Malaria is an infectious disease caused by Plasmodium parasites transmitted through the bite of infected female Anopheles mosquitoes, characterized by cyclical fevers, chills, and hemolytic anemia.

Exam domain	One-glance essentials
Definition / diagnosis	Systemic red-cell infection by Plasmodium, transmitted by female Anopheles mosquitoes ^[1]^[2] P. falciparum causes the most severe disease; P. vivax/ovale form dormant hepatic hypnozoites
Epidemiology / risks	*All malaria diagnosed in Hong Kong is imported: ask exact travel, dates and prophylaxis* ^[1] Highest severe-disease risk: non-immune travellers, pregnancy, young children and immunocompromised patients ^[2]
Core mechanism	Falciparum infects RBCs of all ages → high parasitaemia; PfEMP1-mediated cytoadherence/sequestration → microvascular organ ischaemia ^[2] Cyclic RBC rupture → fever and haemolysis
Clinical picture	Fever, headache, myalgia and GI symptoms after endemic travel; periodic paroxysms may be absent early ^[1]^[2] Severe disease: altered consciousness/seizures, shock, acidosis, hypoglycaemia, AKI, ARDS, severe anaemia or jaundice ^[1]
Investigations	*Urgent thick film for sensitive detection + thin film for species and parasitaemia* ^[1] If suspicion remains, repeat films; RDT is rapid but does not quantify parasitaemia ^[1]^[2] CBC, glucose, renal/liver tests, acid–base/lactate and coagulation screen assess severity
Management	Severe malaria: *IV/IM artesunate for ≥ 24 hours and until oral therapy is tolerated, then complete a full 3-day ACT* ^[3] Uncomplicated falciparum: effective ACT; vivax/ovale needs blood-stage treatment plus radical cure when safe ^[2]^[3]
Complications	Cerebral malaria, severe anaemia, hypoglycaemia, acidosis, AKI, ARDS, DIC/shock and splenic rupture ^[1]^[2] After IV artesunate, monitor for delayed haemolysis; primaquine/tafenoquine can cause oxidative haemolysis
Prevention / follow-up	Bite prevention: DEET, long clothing and insecticide-treated bed nets ^[1]^[2] Destination-specific chemoprophylaxis; no regimen is fully protective *Quantitative G6PD testing before primaquine/tafenoquine radical cure* ^[3]
Exam traps	*Any unexplained fever after endemic travel is malaria until urgently excluded—do not wait for fever periodicity* ^[1] One negative film does not exclude malaria; repeat when suspicion is high Altered consciousness: check bedside glucose immediately as hypoglycaemia is both a complication and treatment risk

References

^[1] Lecture slides: GC 103. Fever after travelling [Handout].pdf, p4–5 ^[2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Malaria, p1852) ^[3] World Health Organization. WHO guidelines for malaria. 13 August 2025.

Malaria

Malaria (瘧疾) is a systemic infection of red blood cells (RBCs) by protozoan parasites of the genus Plasmodium, transmitted to humans principally through the bite of infected female Anopheles mosquitoes ^[1]^[2]^[3].

Breaking down the word: "Mal-aria" comes from Medieval Italian mala aria = "bad air," because the disease was historically associated with the foul-smelling air near swamps (where mosquitoes bred). The name is a relic of the miasma theory.

"The possibility of malaria MUST be considered in all cases of unexplained fever that starts after the 7th day of stay in an endemic area." ^[1]^[3]^[4]

This is the single most important clinical principle — malaria is a "must-not-miss" diagnosis in any febrile returned traveller.

2. Epidemiology

Most malaria cases and deaths occur in sub-Saharan Africa ^[2]^[3]
The WHO African Region carries a disproportionately high share of the global malaria burden — home to ~90% of malaria cases and ~91% of malaria deaths ^[2]^[3]
Globally ~250 million cases and ~600,000+ deaths per year (predominantly children < 5 years) ^[2]^[4]
Malaria in non-endemic regions typically occurs during travel to endemic countries ^[2]^[3]

Hong Kong is non-endemic for malaria. All cases are imported — overwhelmingly from travellers returning from sub-Saharan Africa or South/Southeast Asia. Hong Kong sees approximately 20–40 notified malaria cases per year, but these patients can present very late because clinicians may not think of the diagnosis in a non-endemic setting. The Centre for Health Protection (CHP) maintains malaria as a statutory notifiable disease in Hong Kong.

Factor	Explanation
Age < 5 years	Immature acquired immunity; > 2/3 of global malaria deaths occur in this age group ^[2]^[3]
Pregnancy	Immunomodulation of pregnancy + placental sequestration of parasitised RBCs → ↑ risk of severe disease, anaemia, low birth weight, miscarriage ^[2]^[3]
Travellers to endemic regions	Non-immune individuals have no acquired protective immunity ^[2]^[3]
HIV infection	Impaired cellular immunity → ↑ parasitaemia and ↑ severity ^[2]^[3]
Splenectomy / functional asplenia	Spleen is the major organ for clearing parasitised RBCs
Lack of chemoprophylaxis	Absence of preventive antimalarials during travel ^[5]

These are evolutionary adaptations prevalent in malaria-endemic regions — the concept of balanced polymorphism (the heterozygote advantage):

Condition	Mechanism of protection
G6PD deficiency	Oxidative stress in G6PD-deficient RBCs → premature destruction of parasitised cells before parasite completes development ^[2]^[3]^[6]
Thalassaemia (esp. α-thal trait)	Microcytic RBCs with ↓ Hb content are less hospitable to Plasmodium; also ↑ oxidative stress in parasitised cells
Haemoglobinopathies (HbS, HbC, HbSC, HbE, HbF)	e.g. Sickle cell trait (HbAS): sickling of parasitised RBCs → enhanced splenic clearance; HbF (foetal Hb) inhibits parasite growth ^[2]^[3]
Duffy-negative phenotype	P. vivax uses the Duffy antigen as its receptor to invade RBCs. Duffy-negative individuals (common in West Africa) are essentially resistant to P. vivax
Southeast Asian ovalocytosis	Rigid RBC membrane impedes merozoite invasion

Why Are Thalassaemia and G6PD Deficiency So Common in Hong Kong?

Hong Kong has a high prevalence of α-thalassaemia trait (~4–5%) and G6PD deficiency (~4.5% males, ~0.5% females) ^[6]. Southern China was historically a malaria-endemic region — these gene frequencies are a legacy of centuries of selective pressure from P. vivax and P. falciparum.

Natural infection of human malaria can be caused by one of five Plasmodium species ^[1]:

Species	Key Features	Fever Periodicity	Hypnozoites?	Severity
P. falciparum (惡性瘧原蟲)	Most common globally, most prevalent on the African continent, responsible for most malaria-related deaths globally ^[1]^[2]^[3]. Infects RBCs of ALL ages → very high parasitaemia.	Tertian (48 h) or irregular	No	Most fulminant form of disease; medical emergency ^[1]^[4]
P. vivax (間日瘧原蟲)	Dominant malaria parasite in most countries outside sub-Saharan Africa ^[2]^[3]. Preferentially infects reticulocytes → lower parasitaemia.	Tertian (48 h)	Yes — can relapse months–years later	Usually benign but can cause severe disease
P. ovale	Similar to P. vivax, predominantly in West Africa	Tertian (48 h)	Yes	Usually benign
P. malariae	Low-grade chronic infection, can persist for decades	Quartan (72 h)	No (but can have persistent low-level erythrocytic infection)	Usually benign; associated with nephrotic syndrome (immune-complex GN)
P. knowlesi	A simian/monkey malaria seen only in some Southeast Asian countries ^[1]. Zoonotic, from macaques. 24-hour replication cycle → can escalate rapidly.	Quotidian (24 h)	No	Can be severe (high parasitaemia due to short cycle)

"Among the species that cause human malaria, P. vivax and P. falciparum are the commonest. P. falciparum causes the most fulminant form of disease and accounts for the vast majority of fatality." ^[1]

Transmission occurs via the bite of infected female Anopheles mosquitoes ^[1]^[2]^[3].

Why female? Because only female mosquitoes require a blood meal (for egg production). Male mosquitoes feed on nectar.

Most of the vector species bite between dusk and dawn ^[2]^[3] — this is clinically relevant for advising travellers on when to use insecticide-treated bed nets and apply repellent.

Other (non-mosquito) routes ^[2]^[3]:

Congenital acquisition (transplacental)
Blood transfusion
Sharing of contaminated needles
Organ transplantation
Nosocomial transmission

"Plasmodia are blood protozoa and are transmitted from person-to-person via the bites of female Anopheles mosquitoes and occasionally through blood transfusion. The travel history is crucial." ^[1]

5. Life Cycle and Pathophysiology

Understanding the life cycle is essential because it explains:

Why there is an incubation period
Why fever is cyclical
Why certain species relapse
Why different drugs target different stages
Why severe malaria occurs

5.2 Detailed Phases with Pathophysiological Basis

After inoculation by the mosquito bite, sporozoites circulate briefly in the blood (< 30 minutes) then are taken up by hepatocytes
Within hepatocytes, sporozoites undergo asexual replication (exoerythrocytic schizogony) over 5–16 days, depending on species
Each infected hepatocyte produces thousands of merozoites
The patient is asymptomatic during this stage because there is no RBC destruction yet
P. vivax and P. ovale: some sporozoites become dormant forms called hypnozoites that remain quiescent in hepatocytes ^[4]. These can reactivate weeks to years later, causing relapse — this is why drugs like primaquine (targeting hypnozoites) are needed for radical cure

Released merozoites invade RBCs and undergo cyclic asexual replication (erythrocytic schizogony):
- Ring form → Trophozoite (feeding stage) → Schizont (dividing stage)
- Schizont ruptures, releasing 8–32 new merozoites + haemozoin (malarial pigment, a crystalline by-product of haemoglobin digestion)
Cyclical fever occurs due to regular periodic lysis of erythrocytes and release of invasive merozoites ^[4]
- The fever periodicity is determined by the duration of the erythrocytic cycle:
  - Tertian (every 48 h): P. falciparum, P. vivax, P. ovale
  - Quartan (every 72 h): P. malariae
  - Quotidian (every 24 h): P. knowlesi
- However, classical periodic fever is not normally seen in the early stage of disease ^[1] — initially the parasite broods are asynchronous, so fever is irregular/continuous. Periodicity develops only once the parasite cycles synchronise (usually after several days)

Incubation Period

Incubation period = approximately 2 weeks (range 7–30 days) ^[2]^[3]. Individuals are generally asymptomatic for 12–35 days but can commence symptoms as early as 7 days (minimum = 7 days) ^[2]^[3]. Most infections due to P. falciparum become clinically apparent within 1 month after exposure ^[2]^[3]. This is why the "7-day rule" exists — malaria should be considered in anyone with unexplained fever ≥ 7 days after entering an endemic area. Conversely, symptoms starting < 7 days after first exposure essentially excludes malaria (not enough time for the hepatic phase).

Some intraerythrocytic parasites differentiate into gametocytes (male microgametocytes and female macrogametocytes)
These are the sexual forms that are taken up by mosquitoes during a subsequent blood meal
Gametocytes do NOT cause symptoms but are critical for ongoing transmission
P. falciparum gametocytes persist in the circulation for weeks after treatment — this is why primaquine (which also kills gametocytes) is recommended for P. falciparum in some settings to reduce transmission

5.3 Pathophysiology of Severe Malaria (Primarily P. falciparum)

Why is P. falciparum so dangerous compared to other species? Three key virulence mechanisms:

P. falciparum can infect RBCs of all ages (young and old), whereas P. vivax preferentially infects reticulocytes and P. malariae infects senescent RBCs
This means P. falciparum parasitaemia can reach > 10%, even > 50% — causing massive haemolysis

P. falciparum-infected RBCs express PfEMP1 (Plasmodium falciparum Erythrocyte Membrane Protein 1) on the RBC surface, encoded by highly variable var genes
PfEMP1 binds to endothelial receptors (ICAM-1, CD36, chondroitin sulfate A in placenta, etc.) → parasitised RBCs adhere to vascular endothelium in post-capillary venules of vital organs
Parasitised RBCs adhering to small blood vessels leads to small infarcts, capillary leakage and organ dysfunction ^[4]
This is why peripheral blood smears in P. falciparum may show lower parasitaemia than the true body burden — the mature forms are sequestered in deep tissues and are not circulating

Parasitised RBCs can bind to uninfected RBCs (rosetting) and to platelets (clumping)
This worsens microvascular obstruction

Organ	Pathophysiology	Clinical Manifestation
Brain	Sequestration of parasitised RBCs in cerebral microvasculature → ischaemia, inflammation, BBB disruption	Cerebral malaria: ↓ consciousness, delirium, prostration, seizures ^[4]
Kidneys	Microvascular obstruction + haemoglobinuria (from massive intravascular haemolysis) + ↓ renal perfusion	Renal failure: dark urine (due to ↑ Hb and malarial pigments) ^[4], acute tubular necrosis
Liver	Sequestration + parasite-induced hepatocyte dysfunction	Liver failure: jaundice ^[4]
Lungs	Increased capillary permeability, fluid overload	ARDS (non-cardiogenic pulmonary oedema)
Bone marrow	Dyserythropoiesis + haemolysis	Severe anaemia
Placenta	Parasitised RBCs adhere to chondroitin sulfate A in placental intervillous spaces	Placental insufficiency → IUGR, low birth weight, miscarriage
Spleen	Massive hyperplasia from clearing parasitised RBCs	Splenomegaly (can be massive); risk of splenic rupture
Blood	Consumption of platelets + DIC	Thrombocytopenia ± bleeding
Metabolism	Parasite glucose consumption + impaired gluconeogenesis (quinine effect too)	Hypoglycaemia (especially in children and pregnant women)
Lactate	Microvascular obstruction → tissue hypoxia + anaerobic metabolism	Metabolic (lactic) acidosis

Why Only P. falciparum Causes Severe Malaria?

