Incidence Of Nontuberculous Mycobacteria Infections Research Articles

Incidence of nontuberculous mycobacteria infections among persons with cystic fibrosis in the United States (2010–2019)

BackgroundNontuberculous mycobacteria (NTM) are ubiquitous, environmental bacteria that can cause chronic lung disease. Persons with cystic fibrosis (pwCF) are at high risk for NTM. Approximately 1 in 5 pwCF in the United States (U.S.) is affected by pathogenic NTM species, and incidence rates of NTM have been increasing among pwCF as well as in the general population. Prevalence of NTM pulmonary infections (PI) varies widely across the United States because of geographic variation in environmental exposures. This study will present updated region-level incidence of NTM infections in the cystic fibrosis (CF) population in the U.S.MethodsWe used the Cystic Fibrosis Foundation Patient Registry (CFFPR) data for the period 2010 through 2019. Our study population comprised persons with CF ≥ 12 years of age who had been tested for NTM PI. We included only registry participants with NTM culture results. We defined incident cases as persons with one positive mycobacterial culture preceded by ≥ two negative mycobacterial cultures. We defined non-cases as persons with ≥ two negative mycobacterial cultures. We estimated average annual NTM PI incidence by region. Using quasi-Poisson models, we calculated annual percent change in incidence by region.ResultsWe identified 3,771 incident NTM infections. Of these cases, 1,816 (48.2%) were Mycobacterium avium complex (MAC) infections and 960 (25.5%) were Mycobacterium abscessus infections. The average annual incidence of NTM PI among pwCF in the U.S. was 58.0 cases per 1,000 persons. The Northeast had the highest incidence of MAC (33.5/1,000 persons tested) and the South had the highest incidence of M. abscessus (20.3/1,000 persons tested). From 2010 to 2019, the annual incidence of total NTM PI increased significantly by 3.5% per year in the U.S.ConclusionsNTM PI incidence is increasing among pwCF. Identifying high risk areas and increasing trends is important for allocating public health and clinical resources as well as evaluating interventions.

Changing Incidence and Characteristics of Nontuberculous Mycobacterial Infections in Scotland and Comparison With Mycobacterium tuberculosis Complex Incidence (2011 to 2019).

An increase in infections with nontuberculous mycobacteria (NTM) has been noted globally, and their incidence has overtaken that of Mycobacterium tuberculosis complex (MTBc) in many countries. Using data from a national reference laboratory, we aimed to determine if this trend could be observed in Scotland. We undertook a retrospective review of all NTM isolates received by the Scottish Mycobacteria Reference Laboratory (SMRL) over 9 years from 2011 to 2019 inclusive. Clinical episodes were defined as per 2017 British Thoracic Society and 2020 American Thoracic Society/European Respiratory Society/European Society of Clinical Microbiology and Infectious Diseases/Infectious Diseases Society of America NTM guidelines. These rates were compared with Scottish tuberculosis rates over the same period. Of 8552 NTM isolates from 4586 patients in 2011 to 2019, 7739 (90.5%) were considered clinically relevant. These represented 2409 episodes of NTM infection, with M. avium, M. intracellulare, and M. abscessus complex being most common. A total of 1953 (81.1%) were pulmonary NTM infection episodes from 1470 patients and 456 extrapulmonary episodes from 370 patients. We estimated a rise in incidence from 3.4 to 6.5 per 100 000 person-years (2011-2019 inclusive), with an increase in NTM incidence over MTBc incidence in Scotland by 2017. The incidence of NTM infection in Scotland has overtaken MTBc incidence. NTM infection leads to a costly health care burden, possibly as much as UK£1.47 million (US$ and €1.73 million) annually. We recommend standardization of isolate referral with clinical surveillance and implementation of agreed standards of care delivered through multidisciplinary teams. This would improve diagnosis and patient management as well as assessment of diagnostics and novel treatments through clinical trials.

Nontuberculous mycobacteria infection and pulmonary disease in bronchiectasis.

