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Treatment outcomes for isoniazid-resistant tuberculosis under program conditions in British Columbia,… Romanowski, Kamila; Chiang, Leslie Y; Roth, David Z; Krajden, Mel; Tang, Patrick; Cook, Victoria J; Johnston, James C Sep 4, 2017

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RESEARCH ARTICLE Open AccessTreatment outcomes for isoniazid-resistanttuberculosis under program conditions inBritish Columbia, CanadaKamila Romanowski1, Leslie Y. Chiang1, David Z. Roth1, Mel Krajden2, Patrick Tang2,3, Victoria J. Cook1,4and James C. Johnston1,4*AbstractBackground: Every year, over 1 million people develop isoniazid (INH) resistant tuberculosis (TB). Yet, the optimaltreatment regimen remains unclear. Given increasing prevalence, the clinical efficacy of regimens used byphysicians is of interest. This study aims to examine treatment outcomes of INH resistant TB patients, treated underprogrammatic conditions in British Columbia, Canada.Methods: Medical charts were retrospectively reviewed for cases of culture-confirmed INH mono-resistant TBreported to the BC Centre for Disease Control (BCCDC) from 2002 to 2014. Treatment regimens, patient and straincharacteristics, and clinical outcomes were analysed.Results: One hundred sixty five cases of INH mono-resistant TB were included in analysis and over 30 different treatmentregimens were prescribed. Median treatment duration was 10.5 months (IQR 9–12 months) and treatmentwas extended beyond 12 months for 26 patients (15.8%). Fifty six patients (22.6%) experienced an adverseevent that resulted in a drug regimen modification. Overall, 140 patients (84.8%) had a successful treatmentoutcome while 12 (7.2%) had an unsuccessful treatment outcome of failure (n = 2; 1.2%), relapse(n = 4; 2.4%) or all cause mortality (n = 6; 3.6%).Conclusion: Our treatment outcomes, while consistent with findings reported from other studies in highresource settings, raise concerns about current recommendations for INH resistant TB treatment. Only asmall proportion of patients completed the recommended treatment regimens. High quality studies toconfirm the effectiveness of standardized regimens are urgently needed, with special consideration given totrials utilizing fluoroquinolones.Keywords: Mycobacterium tuberculosis, INH resistance, Tuberculosis treatmentBackgroundTuberculosis (TB) remains a leading cause of infec-tious disease death worldwide, with 10.4 million newcases and 1.8 million deaths annually [1]. While theincidence of TB is decreasing globally, recent surveysindicate that drug-resistant TB exists in virtuallyevery location examined [1]. Isoniazid (INH) is animportant first-line agent for the treatment of TBgiven its potent early bactericidal activity andextensive evidence base as a first line therapy fordrug susceptible TB [2, 3] Unfortunately, resistanceto INH has been detected in 1 in 3 incident TBcases in Eastern Europe and 1 in 7 incidence TBcases in all other regions [4]. Indeed, over 1 millionpeople develop INH resistant TB globally each year.Systematic reviews and meta-analyses have con-firmed that INH resistance reduces the probability oftreatment success and increases the risk of acquiringresistance to other first line drugs including rifampin,thereby increasing the risk of multidrug resistant TB(MDR-TB) [5, 6]. Despite the global burden of INHresistance and reduced probability of treatment* Correspondence: James.Johnston@bccdc.ca1Provincial Tuberculosis Services, BC Centre for Disease Control, Vancouver,BC, Canada4Division of Respiratory Medicine, University of BC, Vancouver, BC, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Romanowski et al. BMC Infectious Diseases  (2017) 17:604 DOI 10.1186/s12879-017-2706-0success, the optimal regimen and duration oftreatment for INHR-TB remains controversial. In thesetting of known first line drug susceptibility results,the World Health Organization (WHO) treatmentguidelines [7] recommend using rifampin (RIF),pyrazinamide (PZA) and ethambutol (EMB) for 6–9 months. The Canadian Tuberculosis Standards 7thedition and American Thoracic Society offer similarrecommendations: 6–9 