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A coughing policeman
CASE REPORT
Case report
A coughing policeman M Duddridge, K P West, J Wales, M J Browning A 26-year-old policeman was referred to respiratory physicians in 1977, following a routine employment chest radiograph that showed patchy opacities and slight reticular patterning in both lung fields. 1 week before being seen, he developed a stiff neck and swelling on the right side of his neck. He had weight loss of about 6 kg over the preceding months. On examination his temperature was normal, with right cervical lymphadenopathy, and moderate hepatosplenomegaly. A lymph-node biopsy showed non-caseating granuloma consistent with sarcoidosis or tuberculosis. Transbronchial lung biopsy showed granulomas. In the absence of evidence of mycobacteria or other predisposing conditions, sarcoidosis was diagnosed. He was given steroids, but with a poor clinical response, and his disease followed a chronic, relapsing course. In 1980, he developed a seronegative thrombocytopenia, and in 1984 he underwent splenectomy. From this time onwards he had recurrent respiratory tract infections, and was admitted on several occasions with pneumonia. By 1998, he had a continuous productive cough, breathlessness, and tightness in his chest. A computed tomographic scan showed bronchiectatic changes. Serum immunoglobulins, measured for the first time in August, 1998, showed severe hypogammaglobulinaemia (IgG 1·4 g/L [normal range 6·0–16·0], IgA <0·1 g/L [0·8–4·0] and IgM=0·1 g/L [0·5–2·0]). He had a normal lymphocyte count and normal numbers and properties of lymphocyte subsets, including a normal CD4+ T cell count. Common variable immunodeficiency (CVID) was diagnosed, and he was started on intravenous immunoglobulin replacement therapy (0·4 g/kg every 3 weeks). On this regimen, his IgG is maintained at >6·0 g/L. He remains generally well, but has persistent, usually dry cough. The diagnosis of sarcoidosis is based on the combination of a compatible clinical picture, histological evidence of non-caseating granuloma, and the exclusion of other conditions known to be associated with gramulomas.1 Historically, the Kveim test was positive in 85–90% of patients with classic acute sarcoidosis, falling to around 30% in chronic fibrotic disease. Raised angiotensin converting enzyme (ACE) concentrations have been identified in up to 80% of individuals with sarcoidosis, and may correlate with disease activity, although are not specific for the condition. Immunoglobulins are often raised in sarcoidosis. However, an association between hypogammaglobulinaemia and granulomatous disease has been recognised for over 30 years. The occurrence of noncaseating granulomas in CVID has been estimated at
Histological section of lymph node biopsy, showing typical, non-caseating granuloma formation and a Langhan’s type giant cell (arrowed)
between 5–20% of CVID patients.2–4 The presence of granulomatous disease may predate the diagnosis of CVID by several years.2 Both Kveim test positive and Kveim test negative cases of hypogammaglobulinaemia with sarcoidlike granulomas have been described.2,3 Raised ACE is unhelpful in discriminating sarcoidosis from CVID, since ACE may be increased in CVID patients without overt evidence of granulomas.2 Individuals with granulomatous disease and CVID may represent a distinct subgroup of CVID patients.2–5 These patients tend to have splenomegaly, reduced CD4+ T cell numbers with CD8+ T cell activation, and a high incidence of autoimmune complications. There is a strong association between granulomatous CVID and a polymorphism in the tumour necrosis factor (TNF) gene.4 In this case, the longstanding history of recurrent pulmonary infections before the diagnosis of CVID suggests that the hypogammaglobulinaemia was present for many years before its diagnosis. The early diagnosis and treatment of hypogammaglobulinaemia in patients with granulomatous disease may prevent the development of irreversible end-organ damage such as bronchiectasis. Measurement of serum immunoglobulins should be included in the investigation of all patients with granulomatous disease. Granulomatous disease may predate the development of hypogammaglobulinaemia and the long-term follow up of these patients should include the monitoring of infections and longitudinal estimation of immunoglobulins. References 1 2
3
Lancet 2000; 355: 804 Departments of Immunology (M Duddridge MRCP, M J Browning MRCPath), and Pathology (K P West FRCPath), Leicester Royal Infirmary NHS Trust, Leicester LE1 5WW, UK; and Division of Respiratory Medicine, Glenfield Hospital NHS Trust, Leicester, UK (J Wales FRCP) Correspondence to: Dr M J Browning
804
4
5
Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336: 1224–34. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997; 127: 613–17. Fasano MB, Sullivan KE, Sarpong SB, et al. Sarcoidosis and common variable immunodeficiency. Medicine (Baltimore) 1996; 75: 251–61. Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol 1997; 159: 6236–41. Wright JJ, Wagner DK, Blaese RM, et al. Characterization of common variable immunodeficiency: identification of a subset of patients with distinctive immunophenotypic and clinical features. Blood 1990; 76: 2046–51.
