Malaria Notes

Malaria

Introduction

• Malaria is a protozoan disease transmitted via the bite of infected female Anopheles mosquitoes.
• It is present in 87 countries, affecting 3 billion people.
• Malaria causes unacceptably high levels of disease and death globally.

Epidemiology

• In 2020:
  • 241 million malaria cases were reported.
  • 627,000 malaria deaths occurred.
  • 96% of deaths were in Sub-Saharan Africa.
  • 77% of deaths were children under five.

Epidemiology in Ethiopia

• Malaria is a leading health problem.
• 75% of the country’s landmass is malaria endemic.
• 52% of the population is at risk of infection.
• Transmission mainly occurs up to 2000 meters elevation.

Classification of Malaria Transmission

1. Stable (endemic)
   • High transmission rates.
   • Not subject to annual fluctuations.
   • High population immunity.
   • Children and pregnant women are most likely to be infected.
   • Epidemics are uncommon.
2. Unstable (epidemic)
   • Seasonal.
   • Lack of immunity.
   • Epidemics are common.
   • All age groups are affected.

Endemicity

Endemicity is defined by parasitemia rates or palpable-spleen rates in children (2-9 years):

1. Hypoendemic: <10%
2. Mesoendemic: 11–50%
3. Hyperendemic: 51–75%
4. Holoendemic: >75%

Trend of Malaria in Ethiopia

• Suspected Malaria Cases
  • 2016: 6,611,801
  • 2017: 6,471,958
  • 2018: 5,913,799
  • 2019: 5,403,951
• Confirmed Malaria Cases
  • 2016: 1,718,505
  • 2017: 1,530,730
  • 2018: 962,087
  • 2019: 904,495
• Malaria-Attributed Deaths
  • 2012: 2173
  • 2013: 1451
  • 2014: 764
  • 2015: 662
  • 2016: 510
  • 2017: 356
  • 2018: 213
  • 2019: 156

Etiology

• Six species of Plasmodium cause nearly all malarial infections in humans:
  • P. falciparum
  • P. vivax
  • P. ovale (curtisi and wallikeri)
  • P. malariae
  • P. knowlesi
• P. falciparum and P. vivax are the most common in Ethiopia.
• Almost all deaths are caused by P. falciparum malaria.
• P. knowlesi and P. vivax can also cause severe illness.

Mode of Transmission and Life Cycle of Parasites

• Modes of transmission:
  • Bite of infected female Anopheles mosquito.
  • Blood transfusion or needle stick injury.
  • Congenital transmission.

Life Cycles

1. Mosquito Stage (Sexual):
   • Female Anopheles mosquito ingests gametocytes from infected individuals.
   • Gametocytes develop sexually in the mosquito’s gut: ookinete >>> oocyte >>> sporozoites.
2. Human Stage (Asexual):
   • Inoculation of plasmodial sporozoites from mosquito's salivary glands during a blood meal.
   • Sporozoites travel to the liver within 30 minutes.
   • Invade hepatocytes and mature to become tissue schizonts (pre-erythrocytic schizogony).
   • Tissue schizonts produce merozoites (10,000 – 30,000) from each sporozoite-infected hepatocyte.
   • Infected liver cells burst, releasing merozoites into the bloodstream.
   • Merozoites invade red blood cells (RBCs) to become trophozoites.
   • Merozoite → ring stage → mature trophozoite → schizont → merozoites (Asexual).
   • Some intra-erythrocytic parasites develop into gametocytes à Sexual cycle.

Parasite Density and Symptomatic Stage

• Symptoms begin when parasites reach densities of ∼50/μL of blood (∼100 million total parasites in an adult).
• In P. vivax and P. ovale, intrahepatic forms do not divide immediately but remain inert (hypnozoite) for 2 weeks to ≥1 year, causing relapses.

Characteristics of Plasmodium Species

Pathophysiology

• Malarial parasite consumes intracellular proteins, mainly hemoglobin.
• Toxic heme is detoxified via lipid-mediated crystallization to hemozoin (malaria pigment).
• RBC membrane is altered, becoming irregular, antigenic, and less deformable.
• P. falciparum can sequester in deep venous microvasculature via:
  • Cytoadherence
  • Rosetting
  • Reduced deformability
  • Agglutination

Host Defence

• Initial response: nonspecific defense mechanisms.
• Augmented splenic immunologic and filtrative clearance.
• Accelerated removal of parasitized and uninfected erythrocytes.
• Induction of monocyte/macrophage activation and the release of pro-inflammatory cytokines à fever.

