Lung Disease Caused by Nontuberculous Mycobacteria Gerardo Alvarez-Uria

Lung disease caused by nontuberculous mycobacteria Gerardo Alvarez-Uria

Department of Infectious Diseases, Fundacion Vicente Purpose of review Ferrer, Rural Development Trust Hospital, Bathalapalli, Anantapur District, Andhra Pradesh, India Although the incidence of tuberculosis has reduced in developed countries, there is a growing interest in nontuberculous mycobacteria (NTM) as a cause of lung disease. Correspondence to Gerardo Alvarez-Uria, Department of Infectious Diseases, Fundacion Vicente Ferrer, Rural However, NTM are a heterogeneous group and most of the data come from only three Development Trust Hospital, Kadiri Road, Bathalapalli species: Mycobacterium avium complex, Mycobacterium kansasii and Mycobacterium 515661, Anantapur District, Andhra Pradesh, India Tel: +91 855 924 2315; abscessus. Still, information about these three species is confusing because it is based e-mail: [email protected] mainly on retrospective studies and series of clinical cases performed in developed

Current Opinion in Pulmonary Medicine 2010, countries. In recent years, new information has appeared about other species and the 16:251–256 pathogenesis of NTM. Recent ﬁndings Epidemiological studies show that NTM infection is a worldwide phenomenon with an increasing presence in developing countries perhaps because of the implementation of tap water. Women with characteristic phenotype are at higher risk of acquiring NTM infection along with patients with defects on cystic ﬁbrosis transmembrane conductance regulators. New studies on Mycobacterium fortuitum, Mycobacterium xenopi, Mycobacterium szulgai and Mycobacterium simiae indicate that the American Thoracic Society criteria for diagnosing NTM disease may not be useful for all species of NTM. Summary New multicentric and prospective studies are needed to clarify the pathogenesis and treatment of NTM. These organisms form a numerous and heterogeneous group and each species should be studied separately.

Keywords nontuberculous mycobacteria, therapeutics, virulence, diagnosis

Curr Opin Pulm Med 16:251–256 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1070-5287

[1]. The predominant NTM species was Mycobacterium Introduction fortuitum. In a reference hospital in Kuwait, the rate of Unlike Mycobacterium tuberculosis, nontuberculous myco- NTM among mycobacteria isolations was higher (9%) [2]. bacteria (NTM) are ubiquitous organisms, present in the Thirteen of these isolations were randomly identified and environment. The number of species of NTM is increas- Mycobacterium avium complex (MAC) was the predomi- ing every year. Previously considered contaminants of nant species (69%). sputum, NTM are able to produce lung disease in humans. However, there are many gaps in the under- In a district hospital in Zambia, patients with productive standing of the pathogenesis and treatment of this hetero- cough for more than 2 weeks were investigated for geneous group. The present review will focus on recent mycobacteria infection [3]. Of the 180 patients, NTM medical literature about NTM. were isolated in 31 (17%) and four patients (2%) were considered to have NTM disease. M. tuberculosis was isolated in 72 patients (40%). A high proportion of not Epidemiology previously identified NTM (32%) were isolated although Most epidemiologic studies of NTM have been per- all cases of NTM disease were produced by MAC. formed in North America, Japan and Europe. In recent Interestingly, NTM isolation was associated with the years, new information about the epidemiology of NTM use of tap water. With the increasing use of tap water, in other parts of the world has appeared. in the future we will probably see an increase in the incidence of NTM diseases in developing countries with Two small studies have been done in the Arabian Penin- high prevalence of HIV infection. Identification of myco- sula. In Oman, NTM were isolated from 4.6% of patients bacteria species is not readily available in these countries with mycobacteria isolation during a period of 6 months so patients with tuberculosis (TB)-like disease produced

