Infectious Disease

Parasitic infections: malaria, toxoplasmosis

Clinical Overview and When to Suspect Malaria or Toxoplasmosis

Malaria → Plasmodium spp. transmitted by female Anopheles mosquito → cyclical erythrocyte invasion and lysis → febrile hemolytic illness. Five species: P. falciparum (most lethal), P. vivax, P. ovale (both form hypnozoites), P. malariae, P. knowlesi.

Toxoplasmosis → Toxoplasma gondii, obligate intracellular protozoan → acquired via cat feces (oocysts), undercooked meat (tissue cysts), or transplacental transmission. Usually latent in immunocompetent hosts; reactivates with CD4 < 100.

Board pearl: Any fever in a returning traveler = malaria until proven otherwise. Delay in diagnosis of P. falciparum → rapid mortality.

Suspect malaria: febrile traveler from endemic area (sub-Saharan Africa, South/Southeast Asia, Central/South America)

Suspect toxoplasmosis: HIV patient with ring-enhancing brain lesions, or pregnant woman with new seroconversion

Malaria — Presentation Patterns and Key History

— 48-hr cycle (tertian): P. falciparum, P. vivax, P. ovale

— 72-hr cycle (quartan): P. malariae

— Periodicity often absent early in disease

Critical history:

— Travel to endemic area within past 12 months (P. falciparum usually within 1 month; P. vivax/ovale can relapse months–years later from hepatic hypnozoites)

— Chemoprophylaxis use and adherence

— Prior malaria episodes

— Sickle cell trait (protective — ↓ severe malaria)

Next best step: Obtain thick and thin blood smears STAT in any febrile returning traveler.

Classic paroxysm: rigors → high fever (39–41°C) → profuse diaphoresis → defervescence

Nonspecific: headache, myalgia, nausea, vomiting, diarrhea — mimics influenza, typhoid, dengue

Splenomegaly (common after several days), hepatomegaly, jaundice

Toxoplasmosis — Presentation Patterns and Key History

Immunocompetent host:

Immunocompromised (HIV, CD4 < 100):

Congenital toxoplasmosis (classic triad):

Ocular toxoplasmosis:

Board pearl: Ring-enhancing brain lesions + HIV + CD4 < 100 + positive Toxoplasma IgG → empiric treatment for TE before biopsy.

80–90% asymptomatic or mild cervical lymphadenopathy ± fatigue ("mono-like" illness)

Self-limited; no treatment needed unless severe or prolonged

Toxoplasmic encephalitis (TE) — most common CNS mass lesion in AIDS

Subacute: headache, confusion, focal neurologic deficits (hemiparesis, aphasia), seizures, fever

Without treatment → rapid deterioration, coma, death

Chorioretinitis, hydrocephalus, intracranial calcifications (diffuse)

Also: seizures, hepatosplenomegaly, thrombocytopenia

Risk highest with 3rd-trimester maternal infection, but severity worse with 1st-trimester infection

Most common cause of infectious posterior uveitis worldwide

"Headlight in the fog" appearance on fundoscopy (focal white retinal lesion with surrounding vitritis)

Diagnostic Workup — Malaria

— Thick smear: ↑ sensitivity (detects parasitemia)

— Thin smear: species identification and parasitemia quantification (%)

— If initial smear negative → repeat every 12–24 hrs × 3 before ruling out

— Useful for quick triage but does not quantify parasitemia

— False negatives with low parasitemia or HRP-2 gene deletions

Key distinction: Thrombocytopenia + fever + travel = think malaria. Thrombocytopenia is present in >80% of malaria cases and is a strong clue on board exams.

Gold standard: Giemsa-stained thick and thin blood smears

Rapid diagnostic test (RDT): detects Plasmodium antigens (HRP-2 for P. falciparum, pLDH for all species)

Labs: normocytic anemia, thrombocytopenia (very common), ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin (hemolysis), ↑ reticulocyte count

Hypoglycemia — especially with P. falciparum and quinine/quinidine use

Metabolic acidosis, ↑ creatinine in severe cases

Diagnostic Workup — Toxoplasmosis

Immunocompetent:

— IgG positive alone → past infection/latency

— IgM positive + IgG negative or rising → acute infection

— IgG avidity testing: high avidity = infection >12–16 weeks ago (useful in pregnancy to date infection)

Toxoplasmic encephalitis (HIV):

— IgG negative makes TE very unlikely

Congenital:

Board pearl: High IgG avidity in a pregnant woman = infection occurred months ago → low risk to current fetus.

