Malaria
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Malaria is a Vector-borne parasitic disease found in 91 countries worldwide. >120 Plasmodium species infect mammals, birds, and reptiles. Only five are known to infect human. Plasmodium falciparum causes majority of deaths due to high levels of parasitemia, sequestration of parasite in critical organs and causing severe anemia
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Malaria
- 1. Malaria
- 2. Introduction Vector-borne parasitic disease found in 91 countries worldwide >120 Plasmodium species infect mammals, birds, and reptiles Only five are known to infect human Plasmodium falciparum Majority of deaths High levels of parasitemia Parasites sequester in critical organs Severe anemia
- 3. Introduction Plasmodium vivax Usually milder disease, but can be severe, and recurrent episodes associated morbidity Plasmodium malariae & Plasmodium ovale are understudied Severity generally similar to uncomplicated vivax malaria Plasmodium knowlesi Primarily zoonotic infection encountered in SEA Cause severe malaria
- 4. Epidemiology Most cases from WHO African Region [213 million or 93%] WHO South-East Asia Region [3.4% of the cases] WHO Eastern Mediterranean Region [2.1%. cause severe malaria] 19 countries in sub-Saharan Africa & India ∼85% of the global malaria burden
- 5. Orissa, Chhattisgarh, West Bengal, Jharkhand and Karnataka contribute the most number of cases Epidemiology
- 6. Epidemiology Risk Population by Province
- 7. Epidemiology The Vector ∼ 40 species of the mosquito genus Anopheles The Parasite Plasmodium spp. Are single-celled eukaryotic organisms P. falciparum Mostly in sub-Saharan Africa Also found in malarious tropical areas around world
- 8. Epidemiology The Parasite P. vivax Found in malarious tropical & temperate areas, primarily SEA, Ethopia and South & Central America P. ovale Prevalent in West Africa Also found in Africa and Asia Plasmodium malariae Found worldwide but is especially prevalent in West Africa
- 9. Epidemiology The Parasite P. knowlesi Macaques are the natural hosts Malaysia have a high burden of knowlesi malaria The true global burden of disease is unknown Parasite is transmitted by Anopheles dirus Human infections with other simian malarias such as Plasmodium cynomolgi and Plasmodium simium can occur
- 10. Life Cycle Transmission Bite of female Anopheles Infective Stage Sporozoites Dormant Stage [P. vivax & P. ovale] Hypnozoites Responsible for relapse
- 12. Life Cycle
- 13. Mechanisms/Pathophysiology The Hepatocytes Invasion
- 14. Mechanisms/Pathophysiology The Red Blood Cell Stage Invasion
- 15. Mechanisms/Pathophysiology The Red Blood Cell Invasion Attachment: Merozoite Surface Proteins [MSP] Pore formation: Through a PfRh5/PfRipr/CyRPA complex Provides secure apical attachment to the RBC Tight Junction Formation/Invagination: Merozoite inserts RON2 into RBC membrane AMA1 ligand creates tight junction with RON2 receptor Tight junction creates a depression in the RBC Tight junction moves via parasite’s actinomyosin motor
- 16. Mechanisms/Pathophysiology The Red Blood Cell Invasion Completion: Rhomboid protease cleaves any adhesive proteins Reseals the membrane Creates a parasitophorous vacuole Inside the RBC, Merozoites mitotically proliferate RBC lysis Re-infect new RBCs Small % of merozoites commit to gametocytogenesis
- 17. Mechanisms/Pathophysiology The Red Blood Cell Invasion
- 18. Mechanisms/Pathophysiology Cytoadherence Infected RBCs attach to endothelium, other RBCs or immune cells
- 21. Immune Evasion & Host Immunity The first encounter with immune system When sporozoites are injected in the skin [~15 per mosquito bite] May be phagocytosed by dendritic cells for antigen presentation The chances of transmission Increased when bitten by mosquitoes carrying larger number of sporozoites How a minority of them can reach the liver and infect the hepatocytes is not well understood!!!
