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  1. 1. Haemoparasite-Malaria A Detailed Study
  2. 2. Introduction 1 <ul><li>Malaria is a major public health problem in warm climates especially in developing countries. </li></ul><ul><li>It is a leading cause of disease and death among children under five years, pregnant women and non-immune travellers/immigrants. </li></ul>Malaria Children under 5 are the major at risk group in malarious regions. Inset: An Anopheles mosquito taking a blood meal
  3. 3. What is malaria ? Malaria is a disease caused by the protozoan parasites of the genus Plasmodium. The 4 species that commonly infect man are: Species Major features P. falciparum <ul><li>The most important species as it is responsible for 50% of all malaria cases worldwide and nearly all morbidity and mortality from severe malaria </li></ul><ul><li>Found in the tropics & sub-tropics </li></ul>P. vivax <ul><li>The malaria parasite with the widest geographical distribution </li></ul><ul><li>Seen in tropical and sub-tropical areas but rare in Africa </li></ul><ul><li>Estimated to cause 43% of all malaria cases in the world </li></ul>P. ovale <ul><li>This species is relatively rarely encountered </li></ul><ul><li>Primarily seen in tropical Africa, especially, the west coast, but has been reported in South America and Asia </li></ul>P. malariae <ul><li>Responsible for only 7% of malaria cases </li></ul><ul><li>Occurs mainly in sub-tropical climates </li></ul>
  4. 4. <ul><li>The “direct” burden of malaria </li></ul><ul><li>– morbidity and mortality </li></ul><ul><li>Every year, there are about 500 million clinical attacks of malaria. Of these, 2-3 million are severe and about 1 million people die (about 3000 deaths every day). </li></ul><ul><li>Malaria in pregnancy accounts for about 25% of cases of severe maternal anaemia and 10-20% of low birthweight. Low birthweight due to malaria accounts for about 5-10% of neonatal and infants deaths. </li></ul><ul><li>The “indirect” burden of malaria </li></ul><ul><li>Human development: Impaired intellectual development, developmental abnormalities (especially following cerebral malaria), lost school attendance and productivity at work </li></ul><ul><li>Economics: Malaria retards economic development in the developing world. The cost of a single bout of malaria is equivalent to over 10 working days in Africa. The cost of treatment is between $US0.08 and $US5.30, depending on the type of drugs prescribed as required by the local pattern of drug resistance. </li></ul>The burden of malaria
  5. 5. Geographical Distribution of Malaria Malaria is transmitted by the female anopheles mosquito. Factors which affect mosquito ecology, such as temperature and rainfall, are key determinants of malaria transmission. Mosquitoes breed in hot, humid areas and below altitudes of 2000 meters. Development of the malaria parasite occurs optimally between 25-30 o C and stops below 16 o C. Indigenous malaria has been recorded as far as 64 o N and 32 o S. Malaria has actually increased in sub-Saharan Africa in recent years. The major factor has been the spread of drug-resistant parasites. Other important factors include the persistence of poverty, HIV/AIDS, mosquito resistance to insecticides, weak health services, conflict and population migration. Although previously widespread, today malaria is confined mainly to Africa, Asia and Latin America. About 40% of the world’s population is at risk of malaria. It is endemic in 91 countries, with small pockets of transmission occurring in a further 8 countries.