1070-5287 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MCP.0b013e3283378fa3 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 252 Infectious diseases

by NTM will not receive specific treatment for their thinner and had more frequently scoliosis, pectum condition. excavatum and mitral valve prolapse than the control group. No differences were seen in the immunological In Asia, information about isolations of NTM from 1993 results whereas 36.5% of patients had some mutations of to 2006 was collected in a reference laboratory in South cystic fibrosis transmembrane conductance regulators. Korea [4]. During this period, 17 915 isolations of NTM Voluntary factors such as cough suppression and shower were collected and it was observed that there was an exposure were not related to NTM disease. Authors increased number of isolations over time. The most conclude that NTM disease occurs in women with a common species was MAC followed by rapid growing characteristic phenotype probably secondary to an mycobacteria (Mycobacterium abscessus, M. fortuitum and unknown genetic defect. Mycobacterium chelonae). In contrast with previous studies done in Japan, the number of isolations of Mycobacterium kansasii was not so frequent although an upward trend Studies involving specific nontuberculous was observed. Unfortunately, no clinical data were pro- mycobacteria species vided in this study. Among rapid growing mycobacteria, M. fortuitum has low virulence. In a study done in Korea, of the 186 patients A referral laboratory in Brazil performed a similar study with M. fortuitum in sputum culture only 14% had from 1996 to 2005 [5]. Of the 1300 isolations of myco- repeated isolations and only one patient (0.5%) was bacteria, 24.4% were NTM and again MAC was the considered to have lung disease produced by this myco- predominant species. bacteria [14]. For patients with at least two isolations, median follow up was 12.5 months and none of them showed clinical or radiological progression. Pathogenesis of nontuberculous mycobacteria disease In one retrospective study in the Netherlands, Mycobac- NTM are present in the environment and the way of terium xenopi was isolated from 49 patients and 25 (51%) transmission to humans is not well known. However, fulfilled the American Thoracic Society (ATS) diagnostic increasing data support that NTM infect human hosts criteria [15,16]. Twenty-one patients received treatment through tap water [3,6]. Moreover, NTM are resistant to which consisted of medication for 17 patients, surgery for chemical disinfectants and ultraviolet irradiation used in two and both for two. Four patients who met ATS criteria water treatment processes [7]. were not treated, one recovered spontaneously, one died and two remained positive for M. xenopi culture. Factors Virulence varies between NTM species [8]. Even within associated with fulfilment of ATS criteria were having the same species, some strains are more virulent than positive acid-fast bacilli (AFB) in sputum smear and others [9–11]. A group of Japanese investigators found a cavity on chest radiograph. In north-east France, the hypervirulent strain of Mycobacterium intracellulare from proportion of patients with M. xenopi isolation who met an immunocompetent patient with rapidly progressive ATS criteria was higher (136 out of 180, 76%) [17]. The lung disease [11]. This strain was highly resistant to authors describe three different clinical and radiological human macrophages and produced rapid progressive lung patterns: cavitary form in patients with preexisting lung disease in mice. disease, nodulary form in immunocompetent patients and diffuse infiltrates in patients with HIV infection. Information about risk factors of the host for NTM As in other NTM studies, there was poor correlation disease is confusing because data come from series of between in-vitro sensitivities to antimycobacterial drugs case reports and retrospective studies. Many factors have and clinical response. In multivariate analysis, use of been involved in the increased susceptibility for NTM rifampicin was associated with increased survival. How- such as preexisting lung disease, immunosuppression or ever, we have to be cautious in interpreting survival data genetic defects of cell-mediated immunity [12]. To clar- from retrospective studies because many confounding ify this issue, a group of North American investigators factors can affect the results of the study. Patients with performed a prospective study of 63 patients with NTM HIV, pulmonary fibrosis, chronic obstructive pulmonary disease [13]. Radiological studies (computed tomogra- disease (COPD) or cystic fibrosis have different prog- phy scan of thorax, chest radiograph and echocardiogra- nostic factors that should be taken into account when phy), pulmonary function testing, clonal proliferation of doing survival analysis. M. xenopi is the most common T or B cells, stimulated cytokine production and flow NTM isolated in Croatia [18]. In one retrospective study, cytometry of peripheral blood and anthropometric of 40 patients with M. xenopi isolation, 24 (60%) met ATS measurements were performed to the patients and com- diagnosis criteria [18]. Twenty patients received antimy- pared with a control group. Patients with NTM lung cobacterial treatment although for a shorter period than disease were predominantly women, were taller and recommended [15]. No one experienced radiological