- 22. Immune Evasion & Host Immunity In The Liver Sporozoites alter the cytokine profile and MHC expression of Kupffer cells CSP on sporozoites suppress NFκβ signaling of hepatocytes Sporozoites form a parasitophorous vacuole in hepatocytes to avoid lysosome Merozoites exit liver by covering themselves with hepatocyte-derived membrane
- 23. Immune Evasion & Host Immunity Cytoadherence Escape clearance by spleen Microaerophilic environment ideal for maturation
- 24. Immune Evasion & Host Immunity Antigenic Variation PfEMP1 is an important target of the host-immune response Each parasite has 60 var genes coding for PfEMP1 Immune response to one type of PfEMP1 develops Parasite switches expression to a different var gene/PfEMP1 Parasites avoid established adaptive immune response by expressing variant PfEMP1
- 25. Immune Evasion & Host Immunity What Controls Parasitemia?
- 26. Immune Evasion & Host Immunity Innate Immunity
- 27. Immune Evasion & Host Immunity Naturally Acquired Immunity First Robert Koch [1900] Effective In Adults After Uninterrupted Lifelong Heavy Exposure Lost Upon Cessation Of Exposure Species Specific Somewhat Stage Specific Acquired At A Rate Which Was Dependent Upon The Degree Of Exposure
- 28. Immune Evasion & Host Immunity Innate to adaptive immunity to blood-stage malaria
- 29. Immune Evasion & Host Immunity Presumed mechanisms of adaptive immunity Antibodies Block invasion of sporozoites into liver cells & merozoites into erythrocytes Bind to adhesion molecules on the vascular endothelium & prevent sequestration of infected erythrocytes Neutralize parasite GPI & inhibit induction of the inflammatory cytokine cascade Mediate complement-dependent lysis of extracellular gametes, prevent fertilization of gametes & development of zygotes IFN-γ & CD8+ T cells Inhibit parasite development in hepatocytes IFNγ & CD4+ T cells Activate macrophages to phagocytose intra-erythrocytic parasites & free merozoites
- 30. Clinical Presentations: Uncomplicated Malaria Fever Chills Body-aches Headache Cough Diarrhoea
- 31. Clinical Presentations: Severe Malaria Neurological Manifestations Cerebral Malaria An acute febrile illness, headache, and/or vomiting Altered sensorium and/or seizure Convulsions [> 50% pediatric patients] Pulmonary Manifestations ALI & ARDS [3%-30%] Pulmonary edema
- 32. Clinical presentation: Severe malaria Acute Renal Failure ATN Metabolic Complications Hypoglycemia Lactic Acidosis Hematological Abnormalities Anemia Thrombocytopenia DIC
- 33. Clinical presentation: Severe malaria Gastrointestinal & Hepatic Complications Hyperbilirubinemia Hepatitis Splenomegaly
- 34. Clinical presentation: Severe malaria Nosocomial Infections &/or ‘‘Algid Malaria’’ Aspiration pneumonia Gram-negative bacteremia CAUTI Algid Malaria Severe malaria complicated with hypovolemic shock & septicemia Salmonella bacteremia
- 35. Clinical presentation: Severe malaria C: Cerebral Malaria H: Hypoglycemia A: Anemia P: Pulmonary Edema L: Lactic Acidosis I: Infections N: Necrosis of Renal Tubules
- 36. Diagnostic criteria: Severe malaria
- 37. Malaria and Pregnancy Pregnant women More susceptible [First Pregnancy] Not yet acquired immunity to parasites that express the protein variant surface antigen 2-CSA (VAR2CSA) VAR2CSA on the surface of infected red blood cells facilitates adhesion to chondroitin sulfate A (which is part of placental proteoglycans) Leading to red blood cell sequestration in the placenta Miscarriage, Stillbirth, Preterm Delivery & Babies With Low Birth Weight
- 38. Diagnosis Clinical Diagnosis Patients’ signs and symptoms Physical findings at examination Laboratory Diagnosis Identifying Malaria Parasites 0r Antigens/Products In Patient Blood
