CORRESPONDENCE

 

Pulmonary non-tuberculous mycobacteria and Mycobacterium tuberculosis complex co-infection: A pragmatic approach to its diagnosis and management in South Africa

 

 

To the Editor: Non-tuberculous mycobacteria (NTM) are acid-fast bacilli that are Ziehl-Neelsen positive, sharing similarities in constitutional symptoms and radiological presentation with Mycobacterium tuberculosis complex (MTBC).^[1] NTM and other organisms, such as MTBC, often share similar risk factors, including structural lung disease.^[2] Despite clinical and radiological similarities, NTM treatment regimens, therapy duration, clinical monitoring and laboratory testing significantly differ from those of MTBC.^[3] NTM is not a diagnosis by exclusion or part of reflex testing. It requires specific line probe assays to be performed by laboratories in South Africa (SA) (Fig. 1). Therefore, tuberculosis healthcare workers must maintain a heightened suspicion for NTM, particularly in symptomatic cases, exhibiting persistent negative results on tuberculosis nucleic acid amplification tests (TB-NAAT) for MTBC (Fig. 1).

There are numerous reports in the literature describing co-infections involving NTM and other organisms, including multiple different NTM species, NTM and aspergillus or other fungi, NTM and MTBC, etc.^[7-9] The 2020 diagnostic criteria outlined by the American Thoracic Society/Infectious Diseases Society of America for diagnosing pulmonary NTM disease have remained unchanged since the previous version almost two decades ago (see back of manuscript for guideline criteria).^[5,6] Although the current guideline mentions co-infections, the 2007 version had dedicated sections to this concept (see back of manuscript for guideline sections acknowledging co-infections). Both versions incorporate the exclusion of an alternative diagnosis to define NTM pulmonary disease. These diagnostic modalities may involve bacterial or viral respiratory panels, GeneXpert MTB/RIF Ultra (Cepheid, USA), special stains to exclude opportunistic infections such as pneumocystis pneumonia, or rapid point-of-care tests for Legionella disease, among others.^[10] TB healthcare workers should be aware that a valid alternative diagnosis does not indefinitely exclude the diagnosis of respiratory NTM disease, and could potentially indicate the presence of a co-infection. Therefore, the word 'appropriate' does suggest the need for individual clinical judgment. In addition, not all NTM disease requires immediate treatment: a 'watchful wait' approach can also be considered.

International guidelines suggest prioritising drug susceptibility-based treatment over empirical NTM management.^[6] In SA, NTM susceptibility testing is performed centrally at the National TB reference laboratory in Johannesburg. Consequently, it is advisable to engage with TB microbiologists to discuss NTM drug susceptibility testing, with consideration given to individual cases. Expert clinical consultation is important when considering NTM disease with organisms typically indicative of environmental contamination or less frequently encountered, such as Mycobacterium gordonea, and those involved in dual infections with other mycobacteria.^[5,6]

Providing explicit guidance for a group of organisms, such as NTM, which are widely distributed in the environment and frequently encountered by human hosts, can be extremely challenging. This challenge is exacerbated by the era of culture-independent diagnostics, as well as the advent of modern-day next-generation sequencing and metagenomics technologies.^[11] These advancements identify multiple organisms simultaneously. In this context, clinicians must, perhaps more than ever, utilise all available clinical clues and their laboratory resources to make a diagnostic determination, while bearing in mind the underlying concern of potentially overdiagnosing NTM colonisation as active disease in co-infections.

International criteria for diagnosis of NTM pulmonary disease includes the following:

Clinical AND radiological imaging (pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules) AND appropriate exclusion of other diagnoses AND confirmatory microbiology (positive same culture results from at least two separate expectorated sputum samples (collected at least one week apart) OR positive culture result from at least one bronchial wash or lavage OR transbronchial or other lung biopsy with mycobacterial histopathological features (granulomatous inflammation or acid-fast bacilli) and positive culture for NTM and one or more sputum or bronchial washings that are culture positive for NTM).

2007: An official American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) statement: diagnosis, treatment and prevention of NTM^[5] - 'Lastly, there are clinical problems not directly addressed by these diagnostic guidelines. For instance, the significance of an NTM isolated from a patient during therapy for pulmonary TB is uncertain. The significance of two NTM species isolated simultaneously from a patient is also unknown. The combination of Mycobacterium avium complex and M. abscessus is especially well recognised. Unfortunately, there is not sufficient information to answer these issues broadly, so that patients in these circumstances must be approached on an individual basis. Both these events are likely to occur with increased frequency because of improved recovery of NTM by mycobacteriology laboratories. Patients who present with these clinical scenarios must be evaluated carefully, on an individual basis, and may require expert consultation.'