The key difference is cytoadherence/sequestration. Other Plasmodium species do NOT express PfEMP1 and their infected RBCs do NOT stick to endothelium. They circulate freely → get efficiently cleared by the spleen → parasitaemia stays low → organ damage is minimal. P. falciparum evades splenic clearance by hiding in the deep microvasculature, achieves high parasitaemia, and causes end-organ damage. P. knowlesi can also cause severe disease but through sheer speed of replication (24 h cycle) rather than sequestration.

6. Classification

6.1 By Species (see Section 3 above)

This distinction is critical because it determines the treatment approach:

Uncomplicated malaria:

Symptomatic malaria with parasitaemia on blood film but no features of severe malaria
Patient can take oral medication

Severe malaria (WHO criteria — primarily P. falciparum): Any of the following constitutes severe malaria and is a medical emergency:

Feature	Definition
Impaired consciousness	GCS < 11 in adults; Blantyre coma score < 3 in children
Prostration	Inability to sit/walk/feed unaided
Multiple convulsions	≥ 2 episodes in 24 h
Acidosis	Base deficit > 8 mEq/L or bicarbonate < 15 mmol/L or venous lactate ≥ 5 mmol/L
Hypoglycaemia	Blood glucose < 2.2 mmol/L ( < 40 mg/dL)
Severe anaemia	Hb < 5 g/dL or Hct < 15% in children; Hb < 7 g/dL in adults
Renal impairment	Creatinine > 265 μmol/L ( > 3 mg/dL) or urine output < 0.4 mL/kg/h
Jaundice	Bilirubin > 50 μmol/L ( > 3 mg/dL) with parasitaemia > 100,000/μL
Pulmonary oedema / ARDS	Radiological confirmation
Significant bleeding	Including DIC
Shock	SBP < 80 mmHg in adults ( < 70 in children) with impaired perfusion
Hyperparasitaemia	> 10% in non-immune patients; > 5% with any other sign of severity

Imported malaria — acquired during travel to endemic area (all HK cases)
Congenital malaria — vertical transmission
Transfusion malaria — via blood products
Relapse — reactivation from hepatic hypnozoites (P. vivax / P. ovale)
Recrudescence — resurgence from persistent low-level erythrocytic infection (P. malariae, or inadequately treated P. falciparum)

7. Clinical Features

"A complete travel history from the patient including exact dates/places, intermediate stops, mode of travel" is essential ^[1]^[4]:

History Component	Rationale
Exact dates and places visited, intermediate stops ^[4]	Determines if the destination is malaria-endemic; calculates if incubation period is plausible
Mode of travel ^[4]	Rural/forest exposure vs. urban areas
Sexual exposure or needle/blood exposure ^[4]	Non-mosquito transmission routes
Drug abuse, tattoos, body piercing, injections, medical procedures ^[4]	Parenteral exposure
Animal and arthropod contact ^[4]	Differentiates from other vector-borne diseases
Water exposure (swimming, walking, rafting) ^[4]	Other tropical infections (e.g. schistosomiasis, leptospirosis)
Food/drink exposure ^[4]	Enteric infections
Any prophylactic measures ^[4]	Chemoprophylaxis compliance affects pre-test probability and species likelihood

GC Exam High Yield: Travel History Components

"History (including travel history, dates and places of exposure, vaccination and prophylaxis history, exposures, and symptomatology) and physical examination is the crucial first step to making a presumptive diagnosis." ^[1] This exact framing is from the GC 103 lecture handout and is highly examinable.

7.2 Symptoms

The textbook triad, occurring in a cyclical pattern:

Cold stage (rigors / chills) — 15–60 minutes
- Pathophysiology: Schizont rupture → release of merozoites, haemozoin, and parasite-derived pyrogens (e.g. GPI anchors) → activate macrophages → TNF-α, IL-1, IL-6 release → hypothalamic set-point raised → peripheral vasoconstriction → patient feels intensely cold and shivers
Hot stage (high fever, often > 40°C) — 2–6 hours
- Pathophysiology: Core temperature catches up to the new hypothalamic set-point → peripheral vasodilation → patient feels burning hot, flushed. Headache, myalgia, nausea, vomiting common
Sweating stage (defervescence, profuse diaphoresis) — 2–4 hours
- Pathophysiology: Hypothalamic set-point resets to normal → sympathetic activation of sweating → evaporative heat loss → temperature drops → patient feels exhausted but temporarily better

Cyclical fever (8%): due to regular periodic lysis of erythrocytes and release of invasive merozoites ^[4]

Tertian fever (every 48 h) — P. falciparum, P. vivax, P. ovale
Quartan fever (every 72 h) — P. malariae

"The classical symptoms of malaria is periodic fever with a 48- or 72-hour cycle. This, however, is not normally seen in the early stage of disease." ^[1]

Important clinical pearl: In practice, most patients (especially with P. falciparum) do NOT present with classic periodic fevers initially. They present with continuous or irregular fever, because parasite broods are asynchronous. Don't wait for periodicity to suspect malaria!

Non-specific illness: diarrhoea, vomiting, flu-like symptoms ^[4]

Headache — very common, due to systemic inflammatory response
Myalgia / arthralgia — cytokine-mediated
Malaise / fatigue — anaemia + systemic inflammation
Anorexia, nausea, vomiting — hepatic involvement + cytokines
Diarrhoea — can mimic gastroenteritis (a common trap)
Cough — mild, non-productive; can mimic URTI

"It is also important to remember that apart from fever, malaria can have protean manifestations which can mimic many other diseases." ^[1]

The Great Mimicker

Malaria is called the "great mimicker" because it can present as what looks like influenza, gastroenteritis, hepatitis, meningitis, sepsis, or even a surgical abdomen. In any febrile returned traveller, always think of malaria first — it is the most important diagnosis to rule out because it can kill rapidly if missed.

Cerebral malaria: ↓ consciousness, delirium, prostration, seizures ^[4]
- Pathophysiology: Sequestration of parasitised RBCs in cerebral microvasculature → microvascular obstruction → ischaemia, inflammation, BBB disruption → cerebral oedema
- Prostration = inability to sit unsupported (children) or inability to walk without assistance (adults)
Jaundice ^[4]
- Pathophysiology: Combination of (1) haemolysis → ↑ unconjugated bilirubin; (2) hepatocyte dysfunction from sequestration/inflammation → ↑ conjugated bilirubin; (3) intrahepatic cholestasis
Dark urine ("Blackwater fever") ^[4]
- Pathophysiology: Dark urine due to ↑ Hb and malarial pigments ^[4] — massive intravascular haemolysis → free haemoglobin overwhelms haptoglobin binding capacity → haemoglobinuria → dark (coca-cola/black-coloured) urine → can precipitate ATN and renal failure
Severe anaemia — due to (1) direct RBC destruction by parasites, (2) splenic clearance of parasitised and bystander RBCs, (3) dyserythropoiesis (bone marrow suppression by cytokines and haemozoin), (4) oxidative damage to uninfected RBCs
Respiratory distress — rapid/laboured breathing due to metabolic acidosis (Kussmaul breathing) and/or ARDS
Hypoglycaemia — especially in children and pregnant women; due to (1) parasite consuming glucose, (2) impaired hepatic gluconeogenesis, (3) quinine/quinidine-induced hyperinsulinaemia (iatrogenic)

Sign	Pathophysiological Basis
Fever (often > 39–40°C, may be intermittent or continuous)	Cytokine release (TNF-α, IL-1, IL-6) triggered by schizont rupture and release of haemozoin/GPI
Pallor (conjunctival, palmar)	Anaemia from haemolysis + dyserythropoiesis
Jaundice (scleral icterus)	Haemolytic + hepatocellular component (see above)
Splenomegaly	Reticuloendothelial hyperplasia — the spleen is working overtime to clear parasitised and damaged RBCs. May be massively enlarged in chronic/recurrent infections. Tender in acute disease
Hepatomegaly	Kupffer cell hyperplasia + congestion + sequestration of parasitised RBCs in hepatic sinusoids
Tachycardia	Fever + anaemia + dehydration → compensatory ↑ heart rate
Hypotension / shock	Severe disease: ↓ intravascular volume (third-spacing, sweating, vomiting) + vasodilation from cytokine storm
Petechiae / bleeding	Thrombocytopenia (platelet consumption + DIC)
Altered consciousness / coma	Cerebral malaria — sequestration in cerebral microvasculature
Seizures	Cerebral malaria; also hypoglycaemia
Kussmaul breathing (deep, laboured)	Metabolic (lactic) acidosis — compensatory respiratory alkalosis
Pulmonary crepitations	ARDS / pulmonary oedema from increased capillary permeability
Retinal changes (malarial retinopathy — pathognomonic for cerebral malaria in children)	Retinal whitening, vessel changes, and haemorrhages from sequestration in retinal microvasculature

Malaria is one of the most important causes of splenomegaly worldwide ^[7]. In the GC 086 (Splenomegaly) lecture, tropical infections including malaria are listed as causes of massive splenomegaly. The mechanism is:

Acute malaria: Reactive splenomegaly from reticuloendothelial hyperplasia (clearing parasitised RBCs)
Chronic/recurrent malaria: Tropical/hyper-reactive malarial splenomegaly (HMS) — a syndrome of massive splenomegaly + elevated IgM + high antimalarial antibody titres, driven by chronic antigenic stimulation

Malaria is a major cause of anaemia worldwide, especially in endemic regions ^[8]. The anaemia of malaria is multifactorial:

Direct haemolysis — parasites destroy RBCs during schizont rupture
Bystander haemolysis — uninfected RBCs are also destroyed (oxidative damage, complement activation, altered membrane)
Splenic trapping — both parasitised and non-parasitised RBCs are removed by an enlarged, hyperactive spleen
Dyserythropoiesis — haemozoin + cytokines (especially TNF-α) suppress erythropoiesis in bone marrow
Iron sequestration — inflammation leads to hepcidin-mediated iron sequestration (anaemia of chronic disease component)

This produces a picture of normocytic normochromic anaemia (or sometimes macrocytic if there is a brisk reticulocyte response) with reticulocytosis and features of haemolysis (↑ LDH, ↑ unconjugated bilirubin, ↓ haptoglobin).

High Yield Summary

Definition: Systemic RBC infection by Plasmodium spp., transmitted by female Anopheles mosquitoes.

5 Species: P. falciparum (most severe, Africa), P. vivax (most common outside Africa, relapses), P. ovale (relapses), P. malariae (quartan fever), P. knowlesi (SE Asia zoonosis, rapid cycle).

Epidemiology: Sub-Saharan Africa carries 90% of global burden. All HK cases are imported. High-risk groups: children < 5, pregnant women, travellers, HIV+.

Protective conditions: G6PD deficiency, thalassaemia, sickle cell trait, Duffy-negative phenotype.

Key pathophysiology of severe malaria (P. falciparum): (1) Infects RBCs of all ages → high parasitaemia; (2) PfEMP1-mediated cytoadherence → sequestration in microvasculature → organ ischaemia; (3) Rosetting → worsened obstruction.

Clinical features:

Classical paroxysm: Cold → Hot → Sweating stage (cyclical but often irregular initially)
Non-specific: fever, headache, myalgia, GI symptoms — the "great mimicker"
Severe: cerebral malaria (seizures, coma), severe anaemia, renal failure, ARDS, hypoglycaemia, acidosis, jaundice, blackwater fever
Signs: splenomegaly, hepatomegaly, pallor, jaundice, tachycardia

The golden rule: Malaria MUST be considered in all unexplained fever starting ≥ 7 days after entering an endemic area. Never wait for classical periodicity.

Active Recall - Malaria (Definition, Epidemiology, Pathophysiology, Clinical Features)

^[1] Lecture slides: GC 103. Fever after travelling [Handout].pdf (Malaria section, pp. 4) ^[2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Malaria section) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Malaria section) ^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 14.2.4, p. 483) ^[5] AOS material: AOS - Microbio.pdf (Question 8 — chemoprophylaxis for malaria) ^[6] Senior notes: Ryan Ho Haemtology.pdf (G6PD deficiency section, p. 40) ^[7] Lecture slides: GC 086. Splenomegaly.pdf ^[8] Lecture slides: GC 076. Pallor_diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf

Differential Diagnosis of Malaria

The core clinical scenario for malaria is the febrile returned traveller. Your job is not just to confirm malaria — it is to systematically consider the full differential of fever after travel, because (a) malaria can mimic almost anything, and (b) co-infections are common in the tropics. Even when malaria is confirmed, you still need to think about concurrent diagnoses.

"Apart from fever, malaria can have protean manifestations which can mimic many other diseases." ^[1]

"History (including travel history, dates and places of exposure, vaccination and prophylaxis history, exposures, and symptomatology) and physical examination is the crucial first step to making a presumptive diagnosis." ^[1]

1. Framework for Thinking About the Differential

The differential of malaria is essentially the differential of fever in the returned traveller, overlaid with differentials driven by dominant clinical features (e.g., if the patient also has jaundice, splenomegaly, anaemia, thrombocytopenia, or altered consciousness). Let's build this logically.

