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Background: Hansen’s disease, is a chronic, infectious disease that primarily affects the skin and the peripheral nerve. Leprosy expresses itself in different clinico-pathological forms depending on the immune status of the host; diagnosis of leprosy is based on different clinical parameters which involves detailed examination of skin lesions and peripheral nerves. Demonstration of acid –fast bacilli in slit skin smears by Ziehl- Neelsen’s staining also aids in diagnosis of leprosy. A reliable diagnosis hinges around a good histopathological diagnosis and demonstration of bacilli in histopathological sections. Clinical classification gives recognition only to gross appearances of the lesions, while the parameters used for the histopathological classification are well defined, precise and also take into account the immunological manifestations which enable it to successfully bridge the pitfalls in leprosy diagnosis. Histopathology provides confirmatory information for suspect cases which can be missed in clinical practice or epidemiological studies and helps in exact typing. Histology also gives indication of progression and regression of disease under treatment. Objective: The aim of the study is to observe the patient of various spectrum of leprosy and correlate clinical findings with histopathological findings. Materials and Method: It is a Cross sectional observational study conducted in Dept. of Dermatology, from central west India, from April 2015 to September 2016. Person with sign and symptoms of leprosy, cases with hypopigmented lesions with definitive sensory impairment, cases with erythematous papule, plaque and nodule with sensory impairment. Person with no known history of prior leprosy treatment, and willingness to do biopsy and signing the informed consent form were included. Subjects with no skin lesions, only sensory loss or thickened nerve, not giving consent for biopsy, history of prior treatment with MDT regime complete or incomplete and patient with lepra reactions were excluded. Prevalence of Leprosy in 2014 at Maharashtra was 0.9 per 10000. So, number of new cases is very low, that’s why I had included all cases of leprosy presented to my department for this study, which was fulfilling the inclusion criteria within study duration. Hence the study sample is 70. Results: The age of the cases included in study ranged from 5 years to 70 years (mean age 34.42 ± 16.02 years). The majority of the cases 32 (36%) were in the age group of 20-40 years (3rd and 4th decade). There were 50(70.4%) males and 21(29.6%) females with a male to female ratio of 2.4: 1.The present study showed the duration of disease ranging 1 to 72 months (mean 9.84 months). Majority of patients (63.8%) presented within 6 months of onset of disease. In this study, most common observed lesion were macule consisting 50 in number, followed by plaque (n=39). 8 cases presented with papule whereas 4patients had nodule.In our study clinical diagnosis of TT and BTH leprosy were found to be common in 20-40 years of age group accounted for 54.5% of total TT cases and 37.83%of total BTH cases respectively. All cases of clinically diagnosed BB cases were seen in 20-40 year of age group. Whereas cases of lepromatous pole of leprosy distributed equally in each age groups of, 20 to 40 yrs, 40 to 60 yrs, > 60 yrs. In this study, upper limb was found to be most common site 46 (64.8%), followed by trunk in 29 (40.8%) patients. 27(38%) cases had lesions over face and 23(32.4%) had lower limb. Most common nerve involved was ulnar nerve which was palpable in total 51 patients, among them 28 were unilateral whereas 23 cases with bilateralinvolvement. Out of 71 cases studied, most commonly observed type of leprosy was BTH presented in 52.1% of cases, followed by TT in 31%. Patient with Lepromatous pole were 9 in number accounted 12.7% of total. Rest 4.2% of cases were of BB. On histopathology, majority of patient observed were BTH contributing 60.6% of total, followed by lepromatous pole 16.9%. 11.3% of patients were found to be indeterminate type of leprosy, whereas 8.5% of patients in BB. Rest 2.8% patients were of TT. TT showed only 4.55% of cases positively correlate with clinical diagnosis. BB showed 33.3% of cases positively correlate with clinical diagnosis. BTH showed 75.7% of cases positively correlate with clinical diagnosis. Lepromatous pole showed highest correlation 88.9%. Limitations of the study were histopathological response during treatment course couldn’t be assessed as it was a cross sectional study and sample size was less. Conclusion: Most common clinical and histopathological diagnosis was observed as borderline tuberculoid Hansen. Most common age group was 20-40 years (3rd and 4th decade). Most patients came to seek health care within 6 months of period. Overall agreement in between clinical and histopathological diagnosis was found to be 53.52%. For treatment purpose parity to be found was 89.83% in paucibacillary and 100% for multibacillary.