Clinical Features

• Caused by:
  • Direct effects of RBC invasion and destruction.
  • Host's reaction.
• Symptomatic manifestation:
  • Chills and rigors followed by fever (up to 40°C).
  • Profuse sweating followed by extreme fatigue and sleep.
  • Malaise, perspiration, anorexia, and vomiting are common.
• Fever patterns:
  • Tertian fever paroxysm [P. falciparum, vivax, ovale].
  • Quartan fever paroxysm [P. malariae].
• Prodromal symptoms: headache, lassitude, abdominal discomfort, muscle and joint aches.

Severe Malaria

• Untreated falciparum malaria: mortality rate of <0.1%.
• Mortality risk rises sharply when >2% of erythrocytes are infected (with target organ damage).

Severity Signs

Poor Prognostic Signs\

Clinical

• Marked agitation
• Hyperventilation (respiratory distress)
• Low core temperature (<36.5°C)
• Bleeding
• Deep coma
• Repeated convulsions
• Anuria
• Shock

Laboratory

Biochemistry

• Hypoglycemia (<2.2 mmol/L)
• Hyperlactatemia (>5 mmol/L)
• Acidemia (arterial pH
• Elevated serum creatinine (>265 μmol/L)
• Elevated total bilirubin (>50 μmol/L)
• Elevated liver enzymes (AST/ALT >3x upper limit of normal)
• Elevated muscle enzymes (CPK, myoglobin)
• Elevated urate (>600 μmol/L)

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 or schizonts
• >5% of neutrophils contain visible malaria pigment

Cerebral Malaria

• Coma is an ominous feature.
• Associated with death rates of ~20% among adults and 15% among children.
• Any obtundation, delirium, or abnormal behavior should be taken seriously.
• Manifests as diffuse symmetric encephalopathy.
• Signs of meningeal irritation are absent.
• Corneal reflexes are preserved (except in deep coma).
• Muscle tone may be increased or decreased.
• Tendon reflexes are variable.
• Abdominal and cremasteric reflexes are absent.
• ~15% of patients have retinal hemorrhages.
• Repeated, generalized convulsions occur in ~10% of adults.
• Adults rarely (<3%) suffer neurologic sequelae, but ~10% of children have residual neurologic deficits.

Hypoglycemia

• Associated with a poor prognosis.
• May be due to impaired hepatic glucose production or release and increased tissue uptake.
• Increased glucose consumption by the parasite.
• Particularly problematic in children and pregnant women.
• Results from a failure of hepatic gluconeogenesis and increased glucose consumption.
• May be compounded by quinine, which stimulates insulin production.

Altered Consciousness or Coma

• Caused by sequestration of parasites in the brain.
• Complete obstruction to blood flow is unlikely.
• Hypoglycemia, convulsion, and concomitant CNS infections may contribute.

Convulsions

• May be due to the direct effect of parasites in the brain.
• May result from metabolic disorders (hypoglycemia, acidosis, hyponatremia, hypoxia).
• High temperature may exacerbate these causes or trigger convulsions.
• Unconsciousness occurs during (ictal) and after (post-ictal) the convulsion.

Raised Intracranial Pressure

• Cause is unclear, probably largely due to cerebral edema.
• Contributing factors may include increased mass of sequestered red blood cells and dilatation of vessels.
• Raised intracranial pressure is not the primary cause of coma or death.
• Does not need specific treatment (steroids or mannitol).

Acidosis

• Results from accumulation of organic acids.
• Important cause of death.
• Hyperlactatemia commonly coexists with hypoglycemia.
• Coexisting renal impairment often compounds acidosis (mainly in adults).
• Acidotic breathing (“respiratory distress”) indicates a poor prognosis.
• Plasma concentrations of bicarbonate or lactate are the best biochemical prognosticators.

Noncardiogenic Pulmonary Edema

• Unclear pathogenesis.
• May develop after antimalarial therapy.
• ARDS may be due to a direct effect of parasites sequestered in the lungs (cytokine release).
• Mortality rate >80%.
• May be precipitated by overhydration.
• Unusual in children in endemic areas.

