Malaria

• Malaria is a parasitic infection transmitted by Anopheles mosquitoes.
• Causes acute, life-threatening disease and is a significant global health threat.
• Two billion people are at risk annually, including those in 90 endemic countries and 125 million travelers.
• Causes 1.5 to 2.7 million deaths per year.

Plasmodium Parasite Lifecycle:

• Sporozoites enter the bloodstream via mosquito bites.
• Sporozoites invade hepatocytes in the liver and divide into merozoites.
• Merozoites invade erythrocytes, causing symptoms like cyclical fevers.

Specific Malaria Types

Falciparum Malaria

• Most common cause of severe malaria.
• Case fatality rates for untreated severe malaria (particularly cerebral malaria) reach 100%.
• High risk in pregnant women, young children, and elderly travelers.
• Increases risk of maternal death, miscarriage, stillbirth, and neonatal death during pregnancy.
• Early diagnosis and appropriate treatment are lifesaving; may be fatal if treatment is delayed even in mild cases.

Vivax, Ovale, Malariae, and Knowlesi Malaria

• Generally uncomplicated and rarely cause severe disease, except for P. knowlesi.
• P. knowlesi is a zoonosis with high parasitemia and a short 24-hour erythrocytic cycle, associated with rapid and severe disease, particularly in Borneo and Malaysia.
• Severe P. vivax malaria can include severe anemia, thrombocytopenia, acute pulmonary edema, cerebral malaria, acute renal failure, or shock.
• Intense transmission of P. vivax in Indonesia and PNG causes significant morbidity and mortality, especially in infants and children.
• P. vivax and P. ovale can persist in the liver as hypnozoites, causing repeated episodes (relapses) over years.
• P. malariae can persist asymptomatically for up to 40 years and cause symptomatic recurrences following triggers like surgery.

Reservoir and Transmission

Reservoir

• Humans are the primary reservoir for P. vivax, P. falciparum, and P. ovale.
• P. malariae infects humans, African apes, and some South American monkeys.
• Macaque monkeys are the natural host for zoonotic P. knowlesi malaria.

Mode of Transmission

• Primarily transmitted via the bite of an infectious female Anopheles mosquito, typically feeding between dusk and dawn.
• Can also be transmitted through blood transfusions, contaminated needles, and rarely, vertical transmission (mother to child).

Incubation Period

Mosquito (Extrinsic) Incubation Period

• Female Anopheles mosquitoes become infectious 8–10 days after ingesting infected blood, extending up to 35 days at lower temperatures.

Human (Intrinsic) Incubation Period

• P. falciparum: 9–14 days
• P. vivax and P. ovale: 12–18 days (some P. vivax strains in temperate areas have 6–12 months incubation)
• P. malariae: 18–40 days
• P. knowlesi: 10–12 days

Period of Communicability

• Humans remain infectious to mosquitoes while infectious gametocytes are present in the blood.
• Gametocytes appear within 3 days of parasitemia for P. vivax and P. ovale, and 10–14 days for P. falciparum.
• Untreated or inadequately treated patients may infect mosquitoes for decades with P. malariae, up to 5 years with P. vivax, and generally no more than one year with P. falciparum.
• Transmission through transfusion or needle stick can occur from an infected donor; stored blood can remain infectious for at least a month.
• Artemisinin-combination treatment reduces gametocyte carriage and onward transmission risk to mosquitoes within 3 days.

Susceptibility

• Universal susceptibility, except for individuals with specific protective traits (e.g., sickle cell trait, other hemoglobin-related disorders, G6PD deficiency).
• Duffy blood group-negative individuals have red blood cells resistant to P. vivax.
• Functional or anatomical asplenia increases susceptibility.
• HIV-infected individuals are at higher risk of symptomatic P. falciparum malaria and severe manifestations.
• Maternal antibodies provide protection to newborns in areas of high P. falciparum transmission.
• Partial immunity in adults in moderate to high transmission areas, with clinical disease mainly in young children.
• Immunity is modified in pregnancy and diminishes after prolonged absence from endemic areas.

Epidemiology

• 40% of the global population resides in or visits malaria-endemic regions annually.
• P. falciparum: Western and sub-Saharan Africa, highest morbidity and mortality.
• P. vivax: South Asia, Western Pacific, Central America.
• P. ovale and P. malariae: Sub-Saharan Africa.
• P. knowlesi: Southeast Asia.
• 500 million malaria cases annually with 1.5 to 2.7 million deaths.
• 90% of malaria-related deaths occur in Africa.
• Highest risk groups: children under 5, pregnant women, disease-naïve populations.

