Clinical relevance of non-tuberculous mycobacteria isolated in the Nijmegen-Arnhem region, The. Netherlands

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1 Respiratory infetion 1 Department of Pulmonary Diseases, Radboud University Nijmegen Medial Centre, Nijmegen, The Netherlands; 2 National Myobateria Referene Laboratory, National Institute for Publi Health and the Environment, Bilthoven, The Netherlands Correspondene to: Mr J van Ingen, National Institute for Publi Health and the Environment (RIVM), National Myobateria Referene Laboratory (LIS; MYC, pb22), PO Box 1, 3720 BA Bilthoven, The Netherlands; jakko.van.ingen@rivm.nl Reeived 21 January 2009 Aepted 4 February 2009 Published Online First 12 February 2009 Clinial relevane of non-tuberulous myobateria isolated in the Nijmegen-Arnhem region, The Netherlands J van Ingen, 1,2 S A Bendien, 1 W C M de Lange, 1 W Hoefsloot, 1 P N R Dekhuijzen, 1 M J Boeree, 1 D van Soolingen 2 ABSTRACT Bakground: The frequeny of linial isolation of nontuberulous myobateria (NTM) in the Netherlands is inreasing, but its linial relevane is often unertain. Objetive: To assess the frequeny and linial relevane of isolation of NTM in four assoiated hospitals in a single region in the Netherlands. Methods: Medial files of all patients from whom NTM were isolated between January 1999 and January 2005 were reviewed retrospetively. Diagnosti riteria for nontuberulous myobaterial disease published by the Amerian Thorai Soiety (ATS) were used to determine linial relevane. Results: 232 patients were found, from whom NTM were isolated from the respiratory trat in 91% of ases. Patients were mostly white men, with an average age of 60 years and pre-existing pulmonary disease. Fifty-three of 212 patients (25%) with pulmonary isolates met the ATS diagnosti riteria for pulmonary NTM disease; this perentage differed by speies. Most patients were treated with rifampiin, ethambutol and larithromyin. Treatment outome for pulmonary NTM disease was suboptimal but differed by speies: overall, improvement was seen in 67% of treated patients, but in only 50% of those with pulmonary M avium disease. Lymphadenitis was the most ommon extrapulmonary disease type. Conlusions: Twenty-five per ent of all patients with pulmonary NTM isolates met the ATS riteria. Clinial relevane differs by speies. NTM isolation inreases over time. Speies distribution differs from that of neighbouring ountries and the M avium omplex isolates have traits different from those reported in the USA. Adherene to diagnosti and treatment guidelines an be improved. The linial isolation of non-tuberulous myobateria (NTM) inreases in many ountries where the inidene of tuberulosis is dereasing, with marked geographial differenes in the speies enountered. 1 3 The NTM are often opportunisti pathogens, apable of ausing disease in patients with impaired immunity, either loal due to preexisting pulmonary disease or systemi for example, haematologial malignany, immunosuppressive drug treatment or HIV/AIDS. 1 The linial relevane of isolated NTM is often unlear. The NTM are ommon in the environment and an survive in flowing water systems. 4 Moreover, NTM resist ommon disinfetants. 5 Thus, pseudo-infetion due to oasional presene of NTM in linial samples as a onsequene of ontamination of medial tools should always be onsidered To differentiate true infetion from pseudoinfetion, and establish the linial relevane of an NTM isolate, is of paramount importane sine treatment of NTM disease is time onsuming and often ompliated. To assist in this differentiation, the Amerian Thorai Soiety (ATS) established general riteria for the diagnosis of pulmonary nontuberulous myobaterial infetion (box 1). 1 We performed a retrospetive ase study to assess the prevalene and linial relevane of NTM isolated in the four assoiated training hospitals of the Nijmegen-Arnhem region, the Netherlands, using the ATS diagnosti riteria to differentiate NTM disease from pseudo-infetion or ontamination. METHODS To determine linial relevane, we examined medial reords of all inpatients and outpatients in four ollaborating hospitals in the Nijmegen- Arnhem region of the Netherlands from whom NTM were isolated between January 1999 and January We reorded demographi, linial and mirobiologial data and status aording to the diagnosti riteria for pulmonary NTM disease by the ATS. 1 We onsidered pulmonary isolates linially relevant if