Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV

INTRODUCTION — The majority of disease due to nontuberculous mycobacteria (NTM) in patients with HIV is caused by Mycobacterium avium complex (MAC); however, other NTM are important pathogens. Infection with NTM other than MAC can be disseminated or localized, and similar to MAC, the risk of disease increases with progressive immunodeficiency. The greatest risk occurs when the CD4 count decreases below 50 cells/microL. Although the numbers of NTM cases have declined dramatically in people treated with antiretroviral therapy (ART), it is important to consider these pathogens in people with HIV who are not receiving ART and those who present with symptoms or signs of an opportunistic infection.

This topic will review the clinical manifestations and treatment of the most commonly isolated NTM species in people with HIV. Topic reviews that discuss MAC and the microbiology, pathogenesis, epidemiology, and clinical manifestations of NTM in people without HIV are found elsewhere. (See "Microbiology of nontuberculous mycobacteria" and "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Overview of nontuberculous mycobacterial infections".)

PRINCIPLES OF DIAGNOSIS AND THERAPY — Diagnosis and therapy of NTM in people with HIV require a thorough clinical assessment combined with culture data and appropriately directed empiric therapy.

When NTM are isolated from a usually sterile site (eg, blood, bone marrow, lymph nodes, synovial fluid), the diagnosis of true disease is generally straightforward. However, when NTM are isolated from non-sterile sites, such as sputum or bronchoalveolar lavage fluid, the diagnosis is less definitive, especially when the colony numbers are low or the isolate is present in only one cultured specimen. A diagnosis of infection then depends upon other clinical findings, radiographic findings, and the presence or absence of other pathogens. Organisms considered in other circumstances to be commensals can be opportunistic pathogens in people with advanced HIV disease and immunodeficiency [1]. A case series from Spain identified 26 people with HIV between 1998 and 2005 with NTM isolates from sputum [2]. Using clinical criteria to establish a diagnosis of colonization versus infection, the factors associated with disease were CD4 counts <50 cells/microL, weight loss, hemoglobin below 11g/dL, duration of symptoms longer than a month, AFB smear positive sputum, and repeated positive NTM cultures.

It is important to remember that experience with NTM other than MAC and Mycobacterium kansasii is limited, and treatment decisions must be individualized. Further reports of infection with new NTM strains characterized by their unique 16S ribosomal RNA continue, adding to a growing list of rare pathogens for which diagnosis and treatment are unclear [3]. In the Spanish study noted above [2], MAC and M. kansasii caused all disease, whereas other NTM were considered to be colonizers.

Species identification of NTM is usually made through traditional biochemical testing of isolates; thus, results are often not available for weeks. However, newer molecular testing methods of clinical specimens, using direct amplification of nucleic acid probes (eg, Gen-Probe and AccuProbe) to rapidly identify Mycobacterium tuberculosis, M. kansasii, and MAC, can produce results in hours. In addition, newer line probe assays (LPAs) have enabled species- and subspecies-level identification of some species of NTM while also allowing for the detection of antibiotic resistance for aminoglycosides and macrolides by the identification of specific gene mutations [4].

The recommendations of the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) for treatment of NTM [5] and the consensus management recommendations for less common NTM pulmonary infections [6] serve as useful guides to the treatment of NTM. Although these guidelines focus on patients without HIV, most of the recommendations can also be applied to people with HIV. However, there are significant drug interactions with rifamycins and the preferred antiretroviral agents used for HIV treatment, and this may impact antiretroviral therapy regimen selection. (See "Overview of antiretroviral agents used to treat HIV" and "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions", section on 'Patients with opportunistic infections'.)

In patients initiating ART, an immune reconstitution inflammatory syndrome (IRIS; the paradoxical worsening of pre-existing infectious processes after the start of combination antiretroviral therapy) has been frequently described among people with HIV and known or previously undiagnosed mycobacterial infection, both tuberculous and nontuberculous. The vast majority of nontuberculous mycobacterial infections resulting in IRIS are due to MAC, but cases of IRIS related to infection with a variety of NTM other than MAC have been reported [7-10]. The immunobiology, pathogenesis, diagnosis, and treatment of IRIS related to mycobacterial infection are reviewed elsewhere. (See "Immune reconstitution inflammatory syndrome".)

MYCOBACTERIUM KANSASII — M. kansasii is the most frequently isolated NTM after MAC [11].

