Malaria

Introduction

• Malaria endemic and sporadic throughout most tropical and subtropical areas below 1500m (except Mediterranean littoral, USA and Australia)
• Five species:
  • Plasmodium vivax/ovale/falciparum/knowlesi/malariae
• In endemic areas, large numbers of the population have malaria infection (asymptomatic parasitaemia) with often mild malarial disease
  • Absolute burden on morbidity/mortality still remains high as infection is almost universal
  • Very few adults in such areas develop severe disease
• P. falciparum in non-immune individuals is a medical emergency as without treatment is likely to be life-threatening
• Once P. falciparum disease has reached severe stage, 5-30% risk of death even if optimal treatment is initiated

Epidemiology

• P. vivax more common in India
• P. falciparum most common in Africa, Haiti and New Guinea
• P. knowlesi most common in Sth East Asia
• P. knowlesi is a zoonosis with Macaques acting as natural host
  • Anopheles leucosphyrus equally bite humans and monkeys
  • Forest fringe habitat of A. leucosphyrus limits spread
• Resistance to antimalarials is increasing, especially in Sth East Asia
• Artemesinin-resistance is on the rise however cure rates have not dropped as yet

Pathophysiology

• Plasmodial sporozoites injected via Anopheles mosquito during blood meal and transported to liver
• Infect hepatic  parenchymal cells within hours and asexual reproduction begins (exoerythrocyte stage)
• Thousands of daughter merozoites form in hepatocyte, then cell ruptures, releasing merozoites into circulation, where they rapidly invade erythrocytes to begin the erythrocytic stage of asexual cycle
• In P. vivax/ovale, a portion of intrahepatic forms released while man lay dormant as hypnozoites which can reactive later
• Once merozoites enter erythrocyte stage, they do not reinvade hepatocytes
• Merozoites mature in erythrocytes, divide into multiple daughter merozoites and forms a schizont
• Infected erythrocyte eventually lyses, releasing merozoites, which infect other erythrocytes
• A portion of merozoites form gametes, which are ingested by mosquitoes during blood meal and undergo sexual reproduction in mosquito gut and migrate as infective sporozoites to salivary glands of female mosquito
• Malaria transmission cannot occur below 15 degrees, as mosquito-portion of lifecycle cannot be completed before mosquito death

Pathophysiology

• Clinical signs
  • First appear during erythrocytic stage
  • Rupture of schizont-containing erythrocytes triggers cytokine release and fever
  • Over time, schizont rupture becomes synchronous, giving rise to periodic fever
    • Fever slows rate of schizont formation, allowing early-stage parasites to catch up with more mature ones
  • Anaemia can develop rapidly in P. falciparum due to high percentage of infected erythrocytes (as can infect erythrocytes of any age = reticulocyte preferenced) + lifespan of uninfected erythrocytes is reduced and bone marrow function is impaired
  • P. falciparum infected erythrocytes secrete red cell surface proteins that can adhere to endothelial cells resulting in sequestration in tissues leading to metabolic deprivation, avoidance of spleen and impaired tissue perfusion
    • Results in acidosis
  • Hypoglycaemia results from enhanced consumption of glucose by actively metabolising parasites, impaired hepatic gluconeogenesis and diversion of glucose to host for anaerobic metabolism
  • Sequestration explains paucity of peripheral mature parasites in P. falciparum

Pathophysiology

Clinical features

• Uncomplicated malaria
  • Fever with prodromal malaise, myalgia, headache and chills
  • Some patients suffer chest pain, cough, abdo pain, arthralgias
  • Easily confused as viral infection or sepsis
  • If non-immune, get paroxysms of malaria = chills and fever followed by diaphoresis and weakness
  • Over time will occur cyclically which corresponds to length of asexual erythrocyte cycles
  • Classic paroxysms often absent in P. falciparum
  • Splenomegaly and abdominal tenderness are common
  • Clinical signs that point to alternative diagnosis include lymphadenopathy and maculopapular or petechial skin rash

Clinical features

• Severe malaria
  • If one or more of:
    • Coma with/without seizures (Cerebral malaria)
    • Prostration
    • Severe anaemia
    • Acidosis
    • Hypoglycaemia
    • Acute renal failure
    • ARDS
    • Pulmonary oedema
    • Jaundice
    • Intravascular haemolysis
    • Shock
    • DIC
    • Parasitaemia >5%

