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  1. Malaria Dr. Kamala Sanjel Internal medicine Resident NAMS
  2. Contents • Introduction • Epidemiology • Pathogenesis • Clinical Features • Diagnosis • Treatment • Prevention
  3. Introduction • Malaria: Italian: Mala aria, literally "bad air, • A protozoal disease transmitted by the bite of infected female Anopheles mosquitoes. • Overwhelming problem in tropical developing countries • Nearly 40% of the world’s population is at risk for acquiring malaria • However Mortality rates have decreased dramatically over the past 15 years as a result of highly effective control programs in several countries after introduction of chloroquine.
  4. Epidemiology • Malaria is endemic throughout most of the tropics, ongoing transmission occurs in 85 countries and territories . • The World Health Organization (WHO) reported 241 million cases and 627 thousand deaths from malaria in 2020. • Over 95 percent of the burden occurs in the African region of the World Health Organization, followed by 2 percent each in the South East Asian and Eastern Mediterranean regions.
  5. In Nepal • Malaria remains a public health priority in Nepal and the country is set for malaria elimination by 2025 • The malaria disease distribution has decreased significantly, 1,187 total malaria cases recorded in 2017/18, and distribution is more towards the far-west region of the country as seen in the recent malaria microstratification 2018. • Plasmodium vivax is the predominant species in Nepal and P. falciparum is the other important species. • P. vivax: increasing from 71 % in 2010 to 95 % in 2018 • P. falciparum: on the decline from around 29 % in 2010 to 5 % in 2018 • P. malariae has not been detected for long time (more than20 years) • P. ovale has been reported from the private sector among patients returning from Africa
  6. Pathogen • Plasmodium parasites belong to the Apicomplexa group of protozoa, which includes other pathogens, such as Babesia, Toxoplasma, and Cryptosporidium species. • Four Plasmodium species are classified as human malaria parasites: P. falciparum, P. vivax, P. ovale, and P. Malaria • Some malaria parasites of other primates (e.g., P. knowlesi, P. cynomolgi, and P. simium) can also infect humans under natural conditions.
  7. Pathogen • P. knowlesi,a natural pathogen of macaque monkeys, has been proposed to be a “fifth human malaria parasite” responsible for significant morbidity and mortality in Malaysia • Two morphologically identical sympatric species of P. ovale (curtisi and wallikeri) • While almost all deaths are caused by falciparum malaria, P. knowlesi and occasionally P. vivax can also cause severe illness.
  8. Pathogen • P. falciparum and P. vivax infections account for most cases of human malaria. • P. falciparum and P. malariae are found worldwide. • P. vivax is infrequent in most of sub-Saharan Africa but is common elsewhere. • P. ovale occurs in Africa and in foci within Asia and Oceania and is often present with other Plasmodium species as a mixed infection.
  9. Vector • Anopheles gambiae and Anopheles funestus transmit malaria with notoriously high efficiency and are the predominant vectors in sub- Saharan Africa. • Bite occurs mainly between dusk and dawn. • Highest levels of transmission typically occur during the wet season in endemic areas. • Malaria may also be acquired from needles shared among drug users, blood transfusion,or solid-organ transplantation and as congenital infection.
  10. Host • Groups at highest risk include young children (6 to 59 month) and pregnant women. • Older children and adults develop partial immunity after repeated infections and are at relatively low risk for severe disease. • Travelers to malarious areas who generally have had no previous exposure to malaria parasites or have lost their immunity if they left the endemic area are at very high risk for severe disease if infected with Plasmodium falciparum.
  11. CHARACTERISTIC FINDING FOR INDICATED SPECIES P. FALCIPARUM P. VIVAX P. OVALE P. MALARIAE P. KNOWLESI Duration of intrahepatic phase (days) 5.5 8 9 15 5.5 Erythrocytic cycle (hours) 48 48 50 72 24 Red cell preference Younger cells (but can invade cells of all ages) Reticulocytes and cells up to 2 weeks old Reticulocytes Older cells Younger cells Morphology Usually only ring forms; banana-shaped gametocytes Irregularly shaped large rings and trophozoites; enlarged erythrocytes Schüffner’s dots Infected erythrocytes, enlarged and oval with tufted ends; Schüffner’s dots Band or rectangular forms of trophozoites common Resembles P. falciparum (early trophozoites) or P. malariae (later trophozoites, including band forms) Ability to cause relapses No Yes Yes No No
  12. Life cycle
  13. Life cycle • Sporozoites are the infective form,are injected by infective mosquito • The injected sporozoites typically take several hours to travel through dermal tissues and migrate across host cell barriers before they enter blood and lymphatic systems and are carried to the liver. • Sporozoites must first invade and replicate in hepatocytes before they can differentiate into merozoites capable of entering the intra-erythrocytic cycle. • All P. falciparum and P. malariae parasites complete their liver-stage development in about 1 to 2 weeks. • P. vivax and P.ovale liver stages also can develop promptly or can remain latent as hypnozoites in the liver for months to years before emerging to produce relapses of malaria.
