Background: Primary immune deficiency (PID) due to humoral defects is associated with recurrent respiratory tract infections (RTIs). Reliable clinical warning signs of PID would facilitate early diagnosis and thereby reduce long-term complications. The aim of the present study was to evaluate the accuracy of the warning sign, 'four or more antibiotic-treated RTIs annually for 3 or more consecutive years,' for detecting PID among adults in a primary health-care setting. Methods: Fifty-three cases with 'four or more antibiotic-treated RTIs annually for 3 or more consecutive years' were selected from a Swedish primary health-care registry of RTIs. In addition, 66 age- and sex-matched controls were selected having a maximum of one antibiotic-treated RTI during the period covered by the study. Levels of immunoglobulin (Ig) IgG, IgA, IgM, IgG subclasses, and IgG antibodies against Haemophilus influenzae and Streptococcus pneumoniae as well as the inflammatory markers, C-reactive protein, interleukin (IL)-6 and IL-8 were determined. Results: IgG subclass deficiencies (IgGsd) were found in 5/53 (9.4%) of the cases and in 7/66 (10.6%) controls. The most frequent deficiency was IgG3sd and this was found in three participants in the case group and seven in the control group. The mean level of IgG3 was lower in the control group (p = 0.02). The mean level of IL-8 was lower in the case group (p = 0.02). Conclusion: The results show that physicians working in primary health care cannot solely rely on the frequency of antibiotic-treated RTIs as a warning sign for the detection of common humoral immune deficiencies.

Background: Immunoglobulin G subclass deficiencies (IgGsd) are associated with recurrent respiratory tract infections. Immunoglobulin substitution therapy may be needed to prevent chronic lung tissue damage but tools for identifying the patients that will benefit from this treatment are still insufficient. Some Fc gamma R polymorphisms seem to predispose for an increased risk for infections. In this study we wanted to evaluate if the Fc gamma R-profile differs between individuals with IgGsd and a control population. Methods: Single nucleotide polymorphisms (SNPs) of Fc gamma RIIa, Fc gamma RIIIa and Fc gamma RIIc in 36 IgGsd patients and 192 controls with similar sex and geographical distribution were analyzed by TaqMan allelic discrimination assay or Sanger sequencing. Results: In the IgGsd-group, homozygous frequency for Fc gamma RIIa-R/R131 (low-binding capacity isoform) was higher (p = .03) as well as for non-classical Fc gamma RIIc-ORF (p = .03) and classical Fc gamma RIIc-ORF tended (p = .07) to be more common compared to the controls. There was no difference between the groups regarding Fc gamma RIIIa. Conclusion: The gene for classical Fc gamma RIIc-ORF tended to be more frequent in individuals with immunoglobulin G subclass deficiency and the genes for non-classical Fc gamma RIIc-ORF as well as low-binding capacity receptor Fc gamma RIIa-R/R131 were more frequent. Further studies on the Fc gamma R polymorphisms may pave way for identifying individuals that will benefit from immunoglobulin substitution.

PurposeIndividuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT. MethodThirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion. ResultsQoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1. ConclusionFatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made.