Background: This study aimed to determine short- and long-term physical and psychosocial impact of Coxiella burnetii infection in three distinct entities: Q-fever fatigue syndrome (QFS), chronic Q-fever, and patients with past acute Q-fever without QFS or chronic Q-fever. Methods: Integrative data analysis was performed, combining original data from eight studies measuring quality of life (QoL), fatigue, physical and social functioning with identical validated questionnaires, from three months to eight years after onset infection. Linear trends in each outcome were compared between Q-fever groups using multilevel linear regression analyses to account for repeated measures within patients. Results: Data included 3947 observations of 2313 individual patients (228 QFS, 135 chronic Q-fever and 1950 patients with past acute Q-fever). In the first years following infection, physical and psychosocial impact was highest among QFS patients, and remained high without significant improvements over time. In chronic Q-fever patients, QoL and physical functioning worsened significantly over time. Levels of fatigue and social participation in patients with past acute Q-fever improved significantly over time. Conclusion: The impact differs greatly between the three Q-fever groups. It is important that physicians are aware of these differences, in order to provide relevant care for each patient group.
Q-fever is a zoonosis caused by the bacterium Coxiella burnetii. Most commonly, humans get infected by inhaling aerosol particles from infected animals, such as goats or sheep [[
The largest Q-fever outbreak to date took place in the Netherlands between 2007 and 2010 [[
This study aimed to gain insight in the impact of Q-fever on physical and psychosocial functioning over time and compare the impact between patients with QFS, chronic Q-fever and patients with past acute Q-fever (without one of the aforementioned diagnoses) by performing an integrative data analysis, i.e. the analysis of original data pooled from multiple studies [[
An integrative data analysis (IDA) was performed on original data from studies measuring physical or psychosocial functioning of Q-fever patients since 2007 in the Netherlands. IDA is the statistical analysis of a single data set that consists of two or more separate samples that have been pooled into one [[
A literature search in PubMed was performed to identify relevant studies (Fig 1). All studies performed in the Netherlands with Q-fever patients since the start of the epidemic in 2007 and measuring any physical or psychosocial outcome measure with validated questionnaires were eligible to be included in this study. Furthermore, by contacting all researchers from the Dutch national Q-fever research network, unpublished psychosocial data were included.
Graph: Fig 1 Flowchart of included studies from literature search.
After identifying all relevant studies, the corresponding researchers were contacted to request the original data from their study for the purpose of this research. When the corresponding researcher agreed, the original data from their study were sent to the research team using separate files for research data and identifiable patient data. Personal data (full name, gender and date of birth) of patients who participated in multiple studies were used to create a single identifier for every patient. Patients who participated in multiple studies were identified through a trusted third party procedure, which ensured privacy protection. This procedure was approved by the Medical Ethical Review Board of the region Arnhem-Nijmegen (2015–2116). The outcome measures from every patient who participated in one or multiple studies were merged into one dataset.
Chronic Q-fever patients were diagnosed by their physician according to the Dutch consensus guideline on chronic Q-fever, which includes laboratory diagnostics, medical examination and radiological imaging findings [[
The date of the initial C. burnetii infection was needed to calculate the time since infection for every observation. A date of onset of infection was based on the date of notification or the inclusion criteria as registered in the original database, and was reported for most study participants (93%). As chronic Q-fever can also develop after an asymptomatic infection, it is understandable that the onset of C. burnetii infection was not reported for many of these patients (38.5%) [[
The following self-reported outcome measures were included in the analysis; 1) Fatigue, as measured with the Checklist Individual Strength Fatigue (CIS-Fatigue) [[
Domain scores of every outcome measure were newly calculated based on original items. The data were merged from different original datasets and not every outcome was measured in every study. Missing data within studies were not imputed, as most studies had a maximum of one percent missing values (Q-Herpen had a maximum of three percent missing values and Snel-Q eight percent). Most of the missing values occurred in the Q-Quest I study, with fifteen percent missing. However, these missing values appeared at random when comparing the mean scores of the previous longitudinal outcome from persons with a missing outcome with persons without missing outcomes. There was also no difference in patient characteristics such as age and gender between people with missing values and people without missing values.
