Mycobacterial Disease In Patients Research Articles

Clinical characteristics and prognostic factors of non-tuberculous mycobacterial disease in patients with rheumatoid arthritis.

This study aimed to identify the clinical characteristics of patients with concurrent rheumatoid arthritis (RA) and suspected non-tuberculous mycobacterial (NTM) infections as well as determine their prognostic factors. We retrospectively reviewed the medical records of 91 patients with RA whose computed tomography (CT) findings suggested NTM infection. Subsequently, we compared the clinical characteristics between patients with and without clinical or radiological exacerbation of NTM-pulmonary disease (PD) and investigated the risk factors for the exacerbation and associated mortality. The mean age of patients with RA and suspected NTM-PD was 65.0 ± 10.2 years. The nodular/bronchiectatic (NB) form of NTM-PD was the predominant radiographic feature (78.0%). During follow-up, 36 patients (41.9%) experienced a radiological or clinical exacerbation of NTM-PD, whereas 12 patients (13.2%) died. Combined interstitial lung disease (ILD), microbiologically confirmed NTM-PD, and NB with the fibrocavitary (FC) form on chest CT were identified as risk factors for the clinical or radiological exacerbation of NTM-PD. Hydroxychloroquine use was identified as a good prognostic factor. Conversely, history of tuberculosis, ILD, smoking, microbiologically confirmed NTM-PD, and NB with the FC form on chest CT were identified as poor prognostic factors for mortality in suspected NTM-PD. ILD and NB with the FC form on chest CT were associated with NTM-PD exacerbation and mortality. Hydroxychloroquine use may lower the risk of NTM-PD exacerbation. Therefore, radiographic features and presence of ILD should be considered when predicting the prognosis of patients with RA and suspected NTM-PD.

Stratification of Nontuberculous Mycobacterial Disease Risk in Type 2 Diabetes Based on Metformin Use: a Population-Based Cohort Study in South Korea.

In a 1:4 case-control matched analysis of data from a nationwide population-based cohort in South Korea, we evaluated whether metformin use mitigates the risk of nontuberculous mycobacterial disease in patients with type 2 diabetes. Multivariable analysis revealed no significant association of metformin use with a diminished risk for incident nontuberculous mycobacterial disease in patients with type 2 diabetes.

Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

Mycobacterial disease in patients with chronic granulomatous disease

Chronic granulomatous disease (CGD) is an inborn error of immunity that affects the functionality of phagocytosis; specifically, there's lack of production of oxygen-free radicals by NADPH oxidase. CGD manifests as severe and recurring bacterial and fungal infections, as well as local and systemic hyperinflammation. In countries where tuberculosis is endemic and the BCG vaccine is mandatory at birth, patients with CGD may present local or systemic reactions to this vaccine as first manifestation; besides, recurrent infections by M. tuberculosis may be present throughout their life. The susceptibility of these patients to mycobacteria is due to the excessive production of pro-inflammatory cytokines and the formation of granulomas that are inefficient in containing mycobacteria. In developed countries, patients with CGD do not present this type of infectious manifestations, except for migrants who come from developing countries. In this review, we present the characteristics of infections by BCG, M. tuberculosis, and other types of mycobacteria. Interestingly, there are no guidelines regarding anti-tuberculosis treatments in patients with CGD, so we propose the realization of a consensus by experts in order to establish guidelines for the treatment of mycobacterial disease in CGD.

Nontuberculous mycobacteria in fistula-in-ano: A new finding and its implications

Objective/background: Nontuberculous mycobacteria (NTM) are not known to be associated with fistula-in-ano. NTM was detected in three fistula-in-ano patients in our series. In this study, related data was reviewed to find the mycobacterial disease in patients in our database. Methods: In this study, 311 consecutive fistula-in-ano patients operated over 2years were analyzed. The histopathology of anal fistula tract epithelial lining of every operated patient was analyzed and other tests (real-time-polymerase chain reaction [RT-PCR], GeneXpert, and mycobacterial culture) were conducted in patients with high index of suspicion of having mycobacterial disease. Results: Two patients had histopathological features suggestive of mycobacterial disease. Of these, one patient had NTM and the other had Mycobacterium tuberculosis (MTB) on RT-PCR. Four patients had normal histopathology features but tested positive on RT-PCR (2 each for NTM and MTB). Therefore, a total of six patients were tested for mycobacterial disease (3 each for NTM and MTB). Mycobacterium culture was performed in two patients (both NTM) but the result was negative. Five of six patients (NTM=2, MTB=3) presented with delayed recurrences after operation (6–18months after complete healing). Conclusion: NTM can cause fistula-in-ano. It could be an undiagnosed contributory factor in fistula recurrence. Mycobacterial disease (both tuberculous and nontuberculous) may be associated with delayed recurrence of fistula. RT-PCR is highly sensitive and can differentiate between NTM and MTB. It should perhaps be performed in all recurrent and refractory cases.

Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. Our objective was to assess the effect of mycobacterial disease in patients with CGD. We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3

AbstractThe signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked–like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4−CD8−) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.

Risk factors for atypical mycobacterial disease in patients with smear positive pulmonary TB

Non Tuberculous Mycobacteria (NTM) can cause severe infection in selected groups of patients and is very difficult to be differentiated from TB infection clinically or radiologically leading to miss diagnosis and wrong treatment in these cases, the Aim of the present study is to study risk factors associated with NTM disease in patients with Acid Fast Bacilli (AFB) smear positive, Subjects and methods: 1402 patients with AFB smear positive were included in the study, only 47 patients from the study group proved to have NTM disease (diagnosis was done according to ATS/IDSA criteria). Results: the mean age of the NTM patients was 61.8±23.2years, NTM was more common in older age groups and more common in white race patients, on using logistic regression analysis NTM disease was more commonly associated with old TB infection (42.6%) and with bed ridden patients on tracheostomy (31.9%). The most common organisms isolated were the MAC complex (55.3%) followed by M. Kansasii (34.04%). Conclusion: NTM disease should be put into consideration in patients with AFB smear positive and suffering from old TB infection or in bed ridden patients who are on tracheostomy, also if smear is positive for AFB and PCR is negative NTM should be suspected.

Nontuberculous Mycobacterial Disease in Patients with HIV in Southeast Asia

Although nontuberculous mycobacteria (NTM) are widely documented as a cause of illness among HIV-infected people in the developed world, studies describing the prevalence of NTM disease among HIV-infected people in most resource-limited settings are rare. To evaluate the prevalence of mycobacterial disease in HIV-infected patients in Southeast Asia. We enrolled people with HIV from three countries in Southeast Asia and collected pulmonary and extrapulmonary specimens to evaluate the prevalence of mycobacterial disease. We adapted American Thoracic Society/Infectious Disease Society of America guidelines to classify patients into NTM pulmonary disease, NTM pulmonary disease suspects, NTM disseminated disease, and no NTM categories. In Cambodia, where solid media alone was used, NTM was rare. Of 1,060 patients enrolled in Thailand and Vietnam, where liquid culture was performed, 124 (12%) had tuberculosis and 218 (21%) had NTM. Of 218 patients with NTM, 66 (30%) were classified as NTM pulmonary disease suspects, 9 (4%) with NTM pulmonary disease, and 10 (5%) with NTM disseminated disease. The prevalence of NTM disease was 2% (19 of 1,060). Of 51 patients receiving antiretroviral therapy (ART), none had NTM disease compared with 19 (2%) of 1,009 not receiving ART. Although people with HIV frequently have sputum cultures positive for NTM, few meet a strict case definition for NTM disease. Consistent with previous studies, ART was associated with lower odds of having NTM disease. Further studies of NTM in HIV-infected individuals in tuberculosis-endemic countries are needed to develop and validate case definitions.

Evolutionary genetics evidence of an essential, nonredundant role of the IFN-γ pathway in protective immunity

Identifying how natural selection has affected immunity-related genes can provide insights into the mechanisms that have been crucial for our survival against infection. Rare disorders of either chain of the IFN-γ receptor, but not of IFN-γ itself, have been shown to confer predisposition to mycobacterial disease in patients otherwise normally resistant to most viruses. Here, we defined the levels of naturally occurring variation in the three specific genes controlling the IFN-γ pathway (IFNG, IFNGR1, IFNGR2) and assessed whether and how natural selection has acted on them. To this end, we resequenced the three genes in 186 individuals from sub-Saharan Africa, Europe, and East-Asia. Our results show that IFNG is subject to strong purifying selection against nonsynonymous variants. Conversely, IFNGR1 and IFNGR2 evolve under more relaxed selective constraints, although they are not completely free to accumulate amino acid variation having a major impact on protein function. In addition, we have identified signatures of population-specific positive selection, including at one intronic variant known to be associated with higher production of IFN-γ. The integration of our population genetic data into a clinical framework demonstrates that the IFN-γ pathway is essential and nonredundant in host defense, probably because of its role in protective immunity against mycobacteria.

