1) Cholera. Etiology, epidemiology. Features of pathogenesis. Cholera. Clinical presentation. Degrees of dehydration. Emergency therapy for dehydratic shock. Cholera. Diagnosis and differential diagnosis of cholera. Principles of treatment.

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Cholera: Complete Review

PART 1: Etiology, Epidemiology, and Features of Pathogenesis

Etiology

Cholera is an acute diarrheal disease caused by Vibrio cholerae, serogroup O1 or O139. V. cholerae is a curved, gram-negative rod (bacillus) that is highly motile, facultatively anaerobic, and oxidase-positive. It belongs to the family Vibrionaceae.

Classification of V. cholerae O1:

Serotypes (based on somatic O-antigens): Inaba, Ogawa, and Hikojima
Biotypes: Classic and El Tor
- The Classic biotype caused the first six pandemics; it is now essentially extinct (confined to southern Bangladesh)
- The El Tor biotype causes the current (seventh) pandemic; it produces more asymptomatic infections than the classic biotype, but variants of El Tor ("hybrid") may cause more severe disease
O139 serogroup: emerged in 1992, genetically close to El Tor O1; also has epidemic potential

The pathogenicity island of V. cholerae encodes toxin-coregulated pilus (TCP), colonization factors, and virulence regulators. The genes encoding cholera toxin (ctxAB) are part of the genome of a bacteriophage (CTXΦ), whose receptor on the bacterial surface is TCP itself - this means horizontal gene transfer can generate new toxigenic strains. - Harrison's Principles of Internal Medicine, 22E

Epidemiology

Natural habitat: V. cholerae lives in coastal salt water and brackish estuaries, associated with plankton, algae, copepods, and crustacean shells. It survives in a viable-but-nonculturable state under adverse conditions. Proliferation increases in summer months (water temperature >20°C).

Transmission routes:

Ingestion of water contaminated by human feces (most common)
Contaminated food: leftover rice, raw fish, cooked crabs, seafood, raw oysters, fresh vegetables
Person-to-person transmission is uncommon (large inoculum required), though household attack rates ~50% in endemic areas
No animal reservoir

Infectious dose: Relatively high in general (10³-10⁸ organisms when water is the vehicle; 10²-10⁴ when food is the vehicle). The dose is markedly reduced in hypochlorhydric persons, those using PPIs/H2-blockers, and when gastric acidity is buffered by a meal.

Host risk factors:

Blood group O - highest risk of severe disease (especially with El Tor biotype)
Achlorhydria (from H. pylori gastritis, PPI/H2-blocker use)
Malnutrition, young children, migrants

Pandemics: Seven pandemics since 1817. Cholera originated in the Ganges delta. The current seventh pandemic began in Indonesia in 1961 (El Tor biotype). Recent major epidemics: Haiti (2022-2023), Yemen (2016-2017). >95% of WHO-reported cases come from Africa and Asia. Africa sees an estimated >1 million cases and ~40,000 deaths annually.

Seasonality: Epidemics tend during the hot season. Climate variability (El Niño-Southern Oscillation) promotes phytoplankton/zooplankton blooms and thereby V. cholerae proliferation. Cholera predominates in children in endemic areas but affects adults and children equally in newly exposed populations. - Goldman-Cecil Medicine

Epidemiological chain:

Source: Patients with cholera (especially mild/asymptomatic) contaminate water
Cholera phages modulate the abundance of V. cholerae in the environment and may determine the beginning and end of epidemics
Factors promoting spread: flooding, population displacement, disrupted water/sanitation systems

Pathogenesis

Cholera is fundamentally a toxin-mediated disease. The bacterium does not invade the intestinal mucosa; rather, it colonizes the small intestine and secretes cholera toxin (CT).

Step-by-step mechanism:

Ingestion and colonization: After surviving gastric acid, V. cholerae reaches the small intestine. TCP (toxin-coregulated pilus) is essential for intestinal colonization. TCP synthesis and CT production are co-regulated by ToxR, a membrane-spanning transcriptional activator that responds to environmental signals via a regulatory cascade. Quorum sensing (density-dependent bacterial signaling) also modulates virulence.
Cholera toxin structure: CT consists of:
- One A subunit (enzymatic moiety) - specifically the A1 peptide
- Five B subunits (pentameric binding moiety)
B subunit binding: The B pentamer binds with high affinity to GM1 ganglioside on the surface of intestinal epithelial cells - this is the toxin receptor. This binding delivers the A subunit into the cytosol.
A subunit action: The activated A1 subunit ADP-ribosylates the GTP-binding regulatory (Gs-alpha) protein of adenylate cyclase. This renders adenylate cyclase constitutively active, leading to massive intracellular accumulation of cyclic AMP (cAMP).
cAMP effects on epithelium:
- Inhibits absorptive Na⁺ transport in villus cells
- Activates secretory Cl⁻ transport in crypt cells
- Net result: accumulation of NaCl in the intestinal lumen; water follows passively to maintain osmolality → isotonic fluid floods the lumen
- When volume exceeds the colon's resorptive capacity, profuse watery diarrhea results
Additional mechanisms: CT also enhances secretion via prostaglandins and neural histamine receptors.
Consequences of fluid loss: Profound loss of isotonic fluid (up to 250 mL/kg/24h in severe cases) leads to:
- Hypovolemic shock (the primary cause of death)
- Metabolic acidosis (loss of bicarbonate in stool; cholera stool contains 44 mEq/L HCO₃⁻)
- Hypokalemia (stool K⁺ ~20 mEq/L)
- Prerenal azotemia, acute tubular necrosis

Note: The intestinal mucosa is not histologically damaged - it remains intact. The glucose-Na⁺ co-transport mechanism (SGLT1) is not affected by cholera toxin - this is the physiological basis for oral rehydration therapy. - Harrison's Principles of Internal Medicine, 22E

PART 2: Clinical Presentation, Degrees of Dehydration, Emergency Therapy for Dehydration Shock

Clinical Presentation

Infected individuals show a spectrum ranging from asymptomatic carriage to life-threatening cholera gravis.

