Severe Malaria: ED Presentation, Evaluation, and Management

Authors: Sarah McLeod (MS-4, University of Missouri-Columbia); Emmanuel Effa, MD (University of Calabar Teaching Hospital, Calabar, Nigeria); Jimmy Atyera, MD (EM Resident Physician, Makerere College of Health Sciences, Kampala, Uganda); Jessica Pelletier, DO (APD/Assistant Professor of EM/Attending Physician, University of Missouri-Columbia) // Reviewed by: Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case

64-year-old female with history of hypertensive heart disease presents to the ED in Uganda with 2 days of high-grade recurrent fevers associated with chills and rigors, loss of appetite, nausea, vomiting, and generalized body weakness. Vital signs are notable for T 37.9°C, HR 109 bpm, BP 95/54 mmHg, RR 19 bpm. Physical examination reveals an elderly woman who is lethargic with bilateral pedal edema. There is no jaundice, pallor, lymphadenopathy, or cyanosis. Capillary refill is < 2 seconds. She is tachycardic with regular rhythm, and there are no murmurs, rubs, or gallops. There is equal bilateral air entry with no adventitious breath sounds. There is no abdominal tenderness to palpation.

Initial diagnostic workup in the ED reveals WBC 4.5 cells/μL, hemoglobin 13.9 g/dL, platelet count 61,000/µL, CRP 120.63 mg/L, INR= 1.5, and blood glucose is within normal limits. Malaria rapid diagnostic test is positive, and blood smear for malaria parasites shows 25-30 malaria parasites per high-power field.

After admission the patient goes on to develop acute liver injury with ALT 77.1 U/L (7.0-40.0), AST 85.8 U/L (10.0-31.0), GGT 55.1 U/L (7.0-45.0), total bilirubin 30.14 mmol/L (0.00-6.80), albumin 5.4 g/dL. She also suffers an acute kidney injury with blood urea nitrogen (BUN) 413.8 mg/dL, creatinine 11.35 mg/dL. There is slight hyponatremia with sodium 132.4 mmol/L and hypokalemia at  2.63 mmol/L. The patient subsequently develops thrombocytopenia with a platelet count 35,000/µL and ecchymoses on the 3rd day of admission, with pulmonary edema.

Introduction

Severe malaria is a life-threatening emergency and represents a major cause of preventable childhood mortality around the world, especially in subtropical areas.  Due to its overall nonspecific signs and symptoms, severe malaria is commonly missed or attributed to another condition, such as sepsis.  Distinguishing these conditions as well as recognizing warning signs of more severe presentations is essential for rapid diagnosis and treatment.

Epidemiology

• According to the WHO, there were an estimated 263 million cases of malaria globally in 2023 (An increase from 252 million in 2022).¹
  • Incidence of 60.4 cases per 1000 population at risk (Increase from 58.6 per 1000 in 2022).¹
• Malaria has the highest prevalence in tropical and subtropical areas such as Africa, Central and South America, Asia, and Oceania. Transmission has been noted in 85 countries and territories across the globe.¹
• Approximately 94% of cases occur in African regions, with subsequent regions accounting for 2% or less of the remainder.²
• Nigeria and the Democratic Republic of Congo accounted for the highest percentage of malaria cases (26%, 12.6%) as well as malaria deaths (30.9%, 11.3%) worldwide in 2023.²
• Children less than 5 years old are at the highest risk of mortality and comprise 76% of all malaria deaths in the African region.²
• Infants, children <5 years, pregnant patients, and patients with HIV, G6PD deficiency, and sickle cell disease are at a particularly high risk of developing severe malaria.³
• Populations traveling from areas of minimal malaria transmission are at greatest risk of severe manifestations and death due to a lack of acquired immunity.³
• Transmission of malaria was eliminated in the United States by 1951.³
  • Remaining yearly cases (~2000) are acquired by travelers to endemic regions.