Disseminated nontuberculous mycobacterial disease in patients with acquired immune deficiency syndrome in the south of Brazil

A retrospective cohort was studied in order to evaluate mortality of patients with disseminated non-tuberculous mycobacterial (NTM) disease in Brazil. This diagnosis was neglected in 44.4% of patients, and in-hospital mortality was 41.7%.

Diagnostic Accuracy of In-House PCR for Pulmonary Tuberculosis in Smear-Positive Patients: Meta-Analysis and Metaregression

In-house PCR (hPCR) could speed differential diagnosis between tuberculosis (TB) and nontuberculous mycobacterial disease in patients with positive smears and pulmonary infiltrates, but its reported accuracy fluctuates across studies. We conducted a systematic review and meta-analysis of hPCR sensitivity and specificity for smear-positive TB diagnosis, using culture as the reference standard. After searching English language studies in MEDLINE and EMBASE, we estimated cumulative accuracy by means of summary receiver operating characteristic analysis. The possible influence of hPCR procedures and study methodological features on accuracy was explored by univariate metaregression, followed by multivariate adjustment of items selected as significant. Thirty-five articles (1991 to 2006) met the inclusion criteria. The pooled estimates of the diagnostic odds ratio, sensitivity, and specificity (random-effect model) were, respectively, 60 (confidence interval [CI], 29 to 123), 0.96 (CI, 0.95 to 0.97), and 0.81 (CI, 0.78 to 0.84), but significant variations (mainly in specificity) limit their clinical applicability. The quality of the reference test, the detection method, and real-time PCR use explained some of the observed heterogeneity. Probably due to the limited study power of our meta-analysis and to the wide differences in both laboratory techniques and methodological quality, only real-time PCR also displayed a positive impact on accuracy in the multivariate model. Currently, hPCR can be confidently used to exclude TB in smear-positive patients, but its low specificity could lead to erroneous initiation of therapy, isolation, and contact investigation. As the inclusion of samples from treated patients could have artificially reduced specificity, future studies should report mycobacterial-culture results for each TB and non-TB sample analyzed.

Mycobacterial disease in patients with rheumatic disease

This Review focuses on the emergence of mycobacterial disease in patients undergoing treatment for rheumatic disease with four new drug classes--tumor necrosis factor (TNF) inhibitors, human interleukin (IL)-1 receptor antagonists, anti-CD20 antibodies and CD4(+) T-cell costimulation modulators--collectively referred to as biologic agents. Mycobacterial disease is a major cause of severe infection in patients undergoing anti-TNF therapy. Reports are now emerging of an association between mycobacterial infection and antirheumatic treatment with anti-IL-1 or anti-CD20 antibodies. Although tuberculosis is the most common mycobacterial disease, nontuberculous mycobacterial (NTM) disease is an increasingly recognized problem in this setting. Among the antirheumatic drugs currently in development, agents that target IL-17, IL-23, Janus kinase-signal transducers and activators of transcription signaling, and metalloproteinases are likely to confer an increased risk of mycobacterial disease. Although screening and preventive treatments have lowered the incidence of active tuberculosis, these tools are not applicable to patients with NTM disease. All patients receiving drugs associated with an increased risk of mycobacterial disease should be carefully monitored, and suspect lesions should undergo Mycobacterium culture. Further studies are needed to determine the prevalence of NTM disease in this setting, and to evaluate the safety of simultaneous anti-TNF and antimycobacterial treatment.

Host genetic factors and mycobacterial infections: lessons from single gene disorders affecting innate and adaptive immunity

This review summarizes the association of increased susceptibility to mycobacterial disease in patients with genetic defects affecting innate and adaptive immunity. The optimum function of CD4 T-cell and macrophage function is critically important for immunity against mycobacteria. Antibody, complement and neutrophil function is not required for effective anti-mycobacterial immunity.

