Post-infectious gastrointestinal symptoms after acute Giardiasis. A 1-year follow-up in general practice

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1 Family Practice Advance Access published March 22, 2010 Family Practice 2010; 0:1 5 doi: /fampra/cmq005 Ó The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org. Post-infectious gastrointestinal symptoms after acute Giardiasis. A 1-year follow-up in general practice Knut-Arne Wensaas a,b, *, Nina Langeland c,d and Guri Rortveit a,b a Section for General Practice, Department of Public Health and Primary Health Care, University of Bergen, Bergen, b Research Unit for General Practice, Uni Health, Bergen, c Department of medicine, Haukeland University Hospital, Bergen and d Institute of Medicine, University of Bergen, Bergen, Norway. *Correspondence to Knut-Arne Wensaas, Research Unit for General Practice, Uni Health, Kalfarveien 31, N-5018 Bergen, Norway; knut-arne.wensaas@isf.uib.no Received 23 July 2009; Accepted 16 February Background.Giardia lamblia is endemic in many tropical and subtropical areas of the world, and in Europe and North America a common cause of waterborne outbreaks of gastroenteritis. In 2004, 5000 people were sick with giardiasis during an outbreak in Bergen, Norway. Objective. To investigate the presence of gastrointestinal complaints and persistent infection in a 1-year period after acute giardiasis. Methods. From a population (N = 7100) assigned to two general practice clinics, a cohort of 134 patients with clinically defined giardiasis was identified. Of these, 118 gave consent to take part in this study. The patients were asked to submit stool samples 6 months after the acute infection and to return questionnaires delivered by mail 6 and 12 months after the outbreak. Main outcome measures were proportion of patients with persistent infection and/or gastrointestinal symptoms. Results. Stool samples were submitted by 69.5% (82/118) of the patients after 6 months, and three were positive for G. lamblia. After 6 months, 37.3% (44/118) of the patients reported gastrointestinal symptoms related to their Giardia infection. This proportion went down to 19.2% (19/99) after 12 months. The reported water intake prior to the outbreak was significantly higher in patients with persistent symptoms, but there was no association with gender and neuroticism as has been shown in other studies of functional gastrointestinal disorders. Conclusion. Persistent gastrointestinal symptoms are a common complication after giardiasis in a population most likely previously unexposed to G. lamblia. The results show the need for further investigation of the mechanism involved. Keywords. Disease outbreaks, Giardia lamblia, giardiasis, parasitic intestinal disease, primary health care. Introduction Giardia lamblia is a common cause of gastroenteritis worldwide. The parasite is endemic in many parts of the world, mostly in lower income countries in tropical and subtropical areas. In North America and Europe, giardiasis occurs as isolated cases or in outbreaks, most often caused by contamination of water supplies. G. lamblia can be found as a cause of acute and chronic infection and also in persons who are asymptomatic carriers. 1 Following bacterial gastroenteritis, post-infectious gastrointestinal complaints are described, 2 4 but there is limited knowledge about late complications after acute giardiasis. In the autumn of 2004, there was a large outbreak in Bergen, Norway, and 5000 people were estimated sick with giardiasis. 5 Generally, patients in the Bergen outbreak had low-grade symptoms during the infection and the treatment of patients was mainly handled in general practice. The aim of the present study was to investigate the presence of gastrointestinal complaints and persistent infection among patients in a 1-year period after the initial infection. Methods Participants We identified a cohort of patients from two general practices serving a total of 7100 people and located inthe area supplied with drinking water from the Page 1 of 5

