Giardia-epidemien del 1: Hvem er parasitten bokstavelig talt?

Tidligere denne uken (5 juli 2012) så plopper det opp i facebook-feederen fra The CFIDS Association of America at der har kommet en ny publikasjon om og etter Giardia-epidemien i Bergen i 2004. «The impact of atopic disease on the risk of post-infectious fatigue and irritable bowel syndrome 3 years after Giardia infection. A historic cohort study” skrevet av Gunnhild S. Hunskar 1, Nina Langeland2, Knut-Arne Wensaas1,3, Kurt Hanevik2,4, Geir Egil Eide5,1, Kristine Mørch4,6 & Guri Rortveit1,3. Forfatterne gir stor grunn til nærmere undersøkelser og ikke uten grunn, CFS/ME er i deres øyne MUPS. Som du nå sikkert allerede har forstått ønsket derfor undertegnede å se på relevansen for om dette omhandler ME-pasienter og sykdommen ME etter Giardia-infeksjon, samt om hvorvidt/hvordan ME både omtales og utskilt som egen subgruppe i de tre foregående publikasjonene. Ett par tastetrykk senere og «parasittene» er detektert i forsknings-ledningsnettet for kloakk og overflatevann.

Knut-Arne Wensaas og en doktorgrad:

Universitetet i Bergens hjemmeside finner vi følgende info: Knut-Arne Wensaas (f. 1964) er oppvokst på Geilo, og tok medisinsk embetseksamen ved Universitetet i Bergen 1993. Han er spesialist i allmennmedisin siden 2001 og jobber som fastlege ved Kalfaret legesenter i Bergen og som forsker ved Allmennmedisinsk forskningsenhet, Uni Helse, Uni Research.

Doktorgradsarbeidet utgår fra Forskningsgruppen for allmennmedisin, Institutt for samfunnsmedisinske fag, Universitetet i Bergen, med professor Guri Rørtveit og professor Nina Langeland som veiledere.

Knut-Arne Wensaas disputerer fredag 25. 11.2011 for ph.d-graden ved Universitetet i Bergen med avhandlingen  “Giardiasis in Bergen. Outbreak and clinical consequences.”

Høsten 2004 ble Bergen rammet av et stort utbrudd med magesyke forårsaket av Giardia lamblia. Det er anslått at mer enn 5000 personer ble syke av parasitten.

To pasientgrupper er undersøkt. 134 personer oppsøkte høsten 2004 fastlege ved to legekontor i Bergen sentrum på grunn av sykdom som passet med akutt Giardia-infeksjon. Hos 119 av disse ble forløpet kartlagt. De fleste ble friske, men det var en del som ikke ble bra. Av 89 som fikk behandling oppsøkte 32 lege på nytt fordi symptomene vedvarte. 25 pasienter fikk ny behandling, og 10 av disse ble også behandlet en tredje gang. Etter dette ble fem pasienter henvist til sykehuset for videre oppfølging.

Da pasientene ble spurt seks måneder etter utbruddet svarte 37 % at de hadde mageplager som var nyoppståtte etter Giardia-infeksjonen. Etter 12 måneder oppga fortsatt 19 % slike plager.

Tre år etter utbruddet ble symptomer kartlagt hos en større gruppe Giardia-pasienter. 1252 personer som hadde fått påvist Giardia i avføringsprøve og en kontrollgruppe uten gjennomgått Giardia-infeksjon fikk tilsendt et spørreskjema i posten.

Blant 817 som hadde hatt Giardia oppfylte 46 % kriteriene for diagnosen irritabel tarm-syndrom, og 46 % hadde symptomer på kronisk utmattelse.

I kontrollgruppen var andelen med slike plager henholdsvis 14 % og 12 %.

Studien har ikke undersøkt forekomst av tilstanden som kalles kronisk utmatteselssyndrom, som er en diagnose som stilles på bakgrunn av legeundersøkelse og omfattende utredning.

Tidspunkt og sted for prøveforelesningen:
24.11.2011, kl. 14.15. Oppgitt emne: «Chronic fatigue, fibromyalgia and other medically unexplained syndromes – separate entities or variations of the same theme?»

***

Hva står i Doktorgradsavhandlingen 25 november 2011?

“Giardiasis in Bergen. Outbreak and clinical consequences.”

Doktorgraden er skrevet på engelsk. Jeg tar med sammendraget, hvilke publikasjoner, metode og kontrollpersoner og annet av relevans. Jeg har ikke oversatt teksten. Se oppsummering/diskusjon og henviser selvsagt til originalpublikasjoner, både avhandlingen og de tre publikasjonene som er oppgitt.

Background

Giardia lamblia is a common cause of waterborne disease. It is endemic in many parts of the world, especially where sanitation is poor, but in Europe and North america it is most often encountered in outbreaks following contamination of drinking water.

The first registered outbreak of giardiasis affecting a large community in Norway happened in Bergen in the autumn of 2004. The reservoir “Svartediket” was the source, and the water probably held Giardia cysts for several weeks.