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Lung disease caused by nontuberculous mycobacteria Alvarez-Uria 253 progression, half improved and half experienced no M. abscessus and other highly resistant NTM. Actually, if improvement in symptoms and radiological changes. patients are selected carefully, resection of the lung area Having COPD was associated with no radiological affected by NTM is usually effective [25]. improvement after treatment. Again, it is uncertain whether these outcomes are due to the underlying lung disease or to lack of response to treatment. Isolation of nontuberculous mycobacteria In places with low incidence of M. tuberculosis, it can The biggest series of cases of Mycobacterium szulgai has be difficult to determine whether AFB smear positive been published recently by a group from the Netherlands sputum is produced by M. tuberculosis or NTM. Myco- [19]. Extrapulmonary infection was seen exclusively in bacteria identification will not be known until at least a five immunocompromised patients. Of the 15 patients few weeks, leading to unnecessary isolation measures. A with M. szulgai isolation from sputum, 11 (73%) fulfilled positive interferon-g release assay using specific M. tuber- ATS diagnostic criteria and all had underlying lung culosis antigens suggests TB infections rather than MAC disease. Three patients did not receive antimycobacterial disease [26]. A commercial direct amplification test has treatment, one died, one refused treatment and one been recently developed to allow rapid identification of experienced spontaneous conversion to negative sputum M. tuberculosis, Mycobacterium avium, M. intracellulare, culture. Treatment outcome was favourable as no patient M. kansasii and Mycobacterium malmoense [27]. Amplifica- suffered relapse. tion was successful in 80–85% using three different approaches for specimen preparation. Results showed Mycobacterium simiae seems to have low virulence in the good specificity, as all identifications were concordant with Netherlands [20]. Of the 28 isolations, only six (21%) cultures, but this assay had problems identifying MAC. fulfilled ATS criteria and no extrapulmonary infection was seen. Moreover, two out of the three patients who Up to 70% of M. xenopi isolations can be missed if met ATS criteria remained clinically stable despite not nonradiometric and fully automated Bactec MGIT 960 receiving antimycobacterial treatment. Treatment results system (Becton Dickinson Microbiology Systems, were poor, with two relapses out of the three treated Sparks, Maryland, USA) is used, especially if bacterial patients. Drug susceptibility testing of 25 samples load is low [28]. Some authors recommend checking for showed in-vitro resistance to most antimycobacterial the presence of granules by visual inspection before drugs but clofazimine, cycloserine and protionamide. discarding MGIT 960 tubes. In one series of 102 patients with repeated M. simiae isolation in Israel, comorbid diseases and involvement of middle and lower lobes in chest radiographs were com- Diagnosis of nontuberculous mycobacteria mon [21]. A small number of patients presented with lung disease pleural effusion and lymphadenitis. In clinical practice, when receiving a positive sputum culture for NTM it is difficult to know whether the As M. tuberculosis, M. kansasii produces infiltrates or isolation means contamination of sputum, transient cavities in the upper lobes in immunocompetent patients colonization, chronic colonization or a true infection. [21]. However, in one series of 83 patients with HIV The ATS has established clinical and microbiological infection, mid and lower zones of the lungs were involved criteria for the diagnosis of NTM lung disease [15]. in 89% of patients, most commonly in the form of con- solidation or nodules [22]. Although less common, cavita- ATS criteria for diagnosing nontuberculous mycobacteria tion was associated with increased mortality. Treatment lung disease [15]: outcome of M. kansasii is generally good if treatment is given for at least 12 months. A Spanish study showed (1) Clinical criteria: relapse in only 6.6% of patients [23]. No acquired drug (a) Pulmonary symptoms and radiological abnormal- resistance was seen and all patients responded to a longer ities (nodules or cavities on chest radiograph or course of treatment for 18 months. multifocal bronchiectasis with multiple small nodules on high-resolution computed tomogra- M. abscessus is highly resistant to medical treatment both phy scan). Other diagnoses must be excluded; in vitro and in vivo. A group of Spanish microbiologists (2) Microbiologic criteria (any of the following): studied multiple combinations of antibiotics against (a) Positive culture results from at least two separate two strains of M. abscessus in vitro [24]. Interestingly, sputum samples; clarithromycin with linezolid and clarithromycin with rifa- (b) Positive culture results from at least one bron- butin and fluoroquinolones exhibited good activity. How- chial wash or lavage; ever, clinical trials are needed to confirm these results (c) Lung biopsy with mycobacterial histopathologic in vivo and surgery still remains as the main treatment for features (granulomata or AFB) and positive

