Malaria

Introduction and Epidemiology

• Definition: Malaria is an acute febrile illness caused by intraerythrocytic protozoa of the genus Plasmodium and transmitted by the bite of an infective female Anopheles mosquito,.
• Burden: It is a leading cause of morbidity and mortality worldwide, with children under 5 years accounting for a significant percentage of deaths,. In India, P. falciparum and P. vivax are the major contributors, with P. falciparum accounting for nearly 50% of cases,.
• Elimination Goals: The National Strategic Plan (NSP) 2023–2027 in India aims for zero indigenous cases by 2027 and maintenance of malaria-free status by 2030.

Etiology

• Causative Agents:
  • Plasmodium falciparum: Causes the most severe disease, including cerebral malaria and death. Predominant in Africa, Haiti, New Guinea, and parts of India (Odisha, Chhattisgarh, North East),.
  • Plasmodium vivax: Causes debilitating illness with a risk of relapse due to dormant liver stages (hypnozoites). Prevalent in India, Central America, and Southeast Asia,.
  • Plasmodium malariae: Causes chronic, milder infection; associated with nephrotic syndrome.
  • Plasmodium ovale: Rare, primarily found in Africa.
  • Plasmodium knowlesi: A primate malaria species causing zoonotic human malaria, documented in Southeast Asia.
• Vector: Transmitted by female Anopheles mosquitoes which bite primarily between dusk and dawn,. In India, An. culicifacies (rural), An. stephensi (urban), and An. fluviatilis (hills/forests) are primary vectors,.

Life Cycle and Pathogenesis

The life cycle involves two hosts: Humans (intermediate host) and Mosquitoes (definitive host).

Human Cycle (Asexual)

• Pre-erythrocytic (Hepatic) Phase: Sporozoites injected by the mosquito enter hepatocytes within minutes. They multiply asexually (schizogony) to form schizonts. Rupture releases thousands of merozoites into circulation,.
  • Hypnozoites: In P. vivax and P. ovale, some parasites remain dormant in the liver, causing relapses weeks to years later,. P. falciparum and P. malariae do not have a dormant hepatic phase.
• Erythrocytic Phase: Merozoites invade red blood cells (RBCs), transforming into ring forms, trophozoites, and schizonts. RBC rupture releases merozoites, causing fever (paroxysms),.
  • P. falciparum infects RBCs of all ages, leading to high parasitemia (>60%).
  • P. vivax/P. ovale infect reticulocytes.
  • P. malariae infects senescent RBCs.
• Gametogony: Some parasites differentiate into male and female gametocytes, which are infective to mosquitoes,.

Mosquito Cycle (Sexual)

• Gametocytes ingested by the mosquito fuse to form a zygote, then a motile ookinete, which forms an oocyst. Sporozoites released from the oocyst migrate to salivary glands, ready for transmission,.

Pathophysiology of Severe Malaria

• Cytoadherence: P. falciparum-infected RBCs adhere to vascular endothelium, causing microvascular obstruction and tissue anoxia,.
• Sequestration: Infected RBCs are sequestered in deep vascular beds (brain, lungs, kidneys), avoiding splenic clearance.
• Cytokines: Excessive production of proinflammatory cytokines (e.g., TNF-alpha) drives fever and tissue injury,.
• Hemolysis: Destruction of infected and uninfected RBCs leads to severe anemia.

Clinical Manifestations

Incubation Period

• P. falciparum: 9–14 days.
• P. vivax: 12–17 days.
• P. malariae: 18–40 days,.

Uncomplicated Malaria

• Prodrome: Nonspecific symptoms like headache, fatigue, anorexia, myalgia, and vomiting precede fever by 2–3 days,.
• Paroxysm: Classic stages (Cold, Hot, Sweating) are often absent in children. Children typically present with high fever (>104°F), headache, drowsiness, vomiting, diarrhea, and pallor,.
• Periodicity: P. vivax/ovale (48 hours - tertian), P. malariae (72 hours - quartan). P. falciparum fever is often irregular or continuous.
• Physical Signs: Splenomegaly (common), hepatomegaly, pallor.

Severe Malaria

Defined by the presence of asexual parasitemia with one or more of the following complications (primarily P. falciparum, but increasingly seen with P. vivax),:

• Impaired Consciousness: Cerebral malaria (coma not attributable to other causes, Blantyre Coma Score <3 in children),.
• Severe Anemia: Hemoglobin <5 g/dL,.
• Respiratory Distress: Acidotic breathing (Kussmaul’s) due to metabolic acidosis,.
• Hypoglycemia: Blood glucose <40 mg/dL (<2.2 mmol/L). Common in children and pregnant women,.
• Multiple Convulsions: >2 episodes in 24 hours.
• Shock: Capillary refill ≥3 seconds or hypotension.
• Acute Kidney Injury: Serum creatinine >3 mg/dL.
• Hyperparasitemia: >10% infected RBCs.