2 Page 2 of 5 Family Practice an international journal contaminated reservoir. Based on a clinical case definition, 134 patients were found to have giardiasis. Excluding 15 patients who either declined to be part of the study or did not respond to the request, 119 were included in a study based on data from the medical records at the general practices. 6 All 119 patients were asked to take part in this follow-up, but one of them did not want further participation. The majority of patients were female, 69.5% (82/118). The mean age was 37 years (SD 18) with most patients being adults, nine (7.6%) were <20 years old and 12 (10.2%) were >60 years. Procedure Six months after the outbreak, the patients were asked to submit three stool samples to be analysed for G. lamblia cysts. The samples were from three different days and they were analysed by direct microscopy at the laboratory at Haukeland University Hospital, Bergen. All patients received questionnaires sent by mail 6 and 12 months after the initial infection. In both questionnaires, patients were asked whether they had gastrointestinal complaints that they attributed to their Giardia infection. Patients who reported complaints were asked to mark from a specified list, which symptoms they had experienced at least 2 days during the last week. The symptoms on this list were chosen based on clinical observations by the authors and known symptoms of acute giardiasis. 7 At 6 months, the patients were also asked to quantify the amount of water they usually drank during a normal day prior to the outbreak (number of glasses of 1.5 dl). At 12 months, they were asked to answer the neuroticism part of the short scale Eysenck Personality Questionnaire (EPQ-N). 8 This consists of 12 questions to be answered by yes or no, giving a total score between 0 and 12. Data concerning previous gastrointestinal complaints (whether or not they had seen their GP for gastrointestinal problems in a 3-year period prior to the outbreak) and the acute phase of the infection (result of stool sample, time from symptoms until treatment and treatment) were obtained from the medical records as part of the previous study. 6 Outcome measures In the primary analysis, we evaluated the presence of persistent infection and symptoms after acute giardiasis in this cohort. In the secondary analysis, we excluded patients with positive stool samples and investigated whether certain characteristics were associated with post-infectious symptoms. Patients who answered that they were unsure if they had symptoms related to giardiasis were classified as being without relevant symptoms. Statistical analyses All data were analysed in SPSS version Chisquare test or Fischer s exact test was used to test differences between proportions and Student s t-test to test differences for continuous variables. Relative risks are given for categorical variables and mean differences for continuous variables in the secondary analysis. All tests were two sided, and level of statistical significance was set at P < Results All 118 patients returned the questionnaire after 6 months, and 99 (83.9%) returned the questionnaire after 12 months. This corresponds to 88% and 74%, respectively, of the original 134 patients identified from the medical records at the two general practices. Six months after the outbreak, 44 individuals (37.3%) reported symptoms, which they related to the infection; another six (5.0%) were unsure. After 12 months, 19 out of 99 patients had symptoms (19.2%), while another 10 were unsure (10.1%). Prevalence of different symptoms is given in Table 1. Stool samples were submitted 6 months after the initial infection by 82 patients (69.5%), among them 36 of the 44 patients with symptoms (82.8%). Three samples (3.4%) were positive for G. lamblia, all among symptomatic individuals. At 12 months, 37% (7/19) of the patients with Giardia-related symptoms, and 10% (1/10) of those who were unsure they had Giardia-related symptoms, had seen a medical doctor about their complaints since answering the previous questionnaire 6 months earlier. In the secondary analysis, the groups with and without persistent symptoms were compared (Table 2). The only characteristic that was significantly different between the groups was that patients with symptoms 6 months after the acute infection reported a higher intake of water before the outbreak. After 12 months, the patients with symptoms also reported a higher TABLE 1 Prevalence of symptoms 6 and 12 months after acute giardiasis Follow-up time 6 months 12 months n % n % Total number of patients Patients with gastrointestinal complaints More frequent stools Loose stools Loose/watery stools >5 times daily Nausea Abdominal pain Distension Foul-smelling stools/flatulence Other complaints a a Constipation, tiredness/fatigue, weight loss and milk intolerance.

