1. Epidemiology

2. Causative Species

3. Life Cycle & Pathogenesis

Fig. 10.8 Life cycle of P. falciparum (Robbins & Kumar Basic Pathology)

1. Mosquito bite - sporozoites injected into bloodstream
2. Hepatic (pre-erythrocytic) stage - sporozoites travel to liver; surface proteins (thrombospondin-related adhesive protein, circumsporozoite protein) bind heparan sulfate proteoglycans on hepatocytes; sporozoites enter and differentiate into merozoites (clinically silent phase, 1-4 weeks)
3. Hepatocyte rupture - thousands of merozoites released into blood
4. Erythrocytic stage - a lectin-like molecule on merozoites binds sialidated glycophorin on RBCs; merozoites invaginate into a digestive vacuole and differentiate into ring trophozoites → trophozoites → schizonts
5. Schizont phase - schizonts express PfEMP1 (P. falciparum erythrocyte membrane protein 1), which forms knob-like extensions on the RBC surface and binds endothelial adhesion molecules (ICAM-1, VCAM-1, CD36) - causing sequestration of infected RBCs in capillary beds
6. Red cell lysis - schizonts differentiate into merozoites; RBCs lyse and release merozoites to infect new RBCs (cycle continues)
7. Gametocyte formation - some trophozoites differentiate into gametocytes, which are taken up by another mosquito and restart the sexual cycle

4. Clinical Features

Typical Presentation

• Episodic fever with rigors/chills corresponding to synchronized RBC lysis and merozoite release
• Headache, myalgia, malaise, nausea/vomiting
• Fever periodicity: 24 h (P. knowlesi), 48 h (P. falciparum, P. vivax, P. ovale), 72 h (P. malariae) - but periodic fever is not a reliable sign, especially in P. falciparum
• Splenomegaly (massive in chronic infection) and hepatomegaly from hyperplasia of mononuclear phagocytes and deposition of malarial pigment (hematin)
• Hemolytic anemia (universal)

Severe Malaria (P. falciparum)

Fig. 58.7 Malaria - bilateral pulmonary opacities in a child (Murray & Nadel)

5. Diagnosis

• Thick smear: detects whether parasites are present (higher sensitivity)
• Thin smear: identifies the species by RBC morphology
• Important note: P. falciparum shows only immature ring forms in peripheral blood (mature forms sequester in microvessels); initial smears may be negative - repeat after 8 hours if high suspicion

• Hemolytic anemia (elevated LDH, indirect bilirubin, reticulocytosis)
• Thrombocytopenia
• Elevated creatinine (in severe disease)
• Hypoglycemia - Rosen's Emergency Medicine, p. 2660

6. Treatment

Uncomplicated Malaria

G6PD deficiency: Primaquine and tafenoquine are contraindicated - they precipitate severe hemolysis. G6PD testing required before use.

Severe Malaria

• IV artesunate - first-line treatment worldwide
  • Dose: 2.4 mg/kg IV at 0, 12, 24 hours, then every 24 h
  • Switch to oral therapy once stable and parasitemia <1%
  • In the US: available via CDC Malaria Hotline (855-856-4713); after hours 770-488-7100
• IV quinine/quinidine: alternative where artesunate unavailable; requires cardiac monitoring (risk of hypoglycemia, QT prolongation)
• Cerebral malaria: IV artesunate/quinine + mechanical ventilation if comatose + antiepileptics + correct acidosis and hypoglycemia
• Exchange transfusion: no longer recommended by CDC (benefit unestablished)
• Fluid management: careful balance - avoid overload to prevent pulmonary edema while maintaining organ perfusion

Artesunate resistance is emerging in SE Asia (manifested as slower parasitemia clearance), requiring longer treatment courses. - Rosen's Emergency Medicine, Murray & Nadel

7. Prevention

Personal Protective Measures

• Insecticide-treated bed nets (ITNs) - most cost-effective intervention
• DEET-containing insect repellents
• Permethrin-treated clothing
• Indoor residual spraying (IRS) - WHO 2025 guidelines updated to include chlorfenapyr and isocycloseram as new approved insecticides
• Spatial emanators / spatial repellents - new recommendation in WHO Malaria Guidelines August 2025