Congenital Malaria

• Acquired transplacentally.
• Symptoms appear between 10 and 30 days of life.
• Clinical features: Fever, irritability, pallor, poor feeding, hepatosplenomegaly, and jaundice,.

Diagnosis

Microscopical Examination (Gold Standard)

• Thick Smear: High sensitivity (detects 5–10 parasites/µL). Used for detection and quantification,.
• Thin Smear: Lower sensitivity but allows species identification and quantification of parasitemia,.
• Samples should be collected before antimalarials are given. If negative, repeat every 12–24 hours for a total of 3 times.

Rapid Diagnostic Tests (RDTs)

• Antigen Detection: Immunochromatographic tests detecting specific antigens.
  • HRP-2 (Histidine-Rich Protein 2): Specific for P. falciparum. Persists for weeks after cure.
  • pLDH (Parasite Lactate Dehydrogenase) / Aldolase: Detects all species (Pan-malarial) or specific to P. vivax. Disappears quickly after cure,.
• Utility: Useful where microscopy is unavailable. Sensitivity decreases at low parasitemia (<100 parasites/µL).

Molecular Methods

• PCR (Polymerase Chain Reaction): Highly sensitive and specific. Useful for mixed infections, low parasitemia, and species confirmation (e.g., P. knowlesi). Not for routine acute diagnosis due to time/cost,.

Differential Diagnosis

• Viral fevers (Dengue, Influenza), Enteric fever, Leptospirosis, Rickettsial infections, Meningitis/Encephalitis, Sepsis,.

Management

Treatment depends on the species, severity, and local drug resistance patterns.

1. Uncomplicated P. vivax Malaria

• Chloroquine (CQ): 25 mg/kg total dose over 3 days.
  • Day 1: 10 mg/kg.
  • Day 2: 10 mg/kg.
  • Day 3: 5 mg/kg.
• Radical Cure (Prevention of Relapse): Primaquine (PQ) to kill hypnozoites.
  • Dose: 0.25 mg/kg/day once daily for 14 days,.
  • Contraindications for PQ: Pregnancy, infants <1 year, G6PD deficiency.
  • Tafenoquine: A single-dose alternative for radical cure in patients ≥16 years (not for G6PD deficient).

2. Uncomplicated P. falciparum Malaria

• Artemisinin-based Combination Therapy (ACT): Treatment of choice to prevent resistance.
• Regimens in India (NVBDCP Guidelines):
  • North-Eastern States: Artemether-Lumefantrine (AL) for 3 days.
    • Dose based on weight bands (e.g., 5–14 kg: 1 tablet twice daily).
  • Other States: Artesunate (AS) + Sulfadoxine-Pyrimethamine (SP) for 3 days.
    • AS: 4 mg/kg daily for 3 days.
    • SP: Single dose on Day 1 (25 mg/kg Sulfadoxine + 1.25 mg/kg Pyrimethamine).
• Gametocidal Therapy: Single dose Primaquine (0.75 mg/kg) on Day 2 to reduce transmission,.

3. Mixed Infections (Pf + Pv)

• Treat as P. falciparum with ACT.
• Add Primaquine 0.25 mg/kg/day for 14 days for P. vivax radical cure.

4. Severe Malaria Management

• Setting: Hospitalization in ICU/HDU.
• Antimalarial Therapy: Parenteral treatment should be started immediately.
  • Drug of Choice: IV Artesunate 2.4 mg/kg at 0, 12, and 24 hours, then once daily,.
    • Pediatric (<20kg): Some guidelines suggest 3 mg/kg/dose.
  • Alternative: IV Artemether or IV Quinine (loading dose 20 mg/kg then 10 mg/kg q8h; requires cardiac monitoring),.
  • Follow-up: Switch to full course of oral ACT once the patient can tolerate oral medication.
• Supportive Care:
  • Coma: Airway protection, exclude hypoglycemia/meningitis.
  • Seizures: Benzodiazepines (Diazepam/Lorazepam); correct hypoglycemia/electrolytes.
  • Hypoglycemia: 10% Dextrose bolus (2–5 mL/kg) followed by maintenance.
  • Severe Anemia: Packed red blood cell transfusion if Hb <5 g/dL (or higher if respiratory distress).
  • Fluids: Avoid fluid overload (risk of pulmonary edema). Treat shock with careful fluid resuscitation and inotropes.
  • Antibiotics: Broad-spectrum antibiotics if bacterial sepsis is suspected.

