In July 2015, a 24-year-old woman was referred to our Department of Internal Medicine for a high fever (39 C) lasting 3 days, fatigue, myalgias, chills, and vomiting. She had been followed since 2008 for primary ITP, initially treated with oral prednisone (1 mg/kg/day), which achieved complete remission. Because of occasional severe relapses (two between 2009 and 2012, with gynecological bleeding), she was subsequently treated with Intravenous Immunoglobulin (IVIg) with good responses. In January 2012, at age 21, she suffered a severe relapse, again justifying the use of IVIg and corticosteroids. At that time, she had detectable autoimmunity with an antinuclear antibody titer of 1 : 250 (anti-SSA specificity but without any sign suggestive of lupus) and platelet-directed anti-glycoprotein IIb/IIIa antibodies. In June 2012 (baseline), a new IVIg cycle was administered, followed by RTX (375 mg/m2 once-a-week for 4 consecutive weeks). A complete platelet response was obtained within 6 weeks and, at the last follow-up (March 2015), her blood platelet level was normal (321 x 109/L) without treatment. Before RTX infusion (June 2012), her blood total gamma-globulin level >3 months before IVIg infusion had been normal (8.9 g/L) but she was lymphopenic (total lymphocytes: 0.513 x 109/L), while her peripheral blood lymphocyte count had been normal at ITP diagnosis (1.199 x 109/L). The previously available phenotype profiles of her peripheral circulating lymphocytes are reported in Table 1. No infection occurred during the 3 years following the last RTX administration and she remained clinically well at biannual consultations in our department.
At admission, in July 2015, at age 24, her temperature was 39.2 C and she complained of lower abdominal pain, vomiting but without diarrhea; her physical examination was normal. Laboratory tests showed elevated C-reactive protein (CRP: 114 mg/L, normal range (NR): <5 mg/L), hepatic cytolysis (aspartate aminotransferase: 144 U/L, NR: 7-40 U/L; alanine aminotransferase: 265 U/L, NR: 5-50 U/L) and cholestasis (alkaline phosphatase: 389 IU/L, NR: 40-130 U/L; gamma-glutamyltranspeptidase: 698 U/L, NR: 5-38 U/L). The hemogram revealed agranulocytosis and thrombocytopenia (leukocytes: 4.9 x 109/L; neutrophils: 0.02 x 109/L; hemoglobin: 14.5 g/dL; platelets: 46 x 109/L). Bone-marrow aspirate showed normal density, several megakaryocytes but hypoplastic granulopoiesis in blocked maturation, without blasts. Computed-tomography (CT) scans of the thorax and abdomen were normal. Once urine and blood samples had been collected, empirical ceftazidime and gentamicin were begun, and achieved apyrexia within 48 h. After 46 h, blood cultures came back positive for Campylobacter jejuni, and the identical strain isolated from the patient's feces; amoxicillin-clavulanic acid (1 g 3 times a day for 2 weeks) was prescribed. Seven days postadmission, CRP, neutrophil and platelet levels returned to normal (3 mg/L, 6.61 x 109/L and 521 x 109/L, respectively); blood cultures were negative; and liver function was improved.
Laboratory evaluation for immunodeficiency yielded: negative serology for human immunodeficiency viruses-1 and -2, very low serum Ig levels (Table 1) and no circulating B cells. Flow-cytometry quantification of T-cell subsets found expansion of circulating CD4+ T lymphocytes expressing surface DR, suggesting their activation; low natural killer cells and CD8+ T-lymphocyte levels. Urine immunofixation electrophoresis was negative. Ig-replacement therapy was started but not pursued by the patient.
Ten months later (May 2016, age 25) she was hospitalized for a 15-day low-grade fever, weight loss, nonproductive cough and progressive dyspnea. CRP, lactate dehydrogenase and beta2-microglobulin levels were 40 mg/L, 340 U/L (NR 5-240 U/L) and 3.53 mg/L (NR 1.2-2.5 mg/L), respectively. As shown in Table 1, hypogammaglobulinemia, CD19+ B lymphopenia and low peripheral CD8+ T-cell count persisted but without T activation, as assessed by HLADR-positivity. CT scans visualized bilateral diffuse infiltrates, ground-glass opacities and large nodules. Bronchoalveolar lavage analysis revealed Pneumocystis jiroveci cysts with positive polymerase chain reaction (PCR) (4,000 copies/mL); high-dose trimethoprim-sulfamethoxazole and corticosteroids were prescribed. Searches for other pathogens, including Mycobacterium tuberculosis, atypical mycobacteria, cytomegalovirus, Cryptococcus and Aspergillus species, were negative. At that time, her bone-marrow biopsy was normal.
Despite appropriate antibiotics and clinical improvement, thoracic CT scans revealed worsened dense infiltrates (Figure 1(a)), pleural effusions, hepatosplenomegaly and nodular lesions of both kidneys (Figure 1(b)). A new bronchoscopy with biopsies found CD20+ large lymphomatous cell infiltration (Figure 2) in bronchi. Those large atypical lymphoid tumor cells were CD10-BCL-6- and MUM1+BCL-2+, with an 80% Ki-67-proliferation index on immunolabeling. EBV, as assessed by in situ hybridization with an EBV-encoded small RNA probe, was diffusely positive in about 80% of tumor cells (Figure 2). The FISH assay for MYC gene rearrangement (MYC FISH DNA Probe, Split Signal, (Y5410), Dako, Locus 8q24) was negative. EBV-positive DLBCL with a nongerminal center phenotype was diagnosed without bone-marrow infiltration. Circulating EBV-DNA was positive (2,430,000 IU/mL). DLBCL treatment consisted of RTX, cyclophosphamide, doxorubicin, vincristine and prednisone. Even with EB viremia becoming negative, she developed fever, cytopenias, liver damage and neurological manifestations, as a consequence of her prominent bone-marrow hemophagocytosis. Unfortunately, she died of multiorgan failure at age 25.