Patients with Diamond Blackfan Anaemia Have Abnormalities of Cellular and Humoral Immunity

Abstract 3484

Diamond Blackfan anaemia (DBA) is an inherited bone marrow failure syndrome characterised by anaemia, physical anomalies and an increased risk of malignancy. Although the hallmark of DBA is anaemia secondary to pure red cell aplasia, some patients exhibit additional cytopaenias, such as neutropaenia, suggestive of a more widespread defect in haemopoietic development. Aberrant immunity causing infections has been reported in a proportion of patients, but the scope and precise nature of these immunological defects are yet to be elucidated.

Fifty-nine patients with clinical and laboratory features consistent with Diamond Blackfan anaemia attend the DBA clinic at St. Mary's Hospital. The median age is 8.8 years (1.1 – 40.9). Two patients presented in utero (3.4%), 36 patients (61%) in the first twelve weeks of life, 12 patients (20.3%) from 3 to 12 months, 6 patients (10.2%) 1 to 5 years, 2 patients (3.4%) 5 to 10 years and 1 patient (1.7%) later than 18 years of age. Thirty-five patients (59.3%) had systemic abnormalities [including cardiac involvement in 17 patients (28.8%)], 7 patients (11.9%) had short stature only and 17 patients (28.8%) no systemic abnormalities. Infection was implicated in the death of 2 out of 3 patients in this cohort. Immunological parameters were available for 37 of the patients (age 18 months to 40 years).

A history of infections was reported in 16/37 (43.2%) patients. Three patients had at least 1 serious infective episode requiring hospital admission (Salmonella gastroenteritis, Clostridum difficile gastroenteritis and neonatal pneumonia) and 13/37 patients experienced recurrent infections (7/37 respiratory tract, 1/7 urinary tract, 2/37 otitis media and 3/37 infections affecting different systems). In 2/16 patients infections occurred during treatment with corticosteroids.

Consistent lymphopenia was found in 7/37 (18.9%) patients. Specific deficiencies in lymphocyte subsets were identified by immunophenotyping as summarised below. Abnormalities in one or more subsets were identified in the 7 patients with low total lymphocyte counts and a further 7 patients with normal total lymphocytes counts. A low B lymphocyte fraction was the most commonly detected abnormality, present in 12/37 (32.4% patients). Three patients (8.1%) had at least 3 abnormalities in lymphocytes subsets.

Low levels of one or more immunoglobulin isotypes were detected in 4/34 (11.8%) patients. An additional 5/32 (15.6%) patients showed a selective deficiency in one of the four IgG subclasses. Importantly, these abnormalities were masked by normal total IgG levels.

Of 30 patients who had undergone immunisation against measles, mumps and rubella, immunity to all 3 pathogens was confirmed in only 13 (43.3%) patients (as determined by positive IgG serology). We observed equivocal or negative specific IgG antibodies to measles in 13/30 (43.3%), mumps in 7/30 (23.3%) and rubella in 6/30 (20%). Haemophilus B antibody titres in 30 patients following immunisation were optimum (>1mg/L) in 14/30 (46.7%), minimally protective (>0.15 mg/L) in 11/30 (36.7%) and inadequate (<0.15 mg/L) in 5/30 (16.7%).

In summary, DBA patients have defects in both cellular and humoral immunity independent of treatment with steroids, with combined abnormalities of both arms of immunity in 5/37 (13.5%) patients and defects in B cells being overall the most common abnormality. In addition, a large number of patients had subnormal responses to vaccination. These findings are likely to have a role in the increased number of infections found in DBA.