Malaria.

Malaria

Overview 1.) Malaria: Pathology Transmission
How and through what route? Main reservoirs? Prevention? Life cycle Tissue schizogony Erythrocytic schizogony Sporogony Clinical manifestation High risk groups Diagnosis Treatment Use of genetically modified mosquitoes 2.) Malaria: Discussion Malaria misdiagnosis Malaria eradication

Transmission How and through which route does Malaria infect humans?
transmitted by the bite of an infected female Anopheles mosquito most frequently between dusk and dawn risk of transmission is increased through exposure between dusk and dawn in rural areas at the end of the rainy season below 2000m rarely: transmission by blood transfusion Transmission by shared needle use Congenital transmission from mother to fetus

Transmission What are the main reservoirs for the disease?
infection caused by eukaryotic single-celled microorganism of genus Plasmodium four species infecting humans: Plasmodium falciparum (may be fatal, sub-Saharan Africa, principal cause of malaria deaths in young children in Africa) Plasmodium vivax (most widespread, but rarely fatal, Indian subcontinent) Plasmodium ovale (least common, West Africa) Plasmodium malariae (worldwide, but low frequency) differences Morphology Immunology Geographical distribution Relapse pattern Drug response

Transmission What can be done in order to prevent transmission?
avoid mosquitoes and bites physical barriers: mosquito nets, clothing chemical barriers: repellents: keep mosquitoes from biting DEET “natural based” repellents other synthetic repellents insecticides: kill mosquitoes treated mosquito nets treated clothing DDT chemoprophylactic drugs

Life cycle Extremely complex
Involves various proteins that ensure intracellular and extra-cellular survival Invasion of different cell types Evasion of the host immune system Three stages Tissue Schizogony Erythrocyte Schizogony Sporogony

Tissue Schizogony [A] Mosquitoes inject the parasite (sporozoites) into the host bloodstream [1] Sporozoites travel to the liver and penetrate liver cells (hepatocytes) Invasion [2] mediated by thrombospondin domains of the circumsporozoite protein and the thrombospondin-related adhesive protein on sporozoites bind to heparin sulphate proteoglycans on hepatocytes Asexual replication [3] 9-16 days

Tissue Schizogony [A] One sporozoite [2] Tens of thousands of merozoites [3] Merozoites released into blood stream [4] One merozoite invades one red blood cell [5]

Erythrocytic Schizogony [B]
Merozoites invade erythrocytes [5] Apical reorientation Junction formation Signalling Recognition Merozoite surface proteins interact with sialic acid residues Invasion Erythrocyte binding antigen 175 interacts with glycophorin A on erythrocytes P. falciparum erythrocytes membrane protein 1 (PfEMP1) Parasite protein Expressed at the surface of infected RBC Bind to various host cell receptors Endothelium Placenta

Erythrocytic Schizogony [B]
In the RBC, merozoites undergo asexual division series of developmental stages Early trophozoite “ring form” Trophozoite Highly metabolic Glycolysis Ingestion of host cytoplasm Proteolysis of hemoglobin Rounds of nuclear division without cytokinesis forming schizonts schizonts contain 20 merozoites, these are released once the RBC is lyzed [6] Cycle of invasion-multiplication-release is repeated Some merozoites differentiate into male and female gametocytes [7]

Sporogony [C] Gametocytes are ingested into the midgut of feeding mosquitoes [8] Fertilization Gametes fuse [9] Zygote formation Development of an oocyst [11] Sporogony in oocyst produces many sporozoites oocyst raptures releasing sporozoites [12] sporozoites migrate to salivary glands cycle begins once a mosquito bites a host [1]

Clinical manifestations in humans
develop 6 days - several months after infected mosquito bite characterized by fever and “flu-like” symptoms: myalgias headache abdominal pain malaise often rigors and chills classically described alternate-day fevers or other periodic fevers are often not present severe malaria (due to P.falciparum) may cause . . . seizures coma renal and respiratory failure anemia (= blood loss), even cerebral anemia (= infected erythrocytes obstruct small blood vessels in brain, often fatal, especially in infants) may lead to death dormancy P. ovale and P. vivax: hyponozoites Dormant liver stages Remain in organ for weeks/years before onset of new round of pre-erythrocytic schizogony  relapses of malaria infection P. malariae May have long-lasting blood-stage infections that persist in human asymptomatically for several decades if left untreated

