|
   
|
Consensus Development Conference Statement January 28-30, 1985
This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/. This statement was originally published as: Travelers' Diarrhea. NIH Consens Statement 1985 Jan 28-30; 5(8):1-19. For making bibliographic reference to the
statement in the electronic form displayed here, it is recommended that
the following format be used: Travelers' Diarrhea. NIH Consens Statement
Online 1985 Jan 28-30 [cited year month day]; 5(8):1-19.
IntroductionDiarrhea is by far the most frequent health problem of travelers to developing countries. Of the estimated 300 million international travelers who will cross the world's frontiers this year, at least 16 million persons from industrialized countries, including more than 8 million U.S. residents, will travel to developing countries. Approximately one-third of these travelers to developing countries will get diarrhea. The economic impact of travelers' diarrhea (TD) is substantial, because fear of sickness is one of the major deterrents to tourism. International tourists worldwide spend over $100 billion annually, and the economies of many nations depend on this travel. For educational, recreational, political, and financial reasons, this international exchange should be fostered. The incidence of TD varies markedly by destination and may depend in part on the number of dietary indiscretions made by the traveler and on the style of travel. TD is caused by a variety of infectious agents, and the spectrum of clinical illness varies considerably. However, this illness in travelers is usually not severe; high fever, vomiting, or bloody stools occur only in a minority of cases. Dietary prudence and hygienic measures are safe and simple preventive techniques, but they do not eliminate entirely the risk of diarrhea. Prophylactic measures such as antidiarrheal drugs and oral antimicrobial agents have been used. TD is treated with a variety of regimens, including oral electrolyte solutions, antidiarrheal compounds, and antimicrobial drugs, prescribed either singly or in combination. There continues to be a debate concerning whether the risk of antimicrobial agents is worth the benefit; whether early therapy of ill travelers is preferable to daily prophylaxis of all travelers; whether all currently employed treatment strategies are useful; and whether given groups of travelers, such as vacationers, students, or business travelers, should be selectively advised to follow special regimens. To resolve some of these questions, the NIH Office of Medical Applications of Research and the National Institute of Allergy and Infectious Diseases convened a Consensus Development Conference on Travelers' Diarrhea on January 28-30, 1985. After 1 1/2 days of expert presentation of the available data, a consensus panel of epidemiologists, biostatisticians, microbiologists, pediatricians, internists, infectious diseases specialists, travel experts, and lay representatives considered the evidence and agreed on answers to the following questions:
What Is the Epidemiology of Travelers' Diarrhea, and Why Is It Important?Travelers' diarrhea is a syndrome characterized by a twofold or greater increase in the frequency of unformed bowel movements. Commonly associated symptoms include abdominal cramps, nausea, bloating, urgency, fever, and malaise. Episodes of TD usually begin abruptly, occur during travel or soon after returning home, and are generally self-limited. Within this context, travelers at risk are defined as individuals from industrialized countries visiting for a period of up to 1 month a region or country where there is an increased risk of developing diarrhea. The public health and medical importance of TD is related to the large numbers of travelers who place themselves at risk each year. Furthermore, TD is but a mild reflection of the severe underlying problem of diarrhea among children in the tropics. The most important determinant of risk is the destination of the traveler. Attack rates in the range of 20 to 50 percent are commonly reported, but recent data are available from relatively few countries. The best available estimates of country-specific attack rates have been reported for Swiss travelers. Examples of high-risk destinations include most of the developing countries of Latin America, Africa, the Middle East, and Asia. Intermediate risk destinations include most of the Southern European countries and a few Caribbean islands. Low risk destinations include Canada, Northern Europe, Australia, New Zealand, the United States, and a number of the Caribbean islands. TD is slightly more common in young adults than in older people. The reasons for this difference are unclear, but may include a lack of acquired immunity, more adventurous travel styles, and different eating habits. Attack rates are similar in men and women. The most common onset of TD is usually within the first week, but onset may occur at any time during the visit, and even after returning home. TD is acquired through ingestion of fecally contaminated food and/or water. Both cooked and uncooked foods may be implicated if improperly handled. Especially risky foods include raw vegetables, raw meat, and raw seafood. Tap water ice, unpasteurized milk and dairy products, and unpeeled fruits are associated with increased risk of TD; bottled carbonated beverages (especially flavored beverages), beer, wine, hot coffee or tea, or water boiled or appropriately treated with iodine or chlorine are safe. The eating place appears to be an important variable, with private homes, restaurants, and street vendors listed in order of increasing risk. TD typically results in four to five loose
or watery stools per day. The median duration of diarrhea is 3 to 4 days.