The timing of fever onset after last possible exposure narrows the differential enormously. Each pathogen has a biological incubation period — it physically cannot cause symptoms before completing its initial replication cycle.

Incubation Period	Differential Diagnoses	Notes
< 7 days (short)	Dengue, chikungunya, Zika, rickettsial infections, acute bacterial enteritis (Salmonella, Shigella, Campylobacter), viral haemorrhagic fevers, plague, anthrax	Malaria is essentially excluded if < 7 days from first endemic exposure ^[1]^[2]^[3]
7–21 days (medium)	Malaria (most common window), typhoid/enteric fever, leptospirosis, acute HIV seroconversion, scrub typhus, acute schistosomiasis (Katayama fever), African trypanosomiasis, viral hepatitis A/E	Most P. falciparum infections become clinically apparent within 1 month ^[2]^[3]
> 21 days (long)	Malaria (esp. P. vivax/ovale relapse), TB, visceral leishmaniasis, amoebic liver abscess, chronic hepatitis B/C, brucellosis, Q fever	P. vivax/ovale hypnozoites can reactivate months–years later

GC Exam High Yield: The 7-Day Rule

The possibility of malaria must be considered in all cases of unexplained fever that starts after the seventh day of stay in an endemic area ^[1]. Conversely, if fever onset is < 7 days after first arriving in an endemic zone, malaria is practically excluded because there hasn't been enough time for the hepatic schizogony phase to complete. This is a favourite exam question.

Where the patient travelled determines which pathogens are plausible:

Region	Key Differentials Besides Malaria
Sub-Saharan Africa	Typhoid, viral haemorrhagic fevers (Ebola, Lassa, Marburg), African trypanosomiasis, schistosomiasis, HIV, TB, rickettsial infections
South/Southeast Asia	Dengue (very common!), typhoid, scrub typhus, leptospirosis, Japanese encephalitis, melioidosis, P. knowlesi malaria, Talaromyces marneffei (if immunocompromised)
Central/South America	Dengue, chikungunya, Zika, Chagas disease, yellow fever, leptospirosis
Indian subcontinent	Typhoid (very common), dengue, chikungunya, visceral leishmaniasis (kala-azar), scrub typhus

This is the most practical clinical approach — you see the patient, note the dominant features, and then reason through the differential:

2. Detailed Differential Diagnoses

2.1 Infections That Most Closely Mimic Malaria

These are the "must-consider" alternatives when you suspect malaria:

Vector: Aedes aegypti/albopictus mosquito (bites during daytime — contrast with Anopheles which bites dusk–dawn)
Geography: Tropics/subtropics globally, very common in SE Asia and South Asia; endemic in Hong Kong (local cases reported)
Incubation: 4–10 days (shorter than malaria)
Key features: High fever, severe headache (retro-orbital pain), myalgia/arthralgia ("breakbone fever"), maculopapular rash (often appears on defervescence), thrombocytopenia, leukopenia
Distinguishing from malaria: Dengue has NO parasitaemia on blood film; has characteristic leukopenia (malaria more often has normal or mildly elevated WCC); dengue is more likely to have rash and retro-orbital pain; dengue NS1 antigen / IgM serology positive
Why it matters: In SE Asia (a common travel destination for HK residents), dengue is actually more common than malaria. Co-infection is possible.

Pathogen: Salmonella enterica serovar Typhi (typhoid) or Paratyphi (paratyphoid)
Transmission: Faecal-oral (contaminated food/water) — so the water/food exposure history differentiates this from mosquito-borne malaria
Incubation: 7–14 days (overlaps with malaria)
Key features: Stepladder fever (gradually increasing over first week), relative bradycardia (Faget sign — pulse doesn't rise proportionally with fever), abdominal discomfort, constipation (early) then diarrhoea (late), rose spots (faint salmon-coloured macules on trunk, ~30% of cases) ^[9], hepatosplenomegaly
Distinguishing from malaria: Blood/stool cultures positive for Salmonella; rose spots; relative bradycardia; no parasitaemia on blood film; often leukopenia with relative lymphocytosis

"Rose spots = Typhoid fever" ^[9] — a characteristic feature to recall in differential diagnosis by examination findings.

Pathogen: Leptospira interrogans (spirochaete)
Transmission: Contact with water contaminated by animal urine (rats) — hence water exposure (swimming, walking, rafting) history is crucial ^[4]
Incubation: 2–30 days
Key features: Biphasic illness — initial septicaemic phase (fever, headache, myalgia esp. calves, conjunctival suffusion) then immune phase (can → Weil's disease: jaundice + renal failure + haemorrhage); thrombocytopenia common
Distinguishing from malaria: Conjunctival suffusion (red eyes without exudate) is fairly characteristic; severe calf pain; exposure to contaminated water; serology (MAT) or PCR positive

Pathogen: Orientia tsutsugamushi (scrub typhus), Rickettsia typhi (murine typhus), etc.
Transmission: Arthropod bites — mites (scrub typhus), fleas (murine typhus), ticks (spotted fevers); animal and arthropod contact history ^[4]
Incubation: 6–21 days
Key features: Fever, headache, myalgia, eschar (painless necrotic lesion at bite site — pathognomonic for scrub typhus), maculopapular rash, lymphadenopathy
Distinguishing from malaria: Eschar is the key distinguishing sign; rash pattern; no parasitaemia

Transmission: Sexual exposure or needle/blood exposure ^[4]; drug abuse, tattoos, body piercing, injection, medical procedure ^[4]
Incubation: 2–4 weeks after exposure
Key features: Fever, pharyngitis, lymphadenopathy, maculopapular rash, oral ulcers, myalgia — an infectious mononucleosis-like syndrome ^[10]
Distinguishing from malaria: Risk factor history; atypical lymphocytosis on blood film ^[10]^[12]; HIV RNA (viral load) positive before antibodies; 4th-gen HIV Ag/Ab combo test
This is an important "do-not-miss" because early diagnosis allows early treatment

Pathogen: Leishmania donovani complex (intracellular protozoan)
Transmission: Sandfly bite
Geography: Indian subcontinent, East Africa, Mediterranean
Incubation: Weeks to months (can be very prolonged)
Key features: Prolonged fever, massive splenomegaly (often bigger than malaria), hepatomegaly, pancytopenia, hypergammaglobulinaemia, wasting, darkening of skin ("kala-azar" = black fever)
Distinguishing from malaria: Much more indolent course; very large spleen; pancytopenia without parasitaemia on standard blood film; diagnosis by bone marrow/splenic aspirate showing Leishman-Donovan bodies or rK39 serology

Transmission: Faecal-oral (HAV, HEV) — food/drink exposure ^[4]; parenteral (HBV)
Key features: Fever → jaundice, nausea, RUQ pain, dark urine (conjugated bilirubinuria), markedly elevated transaminases (ALT/AST often > 1000)
Distinguishing from malaria: Transaminases in malaria are usually only mildly to moderately elevated (< 200); bilirubin in malaria has a significant unconjugated component (haemolytic); hepatitis serology positive; no parasitaemia

Pathogen: Entamoeba histolytica
Key features: Fever, RUQ pain, hepatomegaly, elevated right hemidiaphragm on CXR, "anchovy paste" pus on aspiration
Distinguishing from malaria: Focal hepatic lesion on imaging; amoebic serology positive

In any febrile patient, including travellers, remember the non-infectious causes of fever that can mimic or co-exist with malaria:

Category	Examples	Clinical Clues
Haematological malignancy	Acute leukaemia, lymphoma	Hepatosplenomegaly, lymphadenopathy, pancytopenia, blasts on blood film ^[12]; malaria can co-exist and should not distract from underlying malignancy
Autoimmune / inflammatory	SLE, Adult-onset Still's disease	Fever pattern, rash, joint involvement, autoantibodies; atypical lymphocytosis can occur in autoimmune disease ^[12]
Drug fever	Any new medication	Temporal relationship with drug initiation; diagnosis of exclusion
DVT / PE	—	Fever + pleuritic chest pain + tachycardia in immobilised traveller (long-haul flight)

The Most Common Cause of Fever in a Returned Traveller Is NOT Tropical

"In fact, the most common cause is non-tropical infection!" ^[4] — Many returned travellers with fever have common respiratory viruses (influenza, COVID-19), UTIs, or community-acquired pneumonia. Always consider these mundane diagnoses alongside the exotic tropical ones. Don't anchor on the travel history and miss a simple pneumonia.

2.3 Differential of Malaria-Like Haematological Findings

Malaria characteristically causes specific laboratory abnormalities. The differential of these findings overlaps with other conditions:

Thrombocytopenia is extremely common in malaria (often the earliest and most prominent haematological finding). But other causes include:

Dengue fever (often more severe thrombocytopenia)
Rickettsial infections
Leptospirosis
HIV (acute or chronic)
TTP/HUS
DIC — malaria itself can trigger DIC ^[13]; other causes of DIC include septicaemia, APML, obstetric emergencies

Malaria is a parasitic infection of RBCs causing haemolysis ^[11]. The differential of infectious causes of haemolysis:

Parasitic infection of RBC (malaria) ^[11]
Bacterial infection of RBC (Clostridium perfringens) ^[11]
Babesiosis (Babesia spp. — tick-borne protozoan that also infects RBCs; can look very similar to malaria on blood film, especially P. falciparum ring forms)
Bartonellosis (Bartonella bacilliformis — Oroya fever)

"Infectious causes of haemolytic anaemia: bacterial infection of RBC (C. perfringens) and parasitic infection of RBC (malaria)" ^[11]

Malaria is one of the most important tropical causes of splenomegaly ^[7]. The differential of fever + splenomegaly includes:

Infective: viral (EBV, CMV), bacterial, mycobacterial, parasitic (malaria, leishmaniasis), dimorphic fungi ^[10]
Neoplastic: leukaemias, lymphomas/LPD ^[10]
Autoimmune conditions
Myeloproliferative neoplasms (CML, myelofibrosis)

The splenomegaly lecture (GC 086) framework applies: think infectious → haematological → portal hypertension → autoimmune → infiltrative/storage.

The combination of fever + jaundice has an important differential:

Malaria (haemolytic + hepatocellular)
Viral hepatitis
Leptospirosis (Weil's disease)
Yellow fever
Ascending cholangitis / biliary sepsis
Severe sepsis with hepatic dysfunction

Differential diagnosis of atypical lymphocytes / infectious mononucleosis-like syndromes ^[10]:

Viral: EBV, CMV, HIV, acute viral hepatitis ^[10]
Bacterial: atypical organisms — Mycoplasma pneumoniae, Legionella, Salmonella, Rickettsia ^[10]
Mycobacterial: disseminated TB ^[10]
Dimorphic fungi: Talaromyces marneffei ^[10]
Parasitic: Toxoplasma gondii ^[10]
Drug reactions / hypersensitivity ^[10]

Note: Malaria itself does NOT typically cause atypical lymphocytosis — but if you see it on the blood film, consider these alternatives or co-infections.

A practical bedside approach, synthesising the frameworks above:

Key clinical reasoning steps:

Always test for malaria FIRST in any febrile traveller from an endemic area — it is the most dangerous diagnosis to miss because it can kill within 24–48 hours if untreated
A negative blood film does NOT exclude malaria — parasitaemia can be below detection threshold, especially early in infection or with partial prophylaxis. Repeat films every 12–24 hours for at least 48–72 hours ^[2]^[3]
Co-infection is common — e.g., malaria + typhoid, malaria + HIV, malaria + dengue. Confirming one diagnosis does not exclude others
Remember that the most common cause of fever in a returned traveller is actually non-tropical infection ^[4] — always consider common infections (URTI, UTI, pneumonia) alongside tropical diseases

Diagnosis	Vector / Transmission	Incubation	Key Distinguishing Features	Key Investigation
Malaria	Anopheles mosquito (dusk–dawn)	7–30 d	Cyclical fever, splenomegaly, haemolytic anaemia, thrombocytopenia	Thick/thin blood film, RDT
Dengue	Aedes mosquito (daytime)	4–10 d	Retro-orbital pain, rash, leukopenia, thrombocytopenia	NS1 Ag, dengue IgM/IgG
Typhoid	Faecal-oral	7–14 d	Stepladder fever, relative bradycardia, rose spots	Blood culture, Widal test
Leptospirosis	Water contact (animal urine)	2–30 d	Conjunctival suffusion, calf pain, jaundice, renal failure	Leptospira MAT / PCR
Scrub typhus	Mite bite	6–21 d	Eschar at bite site, rash	Scrub typhus IgM / PCR
Acute HIV	Sexual / parenteral	2–4 wk	Pharyngitis, oral ulcers, lymphadenopathy, rash	HIV RNA, 4th-gen Ag/Ab
Visceral leishmaniasis	Sandfly bite	Weeks–months	Massive splenomegaly, pancytopenia, wasting	rK39 serology, BM aspirate
Hepatitis A/E	Faecal-oral	2–6 wk	Markedly elevated transaminases, dark urine (conjugated)	HAV IgM, HEV IgM
TB (disseminated/miliary)	Airborne	Weeks–months	Chronic fever, weight loss, miliary CXR pattern; consider TB in ALL cases of pyrexia of unknown origin ^[14]	Sputum AFB, BAL, TB PCR
Babesiosis	Tick bite	1–4 wk	Similar to malaria on film (ring forms), but tick exposure, no travel to malaria zone	Blood film ("Maltese cross"), PCR

High Yield Summary — Differential Diagnosis of Malaria

The differential of malaria = the differential of fever in the returned traveller.