High risk groups overall case-fatality rate of P. falciparum malaria imported into Canada varies from approximately 1% to 5% and increases to 30% for those > 70 years of age children pregnant women Diagnosis Combination of clinical observations, case history and diagnostic tests (microscopic examination of blood or rapid “dipstick” tests) the symptoms of malaria are non-specific and diagnosis is not possible without a blood film the most important factors that determine patient survival are early diagnosis and appropriate therapy the majority of infections and deaths due to malaria are preventable

Treatment Problems: widespread resistance of P. falciparum to chloroquine  complicates prevention and treatment of malaria: drug-resistant strains of malaria are now common in much of the world Insecticide-resistant strains of mosquito Lack of licensed malaria vaccines of proven efficacy

Treatment Solution: Goals:
Combination therapy, e.g. Artemisinin +Fansidar/Mefloquine Quinine First widely used antimalarial treatment From bark of Andean Cinchona tree Fansidar and Chloroquine Most commonly used Most affordable antimalarial drugs Goals: Reduce antimalarial resistance Prolong useful life of current drugs Three combined strategies to reduce malaria transmission: Develop clinically approved malaria vaccines Drug treatment Vector control

The Protozoa Class Sporozoa - Malaria
Four species of malaria parasites infect humans, Plasmodium vivax, P. ovale, P. malariae, and P. falciparum. All are transmitted by female Anopheles spp. mosquitoes. Geographical distribution - malaria is present worldwide in tropical and subtropical areas. Transmission - naturally acquired infections are via the bite of infected female Anopheles mosquitoes. Malaria is also transmitted via blood transfusion, sharing of contaminated needles among IV drug abusers, and congenital transmission also has been documented.

Relapse versus Recrudesence - P. vivax is the classic “relapsing” malaria. All can recrudesce due to incomplete therapy. Relapse is due to dormant stages (hypnozoites) in liver cells. Only sporozoite induced malaria can relapse. Prevention - detect and treat infected people; mosquito control. Immunity - incomplete immunity follows infection. Some persons get reinfected over and over.

Sickle cell trait - the malaria parasite is not successful at utilizing “S” haemoglobin. This trait does not confer immunity to infection, but does offer resistance to disease. Duffy factor - represents the “portal of entry” antigen for P. vivax. Persons without this factor are immune to infection with this species, but not the others.

The Protozoa Class Sporozoa - Malaria Pathology/Pathogenesis:
Prodromal stage - time period which can include premonitory symptoms such as headache, myalgia, anorexia & nausea prior to the first paroxysm. Paroxysm - period of chills & fever followed by profuse sweating. Blackwater Fever - a complication of P. falciparum malaria. Hemolysis and hematuria are due to a severe immune reaction.

Treatment: (Often complicated by an increasing resistance of the parasite to drugs) Prophylaxis - administration of drug(s) prior to entering a malarious region. Therapeutic - administration of drug(s) to cure an infection. Drug resistance - only P. falciparum, although strains of P. vivax on Papua, New Guinea have been reported to be developing resistance.

Collection of Blood for Malaria Examination: Finger stick - the preferred specimen. Wipe off first drop of blood in order to avoid “tissue juices”. Venous - acceptable, but a “red-top” tube is best. Smears should be made as close to the time of collection as possible. Midway between fever peaks is the best time to collect blood.

Mixed Infections: Possible, but are rare. Dominant infection - one species will usually be dominant. Confirmation of other species - based upon identifying a stage uniquely different from the same stage of the dominant species present.

The Protozoa Class Sporozoa - Malaria Terms:
Ring stage - a young trophozoite, it still contains a vacuole in the cytoplasm. Developing trophozoite - the vacuole fills in as the organism feeds, adding to its bulk; pigment begins to appear. Pigment - product of the digestion of haemoglobin to hematin.

The Protozoa Malaria Terms: (continued)
Schizont - the stage in which asexual reproduction takes place with the production of merozoites. Gametocyte - the stage picked up by the mosquito vector; initiates sexual reproduction in the mosquito. Sporozoite - the infective stage, a product of sexual reproduction; is present in the salivary gland of the vector mosquito.

The Protozoa Malaria Terms: (continued)
Schuffner’s stippling - a fine, granular eosinophilic stippling seen on the infected red blood cell. Seen only in P. vivax and P. ovale infections. Maurer’s clefts - heavy, clefts of eosinophilic stippling rarely seen on infected red blood cells in P. falciparum infections. Usually sparse in number. Prepatent period - time from infection until first discovery of parasites in a blood film. Incubation period - time from infection until first symptoms appear.

