Our study measures not only the prevalence, but also highlights the severity of fatigue in children with PID. The chart-review based prevalence of fatigue in our pediatric PID population on IgG substitution therapy was 64%, corresponding well with Z-scores less than -1 on the general fatigue score of the PedsQL™ as scored by self-assessment and proxy-report by parents. This is a significantly higher prevalence than reported in the American database study of Hajjar et al. who showed a prevalence of 26% of fatigue in U.S. patients with primary antibody deficiencies [17] and comparable with adult CVID patient reports (76.9%) [21]. Our patients generally score worse on fatigue than pediatric patients with other severe chronic diseases such as multiple sclerosis and childhood cancer; emphasizing the high burden of fatigue symptoms in these patients [24, 25].
Children with PID have lower scores on nearly all subscales compared to the reference group, meaning they are more fatigued than their healthy peers. This is especially obvious concerning General Fatigue (GF): a mean Z-score of -1.78. As children with PID have the lowest scores on the GF subscale and the highest scores on CF it seems their type of fatigue is mainly physical. Studies performed in children with other chronic conditions such as sickle cell disease and Multiple Sclerosis do not report such a difference [24, 26].
In general, literature on CVID patients report fatigue as a result of declining trough levels of IgG in patients who are on intravenous IgG substitution [21]. However, the vast majority of patients in our study receive SCIG; which provides a fairly stable IgG level during treatment. Fatigue symptoms in our patients therefore cannot be explained by low trough levels or other therapeutic factors.
According to other studies a diagnosis of CVID, higher age, female gender, having ahigh BMI, depression, bronchiectasis, auto-immunity and receiving IVIG treatment are factors associated with fatigue [17-19]. These risk factors and their prevalence in our study population were evenly distributed amongst the chart review and the eligible population of the survey as well as between responders and non-responders to the survey. However, the sample size of our study was still too small to analyze signficant factors contributing to fatigue.
The external validity of the postal survey study was warranted by a reasonably high response rate and by using reference values of a large cohort of healthy Dutch peers.
A small number of patients scored extremely high or extremely low. The minimum self-reported Total Fatigue Score (TFS) was 29, whereas the maximum was 94. These so-called ‘floor and ceiling’ effects make response bias unlikely and indicate a strong reliability.
Our observations on the child-parent concordance differ from the findings in literature. In health-related quality of life measurements there usually is a low child-parent concordance with lower scores reported by the children, whereas our results showed higher scores on all subscales in children compared to the proxy report [23, 27]. In our study the concordance between teenagers and parents was relatively high (0,90-0,93). In the 5-7 years age group it was much lower (0,24-0,74). These results indicate that patients in this age group filled out the questionnaires independent from their parents. It may also indicate that the questionnaire is complex for younger children. Furthermore, it may represent parents’ concerns about their child well-being; scoring them far more fatigue than they do themselves.
Future research should focus on sociodemographic variables such as social economic status, but also on disease related factors such as diagnosis, infection burden, type of treatment and IgG trough levels in i.v.-treated PID patients.
The present study has several strengths. To our knowledge it is the first study using PedsQL MFS surveys in children with PID, it represents a broad age-range of participants and was valid and reliable. Limitations include the small sample size. The prevalence of known risk factors of fatigue in PID patients was too low to analyze. Fatigue as a symptom was not routinely noted on consultations; which leads to a reporting bias in the chart review scores. We measured fatigue scores at only one timepoint. To rule out possible seasonal influences, a future study would need to have at least one timepoint in spring and one in fall. By using different measurement tools simultaneously, e.g. the Hospital Anxiety and Depression Scale, psychological causes for fatigue can be excluded. Using PedsQL MFS survey routinely during follow-up at the out-patient clinic would help to see if any therapeutic interventions; medical as well as psychological, influence fatigue symptoms in PID patients.
In conclusion, the results of our study show the presence of severe fatigue in a majority of pediatric PID patients on immunoglobulin substitution therapy. The PedsQL MFS survey is a feasible tool to screen and identify severely fatigued PID patients and their caretakers’ impression. Studies on effective interventions on fatigue are warranted and should be investigated in this patient group to further improve quality of life and well-being.