Malaria

Malaria

Malaria is a parasitic infection endemic in many developing countries and seen in travellers returning to developed nations from these areas

Epidemiology:

one of the most prevalent human infections worldwide with over 40% of the world's population living in endemic areas

- estimated 300-500 million cases and 1.5-2.7 million deaths per year (90% in sub-Saharan Africa; esp children < 5 yrs of age); affects 5% of world's population at any time

- in North America it is an "imported" disease seen in travellers returning from endemic areas

- over 400 cases seen each year in Canada, including a few deaths

- rarely locally acquired due to transfusions, congenital infection, or local mosquitos acquiring infection from migrants / visitors or infected mosquito transported on flight

Biology:

Plasmodia sp. are the parasites responsbile for malaria

- only 4 of the many species are infectious to humans

- most virulent, causing most of deaths is P. falciparum (incl. cerebral malaria)

- others are P. vivax, P. ovale, P. malariae which cause less severe disease

Parasite transmitted by the night-biting female Anopheles mosquitoes

- higher risk in times of high humidity with abundant rainfall (more breeding)

- parasite develops in the liver but damage due to erythrocytic cycle

- infects erythrocytes which then adhere to host endothelium

- this leads to microvascular occlusion and number of complications

- can also cause intravascular hemolysis and parasite can consume glucose

- cytokine release can trigger ARDS

- schizonts (meronts) rupture the erythrocyte after full development cycle

Presentation:

Symptoms usually start weeks to months after infection (ie. after returning from travel)

- P. vivax may have delayed manifestation of infection by several months

- delayed onset also if semi-immune (eg. immigrants from endemic areas) or those on chemoprophylaxis

Any traveller to endemic area who has a fever should seek immediate attention

- misdiagnosis and delay in treatment can lead to severe complications

Classic tertian (every 48 hours) or quartan (every 72 hours) pattern of spiking fevers with rigors

- but more commony hectic fever without this pattern

+/- malaise, headache, myalgias, cough, GI symptoms

Examination will reveal fever and splenomegaly

+/- hepatomegaly, jaundice, abdominal tenderness

- should NOT see rash or lymphadenopathy

Severe manifestations (MULTISYSTEM):

- parasitemia along with 1 of:

1. Prostration (inability to sit up without help)

2. Impaired consciousness (see below - cerebral malaria)

3. Respiratory distress / pulmonary edema

4. Seizures

5. Circulatory collapse

6. Abnormal bleeding

7. Jaundice

8. Hemoglobinuria or anemia (Hb < 50 g/L, Hct < 15%%)

Greater risk of severe infections in non-immune people, children, and pregnant women

Cerebral Malaria:

- most common non-traumatic encephalopathy in the world

- defined by disturbances in LOC complicating a (falciparum) malarial infection once confounding causes reversed / ruled-out (hypoglycemia, meningitis, hyponatremai, uremia and waiting six hours after seizure to r/o post-ictal state)

- usually present when deeply unresponsive (inability to localize to painful stimuli)

Pathology / Pathophysiology:

- engorgement of cerebral capillaries and venules with parasitized RBCs and normal RBCs

- brain swollen with petechial hemorrhages and evidence of disrupted blood-brain barrier

- due to sequestration of RBCs with mature parasitic forms (trophozoites and meronts) in microvasculature where hypoxic venules provide optimal growth environment

- since severe complications due to sequestered RBCs, peripheral blood parasite count is poor predictor of severity (with cerebral parasitemia being usually 40x greater than peripherally, with range of up to 1500 times)

- cytoadherence results from interaction between infected RBCs and endothelium

- this reduces microvascular blood flow and metabolically active parasites compete for substrates including glucose; produce toxins that interfere with host metabolism

- RBCs also less deformable as parasite develops within, contributing to greater risk of RBC destruction, impairing microvascular flow

- pro-inflammatory cytokine release (eg TNF-alpha) with inhibition of anti-inflammatory cytokines (eg IL-10) in comatose patients

Clinical Features:

- diffuse encephalopathy where focal deficits unusual

- associated with fever and coma (incl. divergent gaze, variable tone)

- often no true meningismus (mild resistance to neck flexion may exist)

- no rash or lymphadenopathy as in meningitis

- usually associated with multisystem dysfunction incl. acidosis (with Kussmaul's breathing), anemia and jaundice

- tachycardia with low/normal BP (shock usually only in terminal stages)

- hypoglycemia common esp in kids (20%)

- retinal hemorrhages in 15% (may be flame-shaped or resemble Roth spot's) but papilledema is uncommon

- pupils usually reactive with full extra-ocular movements

- bruxism common

- plantars often upgoing, abdominal reflexes absent

- seizures in 10-50% (may be subtle in children) although status epilepticus uncommon (repetitive seizures common, may be complex and focal)

- CSF opening pressure usually raised and may see brain swelling on CT / MRI

- herniation and severe intracranial hypertension more common in children (due to increased cerebral blood volume from sequestration and reduced venous outflow)

Investigations:

Labs:

1. Hematology:

- Thrombocytopenia (75%)

- Anemia (25%): most common presentation of severe disease in infants < 2 years

- WBC usually normal or low (< 5% leukocytosis, poor prognosis)

2. Liver Enzymes:

- common abnormal with elevated transaminase in 25%, hyperbilirubinemia (1/3), elevated LDH in 80% (clue to hemolysis)

