Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults

Abstract

Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy.

Objectives: To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia.

Methods: We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features.

Results: 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort.

Conclusion: Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.

Keywords: X-linked agammaglobulinemia; common variable immunodeficiency; diagnostic delay; immunoglobulin subclass deficiency; predominantly antibody deficiency; primary immunodeficiency; specific antibody deficiency.

Figure 1

Age at diagnosis and diagnostic features differ between disease groups in Victorian adult patients with predominantly antibody deficiencies. (A) Box–whisker plot of age at diagnosis according to disease classification with median and 5–95% percentiles indicated. (B) Histogram demonstrating age at reported symptom onset, light red, and age at diagnosis (dark red) in common variable immunodeficiency (CVID) patients. (C) Qualitative vaccine responses to pneumococcal polysaccharide vaccine responses measured IgG binding against PPS23 polysaccharides in CVID patients (red), unclassified hypogammaglobulinemia (HGG) patients (green), IgG subclass deficiency (IGSCD) (purple), and specific antibody deficiency (SpAD) (orange). Darker colored columns indicate protective responses, P, and lighter colored columns indicate unprotective responses, U (χ² analysis: **p < 0.01 and ****p < 0.0001). (D) Serum IgG and IgA (g/L, mean ± SD) at diagnosis according to disease classification (**p < 0.01, ***p < 0.001, and ****p < 0.0001, using one-way ANOVA).

Figure 2

CVID is associated with more frequent non-infectious complications than other predominantly antibody deficiencies, and these complications are associated with reduced survival. (A) Histogram depicting frequency of complications in CVID, darker-colored columns, compared with non-CVID cases in lighter-colored columns. Abbreviations: GLILD, granulomatous lymphocytic interstitial lung disease; CVID, common variable immunodeficiency. Purple represents bronchiectasis; yellow represents non-malignant lymphoproliferative complications; brown, autoimmune complications; green, gastrointestinal disease, and blue, malignancies. (Fisher’s exact test: ***p < 0.001; **p < 0.01; and *p < 0.05). (B) Histogram depicting percentage of CVID and non-CVID patients with 0, 1, or more non-infectious complications of disease. (C) Survival after diagnosis in individuals with immune dysregulation is significantly reduced compared with patients with infections only (p < 0.05, Mantel–Cox log rank). Black line indicates survival of individuals without features of immune dysregulation, red line indicates survival of individuals with immune dysregulation. (D) Survival after diagnosis in individuals with bronchiectasis is significantly reduced compared with patients with infections only (p < 0.05, Mantel–Cox log rank). Black line indicates survival of individuals without bronchiectasis, and red indicates survival of individuals with bronchiectasis.