  6. 6. Endemicity <ul><li>Endemicity refers to the amount or severity of malaria in an area or community. Malaria is said to be endemic when there is a constant incidence of cases over a period of many successive years. </li></ul><ul><li>Endemic malaria may be present in various degrees. Recognised categories of endemicity include : </li></ul><ul><li>A. Hypoendemicity - little transmission and the disease has little effect on the population. </li></ul><ul><li>B. Mesoendemicity - varying intensity of transmission; typically found in the small, rural communities of the sub-tropics. </li></ul><ul><li>C. Hyperendemicity - intense but seasonal transmission; immunity is insufficient to prevent the effects of malaria on all age groups. </li></ul><ul><li>D. Holoendemicity - intense transmission occurs throughout the year. As people are continuously exposed to malaria parasites, they gradually develop immunity to the disease. In these areas, severe malaria is mainly a disease of children from the first few months of life to age 5 years. Pregnant women are also highly susceptible because the natural immune defence mechanisms are impaired during pregnancy. </li></ul>
  7. 7. How is malaria transmitted? <ul><li>Malaria parasites are transmitted from one person to another by the bite of a female anopheles mosquito. </li></ul><ul><li>The female mosquito bites during dusk and dawn and needs a blood meal to feed her eggs. </li></ul><ul><li>Male mosquitoes do not transmit malaria as they feed on plant juices and not blood. </li></ul><ul><li>There are about 380 species of anopheles mosquito but only about 60 are able to transmit malaria. </li></ul><ul><li>Like all mosquitoes, anopheles breed in water - hence accumulation of water favours the spread of the disease. </li></ul>Female Anopheles mosquito taking a blood mea
  8. 8. How does infection develop ? <ul><li>Plasmodium infects the human and insect host alternatively and several phases of the parasite life cycle are described. </li></ul><ul><li>During feeding, saliva from the mosquito is injected into the human blood stream. If the mosquito is carrying malaria, the saliva contains primitive stages of malaria parasites called sporozoites. </li></ul><ul><li>Hepatic, tissue or pre-erythrocytic phase : Sporozoites invade and develop in liver cells. The infected hepatocyte ruptures to release merozoites. </li></ul><ul><li>Erythrocytic phase : Merozoites then invade red blood cells. The red cells lyse and this causes bouts of fever and the other symptoms of the disease. This cycle repeats as merozoites invade other red cells. </li></ul><ul><li>Sexual phase : Sexual forms of the parasites develop and are ingested when another female anopheles mosquito feeds. These develop into sporozoites in the gut of the insect host and travel to its salivary glands. Then the cycle starts again… </li></ul><ul><li>The life cycle of the malaria parasite is shown on the next slide </li></ul>
  9. 9. The Malaria Parasite Life Cycle Click on the diagram to explore different areas of the life cycle
  10. 10. The Malaria Parasite Life Cycle 1. Transmission Female anopheles mosquito bites and releases sporozoites into the blood stream. These circulate for about 30 mins and then invade the liver.
  11. 11. The Malaria Parasite Life Cycle 2. Pre-erythrocytic phase Also called the “tissue” or “hepatic” phase Takes place in hepatocytes. The sporozoites mature into schizonts which rupture to release merozoites. Duration of this phase depends on the species. In P. vivax and P. ovale , the schizont may also differentiate into hypnozoites. These are dormant forms of the parasite which may remain in the liver for several months or years and cause relapse in the human host.
  12. 12. The Malaria Parasite Life Cycle 3a. Asexual phase (Erythrocytic schizogony) Merozoites invade red blood cells. Here they grow and mature into trophozoites which appear as ring forms. The trophozoites develop into schizonts. The infected red blood cells then rupture to release numerous merozoites from the schizont to infect other red cells. Merozoite release results in fever, chills, rigours and other symptoms of malaria infection.
  13. 13. The Malaria Parasite Life Cycle 3b. Sexual phase Some merozoites differentiate into male and female gametocytes, the forms of Plasmodia infective to mosquitoes. These are taken up by a mosquito during another blood meal. These fuse to form an ookinette in the gut lumen of the mosquito. The ookinette invades the stomach wall to form the oocyst. This in turn develops and releases sporozoites which migrate to the salivary gland of the mosquito. This mosquito then goes on to infect another human host.
