Acute Infection with Microbes and Their Consequences Mark Riddle, MD, DrPH

Transcription

1 Acute Infection with Microbes and Their Consequences Mark Riddle, MD, DrPH Associate Professor Dept. of Preventive Medicine & Biostatistics Uniformed Services University of the Health Sciences Bethesda, Maryland

2 Gastrointestinal Tract in Health and Disease Digestive tract Detoxification Immunity Mix-ups Food allergies Autoimmune diseases Post-infectious sequelae

3 Acute enteric infection risk: 50M in US each year (Centers for Disease Control & Prevention, 2015)

4 and their consequences Irritable Bowel Syndrome Guilliane Barre Syndrome Reactive arthritis Reflux/Dyspepsia Celiac disease Functional constipation Tropical sprue Inflammatory Bowel Disease Hemolytic Uremic Syndrome

5 Case Study: Campylobacter in the Netherlands In the Netherlands, with approximately 80,000 cases of gastroenteritis per year, the costs of illness caused by campylobacteriosis are about 21 million Euros per year (Silva, 2011).

6 Infection Infectious Causes of Chronic Disease Association Causation Mechanism Sudden, permanent sequelae EXAMPLES polio, malaria, meningitis Progressive disease histoplasmosis, lyme disease Immune process Symptomatic disease Persistent infection Symptomatic disease Dysbiotic process Symptomatic disease Adapted from O Conner, et al, EID, Vol. 12, No. 7, July rheumatic arthritis, systemic lupus, GBS Hepatitis B virus, H. pylori, HPV, HIV IBS, obesity,? mood disorders

7 Important non-gi Post-infectious Complications of Enteric Infections Campylobacter & Guillain-Barré Syndrome Post-dysenteric Reactive Arthritis Guerry P and Szymanski C, Trends Microbiol 2008;16:428 Leading cause of paralysis worldwide Rare: 1 2 per 100,000 per year 1 per 1,058 Campy infections Hannu T. Ann Rheum Dis 2005;64: Occurs 1-3 weeks following Shigella, Salmonella, and Campy infections (1-4%) Persists in 15 30% of patients HLA-B27 genetic predisposition for more severe disease

8 Post-dysenteric colitis (a.k.a. post-infectious Irritable Bowel Syndrome [PI-IBS]) 8

9 Consistency of Acute Infectious Gastroenteritis and IBS Association Is Strong Exposure Bacterial Viral Travelers Diarrhea Unspecified Diarrhea Study Rodriguez ( 99) Parry ( 02) Wang ( 04) Ji ( 05) Mearin ( 05) Marshall ( 06) Thabane ( 10) Jung ( 09) Porter ( 10) Porter ( 13) Zanini ( 12) Porter ( 12) Ilnyckyi ( 03) Okhuysen ( 04) Stermer ( 06) Pitzurra ( 11) Riddle ( 11) Porter ( 11) Cumberland ( 03) Marshall ( 06) Porter ( 10) Odds Ratio (95% CI) Risk Risk Exposure specifics Bacterial gastroenteritis Campylobacter, Salmonella Shigella Shigella Salmonella Campylobacter, EHEC Campylobacter, EHEC Shigella Campy, Shigella, Salmonella Shigella, Salm, Yers, Campy Norovirus Norovirus 55 different countries Mexico Asia, Africa, S America SE Asia, S Asia, E Africa Middle East Iraq / Afghanistan Medical care for acute GE Self-reported diarrhea ICD-9 code (infect. diarrhea)

10 % with IBS visit PI-IBS can be a chronic (? life-long) problem 100 All cases 80 Any IGE Bacterial IGE 60 Viral IGE 42% persistence at 8 years after Campy/STEC infection (Marshall et al.gut 2010) Porter et al. Am J Gastro Years after initial medical encounter In US military active duty, visits persist in 20-30% of cases Likely underestimates persistence of symptoms 57% persistence at 6 years follow-up (Neal et al. Gut 2002) 63% persistence at 5 years after Shigella infection (Jung et al. J Clin Gastro 2009)

11 Post-infectious Dyspepsia (? GERD) Risk Risk OR (95% CI) Self-Report Ford et al (1.74, 3.44) Mearin et al Parry et al (2.62, 11.74) 2.91 (0.48, 17.71) Trivedi et al (0.34, 23.03) Tuteja et al (0.61, 15.72) Subtotal 2.83 (2.10, 3.81) Record Review Porter et al (1.09, 2.08) Porter et al (0.83, 2.43) Porter et al (0.68, 4.02) Porter et al (2.15, 2.80) Subtotal 1.81 (1.26, 2.58) Overall 2.18 (1.70, 2.81) Pike et al. Amer J Gastro

12 Evidence for Post-C. difficile FGD Is Also Emerging September 2016 Among active duty personnel, C. difficile infection was independently associated with gastrointestinal sequelae Gutierrez RL, et.al. Gastroenterology 2015;149: New-onset IBS is common (25%) after CDI. Longer CDI duration, current anxiety and higher BMI are associated with the diagnosis of C. difficile PI-IBS.