3 Post-infectious gastrointestinal symptoms after acute Giardiasis Page 3 of 5 TABLE 2 Characteristics of patients with and without persistent symptoms 6 and 12 months after acute giardiasis Follow-up time 6 months, N = months, N =96 RR Difference No symptoms, n =80 Symptoms, n =16 RR Difference No symptoms, n =74 Symptoms, n =41 Age, years ( 5.7 to 8.4) N/A ( 11.7 to 7.8) N/A Female, % (n) 68.3 (28) 70.3 (52) N/A 0.9 (0.6 to 1.6) 62.5 (10) 76.3 (61) N/A 0.6 (0.2 to 1.5) Stool test positive for Giardia during acute infection, % (n) 56.1 (23) 54.1 (40) N/A 1.1 (0.6 to 1.7) 56.3 (9) 60.0 (48) N/A 0.9 (0.4 to 2.2) Gastrointestinal complaints prior to infection, % (n) 12.2 (5) 12.2 (9) N/A 1.0 (0.5 to 2.1) 12.5 (2) 10.0 (8) N/A 1.2 (0.3 to 4.6) Treatment received for acute giardiasis, % (n) 70.7 (29) 77.0 (57) N/A 0.8 (0.5 to 1.4) 75.0 (12) 76.3 (61) N/A 0.9 (0.4 to 2.6) Mean interval from symptoms until treatment, weeks ( 0.4 to 2.2) N/A ( 2.3 to 1.4) N/A Daily intake of water prior to infection, glasses 1.5 dl (0.4 to 3.9)* N/A ( 1.6 to 3.6) N/A EPQ-N total score (0 12) 12 months after infection (N = 92) ( 0.9 to 1.3) N/A ( 2.2 to 0.7) N/A Three patients with Giardia cysts in stool samples at 6 months are excluded. CI, confidence interval; N/A, not applicable; RR, relative risk. *statistically significant at 0.05 level. water intake prior to the infection than those without symptoms, but the difference was not statistically significant. The mean time interval from start of symptoms until treatment for the whole cohort was 5.7 weeks, SD 3.0, range 1 16 weeks. There was no statistically significant difference in the time from start of symptoms until treatment between the groups 6 or 12 months after the outbreak. Of the 99 patients returning the questionnaire after 12 months, 95 completed the EPQ-N, including the three patients with positive stool samples at 6 months. For the whole study group, females had a higher, however not statistically significant, mean EPQ-N total score than males, 2.7 versus 1.5 (P = 0.055). There was no statistically significant difference in EPQ-N scores between those with and without complaints neither at 6 months nor at 12 months after the acute infection. We also did analyses including the three patients with positive stool samples and reclassifying patients who were unsure whether they had symptoms related to their Giardia infection to the group with symptoms. The results were not changed essentially (data not shown). Discussion The main finding in this study is that a large proportion of the patients had gastrointestinal symptoms which they related to giardiasis up to 1 year after the acute infection but with substantial reduction in the proportion of patients with symptoms from 6 months (37.3%) to 12 months (19.2%) follow-up. We did not find correlations with characteristics observed in previous studies on post-infectious symptoms after bacterial gastroenteritis, like gender and neuroticism. 9 The major strength of the current study is that we followed a high proportion of giardiasis patients belonging to two general practices 6 months (88%) and 12 months (74%) after the outbreak. Due to the size of the outbreak, the location of the two practices and the high participation rate, the actual number of patients in the study is high (n = 118 and n = 99 after six and 12 months, respectively). The use of general practice populations as the source population for the study is highly relevant since the majority of patients was treated by their GP during the outbreak and was never seen in hospital outpatient clinics. Another strength of the study is the use of a clinical case definition, which was possible because we had access to all medical records. When we initiated this study, we could not find any published reports of complications after giardiasis in adults, including risk of developing functional gastrointestinal disorders (FGID). One weakness in our study is that we have little information on severity of symptoms and that questions were not designed to diagnose FGID according to set criteria, for instance

