364 Warfield, Smailman

by tumour cells or local changes in the The authors thank Mr B Sims for his technical advice and concentration of mucopolysaccharides and assistance. inorganic ions in the matrix have also been suggested. Histological changes are usually J Clin Pathol: first published as 10.1136/jcp.47.4.364 on 1 April 1994. Downloaded from not seen in salivary tissue following low dose 1 Thomas K, Hutt MSR. Tyrosine crystals in salivary gland radiation exposure. However, TRC deposi- tumours. J Clin Pathol 1981;34:1003-5. 2 Gnepp DR, Schroeder W, Heffner D. Synchronous tion may be a more subtle indication of dam- tumours arising in a single major salivary gland. Cancer age following higher doses of irradiation. 1989;63:1219-24. 3 Auclair PL, Ellis GL, Gnepp DR, Wenig BM, Janney CG. Other local and possibly systemic factors Salivary gland neoplasms: general considerations. In: might also be expected to contribute. The Ellis GL, Auclair PL, Gnepp DR, eds. Surgical pathology of the salivary glands. Philadelphia: WB Saunders, 1991: focal distribution of crystalloids in this case 135-64. might suggest that local variables within an 4 Valente PT, Hoober JK, Phillips SJ. Tyrosine-rich crystal- loids in pleomorphic adenoma: SEM findings and individual tumour may be important, in partial biochemical characterization. Ultrastruct Pathol addition to differences between left and 1988;12:613-20. 5 Humphrey PA, Ingram P, Tucker A. Crystalloids in sali- right sides. The precise details of any mecha- vary gland pleomorphic adenomas. Arch Pathol Lab Med nism, however, remain obscure and purely 1989;113:390-3. 6 Campbell WG, Priest RE, Weathers DR. Characterization speculative. of two types of crystalloids in pleomorphic adenomas of In conclusion, these findings provide cir- minor salivary glands. A light microscopic, electron microscopic and histochemical study. Am JT Pathol cumstantial evidence to support the hypothe- 1985;118: 194-202. sis that deposition of TRCs in salivary 7 Pearse AGE. Proteins, peptides and amino acids. In: (ed.), Vol. 2 Histochemistry, theoretical and applied. 4th neoplasms is influenced more by local than edn. Edinburgh: Churchill Livingstone, 1985:441-537. by systemic factors. Furthermore, it is pro- 8 Preston-Martin S, Thomas DC, White SC, Cohen D. Prior exposure to medical and dental X-rays related to posed that irradiation of the head and neck tumours of the parotid gland. JNCI 1990;80:943-9. may be one predisposing factor in TRC for- 9 Bottles K, Ferrell LD, Miller TR. Tyrosine crystals in fine needle aspirates of a pleomorphic adenoma of the mation, an observation that has not previ- parotid gland. Acta Cytol 1984;28:490-2. ously been made, and that crystalloid 10 Gould AR, Van Arsdall LR, Hinkle SJ, Harris WR. Tyrosine-rich crystalloids in adenoid cystic carcinoma: deposition may be a subtle reflection of radia- histochemical and ultrastructural observations. 7 Oral tion induced damage in some cases. Pathol 1983;12:478-90.

36436 Clin Pathol 1994;47:364-366 CD4+ lymphocytopenia due to common variable

immunodeficiency mimicking AIDS http://jcp.bmj.com/

R S Kaczmarski, A D B Webster, J Moxham, F Davison, S Sutherland, G J Mufti on September 27, 2021 by guest. Protected copyright.

