M. Avium-intracellulare Complex Research Articles

Development of prevalence and incidence of non-tuberculous mycobacteria in German laboratories from 2016 to 2020

ABSTRACT Numbers of non-tuberculous mycobacteria (NTM) pulmonary diseases (PD) have been repeatedly reported as increasing over the last decades, particularly in Europe. Sound epidemiological data are however missing for most European regions. This study calculated prevalence and incidence of NTM recovered from patients’ lungs in Germany, the largest Central European country, over a five-year period. It furthermore determined regional particularities of NTM species and results from susceptibility testing. 22 German NTM laboratories provided their mycobacteriological diagnostic data of 11,430 NTM isolates recovered from 5998 pulmonary patients representing 30% of all notified NTM-PD cases of Germany from 2016 to 2020. NTM incidence and prevalence were calculated for every study year. The presented epidemiological indicators are particularly reliant as TB surveillance data were used as a reference and TB notification reaches almost 100% in Germany. Laboratory incidence and prevalence of NTM recovered from respiratory samples ranged from 4.5–4.9 and from 5.3–5.8/100,000 for the population of Germany, respectively, and did not change over the five-year study period. Prevalence and incidence were stable also when stratifying for facultative pathogenic NTM, M. avium/intracellulare complex (MAIC), and M. abscessus/chelonae complex (MABSC). The proportion of NTM with drug susceptibility testing (DST) increased from 27.3% (2016) to 43.8% (2020). The unchanging laboratory NTM prevalence/incidence in Germany represents a “ceiling” of possible NTM-PD notification when diagnostic strategies do not change in the coming years. A notable increase in NTM-DST may indicate better notification of NTM-PD and/or awareness of new clinical guidelines but still remains below clinical needs.

Identification of anti-lipoarabinomannan antibodies against mannan core and their effects on phagocytosis of mycobacteria by human neutrophils

Mycobacterium tuberculosis (MTB) and M. avium-intracellulare complex (MAC) enter host phagocytes, such as neutrophils through lipoarabinomannan (LAM) binding to pattern-recognition receptors, inducing innate immune responses including phagocytosis. Phagocytosis of mycobacteria by human neutrophils depends on the binding of α(1 → 2)-monomannose branching α(1 → 6)-mannan core of LAM/lipomannan (LM), a common component among mycobacterial species, to lactosylceramide (LacCer)-enriched lipid microdomains. We investigated the binding specificities of several anti-LAM antibodies (Abs) to LAMs/LM and found anti-LAM monoclonal IgMs TMDU3 and LA066 were directed against mannan core. Each IgM showed different binding specificity to mannan core. Confocal and stimulated emission depletion microscopy revealed TMDU3 and LA066 strongly bind to MTB and MAC, respectively. Flow cytometric analysis revealed human neutrophils do not express Dectin-2, DC-SIGN or mannose receptor. Furthermore, neutrophil phagocytosis of mycobacteria was markedly inhibited by TMDU3 and LA066, respectively. Similarly, treatment of each mAb with neutrophils reduced the numbers of intracellular MAC. Together, our results suggest that the interaction of LacCer-enriched lipid microdomains with mannan core and its blocking are therapeutic or diagnostic targets for both TB and non-tuberculous mycobacteria infection.

Clinical Aspects of Pulmonary Nontuberculous Mycobacteriosis

Nontuberculous mycobacterial (NTM) infections are an emerging problem. Common organisms include Mycobacterium avium, M. intracellulare, and M. kansasii, along with the M. avium intracellulare complex (MAC), which includes both M. avium and M. intracellulare. Typically, NTM infections affect the lungs and subsequently demonstrate a chronic course. Therefore, persistent respiratory symptoms generally indicate of the presence of pulmonary NTM diseases, and chest radiography, along with a sputum examination, are essential for its diagnosis. Because NTM are ubiquitous environmental organisms, a positive culture from a minimum of two separate expectorated sputum samples are required to make a diagnosis. The repertoire of effective drugs for treatment is considerably limited, indicating the need for long-term management with multiple drugs. Establishing a treatment regimen with high therapeutic efficacy and safety is an important issue for the future.