Incubation period: 24-48 hours (range: a few hours to 5 days per Tintinalli; classically 2-3 days)

Onset: Sudden, with painless watery diarrhea - this is the hallmark. No fever (usually absent). Vomiting is common. No blood or pus in stool.

"Rice-water" stools: The classical stool is nonbilious, gray, slightly cloudy fluid with flecks of mucus, no blood, with a faint inoffensive "fishy" odor. It resembles the water in which rice has been washed.

Rice-water cholera stool - note floating mucus and gray watery appearance. (Courtesy of Dr. A. S. G. Faruque, ICDDR,B Dhaka)

Fluid losses: Up to 15 L/day, with severe cases losing >250 mL/kg in the first 24 hours.

Muscle cramps due to electrolyte disturbances (hypokalemia) are common.

Laboratory findings in severe cholera:

Elevated hematocrit (hemoconcentration)
Mild neutrophilic leukocytosis
Elevated BUN and creatinine (prerenal azotemia)
Normal Na⁺, K⁺, Cl⁻ initially (isotonic loss), but progressive hypokalemia
Markedly reduced bicarbonate (<15 mmol/L)
Elevated anion gap (from increased lactate, protein, phosphate)
Arterial pH ~7.2 (metabolic acidosis)

Degrees of Dehydration

From Harrison's 22E (Table 173-1):

Degree of Dehydration	Clinical Findings
None or Mild	Thirst in some cases; <5% loss of body weight
Moderate	Thirst, postural hypotension, weakness, tachycardia, decreased skin turgor, dry mouth/tongue, no tears; 5-10% loss of body weight
Severe	Unconsciousness, lethargy, or "floppiness"; weak or absent pulses; inability to drink; sunken eyes (sunken fontanelles in infants); wrinkled "washerwoman" skin; somnolence, coma; >10% loss of body weight

Clinical correlates of progressive dehydration:

<5% loss: Thirst only
5-10%: Postural hypotension, weakness, tachycardia, decreased skin turgor
10%: Oliguria, weak/absent pulses, sunken eyes, wrinkled skin, somnolence, coma

Emergency Therapy for Dehydration (Hypovolemic) Shock

Dehydration shock = severe dehydration (>10% body weight loss) with hemodynamic collapse. This is the primary cause of death in cholera and requires immediate, aggressive IV rehydration.

Fluid of choice: Lactated Ringer solution (Hartmann's solution)

Its electrolyte composition closely mirrors cholera stool: Na⁺ 130 mEq/L, Cl⁻ 109 mEq/L, K⁺ 4 mEq/L, lactate (bicarbonate equivalent) 28 mEq/L

Electrolyte composition comparison (Goldman-Cecil, Table 278-1):

Solution	Na⁺	Cl⁻	K⁺	HCO₃⁻	Osmolarity
Cholera stool (adult, severe)	130	100	20	44	-
Lactated Ringer (IV)	130	109	4	28*	271
Normal saline (IV)	154	154	0	0	308
WHO standard ORS	90	80	20	10*	311
WHO reduced-osmolarity ORS	75	65	20	10*	245

*as lactate or citrate

Rehydration protocol (two phases):

Phase 1 - Rehydration phase (first 3-4 hours):

For severe dehydration/shock: IV fluids at 100 mL/kg total during the first 3-4 hours
Infuse as rapidly as possible initially to restore intravascular volume
Lactated Ringer preferred; normal saline acceptable if Ringer unavailable (but adds no bicarbonate/potassium)
Add KCl supplementation separately (cholera stool loses ~20 mEq/L K⁺)
Correct metabolic acidosis - usually corrects as volume is restored

Phase 2 - Maintenance phase:

Replace ongoing stool losses volume-for-volume
Transition to ORS (oral) as soon as patient can drink and is no longer in shock
WHO reduced-osmolarity ORS (245 mOsm/L: Na 75, Cl 65, K 20, citrate 10, glucose 75 mmol/L) is the current standard - lower osmolarity reduces stool output and vomiting compared to earlier formulations

IV route is restricted to:

Patients who cannot tolerate oral fluids
Patients vomiting >10-20 mL/kg/hour
All patients with severe dehydration/shock

For moderate dehydration, oral rehydration alone is sufficient. ORS works because the glucose-Na⁺ co-transport (SGLT1) in the gut brush border is unaffected by cholera toxin - glucose drives Na⁺ absorption, and water follows. - Goldman-Cecil Medicine; Harrison's 22E

PART 3: Diagnosis, Differential Diagnosis, and Principles of Treatment

Diagnosis

Clinical suspicion: Cholera should be suspected in:

Any patient ≥5 years presenting with acute watery diarrhea in a cholera-endemic or epidemic area
Any patient with severe dehydration from acute watery diarrhea
Any acute watery diarrhea death, even where cholera is not known

Microbiological confirmation:

Method	Details
Dark-field microscopy	Wet mount of fresh stool shows large numbers of bacteria with characteristic "darting" or "shooting-star" motility; specific antisera immobilize vibrios to confirm serotype
Culture	Selective media required: TCBS (thiosulfate-citrate-bile salts-sucrose) agar or TTG agar; V. cholerae grows as yellow colonies on TCBS (sucrose fermenter). Alkaline peptone water (pH 8.6) as enrichment medium. Cary-Blair transport medium for delayed processing
Biochemical	All vibrios are oxidase-positive; standard Enterobacteriaceae tests also work
PCR	Definitive; detects V. cholerae in stool and environmental samples; most sensitive
Rapid dipstick	Point-of-care antigen detection assays; useful in field settings; must be followed by confirmatory testing

In epidemic settings, dark-field microscopy alone with clinical context is sufficient for a working diagnosis.

