DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Centers for Disease Control and Prevention (CDC)

Atlanta GA 30333

Infectious Causes of Chronic Diseases

Potential Infectious Causes of Crohn's Disease

Recently, scientists have recognized the importance of infectious diseases as causes of chronic diseases. Many of these conditions were long-considered to be caused solely by genetic or environmental factors. The Centers for Disease Control and Prevention recognizes the potential public health impact of these developments, and has designated Infectious Causes of Chronic Diseases as a Target Area within its prevention plan Preventing Emerging Infectious Diseases: A Strategy for the 21st Century. ( http://www.cdc.gov/ncidod/emergplan)

Crohn's disease, one of several Inflammatory Bowel Diseases, causes substantial suffering in affected individuals, and seriously impacts their families and society. Usually Crohn's disease first appears in people between the ages of 20 and 40 years, and it can last a lifetime. Conservative estimates suggest that 400,000-500,000 people in the United States suffer from Crohn's disease. Infectious agents may play a role in this chronic illness. Recent scientific developments in the field underscore a basic need to define potential links between microbes and Crohn's disease.

Many questions regarding the relationship between microbes and Crohn's disease remain unanswered today. Currently, CDC is working to better understand the epidemiology of Crohn's disease in the U.S. and to define the current knowledge of physicians concerning its diagnosis and treatment.

The potential causal role of infectious agents in Inflammatory Bowel Disease and numerous other chronic diseases will only be understood with more intense and collaborative applied research throughout the public health, scientific, and medical communities. Increased understanding and answered questions are certain to create new prevention opportunities that benefit many people.

Potential Infectious Etiologies of Crohn's Disease

Introduction

Infections have recently come to be recognized as important causes of chronic disease. Many of these conditions were long-considered to be "non-communicable". The Centers for Disease Control and Prevention recognizes the potential public health impact of these developments, and has designated Infectious Causes of Chronic Diseases as a Target Area within its plan for Preventing Emerging Infectious Diseases.

Crohn's disease, one of several Inflammatory Bowel Diseases (IBD), imposes substantial suffering and burden upon affected individuals, their families, and society. Usually beginning between the ages of 20 and 40 years, it can last a lifetime. Conservatively, Crohn's disease (CD) afflicts an estimated 400,000-500,000 persons in the United States. Infectious agents may cause some portion of this chronic illness. Recent scientific developments in the field underscore a basic need to define potential links between microbes (e.g., Mycobacterium paratuberculosis and others) and Crohn's disease through application of sound scientific methods and technologies.

Unanswered Questions

(This is not a prioritization or description of necessary studies, but a summary of many related questions.)

In response to the illness and disability caused by this chronic disease, and to evolving scientific data, the Center for Disease Control and Prevention has outlined a number of gaps in the knowledge and understanding of potential causal relationships between infectious agents and Crohn's disease:

1. What are the true incidence and prevalence of Crohn's disease in the U.S. population?

• across geographic regions
• across racial/ethnic groups

2. What are the current knowledge and practices of U.S. physicians surrounding its potential etiologies?

• familiarity with scientific data linking microbes (e.g., M. paratuberculosis) with Crohn's disease
• clinical use of antimicrobial agents, including anti-mycobacterial regimens

3. If one or more microbes are causal in Crohn's disease:

• which infectious agents are responsible --- individually or in synergy?
• is the microbe(s) a trigger for Crohn's disease, or does infection exacerbate established disease, determine its severity, or both?
• who is susceptible to infection-related disease --- due to genetics, other environmental factors?

4. Are current diagnostic technology and study designs sufficient to confirm a causal relationship between microbes (including M. paratuberculosis) and Crohn's disease? i.e., (1) sensitive, specific and standardized assays and culture; (2) applied to well-defined, standardized case definitions and pathologic specimens; (3) with comparable study designs and reproducible results:

• can laboratory tools and epidemiology be improved?
• how can tools be validated for use in determining the attributable fraction of disease?

5. If one or more microbes are causal in Crohn's disease:

• what is the fraction of disease attributable to infection?
• what is the fraction of disease attributable to each implicated agent?
• what determines disease and its severity --- any exposure, repeat exposures, or infectious load?

6. If infection is causal in Crohn's disease:

• can regimens that include antimicrobial agents change the course of disease?
• does outcome differ if antimicrobial (including anti-mycobacterial) treatment is administered early vs. later in the disease course?
• does outcome after antimicrobial therapy differ from that of immune modulating therapies?
• what specific changes in gut microflora occur with antimicrobial therapy vs. regimens that do not include antimicrobial agents (e.g., immune modulating) --- does treatment eradicate or suppress certain microbes, and/or alter inflammation?