Approach:

Incubation period — < 7 d excludes malaria; 7–30 d is the classic window; > 30 d think relapse (P. vivax/ovale) or other chronic infections (TB, leishmaniasis).
Geography — Sub-Saharan Africa (malaria most likely), SE Asia (dengue often more common than malaria), Indian subcontinent (typhoid very common).
Dominant feature — Jaundice (hepatitis, leptospirosis), splenomegaly (leishmaniasis, haematological malignancy), bleeding/rash (dengue, VHF), altered consciousness (cerebral malaria, encephalitis), eosinophilia (helminths, not malaria).
The most common cause of fever in a returned traveller is actually a non-tropical infection (influenza, URTI, UTI).
Always test for malaria first — it is the most dangerous to miss. A negative film does not exclude it — repeat x3 over 48–72 h.
Co-infections are common — confirming malaria does not mean you should stop looking.

Key infectious haemolytic anaemia differentials: Malaria (parasitic RBC infection) and C. perfringens (bacterial RBC infection).

Active Recall - Differential Diagnosis of Malaria

References

^[1] Lecture slides: GC 103. Fever after travelling [Handout].pdf (Malaria section, p. 4) ^[2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Malaria — Epidemiology and Diagnosis sections) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Malaria — Epidemiology section) ^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 14.2.4, p. 483) ^[7] Lecture slides: GC 086. Splenomegaly.pdf ^[9] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Differential diagnosis by characteristic features, p. 89) ^[10] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (Differential diagnosis of atypical lymphocytes) ^[11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (Infectious causes of haemolytic anaemia, p. 2–3) ^[12] Senior notes: Ryan Ho Fundamentals.pdf (Clinical evaluation of leukocytosis, p. 390); Ryan Ho Haemtology.pdf (PBS interpretation, p. 47) ^[13] Senior notes: Ryan Ho Haemtology.pdf (DIC causes — severe malaria, p. 137) ^[14] Senior notes: Ryan Ho Respiratory.pdf (Cryptic TB / PUO, p. 81)

Diagnostic Criteria, Algorithm & Investigations for Malaria

1. Diagnostic Criteria

There is no single set of "diagnostic criteria" for malaria in the way that, say, the Jones criteria exist for rheumatic fever. Instead, the diagnosis rests on a combination of clinical suspicion (based on epidemiological context + compatible symptoms) followed by parasitological confirmation. Let's break this down.

The possibility of malaria must be considered in all cases of unexplained fever that starts after the seventh day of stay in an endemic area ^[1].

The threshold for testing should be extremely low. Any of the following should trigger urgent malaria testing:

Fever (or history of fever) in a patient who has been in a malaria-endemic area within the past 12 months (most P. falciparum within 1 month, but P. vivax/ovale can relapse months–years later)
Fever in a patient with a history of blood transfusion, organ transplant, or needle-sharing in an endemic area
Fever with any combination of: headache, myalgia, rigors, splenomegaly, thrombocytopenia, anaemia, jaundice — even if another diagnosis seems likely

The diagnosis of malaria requires demonstration of the parasite or its antigens/DNA in the patient's blood. Clinical features alone are insufficient because malaria mimics many other diseases.

WHO defines a confirmed case of malaria as:

Detection of Plasmodium parasites on microscopy of blood films, OR
Positive rapid diagnostic test (RDT) for malaria antigens, OR
Positive nucleic acid test (PCR) for Plasmodium DNA/RNA

Once malaria is confirmed, severity assessment determines the management pathway. Severe malaria is defined as the presence of any ONE clinical or laboratory feature of severity ^[15]:

Clinical Criteria of Severe Malaria:

Clinical criteria of severe malaria (need to know!) ^[15]:

Prostration (generalised weakness)

↓ Consciousness

Convulsions

Respiratory distress (acidosis / ARDS)

Circulatory collapse

Radiological pulmonary oedema

Abnormal bleeding, jaundice, haemoglobinuria

Laboratory Criteria of Severe Malaria:

Lab findings of severe malaria ^[15]:

Hypoglycaemia (blood glucose < 2.2 mmol/L)

Metabolic acidosis (base deficit > 8, bicarb < 15, or lactate ≥ 5 mmol/L)

Anaemia (Hb < 7 g/dL in adults; < 5 g/dL in children)

Hyperparasitaemia > 5%

↑ Lactate > 5 mmol/L

AKI (creatinine > 265 μmol/L or urine output < 0.4 mL/kg/h)

Severe Malaria = Any ONE Feature

"Severe malaria (any 1 clinical / lab features)" ^[15] — you do NOT need multiple features. A single criterion (e.g., hyperparasitaemia > 5% alone, or a single seizure alone) is enough to classify the patient as severe malaria, which mandates IV artesunate and ICU care. This is a common exam trap — students sometimes think you need multiple features for "severe."

The overall approach follows a clear logic: suspect → test urgently → confirm species and parasitaemia → assess severity → treat accordingly. The GC 103 lecture provides a structured decision tree ^[1]:

The GC 103 lecture algorithm explicitly asks: "Is malaria considered possible?" as the first branch point ^[1]. If YES → test immediately. If NO → proceed with directed evaluation, tentative diagnosis, or observation with serial examinations.

GC Exam High Yield: The Fever-After-Travelling Algorithm

The GC 103 lecture slide algorithm has three pathways when malaria is NOT considered possible ^[1]:

Focal findings → Directed evaluation → Specific diagnosis → Specific or empirical therapy
Tentative diagnosis → Specific or empirical therapy
No specific diagnosis → Observation and serial examinations → Specific or empirical therapy

This structured approach is directly examinable.

3. Investigation Modalities

3.1 Malaria-Specific Diagnostic Tests

"Detection of parasites on Giemsa-stained smear under light microscopy is the standard for routine laboratory diagnosis of malaria" ^[2]^[3]

This is the gold standard bedside test and remains the cornerstone of malaria diagnosis worldwide. Two types of films are made from the same blood sample:

	Thick Film	Thin Film
Preparation	Large drop of blood, not fixed → RBCs lyse, concentrating parasites	Monolayer of intact RBCs, methanol-fixed
Stain	Giemsa or Field's stain	Giemsa stain
Sensitivity	Higher (concentrates parasites ~20-40x) — can detect as few as 50 parasites/μL	Lower (parasites spread out in monolayer)
Purpose	Screening — detect the presence of parasites	Species identification + Parasitaemia quantification — morphology of parasites and RBCs preserved
Limitation	Species identification more difficult because RBC morphology is lost	May miss low parasitaemias

"Allows identification of Plasmodium species and quantification of parasitaemia" ^[2]^[3]

Why both? The thick film is more sensitive for detecting parasites (it's like a "net" that catches more), while the thin film preserves RBC and parasite morphology for species identification and accurate counting.

Key morphological features on thin film by species:

Species	Infected RBC Size	Characteristic Features
P. falciparum	Normal size	Multiple ring forms per RBC; "headphone" or "appliqué" forms (rings at edge of RBC); banana-shaped gametocytes; usually ONLY rings seen (mature forms sequestered in deep vasculature); Maurer's dots (coarse stippling)
P. vivax	Enlarged (infects reticulocytes)	Schüffner's dots (fine stippling of RBC) ^[15]; amoeboid trophozoites; all stages visible
P. ovale	Enlarged, oval-shaped with fimbriated (ragged) edges	Schüffner's dots; oval RBCs
P. malariae	Normal or slightly small	"Band form" trophozoites (bar across the RBC); rosette schizonts (8 merozoites in daisy pattern)
P. knowlesi	Normal	Resembles P. falciparum (ring forms) or P. malariae (band forms) — can be confused; needs PCR for definitive ID

Critical procedural points:

Thick and thin blood smear x3 (12h apart) ^[15]

Why x3? Because parasitaemia fluctuates with the erythrocytic cycle. A single negative film does NOT exclude malaria. Parasites may be sequestered in deep tissues (especially P. falciparum) or parasitaemia may be below the detection threshold (especially early in infection or with partial chemoprophylaxis).
The standard recommendation: repeat every 12 hours for at least 48–72 hours before confidently excluding malaria.
Labour-intensive and requires substantial training and expertise ^[2]^[3] — this is an important practical limitation, especially in non-endemic settings where microscopists may have limited experience with malaria parasites.

"Rapid antigen detection of blood samples: identification of Plasmodium species and may distinguish between P. falciparum and P. vivax infection" ^[2]^[3]

RDTs are immunochromatographic lateral-flow devices (like a pregnancy test) that detect parasite antigens in a drop of blood:

Antigen Detected	Target	Interpretation
Histidine-rich protein 2 (HRP2) ^[2]^[3]	Specific to P. falciparum	Positive = P. falciparum (or mixed infection including P. falciparum)
Plasmodium lactate dehydrogenase (pLDH) ^[2]^[3]	Pan-Plasmodium (all species) or species-specific variants	Differentiates P. falciparum from non-falciparum species
Aldolase ^[2]^[3]	Pan-Plasmodium	Detects all species but cannot differentiate between them

Advantages of RDTs:

Fast (15–20 minutes)
No microscopy expertise needed
High sensitivity for P. falciparum at moderate-high parasitaemia

Limitations of RDTs:

Cannot quantify parasitaemia — you still need a blood film to determine the percentage of infected RBCs (critical for severity assessment)
HRP2 persists for weeks after successful treatment — so a positive HRP2 RDT does NOT necessarily mean active infection in a recently treated patient (false positive in monitoring)
HRP2-deleted P. falciparum strains — increasingly reported in some regions (Horn of Africa), causing false-negative RDTs
Lower sensitivity at low parasitaemia (< 200 parasites/μL)
May miss non-falciparum species if using HRP2-only tests

In practice, RDT and blood films are complementary — use both. RDT provides a rapid preliminary answer while you wait for expert microscopy. Blood film gives species confirmation, parasitaemia quantification, and can detect mixed infections.

"Nucleic acid test is the gold standard with high sensitivity and allows species differentiation" ^[2]^[3]

"PCR of samples (blood / saliva / urine)" ^[2]^[3]

Feature	Detail
Sensitivity	Highest of all methods — can detect < 5 parasites/μL (vs. ~50/μL for expert microscopy)
Specificity	Excellent — can definitively identify species (critical for P. knowlesi which is morphologically confused with P. falciparum and P. malariae)
Turnaround time	Hours to days (not a point-of-care test)
Role	Confirmation in difficult cases; species identification when microscopy is uncertain; detection of submicroscopic parasitaemia; epidemiological studies
Limitation	NOT useful for acute management decisions due to turnaround time; cannot easily quantify parasitaemia in real-time; requires laboratory infrastructure

When is PCR most useful?

Low parasitaemia where microscopy is equivocal
Species confirmation (especially distinguishing P. knowlesi)
Mixed infections
Monitoring for resistance markers
Post-treatment surveillance

3.2 General Blood Investigations and Their Interpretation

Once malaria is suspected or confirmed, a panel of investigations is needed to assess severity and guide management:

Finding	Explanation	Clinical Significance
Anaemia	Haemolysis (direct parasite-induced + bystander) + dyserythropoiesis + splenic clearance	Normocytic normochromic typically; severity determines need for transfusion
Thrombocytopenia	Splenic sequestration + consumption (immune-mediated platelet destruction + DIC) + decreased production	Very common (> 60% of cases); often the most striking early lab finding; severe thrombocytopenia raises concern for DIC
Leukocytosis or normal WCC	Inflammatory response; leukocytosis suggests secondary bacterial infection or severe disease	Note: malaria does NOT typically cause leukopenia (unlike dengue); marked leukocytosis with left shift → consider secondary bacterial sepsis

"NO rash / LN" ^[15] — This is an important negative finding. Malaria typically does NOT cause rash or lymphadenopathy. If these are present, reconsider the diagnosis or think about co-infection (dengue, rickettsial disease, HIV seroconversion).

