Heyland, Klaas; Friedt, Michael; Buehr, Patrick; Braegger, Christian P.
Division of Gastroenterology and Nutrition, University Children's Hospital Zurich, Zürich, Switzerland.
Address correspondence and reprint requests to Prof Christian P. Braegger, Division of Gastroenterology and Nutrition, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland (e-mail: email@example.com).
Received 25 April, 2011
Accepted 28 July, 2011
The authors report no conflicts of interest.
Objective: The aim of the study was to investigate whether recurrent abdominal pain (RAP) in Blastocystis hominis–positive children can be treated successfully with trimethoprim-sulfamethoxazole (TMP/SMX).
Methods: From October 2004 to December 2008, all of the patients referred to the Division of Gastroenterology and Nutrition of the University Children's Hospital Zurich because of RAP and detection of B hominis in stool samples as the only pathological finding after a standard workup were offered to participate in the study. Patients were randomly assigned into 2 groups. TMP/SMX or placebo was given for 7 days in a double-blind, placebo-controlled manner. Pain index (PI) was measured with a visual analogue scale. Two weeks after completion of treatment, 3 stool samples were collected and patients were followed clinically. If B hominis was still present, metronidazole was given for 7 days.
Results: Forty patients were included; 37 finished the study (TMP/SMX n = 20, placebo n = 17). Mean PI declined from 7.1 to 3.6 for all of the patients, with a decrease from 6.9 to 4.1 in the TMP/SMX and 7.4 to 3.0 in the placebo group, irrespective of detection of B hominis after treatment. There was no statistically significant difference in PI reduction between the 2 groups. Metronidazole treatment led to a further PI decline from 3.7 to 1.9. Eradication rates were 35% (TMP/SMX) and 44% (metronidazole), compared with spontaneous clearance of 29% in the placebo group.
Conclusions: There is no advantage for TPM/SMX over placebo in the treatment of RAP in B hominis–positive children.
Recurrent abdominal pain (RAP) is common in children and many of them are referred to paediatric gastroenterologists for further evaluation. Detection of Blastocystis hominis (a facultative pathogenic protozoan) is limited to the analysis of stool samples. According to recent findings (1–3), there are conflicting data about the pathogenicity of B hominis. Associated symptoms such as abdominal pain, diarrhoea, and meteorism (1,2) can occur. Treatments for B hominis, if indicated, are trimethoprim-sulfamethoxazole (TMP/SMX) (4,5) or metronidazole (6,7). The aim of the present study was to investigate whether RAP in B hominis–positive children can be treated successfully with TMP/SMX. Secondary outcome was to assess the eradication rate of B hominis in response to TMP/SMX and metronidazole treatment.
Subjects for the present study were subsampled from a pool of patients referred to the Division of Paediatric Gastroenterology and Nutrition of the University Children's Hospital Zurich because of RAP from October 2004 to December 2008. Inclusion criteria were age 3 to 16 years, RAP as the only clinical complaint, and B hominis as the only pathological finding after a standard workup (blood sample including full blood count, C-reactive protein, albumin, hepatic and pancreatic enzymes, creatinine, urea nitrogen, total immunoglobulin (Ig) A, anti-gliadin IgG/IgA, anti-endomysial IgA, anti-transglutaminase IgA, Helicobacter pylori diagnostics [C13-breath test or monoclonal antigen stool test], stool culture for bacteria [Salmonella, Shigella, Yersinia, Campylobacter, Aeromonas], and 3 stool samples for parasites [B hominis, Entamoeba histiolytica/dispar, Giardia lamblia, Isospora belli, Cyclospora, Sarcocystis sp, Ascaris, Ancylostoma, Trichuris, Enterobius, Taenia, Hymenolepis, Dipyllobothrium, Fasciola, Schistosoma mansoni, Dientamoeba fragilis]). Exclusion criteria were known gastrointestinal and/or systemic diseases and antibiotic treatment within 4 weeks before study inclusion.