Although interest in nontuberculous mycobacteria (NTM) infection has increased in the last decades, published data vary according to different geographical areas, diagnostic facilities and quality of study design. This study aims at assessing both prevalence and incidence of NTM infection and NTM pulmonary disease (NTM-PD) among adults with bronchiectasis, to describe patients' characteristics, therapeutic options and clinical outcomes. Bronchiectasis adults who had been tested for NTM were enrolled at the Bronchiectasis Program of the Policlinico Hospital in Milan, Italy, from 2016 to 2018. Among the 373 patients enrolled, 26.1% had at least one respiratory sample positive for NTM and 12.6% reached a diagnosis of NTM-PD. Incidence rates for NTM infection and NTM-PD were 13 (95% CI 10-16) and 4 (95% CI 2-6) per 100 person-years, respectively. The most prevalent NTM species causing NTM-PD were M. intracellulare (38.3%), M. avium (34.0%), M. abscessus (8.5%) and M. kansasii (8.5%). Once treatment for NTM-PD was initiated, a favourable outcome was documented in 52.2% of the patients, while a negative outcome was recorded in 32.6%, including recurrence (17.4%), treatment failure (10.9%), re-infection (2.2%) and relapse (2.2%). Treatment halted was experienced in 11 (23.9%) patients. NTM infection is frequent in bronchiectasis patients and the presence of NTM-PD is relevant. The low success rate of NTM-PD treatment in bronchiectasis patients requires a call to action to identify new treatment modalities and new drugs to improve patients' outcomes.

Nontuberculous mycobacterial infection in rheumatoid arthritis patients: a single-center experience in South Korea.

Nontuberculous mycobacteria (NTM) infection has been increasing worldwide in both general population and immunocompromised patients, which has also been reported in rheumatoid arthritis (RA) patients. This study aimed to identify the incidence and clinical characteristics of NTM infection in RA patients living in tuberculosis (TB) infection endemic area.We performed a retrospective analysis of NTM infection cases in our RA registry at a tertiary referral center from January 1995 to December 2013. The clinical features of them were compared to those of 52 TB infection patients from same registry.Among 1,397 patients with RA, NTM infection was newly developed in 26 patients and the incidence of NTM infection was 164.8 per 100,000 patient-years. The Mycobacterium avium complex was the most frequent isolate (76.9%). None of the NTM infections had extrapulmonary involvement, which was rather common in TB infection (26.9%). Patients with NTM infection were older, received higher cumulative steroid doses, and had higher rates of past TB infection history and concomitant interstitial lung disease (ILD) than cases with TB infection.In South Korea, NTM infection is not rare in RA patients, and infection rates are growing. Physicians should be cautious about NTM infection in patients with a history of TB infection or concomitant ILD, even living in TB endemic area.

Preclinical Models of Nontuberculous Mycobacteria Infection for Early Drug Discovery and Vaccine Research.

Nontuberculous mycobacteria (NTM) represent an increasingly prevalent etiology of soft tissue infections in animals and humans. NTM are widely distributed in the environment and while, for the most part, they behave as saprophytic organisms, in certain situations, they can be pathogenic, so much so that the incidence of NTM infections has surpassed that of Mycobacterium tuberculosis in developed countries. As a result, a growing body of the literature has focused attention on the critical role that drug susceptibility tests and infection models play in the design of appropriate therapeutic strategies against NTM diseases. This paper is an overview of the in vitro and in vivo models of NTM infection employed in the preclinical phase for early drug discovery and vaccine development. It summarizes alternative methods, not fully explored, for the characterization of anti-mycobacterial compounds.

A Comparative Genomics Approach for Shortlisting Broad-Spectrum Drug Targets in Nontuberculous Mycobacteria.

