Abstract
Background:
The role of fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) is not well-known.
Purpose:
To assess the efficacy, comparative effectiveness, and harms of FMT for CDI.
Data Sources:
MEDLINE (1980 to January 2015), Cochrane Library, and ClinicalTrials.gov, followed by hand-searching references from systematic reviews and identified studies.
Study Selection:
Any study of FMT to treat adult patients with CDI; case reports were only used to report harms.
Data Extraction:
Data were extracted by 1 author and verified by another; 2 authors independently assessed risk of bias and strength of evidence.
Data Synthesis:
Two randomized, controlled trials (RCTs); 28 case-series studies; and 5 case reports were included. Two RCTs and 21 case-series studies (516 patients receiving FMT) reported using FMT for patients with recurrent CDI. A high proportion of treated patients had symptom resolution; however, the role of previous antimicrobials is unclear. One RCT comparing FMT with 2 control groups (n = 43) reported resolution of symptoms in 81%, 31%, and 23% of the FMT, vancomycin, or vancomycin-plus-bowel lavage groups, respectively (P < 0.001 for both control groups vs. FMT). An RCT comparing FMT route (n = 20) reported no difference between groups (60% in the nasogastric tube group and 80% in the colonoscopy group; P = 0.63). Across all studies for recurrent CDI, symptom resolution was seen in 85% of cases. In 7 case-series studies of patients with refractory CDI, symptom resolution ranged from 0% to 100%. Among 7 patients treated with FMT for initial CDI, results were mixed.
Limitation:
Most studies were uncontrolled case-series studies; only 2 RCTs were available for analysis.
Conclusion:
Fecal microbiota transplantation may have a substantial effect with few short-term adverse events for recurrent CDI. Evidence is insufficient on FMT for refractory or initial CDI treatment and on whether effects vary by donor, preparation, or delivery method.
Primary Funding Source:
U.S. Department of Veterans Affairs.
References
- 1.
Bartlett JG ,Chang TW ,Gurwith M ,Gorbach SL ,Onderdonk AB . Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298:531-4. [PMID: 625309] CrossrefMedlineGoogle Scholar - 2.
Larson HE ,Price AB ,Honour P ,Borriello SP . Clostridium difficile and the aetiology of pseudomembranous colitis. Lancet. 1978;1:1063-6. [PMID: 77366] CrossrefMedlineGoogle Scholar - 3.
Kuntz JL ,Chrischilles EA ,Pendergast JF ,Herwaldt LA ,Polgreen PM . Incidence of and risk factors for community-associated Clostridium difficile infection: a nested case-control study. BMC Infect Dis. 2011;11:194. [PMID: 21762504] doi:10.1186/1471-2334-11-194 CrossrefMedlineGoogle Scholar - 4. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. Accessed at www.cdc.gov/drugresistance/threat-report-2013 on 8 May 2014. Google Scholar
- 5.
Johnson S . Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect. 2009;58:403-10. [PMID: 19394704] doi:10.1016/j.jinf.2009.03.010 CrossrefMedlineGoogle Scholar - 6.
Louie TJ ,Miller MA ,Mullane KM ,Weiss K ,Lentnek A ,Golan Y ,et al ;OPT-80-003 Clinical Study Group . Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422-31. [PMID: 21288078] doi:10.1056/NEJMoa0910812 CrossrefMedlineGoogle Scholar - 7.
Surawicz CM ,McFarland LV ,Greenberg RN ,Rubin M ,Fekety R ,Mulligan ME ,et al . The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis. 2000;31:1012-7. [PMID: 11049785] CrossrefMedlineGoogle Scholar - 8.
McFarland LV ,Elmer GW ,Surawicz CM . Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97:1769-75. [PMID: 12135033] CrossrefMedlineGoogle Scholar - 9.
Wilson KH . The microecology of Clostridium difficile. Clin Infect Dis. 1993;16 Suppl 4:S214-8. [PMID: 8324122] CrossrefMedlineGoogle Scholar - 10.
Cammarota G ,Ianiro G ,Gasbarrini A . Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol. 2014;48:693-702. [PMID: 24440934] doi:10.1097/MCG.0000000000000046 CrossrefMedlineGoogle Scholar - 11.
van Nood E ,Vrieze A ,Nieuwdorp M ,Fuentes S ,Zoetendal EG ,de Vos WM ,et al . Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407-15. [PMID: 23323867] doi:10.1056/NEJMoa1205037 CrossrefMedlineGoogle Scholar - 12.
