Incidence of chronic Q fever and chronic fatigue syndrome: a six year follow-up of a large Q fever outbreak, 2021, Ankert et al

Abstract

Objectives
Acute Q fever is a generally self-limiting infection caused by the intracellular gram-negative bacterium Coxiella (C.) burnetii. For yet unknown reasons, a subset of patients develops chronic a infection. Furthermore, a Chronic Fatigue Syndrome (CFS) as post-acute Q fever sequelae has been described. We here investigated the rates of chronic Q fever and incidences of CFS six years after one of the largest European Q fever outbreaks that occurred in Jena, Germany in 2005 with 331 reported cases, who lived in proximity of a grazing sheep herd.

Methods
A total of 80 patients and 52 non-diseased household members from the former outbreak, were enrolled six years after the outbreak, blood samples collected and tested for a chronic Q fever were determined by seroprevalence using referenced immunofluorescence tests. Also, the presence of a CFS was assessed using the Short Form Symptom Inventory developed by the Centers (United States) for Disease Control and Prevention (SF CDC- SI).

Results
In 80 out of 132 (60.6%) study participants, previous Q fever infection was confirmed serologically, while no previous infection was detected in the 52 household members. None of the participants fulfilled the serological criteria of chronic Q fever. The evaluation of the CDC-SI did not show any differences between the two groups. Also, there was no difference between both groups regarding fulfillment of CFS-defining criteria (n = 3 (3.8 %; sero-positive) vs. n = 2 (3.8 %; sero-negative), p = 0.655).

Conclusion
Our six-year follow-up study of a large Q fever outbreak did not find evidence for chronic Q fever or post Q fever CFS. There was no asymptomatic sero-positivity in household members of Q fever patients.

Open access, https://onlinelibrary.wiley.com/doi/10.1111/tbed.14224

 

Strange finding. The author think that whether there is a chance of developing CFS or not depends on the pathogen strain.

 

The authors relied on the short form of the CDC CFS symptom inventory, which assesses 6 symptoms instead of the full form's 19. It was developed in 2005 by the CDC's Wagner, Unger, Reeves et al. from the answers to the full inventory of "164 subjects (with CFS, other fatiguing illnesses and non fatigued controls) identified from the general population of Wichita, Kansas" by only keeping "symptoms whose scores had a corrected item-total score correlation < 0.60" [1].

The list of symptoms in the short form seems to be at odds with the definition of the Fukuda criteria and the scoring of the full inventory. The Fukuda criteria list 8, not 6, defining symptoms for CFS*, and:

- while the full inventory distinguishes between memory and concentration problems, it states that only one of the two can be counted ("Note that only L or M can be counted, not both"), as the criteria gather them into one single item: "substantial impairment in short-term memory or concentration"

- while unrefreshing sleep is a defining symptom, sleeping problems are considered an accompanying symptom in the full inventory.

Thus, the short form appears to only assess 5 out of 8 of the defining CFS symptoms per the Fukuda criteria (with one of the latter separated into two in the short form, i.e. incorrectly counted twice). It is possible that with the 3 remaining symptoms, the participants in this study would have scored higher and met the cut-off for CFS.

However, Wagner et al. found that the short form score converged well with the full inventory (r = .94, p < 0.001) and the Fukuda case definition (r = .95, p < 0.001) but found with regards to construct validity that it doesn't adequately separate CFS from idiopathic chronic fatigue [1]:

The authors do note that the IOM committee identified criticisms with the CDC CFS symptom inventory (in 2015, so post-data collection), but they justify their choice of its short form rather than "a battery of questionnaires" by "[wanting] to increase the motivation of patients to participate in this follow up". Strangely, they cite a letter to the editor by @Michiel Tack to back this justification, but the letter criticizes the (full) symptom inventory for being outdated and uncharacteristic of ME/CFS. It does not mention the short form or that filling fewer and shorter questionnaires is easier for CFS patients.