Differential Diagnosis

Cholera must be distinguished from other causes of acute profuse watery diarrhea:

Condition	Distinguishing Features
ETEC (enterotoxigenic E. coli)	Most common cause of traveler's diarrhea; similar mechanism (heat-labile toxin activates cAMP); usually milder; culture/PCR differentiates
Rotavirus	Primarily children; vomiting prominent; often low-grade fever; seasonal (winter in temperate climates)
Norovirus	Short incubation (12-48h); prominent vomiting; community outbreaks; self-limited
Cryptosporidiosis	Profuse watery diarrhea; immunocompromised (especially HIV); oocysts on stool microscopy
Other Vibrio spp.	V. parahaemolyticus: associated with raw seafood; watery or dysenteric; non-O1/O139 non-cholera vibrios don't produce CT, cause milder disease
Salmonella typhi	Systemic features (fever, rose spots, bradycardia); blood culture positive; different pattern
Shigella/EIEC	Dysentery (blood and mucus), fever, tenesmus - distinct from cholera's painless watery diarrhea
Acute intestinal obstruction	Surgical emergency; different presentation
Non-infectious causes	VIPoma, Zollinger-Ellison syndrome can produce profuse secretory diarrhea - but no epidemic context, no fever, no infective source

The combination of painless profuse rice-water stool + rapid severe dehydration + no fever in an epidemic context is essentially pathognomonic for cholera. - Harrison's 22E; Tintinalli's Emergency Medicine

Principles of Treatment

Treatment rests on three pillars: rehydration, antimicrobials, and supportive care.

1. Rehydration (Primary and Non-Negotiable)

As detailed above in emergency therapy. Adequate rehydration alone reduces mortality from 50-75% to <1%.

Mild/no dehydration: ORS at 50-100 mL/kg over 4 hours + replace ongoing losses
Moderate dehydration: ORS at 75-100 mL/kg over 4 hours orally
Severe dehydration: IV Lactated Ringer at 100 mL/kg over 3-4 hours, then transition to ORS

Zinc supplementation (10-20 mg/day for 10-14 days) is recommended as adjunct for children - reduces stool output and duration of diarrhea.

2. Antimicrobials

Antibiotics are indicated in moderate-to-severe cholera. Benefits:

Shorten illness duration (from ~4-5 days to ~2 days)
Reduce stool output (decreasing rehydration needs)
Reduce vomiting
Eradicate the organism from stool (decreasing transmission)

Antibiotic choices:

Drug	Dose (Adult)	Notes
Doxycycline (1st choice)	300 mg single dose	Drug of choice; single dose effective
Azithromycin	1 g single dose	Preferred in pregnancy and children
Tetracycline	500 mg QID × 3 days	Alternative
Erythromycin	Alternative	Used in pregnancy if azithromycin not available
Ciprofloxacin	1 g single dose	Resistance increasing in some regions; use with caution

Antibiotic resistance is an increasing concern; local susceptibility patterns should guide choice.

Prophylaxis for contacts is NOT recommended - secondary transmission is rare given the high inoculum required.

3. Supportive Care

Correct hypokalemia (add KCl to IV fluids or supplement ORS)
Correct metabolic acidosis (restored with adequate fluid resuscitation)
Monitor urine output (target >0.5 mL/kg/hr)
Avoid anti-motility agents (they impede toxin clearance)
Zinc supplementation in children
Continue feeding as soon as patient tolerates it (rice-based ORS or food-based ORS may be beneficial)

4. Prevention and Control

Safe water supply and sanitation (primary)
Oral cholera vaccines (OCV): Two WHO-prequalified killed whole-cell oral vaccines (Shanchol, Euvichol-Plus) - recommended in endemic settings and outbreaks; 2-dose schedule; protective for ~3 years
Boiling water, chlorination
Food hygiene
Surveillance and outbreak reporting
Isolation of patients with standard enteric precautions

Key Summary Points:

Cholera is caused by V. cholerae O1 (El Tor biotype) or O139, producing cholera toxin that cAMP-mediated secretory diarrhea
Pathogenesis: CT B-subunit binds GM1 ganglioside → A1 subunit ADP-ribosylates Gs-alpha → constitutive adenylate cyclase → high cAMP → inhibit villus absorption + stimulate crypt secretion → massive isotonic fluid loss
Clinical hallmark: sudden-onset painless, profuse, rice-water diarrhea without fever
Death is from hypovolemic shock - prompt rehydration reduces mortality from >50% to <1%
Emergency treatment: IV Lactated Ringer 100 mL/kg over 3-4 hours for severe cases
Antibiotics (doxycycline/azithromycin) shorten illness but rehydration is primary
Diagnosis: dark-field microscopy, TCBS culture, PCR, or rapid dipstick

Sources: Harrison's Principles of Internal Medicine 22E (2025), Goldman-Cecil Medicine International Edition, Tintinalli's Emergency Medicine

Malaria. Etiology. Epidemiology. Risk groups.Malaria. Life cycle of the malaria parasite. Features of the asexual phase of development of the causative agents of different forms of malaria. Origin of febrile paroxysm. Malaria. Prevention. Pathogenesis of relapses in malaria. Complications of malaria. Malaria. Diagnosis of malaria. Treatment of different forms of malaria (indicate drug groups and main representatives).