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 254 Infectious diseases [24] ] in vitro ] linezolid and þ fluoroquinolones þ Rb þ one retrospective study [16];fluoroquinolones S can and also be used to doxycycline and sulfonamides and fluoroquinolones can be used deciding regimen drugs and testing ofmacrolides susceptibility is to recommended (BIII) 3–6 months if favourable response susceptibility testing is recommended (AII) Clr drug susceptibility testing canin help deciding regimen deciding regimen susceptibility to clofazimine, cycloserine and protionamide [20 Macrolides are the most important R is the most important drug and R Tigecycline effective in one case report [31]; Drug susceptibility testing can help in l for m (CIII) 100 cells/ > þ 0 mg/kg/day (maximum 600 mg); Rb, rifabutin 5 mg/kg/day (maximum 300 mg); RGM, rapidly IV infected patients); Cfx, ciprofloxacin, 500–750 mg bid; Clr, clarithromycin 800–1000 mg/ M. abscessus ecommendations: A, good; B, moderate; C, poor. Quality of evidence for recommendations: I, at least at least 6 monthstreatment on (BII) effective HIV stopped if CD4 15 months if R resistance (AII) imipenem or cefoxitin cangiven be for stopped at if leastimprovement; 2 TIW weeks Am and canclinical clinical be improvement given after if extrapulmonary disease; 12negative months sputum of cultures ifdisease pulmonary (CIII) if extrapulmonary disease; 12negative months sputum of cultures ifdisease pulmonary (CIII) ramatic results in uncontrolled experiments; III, descriptive studies or opinions. Adapted from [15,30]. As per MAC disease (CIII) Good response to treatment [19 As per MAC disease (CIII) As per MAC disease (CIII) As per MAC disease (CIII)As per MAC disease (CIII) In-vitro susceptibility to Am and in some cases Drug susceptibility testing can help in 12 months of negative sputum cultures 12 months of negative sputum cultures 12–18 months of negative sputum cultures Injectable agent can be stopped after At least 12 months; treatment can be 12 months of negative sputum cultures, 4 months (6 months if bone involvement); 6–12 months of negative sputum cultures (CIII) Good activity of Clr 4 months (6 months if bone involvement) 4 months (6 months if bone involvement) l m Am (CIII) As per 50 cells/ þ Am < þ þ Clr Clr (CIII) As per MAC disease (CIII) Use of R associated with increased survival in cotrimoxazole (CIII) As per MAC disease (CIII) Poor response to treatment; in-vitro þ þ fluoroquinolones or þ Clr; fluoroquinolones þ þ E one or two of Am, imipenem, Mxf E þ þ þ E (CIII) As per MAC disease (CIII) Drug susceptibility testing is not helpful; Clr þ RorRb þ þ E (AII). Consider adding one or E R þ can be added two or more drugsfluoroquinolones, of: R Am or or Rb