 Giardia can cause acute and chronic gastroenteritis. Several drugs constitute effective treatment, and metronidazole is the main drug available in Norway.

Prior to the outbreak in Bergen there were no published studies on long term effects after eradication of the parasite.

 Aims

The aim of the studies in this thesis is to investigate the course of giardiasis and its consequences following a large outbreak in an area where Giardia is not endemic.

 Methods

In the first study, we concentrated on patients from general practice. Patients with clinically defined giardiasis were identified through a search in the medical records at two general practice clinics located in the area receiving water from the contaminated reservoir.

Of the 7,100 persons registered, 134 fulfilled the inclusion criteria and 119 consented to take part in the study.

Data were retrospectively obtained from the medical records. The patients were then requested to complete a mailed questionnaire and submit stool samples six months after the outbreak.

A second questionnaire was sent out one year after the outbreak. The main outcome variable was abdominal symptoms that were not present prior to the acute infection.

In the second study, we investigated a historic cohort of 1252 patients with giardiasis verified by detection of Giardia in stool samples submitted as part of regular clinical investigations in Bergen during the outbreak.

A 2:1 control group matched by age and gender was recruited from the general population of Bergen. This group was later expanded so that the whole control group consisted of 3594 individuals.

All participants received a questionnaire by mail three years after the outbreak. Main outcome variables were irritable bowel syndrome (IBS) according to Rome III criteria and “chronic fatigue” as defined by the Fatigue Questionnaire.

 Results

In the group of patients from general practice the majority was between 20 and 39 years of age (51.4%), and there were more women (69.3%) than men. The diagnosis was supported by a positive test for Giardia lamblia in 55% (66/119) of the patients.

Treatment with metronidazole was given to 89 (75%), and after initial treatment 36%

(32/89) returned to their doctor because symptoms recurred. A second prescription was given to 28% (25/89), after which 16% (14/89) returned once more. 11% (10/89) received a third treatment with metronidazole. Six months after the outbreak stool samples were positive for Giardia in three of 82 patients. At this point 37% (44/118) reported gastrointestinal symptoms related to their Giardia infection, and after 12 months this proportion was 19% (19/99).

In the cohort of patients with laboratory verified giardiasis the prevalence of IBS three years after the outbreak was 46% (355/770), compared to 14% in the control group. The adjusted relative risk (RR) was 3.4 (95% confidence interval (CI) 2.9 to 3.8).

The prevalence of chronic fatigue was 46% (366/794) among the Giardia patients, and 12% among the controls, giving an adjusted RR of 4.0 (95% CI 3.5 to 4.5). IBS and chronic fatigue were associated, but there was also an increased risk of having IBS only (RR 1.8, 95% CI 1.4 to 2.3) or chronic fatigue only (RR 2.2, 95% CI 1.7 to 2.8).

Discussion

In the study from general practice we identified patients that would have been missed by a strict laboratory based inclusion criterion, either because stool samples were not submitted or due do misclassification when samples were negative.

Several patients did not receive treatment and this could suggest that they did not have giardiasis, but another reason could be that they called at the medical centre before the outbreak was known and recovered spontaneously without treatment. After clearance of the parasite a substantial proportion of the patients had persisting symptoms 6 and 12 months after the outbreak, which shows that potential negative health effects of giardiasis was more extensive than first anticipated.

In the cohort of persons with verified giardiasis the infection was associated with a high prevalence of IBS and chronic fatigue three years after the outbreak, and the risk was significantly higher than in the control group. This supports the findings in the group from general practice, and shows the consequences in a larger population and over a longer period of time. The prevalence of IBS in this study and gastrointestinal symptoms in the first one differs, but cannot be easily compared. The sample sizes vary, the case definitions are different and the questionnaires used to define the outcomes are not the same. Put together the two studies illustrate a wider range of the clinical consequences after the outbreak.

Conclusions

These studies show that a considerable proportion of patients consistently had persisting symptoms after giardiasis from the time of the acute infection and up to three years after. The association between acute giardiasis and later gastrointestinal symptoms and fatigue is strong. This calls for more research on the mechanisms for both giardiasis and medically unexplained physical symptoms like IBS and chronic fatigue.

List of publications

I. Wensaas KA, Langeland N, Rortveit G. Prevalence of recurring symptoms after infection with Giardia lamblia in a non-endemic area. Scand  J Prim Health Care. 2009;27:12-7. Full tekst

II. Wensaas KA, Langeland N, Rortveit G. Post-infectious gastrointestinal symptoms after acute Giardiasis. A 1-year follow-up in general practice. Fam Pract. 2010;27:255-9. Full tekst

III. Wensaas KA, Langeland N, Hanevik K, Mørch K, Eide GE, Rortveit G. Irritable bowel syndrome and chronic fatigue three years after acute giardiasis: historic cohort study. Manuscript accepted for publication. Publisert online 12 september 2011. Abstrakt.