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Malaria: Complete Review

PART 1: Etiology, Epidemiology, Risk Groups, Life Cycle, Asexual Phase Features, and Febrile Paroxysm

Etiology

Malaria is a protozoan disease caused by obligate intraerythrocytic parasites of the genus Plasmodium. Six species cause nearly all human malarial infections:

Species	Disease	RBC Preference	Cycle	Features
P. falciparum	Malignant tertian malaria	All ages (no preference)	48 h	Most dangerous; cytoadherence; no hypnozoites
P. vivax	Benign tertian malaria	Young RBCs (reticulocytes)	48 h	Hypnozoites → relapses; Duffy antigen required
P. ovale	Benign tertian malaria	Young RBCs	48 h	Hypnozoites → relapses; two species: curtisi and wallikeri
P. malariae	Quartan malaria	Old RBCs	72 h	No hypnozoites; long-term recrudescence; nephrotic syndrome
P. knowlesi	Quotidian malaria	All ages	24 h	Monkey parasite; Southeast Asia; can cause severe disease
P. simium / P. cynomolgi	Rare	-	-	Zoonotic; South America and Southeast Asia respectively

Transmission: Bite of an infected female Anopheles mosquito (only females take blood meals). Other routes include blood transfusion, needle sharing (IV drug users), organ transplantation, and transplacentally (congenital malaria, <5% of neonates born to infected mothers). - Harrison's Principles of Internal Medicine, 22E

Epidemiology

Malaria occurs throughout the tropical and subtropical regions of the world (between latitudes 60°N and 40°S). In 2022, there were an estimated 249 million cases in 85 malaria-endemic countries and 608,000 deaths (~1,660 deaths per day).

Geographic distribution of species:

P. falciparum predominates in: sub-Saharan Africa, New Guinea, Hispaniola (Haiti/Dominican Republic)
P. vivax is more common in: Central and South America, most of Asia, Horn of Africa
P. malariae: found in most endemic areas, especially sub-Saharan Africa
P. ovale: mainly Africa, uncommon elsewhere
P. knowlesi: Southeast Asia only (Malaysia, Indonesia, Philippines)

Two countries (Nigeria and Democratic Republic of Congo) account for ~43% of all malaria deaths. Over 90% of deaths occur in sub-Saharan Africa.

Seasonal/Environmental factors:

Peak transmission during the rainy season and in warm months
Mosquito breeding requires stagnant water and temperatures 20-30°C
Altitude limits transmission (>2000 m is generally malaria-free)
Submicroscopic asymptomatic infections can reach 10-15% of the population in endemic areas

Risk Groups

Children <5 years in endemic areas (most deaths occur in this group - ~80% of fatalities)
Pregnant women (especially primigravidae): severe anemia, low birth weight, fetal loss, pulmonary edema
Non-immune travelers from non-endemic countries visiting endemic regions
People with HIV/AIDS and malnourished individuals: more severe disease
Asplenic patients: extremely high risk of severe, rapidly fatal malaria
Persons with sickle-cell disease or thalassemia: partial protection (heterozygotes) but still susceptible
Persons lacking Duffy antigen (common in West Africans): naturally resistant to P. vivax (Duffy antigen is its RBC receptor)
Blood group O: paradoxically, at greater risk of severe P. falciparum disease (El Tor effect also seen here)
Immunocompromised patients (transplant recipients, on steroids)
People with iron deficiency: some protection (iron-restricted RBCs are less hospitable to parasites)

Life Cycle of the Malaria Parasite

The malaria life cycle involves two hosts: the human (intermediate host, asexual phase) and the female Anopheles mosquito (definitive host, sexual phase).

A. In the Human Host (Asexual Phase)

1. Pre-erythrocytic (Hepatic/Exoerythrocytic) Schizogony:

A female Anopheles mosquito injects sporozoites from her salivary glands during a blood meal
Sporozoites travel via the bloodstream to the liver within minutes
They invade hepatic parenchymal cells and undergo intrahepatic (pre-erythrocytic) schizogony
A single sporozoite produces 10,000 to >30,000 daughter merozoites (massive amplification)
The infected hepatocytes swell into hepatic schizonts, then burst, releasing merozoites into the bloodstream
Duration: ~5-7 days (P. falciparum); ~8 days (P. vivax); ~9 days (P. ovale); ~13-16 days (P. malariae)

Key feature - Hypnozoites (P. vivax and P. ovale only):

A proportion of intrahepatic forms do not divide immediately but enter a dormant state as hypnozoites
They remain inert in hepatocytes for weeks to months to >1 year before reactivating
This is the cause of relapse in vivax and ovale malaria (see Part 2)

2. Erythrocytic Schizogony (Blood Stage):

Merozoites invade red blood cells (RBCs) and become ring-form trophozoites
Trophozoites enlarge, consuming ~2/3 of the hemoglobin; hemozoin (malaria pigment) forms as toxic heme is detoxified by crystallization
The parasite grows to occupy most of the RBC and becomes a schizont (multiple nuclear divisions = schizogony/merogony)
The infected RBC ruptures, releasing 6-30 daughter merozoites per schizont, each capable of invading new RBCs
Each erythrocytic cycle multiplies parasites 6- to 20-fold