  14. Life cycle • Once a merozoite egresses by protease activity from its host hepatocyte (or from its host erythrocyte in the bloodstream cycle),it engages loosely with an uninfected erythrocyte and then reorients so that its apical end faces the cell surface. • An envelope of invaginated membrane surrounds the merozoite as it enters, forming the parasitophorous vacuole once invasion is complete. • A number of studies have also established a dependence of P. vivax merozoites on interaction with erythrocyte Duffy antigen receptor for chemokines (DARC).
  15. Life cycle • Within erythrocytes, merozoites develop from ring forms into trophozoites and then schizonts over 24 hours (P. knowlesi), 48 hours (P. falciparum, P. vivax, and P. ovale), or 72 hours (P. malariae). • After breaking down their host cell membrane by enzymatic digestion, 24 to 32 merozoites enter the bloodstream and are each capable of infecting a new erythrocyte. • Parasites in the bloodstream reproduce asexually in the haploid state. During erythrocytic development, a small minority of parasites undergo a switch to sexual-stage development.
  16. Life cycle • The resulting male and female gametocytes are the forms that are taken up by and infect female anopheline mosquito. • Gametocytes emerge from erythrocytes in the mosquito midgut as male and female gametes that cross-fertilize to form diploid zygotes, which in turn differentiate into ookinetes that burrow through the midgut wall. • Each ookinete develops into an oocyst containing up to 1000 sporozoites, which emerge and are then carried by the insect hemolymph to invade the salivary glands. • These processes in the mosquito require an incubation period of about 1 to 2 weeks. • Female mosquitoes inject sporozoites into humans while taking a blood meal.
  17. Pathogenesis • Cycles of invasion and growth in erythrocytes produce a parasite biomass that enlarges rapidly, causing fever and leading to pathologic processes, such as erythrocyte loss (anemia), sequestration of infected erythrocytes in microvascular beds (cerebral malaria), and adverse sequelae of inflammatory cascades and cytokine release. • Although P. vivax can cause serious and fatal illness, by far the largest fraction of deaths directly attributable to malaria are caused by severe complications of P. falciparum infection, including cerebral malaria, severe anemia, respiratory distress, renal failure, and severe malaria of pregnancy.
  18. Pathogenesis • Erythrocytic Changes:malarial parasite consumes and degrades intracellular proteins ie hemoglobin • Toxic heme is detoxified by lipid-mediated crystallization to biologically inert hemozoin (malaria pigment). • Alters the RBC membrane by changing its transport properties, exposing cryptic surface antigens, and inserting new parasite-derived proteins and RBC becomes more irregular in shape, more antigenic, and less deformable. • Membrane protuberances(knob) appear on the erythrocyte’s surface 12–15h after the cell’s invasion.
  19. Pathogenesis • Membrane adhesive protein (PfEMP1) mediates attachment to receptors on venular and capillary endothelium (cytoadherence). • Erythrocytes containing more mature parasites stick inside and eventually block capillaries and venules. • These infected RBCs may also adhere to uninfected RBCs (to form rosettes) and to other parasitized erythrocytes (agglutination). • Processes of cytoadherence, rosetting, and agglutination are central to the pathogenesis of falciparum malaria.
  20. Pathogenesis • A (CSA )and endothelial protein C receptor, which is involved in the deadly sequestration of parasitized erythrocytes leads to cerebral Malaria • Infected erythrocytes that bind CSA expressed by syncytiotrophoblasts sequester selectively in placental tissue and are responsible for malaria of pregnancy. • P. falciparum can infect erythrocytes of all ages, promoting heavy parasite burdens, high parasite densities, increased parasite multiplication rates and evidence of high parasite.
  21. Pathogenesis • Systemic sequestration of metabolically active parasites, blood cells and platelets likely contributes to the metabolic acidosis and thrombocytopenia commonly seen in severe malaria. • Metabolic acidosis,hypoglycemia, hyperpyrexia, and nonconvulsive status epilepticus can contribute significantly to the cerebral malaria presentation, as suggested by the rapid clinical improvement of some patients after fluid resuscitation,blood transfusion, dextrose infusion, fever reduction, and anticonvulsant therapy in addition to antimalarial treatment.
  22. Pathogenesis
  23. Pathogenesis Host Response: • Splenic immunologic and filtrative clearance functions are augmented, and the removal of both parasitized and uninfected erythrocytes is accelerated. • Removes damaged ring-form parasites (a process known as “pitting”) and returns the once-infected erythrocytes to the circulation, where their survival is shortened. • The parasitized cells escaping splenic removal are destroyed when the schizont ruptures and the release of proinflammatory cytokines, which cause fever with Temperatures of ≥40°C(≥104°F) damage mature parasites. • In untreated infections, the effect of such temperatures is to further synchronize the parasitic cycle, with eventual production of the regular fever spikes and rigors that originally characterized the different malarias.