Pathophysiology

• There are five organisms responsible for causing human malaria: Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi.⁴
• The primary transmission of malaria occurs through the bite of an infected female Anopheles The life cycle that follows occurs in this sequence.⁴
  • 1) As the mosquito feeds, it injects sporozoites into the bloodstream that preferentially infect liver cells.
  • 2) Sporozoites undergo asexual reproduction to produce schizonts.
  • 3) After approximately 1-2 weeks, the schizonts rupture to release merozoites into the bloodstream.
  • 4) Merozoites invade RBCs and undergo a second phase of asexual reproduction, producing rings→ trophozoites → blood stage schizonts.
  • 5) Blood stage schizonts multiply within RBCs until they rupture, destroying them while simultaneously releasing further merozoites into the bloodstream for continuation of the life cycle.
• Severe malaria is predominantly caused by Plasmodium falciparum. falciparum has the unique ability to infect both mature and immature RBCs, has a more rapid rate of asexual reproduction, and can sequester within the central nervous system (specifically in postcapillary venules).^5,6
  • All of these characteristics contribute to worse presentations and outcomes for patients infected with P. falciparum compared to other strains.
• Severe malaria is driven by a complex combination of parasite-induced damage to red blood cells, inflammation/cytokine release, cytoadherence, and sequestration.
  • Parasite-induced RBC damage: rupture of RBCs directly results in significant anemia as well as the release of merozoites and toxic byproducts into the bloodstream. The severity of the disease is likely exacerbated by higher parasite burdens.⁷
  • Inflammatory Response and Cytokines: In response to the release of merozoites into the bloodstream, an inflammatory cascade is triggered to release cytokines (TNF-a, IL-6, IFN-gamma). In severe malaria, the body fails to downregulate these pro-inflammatory cytokines, leading to widespread, uncontrolled inflammation and damage.^8,9
  • Cytoadherence and sequestration: Infected RBCs undergo changes to their surface epithelium, causing them to adhere to the endothelium of capillaries and microvasculature. Overtime this leads to sequestration within various organ systems, small infarcts, and capillary leakage, contributing to tissue hypoxia and widespread organ dysfunction.¹⁰

Clinical Presentation

• Clinical presentation can vary based on prior exposure and/or immunity to malaria and can range from asymptomatic parasitemia to severe with life-threatening anemia, cerebral malaria, metabolic acidosis, hypoglycemia, and multiorgan system involvement.
• Malarial illness should be suspected in patients with recent exposure to highly endemic areas. For non-immune patients, infection with falciparum can take as long as a month to manifest after exposure.¹

Common symptoms

• Uncomplicated Malaria¹¹
  • Initial symptoms are non-specific, including tachycardia, chills, malaise, fatigue, tachypnea, headache, cough, nausea, vomiting, diarrhea, arthralgias, and myalgias.
  • Fever ≥ 37.5°C
  • Febrile paroxysms can occur at irregular intervals each day early in the course of infection and become regular depending on specific strain (e.g., P. vivax and P. ovale with fevers every other day vs every third day for P. malariae).
    • Fever may also represent concomitant infection(s).
•  Severe Malaria¹¹
  • Defined as the presence of P. falciparum parasitemia and one or more of the following manifestations:
    • Impaired consciousness
      • Glasgow Coma Score <11 in adults
      • Blantyre Coma Score ≤2
    • Seizures
      • More than two convulsive episodes within 24 hours
    • Prostration
      • Generalized weakness limiting the patient’s ability to sit, stand, or walk without aid
    • Metabolic Acidosis
      • Base deficit of >8 mEq/L, a plasma bicarbonate level of <15 mmol/L, or venous plasma lactate ≥5 mmol/L.
      • Kussmaul respirations are frequently present
      • Associated with a poor prognosis
    • Hypoglycemia
      • Children <5 years: <54 mg/dL
      • Children ≥5 years and adults: <40 mg/dL
      • Marker of severe disease
    • Severe anemia
      • Hgb ≤5g/dL or Hct ≤15% in children <12 years old.
    • Hyperparasitemia
      • Parasite count ≥ 10,000 parasites/uL
    • Renal impairment
    • Pulmonary Edema
      • O2 saturation <92% on room air with RR >30/min or radiological evidence.
    • Shock
    • Bleeding
      • Recurrent or prolonged bleeding, hematemesis, or melena
•  Cerebral Malaria is a severe and life-threatening complication of P. falciparum parasitemia within the brain vasculature. It can present as encephalopathy, coma, focal neurological deficits (stroke mimic), or significant headache with fever.
  • Lack of meningeal signs helps to distinguish it from bacterial meningitis.
  • Children frequently present with seizures.
  • Retinal hemorrhages and other fundoscopic abnormalities (retinal opacification)are a reliable clinical indicator for cerebral malaria.¹²
  • Cerebral edema, along with elevated intracranial pressure, is associated with higher mortality.¹³
  • Acute hepatitis is another potential complication (uncommon, but seen in our patient case).¹⁴
  • Mortality risk increases significantly (~3X) with the presence of acidosis and renal failure.¹⁵