Epidemiology — The environmental source for the organism is not certain, but person-to-person transmission does not occur. Tap water is thought to be the most likely environmental source of exposure [5]. Areas of greatest endemicity in the United States include Louisiana, Illinois, Texas, and Florida [12]. The incidence of isolation of this emerging pathogen is increasing.

●During the period 1970 to 1990, M. kansasii became the most frequently isolated mycobacterial species overall in a Nebraska Veteran's Affairs hospital [13].

●Case series of M. kansasii infection have been reported from various regions worldwide, including Florida [14] and Spain [15].

Clinical manifestations — The clinical manifestations are most similar to those of M. tuberculosis, although M. kansasii is a less virulent pathogen [1]. Typical symptoms include fever, night sweats, weight loss, cough with sputum, dyspnea, and weakness. Pulmonary disease consists of infiltrates on chest radiograph with isolation of the organism from at least two respiratory specimens. The presentation of M. kansasii pulmonary infection usually does not differ in those who do or do not have HIV, but the incidence of disseminated infection with this organism is higher in people with HIV. Disseminated disease can be diagnosed by isolation of M. kansasii from sites other than the respiratory system, hilar lymph nodes, or skin.

In the series of 46 patients from Florida, the median CD4 count in people with HIV and M. kansasii infection was 34/microL [14]. Forty-two patients (91 percent) had pulmonary infection; six of these cases also had disseminated disease. Only four (8 percent) of the patients had extrapulmonary disease without accompanying pulmonary involvement. The extrapulmonary sites included adenitis, bacteremia, osteomyelitis, and pericarditis.

A population-based survey from California during 1992 to 1996 identified 270 infections with M. kansasii, and found that 69.3 percent of these cases were among individuals with HIV [16]. People with HIV infection were more likely to have mycobacteremia (9.6 percent versus 0 percent) and smear-positive respiratory specimens (41.7 percent versus 20.7 percent). Hospitalization for treatment was more common in the group with HIV.

A case-control study from Spain compared the clinical presentations of M. kansasii and M. tuberculosis in people with HIV and found that presenting symptoms and rates of dissemination were similar, but patients with M. kansasii presented with lower CD4 cell counts (median of 20 versus 90 for M. tuberculosis) [17]. The survival was worse for M. kansasii-infected patients, and central nervous system (CNS) disease was seen exclusively with M. tuberculosis infection.

Radiography — The most common radiographic findings included interstitial and lobar infiltrates [14]. Cavitation, nodules, hilar adenopathy, and pleural effusion occurred less frequently. There is no clear predominance of upper or lower lobe involvement noted in the literature, and the radiographic appearance does not reliably distinguish M. kansasii from M. tuberculosis [18]. Anecdotal reports of unusual presentations, such as cranial osteomyelitis, can be found [19].

Treatment — Treatment of M. kansasii in patients with HIV often begins with empiric therapy for M. tuberculosis after acid-fast organisms are identified upon staining of respiratory specimens. After identification of M. kansasii is confirmed by biochemical testing or nucleic acid probe, therapy can be modified. We agree with the 2020 American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) NTM guidance that supports the use of susceptibility-based testing for rifampin to guide treatment decisions. In patients with rifampin-susceptible M. kansasii pulmonary disease, a regimen of rifampicin, ethambutol, and either isoniazid or a macrolide is recommended. Fluoroquinolones should be reserved for patients with rifampicin resistance or intolerance to one of the other first-line agents. More detailed information on the treatment of M. Kansasii infection is presented elsewhere. (See "Treatment of lung infection with Mycobacterium kansasii and other less common nontuberculous mycobacteria in adults", section on 'M. kansasii'.)

In people with HIV, treatment of M. kansasii conferred a clear survival benefit in various case series, suggesting that this organism should be considered a pathogen in all cases, unless there is absolutely no clinical evidence to support the diagnosis of M. kansasii disease [20,21]. In one retrospective report, treatment with a regimen including clarithromycin was associated with prolonged survival in both the pre- and post-combination antiretroviral therapy (ART) eras [22].

Prognosis — In a series from California, among 127 people with HIV infection and pulmonary M. kansasii infection, 53 percent died [21]. Predictors of survival included higher CD4 cell count, ART, negative smear microscopy, and adequate treatment for M. kansasii [21]. In the New Orleans series [22], median survival in the combination ART era was 10.5 months when pulmonary disease was treated and 4.5 months when disease was not treated, indicating a poor prognosis in this severely immunocompromised population.

