomatous vasculitis in skin lesions is rarely seen in non-infectious granulomatous diseases and other systemic disorders. Herein, we report a unique case of cutaneous vasculitis in which granulomatous phlebitis was observed in a muscular vein at the dermal–subcutaneous junction and necrotizing granulomatous venulitis in the underlying subcutaneous tissues.

Validation of the Sarcoidosis Diagnostic Score in a Multicontinental Study.

Rationale: The Sarcoidosis Diagnostic Score (SDS) has been established to quantitate the clinical features consistent with sarcoidosis in a monocentric study. Objectives: We aimed to confirm the diagnostic value of SDS in a large, multicontinental study and to assess the utility of SDS in differentiating sarcoidosis from alternative diagnoses, including infectious and noninfectious granulomatous diseases. Methods: We included patients with biopsy-confirmed sarcoidosis at nine centers across the world. Patients without sarcoidosis seen at the same sites served as control patients. Using a modified World Association of Sarcoidosis and Other Granulomatous Disorders organ assessment instrument, we scored all patients for the presence of granuloma on biopsy, highly probable symptoms, and least probable symptoms for each area. Two sarcoidosis scores were generated: SDS Biopsy (with biopsy) and SDS Clinical (without biopsy). SDS Clinical and Biopsy were calculated for all patients. We calculated and compared the area under the curve (AUC) for SDS Clinical and Biopsy according to different diagnosis scenarios. Results: A total of 1,041 patients with sarcoidosis and 1,035 without sarcoidosis were included. The results for SDS Clinical (AUC, 0.888; 95% confidence interval [CI], 0.874-0.902) and SDS Biopsy (AUC, 0.979; 95% CI, 0.973-0.985) according to AUC were good to excellent for differentiating sarcoidosis from alternative diagnosis. SDS Clinical was less discriminatory in males (P = 0.01) and in high tuberculosis prevalence centers (P < 0.001). However, SDS Clinical (AUC, 0.684; 95% CI, 0.602-0.766) and SDS Biopsy (AUC, 0.754; 95% CI, 0.673-0.835) were not sufficiently discriminative for noninfectious granulomatous diseases, but both SDSs could differentiate sarcoidosis from infectious granulomatous diseases. Algorithms were proposed for the SDS Clinical and SDS Biopsy to assist the clinician in the diagnostic process, and cutoff values were proposed for the SDS Clinical and SDS Biopsy, allowing the diagnosis of sarcoidosis to be safely confirmed or rejected in most cases except for noninfectious granulomatous disease. Conclusions: This multicontinental study confirms that both SDS Clinical and SDS Biopsy have good to excellent performance in discriminating sarcoidosis from alternative diagnoses. Differences in the AUC were seen for high tuberculosis prevalence versus low tuberculosis prevalence centers and for males versus females. Both SDSs had good discriminatory function for infectious granulomatous disease but failed in cases of noninfectious granulomatous disease such as berylliosis.

Innate and Adaptive Immunity in Noninfectious Granulomatous Lung Disease.

Sarcoidosis and chronic beryllium disease are noninfectious lung diseases that are characterized by the presence of noncaseating granulomatous inflammation. Chronic beryllium disease is caused by occupational exposure to beryllium containing particles, whereas the etiology of sarcoidosis is not known. Genetic susceptibility for both diseases is associated with particular MHC class II alleles, and CD4+ T cells are implicated in their pathogenesis. The innate immune system plays a critical role in the initiation of pathogenic CD4+ T cell responses as well as the transition to active lung disease and disease progression. In this review, we highlight recent insights into Ag recognition in chronic beryllium disease and sarcoidosis. In addition, we discuss the current understanding of the dynamic interactions between the innate and adaptive immune systems and their impact on disease pathogenesis.