We defined RAP as at least 3 episodes of pain occurring during a period of at least 3 months, severe enough to affect normal daily activities, according to the definition of Apley and Naish (8). Pain index (PI) was measured with a visual analogue scale either with numbers 0 to 10 or standardised face drawings, depending on patient's age and stage of development.
After obtaining written informed consent from parents/caregivers and patients (if possible), patients were randomly assigned into 2 groups and TMP (6 mg · kg−1 · day−1)/SMX (30 mg · kg−1 · day−1) or placebo was given in 2 doses per day for 7 days in a double-blind, placebo-controlled manner. Three stool samples were collected 2 weeks after completion of treatment, and patients were followed clinically. If B hominis was still detectable, then metronidazole (30 mg · kg−1 · day−1) was given for 7 days, another 3 stool samples were collected after 2 weeks, and a further clinical follow-up was arranged. The goal of this treatment was a PI reduction to <4. A power analysis revealed a sample size of overall 32 patients (power 0.8, confidence level 0.05) based on a PI reduction of 30% in the placebo treatment and 80% in the TMP/SMX treatment. Statistical analysis was performed using χ2 and Mann-Whitney U tests.
The study was approved by the local and regional ethical committees as well as the Swiss Agency for Therapeutic Products. Procedures were conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines.
Forty-three patients met inclusion criteria, 40 patients were recruited (3 patients with refusal of participation), and 37 children completed the study: Two refused to take the study medication, and 1 withdrew after inclusion. Twenty patients were in the intervention group and 17 patients were in the placebo group. No sociodemographic differences between the 2 groups were identified (Table 1).
Following therapy, the PI declined from 7.1 to 3.6 for all of the patients, with a decrease from 6.9 to 4.1 in the TMP/SMX and 7.4 to 3.0 in the placebo group. There was no significant difference in PI reduction between the 2 groups (Mann-Whitney U test: P = 0.11). The decrease in PI between the 2 treatment groups was independent of detection of B hominis after the end of treatment (Fig. 1).
Metronidazole treatment led to a further decrease of the PI from 3.7 to 1.9 in the remaining 25 patients, independent of the preceding first-line therapy.
Eradication rates were 35% in the TMP/SMX group and 44% with metronidazole as second-line treatment. This is not significantly different from the spontaneous clearance rate of 29% in the placebo group (P = 0.72 vs TMP/SMX, P = 0.34 vs metronidazole).
The potential for pathogenicity of B hominis in humans remains controversial (1–3). Symptoms possibly associated with B hominis infection are abdominal pain, diarrhoea and flatulence (1,2,9), chronic urticaria (10,11), and chronic pruritus (12). More severe symptoms are observed in immunocompromised patients (acquired immune deficiency syndrome (13), immunosuppressive treatment (14)). Furthermore, B hominis has been associated with irritable bowel syndrome (15).
The literature on B hominis in children remains sparse. Most publications report the prevalence of B hominis in both asymptomatic (9) and symptomatic (16) paediatric patients. To our knowledge, this is the first randomised, double-blind, placebo-controlled treatment trial for B hominis in children with RAP.
Several antiprotozoal drugs, particularly metronidazole, ornidazole, iodoquinol, furazolidone, emetine, pentamidine, TMP/SMX, and nitazoxanide, were found to be active antimicrobial agents against B hominis, both in vitro and in vivo (4–7,17,18). The most commonly recommended treatment for B hominis is metronidazole; however, a number of reports show efficacy of TMP/SMX comparable with metronidazole (4,5,7).
In contrast to these results, our study provides no evidence for a decrease of symptom intensity in the TMP/SMX treatment compared with placebo. Furthermore, no significant difference in improvement of RAP symptoms was identified between patients with eradication of B hominis compared with patients with persistence of the parasite.
Eradication rate in response to TMP/SMX treatment in our study was comparable with other data (4,7), except for the study of Ok et al (5) that reported an eradication rate of 94%. This difference may be related to the fact that in their study, the stool samples were collected directly after the end of treatment and not after an interval of 2 weeks. Assuming that TMP/SMX leads in a majority of cases only to a reduction of the number of B hominis and not to permanent eradication, this could be an explanation of the discrepancy in these results. The eradication rate after metronidazole treatment in our study is comparable with other studies (6,7).
