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Infection‐associated haemophagocytic syndrome (IAHS) is an uncommon disorder usually occurring in immunocompromised patients. IAHS is a systemic reactive proliferation of phagocytic histiocytes induced by an infection usually of viral origin.1 We report a fatal case of IAHS arising in a patient with recurrent acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS). The diagnosis of IAHS was made after autopsy and histological evaluation of tissue.
A 60‐year‐old man with a history of acute myelogenous leukaemia (M4 myelomonocytic leukaemia) status post complete remission after chemotherapy 5 years ago was admitted for progressive fatigue and pancytopenia. He was in good health until 1 year ago when he started to develop macrocytic anaemia and thrombocytopenia. A bone marrow biopsy at that time showed changes consistent with myelodysplastic syndrome (refractory anaemia). Over the next few months, he developed a progressive pancytopenia but did not come in for evaluation. He was admitted to his local hospital 1 month before being transferred to our institution for progressive fatigue and pancytopenia (white cells 5300/μl, haemoglobin b 4.1 g/dl and platelets 220000/μl). The patient had intermittent swelling of different parts of the body, including the leg and jaws. The hospital course was dominated by unexplained daily nocturnal fevers with temperatures rising up to 102°F. The patient was transferred to our institution to further investigate the unexplained fever and to manage possibly recurrent AML/MDS. Extensive investigations including microbiological studies did not yield a definite cause for fever. A bone marrow aspirate and biopsy carried out 1 week before admission showed 10% blasts on peripheral blood smear, and bone marrow biopsy showed 90% cellularity with increased numbers of blasts. Chromosomal studies showed normal karyotype. Flow cytometry was carried out on peripheral blood 2 weeks before admission: CD34‐positive cells accounted for about 6% of all events. The second major population comprised of cells that fell into the immature myeloid and monocyte region. These cells were CD13, CD33, CD14, CD64 and myeloperoxidase positive. On the basis of submitted peripheral blood smears, flow cytometry and bone marrow biopsy, the differential diagnosis included MDS (refractory anaemia with excess blasts, type 2) versus evolving acute myelocytic leukaemia from previous MDS.
The patient continued to have unexplained daily nocturnal fevers with neutropenia, anaemia and thrombocytopenia (white cells 3300/μl, absolute neutrophil count 100/mm3, haemoglobin 8.3 g/dl, platelets 3000/μl). An x ray of the chest showed bilateral infiltrates. Liver function tests were normal. On the haematology/oncology ward, he was continued on broad‐spectrum antibiotic treatment for suspected opportunist infection. The patient's overall clinical status continued to deteriorate. Blood and urine cultures were negative. Serum Epstein–Barr virus immunoglobulin G titres were positive. Bronchoalveolar lavage cultures were negative for cytomegalovirus, respiratory syncytial virus, parainfluenza virus, herpes viruses, adenovirus and influenza. Coagulation studies throughout the hospital course showed raised prothrombin time/partial thromboplastin time, raised fibrin degradation product and decreased fibrinogen consistent with disseminated intravascular coagulation. On the ninth day at hospital, the patient developed a distended abdomen and became haemodynamically unstable. The patient stabilised briefly but died later that day.
Autopsy findings showed extensive evidence of cellular interstitial pneumonia with intra‐alveolar multinucleated giant cells present diffusely, consistent with viral infection of unknown aetiology. The giant cells did not show specific diagnostic viral changes. Generalised lymphadenopathy was present, affecting the hilar, pericardiac, peripancreatic and para‐aortic nodes. Histologically, the lymph nodes showed sinus histiocytosis with normal‐appearing histiocytes prominently phagocytosing erythrocytes (fig 11).). The liver showed Kupffer cell hyperplasia and granuloma formation with erythrophagocytosis (fig 22).). The granulomas were negative for bacteria and fungi by special stains. The spleen and bone marrow showed prominent erythrophagocytosis. The bone marrow also showed myelodysplastic changes with excess blasts without evidence of acute leukaemia, although evaluation was limited by postmortem autolysis. The bowel showed gaseous distention and fine mucosal petechiae. Neuropathological examination of the brain and spinal cord was unremarkable. The immediate cause of death was believed to be due to IAHS and interstitial pneumonia.
In this case, the clinical history of immunosuppression as a result of recurrent AML/MDS, recurrent fever, neutropenia, anaemia, thrombocytopenia, coagulopathy and probable viral pneumonia is consistent with that of IAHS, although septicaemia due to viral infection was much more likely with this constellation of symptoms because of its more frequent occurrence. The symptomatology of sepsis and haemophagocytic syndrome overlap to a great degree, but the presence of histiocytic hyperplasia and prominent erythrophagocytosis seen in the bone marrow, lymph nodes, spleen and liver on postmortem examination confirm the diagnosis of IAHS.
IAHS may be underdiagnosed because of its association with a variety of other serious diseases. The onset of IAHS is manifested by an abrupt change in clinical course characterised by high fever, severe constitutional symptoms, organomegaly and pancytopenia. Hepatosplenomegaly is usually present and lymphadenopathy, rash and diffuse pulmonary infiltrates are common. Often, there is a history of a recent viral‐like illness. Many patients with IAHS have a fulminant clinical course. The mortality is 30–40% during the acute illness. Patients surviving the acute manifestations usually recover in 1–8 weeks.1
Haemophagocytic syndrome can arise from several immunocompromised clinical states and must be considered to be a diagnostic possibility in the setting of recurrent AML/MDS.2,3,4,5,6 The bone marrow biopsy 17 days before death did not show haemophagocytosis, but postmortem examination of the bone marrow showed extensive erythrophagocytosis. This case highlights the need for serial examination of the bone marrow, especially in rapidly declining patients. IAHS has been associated with a variety of haematological malignancies, including AML, in the literature.2 It is important to note that IAHS can be a rare but possible aggressive complication in the clinical course of patients with acute leukaemia. IAHS treated with the antineoplastic agent etoposide has resulted in the development of treatment‐related AML and MDS.7,8,9 This case further shows the association between IAHS and recurrent AML/MDS. Further studies should evaluate the cytogenetic changes in IAHS and how they relate to the cytogenetic changes in AML and other haematological malignancies. These studies may help to elucidate the relationship between haematological malignancies and IAHS.
AML - acute myeloid leukaemia
IAHS - infection‐associated haemophagocytic syndrome
MDS - myelodysplastic syndrome
Competing interests: None.
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