Mycobacterial diseases in primary immunodeficiencies.

Primary immunodeficiency diseases comprise over 100 conditions, each associated with a variety of viral, bacterial, fungal and protozoan infections. M. tuberculosis and less virulent mycobacteria, such as bacille Calmette-Guérin vaccines and environmental non-tuberculous mycobacteria, may cause severe disease in patients with primary immunodeficiency diseases. However, no previous review has dealt with the issue of which primary immunodeficiency diseases predispose affected individuals to mycobacterial disease. This information is very useful, not only increasing our understanding of human immunity to mycobacteria, but also for the diagnostic investigation of patients with mycobacteriosis. We review here the medical literature on cases of mycobacterial disease in patients with primary immunodeficiency diseases.

Tuberculous Pericarditis in a Woman Infected With Human Immunodeficiency Virus Type 1, Long-term Nonprogressive

We read with interest the recent article in theArchivesby Graham et al¹regarding the effect of isoniazid chemoprophylaxis on patients infected with human immunodeficiency virus (HIV). Their results showed a significant decrease in the incidence of mycobacterial disease in patients who were treated with isoniazid at various dosages during a 12-month period. However, it is not clear what happened when the secondary prophylaxis was stopped. In this regard, some reports²have recommended lifelong isoniazid chemoprophylaxis, whereas others³argue against it. We present a case that illustrates that a 12-month regimen may not be enough for all patients. Human immunodeficiency virus type 1 (HIV-1) infection, acquired by heterosexual transmission, was diagnosed in a 32-year-old woman in 1986. Since then, her blood lymphocyte CD4 cell count had been above 0.70×10⁹/L. The patient's condition was categorized as long-term and nonprogressive; therefore, she had never received antiretroviral

Mycobacterial disease in patients with human immunodeficiency virus infection

We compared the clinical features of disease due to tuberculosis and to Mycobacterium avium complex (MAC) in 94 patients with human immunodeficiency virus infection. Tuberculosis preceded the diagnosis of acquired immunodeficiency syndrome in 26 (67%) of 39 cases, compared with none of 55 with MAC infection. Chest roentgenographic findings suggested mycobacterial infection in 24 (83%) of 29 patients with pulmonary tuberculosis, compared with 7 (25%) of 28 with MAC infection. Sputum smears revealed acid-fast bacilli in 19 (83%) of 23 patients with pulmonary tuberculosis, but only 4 (16%) of 25 cases of pulmonary MAC infection. In 39 patients with tuberculosis, lymphadenitis and pleuritis were present in 13 (33%) and 8 (20%), respectively, but occurrence was rare in patients with MAC infection. In contrast, mycobacteremia was more frequent in MAC infection, occurring in 47 (85%) of 55 cases. In 5 patients, tuberculosis was unsuspected and probably contributed to death. These findings suggest that clinical features often distinguish tuberculosis from MAC infection in patients with human immunodeficiency virus infection. In addition, more intensive diagnostic use of sputum acid-fast smears may improve the outcome in patients with tuberculosis.

The treatment and prevention of mycobacterial disease in patients with HIV infection.

The treatment and prevention of mycobacterial disease in patients with HIV infection.

Bacteremia due to Mycobacterium avium-intracellulare in the acquired immunodeficiency syndrome.

The presence of Mycobacterium avium-intracellulare has frequently been demonstrated in tissue specimens from patients with the acquired immunodeficiency syndrome. The importance of this mycobacterium as a cause of constitutional symptoms and organ dysfunction has been unclear, however, because of the sparse inflammatory response evoked and the frequent concurrence of other pathogenic organisms. We detected M. avium-intracellulare in blood samples from eight patients with the acquired immunodeficiency syndrome, seven of whom had a previously recognized M. avium-intracellulare infection. Blood cultures were positive on 1 to 14 occasions over 135 days using the Dupont isolator system or the Bactec 12B medium system. Cultures were positive within 14 to 51 or 7 to 14 days with the respective techniques. The ability to rapidly isolate M. avium-intracellulare from blood may provide a useful diagnostic technique for detecting disseminated mycobacterial disease in patients with the acquired immunodeficiency syndrome as well as in other patient populations. This technique may also be useful for assessing the efficacy of drug therapy.