Ten percent of the cases persist longer than 1 week, approximately 2
percent longer than 1 month, and less than 1 percent longer than 3 months.
Persistent diarrhea is thus quite uncommon and may differ considerably
from acute TD with respect to etiology and risk factors. Travelers may
experience more than one attack of TD during a single trip. Approximately
15 percent experience vomiting, and 2 to 10 percent may have diarrhea
accompanied by fever or bloody stools, or both. Rarely is TD
life-threatening. In an extensive survey of several hundred thousand Swiss
travelers, no deaths could be attributed to TD. What Causes Travelers' Diarrhea?Infectious agents are the primary cause of TD. This statement is based on investigations designed to isolate known infectious organisms from diarrheal stools of tourists and on studies that demonstrated the efficacy of antibacterial agents. In addition, induced disease in volunteers has confirmed the causal role of the putative bacterial and viral agents in producing TD. All travelers from industrialized countries going to developing countries quickly develop a rapid, dramatic change in their intestinal flora. These new organisms often include the potential enteric pathogens. Those who develop diarrhea have ingested an inoculum of virulent organisms sufficiently large to overcome individual defense mechanisms, resulting in symptoms. Enteric Bacterial PathogensEnterotoxigenic Escherichia coli (ETEC) are the most common causative agents of TD in all countries where surveys have been conducted. The discovery and understanding of the mechanisms of action of cholera enterotoxin led to investigations that demonstrated enterotoxins in E. coli and other bacteria. These organisms adhere in the small intestine, where they multiply and produce an enterotoxin (either heat stable or heat labile) that causes fluid secretion and diarrhea. Identification of the ETEC is a difficult task, requiring sophisticated techniques that remain somewhat insensitive. Other E. coli have different virulence traits. These have been termed enteroadherent, enteroinvasive, and enteropathogenic E. coli. No systematic search for these other E. coli has been conducted in patients with TD. Limited data suggest that they are a minor cause of TD. Salmonella gastroenteritis is a well-known disease that occurs throughout the world. In the industrialized nations, this large group of organisms is the most common cause of outbreaks of food-associated diarrhea. In the developing countries, the proportion of cases of TD caused by salmonellae varies but is not high. Salmonellae also can cause dysentery characterized by bloody mucus-containing small-volume stools. Shigellae are well known as the cause of bacillary dysentery. They cause TD in about 5 to 15 percent of travelers in a few countries. Few of the infected travelers had dysentery, but most had watery diarrhea. Campylobacter jejuni is a common cause of diarrhea throughout the world. Recent, limited data have shown that C. jejuni is responsible for a small percentage of the reported cases of TD, some with bloody diarrhea. Additional studies are needed to determine how frequently it causes TD. Vibrio parahaemolyticus is associated with the ingestion of raw or poorly cooked seafood and has caused TD in Japanese people traveling in Asia. How frequently it causes disease in other areas of the world is unknown. Other potential bacterial pathogens, including Aeromonas hydrophila, Yersinia enterocolitica, Pleisiomonas shigelloides, Vibrio cholerae (non-01), and Vibrio fluvialis, are known to cause diarrhea in children and adults. In Thailand, Aeromonas and Pleisiomonas have been isolated from stools of Peace Corps volunteers who had TD. A better appreciation of the importance of each of these bacteria as causative agents of TD requires a more intensive search for them, using appropriate selective isolation media or rapid diagnostic techniques. Viral Enteric Pathogens--Rotavirus and Norwalk-Like VirusAlong with the newly acquired bacterial flora, many viruses also are acquired. In six studies, for example, 0 to 36 percent of diarrheal illnesses (median 22 percent) were associated with rotaviruses in the stools. However, a comparable number of asymptomatic travelers also had rotaviruses, and up to 50 percent of symptomatic rotavirus infections were associated with nonviral pathogens. Ten to 15 percent of travelers develop a serologic conversion to Norwalk-like viruses. The roles of adenoviruses, astroviruses, coronaviruses, enteroviruses, or other viral agents in causing TD are even less clear. Although viruses are commonly acquired by travelers, they do not appear to be frequent causes of TD in adults. Parasitic Enteric PathogensThe few studies that have included an examination for parasites