The Protozoa Components of the Malaria Parasite:
Cytoplasm - light blue staining component of parasite. Chromatin - reddish to purplish red staining, nuclear material. Pigment - does not stain. Product of digestion of haemoglobin to hematin. Color varies with species present, generally brown to black.

The Protozoa Malaria: Features in Thin Blood Films:
Appearance of the infected Red Blood Cell: Size - normal or enlarged. Stippling - present or absent.

The Protozoa Malaria: Appearance of the Parasite:
Outline of the developing trophozoite - smooth and rounded or irregular. Density of cytoplasm - compact (dark staining), or diffuse (light staining). Amount & color of pigment - black, brown, etc.; heavy, light. Stages present - is one stage dominant, or are a variety of stages present. Number of merozoites in the mature schizont (a species-specific number).

The Protozoa Malaria: Diagnostic Features seen in Thick Blood Films:
Appearance of the Parasite: (RBC’s have been lysed) Stages present - rings, trophozoites, schizonts, gametocytes. Outline of the developing trophozoite - smooth and round or irregular. Density of cytoplasm - diffuse or compact. Amount & color of pigment - dense, sparse; black, brown. Number of merozoites in the mature schizont - 9, 16, 24. Shape of the gametocyte - round or banana shaped.

The Protozoa Plasmodium vivax - benign tertian malaria
Stages present in blood films - all can be present. Size of infected red blood cells - usually enlarged. Stippling - usually present if stained at a pH of Density of cytoplasm - diffuse, light staining.

The Protozoa Plasmodium vivax - benign tertian malaria (continued)
Pigment - present in older organisms, brownish-black to yellowish-black. Number of merozoites in the mature schizont - average of 16. Length of asexual cycle - 48 hours. Prepatent period - 8 to 17 days. Incubation period - 14 days.

The Protozoa Plasmodium ovale - benign tertian malaria (‘ovale’ tertian) Stages present in peripheral blood films - all can be present, but one is dominant. Size of infected red blood cells - usually enlarged, often oval with fimbrated edges. Stippling - usually present if stained at pH

The Protozoa Plasmodium ovale - benign tertian malaria (continued)
Density of cytoplasm - rounded and compact, therefore dark staining. Number of merozoites in the mature schizont - average of 9. Length of asexual cycle - 48 hrs. Prepatent period - 8 to 17 days. Incubation period - 14 days.

The Protozoa Plasmodium malariae - quartan malaria
Stages present in peripheral blood films - all can be present, but one stage usually is dominant. Size of infected red blood cells - normal or slightly smaller. Stippling - none. Density of cytoplasm - rounded and compact, therefore dark staining.

The Protozoa Plasmodium malariae - quartan malaria (continued)
Pigment - usually present in older organisms, dark black. Number of merozoites in the mature schizont - average of 9. Length of asexual cycle - 72 hrs. Prepatent period - 14 to 30 days. Incubation period - 30 days.

The Protozoa Plasmodium falciparum - malignant tertian malaria
Stages present in peripheral blood films - usually only rings and gametocytes; rarely other stages. Size of infected red blood cells - normal. Stippling - rarely, Maurer’s clefts can be seen.

The Protozoa Plasmodium falciparum - malignant tertian malaria (continued) Density of cytoplasm - compact. Pigment - black. Number of merozoites in the mature schizont - average of 24. Shape of the gametocyte - banana or sausage shaped. Length of asexual cycle - 48 hrs. Prepatent period - 5 to 15 days. Incubation period - 12 days.

The Protozoa

Plasmodium malaria Plasmodium malariae is a parasitic protozoa that causes malaria in humans. It is one of several species of Plasmodium parasites that infect humans including Plasmodium falciparum and Plasmodium vivax which are responsible for most malarial infection. While found worldwide, it is a so-called "benign malaria" and is not nearly as dangerous as that produced by P. falciparum or P. vivax. It causes fevers that recur at approximately three-day intervals (a quartan fever), longer than the two-day (tertian) intervals of the other malarial parasites, hence its alternative names quartan fever and quartan malaria.

