The Control of Malaria

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by Dr. V.J.M. de Silva

Introduction - That the World Health Organisation (WHO) has certified Sri Lanka as a malaria-free nation is indeed a truly remarkable achievement. Sri Lanka has now completed 3 consecutive years without any case of indigenous malaria, an achievement never seen before, and is now eligible for WHO certification as a malaria- free country. Only the Maldives and Singapore have been declared free of the disease in the region; but both countries have less than a quarter of Sri Lanka’s 21 million population.

Some historical facts – The discovery that malaria is spread by mosquitoes is usually regarded as recent. But actually it is not so. Malaria, or disease resembling malaria, has been noted for more than 4,000 years. Deriving its name from the Italian for "bad air" (mal/aria), the disease has probably had a great influence on human populations and human history. As an example, the construction of the Panama Canal could not be completed until malaria (and yellow fever) was controlled, due to the high morbidity and mortality among the workers. The symptoms of malaria were described in ancient Chinese medical writings. The Indian physician Susruta (6th Century BC) mentions types of fevers, and attributes some to insects like mosquitoes. But, as so often happens, these ancient ideas were ignored and forgotten, and they had to be rediscovered many centuries later.

Following their arrival in the New World in the 17th century, Spanish Jesuit missionaries learned from indigenous Indian tribes of the medicinal properties of the bark of a tree they used for the treatment of fevers. With this bark, the Countess of Chinchón, wife of the Viceroy of Peru, was cured of her fever. The bark from the tree was then called Peruvian bark and the tree was named Cinchona after the countess. The medicine from the bark is now known as quinine, which along with artemisinin (isolated from the plant Artemisia annua, sweet wormwood, a herb employed in Chinese traditional medicine) is anti-malarial. Quinine is one of the most effective anti-malarial drugs available today.

Discovery of the parasite – Alphonse Laveran (1845 -1922), a French army surgeon stationed in Constantine, Algeria, was the first to notice the parasites (protozoa, like amoeba), in the red blood corpuscles of a patient suffering from malaria. This occurred on the 6th of November 1880. He showed that in successive blood smears the parasite grew and changed their shape. With each new brood of parasites in the blood, a fresh bout of ‘ague fever’ began. For his discovery, Laveran was awarded the Nobel Prize in 1907.

The parasite has been named as Plasmodia species. There are four main types –the two common types: Plasmodium vivax and P. falciparum causing respectively benign tertian and the more clinically dangerous malignant tertian; one less common type P.malariae, quartan malaria; and there is also a rare one: P.ovale. Another type P. knowlesi has been seen in a long-tailed macaque monkey. The first documented human infection with P. knowlesi was in 1965. The periodicity of the fever is characteristic of each species. In P.falciparum, P. vivax and P. ovalemalaria, a brood of schizonts mature every 48 hr, so the periodicity of fever is tertian ("tertian malaria"), whereas in P malariae disease, fever occurs every 72 hours ("quartan malaria").

Discovery that mosquitoes transmit malaria parasites – The next person to advance our knowledge of malaria was Ronald Ross (1857 -1932), a British army officer in the Indian Medical Service. Whilst he was on leave from India, he met Sir Patrick Manson (1844 -1922), called the "Father of Tropical Medicine". He appraised Ross about his own findings in filariasis, and the cycle in the mosquito. He advised Ross to be on the look-out for something similar in the parasite of malaria. On his return to India, Ross examined various types of mosquitoes under the microscope. He finally found dark spots (cysts) in the walls of the stomach of the female Anopheles mosquito on August 20th, 1897. These cysts were alive and multiplying. He was the first to demonstrate that malaria parasites could be transmitted from infected patients through mosquitoes. In further work with bird malaria, Ross showed that mosquitoes could transmit malaria parasites from bird to bird. This necessitated a sporogonic cycle (the time interval during which the parasite developed in the mosquito) giving rise to sporozoites. These sporozoites then migrate into the salivary glands. When the infected mosquito takes her next blood meal, they are injected into the human. Thus the problem of malaria transmission was solved. For his discovery, Ross was awarded the Nobel Prize in 1902.

