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      Lung India : Official Organ of Indian Chest Society
      Medknow Publications

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          Dear Sir, I read with interest the article ‘Tuberculous Sarcoidosis’ by Shah JR1 published in the recent issue (July-September 2007) of the Lung India. Author has discussed a possible association of two distinct clinical entities i.e. tuberculosis and sarcoidosis that may pose diagnostic & therapeutic problem and also described two such case histories of his experience. While there is no doubt in the second case, the first case requires further diagnostic workup for sarcoidosis i.e. SACE, serum calcium, urinary calcium, tissue biopsy & BAL analysis etc. to support clinical diagnosis of ‘tuberculous sarcoidosis’. Though in clinical practice, I fully agree that sometime complete diagnostic workup is not possible & conclusions are made after therapeutic response with drugs, which I do think is justified in our conditions at times. Author has stressed on considering ‘tuberculous sarcoidosis’ as a definite clinical entity where two diseases present simultaneously or another disease develop in a course of existent disease. I thanks the author, for awaring the clinicians about this distinct entity for personal reason, that now I can suspect retrospective diagnosis of ‘tuberculous sarcoidosis’ in three cases in my previous clinical experience. Two AFB smear positive and tuberculin reactive pulmonary cases with noncaseating granulomas on tissue biopsy, required oral corticosteroid in view of poor response with antituberculosis drugs and another case, a 10 year old male child with lymphocyte predominant exudative pleural effusion and tuberculin reactivity developed cervical lymphadenopathy, nine months after completion of six months antituberculosis therapy with adequate response. The scalene node biopsy showed noncaseating granulomas and a second course with antituberculosis drugs resulted in poor response and patient lost to follow up. Although none of these cases could be investigated for sarcoidosis as diagnosis of tuberculosis was confirmed and the term ‘tuberculous sarcoidosis’ was neither familiar to me nor is mentioned in the standard textbooks of respiratory medicine till date. Since tuberculosis is rampant in our country and may present with various unusual clinical and radiological features, the diagnosis of other coexistent diseases is often overlooked. Lack of infrastructure, financial constraints, and lack of newer diagnostic techniques at most centre of our country, despite adequate clinical material and trained medical persons are possible causes for these situations. The recent studies on possible association of tuberculosis and sarcoidosis are interesting and encouraging further research in this field. Sarcoidosis has pathologic2, immunologic3 and epidemiologic4 features that are similar to bacterial infection, particularly tuberculosis. While no infectious agent has been identified within sarcoidosis lesions, there are immunological and clinical aspects that suggest an infectious origin. Sarcoidosis immunology reflects Th-l cytokine expression, which is based upon antigen specific T-cell response. Studies of T-cell receptor gene expression in sarcoidosis patients reveal oligoclonal collections of αβ+ CD4+ T cells at the sites of granulomatous inflammation, consistent with a MHC-restricted antigen driven process5. Another feature is the transmissibility of sarcoidosis. There are reports of ‘Donor-acquired sarcoidosis’ in presumably naive (non sarcoidosis) transplant recipients who have received tissues or organs from donors having suspected or active sarcoidosis6. Recently, epidemiological studies have also suggested a possible role of certain occupation i.e. an agricultural employment, insecticide exposures and moldy environments that contains opportunistic mycobacterias7. One of the strongest arguments against a potential role of mycobacteria in sarcoidosis pathogenesis is inability to detect microorganism on histological staining or by culture from pathologic tissues. The possible explanations for negative microbial workup noted in sarcoid lesions could be very low concentration of the bacteria's, ultra-slow growth pattern, and lack of certain nutritional requirements etc. or the sarcoidosis pathogenesis may reflect an immune response to infectious antigens that might not be dependent upon actively replicating organisms. Recently newer diagnostic techniques have been emerged for assessing presence of microorganisms in pathologic tissues. Polymerase chain reaction (PCR) analysis of pathologic tissue for 16S r RNA serve as an alternative means of identifying putative infectious agents that are difficult to isolate. One study of PCR analysis for conserved Mycobacterium 16S r RNA and rpo B sequences revealed the presence of slow-growing mycobacteria such as M tuberculosis and M avium, as well as unique 16S r RNA and rpo B sequences that suggest a novel mycobacterium8. Another study used spolingotyping of bronchoalveolar fluid and demonstrated the presence of unique sequence among 50% of sarcoidosis subjects, as well as the presence of sequence consistent with M.tuberculosis9. However, the limitation of PCR studies is that cross contamination may cause false positive results. Another mechanism to identify the causative microorganism is use of antigen specific immune responses to microbial antigens and this has been. recently utilized to identify novel infectious agent in SARS10. A landmark study by Song et al11 involved molecular and immunologic analysis of sarcoidosis specimens for M tuberculosis katG. They demonstrated the presence of M tuberculosis katG in sarcoidosis granulomas by mass spectrophotometry and in-situ hybridization, as well as the presence of humoral immune response to M tuberculosis katG among sarcoidosis subjects. Another recent study has demonstrated a humoral response to M tuberculosis heat shock protein 70 in significant number of sarcoidosis patients12. These recent studies of successful molecular analysis and humoral immunity to mycobacterial antigens from sarcoidosis patients have renewed interest in a potential role of mycobacteria in sarcoidosis and support the hypothesis that mycobacterias may have a causal role in ‘some’ sarcoidosis patients. Further molecular studies with positive and negative controls and investigation of genetic risk factors will be important, in order to explain why some patients are found to have an association with microbial antigens and others are not. In conclusion, we must be flexible on the diagnosis of two co existent diseases and possibility of ‘tuberculous sarcoidosis’ may be considered whenever such clinical situation arises and supported by complete investigation backup.

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          A novel coronavirus associated with severe acute respiratory syndrome.

