Sarcoidosis al descubierto: Lo que deberíamos informar en las imágenes torácicas / Sarcoidosis Uncovered: What we should Report in Thoracic Image

La sarcoidosis es una enfermedad granulomatosa no caseificante, multisistémica, de causa desconocida, que compromete al pulmón y a los ganglios linfáticos mediastinales entre el 90 y el 95% de los casos. También puede afectar otros órganos, como las glándulas salivales, piel, ojos, hígado, bazo, corazón, huesos y sistema nervioso central. La sarcoidosis tiene una baja prevalencia en Latinoamérica y es subdiagnosticada debido a la alta frecuencia de otros trastornos similares, como tuberculosis, lepra y micosis profundas. El diagnóstico presuntivo se establece con hallazgos imagenológicos característicos dentro de un contexto clínico apropiado y se confirma con la evidencia histológica de granulomas no caseificantes de células epiteliales, en ausencia de otras etiologías. Los hallazgos torácicos incluyen la afectación pulmonar, ganglionar y bronquial, los cuales son detectados a través de la radiografía (Rx) y tomografía computada (TC) de tórax, siendo esa última más sensible y específica. En este artículo, resaltamos la importancia de reconocer los patrones de presentación típicos y atípicos de la sarcoidosis en Rx y TC, así como la relevancia de las imágenes torácicas como elemento clave en el algoritmo diagnóstico de esa patología. También describimos la utilidad de la resonancia magnética (RM), como método adicional para el diagnóstico en casos de afectación cardíaca y el papel de la tomografía por emisión de positrones (PET-CT) en el seguimiento terapéutico.

Sarcoidosis is a non-caseating granulomatous, multisystemic disease of unknown cause that involves the lung and mediastinal lymph nodes in 90-95% of cases. It can also affect other organs such as the salivary glands, skin, eyes, liver, spleen, heart, bones and the central nervous system. Sarcoidosis has a low prevalence in Latin America and it is underdiagnosed due to the high frequency of other similar disorders such as tuberculosis, leprosy and deep mycosis. The presumptive diagnosis is established based on characteristic imaging findings within an appropriate clinical setting and is confirmed by histological evidence of non-caseating epithelioid cell granulomas, in the absence of other etiologies. Thoracic imaging findings include pulmonary, nodal and bronchial involvement, which are detected on chest radiography (CXR) and computed tomography (CT), this last one having a higher sensitivity and specificity. In this article, we highlight the importance of recognizing the typical and atypical presentation patterns of sarcoidosis on CXR and CT, as well as the relevance of thoracic images as key elements in the diagnostic algorithm of this pathology. We also describe the usefulness of magnetic resonance (MR) imaging as an additional method for diagnosis in cases of cardiac involvement and the role of positron emission tomography (PET-CT) in therapeutic follow-up.

Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis.

Background: Tuberculosis (TB) remains a major threat to global health. Currently, diagnosis of active TB is hampered by the lack of specific biomarkers that discriminate active TB disease from other (lung) diseases or latent TB infection (LTBI). Integrated human gene expression results have shown that genes encoding complement components, in particular different C1q chains, were expressed at higher levels in active TB compared to LTBI. Methods: C1q protein levels were determined using ELISA in sera from patients, from geographically distinct populations, with active TB, LTBI as well as disease controls. Results: Serum levels of C1q were increased in active TB compared to LTBI in four independent cohorts with an AUC of 0.77 [0.70; 0.83]. After 6 months of TB treatment, levels of C1q were similar to those of endemic controls, indicating an association with disease rather than individual genetic predisposition. Importantly, C1q levels in sera of TB patients were significantly higher as compared to patients with sarcoidosis or pneumonia, clinically important differential diagnoses. Moreover, exposure to other mycobacteria, such as Mycobacterium leprae (leprosy patients) or BCG (vaccinees) did not result in elevated levels of serum C1q. In agreement with the human data, in non-human primates challenged with Mycobacterium tuberculosis, increased serum C1q levels were detected in animals that developed progressive disease, not in those that controlled the infection. Conclusions: In summary, C1q levels are elevated in patients with active TB compared to LTBI in four independent cohorts. Furthermore, C1q levels from patients with TB were also elevated compared to patients with sarcoidosis, leprosy and pneumonia. Additionally, also in NHP we observed increased C1q levels in animals with active progressive TB, both in serum and in broncho-alveolar lavage. Therefore, we propose that the addition of C1q to current biomarker panels may provide added value in the diagnosis of active TB.