Pathophysiology

• Species:
  • P. falciparum, P. ovale, P. vivax, P. malariae, P. knowlesi.
• Transmission:
  • Female Anopheles mosquito ingests gametes, which form sporozoites in the gut.
  • Sporozoites enter the human host’s bloodstream during subsequent bites.
• Disease Mechanism:
  • Sporozoites invade hepatocytes and divide into merozoites.
  • Merozoites invade erythrocytes, causing hemolysis, capillary endothelial adherence, and cell lysis.
  • Free heme release stimulates endothelial activation.
  • Untreated malaria can last 2 to 24 months.
  • P. vivax and P. ovale may have dormant liver parasites (hypnozoites).

Histopathology

• Parasites digest hemoglobin, forming hemozoin.
• Hemozoin makes erythrocyte membranes less deformable, leading to hemolysis or splenic clearance.

Clinical Features of Malaria

General Characteristics

• Severity and clinical course depend on parasite species and host factors such as age, immunity level, or use of chemoprophylaxis.
• Classified as uncomplicated or severe, differentiated by the presence or absence of vital organ dysfunction.

Uncomplicated Malaria

• Symptoms include fever, which may present as malarial paroxysms (cyclical fever, rigors, and profuse sweating), and influenza-like symptoms such as headache, myalgia, and malaise.

Severe Malaria

• Characterized by one or more of the following:
  • Respiratory distress
  • Pulmonary edema
  • Shock
  • Hypoglycemia
  • Jaundice
  • Severe anemia
  • Significant abnormal bleeding
  • Metabolic acidosis
  • Acute kidney injury
  • Hyperparasitemia
  • Seizures
  • Impaired consciousness or coma (cerebral malaria)
  • Inability to tolerate oral medication, vital organ dysfunction, and high parasite counts are associated with higher mortality risk.

Clinical Suspicion

• Focus on unexplained fever or history of fever from the ninth day following first possible exposure (e.g., travel to malaria-endemic areas) up to 12 months (or rarely, longer) after last possible exposure.
• Febrile illness developing less than one week after first possible exposure is not indicative of malaria.
• Symptoms may be intermittent or recur, especially with relapsing malaria (commonly P. vivax and P. ovale).

History and Physical Examination

• History:
  • Inquire about residence, travel, chemoprophylaxis, exposures, HIV status, pregnancy, G6PD deficiency, sickle cell disease, anemia, blood cancers, prior malaria infections.
• Symptoms:
  • Fever is the dominant symptom.
  • Adults: fever, headaches, malaise, gastrointestinal distress, respiratory symptoms, muscle aches, jaundice, confusion, seizures, dark urine.
  • Children: fever, lethargy, nausea, vomiting, abdominal cramps, somnolence, hepatomegaly, splenomegaly, severe anemia.

Differential Diagnosis for Undifferentiated Fever

• General Considerations:
  • Differential diagnosis is broad and varies based on geographic location and age.
• Fever in Returning Travelers:
  • Protozoal Malaria: 77%
  • Bacterial Enteric Fever: 18% (Salmonella enterica, typhi, or paratyphi)
  • Other Infections: 5%
• Fever with Somnolence or Seizures:
  • Consider viral or bacterial meningitis or meningoencephalitis.
  • Prompt consideration of lumbar puncture is necessary.
• Viral Etiologies:
  • Avian influenza
  • Middle East respiratory syndrome coronavirus (MERS-CoV)
  • Hemorrhagic fever (Ebola virus, Lassa fever, Marburg hemorrhagic fever, Crimean-Congo hemorrhagic fever)
  • Yellow fever
  • Dengue
  • Japanese encephalitis
  • Rift Valley fever
  • Hepatitis virus (A or B)
  • Viral gastroenteritis
  • Rabies
• Bacterial Etiologies:
  • Anthrax
  • Epidemic typhus
  • Ehrlichiosis
  • Leptospirosis
  • Melioidosis
  • Murine (endemic) typhus
  • Spotted fever group rickettsioses
  • Q fever
  • Yersinia pestis (plague)

Differential Diagnosis in Children

• Viral or Bacterial Infections:
  • Most common etiology varies by region.
  • Study in a Tropical Region (2014):
    • Malaria: 10.5%
    • Respiratory Infection: 62%
    • Systemic Bacterial Infection: 13.3% (usually staphylococcus or streptococcus bacteremia)
    • Gastroenteritis: 10.3% (viral or bacterial)
• Other Considerations:
  • Urinary tract infection (UTI)
  • Typhoid fever
  • Meningitis must be ruled out in somnolent children.

