Imported Malaria

Imported Malaria, like all imported tropical illnesses, is a Tale of Two Cities. The infection was unknowingly obtained while enjoying a delightful holiday and then brought back in transit to a country where it is not endemic. In these non-endemic countries, we need to always be attentive to patient’s history of recent travel to correctly identify any concerns related to their recent travel. In the last decade, several countries have seen a rise in severe malaria. More specifically they have seen this trend continue to rise in the era of post-COVID travel (Choy 2022). Another change is the CDC approved the use of IV artesunate for malaria treatment in the US in May 2022. This allowed US hospitals to stock the drug to ensure quick treatment of suspected severe cases, rather than having to ship it from the CDC under the prior expanded-access protocol (Thomas 2023). With these changes in malaria presentations and treatment options, it felt an opportune time to revisit this topic. Let’s take a minute to review what we need to know about Malaria: 

Malaria: Basics

  • While eradicated in most high-income countries, it continues to be the most significant parasitic infection in the world endemic to tropical and sub-tropical climates (Forgie 2022)
  • Sub-Saharan Africa has the largest burden with 95% of the world’s cases of malaria and 96% of deaths (WHO 2022) 
    • Nearly 99% of malaria infections in African countries are due to Plasmodium falciparum. (WHO 2022)
    • In a previous PEM morsel, we mentioned Sickle Cell Trait is only protective against P. falciparum. 
  • Worldwide, children <5 years old account for 76% of deaths related to malaria, but these are predominantly in Sub-Saharan Africa (WHO 2022)
  • P. falciparum accounts for >70% of cases of imported malaria, primarily seen in those returning from travel in Sub-Saharan Africa (Mischlinger 2020)
  • Other species include P. vivax, P. ovale, P. malariae, and the less common P. knowlesi and P. simium (Forgie 2022)
    • P. vivax and P. ovale can both lie dormant in the liver, and require additional treatment compared to other strains to fully eradicate them (WHO 2022)
  • The highest-risk group of travelers are those Visiting Friends and Relatives (VFR) which we have discussed previously with Typhoid Fever (Goldman-Yassen 2016)
    • This is likely because these families assume they have immunity in their original country of origin, they travel to high-risk areas for longer periods of time, and they do not seek pre-travel care (Mischlinger 2020)
  • For travelers, they can have a variety of immunity levels including non-immune and semi-immune (Forgie 2022) 
    • Non-immune includes all children <5 years of age, individuals born in non-endemic countries, immigrants living outside of endemic locations for > 6 months
    • Semi-immune includes individuals >5 years of age currently residing in endemic regions

Malaria: Presentation

  • Onset of illness varies based on plasmodium species but is usually within 1 month. P. falciparum typically is within 14 days (Forgie 2022)
    • Semi-immune individuals and those who took incompletely effective prophylaxis can experience longer incubation periods (Arends 2013)
  • Symptoms are non-specific, so fever in a returning traveler from a malaria endemic region with no other explanation should be evaluated (WHO 2023)
  • Other symptoms include headache, fatigue, myalgias, chills, malaise and sometimes mild jaundice. Pediatric patients often also experience abdominal pain in about 40% of cases (Goldman-Yassen 2016)
    • Due to these non-specific symptoms, pediatric patients suffer a higher rate of misdiagnosis (43%) vs adults (13%) (Goldman-Yassen 2016)
    • Semi-immune individuals will often experience less severe symptoms, and don’t develop fevers until they have higher rates of parasitemia compared to non-immune (Mischlinger 2020)
  • Congenital malaria is a rare form which can be seen from transmission at birth, and is most likely to be symptomatic in those newborns born to non-immune mothers (Forgie 2022) 

Malaria: Evaluation

  • In countries where a Rapid Diagnostic Test (RDT) for malaria is available, this can give a quick answer.
    • This is typically only widely available in endemic countries (Forgie 2022)
    • More recently there has been a deletion in the Pfhrp 2/3 gene in some P. falciparum species which is the gene detected by the RDT leading to increased false negatives (Forgie 2022) 
  • In non-endemic countries, it is more likely that you will have to order a thick and thin smear. You should consider ordering this in all febrile children with fever <30 days from travel to a malaria-endemic country (Forgie 2022) 
    • Thick smears are 10 x more sensitive for malaria then thin smears, but thin smears are used to identify species. Both have a range of detection limits, which can be greatly dependent on operator. 
    • 3 thick and thin smears should be obtained at 12-24 hour intervals to fully rule out the possibility of malaria
  • PCR is the most sensitive and specific test for malaria. It is very cost-prohibitive even in high-income countries (Forgie 2022) 
  • We previously discussed hematologic findings associated with malaria, Pancytopenia and Malaria, include leukocytosis, monocytosis, neutropenia, thrombocytopenia, pancytopenia and rarely hemophagocytosis.
    • While these hematologic findings can be seen in uncomplicated cases, they are typically more pronounced in severe malaria (Forgie 2022)