Necrobiosis lipoidica in a non-diabetic female with extensive vitiligo: An uncommon association

Necrobiosis lipoidica diabeticorum (NLD) is a chronic non-infectious granulomatous disease characterized by sclerodermiform plaques, papules, or inflammatory nodules. NLD may be associated with diabetes mellitus (DM), sarcoidosis, rheumatoid arthritis, and inflammatory bowel disease. While reports of patients having NLD, DM, and vitiligo at the same time exist, there are, to the best of our knowledge, no reports of the cooccurrence of NLD and vitiligo in the absence of evidence of DM. Herein, we report a 57-year-old, non-diabetic vitiligo patient, who had developed yellowish-brown plaques over bilateral shins with central scarring and atrophy. Histopathology was compatible with NLD. While there is a case report of a patient having psoriasis, NLD, DM, and vitiligo concurrently, this case, having NLD and vitiligo without clinically evident DM, is prominent. Since around 20–40% of cases of vitiligo may have metabolic syndrome, this case draws attention to the possible overlap in pathogeneses and the need for the intensive monitoring of such patients.

The Immunogenetics of Granulomatous Diseases.

Non-infectious granulomatous skin diseases are a wide category of well-defined reactive inflammatory conditions that share main similarities. While cutaneous sarcoidosis is the prototype of non-infectious (sterile) granulomatous dermatitides, there are several other entities in this group including granuloma annulare and necrobiosis lipoidica. Non-infectious granulomatous diseases are caused by complex associations between genetic situations and environmental triggers resulting in a variety of cutaneous and systemic manifestations. The genetic backgrounds of these diseases are the main topic of this manuscript.

Computed Tomography of Chest in Non-Infectious Granulomatous Lung Diseases: A Pictorial Essay

Non-infectious granulomatous lung diseases represent a group of disorders with relatively non-specific clinical history and imaging findings. Following pathologies are enlisted, (1) Inflammatory: sarcoidosis and necrotizing sarcoid granulomatosis (NSG); (2) Pulmonary lymphoid lesions: lymphomatoid granulomatosis (LYG) and granulomatous-lymphocytic interstitial lung disease (GLILD); (3) Aspiration/exposure: aspiration pneumonia, talcosis, berylliosis, and hypersensitivity pneumonitis (HP); (4) Vasculitis: granulomatosis with polyangiitis and eosinophilic GPA (EGPA) (formerly called as Churg-Strauss syndrome); and (5) Collagen vascular disorders: rheumatoid lung nodules. Role of radiologist is to narrow the diagnosis combining the imaging findings with clinical findings thus following a multidisciplinary approach.

Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets.

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

Elevated Serum Amyloid a Levels Are not Specific for Sarcoidosis but Associate with a Fibrotic Pulmonary Phenotype.

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.

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.

CD14 and CD16 expression in noninfectious granulomatous skin diseases

AbstractObjectivesPeripheral blood monocytes are categorized as classical (CD14++/CD16−) or nonclassical (CD14−/CD16+ and CD14+/CD16+) based on their CD14 expression and CD16 expression. Maturation of classical monocytes produces CD14+/CD16+ macrophages. Our aim was to clarify the in vivo distribution of CD14 and C16 monocytes/macrophages in three granulomatous skin diseases—sarcoidosis, granuloma annulare, and lupus miliaris disseminatus faciei.MethodsCD14 and CD16 immunohistochemistry, and CD14/CD16, CD16/CD11c, CD16/CD68, and CD16/factor XIIIa dual labeling were performed in tissues sampled from three cases of sarcoidosis, four cases of granuloma annulare, and three cases of lupus miliaris disseminatus faciei.ResultsThe main infiltrating cell types were CD14+/CD16+ and CD14−/CD16++ macrophages. A small number of CD14+/CD16− macrophages localized along the granuloma periphery. Dual immunofluorescence showed that CD16+ overlapped the most with CD68+ cells, partially overlapped with CD11c+ cells, and did not overlap with FXIIIa+ cells.ConclusionsInflammatory granulomatous skin diseases are characterized by CD16+, mature and inflammatory macrophages; some of which are in the process of maturation.