Physical Examination Findings:

• Uncomplicated Malaria:
  • Lethargy
  • Febrile
  • Pallor
  • Splenomegaly
  • Mild jaundice
• Severe Malaria:
  • Pallor and petechiae
  • Moderate to severe jaundice
  • Hepatomegaly and/or splenomegaly
  • Respiratory distress
  • Altered mentation and coma

Diagnostic Testing

• Light Microscopy of Blood Smear with Giemsa stain^16,17
  • *Gold standard for diagnosis.
  • Allows for direct visualization of parasites and differentiation between species.
  • Allows for determination of parasite burden; as this burden increases, mortality rises.¹⁸
  • It is not always accessible in resource-limited settings.
• Rapid Diagnostic Tests (RDTs)¹⁹
  • Allow for the detection of the malaria parasite antigen.
    • HRP2 assay can detect Falciparum antigens.
    • pLDH assay can detect all species.
    • Cannot provide a quantitative result of parasite density.
  • Utilized in endemic, resource-limited settings where microscopy is unavailable.
• CBC – with reticulocyte count and LDH¹¹
  • Anemia, thrombocytopenia, and leukocytosis (in case of concomitant infection).
  • Thrombocytopenia is associated with an increased risk of mortality, particularly with severe anemia.²⁰
• CMP¹¹
  • To evaluate for elevated transaminases, elevated BUN/creatinine.
• Coagulation Panel (PT, PTT, INR)¹¹
  • To look for coagulopathy.
• ABG¹¹
  • To evaluate the extent of acidosis.
• Blood and urine cultures¹¹
  • To rule out other primary sources of infection.
• HIV and TB testing¹¹
• Lumbar puncture²¹
  • Findings for cerebral malaria may include: elevated opening pressure and low WBC, glucose, and protein compared to meningitis.
• Other tests to consider:
  • Point of care ultrasound (POCUS) and CXR to evaluate for pulmonary edema.²²
  • CT head when showing signs of increased intracranial pressure (i.e. altered mental status, seizures) to rule out space-occupying lesions prior to LP.²³

