Entamoeba histolytica/Entamoeba dispar Infections in Human ...

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Patients in the United States. We describe the incidence of and laboratory and clinical characteristics associated with Entamoeba histolytica/En- tamoeba dispar ...

CID 2000;30 (June)

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Gram staining of a touch preparation from the necrotic tissue smear showed gram-positive rods with subterminal spores (figure 1). A foul-smelling Clostridium species was recovered from the plate with Centers for Disease Control and Prevention anaerobic agar and Columbia colistin-nalidixic-acid agar. Presumptive identification of Clostridium was made by demonstration of typical colony morphology, Gram staining and fluorescence, and the characteristic p-cresol odor. Definite identification was based on biochemical characteristics [5] revealed by the API Rapid Anaerobic Identification System (bioMe´rieux, Marcy l’Etoile, France). After incubation for 4 h, the following biochemical reactions were positive: hydrolysis of L-proline–b-naphthylamide and hydrolysis of L-phenylalanine–b-naphthylamide. (Hydrolysis of Lproline-b-naphthylamide by proline aminopeptidase releases bnaphthylamine, which complexes with p-dimethylaminocinnamaldehyde in the presence of acetic acid. Hydrolysis of Lphenylalanine-b-naphthylamide by phenylalanine aminopeptidase releases b-naphthylamine, which complexes with p-dimethylaminocinnamaldehyde in the presence of acetic acid.) These results yielded an acceptable identification of C. difficile with a profile number of 0000101. Our microbiology staff performed all biochemical tests; no confirmatory testing by an outside laboratory was done. On the basis of these test results, iv metronidazole was added to the antibiotic regimen. The patient’s condition continued to improve clinically, and she was transferred to a tertiary care facility for further plastic surgery. Since 1982, extraintestinal infections due to C. difficile have been reported, including splenic abscess, peritonitis, diverticulitis, osteomyelitis, and bacteremia [3, 4]. However, to our knowledge there has been no report of C. difficile causing necrotizing fasciitis and gas gangrene. In our case, the source of infection was most likely the environment. The patient was sitting in a bus very close to the toilet, and when the bus crashed she

was thrown out of a window. Her wound might have been contaminated with fecal flora from the water in the toilet. The exact time of onset of infection is still unclear. The importance of early intervention by debridement and parenteral antibiotic treatment in necrotizing fasciitis cannot be overemphasized. C. difficile infection–induced colitis is usually treated with oral metronidazole or vancomycin. The organism is susceptible in vitro to antibiotics including tetracycline, chloramphenicol, and erythromycin [1]. This case illustrates that, for patients with rapidly progressive necrotizing fasciitis with gas gangrene, the differential diagnosis should also include C. difficile infection particularly in situations where the wound might have been contaminated with fecal flora. Patients described elsewhere [3] who had extraintestinal C. difficile infections have been successfully treated with metronidazole, cefoxitin, vancomycin, pefloxacin, and penicillin. However, the role of these antimicrobial agents in the treatment of extraintestinal infections is unclear.

Entamoeba histolytica /Entamoeba dispar Infections in Human Immunodeficiency Virus–Infected Patients in the United States

Entamoeba histolytica and Entamoeba dispar, a recently distinguished morphologically similar but nonpathogenic species, infect 10% of the world’s population [1]. E. histolytica infection has been described in travelers to regions of endemicity (portions of South America, Central America, Africa, and Asia) [2–5]. In the United States, the combined prevalence of E. histolytica/E. dispar is estimated at 4% [6], with increased risk for homosexual men and persons living in group homes for the mentally disabled [7, 8]. High prevalences (40%–50%) were described in homosexual men living in New York City and San

We describe the incidence of and laboratory and clinical characteristics associated with Entamoeba histolytica/Entamoeba dispar infection diagnosed in human immunodeficiency virus (HIV)–infected persons enrolled in the Adult and Adolescent Spectrum of HIV Disease Project. From 1 January 1990 to 1 January 1998 (82,518 personyears of follow-up), 111 patients (98% men) were diagnosed with E. histolytica/E. dispar infection. Among HIVinfected patients in the United States, the incidence of diagnosed E. histolytica disease is low (13.5 cases per 10,000 person-years [95% confidence interval, 7.7–22.2], with diagnosis most common in those patients exposed to HIV through male-male sex.