Silverman MS ,Davis I ,Pillai DR . Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol. 2010;8:471-3. [PMID: 20117243] doi:10.1016/j.cgh.2010.01.007 CrossrefMedlineGoogle Scholar - 13.
Debast SB ,Bauer MP ,Kuijper EJ ;European Society of Clinical Microbiology and Infectious Diseases . European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20 Suppl 2:1-26. [PMID: 24118601] doi:10.1111/1469-0691.12418 CrossrefMedlineGoogle Scholar - 14.
Surawicz CM ,Brandt LJ ,Binion DG ,Ananthakrishnan AN ,Curry SR ,Gilligan PH ,et al . Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-98. [PMID: 23439232] doi:10.1038/ajg.2013.4 CrossrefMedlineGoogle Scholar - 15.
Bakken JS ,Borody T ,Brandt LJ ,Brill JV ,Demarco DC ,Franzos MA ,et al ;Fecal Microbiota Transplantation Workgroup . Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044-9. [PMID: 21871249] doi:10.1016/j.cgh.2011.08.014 CrossrefMedlineGoogle Scholar - 16.
Owens DK ,Lohr KN ,Atkins D ,Treadwell JR ,Reston JT ,Bass EB ,et al . AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol. 2010;63:513-23. [PMID: 19595577] doi:10.1016/j.jclinepi.2009.03.009 CrossrefMedlineGoogle Scholar - 17. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. Accessed at www.cochrane-handbook.org on 6 October 2014. Google Scholar
- 18.
Youngster I ,Sauk J ,Pindar C ,Wilson RG ,Kaplan JL ,Smith MB ,et al . Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58:1515-22. [PMID: 24762631] doi:10.1093/cid/ciu135 CrossrefMedlineGoogle Scholar - 19.
Youngster I ,Russell GH ,Pindar C ,Ziv-Baran T ,Sauk J ,Hohmann EL . Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312:1772-8. [PMID: 25322359] doi:10.1001/jama.2014.13875 CrossrefMedlineGoogle Scholar - 20.
Yoon SS ,Brandt LJ . Treatment of refractory/recurrent C. difficile–associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol. 2010;44:562-6. [PMID: 20463588] doi:10.1097/MCG.0b013e3181dac035 CrossrefMedlineGoogle Scholar - 21.
Tvede M ,Rask-Madsen J . Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet. 1989;1:1156-60. [PMID: 2566734] CrossrefMedlineGoogle Scholar - 22.
Rubin TA ,Gessert CE ,Aas J ,Bakken JS . Fecal microbiome transplantation for recurrent Clostridium difficile infection: report on a case series. Anaerobe. 2013;19:22-6. [PMID: 23182843] doi:10.1016/j.anaerobe.2012.11.004 CrossrefMedlineGoogle Scholar - 23.
Rohlke F ,Surawicz CM ,Stollman N . Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol. 2010;44:567-70. [PMID: 20485184] doi:10.1097/MCG.0b013e3181dadb10 CrossrefMedlineGoogle Scholar - 24.
Pathak R ,Enuh HA ,Patel A ,Wickremesinghe P . Treatment of relapsing Clostridium difficile infection using fecal microbiota transplantation. Clin Exp Gastroenterol. 2013;7:1-6. [PMID: 24421645] doi:10.2147/CEG.S53410 CrossrefMedlineGoogle Scholar - 25.
Paterson DL ,Iredell J ,Whitby M . Putting back the bugs: bacterial treatment relieves chronic diarrhoea [Letter]. Med J Aust. 1994;160:232-3. [PMID: 8309401] CrossrefMedlineGoogle Scholar - 26.
Patel NC ,Griesbach CL ,DiBaise JK ,Orenstein R . Fecal microbiota transplant for recurrent Clostridium difficile infection: Mayo Clinic in Arizona experience. Mayo Clin Proc. 2013;88:799-805. [PMID: 23910407] doi:10.1016/j.mayocp.2013.04.022 CrossrefMedlineGoogle Scholar - 27.
