Pathophysiology: ID & Micro (Fungi & Parasites)

Malaria .................................................................................................................................................................................... 2
Helminth Parasitism ................................................................................................................................................................ 6
Other Protozoa...................................................................................................................................................................... 10

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 Malaria
Global Burden
 Was formerly prevalent in US; eradicated via infection controls & social improvement
 1st global push (‘50s) to eradicate based on DDT+chloroquine; success in some areas, partial in others
o No serious attempt in Africa
o Failed: unrealistic expectations, no integration with existing infrastructure
 Chloroquine-resistant P. falciparum & DDT-resistant Anapholes
 Global distribution today: Africa biggest, SE Asia drug resistant, also other parts of world
o Very different distribution in different countries within Africa – some much higher than others

Epidemiology
 Parasitic, mosquitos; 247M cases/yr, 891K deaths, 85% in sub-saharan Africa (YOUNG KIDS & PREGNANT)
o Resurgence: drug resistance, other factors, no vaccine
 Four species of malaria:
o Plasmodium falciparum: 90% infection; almost all death in Africa, MDR, vaccine efforts
o P. vivax: big contributor in SE Asia morbidity (& mortality)
o P. ovale (Africa only), P. malariae too

 Highly variable around world & within countries with different presentation
o Related to intensity of burden, duration of transmission
o Classic definitions: Spleen rate: hypoendemic < meso < hyper < holo
 Acquired immunity:
o Stable malaria: heavy, perennial transmission; endemic
 Generally protected from severe dz after age 5 (except for in pregnancy
o Unstable malaria: less intense transmission; epidemics / outbreaks
 Protective immunity: later age or not at all; all ages vulnerable

Immunity
 Humoral & Cellular; Initially: innate + spleen
 Maternal Ab last 3-6 mo (don’t see severe dz in children < 6mo)

Protection: slow, need prolonged, repeated exposure; protection from infection is not achieved
 Immunity lost if exposure stops: very common to see expat visit old country & get malaria
 Diminished immunity in pregnancy: increased risk of disease & complications, incl. still birth/miscarriage/low birth wt)
 Limited interaction with HIV: co-infection, not opportunist
o Viral load increases in acute phase; lost protection against malaria
o Biggest interactions in HIV+ pregnant women

Innate immunity:
 Malaria hypothesis: red cell polymorphisms distributed geographically because of selective pressure of malaria
o Hb structure, thalassemias (Hb synth), G6P deficiency (RBC enzyme), Duffy negative blood (PM of cell)
o HLA types? May protect against severe malaria
Duffy receptor and vivax malaria
 Chemoine receptor; spans PM, present in endothelial cells, only P. vivax binds for entry to RBC
 Duffy negative: primarily present in Africans (no vivax)

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 Life Cycle
A. Mosquito bite (female
anopheles mosquito at
night)  Sporozoites
injected; clinically Asx
B. Hepatic stage: multiple
stages, 6d-weeks of
“incubation”, results in
hepatic schizont filled with
merozoites (still Asx)

(P. vivax & P. ovale can

arrest here as hypnozoites in
liver & relapse months to
year after primary infection)

C. Schizont ruptures and

releases merozoites into
blood stream, which infect erythrocytes.
If patient has Sx post-Tx, what’s up?
D. Erythrocytic schizonts filled with merozoites rupture; more red cells
released: periodicity (via asexual reproduction) Recrudesence: P. falciparum & P.
E. Some merozoites differentiate into gametocytes malariae, reappearance of parasites in
F. Gametocytes taken up by female anapholes mosquito; sexual the blood (e.g. after being pushed down
reproduction takes place in her, infects other host below detectable threshold.
Relapse: P. vivax & P. ovale, revival of
Note: SEXUAL forms responsible for transmission
hypnozoites in the liver.
ASEXUAL for periodicity of symptoms
Re-infection: new infection for patient
Invasion of erythrocytes leads to knobs forming (“sticky” RBC)

Species-specific characteristics:

P. falciparum: P. vivax
 ~5.5d incubation in liver  8 day incubation
 48 hr erythrocytic cycle (fever periodicity)  48h periodicity
 Tons of merozoites per schizont  Fewer merozoites /schizont
 Infects ALL KINDS of RBC (HIGH parasitemia)  Invades mostly RETICULOCYTES (LOW parasitemia)
 Need HIGH burden for fever (even more if immune)  Need lower burden for fever
 Can form hypnozoites (dormancy!)
P. malariae: P. ovale:
 72h periodicity  Similar to P. vivax
 Can form hypnozoites (dormancy!)

