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

Gastrointestinal Tract in Health and Disease

Detoxification

Digestive tract

Immunity

Food allergies

Autoimmune diseases

Mix-ups

Post-infectious sequelae

Acute enteric infection risk: 50M in US each year

(Centers for Disease Control & Prevention, 2015)

…and their consequences

Irritable Bowel Syndrome Guilliane Barre Syndrome

Functional constipation

Reactive arthritis

Hemolytic Uremic Syndrome

Reflux/Dyspepsia Celiac disease

Inflammatory Bowel Disease

Tropical sprue

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).

Sudden, permanent sequelae

Progressive disease

Immune process

Persistent infection

Infe

cti

on

Symptomatic disease

Symptomatic disease

Dysbiotic process Symptomatic disease

Infectious Causes of Chronic Disease Association Causation Mechanism

EXAMPLES

•polio, malaria, meningitis

•histoplasmosis,

lyme disease

•rheumatic arthritis,

systemic lupus, GBS

•Hepatitis B virus, H. pylori,

HPV, HIV

•IBS, obesity, ? mood

disorders…

Adapted from O’Conner, et al, EID, Vol. 12, No. 7, July 2006.

Important non-GI Post-infectious

Complications of Enteric Infections

• Leading cause of paralysis worldwide

• Rare: 1–2 per 100,000 per year

• 1 per 1,058 Campy infections

• 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

Guerry P and Szymanski C, Trends Microbiol 2008;16:428

Campylobacter & Guillain-Barré Syndrome Post-dysenteric Reactive Arthritis

Hannu T. Ann Rheum Dis 2005;64:594-598

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

8

Study

Viral Porter (‘12) Norovirus

Unspecified

Diarrhea Porter (‘10)

Marshall (‘06)

Cumberland (‘03)

ICD-9 code (infect. diarrhea)

Self-reported diarrhea

Medical care for acute GE

Exposure specifics

1 10 20

Jung (‘09)

Parry (‘02)

Porter (‘10)

Rodriguez (‘99)

Porter (‘13)

Wang (‘04)

Marshall (‘06)

Ji (‘05)

Mearin (‘05)

Thabane (‘10)

Bacterial

Shigella

Campylobacter, Salmonella

Campy, Shigella, Salmonella

Bacterial gastroenteritis

Shigella, Salm, Yers, Campy

Shigella

Campylobacter, EHEC

Shigella

Salmonella

Campylobacter, EHEC

Risk Risk

Odds Ratio (95% CI)

Exposure

Okhuysen (‘04) Travelers’

Diarrhea

Ilnyckyi (‘03)

Riddle (‘11)

Porter (‘11)

Stermer (‘06)

Pitzurra (‘11)

Mexico

55 different countries

Middle East Iraq / Afghanistan

Asia, Africa, S America SE Asia, S Asia, E Africa

Zanini (‘12) Norovirus

Consistency of Acute Infectious Gastroenteritis and IBS Association Is Strong

PI-IBS can be a chronic (? life-long) problem

• In US military active duty, visits

persist in 20-30% of cases

• Likely underestimates persistence

of symptoms

• 42% persistence at 8 years

after Campy/STEC infection (Marshall et al.Gut 2010)

• 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)

Years after initial medical encounter

0 1 2 3 4 5 6 7

% w

ith

IB

S v

isit

20

40

60

80

100 All cases

Any IGE

Bacterial IGE

Viral IGE

0

Porter et al. Am J Gastro 2010

Overall

Mearin et al. 2005

Parry et al. 2003

Ford et al. 2010

2.18 (1.70, 2.81)

5.55 (2.62, 11.74)

2.91 (0.48, 17.71)

OR (95% CI)

2.45 (1.74, 3.44)

Porter et al. 2011 1.65 (0.68, 4.02)

Porter et al. 2013 1.51 (1.09, 2.08)

Porter et al. 2011 2.45 (2.15, 2.80)

Porter et al. 2012 1.42 (0.83, 2.43)

1 .1 1 10

Tuteja et al. 2008 3.09 (0.61, 15.72) Trivedi et al. 2011 2.79 (0.34, 23.03)

Self-Report

Record Review

Subtotal 2.83 (2.10, 3.81)

Subtotal 1.81 (1.26, 2.58)

Post-infectious Dyspepsia (? GERD)

Risk Risk

Pike et al. Amer J Gastro. 2013

Evidence for Post-C. difficile FGD Is Also Emerging

Among active duty personnel, C. difficile

infection was independently associated

with gastrointestinal sequelae

“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.”

September 2016

Gutierrez RL, et.al. Gastroenterology 2015;149:1406-14.

Something Is Going on with the Microbiome in PI-IBS

• Invasive organisms and intestinal

barrier mucosal disruption

Putative Pathogen Specific Trigger Mechanisms

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. 2009.

• Enterotoxigenic E. coli

heat-labile toxin-

mediated effects on

barrier disruption via lipid

raft sloughing

• tight junction disruption

• ? “adjuvanted” response

to commensals

Acute Gastrointestinal Infection Can Induce Long-Lived Microbiota-Specific T Cell Responses

• Each infection at barrier

surfaces represents an

additional opportunity for the

reactivation of commensal-

specific 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

Belkaid Y. Trends Immunol. 2013; Hand TW. Science. 2012.

Digestive Disease Sciences, 2014

❶

❷

❸

❹

❺

CdtB

ICCs

❻

Vinculin - human membrane

cystoskeletal protein

CdtB - cytolethal

distending toxin,

B subunit

Immunological Biomarkers of Postinfectious Irritable Bowel Syndrome

• 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

• DoD Serum Repository:

pilot study

• Groups:

– ❶ & ❸ PI-IBS

– ❷ healthy (GI infx)

– ❹ idiopathic-IBS

1 3

4

2

4

3

2

3

1 1

4

Geometric Mean and Std. Deviation by Group; Fold-Changes (FC) <1 are presented as x = -1/FC.

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) 193.56 (18.93) 898.84 (7.35) 4.64 0.0134

CBir8 (IgA) 3.07 (10.80) 9.33 (28.52) 3.04 0.0444

EF20 (IgG) 819.83 (8.19) 2245.54 (6.05) 2.74 0.0291

rIB16 (IgG) 287.15 (8.89) 753.18 (3.62) 2.62 0.0314

P3 (IgG) 268.14 (5.43) 615.91 (2.32) 2.30 0.0156

rIB19 (IgG) 5686.21(2.79) 9149.92 (1.73) 1.61 0.0227

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) 337.65 (5.51) 1251.38 (3.27) 3.71 0.0217 <<

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

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)

• Probiotics: Four meta-analyses have been published, only one

showed a significant pooled effect – Ritchie ML, Romanuk TN. PLoS ONE. 2012

– McFarland LV. Travel Medicine and Infectious Disease. 2007

– Takahashi O et al. J Clin Gastroenterol. 2007

– Sazawal S et al. Lancet Infectious Diseases. 2006.

“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. 2001

– Drakoularakou A et al. Eur J Clin Nutr. 2010

– Virk A et al. Journal of Travel Medicine. 2013

Am J Gastro, April 2016

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.

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

• 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

Acknowledgements/Disclaimers

Photograph courtesy of J. Besser, MN Dept Health

If only our next meal came with a warning…

Questions?