Malaria

Malaria is a protozoan infection of red blood cells, which are lysed by the parasite, resulting in recurrent fever and often severe constitutional symptoms. The following text emphasises:

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Introduction

There are four different types of malaria that affect man, all of the genus Plasmodium: Of these, by far the most important is P. falciparum. This is because this parasite can cause enormous parasite loads as it is able to infect red cells of all ages. P malariae can only infect older cells (a maximum of about 10 000/cubic millimeter) while P vivax and ovale only enter younger cells (25 000/mm3). In excess of 20% of circulating red cells may be falciparum-infested with severe disease. This often results in death due to multiple organ failure. Well over a million people worlwide die every year from falciparum malaria, most of them children (particularly in Africa).

The last two organisms (vivax and ovale) differ in another important way: a single infection can recur again and again, even after seeming cure, due to hypnozoites that lurk within the liver, emerging from time to time to cause another bout of malaria.

In the past clinicians emphasised the cyclical nature of malaria, talking about "quartan" (P malaria) and "tertian" malaria (all the rest). This was further complicated by the use of old fashioned inclusive reckoning, so that "tertian" meant a two day cycle, and "quartan" every 3 days! We don't really worry about this sort of thing any more, as nobody is going to play around for days watching the fever. Malaria, especially falciparum malaria is a serious disease which must be diagnosed NOW, if not sooner!


The life cycle of the parasite.

Of the several stages in the life cycle, two stand out: the sporozoites that transmit the infection from the mosquito's saliva to the human host, and the gametocytes that are taken up by the mosquito when it bites the man. The male and female gametocytes fuse sexually in the mosquito (after forming mature gametes) and this results in a 'zygote' which invades the gut of the mosquito.

Simplified malaria life cycle

tissue schizont merozoites/schizogony gametocytes
 
skin

MAN

skin

MOSQUITO

 
sporozoite oocyst zygote


It is easy to fill in the gaps: On the mosquito side, the zygote eventually produces more sporozoites which migrate to the salivary gland of the mosquito, while on the human side, things are a bit more complex. The main player on this side is the merozoite , which invades red cells. Each merozoite then reproduces inside the red cell, which eventually bursts releasing more merozoites, and so on. Some of the parasites differentiate into gametocytes as above {why?}.

What happens initially when the sporozoite is injected by the mosquito? Easy. It goes to the liver where it reproduces inside liver cells, forming the first batch of merozoites! With P vivax and P ovale, some of the organisms lurk within the liver as hypnozoites, as described above.

(By the way, to enlighten/confuse us, the micro chaps have subdivided things further with fancy names: the intermediate form in the liver is the "tissue schizont", and the merozoite as it matures in the red cell goes through "ring", "trophozoite" and "schizont" stages. In the mosquito another fancy name is the gut stage intermediate between zygote and sporozoites, called the "oocyst").

Host Factors

One of the most puzzling things about malaria is how the parasite resists attack by the immune system. Some hosts after repeated infection appear to develop a degree of tolerance of the parasite, but re-infection still occurs. This ability of the parasite to withstand the immune system is a major factor retarding development of a vaccine against malaria. Partial immunity allows over 60% of people with long exposure to carry the parasite asymptomatically! [ Ind J Med Res Aug 1997 106 95-108pp]. T-cells are essential for immunity [ Ind J Med Res Aug 1997 106 130-48pp], especially the gamma-delta T cell [ Int J Parasitol Feb 1997 27(2) 191-200pp]. The "doctrine of original antigenic sin" may partially explain the inadequate immune response [ Parasitology 1996 112 S39-51pp]!

Surprisingly, a lot of the damage done by malaria, especially P falciparum, seems to be related to damage inflicted by the host on itself, in response to the parasite. This is thought to be related to release of Tumour Necrosis factor (TNF), up-regulation of TNF receptors (type 2), and consequent expression of adhesion molecules (ICAM-1 especially). Infected cells stick to endothelium using a large malarial protein called PfEMP1, which binds CD36 and/or thrombospondin [Annu Rev Med 1994 45 283-95pp].



Clinical Findings

The commonest presentation is with fever and chills. Any person with fever who might have been exposed to malaria should be considered to have malaria until otherwise proved! Incubation period is about 7(+) days, and not usually over 3 weeks.

If falciparum malaria is missed the consequences are devastating including

The pathogenesis of the above is thought to be related to TNF release, and microvascular damage. Acute pulmonary oedema in these patients is a disaster, and we therefore stress that vigorous hydration of these patients must be avoided, this may mean a decreased urine output, increased values of urea and creatinin and may require early continuous venous to venous haemodyalisis {authors' opinion}.

Hypoglycaemia is common in severe falciparum malaria, related to glucose consumption by the parasite, patient inanition and insulin release caused by quinine.