The second-line treatment with metronidazole led to further improvement of the PI irrespective of B hominis eradication. This may be because of the nonspecific antibacterial/antiparasitic effects of metronidazole or eradication of parasites not detected in the 3 stool samples.
In summary, the comparable decrease of the PI in the TMP/SMX and placebo group and the fact that there was no significant difference in the subgroups regarding eradication of B hominis showed that there is no advantage for antibiotic treatment over placebo in B hominis–positive children with RAP. These observations imply that there is no evidence for a causative role of B hominis in children with RAP. Even though the recruitment phase was extended twice, it was not possible to increase the sample size. The small sample size reduces the significance of our study.
1. Qadri SM, al-Okaili GA, al-Dayel F. Clinical significance of Blastocystis hominis. J Clin Microbiol 1989; 27:2407–2409.
2. Waghorn DJ, Hancock P. Clinical significance of Blastocystis hominis. Lancet 1991; 337:609.
3. Leder K, Hellard ME, Sinclair MI, et al. No correlation between clinical symptoms and Blastocystis hominis in immunocompetent individuals. J Gastroenterol Hepatol 2005; 20:1390–1394.
4. Schwartz E, Houston R. Effect of co-trimoxazole on stool recovery of Blastocystis hominis. Lancet 1992; 339:428–429.
5. Ok UZ, Girginkardeşler N, Balcioğlu C, et al. Effect of trimethoprim-sulfamethoxazole in Blastocystis hominis infection. Am J Gastroenterol 1999; 94:3245–3247.
6. Nigro L, Larocca L, Massarelli L, et al. A placebo-controlled treatment trial of Blastocystis hominis infection with metronidazole. J Travel Med 2003; 10:128–130.
7. Moghaddam DD, Ghadirian E, Azami M. Blastocystis hominis and the evaluation of efficacy of metronidazole and trimethoprim/sulfamethoxazole. Parasitol Res 2005; 96:273–275.
8. Apley J, Naish N. Recurrent abdominal pains: a field survey of 1,000 school children. Arch Dis Child 1958; 33:165–170.
9. Nimri L, Batchoun R. Intestinal colonization of symptomatic and asymptomatic schoolchildren with Blastocystis hominis. J Clin Microbiol 1994; 32:2865–2866.
10. Gupta R, Parsi K. Chronic urticaria due to Blastocystis hominis. Australas J Dermatol 2006; 47:117–119.
11. Biedermann T, Hartmann K, Sing A, et al. Hypersensitivity to non-steroidal anti-inflammatory drugs and chronic urticaria cured by treatment of Blastocystis hominis infection. Br J Dermatol 2002; 146:1113–1114.
12. Kick G, Rueff F, Przybilla B. Palmoplantar pruritus subsiding after Blastocystis hominis eradication. Acta Derm Venereol 2001; 82:60.
13. Laughon BE, Druckman DA, Vernon A, et al. Prevalence of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome. Gastroenterology 1988; 94:984–993.
14. Lee MG, Rawlins SC, Didier M, et al. Infective arthritis due to Blastocystis hominis. Ann Rheum Dis 1990; 49:192–193.
15. Yakoob J, Jafri W, Jafri N, et al. Irritable bowel syndrome: in search of an etiology: role of Blastocystis hominis. Am J Trop Med Hyg 2004; 70:383–385.
16. Nimri LF. Evidence of an epidemic of Blastocystis hominis infections in preschool children in northern Jordan. J Clin Microbiol 1993; 31:2706–2708.
17. Vdovenko AA, Williams JE. Blastocystis hominis: neutral red supravital staining and its application to in vitro drug sensitivity testing. Parasitol Res 2000; 86:573–581.
18. Rossignol JF, Kabil SM, Said M, et al. Effect of nitazoxanide in persistent diarrhea and enteritis associated with Blastocystis hominis. Clin Gastroenterol Hepatol 2005; 3:987–991.