Toxoplasma IgG and IgM serology

Brain MRI (preferred): multiple ring-enhancing lesions, predilection for basal ganglia, corticomedullary junction

Toxoplasma IgG positive (indicates prior exposure capable of reactivation)

Next best step: Empiric treatment trial × 2 weeks → clinical + radiographic improvement confirms diagnosis

Brain biopsy reserved for: no response to empiric therapy at 10–14 days, or IgG-negative patient

Maternal seroconversion (IgM+ → IgG+), PCR of amniotic fluid

Neonatal: Toxoplasma IgM/IgA (do not cross placenta), brain imaging, ophthalmologic exam

First-Line Management — Uncomplicated Malaria

— Artemisinin-based combination therapy (ACT): artemether-lumefantrine (Coartem) — oral, well-tolerated

— Alternative: atovaquone-proguanil (Malarone)

— Chloroquine phosphate (oral)

— Chloroquine (still effective in most areas; resistance emerging in parts of Indonesia/Papua New Guinea)

— PLUS primaquine × 14 days (radical cure to eliminate hepatic hypnozoites)

— Must check G6PD before primaquine → hemolytic anemia in G6PD-deficient patients

— Alternative to primaquine: tafenoquine (single dose, also requires G6PD testing)

Board pearl: Primaquine kills hypnozoites (P. vivax/ovale) — without it, relapse will occur. Always test G6PD first.

P. falciparum or unknown species, chloroquine-resistant areas (most of the world):

P. falciparum from chloroquine-sensitive areas (Central America west of Panama Canal, Caribbean, parts of Middle East):

P. vivax / P. ovale (uncomplicated):

P. malariae: Chloroquine (no hypnozoite stage)

First-Line Management — Severe Malaria

Criteria for severe malaria (P. falciparum):

Treatment:

— Available in the U.S. via CDC

— Superior to IV quinidine in reducing mortality (SEAQUAMAT & AQUAMAT trials)

— Transition to oral ACT once patient can tolerate PO and parasitemia < 1%

— Requires cardiac monitoring (QT prolongation risk)

— Monitor blood glucose (quinidine stimulates insulin release → hypoglycemia)

Supportive care:

Next best step: Severe malaria with altered mental status → IV artesunate immediately; do not wait for species confirmation.

Parasitemia > 5%, cerebral malaria (altered consciousness, seizures), severe anemia (Hb < 7), ARDS, renal failure, hypoglycemia, acidosis, DIC, shock

IV artesunate — drug of choice for severe malaria worldwide

IV quinidine gluconate — alternative if artesunate unavailable

Exchange transfusion considered if parasitemia > 10% with organ dysfunction

ICU-level monitoring for severe cases

Aggressive fluid management but avoid overhydration (ARDS risk)

First-Line Management — Toxoplasmosis

Toxoplasmic encephalitis (HIV/AIDS):

— Leucovorin prevents bone marrow suppression from pyrimethamine (folate antagonist)

— Pyrimethamine + clindamycin + leucovorin if sulfa allergy

— TMP-SMX is an alternative regimen with good CNS penetration

— Same drugs at reduced doses until CD4 > 200 × ≥6 months on ART

Immunocompetent lymphadenitis:

Ocular toxoplasmosis:

Board pearl: Leucovorin (folinic acid) does NOT reduce antiparasitic efficacy — it selectively rescues mammalian folate metabolism while Toxoplasma cannot use it.

Pyrimethamine + sulfadiazine + leucovorin (folinic acid) × 6 weeks

After 6 weeks of acute therapy → chronic suppressive therapy (secondary prophylaxis):

Start/optimize antiretroviral therapy (ART) — timing within 2 weeks of OI treatment

Usually self-limited → no treatment required

Treat if severe/persistent symptoms or vital organ involvement

Pyrimethamine + sulfadiazine + leucovorin ± corticosteroids (to reduce inflammation)

Special Populations — Malaria in Pregnancy

Treatment:

— Quinine + clindamycin is alternative, especially in 1st trimester if ACT unavailable

Contraindicated in pregnancy:

— Defer hypnozoite treatment until after delivery + G6PD testing

Chemoprophylaxis in pregnancy:

Board pearl: Never give primaquine to pregnant women — fetal G6PD status is unknown.