Clinical presentation & Diagnosis

 Complex; many vital systems involved; Asx in hepatic & sporozoite stages
 Disease from red blood cell stage: stimulates host immune response
 Periodic fever (chillrigorshigh feversweatingrelease), non-specific
o Can also have cough, H/A, body ache, malaise, weakness, diarrhea
o Signs: fever, anemia, jaundice, enlarged spleen/liver

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LAB FINDINGS KEY: DIAGNOSIS: no
1. low platelets (first) later than 1 hour
2. low WBC, low RBC (second, third) after malaria first
suspected
Take blood when FEVER is present (higher burden of organisms)
TREATMENT: no
Suspect in US if: later than 1 hour
1. Any fever in exposed person (cough, diarrhea don’t rule out; think 7-25d incubation; after smear read
can relapse (vivax/ovale))
Tx based on:
2. Fever of unknown origin in “unexposed” (P. vivax/ovale ~3-5yr relapse; P. malariae
1. speciation
up to 50yr recrudescence!) 2. quantification
3. geography (drug
Clinical spectrum resistance?)
Mostly uncomplicated malaria if dz present in patients 4. assessment of
 See above symptoms severe malaria
 Tx: oral antimalarial drugs; confirm drug susceptibility by region
 Follow decline of parasitemia post-Tx initiation

Severe malaria = complicated malaria; set of overlapping problems. UP TO 50% MORTALTITY WITH TX
 Can lead to profound anemia, seizures, coma, death
 CAN BE VERY RAPID (esp. if non-immune, immunocompromised)
 Tx: IV drugs & intensive care

Types of severe malaria

A. Acidosis: final common pathway
a. Oxygen delivery impaired (lack of RBC)  metabolic acidosis
b. Sequestration of infected cells in brain/kidneys/lungs: can be organ specific
c. Proinflammatory cytokines, nitric oxide involved,
organ dysfunction leads to coma Severe malaria manifestation
B. Cerebral malaria: altered consciousness, seizures, rapid onset depends on endemicity
but rapid recovery if not fatal; immune-mediated Holoendemic Young patients; mostly
cerebral malaria
C. Severe anemia: hemolysis
Hyper/ Young patients; cerebral early
a. destroy uninfected RBC in spleen; malaria suppresses mesoendemic then severe anemia later
bone marrow (erythropoieses ineffective) Hypoendemic All ages; mostly severe anemia
b. Making less & destroying more
c. Associated with secondary bacterial infections;
d. Tx: transfusion if blood supply is safe

Pathological features
P. falciparum: cytoadherence important for sequestration (knobs with receptors for endothelial cells)
 Ring stage: circulates freely
 Schizont stage: generally sequestered in capillaries & venules (see more in other forms of malaria)

Sequestration & rosetting (P. falciparum / malariae)

 Sequestration: binding of infected RBC to capillary endothelium (keep away from spleen!)
 Rosetting: binding of uninfected RBC to infected RBC (responsible for pathophysiology): see “rosette” of healthy
RBC around infected RBC

Placental malaria: cytoadherance to placental endothelium; placental sequestration & exudates

 LOW BIRTHWEIGHT IS THE SINGLE MOST IMPORTANT PREDICTOR OF INFANT MORTALITY

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If you suspect malaria
 Ideal: Giemsa stain of thick and thin smears;
o Can quantify (determine risk of severe dz, drug susceptibility)
 Based on RBC (thin) or WBC (thick) count
o Thick: more sensitive, hard to read / speciate, use for quick dx
o Thin: helps with speciation to determine Tx
o quick dry some to read fast: delay can be fatal!
P. falciparum: P. vivax P. malariae
 Normal RBC size; preserved  Fewer merozoites in schizont,  Band-form schizonts
morphology RBCs dysfigured
 Fine delicate rings  Large, irregular rings
 Gametocytes: sickle shaped (but rare)  Round gametocytes
 Rare trophozoites & schizonts  Amoeboid trophozoites present

 Also: dipstick antigen (no quantification or speciation but no microscope needed), PCR

Chemotherapy
 Chemoprophylaxis for travelers
 No prophylaxis generally in endemic countries
o Specific indications are exception sometimes: pregnant women, infants, children
 If it fails: think drug resistance, PK failure, fake drug?