Treatment

• Severe malaria can promptly result in death within hours of presentation. The primary goal of treatment is prompt initiation of antimalarial therapy and supportive care for life-threatening complications (i.e., cerebral edema, acidosis).
• First line: recommended primary treatment for severe malaria in adults is IV artesunate 2.4 mg/kg for a minimum of 24 hours.²⁴
  • The dose is 3 mg/kg for patients < 20 kg.²⁵
  • At institutions where IV artesunate is not available, interim oral or intramuscular antimalarials are recommended while IV artesunate is obtained emergently. See https://www.cdc.gov/malaria/hcp/clinical-guidance/iv-artesunate-us.html.
    • Three dosages of IM artesunate given at 0, 12, and 24 hours, followed by 3 days of oral antimalarial  is preferred.²⁵
      • If IM artesunate is not available, IM artemether (loading dose 3.2 mg/kg) or IM quinidine (loading dose 20 mg/kg) for children ≥6 years old is recommended.²⁵
      • For children <6 years old, rectal artesunate (10 mg/kg) is preferred, followed by IM artemether or IM quinidine.
  • If IV artesunate cannot be obtained following interim treatment, IM or rectal treatment should continue until patients can tolerate oral medications.¹¹
  • IV artesunate for at least 24 hours is the treatment of choice in all trimesters, followed by initiation of oral regimen after at least 3 days for pregnant patients.¹¹
• Empiric antibiotic therapy against gram-negative bacilli should not be initiated in adults without clinical syndrome consistent with serious bacterial infection.²¹
  • Empiric therapy is commonly recommended for children in high endemic areas with suspected malaria due to high rates of concomitant bacterial meningitis.
  • Ceftriaxone is a common choice of antibiotic coverage.
• Benzodiazepines are recommended first-line for seizure management (diazepam 0.4mg/kg IV or rectal).¹¹
  • IM paraldehyde, IV phenobarbital, or phenytoin can be considered if seizures fail to be controlled with first-line therapies based on the World Health Organization (WHO) guidelines.¹¹
• Transfuse patients who are anemic or coagulopathic, ideally with fresh whole blood; if this is not available, use packed red blood cells (PRBCs) for anemia, and replete coagulopathy with platelets, fresh frozen plasma (FFP), or cryoprecipitate as indicated.¹¹
  • The PRBC transfusion threshold for patients with severe malaria should be ≤6 g/dL (60 g/L).²⁶
• Use of adjunctive acetaminophen may be renoprotective for patients with evidence of acute kidney injury in the setting of severe malaria.²⁷
• Hypoglycemic patients should receive an initial bolus of dextrose (0.25g/kg) with repeated boluses after 15 minutes until the patient is normoglycemic. All patients should have their blood glucose monitored for at least 24 hours due to the associated poor prognosis.¹¹
• Volume status should be managed on an individualized basis. Adults with severe malaria appear to be more susceptible to fluid overload compared to children. A balance must be obtained to balance the risk of underhydration (AKI) and fluid overload (cerebral and pulmonary edema).²⁸
• Supportive care, including but not limited to oxygen, ventilatory support, pulse oximetry, frequent neurological examinations, volume management, and cardiac monitoring as needed to treat individual complications.

Prevention

• Three primary tools of prevention have been shown to be beneficial at reducing rates of malaria transmission: Vector control, chemoprevention, and vaccination
  • Vector control: Methods to prevent physical contact with mosquitoes; insecticide-treated nets (ITNs), indoor residual spraying (IRS) and insecticides/chemical repellents.²⁹
  • Chemoprevention: Intermittent administration of antimalarial medicine at a curative dose during the malarial season, particularly for at-risk groups (school-age children in high transmission areas, children <5 years old hospitalized for severe anemia, pregnancy, HIV, etc).³⁰
  • Vaccination: Recommended by the WHO for prevention of P. falciparum in children of endemic areas.³⁰
    • Two vaccines are recommended: RTS,S and R21
    • Between 2019 and 2023, distribution of the vaccine in Ghana, Kenya and Malawi resulted in statistically significant 22% reduction in children hospitalized with severe malaria and 13% reduction of all cause mortality.³¹

Prognosis

• The prognosis for patients with severe malaria is poor, with nearly 100% mortality for patients who do not receive treatment, especially in cases of cerebral malaria.¹³
• Factors associated with poor prognosis/high mortality include metabolic acidosis, hypoglycemia, renal injury, coma, and high-density parasitemia.¹¹
• Children <5 years old have worse outcomes and higher mortality rates compared to adults.³²
• Prompt recognition of symptoms and initiation of antimalarial treatment are associated with improved prognosis and outcomes.¹¹