months of RIF, PZA, and ETHwith the potential addition of a fluoroquinolone(FQN) [8, 9]. However, limited published evidencesupport these regimens and all three bodies acknow-ledge further research is required in this area.In the absence of robust evidence for specifictreatment regimens, a wide variety of treatment regi-mens are used by treating physicians [10–12]. Giventhe increasing prevalence of INH resistance, theclinical efficacy of regimens used by physicians is ofinterest. In this study, we aimed to identify anddescribed the variations in treatment regimens forpatients with confirmed INH mono-resistance andreport on outcomes when treated under routineprogrammatic conditions in British Columbia (BC),Canada.MethodsStudy setting and data sourceBC is a Canadian province of 4.6 million people witha TB incidence of 6.3 per 100, 000 population [13].The BC Centre for Disease Control (BCCDC) is acentralized public health agency that maintains a TBregistry of all active TB cases across BC throughnotification by public health partners and routinereporting from the centralized provincial mycobacter-iology laboratory and provincial pharmacy [13].Data collectionFrom the BCCDC TB registry, we identified all cases ofculture-confirmed, INH mono-resistant TB fromNovember 1, 2002 to December 31, 2014. Cases wereexcluded if treatment duration was ≤30 days, or if end oftreatment outcomes were unavailable at the time of dataextraction. Patient demographics, comorbidities, medicalhistory, bacteriologic information, radiologic data, de-tailed treatment information, adverse events, treatmentoutcomes, and post-treatment follow-up informationwere extracted through individual chart review from theBCCDC TB registry.Specimen processing and drug-susceptibility testingThe BACTEC 460-radiometric method (Becton Dickinson,Franklin Lakes, NJ) or subsequently the BACTEC MGIT960 System (Becton Dickinson) were used to determinedrug susceptibilities of Mycobacterium tuberculosis isolatesat the BCCDC Public Health Laboratory. Drugs and theircritical concentrations for resistance were as follows: INHat 0.1 μg/mL and 0.4 μg/mL, rifampin at 1.0 μg/mL,ethambutol at 5.0 μg/mL, and streptomycin at 1.0 μg/mLin accordance with Clinical and Laboratory StandardsInstitute recommendations [14]. INH resistance was classi-fied as either low level or high level, when there was a > 1%growth of M. tuberculosis in the presence of 0.1 μg/mL or0.4 μg/mL of INH, respectively. INH mono-resistance wasdefined as resistance to INH alone or INH plusstreptomycin, without evidence of resistance to other firstline anti-TB drugs. Patients with resistance to INH and oneother first line anti-TB drug were excluded from analysis.Outcome measures and definitionsTreatment outcomes were defined as per the CanadianTB Standards 7th edition [9]. Cure: culture-negativity at the completion oftreatment. Treatment complete: a complete course of active TBtherapy without culture confirmation of cure orevidence of failure at the end of the treatmentcourse. Treatment non-completion (CTBS term: default):treatment stopped for ≥2 months before completing≥80% of doses. Treatment failure: positive sputum culture after≥4 months of treatment or two positive sputumcultures in different months during the last3 months of treatment, even if final culture wasnegative and no further treatment is planned. Death: mortality from any cause. Recurrence: disease recurrence after initial cure ortreatment complete, without genotypic evidence ofthe same organism by 24-loci MycobacterialInterspersed Repetitive Unit-Variable Number ofTandem Repeats (MIRU-VNTR) testing [15]. Relapse: disease recurrence after initial treatmentcure or complete, with genotypic evidence of thesame organism by MIRU-VNTR testing. For analyticpurposes recurrence was considered the same asrelapse. Acquired drug resistance: new or additionalresistance to one or more of the TB drugs receivedin the setting of failure or relapse.For the purpose of this study, a successful outcomeincluded patients meeting the definition of Cure orTreatment Completed while an unsuccessful outcomeincluded patients meeting the definition ofTreatment Failure, Acquired