The three Q-fever groups were compared on several characteristics (age at C. burnetii infection, gender and education level) with either an ANOVA test (continuous variables) or Chi-square test (categorical variables). In order to analyse the general trends over time in each Q-fever group, a multilevel analysis was performed to account for repeated measures within patients. Models with a random intercept and a random trend over time were used. The impact over time for every Q-fever group was analysed using a two-level multilevel linear regression model, with observation-level data as level 1 and participant-level data as level 2. A linear relation between time and outcome was assumed as, for example, the level of fatigue is expected to gradually increase or decrease over time and not exponentially. The score at baseline (i.e. intercept) was compared between Q-fever groups in order to determine whether the level of each outcome measure at baseline was significantly different between groups. Furthermore, it was tested whether the increase or decrease in the level of each outcome measure per time point (i.e. slope) was different between Q-fever groups by including an interaction term group by time in the model. The model was only corrected for gender, age or education level, if it improved the goodness of fit as determined by the likelihood ratio test. A p-value of < 0.05 was considered to be statistically significant, based on two sided tests. The analyses were performed using SAS version 9.2.
To assess the sensitivity of our basic multilevel model, two different models were analysed and compared to the basic multilevel model including all data. First, in longitudinal analyses the first and last observation may have a large influence on the results. Therefore, the model was recalculated excluding the first and last observations, i.e. all observations from baseline and 8 years after infection. Second, as time point estimations based on few observations in specific Q-fever groups are less reliable, the model was recalculated only including time points with more than 10 observations per Q-fever group. When one of the Q-fever groups had less than 10 observations at a specific time point for a specific domain, all observations from all Q-fever groups were excluded, thereby excluding all observations from time points baseline, 3, 5 and 8 years after infection.
Fig 1 shows the study inclusion from our literature search: 81 references were identified of which 69 were excluded for various reasons (see Fig 1 for details). In total, 12 full-text articles were retrieved covering 7 unique studies. Two studies (Q-HORT and ImpaQt), of which the psychosocial data was not (yet) published at the time of the literature search (March 2018), were additionally retrieved through the Q-fever research network. Table 1 shows the study populations, designs, year of onset of infection and included validated questionnaires for each study. Data collections ranged from 3 months up to 9 years after C. burnetii infection. Including the unpublished studies, 9 separate Q-fever studies were identified of which 8 provided data and were included in the analysis.
Graph
Table 1 Overview of Q-fever studies eligible for the integrative data analysis.
Study name Corresponding author, year of publication(s) Study population ref N Study design Time points of outcome assessment Outcome measures Fatigue (CIS) Quality of Life Physical impairment (SIP) Social participation (SF-36) Case-Control Limonard, 2010, 2016 Q-fever patients from Herpen notified in 2007 [ 54 Cross-sectional 1 year after infection x x x [ 46 4 years after infection x x x Q-Quest I Morroy, 2011 Q-fever patients notified in 2007–2008 [ 515 Prospective Cohort between 12 to 26 months after infection x x x Q-Quest II van Loenhout, 2012, 2013, 2014, 2015 1. Q-fever patients notified in 2007–2008 and non-notified laboratory confirmed Q-fever patients from 2008–2009 [ 448–193 Cross-sectional 4 years after infection x x x 2. Q-fever patients notified in 2010–2011 336 Prospective Cohort at 3, 6, 9, 12, 18 and 24 months after infection x x x x Q-HORT Wielders, 2015 Q-fever patients not included in Q-Quest I notified in 2007–2008 and laboratory confirmed chronic Q-fever patients [ 871 Cross-sectional 4 years after infection x Snel-Q van Dam, 2015 Q-fever patients with lower respiratory tract infection in general practice in 2009 [ 50 Cross-sectional 1 year after infection x x x QAAD Hagenaars, 2015 Vascular chronic Q-fever patients [ 26 Prospective Cohort at 3, 6, 9, 12, 15 and 18 months after diagnosis of chronic Q-fever x Q-Herpen Morroy, 2016 Laboratory confirmed acute Q-fever including confirmed chronic Q-fever [ 510 Cross-sectional between 3 to 7 years after infection x x x Qure Keijmel, 2017 Q-fever fatigue syndrome (QFS) patients [ 154 Randomized controlled trial (RCT) between 1 to 8 years after infection x x x ImpaQt Reukers, 2019 Chronic Q-fever patients [ 80 Cross-sectional between 5 to 9 years after infection x x x x QFS patients 155
1
- 2
2 This study was identified through the literature search, but not included in the integrative data analysis. - 3
3 This study was published, but this publication did not include results on the physical or psychosocial outcome measures. Therefore, this publication was not identified through the literature search [[33 ]]. - 4
4 This study was published after the literature search was performed [[19 ]]. - 5 N = number of participating patients; QFS = Q-fever fatigue syndrome; CIS-fatigue = checklist individual strength fatigue; BDI = Beck's depression index; SWL = satisfaction with life questionnaire; SIP = sickness impact profile; SF-36 Social = short form 36 social functioning.
