Malaria: Introduction and Epidemiology

Introduction to Malaria

• Malaria is a protozoan disease transmitted via bites from infected Anopheles mosquitoes.
• Malaria impacts 107 countries, affecting 3 billion people and causing 1-3 million deaths annually.
• It has been eradicated from some countries, but has reemerged in many tropical regions.
• Resistance is developing in both the parasite and the mosquito vector.

Epidemiology of Malaria

• Malaria is present in most tropical regions.
• The global prevalence is 500 million cases per year.
• Malaria causes 2 million deaths per year.
• 40% of the global population in tropical/subtropical climates are at risk of malaria.
• In 2020, there were 241 million malaria cases worldwide.
• 627,000 malaria deaths were reported globally in 2020.
• Sub-Saharan Africa accounts for 96% of malaria deaths.
• Children under the age of five account for 77% of malaria deaths.
• Endemicity is defined by parasitemia or palpable-spleen rates in children aged 2-9 years, ranging from hypo- to holo-endemic.
• The infant parasite rate is a sensitive indicator of malaria transmission in a locality.
• Endemicity based on parasitemia or spleen rates in children 2-9 yoa:
  • Hypoendemic: <10%
  • Mesoendemic: 11-50%
  • Hyperendemic: 51-75%
  • Holoendemic: >75%

Etiology of Malaria

• Five species of the Plasmodium genus cause the vast majority of malarial infections in humans:
  • P. falciparum, P. vivax, P. ovale, P. malariae, P. knowlesi
• Plasmodium falciparum and vivax are the most common causes in Ethiopia.
• Almost all deaths are caused by falciparum malaria.
• P. knowlesi and P. vivax can also cause severe illness.

Malaria in Ethiopia

• Malaria is a leading public health problem in Ethiopia.
• 75% of Ethiopia is malarious (below 2000m), putting ≈50 million (68% of the population) at risk
• Malaria impedes socio-economic development and coincides with planting/harvesting.
• Major Malaria Parasites in Ethiopia:
  • P. falciparum (≈60%)
  • P. vivax (≈40%)
  • P. malariae (rare)
• Major Malaria Vectors in Ethiopia:
  • An. arabiensis (primary vector, part of the An. gambiae complex)
  • An. funestus
  • An. phareonsis
  • An. nili

Malaria Epidemiology in Ethiopia

• Transmission follows a bimodal pattern:
  • Major transmission: September to December, after the main rainy season (June to August)
  • Minor transmission: April to May, after a short rainy season (February to March)
• Major epidemics occur every 5-8 years; focal outbreaks are also common.
• Distribution changes with climate and altitude.
• Malaria in Ethiopia is unstable, characterized by:
  • Seasonality
  • Lack of immunity
  • Common epidemics
  • Affects all age groups
• In stable malaria:
  • Transmission is intense and perennial.
  • There is high immunity.
  • Epidemics are uncommon.
  • Children and pregnant women are most affected.

Malaria Burden in Ethiopia (Figures)

• Over 600,000 confirmed cases and more than 9 million clinical cases annually.
• Around 70,000 deaths per year.
• Health indicators from 2005/06:
  • 18% of OPD cases are due to malaria (1st)
  • 14% of hospital admissions are due to malaria (2nd)
  • 9% of hospital deaths are due to malaria (2nd)
• There has been a reduction in malaria.

Transmission of Malaria

• Malaria can be transmitted through three modes:
  • Bite of an infected female Anopheles mosquito
  • Blood transfusion or needle stick injury
  • Congenital transmission from mother to baby

Life Cycle of Malaria Parasites

• Mosquito Stage (Sexual): Female Anopheles mosquito ingests gametocytes from infected blood.
• The gametocytes develop sexually in the mosquito's gut, forming ookinetes, then oocytes, and finally sporozoites.
• Human Stage (Asexual): The mosquito inoculates sporozoites into the human host as it feeds
• The sporozoites travel through the bloodstream to the liver in about 30 minutes.
• Sporozoites invade hepatocytes and mature into tissue schizonts (pre-erythrocytic schizogony).
• Tissue schizonts produce a large number of merozoites within each sporozoite-infected hepatocyte.
• Swollen infected liver cells rupture to discharge merozoites into the bloodstream.
• Merozoites invade red blood cells (RBCs) and become trophozoites.
• The cycle continues: Merozoite → ring stage → mature trophozoite → schizont → merozoites (Asexual)
• Some intra-erythrocytic parasites develop into sexual forms (gametocytes), leading to sexual cycle.
• When parasite densities reach ~50/µL of blood (~100 million parasites in total in an adult) the symptomatic stage of infection begins
• P. vivax and P. ovale intrahepatic forms do not divide immediately but remain inert for 2 weeks to ≥1 year (Hypnozoite), resulting in subsequent relapses.