Finding	Explanation
Hyperbilirubinaemia	Predominantly unconjugated (from haemolysis) ± conjugated component (hepatocyte dysfunction, intrahepatic cholestasis from sequestration)
Mildly elevated transaminases (ALT/AST)	Hepatocyte injury from sequestration and inflammation — usually < 200 IU/L (if markedly elevated > 1000, think viral hepatitis instead)
Elevated LDH	Haemolysis marker + hepatocyte injury
Low albumin	Acute phase response + hepatic synthetic impairment in severe disease

Finding	Explanation
Elevated serum urea and creatinine	AKI from: microvascular obstruction in renal vasculature, haemoglobinuria causing ATN, hypovolaemia (dehydration from fever/vomiting), and direct parasite-mediated renal injury
Electrolyte derangements	Hyperkalaemia (from haemolysis + AKI), hyponatraemia (from SIADH-like effect or fluid shifts)

Finding	Explanation
Hypoglycaemia (< 2.2 mmol/L)	Parasite consumes glucose; impaired hepatic gluconeogenesis; quinine-induced hyperinsulinaemia (iatrogenic). Especially common in children and pregnant women. A criterion for severe malaria. Must be monitored frequently (Hstix)

Finding	Explanation
Metabolic acidosis	Lactic acidosis from tissue hypoperfusion (microvascular obstruction → anaerobic metabolism) + renal impairment (failure to excrete H⁺) + hypovolaemia
Elevated lactate > 5 mmol/L	Direct marker of tissue hypoxia → criterion for severe malaria ^[15]

Finding	Explanation
Prolonged PT/aPTT	DIC from intravascular haemolysis triggering coagulation cascade; consumption of clotting factors
Elevated D-dimer	Fibrinolysis secondary to DIC
Low fibrinogen	Consumption in DIC

Test	Expected Finding	Why
LDH	Elevated	Released from lysed RBCs
Haptoglobin	Low / undetectable	Consumed by binding free haemoglobin from intravascular haemolysis
Unconjugated bilirubin	Elevated	Product of haem metabolism from haemolysis
Reticulocyte count	Elevated (usually)	Appropriate bone marrow response to anaemia — but may be inappropriately low if dyserythropoiesis is severe
Direct antiglobulin test (DAT/Coombs)	Negative	Malaria is a non-immune cause of haemolysis (parasitic RBC infection, not antibody-mediated) — this distinguishes it from autoimmune haemolytic anaemia
Peripheral blood smear	Parasitised RBCs, possible schistocytes (if DIC), polychromasia (reticulocytosis)	Direct visualisation of the cause

Rationale: To exclude concurrent bacterial sepsis, which is a well-recognised complication of severe malaria (especially non-typhoidal Salmonella bacteraemia in African children with malaria)
Take blood cultures before starting any antibiotics

Finding	Explanation
Dark urine / haemoglobinuria	Intravascular haemolysis → free Hb in urine (blackwater fever)
Proteinuria	Glomerular involvement (immune-complex deposition, especially P. malariae-associated nephrotic syndrome)
Reduced urine output	AKI

Investigation	When	What to Look For
CXR	Respiratory distress, suspected ARDS/pulmonary oedema	Bilateral infiltrates (ARDS), cardiomegaly (fluid overload)
CT brain	Altered consciousness with focal neurology (to exclude other intracranial pathology)	SOL, haemorrhage, cerebral oedema
Lumbar puncture	If cerebral malaria suspected — mainly to exclude bacterial meningitis/encephalitis	CSF in cerebral malaria is usually normal or shows mildly elevated protein + opening pressure; if WCC significantly elevated, reconsider meningitis
ECG	Baseline, especially if using quinine (QT prolongation risk)	QTc interval monitoring

4. Interpreting Results: Putting It All Together

Parasitaemia quantification on thin film is expressed as percentage of infected RBCs:

Parasitaemia	Interpretation
< 1%	Low — typical of non-falciparum species or early P. falciparum
1–5%	Moderate
> 5%	Hyperparasitaemia — criterion for severe malaria ^[15]
> 10%	Very high — associated with significant mortality

Important caveat for P. falciparum: The peripheral parasitaemia may underestimate the true body burden because mature trophozoites and schizonts are sequestered in the deep microvasculature. If you see mature forms (schizonts) of P. falciparum on the peripheral film, this is actually an ominous sign — it means the sequestered load is so massive that parasites are "spilling over" into the peripheral circulation.

A high-yield table for exam revision:

Investigation	Typical Finding in Uncomplicated Malaria	Additional Findings in Severe Malaria
Hb	↓ (mild–moderate)	↓↓↓ (< 7 g/dL)
Platelets	↓ (very common)	↓↓↓ ± DIC
WCC	Normal or mildly elevated	Leukocytosis (consider secondary sepsis)
Bilirubin	↑ (predominantly unconjugated)	↑↑↑ (> 50 μmol/L)
Transaminases	Mildly ↑ (< 200)	Moderately ↑
Creatinine	Normal	↑↑ (> 265 μmol/L)
Glucose	Normal	↓↓ (< 2.2 mmol/L)
Lactate	Normal	↑↑ (> 5 mmol/L)
ABG	Normal	Metabolic acidosis (low bicarb, high base deficit)
Blood film	Parasites present, low parasitaemia	Hyperparasitaemia > 5%
Haptoglobin	↓	↓↓ (often undetectable)

5. Special Diagnostic Considerations

A single negative blood film does NOT exclude malaria. Reasons for false negatives:

Low parasitaemia (early infection, partial chemoprophylaxis)
Sequestration of P. falciparum in deep microvasculature
Recent self-treatment with antimalarials
Technically suboptimal film or inexperienced microscopist

Action: Repeat thick and thin films every 12 hours, at least 3 sets over 48–72 hours ^[15]. If all negative and clinical suspicion remains, consider PCR.

Co-infection with > 1 Plasmodium species occurs, particularly in areas where multiple species are co-endemic (e.g., P. falciparum + P. vivax in parts of Asia). PCR is the most reliable way to detect mixed infections. Treatment must cover the most dangerous species (P. falciparum).

Repeat blood films every 12–24 hours after starting treatment to monitor parasitaemia clearance
Parasitaemia should decrease by > 75% within 48 hours with effective therapy
Persistent or rising parasitaemia suggests treatment failure or drug resistance
Note: HRP2-based RDTs will remain positive for weeks after successful treatment (antigen persists) — do NOT use RDTs to monitor treatment response

High Yield Summary — Diagnosis of Malaria

Diagnostic confirmation requires parasitological evidence:

Thick and thin blood films (Giemsa-stained) — the standard diagnostic method. Thick film for screening (higher sensitivity), thin film for species ID and parasitaemia quantification. Repeat x3 at 12h intervals before excluding malaria.
Rapid diagnostic test (RDT) — detects HRP2 (P. falciparum-specific), pLDH (pan-Plasmodium), aldolase. Fast but cannot quantify parasitaemia. HRP2 persists weeks after treatment.
PCR — highest sensitivity and specificity, gold standard for species identification. Not point-of-care; used for confirmation and difficult cases.

Key lab findings: Thrombocytopenia (very common, earliest finding), normocytic anaemia with haemolysis markers, mildly elevated transaminases, hyperbilirubinaemia (unconjugated predominant), elevated LDH, low haptoglobin. DAT negative.

Severe malaria criteria (any ONE):

Clinical: prostration, impaired consciousness, convulsions, respiratory distress, circulatory collapse, pulmonary oedema, abnormal bleeding, jaundice, haemoglobinuria
Lab: hypoglycaemia < 2.2, metabolic acidosis, anaemia (Hb < 7), hyperparasitaemia > 5%, lactate > 5, AKI

NO rash or lymphadenopathy in malaria — if present, reconsider the diagnosis.

Active Recall - Diagnosis of Malaria

References

^[1] Lecture slides: GC 103. Fever after travelling [Handout].pdf (Malaria section, p. 4; diagnostic algorithm) ^[2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Malaria — Diagnosis section, p. 1852) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Malaria — Diagnosis section, p. 83) ^[15] Senior notes: Maksim Medicine Notes.pdf (Tropical infections — Malaria, p. 202)

Management of Malaria

The management of malaria is built on four pillars:

Confirm the diagnosis and classify severity — uncomplicated vs. severe (WHO criteria)
Kill the parasite — appropriate antimalarial drug for the species and severity
Support the patient — fluids, glucose, blood products, organ support as needed
Prevent relapse and transmission — radical cure for P. vivax/ovale hypnozoites; gametocidal therapy

The single most important management decision is: Is this severe or uncomplicated malaria? — because the drug, route, and setting are completely different.

3. Treatment of Severe Malaria

"Severe malaria (any 1 clinical / lab features)" ^[15] mandates:

"Artemisinin-combination therapy (ACT) x 7 days: IV artesunate + doxycycline" ^[15]

Aspect	Detail
Drug	Artesunate (arte-sun-ate: derived from artemisinin, extracted from sweet wormwood, Artemisia annua — "artemis" = the Greek goddess of the hunt, because this drug "hunts" the parasite)
Route	IV (can also be given IM if IV access unavailable)
Dose	2.4 mg/kg at 0, 12, 24 hours, then every 24 hours until patient can tolerate oral medication (minimum 24 hours of IV therapy, typically 3+ doses)
Mechanism	Artesunate is a prodrug → activated by haem iron within the parasitised RBC → generates free radicals that alkylate parasite proteins and damage membranes. Kills all erythrocytic stages including young ring forms (before they can sequester). Fastest parasite clearance of any antimalarial
Companion drug	Doxycycline (or clindamycin if doxycycline contraindicated) — a slow-acting blood schizonticide that prevents recrudescence once artesunate clears the bulk of parasites
Duration	7 days total of the combination ^[15]
Switch to oral	Once the patient can take oral medication AND parasitaemia is falling → switch to a full course of oral ACT (e.g., artemether-lumefantrine) to complete treatment

Why artesunate over quinine?

The SEAQUAMAT (2005) and AQUAMAT (2010) landmark trials demonstrated that IV artesunate reduces mortality by ~35% in severe malaria compared to IV quinine in both adults and children
Faster parasite clearance (artesunate kills ring forms BEFORE sequestration; quinine only kills later stages)
Fewer serious side effects (quinine causes hypoglycaemia from hyperinsulinaemia, cardiotoxicity with QTc prolongation, cinchonism)

Important adverse effect of artesunate:

Post-artesunate delayed haemolysis (PADH): Occurs 1–4 weeks after treatment, especially in patients with high initial parasitaemia (> 5%). Mechanism: artesunate causes "pitting" — the spleen removes dead parasites from RBCs but the RBC survives temporarily with a shortened lifespan → these damaged RBCs eventually haemolyse en masse. Monitor Hb weekly for 4 weeks after treatment.

"ICU x organ support: ABC, antipyretic, monitor Hstix, control seizures, transfusion, NIV, RRT, broad-spectrum antibiotics" ^[15]

Supportive Measure	Rationale	Detail
Airway, Breathing, Circulation	Cerebral malaria → ↓ consciousness → airway compromise; ARDS → respiratory failure; shock → circulatory failure	Intubation if GCS ≤ 8; mechanical ventilation for ARDS; cautious IV fluid resuscitation (avoid fluid overload → ARDS)
Monitor Hstix (blood glucose) ^[15]	Hypoglycaemia is common (parasite glucose consumption + quinine-induced hyperinsulinaemia) and can be fatal or mimic cerebral malaria	Check blood glucose every 4–6 hours; treat with 50% dextrose bolus if < 2.2 mmol/L; maintain dextrose infusion
Antipyretics	High fever worsens metabolic demand and can trigger febrile seizures in children	Paracetamol; tepid sponging; avoid aspirin (risk of Reye's syndrome in children, also worsens bleeding)
Control seizures ^[15]	Cerebral malaria causes seizures; hypoglycaemia also causes seizures	IV benzodiazepines (diazepam/lorazepam) first-line; phenytoin or levetiracetam for refractory seizures; always check glucose before attributing seizures to cerebral malaria
Transfusion ^[15]	Severe malarial anaemia (Hb < 7 g/dL in adults, < 5 g/dL in children)	Packed RBC transfusion; consider exchange transfusion if parasitaemia > 10% (removes parasitised RBCs and reduces parasite load rapidly) — though evidence is limited
NIV / ventilation ^[15]	ARDS from increased pulmonary capillary permeability	Lung-protective ventilation strategy (low tidal volume 6 mL/kg); restrictive fluid management
RRT (renal replacement therapy) ^[15]	AKI from ATN, haemoglobinuria, hypoperfusion	Haemodialysis or CRRT for refractory hyperkalaemia, acidosis, fluid overload, uraemia
Broad-spectrum antibiotics ^[15]	Secondary bacterial sepsis is common in severe malaria, especially Gram-negative bacteraemia	Empirical broad-spectrum antibiotics (e.g., ceftriaxone) if sepsis suspected; take blood cultures first

Why Monitor Blood Glucose So Closely?

Hypoglycaemia in severe malaria is a triple threat: (1) the parasite avidly consumes glucose, (2) hepatic gluconeogenesis is impaired by liver dysfunction, (3) quinine (if used) directly stimulates insulin release from pancreatic β-cells → hyperinsulinaemic hypoglycaemia. Hypoglycaemia causes altered consciousness and seizures that can be misattributed to cerebral malaria — if you don't check glucose, you may miss a rapidly reversible cause of coma. "Monitor Hstix" ^[15] is an explicit management point.

4. Treatment of Uncomplicated Malaria

"Non-severe Plasmodium malaria: Options: Malarone (atovaquone/proguanil), Coartem (artemether/lumefantrine), quinine + doxycycline" ^[15]

Regimen	Components	Duration	Notes
Artemether-lumefantrine (Coartem) ^[15]	Artemether (artemisinin derivative) + lumefantrine (kills remaining parasites)	3 days (6 doses: at 0, 8, 24, 36, 48, 60 hours)	First-line ACT worldwide; take with fatty food (lumefantrine is lipophilic — fat ↑ absorption by 16x)
Atovaquone-proguanil (Malarone) ^[15]	Atovaquone (collapses mitochondrial membrane potential in parasite) + proguanil (inhibits dihydrofolate reductase)	3 days	Also used for chemoprophylaxis; well-tolerated; expensive
Quinine + doxycycline ^[15]	Quinine (blood schizonticide — inhibits haem polymerisation) + doxycycline (slow-acting schizonticide)	Quinine 7 days + doxycycline 7 days	Reserve option; quinine has more side effects (cinchonism: tinnitus, nausea, visual disturbance; hypoglycaemia; QTc prolongation)
Dihydroartemisinin-piperaquine (DHA-PQ)	DHA (artemisinin derivative) + piperaquine (long-acting partner drug)	3 days	An alternative ACT used in some SE Asian protocols

"Primaquine 45 mg x 1 at the end to eradicate gametocytes" ^[15]

Why add a single dose of primaquine for P. falciparum? P. falciparum gametocytes (the sexual forms that are taken up by mosquitoes) can persist in circulation for weeks after treatment of the erythrocytic infection. A single dose of primaquine kills gametocytes, reducing onward transmission. This is a public health measure, not for individual patient benefit.