The rashes that lead to cutaneous ulcers

Skin rashes have exanthema as a synonym, a term derived from the Greek words exanthem, meaning “to appear,” and anthos, which denotes “flourishing.” The relevant factors for characterization of a rash include distribution, configuration, and organization of the lesions, in addition to evidence of systemic involvement through toxemia, adenopathy, and conjunctive lesions, hepatosplenomegaly, excoriations or phlogosis, neck rigidity, or neurologic dysfunction. A rash may evolve to cutaneous ulceration in many instances, which is relevant for the diagnosis, the followup, and the therapeutic management of the patient. Systemic diseases with exanthemas that result in ulcerations prevail over diseases that are restricted to signs and/or merely cutaneous clinical manifestations. A variety of etiologies can present cutaneous rashes with ulcers, subject or not to systemic involvement by the underlying disease, among which stand out the bullous diseases, infectious and parasitic diseases, noninfectious granulomatous diseases, vasculitis, paraneoplastic syndromes, autoimmune diseases of the connective tissue, neutrophilic diseases, lichen planus, and drug hypersensitivity syndrome. The authors present a detailed review of some diseases corresponding to each one of the mentioned etiologies, updating the clinical manifestations and therapeutic proposals.

The Occupational Burden of Nonmalignant Respiratory Diseases. An Official American Thoracic Society and European Respiratory Society Statement.

Rationale: Workplace inhalational hazards remain common worldwide, even though they are ameliorable. Previous American Thoracic Society documents have assessed the contribution of workplace exposures to asthma and chronic obstructive pulmonary disease on a population level, but not to other chronic respiratory diseases. The goal of this document is to report an in-depth literature review and data synthesis of the occupational contribution to the burden of the major nonmalignant respiratory diseases, including airway diseases; interstitial fibrosis; hypersensitivity pneumonitis; other noninfectious granulomatous lung diseases, including sarcoidosis; and selected respiratory infections.Methods: Relevant literature was identified for each respiratory condition. The occupational population attributable fraction (PAF) was estimated for those conditions for which there were sufficient population-based studies to allow pooled estimates. For the other conditions, the occupational burden of disease was estimated on the basis of attribution in case series, incidence rate ratios, or attributable fraction within an exposed group.Results: Workplace exposures contribute substantially to the burden of multiple chronic respiratory diseases, including asthma (PAF, 16%); chronic obstructive pulmonary disease (PAF, 14%); chronic bronchitis (PAF, 13%); idiopathic pulmonary fibrosis (PAF, 26%); hypersensitivity pneumonitis (occupational burden, 19%); other granulomatous diseases, including sarcoidosis (occupational burden, 30%); pulmonary alveolar proteinosis (occupational burden, 29%); tuberculosis (occupational burden, 2.3% in silica-exposed workers and 1% in healthcare workers); and community-acquired pneumonia in working-age adults (PAF, 10%).Conclusions: Workplace exposures contribute to the burden of disease across a range of nonmalignant lung conditions in adults (in addition to the 100% burden for the classic occupational pneumoconioses). This burden has important clinical, research, and policy implications. There is a pressing need to improve clinical recognition and public health awareness of the contribution of occupational factors across a range of nonmalignant respiratory diseases.

Cutaneous Granulomatosis: a Comprehensive Review.

Cutaneous granulomatosis is a heterogeneous group of diseases, characterized by a skin inflammatory reaction triggered by a wide variety of stimuli, including infections, foreign bodies, malignancy, metabolites, and chemicals. From a pathogenic point of view, they are divided into non-infectious and infectious granulomas. Pathophysiological mechanisms are still poorly understood. Non-infectious granulomatous skin diseases include granuloma annulare, necrobiosis lipoidica, rheumatic nodules, foreign body granulomas, cutaneous sarcoidosis, and interstitial granulomatous dermatitis. Necrobiosis lipoidica is more frequent in diabetic patients. Infectious granulomas of the skin are caused by mycobacteria, in particular Mycobacterium tuberculosis or atypical mycobacteria; parasites, such as Leishmania; or fungi. Pathogenic mechanisms of M. tuberculosis-related granuloma are discussed. From a clinical point of view, it is useful to divide cutaneous granulomatosis into localized and more disseminated forms, although this distinction can be sometimes artificial. Three types of localized granulomatous lesions can be distinguished: palisaded granulomas (granuloma annulare, necrobiosis lipoidica, and rheumatoid nodules), foreign body granulomas, and infectious granulomas, which are generally associated with localized infections. Disseminated cutaneous granulomas can be divided into infectious, in particular tuberculosis, and non-infectious forms, among which sarcoidosis and interstitial granulomatous dermatitis. From a histological point of view, the common denominator is the presence of a granulomatous inflammatory infiltrate in the dermis and/or hypodermis; this infiltrate is mainly composed of macrophages grouped into nodules having a nodular, palisaded or interstitial architecture. Finally, we propose which diagnostic procedure should be performed when facing a patient with a suspected cutaneous granulomatosis.