- 39. Laboratory Diagnosis Microscopic Examination Stained Thin & Thick PBS [Gold Standard] Thick Blood Films [For Screening Malaria Parasite] Thin Blood Films [For Species’ Confirmation] Shortcoming of Microscopic Examination Low sensitivity when low parasite levels
- 40. Laboratory Diagnosis Microscopic Examination of Stained PBS
- 41. Laboratory Diagnosis Microscopic Examination of Stained PBS
- 42. Laboratory Diagnosis Microscopic Examination of Stained PBS
- 43. Laboratory Diagnosis Microscopic Examination of Stained PBS
- 44. Laboratory Diagnosis Microscopic Examination QBC technique
- 45. Laboratory Diagnosis Rapid Diagnostic Test [RDTs] Antigen-based RDTs • Plasmodium Glutamate dehydrogenase (pGluDH) Presence of pGluDH is known to represent parasite viability Is a marker enzyme for Plasmodium species Ability to differentiate live from dead organisms • Histidine rich protein II [HRP II] Expressed only by P. falciparum trophozoites Antigen can be detected in Erythrocytes, Serum, Plasma, CSF, Urine Takes around two weeks after successful treatment for HRP2-based tests to turn negative Tests will give negative results with non-falciparum malaria
- 46. Laboratory Diagnosis Rapid Diagnostic Test [RDTs] Antigen-based RDTs • Plasmodium Lactate Dehydrogenase [PLDH] Is a marker enzyme for Plasmodium species pLDH levels reduces in the blood sooner after treatment than HRP2 • Fructose-biphosphate Aldolase [PAldo] Is a marker enzyme for Plasmodium species
- 47. Laboratory Diagnosis Rapid Diagnostic Test [RDTs]
- 48. Laboratory Diagnosis Rapid Diagnostic Test [RDTs] Antibody-based RDTs Formats available for IgG &/or IgM Not Suitable for endemic areas
- 49. Laboratory Diagnosis Serological Tests Immunofluorescence antibody testing [IFA] Detects Ab [IgM & IgG] against asexual blood stage Titers > 1 : 20 - Positive < 1 : 20 - Unconfirmed >1 : 200 - Recent infections
- 50. Laboratory Diagnosis Molecular Diagnostic Tests PCR technique Detect as few as 1-5 parasites/μl Can detect drug-resistant parasites Loop-mediated Isothermal Amplification [LAMP] Detects conserved 18S ribosome RNA gene
- 51. Laboratory Diagnosis Molecular Diagnostic Tests Flow Cytometry Detects hemozoin within phagocytes by depolarization of laser light Sensitivity: 49-98%, & Specificity: 82-97% Automated Cell Counters Cell-DynR 3500 apparatus Detect hemozoin in monocytes Sensitivity: 95% & Specificity: 88%
- 52. Laboratory Diagnosis Molecular Diagnostic Tests Mass Spectrophotometry Detects malaria parasites Sensitivity: 10 parasites/μl of blood Microarrays Based on Southern Hybridization Technique Enables probing of multiple gene targets in a single experiment
- 53. Treatment Chloroquine [CHQ] inhibits haem polymerization in the food vacuole Expelled from this compartment by the P. falciparum chloroquine- resistance transporter [PfCRT] Atovaquone [ATO] blocks pyrimidine biosynthesis by inhibiting the expression of the mitochondrial gene pfcytb Pyrimethamine [PYR], P218 and Cycloguanil target P. falciparum dihydrofolate reductase [PfDHFR]
- 54. Treatment DSM265 blocks pyrimidine biosynthesis by directly inhibiting dihydroorotate dehydrogenase [PfDHODH] KAE609 and SJ(557)733 inhibit P. falciparum p-type ATPase 4 [PfATP4] MMV(390)048 inhibits P. falciparum phosphatidylinositol 4-kinase [PfPI(4)K]
- 55. Treatment – Severe Malaria
- 56. Treatment – Uncomplicated Malaria *Choice of ACT to treat P falciparum depends on local resistance patterns; mefloquine is contraindicated in patients with a history of epilepsy or neuropsychiatric disorders. †Chloroquine-resistant P vivax is treated with one of the ACTs [except artesunate plus sulfadoxine–pyrimethamine]. ‡Initial treatment of P vivax or P ovale should be followed by a course of primaquine to prevent relapse, if no contraindications [glucose-6-phosphate- dehydrogenase deficiency, pregnancy, age <6 months].