Pearls and Pitfalls

• Severe malaria can cause multi-organ failure and is a potentially life-threatening disease.
• Light microscopy of blood smear with Giemsa stain is the gold-standard and allows for quantification of parasite burden; RDT is an alternative for quicker diagnosis but can’t quantify parasite burden.
• Prompt diagnosis, appropriate treatment with parenteral antimalarials, and supportive care for complications such as hypoglycemia, hypoxia, anemia, dehydration, and acute kidney injury are essential.
• Vector control, chemoprevention, and vaccination are essential components for disease control.

References

1. World Health Organization (WHO). World Malaria Report 2024 Addressing Inequity in the Global Malaria Response.; 2024. Accessed May 12, 2025. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024
2. World Malaria Report 2023. 1st ed. World Health Organization; 2023.
3. Healer J, Chiu CY, Hansen DS. Mechanisms of naturally acquired immunity to P. falciparum and approaches to identify merozoite antigen targets. Parasitology. 2018;145(7):839-847. doi:10.1017/S0031182017001949
4. Centers for Disease Control and Prevention (CDC). Malaria.; 2024. Accessed May 19, 2025. https://www.cdc.gov/dpdx/malaria/index.html
5. Milner DA. Malaria Pathogenesis. Cold Spring Harb Perspect Med. 2018;8(1):a025569. doi:10.1101/cshperspect.a025569
6. Meibalan E, Marti M. Biology of Malaria Transmission. Cold Spring Harb Perspect Med. 2017;7(3):a025452. doi:10.1101/cshperspect.a025452
7. Kwiatkowski D, Hill AV, Sambou I, et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet Lond Engl. 1990;336(8725):1201-1204. doi:10.1016/0140-6736(90)92827-5
8. Clark IA, Rockett KA. The cytokine theory of human cerebral malaria. Parasitol Today. 1994;10(10):410-412. doi:10.1016/0169-4758(94)90237-2
9. Van Der Heyde HC, Nolan J, Combes V, Gramaglia I, Grau GE. A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol. 2006;22(11):503-508. doi:10.1016/j.pt.2006.09.002
10. Sherman IW, Eda S, Winograd E. Cytoadherence and sequestration in Plasmodium falciparum: defining the ties that bind. Microbes Infect. 2003;5(10):897-909. doi:10.1016/s1286-4579(03)00162-x
11. World Health Organization (WHO). WHO Guidelines for Malaria.; 2023. Accessed June 11, 2023. https://www.who.int/publications/i/item/guidelines-for-malaria
12. Lewallen S, Bronzan RN, Beare NA, Harding SP, Molyneux ME, Taylor TE. Using malarial retinopathy to improve the classification of children with cerebral malaria. Trans R Soc Trop Med Hyg. 2008;102(11):1089-1094. doi:10.1016/j.trstmh.2008.06.014
13. Seydel KB, Kampondeni SD, Valim C, et al. Brain Swelling and Death in Children with Cerebral Malaria. N Engl J Med. 2015;372(12):1126-1137. doi:10.1056/NEJMoa1400116
14. Shoukier H, Dham S, Bergasa NV, Kochar DK, Sirohi P, Abhishek K. Acute Hepatitis in Malaria. Gastroenterol Hepatol. 2006;2(1):35-38.
15. Newton PN, Stepniewska K, Dondorp A, et al. Prognostic indicators in adults hospitalized with falciparum malaria in Western Thailand. Malar J. 2013;12(1):229. doi:10.1186/1475-2875-12-229
16. Centers for Disease Control and Prevention (CDC). Clinical Testing and Diagnosis for Malaria.; 2024. Accessed May 19, 2025. https://www.cdc.gov/malaria/hcp/diagnosis-testing/index.html
