Chronic fatigue syndrome after Giardia enteritis (Naess et al., 2012)

[Dolphin]

Free full text: http://www.biomedcentral.com/1471-230X/12/13

Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence.

BMC Gastroenterol. 2012 Feb 8;12:13.

Naess H, Nyland M, Hausken T, Follestad I, Nyland HI.

Source
Institute of Clinical Medicine, Department of Neurology, and Unit for Gastroenterology, Department for Medicine, Haukeland University Hospital, N-5021 Bergen, Norway. halvor.naess@haukeland.no.

Abstract

ABSTRACT:

BACKGROUND:

A waterborne outbreak of Giardia lamblia gastroenteritis led to a high prevalance of long-lasting fatigue and abdominal symptoms.

The aim was to describe the clinical characteristics, disability and employmentloss in a case series of patients with Chronic Fatigue Syndrome (CFS) after the infection.

METHODS:

Patients who reported persistent fatigue, lowered functional capacity and sickness leave or delayed education after a large community outbreak of giardiasis enteritis in the city of Bergen, Norway were evaluated with the established Centers for Disease Control and Prevention criteria for CFS.

Fatigue was self-rated by the Fatigue Severity Scale (FSS).

Physical and mental health status and functional impairment was measured by the Medical Outcome Severity Scale-short Form-36 (SF-36).

The Hospital Anxiety and Depression Scale (HADS) was used to measure co-morbid anxiety and depression.

Inability to work or study because of fatigue was determined by sickness absence certified by a doctor.

RESULTS:

A total of 58 (60%) out of 96 patients with long-lasting post-infectious fatigue after laboratory confirmed giardiasis were diagnosed with CFS.

In all, 1262 patients had laboratory confirmed giardiasis.

At the time of referral (mean illness duration 2.7 years) 16% reported improvement, 28% reported no change, and 57% reported progressive course with gradual worsening.

Mean FSS score was 6.6.

A distinctive pattern of impairment was documented with the SF-36.

The physical functioning, vitality (energy/fatigue) and social functioning were especially reduced. Long-term sickness absence from studies and work was noted in all patients.

CONCLUSION:

After giardiasis enteritis at least 5% developed clinical characteristics and functional impairment comparable to previously described post-infectious fatigue syndrome.

* I gave each sentence its own paragraph.

 

[Enid]

Yes getting to/understaning slowly - it is after 12 years evident to me of persistant gastro/genital infection (undiagnosed UK - but they are good at that).

 

[Dolphin]

Pre-publication history

One of the interesting things about this paper is the Pre-publication history: http://www.biomedcentral.com/1471-230X/12/13/prepub

Peter White wants to try to break the connection that this shows Giardia enteritis can cause CFS. He may have minor technical points but he could have suggested the authors mention limitations and provisos.

Simon Wessely is called in to act as another reviewer to try to break the impasse, it seems.
Amongst other things, he says:

"Peter white, who is the doyenne of these kind of studies."

He eventually lets it through saying:

I take Peter White comments that comparing to other population data
bases/studies is unsafe, i agree, but nevertheless, the prevalence they report is
sufficiently high to suggest that there might be a link between exposure and CFS.
Frankly, given the rest of the post infectious fatigue literature, this would not
surprise me.

SW also says:

Retrospective assessment of pre exposure fatigue and/or life events is basically worthless.

which is interesting given some other studies such as by the CDC on childhood factors.

I agree with the reviewers that it would have been interesting if they had sampled some of the other 1100-odd initial giardia patients as some of them could also have CFS.
It would have been interesting if the group had been looked* at at 6 months or 1 year as the prevalence of CFS might have been higher. The mean duration of the illness was 2.7 years.

* I can't remember what other papers on the giardia outbreak found - I think they might not have reported CFS specifically??

 

[Dolphin]

Table 1 is at least a little interesting as it doesn't just include the 8 Fukuda criteria.

Based on that, the fatigue scores, the fact that all those working and studying have reduced their output or were classified as "sickness absence" as well as the pattern of SF-36 subscale scores suggests CFS (and probably ME/CFS and ME) is a reasonable diagnosis.

 

[oceanblue]

I find myself agreeing with Simon Wessely, how bizarre. I've highlighted his comment about the worthlessness of retropsective measures on another thread where you had brought up the exact same issue (Birth cohorts).

Giardia Lamblia is the first Protozoan associated with triggering CFS, as far as I know (others are viruses of bacteria).

 

[SickOfSickness]

Great! I hope there are confirmations of their results soon, more different studies are sparked by it.