the patient met the ATS diagnosti riteria in the absene of evidene of other pulmonary infetions. For patients treated for NTM disease, we defined ure as symptomati improvement and reversion to negative ultures sustained throughout our follow-up period. We foused on pulmonary isolates. The Duth National Institute for Publi Health and the Environment (RIVM) subjeted isolates of all patients to laboratory diagnosis. The RIVM is the national referene laboratory that provides identifiation, drug suseptibility testing and genotyping of myobaterial isolates for all hospitals in the Netherlands. To identify NTM, the INNO- LiPA MYCOBACTERIA v2 (Innogenetis, Gent, Belgium) reverse line blot assay was used, after ruling out membership of the M tuberulosis omplex using a Hain GenoType MTBC line probe assay (Hain Lifesiene, Nehren, Germany). If no speies-speifi result was obtained, 16S rdna gene sequening (151 bp hypervariable region A) was performed. Before 2004, 16S rdna gene sequening was performed, after ruling out membership of the M tuberulosis omplex or M avium omplex using the AuProbe MTB and M avium omplex DNA probe kits (GenProbe, San Diego, Thorax: first published as /thx on 12 February Downloaded from on 3 September 2018 by guest. Proteted by opyright. 502 Thorax 2009;64: doi: /thx

2 Respiratory infetion Box 1: Summary of the Amerian Thorai Soiety diagnosti riteria for pulmonary non-tuberulous myobaterial infetion 1 Clinial Pulmonary symptoms, nodular or avitary opaities on hest radiograph, or a high-resolution CT san that shows multifoal bronhietasis with multiple small nodules. and Appropriate exlusion of other diagnoses. Mirobiologial or or Positive ulture results from at least two separate expetorated sputum samples. (If the results from the initial sputum samples are non-diagnosti, onsider repeat sputum aid-fast baillus (AFB) smears and ultures.) Positive ulture results from at least one bronhial wash or lavage. Transbronhial or other lung biopsy with myobaterial histopathologial features (granulomatous inflammation or AFB) and positive ulture for non-tuberulous myobateria (NTM) or biopsy showing myobaterial histopathologial features (granulomatous inflammation or AFB) and one or more sputum or bronhial washings that are ulture positive for NTM. Expert onsultation should be obtained when NTM are reovered that are either infrequently enountered or that usually represent environmental ontamination. Patients who are suspeted of having NTM lung disease but who do not meet the diagnosti riteria should be followed up until the diagnosis is firmly established or exluded. Making a diagnosis of NTM lung disease does not, of itself, neessitate the institution of treatment, whih is a deision based on potential risks and benefits of treatment for individual patients. USA). Sequening results were ompared with the GenBank (National Center for Biotehnology Information, nbi.nlm.nih.gov (aessed 27 Marh 2009) database. A Pearson x 2 test was used for statistial orrelations. The regional ethis ommittee approved the study. RESULTS We found 232 patients with NTM isolates, mostly from the respiratory trat (n = 212, 91%). Primary isolates were ultured from sputum (n = 158; 75%), bronhoalveolar lavage samples (n = 47; 22%) and lung biopsy speimens (n = 7; 3%). The annual number of patients from whom NTM were isolated rose during our researh period, mainly owing to an inrease in pulmonary isolates, espeially M avium omplex (MAC) isolates (fig 1). The annual perentage of patients meeting the ATS riteria did not hange. Table 1 presents the baseline harateristis of the 212 patients with pulmonary NTM isolates. Fifty-three patients (25%) met the ATS diagnosti riteria and were thus likely to have pulmonary NTM disease. Of the 159 patients who did not meet the ATS riteria, 146 (92%) failed to meet mirobiologial riteria and 149 (94%) failed to meet radiologial riteria. For these patients, follow-up for a mean Figure 1 Total number of patients with non-tuberulous myobateria isolates, per year and isolation site. MAC, M avium omplex. duration of 47 months (range months) did not yield additional evidene of NTM disease. Figure 2 visualises the linial relevane of the various NTM speies, defined by the perentage of patients who met the ATS diagnosti riteria. Four ases of pulmonary NTM disease were atually relapses of disease episodes before our study period (two M avium, one M xenopi, one M