Dr R. F. Eichhorn MD, Department of Medicine, Westeinde Hospital, Lijnbaan 32, NL-2501 CK den Haag, The Netherlands (fax: +70 3807160).
In the literature, heterozygosity for haemoglobins S and E is known as a clinically benign condition. Nevertheless, we present a case of double heterozygosity manifesting as an infarctive sickle cell-like crisis with acute chest syndrome and reversible bone marrow necrosis. Importantly, these complications were associated with serologically documented parvovirus B19 infection. Reviewing the literature, this case emphasizes a specific role of parvovirus B19 as a precipitating cause. Furthermore, it demonstrates how important the consideration of haemoglobin disorders can be even outside of the historically known areas.
Within the definition of sickle cell disease there are four major genotypes: homozygous sickle cell (SS) disease, sickle cell/haemoglobin C disease, sickle cell/β+-thalassaemia and sickle cell/β0-thalassaemia. Mortality is highest in SS disease. The geographical distribution of the sickle cell gene includes equatorial Africa, the Arabian peninsula and central India.
Red cell destruction is accelerated in sickle cell disease, the normal red cell survival of 120 days being reduced to 5–15 days in SS disease. Generally, the chronic haemolysis and resulting anaemia are well tolerated. Although sudden acceleration of the haemolytic process ('haemolytic crises') has been described, the clinical features are mainly due to the rheological properties of sickle cells. Deoxygenation results in a tendency to form long polymers, raising the intracellular viscosity with the result that the cells may block blood flow with ischaemia or necrosis of the tissue supplied ('infarctive crises'). The third important form is the aplastic crisis, characterized by a fall in haemoglobin level with reticulocytopenia. During an outbreak of aplastic crises in sickle cell anaemia in Jamaica in 1980, human parvovirus B19 was identified as the causative agent [ 1]. Another haemoglobinopathy, Hb E, may be the most prevalent in the world and is found almost exclusively in individuals of south-east Asian origin. In contrast to haemoglobin S, the homozygous and heterozygous states are clinically benign conditions, without obvious survival disadvantage [ 2].
Despite the prevalence of abnormal haemoglobins S and E in their respective areas of the world, only a few cases of the double heterozygous haemoglobinopathy S/E have been described. The resultant disease is usually mild with normal or slightly low RBC indices [ 3–5]. Our case is the first report of an infarctive sickle cell-like crisis complicated by bone marrow necrosis and associated with serologically detected parvovirus B19 infection in a patient with double heterozygosity for haemoglobins S and E.
A 22-year-old Turkish woman was admitted to our hospital with a 5-day history of high fever, severe diffuse pain in the extremities and sudden onset of somnolence. Except for intermittent pain in the extremities and back in the past few years, her medical history was uneventful. In particular, she had no history of recurrent infection, jaundice or familial diseases. She did not drink or smoke and used no medications, except ibuprofen occasionally.
On admission, she was somnolent and in distress due to severe pain but without shock, cyanosis or jaundice. The blood pressure was 140/70 mmHg, heart rate 160 beats min−1, respiratory rate 20 min−1 and temperature 39.5°C. There was no lymphadenopathy. Except for tachycardia and tachypnoea, pulmonary and cardiac examination were normal, as were the abdominal, genital and rectal examinations. Besides somnolence, neurological and musculo-skeletal examinations were unremarkable. Laboratory tests gave the following results: ESR, 28 mm; Hb, 5.4 mmol−1; RBC, 3.5 × 1012 L−1; MCV, 73 fL; MCH, 1.55 fmol; MCHC, 21.2 mmol L−1; haematocrit, 0.25 L L−1; WBC, 7.80 × 109 L−1; platelet count, 130 × 109 L−1. The blood smear was normal and without fragmentocytes. Electrolytes were normal: creatinine, 93 μmol L−1; albumin, 34.4 g L−1. Protein-electrophoresis was normal: bilirubin, 15 μmol L−1; LDH, 3761 U L−1 (LDH 2, 60%; LDH 3, 20%); haptoglobin, 0.25 g L−1; ASAT, 84 U L−1; ALAT, 59 U L−1. An ECG and chest röntgenogram were normal. Abdominal echography showed splenomegaly but no other abnormalities. EEG and CT of the brain were normal as was cerebral fluid examination.