The Vectors of human malaria – The ‘carriers’ of malaria are Anopheles mosquitoes, which can be distinguished from others by the stance they adopt in the resting position. They rest with the mouth part and body in one straight line, making an acute angle with the resting surface. Non-Anopheles mosquitoes hold their bodies parallel to the resting surface. Also, the wings of Anopheles have dark scales which form distinct markings on the upper margin of the wing.

The transmission of infection is not merely mechanical; the parasites must grow in the mosquito before infection of another human can take place. The time interval for this varies with the temperature. Below 60 F (16 C), it does not happen. Above this, at about 90 F (32 C) it is 8 to 10 days; longer (about 25 days) at lower end of the scale. Optimal is 70-80 F (21-27 C).

In Sri Lanka, the most important is Anopheles culicifacies. Other documented vectors are An. subpictus and An. tessellatus.

Clinical features – In P. vivax malaria after an incubation period of 8-17 days, there is a classical fever which has three phases:

Cold stage – Chills and rigors lasting 30 minutes to 2 hours, preceded by headache, nausea, vomiting and backache

Hot stage – Fever 39 to 42 C lasting 30 minutes to 4 hours.

Sweating stage – with this, the temperature falls to normal.

After a fever-free period of about 48 hours, fever recurs on the third day.

With P. falciparum malaria, symptoms are more severe.

The Exo-erythrocytic (hepatic) cycle in man - The life cycle in humans, however, remained incompletely understood and nobody knew where the parasites developed during the first 10 days or so after infection, during which they could not be seen in the blood. This question was not resolved until 1947 when Henry Shortt and Cyril Garnham, working in London, showed that a phase of division in the liver preceded the development of parasites in the blood. In 1948 when I was studying Zoology for the University Entrance, we had not heard of this cycle. In 1949, in the 1st MBBS at the Science Faculty, Thurstan Road – (those days one had to sit this before entering the Medical Faculty, Kynsey Road), Dr. Hilary Crusz lectured to us in Biology. I remember him telling us that we were the first in this country to be lectured to on the hepatic (pre-erythrocyte) cycle of the malarial parasite, Plasmodium vivax. He had just come back from England and I believe, had worked with Prof. Shortt.

There remained, however, one further question; what caused the long prepatent period between infection and the appearance and reappearance of parasites in the blood, seen in some temperate strains of P. vivax? This led to the discovery of a dormant exo-erythrocytic stage, hypnozoites, by Wojciech Krotoski, working with Garnham's team, in 1982.

The Life cycle of Plasmodium – To summarize this in brief: there are 2 cycles, one in the mosquito, and the other in the human.

A. Human - The life cycle in humans begins with the introduction of sporozoites into the blood. They enter the liver cells within 30 minutes to start the exo-erythrocytic phase. Sporozoites multiply and differentiate into merozoites. These merozoites flood out into the blood and invade red blood cells where they initiate a second phase of asexual multiplication (erythrocytic schizogony) resulting in the production of about 8-16 merozoites which invade new red blood cells. As the infection progresses, some young merozoites develop into male and female gametocytes that circulate in the peripheral blood until they are taken up by a female anopheline mosquito when it feeds on humans.

In P.vivax and P.ovale, maturation of liver-stage schizonts may be delayed for as long as 1 to 2 years. These quiescent liver-phase parasites are called hypnozoites.

B. Mosquito – Each of the gametocytes in the RBCs ingested by the female Anopheles mosquito develop further within her gut. The female gametocyte into a female macrogamete, and the male gametocyte into 8 sperm-like male microgametes. After fertilization, the diploid zygote differentiates into a motile ookinete that burrows into the gut wall, where it grows into an oocyst within which are many haploid sporozoites. These are released and migrate to the salivary glands. They complete the cycle when the mosquito takes her next blood meal and injects them into the bloodstream of the human.

(To be continued)

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