Mellow MH ,Kanatzar A . Colonoscopic fecal bacteriotherapy in the treatment of recurrent Clostridium difficile infection—results and follow-up. J Okla State Med Assoc. 2011;104:89-91. [PMID: 21608450] MedlineGoogle Scholar - 28.
Mattila E ,Uusitalo-Seppl R ,Wuorela M ,Lehtola L ,Nurmi H ,Ristikankare M ,et al . Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology. 2012;142:490-6. [PMID: 22155369] doi:10.1053/j.gastro.2011.11.037 CrossrefMedlineGoogle Scholar - 29.
MacConnachie AA ,Fox R ,Kennedy DR ,Seaton RA . Faecal transplant for recurrent Clostridium difficile–associated diarrhoea: a UK case series. QJM. 2009;102:781-4. [PMID: 19726581] doi:10.1093/qjmed/hcp118 CrossrefMedlineGoogle Scholar - 30.
Khan MA ,Sofi AA ,Ahmad U ,Alaradi O ,Khan AR ,Hammad T ,et al . Efficacy and safety of, and patient satisfaction with, colonoscopic-administered fecal microbiota transplantation in relapsing and refractory community- and hospital-acquired Clostridium difficile infection. Can J Gastroenterol Hepatol. 2014;28:434-8. [PMID: 25014180] CrossrefMedlineGoogle Scholar - 31.
Kelly CR ,de Leon L ,Jasutkar N . Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012;46:145-9. [PMID: 22157239] doi:10.1097/MCG.0b013e318234570b CrossrefMedlineGoogle Scholar - 32.
Hamilton MJ ,Weingarden AR ,Sadowsky MJ ,Khoruts A . Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107:761-7. [PMID: 22290405] doi:10.1038/ajg.2011.482 CrossrefMedlineGoogle Scholar - 33.
Gustafsson A ,Berstad A ,Lund-T nnesen S ,Midtvedt T ,Norin E . The effect of faecal enema on five microflora-associated characteristics in patients with antibiotic-associated diarrhoea. Scand J Gastroenterol. 1999;34:580-6. [PMID: 10440607] CrossrefMedlineGoogle Scholar - 34.
Garborg K ,Waagsb B ,Stallemo A ,Matre J ,Sundy A . Results of faecal donor instillation therapy for recurrent Clostridium difficile–associated diarrhoea. Scand J Infect Dis. 2010;42:857-61. [PMID: 20662620] doi:10.3109/00365548.2010.499541 CrossrefMedlineGoogle Scholar - 35.
Emanuelsson F ,Claesson BE ,Ljungstrm L ,Tvede M ,Ung KA . Faecal microbiota transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients. Scand J Infect Dis. 2014;46:89-97. [PMID: 24354958] doi:10.3109/00365548.2013.858181 CrossrefMedlineGoogle Scholar - 36.
Dutta SK ,Girotra M ,Garg S ,Dutta A ,von Rosenvinge EC ,Maddox C ,et al . Efficacy of combined jejunal and colonic fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2014;12:1572-6. [PMID: 24440222] doi:10.1016/j.cgh.2013.12.032 CrossrefMedlineGoogle Scholar - 37.
Cammarota G ,Ianiro G ,Gasbarrini A ,Masucci L ,Sanguinetti M . Faecal transplantation for Clostridium difficile infection. Three cases treated in Italy [Letter]. Dig Liver Dis. 2014;46:475. [PMID: 24457126] doi:10.1016/j.dld.2013.12.011 CrossrefMedlineGoogle Scholar - 38.
Aas J ,Gessert CE ,Bakken JS . Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. 2003;36:580-5. [PMID: 12594638] CrossrefMedlineGoogle Scholar - 39.
Lee CH ,Belanger JE ,Kassam Z ,Smieja M ,Higgins D ,Broukhanski G ,et al . The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis. 2014;33:1425-8. [PMID: 24627239] doi:10.1007/s10096-014-2088-9 CrossrefMedlineGoogle Scholar - 40.
Zainah H ,Hassan M ,Shiekh-Sroujieh L ,Hassan S ,Alangaden G ,Ramesh M . Intestinal microbiota transplantation, a simple and effective treatment for severe and refractory Clostridium difficile infection. Dig Dis Sci. 2015;60:181-5. [PMID: 25052150] doi:10.1007/s10620-014-3296-y CrossrefMedlineGoogle Scholar - 41.