MYCOBACTERIUM XENOPI — Mycobacterium xenopi can be isolated from water, especially hot water sources, and is often considered a commensal. Reports of the endemicity of this organism vary. In a representative series of 28 patients from Toronto with both HIV and M. xenopi infection, 19 of 24 patients with measured CD4 counts had <100 cells/microL [23]. Only seven patients (25 percent) were thought to have clinically significant disease [24]. Three other patients had pulmonary disease with repeated isolation of M. xenopi, but other potential pathogens were also identified. In a study from Buffalo, 23 of 35 patients (66 percent) with AIDS and pulmonary NTM other than MAC and M. kansasii had isolates of M. xenopi [25]. Cavitary disease was rare, and interstitial and nodular lung disease were more common. A subsequent report from the Netherlands found that 25 of 49 patients (51 percent) with positive cultures for M. xenopi met diagnostic criteria for infection [26].

The isolates were from lower respiratory specimens (sputum, bronchoalveolar lavage fluid, or lung biopsy) in 24 patients (86 percent) in the Ottawa study [23]. Three patients had bacteremia and a prolonged febrile illness with wasting, similar to disseminated MAC. Two had respiratory isolation of M. xenopi and Pneumocystis carinii simultaneously. Three patients had M. xenopi isolated from extrapulmonary sites: one each from inguinal lymph node, diarrheal stool, and urine.

Four of the patients thought to have clinical disease were treated, and one appeared to respond [23]. Sixteen patients died a median of six months after the isolation of M. xenopi, although none of the deaths were directly attributable to the organism. In a retrospective analysis, treated patients survived longer than untreated patients [25]. The distinction between colonization and disease may be difficult upon isolation of M. xenopi.

Case reports describing vertebral osteomyelitis and discitis have been published [26-28]. Few cases of M. xenopi spontaneous vertebral infection have been reported, but the disease course seems similar to that caused by M. tuberculosis.

If M. xenopi is isolated as a single pathogen in a symptomatic patient with HIV, treatment may prolong survival. In vitro susceptibility of M. xenopi to isoniazid, rifampin, and ethambutol is often reduced, but response to therapy does not always correlate with susceptibility data. The 2020 treatment guidelines for NTM acknowledged that there is insufficient evidence to make a recommendation about the use of susceptibility testing for M. xenopi and suggest using a daily regimen that includes at least three drugs; rifampicin, ethambutol, and either a macrolide or quinolone (eg.moxifloxacin [5]). Parenteral amikacin can be added in the presence of severe bronchiectatic disease. (See "Treatment of lung infection with Mycobacterium kansasii and other less common nontuberculous mycobacteria in adults", section on 'M. xenopi'.)

MYCOBACTERIUM HAEMOPHILUM — Mycobacterium haemophilum disease most commonly presents in people with HIV as painful, erythematous, ulcerating skin nodules [1]. Patients with tenosynovitis, arthritis, and osteomyelitis have also been reported. Similar to Mycobacterium marinum and Mycobacterium ulcerans, the organism grows best at 30 to 32°C, explaining its tendency to cause skin and joint disease [29].

M. haemophilum has been isolated from the blood, bone marrow, sputum, and bronchoalveolar lavage fluid of people with HIV. Symptoms suggestive of disseminated disease frequently are present. Cases of central nervous system infection has also been described [30,31]. Although cough is a common symptom, this organism has not definitively been confirmed to be a pulmonary pathogen.

M. haemophilum is more difficult than other NTM to isolate since it requires ferric ions (available in chocolate agar, supplemented media, and often in blood culture systems such as BACTEC or lysis centrifugation). The limited clinical experience in treating patients with M. haemophilum disease and the variable relationship between in vitro susceptibility data and in vivo activity also makes the choice of therapy problematic. Successful use of combinations of three or four drugs including isoniazid, rifamycins, fluoroquinolones, amikacin, doxycycline, and clarithromycin has been reported [32-36].

MYCOBACTERIUM SIMIAE — M. simiae was originally isolated from rhesus monkeys and later from tap water. Infection with this organism may present in a fashion similar to disseminated MAC, with fever, night sweats, weight loss, and adenopathy, although its pathogenicity is not entirely clear [1]. Often thought to be a commensal in respiratory isolates, it has been described to cause pulmonary infection, disseminated disease with isolation from blood, osteomyelitis, and renal infection in people with AIDS [37,38].