Evaluation

• Diagnostic Testing (2 x EDTA tubes)
  • Thick and thin films from finger prick or venepuncture
    and
  • Rapid Diagnostic Test (RDT) for malaria antigen
    • One negative RDT / blood film does not exclude malaria
      (Sensitivity of a single blood film is 85%, sensitivity of RDT is 99% for P. falciparum, 86% for non-falciparum malaria)
    • Repeat 12-24 hourly (total 3 samples) if tests initially negative
    • Perform blood films and RDT in all children with a suggestive history – even if patient is not febrile at time of Emergency Department (ED) presentation
    • Urgent results from Binax^® RDT are available 24/7 through the haematology laboratory – mark samples as ‘urgent’ if required
    • Malaria polymerase chain reaction (PCR) / nucleic acid testing (NAT).
• Microscopy:
  • Gold standard for diagnosis using Giemsa-stained blood smears.
  • Ring stage, trophozoite stage, schizont stage, and gametocyte stage appearance guide speciation.

Prognosis and Complications

• Prognosis:
  • Duration and relapse vary by species and location.
  • P. falciparum and P. ovale: 2 to 3 weeks, relapse 6 to 18 months later.
  • P. vivax: 3 to 8 weeks, relapse up to 5 years later.
  • P. malariae: 3 to 24 weeks, relapse up to 20 years later.
• Complications:
  • Cerebral malaria, severe malarial anemia, nephrotic syndrome.
  • Blackwater fever, bilious remittent fever, algid malaria, acute respiratory distress syndrome, circulatory collapse, disseminated intravascular coagulation, pulmonary edema, coma, and death.
  • Malaria during pregnancy may result in low birth weight or fetal demise.

Severe Malaria

Severe malaria is defined as one or more of the following features: impaired consciousness / coma seizures prostration (unable walk or sit up without assistance) vomiting / unable to tolerate oral intake circulatory collapse / shock / hypotension clinical jaundice plus evidence of other vital organ dysfunction haemoglobinuria spontaneous bleeding respiratory distress / pulmonary oedema

Laboratory findings: hyperparasitaemia (> 2%) severe anaemia (Hb < 50 g/L) hypoglycaemia (BGL < 2.2mmol) metabolic acidosis (plasma bicarbonate < 15 mmol/L) hyperlactataemia (lactate > 5 mmol/L)renal impairment

Treatment of Uncomplicated Malaria

as per eTG

General Principles

• Oral Therapy:
  • Preferred for uncomplicated malaria.
  • If the patient cannot tolerate oral therapy, treat as for severe malaria and seek expert advice.
• Rapid Treatment:
  • Start treatment promptly, especially for P. falciparum or P. knowlesi.
  • Initiate treatment in hospital and monitor for deterioration.
• Preferred Treatment:
  • Artemether+lumefantrine: For all patients, including pregnant women after the first trimester.
  • Atovaquone+proguanil: For first trimester of pregnancy or if artemether+lumefantrine cannot be used.
  • Do not use atovaquone+proguanil if it was used for prophylaxis.

Standard Treatment Regimens

1. Artemether+lumefantrine:
   • Take with fatty food or full-fat milk.
   • Dosage:
     • Adult and child >34 kg: 4 tablets at 0, 8, 24, 36, 48, 60 hours.
     • Child 5-14 kg: 1 tablet at the same intervals.
     • Child 15-24 kg: 2 tablets at the same intervals.
     • Child 25-34 kg: 3 tablets at the same intervals.
2. Atovaquone+proguanil:
   • Take with fatty food or full-fat milk.
   • Dosage:
     • Adult and child >40 kg: 4 tablets daily for 3 days.
     • Child 11-20 kg: 1 tablet daily for 3 days.
     • Child 21-30 kg: 2 tablets daily for 3 days.
     • Child 31-40 kg: 3 tablets daily for 3 days.
3. Quinine Sulfate:
   • Dosage:
     • 600 mg (adult <50 kg: 450 mg) orally, 8-hourly for 7 days.
   • Plus Doxycycline:
     • 100 mg orally, 12-hourly for 7 days (start after day 1 of quinine).
   • For Pregnant Women/Children <8 years:
     • Clindamycin: 450 mg (child: 10 mg/kg up to 450 mg) orally, 8-hourly for 7 days.