If the diagnosis of mycobacterial disease in cattle is challenging, the diagnosis of infection is even more so. This is because of the biology of the organisms involved, the pathogenesis of the diseases characterised by uncertain, frequently prolonged and non-linear progression and intermittent shedding of the infectious organism, and limitations, particularly with respect to sensitivity, of the commonly used testing technologies and strategies. Infected animals, however, need to be identified and managed if disease is to be controlled and perhaps even ultimately eradicated. Possible strategies to facilitate this are discussed.

Summary Mycobacterial infections are rare in horses, donkeys and mules. Although there are a few reports in horses, mycobacterial disease is poorly documented in the donkey. Mycobacterial infection of equine species typically affects the alimentary tract, causing granulomatous enterocolitis resulting in diarrhoea and chronic weight loss, while lymph nodes and liver may also be affected. We now document recurrent oesophageal obstruction, secondary to cranial mediastinal lymphadenitis caused by Mycobacterium avium complex (MAC). To the best of our knowledge, this is the first report of MAC infection in a donkey in the UK.

The US Food and Drug Administration convened a workshop to discuss clinical trial design challenges and considerations related to the treatment of nontuberculous mycobacterial pulmonary disease, to include topics such as clinical trial end points, duration, and populations. The clinicians participating in the meeting provide here their interpretation of the discussion, which included US Food and Drug Administration and industry representatives. The treatment of nontuberculous mycobacterial pulmonary disease typically includes multiple antibiotics for a prolonged period and can be difficult to tolerate; there is a great need for new treatment options. Most individuals have a microbiologic response to therapy, but data correlating decreasing bacillary load with patient-reported outcomes or measured functional improvement are lacking. Accordingly, trial designs for new therapeutic agents should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary end points, and placebo control arms was highlighted during the workshop.

The prevalence of nontuberculous mycobacteria (NTM) pulmonary disease (NTM-PD) is rising worldwide, creating a significant health issue and an unmet need. The diagnosis and decision to treat NTM-PD are often a challenge, with complex criteria for diagnosis and multiple factors weighing in the decision to treat [1]. The treatment is lengthy and the drugs used often associated with adverse effects. Adherence to NTM-PD management guidelines were found to be suboptimal, impacting treatment success [2], with substantial differences in physicians’ decision to treat and in their adherence to treatment guidelines [2–4]., Patients’ experiences of NTM pulmonary disease highlight important and unmet needs for better pharmacological treatment and education of medical staff https://bit.ly/3mjrlwh

Purpose of review Pulmonary nontuberculous mycobacterial disease (NTM) remains a significant clinical challenge with suboptimal therapy. This review focuses on recent understandings around the pathogenesis of NTM disease and nonantibiotic therapeutic approaches that are being pursued. Recent findings The absence of animal models that truly replicate human disease remains a major problem for NTM research with most findings coming from tuberculosis or tuberculosis-like studies. Recent research reiterates the known key roles of interferon gamma (IFNγ), tumor necrosis factor, interleukin-12 and granulocyte-macrophage colony stimulation factor (GM-CSF) in immunity to NTM. Autoantibodies to some of these factors may be important. Recent nonantibiotic research has focused on either boosting the immune response to NTM (e.g. with IFNγ or GM-CSF) or using other compounds to kill these pathogens (e.g. inhaled NO, gallium, etc.). Summary Our poor understanding of the immune deficit leading to NTM disease continues to hinder the development of highly effective therapies. New approaches are promising but need significant validation before being considered viable therapeutic options.

Background Little is known about the impact of the ecosystem disruption and its contribution on the non-tuberculosis mycobacteria (NTM) diseases (cases) rate in Florida (FL), a state with a high prevalence of NTM in the United States. We aimed to evaluate the epidemiological distribution of NTM in FL and identify its association with extreme weather events. Methods We used OneFlorida Clinical Research Consortium dataset and extracted data on NTM cases using ICD codes 9- CM 031.0 and ICD-10 A31 during 2012–2018. The number of hurricanes during the study period which affected FL were extracted data from the National Hurricane Center (NHC) and the National Oceanic and Atmospheric Administration (NOAA). Results Prevalence of NTM gradually increased during the study period. The rate was 2012: 14.3/100,000, 2015; 20.1/100,000 and 2018; 22.6/100,00 except in 2014 where there was an 8% decrease. The incidences were 2012; 6.5/100,00, 2015; 4.9/100,000 and in 2015; 5.4/100,000. Geographical analysis demonstrated a gradual expansion of the NTM cases in Alachua, and Marion Counties throughout the study period. Notably, the 2018 heat map showed higher prevalence of NTM in the northwestern, panhandle region of FL which had been absent in the heat maps for years 2012–2018. High number of the hurricanes was associated with the higher number of the new cases of NTM infection for years 2012, 2016–2018, while the lower number of the hurricanes was associated with the lower number of the new cases of NTM infection for years 2014–2015. Conclusion The current study found the prevalence rates of NTM disease in FL rose from 2012 to 2018. A higher prevalence was seen following the hurricanes.

