1. Malaria Lecure-9- Hazem.K. Al-Khafaji

2. Topics: Definition. Epidemiology Etiology. Pathology. Clinical features. Complications. Diagnosis. Treatment. Prevention.

3. Definition Malaria is protozoan disease produced by intra- erythrocytic parasites of the genus Plasmodium(vivax,ovale,malariae & falciparum) transmitted to human being by insect of female anopheles mosquito,characterized by recurrent fever and chills associated with the synchronous lysis of parasitized red blood cells. It is endemic mostly in sub-Saharan Africa & responsible for about 1 million deaths in children less than 5 years old.

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. The “direct” burden of malaria morbidity and mortality 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). Malaria in pregnancy accounts for about 25% of cases of severe maternal anaemia and 10-20% of low birth weight. Low birth weight due to malaria accounts for about 5- 10% of neonatal and infants deaths. The “direct” burden of malaria morbidity and mortality 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). Malaria in pregnancy accounts for about 25% of cases of severe maternal anaemia and 10-20% of low birth weight. Low birth weight due to malaria accounts for about 5- 10% of neonatal and infants deaths.

7. Malaria in Iraq Malaria control campaign started in Iraq in 1957. This made the country largely free of the disease.Since 1999 following the 1 st gulf war,Iraq has been affected by serious epidemic that started in 3 autonomous governorates. There were about 49,840 malaria cases in 1995. In 2011,the minister of health announced that Iraq in now free of malaria??

8. RESURGENCE Resurgence of malaria in north of Iraq had been reported during last few years, although no reliable reports about the incidences of the disease,but malaria should be kept in your mind.

9. SpeciesMajor features P. falciparum  The most important species as it is responsible for 50% of all malaria cases worldwide and nearly all morbidity and mortality from severe malaria  Found in the tropics & sub-tropics P. vivax  The malaria parasite with the widest geographical distribution  Seen in tropical and sub-tropical areas but rare in Africa  Estimated to cause 43% of all malaria cases in the world P. ovale  This species is relatively rarely encountered  Primarily seen in tropical Africa, especially, the west coast, but has been reported in South America and Asia P. malariae  Responsible for only 7% of malaria cases  Occurs mainly in sub-tropical climates

10. Plasmodium Figure 12.19 Infected mosquito bites human; sporozoites migrate through bloodstream to liver of human Sporozoites undergo schizogony in liver cell; merozoites are produced Merozoites released into bloodsteam from liver may infect new red blood cells Merozoites are released when red blood cell ruptures; some merozoites infect new red blood cells, and some develop into male and female gametocytes 12 3 4 6 Asexual reproduction Intermediate host Merozoite develops into ring stage in red blood cell Ring stage Merozoites Another mosquito bites infected human and ingests gametocytes 7 5 Ring stage grows and divides, producing merozoites Definitive host In mosquito’s digestive tract, gametocytes unite to form zygote 8 Male gametocyte Female gametocyte Zygote Sexual reproduction Resulting sporozoites migrate to salivary glands of mosquito 9 Sporozoites in salivary gland

11. Life cycle of the malaria parasite Hepatic(Exoerythrocytic phase),the duration of this phase usually 8-25 days except for ovale 30 days. Sporozoites from the salivary gland of a female Anopheles mosquito are injected under the skin. They then travel through the blood stream to the liver and mature within hepatocytes to become tissue schizonts. Up to 30,000 parasites are then released into the blood stream as merozoites Important note: some parasites remain dormant in the liver as hypnozoites. They are the parasites that cause relapsing malaria (in P. vivax or P. ovale infection).

12. Asexual erythrocytic cycle This phase produce symptomatic infection as invade and destroy red blood cells. Once the merozoites within the blood stream, invade red blood cells and mature to the ring, trophozoite, and schizont. Schizonts lyse their host red blood cells as they mature and release the next generation of merozoites, which invade previously uninfected red blood cells. Within the red blood cell. Important notes: 1-P.vivax invade RBC with duffy blood group. 2- P.falciparum invade RBC of all ages, they can even invade more then 20% of RBCs. But they not grow well in RBC contain Hb F,C or S. Asexual erythrocytic cycle This phase produce symptomatic infection as invade and destroy red blood cells. Once the merozoites within the blood stream, invade red blood cells and mature to the ring, trophozoite, and schizont. Schizonts lyse their host red blood cells as they mature and release the next generation of merozoites, which invade previously uninfected red blood cells. Within the red blood cell. Important notes: 1-P.vivax invade RBC with duffy blood group. 2- P.falciparum invade RBC of all ages, they can even invade more then 20% of RBCs. But they not grow well in RBC contain Hb F,C or S.