Patients who are severely ill with malaria may also present with predominant abdominal symptoms (abdominal pain, and diarrhoea), and also with jaundice, possibly more commonly in children. [Prasad R & Virk K, P N G Med J 1993 36(4) 337-41pp] Physicians should be aware of the possibility of acute abdominal pain being due to malaria.

As an aside, chronic malaria can manifest in a variety of ways including fever, splenomegaly (which may even be massive), and chronic glomerulonephritis with nephrotic syndrome. Occasionally spontaneous splenic rupture may occur, this being commoner in acute infection! [Clin Infect Dis Feb 1993 16(2) 223-32]
{This section needs upgrading!}


Diagnosis

The most important point in diagnosis is to SUSPECT THE DISEASE. A patient need not have visited a malaria area, (although this is usually the case) as occasionally Anopheles mosquitoes are brought in by e.g. truck or aeroplane and pass on malaria to their unsuspecting victim.

The gold standard for diagnosis is examination of a Giemsa-stained THICK SMEAR. This should pick up parasitaemia of 1-10 per microlitre, as good as any other test. The main problem here is that inexperienced technicians can muck things up, especially as the red cells have been lysed, making identification of the organisms more tricky. (Thin smears may then help). Gametocytes need NOT be present to make the diagnosis of P falciparum malaria.

There are numerous other methods of diagnosis. Several have the advantage of being quicker than our gold standard; others are somewhat more specific (certainly than the thick smear in inexperienced hands). They include:

Note that over 1% P. falciparum parasitaemia is substantial, and over 5% is bad news !
P falciparum may of course occur with other Plasmodia. See [ J Parasitol Aug 1997 83(4) 593-600pp]



How not to get malaria

Important points here are:


Treatment

Management in ICU

Drug Therapy

1. Chloroquine was a major player in the treatment of malaria, and still is in areas where chloroquine resistance doesn't occur. Unfortunately, in most of Africa and the Far East, resistance to this agent is rife and it should not be used for P falciparum in these areas.
Dosage: Recommendations are generally to load with 10mg/kg BASE, followed by 5mg/kg every 12 hr up to a total dose of 25mg/kg (not more). In a 70kg chap this works out to about:

{How does it work? This weak base is concentrated within the acidic food vacuoles of the parasite. Its action is still controversial but it appears to inhibit polymerisation of haem (by the parasite enzyme "heme polymerase"), resulting in the parasite being poisoned by its own waste. Resistance to chloroquine is possibly related to the parasite pumping chloroquine out as fast as it diffuses in!}

2. Quinine and quinidine are still vital agents, in fact more so than ever. There are various regimens for administration. A common (possibly suboptimal) regimen is to load with 6.25mg/kg (BASE, = 10mg/kg quinidine gluconate), and then infuse 0.0125 mg/kg/min (BASE). {does one dose lean body mass?}; In a 70kg adult we have similarly given: Tend to use a slightly smaller dose in kids eg. 25mg/kg/day divided into 3;


3. Tetracycline has been advocated as an adjuvant agent in malaria, especially cerebral malaria {expand on the controversy!}

4. Mefloquine may be useful against chloroquine-resistant P falciparum, but resistance is emerging, especially in e.g. Thailand. Recommended dosage is: {mefloquine and quinine are thought to bind to a red cell protein called stomatin, and then bind to 22 and 36kDa parasite proteins, [Int J Parasitol Feb 1997 27(2) 231-40pp]. For a review of mefloquine see [ Drugs 1993 45(3) 430-75pp], also [Fundam Clin Pharmacol 1994 8(6) 491-502pp] }

5. Halofantrine initially showed promise, but most people are shying away from it because of its cardiotoxicity. It is NOT effective if the parasite is mefloquine-resistant. Halofantrine pharmokinetics are reviewed in [ Clin Pharmacokinet Aug 1994 27(2) 104-19pp]. Bioavailability varies, take it with food. Dosage:
6. Primaquine therapy is IMPORTANT to prevent recurrence of P vivax and P ovale. Before treating one must check the patient for glucose-6-phosphate dehydrogenase deficiency . Only if this is absent, treat with "15mg/day x 14 days" (adult dose).

7. Other possible drugs for malaria (most still investigational) include:

8. Possibly obsolete drugs include: "Stand-by treatment", i.e. empiric self-administration of a drug where prompt medical attention is not available, is controversial. [J Trop Med Hyg Jun 1994 97(3) 151-60].

Antimalarial Safety in Pregnancy is discussed in [ Drug Saf Mar 1996 14(3) 131-45pp].



Disclaimer:
The above text is for educational purposes only. You use it entirely at your own risk. Use none of the above dosages or recommendations without independent corroboration and application of careful clinical judgement. We are not responsible for your clinical errors. (This page is also waaay out of date).