- 57. Treatment Global distribution of drug-resistant P. falciparum
- 58. Treatment Uncomplicated malaria in pregnancy Falciparum malaria First Trimester Quinine and Clindamycin x 7-days After week 12 of gestation As for non-pregnant patients Vivax malaria Chloroquine unless resistance is suspected Radical cure with primaquine is contraindicated
- 59. Treatment Congenital malaria Falciparum malaria Parenteral artesunate or quinine should be given for at least the first dose Followed by ACT Vivax malaria Parentral/Oral chloroquine unless resistance is suspected If chloroquine resistance is likely Either an ACT or quinine
- 60. Prevention Chemoprophylaxis Intermittent preventive treatment Pregnant women Sulfadoxine–pyrimethamine at all ANC visits from second trimester [minimum dose interval of 1 month] Infants Sulfadoxine–pyrimethamine with routine immunizations
- 61. Prevention Chemoprophylaxis Seasonal malaria chemoprevention Children aged 3–59 months Sulfadoxine–pyrimethamine plus amodiaquine at treatment doses, [maximum four courses] Fixed term Travellers Atovaquone–proguanil, Doxycycline, Mefloquine, or Primaquine
- 62. Prevention Vaccination RTS,S/AS01 Subunit Vaccine based on P. falciparum circumsporozoite protein In children aged 5-17 months Four doses The only registered malaria vaccine [still under evaluation]
- 63. Prevention Vector Control & Bite Prevention Long-lasting insecticide-treated bed nets [Pyrethroid treated nets] Indoor residual spraying with insecticides Repellents [topical & spatial
- 64. Prevention
- 65. Prevention
- 66. Thankyou
Editor's Notes
- The South-East Asia Region is the Region with the second highest estimated malaria burden globally.
- Refer Nature Review Article for Details
- Refer Nature Review Article for Details ER, early ring stage; ES, early schizont stage; ET, early trophozoite stage; FM, free merozoites; LR, late ring stage; LS, late schizont stage; LT, late trophozoite stage; U, uninfected red blood cell
- When a mosquito bites the skin, the sporozoites are delivered to the dermis. They transverse the dermis cells using SPECT proteins and glide down using TRAP proteins. When they get to the bloodstream they travel to the liver and enter through fenestrations in the endothelium. There is a barrier of Kupffer cells, liver macrophages, before the sporozoites can reach the hepatocytes. They are able to transverse the Kupffer cells using the proteins SPECT1, SPECT2 and CelTOS. As well, hepatocytes are lined with HSPG (heparin sulfate proteoglycans). The sporozoite surface proteins CSP and TRAP attach to HSPG. The sporozoites then switch from migratory to invasive mode, where they invade hepatocytes by transvering the membrane. Then the sporozoites are able to replicate in the hepatocytes, and become merozoites which will enter the bloodstream.
- After initial contact with the RBC, the parasite redirects its apical pole over the erythrocyte membrane and sequentially releases the contents from micronemes, rhoptries and then the dense granules. These molecular events lead to tight junction (TJ) and parasitophorous vacuole (PV) formation, as well as the biochemical and functional remodelling of host cell architecture. Merozoite surface proteins (MSPs), present along the entire merozoite surface, are strong candidates for invasion ligands that mediate primary encounter with an RBC. [EXPLAINING THE STRUCTURE OF MEROZOITE, LIGANDS AT BASIGIN REQUIRED FOR PORE FORMATION. AMA & RON FOR TIGHTJUNCTION FORMATION.] Ref. NATURE.
- After initial contact with the RBC, the parasite redirects its apical pole over the erythrocyte membrane and sequentially releases the contents from micronemes, rhoptries and then the dense granules. These molecular events lead to tight junction (TJ) and parasitophorous vacuole (PV) formation, as well as the biochemical and functional remodelling of host cell architecture. Merozoite surface proteins (MSPs), present along the entire merozoite surface, are strong candidates for invasion ligands that mediate primary encounter with an RBC. [EXPLAINING THE STRUCTURE OF MEROZOITE, LIGANDS AT BASIGIN REQUIRED FOR PORE FORMATION. AMA & RON FOR TIGHTJUNCTION FORMATION.] Ref. NATURE.