M. simiae often is resistant to isoniazid, rifampin, ethambutol, and aminoglycosides in vitro. Trimethoprim-sulfamethoxazole, quinolones, and clarithromycin may be effective, but experience in treating this infection is limited [38-40]. Overall prognosis was poor unless patients responded to both antiretroviral and antimycobacterial therapy [38].

MYCOBACTERIUM MALMOENSE — Mycobacterium malmoense has been isolated from water and soil, and is a rarely isolated pathogen in the United States [5]. The clinical presentation is similar to pulmonary infection with M. tuberculosis, but soft tissue infections, tenosynovitis, adenitis in children, and disseminated infection has been described [1].

Although in vitro data suggested resistance to isoniazid, rifampin and ethambutol, treatment with these agents for 18 to 24 months has been successful in people without HIV. Clarithromycin has also been shown to be active in vitro [41].

MYCOBACTERIUM FORTUITUM AND MYCOBACTERIUM CHELONAE — These rapidly growing mycobacteria are environmental organisms found worldwide and may grow in culture in less than one week. They are a cause of cutaneous infection, especially following trauma or surgery [1]. In immunocompromised patients, reports of disease include disseminated disease with pustular and nodular cutaneous lesions, localized pulmonary disease with adenopathy, multifocal osteomyelitis, and lymphadenitis. A case series published in 2001 describes patients who predominantly presented with cervical lymphadenitis and fever and received other treatments before Mycobacterium fortuitum infection was diagnosed. The morphologic appearance of the sometimes irregularly staining mycobacteria resulted in misdiagnosis of Nocardia in 7 of 11 patients, highlighting the difficulty in diagnosing this infection [42].

Antimicrobials used with success include intravenous imipenem, amikacin, and cefoxitin, and oral rifampin, ciprofloxacin, clarithromycin, doxycycline, and trimethoprim-sulfamethoxazole [5,43]. The optimal duration of therapy is not defined, but treatment for a minimum of 6 to 12 months should be considered.

A nosocomial pseudo-outbreak of M. fortuitum, linked to a contaminated ice machine on an HIV inpatient ward, was reported in Baltimore [44]. Of 47 patients with at least one sputum specimen positive for M. fortuitum, only one had any signs of progressive pulmonary infection over six months of follow-up.

MYCOBACTERIUM GENAVENSE — M. genavense is a mycobacterial species that was discovered when disseminated infection with an unidentified mycobacterium was reported in 18 patients in Switzerland in 1990 [45]. Cases have since been reported worldwide, but almost exclusively in people with AIDS and CD4 counts <100 cells/microL or other immunocompromising conditions, such as solid organ transplantation [1,46,47].

●Clinical manifestations - The clinical presentation of M. genavense infection can be similar to those with disseminated Mycobacterium avium complex (MAC) infection, since fevers, weight loss, and hepatosplenomegaly are common. In a comparison of 12 patients with HIV and disseminated M. genavense and 24 patients with HIV and disseminated MAC infection, the illness and survival times after diagnosis were similar, but patients with MAC were less likely to have abdominal pain [48].

M. genavense infection can be associated with massive adenopathy and organomegaly, especially splenomegaly, sometimes with splenic abscess. In one report, a syndrome of retractile mesenteritis was described, which was associated with duodenal wall thickening, central mesenteric mass, and thrombotic events [49]. In a case series that described the radiographic finding associated with M. genavense, mesenteric adenopathy was common. In addition, small bowel thickening and hepatic nodules were noted on computed tomography (CT) imaging [50]. Although pulmonary infection has not been clearly demonstrated, one patient had nodular infiltrates and a small upper lobe cavity on chest CT. In a systematic review of 223 mostly European patients (77 percent with HIV), pulmonary symptoms and radiographic changes were seen in 12.6 and 9.5 percent of patients; gastrointestinal involvement was common [51]. Cases of M. genavense infection of the brain mimicking a brain tumor have also been described [52].

In the study that compared patients with HIV who had M. genavense to those with MAC, stool specimens tended to be smear-positive for M. genavense, but the organism was less likely to grow in stool culture compared with MAC (15 versus 71 percent) [48]. By contrast, bone marrow and liver biopsy specimens grew M. genavense more readily; the yield was maximized by using acidic liquid medium and additives and avoiding pretreatment.