• Monitoring:
  • Daily parasite count until negative.
  • Full blood count and malaria microscopy at 7 and 28 days after therapy completion.

Additional Considerations for P. falciparum

• Slow Responders from Greater Mekong Subregion:
  • Seek expert advice for slow responders.
  • Options for reduced efficacy:
    • Extend artemether+lumefantrine duration by 2 days.
    • Switch to oral atovaquone+proguanil for 3 days.
    • Switch to quinine sulfate plus doxycycline or clindamycin for 7 days.
• Prevention of Transmission in Northern Australia:
  • Add primaquine to standard treatment:
    • Primaquine: 15 mg (child >6 months: 0.25 mg/kg) orally, as a single dose.
  • Avoid primaquine in G6PD-deficient patients, pregnant women, infants <6 months, and breastfeeding women with infants <6 months.

Additional Considerations for P. vivax and P. ovale

• Dormant Liver Parasites:
  • Concurrent treatment with primaquine or tafenoquine needed.
• Primaquine:
  • For P. vivax: 30 mg (child >6 months: 0.5 mg/kg) orally, daily for 14 days or until cumulative dose of 6 mg/kg is reached.
  • For P. ovale: 15 mg (child >6 months: 0.25 mg/kg) orally, daily for 14 days.
• Tafenoquine:
  • Requires specific quantitative G6PD testing.
  • Seek expert advice for G6PD testing and tafenoquine dosing.
• Avoid in: Pregnant women, infants <6 months, and breastfeeding women with infants <6 months.

Treatment of Severe Malaria

General Principles

• Intravenous Therapy:
  • Mandatory for severe malaria.
  • Start treatment as soon as possible and seek expert advice.

Standard Treatment

• Preferred Treatment:
  • Artesunate: 2.4 mg/kg IV on admission, at 12 and 24 hours, then daily until improvement.
  • If artesunate unavailable: Quinine dihydrochloride: 20 mg/kg IV over 4 hours, then 10 mg/kg IV over 4 hours, 8-hourly until improvement.
• Combination Therapy for Greater Mekong Subregion:
  • Combination of intravenous artesunate and quinine is recommended.
  • Start with one drug and request urgent shipment of the other if both are not immediately available.
• Adjunctive Therapy:
  • Ceftriaxone: 2 g IV daily for 2 days.
  • Paracetamol: 1 g orally or enterally, 6-hourly for 72 hours.

Switch to Oral Therapy

• Criteria: Clinically improved and able to tolerate oral therapy.
• Options:
  • Artemether+lumefantrine: Same dosage as for uncomplicated malaria.
  • Atovaquone+proguanil: Same dosage as for uncomplicated malaria.
  • Quinine sulfate plus doxycycline/clindamycin: Same dosage as for uncomplicated malaria.

Prophylaxis of Malaria

• First and Foremost – Personal Protective Measures (Risk reduction of 10 fold)
• Chemoprophylaxis – not everyone going to a malarious country needs it
• Standby Treatment – if unable to get timely diagnosis of fever
• Beware Asplenia/Immunosuppression

General Principles

• Vector Avoidance:
  • Use insect repellent, long clothing, mosquito nets, and avoid outdoor activities at dusk/dawn.
• Antimalarial Prophylaxis:
  • Assess risk based on travel destination, duration, and activities.
  • Advise travelers on the importance of seeking medical attention if febrile.
• Personal Protective Measures
  • DEET based insect repellent bd
    • 10% for infants
    • 20-35% for older children
    • 20-40% for adults (Bushman’s)
  • Permethrin for higher risk exposure
  • Avoid perfumes and colognes
  • Take or buy a knock down spray