  24. Pathogenesis • These regular fever patterns (quotidian, daily; tertian, every 2 days; quartan, every 3 days) are seldom seen today as patients receive prompt and effective antimalarial treatment. • Hypoglycemia: In children:hypoglycemia is associated with impaired hepatic gluconeogenesis and increased consumption of glucose by hypermetabolic peripheral tissues. • In adults, hypoglycemia is often associated with hyperinsulinemia which may result from pancreatic islet cell stimulation by parasite- derived factors or parenteral quinine or quinidine therapy, or both.
  25. Pathogenesis Anemia: • multifactorial • Intravascular lysis and phagocytic removal of infected erythrocytes. • Excess removal of uninfected erythrocytes be mediated by processes (e.g., oxidative stress) that accelerate the senescence and reduce the deformability of erythrocytes. • Release of inflammatory cytokines (e.g., TNF) is associated with impaired production of erythropoietin leads to normochromic normocytic anemia seen in malaria and explain the notable absence of a robust reticulocyte response.
  26. Pathogenesis • Metabolic (Lactic) Acidosis: reduced delivery of oxygen to tissues due to combined effects of anemia (decreased oxygen-carrying capacity), sequestration (microvascular obstruction), and hypovolemia (reduced perfusion) resulting from fluid losses caused by fever, decreased oral intake, vomiting, and diarrhea. • Renal Impairment: erythrocyte sequestration and agglutination interfering with renal microcirculatory flow and metabolism, manifests as acute tubular necrosis. • Liver Dysfunction: Severe jaundice results from hemolysis, hepatocyte injury, and cholestasis.
  27. Pathogenesis Pulmonary Edema and Respiratory Distress: • Sequestration of infected erythrocytes in the lungs is thought to initiate regional production of inflammatory cytokines that increase capillary permeability, leading sequentially to pulmonary edema, dyspnea, hypoxia, acute lung injury, and acute respiratory distress syndrome. Malaria of Pregnancy: • Placental malaria results in maternal morbidity and mortality, intrauterine growth retardation, premature delivery, low birth weight, and increased newborn mortality infection. • Placental malaria in subsequent pregnancies is typically less severe than in the first pregnancy , presumably because of a woman’s previous exposure to CSA-binding parasites.
  28. Genetic Resistance to Malaria • Hemoglobins S, C, and E:mechanisms of protection, freshly drawn and infected HbAS and HbAC erythrocytes were found to be impaired in their adherence to microvascular endothelial cells and monocytes • Thalassemias: infected thalassemic erythrocytes bind increased amounts of antibody from both nonimmune and immune sera, which suggests the possibility of enhanced opsonization • Glucose-6-PhosphateDehydrogenase Deficiency: Enhanced phagocytosis of infected G6PD-deficient erythrocytes • Blood group O,DARC negativity, G6PD Deficiency, Southeast Asian Ovalocytosis and Hereditary Xerocytosis
  29. Clinical Presentation Uncomplicated malaria • Uncomplicated malaria typically presents as an undifferentiated febrile illness. • Fever (100%); headache (100%); weakness (94%); profuse night sweats (91%); insomnia (69%); arthralgias (59%); myalgias (56%); diarrhea (13%); and abdominal cramps (8%). • Individuals are generally asymptomatic for 12 to 35 days after infection, but symptoms can commence as early as 7 days (depending on parasite species). • Longer incubation periods are more likely in semi-immune individuals and individuals taking incompletely effective malaria prophylaxis.
  30. Clinical Presentation • Symptoms begin during the erythrocytic stage of the parasite life cycle, when infected red cells rupture and release merozoites, leading to fever and other symptoms. • Malaria presents as an acute febrile illness that is often but not always characterized by the classic malaria paroxysm. • Cyclic paroxysms of chills and rigors, followed by fever spikes up to 40°C (104°F), and then profuse sweating that can ultimately give way to extreme fatigue and sleep is characteristic. • Febrile paroxysms may occur every other day for P. vivax, P. ovale, and P. falciparum and every third day for P. malariae
  31. Clinical Presentation • Malaria is not associated with a rash, lymphadenopathy • A travel history that reveals risk of exposure months to years before in an endemic region is an alert for malaria and should always be sought in presentation of fever. Physical findings • Pallor-Removal of infected erythrocytes by the stimulated spleen , may contribute to anemia • Mild Jaundice • Splenomegaly often accompanies malaria and is thought to indicate an important role of the spleen in parasite clearance.