Gametocytogenesis:

Some blood-stage parasites develop into sexual forms: gametocytes (female > male, ratio ~4:1)
In P. falciparum, several asexual cycles precede the switch to gametocytes
Immature P. falciparum gametocytes (stage I-IV) are sequestered in bone marrow, spleen, and brain; only stage V gametocytes circulate

B. In the Mosquito (Sexual Phase - Sporogony)

A female Anopheles ingests gametocytes during a blood meal
The male gametocyte exflagellates → 8 motile male gametes
Male gamete fuses with female gametocyte → zygote (sexual division/meiosis) in the midgut
Zygote matures into an ookinete, which penetrates the mosquito gut wall
Ookinete forms an oocyst, which expands by asexual division → releases thousands of sporozoites
Sporozoites migrate via hemolymph to the salivary glands, ready for injection
Duration (extrinsic incubation period): 8-30 days depending on temperature and species

Features of the Asexual Phase in Different Forms of Malaria

Feature	P. falciparum	P. vivax	P. ovale	P. malariae	P. knowlesi
Fever cycle	Irregular → tertian (48h)	Tertian (48h)	Tertian (48h)	Quartan (72h)	Quotidian (24h)
RBC preference	All ages	Young (reticulocytes)	Young (reticulocytes)	Old RBCs	All ages
RBC enlargement	No (normal/shrinks)	Yes (Schüffner's dots)	Yes, oval shape (Schüffner's dots)	No	No
Max parasitemia	Very high (>5-10%)	<2%	<2%	<2%	Can be very high
Merozoites per schizont	8-24	12-24	4-16	6-12	10-16
Hypnozoites	No	Yes	Yes	No	No
Sequestration	Yes (cytoadherence via PfEMP1)	No	No	No	No (but can sequester in lungs)
Distinctive morphology	Ring forms only in peripheral blood; banana-shaped gametocytes	Ameboid trophozoites; Schüffner's dots; large infected RBCs	Oval/fimbriated RBCs; Schüffner's dots	"Band form" trophozoites; Ziemann's stippling	Similar to P. vivax but smaller RBCs

Key pathological feature of P. falciparum:

Cytoadherence: Parasitized RBCs express PfEMP1 (P. falciparum erythrocyte membrane protein 1) via "knobs" on the RBC surface 12-15h after invasion
PfEMP1 mediates adherence to vascular endothelium (ICAM-1 and endothelial protein C receptor in the brain; CD36 in most other organs; chondroitin sulfate A via VAR2CSA in the placenta)
This causes sequestration of infected RBCs in capillaries and venules of vital organs, particularly the brain, leading to microcirculatory obstruction
Sequestration keeps mature-stage parasites out of the spleen (evading immune clearance), so only young ring forms appear in peripheral blood - peripheral parasitemia underestimates true parasite burden
Rosetting (infected RBCs adhering to uninfected RBCs) and agglutination (infected RBCs adhering to each other) worsen microvascular obstruction

Origin of the Febrile Paroxysm

The febrile paroxysm is the hallmark of clinical malaria. It arises from the synchronous rupture of erythrocytic schizonts.

Mechanism:

Schizont-infected RBCs rupture synchronously at the end of each erythrocytic cycle
Rupture releases merozoites, hemozoin (malaria pigment), parasitic metabolic products, and remnants of the destroyed RBCs into the bloodstream
These materials activate monocytes/macrophages, triggering release of proinflammatory cytokines: TNF-α, IL-1, IL-6, IL-8, and others
These cytokines act on the hypothalamic thermoregulatory center, causing fever
Temperatures ≥40°C (≥104°F) damage mature parasites, further synchronizing the parasitic cycle, producing the characteristic regular fever pattern

Classic febrile paroxysm - three stages:

Cold stage (rigor/shaking chill): Sudden onset, intense shivering, temperature rising rapidly; lasts 15-60 minutes
Hot stage: Intense fever (40-41°C or higher), headache, nausea, vomiting, delirium; lasts 2-6 hours
Sweating stage: Profuse diaphoresis, rapid defervescence, exhaustion, patient feels temporarily better

Fever periodicity by species:

Tertian (every 48h, i.e., on days 1, 3, 5...): P. falciparum, P. vivax, P. ovale
Quartan (every 72h, i.e., days 1, 4, 7...): P. malariae
Quotidian (daily): P. knowlesi
P. falciparum is often irregular initially, before synchronization is established

Note: With prompt modern treatment, the classic regular fever pattern is seldom seen. - Harrison's 22E

PART 2: Prevention, Pathogenesis of Relapses, and Complications

Prevention

Personal Protection Measures

Insect repellents: DEET (diethyltoluamide)-containing repellents applied to exposed skin
Permethrin-impregnated bed nets (LLINs): Long-lasting insecticidal nets - most effective and cost-effective intervention for endemic areas
Protective clothing: Long sleeves and trousers at dusk/dawn when mosquitoes are most active
Screened windows and air conditioning
Indoor residual spraying (IRS) with insecticides

Chemoprophylaxis

Recommended for non-immune travelers to endemic areas; choice depends on destination and local resistance patterns:

Drug	Indication/Region	Dosing
Atovaquone-proguanil (Malarone)	All regions including chloroquine-resistant areas	1 tablet daily, start 1-2 days before, continue 7 days after return
Mefloquine	Chloroquine-resistant areas	Weekly; start 2-3 weeks before, continue 4 weeks after
Doxycycline	High-resistance areas (SE Asia)	Daily; start 1-2 days before, continue 4 weeks after
Chloroquine	Chloroquine-sensitive areas only (limited regions)	Weekly; start 1-2 weeks before, continue 4 weeks after
Primaquine	Terminal prophylaxis for P. vivax/P. ovale (eradicates hypnozoites); also causal prophylaxis	Requires G6PD testing first
Tafenoquine	Prevention of relapse (P. vivax)	Single dose; requires G6PD testing

Vaccine:

RTS,S/AS01 (Mosquirix): First licensed malaria vaccine; targets P. falciparum circumsporozoite protein; recommended by WHO for children in sub-Saharan Africa; ~36-56% efficacy at 4 doses
R21/Matrix-M: Newer, higher-efficacy (~77%) recombinant vaccine approved in several countries

Community-Level Prevention

Environmental management: draining stagnant water, larviciding
Surveillance, early diagnosis and treatment
Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine

Pathogenesis of Relapses in Malaria

Types of recurrence in malaria must be carefully distinguished:

Term	Mechanism	Species
Relapse	Reactivation of dormant hypnozoites in the liver	P. vivax, P. ovale only
Recrudescence	Re-emergence of blood-stage parasites after inadequate treatment	All species, especially P. malariae
Reinfection	New infection by mosquito bite	All species in endemic areas

Relapse (Vivax/Ovale Malaria)

During the initial infection, some sporozoites in the liver do not proceed to immediate schizogony but instead enter a dormant state as hypnozoites (Greek: hypnos = sleep)
Hypnozoites may persist for months to years in hepatocytes
Triggers for reactivation are incompletely understood but include fever from intercurrent infection, immunosuppression, and physiological stress
Upon reactivation, hypnozoites resume development → hepatic schizogony → merozoite release → new blood-stage infection → clinical relapse
Relapse intervals:
- P. vivax (temperate strains): long incubation variant - initial attack may be delayed up to 6-12 months, then relapse
- P. vivax (tropical strains): relapses every 3-4 weeks
- P. ovale: usually 1-4 months, up to 4 years reported
Blood-stage antimalarials (e.g., chloroquine) treat the erythrocytic phase but do not eliminate hypnozoites - hence relapse still occurs after chloroquine monotherapy
Only 8-aminoquinolines (primaquine, tafenoquine) kill hypnozoites ("radical cure")

G6PD precaution: Primaquine and tafenoquine can cause life-threatening hemolytic anemia in patients with G6PD deficiency (X-linked enzyme deficiency, common in malaria-endemic areas) - G6PD testing is mandatory before use.

Complications of Malaria

Most complications occur with P. falciparum due to cytoadherence and high parasitemia. P. knowlesi can also cause severe disease.

WHO Criteria for Severe P. falciparum Malaria:

Major manifestations:

Complication	Criteria/Features
Cerebral malaria	Unarousable coma (GCS <11; Blantyre <3 in children); diffuse symmetric encephalopathy; no focal signs; convulsions (10% of adults, up to 50% of children); retinal hemorrhages (30-40% with indirect ophthalmoscopy); mortality 15-20% even with treatment
Severe normochromic normocytic anemia	Hematocrit <15%; multiple mechanisms: RBC destruction, dyserythropoiesis, immune-mediated hemolysis
Renal failure	Serum creatinine >265 μmol/L or urine output <0.4 mL/kg/h; "blackwater fever" (massive hemoglobinuria) is a rare severe form
Pulmonary edema / ARDS	Respiratory distress with pulmonary infiltrates; may develop even after treatment begins; high mortality
Hypoglycemia	Blood glucose <2.2 mmol/L; from increased glucose consumption by parasites, impaired gluconeogenesis, and quinine/quinidine-stimulated insulin release; especially common in pregnant women and children
Metabolic acidosis	Arterial pH <7.25; bicarbonate <15 mmol/L; lactate ≥5 mmol/L; manifests as labored deep breathing ("Kussmaul respiration"); major cause of death
Circulatory collapse/shock	Systolic BP <70 mmHg; "algid malaria"; may have concurrent Gram-negative bacteremia (Salmonella spp. associated with P. falciparum)
Abnormal bleeding / DIC	Significant bleeding from gums, nose, GI tract; rarely DIC; thrombocytopenia universal
Hyperparasitemia	>5% infected RBCs (some define severe as >2%); mortality rises steeply
Hyperpyrexia	Core temperature >40°C (>104°F)
Impaired consciousness	Obtundation, delirium, prostration, inability to sit unsupported

Relative frequency of complications by population (Harrison's Table 231-4):

Anemia: most common in children; also in pregnant women
Convulsions: very frequent in children
Hypoglycemia: very frequent in pregnant women and children
Jaundice + renal failure: very frequent in adults
Pulmonary edema: frequent in adults and pregnant women

Neurological sequelae of cerebral malaria in children:

~10% have residual deficits: hemiplegia, cerebral palsy, cortical blindness, deafness, cognitive impairment
Most improve within 6 months, but language deficits, epilepsy, and learning difficulties may persist

Other complications:

Splenomegaly (progressive in chronic malaria → hypersplenism; "tropical splenomegaly syndrome")
Blackwater fever (P. falciparum): massive intravascular hemolysis with hemoglobinuria (dark red-black urine) and acute renal failure; associated with quinine use
Malaria nephropathy (P. malariae): immune-complex-mediated nephrotic syndrome (quartan nephropathy) - deposition of parasite antigens in glomeruli
Placental malaria: sequestration of parasitized RBCs in placenta → low birth weight, premature delivery
Congenital malaria (<5% of neonates of infected mothers)
Rupture of spleen (rare, but catastrophic)
Malarial hepatopathy
Aspiration pneumonia (from seizures in comatose patients)

PART 3: Diagnosis and Treatment

Diagnosis of Malaria

When to suspect malaria: Any febrile illness within 1-3 months of travel to an endemic area; thrombocytopenia + fever in an undiagnosed patient; any fever with atypical features in an endemic area.