Splitting the sentences helped. Thanks.

 

[FancyMyBlood]

This is probably going to end in another multifactorial origin hypothesis, especially for the people with 'late' onset(months) vs 'short' onset (weeks) CFS after Gardia enteritis. But I'm especially trouble by this quote:

CFS is associated with various functional limitations both for work and social life, and assessment of functional ability including sickness abscence is necessary in medical and vocational rehabilitation [42]. The focus on function ability represents a shift in attention from symptoms to resources, possibilities and coping. After the initial evaluation our patients entered a comprehensive multidisciplinary intervention program. The program was individualized and included education focusing on psychology and coping. Rehabilitation included physiotherapy, manageable exercise program, and occupational therapy. We plan to publish a five year follow-up study of the patients.

It's interesting that one of the researchers behind the Gardia-CFS connection, Knut-Arne Wensaas, had a pretty rough (to put it mildly!) discussion with Mella and Fluge about the rituximab paper: (http://www.plosone.org/annotation/l...notation/b3d77c11-5f3c-447c-ae74-a38aa62cf101)

This lead to these quotes from Fluge and Mella:

Could it be that Wensaas hypothesis on the mechanisms of CFS symptom maintenance has influenced his judgment?

However, we do not believe that dr. Wensaas concern is among the possible limitations when interpreting the data.

I think anyone can guess now what the results of that follow-up study will be......

 

[ChuckG]

Blastocystis hominis

I find myself agreeing with Simon Wessely, how bizarre. I've highlighted his comment about the worthlessness of retropsective measures on another thread where you had brought up the exact same issue (Birth cohorts).

Giardia Lamblia is the first Protozoan associated with triggering CFS, as far as I know (others are viruses of bacteria).

http://en.wikipedia.org/wiki/Blastocystosis

"Blastocystis is a protozoal, single-celled parasite"

"Variation in severity
Researchers have sought to develop models to understand the variety of symptoms seen in humans. Some patients do not have symptoms, while others report severe diarrhea and fatigue."

One of my first CFS symptoms, circa 1991, was diarrhea. Great Smokies Lab found B. hominis in my stools.

There were several newspaper articles (not peer reviewed of course!) in the early to mid 90s that associated B. hominis with CFS. Northern California near Incline Village and Oregon are all that come to this old and fading mind.

 

[Guido den Broeder]

A pity that they did not test these patients for ME or at least latent herpes infection.

 

[oceanblue]

A pity that they did not test these patients for ME or at least latent herpes infection.

I'm not sure what test for ME you mean.

 

[oceanblue]

http://en.wikipedia.org/wiki/Blastocystosis

"Blastocystis is a protozoal, single-celled parasite"

"Variation in severity
Researchers have sought to develop models to understand the variety of symptoms seen in humans. Some patients do not have symptoms, while others report severe diarrhea and fatigue."

One of my first CFS symptoms, circa 1991, was diarrhea. Great Smokies Lab found B. hominis in my stools.

There were several newspaper articles (not peer reviewed of course!) in the early to mid 90s that associated B. hominis with CFS. Northern California near Incline Village and Oregon are all that come to this old and fading mind.

Thanks for that. According to that well-referenced Wikipedia article there is some doubt about whether or not B.hominis is a pathogen at all (ie it may be present but does it cause disease?), but the consensus was that it probably is, or can be in some circumstances. Couldn't find any publisehd research linking it to CFS though those newspaper reports are interesting. Like giardiasis B.hominis is not only a protozoan but a gut protozoan which makes the link more intriguing.

There is, it turns out. one report much earlier report, from 1992, of Giardiasis being linked with CFS.

 

[oceanblue]

Problems with diagnosis

I was very impressed when I first read this study: a post-infectious rate of 5%+ CFS cases after 2.7 years is very high. Typically for glandular fever etc it's around 10% after just 6 months and I seem to recall it drops to around 6% after 12 months in prospective studies.

However, there are 2 serious issues around the diagnosis of CFS:

1. The Fukuda case definition wasn't applied properly with no pyschiatric interview and apparently no physical examination or required lab tests. The last time I saw an implementation this weak was in Simon Wessely's 1997 prevalence paper that found a 2.6% rate for Fukuda CFS (see post #10).

2. In the majority of cases (58%) the onset of fatigue was months after the acute illness, which could include more than a year after the acute illness.

As ever, the situation isn't clear-cut so I'll spell out the issues as I see them and hope others will chip in with comments.

