Different pathogens can cause CFS-like illness

After two studies popped up recently (Naess et al. 2012 and Morroy et al. 2012), I thought I'll collect here some of the studies implicating different pathogens. Interesting is that the finding of Hickie et al. 2006 (to paraphrase: "Initial illness severity predicts duration of chronic fatigue") was found in Morroy et al. 2012, albeit reported inversely (as paraphrased: "the majority of persons with mild illness recover spontaneously within a few weeks"). The report of David Bell on patients of the Lyndonville outbreak after 25 years seem to go in a similar direction, that those who got hit the hardest, stayed the most ill.

Some things are missing. First of all, I have no measure of the quality of most of these studies. Hickie 2006 seems solid. John Chia's finding of Enterovirus seems intriguing (and jives well with previous findings of researchers on the British Isles), yet I'm cautious. If half of the people presenting with CF(S) at John Chia's office have persistent Enterovirus infections, then Ian Lipkin will find a comparable number.

Then another thing that is missing is (Chronic) Lyme and other pathogens like Mycoplasma.

And the third thing to keep in mind is that local outbreaks can skew any numbers, as obviously an outbreak increases the number of people who have the same pathogen in that region. Giardia cases may or may not be common now in Haukland, Norway – the incidence of Giardia in CF(S) cases in e.g. California may or may not be neglectable.

So here we go:

Hickie et al. 2006: a prospective cohort study on Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis) in Australia:

Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study

Ian Hickie 1, Tracey Davenport 1, Denis Wakefield 2, Ute Vollmer-Conna 3, Barbara Cameron 2, Suzanne D Vernon 4, William C Reeves 4, Andrew Lloyd 2

Cite this as: BMJ 2006;333:575
Degenerative joint disease Drugs: CNS (not psychiatric) Epidemiologic studies

1 Brain and Mind Research Institute, Sydney University, Sydney, NSW 2050, Australia,
2 School of Medical Sciences, University of New South Wales, Sydney, NSW 2052,
3 School of Psychiatry, University of New South Wales,
4 Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 31033, USA

Correspondence to: A Lloyd

Abstract
Objective To delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections.

Design
Prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis).

Setting
The region surrounding the township of Dubbo in rural Australia, encompassing a 200 km geographical radius and 104 400 residents.

Participants
253 patients enrolled and followed at regular intervals over 12 months by self report, structured interview, and clinical assessment.

Outcome measures
Detailed medical, psychiatric, and laboratory evaluations at six months to apply diagnostic criteria for chronic fatigue syndrome. Premorbid and intercurrent illness characteristics recorded to define risk factors for chronic fatigue syndrome. Self reported illness phenotypes compared between infective groups.

Results
Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors.

Conclusions
A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome.

Naess et al. 2012 on Giardia in Norway:

Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence.
Halvor Naess, Morten Nyland, Trygve Hausken, Inghild Follestad and Harald I Nyland

Institute of Clinical Medicine, Department of Neurology, and Unit for Gastroenterology, Department for Medicine, Haukeland University Hospital, N-5021 Bergen, Norway

BMC Gastroenterology 2012, 12:13 doi:10.1186/1471-230X-12-13

Abstract (provisional)
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.

Morroy et al. 2012 Q-fever (Coxiella burnetii) in The Netherlands:

Self-reported sick leave and long-term health symptoms of Q-fever patients

Gabriella Morroy 1,2, Hans H. J. Bor 2, Johan Polder 3, Jeannine L. A. Hautvast 2, Wim van der Hoek 4, Peter M. Schneeberger5 and Clementine J. Wijkmans 1,2

1 Department of Infectious Disease Control, Municipal Health Service Hart voor Brabant, ‘s-Hertogenbosch, The Netherlands
2 Academic Collaborative Centre AMPHI, Department of Primary and Community Care, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3 Department Tranzo, Tilburg University, Tilburg, The Netherlands
4 Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
5 Laboratory of Medical Microbiology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands

Abstract

Background:
In The Netherlands, 1168 Q-fever patients were notified in 2007 and 2008.

Patients and general practitioners (GPs) regularly reported persisting symptoms after acute Q-fever, especially fatigue and long periods of sick leave, to the public health authorities.

International studies on smaller Q-fever outbreaks demonstrate that symptoms may persist years after acute illness. Data for the Dutch outbreaks were unavailable.

The aim of this study is to quantify sick leave after acute Q-fever and long-term symptoms.

Methods:
Our study targeted 898 acute Q-fever patients, notified in 2007 and 2008 residing in the Province Noord-Brabant.

Patients from the 2008 cohort were mailed a questionnaire at 12 months and those of the 2007 cohort at 12–26 months after onset of illness.

Patients reported underlying illness, Q-fever-related symptoms and sick leave.

Results:
The response rate was 64%.

Forty percent of the working patients reported long-term (>1 month) sick leave.

Pre-existent heart disease odds ratio (OR) 4.50; confidence interval (CI) 1.27–16.09), hospitalization in the acute phase (OR 3.99; 95% CI 2.15–7.43) and smoking (OR 1.69; 95% CI 1.01–2.84) were significant predictors for long-term absence.

Of the patients who resumed work, 9% were—at the time of completing the questionnaire—still unable to function at pre-infection levels due to fatigue or concentration problems.

Of the respondents, 40% reported persisting physical symptoms at the time of follow-up.

Fatigue (20%) was most frequently reported. Daily activities were affected in 30% of cases.

