MALARIA

Paul M. Arguin, MD

 BASICS

DESCRIPTION

•  Acute or chronic infection transmitted to humans by Anopheles spp. mosquitoes

•  Most morbidity and mortality is caused by Plasmodium falciparum. An estimated 214 million cases occur annually, including 438,000 deaths, most of which occur in children <5 years of age in sub-Saharan Africa (1).

•  Nonimmune individuals are most susceptible to rapid progression to severe disease.

•  System(s) affected: cardiovascular, hematologic, renal, respiratory, cerebral, lymphatic, immunologic

EPIDEMIOLOGY

•  Cases imported to the United States: 61% P. falciparum; 14% Plasmodium vivax; 3% Plasmodium malariae; 4% Plasmodium ovale; 2% mixed; 17% unknown

•  Occurs worldwide in tropical latitudes: P. falciparum, P. malariae, P. vivax, and P. ovale. Plasmodium knowlesi in parts of Southeast Asia.

Incidence

•  Most U.S. cases (>99%) are imported.

•  ~1,500 cases and 5 deaths per year in the United States (2)

Prevalence

•  Predominant age: all ages

•  Predominant sex: male = female

ETIOLOGY AND PATHOPHYSIOLOGY

•  Malarial parasites digest red blood cell (RBC) proteins and alter the RBC membrane, causing hemolysis, increased splenic clearance, and anemia.

•  RBC lysis stimulates release of cytokines and tumor necrosis factor-α (TNF-α) causing fever and systemic symptoms.

•  P. falciparum alters RBC viscosity, causing obstruction and end-organ ischemia.

Genetics

Unknown genetic predilection but inherited conditions may affect disease severity and susceptibility (glucose-6-phosphate dehydrogenase deficiency, sickle cell disease or trait, and hereditary elliptocytosis)

RISK FACTORS

•  Travel to or migration from endemic areas (primarily sub-Saharan Africa)

•  Rarely, blood transfusion, mother-to-fetus transmission, and local autochthonous transmission

GENERAL PREVENTION

•  Mosquito avoidance: Use of insect repellent, wear clothing to cover exposed skin, use mosquito nets treated with permethrin, and avoid outdoor activity from dusk to dawn.

•  Malarial chemoprophylaxis when in endemic area

–  Mefloquine: Begin at least 2 weeks before arrival and continue for 4 weeks after leaving area. Adults, 250 mg (1 tablet) weekly; children ≤9 kg, 5 mg/kg; children >9 to 19 kg, 1/4 tablet weekly; children >19 to 30 kg, 1/2 tablet weekly; children >30 to 45 kg, 3/4 tablet weekly; children >45 kg as adult

  Caution: mefloquine-resistant areas

–  Atovaquone/proguanil: Begin 1 to 2 days before arrival and continue for 1 week after leaving area. Adults, 1 adult tablet daily; children 5 to 8 kg, 1/2 pediatric tablet daily; children 9 to 10 kg, 3/4 pediatric tablet daily; children 11 to 20 kg, 1 pediatric tablet daily; children 21 to 30 kg, 2 pediatric tablets daily; children 31 to 40 kg, 3 pediatric tablets daily; children >40 kg, 1 adult tablet daily

–  Doxycycline: Begin 1 to 2 days before arrival and continue for 4 weeks after leaving area. Adults, 100 mg daily; children, 2 mg/kg up to 100 mg daily (not for children <8 years old)

–  Chloroquine: Begin 1 to 2 weeks before arrival and continue for 4 weeks after leaving area. Adults, 500 mg (300-mg base) weekly; children, 8.3 mg/kg (5-mg base/kg) weekly up to 300 mg

  Caution: chloroquine-resistant areas

–  Primaquine: Begin 1 to 2 days before arrival and continue for 1 week after leaving area; adults, 30 mg/day; children, 0.5 mg/kg/day up to adult dose

  For use only in areas predominantly endemic for P. vivax

  Caution: Glucose-6-phosphate dehydrogenase deficiency must be excluded prior to first use.

COMMONLY ASSOCIATED CONDITIONS

Bacterial coinfections sometimes occur.