Full tekst:

Upload pdf:

Kapitel 1.3 om post-infeksiøs konsekvens/komplikasjoner er å lese: 

1.3 Postinfectious complications

Infections can cause permanent injury and evident sequelae. However, in some cases patients experience loss of function and persisting symptoms that are difficult to define and without explanatory objective findings. Two conditions that are often investigated are irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS).

Both are linked to infections, but are also found in patients without a history of preceding infectious disease.

1.3.1 Irritable bowel syndrome

IBS is a common gastrointestinal disorder, both in the general population and in patients seen in clinical practice. The reported prevalence varies between 2.5% and 37%, reflecting differences in settings and diagnostic criteria(123). The Rome process aims to reach consensus on criteria for functional gastrointestinal disorders and develop valid questionnaires to use in research and clinical practice. The criteria have been revised on four occasions, last in 2006 (Rome III)(124).

Diagnosis of IBS is based on the presence of abdominal pain or discomfort for a defined period of time and linked to alterations in bowel habits(125). The practical use of the agreed criteria still faces obstacles, as illustrated by a study comparing Rome II criteria and the clinical judgement of Norwegian general practitioners (GPs)(126). There was poor agreement, both in overall prevalence of IBS and in which patients that were identified. Reasons might be that the GPs also emphasized psychosocial factors and that in clinical practice others symptoms, for instance bloating and loose stools, are often considered essential parts of the syndrome. As a result IBS will be diagnosed more often in patients with co-morbidity, and less often in patients with few symptoms restricted to the alimentary tract.

Increased incidence of IBS has been documented after bacterial gastroenteritis caused by Salmonella(127, 128), Shigella(129, 130) Campylobacter(131, 132) and mixed Campylobacter/E. coli O157:H7(133), as well as after infection with the roundworm Trichinella(134). In one study on IBS following viral gastroenteritis, probably Norovirus-infection, 23% reported IBS after 3 months, but after 6 months the prevalence was no higher than in the control group (135). In a study on hospitalized patients in the UK there was a higher incidence of IBS after gastrointestinal (GI) infections, but unexpectedly also after non-GI infections compared to controls without infection(136). This study was small and the findings should be confirmed in other studies, but it reflects that mechanisms for IBS are complex.

One study found clinical and histological differences between patients with postinfectious IBS (PI-IBS) and IBS without history of precipitating infection(137).

This suggests that PI-IBS is a clinically distinct subgroup of IBS. Several factors have been associated with an increased risk for PI-IBS, both pathogen and patient characteristics(138). In one study the toxicity of the strain was a risk factor for IBS six months after infection with Campylobacter(132). Prolonged duration of the acute illness in bacterial gastroenteritis plays a role(129, 139), but it is not clear whether this is a proxy for bacterial toxicity or patient vulnerability.

Receiving antibiotic therapy for Salmonella infection was associated with increased risk of IBS in an observational study(140). However, since there was no control group interpretation is difficult. Smoking was found to be a risk factor for PI-IBS in one study, but few participants (18 with IBS among a total of 127) and lack of obvious mechanisms for the role of smoking make conclusions uncertain(141).

The biopsychosocial model is considered helpful in the understanding of IBS(142), and different psychosocial factors have been investigated in a few studies on PI-IBS.

Depression(131), hypochondriasis and adverse life events (143) have been shown to be independently associated with IBS in multivariate analyses. Patients with bacterial dysentery who developed PI-IBS scored higher on anxiety, depression, somatization and neuroticism than did controls in another study(144).

IBS is more common among women with a reported female:male ratio up to 2.5. The association is stronger in clinical studies than in population based studies, and stronger in the Western countries compared to Asia(145).

This suggests that both health care seeking behaviour and cultural differences may confound the results. In studies on PI-IBS there are conflicting results on the role of gender, but it seems like the impact of gender is smaller. Following the Walkerton outbreak in 2000 (mixed Campylobacter/E. Coli) a large number of patients developed IBS and the OR for female gender was 1.5 (95% CI 1.1 – 1.9)(133). Some other studies have demonstrated a higher incidence in women(127, 139), but others have not. No gender difference in development of IBS was found among patients with Shigella infection in China(129)or traveller’s diarrhoea in Israel(146), or after outbreaks of Salmonella infection in Spain(128) and Shigella infection in Korea(130).

 1.3.2 Chronic fatigue

Fatigue is a common feature of different diseases such as cancer, infections, hypothyroidism, marked anaemia and psychiatric disorders. It is an unspecific symptom, and most often there is little focus on fatigue in the acute phase. As a symptom in prolonged loss of function after apparent recovery it occupies a more prominent place.

It is the key symptom in chronic fatigue syndrome (CFS) which during the last years has received more attention as it affects people of young age and in many cases causes profound loss of function. Epidemiological data are uncertain, but estimates converge on a prevalence around 0.4-1.0% (147, 148).

There are no specific tests that will confirm CFS. It is a clinical diagnosis based on thorough investigation to exclude other conditions that can explain the fatigue. Several definitions have been proposed for the diagnosis and although they include many of the same criteria they differ to some extent in duration and number of required symptoms (149-151). Presence of persisting severe fatigue of new onset is mandatory in all definitions, and in addition there should be a number of other symptoms, for instance sleep disturbances, muscle or joint pain, headaches, cognitive dysfunction, sore throat or painful lymph nodes.