Abha Bhargava, 1 Purnendu Sen, 1 Anangur Swaminathan, 2 Cora Ogbolu, 1 Susan Chechko, 3 and Frederick Stone 4 Departments of 1Medicine, 2Surgery, 3Microbiology, and 4Pathology, Raritan Bay Medical Center, Perth Amboy, New Jersey

References 1. Levett PN. Antibiotic susceptibility of Clostridium difficile determined by disc diffusion breakpoint methods. J Antimicrob Chemother 1988; 22:167–73. 2. Rampling A, Warren RE. Clostridium difficile in hematologic malignancy. J Clin Pathol 1985; 38:445–51. 3. Gerard M, Defresne N. Polymicrobial septicemia with Clostridium difficile in acute diverticulitis. Eur J Clin Microbiol Infect Dis 1989; 8:300–1. 4. Byl B, Jacobs F. Extraintestinal Clostridium difficile infections. Clin Infect Dis 1996; 22:712. 5. Bailey S, Forbes BA, eds. Diagnostic microbiology. 10th ed. St. Louis: Mosby, 1998:699–713.

Reprints or correspondence: Dr. Mark S. Dworkin, Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention–Surveillance and Epidemiology, 1600 Clifton Rd., NE, Mailstop E-47, Atlanta, GA ([email protected]). Clinical Infectious Diseases 2000; 30:955–9 q 2000 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2000/3006-0028$03.00


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Francisco during the late 1970s [9], although invasive disease seemed uncommon, probably because E. dispar was the dominant species transmitted [5, 10, 11]. Recently, the male homosexual population in Japan was found to have high levels of seropositivity for antibodies to E. histolytica [12, 13]. Nonpathogenic strains have been identified in persons with AIDS in developed countries [14–16]. No epidemiological studies of E. histolytica/E. dispar in the United States have been reported in the medical literature in recent years, and few researchers have studied a large cohort of HIV-infected persons [17]. We describe the incidence of and risk factors for E. histolytica/E. dispar infections in HIV-infected persons in the United States. The Adult and Adolescent Spectrum of HIV Disease (ASD) Project is an ongoing multicenter surveillance study that conducts medical record review for persons with HIV infection or AIDS as a supplement to the Centers for Disease Control and Prevention system of national HIV infection/AIDS surveillance [18]. We used the ASD Project database to identify diagnoses of infections due to Entamoeba species that were reported from 1 January 1990 through 1 January 1998 in 9 US metropolitan areas. Because specimens were unavailable for genetic differentiation, we refer to reports of E. histolytica infection as E. histolytica/E. dispar infection. See editorial by Reed on pages 959–61. A case was defined as documented E. histolytica/E. dispar infection associated with clinical illness, such as infectious diarrhea or other gastrointestinal symptoms. Supplemental medical record reabstraction gathered additional data on diagnosis date, diagnostic method, concomitant infection with other intestinal organisms, symptoms, prescribed treatment and history of steroid use for >2 weeks during the 2 months preceding E. histolytica/E. dispar illness, and history of travel 35 AIDS-defining intestinal parasitic disease c, d Cryptosporidiosis or isosporiasis No cryptosporidiosis or isosporiasis c CD41 count, cells/mL 0–99 100–199 >200 No data

No. of cases per 10,000 person-years a (95% CI)

No. (%) of persons (n = 34,063)

No. (%) of cases (n = 111)

Person-years (n = 82,518)

28,111 (82.5) 5952 (17.5)

109 (98.2) 2 (1.8)

68,270.8 14,247.2

16.0 (12.8–19.2) 1.4 (0.01–2.8)

15,164 14,071 4,336 492

(44.5) (41.3) (12.7) (1.4)