Cutaneous sarcoidosis: clinicopathologic study of 76 patients from Lebanon.

BACKGROUND: Sarcoidosis is a multi-system granulomatous disease of unknown etiology. The skin is involved in 25% of cases. Studies on cutaneous sarcoidosis from our region are lacking. OBJECTIVES: This study was conducted to describe clinical and histopathologic findings in all patients diagnosed with cutaneous sarcoidosis at the American University of Beirut Medical Center between 1992 and 2010 and to compare findings with those published in the literature. METHODS: Clinical charts of patients with cutaneous sarcoidosis were retrospectively reviewed. Extracutaneous lesions were classified by organ involvement. Treatment was documented. Pathology specimens were reviewed. RESULTS: Cutaneous sarcoidosis was diagnosed in 76 Lebanese patients, 79% of whom were women. Mean age at diagnosis was 48 years. A total of 29% of patients had systemic disease that was commonly associated with lupus pernio lesions and subcutaneous sarcoidosis. The most common cutaneous lesions were sarcoidal plaques. The histopathologic features in our series did not differ from those described in the literature, except for the documented presence of a grenz zone. Interestingly, 23% of biopsy specimens contained perineural granulomas, raising the possibility of tuberculoid or borderline tuberculoid leprosy. Foreign bodies were detected in 10% of cases (all had systemic involvement), supporting the opinion that sarcoidosis and granulomatous foreign body reaction are not mutually exclusive. CONCLUSIONS: The clinical and histopathologic features of cutaneous sarcoidosis patients in the present series are generally comparable with those published in the literature, with minor differences. Clinically, the most commonly seen lesion was plaque. Microscopically, cutaneous sarcoidosis may exhibit a grenz zone and may show perineural inflammation and foreign bodies.

Leprosy initially misdiagnosed as sarcoidosis, adult-onset still disease, or autoinflammatory disease.

Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae. We describe the case of a 20-year-old man from India living in Italy since 2003, who presented with erythematous papules and nodules distributed on his arms, legs, and face in 2006. He also had episodes of high fever, polyarthritis, and episcleritis. Sarcoidosis was suspected on the basis of elevated angiotensin-converting enzyme and bronchoalveolar lavage fluid, and the patient was treated with corticosteroids for about a year. A flare of the disease occurred each time corticosteroid was tapered or suspended. An autoinflammatory disease was then suspected and treated with immunosuppressant. Only the third deep skin biopsy revealed the presence of M. leprae. The lack of clinical suspicion and the unfamiliarity with the histology of leprosy delayed diagnosis and treatment. Leprosy should be considered in the differential diagnoses of patients presenting with rheumatic and cutaneous manifestations especially when they come from countries where the disease is endemic.

Mycobacterial ESAT-6 and katG are recognized by sarcoidosis CD4+ T cells when presented by the American sarcoidosis susceptibility allele, DRB1*1101.

INTRODUCTION: Genetic associations of American sarcoidosis susceptibility implicate MHC class II allele, DRB1*1101. We previously reported immune recognition of Mycobacterium peptides from peripheral cells of 26 sarcoidosis subjects, 24 PPD- healthy volunteers, and eight with latent tuberculosis infection. MATERIALS AND METHODS: In order to further link these genetic and immunologic pillars of sarcoidosis pathogenesis, we performed flow cytometry on these same subjects to identify the cells responsible for immune responses to ESAT-6 and katG peptides, followed by HLA typing to determine allelic associations with recognition. DISCUSSION AND CONCLUSION: Sarcoidosis CD4+ T cells were primarily responsible for the systemic responses. Recognition was inhibited by monoclonal antibody against HLA-DR and HLA-DQ, but not HLA-DP. Immune recognition of ESAT-6 peptide NNALQNLARTISEAG was associated with possession of DRB1*1101. ESAT-6 and katG presented by antigen-presenting cells expressing DRB1*1101-induced Th-1 responses from sarcoidosis T cells, thus providing a mechanistic insight for the association of HLA DRB1*1101 with sarcoidosis, and sarcoidosis T cell interaction with microbial antigens.

Reduced T-cell receptor CD3zeta-chain protein and sustained CD3epsilon expression at the site of mycobacterial infection.