Chemoprophylaxis for Travelers

Intermittent Preventive Treatment (IPT)

• IPTp (in pregnancy): Sulfadoxine-pyrimethamine (SP) given at routine antenatal visits in endemic areas. A 2025 Lancet Infectious Diseases meta-analysis notes increasing SP resistance in Africa, raising concerns about IPTp effectiveness - the effectiveness of IPTp with SP is declining in regions with high-level SP resistance
• Seasonal Malaria Chemoprevention (SMC): SP + amodiaquine given monthly to children during peak transmission season in the Sahel

Vaccine

• RTS,S/AS01 (Mosquirix): first licensed malaria vaccine; targets circumsporozoite protein of P. falciparum; partial protection (~30-50%) but expected to prevent thousands of fatal cerebral malaria cases in children when fully deployed
• R21/Matrix-M: newer vaccine showing ~75% efficacy; recommended by WHO 2023 - Robbins & Kumar Basic Pathology, p. 393

Public Health

• Elimination of stagnant water (mosquito breeding sites)
• Community-wide IRS programs
• Surveillance and early case detection

8. Genetic Protection Against Malaria

• Sickle cell trait (HbAS): protective against P. falciparum severe malaria
• Thalassemia (alpha and beta)
• G6PD deficiency
• Pyruvate kinase deficiency
• Duffy antigen negativity (most West Africans lack the Duffy antigen, making them resistant to P. vivax)

Recent Evidence (2024-2026)

• van Eijk et al., Lancet Infect Dis 2025 (PMID 40675171): Updated meta-analysis confirms IPTp with sulfadoxine-pyrimethamine effectiveness is declining in Africa due to SP resistance - a significant concern for malaria control in pregnancy
• Ruisch et al., Malar J 2024 (PMID 39695670): Systematic review on the cost of seasonal malaria chemoprevention (SMC) - informing WHO scale-up decisions

• Fever (high-grade, periodic)
• Anemia (hemolytic)
• Liver/kidney failure (blackwater fever, AKI)
• Cerebral malaria (convulsions, coma)
• Impaired gas exchange (ARDS, pulmonary edema)

1. Definition & Epidemiology

• Prevalence: ~50-100 per 100,000 in Western populations; higher in Asians, Blacks, and Hispanics
• Sex ratio: 9:1 female-to-male predominance
• Peak age: Women of reproductive age (15-45 years)
• Race/ethnicity: More common and more severe in Black and Hispanic patients; Asian patients have higher rates of renal involvement
• Lupus nephritis is the leading cause of secondary glomerular disease in countries such as China, Korea, and Japan (>50% of cases)

2. Pathogenesis

Fig. 19.10 Pathogenesis of SLE (Cellular and Molecular Immunology)

Genetic Factors

• HLA associations: HLA-DR2 and HLA-DR3 (odds ratio 2-3 each; ~5 if both present)
• Complement deficiencies: C1q, C2, or C4 deficiency (seen in ~5% of SLE patients) impairs clearance of immune complexes and apoptotic cells
• FcγRIIB polymorphism: Defective inhibitory Fc receptor - fails to control B cell activation
• PTPN22 and many other genes identified by GWAS
• CCR6 variants: Associated with lupus nephritis susceptibility (especially in Chinese patients)

Key Pathogenic Mechanism

1. Environmental triggers (especially UV radiation) cause apoptosis of skin cells, releasing nuclear antigens
2. Defective clearance of apoptotic bodies (due to complement deficiency, reduced TREX1 nuclease activity) creates a large burden of nuclear antigens
3. Self-reactive B and T cells (not deleted due to failed tolerance) are stimulated by these nuclear antigens
4. Antigen-antibody complexes form and are endocytosed into DCs and B cells
5. Endosomal TLRs (TLR9 recognizes DNA; TLR7 recognizes RNA) are engaged by the nucleic acid components - amplifying B cell activation
6. Plasmacytoid DCs are activated and produce IFN-α (type I interferon) - the "interferon signature" found in blood cells of SLE patients
7. IFN-α further enhances immune responses and may cause more apoptosis → self-perpetuating cycle
8. Net result: Persistent high-level anti-nuclear IgG antibody production and immune complex-mediated tissue injury