Control
 ITN: insecticide-treated nets
 Indoor house spraying, vector control (limited utility), personal barriers
 Integrate with local systems when present; give effective/prompt treatment
o Currently: Tx without definitive Dx in endemic regions (but drug resistance)?
 Monitor drug resistance!
 Vaccine problems: natural protective immunity is present but restricted; immune response contributes to
pathology; antigenic variation + efficient parasite; lack of good outcome measures

Clinical significance review

P. falciparum infection is MEDICAL EMERGENCY: can infect RBC of all ages, severe anemia, high multiplication rate
 sequesters (microvascular obstruction, tissue hypoxia, capillary leakage, end organ failure)
 Almost always cause of severe malaria
o Cerebral: seizures, obtundation, coma
o Severe anemia
o Hyperparasitemia; severe prostration, end organ failure, acidosis, diffuse bleeding, more

P. vivax: Anemia & ruptured spleens

P. malariae: can cause nephrotic syndrome in African kids

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 Helminth Parasitism
Cause more disability than death; neglected tropical diseases
100+ spp of helminthes (vs 40 protozoa)
Nematodes (roundworms ) Flatworms:
 hookworm, Ascaris, Strongyloides,  trematodes (flukes/Schistososma)
pinworm/whip-worm, filaria  cestodes (tapeworms)

General principles of helminth dz

 Don’t multiply within definitive host (reproduce sexually & produce transmission stage but not more adults)
o Exceptions: Strongyloidiasis / capillariasis
 Low worm burdens (minority has high & is important for severe dz/high transmission)
o High worm burden = high exposure, not that they’re reproducing inside you
 Disease correlates with worm burden
Endemic regions Expatriates
 Heavily parasitized  Big inflammatory response
 High worm burden  Severe disease
 Little disease (little inflammation)  Low worm burden
 No TX = long term infection
o can live for years [nematodes] to decades [river blindness] to host’s lifetime [strongyloides stercoralis]
 Most produce eosinophilia + elevated IgE response
o Mast cell proliferation, too; all T-cell dependent & down-regulated with continued exposure
o Can cause pathology

Helminth pathogenesis
Mechanical attachment/damage
 Block internal organs (Ascaris, tapeworms, flukes, filiaria, schistosomes)
 Pressure atrophy (echinococcus, cysticercus) Deficiency Organism
 Tissue migration (helminthic larvae) Iron Hookworm
Nutritional depletion: see table Vitamin B12 Tapeworm
Metaplastic changes Macronutrients Ascariasis, Strongyloides
 Hepatoma = liver flukes; bladder cancer = schistosomes
Immunopathology
 Anaphylactic response (IgE/histamine)
 Immune complexes (Ag+Ab deposition in brain,kidney, etc)
 Cell-mediated reaction (monos & Mϕ)

Just because this will almost certainly be on the exam:

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 Intestinal Roundworms

Organism Mug shot Pathology Transmission Life Cycle Clinical presentation Other
Low worm burden is Asx
Think: irritable kid and
Mechanical GI  Lung High worm burden: abd. pain & intestinal obstruction
Ascaris Ingest egg then these come out after
blockage  GI Migrating larvae/adults: Pulmonary eosinophilia syndrome (Loeffler’s
Tx!
syndrome); biliary/liver inflammation, intestinal obstruction

SKIN: Larva Skin 

Hookworms Blood loss Lose lots of blood; ANEMIA Make anticoagulant
penetrate Lung  GI

Whipworms GI (local Mostly Asx

Think: bloody stools &
(Trichuris damage/rectal Ingest egg All in gut Heavy infection in children: GI problems (abd. pain, bloody diarrhea,
rectal prolapse!
trichiura) prolapse) prolapse; growth retardation)

Hyperinfection into tissues in transplant patients

Strongyloi- Local GI SKIN: Larva Skin  Think: Vietnam vet getting
Initial infection  migration to brain, muscle, other organs with gut
diasis damage penetrate Lung  GI a transplant
flora sepsis (after immune suppression)

