Recurrent abdominal pain (RAP) has been found in 10% to 15% of children at school age. Psychological factors are supposed to play an important role. Recently, attention has been given to protozoan gastrointestinal infections, especially to the role of Dientamoeba fragilis (Df) and Blastocystis hominis (Bh) in patients with abdominal pain and other gastrointestinal symptoms (1–4). Although Bh has been described for the first time as early as 1911 and Df in 1918, it is only since the last few decades that some information has come to light about the role of these protozoa. In particular, presentation with the symptom complex of irritable bowel syndrome (IBS) has been described (1,5).
The aim of the study was to investigate the causal relation between protozoan infections and RAP, as part of a comprehensive study on RAP (6,7), and to investigate whether protozoan infections can be recognized by a characteristic clinical presentation of abdominal pain.
Between May 2002 and May 2004, all consecutive children, ages 4 to 16 years, with RAP according to the Apley criteria (at least 3 bouts of pain severe enough to affect the activities of the patient during a period of not less than 3 months) (8), who were referred by their general practitioner to one of the authors (C.G.), were prospectively evaluated for protozoan infections (Giardia lamblia [Gl], Df, Bh).
Standardized history and physical examination were performed as described earlier (6), with special reference to pain characteristics and concomitant symptoms (Table 1). In all children, fecal testing for parasites was performed according to the specific triple feces test (TFT) protocol as described earlier by Van Gool et al (9): 3 stool samples were collected on 3 separate days into 1 vial each. From the stool samples in the first and third vials, containing sodium acetate acetic acid formalin fixative, parasitological assessment was performed using an iron hematoxylin-Kinyoun staining procedure and a G1-specific enzyme-linked immunosorbent assay. The unpreserved second stool sample was examined for (oo)cysts and spores of protozoa.
When parasites were detected, patients were treated with metronidazole (20 mg · kg−1 · day−1 for Gl, 35–50 mg · kg−1 · day−1 for Df and Bh) for 10 days. Some children, because of intolerance or refusal of metronidazole, were treated with tinidazole (2 dosages of 75 mg/kg 1 week apart) or, in case of Df, paromomycin (25–35 mg · kg−1 · day−1 for 7 days), in case of Bh, cotrimoxazol (36 mg · kg−1 · day−1 for 7 days). At least 10 days after the end of treatment, examination of feces was repeated.
Disappearance of RAP after eradication of parasites with a pain-free follow-up period of at least 6 months was considered indicative of a causal relation with RAP as described earlier (7).
Statistical analysis was performed using SPSS version 17.0 (SPSS Inc, Chicago, IL) to investigate the characteristics of abdominal pain in patients with protozoan infections and their predictive value with respect to protozoan infections as the cause of the pain.
Two hundred twenty consecutive patients were included. Stool samples were obtained from 215 patients (125 girls, 90 boys, mean age 8.8 [range 4.1–16.0] years); 73 (34%) carried parasites. Of 73, 10 had 2 and 2 had 3 species of protozoa (Table 2).
These infections were found in 50 of 120 patients (42%) of western European descent, in 5 of 18 patients (28%) of half-western European descent, and in 18 of 82 patients (22%) of nonwestern European descent (P = 0.003 for the difference between western European and nonwestern European descent). All 3 protozoa were more frequent in patients of western European descent.
Eight of 73 patients had spontaneous resolution of abdominal pain (TFT was not repeated). The remaining 65 patients were treated as described.
Eradication was confirmed in 60 of 65 patients (88%). In 9 patients, ≥2 courses of therapy were necessary. One patient still had a positive TFT after therapy, but did not receive further therapy because abdominal pain resolved. Four patients failed to bring a control stool sample and they were considered lost to follow-up. Following eradication, resolution of abdominal pain was confirmed in 25 of 73 infected patients (34%). In 14 of 25 patients, the pain disappeared after eradication of the parasites; in 11, the pain was considerably reduced after eradication of the parasites, but complete resolution of the pain was only achieved after treatment of Helicobacter pylori infection (1 patient), Yersinia enterocolitica infection (1 patient), or constipation (9 patients) (7).
Five patients who had an infection with Df as the most likely cause of abdominal pain had recurrence of abdominal pain; they had an infection with Df and were again immediately pain-free after eradication of the parasite.
Table 2 shows the characteristics of patients with a parasite as the cause of their pain, compared with those with an asymptomatic parasitic infection and those without parasites. No remarkable differences are observed with respect to age of the patients, duration of pain, localization of pain, and other characteristics. The numbers of the patients in the group “protozoa as cause of the pain” are too small to allow adequate statistics; however, differences between the groups are obviously too small to be clinically relevant.
We performed a prospective cohort study to evaluate the possible relation between RAP and protozoan infections in children. The main findings were that protozoa were present in approximately 30% of all patients and were supposed to be causative in approximately 30% of infected patients. Considering the whole group of 220 patients, we found RAP in 25 patients (11%) to be caused by parasites. We could not identify symptoms or signs at presentations that predicted parasitical infection as cause of the RAP.