 DIAGNOSIS

HISTORY

•  Initial symptoms of malaria are nonspecific. Suspect malaria in ill patients returning from endemic area presenting with

–  Fever, malaise, myalgias, chills, headache, nausea, splenomegaly (with chronic infection), hypotension, anemia (with chronic or severe disease), thrombocytopenia, jaundice, vomiting, and/or diarrhea (resembling gastroenteritis)

•  P. falciparum

–  Incubation usually 12 to 14 days, symptoms within 1 month of infection in most individuals (partially immune individuals such as immigrants may become ill up to 1 year after last exposure)

–  Severe disease and complications: vascular collapse, CNS impairment, renal failure, and acute respiratory distress syndrome

•  P. vivax and P. ovale

–  Incubation period 12 to 18 days for primary infection and up to 12 months (and longer) for relapses; generally presents with fevers

–  Dormant parasites may remain in liver and reactivate years after initial infection.

–  Can be severe

•  P. malariae

–  Incubation period ~35 days

–  May become chronic; untreated can persist asymptomatically in human host for years

•  P. knowlesi

–  Incubation period ~12 days

–  Possibly severe

PHYSICAL EXAM

•  Often not specific

•  General: elevated temperature, fatigue, tachycardia, tachypnea, jaundice

•  Neurologic: mental status and motor–sensory exam (cerebral malaria)

•  Cardiopulmonary exam: hemodynamic stability and signs of vascular leak (effusion)

•  Skin exam: pallor, rash

•  Abdominal exam: organomegaly

DIFFERENTIAL DIAGNOSIS

•  Infections (disseminated or localized): abscess, viral, gastroenteritis, typhoid/paratyphoid, other bacteremias, rickettsial disease, mycobacteria

•  Collagen vascular disease (systemic lupus erythematosus [SLE], vasculitides)

•  Neoplasms (lymphoma, leukemia, other blood dyscrasias, other tropical causes of splenomegaly)

•  Severe malaria infection may mimic hepatitis, pneumonia, stroke, or sepsis.

DIAGNOSTIC TESTS & INTERPRETATION

•  Malarial smear thick and thin preparations (3)[A]

–  Microscopy to evaluate for presence of parasite forms, determine species, and quantify the percentage of RBCs that are infected. Relatively easy to perform with proper training

–  Test should be performed on site, immediately, with results quickly available.

•  Rapid antigen capture enzyme: can detect the presence of malaria parasites within minutes. Cannot determine species or quantify parasitemia. Positive and negative results must always be confirmed by microscopy.

•  Other tests: species-specific PCR; species confirmation by PCR is encouraged.

•  General laboratory findings (nonspecific)

–  In uncomplicated infection

  Elevated liver function tests and lactate dehydrogenase

  Thrombocytopenia, anemia, and leukopenia

•  Note: a low to low-normal platelet count or a slightly high bilirubin should alert the clinician to the diagnosis after exposure in an endemic setting.

•  Note: Antimalarial prophylaxis may reduce parasitemia.

Initial Tests (lab, imaging)

•  CBC with differential and platelets

•  Basic chemistry panel including bilirubin

•  Malaria thick and thin blood films (if negative, repeat q12–24h for at least three sets)

•  Imaging necessary only for respiratory disease (chest x-ray) or cerebral malaria (CT scan prior to lumbar puncture)

Follow-Up Tests & Special Considerations

•  Nonimmune individuals with suspected or confirmed P. falciparum should be hospitalized.

•  Clinical specimens from suspected or confirmed malaria cases in the United States can be submitted to the Centers for Disease Control and Prevention (CDC) for diagnostic confirmation, speciation, and drug resistance surveillance free of charge.

Test Interpretation

Interpretation of microscopy: Spread blood on a microscope slide as a thick/thin prep and stain with Giemsa (most commonly). View slide under 100X oil immersion to examine for ring, gametocyte, trophozoite, and schizont forms. The thick film is better for detecting parasites. The thin film is used to determine species and calculating the percentage of RBCs infected. Both should always be performed.