Drug Resistance, Deathor Relapse. Relapse was assessed using the BCCDCTB registry.Romanowski et al. BMC Infectious Diseases  (2017) 17:604 Page 2 of 7Data analysisStatistical analysis was performed using SPSS (V.23) andR (V.3.2.2), with a level of significance in reference to a2-tailed, type 1 error (P value) set as <0.05. Univariateanalysis was performed using the X2 test or Fisher exacttest for dichotomous variables and Mann-Whitney forcontinuous variables.ResultsBaseline characteristicsIn total, 184 cases of culture confirmed INH mono-resistant TB were identified from the BCCDC TBregistry; 165 of the 184 cases (89.7%) were includedin our analysis. Reasons for study exclusion includedduration of treatment ≤30 days (n = 10) and patienttransfer (n = 9). Of the 10 patients who were treatedfor ≤30 days, 5 patients died, 3 patients transferred,and 2 patients with extra-pulmonary disease hadtheir medications discontinued due to medicalcomplications.The baseline characteristics of the includedpatients are reported in Table 1. Of the 165 includedpatients, 103 (62.4%) were males and median agewas 46 years (IQR 32.5–61 years). The majority ofpatients (n = 155; 69.7%) were born in a countrywith a TB incidence >30 per 100,000 population; 127(77.0%) patients had no prior history of TB treat-ment. The most common comorbidity was diabetesmellitus (n = 19; 11.5%), followed by the use of animmune suppressive medication (n = 13; 7.9%). Sixpatients (3.6%) were identified as HIV positive. Ofthe 106 cases (64.2%) with pulmonary involvement,73 (59.3%) were sputum acid-fast bacillus smearpositive, and 50 (40.7%) had at least one cavitary le-sion present on chest x-ray. Concentrations for INHresistance were reported for all 165 patients. Eightyone patients (49.1%) had low-level INH resistancealone while 84 (50.9%) had both low and high-levelINH resistance.Treatment regimensWithin our cohort, over 30 different regimens wereprescribed; we combined them based on treatmentduration, length of PZA therapy, and the presence offluoroquinolone therapy. Treatment regimens aredescribed in Table 2. A total of 89 patients (53.9%)were prescribed a regimen of RIF, EMB and PZA. Ofthose, 41 patients (24.8%) only received PZA duringthe intensive phase while 48 patients (29.0%)received PZA throughout the entire treatmentcourse.Median length of treatment was 10.5 months (IQR 9–12 months). Treatment was extended beyond 12 monthsfor 26 patients (15.8%). 12 (7.3%) patients receivedextended treatment due to an adverse events (AEs)resulting in treatment modification, 6 (3.6%) patientsreceived extended treatment due to treatment noncom-pliance, while another 6 (3.6%) had extended treatmentdue to physician preference, and 2 (1.2%) because ofextensive disease. Patients with extended treatmentwhere more likely to have their regimen supplementedwith a FQN when compared to patients who completed≤12 months of treatment (65.4% vs. 31.7%, p = 0.002).Table 1 Demographic and clinical characteristicsCharacteristic Total patientsn = 165Sex (n, %)Male 103 (62.4)Female 62 (37.6)Age, years (IQR) 46 (32.5–61)Region of origin (n, %)Canadian born 44 (26.7)Foreign bornTB incidence >30 per 100,000 115 (69.7)TB incidence of ≤30 per 100,000 5 (3.0)Unknown country of birth 1 (0.6)Year of diagnosis2002–2006 37 (22.4)2007–2010 56 (33.9)2011–2014 72 (43.6)Co-morbidities (n, %)Diabetes mellitus 19 (11.5)Immune suppressive medication 13 (7.9)Malignancy 7 (4.2)HIV positive 6 (3.6)Chronic kidney disease 2 (1.2)Prior history of TB treatmentNo prior TB treatment 127 (77.0)Prior TB treatment 24 (14.5)Prior TB treatment unknown 14 (8.5)Disease sitePulmonary 106 (64.2)Extra-pulmonary 42 (25.5)Pulmonary and extra-pulmonary 17 (10.3)Extent of pulmonary diseaseaBaseline positive AFB smear 73 (59.3)Cavitary lesions in chest radiography 50 (40.7)Isoniazid resistance (n, %)INH, both high and low level resistance 84 (50.9)INH, only low level resistance 81 (49.1)aThe denominator used to calculate the percentage for Extent of pulmonarydisease was based on cases with pulmonary involvement (n = 123)Romanowski et al. BMC Infectious Diseases  (2017) 17:604 Page 3 of 7In total, 56 patients (33.6%) experienced an AE thatresulted in a drug regimen modification. Of those, 14(8.9%) patients experienced a second AE for a total of 70events. Of the 70 AEs, 65 could be attributed to a singledrug, and 5 could not. Frequency of AEs can be seen inTable 3. PZA was discontinued for 21(12.7%) patientsdue to 11 cases of drug-induced hepatitis, 7 due to rashand 3 due to nausea and vomiting. Ten patients (6.0%)were intolerant to RIF. Occurrence of AEs was not sig-nificantly associated with any demographic or clinicalcharacteristics in univariate analysis (data not shown).Treatment outcomesTreatment outcomes are summarized in Table 4. Atthe end of treatment, 144 patients (87.3%) experi-enced treatment completion or cure and therefore,met the definition of treatment success. Two patients(1.1%) experienced treatment failure and no patientsacquired drug resistance in the setting of treatmentfailure. All cause mortality during treatment wasreported for 6 (3.6%) patients; 2 patients died fromlung cancer, 2 from respiratory failure, 1 from kidneyfailure, and 1 from cardiac arrest. No deaths resultedfrom side effects of anti-TB drugs.13 patients (7.8%)were classified as treatment non-completion, including2 patients who stopped treatment early due toadverse drug reactions; treatment non-completion wasnot significantly associated demographic or clinicalcharacteristics in univariate analysis.The median follow-up duration post treatment was8 months (IQR 2–18.5 months). Of the 144 patientswith treatment success at the end of treatment, 4patients (2.4%) experienced relapse. MIRU-VNTRconfirmed identical patterns in 2 of 4 relapse strains,while 2 strains were not typed by MIRU-VNTR. Inthe 4 patients with relapse, 2 patients were treatedwith 9HRZE, 1 patient was treated with 12HRZE, and1 was treated with 2HRE/4HR. No demographic orclinical characteristics were associated with patientrelapse in univariate analysis (data not shown). NoTable 2 Treatment regimen composition and characteristicsTreatment RegimenIntensive phase/Continuation phaseTotal patients(n = 165)a6 to <9 Months (n, %)(H)RZE/(H)RE 8 (4.8)(H)RZE/(H)RZE 6 (3.6)(H) RZEQ/REQ 6 (3.6)Other 1 (0.2)≥ 9 to ≤12 Months (n, %)(H)RZE/(H)RE 32 (19.4)(H)RZE/(H)RZE 35 (21.2)(H)RZE(Q)/(H)REQ 14 (8.5)(H)RZE(Q)/(H)RZEQ 10 (6.1)(H)RE/(H)RE 4 (2.4)Other 17 (10.3)> 12 Months (n, %)(H)RZE/(H)RE 1 (0.2)(H)RZE/(H)RZE 6 (3.6)(H)RZE(Q)/(H)REQ 4 (2.4)Other 15 (9.1)I isoniazid, P pyrazinimide, R rifampin, E ethambutol, Q fluoroquinolone,S streptomycina6 (3.6%) patients were on treatment for <6 months due to treatment non-completion or deathTable 3 Frequency of adverse drug reactionsTotal patientsn = 165Number of patient who required drug regimenmodification due to adverse reaction (n, %)56 (33.3)Number of patients who stopped treatment dueto adverse events (n, %)2 (1.21)Total number of adverse events 70Adverse event Number ofeventsDrug induced hepatitis 20Rash 12Nausea and vomiting 11Tendonopathy 8Blurred vision 6Optic Neuropathy 2Arthralgia 2Other 9Table 4 Clinical treatment outcomesTreatment outcomes Total patients(n = 165)End of treatment outcomes (n, %)Treatment success at end of treatment 144 (87.3)Treatment non-completion 13 (7.8)Death 6 (3.6)Failure 2 (1.2)Treatment outcomes in follow-up (n,%)Relapse 4 (2.4)Acquired drug resistance 0 (0)Primary study outcomesSuccessful outcomea 140 (84.8%)Microbiologically confirmed unsuccessful outcomeb 12 (7.2%)aA successful outcome included patients meeting the definition of Cure orTreatment Completed without RelapsebAn unsuccessful outcome included patients meeting the definition ofTreatment Failure, Acquire Drug Resistance, Death, or RelapseRomanowski et al. BMC Infectious Diseases  (2017) 17:604 Page 4 of 7patients acquired drug resistance in the setting ofrelapse.Overall, 140 patients (84.8%) met the study defin-ition of a successful outcome while 12 patients (7.2%)met the definition of an unsuccessful outcome.Treatment success rates were similar in patients withhigh vs. low-level INH resistance profiles (90.7% vs.93.4%; p = 0.547). No statistically significantdifference was observed between patients with suc-cessful outcomes versus microbiologically