Diagnosis of Nontuberculous Mycobacterial Infections

Jakko van Ingen, MD, PhD

Disclosures

Semin Respir Crit Care Med. 2013;34(1):103-109. 

In This Article

Clinical Diagnosis of NTM Diseases

NTM Lung Disease

Because NTM are environmental bacteria that humans encounter on a daily basis,[1] diagnosing pulmonary NTM disease is not straightforward: a single positive culture from nonsterile sources including the respiratory or digestive tract need not indicate infection or disease. The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) have issued statements including a set of criteria to differentiate casual NTM isolation from true pulmonary NTM disease; these are summarized in [Table 1].[5] In short, these criteria denote that to diagnose pulmonary NTM disease, clinical, radiological, and microbiological evidence of disease should be gathered.

Symptoms are generally nonspecific, in part owing to frequent underlying conditions. Most patients present with a chronic cough, with or without sputum production or hemoptysis, and slowly progressive fatigue or malaise. Constitutional symptoms (weight loss, fever, night sweats) are less frequent—occurring in 30 to 50% of patients—and often indicate advanced disease.[5–7]

Radiological abnormalities are more specific and generally follow two distinct patterns. The first manifestation is characterized radiologically by bronchiectasis and nodular lesions, mostly involving the lingula and middle lobe; the second is characterized by fibrocavitary lesions that mostly involve the upper lobes and resemble pulmonary tuberculosis.[5,8,9] Mixed types do occur, as do single large nodular lesions, mimicking malignancy.[5] In cavitary disease, previous authors have suggested that NTM lung disease is characterized by thin-walled cavities, whereas tuberculosis would present with thick-walled cavities;[8] a review of these and later studies has refuted the use of cavity appearance as a diagnostic tool.[9] Cavitary lesions can occur in pulmonary malignancy and sarcoidosis as well as in infections by nonmycobacterial pathogens including fungi and Nocardia species.[10] In nodular bronchiectatic disease, the combination of bronchiectasis, multiple small nodules, and a "tree-in-bud" pattern suggestive of bronchiolitis is quite specific for NTM lung disease. In a series of 105 patients with suggestive computed tomographic (CT) findings in South Korea, 34% were diagnosed with NTM lung disease based on microbiological findings; the remainder were diagnosed with nonspecific bronchiolitis and bronchiectasis (50%), diffuse panbronchiolitis (8%), tuberculosis (6%), or other diseases (2%).[11] Similar abnormalities can be seen in immunocompromised patients diagnosed with pulmonary nocardiosis.[10] Hence other infectious (e.g., nocardiosis, fungal infection, tuberculosis) and noninfectious diseases (e.g., sarcoidosis) that can present with similar clinical and radiographic features have to be properly excluded before a firm diagnosis of NTM lung disease is made. Even in otherwise successful treatment, radiographic abnormalities may persist or even appear to increase in size; only small nodules tend to disappear during successful treatment.[12]

The third piece of evidence comes from the microbiology and pathology laboratories. To diagnose NTM lung disease using the ATS diagnostic criteria, a set of at least three respiratory specimens should be obtained and sent for microbiological analysis whenever possible. Sampling intervals should be up to several weeks, although the exact timing has not been investigated. Short intervals between sampling pose the risk of interpreting accidental temporary presence of NTM in the airways after environmental exposure as a sign of disease. Of these three or more specimens, at least two should yield growth of the same NTM species for a solid diagnosis of NTM lung disease. Apart from the commonsense exclusion of occasional presence after environmental exposure or even of laboratory contamination, this requisite stems from one study which demonstrated that radiological evidence of disease (infiltrates or cavitary lesions) and progression was found in 98% of the patients who had two or more positive sputum cultures for M. avium complex, versus just 2% in those with a single positive culture during 12 months of observation. For 97% of patients, the first two positive cultures grew from the initial three sputum specimens.[13]

This microbiological criterion may be less applicable to the nodular-bronchiectatic type of NTM lung disease because these patients may produce less or no sputum. To diagnose nodular bronchiectatic NTM lung disease, bronchoalveolar lavage (BAL) fluid culture may be more sensitive than sputum culture.[14,15] Similarly, in a case series of 31 patients with mainly nodular bronchiectatic MAC disease, 45% needed bronchoscopy or lung biopsy for diagnosis because sputum cultures were nondiagnostic.[7]