"Non-severe malaria (other spp.): chloroquine + primaquine x 14 days to eradicate hypnozoites if P. vivax / P. ovale" ^[15]

Component	Drug	Duration	Rationale
Blood-stage treatment	Chloroquine (or ACT if chloroquine-resistant area, e.g., parts of Indonesia, Papua New Guinea)	3 days	Chloroquine accumulates in the parasite food vacuole → inhibits haem polymerisation → toxic haem accumulates → kills the parasite. P. vivax remains chloroquine-sensitive in most of the world
Radical cure (anti-hypnozoite)	Primaquine x 14 days ^[15]	14 days	Primaquine is the only widely available drug that kills hypnozoites (dormant liver-stage parasites of P. vivax/ovale). Without radical cure, the patient WILL relapse (months–years later). Alternative: Tafenoquine (single-dose radical cure, newer)

Breaking down drug names:

Chloro-quine: "chloro" = chlorine-containing; "quine" = derived from quinine (from cinchona bark)
Prima-quine: "prima" = first; one of the first 8-aminoquinoline drugs developed; "quine" = quinine family
Arte-mether: "arte" = artemisinin derivative; "mether" = methyl ether form
Lume-fantrine: synthetic aminoalcohol; "fantrine" has no obvious root — just a pharmaceutical naming convention

The Primaquine-G6PD Dilemma

Primaquine causes oxidative haemolysis in G6PD-deficient patients — and G6PD deficiency is highly prevalent in malaria-endemic populations (the very populations most likely to need primaquine!).

You MUST check G6PD status before prescribing primaquine or tafenoquine.

If G6PD-normal → standard 14-day primaquine (0.25–0.5 mg/kg/day)
If G6PD-deficient → either (a) give primaquine at a lower dose over a longer duration (0.75 mg/kg once weekly x 8 weeks) under close monitoring, or (b) accept the risk of relapse and do not give primaquine, or (c) use chloroquine prophylaxis long-term to suppress relapses
In Hong Kong, 4.5% of males and 0.5% of females are G6PD-deficient ^[6] — so this is a real practical issue

P. malariae: Chloroquine x 3 days (no hypnozoites, so no primaquine needed; but note that P. malariae can have persistent low-level erythrocytic infection causing recrudescence years later)
P. knowlesi: ACT (preferred because of rapid 24-hour replication cycle — the short cycle means parasitaemia can escalate quickly, so fast-acting artemisinins are preferred); chloroquine is an alternative for mild cases

Drug Class	Examples	Stage Targeted	Mechanism	Key Side Effects / Contraindications
Artemisinins	Artesunate (IV/IM), artemether (oral/IM), dihydroartemisinin (oral)	Erythrocytic stages (all, including young rings)	Activated by haem iron → free radical generation → alkylation of parasite proteins	Post-artesunate delayed haemolysis; generally very well tolerated; avoid in 1st trimester pregnancy if alternatives exist (though WHO now allows in 1st trimester for severe malaria)
4-Aminoquinolines	Chloroquine, amodiaquine	Erythrocytic stages (trophozoites, schizonts)	Accumulate in parasite food vacuole → inhibit haem polymerisation into haemozoin → toxic haem kills parasite	Retinal toxicity (chronic use), pruritus (especially in dark-skinned individuals), QTc prolongation; C/I: retinopathy, epilepsy
Aryl-aminoalcohols	Quinine, mefloquine, lumefantrine	Erythrocytic stages	Inhibit haem polymerisation (similar to chloroquine)	Quinine: cinchonism (tinnitus, nausea, visual disturbance), hypoglycaemia, QTc prolongation; Mefloquine: neuropsychiatric effects (vivid dreams, anxiety, psychosis) — C/I in psychiatric history, epilepsy, cardiac conduction disorders
8-Aminoquinolines	Primaquine, tafenoquine	Hypnozoites (liver stage) + gametocytes	Generate reactive oxygen species within parasites (mechanism not fully elucidated); also active against liver schizonts	Oxidative haemolysis in G6PD deficiency — MUST check G6PD before use; C/I: G6PD deficiency (relative); pregnancy; breastfeeding if infant is G6PD-deficient
Antifolates	Proguanil, pyrimethamine, sulfadoxine	Erythrocytic stages (slow-acting)	Inhibit folate synthesis pathway (proguanil → dihydrofolate reductase; sulfadoxine → dihydropteroate synthase)	Generally well tolerated; widespread resistance limits use as monotherapy
Electron transport inhibitors	Atovaquone	Erythrocytic stages + causal prophylaxis (liver stage)	Collapses mitochondrial membrane potential by inhibiting cytochrome bc1 complex	Nausea, diarrhoea; must be taken with fatty food for absorption; always combined with proguanil (synergy + prevents resistance)
Antibiotics	Doxycycline, clindamycin	Erythrocytic stages (slow-acting)	Inhibit protein synthesis in the parasite's apicoplast (a vestigial plastid organelle) — parasite dies during the NEXT replication cycle (hence slow-acting, always needs a fast-acting partner)	Doxycycline: photosensitivity, oesophageal ulceration, C/I in children < 8 years and pregnancy; Clindamycin: C. difficile diarrhoea

6. Prevention

"Insect bite: physical barrier (e.g., light-coloured clothing), insect repellents (DEET ≥ 20%), mosquito coils" ^[15]

Measure	Detail	Rationale
Physical barriers	Long sleeves, long trousers, light-coloured clothing ^[15]	Mosquitoes are attracted to dark colours; physical coverage reduces exposed skin
Insect repellents	DEET ≥ 20% ^[15] (N,N-diethyl-meta-toluamide) applied to exposed skin	DEET blocks the mosquito's olfactory receptors for lactic acid and CO₂ → mosquito cannot "smell" you
Insecticide-treated bed nets (ITNs)	Permethrin-impregnated nets	Both a physical barrier and chemical barrier; recommended for sleeping in endemic areas (Anopheles bites between dusk and dawn)
Mosquito coils ^[15]	Pyrethroid-releasing coils	Repels and kills mosquitoes in the immediate vicinity
Indoor residual spraying (IRS)	Applied to walls/ceilings of houses	Public health measure in endemic areas

"Chemoprophylaxis: doxycycline, mefloquine, Malarone" ^[15]

"Chemoprophylaxis can be used as one of the means to prevent malaria" ^[5] (AOS past paper — this was the tested concept)

Drug	Dosing Schedule	When to Start	When to Stop	Advantages	Disadvantages / Contraindications
Doxycycline ^[15]	100 mg daily	1–2 days before travel	4 weeks after leaving endemic area	Cheap; also protects against leptospirosis and rickettsial infections	Photosensitivity (problematic in tropical sun); oesophageal ulceration; C/I in children < 8 yrs, pregnancy
Mefloquine ^[15]	250 mg weekly	2–3 weeks before travel (to detect neuropsychiatric side effects before departure)	4 weeks after leaving	Weekly dosing (convenient); safe in pregnancy (2nd/3rd trimester)	Neuropsychiatric effects (insomnia, vivid dreams, anxiety, psychosis); C/I: psychiatric history, epilepsy, cardiac conduction disorders
Malarone (atovaquone-proguanil) ^[15]	1 tablet daily	1–2 days before travel	7 days after leaving (shorter post-travel course because it has causal prophylactic activity against liver schizonts)	Well tolerated; short post-travel course; causal prophylaxis	Expensive; must take with fatty food; C/I: severe renal impairment (CrCl < 30)

Why do some drugs require 4 weeks of post-travel dosing? Doxycycline and mefloquine are suppressive prophylactics — they only kill erythrocytic-stage parasites. Sporozoites can still infect the liver and complete hepatic schizogony. The drug must be continued for 4 weeks after leaving the endemic area to ensure that any merozoites released from the liver are killed as they enter the blood. In contrast, atovaquone-proguanil (Malarone) has causal prophylactic activity — it kills liver-stage schizonts directly, so you only need 7 days of post-travel dosing.

Chemoprophylaxis Does NOT Provide 100% Protection

No chemoprophylaxis regimen is 100% effective. Breakthrough malaria can occur despite full compliance, especially with P. vivax (hypnozoites are not addressed by standard prophylaxis unless primaquine is added as terminal prophylaxis). Always think of malaria in a febrile returned traveller even if they report taking chemoprophylaxis.

RTS,S/AS01 (Mosquirix) — first WHO-recommended malaria vaccine (2021), now deployed in sub-Saharan Africa for children. Targets the circumsporozoite protein (CSP) on the surface of P. falciparum sporozoites. Efficacy ~30–40% against clinical malaria, ~30% against severe malaria. Requires 4 doses.
R21/Matrix-M — newer vaccine (WHO-recommended 2023), higher efficacy (~75% in initial trials), also targets CSP. Being rolled out in Africa.
These vaccines are for endemic populations, not typically prescribed for travellers.

Population	Key Considerations
Pregnant women	Malaria in pregnancy → severe anaemia, placental malaria, IUGR, miscarriage, maternal death. Treatment: 1st trimester — quinine + clindamycin (artemisinins now also considered acceptable by WHO for severe malaria); 2nd/3rd trimester — ACT (artemether-lumefantrine). Prophylaxis: mefloquine acceptable in 2nd/3rd trimester; doxycycline and primaquine are contraindicated. IPTp (intermittent preventive treatment in pregnancy) with sulfadoxine-pyrimethamine is recommended in endemic areas
Children < 8 years	Doxycycline is contraindicated (tooth staining, bone growth effects) → use clindamycin as the partner drug with quinine; ACTs are safe in children; weight-based dosing essential; higher risk of severe malaria and hypoglycaemia
G6PD-deficient patients	Primaquine and tafenoquine are relatively contraindicated → check G6PD status before prescribing; if deficient, consider reduced-dose primaquine (0.75 mg/kg weekly x 8 weeks) with monitoring, or withhold and accept relapse risk
Travellers returning to HK	All cases are imported; notify CHP (malaria is a statutory notifiable disease); species identification is critical for guiding treatment; consider co-infections

Parameter	Frequency	Purpose
Parasitaemia (blood film)	Every 12–24 hours until negative, then day 7, 14, 28	Confirm clearance; detect treatment failure (parasitaemia should ↓ by > 75% within 48h)
Haemoglobin	Daily (severe), then weekly for 4 weeks	Detect post-artesunate delayed haemolysis (PADH); monitor recovery from malarial anaemia
Blood glucose	Every 4–6 hours (severe malaria)	Detect and treat hypoglycaemia promptly
Renal function	Daily (severe)	Monitor AKI recovery; guide RRT weaning
Reticulocyte count	Weekly	Confirm bone marrow recovery

High Yield Summary — Management of Malaria

Severe malaria (any ONE criterion):

IV artesunate + doxycycline x 7 days → switch to oral ACT when improving
ICU admission with organ support: ABC, Hstix monitoring, seizure control, transfusion, NIV, RRT, broad-spectrum antibiotics
Artesunate is superior to quinine (SEAQUAMAT/AQUAMAT trials: 35% mortality reduction)
Watch for post-artesunate delayed haemolysis (1–4 weeks post-treatment)

Uncomplicated P. falciparum:

Oral ACT: Coartem (artemether-lumefantrine) or Malarone (atovaquone-proguanil) or quinine + doxycycline
Primaquine 45 mg single dose at end to eradicate gametocytes (transmission reduction)

Uncomplicated P. vivax / P. ovale:

Chloroquine x 3 days + primaquine x 14 days (radical cure for hypnozoites)
MUST check G6PD before primaquine (causes oxidative haemolysis in G6PD deficiency)

Prevention:

Personal protection: light-coloured clothing, DEET ≥ 20%, bed nets, mosquito coils
Chemoprophylaxis: doxycycline (daily), mefloquine (weekly), Malarone (daily)
Chemoprophylaxis is NOT 100% protective — always consider malaria in febrile returned travellers

Active Recall - Management of Malaria

References

^[1] Lecture slides: GC 103. Fever after travelling [Handout].pdf (Malaria section, p. 4) ^[5] AOS material: AOS - Microbio.pdf (Question 8 — chemoprophylaxis for malaria) ^[6] Senior notes: Ryan Ho Haemtology.pdf (G6PD deficiency section, p. 40) ^[15] Senior notes: Maksim Medicine Notes.pdf (Tropical infections — Malaria management, p. 202)

Complications of Malaria

Malaria complications arise from the fundamental pathophysiological mechanisms discussed in earlier sections: (1) massive haemolysis, (2) cytoadherence and microvascular sequestration (primarily P. falciparum), (3) systemic inflammatory response, and (4) metabolic derangements. Complications can be categorised as acute (life-threatening, occurring during the acute illness) and chronic/late (occurring after or between episodes). Understanding the "why" behind each complication is essential.

