Case 2: A three-week-old boy with a history of fever and irritability

A three-week-old boy who was previously well presented to hospital with a one-day history of fever and irritability. He was a full-term baby who was delivered by spontaneous vaginal delivery. His birth weight was 3200 g. His mother was G1P0, was originally from Pakistan and had immigrated to Canada one year before delivery. She had experienced an uneventful pregnancy. Antenatal serology was negative for syphilis, hepatitis B surface antigen and HIV, protective for rubella and group B streptococcal screening test was negative. The baby had been breastfeeding well before the day of presentation. On examination, the baby appeared well. His temperature was 39°C. Other vital signs were normal. Examination of the cardiovascular, respiratory and central nervous systems, including anterior fontanel, was unremarkable. The liver was 3 cm and the spleen 2 cm below the costal margins. Skin examination showed several petechiae on the ankles. Initial investigations revealed a hemoglobin level of 117 g/L, white blood cell (WBC) count of 4.2×10⁹/L, neutrophil count of 1.3×10⁹/L, lymphocyte count of 1.85×10⁹/L and platelet count of 44×10⁹/L; and a creatinine level of 24 μmol/L, aspartate tranaminase level of 85 IU/L, alanine transaminase level of 58 IU/L, total bilirubin level of 66 μmol/L and conjugated bilirubin level of 0 μmol/L. Analysis of the cerebrospinal fluid revealed a WBC count of 11 cells/mm³, protein level of 0.45 g/L and glucose level of 3.1 mmol/L. The child was admitted and started on intravenous ampicillin and cefotaxime. An additional test on admission revealed the diagnosis.

CASE 2 DIAGNOSIS: CONGENITAL MALARIA

Peripheral blood smears showed schizonts, gametocytes and trophozoites with Schuffner stippling and 1.5% parasitemia, and rapid antigen detection test was positive for non-falciparum species of malaria, confirming a diagnosis of Plasmodium vivax malaria. Further history revealed that the mother experienced a febrile illness two weeks previously, diagnosed as malaria from P vivax and treated with three days of chloroquine in a peripheral hospital. The mother denied previous treatment for malaria; she had not experienced a febrile illness since arriving in Canada 12 months previously and reported no travel within the past year. The baby was diagnosed with congenital malaria and started on oral atovaquone-proguanil (Malarone; GlaxoSmithKline, Canada), two paediatric tablets. Twenty-four hours later, his platelet count had dropped to 25×10⁹/L and parasitemia was 1.8%. Artesunate 2.4 mg/kg intavenously was started and by the following day the baby was afebrile, his platelet count was increasing and parasitemia was <0.1%. Blood, urine and cerebrospinal fluid cultures were negative. He was discharged on day 4 of admission after three days of artesunate to complete a seven-day course of atovaquone-proguanil.

Malaria is a parasitic disease caused by Plasmodium species. It is most commonly transmitted by female anopheles mosquitoes, but can also be transmitted vertically and by blood transfusion. Congenital malaria occurs when a mother is parasitemic around the time of birth, transmitting Plasmodium trophozoites to the child either through maternal transfusion during pregnancy or delivery, or from direct penetration through the chorionic villi to the fetal circulation. Estimates of the prevalence of congenital malaria in endemic areas range from 0.03% to 46.7%; however, it is challenging to differentiate congenital from postnatally acquired malaria in areas such as sub-Saharan Africa (1). In nonendemic countries with no exposures, as in our case, a positive smear within weeks to months of birth is diagnostic. There have been <100 cases of congenital malaria reported in North America in the past 40 years (2). Most cases have been due to P vivax, presenting on average at three weeks of age, and many babies exhibited negative smears at the time of birth. Passive transfer of maternal antibodies may provide partial protection, resulting in a milder course and delay in symptom onset. The common presenting features would be consistent with those observed in older children with malaria, particularly fever, hepatosplenomegaly, hemolytic anemia and thrombocytopenia (2). Neonates may also present with non-specific signs mimicking sepsis including irritability, vomiting and lethargy. Recognizing congenital malaria can be challenging; however, immigration or travel in a mother from an endemic area should lead one to consider the diagnosis. P vivax and P ovale are the only malaria species with a hypnozoite liver phase and, thus, able to cause disease relapse. Relapse can occur anywhere from weeks to five years following initial infection. P falciparum, P malariae and P knowlesi do not relapse and incubation periods are rarely longer than four weeks. There are no specific guidelines available for the treatment of malaria in neonates. Chloroquine would be an appropriate medication for treating P vivax congenital malaria acquired in nonchloroquine-resistant areas. If species is unknown, treatment for suspected P falciparum should be initiated with intravenous artesunate, or oral atovaquone-proguanil in mild cases. There are very little safety data regarding antimalarial medications for neonates and all should be used cautiously under close observation. Once species identification and clinical response has been documented, the treatment course should be either artemether-based combination therapy or atovaquone-proguanil for P falciparum, or chloroquine for all other species.

Primaquine is indicated for radical cure of P vivax and P ovale because it is the only medication able to eradicate the hypnozoite forms in the liver phase and, therefore, prevent relapse. However, the pathogenesis of congenital malaria involves the direct infusion of blood-stage trophozoites, bypassing the hepatic stage. Therefore, primaquine is not necessary in congenital malaria, and therapy with a blood schizontocide medication only is adequate for radical cure of all Plasmodium species infections.

CLINICAL PEARLS

• The diagnosis of congenital malaria should be considered in febrile neonates born to mothers from endemic counties.

• Congenital malaria should be considered in the differential diagnosis of a febrile infant even with an absence of recent travel in maternal history or a long period between immigration and birth of the child because some malaria species can remain dormant and malaria relapses can occur during pregnancy or at birth even many years after initial infection.