Malaria in pregnancy → ↑ risk of severe disease, maternal anemia, placental sequestration, low birth weight, preterm delivery, fetal loss

P. falciparum is especially dangerous in pregnancy

Uncomplicated (all trimesters): Artemisinin-based combination therapy (ACT) — now recommended by WHO in all trimesters

Severe: IV artesunate (all trimesters) — maternal survival outweighs theoretical teratogenic risk

Primaquine and tafenoquine → risk of fetal hemolysis (unknown G6PD status of fetus)

Doxycycline — teratogenic

Mefloquine — safe in all trimesters

Chloroquine — safe

Atovaquone-proguanil — insufficient safety data, generally avoided

Special Populations — Congenital Toxoplasmosis and Pediatric Considerations

Congenital toxoplasmosis:

Maternal treatment to reduce vertical transmission:

— Concentrates in placenta; reduces transmission ~60%

— Pyrimethamine is teratogenic in 1st trimester → avoid before week 18

Neonatal treatment:

Board pearl: Toxoplasma intracranial calcifications are diffuse/scattered (vs. CMV which causes periventricular calcifications).

Occurs when non-immune mother acquires primary Toxoplasma infection during pregnancy

Transmission risk: ↑ with gestational age (10% 1st trimester → 60–80% 3rd trimester)

Severity: inversely related — 1st-trimester infection → most severe fetal damage

Spiramycin — if maternal infection confirmed before 18 weeks or if amniocentesis negative

Pyrimethamine + sulfadiazine + leucovorin — if fetal infection confirmed (positive amniotic fluid PCR) or infection after 18 weeks

Pyrimethamine + sulfadiazine + leucovorin × 12 months regardless of symptoms

Monitor: CBC every 1–2 weeks (pyrimethamine toxicity), ophthalmologic exams, neuroimaging

Complications and Emergencies — Malaria

— Mechanism: parasitized RBCs adhere to cerebral microvasculature (cytoadherence via PfEMP-1)

— Mortality 15–20% even with treatment; survivors may have neurologic sequelae

— Associated with G6PD deficiency + oxidant stress or quinine use

— Monitor glucose every 4–6 hours during treatment

Next best step: ICU admission for any patient meeting severe malaria criteria; start IV artesunate without delay.

Cerebral malaria (P. falciparum): altered consciousness, seizures, coma

Blackwater fever: massive intravascular hemolysis → hemoglobinuria (dark/black urine) → AKI

Severe malarial anemia: Hb < 5 g/dL → may require transfusion

ARDS/pulmonary edema — can occur even after parasitemia cleared

Hypoglycemia: due to parasite glucose consumption + quinine/quinidine-stimulated insulin secretion

Splenic rupture: especially P. vivax → avoid vigorous abdominal palpation in acute malaria

Tropical splenomegaly syndrome (hyperreactive malarial splenomegaly): chronic/recurrent malaria → massive splenomegaly + pancytopenia + elevated IgM

Complications and Emergencies — Toxoplasmosis

— If untreated → herniation, death

— Seizures: manage with antiepileptics; mass effect may require corticosteroids (dexamethasone) for edema

— Immune reconstitution inflammatory syndrome (IRIS) after ART initiation: paradoxical worsening of TE due to recovering immune response → continue anti-Toxoplasma therapy + consider steroids

— Pneumonitis, myocarditis, hepatitis — seen in severely immunocompromised (transplant recipients, advanced HIV)

— Requires same treatment as TE

— Severe chorioretinitis → blindness

— Hydrocephalus → neurodevelopmental delay

— Hearing loss, seizures

— Highest risk: Toxoplasma IgG-positive donor heart → IgG-negative recipient (D+/R−)

— Prophylaxis with TMP-SMX recommended

Board pearl: After starting ART in a patient with TE, clinical worsening may represent IRIS rather than treatment failure — distinguish by timing (usually within first 4–8 weeks of ART).

Toxoplasmic encephalitis (TE) in AIDS:

Disseminated toxoplasmosis:

Congenital complications if untreated:

Reactivation in transplant recipients:

Key Differentials — Malaria

— Key distinction from malaria: Babesia shows tetrads (Maltese cross), no pigment (hemozoin); different geographic/exposure history

Board pearl: Babesiosis and malaria both cause intraerythrocytic ring forms — look for Maltese cross (Babesia) vs. banana-shaped gametocytes (P. falciparum) on smear.