reveal that 0 to 9 percent have Giardia lamblia or Entamoeba histolytica. Cryptosporidium has recently been recognized in sporadic cases of TD. Dientamoeba fragilis, Isospora belli, Balantidium coli, or Strongyloides stercoralis may cause occasional cases of TD. While not major causes of acute TD, these parasites should be sought in persisting, unexplained cases. Unknown CausesNo data have been presented to support noninfectious causes of TD such as changes in diet, jet lag, altitude, and fatigue. Current evidence indicates that in all but a few instances (e.g., drug-induced or preexisting gastrointestinal disorders) an infectious agent or agents cause diarrhea in tourists. Even with the application of the best current methods for detecting bacteria, viruses, and parasites, in various studies 20 to 50 percent remain without recognized etiologies. The unrecognized causes may be attributed to:
What Prevention Measures Are Effective for Travelers' Diarrhea?There are four possible approaches to prevention of TD. They include instruction regarding food and beverage preparation, immunization, use of nonantimicrobial medications, and prophylactic antimicrobial drugs. Data indicate that meticulous attention to food and beverage preparation, as mentioned above, can decrease the likelihood of developing TD. Most travelers, however, encounter great difficulty in observing the requisite dietary restrictions. No available vaccines and none that are expected to be available in the next 5 years are effective against TD. Several nonantimicrobial agents have been advocated for prevention of TD. Available controlled studies indicate that prophylactic use of difenoxine, the active metabolite of diphenoxylate (Lomotil), actually increases the incidence of TD, in addition to producing other undesirable side effects. No antiperistaltic agents (e.g., Lomotil and Imodium) are effective in preventing TD. No data support the prophylactic use of activated charcoal. Bismuth subsalicylate, taken in liquid form as the active ingredient of Pepto-Bismol (2 oz four times daily), has decreased the incidence of diarrhea by 60 percent in one study. Available data are not extensive enough to exclude a risk to the traveler from the use of such large doses of bismuth subsalicylate over a period of several weeks. In patients already taking salicylates for arthritis, large concurrent doses of bismuth subsalicylate can produce toxic serum concentrations of salicylate. On the basis of its modest potential benefit achieved with large doses, together with its uncertain risks, bismuth subsalicylate is not recommended for prophylaxis of TD. Controlled data are available on the prophylactic value of several antimicrobial drugs. Entero-vioform and related halogenated hydroxyquinoline derivatives (e.g., clioquinol, iodoquinol, Mexaform, Intestopan, and others) are not helpful in preventing TD, may have serious neurological side effects, and should never be used for prophylaxis of TD. Carefully controlled studies have indicated that two agents, doxycycline and trimethoprim/sulfamethoxazole (TMP/SMX), when taken prophylactically, are consistently effective in reducing the incidence of TD by 50 to 86 percent in various areas of the developing world. One study shows that trimethoprim alone is also effective. The benefits of widespread prophylactic use of doxycycline or TMP/SMX or TMP alone in several million travelers must be weighed against the potential drawbacks. The known risks include allergic and other side effects (such as common skin rashes, photosensitivity of the skin, blood disorders, Stevens-Johnson syndrome, and staining of the teeth in children) as well as other infections that may be induced by antimicrobial therapy (such as antibiotic-associated colitis, Candida vaginitis, and possibly salmonella enteritis). Because of the uncertain risk of widespread administration of these antimicrobial agents, their prophylactic use is not recommended. Nor is there any basis for recommending their use prophylactically for special groups of travelers. For example, the physician should not recommend an agent for prophylactic use by a business traveler and deny such use by a honeymoon couple. Furthermore, there is no documented evidence that there are any groups of disease entities that are worsened sufficiently by an episode of TD to risk the rare undesirable side effects of prophylactic antimicrobial drugs. The selective pressure of prophylactic use of antimicrobial agents on the genetic pool of antimicrobial resistance is of concern, but may be insignificant in light of the widespread use of over-the-counter antimicrobial agents in many developing countries. The increasing frequency of resistance to multiple antimicrobial agents (including both doxycycline and TMP/SMX) will limit the effectiveness of these agents in many areas. Available data support only the instruction
