Plasmodium falciparum Malaria in a Man with Sickle Cell Disease, Four Years After Exposure

Abstract & Commentary

By Michele Barry, MD, FACP

Dr. Barry is a Professor of Medicine and Public Health; Director of International Health Program, Department of Medicine, Yale University School of Medicine, New Haven, CT.

Dr. Barry reports no financial relationships relevant to this study.

Synopsis: A case of symptomatic Plasmodium falciparum malaria manifested itself 4 years after a visit to an area of malaria endemicity in an 18-year-old male with sickle cell disease. The exceptionally long incubation period raises questions of how and where P. falciparum parasites could reside for several years before causing disease.

Source: Greenwood T, Vikerfors T, Sjoberg M, et al. Plasmodium falciparum malaria 4 years after exposure in a man with sickle cell disease. Clin Infect Dis 2008 ;47 :e39-41.

An 18-year-old man from Togo was admitted to a hospital in Sweden with a 3-day history of chest, stomach, and back pain with recurrent episodes of sweating and fever. He was known to have hemoglobin SC disease and splenomegaly; he was admitted for presumed sickle cell crisis. Fever continued despite intravenous antibiotics and fluids. Results of bacterial cultures of blood, nasopharynx, urine, and stool specimens were normal as were results of serological tests for Epstein-Barr virus and cytomegalovirus. A blood smear revealed P. falciparum in < 0.01% of erythrocytes with largely ring forms noted on the peripheral smear, but also with a few trophozoites, schizonts, and gametocytes. PCR analysis performed by two methods confirmed the presence of P. falciparum. A species specific PCR test detected only one clone of P. falciparum. The patient was treated successfully over 3 days with oral atovaquone/proguanil.

The patient was born in Togo but had lived for the past 14 years in Sweden. His last visit to Togo was 4 years prior to hospital admission. The patient had taken mefloquine prophylaxis weekly during this visit, but he recalled one episode of fever during which he was treated with a different antimalarial, and then continued taking mefloquine again. He had not received blood transfusions, visited an airport, nor been living close to anyone in Sweden with malaria. Blood smear specimens saved as part of a routine hematologic exam four years before the trip to Togo were reanalyzed and found to be negative for parasites. The authors postulate that this case demonstrates clinical symptoms that can develop from a chronic infection with P. falciparum.

Commentary

This is a very unusual case! In contrast to P. vivax and P. ovale, P. falciparum and P. malariae infections do not have dormant liver hypnozoite stages in their life cycles. P. malariae infections may have very long incubation periods—as long as several decades—but it is not clearly understood where the parasites reside. P. falciparum associated malaria usually presents in > 95% of cases within 2 months after exposure.1 Resistance to malaria associated with sickle cell trait (genotype AS) has been offered as an example of genetic selection for more than half a century. Nevertheless, the mechanism of malaria resistance remains the subject of considerable debate. Abnormal hemoglobins (S, C, E) lead to a "balanced polymorphism" within malaria-endemic areas, in that they are associated both with a reduction in the number of homozygous individuals whose life expectancy is limited by vaso-occlusive crisis or infections and with an extension of the duration of life of heterozygous individuals due to protection against severe malaria. Individuals in malaria endemic areas who have sickle cell anemia or sickle cell trait have reduced levels of parasitemia when compared to individuals with normal AA hemoglobin.2,3 Longitudinal cohorts of children followed with sickle cell trait have revealed that levels of parasitemia are lower in AS individuals during the first 2 years of life, and AA children are more often hospitalized with malaria.3 This differential protection by sickle cell trait against malaria is most marked in the first 5 years of life.4

The mechanism by which HbS trait or Hb SS disease protects is not fully understood but involves both impaired parasite growth or parasite death within sickle trait erythrocytes. Carriers of sickle cell trait have a dramatic acceleration of sickling rates in parasitized cells, followed by subsequent clearance of the parasite. Recent studies also suggest enhanced innate immunity among individuals with sickle cell disease or trait may also be playing a role in reducing malaria mortality and morbidity in young children.2

A recent study has shown that individuals with sickle cell anemia and malaria also have deformed red blood cells that are unable to develop adequate sticky knobs that adhere to endothelial cells in blood vessels, one mechanism felt to be responsible for the severity of P. falciparum malaria.5 Overall, it has been postulated that hemoglobin S trait in early childhood provides 90% protection against severe or cerebral malaria, and 60% protection against malaria that is not severe.4 Hemoglobin C also protects against malaria through the inhibition of parasite growth.

This case is particularly interesting in that light microscopic examination detected not only ring forms but also trophozoites and schizonts, despite a low percentage of infected erythrocytes on peripheral smear. This finding perhaps signifies the inability of sticky knobs to form on this patient's red blood cells, which usually causes sequestration of the more mature schizonts and trophozoites. One might also postulate that splenic dysfunction, which can occur in SC disease associated with splenomegaly, resulted in an inability to clear late stage parasites.

This case really challenges the standard teaching that P. falciparum rears its head within the life-span of an erythrocyte, i.e., 120 days. Many questions are raised. Had these parasites been multiplying in the blood and remained at subpatent levels? Does P. falciparum have a dormant stage in splenic or lymphoid tissue? Was this patient's admission really only precipitated by a sickle crisis, and the malarial parasites found on smear reflect an incidental persistent low-level parasitemia? Did P. falciparum malaria trigger a sickle crisis or did a sickle crisis cause a chronic subpatent parasitemia to develop into clinical malaria by overwhelming splenic function? There have been isolated case reports of acute P. falciparum malaria following splenectomy for lymphoma after prolonged absence from endemic areas, as well as recrudescence in cases after removal of the spleen for misdiagnosed tropical splenomegaly syndrome.6,7 Did splenic dysfunction in this patient, which can occur despite splenomegaly, precipitate malaria parasitemia? Whatever mechanism, this case report should alert clinicians to the possibility of malaria in patients from endemic areas who present in sickle crisis even if there is a history of a prolonged time period since clear exposures to the parasite.

References

  1. Centers for Disease Control. Malaria Surveillance-United States, 2006. MMWR 2008;57(SS05):24
  2. Williams TN, Mwangi TW, Roberts DJ, et al. An immune basis for malaria protection by the sickle cell trait. PLoS Med 2005;2(5):e128. http://medicine.plosjournals.org. Accessed 9/2/08.
  3. Yves Le Hesran J, Personne I, Personne P, et al. Longitudinal study of Plasmodium falciparum infection and immune responses in infants with or without the sickle cell trait. Int J Epidemiol 1999;28:793.
  4. Greenwood B, Marsh K, Snow R. Why do some African children develop severe malaria? Parasitology Today 1991;7(10):277.
  5. Cholera R, Brittain NJ, Gillrie MR, et al. Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. PNAS 2008;105(3):991.
  6. Bidegain F, Berry A, Alvarez M, et al. Acute Plasmodium falciparum malaria following splenectomy for suspected lymphoma in 2 patients. Clin Infec Dis 2005;40:e97-100.
  7. David PH, Hommel M, Miller LH, et al. Parasite sequestration in Plasmodium falciparum malaria: Spleen and antibody modulation of cytoadherence of infected erythrocytes. Proc Natl AcadSci USA 1983;89:5075-5079.