  14. 14. Severity of disease and host factors <ul><li>In addition to parasite factors, several host factors determine the outcome of exposure to malaria: </li></ul><ul><li>Naturally-acquired immunity. People who are constantly exposed to malaria gradually acquire immunity, firstly against clinical disease and later against parasite infection. Clinical manifestations of malaria are most severe in the non-immune. In holoendemic areas, these are children aged <5 years and pregnant women (especially primagravidae). People of any age from areas that are free from malaria, or have limited malaria transmission, are at risk when they are exposed to malaria. </li></ul><ul><li>Red cell and haemoglobin variants. Well known examples of inherited factors that protect against malaria are Haemoglobin S carrier state, the thalassaemias and Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Malaria provides the best known example whereby an environmental factor (malaria) has selected human genes because of their survival advantage. </li></ul><ul><li>Foetal haemoglobin (HbF): High levels of HbF occur in neonates, and in some people with inherited haemoglobin variants, protect against severe forms of P. falciparum malaria. </li></ul><ul><li>Duffy blood group: P. vivax requires the Duffy blood receptor to enter red blood cells. Therefore, people who do not carry the Duffy blood group are resistant to this malaria species. This explains the rarity of P. vivax in Africa, as most Africans are Duffy blood group negative. </li></ul>
  15. 15. The clinical course of P. falciparum <ul><li>Following a bite by an infected mosquito, many people do not develop any signs of infection. If infection does progress, the outcome is one of three depending on the host and parasite factors enumerated in the previous slides: </li></ul><ul><li>Asymptomatic parasitaemia (“clinical immunity”) </li></ul><ul><li>Acute, uncomplicated malaria </li></ul><ul><li>Severe malaria </li></ul>
  16. 16. This is usually seen in older children and adults who have acquired natural immunity to clinical disease as a consequence of living in areas with high malaria endemicity. There are malaria parasites in the peripheral blood but no symptoms. These individuals may be important reservoirs for disease transmission. Some individuals may even develop anti-parasite immunity so that they do not develop parasitaemia following infection. A. Asymptomatic parasitaemia
  17. 17. B. Simple, uncomplicated malaria Children with malaria waiting to be seen at a malaria clinic in the south western part of Nigeria. Identifying children with severe malaria, and giving them prompt treatment, is a major challenge when large numbers attend clinics. This can occur at any age but it is more likely to be seen in individuals with some degree of immunity to malaria. The affected person, though ill, does not manifest life-threatening disease. Fever is the most constant symptom of malaria. It may occur in paroxysms when lysis of red cells releases merozoites resulting in fever, chills and rigors (uncontrollable shivering).
  18. 18. The periodicity of malaria fever <ul><li>Erythrocytic schizogony is the time taken for trophozoites to mature into merozoites before release when the cell ruptures. </li></ul><ul><li>It is shortest in P. falciparum (36 hours), intermediate in P. vivax and P. ovale (48 hours) and longest in P. malariae (76 hours). </li></ul><ul><li>Typical paroxysms thus occur every </li></ul><ul><li>2 nd day or more frequently in P. falciparum (“sub-tertian” malaria) </li></ul><ul><li>3 rd day in P. vivax and P. ovale (“tertian” malaria) </li></ul><ul><li>4 th day in P. malariae infections, (“quartan” malaria) </li></ul>Note how the frequency of spikes of fever differ according to the Plasmodium species. In practice, spikes of fever in P. falciparum , occur irregularly - probably because of the presence of parasites at various stages of development.
  19. 19. Other features of simple, uncomplicated malaria include: <ul><li>Vomiting </li></ul><ul><li>Diarrhoea – more commonly seen in young children and, when vomiting also occurs, may be misdiagnosed as viral gastroenteritis </li></ul><ul><li>Convulsions – commonly seen in young children. Malaria is the leading cause of convulsions with fever in African children. </li></ul><ul><li>Pallor – resulting mainly from the lysis of red blood cells. Malaria also reduces the synthesis of red blood cells in the bone marrow. </li></ul><ul><li>Jaundice – mainly due to haemolysis. </li></ul><ul><li>Malaria is a multisystem disease. Other common clinical features are: </li></ul><ul><li>Anorexia </li></ul><ul><li>Cough </li></ul><ul><li>Headache </li></ul><ul><li>Malaise </li></ul><ul><li>Muscle aches </li></ul><ul><li>Splenomegaly </li></ul><ul><li>Tender hepatomegaly </li></ul><ul><li>These clinical features occur in “mild” malaria. However, the infection requires urgent diagnosis and management to prevent progression to severe disease. </li></ul>
  20. 20. C. Severe and complicated malaria <ul><li>Cerebral malaria </li></ul><ul><li>Severe malaria anaemia </li></ul><ul><li>Hypoglycaemia </li></ul><ul><li>Metabolic acidosis </li></ul><ul><li>Acute renal failure </li></ul><ul><li>Pulmonary oedema </li></ul><ul><li>Circulatory collapse, shock or “algid malaria” </li></ul><ul><li>Blackwater fever </li></ul>Nearly all severe disease and the estimated >1 million deaths from malaria are due to P. falciparum . Although severe malaria is both preventable and treatable, it is frequently a fatal disease. The following are 8 important severe manifestations of malaria: Click on each severe manifestation for details Note: It is common for an individual patient to have more than one severe manifestation of malaria!