Histological or cytological analysis of respiratory samples can be useful in difficult cases, including patients who do not produce sputum and will probably only produce a single positive culture from BAL, to ensure that the disease process is characterized by granulomatous inflammation.[5] Especially in the immunocompromised, granuloma formation may be impaired, and the central caseous necrosis associated with tuberculosis may be absent.[16]

Extrapulmonary and Disseminated Disease

Lymphadenitis caused by NTM usually affects lymph nodes in a single site. The submandibular and cervical lymph nodes are most frequently affected, although axillary and inguinal lymphadenitis has been observed. Patients are typically (though not exclusively) children, under the age of 8 years. This age differs for the different species that cause lymphadenitis, but the background of this phenomenon remains elusive.[17] This disease is relatively benign, and most patients present with an enlarged lymph node without constitutional symptoms; in more advanced disease, fluctuating masses with violaceous overlying skin are seen. Fine-needle aspirates or excised lymph nodes are the specimen of choice to obtain microbiological evidence of NTM disease. In fine-needle aspirates, molecular tools are likely more sensitive than culture, in part because these can detect the more fastidious NTM (e.g., M. haemophilum and "M. tilburgii").[18,19]

The skin disease caused by M. marinum is characterized by single papulonodular, verrucose, or ulcerated granulomatous lesions, mostly on the hand or lower arm; single lesions may progress to form multiple lesions in a typical sporotrichoid pattern if left untreated.[20] Taking a proper history is important to obtain evidence for contact with potential sources of M. marinum. This infection is most commonly seen in fish tank fanciers, though swimming pool visits, diving, and contact with fish have all been associated with development of M. marinum infection.[20] Skin biopsies are the optimal specimens to obtain laboratory confirmation of infection but should be sent for histological examination as well as culture.[20] The relative sensitivities and specificities of culture and histology have not been sufficiently studied.

Mycobacterium fortuitum can cause a similar skin disease, usually consisting of a single lesion, though these infections tend to occur after trauma, in surgical wounds,[21] or in injection sites.[2,5]

Disseminated disease affects the immunocompromised, particularly patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), hematological malignancies, or those treated with immunosuppressive drugs after solid organ transplantation.[2,5] More recently recognized risk groups are patients treated with the so-called biologicals(e.g., anti-tumor necrosis factor agents) for immune-mediated inflammatory diseases.[22] Disseminated NTM diseases present as two distinct clinical syndromes. The first is a disease characterized by fever of unknown origin and generalized lymphadenopathy, although the latter may only develop over time or be most pronounced in abdominal lymph nodes. Owing to bone marrow infiltration, this disease may be accompanied by leucopenia or pancytopenia.[5,23] This disease type is most strongly associated with MAC and M. simiae and has occurred in HIV/AIDS, hematological malignancies, and after solid organ transplantation. Diagnosis is usually by blood culture; staining and culture of biopsy specimens of bone marrow offer a similar (60 to 75%)[23,24] or slightly higher sensitivity.[25] Two studies have reported that staining and culture of liver biopsy specimens may provide a faster and slightly more sensitive alternative.[26,27]

The second manifestation is a disseminated skin disease that presents with nodules, subcutaneous abscesses, pustules, ulcers, or combinations thereof. This disease manifestation has been associated with rapid growers (M. abscessus, M. chelonae) and M. haemophilum and tends to affect patients with hematological malignancies or solid organ transplants but not HIV/AIDS.[2,5,28] The reason for its absence in HIV/AIDS patients is unknown, and the skin tropism has been attributed to the preference of the causative species for lower temperatures (30°C rather than 37°C), although this concept has not been experimentally tested. This disease manifestation is usually diagnosed by histological examination of skin biopsy specimens and culture. Granulomas are found in 30 to 50% of cases,[21,29] thus rendering culture most important in the diagnosis. The exact sensitivities and specificities of these approaches have not been systematically studied.

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