Risk factors for CFS are often divided into predisposing, precipitating and perpetuating factors(147).

Neuroticism and introversion are personality characteristics that have been linked to increased vulnerability to CFS. Around 75% of patients are women, but the reason for this gender difference is not clear(147).

A majority of patients with CFS can relate onset to some sort of infection(152). Studies have shown that several infections can trigger the condition, including Epstein-Barr virus, parvovirus B19, enteroviruses and Coxiella Burnetti(148).

Adverse life events may also trigger CFS. Case-control studies have shown a higher rate of such events among CFS patients in the period prior to onset(153, 154).

Factors that may influence the course and prognosis in CFS can be divided into two main groups. Patients own ideas about the condition and their level of function, their sense of control over symptoms and how they relate to physical activity are linked to degree of fatigue. Interactions with others, such as partner, family and health personnel, also play a role as this will influence perception and behaviour(147).

Treatment studies support that these factors are important as both cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are found to be beneficial(155, 156).

Fatigue will change over time, as observed in patients with CFS. A systematic review concluded that 40% of patients improved over time and 5% eventually recovered fully(157). A more precise account of the time perspective was difficult as the duration of symptoms at inclusion and follow-up period varied between studies.

The degree of perceived fatigue or tiredness will vary along a continuum, with no clear cut-off to differentiate a medical condition from a normal situation in a healthy individual. The degree of fatigue in CFS should be substantial and lead to profound reduction in previous activity-levels. None of the criteria for CFS are based on results from questionnaires that measure fatigue. From this follows that epidemiological studies utilizing questionnaires to assess fatigue cannot identify cases of CFS or “fatigue similar to what is seen in CFS”.

Caseness will be based on a set cut-off to define “fatigue”, “substantial fatigue” or “chronic fatigue” (CF). The value of these studies will depend on using questionnaires that are validated and tested on individuals in different populations.

 1.3.3 Medically unexplained physical symptoms

CFS and IBS belong to a group of conditions labelled “medically unexplained physical symptoms” (MUPS) that also include fibromyalgia and other pain syndromes.

They share the characteristic that the symptoms are not explained by clinical findings or results of laboratory tests. Some investigators argue that these should be considered different manifestations of some common pathologic mechanism(158).

Opposed to this is the view that these conditions are not similar and are better viewed as distinct entities(158).

IBS, CFS and other syndromes are most often investigated separately, but when studied together reviews have concluded that overlap in prevalence is substantial (159, 160). On the other hand, a prospective study on patients with Campylobacter gastroenteritis and mononucleosis found that the two infections predisposed to different postinfectious conditions; gastroenteritis to IBS and mononucleosis to CF/CFS(161).

Om kontrollgruppen som ble brukt (kap. 3, s. 40) kan vi lese:

 3.3.3 Control group

In the study on which Paper III is based we included a control group. Three main issues had to be resolved before the group could be selected. First, we had to define which criteria the individuals in the group should meet. We knew that among those with verified giardiasis there were more women than men, and nearly 50% were in the age group 20 – 29 years(162). In order to balance this we matched the controls by age and gender.

The second issue was to decide which population the controls should be drawn from. We wanted the controls to differ as little as possible from those exposed, and were concerned about the risk of uncontrollable confounders if the sample was drawn from a population in another city in Norway, for instance Oslo or Trondheim.

We ended up recruiting controls from the general population in Bergen, and were aware that some of the controls could have been exposed to Giardia and also infected.

We considered the risk of such misclassification to be acceptable as controls were sampled from the whole of Bergen, and those who reported giardiasis during the outbreak were excluded. Third, we had to decide on the number of controls. Based on the results from a population based study in Norway(169) we assumed the prevalence for chronic fatigue to be 0.11 among the exposed, and a statistician performed a calculation of statistical power using the software East4. When introducing a 2:1 matched control group of 2,500 individuals we would identify a difference in prevalence of 0.04 between the groups at the 95% power level (two-sided).

We expected the actual difference to be larger, but since we could not meet all the requirements in the model (the designed model is a randomized trial) and we wanted to compensate for potential loss of power after adjusting for other variables in the analyses we concluded that this would be an appropriate sample size.

According to this, Statistics Norway mailed the questionnaire to a group of 2504 control persons matched by age and gender and drawn from the general population in Bergen. Of these, 862 responded (34.4%). In an effort to reduce possible bias caused by this low response rate we decided to expand the control group by adding two more controls for each exposed individual when none of the first two controls had responded. As a result the questionnaire was mailed to 1,094 additional controls six months later (Figure 5).

Fatigue (s. 43/44)

When patients did not get well after the Giardia-infection we expected gastrointestinal symptoms, and in the clinical setting this is what we looked for. But it became evident that fatigue might also be a problem, as several patients spontaneously complained of this. As a consequence we addressed this through a single question in the study performed two years after the outbreak on the group with verified giardiasis, and found a prevalence of 41%(170). We felt it urgent to elucidate this finding and include a validated set of questions on fatigue in the follow-up study.