7. With respect to M. paratuberculosis, one potential pathogen in Crohn's disease:

• are current laboratory diagnostic assays and culture methods sufficiently sensitive, specific, and standardized to confirm or refute a causal association between M. paratuberculosis (M. para) and Crohn's disease?
• have diagnostic tools been validated sufficiently to determine a M. paratuberculosis attributable fraction of disease?
• are preceding and current experimental and epidemiologic studies sufficiently comparable and reproducible, using standardized case definitions and pathologic specimens, to confirm or refute a causal association between M. para and Crohn's disease?
• what validations have been performed for the diagnosis of human M. para infection --- including translation of ruminant assays to human subjects?
• if validated tests become available, what are the U.S. incidence and prevalence of human M. para infection, and is infection persistent?
  
  
  • across geographic regions
  • in different racial/ethnic or cultural groups
    
    
• is M. para pathologic to humans and, if so, how is it transmitted to immunocompetent and to immunocompromised hosts?
  
  
  • is the organism found in food products?
  • do differences in U.S. and European milk pasteurization processes alter/minimize risk of human M. para infection?
  • if M. para enters ground or surface water, do U.S. water treatment processes minimize risk of human infection?
  • if it is present in soil, can agricultural and urban ecological practices minimize risk of human infection?
    
    

Potential NCID Response

(Intramural and extramural activities are dependent upon new and sustained sources of funding, excepting the first two Short-term Response items.)

To address the public health implications and the individual suffering caused by IBD, specifically Crohn's disease, the CDC/NCID is developing a research agenda designed to define these unresolved issues. These intra- and extramural NCID research activities, coordinated with those of NIH, other federal agencies, and external investigators, would advance our understanding of the potential portion of Crohn's disease due to infection. Implementing this research could notably advance the prevention or treatment of Crohn's disease.

Programs would draw upon the expertise of other agencies and outside researchers, as well as that of CDC. Proposed activities must be flexible and may change as the field evolves. This document represents an internal, working outline of the potential response.

Short-term Response:

• Completed first- of multi-stage Emerging Infections Network Query (with feedback education component) to assess current knowledge of U.S. physicians on the potential role of infection (including M. paratuberculosis) in Crohn's disease (CD), and current use of antimicrobial agents for the treatment of CD
• Completed first- of multi-level analysis in FoodNet database to determine and compare CD prevalence in each regional site and across racial/ethnic lines, with special attention to variations in prevalence that may be tied to specific exposures
• Advise on pilot epidemiologic studies designed to correlate food, environmental and habitation exposures, along with age and duration of exposure, to prevalent CD
• Analyze comprehensive patient data bases (e.g., HMO network database) to determine the true incidence and prevalence of CD on national, regional and racial/ethnic levels
• Developing a transparent network through which CDC may offer technical advice to ongoing epidemiologic and laboratory investigations on potential infection-CD links

Intermediate-range Response:

• Lead development and use of innovative diagnostic assays able to confirm or refute a causal and temporal (infection precedes disease) relationship between specific microbes and Crohn's disease (e.g., microarray host gene expression, microarray microbial gene expression)
• Promote use of validated and standardized assays to define the routes of human infection with proposed agents
• Lead cooperative development and collection of well-defined case definitions and pathology specimens, particularly from incident cases and from sterile sites less likely to harbor nonpathogens or commensals
• Lead cooperative validation and standardization of improved, sensitive and specific diagnostic tests for human M. paratuberculosis infection
• Extend epidemiologic studies (e.g., pilots, FoodNet network or HMO network) to investigation of incident CD and its correlation with exposures, including childhood and local environmental exposures (e.g., regional milk supply, food consumption habits, water treatment processes)
• Advise and provide technical assistance for well-designed clinical studies that assess the effects of antimicrobial/anti-mycobacterial treatment regimens upon Crohn's disease symptoms and tissue pathology (e.g., initial remission, persistent remission, "cure")
• If an association between infectious agents and Crohn's disease is confirmed, lead cooperative studies that define the true fraction of Crohn's disease attributable to one or more microbes, and the population/persons susceptible to infection-induced disease
• Provide technical assistance for research that compares changes in gut microflora or microbial "load" after certain antimicrobial regimens, immunotherapy and anti-inflammatory agents
• Lead appropriate public health prevention/intervention response to validated associations

Long-term Response:

• Assist in prospective evaluation of family members of Crohn's disease patients for asymptomatic infection with implicated agents
• Extend intermediate-range responses to define the distribution of risk for exposure to confirmed causal agents, identifying strategies that minimize these exposures
• Monitor changes in incident and prevalent Crohn's disease through FoodNet or HMO networks --- particularly as measures to prevent or treat infection with implicated agents are implemented
• Define risk co-factors (e.g., genetics, co-infections or other environmental factors) for proven infection-related Crohn's disease through large-scale studies that integrate laboratory and behavioral analyses
• Target appropriate public prevention and intervention strategies towards high-risk populations