of travelers in regard to sensible dietary practices as a prophylactic
measure. On the basis of apparent risk/benefit ratios, prophylactic
antimicrobial agents are not recommended for travelers. This
recommendation is justified by the excellent results of early treatment of
TD as outlined below. By avoiding prophylactic antimicrobial agents, only
those people traveling to high-risk areas who develop moderate to severe
TD (less than 30 percent of travelers at risk) will be exposed to the side
effects of antimicrobial agents, and the exposure will be restricted to 3
days or fewer in those individuals. Some travelers may wish to consult
with their physician and may elect to use prophylactic antimicrobial
agents for travel under special circumstances, once the risks and benefits
are clearly understood. What Treatment Measures Are Effective for Travelers' Diarrhea?The individuals with TD have two major complaints for which they desire relief--abdominal cramps and diarrhea. Many agents have been proposed to control these symptoms, but few have been demonstrated to be effective by rigorous clinical trials. Nonspecific AgentsA variety of "adsorbents" have been used in the treatment of diarrhea. For example, activated charcoal has been found ineffective in the treatment of diarrhea. Kaolin and pectin have been widely used for diarrhea. The combination appears to give the stools more consistency but has not been shown to decrease cramps and frequency of stools nor to shorten the course of infectious diarrhea. Lactobacillus preparations and yogurt have also been advocated, but no evidence supports these treatments for TD. Bismuth subsalicylate preparation (1 oz every 30 minutes for eight doses) decreased the rate of stooling by one-half in a study of travelers with diarrhea when compared with a placebo group. However, there was no difference between the two groups in stool output in the first four hours of the study. There is concern about taking, without supervision, large amounts of bismuth and salicylate, especially in individuals who may be intolerant to salicylates, who have renal insufficiency, or who take salicylates for other reasons. Antimotility AgentsAntimotility agents are widely used in the treatment of diarrhea of all types. Natural opiates (paregoric, deodorized tincture of opium, and codeine) have long been used to control diarrhea and cramps. Synthetic agents, diphenoxylate and loperamide, come in convenient dosage forms and provide prompt symptomatic but temporary relief. However, they should not be used in patients with high fever or with blood in the stool. These drugs should be discontinued if symptoms persist beyond 48 hours. Diphenoxylate and loperamide should not be used in children under the age of 2. Oral FluidsMost individuals with TD do not develop serious dehydration. Fluid and electrolyte balance can be maintained by potable fruit juices, caffeine-free soft drinks, and salted crackers. The individual with TD should avoid alcohol and caffeine-containing beverages. Dairy products aggravate diarrhea in some people and should be avoided. Individuals with severe dehydration may require special fluid and electrolyte replacement in the form of oral replacement solutions such as those recommended by the World Health Organization. Antimicrobial TreatmentTravelers who develop diarrhea with three or more loose stools in an 8-hour period, especially if associated with nausea, vomiting, abdominal cramps, fever, or blood in the stools, may benefit from antimicrobial treatment. A typical 3- to 5-day illness can be shortened to 1 to 1 1/2 days by effective antimicrobial agents. Those best studied to date are TMP/SMX, 160 mg TMP and 800 mg SMX, or TMP alone, 200 mg taken twice daily. Preliminary evidence suggests that doxycycline taken 100 mg twice daily is also effective. Three days of treatment is recommended, although 2 days or fewer may be sufficient. Nausea and vomiting without diarrhea should not be treated with antimicrobial drugs. Precautions in Children and Pregnant WomenAlthough children do not make up a large proportion of travelers to high-risk areas, some children do accompany their families. Teenagers should follow the advice given to adults, with possible adjustment of doses of medication. Physicians should be aware of the risks of tetracyclines to children under 12 years. There is a paucity of data available about usage of antidiarrheal drugs in children. Drugs should be prescribed with caution for pregnant women and nursing mothers. Summary Recommendation for TreatmentTD is usually a mild, self-limited disorder, with complete recovery even in the absence of therapy; hence, therapy should be considered optional.