Several questionnaires are designed to measure fatigue, and we wanted one that had been used in similar setting previously. We considered the scale used by Hickie in an often cited prospective study on postinfectious fatigue following infection with Epstein-Barr virus, Coxiella Burnetti (Q fever) or Ross River virus(176), but it was impossible to elicit which scale had actually been used. The article refers to a 12-item “SOMA”-scale, but the reference given discusses a 10-item “SOFA”-scale(177).

We ended up assessing two scales that have been widely used in different settings; the Fatigue Severity Scale (FSS)(178) and the Fatigue Questionnaire (FQ)(179) in its revised version(180).

Some researchers in the group were familiar with the FSS as it had been used in patients with chronic fatigue syndrome in our area.

However, we landed on the FQ, most importantly because it has been used in a study on fatigue in the general population in Norway(169). The FQ has also been widely used to measure cancer-related fatigue (CRF)(181), and has been considered a useful tool for assessing fatigue in a variety of conditions(182). A later review, from 2009, has questioned whether it discriminates cases from non-cases with acceptable sensitivity and specificity, and its ability to act as an outcome measure sensitive to change with disease progression or treatment. In these respects the FSS is considered to perform better(183).

As with IBS we also designed two categories of more serious fatigue. “Severe fatigue” was defined as the combination of chronic fatigue and a total fatigue score of 23 or more, and “consistent fatigue” as chronic fatigue combined with fatigue present at least 75% of the time.

The term “fatigue” when used in conversation or as a symptom is not easily defined.

Even though we use the generally accepted Fatigue Questionnaire we decided to elaborate further the aspects of this symptom and included Epworth Sleepiness Scale in the questionnaire(184). These data are not yet published.

Predisposing or perpetuating factors (s 44/45)

The group of patients from general practice where asked about prior abdominal complaints in the questionnaire mailed six months after the outbreak. There was poor agreement between the answers to that question and what was documented in the medical records during the previous two years. We decided to use the data from the medical records in the analyses, as they were not influenced by recall bias.

Since both IBS and CFS is associated with several psychosocial factors it would be of interest to obtain data on this. Twelve months after the outbreak the patients were asked to complete the neuroticism-part of the short scale Eysenck Personality Questionnaire (EPQ-N).

When we designed the questionnaire for the three year follow-up, we were unsure about introducing questions on psychosocial factors, like anxiety, depression, hypochondriasis, neuroticism or adverse life events.

We feared that some patients would find the questions irrelevant and that introducing them could reduce the response rate, even if the response rate among those who received the EPQ-N was 81% (95/118).

Another aspect was that the questionnaire should not be too extensive, and the one prepared for the cohort with verified giardiasis (Paper III) already was six pages. As a result we decided not to introduce these variables in the questionnaire.

I Kap 5.2 er ulike tolkninger for vedvarende symptomaktivitet diskutert:         

It is not clear why symptoms persist. A broad approach to the pathogenesis is needed, and focus should be on both pathogen and host factors. The immune response may be important, in particular T-lymphocytes. Their role has been linked to acute giardiasis(199).

In postinfectious IBS T-lymphocyte infiltration has been reported(138) and the conclusion of a systematic review was a trend towards increased T-cell activity in patients with CFS(201).

Another approach to the understanding of both IBS and chronic fatigue has been to focus on the hypothalamus-pituitary-adrenal axis (HPA axis)(202, 203).

There is no obvious one-dimensional connection between giardiasis, or infections in general, and the HPA axis, but this scope opens for a more multidimensional understanding of the pathogenesis of unexplained somatic disorders, including immunological, endocrinological, psychological and even cultural influences.

We have not investigated patient factors that might sustain symptoms, like anxiety, depression, hypochondriasis, adverse life events and patients coping ability and strategies.

The municipality of Bergen claimed full responsibility for the outbreak and decided to give compensation to those affected. The conclusion was reached in the beginning of April 2005, after a period when several patients had voiced their discontent in the media and in meetings with politicians.

This could possibly lead to aggravation of symptoms, both because the dissatisfaction with the authorities could counteract health promoting mechanisms and because symptoms could have consequences for the claims.

On the other hand, having somewhere to place responsibility and blame could move focus from what had happened during the outbreak towards future improvement and coping. Also the benefit of exaggerating the symptoms would be limited as compensation was restricted to any verified economical loss.

Although these considerations will apply in all outbreaks of disease caused by contamination of public water we have not seen this addressed in other studies published after waterborne outbreaks.

We were reluctant to retrospectively introduce questions on psychological factors and adverse life events in mailed questionnaires. We feared that participants would find these issues of limited relevance, and possibly lead to lower response rate. The results would also be vulnerable to recall bias as discussed above. However, in paper II we did include the neuroticism-part of the short-scale Eysenck Personality Questionnaire (EPQ-N) at 12 months. This consists of 12 questions to be answered by “yes” or “no”, giving a total score between 0 and 12(193). Of the 118 persons invited to participate, 99 returned the questionnaire and 95 completed the EPQ-N (80.5% response rate).