57 26 25 3

(51.4) (23.4) (22.5) (2.7)

38,619.1 33513.9 9280.0 1105.0

14.8 7.8 26.9 27.1

(10.7–18.9) (4.7–10.9) (16.1–37.7) (0.3–53.9)

17,749 5157 3788 2811 692 3866

(52.1) (15.1) (11.1) (8.3) (2.0) (11.3)

87 1 15 2 2 4

(78.4) (0.9) (13.5) (1.8) (1.8) (3.6)

44,830.1 12,065.0 9359.9 6855.0 1631.3 7776.8

19.4 0.8 16.0 2.9 1.2 5.1

(15.3–23.5) (0.001–1.6) (7.2–24.8) (0.03–5.8) (0.01–2.4) (0.1–10.1)

1724 (5.1) 319 (0.9) 32,046 (94.1)

13 (11.7) 2 (1.8) 96 (86.5)

3550.8 682.6 78,330.8

36.6 (14.6–58.6) 2.9 (0.03–5.8) 12.3 (9.8–14.7)

68,881 (48.3) 73,702 (51.7)

56 (50.5) 55 (49.5)

41,291.92 41,226.08

13.6 (9.9–17.3) 13.3 (9.7–16.9)

1111 (0.08) 141,353 (99.2)

13 (11.7) 98 (88.3)

566.3 81,951.8

230 (92–368) 12.0 (9.6–14.4)

42 15 33 21

18,133.0 8434.3 31,864.8 24,085.9

29,384 13,795 51,141 47,046

(20.8) (9.8) (36.2) (33.3)

(37.8) (13.5) (29.7) (18.9)

23.2 17.8 10.4 8.7

(16.0–30.4) (8.4–27.2) (6.8–14.0) (4.9–12.5)


Overall incidence was 13.5 cases per 10,000 person-years (95% CI, 7.7–22.2). Other includes American Indian or Alaska Native, Asian or Pacific Islander, and unknown race or ethnicity. Time-dependent characteristic: examined as episode during 6-month interval of medical record follow-up (total episodes, 142,583). d Either cryptosporidiosis or isosporiasis was recorded during the same 6-month interval of medical record follow-up as E.histolytica/E.dispar infection. b c

for MSM (including MSM and injection drug users) than for persons with all other HIV exposures combined (table 2). Persons born in Latin America were at higher risk than were those born in regions of nonendemicity. Diagnosis was more likely during a 6-month follow-up period in which cryptosporidiosis or isosporiasis was also diagnosed and during a period in which the CD4 cell count was !100 cells/mL, compared to a period when the CD4 count was >200 cells/mL. The median CD41 cell count (interquartile range) for persons with diagnosed E. histolytica/E. dispar infection was 116 cells/mL (range, 40–330 cells/mL); persons without diagnosed E. histolytica/E. dispar infection had a median CD41 cell count of 232 cells/mL (range, 63–427 cells/mL). The likelihood of a diagnosis of E.histolytica/ E. dispar infection was similar for persons aged 13–34 years and persons aged >35 years. However, of persons born in Latin America, Asia, or Africa (regions of endemicity; 15 cases), those aged !35 years had an increased likelihood of diagnosis (RR, 6.0; 95% CI, 2.8–9.2). E. histolytica/E. dispar infection was more often diagnosed

in MSM than in persons with other HIV exposures. The diagnosis rate was higher for persons born in Latin America than for persons born in regions of nonendemicity; however, Hispanics born in regions of nonendemicity did not have an increased likelihood of diagnosis. Persons born in Asia or Africa, regions where E. histolytica/E. dispar is endemic, had an increased likelihood of diagnosis; however, this finding was not statistically significant, possibly because few persons in the ASD Project were from these regions. Laboratory diagnosis by stool microscopy was common, as was treatment without further serological examination or determination of strain pathogenicity. More reliable methods of detecting E. histolytica (serological testing or stool ELISA) were uncommon, which limits interpretation of our results. Because of the prevalence of E. dispar among US populations, studies have suggested that treatment is not necessary when data on strain identification are lacking [20]. Other researchers believe that empirical treatment is reasonable because E. histolytica is a treatable cause of diarrhea and diagnostic techniques for


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Table 2. Results of a Poisson multivariate regression model of risk for developing Entamoeba histolytica/Entamoeba dispar infection among HIV-infected patients in the United States.