  32. P. vivax and P. ovale • Infections with P. vivax and P. ovale can be considered similar • P. vivax infections can be tremendously debilitating and are sometimes associated with serious complications, including acute lung injury and splenic pathology. • Splenic rupture has been associated with acute and chronic infections and can occur spontaneously or with minor trauma, including manual examination of the spleen. • P. vivax merozoites selectively invade reticulocytes. • Because these cells account for only a small proportion of the total erythrocyte mass, parasitemias in P. vivax infections are usually less than 1% even when the pathology of vivax malaria is severe.
  33. Plasmodium malariae • The quartan malaria of P. malariae usually presents with fever and paroxysms similar to those of P. vivax but with a 3-day rather than 2- day periodicity. • P. malariae often establishes parasitemias that are below the level of detection by microscopy. • Patients can remain infected and asymptomatic for many years before presenting with fevers, malaise, and splenomegaly decades after they have left an endemic area. • Chronic P. malariae infection can lead to nephrotic syndrome in young children living in endemic areas.
  34. P. knowlesi • A large focus of human malaria caused by P. knowlesi occurs in Malaysia, where high case-fatality rates have been reported. • P. knowlesi is indistinguishable from P. malariae on blood smear examination, showing both immature and mature forms in the circulation. • Unlike P. malariae, however, P. knowlesi replicates every 24 hours and can cause daily fever spikes and hyperparasitemias that are life threatening. • In addition to hyperparasitemia, severe P. knowlesi malaria cases have been associated with metabolic acidosis, hepatorenal dysfunction, respiratory distress, severe anemia, and refractory hypotension.
  35. Sever Falciparum Malaria • WHO has established clinical and laboratory criteria for severe P. falciparum malaria, which must be treated as an emergency requiring intensive medical care. • Severe malaria is defined as presence of P. falciparum parasitemia and one or more of the manifestations of severe malaria and with reasonable exclusion of an alternative diagnosis. • Severe complications of P. falciparum infection, including cerebral malaria, severe anemia, respiratory distress, renal failure, and severe malaria of pregnancy occurs.
  36. Diagnostic features of Severe malaria
  37. Severe falciparum malaria Unarousable coma/cerebral malaria Failure to localize or respond appropriately to noxious stimuli; coma persisting for >30 min after generalized convulsion,GCS <11 Acidemia/acidosis Arterial pH of <7.25, base deficit >8 meq/L, or plasma bicarbonate level of <15 mmol/L; venous lactate level of >5 mmol/L; manifests as labored deep breathing, often termed “respiratory distress” Severe normochromic, normocytic anemia (Hb< 5g/dl, packed cell volume < 15% in children; <7g/dl, PCV < 20% in adults) Renal failure Serum or plasma creatinine level of >265 μmol/L (>3 mg/dL); urine output (24 h) of <400 mL for adults or <12 mL/kg for children; no improvement with rehydration Pulmonary edema/ARDS Noncardiogenic pulmonary edema, often aggravated by overhydration,(Oxygen saturation < 92% on room air with a respiratory rate > 30/min,often with chest indrawing and crepitations on auscultations) Hypotension/ shock Systolic blood pressure of <50 mmHg in children 1–5 years or <80 mmHg in adults; core/skin temperature difference of >10°C; capillary refill >2 s Convulsions More than two generalized seizures in 24 h; signs of continued seizure activity, sometimes subtle (e.g., tonic clonic eye movements without limb or face movement)
  38. Severe falciparum malaria Hemoglobinuria Macroscopic black, brown, or red urine; not associated with effects of oxidant drugs and red blood cell enzyme defects (such as G6PD deficiency) Bleeding/DIC Significant bleeding and hemorrhage from the gums, nose, and gastrointestinal tract and/or evidence of DIC Hypoglycemia Plasma glucose level of <2.2 mmol/L (<40 mg/dL) Extreme weakness Prostration; inability to sit unaided Hyperparasitemia Parasitemia level of >5% in nonimmune patients (>10% in any patient) Jaundice Serum bilirubin level of >50 mmol/L (>3 mg/dL) if combined with a parasite density of 100,000/μL or other evidence of vital-organ dysfunction
  39. Severe Falciparum Malaria • Cerebral Malaria is a characteristic and ominous feature of falciparum malaria and, even with treatment, has been associated with death rates of ~20% among adults and 15% among children. • Cerebral malaria is a syndrome characterized by diminished consciousness, seizures, or both. • Risk factors for cerebral malaria include age (children and older adults), pregnancy, poor nutritional status, host genetic susceptibility, and history of spleenectomy..