Clinical features

• If cerebral malaria is suspected, need to rule out meningitis/encephalitis but LP may not be safe
• At LP, opening pressure raised but CSF normal on routine tests
• In a child from endemic region, high parasitaemia and malarial retinopathy greatly favour acute infection in child with coma
• 1/5 children and 1/20 adults suffer neurological sequelae following cerebral malaria (if survive)
• Risk factors for severe disease include very young, very old, pregnant, immunosuppression, asplenia, failure to take chemoprophylaxis, refusal or delay in medical care and late diagnosis

Diagnosis

• Clues to P. falciparum
  • Small ring forms with double chromatin dots within erythrocytes
  • Multiple infected rings in individual red blood cells
  • Paucity or absence of mature trophozoites and schizonts on smear
  • Infected erythrocytes not enlarged with no basophilic stippling
  • Gametocytes (if seen) are banana-shaped
  • Parasite densities >4% are rare in other forms of malaria
• P. knowlesi
  • Usually misdiagnosed as P. malariae as appear identical on microscopy and requires PCR for identification
  • If high parasite burden and Sth East Asia exposure = P. knowlesi

Diagnosis

• Thick-blood film
  • Contains several layers of red cells (lysed by staining procedure) allowing very low parasitaemias to be detected (highly sensitive)
• Thin blood film
  • Single sheet of red cells (remain intact) thus allowing both parasite and red cell morphology to be examined
  • Enables more accurate diagnosis of species
  • Not as sensitive if very low parasitaemia count but useful if very high parasitaemia to get true count + species diagnosis
• If highly suspicious, negative smears should not be taken as 100% sensitive (esp. in early P. falciparum) and treat accordingly
  • Sequestration can lead to false negative
• First smear positive in >90%
• If negative but highly suspicious thick film, obtain repeat thick films twice daily until better or diagnosis no longer suspected
  • If negative for 2-3 days, this confirms negative for malaria
• May be falsely negative if recently taken antimalarials (including antibiotics used for other purposes e.g. Bactrim, doxycycline)

Diagnosis

• Additional
  • Rapid tests have excellent sensitivity for high parasitaemias but are poorly sensitive for non-falciparum lower parasitaemia infections
• Additional lab tests
  • Normochromic normocytic anaemia
  • Raised LDH, reduced serum haptoglobin, raised unconjugated bilirubin, normal or low WCC, thrombocytopaenia (almost universal), raised ESR
  • Severe – Hypoglycaemia, raised lactate, severe anaemia, electrolyte disturbances, AKI and DIC

Treatment

• Uncomplicated malaria
  • If P. falciparum or P. knowlesi start treatment in hospital due to risk of deterioration
  • Assume chloroquine resistance
  • Artemether + Lumafantrine PO or Atovaquone + Proguanil
  • If P. vivax/ovale need to add primaquine (once G6PD ruled out) to eliminate hypnozoites
  • If P. falciparum and in northern Australia (where female Anopheles reside) give single dose Primaquine (once G6PD ruled out) to prevent transmission

Treatment

• Severe malaria
  • Urgent treatment indicated if:
    • ALOC, jaundice, oliguria, respiratory distress, severe anaemia, hypoglycaemia, parasite count > 100 000/mm3 (or >2%), vomiting, clinical acidosis or AKI
  • IV artesunate 2.4mg/kg BD
  • Switch to oral therapy when able

Prophylaxis

• Depends on resistance patterns in region of travel and should be individualised by travel health specialists if complex itinerary, >8 weeks travel, children, pregnant, immunosuppressed or high-risk areas
• Vector avoidance
  • Insect repellent and other insecticide product use
  • Light-coloured long sleeve clothes in evening
  • Screens and pyrethroid coating
  • Avoid outside activities at dawn and dusk
  • Avoid perfume and aftershave

Prophylaxis

• Chemoprophylaxis
  • Advise pregnant women and asplenic patients not to travel to malaria endemic regions (especially if resistance)
  • Do not use mefloquine for Greater Mekong due to resistance
  • Atovaquone-Proguanil 1 tab daily starting 1-2 days before and continuing for 7 days after leaving
  • Doxycycline 100mg daily starting 1-2 days prior and continuing for 4 weeks after
  • Mefloquine orally once weekly starting 2-3 weeks before and continuing until 4 weeks afterwards
  • Difficult in children as doxycycline not recommended if <12 yo and others not licensed (but often used)
  • If inadequately taken, may present in delayed fashion

Parasite density

• >4% is seen only in P. falciparum really
• The higher the parasitaemia, the more likely to be severe
• Should be monitored during treatment

Last Updated on October 2, 2020 by Andrew Crofton