Lymphoid Interstitial Pneumonitis Associated with Common Variable Hypogammaglobulinaemia Thorax: First Published As 10.1136/Thorax.55.1.88 on 1 January 2000

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Lymphoid Interstitial Pneumonitis Associated with Common Variable Hypogammaglobulinaemia Thorax: First Published As 10.1136/Thorax.55.1.88 on 1 January 2000 88 Thorax 2000;55:88–90 Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia Thorax: first published as 10.1136/thorax.55.1.88 on 1 January 2000. Downloaded from treated with cyclosporin A ChristopherWHDavies, Mark C Juniper, Winifred Gray, Fergus V Gleeson, Helen M Chapel, RobertJODavies Abstract diagnosed as having bronchiectasis which was Lymphoid interstitial pneumonitis (LIP) treated with long term antibiotics, and autoim- is a rare clinicopathological entity that mune haemolytic anaemia which was treated may be associated with common variable with corticosteroids and splenectomy. As a immune deficiency (CVID) and may lead result of steroid treatment she had developed to respiratory failure and death. Some severe osteoporosis with multiple previous patients may respond to prolonged pathological bone fractures. corticosteroid treatment. We hypothesised On admission she complained of fever, that, in view of the predominant T cell sweats, and progressive dyspnoea with noctur- nature of LIP, cyclosporin A would be a nal cough increasing over the preceding two more appropriate choice of immunosup- weeks. She had been given several courses of pressive agent and report the first case of oral antibiotics and inhaled budesonide with its successful use in a woman with LIP no improvement. She had never smoked. On associated with CVID. examination she was apyrexial with bilateral (Thorax 2000;55:88–90) crackles on auscultation and a splenectomy Keywords: lymphoid interstitial pneumonitis; common scar. variable immune deficiency; cyclosporin A Initial investigations showed leucocytosis at 12.9 × 109/l (neutrophils 6.5 × 109/l, total lym- phocytes 4.2 × 109/l, T cells 2.5 × 109/l, CD4 Lymphoid interstitial pneumonitis (LIP) is a lymphocytes 1.82 × 109/l, CD8 lymphocytes rare clinicopathological entity that is character- 0.68 × 109/l) and C reactive protein concentra- ised by a diVuse or multifocal reactive lym- tions of 36 mg/l. Chest radiography and high phoid infiltrate involving the alveolar resolution computed tomography (HRCT) interstitium.1–4 Most cases show a preponder- showed patchy ground glass opacification, ance of lymphocytes.1–5 The condition has been peribronchovascular nodules, discrete nodules, http://thorax.bmj.com/ associated with a number of diverse systemic and areas of bronchiectasis. Antinuclear anti- illnesses such as AIDS, Epstein-Barr virus bodies, Aspergillus precipitins, and blood cul- infection, autoimmune disorders, and various tures were negative. Her immunoglobulin pro- Osler Chest Unit, immunodeficiency states including common file at admission after recent infusion of Churchill Hospital, variable immune deficiency (CVID), also immunoglobulin (normal ranges) was IgG 14 Oxford RadcliVe Trust, known as primary antibody deficiency.1–3 (6–13) g/l, IgA <0.1 (0.8–3.9) g/l, IgM 1.6 Oxford OX3 7LJ, UK The association of LIP with CVID was first (0.4–2.5) g/l, and IgE 4 (<120) kU/l. Pulmo- CWHDavies reported by Liebow and Carrington in 19736 M C Juniper nary function showed a restrictive pattern on October 1, 2021 by guest. Protected copyright. RJODavies and up to 10% of patients with LIP may have (forced expiratory volume in one second hypogammaglobulinaemia.13 The clinical (FEV1) 1.72 l (58% predicted), forced vital Department of course of non-AIDS LIP is variable but death capacity (FVC) 1.90 l (56% predicted) with Radiology may occur due to progressive pulmonary fibro- F V Gleeson reduced gas transfer coeYcient (KCO) 62% sis though some patients may respond to predicted). corticosteroid therapy taken for prolonged Department of 2–5 Immediate management included broad Cellular Pathology, periods. There are only occasional reports of spectrum antibiotics but, after no improvement John RadcliVe treatment with alternative immuno- 27 and continued fever, bronchoscopic lavage was Hospital, Oxford suppressants. We hypothesised that, in view performed; this did not identify any bacteria, RadcliVe Trust, Oxford of the predominant T cell nature of LIP, mycobacteria, virus or fungi on culture. OX3 9DU, UK cyclosporin A would be a more appropriate W Gray Polymerase chain reaction (PCR) for DNA to choice of immunosuppressive agent and report Epstein-Barr virus, cytomegalovirus, and the first case of its successful use in a patient Department of was negative. Ten days with LIP associated with CVID. Mycoplasma pneumoniae Immunology after admission the patient underwent an open H M Chapel lung biopsy (lingula) for diagnosis. Correspondence to: Case report Histological examination showed an exten- Dr CWH Davies In October 1995 a 34 year old woman with sive lymphocytic infiltrate of the lung paren- known CVID diagnosed in 1989 was admitted chyma with peribronchial germinal centre for- Received 9 October 1997 Returned to authors to our unit complaining of dyspnoea and mation and epithelialisation of some alveoli (fig 21 January 1998 