Malaria parasite (plasmodium)
Pathogen of malaria P.vivax ; P.falciparum ;P.malariae ; P.ovale P.vivax ; P.falciparum are more common Plasmodium is a wide distribution in many tropical or subtropical regions of the world

Morphology Late trophozoite Early trophozoite (ring form)
Wright’s stain---reddish nuclei; bluish cytoplasma and yellowish brown malarial pigment 1. Morphological features of P. vivax Early trophozoite (ring form) 1 red nucleus on the ring-like light blue cytoplasm ; single infection in a cell. infected RBC like normal RBCs. Late trophozoite It is irregular shape like ameboid form with pseudopodia; within cytoplasm ,brown pigment granules (malarial pigment---haemozoin) appear. infected RBCs are pale in color,and have schuffner’s dots in it (fine red granules) .

Immature schizont Mature schizont Male gametocyte Female gametocyte
oval in shape , nucleus divided into 2-4 or more , malarial pigment begins to concentrate in a mass. Mature schizont nucleus divided into 12-24 ;and cytoplasm also divided , each nucleus surrounded by a portion of cytoplasm to form merozoites, malarial pigment clumped. Male gametocyte oval in shape; 1 loose nucleus in centre of it ; malarial pigments diffuse . Female gametocyte oval in shape ; 1 compact nucleus not in centre of it .

Early trophozoite (ring form)
2. Morphological features of P. falciparum Early trophozoite (ring form) 1or 2 red nuclei on the ring-like light blue cytoplasm ; multiple infection in a cell. infected RBC like normal RBCs. P. falciparum: only can the early trophozoites and gametocytes be seen in the peripheral blood . Male gametocyte Sausage in shape; 1 loose nucleus in centre of it ; malarial pigment diffuse . Female gametocyte Crescentic in shape ; 1 compact nucleus in centre of it .

Life cycle In mosquito (final host) In human body
Gametocytes(♀♂) gametes (♀♂) (blood—stomach) (stomach of insect) union of zygote rupture/release rounds up into sporozoites oocyst motile ookinete (Salivary glands) ( the body cavity side) In human body Exoerythrocytic stage bite/inject into sporozoites exoerythrocytic schizonts (mosquito blood) (hepatic cell) rupture/release exoerythrocytic sporozoites ( blood)

Treatment Chlorquine and quinine----anti-erythrocytic stage drugs. (question: Which stage of plasmodium can these drugs kill?) Primaquine and pyrimethamine ----anti-exoerythrocytic stage drugs. Prevention Chemoprophylaxis -----Chloroquine / pyrimethamine used for prophylaxis of malaria -----Chemotherapy: 1 week before entry into the endemic area ; for 4 weeks after returning from the endemic area.

Mosquito control (1). Reconstruction of environment: eradicate the breeding places of mosquitoes. (2). Spry insecticides: DDVP and so on. (3). Use mosquito nets, screen, or mosquito repellents to protect the person from mosquito bites.

Genetically Modified Mosquitoes
Germ-line transformations Identification of effector molecules Transgenic mosquitoes Prevent the transmission of the parasite

Genetically Modified Mosquitoes
Well studied in the laboratory Must survive in the wild Out-compete their wild-type counterparts Genetic modifications must be permanent

Discussion: Malaria misdiagnosis
“In a recent study of children reporting to health centres in Uganda, Karin Kallander and colleagues found that 30% had symptoms compatible with both pneumonia and malaria and required dual treatment. This report, and previous studies, have concluded that community treatment of all childhood fevers as malaria is likely to result in malaria over-diagnosis with consequent under-diagnosis of other fever-causing disorders such as pneumonia.” (Amexo et al Malaria misdiagnosis: effects on the poor and vulnerable) 1.) Discuss the challenge and problems of this issue. 2.) What do you consider the most ethical and cost-effective policy?