Abstract noses can mimic the clinical characteristics of There are an increasing number of pub- AIDS and must not be overlooked. A case of Department of lished reports of patients with acquired Pneumocystis carinii pneumonia (PCP) is Haematological Medicine, King's immunodeficiency without evidence of reported here in a young, single man who College School of HIV infection, who have been labelled as presented with weight loss, generalised lym- Medicine and having "idiopathic CD4 + lymphocy- phadenopathy, and lymphopenia, and who Dentistry, Denmark The case is Hill, London SE5 8RX topenia". reported here of a was persistently HIV negative. R S Kaczmarski young man who presented with G J Mufti Pneumocystis carinii pneumonia (PCP), Department of CD4 + lymphopenia, and hypogamma- Case report Thoracic Medicine globulinaemia attributable to common A previously fit 37 year old man presented in J Moxham variable immunodeficiency (CVID). The October 1989 with a two month history of Inumunodeficiency Research Group, presentation of this condition, with many pruritis, night sweats, and cough. He was CRC, Northwick Park of the clinical and laboratory features of unmarried, heterosexual, and denied any Hospital, Harrow, AIDS, highlights CVID as a diagnosis to homosexual contact, drug abuse, or travel Middlesex be considered in the differential diagno- overseas. On examination he had bilateral A D B Webster sis of CD4 + lymphocytopenia. axillary and supraclavicular lymphadenopathy Department of Virology, Dulwich and hepatosplenomegaly. He declined further Hospital, London (7 Clin Pathol 1994;47:364-366) investigation. Six months later he returned F Davison with symptoms of anorexia, 20 kg weight loss, S Sutherland productive cough, and breathlessness. He was Correspondence to: Dr G J Mufti Recent reports have described cases of cachectic, febrile (38°C), tachypnoeic, and Accepted for publication acquired immunodeficiency without evidence had bilateral inguinal lymphadenopathy. 7 October 1993 of infection by HIV. However, other diag- Chest examination showed bilateral crackles CD4+ lymphocytopenia due to common variable immunodeficiency mimicking AIDS 365

T cell subsets and immunoglobulin levels at presentation and during steroid treatment and immunoglobulin therapy sarcoma, lymphoma, or other infiltrating processes. Lymphopenia persisted and once CD4 CD8 IgG IgA IgM (775-1385 (390-785 (5-16 (1 2-45 (0-47-2 2 again hypogammaglobulinaemia was noted