 TREATMENT

MEDICATION

First Line

•  For uncomplicated chloroquine-resistant P. falciparum (most P. falciparum), chloroquine-resistant P. vivax, or when species is unknown, the following regimens are recommended (4)[A]:

–  Atovaquone-proguanil (Malarone): adult tablet: 250 mg atovaquone and 100 mg proguanil. Pediatric tablet: 62.5 mg atovaquone and 25 mg proguanil. Adults: 4 adult tablets once per day for 3 days. Children 5 to 8 kg: 2 pediatric tablets once per day for 3 days; children 9 to 10 kg: 3 pediatric tablets once per day for 3 days; children 11 to 20 kg: 1 adult tablet once per day for 3 days; children 21 to 30 kg: 2 adult tablets once per day for 3 days; children 31 to 40 kg: 3 adult tablets once per day for 3 days; children >40 kg: 4 adult tablets once per day for 3 days

–  Artemether-lumefantrine (Coartem): tablet contains 20 mg artemether and 120 mg lumefantrine. Persons 5 to <15 kg: 1 tablet BID for 3 days; persons 15 to <25 kg: 2 tablets BID for 3 days; persons 25 to <35 kg: 3 tablets BID for 3 days; persons ≥35 kg: 4 tablets BID for 3 days

–  Quinine sulfate plus doxycycline or clindamycin: adults: quinine sulfate 650 mg (salt) TID for 3 days (should be extended to 7 days for infections acquired in Southeast Asia). Doxycycline 100 mg BID for 7 days. Clindamycin 20 mg (base)/kg/day divided TID for 7 days. Children: quinine sulfate 10 mg (salt)/kg TID for 3 days (should be extended to 7 days for infections acquires in Southeast Asia) plus clindamycin dosed as above.

–  Mefloquine: adults: 750 mg followed by 500 mg 8 hours later. Children: 15 mg/kg followed by 10 mg/kg 8 hours later (maximum total dose: 1,250 mg)

•  PO therapy for P. ovale, P. malariae, chloroquine-sensitive P. falciparum (rare), and chloroquine-sensitive P. vivax (New Guinea has highest rates of chloroquine-resistant P. vivax); in addition to the treatment regimens listed above, other options are as follows:

–  Chloroquine: adults: 1 g (600-mg base) followed by 500 mg (300-mg base) at 6, 24, and 48 hours after first dose. Children: 16.6 mg/kg (10-mg base/kg) on day 1 (max 1,000 mg [600-mg base]), then 8.3 mg/kg (5-mg/kg base) at 6, 24, and 48 hours after first dose

–  Primaquine (should be added to the acute treatment regimen for cure of dormant forms of P. vivax and P. ovale): adults: 30-mg base (52.6 mg) daily for 2 weeks. Children: 0.6-mg base/kg/day for 2 weeks

•  Therapy for severe malaria

–  Clinical features defining severe malaria:

  Impaired level of consciousness (LOC)

  Respiratory distress, jaundice

  Repeated convulsions, shock

  Renal failure

–  Laboratory features:

  Parasitemia >5%

  Hypoglycemia

  Acidosis (usually lactic acidosis)

•  Parenteral therapy

–  Quinidine gluconate 10 mg/kg in normal saline over 1 to 2 hours followed by 0.02 mg/kg/min continuous infusion

–  Intensive care monitoring is necessary, especially when initiating quinidine therapy.

•  In severe malaria, contact the CDC for assistance; CDC Malaria Branch: 770-488-7100; http://www.cdc.gov/Malaria/

•  In 2007, the CDC made artesunate available in the United States for severe malaria in special circumstances under an investigational protocol. Contact the CDC for assistance.

ISSUES FOR REFERRAL

Infectious disease or tropical medicine consultation advised. Malaria is a reportable disease (http://www.cdc.gov/malaria/features/new_report_form.html).

ADDITIONAL THERAPIES

None

Pediatric Considerations

•  Children are particularly susceptible to severe disease.

•  All children, even infants, should receive chemoprophylaxis if traveling to an endemic area.