Background An elevated risk of tuberculosis (TB) disease in persons who have received tumor necrosis factor alpha inhibitor medications (TNF-α inhibitors) has been reported for nearly two decades, but clinical diagnostic features and outcomes of TB in this population remain poorly described. Methods We analyzed national surveillance data for TB cases among persons aged 15 years and older reported in the United States during 2010–2017 and associated mortality data reported through 2019 to describe the clinical characteristics of those receiving TNF-α inhibitors. Results Of 70 129 TB cases analyzed, 504 (0.7%) of the patients had TNF-α inhibitor use reported at TB diagnosis. Patients with TNF-α inhibitor use at TB diagnosis were more likely than TB patients not receiving TNF-α inhibitors to have TB diagnosed in extrapulmonary sites in conjunction with pulmonary sites (28.8% vs 10.0%, P Conclusions Clinicians evaluating TNF-α inhibitor–treated patients should have a high index of suspicion for TB and be aware that extrapulmonary or sputum smear–negative TB disease is more common in these patients. No significantly diminished survival of TB patients treated with TNF-α inhibitor therapy before TB diagnosis was noted.

La enfermedad granulomatosa crónica (ECG) es un error innato de la inmunidad que afecta la funcionalidad de la fagocitosis, específicamente hay una falta de producción de radicales libres de oxígeno por la NADPH oxidasa. La EGC se manifiesta con infecciones bacterianas y fúngicas, recurrentes y graves e hiperinflamación local y sistémica. En países en donde la tuberculosis es endémica y la vacuna BCG es obligatoria al nacer, los pacientes con EGC pueden presentar como primera manifestación las reacciones locales o sistémicas a esta vacuna y además a lo largo de su vida infecciones recurrentes por M. tuberculosis. La susceptibilidad de estos pacientes a micobacterias es debida a la producción excesiva de citocinas proinflamatorias y la formación de granulomas ineficientes en la contención de la micobacteria. En los países desarrollados, los pacientes con EGC no presentan este tipo de manifestaciones infecciosas, salvo los migrantes de países en desarrollo. En esta revisión, presentamos las características de las infecciones por BCG, M. tuberculosis y otras micobacterias. Interesantemente no existen lineamientos en cuanto a los tratamientos antituberculosos en pacientes con EGC, por lo que proponemos realizar un consenso por expertos para establecer lineamientos para el tratamiento de la enfermedad por micobacterias en EGC.

Background: Post-vaccination BCG disease typically attests to underlying inborn errors of immunity (IEIs), with the highest rates of complications in patients with Mendelian susceptibility to mycobacterial disease (MSMD). However, therapeutic protocols for the management of BCG-osis (disseminated) and persistent BCG-itis (localized) are still controversial. Methods: Twenty-four Iranian patients with MSMD (BCG-osis or BCG-itis), followed from 2009 to 2020 in Tehran, were included in the study. Their medical records were retrospectively reviewed for demographics, clinical features, laboratory findings, and molecular diagnosis. The therapeutic protocol sheets were prepared to contain the types and duration of anti-mycobacterial agents. Results: BCG disease either as BCG-itis (33.3%) or BCG-osis (66.7%) was confirmed in all patients by positive gastric washing test (54.2%), microbial smear and culture (58.3%), or purified protein derivative (PPD) test (4.2%). The duration between BCG-osis onset and MSMD diagnosis was 21.6 months. All except three patients were initiated on second-line anti-mycobacterial agents with either a fluoroquinolone (levofloxacin: 15 mg/kg/day, ciprofloxacin: 20 mg/kg/day, ofloxacin: 15 mg/kg/day), aminoglycoside (amikacin: 10-15 mg/kg/day, streptomycin: 15 mg/kg/day), and/or macrolide (clarithromycin: 15 mg/kg/day) along with oral rifampin (10 mg/kg/day), isoniazid (15 mg/kg/day), and ethambutol (20 mg/kg/day). Three patients showed a clinical response to rifampin, despite in vitro resistance. Fourteen (58.3%) patients received also adjuvant subcutaneous IFN-γ therapy, 50 µ/m2 every other day. At the end of survey, most patients (n=22, 91.7%) were alive and two patients died following BCG-osis and respiratory failure. Conclusions: We recommend the early instigation of second-line anti-mycobacterial agents in MSMD patients with BCG disease.