Specific issues with diagnosis

Fukuda requirements:
Thorough history of medical and psychological circumstances at the onset of fatigue - as well as many other factors
A mental status examination
A thorough physical examination
A minimum battery of lab screening tests

Naess 2012 diagnosis:
Primary care records were available and examined. In addition to written self-report of past medical and psychiatric history the patients were interviewed about exclusionary medical and psychiatric diagnosis (psychosis, bipolar disorder, substance misuse, an organic brain disorder, or an eating disorder) by an experienced clinical neurologist.

There is clearly a thorough medical history. However, a neurologist interviewing patients about psychiatirc diagnoses is not the same as a psychiatric evaluation; there is no mention of a physical examination or the lab tests required by Fukuda. In pre-publication comments, the authors don't explain why they didn't implement Fukuda properly, despite being challenged about it by reviewers, though they do say "The patients were classified as CFS based on the CDC criteria for CFS (see reference 10- [Fukuda]) by a specialist on chronic fatigue in our department".

Mean SF-36 Physical Function score was 60, pretty high even for an outpatient group (I think). No SD is given but probably a good chunk of this group would have not been impaired enough to meet the PACE trial entry criteria of 65 or less. The mean FSS fatigue score was 6.6/7, which is pretty high, though I'm not sure if FSS has a ceiling effect like the Chalder Scale.

There is also no explicit exclusion of patients who were fatigued before the Giardia infection, though you like to think this was covered by the medical history.

Time to fatigue after onset of enteritis was defined as immediately, taking weeks, or months.

...The mean duration of the illness was 2.7 years (SD .4; range 1.5 to 3.0 years).

So fatigue onset for 58% of CFS diagnoses could be many months or even over a year after enteritis. The authors do add that they "excluded patients with an interval free of symptoms between the giardiasis enteritis and the development of CFS." Nonetheless, if patients have enteritis for 6 months without fatigue, and then develop fatigue, that fatigue may not be a consequence of the enteritis. The authors suggest

A possible explanation is that many initial symptoms either masked the experience of early fatigue or the recall of early fatigue among some patients.

but i don't think you can be ill for 6 months without noticing you are fatigued.

On the other hand, I would be pretty confident that patients whose fatigue started within weeks of the onset of enteritis did have fatigue as a consequence of the illness and in their case the lack of proper psychiatric interview etc doesn't bother me as much. It would be a freaky conincidence if so many patients spontaneously developed CFS or another fatiguing illness within weeks of gardiasis.

Putting some guesstimates together

For the reasons above, I don't accept the authors findings that the 5% prevalence of CFS

represent a lower limit for the frequency of CFS after Giardia lamblia enteritis

42% of CFS diagnoses (24/58) had rapid onset of fatigue [within weeks] , which works out as 1.9% (24 ex 1,262 lab confirmed Giardia cases) as pretty certain CFS cases after Giardiasis. That leaves some doubt over the remaining CFS diagnoses (34/58, or 2.5% of the original Giarida cases).

However, some of the 'dodgy 2.5%' are probably genuine Post-Infectious CFS cases. Simon Wessely's 1997 study only found 2.5% of CFS cases of any duration, wheras the dodgy 2.5% must have occurred within a couple of years of the initial infection. Lets conservatively assume just 1 in 5 of these (ie 0.5% of all cases) are post-infectous cases which bumps the total of 'real' cases up from 1.9% to 2.4%. That excludes any cases of post-giardiasis CFS cases that hadn't reached the referral clinic in this study, and there must have been some of these (sadly the authors didn't attempt to take a random sample of the original infected patients who didn't wind up in their clinic).

So a true 'lower limit' to the rate of CFS post-giardiasis is probably around 2.5%, and with an average duration of 2.7 years that is still a pretty high rate.

Comments welcome... I've made numerous assumptions along the way, feel free to challenge any and all of them. As if you need permission.

 

[oceanblue]

There is also no explicit exclusion of patients who were fatigued before the Giardia infection, though you like to think this was covered by the medical history.

I emailed the lead author and he confirmed they were excluded, so there were no pre-existing cases of CFS in this cohort.

 

[Marco]

So fatigue onset for 58% of CFS diagnoses could be many months or even over a year after enteritis. The authors do add that they "excluded patients with an interval free of symptoms between the giardiasis enteritis and the development of CFS." Nonetheless, if patients have enteritis for 6 months without fatigue, and then develop fatigue, that fatigue may not be a consequence of the enteritis. The authors suggest - but i don't think you can be ill for 6 months without noticing you are fatigued.