Malaria: Severe

  • Symptoms that define severe malaria include AMS, seizures, abnormal brain stem reflexes, respiratory distress, acute pulmonary edema, jaundice, coagulopathy, and shock (WHO 2023)
    • Some patients may have even noted darkening of their urine which is attributed to hemoglobinuria. This is otherwise known as Blackwater fever (Forgie 2022) 
  • Severe Malaria laboratory findings include acute kidney injury, hyperbilirubinemia, hemoglobinuria, severe anemia, hypoglycemia, lactic acidosis, and hyperparasitemia (Forgie 2022)
    • Severe Malaria is almost entirely attributed to infection with P. falciparum (Forgie 2022)
    • Approximately 20% of cases of severe malaria occur in the pediatric population with approximately half occurring in those < 5 years of age (Forgie 2022) 
    • In one European multi-center study, most common lab findings of severe malaria included anemia at diagnosis, elevated WBC, and elevated CRP (Comelli 2021) 
    • AKI is present in approximately 40% of those with severe malaria and is associated with higher morbidity, mortality, and risk of CKD (Conroy 2016)
  • Hyperparasitemia is defined by age (Forgie 2022): 
    • >2% parasite burden in children < 5 years of age
    • >5% parasite burden in children > 5 years of age who are non-immune
    • >10% parasite burden in children > 5 years of age who are semi-immune
  • Cerebral malaria is one of the most severe forms of malaria and is defined by GCS < 11 for >1 hour after a seizure, P. falciparum parasitemia, and no other defined cause of AMS (WHO 2023).
    • This carries a mortality rate of up to 40% and a neurological sequalae rate of 50% (Johnson 2022)

Malaria: Management per WHO guidelines (WHO 2023)

  • Uncomplicated malaria by P. falciparum species 
    • Oral artemisinin combination therapy
      • In the US, CDC recommends a 3-day course of oral Coartem (artemether–lumefantrine) if readily available. 
      • Most countries health departments have their own recommendations for treatment as there are several options for combination therapy. These can be easily found online on their websites. 
    • If unable to tolerate oral, IV artesunate is recommended
    • Chloroquine can be used if infection was acquired in areas with chloroquine-sensitive malaria. As chloroquine resistance is widely spread, the remaining susceptible regions are the Caribbean and Central America (Forgie 2022)
  • Uncomplicated malaria by P. vivax and P. ovale and less common species
    • Artemisinin combination therapy is again generally recommended 
    • Chloroquine is also an option if travel from an area with chloroquine-sensitive P. vivax,  and is likely effective for all P. ovale, P. malariae, and P. knowlesi infections
    • Must add Primaquine for P. vivax and P. ovale to cover the hypnozoite that can stay dormant in the liver and cause a secondary infection in the future
  • Severe Malaria
    • IV artesunate is currently the accepted first line treatment
      • Previously IV quinine was first line, however it was associated with higher incidence of hypoglycemia, cardiac dysrhythmias, seizures, and comas. Additionally in a head-to-head study, there was improved mortality with IV artesunate (Forgie 2022) 
    • IV artesunate is extremely expensive to stock and may not be available at every hospital in non-endemic regions. Starting a patient with oral artesminin combination therapy and either rapidly ordering IV artesunate or transferring the patient to a hospital with access to IV artesunate is the next best option (Thomas 2023)
    • A 3 day course of artemisinin combination therapy must always follow IV treatment once patient is improving (WHO 2023) 

Malaria: Sequalae 

  • These sequalae of infection are much more common after severe malaria (Yadava 2019)
    • Chronic Kidney Disease was found in 7.8% of children who had experience AKI with severe malaria (Conroy 2019)Neurologic sequalae can include delayed Cerebellar Ataxia, Acute Inflammatory Demyelinating Polyneuropathy (AIDP) and Acute Disseminated Encephalomyelitis (ADEM) (Yadava 2019)
    • Post-malaria Neurologic Syndrome (PMNS) is specific to malaria, but it is very rare with only about 50 cases reported worldwide, although this may be underreported in endemic countries. It appears after an asymptomatic period. It is characterized by a variety of symptoms from mild ataxia or tremor alone to severe encephalopathy accompanied with fever, seizures, aphasia, and sometimes psychiatric symptoms (Yadava 2019)
  • Treatment with artesunate can lead to Post-Artesunate Delayed Hemolysis (PADH) (Forgie 2022)
    • Typically seen 7-21 days after treatment
    • 15% of those treated with artesunate can develop it, and 73% of them likely will a blood transfusion
    • Believed to be a distinct mechanism of hemolytic anemia due to damage from the eradication of the malaria parasite which reduces the lifetime of the RBC’s to 1-3 weeks