Clinical disease caused by the agent of tuberculosis, Mycobacterium tuberculosis, and by less virulent mycobacteria, such as bacillus Calmette-Guerin (BCG) vaccines and environmental mycobacteria, can result from inborn errors of immunity (IEIs). IEIs underlie more than 450 conditions, each associated with an impairment of the development and/or function of hematopoietic and/or non-hematopoietic cells involved in host defense. Only a minority of IEIs confer predisposition to mycobacterial disease. The IEIs underlying susceptibility to bona fide tuberculosis are less well delineated than those responsible for susceptibility to less virulent mycobacteria. However, all these IEIs share a defining feature: the impairment of immunity mediated by interferon gamma (IFN-γ). More profound IFN-γ deficiency is associated with a greater vulnerability to weakly virulent mycobacteria, whereas more selective IFN-γ deficiency is associated with a more selective predisposition to mycobacterial disease. We review here recent progress in the study of IEIs underlying mycobacterial diseases.

Mycobacterial pathogens pose a sustained threat to human health. There is a critical need for new diagnostics, therapeutics, and vaccines targeting both tuberculous and nontuberculous mycobacterial species. Understanding the basic mechanisms used by diverse mycobacterial species to cause disease will facilitate efforts to design new approaches toward detection, treatment, and prevention of mycobacterial disease. Molecular, genetic, and biochemical approaches have been widely employed to define fundamental aspects of mycobacterial physiology and virulence. The recent expansion of genetic tools in mycobacteria has further increased the accessibility of forward genetic approaches. Proteomics has also emerged as a powerful approach to further our understanding of diverse mycobacterial species. Detection of large numbers of proteins and their modifications from complex mixtures of mycobacterial proteins is now routine, with efforts of quantification of these datasets becoming more robust. In this review, we discuss the “genetic proteome,” how the power of genetics, molecular biology, and biochemistry informs and amplifies the quality of subsequent analytical approaches and maximizes the potential of hypothesis-driven mycobacterial research. Published proteomics datasets can be used for hypothesis generation and effective post hoc supplementation to experimental data. Overall, we highlight how the integration of proteomics, genetic, molecular, and biochemical approaches can be employed successfully to define fundamental aspects of mycobacterial pathobiology.

International audience; Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αβ T, and CD4+ αβ TH1∗ cells unable to compensate for this deficit.

This overview provides an update on silicosis epidemiology with review of exposures and emerging trends in acute and accelerated silicosis in the twenty-first century. The silicosis epidemics in mining, denim sandblasting, and engineering stone industries are highlighted. Clinical presentations of silicosis and silica-related conditions such as autoimmune, kidney, and mycobacterial disease, as well as lung cancer, are discussed. Important aspects of the new OSHA 2017 Silica Standard are presented. This review also includes practical guidance for clinicians to address questions that may arise when evaluating silica-exposed patients and to the public health responses needed following a diagnosis of silica-related disease.

SummaryInborn errors of human IFN-γ immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG, by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-γ. Other IFN-γ-producing lymphocyte subsets however develop normally, but with low levels of IFN-γ production, with exception of Vδ2− γδ T lymphocytes, which produce normal amounts of IFN-γ in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-γ production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells), with mycobacterial-specific, IFN-γ-producing, purely adaptive αβ TH1* cells unable to compensate for this deficit.

Nontuberculous mycobacteria (NTM) are ubiquitous organisms in our surrounding environment. Four distinct clinical syndromes associated with NTM infection have been described: skin and soft tissue disease, lymphadenitis, disseminated disease and pulmonary disease. In children, lymphadenitis is the most common NTM clinical entity, particularly affecting those aged 1-5 years who have no known risk factors for disease. Optimal management of NTM lymphadenitis is not entirely clear, although surgical intervention is likely a definitive therapy. Disseminated NTM disease is uncommon and only seen in the setting of immunocompromise. In previously well children, this presentation should always lead to consideration of an underlying immune defect, such as Mendelian susceptibility to mycobacterial disease. Identification of the underlying cause enables more targeted therapy and better prognostic understanding. Pulmonary NTM disease is fundamentally different to the other clinical syndromes, presenting in different hosts, who have different comorbidities, and follow a different clinical course.