kansasii). Eighty-five patients (40%) had MAC isolates (59 M avium, 16 M intraellulare, 10 other MAC) of whom 26 (24 M avium, 2M intraellulare; 31%) met the ATS diagnosti riteria. M avium isolation was linially more relevant than M intraellulare (24/59 = 41% vs 2/16 = 13% of patients met the ATS diagnosti riteria). A radiographi presentation with fibrosis and avities was more prevalent than nodular bronhietati disease (12 vs 3 ases for M avium and one ase eah for M intraellulare). Whereas MAC was most frequently seen, the degree of linial relevane was higher for isolation of M malmoense (2/3), M kansasii (12/17, 71%), M xenopi (3/5), M szulgai (4/4), M elatum (2/2) and M genavense (1/1; fig 2). Symptoms reorded at presentation varied widely; only fever (p = 0.014, OR = 2.422, 95% CI to 4.978) and fatigue (p,0.001, OR = 3.477, 95% CI to 7.024) at presentation were assoiated with meeting the ATS diagnosti riteria (table 1). Chest radiographs were performed for 206 of the 212 patients and abnormalities were noted in 161 patients (78%; table 1). Abnormalities did not differ signifiantly by NTM speies. Three patients with pulmonary NTM disease presented with a pulmonary mass, mimiking malignany. Computed tomography (CT) sans were performed in 107 patients (50%); among patients meeting the ATS diagnosti riteria, five ases of fibroavitary disease and six ases of nodular-bronhietati disease were noted in patients with inonlusive hest radiographs. On hest radiographs, these ases of fibroavitary disease presented with dense air-spae opaities; the nodularbronhietati disease appeared as oarse linear sarring. Drug treatment for myobaterial infetion was started in 44 patients; 31 started treatment for tuberulosis (TB) and swithed to an NTM treatment regimen, 13 patients reeived standard TB treatment only. Of these 44 patients, 30 met the 1997 ATS diagnosti riteria available during the study period. 8 Among those 30, 20 (67%) were ured, defined by symptomati improvement and reversion to negative ultures, five died during treatment (three with M avium, one with M intraellulare, one with M xenopi disease; 17%) and five had a relapse after Thorax: first published as /thx on 12 February Downloaded from on 3 September 2018 by guest. Proteted by opyright. Thorax 2009;64: doi: /thx

3 Respiratory infetion Table 1 Baseline harateristis of patients with pulmonary nontuberulous myobateria (NTM) isolates Charateristis ATS+ (n = 53) ATS2 (n = 159) Total (n = 212) Demography Male 37 (70) 95 (60) 132 (62) Mean age (years) Duth origin 48 (91) 145 (91) 193 (91) Predisposing onditions Pre-existing pulmonary disease 37 (70) 125 (79) 162 (76) COPD 23 (43) 80 (50) 103 (49) Lung aner 4 (8) 17 (11) 21 (10) Healed tuberulosis 6 (11) 22 (14) 28 (13) Previous pulmonary NTM disease 4 (8) 0 4 (2) Asthma 4 (8) 21 (13) 25 (12) Bronhietasis 8 (15) 8 (5) 16 (8) Current or past smoker 35 (66) 94 (59) 129 (61) Alohol abuse 8 (15) 16 (10) 24 (11) High-dose steroid use* 2 (4) 6 (4) 8 (4) HIV infetion 6 (11) 7 (4) 13 (6) Haematologial malignany 1 (2) 4 (3) 5 (2) Anti-TNF treatment 1 (2) 1 (1) 2 (1) Otherwise impaired immunity 3{ 3{ 6 Symptoms Produtive ough 40 (75) 126 (79) 166 (78) Haemoptysis 10 (19) 28 (18) 38 (18) Dyspnoea 29 (55) 85 (54) 114 (54) Fever 19 (36)1 30 (19) 49 (23) Night sweats 7 (13) 16 (10) 23 (11) Weight loss 14 (26) 29 (18) 43 (20) Fatigue 28 (53)" 37 (23) 65 (31) Chest radiograph features Air-spae opaities 22 (42) 42 (26) 64 (30) Cavity 15 (28) 2 (1) 17 (8) Nodules 4 (8) 2 (1) 6 (3) Bronhietasis 4 (8) 5 (3) 9 (4) Emphysema 14 (26) 23 (15) 37 (17) Mirobiology Mean number of ultures performed Mean number of positive ultures AFB smear positive 26 (49)** 6 (4) 32 (15) Results are shown as n (%) unless stated otherwise. *.15 mg prednisone/day for.3 months before primary NTM ulture; {anorexia nervosa, lymphopenia and omplement C4 defiieny, diabetes mellitus (all n = 1); {intravenous drug abuse (n = 2), azathioprine use (n = 1); 1p = 0.014, OR = 2.422, 95% CI to 4.978; "p,0.001, OR = 3.477, 95% CI to 7.024; **p,0.001, OR = , 95% CI to AFB, aid-fast baillus; COPD, hroni obstrutive pulmonary disease; TNF, tumour nerosis fator. treatment (four with M avium, one with M elatum disease; 17%) The mean interval between the end of treatment and ulture-proven relapse was 31 months (range 23 44). Of 14 patients treated for pulmonary M avium disease, only seven improved. The regimens used mostly onsisted of rifampiin