Discussion: Malaria misdiagnosis
“In a recent study of children reporting to health centres in Uganda, Karin Kallander and colleagues found that 30% had symptoms compatible with both pneumonia and malaria and required dual treatment. This report, and previous studies, have concluded that community treatment of all childhood fevers as malaria is likely to result in malaria over-diagnosis with consequent under-diagnosis of other fever-causing disorders such as pneumonia.” (Amexo et al Malaria misdiagnosis: effects on the poor and vulnerable) Discuss the challenge and problems of this issue. rapid, simple, accurate, inexpensive malaria diagnosis methods are not widely available, particularly in poor communities where they are most needed and individuals are least able to withstand the consequences of the illness how can one ensure that the more expensive combination therapies reach most of those who truly have malarial illness and not just an elite minority? What do you consider the most ethical and cost-effective policy? newer drug combinations used only for true cases of malaria requirement: accurate malaria diagnosis

30 % 70 % malaria ( = fever symptoms) home treatment: -traditional remedies drugs from local stores health centres on community level = peripheral health facilities Diagnosis: solely based on clinical features (i.e. fever) bad quality diagnosis pro: can reduce morbidity contra: over-diagnosis/over-treatment of malaria as many infectious diseases mimic malaria pathology health centres on district level = district hospitals 1) Microscopy standard for malaria diagnosis (accuracy 70-75%) challenge: well-maintained equipment constant supply of good-quality reagent trained staff: monitoring, supervising 2) Rapid Diagnostic Tests when microscopy unavailable based on detection of Plasmodium specific proteins cost not quantitative = inability to provide information about density of infection Not species specific: can only diagnose P. falciparum specifically Design an educational step-by-step plan for elucidating locals about successful self-treatment.

Proposal for educational self-treatment plan
Discuss common errors concerning malaria recognition i.e. false assumptions such as “malaria can be recognized from its symptoms” Advise that malaria presents in various ways i.e. differing malarial symptoms may mimic other diseases Indicate need to seek professional medical care as soon as possible i.e. self-treatment is a temporary, life-saving measure while seeking medical attention or if medical care is not available within 24h Select self-treatment drug with care i.e. consider drug’s safety, efficacy, individual’s drug tolerance, other medication etc. Educate about drugs to avoid i.e. potential severe adverse effects and/or poor efficacy

Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and deepening poverty Poor and Vulnerable less likely to seek modern medical care for treatment of fevers wait-and-see approach unaffordable fees long waiting lists unavailability of drugs poor attitude among staff

contribution to a vicious cycle of increasing ill-health and deepening poverty Poor and Vulnerable less likely to seek modern medical care for treatment of fevers wait-and-see approach unaffordable fees long waiting lists unavailability of drugs poor attitude among staff inaccurate diagnosis delayed diagnosis & treatment

contribution to a vicious cycle of increasing ill-health and deepening poverty Poor and Vulnerable less likely to seek modern medical care for treatment of fevers wait-and-see approach unaffordable fees long waiting lists unavailability of drugs poor attitude among staff inaccurate diagnosis delayed diagnosis & treatment more prolonged and severe disease

contribution to a vicious cycle of increasing ill-health and deepening poverty Poor and Vulnerable less likely to seek modern medical care for treatment of fevers wait-and-see approach unaffordable fees long waiting lists unavailability of drugs poor attitude among staff inaccurate diagnosis delayed diagnosis & treatment more prolonged and severe disease Misallocation of Resources: underlying fatal conditions are masked exposure to unnecessary side-effects - lost confidence in allopathic health services in favour of traditional healers lost productive time through illness (no insurance or savings) impacts on anyone: men, women, children (leave school to look after relatives  reduced employment prospects

Discussion: The long road to malaria eradication
We saw that poverty was a contributing factor to the misdiagnosis of malaria, Peter Russell in 1946 wrote: “but all the evidence we possess would seem to indicate not that poverty is responsible for malaria but that malaria maintains poverty” (Majori The long road to malaria eradication) With this in mind consider the following: Three approaches have been identified in the fight against malaria: drug administration, vector control (insecticides or insecticide sprayed bed nets) and vaccine development. Of these three which approach do you think is the most feasible? Which would you allocate funds to?

Discussion: The long road to malaria eradication
The Director General of the WHO wrote to the 8th World Health Assembly: “... At present time there are no obvious technical or economic reasons why malaria could not be driven out of the Americas, Europe, Australia and much of Asia within the next quarter of a century. As regards tropical Africa the situation is not quite so promising…one cannot foresee the elimination of malaria from Africa in the near future”. (Majori The long road to malaria eradication) Do you agree or disagree with the latter part of this statement? Why do you think the outcomes of malaria eradication differed between countries of tropical Asia and countries of sub-Saharan Africa?

Global distribution of malaria
Sachs and Malaney, The economic and social burden of malaria.

Global distribution of per capita GDP
Sachs and Malaney, The economic and social burden of malaria.

Reference Charis Segeritz and Jo-Ann Osei-Twum

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