Baseline stool specimens were obtained for 485 of 604 subjects (80.3%), and stool specimens were obtained during 40 of the 50 persistent diarrhea episodes (80.0%). For baseline specimens, the median time from collection of the specimen to receipt by the laboratory was 2.0 days (25th, 75th percentiles: 1.0, 3.0). For the persistent diarrhea specimens, the median time from the onset of diarrhea to collection of specimen was 2.0 days (25th, 75th percentiles: 0, 5.0) and the median time from collection of specimen to receipt by the laboratory was 1.5 days (25th, 75th percentiles: 1.0, 2.0).
Astrovirus, C. difficile, atypical EPEC, EAEC, norovirus, rotavirus and sapovirus were each detected in at least one persistent diarrhea stool sample. A comparison between the prevalence of each of the microorganisms assayed for in the baseline and diarrhea stool specimens is shown in Table 3. Of the 39 persistent diarrhea episodes for which sufficient stool was available for all microbiologic assays, 23 (59.0%) were negative for all studied pathogens. For the 3 studied pathogens that were associated with PD (norovirus, rotavirus and sapovirus), we calculated the proportion of all the infections identified in the study that lasted 14 days are longer, that is, progressed to PD. For norovirus, 4 of 8 cases became persistent (50.0%); for rotavirus, 4 of 23 cases (17.4%) and for sapovirus, 2 of 13 cases (15.4%).
To determine whether PD cases associated with a viral pathogen (n = 9) differed from nonviral cases (cases with all assays negative or positive for EAEC, atypical EPEC or C. difficile; n = 31), we compared characteristics of the two and found no statistically significant differences in terms of duration of diarrhea, presence of fever, vomiting, abdominal pain, blood in the stool, use of antibiotics in 10 days before onset of diarrhea, proportion with a household contact with diarrhea or proportion of cases resulting in an outpatient medical visit (data not shown). Viral episodes were more likely than nonviral episodes to involve loss of appetite (100.0% vs 72.0%; P = 0.04) and mucus in the stool (55.6% vs 30.0%; P = 0.02).
This study suggests that PD is experienced by approximately 1 in 5 young US children over the course of a year. It seems, however, that PD in the United States is a much more benign illness than it is in the developing world. In a wide variety of developing countries, studies have demonstrated that PD in young children is associated with considerable morbidity and mortality and accounts for approximately half of diarrhea-related deaths (3). There is also an important interplay between PD and malnutrition in the developing world-malnourished children are more likely to experience persistence of diarrhea episodes and PD can cause or exacerbate malnutrition (8). In contrast, PD episodes in our US cohort were quite benign. Only 1 episode in 4 resulted in an outpatient medical visit, and none led to hospitalization. Almost half of the episodes ended between days 14 and 21; although these episodes fit the formal definition of PD, many of them likely represent the tail end of the distribution of normal acute diarrhea in young children and probably have limited health significance. Such prolonged illnesses may, however, have significant social and economic impact on families in terms of lost days of day care, school and work.
Although all of the PD episodes ascertained in our study were followed to resolution and none led to a diagnosis of serious gastrointestinal disease during the study period, we do not have follow-up beyond our 6-month observation to know if any of our subjects subsequently experienced recurrent bouts of PD or manifested serious gastrointestinal disorders. It is likely that an infant or young child presenting with recurrent bouts of PD would undergo a diagnostic evaluation for conditions such as food allergies or intolerances, celiac disease and cystic fibrosis (9); further research to define the risk of serious gastrointestinal disease in a child presenting with PD would be useful.
We extensively assayed stool specimens from the PD episodes for a wide variety of potential bacterial, parasitic and viral pathogens. When compared with the prevalence of various microorganisms in baseline stool specimens, only rotavirus, norovirus and sapovirus were significantly associated with PD. These findings are in contrast to data from the developing world where viral pathogens have generally not been associated with PD in immunocompetent children (10,11); however, older studies may have lacked sensitivity to detect viral infections (12), and more recent studies from Brazil and Bangladesh suggest that rotavirus may be responsible for at least a small proportion of PD in those countries (8,13). An important remaining research question is what factors (eg, infectious load, host immune factors, micronutrient deficiencies etc) may cause some children to develop prolonged diarrhea when infected with viruses, such as rotavirus and the caliciviruses, which are usually associated with acute diarrhea (13,14).
C. difficile, enteroaggregative E. coli and atypical enteropathogenic E. coli were also each encountered in at least one PD stool specimen; but each was found with roughly the same frequency in baseline specimens and PD specimens. This finding suggests that, although these bacteria are often present in the stools of young children, they are probably not associated with PD in this population.
We detected no Aeromonas sp., C. perfringens, C. parvum, enteric adenovirus, enterohemorrhagic E. coli, enterotoxigenic E. coli, G. lamblia, Salmonella sp., Shigella sp., typical enteropathogenic E. coli, Y. enterocolitica or Vibrio sp. in any of our PD stool specimens. It is probably most surprising that we did not identify any cases of giardiasis or cryptosporidiosis in our study, as surveillance data suggest that these conditions occur with a fairly high frequency in young US children and both pathogens are known to cause prolonged diarrhea in some cases (15-17). However, with our sample size of 40 PD specimens assayed, the upper 95% confidence limit for the prevalence of each of the pathogens that we did not detect in any specimens is approximately 7.5% (18).
