Decreased Cytokine Production in Patients with Nontuberculous Mycobacterial Lung Disease

Nontuberculous mycobacteria (NTM) are intracellular pathogens that elicit a specific T-cell response characterized by the production of proinflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-12. However, little information exists regarding the levels of specific cytokines in patients with NTM lung disease. Therefore, we compared cytokine production in peripheral blood mononuclear cells (PBMCs) from patients with NTM lung disease with that in PBMCs from healthy controls. Pro- and anti-inflammatory cytokine production was measured by enzyme-linked immunosorbent assay in the PBMCs of 29 patients with NTM lung disease and 15 healthy controls. Phytohemagglutinin (PHA)-induced IFN-γ production and lipopolysaccharide (LPS)-induced production of TNF-α and IL-12p40 were significantly lower in the PBMCs of patients with NTM lung disease than in those of the healthy controls. The production of these cytokines did not differ significantly between patients infected with Mycobacterium avium complex (MAC) and those infected with Mycobacterium abscessus; however, IL-10 production was lower in patients infected with M. abscessus than in those infected with MAC. Decreased IFN-γ, TNF-α, and IL-12 production may be associated with host susceptibility to the development of MAC and M. abscessus lung disease.     

HLA Antigens and Nontuberculous Mycobacterial Lung Disease in Korean Patients

Background  Human leukocyte antigen (HLA) molecules are known to play an important role in host-defense mechanisms. The aim of this study was to evaluate the association between HLA alleles and lung disease caused by nontuberculous mycobacteria (NTM) in Korean patients. Methods  Seventy-eight patients with NTM lung disease (48 patients with Mycobacterium avium-intracellulare complex [MAC] infection and 30 patients with Mycobacterium abscessus infection) were included in the study. HLA-A, -B, and -DRB1 genotyping was performed by polymerase chain reaction using sequence-specific primers. Data from 485 healthy Korean individuals were used as a control. Results  When compared to controls, patients with NTM lung disease showed an increased frequency of DRB1*11 (OR = 1.91, 95% confidence interval [CI] = 1.01–3.64, p = 0.045, corrected p [pC] > 0.05). In the subgroup analysis, patients with MAC lung disease had an increased frequency of B*46 (OR = 2.23, 95% CI = 1.05–4.73, p = 0.044, pC > 0.05). Conclusions  Our data suggest that in a Korean population, patients with NTM lung disease and healthy subjects differ in the frequencies of some HLA alleles. However, when considering corrected p values, our findings are inconclusive. S.-W. Um and C.-S. Ki contributed equally to this work.     

Clinical Characteristics and Prognosis of Nontuberculous Mycobacterial Lung Disease with Different Radiographic Patterns

Rationale  

The clinical characteristics and prognostic impact of radiographic patterns of patients with nontuberculous mycobacterial lung disease (NTM-LD) are rarely evaluated.     

Nontuberculous Mycobacterial Pulmonary Infection in Patients with Cystic Fibrosis

The prevalence of nontuberculous mycobacteria (NTM) recovered from patients with cystic fibrosis (CF) appears to be increasing, probably related to improved surveillance and microbiological procedures and an increase in the life expectancy of patients with CF. The distinction between active lung infection and colonization is often difficult to assess in patients with CF because of the marked overlap in the clinical and radiological presentation of CF lung disease and lung disease caused by NTM infection. The possibility of active NTM lung infection should be considered in those patients with compatible radiographic changes and/or progressive deterioration in lung function who do not improve with specific antibiotic therapy and who have repeatedly positive sputum cultures and smears for NTM. Patients with repeatedly positive results of acid-fast smears are more likely to be infected than colonized. Pseudomonas overgrowth may confuse the results of sputum and bronchoalveolar lavage fluid cultures. Decontamination of respiratory samples from patients with CF with 5% oxalic acid results in improved bacteriological recovery of NTM. Skin tests are of limited value as a screening tool for NTM. Since the course of NTM lung infection is often slow, careful follow-up with repeated sputum cultures, chest radiographs and computed tomography (CT) scans may be needed.Treatment of NTM lung disease in patients with CF presents great difficulties because of abnormal gastrointestinal drug absorption and pharmacokinetics in this patient population. Treatment varies according to the mycobacterial species isolated. Long-term multidrug regimens including rifampin (rifampicin) and ethambutol are usually required. Monitoring serum drug levels is a useful indicator of correct dosage in order to prevent adverse effects due to potential drug interactions and altered pharmacokinetics in patients with CF.     