5-Aminosalicylic Acid Modulates the Immune Response in Chronic Beryllium Disease Subjects.

Chronic beryllium disease (CBD) is characterized by accumulation of macrophages and beryllium-specific CD4+ T cells that proliferate and produce Th1 cytokines. 5-Amino salicylic acid (5-ASA) is currently used to treat inflammatory bowel disease and has both antioxidant and anti-inflammatory actions. We hypothesized that 5-ASA may be a beneficial therapeutic in CBD. Seventeen CBD patients were randomized 3:1 to receive 5-ASA 500-mg capsules or placebo four times daily for 6weeks orally. Primary study endpoints included changes in beryllium lymphocyte proliferation (BeLPT). Secondary endpoints included changes in bronchoalveolar lavage (BAL) fluid, cells, serum, and blood cell glutathione (GSH) levels, BAL cell TNF-α levels, lung function, and quality of life measures. 5-ASA decreased BAL cell BeLPT by 20% within the 5-ASA treatment group. No significant changes were observed in serum, PBMCs, BALF, or BAL cell GSH levels in either the 5-ASA or placebo treatment group. 5-ASA treatment decreased ex vivo Be-stimulated BAL cell TNF-α levels within the 5-ASA group and when compared to placebo. Significant improvements were noted in quality of life measurements with 5-ASA treatment. 5-ASA's ability to decrease BAL cell BeLPT and Be-stimulated BAL cell TNF-α levels suggests that 5-ASA may impact the beryllium-specific immune response in CBD. 5-ASA use in other non-infectious granulomatous lung diseases, such as sarcoidosis, may prove to be a useful alternative treatment to corticosteroids for those with mild to moderate disease.

Paradoxical Reactions and the Immune Reconstitution Inflammatory Syndrome.

In HIV-infected individuals, paradoxical reactions after the initiation of antiretroviral therapy (ART) are associated with a variety of underlying infections and have been called the immune reconstitution inflammatory syndrome (IRIS). In cases of IRIS associated with tuberculosis (TB), two distinct patterns of disease are recognized: (i) the progression of subclinical TB to clinical disease after the initiation of ART, referred to as unmasking, and (ii) the progression or appearance of new clinical and/or radiographic disease in patients with previously recognized TB after the initiation of ART, the classic or "paradoxical" TB-IRIS. IRIS can potentially occur in all granulomatous diseases, not just infectious ones. All granulomatous diseases are thought to result from interplay of inflammatory cells and mediators. One of the inflammatory cells thought to be integral to the development of the granuloma is the CD4 T lymphocyte. Therefore, HIV-infected patients with noninfectious granulomatous diseases such as sarcoidosis may also develop IRIS reactions. Here, we describe IRIS in HIV-infected patients with TB and sarcoidosis and review the basic clinical and immunological aspects of these phenomena.

Non-infectious granulomatous inflammation: Focus on the lungs and skin

Whereas a granulomatous reaction represents a physiologically useful immune defense mechanism against many infections, in autoimmune diseases granuloma formation and the concomitant inflammatory mechanisms may provoke a potentially organ-threatening reaction. Morphologically, several defined sub-types of granuloma have long been known, e.g. foreign body granuloma, tuberculous granuloma,sarcoid, pseudosarcoid, rheumatoid and rheumatic fever granulomas. However, in practice, assigning granulomas to a certain etiology from a biopsy or resection specimen can be a challenging diagnostic process. This article gives a practically oriented overview of the clinically most relevant non-infectious granulomatous diseases. The etiology, epidemiology, clinical correlation and morphology of granulomatous diseases are discussed, focussing on the lungs and skin.