Pathogenicity of intestinal parasites is mainly based on microbiologically initiated studies (1–3). In these studies, patients with gastrointestinal complaints who tested positive for fecal protozoa were treated. After eradication of the parasites, the symptoms disappeared in a high percentage, varying from 82% to 100% (2–4), especially with respect to Gl and Df, leading to the opinion that these protozoa can be considered pathogens; however, prospective double-blind, placebo-controlled studies are not available, except for a study on Bh (10). A limitation of these studies is that hardly any study describes the time relation between eradication of the parasite and disappearance of the pain.
Gl has been accepted as a pathogen. Diarrhea may have an acute onset, but may last for years and may be continuous or intermittent. Abdominal pain may be present, independent of the presence of diarrhea. Flatulence, anorexia, nausea, vomiting, weight loss, and general malaise are reported as symptoms of a Gl infection. Chronic Gl infection can present as IBS (1,3) or dyspepsia (11,12). Grazioli et al (12) found Gl in 6.5% of patients diagnosed as having IBS. At least 50% of people spontaneously clear Gl without symptoms (1).
Nowadays, Df is accepted as a pathogen, although its exact role in disease is still the subject of discussion (13). The duration of disease varies from 2 weeks to years (1). Reported symptoms of an infection with Df are acute or chronic and include abdominal pain, diarrhea and looseness of stools, flatulence, anorexia, nausea, vomiting, weight loss, and malaise (1,3,14). Infection with Df can present with symptoms of IBS (15). Several unusual presentations are reported (16–19).
Vandenberg et al (3) found abdominal pain in a high percentage of patients with Df or Gl infection; all reported a clinical cure after eradication of their parasites. Stark et al (2) found abdominal pain or discomfort in a high percentage of patients with Df; symptoms disappeared in 94% after eradication of the parasite. Bosman et al (4) in a retrospective study found 82% of 33 patients with Df and gastrointestinal complaints to have considerably less or no complaints after eradication of Df.
Pathogenicity of Bh is the subject of more discussion. Symptoms attributed to Bh include abdominal pain, cramps or discomfort, diarrhea, and nausea (1). Bh has been found in considerable numbers as the sole identified potential pathogen in patients with gastrointestinal symptoms; their symptoms disappeared with eradication. A role of Bh as a cause of IBS-like symptoms is suggested but is still controversial; several clinical and epidemiological studies implicate Bh as a pathogen, but others consider it to be a commensal (1,20). Windsor et al (13) advised that Df not be overlooked in these patients because Df could be the cause of the symptoms, but it is more difficult to detect. In a recent double-blind placebo-controlled study, 37 children with RAP as their only complaint and Bh as the only pathological finding were treated with trimethoprim/sulfamethoxazol or placebo. Eradication was 35% in the trimethoprim/sulfamethoxazol group and 29% in the placebo group. Decrease in the pain score was comparable in both groups and independent of the detection of Bh at the end of treatment (10).
Df and Gl have a worldwide distribution; Bh is suggested to be more frequent in developing countries (2,3,20). We found protozoa more often in patients of western European descent than in patients of nonwestern European descent.
The characteristics of the patients, including pain in the different patient groups, showed no remarkable differences. We conclude that clinical presentation does not indicate which patients should be tested for parasites. We found a causal relation between RAP and protozoan infection in 25 of 73 patients, whereas in the remaining patients, the abdominal pain appeared not to be related to the parasites.
Our results suggest that Df can be associated with RAP. Our observations in 5 patients with reinfection with Df can be seen as a confirmation of the causal relation.
Only 2 of 25 patients with abdominal pain caused by protozoan infections had Bh only; all of the other patients had Df, Gl, or a combination. This number is too small to conclude that Bh infection can cause RAP on its own, more so because Df can easily be overlooked by the presence of Bh in a stool sample (13).
It is of interest that 11 of 25 patients with a causative protozoan infection had a second diagnosis (7): there was a lasting, remarkable reduction of their pain by eradication of the parasite, but sometimes pain was still present; after a second intervention, laxative therapy in most, the pain totally disappeared.
The percentage of infected patients in our study is 34%, and is comparable with other studies (2,3). Success of eradication on complaints (34%) is lower than found in these studies (82%–100% (2–4)). This difference is probably explained by selection bias because TFT in these studies is performed because of acute gastrointestinal complaints as opposed to the RAP in our study. Moreover, our strict criteria for a causal relation of protozoan infection and RAP could play a role. In total, 11% of patients with RAP have a protozoan infection as the cause of the pain (21–23).
The limitation lies in the difficulty of diagnosing parasitic disease with certainty as the cause of the pain. We chose a follow-up of at least 6 months to restrict the possibility that parasites were falsely considered to be the cause of the pain (24); however, these data need confirmation from other studies to acquire more certainty about the effects of protozoan infections.
The strengths of this prospective study lie in the diagnostic procedure based on therapeutic intervention and a pain-free follow-up and in the comparison of pain characteristics in patients diagnosed as having and as not having parasites as the cause of the pain.
In conclusion, protozoa were found in 6% of children, with RAP as the cause of the pain, and possibly in another 5% in combination with another diagnosis, according to our criteria. Patients with protozoan infections as the cause of RAP did not show a characteristic presentation when compared with patients with other causes of abdominal pain.
The authors thank Rimke Vos for statistical support.
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