3. Hyponatremia

4. Renal failure

- ARF more common in adults with severe malaria

5. Hypoglycemia

- suggest greater level of parasitemia, rare at presentation

6. Metabolic acidosis (elevated lactate)

Blood Smears:

- thick and thin blood smears stained with Giemsa stain is "gold standard"

- allows species identification and quantification (% of erythrocytes infected, or parasites per microliter)

- do not exclude malaria as diagnosis unless 3 negative blood smears within 48 hours

- ensure trained laboratory used

Rapid diagnostic tests such as rapid antigen detection (using finger-prick samples) may be used if available, but currently only pick up falciparum and vivax subtypes

- unable to quantify parasitemia and low sensitivity if low-level parasitemia

PCR sensitive (> 90%) and specific (almost 100%) test even for low level parasitemia

- but slower turnaround time than preferred for real-time diagnosis

Therapy:

Treatment depends on which species infected, area of acquisition (likelihood of drug resistance) and severity of infection

- falciparum malaria in non-immune person is the most severe and requires rapid Rx

- if species not identified then assume drug-resistant falciparum malaria till proven otherwise

If uncomplicated falciparum then oral therapy acceptable

- chloroquine if acquired in Latin America, Argentina, Saudi Arabia (dose is 600 mg, then 600 mg 24hr later, and 300 mg 48 hr later)

- if acquired in chloroquine-resistant area then mefloquine alone (but poorly tolerated) or atovaquone + proguanil OR quinine-doxycycline

For vivax and ovale infection (outside of New Guinea) as well as P. malariae

- chloroquine then primaquine 30 mg/d x 14 d (prevents relapse and eradicate organism)

Caution: avoid doxycycline, primaquine, mefloquine or atovaquone-proguanil in pregnant women and doxycycline during breasfeeding

If severe falciparum malaria or unable to tolerate oral regimen:

- parenteral therapy with quinine unless chloroquine-sensitive area (then chloroquine 10 mg/kg IV over 8 hrs then 15 mg/kg IV over 24 hrs)

(quinine IV requires cardiac monitoring of QT interval; given 5.8 mg/kg loading dose, 7 mg/kg of salt IV by infusion pump over 30 mins then 10 mg/kg salt in 10 mL isotonic fluid/kg by infusion over 4 hrs, repeated q 8hrs up to 72 hrs or until swallowing, then quinine tablets x 7d)

- quinidine given 20 mg salt/kg infused over 4 hours then 10 mg/kg infused over 4 hours every 8-12 hrs

- substitute oral therapy when patient able to swallow and may add course of oral sulfadoxine/pyrimethamine or tetracycline / doxycycline for 7 days (clindamycin if pregnant)

alternatively artesunate or artemether (artemisinin derivates) IV 3.2 mg/kg (former) or IM 3.2 mg/kg then 1.6 mg/kg repeated q12-24 hrs

Exchange transfusion may have role in severe disease with parasitemia > 30% or > 10% with cerebral complications

Avoid steroids and anticoagulants

- may consider mannitol for raised ICP (as a temporizing measure)

- treat pyrexia, seizures, hypoglycemia and anemia, correcting metabolic derangements

- careful fluid balance and ICU nursing care

- may require blood transfusions

- follow blood glucose frequently and treat hypoglycemia

- intubate and ventilate if necessary and avoid hypoxia / hypercapnia which can lead to severe rises in ICP

- hemofiltration for renal failure

Repeat blood films at 2,7, and 28 days after therapy to test of cure, and if symptoms recur

Prognosis:

Mortality of severe cases is 20% or greater

- depends on degree of multi-organ dysfunction

- only 8% if "pure" cerebral malaria without other organ dysfunction while 50% if also renal failure and metabolic acidosis

- also accentuated by lack of intensive care facilities

- provision of artificial ventilation and/or hemofiltration for renal failure reduces mortality

- may die from respiratory arrest, shock, hypoxia / pulmonary edema, aspiration pneumonia

- usually die within 48 hours of admission

- full recovery takes 2-7 days (for normal LOC) from start of treatment

Neurological Sequelae:

- higher risk if protracted seizures, prolonged and deep coma, hypoglycemia, anemia

- may see slow improvement in hemiparesis or cortical blindness (+/- residual deficits)

- in severe cases, vegetative state or spastic tetraparesis (usually when refractory elevations in ICP)

- in survivors may see subtle cognitive, language or behavioural problems

- uncertain elevated risk of epilepsy after cerebral malaria

Prevention:

1. Chemoprophylaxis in travelers to endemic areas:

- mefloquine is preferred even in 2nd-3rd trimesters (250 mg po once weekly), can use chloroquine in sensitive areas (300 mg orally once weekly)

- doxycycline if mefloquine-resistance as well (100 mg/d orally)

- alternative is atovaquone-proguanil 1 tab daily

NB: start 1 week before (for weekly regimens) or 1 day prior for daily dosing drugs, and continue through trip and 1-4 weeks after returning

2. Exposure avoidance:

- avoid outdoor activity after dusk, wear long-sleeved clothing / DEET spray, and bed netting

References:

Newton et al. Cerebral malaria. J Neurol Neurosurg Psychiatry 2000; 69: 433-41.

Suh KN, et al. Malaria. CMAJ 2004; 170: 1693-1702.

Last update: August 2004

Reviewed by: pending

Neurological Medicine Pocketbook

http://www.uwo.ca/cns/resident

Disclaimer