Characteristic HIV exposure mode a Male-male sex No identified risk b Other Sex Male Female Place of birth (ethnicity) Latin America Asia or Africa Area of nonendemicity (Hispanic) Area of nonendemicity CD41 count, cells/mL 0–90 100–199 No count >200 AIDS-defining intestinal parasitic illness Cryptosporidiosis or isosporiasis No cryptosporidiosis or isosporiasis Age, years 13–34 >35

No. (%) of cases (n = 111)

No. of person-years (n = 82,518)

Risk ratio (95% CI)

102 (91.9) 4 (3.6) 5 (4.5)

54,190.0 7776.8 20,551.3

4.5 (3.6–5.4) 1.7 (0.3–3.4) Referent

.003 .43

109 (98.2) 2 (1.8)

68,270.8 14,247.2

3.2 (2.6–3.8) Referent


13 (11.7) 2 (1.8)

3550.8 682.6

2.9 (1.1–4.7) 2.6 (0.3–5.2)

.0004 .18

12 (10.8) 84 (75.7)

5729.2 72,555.4

1.4 (0.5–2.3) Referent


42 15 21 33

(37.8) (13.5) (18.9) (29.7)

18,133.0 8,434.3 31,864.8 24,085.9

1.7 (1.2–2.2) 1.5 (0.7–2.3) 0.8 (0.5–1.1) Referent

.028 .22 .42

13 (11.7)


13.4 (5.4–21.4)


98 (88.3)



56 (50.5) 55 (49.5)

41,291.92 41,266.08

1.0 (0.7–1.3) Referent




Male-male sex and male-male sex plus injection drug use. Injection drug use, heterosexual contact, and transfusion or transplant recipient. b

strain identification are not widely available. In this study, most patients were prescribed treatment with broad-spectrum agents effective against other copathogens. The diagnosis of E. histolytica/E. dispar infection was more likely during a 6-month period in which persons were diagnosed with AIDS-defining parasitic illnesses than during a period in which such infections were not diagnosed, possibly because stool specimens were under careful scrutiny during this period or because of similar risk factors for infections due to intestinal parasites (and other concurrent organisms), such as fecal-oral spread. The likelihood of the diagnosis of E. histolytica/E. dispar infection increased as CD41 cell counts decreased. Patients with lower CD41 cell counts may receive more regular medical care and more diagnostic testing for gastrointestinal symptoms. The risk for E. histolytica/E. dispar disease may increase when CD41 cell counts are !100 cells/mL, possibly because of reactivation of latent infection or because of increased susceptibility to new infection (although Law et al. [11] did not find any correlation between HIV disease and severity of E. histolytica disease). Cases may have been underreported because identification of cysts and trophozoites requires an experienced technician, because patients with infectious diarrhea of unknown cause may have been infected with E. histolytica/E. dispar, and because we included only persons whose records could be re-

CID 2000;30 (June)

viewed again. In addition, male-male sex could have emerged as a risk factor because of exclusion bias. It is also possible that persons categorized as having no identified risk were exposed by engaging in male-male sex. Our study confirms reports of a low incidence of E. histolytica/E. dispar disease among HIV-infected persons in the United States [17], with rates of extraintestinal disease lower than those of intestinal disease. The role of E. histolytica as a cause of gastrointestinal symptoms in HIV-infected persons needs further study with serology and stool antigen testing because of a lack of differentiation between E. histolytica and E. dispar.