2020: Treatment of NTM pulmonary disease: an official ATS/ European Respiratory Society (ERS)/ European Society of Clinical Microbiology and Infectious Diseases (ESCMID)/IDSA clinical practice guideline^[6] - 'However, the risk of acquiring resistance to other co-infecting pathogens must be considered when macrolides are used for immunomodulatory purposes in patients whose isolate has documented inducible or mutational macrolide resistance.' 'Although macrolides might still be useful for immunomodulatory effects or antimicrobial effects against other co-infecting organisms, they are not counted as an active drug against M. abscessus when inducible or mutational resistance is noted.'

C Opperman

National Health Laboratory Service, Green Point TB Laboratory, Cape Town, South Africa; SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa; Division of Medical Microbiology, Department of Pathology, University of Cape Town, South Africa Christoffel.opperman@nhls.ac.za

S Singh

National Health Laboratory Service, Green Point TB Laboratory, Cape Town, South Africa; SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa

Y Ghebrekristos

National Health Laboratory Service, Green Point TB Laboratory, Cape Town, South Africa; SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa

R Warren

SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa

W Goosen

SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa

Author contributions. CO drafted the first version of the manuscript. CO, SS, YG, RW, and WG contributed to the editing, provided critical revisions, and approved the final version of the manuscript for submission.

Conflicts of interest. None.

 

References

1. Opperman CJ, Singh S, Goosen W, Cox H, Warren R, Esmail A. Incorporating direct molecular diagnostics in management algorithms for nontuberculous mycobacteria: Is it high time? IJID Reg 2023;10:140-145. https://doi.org/10.1016/j.ijregi.2023.12.003        [ Links ]

2. Sharma SK, Upadhyay V. Epidemiology, diagnosis and treatment of nontuberculous mycobacterial diseases. Indian J Med Res 2020;152(3):185-226. https://doi.org/10.4103/ijmr.IJMR_902_20        [ Links ]

3. Lange C, Bottger EC, Cambau E, et al. Consensus management recommendations for less common nontuberculous mycobacterial pulmonary diseases. Lancet Infect Dis 2022;22(7):e178-e190. https://doi.org/10.1016/S1473-3099(21)00586-7        [ Links ]

4. Kumar VG, Urs TA, Ranganath RR. MPT 64 antigen detection for rapid confirmation ofM. tuberculosis isolates. BMC Res Notes 2011;4:79. https://doi.org/10.1186/1756-0500-4-79        [ Links ]

5. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367-416. https://doi.org/10.1164/rccm.200604-571ST        [ Links ]

6. Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: An official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J 2020;56:2000535. https://doi.org/10.1183/13993003.00535-2020        [ Links ]

7. Joao I, Bujdáková H, Jordao L. Opportunist coinfections by nontuberculous mycobacteria and fungi in immunocompromised patients. Antibiotics 2020;9(11):771. https://doi.org/10.3390/antibiotics9110771        [ Links ]

8. Thangavelu K, Krishnakumariamma K, Pallam G, et al. Prevalence and speciation of non-tuberculous mycobacteria among pulmonary and extrapulmonary tuberculosis suspects in South India. J Infect Public Health 2021;14(3):320-323. https://doi.org/10.1016/j.jiph.2020.12.027        [ Links ]

9. Yilmaz N, Uçar EY, Saglam L. Mycobacterium tuberculosis and nontuberculous mycobacteria coinfection of the lungs. Turk Thorac J 2017;18(1):23-26. https://doi.org/10.5152/TurkThoracJ.2017.16034        [ Links ]

10. Brink AJ, Centner CM, Opperman C. Microbiology assessments in critically ill patients. Semin Respir Crit Care Med 2022;43(1):75-96. https://doi.org/10.1055/s-0041-1741018        [ Links ]

11. Wang L, Liu D, Yung L, et al. Co-infection with 4 species of Mycobacteria identified by using next-generation sequencing. Emerg Infect Dis 2021;27(11):2948-2950. https://doi.org/10.3201/eid2711.203458        [ Links ]