Fulminant hemophagocytic lymphohistiocytosis secondary to a reactivated EBV infection: A case report
The patient was a 60-year-old woman with tablet-treated diabetes mellitus who presented with fever, pain in the throat, and a skin rash. In primary care she received antibiotics due to high CRP and sedimentation rate (SR). The fever persisted, and the patient was admitted to hospital. Concentrations of inflammatory variables (P-CRP and B- leukocytes) were high, and on suspicion of underlying bacterial infection the patient received intravenous antibiotic with cefotaxime without response. Due to deterioration with low systolic blood pressure, confusion, an intensive skin rash on arms, legs, and chest/abdomen, and fever she was admitted to the intensive care unit. Blood plasma test showed a high ferritin level of 145,000 (8–140 µg/L), and Still's disease was suspected.\nFurther blood/plasma tests showed signs of disseminated intravascular coagulation (DIC) with high Protrombinkomplex International Normalized Ratio (PK-INR), high activated partial thromboplastin time (APT), elevated fibrin D-dimers, and successively low fibrinogen. The patient had high CRP (237 mg/L) and blood sedimentation rate (110 mm/h), anemia (89 g/L), thrombocytopenia (70 × 109/L), and leukopenia (3.1 × 109/L). Procalcitonin was 35 µg/L, which is 700 times higher than normal. The initial antibiotic treatment was changed to meropenem, gensumycin, and fluconazole. Despite treatment with antibiotics and antifungal medication, no significant improvement was seen.\nAdditional blood plasma tests showed high triglyceride values and soluble CD25R (IL-2R-alpha) exceeded 2,400 kU/L, indicating a high cytokine production. The patient had five of eight criteria for HLH, and thereby the diagnosis was confirmed.\nSeveral biopsies were performed in order to find an underlying disease without success. Bone-marrow biopsy showed slight alterations of maturity in megakaryocytes and erythropoiesis and no signs of lymphoma or other malignancies. An initial phase of myelodysplastic syndrome could not be excluded, but later bone-marrow biopsies could not confirm that diagnosis. Biopsy of the skin showed non-specific inflammation with edema and infiltrations of lymphocytes round blood vessels. There were no signs of vasculitis, necroses, or granulomas.\nAn 18F-FDG PET/CT scan was performed, in order to evaluate a possible enhanced uptake reflecting an augmented metabolism typical for e.g. malignancy. The scan showed symmetrical and bilateral uptakes in the lymph nodes of the neck, mediastinum, lung hili, liver hilum, along a. iliaca externa and inguinal regions, and in the spleen (). The uptake was strongest in the lymph nodes of the neck and in the spleen.\nWe could not detect any antibodies against parvovirus B19, Human Immunodefficiency Virus (HIV), Human Immunodefficiency Virus (HHV) 6 and 8, influenza A and B, adenovirus, coronavirus, and Respiratory syncytial virus (RSV) A and B. Rhinovirus, parainfluenza 1, 2, and 3, and RSV A and B in nasopharynx were negative. She had elevated IgG against HSV and Varicella Zoster Virus (VZV), but was IgM-negative against both viruses.\nThere were no pre-existing clinical features of a background of chronic, active EBV infection. The patient had signs of previous infection from EBV by EBNA in repeated tests (presence of IgG). Despite this, the patient had an EBV load of 2,400 copies/mL in whole blood (DNA). A new assessment of EBV IgG was negative 7 days later. No bacterial or fungal infection was found despite repeated cultures from urine, blood, sputum, and bone-marrow.\nAccording to the geneticist, the fact that our patient was a woman, 60 years old, and had no medical history of dysgammaglobulinemia or lymphoma, an X-linked proliferative syndrome was improbable. Further, the patient's age showed that a familiar form of HLH was unlikely.\nThe clinical presentation was not typical for morbus Still, and no other rheumatologic disease or malignancy could be confirmed.\nTreatment with steroids was started first with 60 mg prednisolone and then with 16.5 mg dexamethasone. The duration of the therapy was 3 months and 17 days, and the dose was gradually decreased before the therapy was discontinued. The patient had a very good response to steroid therapy, and no treatment with etoposide or cyclosporine was necessary.\nThe clinical condition of the patient improved after 2 weeks of treatment with steroids. Fever disappeared, blood pressure and general condition improved, and the skin rash decreased. Hemoglobin increased from 89 g/L to 126 g/L and platelets from 70 × 109/L to 188 × 109/L within a week. Ferritin decreased from 145,000 to 18,000 µg/L in a couple of weeks.\nThe patient had intense fatigue in her convalescence. She was admitted to a rehabilitation unit for training, and an improvement of her general condition was gradually seen during that period. During her latest follow-up visit, the patient was feeling well, with normalized plasma ferritin and no signs of HLH activation.