Non-Infectious Granulomatous Diseases of the Skin and their Associated Systemic Diseases

Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities. As a group, they are relatively difficult to diagnose and distinguish both clinically as well as histologically. Many of these disorders have significant associations with systemic diseases that impact the patient's overall prognosis. In this update, we offer a discussion of emerging concepts and controversies in this field, as presented through evidence-based answers to seven important clinical questions regarding palisading and epithelioid granulomata. These questions offer an opportunity to review ten non-infectious granulomatous conditions that have implications for systemic disease: granuloma annulare, annular elastolytic giant cell granuloma, necrobiosis lipoidica, methotrexate-induced accelerated rheumatoid nodulosis, necrobiotic xanthogranuloma, interstitial granulomatous dermatitis, interstitial granulomatous drug reaction, palisaded neutrophilic granulomatous dermatitis, sarcoidosis, and metastatic Crohn disease. Recent clinical, epidemiologic, and laboratory studies have shed some light on these diseases, the association of these conditions with systemic disorders, and their overall prognoses.

Fever of unknown origin: A value of 18F-FDG-PET/CT with integrated full diagnostic isotropic CT imaging

Aim The aim of presented work is to evaluate the clinical value of 18F-FDG-PET/CT in patients with fever of unknown origin (FUO) and to compare PET/CT finding with the results of the following investigation. Material and method 48 patients (24 men, 24 women, mean age 57.6 years with range 15–89 years) underwent 18F-FDG-PET/CT due to the fever of unknown origin. All examinations were performed using complex PET/CT protocol combined PET and whole diagnostic contrast enhanced CT with sub-millimeter spatial resolution (except patient with history of iodine hypersensitivity or sever renal impairment). CT data contained diagnostic images reconstructed with soft tissue and high-resolution algorithm. PET/CT finding were compared with results of biopsies, immunology, microbiology or autopsy. Results The cause of FUO was explained according to the PET/CT findings and followed investigations in 44 of 48 cases—18 cases of microbial infections, nine cases of autoimmune inflammations, four cases of non-infectious granulomatous diseases, eight cases of malignancies and five cases of proved immunity disorders were found. In 46 cases, the PET/CT interpretation was correct. Only in one case, the cause was overlooked and the uptake in atherosclerotic changes of arteries was misinterpreted as vasculitis in the other. The reached sensitivity was 97% (43/44), and specificity 75% (3/4) respectively. Conclusion In patients with fever of unknown origin, 18F-FDG-PET/CT might enable the detection of its cause.

Extrinsic allergic alveolitis: A not-very-well known condition in Nigeria

Background: Extrinsic allergic alveolitis (EAA) is a non-infectious granulomatous lung disease which results from the repeated inhalation of antigenic particles. These particles penetrate the distal airways and reach the alveoli where they provoke principally type III hypersensitivity reactions, and to a smaller extent type IV hypersensitivity reactions in the outer alveolar wall. This review highlights some critical aspects of the disease. Aim: To evaluate critical issues about extrinsic allergic alveolitis. Methods: Databases such as Medline, Elsevier, Emedicine and Pubmed were searched for relevant literature which included epidemiological data, clinical studies and case studies. The key areas discussed were the probable forms of the disease, pathology, pathogenesis and diagnosis. Results: EAA is often characterized by early lymphocyte alveolitis which may progress to pulmonary fibrosis. Sensitized individuals could have the acute, sub-acute or the chronic forms of the disease. The symptoms exhibited by the disease resemble those of other infectious respiratory disorders. Hence, it is often unrecognized and thus is misdiagnosed as respiratory infections. Conclusion: EAA may not be well- known in Nigeria. It is the responsibility of the medical community to evaluate the consequences and enlighten the Nigerian public about the disease. Keywords : Extrinsic allergic alveolitis, Antigenic, Hypersensitivity, Respiratory, Infectious, Fibrosis Port Harcourt Medical Journal Vol. 3 (1) 2008: pp. 3-9