13. Sexual erythrocytic cycle Some parasites differentiate to sexual forms (male and female gametocytes ). When taken up by a female Anopheles mosquito, the gametocytes mature to male and female gametes, which produce zygotes. The zygote invades the gut of the mosquito and develops into an oocyst. Mature oocysts produce sporozoites, which migrate to the salivary gland of the mosquito and repeat the cycle. An absence of the mosquito vector prevents natural transmission by means of this cycle. Infection by the injection of contaminated blood bypasses this constraint and permits transmission among intravenous drug addicts or to recipients of blood transfusions.

14. PATHOGENESIS SPECIES-DEPENDENT FACTORS. Malaria is a multifactorial disease that can be explained in part by the magnitude of the parasitemia. P. falciparum is the most lethal parasite because it can invade red blood cells of any age and can produce unrestricted parasitemias involving 10 6 or more parasitized red blood cells per cubic millimeter of blood (>20% of circulating red blood cells)., P. vivax and P. ovale, which invade only young red blood cells, are limited to parasitemias less than 25,000/mm 3, and P. malariae, which invades only older red blood cells, is limited to parasitemias of less than 10,000/mm 3.

15. PERIPHERAL SEQUESTRATION OF PARASITIZED RED BLOOD CELLS. Red blood cells containing P. falciparum parasites (Schizonte)develop knobs that contain histidine-rich proteins. These knobs adhere to endothelial cells in the peripheral microvasculature(brain,kidney,spleen,lung&others) by means of certain receptors. This phenomenon has at least two consequences. First, it exacerbates the microvascular pathology produced by the parasite, and second, it removes mature P. falciparum parasites from the circulation, so that only early asexual erythrocytic stages, such as rings, are seen on peripheral blood smears.

16. Clinical features 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: 1-Asymptomatic parasitaemia (“clinical immunity”) 2-Acute, uncomplicated malaria 3-Severe & complicated malaria 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: 1-Asymptomatic parasitaemia (“clinical immunity”) 2-Acute, uncomplicated malaria 3-Severe & complicated malaria

17. Asymptomatic parasitaemia 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.

18. Simple, uncomplicated malaria 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).

19. 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.

20. Clinical features of un-complicated malaria Diarrhoea – more commonly seen in young children and, when vomiting also occurs, may be misdiagnosed as viral gastroenteritis Convulsions – commonly seen in young children. Malaria is the leading cause of convulsions with fever in African children. Pallor – resulting mainly from the lysis of red blood cells. Malaria also reduces the synthesis of red blood cells in the bone marrow. Jaundice – mainly due to haemolysis. Malaria is a multisystem disease. Other common clinical features are: Anorexia Cough Headache Malaise Muscle aches Splenomegaly Tender hepatomegaly

21. The periodicity of malaria fever Most patients with malaria have recurrent fever and chills at 48-hour intervals for P. vivax and P. ovale and at 72-hour intervals for P. malariae. Patients with P. falciparum infection typically have irregular fever and chills and rarely present with a regular 48-hour cycle of symptoms despite the 48-hour erythrocytic cycle of the asexual parasite. Typical paroxysms thus occur every 2 nd day or more frequently in P. falciparum (“sub-tertian” malaria) 3 rd day in P. vivax and P. ovale (“tertian” malaria) 4 th day in P. malariae infections, (“quartan” malaria) Most patients with malaria have recurrent fever and chills at 48-hour intervals for P. vivax and P. ovale and at 72-hour intervals for P. malariae. Patients with P. falciparum infection typically have irregular fever and chills and rarely present with a regular 48-hour cycle of symptoms despite the 48-hour erythrocytic cycle of the asexual parasite. Typical paroxysms thus occur every 2 nd day or more frequently in P. falciparum (“sub-tertian” malaria) 3 rd day in P. vivax and P. ovale (“tertian” malaria) 4 th day in P. malariae infections, (“quartan” malaria)

22. Severe and complicated malaria 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: 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: Cerebral malaria Severe malaria anaemia Hypoglycaemia Metabolic acidosis Acute renal failure Pulmonary oedema Circulatory collapse, shock Blackwater fever

23. Cerebral malaria The most well-known severe manifestation of malaria unarousable coma persisting for more than one hour with asexual forms of P. falciparum in the peripheral blood other common causes of encephalopathy excluded* Occurs most commonly in young children although non-immune adults are also at risk Cerebral malaria can rapidly progress to death, even with appropriate treatment. Case fatality is between 20-30%. 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.