  40. Cerebral Malaria • Cerebral malaria manifests as diffuse symmetric encephalopathy; focal neurologic signs are unusual. • Some passive resistance to head flexion may be detected, signs of meningeal irritation are absent • Muscle tone may be either increased or decreased • The tendon reflexes are variable, and the plantar reflexes may be flexor or extensor • Flexor or extensor posturing may be seen
  41. Cerebral Malaria • 30–40% retinal hemorrhages • Convulsions: usually generalized but can be subtle, partial motor with secondary generalisation occur in ~10% of adults and upto 50% of children with cerebral malaria. • The incidence of epilepsy is increased and life expectancy decreased among children.
  42. Cerebral Malaria • Laboratory examination of cerebrospinal fluid (CSF) is generally normal. • Cerebral edema and elevated intracranial pressure may contribute to a fatal outcome. • A CSF glucose concentration below 3.4 mmol/L (61 mg/dL) was the best discriminator of cerebral malaria from presumed viral encephalitis. • Residual deficits may include hemiplegia, cerebral palsy, cortical blindness, deafness, epilepsy, language deficit, and impaired cognition .
  43. Biochemistry Hypoglycemia (<2.2 mmol/L) Hyperlactatemia (>5 mmol/L) Acidemia (arterial pH <7.25, base deficit >8 meq/L, or serum HCO3 <15 mmol/L) Elevated serum creatinine (>265 μmol/L) Elevated total bilirubin (>50 μmol/L) Elevated liver enzymes (AST/ALT 3 times upper limit of normal) Elevated muscle enzymes (CPK ↑, myoglobin ↑) Elevated urate (>600 μmol/L) Features Indicating a Poor Prognosis in Severe Falciparum Malaria Marked agitation Hyperventilation (respiratory distress) Low core temperature (<36.5°C; <97.7°F) Bleeding Deep coma Repeated convulsions Anuria Shock Hematology Leukocytosis (>12,000/μL) Severe anemia (PCV <15%) Coagulopathy Decreased platelet count (<50,000/μL) Prolonged prothrombin time (>3 s) Prolonged partial thromboplastin time Decreased fibrinogen (<200 mg/dL) Parasitology Hyperparasitemia Increased mortality at >100,000/μL High mortality at >500,000/μL >20% of parasites identified as pigment-containing trophozoites and schizonts >5% of neutrophils contain visible malaria pigment
  44. Differential diagnosis • Influenza: Prominent upper respiratory symptoms (rhinorrhea, sore throat, or dry cough) may help to distinguish influenza from malaria. • Enteric Fever: Prominent gastrointestinal symptoms (abdominal pain, constipation or diarrhea), the findings of rose spots or relative bradycardia, and a history of unsanitary food or water consumption • Dengue Fever: Myalgias tend to be much more severe than those experienced during malaria episodes. • Incubation period is 4-5 days in dengue ,usually more than 7 days in malaria • Centrifugal rash, petechiae, lymphadenopathy, conjunctival injection, pharyngeal erythema, and relative bradycardia
  45. Differential diagnosis • Leptospirosis: findings of conjunctival suffusion or rash but may progress to hepatic and renal insufficiency marked by hemorrhagic manifestations and extremely high bilirubin (Weil syndrome) • Bacteremia/Sepsis:The fever, hypotension, evidence of poor peripheral perfusion, altered mental status, and multiorgan dysfunction that characterize bacteremia and sepsis can mimic severe malaria • Acute Schistosomiasis (Katayama Fever) :generalized urticaria and the findings of a pruritic rash at the site of cercarial penetration (usually on the legs), lymphadenopathy, and blood eosinophilia • Yellow Fever:conjunctival suffusion or relative bradycardia and short incubation period (average, 3–6 days)
  46. Diagnosis • Thick and Thin Blood Smears • Thick smears concentrate red cell layers approximately 40-fold and are used to screen a relatively large amount of blood for the presence of parasite • Giemsa-stained thin smears are prepared from a much smaller amount of blood than thick smears and are used to determine the Plasmodium species • P. falciparum infection may not be apparent on an initial blood smear if the parasites are predominantly mature cytoadherent forms (i.e.,trophozoite and schizont-infected erythrocytes) and are sequestered in the microvasculature • If the initial blood smear is negative and malaria remains possible, the smear should be repeated every 12 hours for a total of three sets before ruling out malaria .
  47. Thick blood films of Plasmodium falciparum. A. Trophozoites. B. Gametocytes Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Gametocytes
  48. Rapid Diagnostic Tests • The first type is based on the detection of Plasmodium histidine-rich protein-2 (HRP-2): had 96% sensitivity and 99% specificity for Plasmodium infection when compared with microscopy • The second type of RDT is based on detection of P. falciparum–specific lactate dehydrogenase (LDH) and pan-Plasmodium LDH:test had 80% sensitivity and 98% specificity for Plasmodium infection when compared with microscopy • Molecular diagnosis by polymerase chain reaction (PCR) amplification of parasite nucleic acid is more sensitive than microscopy or rapid diagnostic tests for detecting malaria parasites and defining malarial species used in making the distinction between recrudescence and re- infection, as well as in other specialized epidemiological investigations.