1. Acute Complications of Severe Malaria

These correspond directly to the WHO criteria for severe malaria ^[1]^[16]:

Severe malaria is defined by the presence of any one of the following conditions: ^[1]

Impaired consciousness

Acidosis

Hypoglycaemia

Severe malarial anaemia

Renal impairment (acute kidney injury)

Jaundice

Pulmonary oedema

Significant bleeding

Shock

Hyperparasitaemia: P. falciparum parasitaemia > 10% ^[1]

Each of these severity features is itself a complication that demands specific management. Let us elaborate on each systematically.

Aspect	Detail
Definition	Impaired consciousness ^[1] — GCS < 11 in adults (Blantyre coma score < 3 in children) with confirmed P. falciparum parasitaemia, after excluding other causes (hypoglycaemia, meningitis, post-ictal state)
Pathophysiology	Parasitised RBCs adhering to small blood vessels, leading to small infarcts, capillary leakage and organ dysfunction ^[4]. PfEMP1 on infected RBCs binds ICAM-1 on cerebral endothelium → microvascular obstruction → ischaemia → BBB disruption → cerebral oedema → raised ICP → brain herniation if untreated
Clinical features	↓ Consciousness, delirium, prostration, seizures ^[4]. Seizures occur in ~20% of adults and ~80% of children with cerebral malaria. Retinal changes (malarial retinopathy: retinal whitening, haemorrhages, vessel changes) are pathognomonic in children
Mortality	15–20% even with optimal treatment; higher in children
Sequelae	Neurological deficits in 5–15% of survivors (especially children): cognitive impairment, epilepsy, behavioural disorders, cortical blindness, hemiplegia, ataxia, speech disorders
Management	IV artesunate (fastest parasite clearance from cerebral microvasculature); seizure control (benzodiazepines); avoid lumbar puncture if signs of raised ICP; exclude and treat hypoglycaemia; mannitol is NOT recommended (no proven benefit and may be harmful)

Cerebral Malaria vs. Hypoglycaemia

Both cause altered consciousness and seizures. Always check blood glucose (Hstix) ^[15] before attributing coma or seizures to cerebral malaria — hypoglycaemia is rapidly reversible with dextrose and is a common co-existent or mimicking condition. A patient can have both simultaneously.

Aspect	Detail
Definition	Severe anaemia — Hb < 7 g/dL in adults; < 5 g/dL in children ^[1]^[16]
Pathophysiology	Multifactorial: (1) Direct lysis of parasitised RBCs during schizont rupture; (2) "Bystander" destruction of uninfected RBCs (complement deposition, oxidative damage, altered membrane → splenic clearance); (3) Splenic sequestration and hyperplasia; (4) Dyserythropoiesis — TNF-α and haemozoin suppress erythroid progenitor proliferation; (5) Iron sequestration (hepcidin-mediated, anaemia of chronic disease component in repeated infections)
Clinical features	Pallor, tachycardia, tachypnoea, high-output cardiac failure, fatigue, dizziness
Management	Packed RBC transfusion; treat the underlying malaria to stop ongoing haemolysis; monitor for delayed haemolysis (especially post-artesunate)

Malaria is a parasitic infection of RBC causing haemolysis ^[11] — it is classified under non-immune, infectious causes of haemolytic anaemia, alongside C. perfringens ^[11].

Aspect	Detail
Definition	Renal impairment (acute kidney injury) ^[1] — creatinine > 265 μmol/L or urine output < 0.4 mL/kg/h ^[16]
Pathophysiology	Multiple mechanisms: (1) Microvascular sequestration → renal ischaemia; (2) Haemoglobinuria → haemoglobin precipitates in renal tubules → acute tubular necrosis (ATN) — dark urine due to ↑ Hb and malarial pigments ^[4]; (3) Hypovolaemia from fever, vomiting, third-spacing → pre-renal AKI; (4) Myoglobinuria (rare, if rhabdomyolysis occurs); (5) Immune-complex deposition (especially P. malariae → membranoproliferative glomerulonephritis → nephrotic syndrome)
Clinical features	Oliguria/anuria, dark or cola-coloured urine (haemoglobinuria — "blackwater fever"), peripheral oedema, uraemic symptoms
Management	IV fluid resuscitation (cautious — avoid fluid overload → ARDS); renal replacement therapy (haemodialysis/CRRT) if refractory hyperkalaemia, acidosis, fluid overload, uraemia; artesunate (dose adjustment not needed); avoid nephrotoxins

Blackwater fever deserves special mention — this is an older clinical term for massive intravascular haemolysis in P. falciparum malaria leading to haemoglobinuria (dark/black urine) and AKI. It can be triggered or exacerbated by quinine in patients with repeated malaria infections. It represents a particularly dangerous complication with high mortality.

Aspect	Detail
Definition	Acidosis ^[1] — base deficit > 8 mEq/L, bicarbonate < 15 mmol/L, or lactate ≥ 5 mmol/L ^[16]
Pathophysiology	(1) Tissue hypoperfusion from microvascular obstruction → anaerobic glycolysis → lactate production (hyperlactatemia ^[16]); (2) Renal failure → impaired acid excretion; (3) Parasite metabolism produces organic acids; (4) Hypovolaemia → poor tissue perfusion
Clinical features	Deep, laboured breathing (Kussmaul respiration — the body's attempt to blow off CO₂ to compensate for metabolic acidosis), ↓ consciousness (severe acidosis depresses CNS)
Management	Treat the cause: antimalarials to clear parasites, IV fluid resuscitation, RRT if needed; sodium bicarbonate infusion only if pH < 7.1 and as a temporising measure

Aspect	Detail
Definition	Hypoglycaemia ^[1] — blood glucose < 2.2 mmol/L ^[16]
Pathophysiology	Triple mechanism: (1) Parasites avidly consume glucose (high metabolic rate); (2) Impaired hepatic gluconeogenesis (liver dysfunction from sequestration); (3) Quinine/quinidine stimulate pancreatic β-cell insulin secretion → hyperinsulinaemic hypoglycaemia (iatrogenic)
At-risk groups	Children (low glycogen reserves), pregnant women (increased glucose demands), patients receiving quinine
Clinical features	Seizures, altered consciousness (mimics cerebral malaria!), diaphoresis, tachycardia
Management	50% dextrose IV bolus (0.5 g/kg); dextrose-containing IV maintenance fluids; frequent Hstix monitoring (every 4–6 hours); if on quinine, switch to artesunate if possible

Complication	Pathophysiology	Clinical Features
Pulmonary oedema ^[1] / ARDS	Increased alveolar-capillary permeability from (1) cytokine-mediated endothelial injury, (2) sequestration of parasitised RBCs in pulmonary microvasculature, (3) iatrogenic fluid overload (aggressive IV fluids in a patient with impaired cardiac output/renal function)	Acute dyspnoea, hypoxia, bilateral infiltrates on CXR; can develop even AFTER treatment has begun (day 2–3), when parasitised RBC lysis releases inflammatory material
Respiratory distress (acidotic breathing) ^[1]	Metabolic acidosis → compensatory hyperventilation (Kussmaul breathing)	Deep, laboured breathing without crackles (purely compensatory, not primary lung disease)

Management: Lung-protective ventilation (low tidal volume 6 mL/kg); restrictive fluid strategy; treat underlying malaria and acidosis; diuretics if fluid overloaded.

ARDS Can Develop After Treatment Starts

A common exam trap: pulmonary oedema/ARDS can worsen or appear for the first time 24–72 hours AFTER antimalarial treatment is initiated. Why? Schizont rupture releases inflammatory debris → endothelial activation → capillary leak. Over-enthusiastic IV fluid resuscitation worsens this. Fluid balance must be carefully monitored.

Aspect	Detail
Definition	Significant bleeding ^[1] — including DIC
Pathophysiology	Intravascular haemolysis → activation of coagulation cascade → widespread microvascular thrombi → consumption of clotting factors and platelets → paradoxical bleeding. "Immune activation — intravascular haemolysis (severe malaria, ABO haemolytic transfusion reaction, PNH) → activation of coagulation cascade" is listed as a cause of DIC ^[13]
Clinical features	Petechiae, ecchymoses, gum bleeding, haematemesis, melaena, haematuria; prolonged PT/aPTT, ↑ D-dimer, ↓ fibrinogen, ↓↓ platelets, schistocytes on blood film
Management	Treat the underlying malaria; platelet transfusion if active bleeding with platelets < 50; FFP/cryoprecipitate if coagulopathy with active bleeding; avoid IM injections

Aspect	Detail
Definition	Shock ^[1] — SBP < 80 mmHg in adults with signs of impaired perfusion
Pathophysiology	(1) Hypovolaemia from dehydration (fever, vomiting, poor intake); (2) Vasodilatory component from systemic inflammatory response (TNF-α, IL-6); (3) Secondary Gram-negative bacteraemia (common in severe malaria, especially non-typhoidal Salmonella in African children)
Clinical features	Hypotension, cold peripheries, prolonged capillary refill, tachycardia, ↓ urine output
Management	IV fluid resuscitation; vasopressors if fluid-refractory; empirical broad-spectrum antibiotics (blood cultures first); treat malaria aggressively

Aspect	Detail
Definition	Jaundice ^[1] — bilirubin > 50 μmol/L with parasitaemia > 100,000/μL ^[16]
Pathophysiology	(1) Pre-hepatic: ↑ unconjugated bilirubin from massive haemolysis; (2) Hepatic: Kupffer cell activation, sequestration in hepatic sinusoids → hepatocyte dysfunction, intrahepatic cholestasis; (3) Liver failure: jaundice ^[4]
Clinical features	Scleral icterus, dark urine (if conjugated component), hepatomegaly, coagulopathy (synthetic failure)
Key distinction	Transaminases in malaria are usually only mildly elevated (< 200 IU/L). Markedly elevated transaminases (> 1000) should prompt consideration of concurrent viral hepatitis

Complication	Pathophysiology	Clinical Features	Management
Splenomegaly	Reticuloendothelial hyperplasia — the spleen is working overtime to clear parasitised and damaged RBCs	LUQ fullness, palpable spleen, often tender in acute malaria	Treat malaria; spontaneous resolution as parasitaemia clears
Splenic rupture	Acute capsular distension from rapid splenic enlargement → rupture; can occur spontaneously or with minor trauma	Sudden severe LUQ pain radiating to left shoulder (Kehr's sign), haemodynamic instability, peritonism	Emergency — surgical (splenectomy) or interventional radiology (embolisation); aggressive fluid and blood product resuscitation

Infected RBC sequestered in end-organ capillaries → Splenic rupture ^[15]

Complication	Drug	Mechanism	Prevention / Management
Post-artesunate delayed haemolysis (PADH)	Artesunate	"Pitting" — spleen removes dead parasites from RBCs but the once-infected RBC survives temporarily with shortened lifespan → delayed mass haemolysis 1–4 weeks later	Monitor Hb weekly for 4 weeks post-treatment; transfuse if symptomatic anaemia
Hypoglycaemia	Quinine	Quinine stimulates pancreatic β-cell insulin release → hyperinsulinaemic hypoglycaemia	Monitor Hstix; infuse dextrose-containing fluids; prefer artesunate over quinine
Cinchonism	Quinine	Direct drug toxicity to CN VIII and other neural structures	Tinnitus, nausea, visual disturbance; usually reversible on dose reduction
QTc prolongation	Quinine, chloroquine, mefloquine	Block cardiac potassium channels (hERG) → delayed repolarisation → risk of torsades de pointes	ECG monitoring; avoid concomitant QT-prolonging drugs; correct electrolytes (K⁺, Mg²⁺)
Oxidative haemolysis	Primaquine, tafenoquine	Generate reactive oxygen species within RBCs → overwhelm glutathione-dependent antioxidant pathway in G6PD-deficient RBCs → Heinz body formation → haemolysis	MUST check G6PD before prescribing ^[1]; if G6PD-deficient, reduced-dose primaquine weekly or withhold
Neuropsychiatric effects	Mefloquine	Crosses BBB → uncertain mechanism, possibly GABAergic disruption	Vivid dreams, insomnia, anxiety, psychosis; contraindicated in psychiatric history/epilepsy

These occur with repeated or chronic malaria infections, mainly in endemic settings:

Complication	Species	Pathophysiology	Clinical Features
Tropical / Hyper-reactive Malarial Splenomegaly (HMS)	Any (chronic)	Chronic antigenic stimulation → aberrant immune response → massive polyclonal IgM production → splenomegaly from immune-complex deposition and reticuloendothelial hyperplasia	Massive splenomegaly, elevated IgM, high antimalarial antibody titres; responds to long-term antimalarial prophylaxis
Quartan malarial nephropathy	P. malariae	Immune-complex deposition (parasite antigen–antibody complexes) in glomerular basement membrane → membranoproliferative glomerulonephritis	Nephrotic syndrome (proteinuria, hypoalbuminaemia, oedema); often progressive; poorly responsive to treatment
Chronic malarial anaemia	Any (repeated infections)	Chronic haemolysis + dyserythropoiesis + iron sequestration	Chronic normocytic anaemia; failure to thrive in children
Burkitt lymphoma	P. falciparum (co-factor)	Chronic malaria → chronic B-cell stimulation → ↑ EBV viral load in B cells → dysregulated c-MYC translocation → malignant transformation	Endemic Burkitt lymphoma (jaw/facial tumour in African children); strongly associated with EBV + malaria co-endemicity
Pigment gallstones	Any (chronic haemolysis)	Chronic haemolysis → ↑ unconjugated bilirubin → ↑ bilirubin in bile → precipitation as calcium bilirubinate pigment stones	Biliary colic, cholecystitis

Malaria is a chronic infection potentially transmitted by blood transfusion ^[17]. Among the transfusion-transmitted infections listed:

"HBV, HCV, HIV, Malaria" ^[17] — these are among the routinely tested/deferred chronic infections in transfusion medicine.