Many members of nontuberculous mycobacteria (NTM) are opportunistic pathogens causing several infections in animals. The incidence of NTM infections and emergence of drug-resistant NTM strains are rising worldwide, emphasizing the need to develop novel anti-NTM drugs. The present study is aimed to identify broad-spectrum drug targets in NTM using a comparative genomics approach. The study identified 537 core proteins in NTM of which 45 were pathogen specific and essential for the survival of pathogens. Furthermore, druggability analysis indicated that 15 were druggable among those 45 proteins. These 15 proteins, which were core proteins, pathogen-specific, essential, and druggable, were considered as potential broad-spectrum candidates. Based on their locations in cytoplasm and membrane, targets were classified as drug and vaccine targets. The identified 15 targets were different enzymes, carrier proteins, transcriptional regulator, two-component system protein, ribosomal, and binding proteins. The identified targets could further be utilized by researchers to design inhibitors for the discovery of antimicrobial agents.

Non-tuberculous mycobacterial infections—A neglected and emerging problem

Non-tuberculous mycobacteria (NTM) are ubiquitous dwellers of environmental niches and are an established cause of natural and nosocomial infections. The incidence of NTM infections is rising owing to a growing population of immunocompromised and vulnerable individuals, complex medical and surgical procedures, as well as increased awareness and diagnostic capabilities. The prevalence of different NTM varies between continents, regions, and countries. The true global burden of pulmonary and extrapulmonary disease is unknown and estimates are subject to under and/or over-estimation. Diagnosis requires confirmation by isolation of NTM along with clinical and radiological criteria, which may be suboptimal at all levels. Susceptibility testing is complex and clinical breakpoints are not available for many of the drugs. Frequently, NTM infections are not considered until late in the course of disease. Improved and rapid detection of tuberculosis cases in high-burden countries has, however, also brought NTM infections into the limelight, and has identified a need for research efforts towards rapid diagnostic tests and the identification of biomarkers to monitor the treatment response in patients with NTM infections.

Incidence, comorbidities, and treatment patterns of nontuberculous mycobacterial infection in South Korea.

Nontuberculous mycobacteria (NTM) are important pathogens in humans, and hospital-based studies have shown an increased incidence of NTM infection. However, little is known about the treatment pattern of NTM infection with respect to the number of cases per population in South Korea. This study evaluated the trends in the incidence of NTM infection, respiratory comorbidities, and treatment patterns in South Korea.National claims data from the Health Insurance Review and Assessment service database for the years 2009 to 2015 were reviewed, and codes related to NTM infection, respiratory comorbidities occurring from one year before NTM infection and associated treatments were identified.In total, 52,551 patients were included in the study and the average annual incidence per 100,000 person-years was 12.8. The annual incidence was found to have increased from 6.6 to 26.6 per 100,000 persons. Accompanied comorbidities were tuberculosis (33.7%), followed by bronchial asthma (33.2%), chronic obstructive pulmonary disease (25.6%), and lung cancer (5.8%). A total of 76.6% of patients did not receive any combination treatment within one year after the diagnosis of NTM infection. Macrolide-based treatment was administered to 18.8% of patients.A dramatic increase in the incidence of NTM infection was noted in the population of South Korea. Approximately three-fourth of the patients with NTM infection were clinically observed without treatment for at least 1 year after the identification of NTM infection and most patients who treated NTM infection received macrolide-based combination therapy.

Cutaneous Nontuberculous Mycobacterial Infections in Alberta, Canada: An Epidemiologic Study and Review.

Cutaneous infections caused by nontuberculous mycobacteria (NTM) occur infrequently. Nonetheless, the incidence of NTM infections is reported to be increasing. In Canada, cutaneous NTM infections have not been well described. A database review from 2006 to 2016 was done to assess species frequency, incidence, and trends of the most common cutaneous NTMs in the province of Alberta, Canada. We also reviewed major diagnostic and epidemiologic aspects of NTM cutaneous infections with a focus on Mycobacterium marinum. A database search identified 244 cases of NTM infections. Mycobacterium avium-intracellulare complex had the highest incidence, causing 64% of cases. Rapid growers ( Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum) caused 23% and M marinum 13%. Information on infection site was available for 117 cases. There was no difference noted in sex distribution; however, differences in age groups between species were noted. The incidence of NTM cutaneous infections in Alberta, Canada, was reported for the first time and the incidence of M marinum was found to be similar to that reported in the worldwide literature. Patients' age groups were different between species. Knowledge of the unique microbiological features of NTMs and the role of the diagnostic laboratory are important.

