# Presentation: 218267

## Infectious Etiologies of Chronic Diseases:  

**Infectious Etiologies of Chronic Diseases:  **
**A Spectrum of Proof, Opportunities & Challenges**

**April 9, 2002**

## Sudden insult leaves permanent deficits (e.g., Polio)
Outcome of infection predisposes to chronic sequelae                                                   (e.g., lung disease after pre-term birth)
Microbe causes chronic illness and disability through progressive pathology

- Outcome of infection predisposes to chronic sequelae                                                   (e.g., lung disease after pre-term birth)
**Microbe causes chronic illness and disability through progressive pathology**

**Infectious Etiologies of Chronic Diseases**

**DEFINITION**

## Infectious Etiologies of Chronic Diseases

- 1958*	**	**Schistosoma* spp.	Bladder cancer
- 1964		Epstein-Barr virus	Burkitt’s lymphoma
- 1975		Hepatitis B virus	Hepatocellular carcinoma
- 1984*	**	**Helicobacter pylori*	Duodenal & gastric ulcers
- 1987		Human papillomavirus 	Cervical cancer
- 1989		Hepatitis C virus	Chronic liver disease
- 1989			Hepatocellular carcinoma
- 1990			Mixed cryoglobulinemia
- 1991		KSHV/ human herpesvirus 8 	Kaposi sarcoma
- 1992		*Tropheryma whippelii**	*Whipple’s disease

**EXAMPLE CAUSAL ASSOCIATIONS**

## Syndromes & Organ systems

**Infectious Etiologies of Chronic Diseases**

**Syndromes & Organ systems**

## Syndromes & Organ systems
Pathogens			bacteria
						parasites
						prions
						viruses

**Infectious Etiologies of Chronic Diseases**

**Syndromes & Organ systems**
**Pathogens****	****	****	****bacteria**
**	****	****	****	****	****	****parasites**
**	****	****	****	****	****	****prions**
**	****	****	****	****	****	****viruses**

## Syndromes & Organ systems
Pathogens				bacteria
							parasites
							prions
							viruses
Triggers & outcomes		1 microbe   >1 syndrome
						>1 microbe     1 outcome

**Infectious Etiologies of Chronic Diseases**

**Syndromes & Organ systems**
**Pathogens****	****	****	****	****bacteria**
**	****	****	****	****	****	****	****parasites**
**	****	****	****	****	****	****	****prions**
**	****	****	****	****	****	****	****viruses**
**Triggers & outcomes****	****	****1 microbe ********  >1 syndrome**
**	****	****	****	****	****	****>1 microbe ********    1 outcome**

## Infectious Etiologies of Chronic Diseases

**SPECTRUM OF TIMING**

## Infectious Etiologies of Chronic Diseases

**SPECTRUM OF TIMING**

## Infectious Etiologies of Chronic Diseases

**SPECTRUM OF TIMING**

## Infectious Etiologies of Chronic Diseases

**SPECTRUM OF TIMING**

## Proven causality
Strong evidence
Speculation 

**Infectious Etiologies of Chronic Diseases**

**Proven causality**
**Strong evidence**
**Speculation **

## Infectious Etiologies of Chronic Diseases

*“**Classics”*
- 	Polio		Polio virus
- 	Trachoma		*Chlamydia trachomatis*
- 	Chagas cardiomyopathy		*Trypanosoma cruzi*
*Chronic Infection or Disease Process*
- 	Cervical cancer		Human papillomavirus
- 	CLD, Liver cancer		Hepatitis B and C viruses
- 	Lyme arthritis		*Borrelia burgdorferi*
*	*Peptic ulcer disease		*Helicobacter pylori*
- 	Whipple’s disease		*Tropheryma whippelii*
- 	Bladder cancer		*Schistosoma haematobium*

**Examples:  WELL-RECOGNIZED ASSOCIATIONS**

## Infectious Etiologies of Chronic Diseases

*Sequelae of Acute Event or Intra-partum Infection*
- 	Hearing loss	Cytomegalovirus (CMV)
*Chronic Infection or Disease Process*
- 	Cryoglobulinemia	Hepatitis C virus
- 	Gastric cancer	*Helicobacter pylori*
- 	Neuroborreliosis	*Borrelia burgdorferi*
*	*Reactive arthritis	Enteric bacteria,                                    	*Chlamydia trachomatis*
- 	Uveitis, Retinitis	*Borrelia burgdorferi* *	**	**Toxoplasma gondii*
*	** *Vasculitis 	HBV, HCV

**Examples:  ESTABLISHED or STRONG ASSOCIATIONS**

## Infectious Etiologies of Chronic Diseases

*Sequelae of Acute Event or Intra-partum Infection*
- 	Atherothrombosis	*Chlamydia pneumoniae*, CMV
*	*Pre-term birth sequelae	*Ureaplasma urealyticum*
*	*(neurologic, pulmonary)
*Chronic Infection or Disease Process*
- 	Atherosclerosis	*Chlamydia pneumoniae*
- 	Diabetes mellitus	Enteroviruses/Coxsackie B virus
- 	Inflammatory bowel	*Mycobacterium avium* subspp.   disease	*paratuberculosis*, *Yersinia,*	 *	**	*luminal bacteria
- 	Obsessive-compulsive 	Group A *Streptococcus              *disorders (PANDAS)
*	*Lupus	Epstein-Barr virus/Viruses**	**