Date x 10I/l)* x 106/1) gil) gil) gil) (table). Serological tests for HIV 1 and 2 and J Clin Pathol: first published as 10.1136/jcp.47.4.364 on 1 April 1994. Downloaded from PCR for HIV 10.5.90 11 227 <3 54 0 37 0-58 remained negative, and anti- 23.5.90t - - 3-54 <0-27 <0 30 body to HTLV-I was not detected. He 6.6.90tt 914 291 6-48 0-62 0-93 declined 10.12.90 309 310 6 57 0-61 0 47 further investigations, but five 12.8.91 52 62 3 99 0-38 0-24 months later complained of further weight 24.9.91§ - - 4-62 0-56 0-38 loss and a 28.1.92§ 220 110 - - - large suppurating ulcer in the left 11.5.92§ - - 8-33 0 43 0-44 groin. However, the skin nodules had 25.9.92§ 51 83 6-98 0-42 0 51 regressed, leaving discoloured, indurated 4.5.93§ - - 6-79 0-42 0-32 skin. The lymphadenopathy and hepato- *Normal ranges in parentheses splenomegaly were unchanged. He was tPrednisolone for acute PCP tSingle dose intravenous immunoglobulin receiving no medication. §Intravenous immunoglobulin replacement, ciprofloxacin, and prednisolone Computed tomograms showed pretracheal lymph nodes in addition to previous changes. A repeat skin biopsy and bone marrow exami- and wheezes. Investigations showed a haemo- nation were unchanged; but a lymph node globin of 14 g/l, white cell count of biopsy specimen showed non-caseating gran- 10-2 x 1094/ (neutrophils 9-4 x 1071, lympho- ulomata with absence of germinal centres. cytes 0-6 x 109/1, monocytes 0-2 x 109/1), and Immunocytochemistry was negative for CD20 platelets of 332 x 109/1. Urea and electrolytes (Pan-B), with strongly positive CD45 RA were normal. Liver function tests showed (T cell, natural killer cell). Special stains for total protein 43 g/l, albumin 25 g/l, bilirubin mycobacteria and fungi were negative. The 6 mmol/l (normal range 3-20), alkaline phos- appearances were those of a B cell immuno- phatase 252 IU/l (normal range 30-120), deficiency with granulomatous reaction, con- aspartate aminotransferase 41 IU/l (normal sistent with the diagnosis of common variable range 10-50), and gamma glutamyl trans- immunodeficiency (CVID). ferase 50 IU/l (normal range 5-55). Chest The patient was given regular intravenous x-ray pictures and computerised tomography immunoglobulin replacement treatment (CT) scans showed bilateral patchy consoli- (200 mg/kg every two weeks) in August 1991. dation, pleural effusions, and hilar and medi- In view of the substantial granulomatous astinal lymphadenopathy. A lymph node reactions affecting lymph nodes, skin, liver, biopsy specimen, bone marrow aspirate, and and spleen, he was treated with prednisolone trephine biopsy specimen showed reactive 10 mg daily. He also took ciprofloxacin 500 mg changes only. He did not respond to broad twice a day and inhaled pentamidine for PCP spectrum antibiotics. A lung biopsy was per- prophylaxis. By September the 1992, groin http://jcp.bmj.com/ formed and the histology showed florid PCP. ulcer had healed completely; lymphadeno- In view of the persistent lymphopenia HIV pathy, hepatosplenomegaly, and pleural effu- infection was thought likely, although the sions had resolved. At the time of writing, the patient denied any history of known risk fac- patient continues to take prednisolone and tors. Lymphocyte subsets showed a sharp immunoglobulin therapy which maintains reduction in CD4 + (11 x 106/1) and CD8 + IgG concentrations in the normal range; but (227 x T a 106/1) cells with reversed IgA and IgM remain low (table). He is well on September 27, 2021 by guest. Protected copyright. CD4:CD8 ratio (table). Tests for HIV 1 and and has not had any further infective 2 antibodies and p24 antigen in serum, episodes. and polymerase chain reaction (PCR) ampli- fication for HIV env and gag sequences in circulating mononuclear cells were negative Discussion on two occasions. The patient was treated This case illustrates how the presentation of with high dose intravenous co-trimoxazole CVID can be mistaken for HIV infection. (120 mg/kg/day) and prednisolone 40 mg CVID is a heterogeneous disease which can daily, reducing over four weeks. The table present at any age with a wide range of symp- shows the results of immunological tests, toms. Typically, patients present in childhood including T cell subsets (CD4, CD8) and or early adulthood with recurrent bacterial immunoglobulin concentrations: hypogam- infections. There may or may not be a family maglobulinaemia was noted during treatment history. Patients also have an increased inci- of PCP, and the patient was given a single dence of opportunistic viral and fungal infec- dose of intravenous immunoglobulin. The tions and an increased risk of developing PCP resolved and he was discharged in June malignancy.'-3 A significant number develop 1990: CD4, CD8 counts, and immunoglobu- non-caseating granulomata, lymphoid hyper- lin concentrations had improved (table). All plasia, and splenomegaly.4 Although this medication was discontinued on follow up six patient had pronounced CD8 + neutropenia, weeks later. this is unusual in CVID5; an increase in sup- The patient presented again in August pressor T cells, which block B cell differentia- 1991, with a swollen left leg and an ulcerating tion, is thought to have a role in the lymph node mass in the left groin. Hard, pur- pathophysiology of CVID. Treatment with ple nodules had appeared over his trunk. A immunoglobulin replacement and prophylac- skin biopsy specimen showed chronic inflam- tic antibiotics usually leads to substantial clin- matory changes, with no evidence of Kaposi's ical improvement.2 PCP prophylaxis is not 366 Kaczmarski, Webster, Moxham, Davison, Sutherland, Mufti

routinely given in these cases, unless there is associated with hypergammaglobulinaemia as a history. Intravenous immunoglobulin and a result of chronic immune stimulation by antibiotics alone have no effect on the granu- HIV and opportunistic pathogens, and the lomatous lesions seen in these patients; but action of B cell active