On the other hand, I would be pretty confident that patients whose fatigue started within weeks of the onset of enteritis did have fatigue as a consequence of the illness and in their case the lack of proper psychiatric interview etc doesn't bother me as much. It would be a freaky conincidence if so many patients spontaneously developed CFS or another fatiguing illness within weeks of gardiasis.

Hi oceanblue. I haven't read the paper and don't intend to so I can't make any more comments on your estimates.

All I want to say is that I wouldn't discount 'delayed' fatigue emerging following enteritis.

My own experience (now meeting the CCC and ICC criteria) was initially gastro symptoms and PEM but I didn't start to experience generalised 'fatigue', either physical or cognitive until over 10 years after onset.

Given that my various doctors approached the problem on a symptom by symptom basis, I was initially given a full gastro work over and PEM wouldn't have even entered into the conversation.

It was some 12 years or so before a ME diagnosis was suggested.

My case may be unusual but I wouldn't be surprised if some symptoms necessary for a 'CFS' diagnosis don't present simultaneously with the initial trigger.

 

[redo]

The best would be if they'd use the CCC criteria, but none the less, this is good news. The first study of the outbreak only looked at "chronic fatigue". I think giardiasis plays exactly the same triggering role as EBV, borreliosis, the flu and so forth. Giving the immune system more to handle for a short period of time. That's the only common nominator I can find of the various triggers.

 

[Snow Leopard]

One of the problems with this study is that it was not a proper cohort based incidence study, so the overall incidence is uncertain. The results are interesting, but might simply suggest that this is just one of many post-infectious triggers for CFS.

oceanblue - I guess one of the points about the latency between infection and onset is that some people have a relapsing-remitting phase initially.

 

[oceanblue]

Thanks for that, Marco & Snow Leopard.I agree that many cases with delayed onset fatigue could be linked to the intial Giardia infection, but we can't be sure, particularly as the CFS cases were not properly diagnosed. What I have tried to do is to tease out what we can confidently deduce (i.e. a minimum incidence of 1.9% CFS more than 2 years on, as a direct result of the Giardia infection) as opposed to what is likely (a much higher incidence, perhaps 5% or more).

 

[redo]

The results are interesting, but might simply suggest that this is just one of many post-infectious triggers for CFS.

I, like you Snow Leopard, see vaccines as one of many in the list of CFS triggers. There are several I've been in contact with which have got it triggered by just that. Since you're pretty updated on the litterature, I've got a question for you: Besides EBV and now giardisis, do you know which stressors which have been scientifically linked to CFS as a trigger? I am not talking about large peer reviewed studies only, but also smaller case series etc.

 

[Dolphin]

So fatigue onset for 58% of CFS diagnoses could be many months or even over a year after enteritis.

The authors do add that they "excluded patients with an interval free of symptoms between the giardiasis enteritis and the development of CFS."

Nonetheless, if patients have enteritis for 6 months without fatigue, and then develop fatigue, that fatigue may not be a consequence of the enteritis. The authors suggest

A possible explanation is that many initial symptoms either masked the experience of early fatigue or the recall of early fatigue among some patients.

but i don't think you can be ill for 6 months without noticing you are fatigued.

I don't know. Like Marco, PEM rather than fatigue was more my main symptom for a long time. Once I avoided sports, the fatigue wasn't particularly noticeable, more the muscle problems. Cognitive problems weren't so noticeable initially. Looking back, I was maybe down 5% in the first 12 months (approx.) and maybe 10% after that, in terms of quantity I could learn with a period, say (v. approximate figures). Clerical errors probably crept in over a similar period.

 

[Dolphin]

1. The Fukuda case definition wasn't applied properly with no pyschiatric interview and apparently no physical examination or required lab tests. The last time I saw an implementation this weak was in Simon Wessely's 1997 prevalence paper that found a 2.6% rate for Fukuda CFS (see post #10).

Thanks for going to all this trouble, oceanblue.

However, I don't see it as that close to that Wessely study. I think making diagnoses using written records alone is at a different level to how these patients were assessed. For example, they may not have explicitly said they use all the Fukuda blood tests, but I imagine a consultant running a service for such patients would run most indicated tests.

My guess is that if one looked at a lot of CFS cohorts not all of the following are done exactly:

Fukuda requirements:
Thorough history of medical and psychological circumstances at the onset of fatigue - as well as many other factors
A mental status examination
A thorough physical examination
A minimum battery of lab screening tests