Dengue fever: travel to tropics, fever, severe myalgia ("breakbone"), retro-orbital pain, thrombocytopenia, rash, ↑ HCT (hemoconcentration) — NO hemolytic anemia (key distinction)

Typhoid fever (Salmonella typhi): travel to South Asia, stepwise fever, relative bradycardia, rose spots, hepatosplenomegaly — diagnose with blood culture

Leptospirosis: fresh water exposure in tropics, conjunctival suffusion, jaundice + renal failure (Weil disease)

Viral hemorrhagic fevers (Ebola, Marburg): travel to sub-Saharan Africa, hemorrhagic manifestations, high mortality — requires BSL-4 precautions

Babesiosis: tick-borne (Ixodes), northeastern U.S., intraerythrocytic ring forms ("Maltese cross" on smear), asplenic patients at highest risk

Rickettsial infections: tick exposure, rash, headache, fever

Key Differentials — Toxoplasmic Encephalitis

— Also ring-enhancing lesion(s) in HIV/AIDS, typically CD4 < 50

— Usually single lesion (vs. multiple in TE), periventricular, crosses midline

— EBV PCR positive in CSF; Toxoplasma IgG often negative

— Key distinction: Empiric TE treatment × 2 weeks → no improvement → biopsy → PCNSL likely

— Thallium SPECT or PET: ↑ uptake in lymphoma, ↓ in toxoplasmosis

— JC virus, CD4 < 200, non-enhancing white matter lesions, no mass effect

— No fever; subacute progressive focal deficits

— History of sinusitis, endocarditis, or immunosuppression

— Often single lesion with prominent surrounding edema

Next best step: HIV patient with ring-enhancing brain lesions → check Toxoplasma IgG → if positive, start empiric TE treatment → reassess in 2 weeks.

Primary CNS lymphoma (PCNSL):

Progressive multifocal leukoencephalopathy (PML):

Brain abscess (bacterial, fungal):

Cryptococcoma: ring-enhancing, but meningitis features predominate; India ink, serum/CSF CrAg positive

Tuberculoma: endemic exposure, may have pulmonary TB; ring-enhancing with surrounding edema

Malaria Prevention and Prophylaxis

Chemoprophylaxis for travelers (by region and resistance):

— Atovaquone-proguanil (Malarone): daily, start 1–2 days before, continue 7 days after (shortest post-travel course)

— Doxycycline: daily, start 1–2 days before, continue 4 weeks after

— Mefloquine: weekly, start 2–3 weeks before, continue 4 weeks after

Non-pharmacologic:

Board pearl: Atovaquone-proguanil has the shortest post-travel course (7 days) — preferred for short trips. Doxycycline and mefloquine require 4 weeks post-travel.

Chloroquine-sensitive areas: chloroquine weekly (start 1–2 weeks before, continue 4 weeks after)

Chloroquine-resistant areas (most endemic regions):

Mefloquine — avoid in patients with psychiatric history or seizure disorder

Doxycycline — photosensitivity; contraindicated in pregnancy and children < 8

Primaquine: terminal prophylaxis for P. vivax/ovale exposure areas (given at end of trip to kill hypnozoites) — requires G6PD testing

Insecticide-treated bed nets, DEET-based repellents, long-sleeved clothing, avoiding outdoor exposure at dusk/dawn (peak Anopheles biting)

Toxoplasmosis Prevention, Prophylaxis, and Monitoring

Primary prophylaxis in HIV (CD4 < 100 + Toxoplasma IgG positive):

Secondary prophylaxis (after treated TE):

Prevention in pregnancy:

Transplant recipients:

Board pearl: TMP-SMX covers both PCP and Toxoplasma — one drug, two prophylaxis indications in HIV patients.

TMP-SMX (same dose used for PCP prophylaxis provides dual coverage)

Alternative: dapsone + pyrimethamine + leucovorin, or atovaquone ± pyrimethamine

Discontinue when CD4 > 200 × ≥3 months on ART

Pyrimethamine + sulfadiazine + leucovorin (at reduced maintenance doses)

Discontinue when CD4 > 200 × ≥6 months on ART AND completed initial therapy AND no symptoms/signs of TE

Avoid undercooked/raw meat, wash fruits/vegetables thoroughly

Avoid changing cat litter (or wear gloves + wash hands)

Screen seronegative pregnant women periodically in high-prevalence countries (not routine in U.S.)