and ethambutol, despite frequent in vitro resistane (15/25 primary isolates were resistant to rifampiin, 18/25 to ethambutol; five were not tested); isoniazid was added in 11 patients (despite in vitro resistane in all ases), larithromyin in 19, iprofloxain in four. Clarithromyin and iprofloxain were used only in patients with suseptible isolates. Three patients reeived 6 months of standardised TB treatment only. The mean treatment duration was 13 months (range 1 37). Three patients reeived additional surgial treatment that onsisted of resetion of a solitary pulmonary mass in two and lobetomy for persisting fibroavitary disease in one; all three were ured. The mean duration of follow-up after treatment was 34 months (range 17 91). Treatment was not given in 168 patients, though eight of them met the 1997 ATS diagnosti riteria. 8 Four patients were onsidered to have too few symptoms or radiographi deterioration, one refused treatment and one patient spontaneously reversed to negative ultures. Slow radiographi deterioration of pulmonary disease was apparent in all seven persistently symptomati and ulture-positive, untreated patients. During the study period, NTM were isolated from extrapulmonary samples only of 20 patients. Lymphadenitis was the most ommon extrapulmonary NTM disease type; six hildren and one elderly woman had ervial lymphadenitis (three M avium, two M malmoense, one M intraellulare, one M haemophilum) and one patient with AIDS (CD4 ount 1) had axillar and mediastinal lymphadenitis with extensive absess formation, aused by M gordonae. We reorded three ases of skin infetion: two aused by M marinum in fish tank owners and one by M malmoense in a patient with haematologial malignany. We also noted single ases of M kansasii tenosynovitis in a gardener, M absessus otomastoiditis after tympanostomy tube plaement in a hild and disseminated M avium disease in an AIDS patient (CD4 ount 40). The remaining six patients had MAC isolated from the digestive trat, in the absene of further evidene of NTM disease. DISCUSSION Twenty-five per ent of all patients in this study had pulmonary NTM disease aording to the ATS diagnosti riteria, and the linial relevane differed signifiantly by speies (fig 2). Isolation of M malmoense, M xenopi, M szulgai, M kansasii, M elatum and M genavense warrants speial attention, as this usually reflets true NTM disease; an observation onfirmed in previous studies. 1 Although in the urrent study the number of isolates of many speies is too low to permit firm onlusions, similar rates of linial relevane have already emerged for M xenopi (21/45 patients; 47%), M helonae (7/35; 20%), M absessus (13/39; 33%), M simiae (3/28; 11%) and M szulgai (11/15; 73%) in nationwide studies of pulmonary isolates in the Netherlands These data and the additional data in our urrent study strengthen a presentation suh as that shown in fig 2. The 25% of patients who met the ATS riteria is similar to the 33% reently found in a Canadian referral entre study, 25% reorded among patients in Korea and the results of earlier studies reviewed by Marras and Daley. A differene in linial relevane by speies has also been noted in the reently published Korean study with results similar to ours, exept for a very limited relevane of M szulgai (2/32 patients; 6%) and M elatum (1/11; 9%). 13 These differenes in linial relevane between NTM speies emphasise the major role of the bateriologial laboratory in the management of these emerging infetions; orret identifiation of NTM isolates is a prerequisite for orret patient handling. These apparent regional differenes in linial relevane of NTM speies require further study. The ATS diagnosti riteria are based on experiene with M avium, M kansasii and M absessus 1 ; their appliability to less studied speies may be limited. 1 9 The linial appliability of the ATS riteria is supported by those patients who did not meet the ATS riteria and who had no linial event or new radiologial events during follow-up. Very few follow-up Thorax: first published as /thx on 12 February Downloaded from on 3 September 2018 by guest. Proteted by opyright. 504 Thorax 2009;64: doi: /thx