Weingarden AR ,Hamilton MJ ,Sadowsky MJ ,Khoruts A . Resolution of severe Clostridium difficile infection following sequential fecal microbiota transplantation [Letter]. J Clin Gastroenterol. 2013;47:735-7. [PMID: 23632358] doi:10.1097/MCG.0b013e31829004ae CrossrefMedlineGoogle Scholar - 42.
Bowden TA ,Mansberger AR ,Lykins LE . Pseudomembraneous enterocolitis: mechanism for restoring floral homeostasis. Am Surg. 1981;47:178-83. [PMID: 7224366] MedlineGoogle Scholar - 43.
Eiseman B ,Silen W ,Bascom GS ,Kauvar AJ . Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44:854-9. [PMID: 13592638] MedlineGoogle Scholar - 44.
Kelly CR ,Ihunnah C ,Fischer M ,Khoruts A ,Surawicz C ,Afzali A ,et al . Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109:1065-71. [PMID: 24890442] doi:10.1038/ajg.2014.133 CrossrefMedlineGoogle Scholar - 45.
Solari PR ,Fairchild PG ,Noa LJ ,Wallace MR . Tempered enthusiasm for fecal transplant [Letter]. Clin Infect Dis. 2014;59:319. [PMID: 24759832] doi:10.1093/cid/ciu278 CrossrefMedlineGoogle Scholar - 46.
Kleger A ,Schnell J ,Essig A ,Wagner M ,Bommer M ,Seufferlein T ,et al . Fecal transplant in refractory Clostridium difficile colitis. Dtsch Arztebl Int. 2013;110:108-15. [PMID: 23468820] doi:10.3238/arztebl.2013.0108 CrossrefMedlineGoogle Scholar - 47.
Quera R ,Espinoza R ,Estay C ,Rivera D . Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn's disease and recurrent Clostridium difficile infection [Letter]. J Crohns Colitis. 2014;8:252-3. [PMID: 24184170] doi:10.1016/j.crohns.2013.10.002 CrossrefMedlineGoogle Scholar - 48.
De Leon LM ,Watson JB ,Kelly CR . Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11:1036-8. [PMID: 23669309] doi:10.1016/j.cgh.2013.04.045 CrossrefMedlineGoogle Scholar - 49.
Schwartz M ,Gluck M ,Koon S . Norovirus gastroenteritis after fecal microbiota transplantation for treatment of Clostridium difficile infection despite asymptomatic donors and lack of sick contacts [Letter]. Am J Gastroenterol. 2013;108:1367. [PMID: 23912408] doi:10.1038/ajg.2013.164 CrossrefMedlineGoogle Scholar - 50.
Brandt LJ ,Aroniadis OC ,Mellow M ,Kanatzar A ,Kelly C ,Park T ,et al . Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107:1079-87. [PMID: 22450732] doi:10.1038/ajg.2012.60 CrossrefMedlineGoogle Scholar - 51.
Johnson S ,Schriever C ,Galang M ,Kelly CP ,Gerding DN . Interruption of recurrent Clostridium difficile–associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44:846-8. [PMID: 17304459] CrossrefMedlineGoogle Scholar - 52.
Tedesco FJ ,Gordon D ,Fortson WC . Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis. Am J Gastroenterol. 1985;80:867-8. [PMID: 4050760] MedlineGoogle Scholar - 53.
Moore TA ,Rodriguez A ,Bakken JS . Reply to Solari et al [Letter]. Clin Infect Dis. 2014;59:319-20. [PMID: 24759828] doi:10.1093/cid/ciu279 CrossrefMedlineGoogle Scholar - 54.
Lund-T nnesen S ,Berstad A ,Schreiner A ,Midtvedt T . [Clostridium difficile–associated diarrhea treated with homologous feces]. Tidsskr Nor Laegeforen. 1998;118:1027-30. [PMID: 9531822] MedlineGoogle Scholar - 55.
Nieuwdorp M ,van Nood E ,Speelman P ,van Heukelem HA ,Jansen JM ,Visser CE ,et al . [Treatment of recurrent Clostridium difficile–associated diarrhoea with a suspension of donor faeces]. Ned Tijdschr Geneeskd. 2008;152:1927-32. [PMID: 18808083] MedlineGoogle Scholar - 56.
