Let’s Not Miss the Treatable Ones: Two Cases of Neonatal Sepsis Due to Malaria

India is responsible for 70% of malaria cases and 69% of malaria deaths in the Southeast Asia region. Eighty-two percent of the country’s population lives in areas at risk for malaria transmission [1]. Despite India’s efforts to eradicate malaria, it remains a country with a high malaria burden [2]. Infection with malaria parasites during pregnancy is associated with poor birth outcomes, resulting in significant perinatal morbidity and neonatal mortality [3,4]. Congenital malaria is the direct infection of a child as a result of transplacental transmission of the malaria parasite from the mother in utero or during birth. Detection of asexual forms of malaria parasite in the peripheral swab of a newborn in the first seven days of life or later if there is no possibility of postpartum infection from infectious mosquito bites confirms this diagnosis [5]. Neonatal malaria is vector-borne and is caused by the bite of an infectious mosquito after birth. About 150 cases of congenital malaria are reported worldwide [6,7].

We present two cases of malaria in newborns from a pediatric hospital with a level 2 neonatal unit from a second city in South India, emphasizing the importance of considering an underdiagnosed condition which, if not treated in the differential , can be harmful.

Case 1

A full-term (38+1 weeks) female newborn, born to a primary mother and non-consanguineous parents through an uncomplicated vaginal delivery, presented with jaundice at 18 hours of life in November 2019. Mother had a peaceful pregnancy and delivery. She was on no medications and there was no history of febrile illness during her pregnancy. The infant’s serum bilirubin was 18.4 mg/dl (exchange transfusion range – 18.5 mg/dl) at 18 hours. American Academy of Pediatric Nomograms was used in the treatment of hyperbilirubinemia. Intensive phototherapy started and repeated serum bilirubin done at 24, 36 and 60 hours of life was 16 mg/dl (below the exchange range), 13.5 mg/dl (above the phototherapy range) and 10 mg/dl (below the phototherapy range), respectively. Research showed that the blood group of the mother and the child was B+ve. The direct Coombs test, performed to rule out major and minor blood type incompatibilities, was negative, and a peripheral swab showed a hemolytic picture with neutrophilia and a reticulocyte count of 33%. Glucose-6-phosphate dehydrogenase (G6PD) levels were normal. The osmotic fragility test was normal. Sepsis screening is done on admission and 48 hours of life was negative. She was discharged on the fourth day of her life and with regular follow-up, she appeared to be doing well.

on the 20e On the day of life, the baby was brought in with complaints of fever, skin rash and a day of inconsolable crying. Systemic examination revealed a febrile child with a macular rash all over the body. Studies revealed a C-reactive protein (CRP) of 10 mg/dl, erythrocyte sedimentation rate (ESR) of 52 mm/hr, platelet count of 81,000/cumm, hemoglobin (Hb) of 9.0 g/dl, and white blood cell count (WBC) ) of 5,400 cells/cumm. Complete urinalysis (CUE) was normal. With a working diagnosis of probable late onset sepsis, the baby was admitted and started empirical intravenous antibiotics after sending blood for culture. A lumbar puncture was discussed, but not performed according to the family’s wishes. She continued to have occasional fever spikes, even though she was feeding well. She eventually developed abdominal distention and slow bowel sounds. Repeated examinations at 48 hours showed a total leukocyte count (TLC) of 11,300/cumm, Hb of 7.8 g/dL platelets, count of 45,000/cumm, and CRP of 35 mg/L.

Abdominal ultrasound showed mild hepatomegaly and gallbladder wall edema. X-rays of the chest and abdomen were normal. The cranial ultrasound was normal. Blood culture showed no growth. At this stage, a rapid test for malaria was performed, which turned out to be positive for Plasmodium vivax. Peripheral smears showed Schizonts and ring trophozoites from Plasmodium vivax (Figure 1).

Peripheral-smears-showing-schizonts-and-ring-trophozoites-of-Plasmodium-vivax

She was treated with oral chloroquine at a dose of 10 mg/kg, followed by 5 mg/kg after 6 hours, 24 hours and 48 hours, according to the National Vector Borne Disease Control Program (NVBDCP) guidelines of the Indian guidelines. [8]. She developed a fever and the intravenous antibiotics were stopped. The baby was discharged on oral iron and vitamin D3 supplements. The baby was not present for follow-up, but was found to be growing and gaining weight after telephone examination.