4 Respiratory infetion Figure 2 Clinial relevane of pulmonary non-tuberulous myobateria isolates in this study, per speies. (x/y), number of patients who met the Amerian Thorai Soiety diagnosti riteria/total number of patients per speies. ultures were performed (table 1), although this was advoated in the ATS statement available during the study period. 8 Although for some speies the small number of isolates dereases the weight of the onlusions of the analysis, the differene in linial relevane of the various NTM speies may mean that for the speies to the left of fig 2 the ATS riteria should be very stritly applied or even be made more stringent, whereas among the upper half ( % linial relevane) a diagnosis of NTM disease may be justified after the first positive ulture. The inrease in the annual number of patients from whom NTM were isolated (fig 1) is a ause for onern and has also been noted in previous studies. This inrease was often thought be related to improvements in laboratory tehniques; in the Netherlands, the use of (automated) liquid ulture systems inreased during the study period A reent study, however, demonstrated that skin sensitisation to M intraellulare has also inreased signifiantly over reent deades in the USA, onsistent with observed inreases in the rate of pulmonary NTM infetions. 17 Several aspets may influene this inrease in NTM isolation. First, the Duth population, as in many developed ountries, is ageing and an inreasing prevalene of hroni obstrutive pulmonary disease is observed The baseline harateristis of our study group, predominantly men with an average age of 60 years, similar to previous NTM studies in soieties with low HIV prevalene, reflet these hanges. Seond, for hroni inflammatory diseases, immunosuppressive drugs, inluding tumour nerosis fator a neutralising agents, are inreasingly used. Both these aspets may have an impat on the future prevalene of NTM disease. In addition, the exposure to aerosols of tap water may have inreased over time, as frequeny of showering has risen dramatially over reent deades. The minor role of HIV infetion probably reflets the low prevalene of HIV infetion in the Netherlands, ompared with hroni pulmonary disease, and the advent of highly ative antiretroviral treatment. This limits the number of ases of severe HIV immunosuppression and its o-infetions, 21 whih may be refleted in the dereasing NTM isolation from extrapulmonary samples (fig 1). Besides, the hospitals partiipating in the study are situated in the eastern part of the Netherlands, where HIV inidene is lower than in the more urbanised western part. 22 The limited assoiations between symptoms, hest radiography results and NTM disease aording to the ATS diagnosti riteria underline the fat that diagnosis of NTM remains diffiult. Hene, the NTM merit speial attention by dotors and mirobiologists. Despite inherent limitations, the speies found in this study and their frequenies probably reflet the urrent epidemiologial situation for NTM in the Netherlands. This situation is remarkably different from nearby southeast England, where M xenopi is most ommon and Sotland and Sandinavia, where M malmoense is espeially prevalent The speies distribution and linial relevane among MAC isolates seen in this study differs from reent reports from the USA where M intraellulare is the more ommon respiratory pathogen, 1 linially more relevant than M avium in non-hiv patients, 24 and nodularbronhietati pulmonary MAC disease, assoiated with postmenopausal immunoompetent women, is as prevalent as avitary disease. 24 Possibly, the predominane of M avium and avitary disease in our study group are inter-related; different MAC subtypes are known to ause different disease types in humans. 25 Cases of nodular-bronhietati disease may have also been missed owing to the infrequent use of CT sanning and small number of follow-up ultures performed; diagnosing this pauibaillary disease type generally demands prolonged, intense follow-up. 1 Alternatively, sine we used hospital inpatient and outpatient file review, ases of nodular-bronhietati disease may have been missed as they are less often referred to hospitals for diagnosis, owing to a more indolent linial ourse 1 ompared with avitary MAC disease. Previous studies have reorded high degrees of linial relevane of M kansasii, omparable to the 71% in this study. 