Recommended Prophylaxis

• Atovaquone+proguanil:
  • 250+100 mg (adult and child >40 kg): 1 tablet daily with fatty food/full-fat milk.
  • Paediatric formulation: 62.5+25 mg tablets, dose based on weight.
• Doxycycline:
  • 100 mg daily.
  • Not recommended for children <8 years.
  • Daily dosing
  • Start 1-2 days prior
  • 4 weeks post exposure
  • GI upset, Photosensitivity, Thrush
  • Cheaper per dose– 50c per tablet
  • Also protects against leptospirosis, rickettsia and ? Travellers Diarrhoea
• Malarone:
  • Daily dosing
  • Start 1-2 days prior
  • 1 week post exposure
  • Abdominal side effects though less than Doxy
  • More expensive – $4-5 per tablet
  • Most effective against both P.falciparum and P. vivax
• Tafenoquine (Kodatef)
  • Need to test G6PD status
  • Contraindications
    • G6PD deficiency
    • Pregnancy and Breast Feeding
    • Allergy to 8-aminoquinolones eg Primaquine
  • Precautions
    • Psychiatric disorders – mood and sleep disturbance
    • Interacts with Metformin and Procainamide
  • Side effects
    • Nausea, vomiting and headache
    • Vortex keratopathy
  • Dosing
    • 2 tabs daily for 3 days loading dose,
    • 2 tabs once weekly for up to 6 months.
  • Cost – ???

Stand-By Emergency Treatment

• For travelers who opt out of prophylaxis:
  • Artemether+lumefantrine or Atovaquone+proguanil for self-treatment if febrile illness occurs and medical care is unavailable.

Preventive Measures

Health Education for Travellers

• Reduce the risk to travellers both for their own protection and to reduce the risk of imported cases to receptive areas in Australia.
• Pre-travel advice for travellers to malaria-endemic countries should include:
  • Use appropriate anti-malarial prophylactic medication according to a trip risk assessment and prescriber’s instructions.
  • Prevent mosquito bites using repellents, protective clothing, and mosquito nets if rooms are not screened or air-conditioned.
• Warn travellers that no prophylactic measures are completely effective, and medical attention should be sought if they develop fever during travel or within 12 months of return from a malarious area.

Clinician Education

• Encourage medical practitioners to have a high index of suspicion for malaria when a patient presents with symptoms compatible with malaria following a visit to a malarious area or in response to local public health awareness campaigns.

Community Health Education

• Messaging for malaria prevention may include:
  • Avoid mosquitoes when they are most active; Anopheles mosquito is mainly active between sunset and sunrise.
  • Use an effective insect repellent on exposed skin, reapply within a few hours following the manufacturer’s instructions. The best mosquito repellents contain DEET, Picaridin, or Oil of Lemon Eucalyptus (PMD).
  • Repellents containing less than 10% DEET or picaridin are safe for children; use physical barriers for infants under 3 months.
  • Cover up with light-colored, loose-fitting clothing with long sleeves, long trousers, socks, and covered footwear when outside.
  • Ensure intact flyscreens are fitted in homes, tents, caravans, or other accommodation.
  • Use treated mosquito nets over the bed when sleeping if accommodation is not air-conditioned or if screens on doors and windows are compromised.
  • Use insecticide sprays, vaporising dispensing units (indoors), or mosquito coils (outdoors) at night.

Vaccination

• RTS,S/AS01 vaccine was recommended by WHO in 2021 for the prevention of P. falciparum malaria in children in regions with moderate to high transmission, as part of a comprehensive malaria strategy.
• This vaccine is not available in Australia.

Disinsection of Aircraft, Ships, etc.

• The Department of Agriculture, Fisheries and Forestry has disinsection requirements for international aircraft arrivals into Australia.

Blood Transfusion Transmission

• Screening procedures are in place.
• Donation can often still be made by those who have had malaria, but only the plasma component of the blood is used.

Needle Stick Injury

• Standard infection control precautions apply for healthcare workers caring for patients with malaria.

Locally Acquired Cases/Community Outbreaks

• Any locally acquired case of malaria in Queensland requires a public health response tailored to the location and circumstances.
• This response may include active case finding, surveillance, and entomological management.
• Notify all locally acquired cases to the Communicable Diseases Branch.
• Contact Tracing
  • Consider active case finding (symptom screening and appropriate laboratory testing) in response to a locally acquired case of malaria.
  • Contacts may include household members, neighboring households, co-travellers, or work colleagues.
• Vector Control
  • Response to locally transmitted disease, including vector management, will be undertaken according to local protocols and in coordination with local government.
  • This may include revised routine vector management and enhanced monitoring and control of mosquito populations.