Moral of the Morsel

  • Ken-ya tell me if you recently travelled and why? Yes, we used this moral previously with Typhoid fever, but as with all imported tropical illnesses you won’t think about them unless you ask about recent travel history. The reason for travel is also important because many tropical illnesses are higher in those travelling to visit friends and relatives!
  • Who else loves their immune system? Anti-body? With concern for malaria, it is very important to identify who is non-immune and semi-immune as this can affect both the timeframe for illness after departure from the endemic country as well as severity of illness. 
  • Third times the charm! A single thick and thin smear is not enough to effectively rule out malaria. It takes 3 negative smears collected at 12-24 hours to exclude malaria as the cause of fever in a returning traveler from an endemic region. 
  • Treating malaria is an ART! If concerned for severe malaria or inability to tolerate PO always start with IV ARTesunate. For non-complicated malaria use oral CoARTem. Add oral Primaquine if known to have P. vivax or P. ovale. Most country’s health departments also have local recommendations for imported malaria treatment. 
  • Blackwater fever isn’t that a name of a rock band? Remember serious complications can occur in malaria including hemoglobinuria that turns the urine dark, called Blackwater fever, and can indicate possible impending renal failure. Pulmonary edema, hypotension and severe neurologic complications including seizures and comas. 

References

Arends JE, Oosterheert JJ, Kraaij-Dirkzwager MM, Kaan JA, Fanoy EB, Haas PJ, Scholte EJ, Kortebeek LM, Sankatsing SUC. Two Cases of Plasmodium falciparum Malaria in the Netherlands without Recent Travel to a Malaria-Endemic Country. Am J Trop Med Hyg. 2013 Sep 4; 89(3): 527–530. PMID: 23857021

Centers for Disease Control. Treatment of Malaria: Guidelines for Clinicians. June 28, 2023. https://www.cdc.gov/malaria/diagnosis_treatment/clinicians1.html

Choy B, Bristowe H, Khozoee B, Lampejo T. Increased imported severe Plasmodium falciparum malaria involving hyperparasitaemia (>10%) in a UK hospital following relaxation of COVID-19 restrictions compared to the pre-pandemic period. J Travel Med. 2022 Dec 27;29(8). PMID: 36209409

Comelli A, Guarner ME, Tomasoni LR, Zamboni AF, Pavo BM, Zanotti P, Caligaris S, Matteeli A, Soriano-Arandes A, Castelli F. Severe imported Plasmodium falciparum malaria in children: characteristics and useful factors in the risk stratification. Travel Medicine and Infectious Disease 44 (2021) 102196. PMID: 34748988

Conroy AL, Hawkes M, Elphinstone RE, Morgan C, Hermann L, Barker KR, Namasopo S, Opoka RO, John CC, Liles WC, Kain KC. Acute Kidney Injury Is Common in Pediatric Severe Malaria and Is Associated with Increased Mortality. PMID: 27186577

Conroy AL, Opoka RO, Bangirana P, Idro R, Ssenkusu JM, Datta D, Hodges JS, Morgan C, John CC. Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria. BMC Med. 2019; 17: 98. PMID: 31109328

Forgie EME, Brooks HM, Barton M, Hawkes M. Pediatric Malaria: Global and North American Perspectives. Pediatr Clin N Am 69 (2022) 47–64. PMID: 34794676

Goldman-Yaseen AE, Mony VK, Arguin PM, Daily JP. Higher Rates of Misdiagnosis in Pediatric Patients versus Adults Hospitalized with Imported Malaria. Pediatr Emerg Care. 2016 Apr; 32(4): 227–231. PMID: 25322145

Johnson H Raees M, Urbina E, Muszynski J, Seydel K, Taylor T, O’Brien N. Multiple Organ Dysfunction Syndrome and Pediatric Logistic Organ Dysfunction-2 Score in Pediatric Cerebral Malaria. Am J Trop Med Hyg. 2022 Sep 6;107(4):820-826. PMID: 36067988

Mischlinger J, Ronnberg C, Alvarez-Martinez J, Buhler S, Paul M, Schlagenhauf P, Petersen E, Ramharter M. Imported Malaria in Countries where Malaria Is Not Endemic: a Comparison of Semi-immune and Nonimmune Travelers. Clin Microbiol Rev. 2020 Mar 11;33(2):e00104-19. PMID: 32161068

Thomas CM, Stauffer WM, Alpern JD. Food and Drug Administration Approval of Artesunate for Severe Malaria: Enough to Achieve Best Practice? Clin Infect Dis. 2023 Feb 1; 76(3): e864–e866. PMID: 36056897

World Health Organization. WHO Guidelines for Malaria. Geneva. 16 Oct 2023. 

World Health Organization. World malaria report 2022. Geneva. 8 Dec 2022.

Yadava SK, Laleker A, Fazili T. Post-malaria neurological syndrome: a rare neurological complication of malaria. Infection. 2019; 47(2): 183–193. PMID: 30666615

Erica Scott
Erica Scott
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