S, (CIII) Clr or Azr, E, Rb, fluoroquinolones (CIII) or Azr, R or Rb, fluoroquinolones (CIII) sulfonamides (CIII) 2–3 months of treatment (BII) or not effective HIVCfx treatment: or Rb, Lfx oradded Mxf. for Am the or firstof S 2–3 treatment can months be of the following accordingtesting to (AII): susceptibility H (900mg/day),E Clr (25mg/kg/day), or sulfamethozaxole; Azr, SAm Mfx, or can be given2–3 during months the of first treatment abscess or treatment failure treatments of Clr two drugs if CD4 fluoroquinolones, doxycycline or linezolid (CIII) Clr or Azr, Am,fluoroquinolones, tetracyclines, sulfonamides (CIII) þ þ If resistance to R, give at least three drugs Control symptoms with periodic E Lfx þ þ Rb þ imipenem E þ þ S or Am (BII) 12 months of negative sputum cultures Am þ þ R (600 mg TIW; BII) Clr þ þ R (AII)RorRb Am or S can be added for the first þ þ E E imipenem or cefoxitin (BIII) Surgical treatment if extensive disease, S or Am (CIII) þ þ þ þ E (AII); Clr or Azr can be added þ Am E (AI). Rb can be added (CI) Azr R þ þ (25 mg/kg TIW) or Mxf in HIV patients (BIII) or cefoxitin (AII) þ UnknownUnknownUnknownUnknownUnknown H Combination of Clr or Azr with one or Combination of two or more drugs of Combination of two or more drugs of H Clr Unknown R or Rb Clr (1 g TIW) or Azr (0.5–0.6g TIW) Clr or Azr Surgical removal if feasible H Clr Surgical removal Clr Unknown Surgical removal Unknown Clr or Azr complex Unknown Clr or Azr extrapulmonary lung disease Mycobacterium (RGM) Unknown Clr or Azr (RGM) Unknown Combination of two or more drugs of complex lung disease or previously treated lung disease disease disease (RGM) (RGM) avium (MAC) disease (RGM) M. xenopi Mycobacterium genavense Mycobacterium gordonae Mycobacterium haemophilum M. malmoense Mycobacterium terrae Am, amikacin 25 mg/kg TIWday; (three E, times ethambutol weekly) 15 intravenous mg/kg/day; (i.v.; H,growing 10–15 mycobacteria; isoniazid S, 5 mg/kg/day mg/kg/day streptomycin for (maximum 25 severe mg/kg 300one disease); mg); TIW randomized Azr, Lfx, intramuscular azithromycin levofloxacin or clinical 250 500 i.v. mg/day mg/day; trial; (1 (500 Mxf, g/day II, mg/day moxifloxacin for for at 400 severe mg/day; H disease). least R, Evidence-based rifampicin one classification, 1 strength not of randomized r clinical trial, cohort or case–control analytic studies or multiple time-series, or d M. szulgai MAC nodular/bronchiectatic MAC cavitary lung diseaseMAC advanced (severe) ClrMacrolide-resistant or MAC Azr M. kansasii M. abscessus M. abscessus Table 1 Treatment of nontuberculousNontuberculous mycobacteria mycobacteriaDisseminated Preferred regimen Alternative regimen DurationM. chelonae Comments M. fortuitum Mycobacteria immunogenum M. simiae

