Date Published: April 14, 2009
Publisher: Public Library of Science
Author(s): Liran Levy, Abedelmajeed Nasereddin, Moshe Rav-Acha, Meirav Kedmi, Deborah Rund, Moshe E. Gatt, Ronald C. W. Ma
Abstract: Liran Levy and colleagues discuss the differential diagnosis, investigation, and management of a 46-year-old woman with fever, weakness, night sweats, and weight loss.
Partial Text: A 46-year-old woman was hospitalized due to fever of up to 39°C of one week’s duration. The patient complained of weakness, night sweats, and weight loss for two weeks prior to admission. The patient had no past medical history, and did not take any medications, supplements, or illicit drugs. She was born and lived all her life in a rural village. She was indirectly exposed to farm animals and pets, yet had no close contact with these, and her family was not engaged in agricultural work. She denied having been bitten by ticks or fleas. There was no history of recent foreign travel or eating raw meat or unpasteurized milk. She reported no rashes, arthralgia, dryness of eyes, mouth ulcers, or mucocutaneous bleeding.
Physicians commonly see patients with prolonged fever. There are many different possible etiologies, most commonly infectious, but neoplastic and inflammatory or autoimmune disorders may also be a possibility. Less common conditions include drug-related fevers, factitious (i.e., self-induced) fevers, and other rare diseases. Some patients with prolonged fever will remain undiagnosed despite an intensive diagnostic work-up.
Multiple blood, urine, and stool cultures were negative. The patient’s laboratory results revealed pancytopenia with 2,800 leukocytes/mm3 (2,200 neutrophils, 400 lymphocytes, 200 monocytes, and no eosinophils or basophils/mm3). The hemoglobin level was 98 g/l, and the platelet count was 59,000/mm3. The reticulocyte count was 1.5%. The erythrocyte sedimentation rate was elevated at 104 mm/h. Her prothrombin time and partial thromboplastin time were prolonged (41.5% and 46.6 seconds, respectively), and the fibrinogen level was low at 82 mg/dl. The peripheral blood smear showed mature white blood cells with a mild left shift, and a few red blood cell schistocytes. The serum creatinine and urea levels and electrolytes were all normal. Liver function tests (LFTs) were elevated at three to four times the normal values, with hyperbilirubinemia of 27 mmol/l (0–17 mmol/l). The lactate dehydrogenase was markedly elevated at 4,245 U/l (300–620 U/l). Anti-nuclear antibody, rheumatoid factor, anti-neutrophilic cytoplasmatic antibody, anti-cardiolipin and circulating anticoagulants were all negative, as were direct Coombs tests. Serology for Mycoplasma, Brucella, Legionella, Q fever, spotted fever, murine typhus, HIV, EBV, CMV, hepatitis A, B, and C, parvovirus B19, and leishmaniasis (Leishmania infantum, L. donovani, and L. chagasi) were all negative. Acid-fast stains of sputum and blood cultures for tuberculosis were negative. Thick blood films for malaria and Borrelia were negative. A computed tomography scan of the chest, abdomen, and pelvis showed a homogeneously enlarged liver and spleen (splenic long axis, 24 cm). The echocardiography showed normal ventricular function, and no valvular abnormalities. The patient continued to have daily spiking fevers and sweats, and her cytopenias, coagulation defects, and LFTs worsened.
The main laboratory feature observed is the pancytopenia. However, most, if not all of the differential diagnosis of prolonged fever and splenomegaly may comprise that of blood cytopenias to some extent. Hematologic malignancies may involve the bone marrow and therefore lead to cytopenia. The lack of eosinophils, basophils, or nucleated red cells and the morphologically normal circulating white blood cells make a myeloproliferative disease unlikely. The lack of enlarged lymph nodes and the absence of atypical cells in the peripheral blood make another hematologic malignancy less likely. Furthermore, the splenomegaly may itself cause hypersplenism and peripheral blood cytopenias. The coagulation abnormalities of both prothrombin time and partial thromboplastin time, with low fibrinogen (which is an acute phase reactant expected to rise in any inflammatory state) and circulating schistocytes, implies the presence of disseminated intravascular coagulation (DIC), and the markedly elevated LFTs point to a more severe disease. The unremarkable autoimmune serologies are also against such an ongoing process. Infections that cause immune hyperplasia or organ infiltration may involve the bone marrow, causing cytopenias as well. Because all the above tests do not reveal the etiology for this patient’s severe disease, a tissue biopsy is needed. As the liver and spleen appear radiologically homogenous with no focal lesions for biopsy, a bone marrow biopsy and aspiration, including multiple cultures for the different infectious diseases discussed, should be the next step.
Hemophagocytic syndrome is a clinicopathologic entity. Its diagnosis is defined by a set of presenting major signs and symptoms (Box 2). The disease may be familial or primary, and is observed mostly in children, though it may be secondary to malignancy (mostly T cell lymphomas), infections (most often EBV related), autoimmune diseases, or drugs. In this case the criteria are completely fulfilled, but considering her age and the absence of a relevant family history, the main question that should be asked repeatedly is: what is the primary process due to which this hemophagocytosis results? Primary hemophagocytosis is so rare at this age as to be practically nonexistent. A continued search for a malignancy or an infectious organism should be performed, and splenectomy should be considered.
The treatment for primary hemophagocytic syndrome in children consists of high-dose dexamethasone, cyclosporin A, and etoposide-based chemotherapy. In this patient, the use of this treatment modality seemed appropriate considering her severe clinical deterioration with no underlying etiology found. It is still a mystery that the primary cause of this patient’s disease has not been found. The patient’s response to immunosuppressive therapy is not unusual. It should be kept in mind that T cell lymphomas tend to present with hemophagocytosis, even with minimal disease, and that this type of neoplasm may respond to lympholytic steroids and cyclosporine A, which are T cell depressants.
The term hemophagocytosis describes the pathologic finding of activated macrophages and engulfing erythrocytes, leukocytes, platelets, and their precursor cells ,  as shown in this patient. It may also be more properly termed hemophagocytic lymphohistiocytosis (HLH). The most typical presenting signs and symptoms are fever, hepatosplenomegaly, and cytopenias. Less frequently observed clinical findings are neurological symptoms, lymphadenopathy, edema, skin rash, and jaundice , , . Common laboratory findings include hypertriglyceridemia, a coagulopathy with hypofibrinogemia, and elevated LFTs.
Hemophagocytosis, being rare in itself, is a diagnosis that is usually performed in seriously ill, hospitalized patients. Leishmaniasis, endemic in certain areas, yet rare in most of the industrialized world, may therefore be too rare for the treating in-hospital clinician. The diagnosis thus may be delayed in this setting. In the patient described above, the tentative diagnosis of primary or familial HLH together with the presumed clinical improvement under immunosuppressive therapy may have initially saved her life. Nevertheless, this treatment had a major contribution in the delay of ultimately achieving the correct diagnosis. Perhaps a splenectomy or splenic biopsy (both of which have considerable risks in pancytopenic patients) could have revealed the correct diagnosis earlier.