Malaria

General paediatrics, Infectious disease

Protozoal infection, spread by Anopheles mosquitoes.

A crippling problem in sub-Saharan Africa but also seen in South and South East Asia, Caribbean (Dominican Republic has low risk). The only malaria free zones in the tropics are cities (some) and communities at altitude. Used to be endemic in Europe (even Southern England) and southern states of US.  800 000 deaths per year, mostly young African children.  Hypoendemic areas eg SE Asia do not acquire immunity and whole population is at risk of severe disease.

Resistance continues to be a major problem and a vaccine remains elusive. The prevalence of fake medicines in endemic countries is another major problem.

Malaria has been with human beings for a long time in evolutionary terms, as seen in the numerous genetic mutations that occur for the express benefit of conferring partial immunity eg sickle cell trait, G6PD, hereditary spherocytosis, HLA B53 (confers 40% protection vs severe malaria). At the same time, the parasite has evolved multiple ways of avoiding the immune system, which is why developing a vaccine has proved so difficult.

  • Plasmodium falciparum – causes the most severe disease, predominates in Africa, widespread resistance, but no liver stage
  • Plasmodium vivax/ovale – cause less severe disease, predominates in Asia, resistance rare, liver stage
  • Plasmodium malariae – causes less severe disease, predominates in Asia, resistance rare, but no liver stage
  • Plasmodium knowlesi – rarely severe

The parasite sporozoite form is injected with salivary secretions into the human host. It circulates until it reaches hepatocytes, where it replicates and forms clusters called schizonts. These release trophozoites into the blood stream, where red cells are infected and further replication occurs. Disease only appears once widespread haemolysis has occurred, usually 3 weeks or more after initial infection. A proportion of trophozoites transform into gametocytes. When these are ingested along with human blood by another mosquito, they can then continue the life cycle in the mosquito. In P vivax and ovale, longlasting hypnozoites may persist in the liver, which can be responsible for late reactivation of disease. So suspect for up to a year after exposure (although Falciparum will present within 3 months).

Clinical

Young children, hyposplenic, pregnant at particular risk (even if prev immunity).

Incubation period 10-21 days, but up to 3 months for falciparum, and note liver stage and late reactivation above.

No typical clinical features! Even fever is not a reliable sign!  Can present with GI symptoms, sore throat, lower respiratory complaints!

Clinical effects due to RBC destruction, cytokines release, micro circulation disturbance.

In endemic areas, intermittent asymptomatic low level parasitaemia is seen commonly, with recurrent, usually self-limiting, episodes of mild disease (plus chronic anaemia). Severe disease on the other hand can present as:

  • cerebral malaria
  • severe haemolysis
  • ARDS
  • acidosis

In non-endemic disease, particularly travellers or people who have lost their immunity by long term lack of exposure after emigration, the infection is more likely to be symptomatic, and the disease is more likely to be severe.

Mild disease

Fever, chills, sweats, myalgia, headache.  Anaemia, splenomegaly. Gastro and resp symptoms (even sore throat) common! Fever periodicity traditionally described as daily (falciparum), Tertian (vivax/ovale), Quartan (malariae) ie spikes every 3 or 4 days.  In practice this is wholly unreliable!

Moderate Risk

Parasitaemia >5% (not very well correlated, and not relevant for non-falciparum)

Sickle cell disease (who have worse outcomes, despite being relatively protected!)

High Risk

  • Pregnancy (high levels in placenta, even if not so obvious in blood).  Use clinda instead of doxy.
  • Asplenic or splenic dysfunction
  • Acidosis (BE >-8)
  • Hyperkalaemia (>5.5mmol/L)
  • Hypoglycaemia
  • Impaired conscious level

Respiratory distress usually due to acidosis rather than cardiac failure. Hence Kussmaul breathing predicts death.

Diagnosis

Do not wait for the results of tests if symptoms/signs suggestive, since falciparum can be rapidly aggressive.  Stop chemoprophylaxis, as can obscure!

Malarial retinopathy (Malawi eye) found in severe malaria: patchy white spots similar to hard exudates, frosted branch appearance of vessels, and ring shaped haemorrhages (not pathognomic though, seen in infarction).