1. Microscopy (Gold Standard)

Thick blood film:

More sensitive - concentrates parasites; used to detect infection and quantify parasitemia
Dehaemoglobinized - allows visualization of parasites free of RBC stroma
Can detect as few as 5-10 parasites/μL
Less species-specific than thin film

Thin blood film:

Better for species identification - RBC morphology preserved, allowing identification of inclusions (Schüffner's dots, Maurer's clefts, size changes)
Useful for estimating % parasitemia

Both films should be prepared simultaneously.

Species-specific microscopic features:

Feature	P. falciparum	P. vivax	P. ovale	P. malariae
RBC size	Normal or small	Enlarged	Enlarged, oval	Normal
Inclusions	Maurer's clefts	Schüffner's dots	Schüffner's dots	Ziemann's stippling
Trophozoite	Delicate ring; double chromatin dots; multiple rings/cell; appliqué position	Ameboid, irregular	Compact, rounded	Band form (across RBC)
Gametocyte	Banana/crescent shaped	Round/oval	Round/oval	Round
Stages in peripheral blood	Ring forms only (mature forms sequestered)	All stages	All stages	All stages
Multiple infections/cell	Common	Rare	Rare	Rare

Dark-field microscopy can detect darting motility of merozoites in fresh stool/blood; not routine for malaria.

If the initial smear is negative but malaria is strongly suspected, repeat thick films at 1 and 2 days (a negative film by an experienced microscopist makes malaria very unlikely but does not rule it out completely).

2. Rapid Diagnostic Tests (RDTs)

Detect parasite antigens in blood: HRP2 (P. falciparum-specific), pLDH (pan-specific), aldolase
Results in 15-20 minutes
Sensitivity ~95% for P. falciparum at clinically significant parasitemia levels; lower for non-falciparum species
Can be false negative at very low parasitemia and false positive (HRP2-based) if antigen persists after treatment
WHO recommends RDTs where microscopy unavailable; should not replace microscopy for species ID and parasitemia quantification when possible

3. PCR (Molecular Diagnosis)

Most sensitive (~1000x more sensitive than microscopy)
Useful for: low-density infections, mixed infections, species confirmation, antimalarial resistance genotyping
Too slow and technically demanding for routine acute care; used in reference labs and epidemiological surveys

4. Serologic Methods

Indirect fluorescent antibody (IFA) and ELISA
Useful for blood donor screening and epidemiologic studies
No role in acute illness (detects past exposure, not current infection)

5. Laboratory Findings in Acute Malaria

Thrombocytopenia (platelet count ~10⁵/μL): almost universal in malaria; a normal platelet count makes malaria unlikely
Normochromic normocytic anemia; elevated reticulocyte count
Leukocyte count generally normal (leukocytosis in very severe disease)
Monocytosis, lymphopenia, eosinopenia
Elevated ESR, CRP, acute phase proteins
Severe malaria: metabolic acidosis (low glucose, Na, HCO₃, PO₄, albumin), elevated lactate, BUN, creatinine, urate, LFTs, unconjugated bilirubin
CSF in cerebral malaria: opening pressure ~160 mmH₂O; usually normal or slight elevation of protein (<1.0 g/L) and cells (<20/μL) - helps differentiate from meningitis

Treatment of Different Forms of Malaria

Principle: Treatment must be urgent - malaria can be rapidly fatal.

The choice of treatment depends on: (1) infecting species, (2) severity of illness, (3) geographic origin/likely resistance, (4) patient factors (pregnancy, G6PD status, age).

I. Uncomplicated P. falciparum Malaria (or Unknown Species in Endemic Areas)

First-line: Artemisinin-Based Combination Therapy (ACT)

WHO recommends ACT as first-line everywhere. The artemisinin component (rapidly eliminated, fast-acting) kills the bulk of parasites; the longer-acting partner drug eliminates residual parasites.

Six WHO-recommended ACT regimens (all 3 days):

ACT Regimen	Notes
Artemether-lumefantrine (Coartem)	Most widely used; preferred in first trimester pregnancy
Artesunate-mefloquine	SE Asia; GI tolerability issues
Dihydroartemisinin-piperaquine (DHA-PPQ)	Once daily; good tolerability
Artesunate-amodiaquine	Africa; watch for CNS effects
Artesunate-sulfadoxine-pyrimethamine	Africa where SP still effective
Artesunate-pyronaridine	Newer combination

Alternative (where no ACT available or non-endemic country):

Atovaquone-proguanil (20/8 mg/kg/day × 3 days): highly effective everywhere; expensive; not for prophylaxis of same patient

Add gametocytocide: Single dose primaquine 0.25 mg/kg to all falciparum malaria (to prevent transmission); safe even in G6PD deficiency at this low dose.