  21. 21. Summary of differences in the clinical features of severe malaria in adults and children Frequency of occurrence Clinical Manifestation Children Adults <ul><li>Similar in adults and children </li></ul><ul><li>Prostration </li></ul><ul><li>Circulatory collapse </li></ul>+++ + +++ + <ul><li>More common in children </li></ul><ul><li>Cerebral malaria </li></ul><ul><li>Severe anaemia </li></ul><ul><li>Multiple convulsions </li></ul><ul><li>Metabolic acidosis </li></ul><ul><li>Hypoglycaemia </li></ul>+++ +++ +++ +++ ++ ++ + + + + / - <ul><li>More common in adults </li></ul><ul><li>Jaundice </li></ul><ul><li>Pulmonary oedema </li></ul><ul><li>Haemoglobinuria </li></ul><ul><li>Abnormal bleeding </li></ul><ul><li>Renal failure </li></ul>+ + / - + / - + / - + / - +++ ++ + + +
  22. 22. <ul><li>Malaria is a multisystem disease. It presents with a wide variety of non-specific clinical features: there are no pathognomonic symptoms or signs. Many patients have fever, general aches and pains and malaise and are initially misdiagnosed as having “flu”. </li></ul><ul><li>P. falciparum malaria can be rapidly progressive and fatal. Prompt diagnosis saves lives and relies on astute clinical assessment: </li></ul><ul><li>A good history </li></ul><ul><ul><li>Residence or a recent visit (in the preceding 3 months) to a malaria endemic area </li></ul></ul><ul><ul><li>History of fever (may be paroxysmal in nature) </li></ul></ul><ul><ul><li>Recognise significance of non-specific clinical features such as vomiting, diarrhoea, headache, malaise </li></ul></ul><ul><li>Physical examination </li></ul><ul><ul><li>Identify signs consistent with malaria: fever, pallor, jaundice, splenomegaly </li></ul></ul><ul><ul><li>Exclude other possible causes of fever (e.g. signs of viral and bacterial infections) </li></ul></ul><ul><li>The diagnosis of malaria should be considered in any unwell person who has been in a malarious area recently </li></ul>Diagnosis
  23. 23. Investigations Blood Film Examination Thick and thin blood films (or “smears”) have remained the gold standard for the diagnosis of malaria. The films are stained and examined by microscopy. Thick blood film - Used for detecting malaria: a larger volume of blood is examined allowing detection of even low levels of parasitaemia. Also used for determining parasite density and monitoring the response to treatment. Thin blood film – Gives more information about the parasite morphology and, therefore, is used to identify the particular infecting species of Plasmodium. Show Me Show Me
  24. 24. <ul><li>A drop of blood is spread over a small area. When dry, the slide is stained with Field’s or Giemsa stains. The red cells lyse leaving behind the parasites. </li></ul><ul><ul><li>Used to detect parasites, even if parasitaemia is low </li></ul></ul><ul><ul><li>Less useful for speciation </li></ul></ul>Thick blood film Back
  25. 25. <ul><li>A small drop of blood is spread across a microscope slide, fixed in methanol and stained with Giemsa stain. </li></ul><ul><li>The microscopist finds the area of the film where red cells are lying next to each other. The fine details of the parasites can be examined to determine the species. </li></ul><ul><ul><li>Used for speciation </li></ul></ul><ul><ul><li>Does not detect low parasitaemia </li></ul></ul>Thin blood film Back
  26. 26. Appearance of P. falciparum in thin blood films Ring forms or trophozoites; many red cells infected – some with more than one parasite Gametocytes (sexual stages); After a blood meal, these forms will develop in the mosquito gut
