The case history is presented of a patient with common variable immunodeficiency in whom heart lung transplantation has been carried out with success. Transplantation was the only long term therapeutic option in this patient due to the progressive respiratory failure resulting from bronchiectasis, emphysema, and granulomatous lung disease.
- common variable immunodeficiency
- granulomatous lung disease
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Common variable immunodeficiency is a primary immunodeficiency characterised by hypogammaglobulinaemia and has an estimated prevalence ranging from 1:50 000 to 1:200 000.1 The immunodeficiency affects men and women equally and the onset is usually in the second or third decade of life.1 It is characterised by recurrent bacterial infections of the respiratory tract usually with non-typable Haemophilus influenzae and Streptococcus pneumoniae.1 Recurrent bacterial infections can lead to irreversible chronic lung disease with bronchiectasis.1
A 37 year old man, an aircraft inspector, presented with a one year history of progressive dyspnoea, expectoration of a cupful of mucopurulent sputum daily, weight loss, and frequent sinus headaches. Past history included staphylococcal pneumonia at the age of six, pneumonia age of seven, delayed puberty, short stature, and frequent chest infections. He had a 10 year pack history of smoking, having stopped 10 years previously. His nephew had frequent infections including osteomyelitis as a child.
Pulmonary function tests were compatible with emphysema: forced expired volume in one second (FEV1) 0.61 l (15% predicted), forced vital capacity (FVC) 2.66 l (55% predicted), total lung capacity (TLC) 8.05 l (125% predicted), residual volume (RV) 5.11 l (302% predicted), and gas transfer coefficient (Kco) estimated using a 10 second breath hold method at 10.77 (38% predicted). Sputum microbiology culturedHaemophilus influenzae (mycobacterial and fungal cultures were negative). Chest radiography revealed hyperinflated lung fields and bilateral basal cystic shadowing. Computed tomographic (CT) scanning of the lungs revealed emphysematous bullae and diffuse interstitial shadowing associated with structural lung and bronchial damage (fig 1). Although there was uncertainty whether there was bronchiectasis on the CT scan, a bronchogram carried out eight years earlier revealed bilateral bronchiectasis.
Full blood count and biochemistry were normal including angiotensin converting enzyme, α1-antitrypsin, aspergillus precipitins, rheumatoid and antinuclear factor. A sweat sodium and chloride test to exclude cystic fibrosis was normal. Immunoglobulin screening prior to treatment revealed a low IgG at 4.6 g/l (normal range 6–16) but normal IgA at 1.8 g/l (0.75–4) and IgM 0.65 g/l (0.25–2). Immunoglobulin subclasses revealed IgG subclass 1 and 3 deficiency: IgG1 3.5 g/l (4.2–12.9) and IgG30.13 g/l (0.4–1.3). He had low antibody levels to the recall antigens of Haemophilus and pneumococcal polysaccharides, as well as diphtheria and tetanus toxoid, and the latter failed to normalise after vaccination. There were low numbers of both T and B lymphocytes with a low T4 level and a reversed T4/T8 ratio (CD4 0.12 × 109/l (healthy control 0.74 × 109) and CD8 0.69 × 109/l (0.77 × 109)). The lymphocytes also showed poor in vitro functional activity with subnormal lymphocyte proliferative responses to phytohaemagglutinin, concanavalin A, pokeweed mitogen, purified protein derivative, and Candida albicans.
Immunoglobulin replacement intravenous infusions (Sandoglobulin) at 150 mg/kg were commenced three weekly correcting the hypogammaglobulinaemia up to within the normal range (>6 g/l). Following replacement therapy the frequency of chest infections reduced. Despite this, over the next six years he progressively deteriorated becoming breathless on minimal exertion and requiring long term oxygen therapy, home nebulised bronchodilators, and cyclical antibiotics. At this stage his FEV1 was 0.4 l and he was referred for heart lung transplantation.
Seventeen months later he had a successful heart lung transplant. The macroscopic appearance of the explanted lung revealed extensive bronchiectasis and emphysema through all lobes. Microscopy revealed evidence of bronchiectasis and emphysema, but also evidence of interstitial fibrosis and less frequent granulomas in all lobes.
He was put on standard post-transplant immunosuppressive therapy with cyclosporin, azathioprine and prednisolone. Replacement immunoglobulin therapy was continued every three weeks with IgG levels maintained at >6 g/l and co-trimoxazole was used as prophylactic treatment againstPneumocystsis carinii. The CD4 T cell count was not monitored. Since transplantation he has had one minor episode of rejection at two months. Spirometric tests at two years showed that lung function was maintained with FEV1 4.24 l (119% predicted) and FVC 4.96 l (114% predicted) and he is back at work.
Patients with common variable immunodeficiency have hypogammaglobulinaemia leading to defects in humoral immunity.1-4 The marked decrease in serum IgG is usually associated with depressed serum IgM and IgA levels2 which was not seen in this case, reflecting the spectrum of disease that occurs. Defects in cell mediated immunity may also occur in common variable immunodeficiency and, rarely, patients can become infected with mycobacteria, fungi andPneumocystis.1-4 This patient had immunodeficiency in both the humoral and cellular arms, although he suffered mainly from bacterial infections and had no evidence of fungal or mycobacterial infection.
Multisystem involvement, resembling sarcoidosis, with non-caseating granulomas is recognised in common variable immunodeficiency.1-6 The granulomas most commonly occur in the lung, lymph nodes, skin, bone marrow, and liver.1-6 The aetiology of the granulomas is unclear and during their course they often undergo spontaneous expansion and regression without therapy.1-4 Occasionally the granulomatous process will become aggressive and steroid therapy is useful in these cases.1-5 The granulomatous lung disease was found diffusely in the explanted lung, but might have been picked up earlier by lung biopsy.
Immunoglobulin replacement was first commenced for hypogammaglobulinaemia in 1952.1 The decision to replace immunoglobulins should be based on the frequency and severity of recurrent infections and a demonstrated inability to mount a functional antibody response.2 Following replacement immunoglobulin therapy there was a reduced number of chest infections compared to preceding years, body weight improved, and the decline in lung function stabilised; however, this progressed to the point of requiring transplantation.
Heart lung transplantation has successfully been carried out in this patient with end stage lung disease due to common variable immunodeficiency. There was, however, initial reluctance by the transplant team to pursue transplantation, since it was felt that an immunodeficient patient would be at increased risk of chest and other infections with post-transplant immunosuppression. This does not appear to have been the case, and an important factor was the maintenance of adequate replacement immunoglobulins. It is possible that the degree of impairment in his cell mediated immunity, as evidenced by abnormal parameters of in vitro lymphocyte function, may have made it easier for the transplant to become established.