  49. Treatment Hospitalization is appropriate for patients in the following categories, who may deteriorate rapidly • Young children • Immunocompromised patients • Individuals with no acquired immunity (ie, individuals from nonendemic areas) • Patients with hyperparasitemia (4 to 10 percent) but no signs of severe infection such patients are at increased risk for progression to severe malaria and/or treatment failure.
  50. Treatment
  51. Treatment • The 4 major drug classes currently used to treat malaria includes • Quinoline-related compounds • Antifolates- sulfonamides, pyrimethamine, proguanil, and dapsone • Artemisinin derivatives- Artemether, Arteether, dihydroartemisinin, and Artesunate • Antimicrobials-Tetracycline, doxycycline and clindamycin
  52. Quinoline derivatives Chloroquine,amodiaquine,quinine, quinidine, mefloquine, primaquine, lumefantrine, tafenoquine and halofantrine. Drugs act by accumulating in the parasite food vacuole and forming a complex with heme that prevents crystallization in the Plasmodium food vacuole. • These drugs have activity against the erythrocytic stage of infection; primaquine also kills intrahepatic forms and gametocytes. • Tafenoquine is a new drug,is a long-acting 8-aminoquinoline that targets P. vivax hypnozoites. • It can be used as single-dose for prevention of P. vivax relapse and for prophylaxis of malaria, including P. falciparum and P. vivax.
  53. Quinoline derivatives • Side effects of chloroquine include headaches, dizziness, abdominal discomfort, vomiting, and diarrhea • The adverse effects of quinine and quinidine include a complex of symptoms referred to as cinchonism: tinnitus, nausea, headaches, dizziness, and disturbed vision • Adverse effects of mefloquine include vomiting and dizziness. • Mefloquine is contraindicated for individuals with neurologic and psychiatric disorders. • Both primaquine and tafenoquine can cause hemolytic anemia in patients with G6PD deficiency;
  54. Artemisinin derivatives- • The artemisinins are derived from the leaves of the Chinese sweet wormwood plant, Artemisia annua. • Artemisinins appear to act by binding iron, breaking down peroxide bridges, leading to the generation of free radicals that damage parasite proteins . • They act rapidly, killing blood stages of all Plasmodium species and reducing the parasite biomass. • Artemisinins have the fastest parasite clearance times of any antimalarial. • Artemisinins are active against gametocytes.
  55. Adverse effects • Transient neurologic abnormalities, including nystagmus and disturbances in balance • Transient neutropenia • Hypersensitivity reactions • Possible Teratogenic in first trimester Artemisinin-based combination therapy combines the highly effective short-acting artemisinins with a longer-acting partner to protect against artemisinin resistance and to facilitate dosing convenience.
  56. Treatment • Treatment of uncomplicated P.vivax, P.ovale, P.malariae or P.knowlesi • First line treatment The first line treatment is chloroquine (CQ) for 3 days. Day 1: chloroquine is given at an initial dose of 10 mg base/kg body weight. Day 2: followed by 10 mg/kg body weight. Day 3: 5 mg/kg body weight • Second line treatment The recommended 2nd line option in Nepal is dihydroartemisinin + piperaquine (DHA/PPQ) • DHA/PPQ is given over 3 days : dihydroartemisinin at a dose of 4 mg/kg bw per day and 18 mg/kg bw per day piperaquine once a day for 3 days
  57. • A second line antimalarial (DHA/PPQ) should be used in the following situations: • Where a patient does not tolerate or has adverse reactions to the first line medicine. • Recrudescence (treatment failure) - reappearance of symptoms and parasites within 28 days following initial antimalarial treatment of the 1st line drug • Suspected chloroquine resistant vivax infection – all cases imported from areas with chloroquine-resistant infections (Mekong Region, Countries in South America and Africa, Indonesia, Timor Leste and PNG) should be considered as potentially CQ resistant and treated with 2nd line medicine.
  58. • Anti-relapse treatment P. vivax malaria should be treated in children and adults (except pregnant women, infants aged <6 months, and women breastfeeding infants <6 months) with a 14-day course of primaquine at 0.25 mg/kg body weight per day • Primaquine generates reactive intermediate metabolites that are oxidant and cause variable haemolysis in G6PD-deficient individuals. The severity of haemolytic anaemia depends on the dose of primaquine and on the variant of the G6PD enzyme.