culture for nontuberculous mycobacteria from individualized. Immunocompromised patients with dis- biopsy, bronchial wash or sputum. seminated disease may have normal chest radiograph. Current ATS microbiologic criteria may be useful for Despite being a useful tool, these criteria are far from virulent NTM, but more demanding criteria might be being adequate for all patients from whom NTM are preferable for less virulent NTM. Patients with NTM isolated. ATS diagnostic criteria were designed for disease have slowly progressive disease, so treatment of M. avium, M. kansasii and M. abscessus. However, more NTM is generally not urgent. The presence of AFB in than 100 NTM species have been catalogued and not all sputum smear indicates high burden of mycobacteria and NTM have the same level of virulence. it is unlikely to happen in NTM contamination or colonization. Introducing a time-factor can be also useful. For Most of the patients will meet clinical criteria as the example, three repeated isolations of NTM from sputum majority will have pulmonary symptoms and radiological samples separated by 1 month will be rare in contami- abnormalities are not specific for NTM. Only one nation or transient colonization. Moreover, in cases of positive culture from a bronchial specimen is needed NTM with low virulence, histopathologic features of to meet microbiological criteria because bronchial wash- mycobacterial infection such as granulomata or AFB in ing can avoid contamination of NTM from the mouth. lung biopsy may be desirable for initiating treatment. Still, contamination of bronchoscopes has been described Radiological criteria are difficult to interpret in patients [29]. Repeated NTM positive sputum culture is very with underlying lung disease or immunosuppression, but unlikely to occur in contaminations and only two separate they can be specific for NTM in patients with nodulary- positive sputum samples are needed to meet microbio- bronchiectatic lesions and no other comorbidities. logical criteria. Nevertheless, patients with transient colonization will have negative sputum cultures after a period of time despite not receiving any antimycobacter- Treatment ial treatment [14,16,19,20]. Patients with preexisting Treatment of NTM with evidence-based classification is lung cavity or bronchiectasis can be colonized by fungus summarized in Table 1 [15,16,19,20,24,30,31]. In some or NTM and they will have persistent positive NTM cases of resistant NTM, surgical treatment is needed. In a cultures. These patients will meet ATS criteria but it is referral hospital in South Korea, 23 patients underwent uncertain whether they would benefit from a long and pulmonary resection because of resistant NTM infection expensive treatment with side effects and drug inter- [25]. One patient died because of late bronchopleural actions [18]. fistula, but there was no NTM relapse in the rest of the patients. However, postoperative complications occurred Basically, we can distinguish three main groups of human in 35% of patients, including postoperative pneumonia hosts, immunocompromised patients, healthy patients and late bronchopleural fistula. Authors concluded that with nodulary-bronchiectatic form and patients with despite high postoperative morbidity, resectional surgery underlying lung disease. Isolation of NTM in sputum is an effective treatment for those patients who can of immunocompromised patients may reflect a dissemi- tolerate the operation and there has been poor response nated disease rather than localized lung disease [8]. ATS to medical treatment or life-threatening complications radiological criteria may not be fulfilled because up to such as haemoptysis. 50% of patients will have normal chest radiograph [8]. In one Spanish study, the presence of AFB in sputum smear and symptoms for more than 1 month were useful Conclusion indicators of NTM disease in HIV patients [8]. Not all Recent findings indicate that NTM infection of the lungs species of NTM had the same clinical significance. All is a worldwide phenomenon. NTM form a heterogeneous cases with M. xenopi isolation were considered as coloniza- group with variable virulence among species. In patients tion and all cases with M. kansasii isolation were considered without underlying lung disease or immunosuppression, as true infection. In immunocompromised patients, iso- factors related to host susceptibility are associated with a lation of NTM from a normally sterile site such as liver or characteristic phenotype and defects on cystic fibrosis bone marrow must be investigated, because this will give a transmembrane conductance regulators. ATS diagnostic definitive diagnosis of NTM disease. criteria are a useful tool but they may lead us to treat many patients unnecessarily. Factors such as the viru- NTM are a heterogeneous group that affects a wide range lence of the NTM species and characteristics of the host of human hosts with different characteristics, so it might should be taken into account when deciding whether to be too optimistic to expect that a single set of diagnostic treat a patient with NTM isolation. However, more criteria would be accurate for all kind of patients. Pro- information about the pathogenesis and treatment of bably, there are no correct universal criteria for deciding NTM is needed. Because NTM infections are rare, when to treat NTM as a whole. Decisions must be physicians and scientists should join efforts to perform

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