•  Malaria commonly resembles acute gastroenteritis in children.

•  Children with severe disease are particularly prone to hypoglycemia. Use IV fluids with glucose for maintenance and monitor blood glucose frequently.

Pregnancy Considerations

•  Chloroquine is safe in the doses recommended for prevention and treatment of malaria; FDA pregnancy Category C.

•  Mefloquine is safe in the doses recommended for prevention and treatment of malaria; FDA pregnancy Category B.

•  Atovaquone-proguanil (Malarone) has not been studied in pregnant women; it has not been shown to cause birth defects or other problems in animal studies; FDA pregnancy Category C.

•  No primaquine (FDA class undetermined) or tetracyclines (FDA pregnancy Category D) in pregnancy

•  Quinine/quinidine (FDA pregnancy Category C, respectively) should be used during pregnancy because benefit outweighs risk.

COMPLEMENTARY & ALTERNATIVE MEDICINE

None. Deaths have resulted from using unapproved alternatives to recommended medications.

SURGERY/OTHER PROCEDURES

Rarely, splenectomy must be performed in patients with splenic rupture.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

•  Inpatient care for all cases of P. falciparum malaria. Hospitalize patients with signs of severe illness, regardless of species; outpatient care for others

•  Nonimmune patients with P. falciparum may progress from mild symptoms to death within 12 hours.

•  All patients treated on outpatient basis should have follow-up within 24 hours.

•  Maintenance IV fluids with glucose because of risk of hypoglycemia are recommended if unable to tolerate fluids by mouth. Excess fluids may result in iatrogenically induced pulmonary edema.

•  Observe for fluid excess, renal insufficiency (urine output), and hypoglycemia.

•  Discharge criteria: clinical improvement and ability to tolerate oral medications and fluids, with documented decreasing parasitemia levels

 ONGOING CARE

PATIENT EDUCATION

•  Malarial chemoprophylaxis prior to travel

•  Travel information may be obtained at the CDC travel Web site: http://www.cdc.gov/travel

•  http://www.cdc.gov/malaria/new_info/2014/malaria_ebola.htm

PROGNOSIS

Malaria infection (particularly P. falciparum) can carry a high mortality if untreated. If diagnosed early and treated appropriately, the prognosis is excellent.

COMPLICATIONS

•  If not treated early: cerebral malaria, acute renal failure, acute gastroenteritis, respiratory distress syndrome, and massive hemolysis

•  Other complications: seizures, anuria, delirium, coma, dysentery, algid malaria, blackwater fever, hyperpyrexia

•  P. malariae: Nephrotic syndrome may develop in patients with chronic infection.

REFERENCES

1.  World Health Organization. World Malaria Report 2015. Geneva, Switzerland: WHO Press; 2015.

2.  Cullen KA, Mace KE, Arguin PM. Malaria surveillance—United States, 2013. MMWR Surveil Summ. 2016;65(2):1–22.

3.  Centers for Disease Control and Prevention. Guidance for malaria diagnosis in patients suspected of Ebola infection in the United States. http://www.cdc.gov/malaria/new_info/2014/malaria_ebola.htm. Accessed January 15, 2015.

4.  Griffith KS, Lewis LS, Mali S, et al. Treatment of malaria in the United States: a systematic review. JAMA. 2007;297(20):2264–2277.

ADDITIONAL READING

Centers for Disease Control and Prevention: http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/malaria

 CODES

ICD10

•  B54 Unspecified malaria

•  B50.9 Plasmodium falciparum malaria, unspecified

•  B51.9 Plasmodium vivax malaria without complication

CLINICAL PEARLS

•  Consider malaria in travelers returning from endemic areas who present with fever or nonspecific flulike illness.

•  Early identification (sometimes requiring a high index of suspicion) and aggressive treatment, particularly of nonimmune persons with suspected or confirmed P. falciparum malaria, is essential.

•  Patients who develop clinical malaria despite chemoprophylaxis should be treated with a medication different than their chemoprophylaxis agent.

•  P. falciparum malaria can be rapidly fatal and should be cared for in the inpatient setting.