Pathogenesis of Malaria

• Four plasmodium species cause nearly all malarial infections in humans: P. falciparum (≈60%), P. vivax (≈40%), P. malariae (rare), P.ovale.
• Almost all deaths result from P. falciparum infections.
• Human disease results from the direct effects of RBC invasion/destruction by the asexual parasite, along with the host's immune response.

Erythrocyte Changes in Malaria

• Hemoglobin is consumed and degraded.
• Heme is detoxified into nontoxic hemozoin (malaria pigment).
• Alterations occur in the RBC membrane.
  • Changing transport properties.
  • Exposing cryptic surface antigens.
  • Inserting new parasite-derived proteins.
• RBCs become more irregular, antigenic, and less deformable.
• In Pf infections, membrane protuberances appear on infected erythrocytes 12-15 hours post-invasion.
• "Knobs" extrude HMW, antigenically variable, strain-specific erythrocytic membrane adhesive protein (PfEMP).
  • This mediates attachment to venular/capillary endothelium, termed cytoadherence.
• Vascular receptors involved in cytoadherence:
  • ICAM-1 is important in the brain.
  • Chondroitin sulfate B is important in the placenta.
  • CD36 in is important in most other organs.
• Infected erythrocytes stick to capillary/venule walls, causing blockages.
• Infected RBCs adhere to uninfected RBCs forming rosettes.
• Cytoadherence, rosetting, and agglutination are central to the pathogenesis of Pf malaria.
• These processes lead to:
• Sequestration of infected erythrocytes
• Escape from host defense mechanisms
• Underestimation of parasite levels
• Decreased deformability of uninfected RBCs

Host Response

• Non-specific defense mechanisms exist.
• Certain genetic disorders confer protection.
• Formation of specific immunity occurs.
• Several factors can retard the development of cellular immunity:
  • Absence of MHC antigens on infected RBCs
  • Malaria antigen-specific unresponsiveness
  • Enormous strain diversity
  • Antigen variation

Clinical Features of Malaria

• Malaria is a common cause of fever in tropical countries
• Symptoms are non-specific
• Depend on type of malaria:
  • P. falciparum: most dangerous
    • Gradual onset
    • Malaise, headache, vomiting
    • Fever
    • Cough, diarrhea
    • Jaundice
    • Tender hepatosplenomegaly
    • Anemia develops rapidly
  • P. vivax and P. ovale:
    • Fever every 48 hours
    • Rigors
    • Gradual hepatosplenomegaly
    • Anemia develops slowly
    • Relapse is common
  • P. malariae: - Fever every third day - Mild symptoms - Parasitemia may persist for many years - Causes glomerulonephritis and nephrotic syndrome in children

Complications of P. falciparum malaria

• Cerebral malaria (coma)
• Convulsions
• Hyperpyrexia
• Severe anemia
• Metabolic (Lactic) Acidosis
• Jaundice
• Renal failure
• Pulmonary edema & ARDS
• Hypoglycemia
• Hypotension & shock
• Bleeding & clotting disorder
• Hemoglobinuria

Other Complications of Malaria

• Rupture of spleen
• Hepatic dysfunction
• Thrombocytopenia
• Severe anemia
• Malarial nephropathy

Predisposing Factors for Complications

• Extremes of age.
• Pregnancy, especially in primigravidae and in 2nd half of pregnancy.
• Immunosuppressed patients, such as those on steroids or anti-cancer drugs.
• Immunocompromised individuals, such as patients with tuberculosis, HIV and cancers.
• Splenectomy
• Lack of previous exposure to malaria (non-immune) or lapsed immunity
• Pre-existing organ failure