  27. 27. Other methods of diagnosis of malaria <ul><li>These are not routinely used in clinical practice. They include : </li></ul><ul><li>Antigen capture kits. Uses a dipstick and a finger prick blood sample. Rapid test - results are available in 10-15 minutes. Expensive and sensitivity drops with decreasing parasitaemia. </li></ul><ul><li>PCR based techniques. Detects DNA or mRNA sequences specific to Plasmodium. Sensitivity and specificity high but test is expensive, takes several hours and requires technical expertise. </li></ul><ul><li>Fluorescent techniques. Relatively low specificity and sensitivity. Cannot identify the parasite species. Expensive and requires skilled personnel. </li></ul><ul><li>Serologic tests. Based on immunofluorescence detection of antibodies against Plasmodium species. Useful for epidemiologic and not diagnostic purposes. </li></ul>
  28. 28. Malaria in pregnancy <ul><li>More than 45 million women (30 million in Africa) become pregnant in malaria endemic areas each year. </li></ul><ul><li>Common adverse effects of malaria in pregnancy include: </li></ul><ul><li>Maternal anaemia </li></ul><ul><li>Stillbirths </li></ul><ul><li>Premature delivery and intrauterine growth retardation result in the delivery of low birth weight infants </li></ul><ul><li>The WHO now recommends intermittent preventive treatment (IPT): the administration of anti-malarial drugs (e.g. sulphadoxine-pyrimethamine) during antenatal care whether or not women show symptoms. IPT has been shown to substantially reduce the risk of maternal anaemia in the mother and low birth weight in the newborn. </li></ul><ul><li>Previously, chemoprophylaxis (e.g. with chloroquine) was recommended for all women living in malaria endemic areas. </li></ul>Source:
  29. 29. Sources of information <ul><li>Malaria. Greenwood BM, Bojang K, Whitty CJ, Targett GA. Review; Lancet 2005; 365: 1487-98. </li></ul><ul><li> </li></ul><ul><li>These WHO fact sheets developed by the Roll Back Malaria Partnership cover many different aspects of malaria – including prevention with insecticide-treated bed nets and treatment with atemesinin-based combination therapies </li></ul><ul><li> </li></ul><ul><li>The US Centre for Disease Control and Prevention site for malaria </li></ul><ul><li> </li></ul><ul><li>Follow the “Learn about malaria” link on the Malaria Foundation’s website. This contains numerous useful and accessible resources. </li></ul><ul><li> </li></ul><ul><li>An interactive resource from the Royal Perth Hospital, Western Australia. Contains useful self-assessment exercises in malaria diagnosis by microscopy that are set in the context of clinical cases. </li></ul>
  30. 30. 1. Cerebral malaria - clinical <ul><li>The most well-known severe manifestation of malaria </li></ul><ul><li>Defined as: </li></ul><ul><ul><li>unarousable coma persisting for more than one hour </li></ul></ul><ul><ul><li>with asexual forms of P. falciparum in the peripheral blood </li></ul></ul><ul><ul><li>other common causes of encephalopathy excluded* </li></ul></ul><ul><li>Occurs most commonly in young children although non-immune adults are also at risk </li></ul><ul><li>Cerebral malaria can rapidly progress to death, even with appropriate treatment. Case fatality is between 20-30%. </li></ul><ul><li>In survivors, resolution of coma usually occurs within 1-2 days in children and within 2-4 days in adults but may be complicated by neurological sequelae in ~5% adults and >10% of children. </li></ul>A 4 year old boy who was deeply comatose and had persistent deviation of the eyes The illness may start with drowsiness and confusion and then progress to coma. The loss of consciousness is often preceded by repeated convulsions. Retinal haemorrhages may be seen on fundoscopy. * None of the clinical features are pathognomonic, malaria parasitaemia is common in people living in endemic areas and coma may complicate many illnesses. Therefore, a clinical diagnosis of cerebral malaria is made only after other common causes of coma (e.g. meningitis) have been excluded. Next Back