Skin and Soft Tissue Infections Due to Nontuberculous Mycobacteria.

This review describes recent trends in the epidemiology of nontuberculous mycobacteria (NTM), emerging pathogens, new insights into NTM pathogenesis, and advances in diagnosis and treatment. Emerging pathogens include Mycobacterium chimaera and drug-resistant subspecies of Mycobacterium abscessus. Important virulence mechanisms of pathogenic NTM include the ability to alter the macrophage's permissiveness to intracellular bacterial growth. New diagnostic tools consist of DNA probes, gene sequencing, and matrix-assisted laser desorption ionization-time of flight. These methods allow rapid speciation of NTM species, in some cases directly from patient samples. There are few novel agents available to treat NTM, although some repurposed drugs show excellent activity. The incidence of NTM infections appears to be increasing in a number of regions around the world. Molecular methods are now the diagnostic tools of choice. Discovery of novel effective agents and/or drug combinations with greater likelihood of cure, shorter treatment duration, and fewer side effects are research priorities.

Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation

Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001 to 2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1097 allogeneic HCT patients, 45 (4.1%) had NTM isolated and 30 (2.7%) had NTM disease (28 [93.3%] exclusively pulmonary, 2 [6.7%] pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9% to 4.0%). The median time to diagnosis was 343 days (range, 19 to 1967). In Fine-Gray proportional hazards modeling, only global severity of chronic graft-versus-host disease (cGVHD) (HR, 1.99; 95% CI, 1.12 to 3.53; P = .019,) and cytomegalovirus (CMV) viremia (HR, 5.77; 95% CI, 1.71 to 19.45; P = .004) were significantly associated with NTM disease. Using these variables a risk score was calculated: 1 point for CMV viremia or moderate cGVHD and 2 points for severe cGVHD. The score divided patients into low risk (0 to 1 points, n = 820 [77.3%], 3-year NTM risk 1.2%), intermediate risk (2 points, n = 161 [15.4%], 3-year NTM risk 7.1%), and high risk (3 points, n = 56 [5.4%], 3-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification.

Non-tuberculous mycobacterial infections at San Francisco General Hospital.

The epidemiology of non-tuberculous mycobacteria (NTM) infection is not well defined. We evaluated the trends in incidence of NTM infections at San Francisco General Hospital (SFGH), a large metropolitan county hospital. We performed a retrospective review of microbiologic and clinical records of all patients with a positive NTM culture reported from 1993 to 2001. NTM infection was defined by the isolation of >1 NTM from any clinical specimen. Patients were stratified by human immunodeficiency virus (HIV) status. Univariate and multivariate logistic regression were used to identify factors that were independently associated with NTM infection. Trends over time were assessed using Poisson test for trend. During the study period, 25 736 samples from 7395 patients were cultured for mycobacteria. Of these samples, 2853 (11.1%) from 1345 patients (18.2%) were culture positive for NTM. Patient characteristics associated with infection included younger age (P < 0.001), male gender (P < 0.001), White ethnicity compared with Asian and Hispanic (P < 0.001 and P = 0.01, respectively), and HIV positivity (P < 0.001). Overall, NTM infection at SFGH decreased significantly from 319 cases in 1993 to 59 in 2001 (P < 0.001). Mycobacterium avium was predominant in both HIV-positive and HIV-negative populations (74.5% and 44.6% of isolates, respectively), and Mycobacterium kansasii was the second most common NTM species isolated. The proportion of other NTM species isolated in these groups differed. In contrast to other published studies, time-series analyses show that NTM isolation rates decreased during the study period at SFGH, where NTM was most strongly associated with HIV infection.