The interpretation of the results will be restricted by the cross-sectional design and the low number of patients, but we did not find any correlation between EPQ-N score and persistent symptoms.

Kommentarer og diskusjon:

Som det fremgår av informasjonen fra Universitetet i Bergen:  Studien har ikke undersøkt forekomst av tilstanden som kalles kronisk utmatteselssyndrom.

 Dette betyr at de i realiteten ikke har skilt ut gruppen som utviklet ME etter Giardia-epidemien.

I avhandlingen er likevel CFS nevnt minst 23 steder.

I hovedtrekk diskuterer avhandlingen og de publiserte studiene fra dette forskerteamet Post-infeksiøs IBS (PI-IBS) og trøtthet/utmattelse som vedvarende symptomer.

Om PI-IBS sier han følgende:

“This suggests that PI-IBS is a clinically distinct subgroup of IBS. Several factors have been associated with an increased risk for PI-IBS, both pathogen and patient characteristics(138). In one study the toxicity of the strain was a risk factor for IBS six months after infection with Campylobacter(132). Prolonged duration of the acute illness in bacterial gastroenteritis plays a role(129, 139), but it is not clear whether this is a proxy for bacterial toxicity or patient vulnerability.”

På bakgrunn av tidligere studier foreslås det her at PI-IBS representerer en klinisk undergruppe av IBS. Vedvarende sykdomsaktivitet som følge av akutt bakteriell gastroenteritt spiller en rolle, men det er ikke avklart hvorvidt årsaken er toksisk belastning fra bakterieinfeksjonen eller pasientens sårbarhet.

“The biopsychosocial model is considered helpful in the understanding of IBS(142), and different psychosocial factors have been investigated in a few studies on PI-IBS.”

Her sies det følgende at den bio-psyko-sosiale forklaringsmodellen er fordelaktig i forståelse av IBS og at ulike psykososiale faktorer har vært undersøkt i noen studier på PI-IBS.

“Depression(131), hypochondriasis and adverse life events (143) have been shown to be independently associated with IBS in multivariate analyses. Patients with bacterial dysentery who developed PI-IBS scored higher on anxiety, depression, somatization and neuroticism than did controls in another study(144).”

Depresjon, hypokondri og negative livshendelser har blitt vist til å være uavhengig assosiert med IBS i multivariable analyser. Pasienter med bakteriell dysentri som senere utviklet PI-IBS hadde høyer skår på engstelse/bekymring, depresjon, somatisering og angst enn kontroller i en annen studie.

Kronisk utmattelse:

Denne delen fremkommer synet på sykdommen ME og som en ser av underkapittelet så trekkes her ME i sammenheng med medisinske uforklarte tilstander (MUPS).

“Factors that may influence the course and prognosis in CFS can be divided into two main groups. Patients own ideas about the condition and their level of function, their sense of control over symptoms and how they relate to physical activity are linked to degree of fatigue. Interactions with others, such as partner, family and health personnel, also play a role as this will influence perception and behaviour(147).”

Faktorer som kan influere med utviklingen og prognosen av ME kan deles i to hovedgrupper:

Pasienters egne ideer om deres sykdomstilstand og funksjonsnivå, opplevelse av symptomkontroll og hvordan de relaterer fysiske aktivitet linket til egen sykdomstilstand og graden av utmattelse.

Interaksjon med andre, som parter, familie og helsepersonell, spiller også en rolle og vil influere oppfattelse/opplevelse og adferd.

«Treatment studies support that these factors are important as both cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are found to be beneficial(155, 156).”

Behandlingsstudier med kognitiv behandlingsterapi (CBT) og gradert treningsterapi støtter opp om at disse faktorene er viktig siden disse to behandlingsformene er funnet å være fordelaktige.

—-

Som vi ikke trenger å kommentere vet vi at i praksis stemmer dette ikke overens med sykdommen ME, da bare de med lettere grad kan ha nytte av CBT og GET bør brukes kun for å lære aktivitetsavpasning for å forhindre progressering/forverring av sykdommen. Så da presiserer vi det atter en gang!

Både IBS (irritert tarm syndrom) og sykdommen ME er i dette forskningsteamet i utgangspunktet såkalte diffuse lidelser og går under betegnelsen medisinsk uforklarte sykdomstilstander (MUPS). Vi ser at bio-psyko-sosiale forklaringsmodeller er det som denne forskningsgruppen mener passer best forklart på bakgrunn av at det er få objektive tester og symptomene er forklart av pasienten selv.

Noe som fremkommer også under tolkningsdelen i avhandlingen, der det er foreslått en rekke ulike forklaringer på vedvarende PI-IBS og kronisk utmattelse (CF).

 Pasienter og kontroller:

Pasientene er bekreftet infisert med Giardia via avføringsprøve og det er tatt utgangspunkt i journaler fra disse pasientene.