The discrepancy with other studies on the incidence of QFS is also noted in the discussion, but only explained with weak suppositions about psychosocial aspects of CFS and the strain of Coxiella burnetii:

Finally, it is intriguing that the authors are publishing their data 10 years after collection. In 2011, they contacted by mail 311 patients who had tested positive to Coxiella burnetii in 2005; 94 responded and, of those, 80 agreed to take part in the study. Presumably, most sequelae-free patients wouldn't have taken the time to respond, but whether there was any other form of selection bias is unknown.

Is there a German QFS patient association? They would likely know more about the patients who remain ill and about this study.

* post-exertional fatigue, unrefreshing sleep, problems remembering or concentrating, muscle aches and pains, joint pain, sore throat, tender lymph nodes and swollen glands, and headaches

[1] Wagner, D., Nisenbaum, R., Heim, C. et al. Psychometric properties of the CDC Symptom Inventory for assessment of Chronic Fatigue Syndrome. Popul Health Metrics 3, 8 (2005). https://doi.org/10.1186/1478-7954-3-8

ETA: the researchers are part of the consortium of the Q fever German Interdisciplinary Program for Research (Q-GAPS), which is supported by the German Federal Ministry of Education and Research. Dr Katharina Boden is the principal investigator of a subproject aiming to assess the efficacy of a disinfectant against C. burnetii.

The Q-GAPS FAQ entry on "What is Q fever fatigue syndrome" reads (bolding mine):

 

That the study was statistically underpowered to detect years-long cases of QFS seems to be the most plausible argument behind the findings, and a much more compelling one than potential issues around the short form of the CDC CFS symptom inventory.

The authors note that one of the "strength of our study is the large number of sero-positive subjects (...)". Indeed, they likely did not want the low number of patients (with regard to CFS incidence) to be seen as a weakness.

In 2006, the Dubbo study group (Hickie et al.) reported an incidence of CFS, respectively at 6 and 12-month follow-up, of 11% (29/253 but with 28 meeting CFS criteria) with 3 from Q fever and 9% (22/253):

There was no follow-up data after 1 year in the Dubbo study. The German authors may have mistaken the number of confirmed cases of CFS at 6 months (28) with the percentage (11%).

Unfortunately the large 4-year follow-up study by Limonard et al. (2016, NL outbreak in 2010) did not evaluate CFS caseness but assessed patients with the Nijmegen Clinical Screening Instrument [1], which was originally developed for COPD and later applied to Q fever. This is problematic because, while it found that 50% of patients had excessive fatigue and reduced QoL, the 10-year follow-up study by Waldman et al. (2002, UK outbreak in 1989) that the authors also cite shows that fatigue, ICF and CFS must be clearly delineated: respectively, they affected 66.7%, 34.7%, 19.4% of the cohort [2]. Excluding comorbidities, this dropped to 8% CFS cases.

[1] Limonard GJ, Peters JB, Besselink R, Groot CA, Dekhuijzen PN, Vercoulen JH, Nabuurs-Franssen MH. Persistence of impaired health status of Q fever patients 4 years after the first Dutch outbreak. Epidemiol Infect. 2016 Apr;144(6):1142-7. doi: 10.1017/S0950268815002216. Epub 2015 Oct 28. PMID: 26508155.

[2] Wildman MJ, Smith EG, Groves J, Beattie JM, Caul EO, Ayres JG. Chronic fatigue following infection by Coxiella burnetii (Q fever): ten-year follow-up of the 1989 UK outbreak cohort. QJM. 2002 Aug;95(8):527-38. doi: 10.1093/qjmed/95.8.527. PMID: 12145392.

 

I am mistaken. The 28% figure was taken from the systematic review by Morroy et al. (2016), specifically the paragraph on CFS (bolding mine):

This 28% figure comes from a 2+ year follow-up retrospective survey of the 1989 UK outbreak of 147 cases. The survey included 39 patients with confirmed acute Q fever and 3 control groups, each with 39 participants.

The 42% CFS figure comes from the 10-year follow-up of the same outbreak, with 71 responses (less than half the initial number of cases). However, doubt can be cast on this prevalence given that 26% controls were also diagnosed with CFS.

Unlike the Dubbo study, neither of these were prospective, so it is understandable that they would report higher rates of CFS.