14 Whereas the latest ATS statement states that for M kansasii the treatment deision may be based on a single positive ulture in selet ases, 1 we reorded single positive sputum ultures in five patients with non-suspet radiographi hanges and repeatedly negative followup ultures. This would have meant an unneessary treatment for these patients when applying the new ATS riteria. We observed possible instanes of both undertreatment (not treating those who meet the diagnosti riteria) and overtreatment (treatment of those who do not meet diagnosti riteria), as well as the use of treatment regimens that have never proved to be effetive. This may harm patients. This, as well as the fat that few (high-resolution) CT sans and followup ultures, both strongly advoated in the ATS riteria, 1 8 were performed in patients with NTM isolates in non-avitary pulmonary disease, ould reflet a lak of knowledge of and experiene with the diagnosis and management of NTM disease Thorax: first published as /thx on 12 February Downloaded from on 3 September 2018 by guest. Proteted by opyright. Thorax 2009;64: doi: /thx

5 Respiratory infetion in dotors, or linial irumstanes not aptured in our file review. All these aspets emphasise the need for entralisation of knowledge, experiene and are for patients with (suspeted) NTM disease or inreased expert onsultation. Treatment duration reorded in our study was not in aordane with the British Thorai Soiety (BTS) and ATS guidelines A favourable outome for 67% of patients with pulmonary NTM disease is higher than the 36% observed in the reently published BTS linial trial omparing regimens with larithromyin or iprofloxain as adjunts to rifampiin and ethambutol. 27 In that trial, patients with MAC and M xenopi had worse outomes than those with M malmoense. 27 The differenes in treatment outome between our study and the BTS trial may result, first, from our more lenient definition of ure, seond, our limited follow-up period and finally, the NTM speies ausing pulmonary disease in our patients. Whereas the first trials of marolide-based regimens in pulmonary MAC disease in HIV-negative patients in the USA reported ure rates of 59 92%, with omparable definitions of ure, 1 the outome of treatment for pulmonary MAC disease seen in our study and the BTS trial was disappointingly poorer. The treatment results, over-representation of men and avitary disease, MAC speies distribution and linial relevane all suggest differenes in MAC organisms enountered in the USA and Europe. Although, generally, outome of NTM treatment is suboptimal, 1 various fators may have influened our results. First, the onditions predisposing to NTM disease influene the outome of the patient. Seond, the 1997 ATS diagnosti riteria 8 available to dotors in the study period might not have seleted the group of patients who would have benefited from treatment. More patients meet the reently published riteria, 12 though herein it is stated that meeting the riteria does not of itself neessitate treatment. 1 Still, this may lead to improved seletion of patients to reeive treatment and thus improve outome rates. In this perspetive, the term under-treatment will beome invalid. Third, previous trials for pulmonary MAC disease have reorded better treatment outome using similar definitions, but in a different MAC population. In our group more patients had avitary disease, whih in general is assoiated with a worse treatment outome. 1 Finally, one of the entres inorporated in this study is a referral entre for NTM disease treatment, whih may reate a seletion bias. Extrapulmonary disease was rare, though its overall frequeny (9%) and distribution of disease types are in line with previous studies, summarised in the reent ATS statement. 1 In onlusion, linial isolation of NTM was relevant in 25% of the 212 patients with pulmonary isolates. Clinial relevane differs markedly by speies and there are important regional differenes in speies distribution and relevane. This, as well as the rising isolation rates of NTM, warrants speial attention by dotors and mirobiologists. Treatment outome of pulmonary NTM disease was disappointing. Both overtreatment and insuffiient treatment were noted. Extrapulmonary NTM disease is rare. Ations to inrease awareness of the ATS diagnosti riteria and management guidelines and entralisation of NTM disease management are strongly reommended. Competing interests: None. Ethis approval: Regional ethis ommittee approval obtained. REFERENCES 1. Griffith DE, Aksamit T, Brown-Elliot BA, et al. An offiial ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberulous myobaterial diseases. Am J Respir Crit Care Med 2007;175: Marras TK, Chedore P, Ying AM, et al. 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