The database contained 3947 observations of 2313 individual Q-fever patients, divided in 228 QFS patients, 135 chronic Q-fever patients, and 1950 patients with past acute Q-fever. Fig 2 shows the number of observations per Q-fever group and time point (since C. burnetii infection). The largest number of observations was collected at 4 years (n = 1607) after infection and the smallest number of observations at 8 years (n = 57, of which 7 were measured at 9 years) after infection. Patient characteristics are presented in Table 2. A significant difference in average age between the three groups was found. Chronic Q-fever patients were on average older (63 years) at onset of infection, while QFS patients were on average younger (40 years) than patients with past acute Q-fever (49 years). The distribution of males and females was significantly different between the three groups. Chronic Q-fever patients were more often male (78.5%) and QFS patients less often male (46.5%) compared to patients with past acute Q-fever (56.3%). Chronic Q-fever and patients with past acute Q-fever had more often a low education (51.1% and 48.6%, respectively) compared to QFS patients (24.0%).
Graph: Fig 2 Number of observations per Q-fever group and time point.QFS = Q-fever fatigue syndrome.
Graph
Table 2 Description of study populations.
QFS Chronic Q-fever past acute Q-fever p-value Total N patients 228 135 1950 2313 N observations 631 362 2954 3947 Age at mean (sd) 40 (12.2) 63 (11.3) 49 (13.6) <.001 49 (14.1) Gender (male) % 46.5 78.5 56.3 <.001 56.6 Education level low % 24.0 51.1 47.3 <.001 44.9 moderate % 44.3 28.9 28.1 29.9 high % 31.7 20.0 24.6 25.2 missing n 7 45 273 325 Onset % 99.1 61.5 94.9 93.3
6 QFS = Q-fever fatigue syndrome; sd = standard deviation.
The results (mean and 95% confidence intervals) as estimated by the multilevel model for each outcome measure in each Q-fever group are presented in Table 3 and visualised in Fig 3. The mean level of fatigue at baseline for QFS patients was significantly higher compared to chronic Q-fever patients and patients with past acute Q-fever (45.8 vs 35.6 and 37.1, Table 3). There was no significant difference in baseline levels of fatigue between chronic Q-fever patients and patients with past acute Q-fever. Over time, the mean level of fatigue for QFS and chronic Q-fever patients did not significantly change (see also Fig 3A). The mean level of fatigue significantly decreased in patients with past acute Q-fever over time (-0.91 point/year (95%CI: -1.23 to -0.59)), and this change in fatigue was significantly different from the QFS and chronic Q-fever patients.
Graph: Fig 3 Error bars representing the estimated mean and 95% confidence interval (corrected for gender) of every outcome measure (fatigue, quality of life, physical impairment and social participation) on every time point since acute Q-fever infection separate for every Q-fever group.1Participants with a score higher (fatigue, physical impairment) or lower (Quality of Life) than the cut-off value are classified as 'impaired' in that specific domain. QFS = Q-fever fatigue syndrome.
Graph
Table 3 Results (intercept and slope) from the multilevel linear regression model by Q-fever group corrected for gender.