Renal Impairment

• AKI is common in severe falciparum malaria.
• Pathogenesis is unclear; may relate to erythrocyte sequestration interfering with renal microcirculatory flow.
• Renal failure is most likely to develop after low blood pressure or shock.
• Sequestration is also observed in the kidneys; manifests as ATN.
• Fully reversible if the patient survives.

Hematologic Abnormalities

• Mechanism of Anemia
  1. Accelerated RBC removal by the spleen
  2. RBC destruction at parasite schizogony
  3. Ineffective erythropoiesis.
• Develop rapidly in areas with unstable transmission.
• Mild thrombocytopenia is usual with falciparum malaria.
• Fewer than 5% with severe malaria have significant bleeding with evidence of DIC.

Liver Dysfunction

• Severe jaundice is associated with P. falciparum.
• Results from hemolysis, hepatocyte injury, and cholestasis.
• Hepatic dysfunction contributes to hypoglycemia, lactic acidosis, and impaired drug metabolism.

Others

• Hemoglobinuria
  • Results from rapid breakdown of red blood cells in the circulation (massive intravascular hemolysis).
• Jaundice
  • More common in adults; due to hemolysis and liver dysfunction.
• Shock
  • May occur concurrently with bacteremia.

Relative Incidence of Severe Complications of Falciparum Malaria

Malaria in Pregnancy

• Malaria in early pregnancy causes fetal loss.
• Associated with low birth weight (average reduction ~170 g).
• In areas with unstable malaria transmission, pregnant women are prone to severe infections.

Uncomplicated Malaria

• Symptomatic Plasmodium falciparum infection with a positive parasitologic test and parasitemia <4% without severe malaria symptoms.
• Antimalarial selection is guided by chloroquine sensitivity/resistance in the acquisition area and local availability of therapeutic agents.
• Patients on malaria prophylaxis should receive a different treatment medication.
• Chloroquine is suggested for chloroquine-sensitive P. falciparum malaria can be predicted with certainty (region).
• Treatment for chloroquine-resistant P. falciparum should be administered:
  1. Known exposure to a chloroquine-resistant region.
  2. Unknown prevalence of chloroquine resistance.
  3. Uncertain exposure history.
• Artemisinin combination therapy (ACT) is suggested for chloroquine-resistant P. falciparum in endemic areas.
• ACT or atovaquone-proguanil is suggested for chloroquine resistance outside endemic areas.

Treatment at Different Levels of Health Facility

Treatment of Severe Malaria

• Objectives:
  • Prevent death.
  • Prevent recrudescence.
  • Prevent transmission or emergence of resistance.
  • Prevention of disabilities.
• Urgent Measures:
  • Immediate resuscitation (ABC of life).
  • Secure IV line immediately.
  • Correct hypoglycemia:
    • Children: 4ml/kg of 10% dextrose by slow IV infusion.
    • Adults: 40–60ml of 40% dextrose as IV bolus.
    • Sugar solution by nasogastric tube (NGT) if IV access is difficult.
    • Measure RBS every 2-4 hours.
  • Rectal paracetamol if temperature is above 39°C.
  • Convulsions:
    • Diazepam by slow intravenous injection (0.15ml/kg body weight, maximum 10mg for adults) if convulsions continue for >5 minutes.
    • Second dose of diazepam after 10 minutes if needed.
    • Phenytoin 18mg/kg infused over 20 minutes, followed by 2.5mg/kg twice daily for 48 hours if seizures continue.
  • Assess fluid requirements.
  • Reduce body temperature if >39.5ºC.
  • Consider blood transfusion.
  • Consider urinary catheter insertion.
  • Consider central venous pressure line.
  • Consider intubation.
  • Consider antibiotics for concomitant bacterial infection.