cytokines, particularly J Clin Pathol: first published as 10.1136/jcp.47.4.364 on 1 April 1994. Downloaded from this case illustrates the benefit of steroids, interleukin-6."1 This is also reflected in the which have been effective in other cases with plasmacytosis frequently seen in bone marrow severe granulomatous reactions (A D B aspirates and lymph node biopsy specimens. Webster, personal observation). In conclusion, there are many overlapping A number of features in this case differenti- clinical and laboratory features of HIV infec- ate it from HIV infection. Although HIV anti- tion and CVID. In view of recent reports of body and p24 antigen tests may be negative "HIV negative AIDS",'2 this case illustrates in early disease,6 in HIV infection they are the importance of considering CVID in the unlikely to remain negative when the tests are differential diagnosis of patients presenting performed several months apart. Further- with opportunistic or atypical infections and more, gene amplification by PCR for the HIV who are HIV negative. genome has been shown to detect HIV in these "seronegative" cases.7 Primary HIV infection can cause a transient lymphopenia and lymphadenopathy.89 This was unlikely in 1 Primary immunodeficiency diseases. Report of a World this patient, however, as he presented with Health Organization sponsored meeting. Immunodefic persistent generalised lymphadenopathy Rev 1989;1:173-205. 2 Asherson GL, Webster ADB. Diagnosis and treatment (PGL) and an opportunistic infection, fea- of immunodeficienc disease. Edinburgh: Blackwell tures which are consistent with Scientific, 1980. advanced 3 Hermans PE, Diaz-Buxo JA, Stobo JD. Idiopathic late HIV disease, when serological tests should onset immunoglobulin deficiency. Clinical observations detect HIV and the CD4 + count would in 50 patients. AmJMed 1976;61:221-37. be 4 Davis SD, Eidelman S, Loop JW. Nodular lymphoid consistently low. Lymph node biopsy speci- hyperplasia of the small intestine and sarcoidosis. Arch mens in primary HIV infection show a nor- Intern Med 1970;126:668-72. 5 Spickett GP, Matamoros N, Farrant J. Lymphocyte sur- mal pattern of germinal centre, and in PGL face phenotype in common variable immunodeficiency. there is follicular hyperplasia.'0 With progres- Dis Markers 1992;10:67-80. 6 Imagawa DT, Lee MH, Wolinsky SM, et al. Human sive disease the follicles atrophy and fibrose. immunodeficiency virus type 1 infection in homosexual The absence of in men who remain seronegative for prolonged periods. N germinal centres this case EnglJMed 1989;320: 1458-62. is consistent with the B cell immunodefi- 7 Wolinsky SM, Rinaldo CR, Kwok S, et al. Human ciency in CVID. immunodeficiency virus type 1 (HIV-1) infection a median of 18 months before a diagnostic westem blot. Immunoglobulin and T cell counts can Evidence from a cohort of homosexual men. Ann Intern show considerable variation in CVID. This Med 1989;111:961-72. 8 Cooper DA, Tindall B, Wilson B, Imrie AA, Penny R. case illustrates this (table), when on some Characterization of T-lymphocyte responses during pri- occasions T cell and immunoglobulin subsets mary HIV infection. JInfect Dis 1988;157:889-96. 9 Tindall B, Barker S, Donovan B, et al. Characterization of http://jcp.bmj.com/ fell within the normal range. This can make the acute illness associated with human immunodefi- the diagnosis of CVID difficult and illustrates ciency virus infection. Arch Int Med 1988;148:945-9. 10 Meyer P, Yanagihara ET, Parker JW, Lukes RJ. A distinc- the value of serial measurements. Conversely, tive follicular hyperplasia in the acquired immunodefi- in HIV infection there is a ciency syndrome and AIDS-related complex. Haematol progressive decline Oncol 1984;2:319-47. in CD4 + counts, with temporary improve- 11 Birx DL, Redfield RR, Tencer K, et al. Induction of inter- ment in CD4 + counts only as a leukin-6 during human immunodeficiency virus infec- result of tion. Blood 1990;76:2303-10. antiretroviral treatments using zidovudine 12 Laurence J, Siegal FP, Schattner E, Gelman IH, Morse S. (AZT), dideoxyinosine or Acquired immunodeficiency without evidence of infec- on September 27, 2021 by guest. Protected copyright. (ddI), dideoxycyti- tion with human immunodeficiency virus types 1 and 2. dine (ddC). HIV infection is also commonly Lancet 1992;340:273-4.