Incidence of tuberculous and non-tuberculous mycobacteria, differentiated by multiplex PCR, in clinical specimens of a large general hospital

OBJECTIVE:To determine the incidence of Mycobacterium tuberculosis complex and non-tuberculous mycobacterial isolates in the routine setting of a large general hospital using an "in-house" multiplex polymerase chain reaction method and to establish a paradigm for the definitive identification of mycobacteria isolated using semi-automated equipment.METHODS:Established tests, including polymerase chain reaction restriction enzyme analysis, PNB, and NAP inhibition tests as the gold standard, showed 100% agreement with an IS6110/hsp65 multiplex polymerase chain reaction when used to identify stock strains (n = 117).RESULTS:In a subsequent study, 8,790 clinical specimens producing 476 isolates were evaluated with multiplex PCR and also showed 100% agreement in identification using PRA-polymerase chain reaction as the gold standard. The application of this technique to routine analysis was demonstrated in this study. A method was established with the initial application of multiplex PCR for all positive liquid cultures and the subsequent identification of non-tuberculous mycobacteria by polymerase chain reaction restriction enzyme analysis. In total, 77% of isolates belonged to the Mycobacterium tuberculosis complex, and 23% were non-tuberculous mycobacteria.CONCLUSIONS:Several non-tuberculous mycobacterial species were identified, primarily M. avium, but other potentially pathogenic species were also frequently observed, including M. fortuitum, M. abscessus, and M. kansasii. The expeditious communication of these data to the clinical staff was fundamental for the diagnosis of clinical cases. Even in settings where tuberculosis is of major importance, the incidence of non-tuberculous mycobacteria infection is substantial.

Systemic Mycobacterium avium Complex Infection During Antitumor Necrosis Factor‐α Therapy in Pediatric Crohn Disease

Systemic <i>Mycobacterium avium</i> Complex Infection During Antitumor Necrosis Factor‐α Therapy in Pediatric Crohn Disease

Non-Tuberculous Mycobacteria in TB-Endemic Countries: Are We Neglecting the Danger?