Gastroesophageal Reflux Disease Increases Susceptibility to Nontuberculous Mycobacterial Pulmonary Disease

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Role of Soluble T-Cell Immunoglobulin Mucin Domain-3 in Differentiating Nontuberculous Mycobacterial Lung Disease from Pulmonary Colonization

BackgroundDifferentiating between nontuberculous mycobacterial lung disease (NTM-LD) and pulmonary NTM colonization (NTM-Col) is difficult. Compared with healthy controls, patients with NTM-LD generally present immune tolerance along with increased expressions of T-cell immunoglobulin mucin domain-3 (TIM-3) and programmed cell death-1 (PD-1) on T lymphocytes. However, the role of soluble TIM-3 (sTIM-3) and soluble PD-1 (sPD-1) in differentiating NTM-LD from NTM colonization (NTM-Col) remains unclear.MethodsPatients with NTM-positive respiratory samples and controls were enrolled from 2016 to 2019. Patients were classified into NTM-Col and NTM-LD groups. Levels of sTIM-3, sPD-1, soluble PD-ligand-1 (sPD-L1), and TIM-3 expression were measured. Factors associated with NTM-LD were analyzed by logistical regression.ResultsTIM-3 expression on CD4⁺ and CD8⁺ T lymphocytes were highest in NTM-LD group, followed by NTM-Col, and control (P = .017 and P = .011 for trend). sTIM-3 elevated in the NTM-Col group compared with the NTM-LD and control groups (856.3 ± 518.7 vs. 595.3 ± 352.6 pg/mL, P = .009; vs. 437.0 ± 267.4 pg/mL, P < .001). Levels of soluble PD-1 and its ligand were similar among groups. Among the 79 NTM-positive patients, sTIM-3 was associated with NTM-LD (100-pg/mL increase, adjusted odds ratio (aOR) 0.658 [95% CI, 0.502–0.864], P = .003). Patients with ≥2 risk factors (sTIM-3 ≤ 530 pg/mL, BMI ≤ 22.5, and radiographic score ≥5) were 13 times more likely to exhibit NTM-LD than those without (aOR 13.234 [2.983–58.709], P = .001).ConclusionssTIM-3 was an independent factor for differentiating NTM-LD from NTM-Col, suggesting the immunologic role of sTIM-3 in NTM-LD pathogenesis. By assessing sTIM-3 levels and other risk factors, physicians may be able to identify NTM-LD cases in a simplified manner.     

The Importance of Local Subcutaneous Fat Thickness in Pilonidal Disease

Purpose This study was designed to investigate the local subcutaneous fat thickness in sacrococcygeal pilonidal disease. Methods Subcutaneous fat thickness was measured by ultrasonography in 125 patients with sacrococcygeal pilonidal disease and 125 age-matched, body mass index-matched and gender-matched controls. Results The sacrococcygeal subcutaneous fat thickness was 14.4 ± 2.9 mm, 18.3 ± 3.1 mm, and 22 ± 2.2 mm, respectively, in normal, overweight, and obese patients with sacrococcygeal pilonidal disease and 9.1 ± 3.1 mm, 11.3 ± 2.6 mm, and 20 ± 1.8 mm, respectively, in normal, overweight, and obese controls. Sacrococcygeal fat was significantly thicker in normal and overweight patients with pilonidal disease compared with controls with same body mass index (P< 0.01). There were no significant differences in fat thickness between obese patients and obese controls (P > 0.05). Conclusions Sacrococcygeal fat thickness, as a local factor, is closely associated with pilonidal disease.     

Nontuberculous Mycobacterial Lung Infections in Ontario, Canada: Clinical and Microbiological Characteristics

Study Objectives The aim of this study was to determine gender and clinical phenotype frequencies in pulmonary nontuberculous mycobacterial (NTM) infection and the frequency of disease in NTM isolates. Design The study is a retrospective observational cohort study of two overlapping cohorts: population cohort and clinical cohort. Setting The study was conducted at the University Health Network and Ontario Mycobacteriology Laboratory in Toronto, Ontario, Canada. Patients or Participants The population cohort consisted of all patients with one or more pulmonary NTM isolates in Ontario in 2003. The clinical cohort consisted of all patients with one or more pulmonary NTM isolates at our hospital in 2002–2003. Interventions The study entailed the review of laboratory records and demographics (both cohorts) and detailed clinical records (clinical cohort). Measurements and Results In the population cohort (N = 1651), females comprised 48% overall and 51% with microbiological disease criteria. In the clinical cohort (N = 552), females comprised 48% overall and 55% with NTM disease. In the population cohort, 45% fulfilled microbiological disease criteria, and in the clinical cohort 46% of patients had disease. Patients with MAC isolates fulfilled microbiological disease criteria in 51% of population cohort cases and all disease criteria in 52% of clinical cohort cases. Women more commonly fulfilled microbiological disease criteria in the population cohort (51 vs. 45%, P = 0.02) and all disease criteria in the clinical cohort (53 vs. 40%, P = 0.03). Among clinical cohort patients, 26% (13 women, 44 men) had fibrocavitation, while 62% (101 women, 37 men) had nodular bronchiectasis. Conclusions Women comprised a small majority with disease. Nodular bronchiectasis in women was most common, but significant proportions of each gender with each radiographic type were observed. NTM isolation, particularly MAC, was frequently associated with disease.     

