Advertisement
The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Risk factors and outcomes of non-tuberculous mycobacteria infection in lung transplant recipients: A systematic review and meta-analysis

Published:October 11, 2022DOI:https://doi.org/10.1016/j.healun.2022.10.004

      Background

      Patients with structural lung disease and immunocompromised status are at increased risk of pulmonary non-tuberculous mycobacteria (NTM) infection. However, literature on NTM in lung transplant recipients (LTR) is limited. We sought to systematically review the literature and perform a meta-analysis to examine associations with NTM disease and isolation in LTRs and their influence on mortality and chronic lung allograft dysfunction (CLAD).

      Methods

      A literature search of MEDLINE and Embase was performed on February 23, 2022. NTM disease was defined according to international guidelines. Isolation was defined as any growth of NTM in culture. Odds ratios (OR) were pooled for risk factors of NTM disease or isolation, and hazard ratios (HR) were pooled for mortality or CLAD.

      Results

      Eleven studies totaling 3,371 patients were eligible for inclusion, 10 of which underwent meta-analysis. Cystic fibrosis (OR 1.84, 95% confidence interval [CI] 1.03-3.30; I2 = 0%) and pre-transplant NTM isolation (OR 2.40, 95% CI 1.20-4.83; I2 = 0%) were associated with NTM disease. Only male sex was associated with NTM isolation (OR 1.45, 95% CI 1.01-2.10; I2 = 0%). NTM disease was associated with increased mortality (HR 2.69, 95% CI 1.70-4.26; I2 = 0%) and CLAD (HR 2.11, 95% CI 1.03-4.35; I2 = 44%). NTM isolation was not associated with mortality in pooled analysis or CLAD in 1 included study.

      Conclusions

      NTM disease, but not isolation, is associated with worse outcomes. Several factors were associated with development of NTM disease, including cystic fibrosis and pretransplant NTM isolation. Strategies to optimize prevention and treatment of NTM disease in lung transplant recipients are needed.

      Keywords

      Abbreviations:

      AFB (Acid-fast bacilli), ATS/IDSA (American Thoracic Society/Infectious Diseases Society of America), BOS (Bronchiolitis obliterans syndrome), CF (Cystic fibrosis), CI (Confidence interval), CLAD (Chronic lung allograft dysfunction), CMV (Cytomegalovirus), HR (Hazard ratio), ILD (Interstitial lung disease), LTR (Lung transplant recipient), MAC (Mycobacterium avium complex), NOS (Newcastle-Ottawa scale), NTM (Non-tuberculous mycobacteria), OLD (Obstructive lung disease), OR (Odds ratio)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Heart and Lung Transplantation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Stout JE
        • Koh W-J
        • Yew WW
        Update on pulmonary disease due to non-tuberculous mycobacteria.
        Int J Infect Dis. 2016; 45: 123-134https://doi.org/10.1016/j.ijid.2016.03.006
        • Chandrashekaran S
        • Escalante P
        • Kennedy CC.
        Mycobacterium abscessus disease in lung transplant recipients: Diagnosis and management.
        J Clin Tuberc Other Mycobact Dis. 2017; 9: 10-18https://doi.org/10.1016/j.jctube.2017.08.002
        • Friedman DZP
        • Doucette K
        Mycobacteria: Selection of transplant candidates and post-lung transplant outcomes.
        Semin Respir Crit Care Med. 2021; 42: 460-470https://doi.org/10.1055/s-0041-1727250
        • Chernenko SM
        • Humar A
        • Hutcheon M
        • et al.
        Mycobacterium abscessus Infections in lung transplant recipients: The International Experience.
        J Hear Lung Transplant. 2006; 25: 1447-1455https://doi.org/10.1016/j.healun.2006.09.003
        • Morales P
        • Gil A
        • Santos M.
        Mycobacterium abscessus infection in transplant recipients.
        Transplant Proc. 2010; 42: 3058-3060https://doi.org/10.1016/j.transproceed.2010.08.004
        • Redelman-Sidi G
        • Sepkowitz KA.
        Rapidly growing mycobacteria infection in patients with cancer.
        Clin Infect Dis. 2010; 51: 422-434https://doi.org/10.1086/655140
        • Longworth SA
        • Vinnard C
        • Lee I
        • Sims KD
        • Barton TD
        • Blumberg EA.
        Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case-control study.
        Transpl Infect Dis. 2014; 16: 76-83https://doi.org/10.1111/tid.12170
        • Longworth SA
        • Blumberg EA
        • Barton TD
        • Vinnard C.
        Non-tuberculous mycobacterial infections after solid organ transplantation: a survival analysis.
        Clin Microbiol Infect. 2015; 21: 43-47https://doi.org/10.1016/j.cmi.2014.07.001
        • Liberati A
        • Altman DG
        • Tetzlaff J
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; : 339https://doi.org/10.1136/bmj.b2700
        • Stroup DF
        • Berlin JA
        • Morton SC
        • et al.
        Meta-analysis of observational studies: a proposal for reporting.
        J Am Med Assoc. 2000; 283: 2008-2012https://doi.org/10.1007/978-94-007-3024-3_10
        • Daley CL
        • Iaccarino JM
        • Lange C
        • et al.
        Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.
        Clin Infect Dis. 2020; 71: e1-e36https://doi.org/10.1093/cid/ciaa241
        • Griffith DE
        • Aksamit T
        • Brown-Elliott BA
        • et al.
        An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.
        Am J Respir Crit Care Med. 2007; 175: 367-416https://doi.org/10.1164/rccm.200604-571ST
        • Verleden GM
        • Glanville AR
        • Lease ED
        • et al.
        Chronic lung allograft dysfunction: definition, diagnostic criteria, and approaches to treatment―a consensus report from the Pulmonary Council of the ISHLT.
        J Hear Lung Transplant. 2019; 38: 493-503https://doi.org/10.1016/j.healun.2019.03.009
        • Meyer KC
        • Raghu G
        • Verleden GM
        • et al.
        An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.
        Eur Respir J. 2014; 44: 1479-1503https://doi.org/10.1183/09031936.00107514
      1. Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed September 13, 2021. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