confirmedunsuccessful outcomes despite multiple comparisonsbetween treatment regimens and patient characteris-tics (Table 5). Multivariate analysis was not performeddue to the small number of patients with thecombined endpoint of a microbiologically confirmedunsuccessful outcome.DiscussionIn this study, we found that 84.4% of patients expe-rienced a successful treatment outcome under pro-grammatic conditions in BC. Our treatmentoutcomes are consistent with those from other INHresistant treatment cohorts in high resource, low in-cidence settings [10–12, 16]. In resource-limited set-tings, where detailed individual level drugsusceptibility results are not always accessible, theproportions of patients experiencing unsuccessfuloutcomes are often much higher. For example, in anINH resistance treatment cohort in rural South Af-rica, 15% of patients experienced treatment failure,of which 61% progressed to MDR-TB [17].While thedifferences in treatment outcomes may be reflectiveof differences in patient and health care resourcesrather than regimen efficacy, it is worth noting thatin studies where resistance was detected early anddrug regimens were modified, a higher proportion ofpatient’s experienced successful outcomes [11, 12].This suggests that outcomes of treatment in INH re-sistant disease may be related to early detection ofresistance and individualized therapy.Within our cohort, over 30 different treatment regi-mens were prescribed; regimens were adjusted basedon DST patterns, adverse events, severity of disease,and physician preference. Regimens were also oftenextended. However, similar to other studies [12],12.7% of patients in our study were unable to toleratePZA and the high incidence of drug toxicity suggeststhat new treatment regimens are needed to improveINH-resistant TB treatment outcomes.In our cohort, 3 cases of relapse that occurred inpatients who completed on a 9–12 month regimentof only RIF, PZA and EMB. Meanwhile, no cases ofrelapse developed in the 61 (37.0%) patients receiv-ing an FQN-containing regimen. This finding, whilenot statistically significant, is in line with growingevidence suggesting that supplementation with FQNsmay strength treatment regimens among patientswith INH-resistant disease [16, 18, 19]. In a recentretrospective analysis of treatment outcomes withFQN containing regimens [18], the authorsconcluded that INH resistant pulmonary TB isassociated with improved outcomes when FQNs areadded to standard treatment regimens (97.3% vs.84.6%, P = 0.007).Table 5 Comparison of characteristics with favourable versus unfavourable outcomesCharacteristic (n, %) Successful outcomea(n = 140)Unsuccessful outcomeb(n = 12)P valuePatient characteristicsCo-morbidity (HIV, DM, Malignancy, CKD,immune suppressive medication)36 (25.7) 3 (25.0) 1.00Smear positive diseasec 64 (60.4) 5 (50.0) 0.523Cavitary diseasec 41 (38.7) 5 (50.0) 0.515Prior TB treatmentd 19 (14.4) 2 (22.2) 0.623Resistance profileHigh level INH resistance 69 (49.3) 7 (58.3) 0.547Treatment regimen> 2 months pyrazinamide 66 (47.1) 7 (58.3) 0.456> 9 months rifampin 69 (49.3) 3 (25.0) 0.106≥ 4 effective drugs in intensive phase 25 (17.9) 3 (25.0) 0.464Fluoroquinolone containing regimen 52 (37.1) 4 (33.3) 0.793aA successful outcome included patients meeting the definition of Cure or Treatment Completed without RelapsebAn unsuccessful outcome included patients meeting the definition of Treatment Failure, Acquire Drug Resistance, Death, or RelapsecThe denominator used to calculate percentage for smear positive disease was based on those with pulmonary involvement and primary study outcome(successful outcome n = 106; unsuccessful outcome n = 10)dMissing data for 8 successful outcomes and 1 unsuccessful outcomeRomanowski et al. BMC Infectious Diseases  (2017) 17:604 Page 5 of 7In 2011, Jenkins et al. reviewed the global burden andtrends of INH resistant TB using surveillance datareported to the WHO [4]. The authors concluded thatin several geographically disparate settings, the numberof new TB cases with INH resistance is increasing [4].This is consistent with routine surveillance data fromBC and Canada, which show an increase in theprevalence