Nontuberculous Mycobacterial Infections Associated With Left Ventricular Assist Devices in 3 Patients

Durable left ventricular assist devices (LVADs) provide circulatory support in patients with end-stage heart failure; however, complications include infection of the driveline exit site. Nontuberculous mycobacterial infections are rare in patients with LVADs, but they should be considered in those who have undergone device exchanges and have bacterial infections with driveline exit-site discharge but no fever or leukocytosis.We reviewed the charts of patients who had an LVAD implanted at our institution from January 2009 through December 2019, to identify those with a device-related nontuberculous mycobacterial infection. Collected data included patient demographics, premorbid conditions, infection type, previous device complications, treatment, and outcomes. We identified infections in 3 patients (mean age, 41 yr): Mycobacterium abscessus in 2 and M. chimaera in 1. All had a HeartMate II device and had undergone device exchanges for pump thrombosis or for driveline fault or infections. All presented with driveline exit-site discharge without fever or leukocytosis. The mean time between initial device implantation and diagnosis of a nontuberculous mycobacterial infection was 55 months. All 3 patients were treated with antibiotics and underwent localized surgical débridement; one underwent an additional device exchange. The M. abscessus infections disseminated, and both patients died; the patient with M. chimaera infection continued to take suppressive antibiotics.Nontuberculous mycobacterial infections are associated with high morbidity and mortality rates, warranting prompt diagnosis and treatment.     

The Child with Recurrent Mycobacterial Disease

Purpose of Review

Many genetic conditions predispose affected individuals to opportunistic infections. A number of immunodeficiency diseases, including genetic defects termed Mendelian susceptibility to mycobacterial disease (MSMD), permit infection from many different strains of mycobacteria that would otherwise not cause disease. These include tuberculous and nontuberculous mycobacteria, and bacille Calmette-Guérin vaccine (BCG). Patients may present with infections from other organisms that depend on macrophage function for containment. Defects in multiple genes in the IL-12 and NFKB signaling pathways can cause the MSMD phenotype, some of which include IL12RB1, IL12B, IKBKG, ISG15, IFNGR1, IFNGR2, CYBB, TYK2, IRF8, and STAT1.

Recent Findings

Multiple autosomal recessive and dominant, and 2 X-linked recessive gene defects resulting in the MSMD phenotype have been reported, and others await discovery. This review presents the known gene defects and describes clinical findings that result from the mutations.

Summary

If MSMD is suspected, a careful clinical history and examination and basic immunodeficiency screening tests will narrow the differential diagnosis. A specific diagnosis requires more sophisticated laboratory investigation. Genetic testing permits a definitive diagnosis, permitting genetic counseling. Mild cases respond well to appropriate antibiotic therapy, whereas severe disease may require hematopoietic stem cell transplantation.

     

Newly Detected Pulmonary Nontuberculous Mycobacterial Infection and Peripheral Lung Cancers in Patients During Follow-Up of Idiopathic Interstitial Pneumonia: Comparison of CT Findings

This article describes the difference between the computed tomography (CT) findings in patients with newly detected pulmonary nontuberculous mycobacterial infection (NTM-IIP) and Cancer-IIP.We retrospectively evaluated 35 NTM-IIP and 78 Cancer-IIP patients in reference to their null idiopathic interstitial pneumonia CT (n = 113), using >10 years of data. Two independent radiologists analyzed the CT characteristics and the axial location of the main opacity.The interobserver agreement was good (κ > 0.771). The NTM-IIP patients were older (P = 0.034). The median size of the main opacity in the NTM-IIP (27 mm; 11–73) was larger (19 mm; 5–60; P = 0.002). Consolidation (n = 30; 85.7%; odds ratio [OR], 45) and cavities (n = 14; 40%, OR, 25) were more common in NTM-IIP (all P < 0.001). The midst of the fibrotic cysts including honeycomb cysts (n = 16; 45.7%, OR, 4.95) was more common in NTM-IIP (P = 0.006).NTM-IIP appeared larger, with more frequent consolidation and cavities, and was more likely to have been located in the midst of the fibrotic cysts including honeycomb cysts at the CT, which showed that it was older than Cancer-IIP.