Transfusion-transmitted malaria is rare in non-endemic settings but has occurred. The mechanism is straightforward: donor blood containing parasitised RBCs (or even low-level parasitaemia) is transfused to the recipient. There is no hepatic stage because sporozoites are NOT involved — the parasites go directly into the erythrocytic cycle. Implications:

No hypnozoites → no relapse (even for P. vivax/ovale transmitted this way)
Very short incubation (can be as early as hours–days post-transfusion, bypassing the usual minimum 7-day rule)
Donor deferral policies serve as the primary prevention strategy

5. Complications in Special Populations

Complication	Pathophysiology
Severe maternal anaemia	Enhanced haemolysis + haemodilution of pregnancy
Placental malaria	Parasitised RBCs adhere to chondroitin sulfate A (CSA) in placental intervillous spaces → inflammatory infiltrate → impaired nutrient/oxygen transfer
Intrauterine growth restriction (IUGR) / Low birth weight	Placental insufficiency from above
Miscarriage / Stillbirth	Severe placental dysfunction
Congenital malaria	Transplacental transmission of parasites to the foetus
Maternal mortality	Pregnant women are at higher risk of severe malaria

Higher risk of cerebral malaria, severe anaemia, and hypoglycaemia
Faster clinical deterioration (lower physiological reserves)
2/3 of all malaria deaths occur in this age group ^[2]^[3]

High Yield Summary — Complications of Malaria

Acute complications (each is a WHO severe malaria criterion):

Cerebral malaria — sequestration in cerebral microvasculature → coma, seizures; 15–20% mortality even with treatment; neurological sequelae in survivors
Severe anaemia — Hb < 7; haemolysis + dyserythropoiesis + splenic clearance
AKI — ATN from haemoglobinuria ("blackwater fever"), microvascular obstruction, hypovolaemia
Metabolic acidosis / hyperlactatemia — tissue hypoxia from microvascular obstruction
Hypoglycaemia — parasite glucose consumption + liver dysfunction + quinine-induced hyperinsulinaemia; ALWAYS check glucose in altered consciousness
Pulmonary oedema / ARDS — can worsen AFTER treatment starts (inflammatory debris from schizont lysis)
DIC / bleeding — intravascular haemolysis activates coagulation cascade → consumptive coagulopathy
Shock ("algid malaria") — hypovolaemia + vasodilation + secondary bacterial sepsis
Jaundice — haemolytic + hepatocellular
Splenic rupture — acute capsular distension; surgical emergency

Treatment complications: Post-artesunate delayed haemolysis (1–4 weeks), quinine-induced hypoglycaemia and cinchonism, primaquine-induced oxidative haemolysis in G6PD deficiency.

Chronic complications: Hyper-reactive malarial splenomegaly, quartan malarial nephropathy (P. malariae), Burkitt lymphoma (P. falciparum + EBV), pigment gallstones.

Special populations: Pregnancy (placental malaria → IUGR, miscarriage); children < 5 (highest mortality risk).

Active Recall - Complications of Malaria

References

^[1] Lecture slides: GC 103. Fever after travelling [Handout].pdf (Severe malaria criteria, p. 5) ^[2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Malaria — Epidemiology) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Malaria — Epidemiology) ^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 14.2.4, p. 483) ^[11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (Infectious causes of haemolytic anaemia, p. 2) ^[13] Senior notes: Ryan Ho Haemtology.pdf (DIC causes — severe malaria, p. 137) ^[15] Senior notes: Maksim Medicine Notes.pdf (Tropical infections — Malaria, p. 202) ^[16] Lecture slides: Handbook of Internal Medicine 2024.pdf (Malaria — severe malaria definition and treatment, p. 259) ^[17] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (Infectious risk of transfusion, p. 25)

High Yield Summary

Definition: Systemic RBC infection by Plasmodium spp., transmitted by female Anopheles mosquitoes.

Epidemiology: Sub-Saharan Africa carries 90% of global burden. All HK cases are imported. High-risk groups: children < 5, pregnant women, travellers, HIV+.

Protective conditions: G6PD deficiency, thalassaemia, sickle cell trait, Duffy-negative phenotype.

Clinical features:

Classical paroxysm: Cold → Hot → Sweating stage (cyclical but often irregular initially)
Non-specific: fever, headache, myalgia, GI symptoms — the "great mimicker"
Severe: cerebral malaria (seizures, coma), severe anaemia, renal failure, ARDS, hypoglycaemia, acidosis, jaundice, blackwater fever
Signs: splenomegaly, hepatomegaly, pallor, jaundice, tachycardia

The golden rule: Malaria MUST be considered in all unexplained fever starting ≥ 7 days after entering an endemic area. Never wait for classical periodicity.

High Yield Summary — Differential Diagnosis of Malaria

The differential of malaria = the differential of fever in the returned traveller.

Approach:

Incubation period — < 7 d excludes malaria; 7–30 d is the classic window; > 30 d think relapse (P. vivax/ovale) or other chronic infections (TB, leishmaniasis).
Geography — Sub-Saharan Africa (malaria most likely), SE Asia (dengue often more common than malaria), Indian subcontinent (typhoid very common).
Dominant feature — Jaundice (hepatitis, leptospirosis), splenomegaly (leishmaniasis, haematological malignancy), bleeding/rash (dengue, VHF), altered consciousness (cerebral malaria, encephalitis), eosinophilia (helminths, not malaria).
The most common cause of fever in a returned traveller is actually a non-tropical infection (influenza, URTI, UTI).
Always test for malaria first — it is the most dangerous to miss. A negative film does not exclude it — repeat x3 over 48–72 h.
Co-infections are common — confirming malaria does not mean you should stop looking.

Key infectious haemolytic anaemia differentials: Malaria (parasitic RBC infection) and C. perfringens (bacterial RBC infection).

High Yield Summary — Diagnosis of Malaria

Diagnostic confirmation requires parasitological evidence:

Thick and thin blood films (Giemsa-stained) — the standard diagnostic method. Thick film for screening (higher sensitivity), thin film for species ID and parasitaemia quantification. Repeat x3 at 12h intervals before excluding malaria.
Rapid diagnostic test (RDT) — detects HRP2 (P. falciparum-specific), pLDH (pan-Plasmodium), aldolase. Fast but cannot quantify parasitaemia. HRP2 persists weeks after treatment.
PCR — highest sensitivity and specificity, gold standard for species identification. Not point-of-care; used for confirmation and difficult cases.

Severe malaria criteria (any ONE):

Clinical: prostration, impaired consciousness, convulsions, respiratory distress, circulatory collapse, pulmonary oedema, abnormal bleeding, jaundice, haemoglobinuria
Lab: hypoglycaemia < 2.2, metabolic acidosis, anaemia (Hb < 7), hyperparasitaemia > 5%, lactate > 5, AKI

NO rash or lymphadenopathy in malaria — if present, reconsider the diagnosis.

High Yield Summary — Management of Malaria

Severe malaria (any ONE criterion):

IV artesunate + doxycycline x 7 days → switch to oral ACT when improving
ICU admission with organ support: ABC, Hstix monitoring, seizure control, transfusion, NIV, RRT, broad-spectrum antibiotics
Artesunate is superior to quinine (SEAQUAMAT/AQUAMAT trials: 35% mortality reduction)
Watch for post-artesunate delayed haemolysis (1–4 weeks post-treatment)

Uncomplicated P. falciparum:

Oral ACT: Coartem (artemether-lumefantrine) or Malarone (atovaquone-proguanil) or quinine + doxycycline
Primaquine 45 mg single dose at end to eradicate gametocytes (transmission reduction)

Uncomplicated P. vivax / P. ovale:

Chloroquine x 3 days + primaquine x 14 days (radical cure for hypnozoites)
MUST check G6PD before primaquine (causes oxidative haemolysis in G6PD deficiency)

Prevention:

Personal protection: light-coloured clothing, DEET ≥ 20%, bed nets, mosquito coils
Chemoprophylaxis: doxycycline (daily), mefloquine (weekly), Malarone (daily)
Chemoprophylaxis is NOT 100% protective — always consider malaria in febrile returned travellers

High Yield Summary — Complications of Malaria

Acute complications (each is a WHO severe malaria criterion):

Cerebral malaria — sequestration in cerebral microvasculature → coma, seizures; 15–20% mortality even with treatment; neurological sequelae in survivors
Severe anaemia — Hb < 7; haemolysis + dyserythropoiesis + splenic clearance
AKI — ATN from haemoglobinuria ("blackwater fever"), microvascular obstruction, hypovolaemia
Metabolic acidosis / hyperlactatemia — tissue hypoxia from microvascular obstruction
Hypoglycaemia — parasite glucose consumption + liver dysfunction + quinine-induced hyperinsulinaemia; ALWAYS check glucose in altered consciousness
Pulmonary oedema / ARDS — can worsen AFTER treatment starts (inflammatory debris from schizont lysis)
DIC / bleeding — intravascular haemolysis activates coagulation cascade → consumptive coagulopathy
Shock ("algid malaria") — hypovolaemia + vasodilation + secondary bacterial sepsis
Jaundice — haemolytic + hepatocellular
Splenic rupture — acute capsular distension; surgical emergency

Treatment complications: Post-artesunate delayed haemolysis (1–4 weeks), quinine-induced hypoglycaemia and cinchonism, primaquine-induced oxidative haemolysis in G6PD deficiency.

Chronic complications: Hyper-reactive malarial splenomegaly, quartan malarial nephropathy (P. malariae), Burkitt lymphoma (P. falciparum + EBV), pigment gallstones.

Special populations: Pregnancy (placental malaria → IUGR, miscarriage); children < 5 (highest mortality risk).

Malaria

1. Definition

2. Epidemiology

2.1 Global Burden

2.2 Hong Kong Context

2.3 Risk Factors for Transmission, Morbidity and Mortality

2.4 Conditions That Confer Relative Protection Against Malaria

3. Microbiology and Species

4. Mode of Transmission

5. Life Cycle and Pathophysiology

5.1 Life Cycle Overview

5.2 Detailed Phases with Pathophysiological Basis

Phase 1: Hepatic (Exoerythrocytic) Stage — Clinically Silent

Phase 2: Erythrocytic Stage — Symptomatic Disease

Phase 3: Gametocytogenesis — Transmission Stage

5.3 Pathophysiology of Severe Malaria (Primarily P. falciparum)

(a) High Parasitaemia

(b) Cytoadherence and Sequestration

(c) Rosetting and Clumping

Combined Effect → Multi-Organ Dysfunction:

6. Classification

6.2 By Severity: Uncomplicated vs. Severe Malaria

6.3 By Clinical Context

7. Clinical Features

7.1 Approach: The Travel History is Everything

7.2 Symptoms

(a) Classical Malarial Paroxysm

(b) Non-specific Constitutional Symptoms

(c) Symptoms of Severe Malaria (primarily P. falciparum)

7.3 Signs

7.4 Splenomegaly in Malaria — Link to GC 086

7.5 Anaemia in Malaria — Link to GC 076

8. Summary of Clinical Approach to Suspected Malaria

Active Recall - Malaria (Definition, Epidemiology, Pathophysiology, Clinical Features)

References

1. Framework for Thinking About the Differential

1.1 By Incubation Period

1.2 By Geography

1.3 By Dominant Clinical Feature

2. Detailed Differential Diagnoses

2.1 Infections That Most Closely Mimic Malaria

(a) Dengue Fever

(b) Typhoid / Enteric Fever

(c) Leptospirosis

(d) Rickettsial Infections (including Scrub Typhus)

(e) Acute HIV Seroconversion (Acute Retroviral Syndrome)

(f) Visceral Leishmaniasis (Kala-azar)

(g) Viral Hepatitis (A, B, E)

(h) Amoebic Liver Abscess

2.2 Non-Infectious Differentials to Consider

2.3 Differential of Malaria-Like Haematological Findings

(a) Fever + Thrombocytopenia

(b) Fever + Haemolytic Anaemia

(c) Fever + Splenomegaly

(d) Fever + Jaundice

(e) Fever + Atypical Lymphocytosis

3. Approach to Narrowing the Differential

4. Summary Table: Key Differentials of Malaria

Active Recall - Differential Diagnosis of Malaria

1. Diagnostic Criteria

1.1 Clinical Suspicion — When to Test

1.2 Parasitological Confirmation — The Definitive Diagnosis

1.3 Criteria for Severe Malaria (WHO 2024)

2. Diagnostic Algorithm

3. Investigation Modalities

3.1 Malaria-Specific Diagnostic Tests

(a) Peripheral Blood Smear — Thick and Thin Films (The Standard)

(b) Rapid Diagnostic Test (RDT) — Malaria Antigen Detection

(c) PCR — Nucleic Acid Amplification Test

3.2 General Blood Investigations and Their Interpretation

(a) CBC with Differentials [2][3]

(b) LFT [2][3]

(c) RFT [2][3]

(d) Serum Blood Glucose [2][3]

(e) Arterial Blood Gas (ABG) [2][3]

(f) Coagulation Profile

(g) Haemolysis Screen

(h) Blood Culture

(i) Urinalysis

(j) Other Investigations as Indicated