Complications

• Cerebral Malaria: 15–40% mortality; sequelae include cognitive impairment, epilepsy, and motor deficits,.
• Severe Malarial Anemia: Leads to significant morbidity and neurocognitive impairment.
• Hyperreactive Malarial Splenomegaly (HMS): Massive splenomegaly with high IgM, requiring long-term prophylaxis.
• Blackwater Fever: Macroscopic hemoglobinuria causing acute kidney injury, associated with quinine or artemisinin use in G6PD deficiency or irregular treatment

Newer Drugs for Malaria

1. Tafenoquine (Krintafel/Arakoda)

Tafenoquine is a long-acting 8-aminoquinoline derivative (an analogue of primaquine) recently approved for the radical cure of P. vivax and for malaria prophylaxis.

• Mechanism: It is active against the pre-erythrocytic (liver) and erythrocytic (blood) forms of the parasite, as well as the dormant liver stages (hypnozoites) responsible for relapses in P. vivax and P. ovale infections.
• Indications & Dosage:
  • Radical Cure (prevention of relapse): Approved as a single oral dose (300 mg) for patients $\ge$16 years old, making it a significant improvement over the 14-day course required for primaquine.
  • Prophylaxis: Approved for prophylaxis in adults (Arakoda). The regimen involves a loading dose daily for 3 days, followed by weekly dosing during travel and a single dose one week after return.
• Contraindications: Like primaquine, it causes severe hemolysis in individuals with G6PD deficiency. Quantitative G6PD testing is mandatory before administration. It is contraindicated in pregnancy and breastfeeding.

2. Arterolane

Arterolane (also known as OZ277) is a newer synthetic trioxolane compound.

• Class: It acts similarly to artemisinin derivatives but is fully synthetic.
• Activity: It is rapidly acting and has a broad time window of antimalarial effect, ranging from ring forms to mature trophozoites.
• Use: It is typically marketed in combination with piperaquine (e.g., Arterolane-Piperaquine) for the treatment of uncomplicated falciparum malaria.

3. Piperaquine

While structurally related to older drugs, piperaquine is used in newer Artemisinin-based Combination Therapies (ACTs).

• Role: It is a bisquinoline with a long half-life, used as a partner drug with dihydroartemisinin or arterolane to prevent recrudescence.
• Use: Dihydroartemisinin-piperaquine is used for the treatment of severe anemia in children in African countries and reduces the risk of readmission and death.

4. Malaria Vaccines (New Tools)

• RTS,S/AS01 (Mosquirix): Approved by the WHO in 2021 for children <2 years in endemic regions. It targets the pre-erythrocytic circumsporozoite protein of P. falciparum. It reduces severe malaria by approximately 30%.
• R21/Matrix-M: Approved by the WHO in 2023 for use in children <2 years. Like RTS,S, it targets the circumsporozoite protein but has shown higher efficacy in initial trials.

5. Monoclonal Antibodies

• Recent trials have shown that monoclonal antibodies against P. falciparum can provide short-term protection. This intervention is being explored for travelers, the military, and potentially for seasonal malaria prevention in children.

Prevention and Control

Vector Control

• Long-Lasting Insecticidal Nets (LLINs): Recommended for universal coverage in high-risk areas (API >1).
• Indoor Residual Spraying (IRS): Focal application in high-risk areas. Used for outbreak containment (in and around 50 houses of positive cases),.
• Larval Source Management: Biological control (larvivorous fish like Gambusia), chemical larvicides (Temephos), and environmental management,.

Chemoprophylaxis

• Travelers:
  • Chloroquine-sensitive areas: Chloroquine.
  • Chloroquine-resistant areas: Mefloquine (weekly), Atovaquone-Proguanil (daily), or Doxycycline (daily, >8 years),.
• Intermittent Preventive Treatment (IPT): Used in high-transmission areas (e.g., Africa) for infants and pregnant women.

Vaccines

• RTS,S/AS01 (Mosquirix): Approved by WHO for children in sub-Saharan Africa. Reduces severe malaria by ~30%.
• R21/Matrix-M: Recently approved, showing high efficacy.

National Framework for Malaria Elimination (India)

• Goal: Zero indigenous cases by 2027; Malaria-free India by 2030.
• Strategy: "Test, Treat, and Track."
• Surveillance: Transformation to case-based surveillance (1-3-7 approach: Notification in 1 day, Investigation in 3 days, Foci management in 7 days).
• Stratification: Districts classified into Categories 0 (No cases), 1 (Elimination phase, API <1), 2 (Pre-elimination), and 3 (Intensified control).