If seroconversion detected → spiramycin to reduce transmission; amniocentesis PCR to assess fetal infection

D+/R− (heart transplant highest risk) → TMP-SMX prophylaxis for ≥6 months

Ethical, Legal, and Patient Safety Considerations

— Reportable disease in the United States — notify public health authorities

— Pre-travel counseling is a physician responsibility; document chemoprophylaxis discussion and adherence counseling

— Blood bank safety: travelers to endemic areas deferred from blood donation for specified periods to prevent transfusion-transmitted malaria

— Delayed/missed diagnosis is a common medicolegal issue — maintain high index of suspicion in febrile travelers

— Congenital toxoplasmosis: failure to screen or counsel pregnant women about food/cat hygiene in high-risk settings is a patient safety concern

— HIV patients: ensure Toxoplasma IgG is checked at diagnosis of HIV to guide future prophylaxis decisions

— Informed consent for brain biopsy in empiric TE treatment failure — discuss risks vs. diagnostic necessity

— Organ transplant: Toxoplasma serostatus of donor and recipient must be documented; failure to provide prophylaxis in D+/R− is a preventable error

Board pearl: All HIV patients should have Toxoplasma IgG checked at baseline — a negative result essentially rules out reactivation TE later.

Malaria:

Toxoplasmosis:

High-Yield Associations and Rapid-Fire Facts

Board pearl: Duffy antigen is the receptor for P. vivax — Duffy-negative individuals are naturally resistant.

P. falciparum: banana/crescent-shaped gametocytes, multiple ring forms per RBC, highest parasitemia, cerebral malaria, no hypnozoites

P. vivax/ovale: hypnozoites → relapse; Schüffner stippling on smear; require primaquine for radical cure

P. malariae: quartan fever (72 hr), band forms, associated with nephrotic syndrome (immune complex)

Sickle cell trait (HbAS): protective against severe P. falciparum malaria

Duffy-negative RBCs: protective against P. vivax (common in West Africans)

Toxoplasma: tachyzoites (active infection) vs. bradyzoites (latent tissue cysts)

Cat is the definitive host; humans are intermediate hosts

Toxoplasma IgG negative in AIDS patient → TE extremely unlikely → think PCNSL

Calcifications: Toxoplasma = diffuse; CMV = periventricular

Quinine/quinidine → cinchonism (tinnitus, hearing loss, visual disturbance)

G6PD test before primaquine/tafenoquine → ALWAYS

Exchange transfusion: consider for P. falciparum parasitemia > 10%

Board Question Stem Patterns

28M, returned from Nigeria 10 days ago, fever + rigors + jaundice + thrombocytopenia → Malaria → thick/thin blood smear STAT

Smear: crescent-shaped gametocytes, parasitemia 8%, AMS → Severe P. falciparum → IV artesunate + ICU

Traveler treated for P. vivax, fever recurs 3 months later → Hypnozoite relapse → primaquine × 14 days (after G6PD check)

Pregnant woman with P. vivax, treated with chloroquine → Do NOT give primaquine — defer radical cure until postpartum + G6PD testing

HIV patient, CD4 50, headache + focal deficits, MRI: multiple ring-enhancing basal ganglia lesions, Toxoplasma IgG+ → Empiric pyrimethamine + sulfadiazine + leucovorin

Same patient, no improvement after 2 weeks of empiric TE therapy → Brain biopsy → likely PCNSL

HIV patient, CD4 80, Toxoplasma IgG+, starting prophylaxis → TMP-SMX (covers PCP + Toxoplasma)

Pregnant woman, new cat, IgM+ IgG−, low avidity → Acute Toxoplasma infection → spiramycin; amniocentesis PCR

Neonate with hydrocephalus + diffuse intracranial calcifications + chorioretinitis → Congenital toxoplasmosis → pyrimethamine + sulfadiazine + leucovorin × 12 months

Febrile traveler, smear shows intraerythrocytic tetrads (Maltese cross) → Babesiosis, not malaria

One-Line Recap

Malaria is a mosquito-borne Plasmodium infection diagnosed by thick/thin blood smears, with P. falciparum causing the most severe disease (cerebral malaria, ARDS, severe hemolysis) treated with IV artesunate for severe cases and oral ACT for uncomplicated disease, requiring primaquine (after G6PD testing) for P. vivax/ovale hypnozoite eradication and chemoprophylaxis for travelers; toxoplasmosis is caused by Toxoplasma gondii, usually latent in immunocompetent hosts but causing life-threatening encephalitis in HIV/AIDS (CD4 < 100) presenting as multiple ring-enhancing basal ganglia lesions treated empirically with pyrimethamine + sulfadiazine + leucovorin (with brain biopsy if no response in 2 weeks), congenital infection producing the triad of chorioretinitis + hydrocephalus + diffuse intracranial calcifications, prevented by TMP-SMX prophylaxis in HIV when CD4 < 100 with positive IgG, and counseling pregnant women on food hygiene and cat exposure avoidance.

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