of INH resistance [13]. As the burden of INHresistant disease increases, the need for a standard,cost-effective, evidence-based treatment regimen be-comes more pressing. Prolonged, individualized coursesfor INH resistant TB are not practical, and would be dif-ficult to implement in resource limited settings wherethe highest INH resistance burden exists [1, 4]. TheWHO currently recommends two different treatmentregimens for INH resistance; one for countries with anassumed ‘high’ level of INH resistance and another basedon a setting of known first line drug susceptibility results[7, 20]. Unfortunately, the controversies regarding bothof these treatment regimens outweigh the evidence [5, 6]and highlight the need for controlled trials to validatespecific standardized recommendations.Our study had several limitations. The most importantwas our inability to control for potential confoundingvariables and effect modification. Instead, we had to relyexclusively on univariate analysis for our analysis ofoutcomes due to the small sample size of unsuccessfuloutcomes. Whereas prior studies have identifiedcharacteristics of different treatment regimens associatedwith improved treatment outcomes, such as extendingPZA duration [21], addition of fluoroquinolones [18], oruse of four effective drugs in the intensive phase [5],these findings were not statistically evident in our co-hort, possibly the result of the relatively small combinedendpoint.We were also limited by the variation in the com-position and duration of treatment regimens. Therewas great variation in the composition and durationof treatment regimens making it impossible toidentify superior or inferior regimens given the typeof study and the sample size. Additionally, withineach regimen group, there may have been clinicallyimportant differences that we could not account for.Highly heterogeneous treatment regimens are a widelyrecognized to be present in clinical practice, particu-larly when evidence behind treatment regimens isscarce [10–12, 16]. The wide variety of treatmentregimens presented here reflects the uncertainty ofclinicians in appropriate treatment of INH resistantdisease.Despite these limitations, our study raises importantconcerns about the currently recommended treatmentregimens for INH resistant TB. It highlights the need forhigh quality studies to firmly establish standardizedtreatment regimens, with special consideration given totrials that utilize fluoroquinolones. Currently, there is lit-tle evidence and much controversy regarding the recom-mended treatment regimens, and given the globalburden of INH resistance, solid evidence validating thevarious recommendations for treatment is urgentlyneeded.AbbreviationsAE: Adverse event; DST: Drug susceptibility testing; EMB: Ethambutol;FQN: Fluoroquinolone; INH: Isoniazid; MDR-TB: Multi-drug resistant TB;PZA: Pyrazinamide; RIF: Rifampin; TB: TuberculosisFundingJCJ is supported by the Michael Smith Foundation for Health Research.Availability of data and materialsThe data that supported the findings of this study are available on request fromthe corresponding author upon reasonable request. Identifying/confidentialpatient data however will not be shared.Authors’ contributionsAll authors provided important intellectual content and approved the finalversion of the manuscript.Ethics approval and consent to participateThe University of British Columbia Clinical Research Ethics Board approvedthis study.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Provincial Tuberculosis Services, BC Centre for Disease Control, Vancouver,BC, Canada. 2BC Centre for Disease Control Public Health LaboratoryMedicine, University of BC, Vancouver, BC, Canada. 3Department ofPathology, Sidra Medical and Research Center, Doha, Qatar. 4Division ofRespiratory Medicine, University of BC, Vancouver, BC, Canada.Received: 31 October 2016 Accepted: 24 August 2017References1. 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Int J TubercLung Dis 2002;6:952–958.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Romanowski et al. BMC Infectious Diseases  (2017) 17:604 Page 7 of 7


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