  31. 31. A young girl with cerebral malaria. Note the abnormal, decerebrate posturing <ul><li>The exact pathogenesis of cerebral malaria is not well understood. It is believed to result from sequestration of parasitised red cells in the small blood vessels in the brain. The consequences of this include: </li></ul><ul><li>reduced cerebral blood flow </li></ul><ul><li>cerebral hypoxia </li></ul><ul><li>release of cytokines which in turn induce the release of nitrous oxide, a known depressor of consciousness </li></ul>Cerebral malaria - pathophysiology A 3 year old boy with impaired consciousness, grimacing and marked extensor posturing of the arms Sequestration of parasitised red cells in different tissues probably underlies most severe manifestations of malaria Back
  32. 32. 2. Severe malaria anaemia <ul><li>Defined as a haematocrit of <15% or haemoglobin concentration <5 g/dl. </li></ul><ul><li>Occurs commonly in young children and pregnant women. </li></ul><ul><li>Anaemia in malaria results from a combination of factors: </li></ul><ul><li>Destruction of parasitised red blood cells </li></ul><ul><li>Destruction of unparasitised red cells by complement-mediated lysis </li></ul><ul><li>Bone marrow suppression by cytokines produced by malaria parasites </li></ul><ul><li>Haemolysis induced by medications in individuals with glucose-6-phosphate dehydrogenase deficiency </li></ul><ul><li>Many patients require urgent transfusion. The condition may be rapidly fatal when blood transfusion is delayed. </li></ul>Marked pallor in an African child with severe anaemia due to P. falciparum infection Back
  33. 33. <ul><li>Blood sugar <2.5 mmol/L </li></ul><ul><li>Increases the risk of mortality and sequelae in children with cerebral malaria; may present with convulsions or a deterioration in level of consciousness. </li></ul><ul><li>Results from a combination of factors: </li></ul><ul><ul><li>reduced glycogen stores because of reduced food intake </li></ul></ul><ul><ul><li>increased metabolism due to fever and repeated convulsions </li></ul></ul><ul><ul><li>glucose consumption by malaria parasites </li></ul></ul><ul><ul><li>cytokine or quinine-stimulated hyperinsulinaemia </li></ul></ul>Back 3. Hypoglycaemia
  34. 34. <ul><li>Lactic acidosis is a major contributor and probably results from tissue anoxia and anaerobic glycolysis </li></ul><ul><li>Presents with deep, rapid respirations (as in diabetic ketoacidosis) </li></ul>Back 4. Metabolic acidosis
  35. 35. <ul><li>occurs almost exclusively in adults and older children in areas of unstable malaria </li></ul><ul><li>affected patients are usually oliguric (urinary output <400 ml/day) or anuric (<50 ml/day) </li></ul><ul><li>serum creatinine levels are elevated </li></ul>Back 5. Acute renal failure
  36. 36. Acute pulmonary oedema, developing shortly after delivery in a woman with severe P. falciparum malaria 6. Acute pulmonary oedema Back This is a grave and usually fatal manifestation of severe falciparum malaria and occurs mainly in adults. Hyperparasitaemia, renal failure and pregnancy are recognised predisposing factors and the condition is commonly associated with hypoglycaemia and metabolic acidosis.
  37. 37. Features of circulatory collapse (cold/clammy skin, hypotension, peripheral cyanosis, weak/thready pulses) may be seen in patients with severe P. falciparum malaria. “ Algid malaria” is characterised by hypotension, vomiting, diarrhoea, rapid respiration and oliguria. This condition is associated with a poor prognosis. 7. Circulatory collapse, shock, “algid malaria ” Back
  38. 38. This results from massive intravascular haemolysis. The condition presents with severe pallor, jaundice and passage of dark urine due to haemoglobinuria. It may be associated with acute renal failure. Typical, dark urine of haemoglobinuria on day 0 which has cleared by day 3 8. Haemoglobinuria or “Blackwater Fever” A 3 year old boy with severe anaemia (Hb 3.3 g/dl) and dark urine (shown in the container) Back