Artemisinin resistance (SE Asia, now emerging in East Africa):

Characterized by slow parasite clearance (half-life >5h, clearance time >3 days)
Pfkelch13 mutations are molecular marker
Triple combinations under evaluation

II. Severe P. falciparum Malaria (Medical Emergency)

First-line: IV Artesunate (superior to quinine - 35% lower mortality in SE Asia, 22.5% lower in Africa)

Protocol (Harrison's Table 231-6):

Artesunate: 12.4 mg/kg IV stat, then 2.4 mg/kg at 12h and 24h, then daily if needed
- For children <20 kg: 3 mg/kg per dose
Transition to oral ACT as soon as patient can swallow

If artesunate unavailable:

Artemether: 3.2 mg/kg IM stat, then 1.6 mg/kg/day (erratic IM absorption - less preferred)
Quinine dihydrochloride: 20 mg salt/kg IV over 4h, then 10 mg salt/kg over 2-8h every 8h (requires cardiac monitoring - QT prolongation; hypoglycemia from insulin stimulation)
- In artemisinin-resistance areas: give artesunate + quinine together at full doses

Supportive care in severe malaria:

Antipyretics (paracetamol/acetaminophen) - do NOT use aspirin/NSAIDs (platelet dysfunction, GI bleeding)
Management of hypoglycemia (IV glucose)
Seizure management (benzodiazepines)
Careful fluid balance (risk of ARDS from aggressive fluids)
Renal replacement therapy for acute kidney injury
No corticosteroids in cerebral malaria (shown to be harmful)
Transfusion for severe anemia (Hct <15-20%)
Treat concurrent bacterial infection empirically

III. Uncomplicated P. vivax and P. ovale Malaria

Step 1 - Kill blood-stage parasites (schizontocide):

Chloroquine: 25 mg base/kg total (10 mg/kg day 1, 10 mg/kg day 2, 5 mg/kg day 3) - still effective for vivax in most areas, EXCEPT chloroquine-resistant P. vivax (Papua New Guinea, Indonesia, parts of South America and SE Asia → use ACT instead)
Or: any ACT regimen (effective for vivax/ovale)

Step 2 - Kill hypnozoites ("radical cure" to prevent relapse):

Primaquine: 0.25-0.5 mg base/kg/day × 14 days
- Must test for G6PD deficiency first
- G6PD-deficient patients: may use 0.75 mg/kg once weekly × 8 weeks (lower hemolytic risk)
- Contraindicated in pregnancy (use weekly chloroquine throughout pregnancy, then primaquine postpartum)
Tafenoquine: Single dose 300 mg (adults); requires G6PD testing; not for children <16 years

IV. P. malariae Malaria

Chloroquine alone (25 mg base/kg total); no hypnozoites, so no primaquine needed
No radical cure required; but long-term low-level recrudescence can occur

V. P. knowlesi Malaria

Treat as P. falciparum (same potential for severe disease and rapidly increasing parasitemia due to 24-h cycle)
ACT or chloroquine (if mild, as knowlesi remains chloroquine-sensitive) - use ACT to be safe

VI. Drug Groups Summary

Drug Group	Main Drugs	Mechanism	Use
Artemisinins	Artesunate, artemether, dihydroartemisinin	Free radical generation from endoperoxide bridge; broad-stage schizontocidal	First-line (uncomplicated + severe); fastest parasite clearance
Aminoquinolines	Chloroquine, amodiaquine, piperaquine	Inhibit heme detoxification → hemozoin block → toxic heme accumulates	Blood-stage schizontocides; chloroquine resistance widespread in P. falciparum
Quinoline-methanols	Quinine, quinidine, mefloquine	Similar to chloroquine; also inhibit parasite protein synthesis	Quinine for severe malaria backup; mefloquine in ACT
8-Aminoquinolines	Primaquine, tafenoquine	Oxidative stress; active against hypnozoites and gametocytes	Radical cure (P. vivax/ovale); gametocytocide; causal prophylaxis
Antifolates	Sulfadoxine-pyrimethamine, proguanil	Inhibit dihydropteroate synthase and dihydrofolate reductase (sequential block)	Proguanil in atovaquone combination; SP in ACT (Africa); IPTp in pregnancy
Hydroxynaphthoquinone	Atovaquone	Inhibits mitochondrial electron transport (cytochrome bc1 complex)	In combination with proguanil (Malarone) for prophylaxis and treatment
Tetracyclines	Doxycycline, tetracycline	Inhibit apicoplast translation	Second-line in combination; not in pregnancy or children <8 years
Lincosamides	Clindamycin	Inhibit apicoplast translation	Used with quinine in pregnancy/children

Key Summary Points:

6 species cause human malaria; P. falciparum is most lethal; P. vivax/ovale have hypnozoites causing relapse
Febrile paroxysm: synchronous schizont rupture → cytokine storm (TNF-α, IL-1, IL-6) → hypothalamic fever response
Relapse (P. vivax/ovale): reactivation of dormant hepatic hypnozoites; treated with primaquine/tafenoquine (radical cure)
Severity of P. falciparum: cytoadherence via PfEMP1 → sequestration in brain, placenta, other organs → cerebral malaria, ARDS, renal failure
Diagnosis: thick + thin blood films remain gold standard; RDTs for field use; PCR most sensitive
Thrombocytopenia is near-universal in malaria
First-line treatment: ACT for uncomplicated falciparum; IV artesunate for severe malaria; chloroquine + primaquine for sensitive vivax/ovale

Sources: Harrison's Principles of Internal Medicine 22E (2025), Goldman-Cecil Medicine International Edition

Viral hepatitis A and E. Etiology, epidemiology. Clinical classification. Clinical presentation of various forms. Diagnosis. Treatment

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