Intravenous treatment with fluids and antibiotic therapy with a combination of gentamicin and cefuroxime was started in suspicion of sepsis. Several hours later, her condition deteriorated with development of an acute respiratory insufficiency – arterial blood gas: pH 7.415; Paco2, 26.0 mmHg; Pao2, 58 mmHg (without oxygen). The patient was transferred to the ICU. A repeated chest röntgenogram showed bilateral interstitial-alveolar infiltrates. At bronchoscopy, small bleeding spots were seen, and Gram stain and cultures of BAL-fluid were negative. Transbronchial biopsies showed no specific pathology. Within a few hours the haemoglobin decreased from 5.4 to 4.1 mmol L−1 without signs of bleeding. The reticulocyte count corrected by haematocrit was 1.2%, bilirubin and LDH remained stable, and a direct antiglobulin test was negative. At the same time, erythroblasts and normoblasts were noted in the blood smear. A bone marrow examination showed necrosis and lysis of the bone marrow ( Fig. 1). There were no signs of disseminated intravascular coagulation. Antinuclear antibodies were negative. An alkaline and acid haemoglobin-electrophoresis revealed the presence of 60% HBS and 40% HBE. There was neither HBC nor HBA. Tests for glucose-6 phosphate dehydrogenase deficiency were negative.
The patient was symptomatically treated with oxygen and packed red cell transfusions. After a week her condition improved: her temperature fell and the haemoglobin level stabilized. Because of persistent pain in the left upper quadrant, an echography and a Technetium-labelled nanocolloid scintiscan of the abdomen were performed which showed multiple infarctions in the spleen. After 8 days, bone marrow examination was repeated. Now a reactive, hyperplastic bone marrow was found. Human parvovirus (B19) specific IgM antibodies and a high IgG antibody titre (1 : 2048) were detected by immunofluorescence in the serum. Four months later these IgM antibodies disappeared. A hypochromic microcytic anaemia (Hb, 6.6 mmol L−1) persisted without signs of active haemolysis.
With regard to the age of our patient and the unremarkable familial history, there was nothing to suggest a form of sickling disorder. Nevertheless, clinical manifestations were retrospectively directly attributable to intravascular sickling: pain in the extremities and altered consciousness, infarcts of the spleen and the clinical picture of acute chest syndrome [ 6]. It is a common clinical observation that sickle cell crises may be precipitated by hypoxia, dehydration, acidosis and various infections. In our case, we could detect serologically a recent human parvovirus B19 infection.
In the past years, this smallest DNA-containing virus is identified as a causative agent of a broad spectrum of diseases including aplastic anaemia. The target of the virus is an immature erythroid cell close to the CFU-E stage. To these erythroid progenitor cells, infection is directly cytotoxic followed by arrest of red cell production for 10–12 days. The infection resolves before a significant decrease in peripheral red cell numbers occurs if red cell survival time is normal. In patients suffering from increased red cell destruction or in immunocompromised patients, who cannot clear the infection, severe transient anaemia occurs [ 7]. Nevertheless in our patient bone marrow aspirate showed severe necrosis and not a decrease in erythroid precursors. Yet investigators generally agree that marrow infarction is more common than is clinically diagnosed and that the results of bone marrow aspirate analysis may be misleading due to sampling error [ 8]. Most frequently, bone marrow necrosis is associated with leukaemia, carcinoma and malignant lymphoma, and less frequently with infections and sickle cell disease.
In a recent review of world literature, we found only a few cases of acute severe anaemia in known sickle cell disorders associated with human parvovirus infection with bone marrow necrosis [ 9–11]. In this combination, it has been postulated that the parvovirus B19 infection may enhance the sickling of red blood cells within the pulmonary vasculature, resulting in hypoxaemia and indirectly inducing bone marrow necrosis. On the other hand, hypoxaemia due to fat and necrotic bone marrow embolization has been reported [ 12, 13]. However, recently, in a case of acute lymphoblastic leukaemia, it was suggested that the virus might act as a cofactor for the induction of bone marrow necrosis [ 14]. Concerning the discrepancy between the usual benign course of the double heterozygous haemoglobinopathy S/E and the severe, life-threatening illness of our described patient, a specific and important role of parvovirus B19 in the pathogenesis of bone marrow necrosis may be postulated. Furthermore, this case demonstrates how important the consideration of haemoglobin disorders can be even in non-Negroid and non-Oriental persons.
Turkey, the native country of our patient, has been the gateway between the continents of Asia, Europe and Africa. The prevalence of Hb S and other haemoglobin variants closely related to ethnic origin was recently described in the southern part of Turkey [ 15]. During the last 30 years, there has been further distribution to western Europe by voluntary migration, thus increasing the possibility of sickling haemoglobin disease outside of the historically known areas.
Received 11 November 1997; accepted 13 August 1998.