Intercept: score at baseline Slope: change in score (per year) QFS Chronic Q-fever past acute Q-fever QFS Chronic Q-fever past acute Q-fever β (95% CI) β (95% CI) β (95% CI) β (95% CI) β (95% CI) β (95% CI) Fatigue 45.8 (43.3; 48.3) 35.6 (30.5; 40.8) 37.1 (35.8; 38.3) -0.18 (-0.75; 0.39) 0.52 (-0.50; 1.53) -0.91 (-1.23; -0.59) Quality of life 72.2 (68.5; 75.9) 87.4 (81.5; 93.3) 84.9 (83.5; 86.3) 0.28 (-0.34; 0.90) -1.4 (-2.37; -0.43) 0.12 (-0.19; 0.43) Physical impairment 13.9 (12.0; 15.8) 12.6 (8.2; 16.9) 8.4 (7.3; 9.4) 0.51 (0.14; 0.87) 1.28 (0.54; 2.02) -0.06 (-0.32; 0.19) Social participation 50.5 (43.1; 57.8) 44.6 (36.1; 53.0) 68.5 (64.5; 72.5) 0.12 (-1.20; 1.40) 1.10 (-0.54; 2.80) 5.20 (3.30; 7.20)
- 7
a,b,c The same superscript letter in each row denotes which intercept (score at baseline) does not differ significantly between Q-fever groups, based on overlapping 95% CI, and which slope (score per time point) does not differ significantly between Q-fever groups by testing the significance of fixed effects at the 0.05 level. Consequently, different letters represent significant differences. - 8 * Change in slope (score per year) is significant at the 0.05 level (every intercept (score at baseline) is significant at the 0.05 level).
- 9
1 Higher scores mean higher levels of fatigue; more physical impairment. A positive slope indicates deterioration, i.e. an increase in levels of fatigue, or an increase in physical impairment. - 10
2 Higher scores mean higher levels (better) quality of life or social participation. A positive slope indicates an improvement, i.e. an increase in quality of life, or an increase in social participation. - 11 QFS = Q-fever fatigue syndrome; CI = confidence interval.
Similarly, the mean level of QoL at baseline for QFS patients was significantly lower compared to chronic Q-fever patients and patients with past acute Q-fever (72.2 vs 87.4 and 84.9 respectively). The mean level of QoL did not significantly change over time for QFS and patients with past acute Q-fever (see also Fig 3B), but significantly decreased for chronic Q-fever patients (-1.4 point/year (95%CI: -2.37 to -0.43)). The change in QoL in chronic Q-fever patients was also significantly different from QFS and patients with past acute Q-fever.
The mean level of physical impairment at baseline for QFS patients was higher compared to patients with past acute Q-fever (13.9 vs 8.4), and the level for chronic Q-fever patients overlapped with both QFS patients and patients with past acute Q-fever (12.6, see Table 3). The mean level of physical impairment increased significantly over time for QFS (0.51 point/year (95%CI: 0.14 to 0.87)) and chronic Q-fever patients (1.28 point/year (95%CI: 0.54 to 2.02)), but not for patients with past acute Q-fever (-0.06 point/year (95%CI: -0.32 to 0.19)) (see also Fig 3C). This effect in patients with past acute Q-fever was also significantly different compared to QFS and chronic Q-fever patients.
At baseline, patients with past acute Q-fever showed a higher level of social participation than QFS and chronic Q-fever patients (68.5 vs 50.5 and 44.6, respectively). Also, over time, the mean level of social participation significantly increased for this group (5.20 point/year (95%CI: 3.30 to 7.20)), while for QFS and chronic Q-fever patients it remained constant over time. This effect in in patients with past acute Q-fever was significantly different from QFS and chronic Q-fever patients. In patients with past acute Q-fever, social participation was not measured beyond 4 years after infection in any of the individual studies. As there was no data available to support a long-term estimate, the mean and 95% confidence interval were not calculated beyond this time point for this Q-fever group (see also Fig 3D).
The first (excluding all observations from time-points baseline and 8 years after infection) and second (excluding all observations from time points baseline, 3, 5 and 8 years after infection) sensitivity analyses showed no major differences compared to the basic model in any of the outcome measures (Table 4 in S1 Appendix).