«Svartediket» forsyner ca 7000 innbyggere i Bergen med drikkevann. Vi ser at forskningsgruppen valgte å bruke kontroller fra Bergen som faktisk kan være eksponert for smitte. Selv om bias blir gjennomgått, så hadde det vært en fordel å bruke kontroller der en med visshet vet at ikke har blitt smittet med Giardia fra epidemien eller ved tidligere eksponering (serologi-test), samt at kontrollen burde ha vært forsikret at de ikke tilfredsstilte kriterier for IBS eller hadde selvrapporterte plager. Det normale er at når en bruker/rekrutterer kontroller så sørger en for at de er absolutt helt friske uten andre sykdommer, lidelser eller plager.

Dette er en svakhet ved sammenligning når vi kommer til både IBS og kronisk trøtthet/utmattelse. Jeg stiller meg derfor både undrende og kritisk til at de faktisk ikke fulgte forskningsetisk standard, samtidig som at det ikke har blitt kritisert mer. De unnskylder seg med at prøvetakning i annen by vil medføre bias, men med daglig fly synes den unnskyldningen noe drøy med hensyn til omfanget i studien og målsetting.

Vi ser også at det berettes at det måtte rekrutteres ytterligere kontroller på grunn av lav svarprosent.

Når vi kommer til bruk av spørsmålskjema, ser vi at de faktisk valgte å avstå fra å benytte seg av the Fatigue Severity Scale (FSS), men heller gå for en generell trøtthet/slitenhetsskala.

I den andre publikasjonen, paper II, så velger de å legge til «neuroticism-part of the short-scale Eysenck Personality Questionnaire (EPQ-N) at 12 months. This consists of 12 questions to be answered by “yes” or “no”, giving a total score between 0 and 12”, altså spørsmål om angst på skala fra 0 til 12, 12 spørsmål ja eller nei.

“The interpretation of the results will be restricted by the cross-sectional design and the low number of patients, but we did not find any correlation between EPQ-N score and persistent symptoms.”

Ingen korrelasjon mellom angst og vedvarende symptomer ble funnet.

 Ett høyt ønske?

“When we designed the questionnaire for the three year follow-up, we were unsure about introducing questions on psychosocial factors, like anxiety, depression, hypochondriasis, neuroticism or adverse life events.

We feared that some patients would find the questions irrelevant and that introducing them could reduce the response rate, even if the response rate among those who received the EPQ-N was 81% (95/118).

Another aspect was that the questionnaire should not be too extensive, and the one prepared for the cohort with verified giardiasis (Paper III) already was six pages. As a result we decided not to introduce these variables in the questionnaire.”

Dette er gjentatt og er ett gjennomgående tema i avhandlingen. Spørsmålet om PI-IBS og CF har sin årsak i psykologiske faktorer og kan støtte bedre under bio-psyko-sosiale forklaringsmodeller. Istedet blir det derfor brukt referanser til andre studier hvor disse spørsmålene er tatt opp og i tolkningsdelen av avhandlingen satt opp nye teser som kanskje kan forklare vedvarende IBS-plager og CF.

For å vite den egentlige årsaken til at de ikke valgte å sette inn ett par ekstra spørsmål må en faktisk inn å se om de egentlig fikk tillatelse fra REK å føye til mer enn det som i utgangspunktet var oppsatt i søknaden. Det er ett ubesvart spørsmål.

Kapitlene 1.1 og 1.2 gir en fin og bra oversikt og er det eneste pluss i denne doktoravhandlingen.

Hovedkonklusjon:

Det har til nå kommet fire publikasjoner, hvor av de første tre er også grunnlaget for doktoravhandlingen til KA Wennsaas.

I. Wensaas KA, Langeland N, Rortveit G. Prevalence of recurring symptoms after infection with Giardia lamblia in a non-endemic area. Scand  J Prim Health Care. 2009;27:12-7. Full tekst

II. Wensaas KA, Langeland N, Rortveit G. Post-infectious gastrointestinal symptoms after acute Giardiasis. A 1-year follow-up in general practice. Fam Pract. 2010;27:255-9. Full tekst

III. Wensaas KA, Langeland N, Hanevik K, Mørch K, Eide GE, Rortveit G. Irritable bowel syndrome and chronic fatigue three years after acute giardiasis: historic cohort study. Manuscript accepted for publication. Publisert online 12 september 2011. Abstrakt.

Full tekst:

Ingen av publikasjonene har skilt ut sykdommen ME som egen gruppe, selv om den i selve avhandlingen er hyppig referert til. Sykdommer som ME og IBS er i denne forskningsgruppen ansett som diffuse lidelser og går under medisinsk uforklarte tilstander (MUPS), sammen med FM og andre kroniske smertetilstander.

MUPS tilstandene blir forklart ut i fra ett bio-psyko-sosialt forklaringsmodell med faktorer som angst, depresjon, engstelse/bekymring, hypokondri, kulturelle og sosiale årsaksforklaringer til vedvarende sykdomstilstand hvor stressteorier og forventninger til egen helsetilstand omtrent er symptomoverført, samt negative livshendelser trigger sykdom. Altså pasienten lider av somatisering eller pseudo-somatisk tilstand.