THE LANCET • Vol 355 • March 4, 2000
Case report
A coughing policeman M Duddridge, K P West, J Wales, M J Browning A 26-year-old policeman was referred to respiratory physicians in 1977, following a routine employment chest radiograph that showed patchy opacities and slight reticular patterning in both lung fields. 1 week before being seen, he developed a stiff neck and swelling on the right side of his neck. He had weight loss of about 6 kg over the preceding months. On examination his temperature was normal, with right cervical lymphadenopathy, and moderate hepatosplenomegaly. A lymph-node biopsy showed non-caseating granuloma consistent with sarcoidosis or tuberculosis. Transbronchial lung biopsy showed granulomas. In the absence of evidence of mycobacteria or other predisposing conditions, sarcoidosis was diagnosed. He was given steroids, but with a poor clinical response, and his disease followed a chronic, relapsing course. In 1980, he developed a seronegative thrombocytopenia, and in 1984 he underwent splenectomy. From this time onwards he had recurrent respiratory tract infections, and was admitted on several occasions with pneumonia. By 1998, he had a continuous productive cough, breathlessness, and tightness in his chest. A computed tomographic scan showed bronchiectatic changes. Serum immunoglobulins, measured for the first time in August, 1998, showed severe hypogammaglobulinaemia (IgG 1·4 g/L [normal range 6·0–16·0], IgA <0·1 g/L [0·8–4·0] and IgM=0·1 g/L [0·5–2·0]). He had a normal lymphocyte count and normal numbers and properties of lymphocyte subsets, including a normal CD4+ T cell count. Common variable immunodeficiency (CVID) was diagnosed, and he was started on intravenous immunoglobulin replacement therapy (0·4 g/kg every 3 weeks). On this regimen, his IgG is maintained at >6·0 g/L. He remains generally well, but has persistent, usually dry cough. The diagnosis of sarcoidosis is based on the combination of a compatible clinical picture, histological evidence of non-caseating granuloma, and the exclusion of other conditions known to be associated with gramulomas.1 Historically, the Kveim test was positive in 85–90% of patients with classic acute sarcoidosis, falling to around 30% in chronic fibrotic disease. Raised angiotensin converting enzyme (ACE) concentrations have been identified in up to 80% of individuals with sarcoidosis, and may correlate with disease activity, although are not specific for the condition. Immunoglobulins are often raised in sarcoidosis. However, an association between hypogammaglobulinaemia and granulomatous disease has been recognised for over 30 years. The occurrence of noncaseating granulomas in CVID has been estimated at
Histological section of lymph node biopsy, showing typical, non-caseating granuloma formation and a Langhan’s type giant cell (arrowed)
between 5–20% of CVID patients.2–4 The presence of granulomatous disease may predate the diagnosis of CVID by several years.2 Both Kveim test positive and Kveim test negative cases of hypogammaglobulinaemia with sarcoidlike granulomas have been described.2,3 Raised ACE is unhelpful in discriminating sarcoidosis from CVID, since ACE may be increased in CVID patients without overt evidence of granulomas.2 Individuals with granulomatous disease and CVID may represent a distinct subgroup of CVID patients.2–5 These patients tend to have splenomegaly, reduced CD4+ T cell numbers with CD8+ T cell activation, and a high incidence of autoimmune complications. There is a strong association between granulomatous CVID and a polymorphism in the tumour necrosis factor (TNF) gene.4 In this case, the longstanding history of recurrent pulmonary infections before the diagnosis of CVID suggests that the hypogammaglobulinaemia was present for many years before its diagnosis. The early diagnosis and treatment of hypogammaglobulinaemia in patients with granulomatous disease may prevent the development of irreversible end-organ damage such as bronchiectasis. Measurement of serum immunoglobulins should be included in the investigation of all patients with granulomatous disease. Granulomatous disease may predate the development of hypogammaglobulinaemia and the long-term follow up of these patients should include the monitoring of infections and longitudinal estimation of immunoglobulins. References 1 2
3
Lancet 2000; 355: 804 Departments of Immunology (M Duddridge MRCP, M J Browning MRCPath), and Pathology (K P West FRCPath), Leicester Royal Infirmary NHS Trust, Leicester LE1 5WW, UK; and Division of Respiratory Medicine, Glenfield Hospital NHS Trust, Leicester, UK (J Wales FRCP) Correspondence to: Dr M J Browning
804
4
5
Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336: 1224–34. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997; 127: 613–17. Fasano MB, Sullivan KE, Sarpong SB, et al. Sarcoidosis and common variable immunodeficiency. Medicine (Baltimore) 1996; 75: 251–61. Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol 1997; 159: 6236–41. Wright JJ, Wagner DK, Blaese RM, et al. Characterization of common variable immunodeficiency: identification of a subset of patients with distinctive immunophenotypic and clinical features. Blood 1990; 76: 2046–51.
THE LANCET • Vol 355 • March 4, 2000