ASD Project Investigators Melanie Thompson (AIDS Research Consortium of Atlanta); Susan Burkham and Sharon Melville (Texas Department of Health, Austin); David L. Cohn, Arthur Davidson, and Cornelius Rietmeijer (Denver Department of Health and Hospitals); Eve D. Mokotoff and Linda Wotring (Michigan Department of Community Health, Detroit); Wes McNeely and Kaye Reynolds (Houston Department of Health and Human Services); Dorothy Masters and Frank Sorvillo (Los Angeles County Department of Health Services); Anne Morse and Susan Troxler (Louisiana Office of Public Health, New Orleans); Jeffrey McFarland and Judy Sackoff (City of New York Department of Health); Maria de los Angeles Gomez, Robert Hunter, and Jose Otero (University Central del Caribe, Bayamo´n, Puerto Rico); Sandra Miranda (Puerto Rico Department of Health, San Juan); and Susan Buskin and Sharon G. Hopkins (Seattle–King County Department of Public Health, Seattle). Acknowledgments We thank John McGowan for his advice on this project and Tom Navin, Anthony Mounts, and David K. Shay for critical review of the manuscript. Sara A. Lowther, Mark S. Dworkin, Debra L. Hanson, and the Adult and Adolescent Spectrum of HIV Disease Project Division of HIV/AIDS Prevention-Surveillance and Epidemiology, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia

References 1. Walsh JA. Problems in recognition and diagnosis of amebiasis: estimation of the global magnitude and morbidity and mortality. Rev Infect Dis 1986; 8:228–38. 2. Caballero-Salcedo A, Viveros-Rogel M, Salvatierra B, et al. Seroepidemiology of amebiasis in Mexico. Am J Trop Med Hyg 1994; 50:412–9. 3. Erko B, Birrie H, Tedla S. Amebiasis in Ethiopia. Trop Geogr Med 1995; 47:30–2.

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4. Braga LL, Lima A, Sears C, et al. Seroepidemiology of Entamoeba histolytica in a slum in northeastern Brazil. Am J Trop Med Hyg 1996; 55:693–7. 5. Weinke T, Friedrich-Janiche B, Hopp B, Janitschke K. Prevalence and clinical importance of Entamoeba histolytica in two high-risk groups: travelers returning from the tropics and male homosexuals. J Infect Dis 1990; 161: 1029–31. 6. Ravdin JI. Amebiasis. Clin Infect Dis 1995; 20:1453–66. 7. Sexton DJ, Krogstad DJ, Spencer HC, et al. Amebiasis in a mental institution: serologic and epidemiologic studies. Am J Epidemiol 1974; 100:414–23. 8. Sahara K, Hori W, Masuda T, et al. Invasive amebiasis at an institution for the mentally retarded in Schzuoka Prefecture. Kansenshogaku Zasshi 1996; 70:1–6. 9. Ortega HB, Borchardt HK, Hamilton R, Ortega P, Mahood J. Enteric pathogenic protozoa in homosexual men from San Francisco. Sex Transm Dis 1984; 11:59–63. 10. Sorvillo FJ, Strassburg MA, Seidel J, et al. Amebic infections in asymptomatic homosexual men, lack of evidence of invasive disease. Am J Public Health 1986; 76:1137–9. 11. Law CL, Walker J, Qassim MH. Factors associated with the detection of Entamoeba histolytica in homosexual men. Int J STD AIDS 1991; 2: 346–50. 12. Takeuchi T, Kobayashi S, Okusawa E, Tachibana H, Takada S, Ohtomo H. Pathogenicity of Entamoeba histolytica in Japanese male homosexual population [abstract PB0189]. In: Program and abstracts of the 10th Inter-