To our knowledge, this is the largest study on the short- and long-term physical and psychosocial impact of Q-fever ever performed and the first study comparing three groups of distinct entities following a C. burnetii infection. This study showed that QFS patients report significantly more fatigue, more physical impairment, lower QoL, and lower social participation than patients with past acute Q-fever without the development of QFS or chronic Q-fever in the first six months after C. burnetii infection. They also report significantly more fatigue and lower QoL than chronic Q-fever patients in the first six months after C. Burnetii infection. Furthermore, QFS patients showed no improvement in any of the measures and even showed an increase in physical impairment over time. In the first six months following C. burnetii infection, chronic Q-fever patients do not show a lower physical or psychosocial functioning compared to patients with past acute Q-fever, except for social participation. However, levels of physical impairment and QoL deteriorate significantly over time in chronic Q-fever patients. Furthermore, the largest group, patients with past acute Q-fever, shows significant improvements in functioning over time.
The finding that QFS patients experience more impact on physical and psychosocial functioning in the first six months after infection than both chronic Q-fever patients and patients with past acute Q-fever has not been previously reported. In addition, our results demonstrated no significant improvements over time in QFS patients, despite the fact that some of these patients had received treatment for QFS [[
Our study demonstrated that the physical and psychosocial functioning deteriorates over time for chronic Q-fever patients. As chronic Q-fever is a life threatening illness with severe complications, such as acute aneurysm, heart failure or non-cardiac abscesses, which occur in more than 60% of proven chronic Q-fever patients over time, this finding is not surprising [[
The largest group, patients with past acute Q-fever without subsequent development of QFS or chronic Q-fever, showed a higher physical and psychosocial functioning in the first six months after infection compared to QFS and chronic Q-fever patients. However, this does not mean their physical and psychosocial functioning was not impaired. To give some indication about recovery or impairment, it is possible to compare the scores to a reference group from the general population as reported in Reukers et al. [[
This study had several strengths. First, this study had a large sample size, which reduced the margin of error from missing data and possible outliers. The sample size for the group of chronic Q-fever patients was relatively small. However, 135 patients is still a sufficiently large study group in order to draw valid conclusions. In addition, since the number of chronic Q-fever patients in our study comprises around 50% of the nationally registered proven chronic Q-fever patients (n = 249), our results represent a large proportion of chronic Q-fever patients in the Netherlands [[
A limitation of this study were the possible differences in the methods of data collection and the response rates between studies. However, each study used the same validated questionnaires, which were compared between studies. Second, individual studies included in this IDA potentially had participation bias related to outcome measures. It is possible that recovered Q-fever patients may perceive participation not relevant and be less inclined to participate. In addition, severely impaired Q-fever patients might also be underrepresented as they might not prioritize participation in research studies. The results in this study might therefore over- or underestimate the impact of Q-fever. However, this remains speculative, as it was not possible to determine if and what kind of participation bias occurred in the individual studies. Third, the model assumed a linear disease course, while individual patients may have a fluctuating illness trajectory over time, as shown in patients who developed chronic fatigue syndrome after giardiasis [[
QFS patients reported a continuously high physical and psychosocial impact, from the start of the infection onwards. In contrast, the impact for chronic Q-fever patients worsens over time, while the overall majority of patients, belonging to the group of patients with past acute Q-fever, showed significant improvements over time. In conclusion, the physical and psychosocial impact differs greatly between QFS, chronic Q-fever and patients with past acute Q-fever without subsequent development of QFS or chronic Q-fever. It is important that physicians and policy makers are aware of these differences, in order to provide tailored information and offer relevant care for each patient group.
S1 Appendix.
(DOCX)
By Daphne F. M. Reukers; Cornelia H. M. van Jaarsveld; Reinier P. Akkermans; Stephan P. Keijmel; Gabriella Morroy; Adriana S. G. van Dam; Peter C. Wever; Cornelia C. H. Wielders; Koos van der Velden; Joris A. F. van Loenhout and Jeannine L. A. Hautvast
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