17. Mathison BA, Pritt BS. Update on Malaria Diagnostics and Test Utilization. J Clin Microbiol. 2017;55(7):2009-2017. doi:10.1128/JCM.02562-16
18. White NJ. Severe malaria. Malar J. 2022;21(1):284. doi:10.1186/s12936-022-04301-8
19. Centers for Disease Control and Prevention (CDC). Blood Specimens – Detection of Parasite Antigens.; 2016. Accessed May 19, 2025. https://www.cdc.gov/dpdx/diagnosticprocedures/blood/antigendetection.html#:~:text=These%20tests%20generate%20results%20within,and%20therefore%20diagnose%20only%20P
20. Lampah DA, Yeo TW, Malloy M, et al. Severe Malarial Thrombocytopenia: A Risk Factor for Mortality in Papua, Indonesia. J Infect Dis. 2015;211(4):623-634. doi:10.1093/infdis/jiu487
21. Misra UK, Kalita J, Prabhakar S, Chakravarty A, Kochar D, Nair PP. Cerebral malaria and bacterial meningitis. Ann Indian Acad Neurol. 2011;14(Suppl 1):S35-39. doi:10.4103/0972-2327.83101
22. Pugliese CM, Adegbite BR, Edoa JR, et al. Point-of-care ultrasound to assess volume status and pulmonary oedema in malaria patients. Infection. 2022;50(1):65-82. doi:10.1007/s15010-021-01637-2
23. Beltagi AE, Elsotouhy A, Al-warqi A, Aker L, Ahmed M. Imaging features of fulminant cerebral malaria: A case report. Radiol Case Rep. 2023;18(10):3642-3647. doi:10.1016/j.radcr.2023.06.066
24. Centers for Disease Control and Prevention (U.S.). Treatment of Severe Malaria.; 2024. Accessed August 23, 2024. https://www.cdc.gov/malaria/hcp/clinical-guidance/treatment-of-severe-malaria.html
25. The Republic of Uganda Ministry of Health. Uganda Clinical Guidelines 2023: National Guidelines for Management of Common Health Conditions.; 2023. Accessed May 11, 2024. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.health.go.ug/wp-content/uploads/2023/11/UCG-2023-Publication-Final-PDF-Version-1.pdf
26. Ackerman H, Ayestaran A, Olola CHO, et al. The effect of blood transfusion on outcomes among African children admitted to hospital with Plasmodium falciparum malaria: a prospective, multicentre observational study. Lancet Haematol. 2020;7(11):e789-e797. doi:10.1016/S2352-3026(20)30288-X
27. Plewes K, Kingston HWF, Ghose A, et al. Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial. Clin Infect Dis Off Publ Infect Dis Soc Am. 2018;67(7):991-999. doi:10.1093/cid/ciy213
28. Hanson JP, Lam SWK, Mohanty S, et al. Fluid resuscitation of adults with severe falciparum malaria: effects on Acid-base status, renal function, and extravascular lung water. Crit Care Med. 2013;41(4):972-981. doi:10.1097/CCM.0b013e31827466d2
29. Centers for Disease Control and Prevention (CDC). Insecticide-Treated Nets.; 2024. Accessed May 20, 2025. https://www.cdc.gov/malaria/php/public-health-strategy/insecticide-treated-nets.html
30. Centers for Disease Control and Prevention (CDC). Core Drug-Based Malaria Prevention Strategies.; 2024. Accessed May 20, 2025. https://www.cdc.gov/malaria/php/public-health-strategy/drug-strategies.html
31. Asante KP, Mathanga DP, Milligan P, et al. Feasibility, safety, and impact of the RTS,S/AS01E malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi. Lancet Lond Engl. 2024;403(10437):1660-1670. doi:10.1016/S0140-6736(24)00004-7
32. Ranjha R, Singh K, Baharia RK, Mohan M, Anvikar AR, Bharti PK. Age-specific malaria vulnerability and transmission reservoir among children. Glob Pediatr. 2023;6:None. doi:10.1016/j.gpeds.2023.100085