●Treatment - Treatment regimens usually include macrolides, rifamycins, ethambutol, and quinolones. M. genavense shows resistance to isoniazid in vitro [48]. A French case series described successful treatment with clarithromycin, ethambutol, rifabutin, and quinolones in various combinations for durations of 12 to 15 months [47]. In the systematic review of 223 cases mentioned above [51], most patients were treated with macrolides, rifamycins and ethambutol. Treatment with a macrolide was associated with improved outcome.

●Impact of ART and IRIS - ART is an important component of therapy and is associated with improved mortality outcomes. In a systematic review of 223 mostly European cases from 1992 to 2021 (77 percent with HIV), 94 patients died in the pre-combination antiretroviral therapy (cART) era (89.9 percent mortality after 24 months) and 77 in the cART era (39.3 percent five-year mortality) [51].

IRIS can occur after the initiation of ART in this patient population and can be difficult to distinguish from poor response to NTM therapy. In a French case series of 19 patients who initiated ART after the diagnosis of M. genavense infection, five (25 percent) developed an immune reconstitution syndrome [47]. A case series of three patients with advanced HIV and M. genavense infection demonstrated the significant clinical challenge to distinguish poor response to antimycobacterial therapy from immune reconstitution inflammatory syndrome (IRIS) requiring anti-inflammatory therapy [10].

MYCOBACTERIUM SZULGAI — Mycobacterium szulgai can be found in water sources and is usually associated with pulmonary disease in a presentation similar to that of M. tuberculosis. Extrapulmonary presentations have been described in people with HIV infection, and include cutaneous disease, osteomyelitis [53], and septic arthritis [54].

Pulmonary disease has been successfully treated with various three- and four-drug regimens including macrolides and quinolones for a duration of 12 months with negative sputum cultures [5]. Extrapulmonary disease has been successfully treated with combinations including clarithromycin, ethambutol, and ciprofloxacin for 12 months [53,54]. A case of pulmonary disease was reported with multidrug resistance to isoniazid, rifampin, ethambutol, and pyrazinamide [55]. After susceptibility results were available, the patient responded well to treatment with clarithromycin, doxycycline, ciprofloxacin, and amikacin.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV".)

SUMMARY AND RECOMMENDATIONS

●Introduction - Although the majority of disease due to nontuberculous mycobacteria (NTM) in people with HIV is caused by Mycobacterium avium complex (MAC), other NTM are important pathogens as well. The risk of disease from NTM increases with progressive immunodeficiency, with the greatest risk experienced as the CD4 cell count decreases below 50 cells/microL. (See 'Introduction' above.)

●Principles of diagnosis and therapy - When NTM are isolated from a sterile site (eg, blood), the diagnosis of true disease is generally straightforward. However, when NTM are isolated from non-sterile sites, such as sputum, the diagnosis is less definitive. In the latter situation, a diagnosis of true NTM infection depends upon other clinical findings, radiographic findings, and the presence or absence of other potential pathogens. (See 'Principles of diagnosis and therapy' above.)

●Mycobacterium kansasii - Mycobacterium kansasii is the most frequently isolated NTM after MAC. The clinical manifestations are most similar to those of tuberculosis, although Mycobacterium kansasii is a less virulent pathogen. Typical symptoms include fever, night sweats, weight loss, cough with sputum, dyspnea, and weakness. (See 'Mycobacterium kansasii' above.)

●Mycobacterium xenopi - Mycobacterium xenopi can cause fevers, wasting and pulmonary infiltrates, similar to disseminated M. avium complex. (See 'Mycobacterium xenopi' above.)

●Mycobacterium haemophilum - Mycobacterium haemophilum disease most commonly presents as painful, erythematous, ulcerating skin nodules. Patients with tenosynovitis, arthritis, and osteomyelitis have also been reported. (See 'Mycobacterium haemophilum' above.)

●Mycobacterium fortuitum and mycobacterium chelonae - The rapidly growing mycobacteria, Mycobacterium fortuitum and Mycobacterium chelonae, can cause disseminated disease with pustular and nodular cutaneous lesions, localized pulmonary disease with adenopathy, multifocal osteomyelitis, and lymphadenitis. (See 'Mycobacterium fortuitum and mycobacterium chelonae' above.)

●Mycobacterium genavense - Mycobacterium genavense infection has been associated with massive adenopathy and organomegaly. (See 'Mycobacterium genavense' above.)

●Mycobacterium szulgai - Mycobacterium szulgai has been associated with pulmonary disease, cutaneous lesions, osteomyelitis, and septic arthritis. (See 'Mycobacterium szulgai' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.