• Cellular and Molecular Immunology, p. 1275-1276

3. Autoantibodies in SLE

• Goldman-Cecil Medicine, p. 2817

4. Clinical Features

Mucocutaneous (80%)

• Malar (butterfly) rash: Erythema over malar eminences and nasal bridge, sparing nasolabial folds; triggered/worsened by sun exposure
• Discoid lupus: Scarring, hyperpigmented plaques; can occur without systemic disease
• Subacute cutaneous lupus (SCLE): Annular or papulosquamous non-scarring rash; strongly linked to anti-Ro/La antibodies
• Photosensitivity: Rash or flare after UV exposure
• Oral ulcers: Usually painless (21% of patients)
• Non-scarring alopecia: Diffuse hair loss during flares
• Bullous lupus

Musculoskeletal (>90%)

• Arthritis/arthralgia: Most common presenting symptom; typically non-erosive, non-deforming polyarthritis (unlike RA)
• Jaccoud arthropathy: Reducible deformities from ligamentous laxity
• Myositis: Less common

Renal (50-60%)

• Lupus nephritis (LN): Leading cause of morbidity and mortality
• Presents with proteinuria, hematuria, cellular casts, hypertension, declining GFR
• WHO/ISN classification (Classes I-VI):
  • Class I: Normal light microscopy, minimal mesangial deposits
  • Class II: Mesangial hypercellularity
  • Class III: Focal proliferative GN (<50% glomeruli)
  • Class IV: Diffuse proliferative GN (≥50% glomeruli) - most severe, "wire-loop" lesions
  • Class V: Membranous LN
  • Class VI: Advanced sclerotic

Cardiovascular

• Libman-Sacks endocarditis: Non-bacterial verrucous endocarditis on both surfaces of mitral valve
• Pericarditis / pericardial effusion: Most common cardiac manifestation
• Myocarditis, premature atherosclerosis (major cause of long-term mortality)
• Thrombosis: From antiphospholipid antibodies

Neuropsychiatric (NPSLE)

• Wide spectrum: headache, cognitive dysfunction ("lupus fog"), psychosis, seizures, stroke, transverse myelitis, peripheral neuropathy
• MRI shows white matter lesions, cerebral infarction, venous sinus thrombosis in 19-70% of patients
• Anti-ribosomal P antibodies associated with psychosis

Pulmonary

• Pleuritis/pleural effusion: Most common pulmonary manifestation (exudative)
• Shrinking lung syndrome: Diaphragmatic dysfunction
• Pulmonary hypertension
• Lupus pneumonitis and rarely diffuse alveolar hemorrhage (life-threatening)

Hematologic

• Cytopenias common: hemolytic anemia (Coombs-positive), leukopenia, lymphopenia, thrombocytopenia
• Thrombocytopenia can be from antiphospholipid antibodies or anti-platelet antibodies

Constitutional

• Fever, fatigue, weight loss (often present during flares)

5. Diagnosis

2019 EULAR/ACR Classification Criteria (Score-Based)

• Goldman-Cecil Medicine, p. 2817; Andrews' Diseases of the Skin, p. 189

Key Investigations

• ANA (screening) - nearly universal in SLE
• Anti-dsDNA, anti-Sm - confirmation and specificity
• Complement levels (C3, C4): low in active disease (consumed by immune complexes); useful for monitoring activity
• CBC: cytopenias
• Urinalysis with microscopy: proteinuria, RBC casts
• Spot urine protein:creatinine ratio / 24-h urine protein
• Serum creatinine/GFR
• Antiphospholipid antibody panel
• Renal biopsy: mandatory for classification of lupus nephritis and guiding therapy

6. Treatment

2025 ACR / EULAR Treatment Goals

• Achieve low disease activity (SLEDAI score 0-4) or ideally remission (SLEDAI = 0)
• Use minimum prednisone ≤5 mg/day (or equivalent) for maintenance
• Minimize organ damage and treatment-related complications
• Prevent flares