13 Something Is Going on with the Microbiome in PI-IBS

14 Putative Pathogen Specific Trigger Mechanisms Invasive organisms and intestinal barrier mucosal disruption Enterotoxigenic E. coli heat-labile toxinmediated effects on barrier disruption via lipid raft sloughing tight junction disruption? adjuvanted response to commensals A. Epithelial tight junctions disruption B. Δ cellular polarity/receptor relocation C. internalization of non-invasive E. coli D. Defective NOD2 interaction/regulation Kalischuk. 2009; Glenn

15 Acute Gastrointestinal Infection Can Induce Long-Lived Microbiota-Specific T Cell Responses Belkaid Y. Trends Immunol. 2013; Hand TW. Science Each infection at barrier surfaces represents an additional opportunity for the reactivation of commensalspecific T cells May be beneficial through promoting innate and adaptive effect mechanisms May be harmful if results in dysregulation of microbiome and/or altered barrier function

16 Digestive Disease Sciences, 2014 CdtB - cytolethal distending toxin, B subunit ❸ CdtB ❻ ❶ ❺ ❷ ❹ ICCs Vinculin - human membrane cystoskeletal protein

17 Immunological Biomarkers of Postinfectious Irritable Bowel Syndrome DoD Serum Repository: pilot study Groups: 1 ❶ 1 & ❸ 3 PI-IBS ❷ 2 healthy (GI infx) ❹ 4 idiopathic-ibs Serum at time of initial ICD-9-CM diagnosis for IBS onset (or matched time of censure for healthy controls) Biomarkers: cytokines, microbiome antigens (C. Elson) & vinculin

18 Antibodies Directed against Antigens of Gut Commensals Differed between PI-IBS Cases and Those IBS Cases Lacking a Prior IGE Episode idiopathic IBS [Mean (SD)] n = 30 PI-IBS (all cause) [Mean (SD)] n = 60 FC p-value MDR254 (IgG) (18.93) (7.35) CBir8 (IgA) 3.07 (10.80) 9.33 (28.52) EF20 (IgG) (8.19) (6.05) rib16 (IgG) (8.89) (3.62) P3 (IgG) (5.43) (2.32) rib19 (IgG) (2.79) (1.73) Geometric Mean and Std. Deviation by Group; Fold-Changes (FC) <1 are presented as x = -1/FC.

19 Anti-Vinculin Antibody Higher in Campylobacter Specific PI-IBS vs Other PI-IBS Post- Other IBS [Mean (SD)] n = 20 Post-Campy IBS [Mean (SD)] n = 10 FC p-value Vinculin (IgG) (5.51) << (3.27)

20 Emerging concern about ESBL (Extended-Spectrum β-lactamase) producing Enterobacteriacea carriage 10-80% of travelers may be colonized with ESBL-PE Risk Factors: region, TD; abx use; diet, hospital exposure Growing argument to avoid antibiotics in TD treatment May be a transient phenomenon? (Ruppe, 2015) Kantele, 2015 Colonization by less virulent strains/ pathovars (Vading, 2016) Nonetheless, dissemination from healthy travelers to vulnerable individuals, and bacterial conjugation to more virulent strains must still be considered

21 On the topic of possible therapeutics Known risk factors for post-infectious IBS (and other FGD) Severity of disease Duration of disease Invasiveness of pathogens Concomitant stress Attractive is the concept of naturally boosting the individuals colonization resistance to pathogen infection Interception of dysregulatory trigger process (in theory)

22 Probiotics: Four meta-analyses have been published, only one showed a significant pooled effect Ritchie ML, Romanuk TN. PLoS ONE McFarland LV. Travel Medicine and Infectious Disease Takahashi O et al. J Clin Gastroenterol Sazawal S et al. Lancet Infectious Diseases Difficult to interpret the findings given differing probiotic species, formulations and dosages, and methodological problems within the studies themselves (i.e. poor compliance, recall bias). Prebiotics/synbiotics: preventive effects in TD is limited and mixed Cummings J et al. Aliment Pharmacol Ther Drakoularakou A et al. Eur J Clin Nutr Virk A et al. Journal of Travel Medicine Am J Gastro, April 2016

23 Practical Advice for the Clinician (Part 1) Diagnosis Work-up cases of dysentery, moderate severe disease, and symptoms lasting >7 days to clarify the etiology and enable specific directed therapy. Treatment Don t use antibiotics routinely for community acquired diarrhea (mostly viral) Do encourage use of single dose antibiotic therapy (with loperamide) for treatment of travelers diarrhea Counseling Prevention counseling of acute enteric infection is not routinely recommended but may be considered in the individual or close contacts of the individual who is at high risk for complications.

24 Practical Advice for the Clinician (Part 2) Prophylaxis Bismuth subsalicylates have moderate effectiveness and may be considered for travelers who do not have any contraindications to use and can adhere to the frequent dosing requirements Probiotics, prebiotics, and synbiotics for prevention of TD are not recommended. Antibiotic chemoprophylaxis has moderate to good effectiveness and may be considered in high-risk groups for short-term use. Gaps No current guidelines on work-up of post-infectious FGD No unique studies evaluating therapeutic effectiveness in PI-FGD No studies evaluating effect of TD prevention on reduction of PI-FGD risk Studies evaluating TD prevention in IBS patients are needed

25 Acknowledgements/Disclaimers Naval Medical Research Center Chad Porter, Brian Pike, Ramiro Gutierrez Armed Forces Health Surveillance Center Angie Eick-Cost and entire staff AFHSC/DoDSR staff University of Alabama Chuck Elson, Ben Christmann Uniformed Services University David Tribble The study protocols of presenter s data were approved by institutional review boards in compliance with all applicable Federal regulations governing the protection of human subjects. Funding: Department of Defense, International Society of Travel Medicine

26 If only our next meal came with a warning Questions? Photograph courtesy of J. Besser, MN Dept Health