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

Abstract

BackgroundPredominantly 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.ObjectivesTo characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia.MethodsWe 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.Results179 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.ConclusionOur 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.

Characterization of adult patients with IgG subclass deficiency and subnormal IgG2

“…The present study characterizes 18 adult patients with IgGSD whose subnormal IgG subclasses included IgG2. General characteristics of this cohort are similar to those of cohorts of adults with IgGSD without subnormal IgG2, including: age at diagnosis [25,26,31,38,42]; predominance of women [26,31,38,42]; duration of frequent or severe respiratory tract infection and age of onset of frequent or severe respiratory tract infection before diagnosis of IgGSD [30,42]; Table 3. Blood lymphocyte subpopulations in 16 adults with IgGSD and subnormal IgG2 a .…”

Influenza‐specific IgG1+ memory B‐cell numbers increase upon booster vaccination in healthy adults but not in patients with predominantly antibody deficiency

“…[1][2][3][4][5] Patients are defined by an impaired antibody (Ab) response to antigen stimulation. [6][7][8] Within the group of PAD patients, those with a complete absence of serum immunoglobulin (Ig) and of circulating B cells are defined as having agammaglobulinemia. This subgroup is genetically well defined with the majority being males having X-linked inheritance because of mutations in the BTK gene, 9,10 and others having autosomal recessive inheritance because of mutations in pre-B-cell receptor signalling molecules or critical transcription factors.…”

“…5,6,20,21 Typically, treatment of PAD involves Ig replacement therapy (IgRT) and prophylactic antibiotics to reduce the number and severity of infections. 7,21,22 This is important to reduce the risk of irreversible organ damage, such as bronchiectasis because of recurrent respiratory infections that is a major contributor to the high morbidity and reduced life expectancy of patients. 7,22,23 PAD patients can also develop non-infectious complications such as autoimmunity and malignancy.…”

“…7,21,22 This is important to reduce the risk of irreversible organ damage, such as bronchiectasis because of recurrent respiratory infections that is a major contributor to the high morbidity and reduced life expectancy of patients. 7,22,23 PAD patients can also develop non-infectious complications such as autoimmunity and malignancy. 6,7,21,22,24 These complications are difficult to treat and, if prominent, can mask a PAD diagnosis resulting in a significant delay in diagnosis and initiation of optimal treatment.…”

“…7,22,23 PAD patients can also develop non-infectious complications such as autoimmunity and malignancy. 6,7,21,22,24 These complications are difficult to treat and, if prominent, can mask a PAD diagnosis resulting in a significant delay in diagnosis and initiation of optimal treatment. 7,23 With the diagnostic rate of genomics in PAD being only~20%, 5,7,[25][26][27] immunophenotyping of the blood B-cell compartment is frequently performed to support the clinical diagnosis.…”