          A worldwide outbreak of severe acute respiratory syndrome (SARS) has been associated with exposures originating from a single ill health care worker from Guangdong Province, China. We conducted studies to identify the etiologic agent of this outbreak. We received clinical specimens from patients in seven countries and tested them, using virus-isolation techniques, electron-microscopical and histologic studies, and molecular and serologic assays, in an attempt to identify a wide range of potential pathogens. None of the previously described respiratory pathogens were consistently identified. However, a novel coronavirus was isolated from patients who met the case definition of SARS. Cytopathological features were noted in Vero E6 cells inoculated with a throat-swab specimen. Electron-microscopical examination revealed ultrastructural features characteristic of coronaviruses. Immunohistochemical and immunofluorescence staining revealed reactivity with group I coronavirus polyclonal antibodies. Consensus coronavirus primers designed to amplify a fragment of the polymerase gene by reverse transcription-polymerase chain reaction (RT-PCR) were used to obtain a sequence that clearly identified the isolate as a unique coronavirus only distantly related to previously sequenced coronaviruses. With specific diagnostic RT-PCR primers we identified several identical nucleotide sequences in 12 patients from several locations, a finding consistent with a point-source outbreak. Indirect fluorescence antibody tests and enzyme-linked immunosorbent assays made with the new isolate have been used to demonstrate a virus-specific serologic response. This virus may never before have circulated in the U.S. population. A novel coronavirus is associated with this outbreak, and the evidence indicates that this virus has an etiologic role in SARS. Because of the death of Dr. Carlo Urbani, we propose that our first isolate be named the Urbani strain of SARS-associated coronavirus. Copyright 2003 Massachusetts Medical Society
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            Role of IL-18 in CD4+ T lymphocyte activation in sarcoidosis.

            Sarcoidosis is a granulomatous disease of unknown etiology associated with the expansion of IL-2-producing activated CD4(+) T lymphocytes. A number of factors including the recently described IL-18 have been implicated in IL-2 expression in vitro. We investigated the role of IL-18 in IL-2 expression in sarcoidosis. Eighteen individuals with sarcoidosis and 15 normal controls were studied. IL-18R expression and epithelial lining fluid (ELF) concentrations of IL-18 were significantly elevated in the sarcoid group (p = 0.0143 and 0.0024, respectively). Both AP1 and NF-kappaB, transcription factors that regulate IL-2 gene expression, were activated in vivo in sarcoid pulmonary CD4(+) T lymphocytes. Transcription factor activity was not detected in pulmonary CD4(+) T lymphocytes from normal controls or from peripheral blood CD4(+) T lymphocytes from individuals with sarcoidosis, further evidence of compartmentalization of the lymphoproliferative process in this condition. We examined the effects of IL-18 on AP1 and NF-kappaB in Jurkat T cells in vitro. These effects were both time and dose dependent. Examination of transcription factor activation and IL-2 gene expression in Jurkat T cells revealed that sarcoid but not normal ELF activated AP1 and NF-kappaB, induced IL-2 gene transcription, and up-regulated IL-2 protein production. Addition of IL-18 to normal ELF also induced IL-2 mRNA accumulation, whereas correspondent depletion of IL-18 from sarcoid ELF using neutralizing Abs abrogated all of the effects. These data strongly implicate IL-18 in the pathogenesis of sarcoidosis via activation of AP1 and NF-kappaB, leading to enhanced IL-2 gene expression and IL-2 protein production and concomitant T cell activation.
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              Serum anti-mycobacterial heat shock proteins antibodies in sarcoidosis and tuberculosis.

              Sarcoidosis (SA) is a multisystem granulomatous disorder of unknown etiology. Infectious organisms, e.g. Mycobacterium tuberculosis, genetic factors and autoimmunity are considered as etiologic agents. Pathologic similarities between SA and tuberculosis (TB) suggest M. tuberculosis heat shock proteins (Mtb-hsp) as causative factors. To test the "mycobacterial" origin of SA, we evaluated the presence of serum anti-Mtb-hsp70, -Mtb-hsp65 and -Mtb-hsp16 antibodies in SA and TB. Analysis of anti-Mtb-hsp antibodies was carried out in 37 patients with SA, 29 patients with TB and 18 healthy individuals by ELISA. Our results show a significantly higher occurrence of anti-Mtb-hsp70 antibodies in SA and TB patients than in controls. The anti-Mtb-hsp65 and -Mtb-hsp16 antibodies occured significantly more often in TB than in controls and SA. We found significantly higher percentages of anti-Mtb-hsp70 and -Mtb-hsp65 antibodies in Stage II compared to Stage I of SA. Analysis of anti-Mtb-hsp antibodies levels revealed significantly higher anti-Mtb-hsp70 antibodies level in SA and TB than in controls. Significantly higher frequency and levels of anti-Mtb-hsp70 than anti-Mtb-hsp65 and -Mtb-hsp16 antibodies was found in SA only. In summary, the frequency and level of anti-Mtb-hsp70 antibodies were comparable between SA and TB but were significantly higher compared to controls and other tested Mtb-hsp. These data may suggest a role for Mtb-hsp70 protein in the pathogenesis of sarcoidosis.

                Author and article information

                Role: MD, DNB
                Lung India
                Lung India : Official Organ of Indian Chest Society
                Medknow Publications (India )
                Jan-Mar 2008
                : 25
                : 1
                : 38-39
                Department of Respiratory Medicine and Tuberculosis, J.L.N. Medical College, Ajmer., India
                Author notes
                Correspondence : Dr. Ramakant Dixit, Consultant Chest Physician, 381/26, Ramganj, Ajmer-305001; India.
                © Lung India

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : September 2007

                Respiratory medicine
                Respiratory medicine


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