      2. Guyatt G, Busse J. Methods Commentary: Risk of Bias in Cohort Studies. Evidence partners. Accessed February 20, 2021. https://www.evidencepartners.com/resources/methodological-resources/risk-of-bias-in-cohort-studies/

        • DerSimonian R
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188https://doi.org/10.1016/0197-2456(86)90046-2
        • Higgins JPT
        • Thompson SG.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558https://doi.org/10.1002/sim.1186
        • Friedman DZP
        • Cervera C
        • Halloran K
        • Tyrrell G
        • Doucette K.
        Non-tuberculous mycobacteria in lung transplant recipients: prevalence, risk factors, and impact on survival and chronic lung allograft dysfunction.
        Transpl Infect Dis. 2020; 22: 1-7https://doi.org/10.1111/tid.13229
        • George IA
        • Santos CAQ
        • Olsen MA
        • Bailey TC.
        Epidemiology and outcomes of nontuberculous mycobacterial infections in solid organ transplant recipients at a midwestern center.
        Transplantation. 2016; 100: 1073-1078https://doi.org/10.1097/TP.0000000000001123
        • Gorsuch TT
        • Crossingham I
        • Cullen M
        • Al-Aloul M
        P61 Pulmonary nontuberculous mycobacterial (NTM) culture is common following lung transplantation, and NTM lung disease is associated with poor prognosis.
        Thorax. 2010; 65 (-A103): A103https://doi.org/10.1136/thx.2010.150979.12
        • Grimes R
        • Cherrier L
        • Nasar A
        • Nailor MD
        • Walia R
        • Goodlet KJ.
        Outcomes of nontuberculous mycobacteria isolation among lung transplant recipients: A matched case-control with retrospective cohort study.
        Am J Heal Pharm. 2022; 79: 338-345https://doi.org/10.1093/ajhp/zxab389
        • Hamad Y
        • Pilewski JM
        • Morrell M
        • D'Cunha J
        • Kwak EJ
        Outcomes in lung transplant recipients with mycobacterium abscessus infection: a 15-year experience from a large tertiary care center.
        Transplant Proc. 2019; 51: 2035-2042https://doi.org/10.1016/j.transproceed.2019.02.028
        • Huang HC
        • Weigt SS
        • Derhovanessian A
        • et al.
        Non-tuberculous mycobacterium infection after lung transplantation is associated with increased mortality.
        J Hear Lung Transplant. 2011; 30: 790-798https://doi.org/10.1016/j.healun.2011.02.007
        • Izhakian S
        • Frajman A
        • Mekiten O
        • et al.
        Nontuberculous mycobacterial pulmonary infection among lung transplant recipients.
        Exp Clin Transpl. 2021; 19: 1076-1081https://doi.org/10.6002/ect.2021.0177
        • Knoll BM
        • Kappagoda S
        • Gill RR
        • et al.
        Non-tuberculous mycobacterial infection among lung transplant recipients: a 15-year cohort study.
        Transpl Infect Dis. 2012; 14: 452-460https://doi.org/10.1111/j.1399-3062.2012.00753.x
        • Park Y
        • Kim NE
        • Kwak SH
        • et al.
        Nontuberculous mycobacterial infection after lung transplantation: a single-center experience in South Korea.
        J Microbiol Immunol Infect. 2022; 55: 123-129https://doi.org/10.1016/j.jmii.2020.08.021
        • Shah SK
        • McAnally KJ
        • Seoane L
        • et al.
        Analysis of pulmonary non-tuberculous mycobacterial infections after lung transplantation.
        Transpl Infect Dis. 2016; 18: 585-591https://doi.org/10.1111/tid.12546
        • Workman A
        • Kaza V
        • Bennett S
        • Chong P.
        Impact of azithromycin prophylaxis in lung transplant recipients on the risk of nontuberculous mycobacterial infections.
        Open Forum Infect Dis. 2018; 5: S288
        • Sexton P
        • Harrison AC.
        Susceptibility to nontuberculous mycobacterial lung disease.
        Eur Respir J. 2008; 31: 1322-1333https://doi.org/10.1183/09031936.00140007
        • Doucette K
        • Fishman JA.
        Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients.
        Clin Infect Dis. 2004; 38: 1428-1439https://doi.org/10.1086/420746
        • Henkle E
        • Winthrop KL.
        Nontuberculous mycobacteria infections in immunosuppressed hosts.
        Clin Chest Med. 2015; 36: 91-99https://doi.org/10.1016/j.ccm.2014.11.002
        • Yamazaki Y
        • Kubo K
        • Takamizawa A
        • Yamamoto H
        • Honda T
        • Sone S.
        Markers indicating deterioration of pulmonary Mycobacterium avium-intracellulare infection.
        Am J Respir Crit Care Med. 1999; 160: 1851-1855https://doi.org/10.1164/ajrccm.160.6.9902019
        • Koh W-J
        • Moon SM
        • Kim S-Y
        • et al.
        Outcomes of Mycobacterium avium complex lung disease based on clinical phenotype.
        Eur Respir J. 2017; 501602503https://doi.org/10.1183/13993003.02503-2016
      3. Ramos AL, Carvalho T, Guimarães JT. The importance of multiple samples in mycobacterial recovery: a 10-year retrospective study. Int J mycobacteriol. 8:175-179. doi:10.4103/ijmy.ijmy_68_19

