Malaria — Comprehensive Clinical Reference

1. Epidemiology

2. Causative Organisms

3. Life Cycle & Pathogenesis

Hepatic (exoerythrocytic) stage

1. The mosquito inoculates sporozoites into the bloodstream
2. Sporozoites bind to hepatocytes via thrombospondin-related adhesive protein and circumsporozoite protein (binding heparan sulfate proteoglycans)
3. Within 1–4 weeks, sporozoites differentiate into merozoites inside hepatocytes
4. Infected hepatocytes rupture, releasing merozoites into blood
5. P. vivax and P. ovale can form dormant hypnozoites in the liver — the source of relapses months to years later

Erythrocytic stage

1. A lectin-like molecule on the merozoite surface binds sialylated glycophorin on RBCs → invagination into a digestive vacuole
2. Merozoites differentiate into trophozoites → schizonts
3. Schizonts express PfEMP1 (knob-like extensions on RBC surface), which binds endothelial adhesion molecules (ICAM-1, VCAM-1, CD36) → cytoadherence and microvascular sequestration
4. After ~48 h, schizonts differentiate into new merozoites → RBC lysis → next cycle
5. Some trophozoites become gametocytes — taken up by another mosquito to restart the sexual cycle

4. Pathology & Morphology

• Hemolytic anemia — destruction of RBCs; severity varies by species
• Malarial pigment (hematin/hemozoin) — brown pigment derived from hemoglobin degradation; deposits in spleen, liver, lymph nodes, bone marrow
• Splenomegaly (often massive) and hepatomegaly — from hyperplasia of mononuclear phagocytes
• Cerebral malaria (P. falciparum) — small cerebral vessels engorged and occluded by PfEMP1-mediated cytoadherence; rapidly progressive with convulsions, coma, death
• Blackwater fever — massive intravascular hemolysis → hemoglobinemia, hemoglobinuria, jaundice, renal failure (complication of P. falciparum)
• Nephrotic syndrome — particularly with P. malariae (quartan malaria nephropathy)

5. Clinical Features

6. Diagnosis

• Thick and thin blood smears (Giemsa stain) — gold standard; thick smear for detection, thin smear for species ID
• Rapid antigen tests — HRP2 (P. falciparum), pan-malaria LDH
• PCR — most sensitive; species and resistance genotyping
• CBC — thrombocytopenia, anemia, leukopenia common
• LFTs, creatinine, blood glucose — assess severity and complications

7. Treatment & Pharmacology

Guiding principles (Goldman-Cecil)

• Most drugs act on erythrocytic (blood) stages
• Drug choice depends on species and regional resistance patterns
• Artemisinin-based combination therapy (ACT) — e.g., artemether-lumefantrine — is first-line for acute malaria from chloroquine-resistant areas
• Chloroquine — treatment and prophylaxis only where Plasmodium remains sensitive (very limited geography for P. falciparum)
• Primaquine and tafenoquine are the only agents that eradicate liver hypnozoites (P. vivax, P. ovale)

Key Drug Summary

Radical Cure (Preventing Relapse)

• Primaquine 15 mg/day × 14 days (or 30 mg/day × 7 days)
• Tafenoquine single dose (450 mg) — requires G6PD quantitative testing prior to administration

Severe/Cerebral Malaria

• IV artesunate is first-line
• IV artesunate superior to IV quinine (fewer adverse effects, faster parasite clearance)
• Adjunctive care: maintain glucose (quinine causes hypoglycemia), control seizures, manage fluid balance carefully (risk of ARDS and cerebral edema)

8. Prophylaxis

9. Resistance

• Chloroquine resistance in P. falciparum: near-universal globally (mediated by mutations in pfcrt and pfmdr1 — chloroquine efflux from parasite vacuole)
• Partial artemisinin resistance emerging in Southeast Asia (kelch13 mutations); managed by switching ACT partner drugs
• P. vivax chloroquine resistance documented in parts of SE Asia and Oceania

10. Prevention (Public Health)

• Insecticide-treated bed nets
• Indoor residual spraying
• Elimination of standing water (larval breeding sites)
• RTS,S/AS01 (Mosquirix) — first approved malaria vaccine; targets circumsporozoite protein of P. falciparum; partial protection (~30–56%), deployed in sub-Saharan Africa for children; expected to prevent thousands of cerebral malaria deaths
• R21/Matrix-M — newer vaccine with higher efficacy (~75%) now approved in several endemic countries

• Robbins & Kumar Basic Pathology, p. 391–393
• Goldman-Cecil Medicine (International Ed.), p. 3381
• Lippincott Illustrated Reviews: Pharmacology, pp. 1167–1177

CRL of 66.3 mm → Gestational Age

Gestational age (weeks) = (CRL [mm] + 65) / 10

(66.3 + 65) / 10 = 131.3 / 10 = 13.13 weeks

Result: approximately 13 weeks gestational age (by last menstrual period)

Converting to months

Important caveats

• CRL is most accurate for dating between 7–12 weeks. At ≥13 weeks, the fetus begins to flex and extend significantly, making it difficult to obtain the true maximal diameter — so CRL becomes less reliable beyond this point, and biparietal diameter (BPD), head circumference, femur length, and abdominal circumference become the preferred dating parameters.
• The formula gives gestational age from LMP (menstrual/obstetric age), which is 2 weeks ahead of embryologic (post-fertilization) age.
• Measurements should be averaged from three satisfactory sagittal images, measuring the longest straight-line dimension excluding limb buds and yolk sac.