Severe Malaria

• Appropriately treated uncomplicated falciparum malaria carries a mortality rate of <0.1%.
• The mortality risk rises steeply when total proportion of infected erythrocytes increases to >2% with target organ damage.
• Manifestations of Severe Falciparum Malaria (TABLE 219-2):
  • Major Signs:
    • Unarousable coma/cerebral malaria
      • Failure to localize or respond appropriately to noxious stimuli; coma persisting for >30 min after generalized convulsion
    • 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
      • Hematocrit of <15% or hemoglobin level of <50 g/L (<5 g/dL) with parasitemia level of <10,000/μL
    • 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
• Manifestations of Severe Falciparum Malaria (CONT):
  • Pulmonary edema/adult respiratory distress syndrome
    • Noncardiogenic pulmonary edema, often aggravated by overhydration
  • Hypoglycemia
    • Plasma glucose level of <2.2 mmol/L (<40 mg/dL)
  • 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
  • Bleeding/disseminated intravascular coagulation
    • Significant bleeding and hemorrhage from gums, nose, gastrointestinal tract and/or evidence of disseminated intravascular coagulation
  • 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)
• Additional Manifestations of Severe 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)
  • 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
  • Hemoglobinuria may also occur in uncomplicated malaria and in patients with G6PD deficiency who take primaquine

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

Cerebral Malaria

• Causes of neurological manifestations in malaria are:
  • High-grade fever
  • Antimalarial drugs
  • Hypoglycemia
  • Hyponatremia
  • Severe anaemia
• Coma is a characteristic and ominous feature (MR 15-20% despite treatment).
• 10% of all admissions and 80% of deaths are due to C.N.S. involvement
• Any obtundation, delirium, or abnormal behavior should be taken seriously.
• Cerebral malaria manifests as diffuse symmetrical encephalopathy
• No meningeal sign
• Primitive reflexes are absent
• Corneal reflexes are reserved
• Muscle tone either increase or decrease
• Flexor or extensor posturing may be seen.
• Approximately 15% of pts have retinal haemorrhage
• Generalized convulsion(50%)
• Neurological deficit in 3-15%
• 10% of children has language deficit
• The incidence of epilepsy increase
• Life expectancy decrease among these children.

Hypoglycemia

• Plasma glucose level of <2.2mmol/l(<40mg/dl)
• Indicate poor prognosis
• Dxic difficulty
• Causes:
  • Failure in hepatic gluconeogensis
  • Increase consumption
  • drugs

Acidosis/Acidemia

• Arterial PH<7.25 or plasma bicarbonate level of < 15mmol/l; venous lactate level of>5mmol/l
• Manifests as laboured deep breathing often termed "respiratory disteress”
• Is a sign of poor prognosis
• Results from accumulation of organic acid.
• In adults, coexisting renal impairment often compounds the acidosis
• Other still-undefined organic acids are major contributor of acidosis.
• The plasma concentration of bicarbonate or lactate are the best biochemical progonosticators in severe malaria
• Often followed by circulatory failure
• Causes:
  • Anaerobic glycolysis
  • Hypovoleumia
  • Lactate production
  • Decreased clearance
• the prognosis of severe acidosis is poor.

Noncardiogenic Pulmonary Edema

• Pathogenesis of this variant of ARDS is unclear.
• The MR is >80%
• This condition can be aggravated by overly vigorous administration of IV fluids

Renal Impairment

• Common among adults
• Pathogenesis is unclear but may be related to erythrocyte sequestration in renal microcirculatory flow and metabolism.
• Clinically and pathologically, this syndrome manifests as ATN, but renal cortical necrosis never occur.
• ARF may occur with other vital-organ dysfunction in w/c case mortality will be high
• Early dialysis or hemofiltration considerably enhances the likelihood of a patient's survival, particularly in acute hyper catabolic renal failure.
• In survivors urine flow resumes within 4 days and serum creatnine normalizes with in 17 days.

Hematologic Abnormalities

• Anaemia occurs as a result of:
  • Accelerated all RBC removal by the spleen
  • Obligatory RBC destruction at parasite schizogony
  • Ineffective erythropoiesis
• In severe malaria both infected and uninfected RBCs show reduced deformability, which correlates with prognosis and development of aneaemia.
• In areas with unstable transmission anemia can develop rapidly and transfusion is often required.
• Anaemia is a common consequence of ant malarial drug resistance, which results in repeated or continued infection.