fatigue for two months. She had been treated 1). Immunohistochemistry showed the lym- Revised manuscript received with intravenous immunoglobulin replacement phocytes to be predominantly T cells with only 25 February 1998 Accepted for publication therapy since 1989 at a dose of 0.3 g/kg/month sparse representation of B cells. Most of the T 16 March 1998 in divided doses. She had previously been cells were CD4 positive with only a few CD8 Lymphoid interstitial pneumonitis 89 ated with bilateral new pulmonary nodules and increased ground glass opacification on the HRCT chest scan. She remained on pred- Thorax: first published as 10.1136/thorax.55.1.88 on 1 January 2000. Downloaded from nisolone in a dose of 7.5 mg on alternate days and the dose of cyclosporin was increased to 125 mg/day with a subsequent improvement in clinical symptoms and lung function (FEV1 2.32 l; FVC 2.61 l; KCO 93% predicted). There was associated resolution of the chest radiograph and CT scan infiltrates and nod- ules. Currently the patient is in remission on prednisolone in a dose of 7.5 mg on alternate days with a serum cyclosporin level of 76 ng/ ml. Discussion Lymphoid interstitial pneumonitis (LIP) is by definition a reactive lymphoid infiltrate involv- ing the pulmonary interstitium1–4 and is also Figure 1 Lymphocytic infiltration of alveolar walls with peribronchiolar lymphoid follicles × known as diVuse hyperplasia of the bronchus and germinal centre formation. Epithelialised alveoli are also present. Stain: H&E( 3 medium power). associated lymphoid tissue (BALT). BALT is thought to be an important factor in the positive cells. There was no evidence of a immunological response to inhaled antigens monoclonal proliferation to suggest transfor- landing on the mucosal surfaces and is part of mation to malignant lymphoma. the more widely recognised mucosa associated A diagnosis of LIP was made and she was immune system. The entity of LIP may be seen recommenced on prednisolone 40 mg/day. in association with a variety of conditions such Over the following three months the patient’s as paediatric AIDS, primary immuno- symptoms improved and there was resolution deficiency, Sjögren’s syndrome, myasthenia of crackles and improved lung function (FEV1 gravis, chronic liver disease, and dysprotein- 2.12 l; FVC 2.42 l; KCO 79% predicted) with aemic states including hyper- and reduction in the extent of nodularity and hypogammaglobulinaemia.1–4 A small number ground glass opacification on the HRCT scan, of cases may in fact be a diVuse interstitial low and the dose of corticosteroids was reduced. grade B cell lymphoma with microscopic foci She continued to receive immunoglobulin resembling LIP.1 Up to 80% of patients with replacement (0.7 g/kg/month), though at LIP will have evidence of dysproteinaemia, weekly intervals to maintain a higher trough most frequently hypergammaglobulinaemia 3 level. due to elevation of IgM and IgG. However, http://thorax.bmj.com/ In January 1996 when prednisolone was hypogammaglobulinaemia occurs in about down to 10 mg/day she developed identical 10% of adults with this condition, and the features as at presentation associated with a fall association of LIP with CVID has been 13 in FEV1 (from 2.1 l to 1.9 l) and FVC (from documented for over 20 years. 2.4 l to 2.15 l) and the prednisolone was Histologically, LIP associated with hypo- increased back to 30 mg/day with rapid im- gammaglobulinaemia is characterised by infil- provement in symptoms and lung function. A tration of the alveolar interstitium by T further relapse occurred in June when down to lymphocytes and also plasma cells, fibroblasts, 15 mg prednisolone on alternate days, again and scattered macrophages.1–4 In non-AIDS on October 1, 2021 by guest. Protected copyright. responding to higher doses. In view of her patients the lymphoid infiltrate is centred on known osteoporosis it became clear that a the airways but invariably infiltrates the inter- steroid-sparing agent would be necessary to stitium and lymphoid follicles, usually peri- reduce further morbidity from corticosteroids. bronchiolar, are present in many cases.1 The In view of the T cell features of LIP, pattern is similar to that seen in reactive lymph cyclosporin A was chosen and she commenced nodes, suggesting that the lung is acting like a treatment at a dose of 150 mg/day in July 1996. giant lymphoid organ. In cases of LIP associ- The patient had a good response over the ated with CVID the cells consist largely of T following months and the prednisolone was cells, particularly CD4+ T helper cells.1 It is reduced to 7.5 mg on alternate days. At an important to exclude monoclonality in the cell early stage cyclosporin levels were higher than populations which would favour an alternative planned at 190 ng/ml and the cyclosporin dose diagnosis of lymphoma, also a recognised was reduced to 75 mg/day. The serum levels association with CVID.35 began to fall gradually and it was decided to CVID is primarily a defect in the function of allow the level to fall to undetectable levels B lymphocytes, usually characterised by the without any change in dose and with the presence of low or normal numbers of B cells patient unaware of the fall.
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