In conclusion, travelers to areas of high
risk should obtain an antimotility drug or bismuth subsalicylate for
milder forms of TD, and an antimicrobial agent (TMP/SMX or TMP alone or
doxycycline) for more severe TD. Advice concerning side effects of these
drugs and various aspects of hygiene and dietary precautions should be
obtained. By obtaining the proper drugs in advance, the beleaguered
traveler might avoid buying over-the-counter drugs abroad with potentially
dangerous ingredients. What Should Be the Direction of Future Research?Although much has been learned about TD over the past 25 years, there is considerable need for additional research on this important syndrome. Epidemiology
Etiology
Prevention and Treatment
Summary and ConclusionsDiarrhea is the major health problem in travelers to developing countries. Travel to high-risk areas in Latin America, Africa, the Middle East, and Asia is associated with diarrhea rates of 20 to 50 percent. The syndrome is caused by an infection acquired by ingesting fecally contaminated food or beverages. Escherichia coli, a common species of enteric bacteria, is the leading pathogen, although a host of other bacteria, viruses, and protozoa have been implicated in some cases. Prudent dietary and hygienic practices should be followed, and they will prevent some, but not all, diarrhea. Antimicrobial agents are not recommended for prevention of TD. Such widespread usage in millions of travelers would cause many side effects, including some severe ones, while preventing a disease that has had no reported mortality. Instead of universal antimicrobial prophylaxis, a more sensible approach is rapid institution of effective treatment that can shorten the disease to 30 hours or less in most people. For mild diarrhea, an antimotility drug such as diphenoxylate or loperamide could be taken. Alternatively, bismuth subsalicylate, which works somewhat slower, can be used. For more severe diarrhea, an antimicrobial drug may be used for treatment, and trimethoprim/sulfamethoxazole, trimethoprim alone, and doxycycline are among the choices. These drugs could be carried by the traveler for use in the event of illness. Oral rehydration should be instituted when necessary. The millions of Americans who travel
annually to developing countries and their physicians must be warned of
the potential risks of prophylactic antimicrobial drugs, with the
attendant side effects in otherwise healthy individuals, and should be
informed of the alternative method of prompt, effective treatment for
diarrhea. Consensus Development Panel
Professor of Medicine and Microbiology Tufts University School of Medicine Chief, Infectious Diseases Division New England Medical Center Boston, Massachusetts
Professor and Chairman Department of Medicine Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio
Clinical Professor of Pediatrics University of Miami School of Medicine Miami, Florida
Professor of Pediatrics Chief, Pediatric Gastroenterology Yale University School of Medicine New Haven, Connecticut
Professor of Medicine Head, Division of Geographic Medicine University of Virginia School of Medicine Charlottesville, Virginia
Paulson Professor of Gastroenterology Department of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland
Chairman Department of Medicine University of Rochester School of Medicine and Dentistry Rochester, New York
Assistant Medical Director Exxon Corporation New York, New York
Travel Editor Boston Globe Boston, Massachusetts
Associate Professor of Epidemiology and Medicine Department of Epidemiology Johns Hopkins School of Hygiene and Public Health Baltimore, Maryland
President Child & Waters, Inc. New York, New York
Chairman Department of Biostatistics and Epidemiology Cleveland Clinic Foundation Cleveland, Ohio
Director Traveler's Medical Service of Washington Washington, D.C. Speakers
"Treatment of Travelers' Diarrhea: Fluid and Diet" Professor of Medicine Director, Division of Gastroenterology Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio
"Pathogens That Cause Travelers' Diarrhea in Latin America and Africa" Chief, Epidemiology Section Center for Vaccine Development Division of Geographic Medicine University of Maryland School of Medicine Medical School Teaching Facility Baltimore, Maryland
"Environmental Interventions to Prevent Travelers' Diarrhea" Chief, Infectious Disease Section Veterans Administration Medical Center Assistant Professor of Medicine University of Colorado School of Medicine Denver, Colorado