Editorial Response: Entamoeba Infections in Human Immunodeficiency Virus–Infected Patients: Not Just a Tropical Problem In this issue of Clinical Infectious Diseases, Lowther et al. update the prevalence of and risk factors for Entamoeba histolytica/Entamoeba dispar infection in HIV-infected patients as part of the Adult and Adolescent Spectrum of HIV Disease Project. Their cohort of 34,063 patients is the largest ever evaluated for Entamoeba infection in a developed country. Patients with AIDS-defining protozoan infections due to Cryptosporidium or Isospora had the highest relative risk (13.4). Sixty-eight percent of the patients in the cohort were also coinfected with another protozoan parasite, including Giardia, Blastocystis, Endolimax nana, or Entamoeba coli. These findings underscore the importance of oral-fecal exposure in the spread of infection. Although colonization with nonpathogenic protozoa, such as Blastocystis, Endolimax, or E. coli, does not require treatment, the presence of these organisms should alert the clinician to potential fecal exposure. See article by Lowther et al. on pages 955–9. The elevated relative risk of 2.9 for patients born in Latin America is not surprising, since the highest incidence of ameReprints or correspondence: Dr. Sharon L. Reed, Division of Infectious Diseases, UCSD Medical Center, 200 West Arbor Dr., San Diego, CA 921038416 ([email protected]). Clinical Infectious Diseases 2000; 30:959–61 q 2000 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2000/3006-0029$03.00

13. 14.



17. 18. 19.



national Conference on AIDS. Yokohama, Japan: Conference Organizing Committee, 1994:190. Takeuchi T, Okuzawa E, Nozake T, et al. High seropositivity of Japanese homosexual men for amebic infection. J Infect Dis 1989; 159:808. Allason-Jones E, Mindel A, Sargeaunt P, Katz D. Outcome of untreated infection with Entamoeba histolytica in homosexual men with and without HIV antibody. BMJ 1988; 297:654–7. Burchard GD, Hufert FT, Mirelman D. Characterization of 20 Entamoeba histolytica strains isolated from patients with HIV infection. Infection 1991; 19:164–9. de Alencar LC, Magalhaes V, de Melo VM, Aka I, Magalhaes M, Kobayashi S. The absence of invasive amebiasis in male homosexual AIDS patients in Recife. Rev Soc Bras Med Trop 1996; 29:319–22. Reed SL, Wessel DW, Davis CE. Entamoeba histolytica infection and AIDS. Am J Med 1991; 90:269–71. Farizo K, Buehler JW, Chamberland ME, et al. Spectrum of disease in persons with HIV infection in the United States. JAMA 1992; 267:1798–805. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992; 41(RR-17):1–19. Allason-Jones E, Mindel A, Sargeaunt P, Williams P. Entamoeba histolytica as a commensal intestinal parasite in homosexual men. N Engl J Med 1986; 315:353–6.

biasis is in Latin America, Africa, and Asia. A survey conducted a decade ago revealed that 8.4% of Mexicans were seropositive for E. histolytica [1]. Worldwide, 40–50 million patients develop amebic colitis or liver abscesses each year, and among protozoan infections, E. histolytica infection has a mortality rate second only to that of malaria [2, 3]. Studies from Bangladesh [4] and South Africa [5] have shown, however, that even in areas of endemicity, E. dispar is more common than E. histolytica. In a recent study from Bangladesh by Haque et al. [4], Entamoeba species were specifically identified as E. histolytica or E. dispar by isoenzyme analysis or antigen detection testing; 6.5% of urban children with diarrhea were infected with E. dispar, compared with only 4.2% of those who were infected with E. histolytica. In asymptomatic children, E. dispar was 7 times more common. The overall prevalence of 3.3% confirms the findings of several other studies indicating that the incidence of all enteric infections, including those due to E. histolytica/E. dispar, has dramatically decreased among HIV-infected patients. This relatively low prevalence contrasts markedly to studies in the 1970s and 1980s, which documented that at least 30% of homosexual men in the United States [6, 7], United Kingdom [8], and Canada [9] were infected with Entamoeba. The decline most likely reflects a decrease in high-risk sexual practices [10]. Although the prevalence of Entamoeba infection is low, its identification presents a major treatment dilemma and highlights the importance of differentiating E. histolytica from E. dispar infection. The study by Lowther et al. is informative because of its size, but it was retrospective, and so could not use serology or further stool examinations to establish the Entamoeba species. Of 111 patients infected with E. histolytica/ E. dispar, only 2 could be definitively diagnosed with E. his-

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