        • Gottlieb J
        • Mattner F
        • Weissbrodt H
        • et al.
        Impact of graft colonization with gram-negative bacteria after lung transplantation on the development of bronchiolitis obliterans syndrome in recipients with cystic fibrosis.
        Respir Med. 2009; 103: 743-749https://doi.org/10.1016/j.rmed.2008.11.015
        • Botha P
        • Archer L
        • Anderson RL
        • et al.
        Pseudomonas aeruginosa colonization of the allograft after lung transplantation and the risk of bronchiolitis obliterans syndrome.
        Transplantation. 2008; 85: 771-774https://doi.org/10.1097/TP.0b013e31816651de
        • Combs MP
        • Wheeler DS
        • Luth JE
        • et al.
        Lung microbiota predict chronic rejection in healthy lung transplant recipients: a prospective cohort study.
        Lancet Respir Med. 2021; 9: 601-612https://doi.org/10.1016/S2213-2600(20)30405-7
        • Charlson ES
        • Diamond JM
        • Bittinger K
        • et al.
        Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant.
        Am J Respir Crit Care Med. 2012; 186: 536-545https://doi.org/10.1164/rccm.201204-0693OC
        • Chambers DC
        • Perch M
        • Zuckermann A
        • et al.
        The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-eighth adult lung transplantation report — 2021; Focus on recipient characteristics.
        J Hear Lung Transpl. 2021; 40: 1060-1072https://doi.org/10.1016/j.healun.2021.07.021
        • Malouf MA
        • Glanville AR.
        The spectrum of mycobacterial infection after lung transplantation.
        Am J Respir Crit Care Med. 1999; 160: 1611-1616https://doi.org/10.1164/ajrccm.160.5.9808113
        • Thomson RM
        • Armstrong JG
        • Looke DF.
        Gastroesophageal reflux disease, acid suppression, and mycobacterium avium complex pulmonary disease.
        Chest. 2007; 131: 1166-1172https://doi.org/10.1378/chest.06-1906
        • Novick RJ
        • Moreno-Cabral CE
        • Stinson EB
        • et al.
        Nontuberculous mycobacterial infections in heart transplant recipients: a seventeen-year experience.
        J Heart Transplant. 1990; 9: 357-363
        http://www.ncbi.nlm.nih.gov/pubmed/2398429
        Date accessed: April 16, 2022
        • Ramos KJ
        • Smith PJ
        • McKone EF
        • et al.
        Lung transplant referral for individuals with cystic fibrosis: Cystic Fibrosis Foundation consensus guidelines.
        J Cyst Fibros. 2019; 18: 321-333https://doi.org/10.1016/j.jcf.2019.03.002
        • Martinu T
        • Koutsokera A
        • Benden C
        • et al.
        International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation.
        J Hear Lung Transpl. 2020; 39: 1171-1190https://doi.org/10.1016/j.healun.2020.07.006