**Examples:  POTENTIAL to SPECULATIVE ASSOCIATIONS**

## Infectious Etiologies of Chronic Diseases

- Analytic Tool
- Tissue (ulcer) – histology
- Human challenge
- Culture
- PCR – strain identification
- Virulence factors – Ab, PCR
- Treatment trials
- Urea breath test
- Serology, stool antigen detection
- Animal models

- Strength Of Association
- +   +  +   +
- +   +   +   +
- +   +   +
- +   +   +   +
- +   +
- +   +   +   +
- +   +   +  (+)
- +   +   +
- +   +

*Helicobacter pylori *in Peptic Ulcer Disease

***CAUSAL***

## Infectious Etiologies of Chronic Diseases

- Analytic Tool
- Epidemiology and time-space
- Serology – HBsAg      	     	      (HBeAg, anti-HBc)
- Serum viral assays
- Tissue – PCR, IHC
- Vaccine & other prevention
- Treatment trials
- Animal model

- Strength Of Association
- +   +   +
- +   +   +   +
- +   +  (+)
- +   +   +   +
- +   +   +   +
- +   +   +
- +   +   +

- Hepatitis B virus in CLD, Liver Cancer

***CAUSAL***

## Infectious Etiologies of Chronic Diseases

- Analytic Tool
- Serology
- PCR on PBMC
- Tissue (atheroma) – IHC, ICC
- Tissue (atheroma) – PCR
- Culture
- Animal models
- Treatment trials

- Strength Of Association
- +   +
- +
- +   +  (+)
- +   +  (+)
- +
- +   +
- +

*Chlamydia pneumoniae* in Atherosclerotic CVD

***CAUSALITY   ***_***NOT***_***   PROVEN***

## Infectious Etiologies of Chronic Diseases

## Infectious Etiologies of Chronic Diseases

**PREVENTION OPPORTUNITY**

**90 million with Chronic Illness and Disability**
**In the U.S.**

## Infectious Etiologies of Chronic Diseases

**PREVENTION OPPORTUNITY**

**90 million with Chronic Illness and Disability**

**suppose**
**10%**
**attributable to   Infectious Diseases**

## Infectious Etiologies of Chronic Diseases

**PREVENTION OPPORTUNITY**

**90 million with Chronic Illness and Disability**

**suppose**
**10%**
**attributable to   Infectious Diseases**

**Impact 9 million people in U.S.**

## Infectious Etiologies of Chronic Diseases

**Infectious Etiologies of Chronic Diseases**

## Infectious Etiologies of Chronic Diseases

**POTENTIAL FOR PREVENTION**

**Peptic Ulcer Disease**

## Infectious Etiologies of Chronic Diseases

**POTENTIAL FOR PREVENTION**

**Peptic Ulcer Disease**

## Infectious Etiologies of Chronic Diseases

**POTENTIAL FOR PREVENTION**

**Peptic Ulcer Disease**

## Infectious Etiologies of Chronic Diseases

**FUTURE OPPORTUNITIES?**

## Infectious Etiologies of Chronic Diseases

**FUTURE OPPORTUNITIES?**

## Infectious Etiologies of Chronic Diseases

**Recognize associations early**
**Detect causal agents **
**Identify populations at risk for**
- Infection
- Chronic outcome
**Determine pathogen-specific attributable fraction**
**Assess long-term impact**
- Disability prevalence
- Microbe eradication, antimicrobial resistance** **

**HURDLES AND CHALLENGES**

## Ubiquitous agents
“New” and “old” microbes – new sites
Multiple agents – ONE outcome
ONE microbe – multiple outcomes
Multifactorial disease

**“****New” and “old” microbes – new sites**
**Multiple agents – ONE outcome**
**ONE microbe – multiple outcomes**
**Multifactorial disease**

**TECHNICAL CHALLENGES**

**Infectious Etiologies of Chronic Diseases**

## Exposure-disease interval                       (agent may have cleared)
Technology
Culture methods (improved)
Sensitive and specific detection tools
Validated assays
Distinguishing active, latent & past infection

**Technology**
- Culture methods (improved)
- Sensitive and specific detection tools
- Validated assays
- Distinguishing active, latent & past infection

**Infectious Etiologies of Chronic Diseases**

**MORE TECHNICAL CHALLENGES**

## Infectious Etiologies of Chronic Diseases

**Heterogeneity of U.S. population**
- Geographic diversity
- Racial/ethnic diversity
**Migration**
**Changing epidemiology**
**Diverse environmental exposures**

**EVALUATION CHALLENGES IN THE U.S.****  **

**	****	**

## Infectious Etiologies of Chronic Diseases

**Uniform case definitions**
**Networks of populations and laboratories**
**Prospective collection and storage**
- Appropriate specimens & appropriate collection
**Careful interpretation of data                                    **
- 		• 	Molecular detection **** causality
- 		• 	Common exposures  high prevalence in all
- 		• 	IgG serology = a past exposure

**PROGRESS REQUIREMENTS**

## Infectious Etiologies of Chronic Diseases

**Standardized, reproducible diagnostic tools**
**Specific and sensitive assays, validated in tissues under study**
**Validation against “gold standard”**
**Assays that differentiate between past and current infection**
**High throughput assays?**

**LABORATORY PROGRESS REQUIREMENTS**

## Infectious Etiologies of Chronic Diseases

**Infectious Etiologies of Chronic Diseases**

## Infectious Etiologies of Chronic Diseases

**PREVENTION OPPORTUNITY**

- Potential among 90 million with Chronic Diseases?

**INFECTIOUS DISEASE**

**PREVENTION**
**Evidence**
**Diagnostic tools****	**
**Exposure**
**Antimicrobial therapy**
**Vaccines**