Publikasjonene tar utgangspunkt i generell trøtthet/slitenhet, som ofte er sett ved IBS.

Kontrollgruppen som er brukt er hentet fra Bergen og kan ha vært eksponert for Giardia. Dette er den største svakheten til både avhandling og alle publikasjonene som er utgitt, fordi det er metodisk forskningsetisk bias og ikke benytte helt friske kontroller i forskningsstudier.

Dermed mister også alle publikasjonene og avhandlingen mye av sin troverdighet, samt relevans.

De konkluderer med at der Giardia var påvist har 46,1 % av individene (av totalt 817) utviklet vedvarende symptomer og IBS.

IBS forekommer ca 10 til 20 % av befolkning i følge gastroenterologen Berstad.

———–

I kunnskapssenterets notat fra 2011 kan vi videre lese at det er igangsatt behandlingsintervensjon fra forskningsteamet:

Haukeland Universitetssykehus, sekj for indremed ved prosjektleder Kurt Hanevik forskningsstudie “Giardia induced fatigue and functional gastrointestinal diseases”. NCT00860236.

Vitenskapelig tittel: Chronic Fatigue Syndrome and Abdominal Symptoms After Giardia Infection: Clinical Evaluation, Biomarkers, Risk Factors and the Effect of Intervention.

Prosjektet tidsramme: Studiestart i mars 2009, forventes avsluttet i desember 2010

Formål:

Giardia utbruddet i Bergen har gitt oss muligheten til å nærme oss to grunnleggende problemstillinger av nasjonal og global betydning:

Studere patoimmunologi av giardiasis i en naturlig setting, og følge genetiske og immunologiske responser som fører til bedring eller vedvarende sykdom og følgetilstander.

Studere de to sykdommene FGID og CFS ved indusert av akutt giardiainfeksjon og deres risikofaktorer.

Intervensjonsbehandling med kognitiv atferdsterapi er den eneste intervensjon som dokumenteres å ha signifikant effekt på CFS utfall, og konvensjonell kognitiv atferdsterapi vil bli sammenlignet med en psyko-utdannings program i form av en randomisert kontrollert studie. (fase IV)

Hovedmål: Behandling, fase IV.

Deltakere (rekrutterer ikke):

Pasienter med kronisk utmattelsessyndrom (problemer med utmattelse i alle grader etter Giardiainfeksjon)

Alder: 18 år og eldre

Forventet antall deltakere: 40 (ble ikke oppnådd, noe færre deltakere enn forventet*)

Kriterier: Spesifikke sett av diagnosekriterier ikke oppgitt.

Studiedesign:

Deltakerne blir inndelt i to grupper:

Kognitiv atferdsterapi (fase IV): 4 dagers intensiv trening i forståelse og adferdsforandringer

Psyko-opplæring (fase IV): 2 dagers undervisning i sykdomsmekanismer og mestringsstrategier

Primære utfallsmål:

Utmattelse (minimum 6 poengs forbedring i ”Chalder Fatigue scale score” (Tidsramme: 6 måneder))

Sted: Frihamnsenteret i Skånevik.

Fra prosjektgruppen som undersøker Giardia utbruddet i Bergens hjemmeside kan vi lese (4):

Giardia indusert utmattelse og funksjonelle mageplager – karakterisering og behandlingsstudie

Fra våren 2009 til våren 2010 rekrutterte en pasienter og kontroller til en studie av immunresponser, funksjonelle endringer i hjernen og andre mulige biomarkører for utmattelsessyndromet som er observert etter Giardia-infeksjon. Personer med vedvarende utmattelsesplager ble tilbudt et av to behandlingstilbud. Det ene er et undervisningsprogram som tar for seg årsaker til kronisk utmattelsessyndrom (infeksjon, immun- og hormonpåvirkning, stress (…), og går gjennom ulike mestringsstrategier som har vist seg effektive for å redusere utmattelsessymptomer og øke funksjonsnivået. I det andre behandlingstilbudet gis også opplæring i stressreduksjon, kognitive øvelser med vekt på å redusere negative tanker og mobilisere positive mestringsbilder, samt lett fysisk aktivitet.

***

Dette poengterer dessverre synet denne forskningsgruppen har på funksjonelle tarmlidelser som irritert tarm med utmattelses-symptomer, selv med kjent triggerfaktor.

Hvor mange som fikk ME etter Giardia-epidemien og tydeligvis en publikasjon til besvær skal vi se på i del II

Legg igjen en kommentar

Fyll inn i feltene under, eller klikk på et ikon for å logge inn:

WordPress.com-logo

Du kommenterer med bruk av din WordPress.com konto. Logg ut / Endre )

Twitter picture

Du kommenterer med bruk av din Twitter konto. Logg ut / Endre )

Facebookbilde

Du kommenterer med bruk av din Facebook konto. Logg ut / Endre )

Google+ photo

Du kommenterer med bruk av din Google+ konto. Logg ut / Endre )

Kobler til %s