"The Epidemiology of Travelers' Diarrhea: An Overview" Acting Assistant Director for Medical Service Division of Bacterial Diseases Center for Infectious Diseases Centers for Disease Control Atlanta, Georgia
"Antisecretory (Nonantimicrobial) Therapy of Diarrhea in General" Professor of Medicine Gastrointestinal Unit New England Medical Center Boston, Massachusetts
"Studies of Antimicrobial Agents in the Prevention of Travelers' Diarrhea" "Antimicrobial Therapy of Travelers' Diarrhea" Professor and Director Program in Infectious Diseases and Clinical Microbiology University of Texas Medical School Houston, Texas
"Symptomatic (Nonantimicrobial) Therapy of Travelers' Diarrhea" Associate Professor of Medicine Program in Infectious Diseases and Clinical Microbiology University of Texas at Houston Medical School Houston, Texas
"Workup and Treatment of Protracted Diarrhea in the Traveler" Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati Cincinnati, Ohio
"Overview" Clinical Professor (Emeritus) of Tropical Medicine and Public Health Cornell University Medical College New York, New York
"Antimicrobial Therapy of Infectious Diarrhea in General" Director Center for Vaccine Development Professor of Medicine and Pediatrics University of Maryland School of Medicine Division of Geographic Medicine Baltimore, Maryland
"Antimicrobial-Resistant Patterns of Enteric Pathogens" Assistant Professor of Medicine Department of Medicine and Program in Infectious Diseases and Clinical Microbiology University of Texas at Houston Medical School Houston, Texas
"Antimicrobial Prophylaxis of Travelers' Diarrhea: An Overview" Chief, Division of Geographic Medicine Johns Hopkins University School of Medicine Baltimore, Maryland
"Epidemiological Studies" "Prevention of Travelers' Diarrhea by Nonantibiotic Drugs" Head, Vaccination Cancer Institute for Social and Preventive Medicine University of Zurich SWITZERLAND
"The Etiology of Travelers' Diarrhea in Asia" Department of Bacteriology Armed Forces Medical Research Institute of Infectious Diseases APO San Francisco, California Planning Committee
Chief, Clinical and Epidemiological Studies Branch Deputy Director, Microbiology and Infectious Diseases Program National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland
Director of Communications Office of Medical Applications of Research Office of the Director National Institutes of Health Bethesda, Maryland
Professor and Director Program in Infectious Diseases and Clinical Microbiology University of Texas Medical School Houston, Texas
OMAR Coordinator Program Analyst Office of Medical Applications of Research Office of the Director National Institutes of Health Bethesda, Maryland
Professor of Medicine and Microbiology Tufts University School of Medicine Chief, Infectious Diseases Division New England Medical Center Boston, Massachusetts
Medical Officer Clinical and Epidemiological Studies Branch Microbiology and Infectious Diseases Program National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland
Professor and Director Center for Vaccine Development Division of Geographic Medicine University of Maryland School of Medicine Baltimore, Maryland
Public Affairs Specialist Office of Research Reporting and Public Response National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland
Chief Office of Program Planning and Evaluation National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland
Medical Epidemiologist Centers for Disease Control Atlanta, Georgia Conference Sponsors
Itzhak Jacoby, Ph.D. Acting Director
Anthony S. Fauci, M.D. Director Supplemental Information for NIH Consensus Statement on Travelers' DiarrheaSince the NIH Consensus Statement on Travelers' Diarrhea was issued, additional information has become available that supplements the original statement. In addition to the previously recommended treatment (TMP/SMX), any one of the flouro-quinolone antibiotics (such as ciprofloxacin or norfloxacin) is recommended. The regular dose, which is different for each drug, should be prescribed. For severe diarrhea, 3 days of therapy is recommended, while 2, or even 1, day of therapy may be sufficient for less severe cases. The following two articles also provide additional information to the original consensus statement.
|
|
Contact
Consensus Program
|
Privacy Notice
| Disclaimer
| Accessibility
| Contact NIH |