Microbiologic distribution and clinical features of nontuberculous mycobacteria in the tertiary hospital in Daegu

Background: Recent studies have shown that the nontuberculosis mycobacterium (NTM) recovery rate in clinical cultures has increased within Korea. However, another study conducted by a secondary hospital within Daegu reported different results. Therefore, the purpose of this study is to understand and evaluate the microbiological distribution and clinical features of NTM in Daegu. Methods: A retrospective study was conducted on 11,672 respiratory specimens undergoing acid fast bacilli (AFB) culture from 6,685 subjects who visited Yeungnam University Respiratory Center from January 2012 to December 2013. Results: Of the 11,672 specimens undergoing AFB culture, 1,310 specimens (11.2%) showed positive results. Of these specimens, NTM was recovered from 587 specimens, showing a recovery rate of 44.8%. Identification test for NTM was performed on 191 subjects; the results were as follows: M. avium-intracellulare complex (MAC) 123 (64.4%), M. abscessus 20 (10.5%), M. kansasii 12 (6.3%), and 33 other NTM germ strains. Of the 382 subjects with NTM, 167 were diagnosed with pulmonary NTM disease (43.7%), however virulence differed depending on NTM strain. Multivariate analysis showed that nodular bronchiectasis, the nodules, and finding consistent with cavity under imaging study were statistically significant for triggering pulmonary NTM disease. AFB culture showing MAC and M. abscessus was statistically significant as well. Positive predictive value for NTM polymerase chain reaction (NTM-PCR) was 88.6%. Conclusion: Results for NTM recovery rate within the Daegu area were similar to those for the Seoul metropolitan area. We can assume that NTM infection is increasing in our community, therefore AFB-positive subjects (1) should undergo NTM-PCR, (2) should have their culture results checked for differentiation of mycobacterium tuberculosis complex (MTB) from NTM, and (3) undergo NTM identification test to confirm its type. Administration of treatment with the above results should be helpful in improving the patients’ prognosis.

Non-tuberculous mycobacteria in cystic fibrosis

Non-tuberculous mycobacteria (NTM) are environmental organisms found in soil and water throughout the world that can cause chronic lung infection, usually in the context of structural lung disease or immunodeficiency.1 There is considerable evidence that rates of NTM infection are increasing in patients with Cystic Fibrosis (CF).2 In contrast to Mycobacterium tuberculosis, NTM do not seem to be transmissible from person to person nor re-activate following latent infection.3 Observed increases in NTM infection in CF patients are therefore likely to reflect increased exposure and/or increased susceptibility to infection. This review aims to summarize the epidemiology, diagnosis and treatment of NTM infection in CF patients focusing on the two most common mycobacterial groups causing disease: the M. avium-intracellulare complex (MAC) and the M. abscessus complex (MABSC).

Nontuberculous Mycobacteria Isolated from Respiratory Specimens during Recent Two Years: Distribution and Clinical Significance

Background: The isolation of nontuberculous mycobacteria (NTM) has been increasing worldwide as well as its clinical importance. The aim of this study was to investigate the distribution and clinical significance of NTM that has been isolated from respiratory specimens during a recent two-year period at a tertiary hospital. Methods: We analyzed respiratory samples that were obtained between January 2009 and December 2010 for AFB culture. We retrospectively reviewed the electronic medical records of these patients to obtain both clinical and radiologic information. NTM pulmonary disease was defined by using the guidelines provided by the America Thoracic Society/Infectious Diseases Society of America. Results: Among the 1,601 specimens that resulted in a positive AFB culture, 310 (19.4%) were NTM. In 189 patients, the most common isolate was M. aviumintracellulare complex (MAC) (127, 67.2%), which was then followed by M. abscessus (31, 16.4%), M. fortuitum (10, 5.3%), M. kansasii (9, 4.8%), and other NTM species. Of these, 93 (49.2%) patients were diagnosed with NTM pulmonary disease. MAC, M. abscessus, and M. kansasii were more virulent than the other species. None of the cases of NTM pulmonary disease were caused by M. fortuitum, M. chelonae, M. peregrinum, M. terrae complex, or M. gordonae. Conclusion: In Korea, the prevalence of NTM isolates is increasing, as are the cases of pulmonary disease. The pathogenic potential of NTM differs enormously by species and as a result the treatment of NTM lung disease depends on which species has caused the infection. The isolation and identification of NTM isolated from respiratory specimens are mandatory in order for clinical microbiology laboratories to make an accurate diagnosis and suggest the proper treatment of the NTM disease. (Korean J Clin Microbiol 2012;15:98-103)

Mycobacterium heckeshornenseInfection in HIV-infected Patient

<i>Mycobacterium heckeshornense</i>Infection in HIV-infected Patient

Skin and soft-tissue infection caused by non-tuberculous mycobacteria in Taiwan, 1997–2008