There are more than 120 members of the genus Mycobacterium, which are diverse in pathogenicity, in vivo adaptation, virulence, response to drugs, and growth characteristics. Mycobacteria other than M. tuberculosis complex and M. leprosy are known as Non-Tuberculous Mycobacteria (NTM) and are known by various acronyms. They attracted abrupt attention only after the AIDS epidemic, but most of the reports were published from TB non-endemic countries [1] and only rarely from TB-endemic countries. This is probably because the chances of missing NTM species are higher in TB-endemic countries, which are poorly equipped and overburdened with other diseases (Box 1). The information regarding their true incidence and prevalence in these countries is scarce [2]. In the absence of such authentic information, the current dogma has been that the NTM are of the least consequence. However, we do not agree with this myth and wish to present our viewpoint on this important aspect and emphasize the need for a fresh look at this neglected aspect. Box 1. Possible Factors for Under-reporting of NTM from TB-Endemic Countries NTM infections are not reportable in any country. Awareness is lacking among treating physicians and microbiologists. Laboratory infrastructure is lacking for culture and identification of non-tuberculous mycobacteria. High burden of TB and HIV attracts the bulk of the attention of the health care system; governmental fiscal inputs toward the costs of these neglected infections continue to be neglected. Standardized or accepted criteria to define NTM respiratory disease are lacking. Prevalence of NTM Infections before and after the AIDS Epidemic We searched methodological search terms and phrases such as “non-tuberculous mycobacteria and AIDS” in Medline records and found that 3,020 articles were published between 1981 and 2009. Using the same phrase, only 59 articles were published between 1900 and 1981, indicating a clear upsurge of NTM disease in the post-AIDS era. However, most of these publications were from TB non-endemic countries [1]–[5], but not much significance could be adhered to these isolations [2]. The disseminated NTM infection is typically seen when the CD4+ T lymphocyte number falls below 50 µl. For this reason, it is argued that in TB-HIV co-endemic countries, AIDS patients usually die of tuberculosis or other infections before their CD4+ count falls low enough for NTM to cause a disease (Box 2). Nevertheless, we feel that besides this argument, in a majority of the patients, the diagnosis of NTM disease gets missed in these countries. Box 2. Facts about Non-tuberculous Mycobacterial Disease AIDS patients are significantly more vulnerable to NTM infections due to severe T cell immunodeficiency. Solid organ transplant patients, even though immunocompromised, are not at as high a risk as their HIV-positive counterparts. Although some genetic and anatomical factors predispose to NTM, no proven associations have been proven among geographical, occupational, or ethnic factors and NTM infections. Anatomical abnormalities and other co-morbidities such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis (CF), pneumoconiosis, past history of TB, pulmonary alveolar proteinosis, and esophageal motility disorders are well-established predisposing conditions. Disseminated NTM infections have been associated with specific genetic syndromes such as mutations in interferon (IFN)-γ, interleukin (IL)-12 synthesis, and in response pathways and the nuclear factor-κB essential modulator (NEMO). Conventional methods are not sufficiently sensitive to estimate prevalence and incidence of NTM infections. Monoplex TB-specific PCR needs to be replaced by multiplex PCR systems on relevant clinical samples along with blood and urine samples in tertiary-care settings. Multiplex PCR primers have been designed to amplify genus-specific regions, M. tuberculosis complex specific, M. avium complex specific, M fortuitum complex specific, and species-specific gene targets, that can be performed in a single tube. Geographical Distribution of NTM Some workers also consider that the low detection rate of NTM is due to diversity in the environmental and climatic conditions in the HIV-TB-endemic countries, but this argument is not supported by the literature [3]–[5]. In most of the surveys, the rate of human NTM infections is estimated by non-specific antibody assays or skin tests [6]. Hence, these findings may not be a reliable source of information. The International Union against Tuberculosis and Lung Diseases (IUATLD) reviewed data from 14 countries and found that the M. avium complex (MAC) was the most frequently isolated species in all these countries, which included China, India, and Korea. While M. fortuitum was the most frequently encountered species in Belgium (2.1%), the Czech Republic (17.5%), Denmark (5.3%), Finland (6.7%), France (6.5%), Germany (12.2%), Italy (2.5%), Portugal (16.5%), Spain (10.8%), Switzerland (17.5%), Turkey (33.9%), and the United Kingdom (6.0%), undoubtedly, environment is the main reservoir of NTM. There is no evidence of human-to-human or animal-to-human transmission [6]. Most infections are acquired either from the water (treated or untreated) or soil. MAC and M. fortuitum are frequently isolated from the drinking water distribution systems and swimming pools in both developing and developed countries.

Isolation of Nontuberculous Mycobacteria Using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism

The isolation rate of nontuberculous mycobacteria (NTM) in clinical laboratories and the incidence of NTM infections are on the increase recently in Korea, but there have been only a few studies that reveal the general aspect of NTM isolation or species distribution. Therefore, this study was performed to examine the isolation rate of NTM, species identification, and the clinical significance of mycobacterial cultures. From August 2004 to May 2005, we examined mycobacterial isolates by AccuProbe test to differentiate NTM from Mycobacterium tuberculosis complex. NTM was then identified by polymerase chain reaction-restriction fragment length analysis (PCR-RFLP). A total of 6,742 specimens from 2,784 patients were requested for mycobacterial culture. Mycobacteria were isolated from 776 specimens (11.5%). The isolation rates of NTMs among the total culture positive specimens and culture positive sputum specimens were 24.4% (189/776) and 25.3% (169/667), respectively. Fourteen species of NTM identified in 172 of the 175 specimens tested included M. avium (39.0%), M. intracellulare (22.7%), and M. abscessus (19.8%). Using AccuProbe tests and PCR-RFLP method for mycobacterial cultures processed in a clinical laboratory, we were able to identify NTMs to the species level. The isolation rate of NTM in this study was similar to that reported in past studies in Korea. In addition, we found that some of the NTMs isolated in this study could cause pulmonary diseases.