NTEP — National Tuberculosis Elimination Programme (India)

What is NTEP?

• Nodal ministry: Ministry of Health & Family Welfare, Government of India
• Implemented through: Central TB Division (CTD)

Historical Evolution

Core Strategy

1. Integrated, patient-centred care and prevention
2. Bold policies and supportive systems
3. Intensified research and innovation

Key Components of NTEP

1. Case Finding

• Presumptive TB cases identified at all health facilities
• Active case finding in high-risk groups (PLHIV, contacts, undernourished, diabetics, prisoners, etc.)
• Nikshay — national TB notification and patient management IT portal (mandatory notification of all TB cases, public and private)

2. Diagnosis

• CBNAAT/GeneXpert (Cartridge Based Nucleic Acid Amplification Test) — first-line molecular diagnostic at district level; detects TB + rifampicin resistance simultaneously
• TrueNat — chip-based PCR platform; deployable at PHC level
• LPA (Line Probe Assay) — rapid detection of MDR/XDR-TB
• Liquid culture (MGIT) — Drug susceptibility testing (DST) at Intermediate Reference Laboratories (IRLs)
• Sputum smear microscopy — still used for monitoring (not primary diagnosis)
• Chest X-ray with AI-assisted reading being scaled up

3. Treatment Regimens (as per NTEP 2022 guidelines)

Drug-Sensitive TB (DS-TB)

• H = Isoniazid, R = Rifampicin, Z = Pyrazinamide, E = Ethambutol, S = Streptomycin
• Daily dosing (not intermittent) — moved away from thrice-weekly DOT
• Fixed Dose Combinations (FDCs) — weight-based dosing

Drug-Resistant TB (DR-TB)

• Bedaquiline and Delamanid — newer drugs available under NTEP for DR-TB
• Pretomanid — added for XDR-TB regimens

4. DOT (Directly Observed Treatment)

• Shifted to 99-DOTS (digital adherence monitoring via IVR/missed-call system)
• Medication given in sealed blister packs with unique codes — patient calls a number to confirm dose
• Reduces need for physical supervision while maintaining accountability

5. Nikshay Poshan Yojana (NPY)

• Direct Benefit Transfer (DBT) of ₹500/month to every notified TB patient for nutritional support throughout treatment
• Aims to address undernutrition — a major risk factor for TB in India

6. Pradhan Mantri TB Mukt Bharat Abhiyaan (PMTBMBA)

• Community-based initiative (2022) — enlisting Ni-kshay Mitras (donors/supporters — individuals, corporates, elected representatives) to adopt TB patients and provide nutritional, diagnostic, and vocational support

7. Preventive Therapy

• TB Preventive Therapy (TPT) for high-risk contacts:
  • PLHIV: 6H (6 months isoniazid) or 3HP (3 months weekly isoniazid + rifapentine)
  • Household contacts of bacteriologically confirmed TB cases (especially children <5 years and immunocompromised)

8. HIV-TB Co-management

• All TB patients tested for HIV (provider-initiated)
• All HIV-TB co-infected patients initiated on ART irrespective of CD4 count
• Co-trimoxazole preventive therapy given

NTEP Programme Structure

Central TB Division (CTD) — National level
        ↓
State TB Cell (STC) — State level
        ↓
District TB Centre (DTC) — District level
        ↓
Tuberculosis Unit (TU) — covers ~500,000 population
        ↓
DMC (Designated Microscopy Centre) / CBNAAT site
        ↓
PHC / Sub-centre / ASHA (community level)

Targets & Indicators

Private Sector Engagement

• Mandatory notification — all TB cases must be notified on Nikshay (legal requirement under Notifiable Diseases)
• PPSA (Public-Private Support Agency) model
• Ni-kshay digital platform links private providers
• Ni-kshay drug supply — free FDCs provided to private sector patients

Key Drugs Available Free Under NTEP

India's TB Burden (Context)

• India accounts for ~26% of global TB burden (highest in the world)
• ~2.8 million estimated TB cases per year
• ~480,000 estimated deaths per year (pre-NTEP scale-up era)
• Significant co-morbidity load: DM + TB, malnutrition + TB, HIV + TB