  59. Treatment of P. falciparum malaria • Uncomplicated falciparum malaria • World Health Organization (WHO) recommends use of artemisinin combination therapy (ACT) for treatment of uncomplicated P. falciparum malaria (irrespective of chloroquine sensitivity) • First line treatment:The first line treatment for falciparum malaria is artemether + lumefantrine (AL) given over three days and a single dose primaquine (0.25 mg/kg single dose) on the first day of malaria treatment to nonpregnant adults and children ≥6 months • Target dose range of artemether + lumefantrine (AL): Total dose of 5-24 mg/kg -artemether and 29-144 mg /kg lumefamtrine
  60. Treatment of P. falciparum malaria • Second line treatment • dihydroartemisinin + piperaquine (DHA/PPQ) at a dose of dihydroartemisinin 4 mg/kg bw per day and 18 mg/kg bw per day piperaquine once a day for 3 Days and a single dose primaquine. • A second line antimalarial should be used in the following situations: • Patients not tolerating or adverse reactions to the first line medicine. • Recrudescence (treatment failure) - reappearance of symptoms and parasites within 28 days following initial antimalarial treatment of the 1st line drug.
  61. Severe Falciparum malaria • The antimalarial medicine recommended for the treatment of severe malaria is an initial treatment with injectable (IV/IM) artesunate followed by a full course of AL as soon as the patient is stable enough and able to tolerate oral medication • Artesunate • Recommended Dosage for injectable artesunate: • Children less than 20kg – artesunate 3.0 mg/kg bw • Older children and adults – artesunate 2.4mg/kg bw Dosage regimen - Give 3 parenteral doses of injection artesunate in the first 24 hours • first dose on admission (time zero), • second dose 8 hours after the first dose and • third dose at 24 hours after the first dose. • Thereafter every 24 hours until patient is able to tolerate oral medication
  62. Severe Falciparum malaria • ACTs have a low side effect profile, are potent against all blood stages (asexual forms) of malaria, and have the most rapid clearance time relative to other antimalarial drugs. • Artemisinins should be administered with a second agent that has a longer half-life than the artemisinin drug. • Administration of artemisinins alone would result in recrudescence (treatment failure). • No ACT has been proven to be superior to any other.
  63. Malaria in pregnancy • ƒ Non falciparum malaria should be treated with CQ as in non-pregnant women ,however the use of primaquine to prevent relapse is contraindicated in pregnancy and lactating mothers • Chloroquine (25mg/kg) over 3 days to cure the current blood stage infection, then • CQ 300mg every week as chemoprophylaxis for the remaining duration of the pregnancy and until the breastfed baby is up to 6 months of age. • This is to prevent development of clinical disease by hypnozoites released intermittently from the liver. • Once the breastfeed baby is older than 6 months of age, the mother should receive a 14 course of primaquine to ensure radical cure.
  64. Falciparum malaria in pregnancy • Uncomplicated Falciparum malaria is treated in pregnant women all trimesters and lactating mothers with the first line ACT (AL) as in non- pregnant women. • During the first trimester, the World Health Organization (WHO) recommends treatment of uncomplicated P. falciparum malaria with quinine plus clindamycin for seven days • ACT in second and third trimester. • Complicated falciparum malaria -Parenteral artesunate is the treatment of choice in all trimesters.
  65. MALARIA PREVENTION • PERSONAL PROTECTION AGAINST MALARIA: • avoidance of exposure to mosquitoes at their peak feeding times (usually dusk to dawn) • the use of insect repellents containing 10–35% DEET (or, if DEET is unacceptable, 7% picaridin), • Suitable clothing, and ITNs or other insecticide-impregnated materials.
  66. CHEMOPROPHYLAXIS Administration of a medicine, at predefined intervals, to prevent either the development of an infection or progression of an infection to manifest disease. • The choice of prophylaxis depends on the several factors including the species, resistant profile to antimalarial medicine in the destination country • Mefloquine:250 mg (one tablet) once per week. • It is preferable to start 2–3 weeks before arrival in the malaria-risk area to achieve higher pre-travel blood levels and to allow side effects to be detected before travel so that possible alternatives can be considered • Continue the drug for 4 weeks after leaving malaria-risk zone
  67. CHEMOPROPHYLAXIS • Minor side effects (fairly common): Headache, nausea, dizziness, sleep disturbance, anxiety, vivid dreams, visual disturbance. Do not usually require stopping the drug. Rare side effects: Seizures, depression, psychosis. Stop the drug if serious ADR occur. • Can be used in pregnancy
  68. Doxycycline: 100 mg once daily. Should be taken at same time each day • Begin 1 or 2 days before arrival in the malaria-risk and Continue for 4 weeks after leaving malaria-risk area • Minor side effects (fairly common): Sun sensitivity, vaginal yeast infection, nausea, gastro-esophageal reflux • Contraindications: <8yr,pregnancy Atovaquone/Proguanil (Malarone):250 mg/100mg • Should be started 1-2 days prior to travel and continued for 1 week after the visit to the malaria-risk area • rare side effects but high cost Chloroquine: 300 mg base weekly in 1 dose. • Start 1 week before departure and continue for 4 weeks after return • Recommended for prophylaxis to areas with only vivax transmission