4 Page 4 of 5 Family Practice an international journal Rome III. 10 On the other hand, the questions were aimed specifically at gastrointestinal symptoms observed by the authors in their clinical practice after the outbreak, and the findings in the current study guided the development of a questionnaire used in another study from this outbreak. 11 Most patients in this study received treatment during the acute phase of the infection, and many received several courses of metronidazole. Analyses of stool samples after 6 months showed a high success rate of treatment, and we conclude that the majority of patients with symptoms at this time point had a post-infectious condition and not persistent infection. Furthermore, we conclude that the reported symptoms were caused by giardiasis and were not merely irritable bowel syndrome (IBS)-symptoms that the patients might have had previously. The patients were specifically asked only about symptoms that they related to their Giardia infection. The conclusion is also supported by a study that reported the prevalence of IBS to be 8.4% in a general Norwegian population, 12 which is much lower than the prevalence of symptoms in the current study. Few patients saw a physician in the period between 6 and 12 months after the acute infection, even if they still had symptoms. This could imply that the symptoms were mild, but other explanations are possible. Patients may have had low expectations about what could be done since most of them had tried several courses of antibiotic treatment, 6 and the treatment options for FGID are limited. 13 The finding that the majority of patients with persistent symptoms did not seek medical care points out some of the challenges facing investigators. There is a risk of selection bias when recruiting patients from medical centres, even in primary care. The problem will be even greater if a study population is recruited from secondary or tertiary care. It also addresses the limitations when using doctor-seeking behaviour as a method for describing disease burden in a society. The local authorities in Bergen claimed full responsibility for the contamination of the water reservoir, and 5 months after the outbreak was first known, the municipality of Bergen publicly informed that they would give patients compensation for any economic loss. This may have influenced how patients responded to the questionnaires, but several factors suggest that the impact is small. Compensation was restricted to economic loss, and therefore relatively independent of persistence or severity of post-infectious symptoms. If focus on compensation should make patients report more symptoms, we would expect them also to see physicians with their complaints, but few patients did so in the follow-up period. Therefore, we do not think that symptoms were exaggerated to support demand for economic compensation, but we cannot rule out that patients had a greater focus on complications as a result of sustained focus on the matter in the mass media and the community. Water intake prior to the infection was the only factor that was significantly different in the groups with and without persistent symptoms, but since the answers were given 6 months after the outbreak, there is a risk of recall bias. Water intake can be taken as an indirect measure of ingested cysts and parasite load. A previous study showed that high water intake was associated with giardiasis during this outbreak (OR 5.9). 5 Our findings suggest that high parasite load may also increase the risk of post-infectious disorders. In accordance with this, it could be expected that prolonged time from infection until treatment would also play a role. We did not find this time frame to be significantly different between the groups, but our study lacks power to rule out such a correlation. More women than men were infected during the outbreak, and the ratio (2:1) is reflected in our study. This has been explained by higher water intake among women. 5 We did not find any difference in prevalence of long-term gastrointestinal symptoms between genders. Some studies have shown a higher prevalence of post-infectious irritable bowel syndrome (PI-IBS) in women. 4,14 On the other hand, two studies investigating development of IBS after gastroenteritis with a specific time frame and known pathogens, Salmonella and Shigella, do not show any differences between genders. 3,15 Even though women are more at risk of FGID overall, 16 the findings in this and the other studies may imply that the risk of developing IBS is not higher among women following certain types of specific gastroenteritis. If so, it is possible that previously found correlations between gender and PI-IBS are due to confounding factors, like co-morbidity, psychological distress or health seeking behaviour, as has been discussed elsewhere. 