Department of Medicine and Immunology Institute, Kaplan Medical Center, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
Correspondence to: A. Schattner, Hebrew University-Hadassah Medical School Head, Department of Medicine, Kaplan Medical Center, Rehovot 76100, Israel. E-mail: amiMD{at}clalit.org.il
SIR, Patients with primary Sjögren's syndrome (SS) usually present with glandular (sicca) symptoms or systemic manifestations [1]. Immune-mediated cytopenias may occur but are unusual as presenting manifestations [2]. We report a patient with serious opportunistic infection due to severe CD4+ T lymphocytopenia, immune activation markers and a concurrent diagnosis of SS.
A 62-yr-old woman developed progressive headache, nausea and low-grade fever over 4 weeks. On admission, obtundation and Brudzinski's sign were the only notable findings. Chest radiography, ECG, electroencephalogram, head CT and laboratory tests were normal, except for a serum sodium level of 126 mEq/l [consistent with syndrome of inappropriate antidiuretic hormone secretion (SIADH)] and transaminases of 150200 IU/l. Cerebrospinal fluid pressure and protein were elevated, with low glucose and a 43/mm3 white blood cell count (93% lymphocytes). Staining revealed a few encapsulated yeasts, latex cryptococcal antigen test was positive (1:32) and cultures of cerebrospinal fluid and blood grew Cryptococcus neoformans. Amphotericin B (0.7 mg/kg per day) was given for 8 weeks, followed by fluconazole. The patient remained somnolent and poorly responsive, but after a month she slowly improved and the sodium level normalized.
The patient was previously healthy. She neither kept pigeons, nor had risk factors for HIV or immunosuppression. Work-up for tuberculosis was negative. Serology showed past infection with EpsteinBarr virus, cytomegalovirus and hepatitis B virus (HBV). Hepatitis C virus RNA and antibodies were negative. Liver biopsy demonstrated early HBV-related active cirrhosis. HIV was repeatedly negative (ELISA, Western blot and polymerase chain reaction). Extensive studies at a highly experienced research laboratory failed to uncover any known retrovirus (David Ho, New York University). Polyclonal hyperglobulinaemia, mildly elevated serum globulins and normal complement were found. Total lymphocyte count was 1104 cells/mm3 with 72% T cells (CD3+), 2% CD4 (22 cells/mm3, range 1926) and 70% CD8, yielding CD4/CD8 ratio <0.003 (normal >1.0). Lymphocyte transformation responses were markedly depressed and intradermal injection of test antigens elicited no response, reflecting T-cell deficiency.
To examine the mechanism, we looked for anti-CD4 antibodies, but results were repeatedly negative. Assays of cytotoxic T lymphocyte-mediated CD4 killing in vitro failed owing to the meager number of cells present. Lymphocyte surface antigen staining and serum cytokines revealed intense immune activation (Table 1), which persisted long (>30 months) after her recovery from the meningitis. Serum antinuclear antibodies (+3, speckled) and IgG autoantibodies to histone H2B were found (80 U/ml; normal <25). A review of systems then revealed dryness of the eyes and mouth over several months. Schirmer test was positive (12 mm/5 min) as was the Rose Bengal corneal stain. Rheumatoid factor was absent, serum autoantibodies to Ro/SS-A and La/SS-B were positive and minor (labial) salivary gland biopsy showed two focal lymphocytic aggregates of >50 mononuclear cells per 4 mm2 of tissue (focus score 2), consistent with SS [1]. The patient remains well on oral fluconazole and trimethopzim/sulphamethoxazole (TMP/SMX) prophylaxis. A course of corticosteroids had no effect on the lymphocyte counts, which remain at 25 CD4/mm3.
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This association raises several issues. First, marked chronic immune activation (Table 1) and antibodies to histones with no anti-CD4 antibodies suggest CD4+ apoptosis as a possible pathogenetic mechanism. This is reminiscent of AIDS [5, 6], but no retrovirus could be found. Second, at least three viruses (HIV, HTLV-1 and hepatitis C) are known to be associated with a SS-like syndrome [7]. These have been ruled out here, and HBV without HIV co-infection has not been linked to either SS or CD4 depletion. Thus, the triad of SS, severe CD4 lymphocytopenia and protracted immune activation with no evidence of retroviral infection has not been previously reported. Third, patients with unexplained CD4+ lymphocytopenia should be carefully evaluated for an occult SS.
Haematological or immunological presentations of SS already include a wide spectrum [2], including lymphoma. CD4 depletion can be an important underlying condition. Two studies identified a 5% prevalence of CD4 lymphocytopenia in SS, below the level used in the case definition of the CDC [8] and 13% had anti-CD4 antibodies [9]. However, the two are not correlated, pointing to another aetiology, in agreement with our findings. In HIV, CD4+ T-cell depletion is more strongly correlated with markers of immune activation than with the viral load [6]. Perhaps our patient's immune activation and the enhanced production of cytokines known to occur in SS [10] mediate apoptosis and T-cell depletion in some patients.
The authors have declared no conflicts of interest.
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