Case 2

A 26-day-old male newborn born to a fourth gravida mother developed a two-day history of fever in March 2022. Her maternal history was notable for malarial fever in the first trimester and a history of blood transfusion in her third trimester for anemia. The baby’s birth history was unremarkable, with normal APGAR scores. Clinical study on the day of presentation (26e day of life) revealed a febrile newborn with pallor and hepatosplenomegaly.

Studies revealed a WBC count of 10,500 cells/cumm (lymphocytes 51.4%, neutrophils 41%), Hb of 8 g/dL, platelets of 77,000/cumm, CRP of 84 mg/L, random blood sugar (RBS) of 96 mg/dl and normal CUE. No COVID-19 testing has been performed. A rapid test for malaria was positive for both Plasmodium falciparum and Plasmodium vivax. A rapid test for Dengue was negative. A peripheral swab from the mother was negative for the malaria parasite. The baby’s peripheral swab was also negative for malaria parasite, but showed many fragmented red blood cells and target cells. Leukocytosis with a left shift of myeloid array cells was present. G6PD levels were normal. The baby was admitted, and after sending blood for culture and sensitivity, intravenous antibiotics and oral Artemether and Lumefantrine syrup were started, according to NVBDCP guidelines.

He developed a fever within 48 hours of starting oral Artemether and Lumefantrine syrup, after which the antibiotics were discontinued because the blood culture showed no growth. Repeated studies revealed a WBC count of 41,000/cumm, Hb of 9.9 gm/dL, platelets of 4.72,000/cumm, and C-reactive protein (CRP) decreased to 4 mg/L. He was discharged on oral iron and vitamin D3 supplements. With further follow-up in the outpatient setting, he gained weight, and hepatosplenomegaly decreased.

Sepsis is one of the most common causes of death among newborns worldwide, especially in low- and middle-income countries. The burden of neonatal sepsis in India is very high [9]. The most common cause of neonatal sepsis in India is a bacterial infection. There is also a significant burden of culture-negative sepsis leading to neonatal mortality [10]. Although not uncommon, neonatal and congenital malaria (NCM) as a cause of neonatal sepsis is not commonly reported, presumably due to low suspicion among clinicians.

The most common symptom of NCM is fever. Other features may include vomiting, diarrhea, anemia, jaundice, lethargy, malnutrition, respiratory distress, hepatosplenomegaly, convulsions, and sepsis-like presentation [11]. Although rapid tests are used for diagnosis, Giemsa-stained peripheral swab remains the gold standard despite its relative unavailability in remote areas and its susceptibility to subjective error. Plasmodium vivax is estimated to be the leading cause of NCM in Europe, while Plasmodium falciparum infection remains the most common cause in Africa and India. Although Chloroquine is still considered the drug of choice for Plasmodium vivax infections, due to the high prevalence of chloroquine resistance, artemisinin-based combination therapy (ACT) is the recommended therapy for Plasmodium falciparum infections. [8]. World Health Organization (WHO) currently recommends treatment with ACT for infants weighing less than 5 kg with Plasmodium falciparum malaria at the same dose as for children weighing 5 kg [11].

With these two case reports, we emphasize the importance of considering malaria in the differential diagnosis of not only neonatal sepsis but also neonatal jaundice. In our first case, the newborn presented with jaundice and later with sepsis in the setting of congenital malaria. We could find no other etiology for pathological jaundice. No malaria parasites were detected on the first peripheral smear, which could be due to a low parasitemia. The possible reasons for low parasitemia may be due to the transplacental transmission of maternal antibodies (IgG) against malaria [12]. Fetal hemoglobin (HbF) may also provide some protection against high parasitemia [13]. Passive immunity can alter the severity of the presentation as both IgG and HbF decline with age, making the infants more susceptible. This can also delay the onset of symptoms for up to three to six weeks after birth, making it difficult to distinguish between the two entities of congenital and neonatal malaria. However, vector-born neonatal malaria cannot be ruled out. In the second case we presented, the maternal history was notable for malarial fever in the first trimester and blood transfusion in the third trimester. This presentation may also likely be due to congenital malaria with the delayed presentation, although neonatal malaria cannot be ruled out. The smear was negative for malaria parasites, but showed a hemolytic picture, which may be due to low parasitaemia due to the above reasons.

Neonatal and congenital malaria is not as uncommon as previously thought, and a high index of suspicion is required. NCM can present as hyperbilirubinemia and neonatal sepsis. Rapid tests and swabs of peripheral blood for malaria parasites should probably be routinely included in the treatment of such newborns, which could provide major benefits in helping clinicians pick up this common and easily treated but potentially deadly infection, especially in endemic countries such as India.

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