Pinworm
Perianal Scotch tape test to see
(Enterobious Ingest egg All in gut Itchy butt at night; adults migrate to anus to lay eggs (E.g. kids) st
pruritus eggs! (1 thing in morning)
vermicularis)

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 Tissue Roundworms: Filaria
Insect vectors
blood = microfilia; tissues = adult worms

Organism Mug shot Pathology Transmission Life Cycle Clinical presentation Other
Spectrum of disease:
Filiarasis Damage Microfiliare circulate at
Mosquito/ 1. Asymptomatic
(Wucheria & lymph vessels Mosquitos night when mosquitos
human 2. Night fevers (when microfiliare circulate)
Brugia spp) (elephantiasis) feed!
3. Chronic: elephantiasis

Migrate to,
Calabar swelling; can migrate to eye!
Loa loa across sclera Flies Fly /human
Doesn’t cause blindness!
of eye

Inflammatory reaction due

Chronic
Oncheo- RIVER BLINDNESS (whole towns sometimes in Africa) to bacterial co-infection
inflammation Flies Fly/human
cerciasis Subcutaneous nodules (LPS) brought in by
of eye
parasite

Flatworms

Organism Mug shot Pathology Transmission Life Cycle Clinical presentation Other
Liver/bladder fibrosis; cancer
Cercariae
Granuloma S. mansoni: GI disease (in portal veins): cirrhosis, etc. Ingest RBC to eat Hb
Schisto- penetrate skin Snail /
reaction to S. haematobium: (in bladder)  ureter obstruction, bladder cancer Eggs have characteristic
somiasis after release human
eggs Can go to CNS, inflame  paralysis! shapes / spines : see slide
from snail
Swimmer’s itch in Great Lakes: from bird schisto (penetrates only)
Nutritional
Pigs or
deprivation; Ingest larvae Taenia solium: pork/pigs
cows / Make & excrete adults
big worm in (via raw meat) Taenia saginata: beef/cows
humans
intestine
Cestodes Cysticercosis (T. solium ONLY) – can go to all kinds of tissues
(Tapeworms) Larval forms Neurocysticercosis is most serious Note EGG not larva
Pigs or
in tissues Ingest egg  3-5y incubation ingested
cows /
(cysticercus in (fecal/oral)  Psychiatric syndromes; epilepsy, cysts, rarely SC involved/eye Make larvae; can go all
humans
brain, etc.) Dx: CT+ELISA or Western around!
Tx: steroids/albendazole +/- surgery

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 Eosinophilia:
Worms, wheezes & weird diseases Eosinophilia & Helminths
 Asthma, IBD, cancer, rheum stuff, drugs, etc.
 Not caused by protozoa
 Higher in short-term visitors
Helminth eosinophilia: Usually higher in acute infection
 Often highest before eggs form
o Chronic, high eosinophilia – think helminth!
 Infections with eosinophilia often
o Differs among species (often absent or lower in adult forms)
Asx (sx months to years later)
 Ascariasis: often absent with adult worms
 Hookworm can be low too in adult worms  Absence doesn’t exclude helminth
 Malaria, other bacterial infections
can suppress eosinophilia
Life cycle vocabulary for eukaryotic parasites  Chronic: can cause endomycardial
fibrosis
Malaria: ring trophozoite / trophozoite / schizont containe merozoites
Toxoplasma: tachyzoite divides rapidly, infectious; bradyzoite slowly
Cryptosporidium: sporozoites shed infective eggs;
Leishmania: amastigote in reticuloendothelial cells is infective
Trypanosoma: trypomastigote is infective (fly human); amastigote is intracellular
Giardia: trophozoite is active & replicating
Entoamoeba: cyst; no replication for transmission
Trichomonas: trophozoite only

Helminths

Roundworm
 Adult in intestine, eggs shed in feces, larva (freeliving/parasitic) can go to various tissues, encyst, etc.
Filarial roundworm
 Adult in bloodstream, microfilariae cause disease in tissues; are infective for insect
Fluke flatworm
 Adult in portal/bladder veins, shed eggs in bloodstream
Cestode flatworm
 Adult in intestine, release proglottid with eggs, form cysterci / hydatid cysts in mm/brain

GUINEA WORM is almost eradicated (dracunculiasis) , a roundworm

 99% eradicated
 Roll up on stick!
 If you put your foot in water to cool, larvae burst out