Step 1 - Universal Measures (ALL SLE patients)

• Daily sunscreen on sun-exposed areas (avoid UV triggers)
• Avoid smoking (interferes with antimalarial efficacy)
• Regular exercise, healthy diet, BP/lipid/glucose control
• Vaccination (avoid live vaccines if immunosuppressed)
• Hydroxychloroquine (HCQ) in ALL patients unless contraindicated

Step 2 - Hydroxychloroquine (Cornerstone Therapy)

• Dose: up to 5 mg/kg/day (actual body weight); typically 200-400 mg/day
• Benefits: prevents flares, reduces overall mortality, decreases renal disease and accelerated atherosclerosis, anti-thrombotic effects, improves fatigue, safe in pregnancy
• Monitoring: Baseline ophthalmologic exam + annual eye exams (macular toxicity with prolonged use)
• Tobacco smoking reduces antimalarial efficacy

Step 3 - Disease Severity-Based Treatment (Non-Renal)

• Harrison's Principles of Internal Medicine 22E (2025), EULAR recommendations

Step 4 - Lupus Nephritis Treatment (ISN Class III/IV)

• Induction: High-dose corticosteroids + mycophenolate mofetil (MMF) (preferred over cyclophosphamide in most patients) OR cyclophosphamide (NIH regimen or Euro-Lupus low-dose)
• Adjunct: Belimumab (BLISS-LN trial: improved renal response when added to standard therapy)
• Maintenance: MMF or azathioprine (AZA) + HCQ
• Membranous LN (Class V): MMF or calcineurin inhibitors (voclosporin, tacrolimus)

Biologic Agents

Note on anti-IFN-α therapy: Despite IFN-α being central to SLE pathogenesis, anti-IFN-α antibodies had disappointing clinical trials. However, anifrolumab (blocking the IFN-α/β receptor) has shown efficacy and is now approved. - Cellular and Molecular Immunology, p. 1276

Pregnancy Considerations (EULAR 2025)

• Safe to continue: HCQ, low-dose steroids, AZA, calcineurin inhibitors
• Discontinue: Mycophenolate, cyclophosphamide, methotrexate (teratogenic)
• Belimumab: EULAR 2025 allows use if no pregnancy-compatible medication controls disease; no data on anifrolumab in pregnancy
• Antiphospholipid antibody-positive patients: aspirin ± LMWH during pregnancy

7. Complications & Prognosis

• Flare triggers: UV light, infections, pregnancy, certain drugs (procainamide, hydralazine, isoniazid cause drug-induced lupus)
• 10-year survival now >90% in high-resource settings; prognosis worsened by renal involvement, NPSLE, antiphospholipid syndrome, delayed diagnosis

8. Drug-Induced Lupus

• Procainamide (highest risk), hydralazine, isoniazid, minocycline, anti-TNF agents
• Usually associated with anti-histone antibodies (positive in ~95%)
• Typically anti-dsDNA negative (distinguishes from idiopathic SLE)
• Resolves after stopping the offending drug

9. Monitoring Disease Activity

• SLEDAI (SLE Disease Activity Index) - most widely used scoring tool
• BILAG (British Isles Lupus Assessment Group)
• Key monitoring labs: anti-dsDNA titers, C3/C4 levels, CBC, urine protein - correlate with disease activity
• High anti-dsDNA + low complement = active disease / impending flare

• Serositis, Oral ulcers, Arthritis, Photosensitivity
• Blood disorders (hemolytic anemia, leukopenia, thrombocytopenia), Renal (proteinuria/casts), ANA, Immunologic (anti-dsDNA, anti-Sm, aPL)
• Neurologic (seizures/psychosis), Malar rash, Discoid rash

2025 Updates: The ACR released its first SLE guideline since 1999 in November 2025. The EULAR 2025 guidelines added recommendations for anifrolumab and belimumab use in pregnancy (with restrictions). The 2024 ACR Lupus Nephritis guideline updated treatment algorithms with voclosporin and belimumab as part of standard induction therapy. EULAR 2025 also updated recommendations for lupus nephritis management incorporating evidence from newer biologics.