Liver Dysfunction

• Mild to severe jaundice
• Results from haemolysis, hepatocyte injury and cholestasis
• Associated with hypoglycaemia, acidosis & impaired drug metabolism
• Carries poor prognosis when associated with other vital organ dysfunction

Other Complications

• Septicaemia may complicate severe malaria, particularly in children
• In endemic areas Salmonella bacteraemia has been associated specifically with Pf infection
• In comatose pts(for >3 days) chest infection, catheter induced UTI, aspiration pneumonia
• Recrudesce, relapse, re infection

Malaria in Pregnancy

• Low birth wt(~ reduction in BWT of 170 gm)
• In areas with unstable transmission severe infection results in- oedema, fetal distress, premature labour, and still birth or LBW.

HIV & Malaria

• HIV infection is associated with increased susceptibility, higher parasitemia, and an increased risk for recurrent malaria infection, particularly in patients with CD4 counts <200 cells/microL
• Dual infection with HIV and malaria during pregnancy leads to adverse maternal and perinatal outcomes.
• ART decreases the incidence of malaria in malaria-endemic areas

Transfusion Malaria

• Can be transmitted via blood transfusion, needle prick injury, sharing of needles by infected injection drug users, or organ transplantation.
• Incubation period is short b/c no pre erythrocytic stage of development.

Chronic Complication of Malaria

• TROPICAL SPLENOMEGALY (HMS)
• Chronic or repeated malarial infections produce hypergammaglobulinemia, NCNC anaemia, and in certain situations, splenomegaly.
• Abnormal immune response to repeated infection leads to massive splenomegaly, hepatomegaly, marked elevation in serum titer of IgM and malarial antibody

Quartan Malaria Nephropathy

• Chronic or repeated infections with P.malariea may cause soluble immune-complex injury to the renal glomeruli, resulting in nephrotic syndrome.
• The histological appreance is that of focal or segmental GN with splitting of the capillary BM.
• Quartan nephropathy usualy responds poorly to treatment with either antimalarial agents or glucocorticoides, and cytotoxic drugs.

Malaria and Burkitt's Lymphoma

• Malaria related immuno-suppression provkes infection with lymphoma viruses.
• The prevalence of BL is high in malarious areas of Africa.

Diagnosis of malaria

• Can be done via:
  • Clinical diagnosis
  • Microscopic examination of thin and thick blood films
  • Serology (rapid diagnostic test) like the RDT

Light Microscopy

• Examination of Giemsa-stained blood film
• Examination of Thick and Thin Blood Smears
  • Thick smears detect parasite
  • Thin smears used to differentiate species

Treatment and Monitoring

• Treatments include:
  • General management
  • Treating complications
  • Specific anti malarial treatment with two classes of drugs:
    • Cinchona alkaloids (quinine and quinidine)
    • Artemisinin derivatives (artesunate, artemether & artemotil)
• Monitoring includes:
  • Fluid Balance
  • Therapeutic Response
  • Input and output
  • Oxygenation
  • V/s, level of consciousness
  • RBs (4-6hrs)
  • Hct and parasite count (6-12 hrs)
  • RFT- daily

Prevention of Malaria

• Prevention includes:
  • Rapid Dx and Rx.
  • Mosquito Avoidance
  • Remaining in screened areas.
  • Bed nets.
  • Suitable clothing.
  • Applying insect Repellent.
  • Use of insecticides.
• Elimination of mosquito breeding sites.
• Chemoprophylaxis.
• Vaccination- no safe & effective vaccine.

ETHIOPIA MALARIA ELIMINATION STRATEGIC PLAN: 2021-2025

• By 2021 and beyond:
  • Conduct confirmatory testing for 100% of suspected malaria cases and treat all confirmed cases according to the national guidelines
  • Cover 100% of the population at risk of malaria with one type of globally recommended vector control interventions
  • Generate 100% evidence that facilitates appropriate decision-making
  • Build capacity of all levels of the health offices to coordinate and implement malaria elimination interventions
• Goals of the ETHIOPIA MALARIA ELIMINATION STRATEGIC PLAN:
  • By 2025, reduce malaria morbidity and mortality by 50 percent from baseline of 2020.
  • By 2025, achieve zero indigenous malaria in districts with annual parasite incidence less than 10 and prevent reintroduction of malaria in districts reporting zero indigenous malaria cases.
• Strategic Objectives:
  • By 2025, achieve adoption of appropriate behaviour and practices towards antimalarial interventions by 85% households living in malaria endemic areas