The blood smear is the classic test. Thin smears are best for identifying the particular type of malaria and the percentage parasitaemia (percentage of erythrocytes infected), but thick smears are more sensitive. Repeat testing is important – at 12-24hrs and again at another 24hrs. Best at time of fever spike? Sensitivity is only 70% on a single smear, but rises to over 95% with 3 smears.

Having >20% of periph forms with pigment (mature) reflects high burden of deep circulating parasites cf young ring forms, so a risk factor for poor outcome. >5% neutrophils containing ingested pigment is another risk indicator.

New molecular based antigen tests are expensive but are less reliant on operator experience.

  • HRP2 (histidine rich protein) is specific to falciparum.
  • pLDH versions are available for falciparum and vivax.
  • Aldolase is a pan-specific antigen, but probably not as sensitive as the others.

These are pretty much as good as smears for falciparum and vivax, not quite as good for other species.

Thrombocytopenia common, not significant in isolation.  Check FBC, U&Es, LFTs, Glucose.  If ill, lactate, blood gas, blood cultures (accompanying bacterial sepsis common esp salmonella in endemic areas). Consider LP if impaired consciousness, seizures.

Notifiable! Other family members likely to be infected too?

Differential

Typhoid, hepatitis, dengue, VHF, HIV, avian influenza

Treatment

UK Guidelines 2016. Journal of Infection. 72(6), 635-649 (Lalloo, Shingadia).

Treatment of choice for non-falciparum is 3/7 oral Chloroquine or Co-artemether.  Co-artemether if mixed infection or concern about chloroquine resistant vivax (some areas). Must be followed by Primaquine, the only effective treatment for liver stage – beware G6PD deficiency (test at same time as doing films! Use only under expert supervision!)

For falciparum, treatment of choice for uncomplicated is Riamet (co-artemether) – alternative is Eurartesim.  If not available, use oral quinine or atovaquone-proguanil (Malarone).

Admit falciparum initially – risk of deterioration on  treatment, and check tolerating oral therapy.

Quinine is effective but poorly tolerated in prolonged treatment, and should always be supplemented by additional treatment, typically doxycycline in adults, clindamycin or Fansidar (Pyremethamine-sulfadoxine) in children.  All with falciparum should be admitted for at least 24hrs, given risk of sudden deterioration even with treatment.

IV artesunate should be used for severe disease, or infections with >2% parasitaemia, until well enough to tolerate oral treatment.  IV artesunate works quicker and is more effective in selected situations than IV quinine but is unlicensed, obtain through specialist centre on named patient basis. If not immediately available start IV quinine (and monitor for hypoglycaemia).

Adjunctive

  • Broad spectrum antibiotics in severe cases until bacterial infection excluded.
  • Surprisingly, shock usually responds to just 1 bolus of fluid. Excessive fluid resuscitation is likely to precipitate cardiac failure in severe anaemia, may exacerbate anaemia and raised intracranial pressure. Albumin appears to be superior to crystalloid (esp in coma – less mortality, ?membrane stabilizing).
  • Oxygen for respiratory distress
  • Glucose if hypoglycaemia
  • Poor evidence for exchange transfusion – consider for persistent acidosis or multiorgan failure, sickle cell
  • Seizures: follow standard guidelines. Partial, subtle seizures are common. No evidence to support prophylactic phenobarbitone.  Posturing common, assoc with spike in ICP so ventilation with paralysis may be advantageous. Exclude hypoglycaemia.

Follow up

Haemolysis occurs in 10-15% of patients treated with IV artesunate – check FBC at 14 days.

Vaccine?

A vaccine would be fantastic, but a potential candidate is yet to be found. There are several barriers:

  • Antigens of the different life cycle stages differ
  • Need to generate v high immune response
  • Need to overcome escape mechanisms

First phase III results in 2011 in Africa showed that RTS,S vaccine reduced clinical reports of malaria by 51 per cent.  After 3 years, reduces cases by 36%.  60 000 to be recruited across 7 countries.  Works against circumsporozoite protein (CSP) so blocks liver infection, has HBsAg adjuvant.