DDx of fever in endemic area: Malaria, malaria, malaria – then other parasites/virus/bacteria, other causes of fever
MALARIA DOESN’T HAVE EOSINOPHILIA

N. meningitides & malaria are two infectious diseases that can kill you in 24h

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 Other Protozoa
Organism Mug shot Pathology Transmission Life Cycle Clinical presentation Other

1. Cutaneous ulcer: worldwide (esp. Middle East, Central Asia, N.

Africa; Argentina  TX); at sandfly bite site. 2wks-years of
incubation. Non- or slow-healing ulcer on exposed skin, heaped up
edges
Leishmania Lives in Mϕ Dogs / Cutaneous: think vet from
and other RES Sandfly bites; 2. Mucosal: (Central/South America); metastatic from skin; extensive
Sandfly / Iraq or tourist from /to
(Leishman- cells IV drug use non-healing ulcers on mucosa (nose, oral cavity, pharynx, larynx)
Humans South/Central America
iasis) (promastigote)
3. Visceral: (Asia, southern Europe, Brazil): disseminates within RES
cells; 3-8mo incubation; EXTENSIVE NONTENDER
HEPATOSPLENOMEGALY, fever, weakness, weight loss, GRAY
DISCOLORATION of EXTREMITIES (kala-azar; “black fever”)

Think: Primary in healthy

1. Immune-competent: primary infection usually subclinical; can
Forms cysts patient = mono
produce mononucleosis-like syndrome with painless lyphadenitis
(latent;
(esp. cervical)
bradyzoites) if HIV patient reactivates &
Toxoplasma Undercooked
immune Cat/rat, gets brain lesions / neuro
beef/pork; 2. Immunocompromised: reactivation of dormant infection
reaction; Cat-feces- problems
(Toxoplasm- eggs in cat (encephalitis, brain lesions, chorioretinitis, myocarditis,
otherswise human
osis) feces pneumonitis)
proliferates in Pregnant woman changes
lots of tissues litterbox for the first time
3. Pregnant: Primary infection  transinfection of fetus  CNS
as tachyzoites (primary) & fetus gets birth
sequelae, chorioretinitis, severe disease.
defects
Leading curable STI in US
Trichomonas
(7.3M new cases/yr)
vaginalis Pear-shaped Human / Women: 50% Asx  PID & severe complications
Sexual
Motile Sex /
intercourse Theoretically survives up to
(Trichomon- Flagella Human Men: 75% Asx  severe infection, epidiymitis / prostatitis
45m on clothes,
iasis)
washcloths, bath water

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 Diarrheal Protozoa
Organism Mug shot Pathology Transmission Life Cycle Clinical presentation Other
Cyst active
trophozoite in
Developing countries mostly (also immigrants, travelers, MSM in US) Cyst outside host;
Entamoeba GI tract; Human:
Ingest cyst trophozite (active) inside –
histolytica ingestGI
(water, soil, 1. Diarrhea (severe & bloody – dysentery) see pictures
can invade liver /
food) 2. Liver abscesses
(Amebiasis) (flask abcess) brain
3. Brain abscesses Dx: stool o+p (about 50%)
& spread to
liver, brain
Worldwide: epidemic diarrhea (contaminated water)
AIDS pts: severe diarrhea if low CD4 ct
Oocyst Contaminated
Cryptospor- Sporadic: day care, child care, travelers, backpacker/hiker/swimmer Need special stains (Stool
outside / water (shallow GI only
idium O+P with AFB)
troph inside wells, other)
Large volume secretory diarrhea with nausea/cramps/vomiting/wt loss
Self limited (2-3wks; >2mo in AIDS)
#1 fecal parasite for diarrhea in USA
Think: hiker who drank the
Contaminated Day care, travel to endemic areas, ingestion of unfiltered water while water; smelly stool
Giardia Cyst outside water camping; fecal-oral sex contact (esp. MSM), well water on farms
GI only
lamblia Troph inside (mountain Both trophs & cysts shed in
streams) Acute diarrhea, abdominal cramping, bloating, flatulence, stool; only cyst survives
Stools become NASTY SMELLING & GREASY over time (malabsorptive) Dx: Stool O&P; antigen
No blood/pus/mucous

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