Control of mycobacterial infection by the cellular immune system relies both on antigen-presenting cells and on T lymphocytes. The quality of an effective cellular immune response is dependent on functional signal transduction residing in the cytoplasmic tails of the T-cell receptor CD3 components. In order to investigate potential effects of mycobacteria on T-cell receptor signalling, we examined the protein expression of T-cell signal transduction molecules (CD3zeta, ZAP-70, p59fyn, p56lck). In Western blots of peripheral blood mononuclear cells of Mycobacterium tuberculosis infected patients, only the CD3zeta-chain showed a marked reduction in protein expression. To investigate the situation in situ, immunoenzymatic and immunofluorescence stainings for CD3epsilon and CD3zeta expression were performed on sections of normal lymphoid tissue, M. leprae infected and sarcoid tissue. CD3epsilon and CD3zeta expression were similar with respect to intensity, localization and the number of cells stained in normal lymphoid tissue and in sarcoid granulomas. In contrast, the granulomas of M. leprae infected tissues showed a significantly reduced expression of CD3zeta compared to CD3epsilon. Using double immunofluorescence analysis, virtually no CD3zeta expression could be detected in comparison to the CD3epsilon expression in the lesions. Apparently, mycobacteria are capable of significantly reducing CD3zeta-chain expression, which may be restored by cytokines. IL-2-enhanced zeta-chain expression and T-cell effector functions, defined by interferon-gamma release, in M. tuberculosis-specific and human leucocyte antigen-DR restricted CD4+ T cells isolated from granuloma lesions from patients with pulmonary tuberculosis. Because CD3zeta is essential for CD3 signalling and for eliciting T-cell effector functions, reduced CD3zeta protein expression could result in altered signal transduction and inefficient T-cell effector functions. Alternatively, reduced CD3zeta-chain expression may protect T cells from repetitive TCR stimulation associated with anergy or apoptosis.

Immunolocalization of cell-wall-deficient forms of Mycobacterium tuberculosis complex in sarcoidosis and in sinus histiocytosis of lymph nodes draining carcinoma.

In sarcoidosis, pleomorphic chromogens (PCs) occur as multivariate pigmented elements within sinusoids of lymph nodes (sinusoidal phase) and as tiny "round bodies" detectable in granulomas (generalized phase). The sinusoidal phase occurs in other conditions as well and characteristically contains yeastlike bodies also known as H-W bodies. To elucidate the antigenic profile of all variant forms, 28 cases of sarcoidosis (series A) and 14 cases of malignancy associated sinus histiocytosis (series B) were studied immunohistochemically with panels of various antibodies, including antimycobacterial MAbs specific for M tuberculosis complex (TB68, TB71), for M. leprae (MMP-I-3C3) and for cross-reactive mycobacterial antigens (F24-2-3 and F116-5, the latter recognizing superoxide dismutase). Results for series A indicate that: 1) PCs are cell-wall-deficient (CWD) mycobacterial forms belonging to M. tuberculosis complex (over 95%); 2) both phases are antigenically identical parts of the L-cycle; 3) "round bodies" of the "infective" phase have an endolysosomal evolution; 4)uncommon vacuolated forms represent a labile spheroplast stage; 5) the yeastlike bodies are specialized sinusoidal large bodies of unknown function. Results for series B show that in roughly two thirds of cases the pigmented forms are also CWD mycobacteria, have the same immunophenotype as sarcoid PCs in 35.7% of cases, have a much higher incidence of labile vacuolated forms and, finally, that malignancy associated "pseudosarcoid" granulomas do not differ antigenically from genuine sarcoid granulomas. Unlike conventional mycobacteria, PCs do not express cytoskeletal proteins consistently. Their general reactivity for HBcAg raises the possibility of phage interactions being responsible for the L-cycle since it may reflect shared epitopes between unrelated virus entities.

[Cutaneous-pulmonary sarcoidosis. Diagnostic difficulties in the Black African milieu]. / Sarcoïdose cutanéo-pulmonaire. Difficultés diagnostiques en milieu Noir Africain.

About a case of pulmonary and dermatologic manifestations of sarcoidosis, in a Black African patient, the authors emphasize the clinical polymorphism of sarcoidosis. They insist on the diagnostic criteria of sarcoidosis which are not at all specific of the disease but necessitate a compatible interpretation; particularly in Black Africa where leprosy, tuberculosis and many others granulomatous diseases are endemic.