- Cytoadherence is the unique ability of IRBCs to stick to the endothelium (called sequestration) and to other RBCs and immune cells (called rosetting/clumping). This is advantageous for the parasite because it creates a microaerophilic environment that is ideal for its reproduction and by sequestering/clumping, it can avoid being cleared by the spleen. The way in which it does this is by the merozoite producing and presenting PfEMP1 (plasmodium falciparum erythrocyte protein 1) onto the RBC’s surface. PfEMP1 can bind to several endothelial cell receptors like CD36, ICAM1, PECAM1 and EPCR. Binding to these receptors can also lead to proinflammatory and procoagulant responses, permeability in the endothelial membrane and impairment of the vasomotor tone. All these changes ultimately lead to the sever clinical manifestations of malaria such as microcirculatory obstruction, hypoxia, metabolic disturbances and multi-organ failure.
- Of course, the parasites must overcome the immune system in order to effectively infect the person and be able to replicate. Firstly, the liver is an immunoprivilged organ, meaning there is no strong immune responses in the liver. The sporozoites are able to alter the cytokine profile and MHC expression of Kupffer cells so that they are not able to clear the parasite. Sporozoites also suppress the NFkB signaling of hepatocytes using CSP protein, so the inflammatory response is suppressed. As well, the parasites form a a parasitophorous vacuole inside the hepatocyte, which keeps them isolated from the lysosome to avoid the cell from being able to defend itself by apoptosis or autophagy. Lastly, merozoites avoid the Kuppfer cells in the liver by covering themselves in hepatocyte-derived membranes when they are exiting the liver.
- Of course, the parasites must overcome the immune system in order to effectively infect the person and be able to replicate. Firstly, the liver is an immunoprivilged organ, meaning there is no strong immune responses in the liver. The sporozoites are able to alter the cytokine profile and MHC expression of Kupffer cells so that they are not able to clear the parasite. Sporozoites also suppress the NFkB signaling of hepatocytes using CSP protein, so the inflammatory response is suppressed. As well, the parasites form a a parasitophorous vacuole inside the hepatocyte, which keeps them isolated from the lysosome to avoid the cell from being able to defend itself by apoptosis or autophagy. Lastly, merozoites avoid the Kuppfer cells in the liver by covering themselves in hepatocyte-derived membranes when they are exiting the liver.
- Shown for wild-type mice (a), CD4+ T-cell-depleted mice (b), interferon-γ(IFN-γ)-deficient mice (c), γδT-cell-deficient mice (d), B-cell-depleted or B-cell-deficient mice (e) and natural killer (NK)-cell-depleted mice (f). Note that infection consists of an acute phase and a chronic phase. In intact wild-type mice, the first wave of parasitaemia (peak parasitaemia) is controlled during the acute phase by a CD4+ T helper 1 (TH1)-, IFN-γdependent mechanism that is antibody independent. The parasite is eliminated during the chronic phase by a mechanism that requires both CD4+ T cells and malaria-specific antibody. Depletion or deficiency of CD4+ T cells or NK cells alters the course of infection during both the acute and chronic phases, whereas depletion or deficiency of B cells alters the course of infection during the chronic phase only. γδT cells are not essential for resolution of infection.
- DC, dendritic cell; GPI, glycosylphosphatidylinositol; IFN-γ, interferon-γ; IL, interleukin; MBL, mannose-binding lectin; Myd88, myeloid differentiation factor 88; N.D., not determined; NK, natural killer; P. berghei, Plasmodium berghei; P. falciparum, Plasmodium falciparum; P. yoelii, Plasmodium yoelii; PfEMP1, P. falciparum-encoded erythrocyte membrane protein 1; TCR, T-cell receptor; TLR, Toll-like receptor; TNF, tumour-necrosis factor.
- In 1900, Robert Koch first reported a scientific basis for naturally acquired protection against malaria. Using cross-sectional studies of stained blood films, Koch examined the frequency and density of parasitemia in two distinct populations: (i) those in an area of low endemicity and (ii) those in an area of high endemicity.
- DC, dendritic cell; GPI, glycosylphosphatidylinositol; IFN-γ, interferon-γ; IL, interleukin; MBL, mannose-binding lectin; Myd88, myeloid differentiation factor 88; N.D., not determined; NK, natural killer; P. berghei, Plasmodium berghei; P. falciparum, Plasmodium falciparum; P. yoelii, Plasmodium yoelii; PfEMP1, P. falciparum-encoded erythrocyte membrane protein 1; TCR, T-cell receptor; TLR, Toll-like receptor; TNF, tumour-necrosis factor.