9,17 It is still possible that some of the inconsistency between the studies is explained by different pathogens being involved. These are issues that need to be investigated further. Studies have shown that psychological factors, like neuroticism, anxiety and depression, increase the risk of PI-IBS 18 and other FGID. 19 These findings have been discussed in relation to gender as women generally seem to experience more psychological distress in population-based studies. 9 In our study, there was a difference in EPQ-N score between the genders, although not statistically significant, which to some extent support that the scores obtained in this study are valid by reflecting previously found gender differences. However, we did not find any correlation between EPQ-N score and persistent symptoms. The range of the 95% confidence intervals gives reason to conclude that gender and neuroticism are not important risk factors for development of postinfectious symptoms after acute giardiasis in this cohort. It is not clear whether this lack of correlation

5 Post-infectious gastrointestinal symptoms after acute Giardiasis Page 5 of 5 should be interpreted as something specific to giardiasis, suggesting that there are special mechanisms involved in parasitic infection. Alternatively, this could pertain to a more universal understanding of psychological factors and their role in FGID. The conclusion of the current study is that giardiasis seems to induce post-infectious gastrointestinal symptoms resembling IBS in a population with previously little or no exposure to giardiasis. The symptoms are attenuated from 6 to 12 months after the infection. Factors otherwise known to be associated with IBS do not seem to be associated with the persistent bowel symptoms in patients who have experienced giardiasis. Declaration Funding: Municipality of Bergen. Norwegian Medical Association s Funds for Research in General Practice (KAW). Ethical approval: Regional Committee for Medical Research Ethics and by the Ombudsman for Privacy in Research, Norwegian Social Science Data Services. Conflict of interests: none. References 1 Farthing MJ. Giardiasis. Gastroenterol Clin North Am 1996; 25: Spiller R, Campbell E. Post-infectious irritable bowel syndrome. Curr Opin Gastroenterol 2006; 22: Mearin F, Perez-Oliveras M, Perello A et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 2005; 129: Marshall JK, Thabane M, Garg AX et al. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology 2006; 131: Nygard K, Schimmer B, Sobstad O et al. A large community outbreak of waterborne giardiasis delayed detection in a nonendemic urban area. BMC Public Health 2006; 6: Wensaas KA, Langeland N, Rortveit G. Prevalence of recurring symptoms after infection with Giardia lamblia in a nonendemic area. Scand J Prim Health Care 2009; 27: Hopkins RS, Juranek DD. Acute giardiasis: an improved clinical case definition for epidemiologic studies. Am J Epidemiol 1991; 133: Eysenck SBG, Eysenck HJ, Barrett P. A revised version of the psychoticism scale. Pers Individ Dif 1985; 6: Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology 2003; 124: Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006; 130: Morch K, Hanevik K, Rortveit G, Wensaas KA, Langeland N. High rate of fatigue and abdominal symptoms 2 years after an outbreak of giardiasis. Trans R Soc Trop Med Hyg 2009; 103: Vandvik PO, Lydersen S, Farup PG. Prevalence, comorbidity and impact of irritable bowel syndrome in Norway. Scand J Gastroenterol 2006; 41: Spiller R, Aziz Q, Creed F et al. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007; 56: Gwee KA, Graham JC, McKendrick MW et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996; 347: Ji S, Park H, Lee D et al. Post-infectious irritable bowel syndrome in patients with Shigella infection. J Gastroenterol Hepatol 2005; 20: Chang L, Toner BB, Fukudo S et al. Gender, age, society, culture, and the patient s perspective in the functional gastrointestinal disorders. Gastroenterology 2006; 130: Gwee KA, Leong YL, Graham C et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999; 44: Drossman DA, McKee DC, Sandler RS et al. Psychosocial factors in the irritable bowel syndrome. A multivariate study of patients and nonpatients with irritable bowel syndrome. Gastroenterology 1988; 95: Tanum L, Malt UF. Personality and physical symptoms in nonpsychiatric patients with functional gastrointestinal disorder. J Psychosom Res 2001; 50:

Irritable Bowel Syndrome and Chronic Fatigue 6 Years After Giardia Infection: A Controlled Prospective Cohort Study

MAJOR ARTICLE Irritable Bowel Syndrome and Chronic Fatigue 6 Years After Giardia Infection: A Controlled Prospective Cohort Study Kurt Hanevik, 1 Knut-Arne Wensaas, 2 Guri Rortveit, 2,3 Geir Egil Eide,