Despite testing for a wide variety of potential pathogens, we found none in 59.0% of the fully assayed PD specimens. If we exclude specimens where only C. difficile, enteroaggregative E. coli, or atypical enteropathogenic E. coli were found, which our data suggest are not related to PD in this population, 76.9% of the specimens were negative for a likely pathogen. This raises the question of what caused the PD in the assay-negative episodes. Some may be due to pathogens other than those for which we assayed. Another possibility is that they were due to noninfectious causes such as dietary disturbances, food allergies/intolerances or nutritional deficiencies. At least some of the episodes we identified might fall into the category of chronic nonspecific diarrhea of childhood (CNDC), also known as "toddler's diarrhea" or "irritable colon of infancy" (19,20). CNDC is a condition in which persistent diarrhea occurs without impairment of weight gain or growth and without evidence of gastrointestinal infection or other defined disorder, which would be consistent with the benign nature of the episodes found in our study. CNDC is thought to be due to disturbances in diet including an excessively low-fat, high-carbohydrate diet or excessive fluid intake overwhelming the absorptive capacities of the intestinal tract (21-23). Inasmuch as there is no specific diagnostic test for it, CNDC remains a diagnosis of exclusion and our data do not allow us to determine what proportion of our cases may have been due to CNDC.
Although this study provides new data on the occurrence of PD in infants and young children in the US and suggests that it is generally a much more benign disease than its counterpart in the developing world, many important questions about this entity remain. Larger and longer-duration studies will be needed to further define the microbiology of PD (especially in terms of pathogens that occur with low frequency) and to determine what proportion of PD cases ultimately lead to a diagnosis of serious gastrointestinal disease. Such data would be useful in guiding pediatric primary care providers and gastroenterologists in the evaluation of young children with PD and in counseling parents about the causes and likely outcomes of this condition.
The authors thank the following physician-members of the Slone Center Office-based Research Network who enrolled subjects for the study: Charles P. Anderson, MD (San Marcos, TX); Robert F. Anderson, MD (Bettendorf, IA); Russell C. Applegate, MD (Media, PA); David Armsby, MD (Quincy, MA); William Baier, MD (Lockport, NY); Jeffrey H. Baker, MD (State College, PA); Glen S. Bartlett, MD (Hershey, PA); Barbara P. Belcher, MD (San Antonio, TX); Prafulchandra U. Bhatt, MD (Lock Haven, PA); Susan Bollinger, MD (Westminster, MD); Judith A. Brown, MD (Barrington, IL); Alan Chen, MD (Dexter, MO); Amar L. Dave, MD (Ottawa, IL); Philip J. Dawson, MD (Richmond, VA); Jacques Days, MD (Columbia, SC); Archibald W. Dettman, MD (Corunna, MI); Mark DiDea, MD (Orlando, FL); Paul M. Douthitt, MD (Springfield, TN); Arthur S. Dover, MD (Freedom, CA); Patricia Edwards, MD (Concord, NH); Lawrence A. Elfman, MD (Madison, WI); Robert Farron, MD (Far Rockaway, NY); Eileen Fox, MD (Norman, OK); Lawrence M. Galtman, MD (Bethlehem, PA); Michael F. Grossberg, MD (Chambersburg, PA); Daniel E. Halm, MD (Bellevue, NE); Karen M. Hearty, MD (Springfield, MO); Karen C. Hester, MD (Blytheville, AR); C. David Hill, MD (Cullman, AL); David J. Holzsager, MD (Hampton, VA); Michael S. Hortner, MD (Northampton, PA); Hae M. Hwang, MD (Shelby, OH); Mirza G. Jesani, MD (Chicago, IL); Michael Jordan, MD (Newark, NY); F.S. Kapadia, MD (Waterford, MI); Chyung Kim, MD (Riverdale, GA); William E. Kobler, MD (Rockford, IL); Robert Leavitt, MD (Longmeadow, MA); Rhonda Levitt, MD (Seattle, WA); Young K. Lim, MD (Mt. Pleasant, PA); Tich-Hao Machm, MD (Phoenix, AZ); Jane A. Mack, MD (Bridgeport, CT); Carole Mangrem, MD (Clarksdale, MS); Jennifer Margolis, MD (Cincinnati, OH); Forough B. Mokhtari, MD (Indianapolis, IN); David M. Muhs, MD (Jamestown, ND); Sree K. Mulpuru, MD (Fairmont, WV); Edward G. Myers, MD (Warren, OH); Lawrence A. O'Brien, MD (Del Rio, TX); John M. Packard, MD (Guntersville, AL); Ishvarlal U. Patel, MD (New Brunswick, NJ); Jagdish Patel, MD (Bronx, NY); Isabel Rosenbloom, MD (Bridgeton, MO); Barbara H. Rumberger, MD (Marco Island, FL); Zdenka K. Safar, MD (Silver Creek, NY); James Satt, MD (Rocky Ford, CO); Marty Schmidt, MD (Fort Scott, KS); Bruce R. Schober, MD (Westbrook, ME); Suzanne W. Schuessler, MD (Lagrange, GA); Rita M. Seck, DO (Gladwin, MI); David D. Sova, DO (Grand Rapids, MI); Neil J. Stalker, MD (Peru, IN); Alan N. Swartz, MD (Miami, FL); Jeb S. Teichman, MD (Jeffersonville, IN); Jeffrey T. Van Gelderen, MD (Bay City, MI); Louis Vernacchio, MD (Boston, MA); Robert J. Whelpley, MD (Hornell, NY); Scott L. Williamson, MD (Wichita Falls, TX); Gerald G. Woodruff, Jr, MD (Anniston, AL); George Wortley, MD (Big Island, VA); Michael F. Yeiser, MD (Owensboro, KY) and Sabah E. Zara, MD (Trenton, MI).
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Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
Persistent diarrhea; Gastroenteritis; Microbiology