The aim of this study was to investigate the clinical, microbiological, and pathological characteristics and the outcomes of skin and soft-tissue infection (SSTI) caused by non-tuberculous mycobacteria (NTM). Medical records of 50 patients with SSTI caused by NTM identified from 2005 to 2008 and 63 patients previously reported in a medical centre from 1997 to 2004 were reviewed. The annual incidence (per 100,000 outpatients and in-patients) ranged from 0·57 in 2005, 0·38 in 2007, to 1·1 in 2008, with an average of 0·62/100,000. From 1997 to 2008, the average incidence was 1·39/100,000 patients. The average annual incidence of SSTI caused by NTM was 0·62/100,000 outpatients and in-patients during 2005 and 2008. Of the total of 113 patients identified during the 12-year period, patients infected with Mycobacterium fortuitum and M. marinum were younger than those infected with M. avium-intracellulare complex (MAC) (36 and 44 years vs. 55 years, P=0·004 and P=0·056, respectively), and were more likely to have previous invasive procedures than those infected with MAC and M. abscessus (81·8% and 72·0% vs. 27·8% and 54·8%, P=0·007), and less likely to have associated immunosuppression (9·1% and 24% vs. 66·7% and 45·2%, P=0·006). Granuloma was more often observed in immunocompetent patients (60·1% vs. 40%, P=0·019), and in M. marinum-infected specimens (78·3%). There were significant differences in the demographic and clinical features of patients with NTM SSTI, including immunosuppression, trauma experience, and depth of tissue infections.

Zoonotic aspects of Mycobacterium bovis and Mycobacterium avium-intracellulare complex (MAC)

Pathogens that are transmitted between the environment, wildlife, livestock and humans represent major challenges for the protection of human and domestic animal health, the economic sustainability of agriculture, and the conservation of wildlife. Among such pathogens, the genus Mycobacterium is well represented by M. bovis, the etiological agent of bovine tuberculosis, M. avium ssp. paratuberculosis (Map) the etiological agent of Johne disease, M. avium ssp. avium (Maa) and in a few common cases by other emergent environmental mycobacteria. Epidemiologic surveys performed in Europe, North America and New Zealand have demonstrated the existence and importance of environmental and wildlife reservoirs of mycobacterial infections that limit the attempts of disease control programmes. The aim of this review is to examine the zoonotic aspects of mycobacteria transmitted from the environment and wildlife. This work is focused on the species of two main groups of mycobacteria classified as important pathogens for humans and animals: first, M. bovis, the causative agent of bovine tuberculosis, which belongs to the M. tuberculosis complex and has a broad host range including wildlife, captive wildlife, domestic livestock, non-human primates and humans; the second group examined, is the M. avium-intracellulare complex (MAC) which includes M. avium ssp. avium causing major health problems in AIDS patients and M. avium ssp. paratuberculosis the etiological agent of Johne disease in cattle and identified in patients with Crohn disease. MAC agents, in addition to a broad host range, are environmental mycobacteria found in numerous biotopes including the soil, water, aerosols, protozoa, deep litter and fresh tropical vegetation. This review examines the possible reservoirs of these pathogens in the environment and in wildlife, their role as sources of infection in humans and animals and their health impact on humans. The possibilities of control and management programmes for these mycobacterial infections are examined with regards to the importance of their natural reservoirs.

Clinical features of eleven cases of Mycobacterium avium-intracellulare complex pulmonary disease associated with pneumoconiosis

The relationship between silicosis and tuberculosis is well known. Also other mycobacteria such as Mycobacterium kansasii often occur in association with pneumoconiosis. However, there are few reports describing an association of M. avium-intracellulare complex (MAC) lung disease and pneumoconiosis. The purpose of the present study is to describe clinical features of MAC respiratory infection associated with pneumoconiosis. Eleven patients with MAC respiratory infection associated with pneumoconiosis (all men, 6 with silicosis and 5 with welders’ pneumoconiosis) were collected. A determination of whether or not MAC caused pulmonary disease was made using the 1997 criteria required by the American Thoracic Society. Radiologically, cavity formation as well as upper lung field predominance of MAC disease were observed in 8 of 11 cases (72.7%). Two of 11 patients died of respiratory failure. Our present study clearly demonstrates that clinical features of MAC respiratory infection associated with pneumoconiosis were different from MAC without underlying diseases.

The Mycobacterium avium-intracellulare Complex dnaB Locus and Protein Intein Splicing

Intein is a protein sequence mebedded in-frame within a precursor protein and is posttranslationally excised by a self-catalytic protein splicing process. Protein splicing is believed to follow a pathway requiring Cys, Ser, or Thr residues at the intein N-terminus and substitutions other than Cys, Ser, or Thr residues prevent splicing. We show that the dnaB locus in some strains of M. avium-intracellulare complex (MAC) contains intein and that the intein N-terminal amino acid is Ala [Ala-type]. We demonstrate that the M. avium DnaB precursor protein undergoes posttranslational proteolytic processing producing proteins corresponding to the sizes of the DnaB and intein. Further, by Western analysis we detect a protein corresponding to the size of the spliced DnaB protein in MAC cell extracts. Together, these results indicate that the Ala-type MAC DnaB inteins can splice and provide another example that points to an interesting alternative splicing mechanism (Southworth, M. W., Benner, J., and Perler, F. B., EMBO J. 19, 5019–5026, 2000).

Increased production of interleukin-10 by human blood monocytes stimulated with Mycobacterium avium-intracellulare complex.