- Malaria is separated conveniently into two disease presentations: uncomplicated and severe. Symptoms of uncomplicated malaria are very non-specific, and can include fever, chills, body-aches, headache, cough, and diarrhoea, making clinical diagnosis unreliable. In nonendemic areas, taking an accurate travel history in all patients with fever is the key to making the diagnosis. Thrombocytopenia can provide another clue. The differential diagnosis will vary depending on location. Once malaria is suspected, the most appropriate course of action is to expedite laboratory testing
- Patient develops an acute febrile illness, headache, and/or vomiting followed by altered sensorium and/or seizure. Convulsions, usually generalized, occur in more than 50% pediatric patients. Acute lung injury (ALI) and ARDS occur in 3% to 30% of patients with severe malaria and has been described with P falciparum as well as with P vivax and P ovale. Pulmonary edema due to fluid overload and heart failure secondary to severe anemia may contribute to acute respiratory failure in a minority of patients.
- Clinically significant renal dysfunction mainly occurs with P falciparum and P malariae rarely with P vivax. Malarial acute renal failure in falciparum malaria is mostly due to acute tubular necrosis (ATN). Factors such as hypovolemia hyperparasitemia, hyperbilirubinemia, intravascular coagulation, hemolysis, rhabdomyolysis, severe pyrexia, and sepsis contribute to MARF. The characteristic metabolic dysfunction of severe malaria is hypoglycemia, a poor prognostic sign. The potential mechanisms include impaired hepatic gluconeogenesis, metabolic demands of parasite and increased glucose consumption because of fever, infection, and anaerobic glycolysis. Iatrogenic factors such as quinine, a potent stimulant of pancreatic insulin secretion, also contribute to the occurrence of hypoglycemia. Contributing factors for lactic acid acidosis include anemia, hypovolemia and shock, interference of microcirculatory flow, impaired hepatic and renal function, derangements in glucose, and organic acid metabolism.
- The most common infections in patients with severe malaria are aspiration pneumonia and primary gram-negative bacteremia due to splanchnic ischemia and transmigration of enteric organisms and later may occur due to nosocomial infections. The term ‘‘algid malaria’’ is used for severe malaria complicated with hypovolemic shock and septicemia. In endemic area, Salmonella bacteremia has been associated specifically with P falciparum infections
- The most common infections in patients with severe malaria are aspiration pneumonia and primary gram-negative bacteremia due to splanchnic ischemia and transmigration of enteric organisms and later may occur due to nosocomial infections. The term ‘‘algid malaria’’ is used for severe malaria complicated with hypovolemic shock and septicemia. In endemic area, Salmonella bacteremia has been associated specifically with P falciparum infections
- The risk of placental malaria is reduced in multigravid women from endemic areas, who generally have antibodies against VAR2CSA. Malaria during pregnancy leads to increased risks to the mother and fetus. Placental malaria might be asymptomatic or clinically mild, but it also leads to an increased risk of death for both the fetus and the mother. It predisposes to miscarriage, stillbirth, preterm delivery and babies with low birth weight
- Shortcoming of microscopic examination is its relatively low sensitivity, particularly at low parasite levels. Although the expert microscopist can detect up to 5 parasites/μl, the average microscopist detects only 50-100 parasites/μl
- Given the global spread of P falciparum resistant to chloroquine and antifols, artemisinin-based combination treatments (ACTs) are recommended for the treatment of falciparum malaria or falciparum mixed with non-falciparum species, except in the first trimester of pregnancy. The leading ACTs in use are artemether–lumefantrine, artesunate–amodiaquine, dihydroartemisinin– piperaquine, artesunate–mefloquine, and artesunate plus sulfadoxine–pyrimethamine. Artemether– lumefantrine should be given with milk or food containing fat to enhance lumefantrine absorption.
- Vivax malaria in pregnancy is treated with (when quinine should be given), but radical cure with primaquine is contraindicated as the glucose-6-phosphate-dehydrogenase (G6PD) status of the foetus cannot be ascertained.
- Countries eliminating malaria since 2000. Countries are shown by the year that they attained 3 consecutive years of zero indigenous cases; countries that have been certified as free from malaria are shown in green (with the year of certification in parentheses). Source: Country reports and WHO.