Specific Antimalarial Treatment

1. Artesunate:
   • 2.4 mg/kg IV on time 0 (admission), 12h and 24h after admission for > 20kg
   • For children under 20kg The dose of Artesunate is 3mg/kg
   • IM artesunate (2.4 mg/kg on time 0 (admission), 12h and 24h after admission
   • Discontinue when patient tolerates oral treatment any time after 24 hours of parenteral artesunate
2. Artemether:
   • Adults and children –
     • 3.2 mg/kg body weight on first day
     • 1.6 mg/kg body weight second and third day
     • Administration: IM (NEVER ADMINISTER BY IV ROUTE)
3. Quinine Dihydrochloride:
   • Alternative parenteral treatment when artesunate and artemether are not available.
     • Adults and children –
       • 20 mg/kg body weight on first dose (loading dose)
       • 10 mg/kg body weight eight hours after start of loading dose (maintenance dose)
       • Administration: IV or IM (IV preferred and IM is provided if IV is not possible)

• Parenteral antimalarials should be given for a minimum of 24 hours (48 hours for quinine), once started ( irrespective of the patient’s ability to tolerate oral medication earlier).

Appropriate actions (in case of abnormality)

Breathing

Increased rate or difficulty, Deep breathing in children -> Review urine output and fluid balance. Assess lung, heart and liver size. Chest X-ray if available. If pulmonary oedema is demonstrated, or seems likely, prop the patient up, give oxygen, IV frusemide 2-4mg/kg. Treat acidosis with normal saline and bicarbonate.

Body Temperature

Rectal temperature: > 40°C OR axillary temperature: > 39.5°C -> Give paracetamol (rectal or oral) if not already given within past 4 hours. Tepid sponging and fanning. Aspirin can be given to adults (instead of paracetamol) but not to children. If temperature remains high or rises despite 24 hours of antimalarial therapy, reconsider your diagnosis, while continuing treatment

Blood Pressure

Falls < 80mmHg systolic in an adult, and

Fluid Balance

Oliguria:

Coma

Deterioration Score -> Immediately check blood glucose. Reconsider other diagnoses, provide appropriate nursing care for the unconscious patient.

Treatment of Severe Malaria in Pregnancy

• Parenteral artesunate is more effective than parenteral quinine in reducing the risk of death from severe malaria
• Artesunate (IV or IM) is the preferred drug for all severe forms of malaria in all trimesters of pregnancy
• IM Artemether is the second option while Quinine (IV or IM) may be considered as the last option
• After 24 hours of parenteral drug administration, treatment should be completed with full dose of AL including the first trimester
• Treat pregnant women with uncomplicated P. falciparum malaria during the first trimester with 7 days of quinine + clindamycin .

Treatment Failure

• Majority of treatment failures occur more than 2 weeks after treatment
• Recurrence of malaria can be the result of a reinfection, a recrudescence (i.e. failure) or, a relapse malaria due to P. vivax and P. ovale
• Wherever possible, treatment failure must be confirmed parasitologically – preferably by blood slide examination
• Recurrence of fever and parasitaemia more than 2 weeks after treatment (either recrudescence or new infection), can be retreated with the first-line ACT

Malaria Laboratory Diagnosis and Quality Assurance

• Laboratory diagnostic methods can be classified in to two:
  • Routine (Microscopy & Rapid Diagnostic Testing/RDT)
  • Advanced diagnostic methods
    • Quantitative Buffy Coat /QBC/test
    • Microscopy using fluorochromes
    • Polymerase chain Reaction/PCR/
    • Serology: Ab detection
    • Flowcytometry

Types of Blood Films

• Diagnosis rests on the demonstration of asexual forms of the parasite in blood smears.
• Both thin and thick blood smears should be examined.
• Thick blood smears confirm malaria infection [sensitive] while thin blood smears identify the species of infecting parasite [specific].
• Repeat blood smears should be performed at least every 12–24 h for 2 days if the first smears are negative and malaria is strongly suspected.
• Alternatively, a rapid antigen detection card or stick test should be performed.

Slide examination

• Giemsa stain thick blood smears are the basis for microscopic diagnosis with a standard of looking at 100 fields.
• The limit of detection is usually 5-10 parasites per μl of blood

Malaria Rapid Diagnostic Testing

• Malaria RDTs detect antigens (eg. Histidine Rich Protein 2 (HRP2) or Plasmodium lactate dehydrogenase ( pLDH)
• An antigen-antibody reaction leads to a visible colour change that indicates a positive test result.
• Do not require a laboratory, electricity, or any special equipment.
• Multi-species RDTs
• Recommended to be used in the health posts.