Macrophages produce various cytokines in response to mycobacteria, including interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha). IL-10 has been shown to down-regulate numerous macrophage functions, including microbicidal activity against intracellular bacteria and parasites. IL-10 also inhibits interferon-gamma (IFN-gamma) production and antigen-specific proliferation of Th1 cells mediating immunologic resistance to mycobacterial infection. In contrast, TNF-alpha activates macrophages and may augment their mycobacterial activity. In this study, peripheral blood mononuclear cells (PBMC) or blood monocytes obtained from healthy tuberculin reactors were stimulated in vitro with heat-killed Mycobacterium tuberculosis or heat-killed M. avium-intracellulare complex (MAC) to produce IL-10 and TNF-alpha. We studied a total of 26 clinical isolates of M. tuberculosis and 28 isolates of MAC. MAC-stimulated PBMC and monocytes released significantly larger amounts of IL-10 than those cells stimulated with M. tuberculosis. However, there was no difference in induction of TNF-alpha production between MAC and M. tuberculosis. When TNF-activity was neutralized by the addition of anti-TNF-alpha mAb in culture, MAC still induced more IL-10 secretion than did M. tuberculosis. These findings suggest that increased production of IL-10 by MAC-stimulated monocytes may play a role in the intractable disease caused by these organisms.

Identification of Mycobacterium avium complex isolated in eastern and central Japan by using DNA probes.

An attempt was made to identify Mycobacterium avium and Mycobacterium intracellulare in the M. avium intracellulare complex (MAC) isolated in the Tohoku (38 strains) and Tokai (30 strains) districts of Japan by using DNA probes which are specific for M. avium, M. intracellulare and M. tuberculosis complex, respectively. The incidence of M. avium infection (82%) by far exceeded that of M. intracellulare infection in the Tohoku district of eastern Japan. In the Tokai district of central Japan, the incidence of M. avium infection (57%) were slightly larger than that of M. intracellulare infection. Five of 68 strains showed a positive reaction with two different DNA probes. Thus a possibility of mixed infection could not be ruled out, because reference strains showed a positive reaction with only one species-specific DNA probe.

Pentoxifylline aggravates impairment in tumor necrosis factor-alpha secretion and increases mycobacterial load in macrophages from AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection.

Pentoxifylline, which inhibits tumor necrosis factor-alpha (TNF alpha), decreases human immunodeficiency virus replication in peripheral blood mononuclear cells. However, TNF alpha is important in cellular defense against M. avium-intracellulare complex (MAC), a common infection in advanced AIDS. The effect of pentoxifylline on mycobacterial colony counts in macrophages with in vivo MAC infection was evaluated, and differences in lipopolysaccharide (LPS)-induced TNF release in infected and uninfected macrophages were determined. Macrophages with in vivo MAC infection released much less TNF alpha in response to LPS (P = .01). The response was partially restored after antimycobacterial therapy. Pentoxifylline, in a concentration that inhibited LPS-induced TNF alpha by 52.4%, increased MAC counts by 2.5- to 50.0-fold. Thus, macrophages from AIDS patients with disseminated MAC infection are deficient in their ability to release TNF alpha, and further inhibition by pentoxifylline may be detrimental.

Rifabutin in combination with clofazimine, isoniazid and ethambutol in the treatment of AIDS patients with infections due to opportunist mycobacteria

96 AIDS patients with fever and either acid-fast bacilli on microscopic examination of bacteriological samples or mycobacteria isolated by culture were treated with a daily 4-drug combination of 7–10 mg/kg rifabutin, 5 mg/kg isoniazid, 20 mg/kg ethambutol and 100 mg clofazimine. 46 patients were excluded from efficacy assessment: 13 died before or within the first days of treatment, 5 had negative initial cultures, 14 had initial cultures positive for M. tuberculosis, 4 for M. kansasii, 1 for M. flavescens, 1 for M. gordonae, 7 were lost to follow-up and 1 received no rifabutin. In the 50 remaining patients, 31 had disseminated disease due to M. avium intracellulare complex (MAIC) and 19 had apparently localised disease, due to MAIC in 15 cases and to M. xenopi in 4 cases. Side-effects led to withdrawal of isoniazid in 1 case (hepatic enzymes increased) and rifabutin in another (thrombocytopenia). After 1 month of treatment, fever decreased from 38.4 ± 0.6 °C to 37.7 ± 0.5 °C (p < 0.01) and patients stopped losing weight. After 3 months treatment, only 37 patients were alive and still under treatment. Cultures became negative in 16 of 23 patients with available bacteriological data (9 of 14 patients with disseminated disease and 7 of 9 patients with localised disease), relapse occurred before death in 4 patients. 34 patients died before treatment was completed. Death was considered to be related to mycobacterial infection in 5 cases. We conclude that the 4-drug combination is safe and, in some cases, it appears to be effective.