  69. Vaccination • RTS,S/ASO1 vaccine:WHO approved the RTS,S vaccine in October 2021 for children in Sub-Sahara Africa and other regions with high transmission • "RTS" stands for "repeat T epitopes" derived from the circumsporozoite protein, "S" stands for the S antigen derived from hepatitis B surface antigen (HBSAg), and AS01 is a proprietary adjuvant • recombinant fusion protein created based on an antigen target consisting of a repetitive sequence of four amino acids in the circumsporozoite antigen on the surface of the P. falciparum sporozoite • 4 doses in children from 5 months of age • R21/MM vaccine:the R21 vaccine is a virus-like particle based on the circumsporozoite protein from P. falciparum strain NF54, fused to the N- terminus of HBsAg; it is manufactured using Matrix-M, a proprietary adjuvant
  70. • Recrudescence occurs most often within days or weeks • Relapse occurs within weeks or months. • In recrudescence, parasites remain in the bloodstream undetected due to ineffective treatment or host immunological response (or both). • In relapse, new blood stage parasites are released from dormant parasite stages (hypnozoites) in liver cells, causing a repeat episode of peripheral parasitemia. • P. falciparum is the usual cause of recrudescent infection, although P. malariae can remain present at low levels of parasitemia for years prior to clinical presentation. • P. vivax and P. ovale may cause relapse months after the primary blood stage infection is cured, as these species have hypnozoite forms.
  71. HIV and malaria • HIV and malaria often coexist. • HIV infection is associated with increased susceptibility to malaria, higher parasitemia, and increased risk for recurrent malaria infection, particularly in patients with CD4 counts <200 cells/microL. • HIV and malaria independently lead to anemia. Coinfection may be associated with anemia of greater severity among children P. falciparum infection in children. • In addition, malaria infection in patients with HIV infection has been associated with more rapid CD4 cell decline relative to patients with HIV infection in the absence of malaria.
  72. • References • Mandell, Douglous Principle of practice of infectious disease • Harrison Principle of Medicine • National Guideline of Nepal
  73. Thank You

Notes de l'éditeur

  1. Apicomplexa are distinguished morphologically by the presence of a specialized complex of apical organelles (i.e., micronemes, rhoptries, and dense granules) involved in host cell invasion
  2. but this may not be an absolute requirement considering that P. vivax infections occur in DARC-negative populations of Africa.
  3. P. falciparum erythrocyte membrane protein 1
  4. biomass (e.g., intraleukocytic pigment, mature trophozoites, and schizonts) on peripheral blood smears are associated with increased severity of malaria and death
  5. he classic histopathologic finding of fatal cerebral falciparum malaria is the intense sequestration of infected erythrocytes in cerebral microvessels
  6. Febrile patients presenting within 7 days of entering anendemic area are unlikely to have malaria, unless there has been earlier exposure to infective mosquito bites. all travelers who have visited a malaria-endemic area in the 3 months before onset of fever or other suggestive symptoms should be considered to have malaria until proven otherwise.
  7. Seizures and severe anemia are more common in children, whereas hyperparasitemia, ARDS, and jaundice are more common in adults 
  8. In asplenic individuals, P. falciparum malaria can progress extremely rapidly to high parasitemias that include mature forms not usually found circulating in the bloodstream.
  9. Large amounts of hemoglobin and malarial pigments may be present in the urine secondary to intravascular hemolysis. This uncommonly manifests in very dark urine following several attacks of falciparum malaria; mortality is high
  10. ARDS-The pathogenesis is uncertain but may be related to sequestration of parasitized red cells in the lungs and/or cytokine-induced leakage from the pulmonary vasculature. 
  11. Latent attacks from the reactivation of P. vivax or P. ovale hypnozoites usually occur within 3 years and are rare more than 5 years after exposure Recrudescence of P. malariae symptoms in individuals with subclinical parasitemia has been reported decades after initial infection
  12. When possible, suspected treatment failure should be confirmed parasitologically, with microscopy or rapid diagnostic tests (RDTs). RDTs based on lactate dehydrogenase are preferred for diagnosis of treatment failure, since RDTs based on histidine-rich protein 2 may remain positive for weeks after treatment of the initial infection, in the absence of recrudescence
  13. The total artemisinin dose (10 to 12 mg/kg) is given over three days.  reinfection may be assumed in the setting of fever and parasitemia >28 days following treatment
  14. An orally disintegrating flavored tablet is available in some areas. Take after a full meal or whole milk. If patient vomits within 30 minutes of taking a dose, he or she should repeat the dose. Ideally, the first two doses should be taken 8 hours apart.
  15. No ACT has been proven to be superior to any other; the compounds differ slightly in their stability, oral absorption, bioavailability, metabolism, and adverse event profile.