Prevention

• Personal Protection Against Malaria

• Simple measures to reduce the frequency of infected- mosquito bites in malarias areas are very important

• The avoidance of exposure to mosquitoes at their peak feeding times (usually dusk to dawn); and

• Use of insect repellents, suitable clothing, and insecticide- impregnated bed nets (ITN) or other materials.

• Chemoprophylaxis

  • Recommendations for prophylaxis depend on
    1. Local patterns of Plasmodium species
    2. Drug sensitivity and the likelihood of acquiring malarial infection

• When there is uncertainty, drugs effective against resistant P. falciparum should be used

• Atovaquone-proguanil (Malarone), Doxycycline, or Mefloquine

• Chemoprophylaxis is never entirely reliable, and malaria should always be considered in the differential diagnosis of fever in patients who have traveled to endemic areas, even if they are taking prophylactic ant malarial drugs.

• -Chloroquine weekly or proguanil , intermitent SP for pregnant mothers
  -Travellers: (1 wk before and 4 wk after)-atavaquone- proguanil 3.75/1.5mg /kg daily, mefloquine 250mg wkly, doxycycline 100mg/d

• Rapid dx and Rx

• Primaquine contraindicated for prophylaxis
  *Intermittent Preventive Treatment of Malaria in Pregnancy (IPT)

*In malaria-endemic areas in Africa, provide intermittent preventive treatment with SP to all women in their first or second pregnancy (SP-IPTp) as part of antenatal care. Dosing should start in the second trimester and doses should be given at least 1 month apart, with the objective of ensuring that at least three doses are received.
*Strong recommendation, high-certainty evidence (WHO 2021)

Malaria Vaccines

• As malaria day approach (25 April), more than 1 million children in Ghana, Kenya, and Malawi recieved one or more doses of world’s malaria vaccine (WHO News, 21 April 2022 )
• The malaria vaccine pilots, first launched by government of Malawi in April 2019 have shown that the RTS,S/AS01 (RTS,S) vaccine is safe and feasible to deliver, and that it substantially reduces deadly severe malaria
• Worlds 1st malaria vaccine approved on October 7, 2021
  *4 doses should be given. the 1st 3 are monthly and z 4th is after 2 yrs

Chronic Complications of Malaria

• Tropical Spleenomegaly (Hyper reactive Malarial Spleenomegaly) Syndrome -- HMS
• Quartan Malarial Nephropathy
• Burkitt's Lymphoma and Epstein-Barr Virus Infection
• Neuropsychiatric and cognitive disorders may also follow severe malaria

Quartan Nephropathy

• chronic soluble immune complex nephropathy
• The nephrotic syndrome, with albuminuria, hypoalbuminaemia, oedema and variable renal impairment
• Repeated or continuous P. malariae infection is associated with childhood nephrotic syndrome in West Africa
• It has disappeared from countries where P. malariae has been eradicated
• The other species of malaria are also suspected of causing occasional glomerulonephritis, but the evidence is less convincing

Tropical Spleenomegaly (HSM)

• Gross splenomegaly with normal architecture and lymphocytic infiltration of the hepatic sinusoids with Kupffer cell
• massively enlarged spleen leads to hypersplenism with anaemia, leukopenia and thrombocytopenia
• polyclonal hypergammaglobulinaemia with high serum concentrations of IgM
• High titres of malaria antibodies and a variety of autoantibodies
• Immunoglobulin gene rearrangements have been demonstrated in a sub-group of patients with HMS >>> progression to malignant lymphoma or leukaemia
• Most patients present with abdominal swelling and a dragging sensation in the abdomen
• The malaria blood slide is usually negative.
• Acute left-sided abdominal pain suggests splenic infarction
• The long-term prognosis of HMS is not good, with an increased mortality from infection
• pre-malignant condition developing into lymphoma in some patients
• Burkitt’s lymphoma is the most common malignancy of childhood
• uncontrolled proliferation of B lymphocytes and is associated with Epstein–Barr (EB) virus infections and malaria
• The epidemiological association between malaria and Burkitt’s tumour is very strong

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.
• By 2021 and beyond, cover 100% of the population at risk of malaria with one type of globally recommended vector control interventions.
• By 2021 and beyond, generate 100% evidence that facilitates appropriate decision-making.
• By 2021 and beyond, build capacity of all levels of the health offices to coordinate and implement malaria elimination interventions.

Goals

• 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