Conclusions:
Q-fever poses a serious persisting long-term burden on patients and society.

In 2007, the Netherlands began a large, drawn-out outbreak of Q fever, which resulted in thousands being infected and a dozen or so fatalities.

In a study just released in the European Journal of Public Health, Dutch researchers show that many of those infected with Coxiella burnetti previously, now face chronic fatigue syndrome and other physical symptoms.

1,168 Q-fever patients were notified in 2007 and 2008 in the Netherlands. The study targeted 898 acute Q-fever patients, notified in 2007 and 2008 residing in the Province Noord-Brabant. Patients from the 2008 cohort were mailed a questionnaire at 12 months and those of the 2007 cohort at 12-26 months after onset of illness. In the questionnaire, patients reported underlying illness, Q-fever-related symptoms and sick leave.

Some of the key results found in the study include:

• Forty percent of the working patients reported long-term (greater than 1 month) sick leave.
• Daily activities were affected in 30% of cases.
• 20% of respondents reported issues with fatigue.
• 9% of those who did return to work reported they were (up to 2 years post-Q fever infection) still unable to function at pre-infection levels due to fatigue or concentration problems.

Based on the results of the study, the authors conclude that Q-fever poses a serious persisting long-term burden on patients and society.

Q fever is caused by the obligate intracellular pathogen, Coxiella burnetii. The disease is usually transmitted to people through either infected milk or through aerosols.

This disease is found on most continents with the reported incidence probably much lower than the actual because so many cases are so mild.

Animal reservoirs of C. burnetii include sheep, cattle, goats, dogs and cats. In areas where these animals are present, Q fever affects veterinarians, meatpacking workers, and farmers.
…

The mortality rate for acute Q fever is low (1–2%), and the majority of persons with mild illness recover spontaneously within a few weeks although antibiotic treatment will shorten the duration of illness and lessen the risk of complications.

John Chia 1999 about Chronic Chlamydia Pneumoniae:

Chronic Chlamydia pneumoniae infection: a treatable cause of chronic fatigue syndrome.

John K. S. Chia and Laura Y. Chia

Torrance Memorial Medical Center, Torrance, California

…
Over the past 3 years, we encountered 10 of 171 patients with symptoms of chronic fatigue who had elevated titers of antibody to C. pneumoniae long after initial respiratory infection. Most pa- tients had favorable clinical and serological responses to a 1- to 2-months course of azithromycin therapy, although relapse was common. The clinical symptoms of and titers of antibody to C. pneumoniae for our 10 patients over the course of treatment are summarized in table 1.
…

The spontaneous rise of titers for several patients correlated with an increased severity of fatigue and a concomitant increase in respiratory symptoms. This observation suggests that relapses of symptoms could be due to persistent infection with periodic reac- tivation rather than reinfection. All of the patients with relapses responded to additional azithromycin treatment.
…

Collectively, these results suggest that C. pneumoniae is an uncommon yet treatable cause of chronic fatigue. The sensitivity, specificity, and interlaboratory variability of the DNA test will need to be better defined.…

And John Chia 2003 again, this time with his son, about many different pathogens, but obviously implicating Enteroviruses:

Diverse Etiologies for Chronic Fatigue Syndrome

John K. S. Chia and Andrew Chia

I D Med, Torrance, California

Clinical Infectious Diseases 2003;36:671–2
…

Probable cause	Criteria for inclusion	No. of patients (n = 200)
Chlamydia pneumoniae infection	High antibody titer compared with control subjects from the community; response to macrolide therapy	18
Epstein-Barr virus infection	Whole blood (at 1:1000 dilution) or urine sample positive for EBV DNA; response to Val or iv Cid therapya	6
Cytomegalovirus infection	Surveillance of acute infection for a period 16 months; positive culture results; response to iv Cid or IVIG therapy	3
Recurrent VZV infection	Recurrent lesions; response to antiviral drugs	6
Recurrent HHV6-like disease	Recurrent roseola-like illness for a period of 3 years; response to iv Cid therapy	1
Parvovirus B19 infection	Test results positive for IgM or viral DNA	3
Hepatitis C	Resolution of symptoms after interferon/ribavirin therapy	3
Neurocardiogenic hypotension	Initial flulike illness; tilt test positive for NMS; response to midodrine therapy	2
Toxic mold exposure	Documented cultures of environmental samples positive for toxic mold; 11 household member was affected; symptoms improved after leaving the house	2
Postvaccination	Received pneumovax, MMR, or influenza vaccine	3
Enterovirus infection	Persistent, significantly elevated levels of neutralizing antibody for coxsackievirus B or high echovirus titer compared with controls from the community; PBMC sample positive for enteroviral RNAb	109
Unknown	—	44

Chia's study is surely not made to gold standards and any numbers should be taken not to be poured in concrete. Chia claims here to have found enteroviral RNAb in PBMCs, while later he opted to search for enteroviral protein VP1 in gut biopsies - something that seems to me to be unnecessarily complicated. If there is actual enteroviral RNAb in PBMCs in the majority of CFS patients, then Ian Lipkin will find it.

Taken together, it looks like there is a clear indication that different pathogens are likely invovled in different CF(S) subgroups and that there is not one single cause involved in all nor even most CF(S) cases – and though the group of likely pathogens is small, it is not exhaustive. While I am hopeful that it is possible to establish the etiology for a considerable portion of CF(S) cases within the next years, I am pessimistic and think that in the foreseeable future a substantial part of CF(S) patients will remain without a established etiology.