Case 1: The never-ending fever

A 14-year-old boy from Ghana with sickle cell anemia (hemoglobin SS genotype [HbSS]) presented to the emergency department with a five-day history of bilateral leg pain and a painful swelling of the left eye. He had immigrated to Canada nine months before admission and was being treated with prophylactic oral penicillin for his sickle cell anemia. On presentation to the emergency department, he was found to be febrile (38.9°C) and tachycardic (heart rate of 110 beats/min), but did not look toxic. He had bilateral nontender shin pain and left periorbital swelling. His extra-ocular movements were normal and he had normal visual acuity. He had a soft grade II/VI systolic ejection murmur. There was no organomegaly or lymphadenopathy. Laboratory investigations revealed a hemoglobin level of 88 g/L (his baseline level was between 70 g/L and 80 g/L) and a white blood cell count of 22.8×109/L. The patient was admitted to hospital with a diagnosis of a vaso-occlusive crisis of the shins and periorbital cellulitis. He was started on a morphine infusion and intravenous antibiotics. Within 48 h, his cellulitis had improved, his white blood cell count had normalized and he no longer required the morphine infusion. However, he remained febrile with a palpable spleen tip. A diagnostic workup for prolonged fever was initiated. Multiple blood and urine cultures were sterile. A bone scan and a magnetic resonance imaging scan of the orbits did not demonstrate any evidence of osteomyelitis. Thick and thin smears for malaria were negative on two occasions. A tuberculosis skin test and an HIV serology test were negative. A further laboratory investigation revealed the diagnosis. Although the initial blood smears were negative, the third smear demonstrated the presence of Plasmodium falciparum malaria (0.1% parasitemia). The patient was started on oral quinine and doxycycline, and rapidly defervesced before discharge. Malaria is a disease of global importance that leads to 1.5 to 2.7 million deaths annually. The disease is of particular relevance to paediatricians because it is estimated that at least one-half of the deaths occur in children younger than five years of age. The malaria parasite, Plasmodium species, is transmitted by the bite of the infected female Anopheles mosquito. Clinical features vary depending on the species of the Plasmodium parasite, but the most severe manifestations are usually associated with Ps falciparum. Diagnosis is made by microscopy with thick blood smears (to maximize sensitivity) and thin blood smears (for speciation). The rise in global travel, immigration from malaria-endemic regions of the world and increased prevalence of drug-resistant malaria have contributed to a rise in the incidence of imported malaria in Canada in recent years. Despite this, it is not uncommon for the diagnosis of malaria to be missed on presentation. In one recent prospective study (1), the diagnosis was missed in 59% of patients who presented with malaria to a physician in Toronto, Ontario. Also, laboratories may incorrectly prepare or interpret malaria smears, leading to delays in instituting the appropriate therapy. This is especially relevant in cases with low-density parasitemia. Thus, if a diagnosis of malaria is suspected, it is important that multiple smears are sent to a laboratory with experience in interpreting malaria smears to ensure that the diagnosis is not missed. It has long been believed that the unusually high frequency of the sickle cell trait (HbAS) in people of African or Mediterranean descent has been maintained by the protective effect of sickled hemoglobin against severe malarial anemia, high-density parasitemia and death. Postulated mechanisms for this protection include poor growth of intra-cellular parasites in sickled cells and the shortened lifespan of infected, sickled red blood cells before parasite maturation and replication. Similar protection against severe malaria (high parasitemia) is also thought to occur in patients homozygous for sickle cell anemia (HbSS). However, even a mild degree of hemolysis from malarial infection can lead to significant anemia and even death in patients with HbSS. Imported malaria from P falciparum presents within the first month of arrival in 90% of cases, but can occur many months later. Other forms of malaria, such as Plasmodium vivax or Plasmodium ovale, can present months or years later because they have a dormant exoerythrocytic liver phase (the hypnozoite form). The patient in the present case presented with symptoms of P falciparum malaria later than typically described and with a very low parasite count. This could be because he had acquired partial immunity to P falciparum from having lived in a malaria-endemic region his entire life, as well as his partial protection due to sickled hemoglobin. Treatment regimens for imported malaria depend on the age of the patient, the malaria species and parasitemia, the clinical severity and the regional resistance patterns. A parasitemia of greater than 1% should be considered a medical emergency requiring hospital admission. It is recommended that treatment decisions be made in consultation with an infectious disease specialist. Fever in the returning traveller or new immigrant from a malaria-endemic region should be considered to be malaria until proven otherwise. Multiple thick and thin smears sent to a laboratory experienced in the diagnosis of malaria are necessary to rule out the disease. Although the sickle cell trait protects against severe P falciparum malaria, patients with sickle cell disease can still get malaria, leading to significant morbidity and mortality. Patients immigrating from regions where malaria is endemic may have a delayed or milder presentation of their disease due to acquired partial immunity. The case presentation should not exceed 200 words and should give the reader enough information to suspect the diagnosis without making it obvious. The discussion should not exceed 600 words and should be followed by a couple of ‘clinical pearls’. A maximum of two references may be included, if helpful. The submitted cases will undergo peer review and revision at the discretion of the editors. Priority is given to cases illustrating an approach to common problems or important clinical clues to less common diagnoses that should not be missed. The Editorial Board hopes that this provides an opportunity for trainees and paediatricians practising outside of the teaching hospitals to share their clinical experiences and to publish in Paediatrics & Child Health. If you have a case to submit, contact Dr Friedman by e-mail at jeremy.friedman@sickkids.ca.

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