Pol k P ,Freibergerov M ,Jurnkov J ,Kocourkov H ,Mikešov L ,Svacina R ,et al . [First experiences with faecal bacteriotherapy in the treatment of relapsing pseudomembranous colitis due to Clostridium difficile]. Klin Mikrobiol Infekc Lek. 2011;17:214-7. [PMID: 22247032] MedlineGoogle Scholar - 57.
Sihvonen R ,Paavola M ,Malmivaara A ,It l A ,Joukainen A ,Nurmi H ,et al ;Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group . Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med. 2013;369:2515-24. [PMID: 24369076] doi:10.1056/NEJMoa1305189 CrossrefMedlineGoogle Scholar - 58.
Bhatt DL ,Kandzari DE ,O'Neill WW ,D'Agostino R ,Flack JM ,Katzen BT ,et al ;SYMPLICITY HTN-3 Investigators . A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-401. [PMID: 24678939] doi:10.1056/NEJMoa1402670 CrossrefMedlineGoogle Scholar - 59.
Redberg RF . Sham controls in medical device trials. N Engl J Med. 2014;371:892-3. [PMID: 25184861] doi:10.1056/NEJMp1406388 CrossrefMedlineGoogle Scholar
Author, Article, and Disclosure Information
Dimitri Drekonja,
From Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Health Care System, and University of Minnesota School of Medicine, Minneapolis, Minnesota.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the U.S. Department of Veterans Affairs or the U.S. government.
Grant Support: By the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative.
Disclosures: Dr. Drekonja reports grants under review from the U.S. Department of Veterans Affairs (VA) Cooperative Studies Program and personal fees from Rebiotix during the conduct of the study. Dr. Shaukat reports grants from the VA Office of Research and Development during the conduct of the study. Dr. Greer reports grants from the VA Office of Research and Development Quality Enhancement Research Initiative during the conduct of the study. Mr. MacDonald reports grants from the VA Office of Research and Development Quality Enhancement Research Initiative during the conduct of the study. Dr. Wilt reports funding from the VA Evidence Synthesis Program to conduct this review and that he is the Minneapolis Evidence Synthesis Program director and principal contract recipient. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2693.
Corresponding Author: Dimitri Drekonja, MD, MS, Minneapolis Veterans Affairs Health Care System, 1 Veterans Drive, Mail Code 111-F, Minneapolis, MN 55417; e-mail, drek0002@umn.
Current Author Addresses: Dr. Drekonja: Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Mail Code 111-F, Minneapolis, MN 55417.
Drs. Reich and Shaukat: Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Mail Code 111-D, Minneapolis, MN 55417.
Dr. Gezahegn: Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Mail Code 111, Minneapolis, MN 55417.
Dr. Greer: Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Mail Code 152, Minneapolis, MN 55417.
Mr. MacDonald: Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Mail Code 151, Minneapolis, MN 55417.
Mr. Rutks: Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Mail Code 151/152, Minneapolis, MN 55417.
Dr. Wilt: Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Mail Code 111-O, Minneapolis, MN 55417.
Author Contributions: Conception and design: D. Drekonja, S. Gezahegn, N. Greer, A. Shaukat, T.J. Wilt.
Analysis and interpretation of the data: D. Drekonja, J. Reich, S. Gezahegn, N. Greer, A. Shaukat, R. MacDonald, T.J. Wilt.
Drafting of the article: D. Drekonja, J. Reich, A. Shaukat.
Critical revision of the article for important intellectual content: D. Drekonja, S. Gezahegn, N. Greer, A. Shaukat, T.J. Wilt.
Final approval of the article: D. Drekonja, S. Gezahegn, N. Greer, A. Shaukat, I. Rutks, T.J. Wilt.
Provision of study materials or patients: N. Greer, I. Rutks.
Statistical expertise: R. MacDonald, T.J. Wilt.
Obtaining of funding: T.J. Wilt.
Administrative, technical, or logistic support: N. Greer, I. Rutks, T.J. Wilt.
Collection and assembly of data: D. Drekonja, J. Reich, S. Gezahegn, N. Greer, A. Shaukat, R. MacDonald, I. Rutks.
Submit a Comment
Contributors must reveal any conflict of interest. Comments are moderated. Please see our information for authorsregarding comments on an Annals publication.
*All comments submitted after October 1, 2021 and selected for publication will be published online only.