24. A 4 year old boy who was deeply comatose and had persistent deviation of the eyes

26. Acute pulmonary oedema, developing shortly after delivery in a woman with severe P. falciparum malaria 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.

27. 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 Haemoglobinuria or “Black water Fever” A 3 year old boy with severe anaemia (Hb 3.3 g/dl) and dark urine (shown in the container )

28. Diagnosis 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”. P. falciparum malaria can be rapidly progressive and fatal. Prompt diagnosis saves lives and relies on clinical assessment. The diagnosis of malaria should be considered in any unwell person who has been in a malarious area recently

29. Investigations Blood Film Examination:Giemsa - stained 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. Blood Film Examination:Giemsa - stained 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.

30. Ring forms or trophozoites; many red cells infected – some with more than one parasite G ametocytes (sexual stages); After a blood meal, these forms will develop in the mosquito gut Appearance of P. falciparum in thin blood films

31. Other methods of diagnosis of malaria These are not routinely used in clinical practice & should be used with thin & thick blood film. They include : 1- Immunochromatographic test: p Specific & sensitive for P.falciparum. 2- 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..

32. TREATMENT Successful treatment of patients with malaria depends primarily on effective antimalarial drugs, but it also depends on supportive measures: as 1- Infusion of glucose&monitoring of the blood glucose level is important because hypoglycemia is a common cause of coma and because both quinine and quinidine stimulate the release of insulin. 2- Steroids are contraindicated in cerebral malaria because they prolong the duration of coma. 3- Admission to the intensive care unit in case of severe pulmonary oedema or acute circulatory collapse. 4- Dialysis in case of acute renal failure. TREATMENT Successful treatment of patients with malaria depends primarily on effective antimalarial drugs, but it also depends on supportive measures: as 1- Infusion of glucose&monitoring of the blood glucose level is important because hypoglycemia is a common cause of coma and because both quinine and quinidine stimulate the release of insulin. 2- Steroids are contraindicated in cerebral malaria because they prolong the duration of coma. 3- Admission to the intensive care unit in case of severe pulmonary oedema or acute circulatory collapse. 4- Dialysis in case of acute renal failure.

33. Antimalarial drugs } Chloroquine indicated for chloroquine-susceptible malaria ( P. vivax, P. ovale, or P. malariae malaria and chloroquine- susceptible P. falciparum malaria) & is satisfactory because chloroquine is a safe and effective antimalarial in those situations. Patients with chloroquine-resistant P. vivax have been treated successfully with mefloquine. The treatment of chloroquine-resistant P. falciparum infection is mefloquine alone in areas without mefloquine resistance. In areas with mefloquine resistance, treatments include quinine plus pyrimethamine-sulfadoxine Or doxycycline, or clindamycin; atovaquone plus proguanil. For patients who cannot tolerate oral medications, potential strategies include intravenous quinidine or intravenous quinine. Patients with P. vivax or P. ovale infection should be tested for glucose-6-phosphate dehydrogenase deficiency before treatment with primaquine, which is used to eradicate persistent hypnozoites in the liver to prevent relapse. For complicated falciparum infection, artesunate i.v is indicated. Antimalarial drugs } Chloroquine indicated for chloroquine-susceptible malaria ( P. vivax, P. ovale, or P. malariae malaria and chloroquine- susceptible P. falciparum malaria) & is satisfactory because chloroquine is a safe and effective antimalarial in those situations. Patients with chloroquine-resistant P. vivax have been treated successfully with mefloquine. The treatment of chloroquine-resistant P. falciparum infection is mefloquine alone in areas without mefloquine resistance. In areas with mefloquine resistance, treatments include quinine plus pyrimethamine-sulfadoxine Or doxycycline, or clindamycin; atovaquone plus proguanil. For patients who cannot tolerate oral medications, potential strategies include intravenous quinidine or intravenous quinine. Patients with P. vivax or P. ovale infection should be tested for glucose-6-phosphate dehydrogenase deficiency before treatment with primaquine, which is used to eradicate persistent hypnozoites in the liver to prevent relapse. For complicated falciparum infection, artesunate i.v is indicated.

34. PREVENTION 1- CHemoprophylaxis Doxycycline and atovaquone-proguanil are good choice. The advantage of doxycycline is that it reduces the frequency of traveler's diarrhea; its disadvantages include the need for daily dosing, photosensitivity reactions.usually taken during exposure & 4 weeks after leaving. 2- Eradication of mosquitoes.

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