Pathophysiology: ID & Micro (Fungi & Parasites

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


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

  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

  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)


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. D. Erythrocytic schizonts filled with merozoites rupture; more red cells released: periodicity (via asexual reproduction) E. Some merozoites differentiate into gametocytes F. Gametocytes taken up by female anapholes mosquito; sexual reproduction takes place in her, infects other host Note: SEXUAL forms responsible for transmission ASEXUAL for periodicity of symptoms Invasion of erythrocytes leads to knobs forming (“sticky” RBC) Species-specific characteristics: P. falciparum:  ~5.5d incubation in liver  48 hr erythrocytic cycle (fever periodicity)  Tons of merozoites per schizont  Infects ALL KINDS of RBC (HIGH parasitemia)  Need HIGH burden for fever (even more if immune) P. malariae:  72h periodicity P. vivax  8 day incubation  48h periodicity  Fewer merozoites /schizont  Invades mostly RETICULOCYTES (LOW parasitemia)  Need lower burden for fever  Can form hypnozoites (dormancy!) P. ovale:  Similar to P. vivax  Can form hypnozoites (dormancy!)

If patient has Sx post-Tx, what’s up? Recrudesence: P. falciparum & P. malariae, reappearance of parasites in the blood (e.g. after being pushed down below detectable threshold. Relapse: P. vivax & P. ovale, revival of hypnozoites in the liver. Re-infection: new infection for patient

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


LAB FINDINGS KEY: 1. low platelets (first) 2. low WBC, low RBC (second, third) Take blood when FEVER is present (higher burden of organisms) Suspect in US if: 1. Any fever in exposed person (cough, diarrhea don’t rule out; think 7-25d incubation; can relapse (vivax/ovale)) 2. Fever of unknown origin in “unexposed” (P. vivax/ovale ~3-5yr relapse; P. malariae up to 50yr recrudescence!)

DIAGNOSIS: no later than 1 hour after malaria first suspected TREATMENT: no later than 1 hour after smear read
Tx based on: 1. speciation 2. quantification 3. geography (drug resistance?) 4. assessment of severe malaria

Clinical spectrum
Mostly uncomplicated malaria if dz present in patients  See above symptoms  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, Severe malaria manifestation organ dysfunction leads to coma depends on endemicity B. Cerebral malaria: altered consciousness, seizures, rapid onset Holoendemic Young patients; mostly but rapid recovery if not fatal; immune-mediated 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 4

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:  Normal RBC size; preserved morphology  Fine delicate rings  Gametocytes: sickle shaped (but rare)  Rare trophozoites & schizonts P. vivax  Fewer merozoites in schizont, RBCs dysfigured  Large, irregular rings  Round gametocytes  Amoeboid trophozoites present P. malariae  Band-form schizonts

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

   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?

     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


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 o Exceptions: Strongyloidiasis / capillariasis High worm burden = high exposure, not that they’re reproducing inside you Endemic regions  Heavily parasitized  High worm burden  Little disease (little inflammation) Expatriates  Big inflammatory response  Severe disease  Low worm burden

Low worm burdens (minority has high & is important for severe dz/high transmission) Disease correlates with worm burden

No TX = long term infection
o o o can live for years [nematodes] to decades [river blindness] to host’s lifetime [strongyloides stercoralis] Mast cell proliferation, too; all T-cell dependent & down-regulated with continued exposure Can cause pathology

Most produce eosinophilia + elevated IgE response

Helminth pathogenesis
Mechanical attachment/damage  Block internal organs (Ascaris, tapeworms, flukes, filiaria, schistosomes)  Pressure atrophy (echinococcus, cysticercus)  Tissue migration (helminthic larvae) Nutritional depletion: see table Metaplastic changes  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:

Deficiency Iron Vitamin B12 Macronutrients

Organism Hookworm Tapeworm Ascariasis, Strongyloides


Intestinal Roundworms

Mug shot

Mechanical blockage

Ingest egg

Life Cycle
GI  Lung  GI

Clinical presentation
Low worm burden is Asx High worm burden: abd. pain & intestinal obstruction Migrating larvae/adults: Pulmonary eosinophilia syndrome (Loeffler’s syndrome); biliary/liver inflammation, intestinal obstruction

Think: irritable kid and then these come out after Tx!


Blood loss

SKIN: Larva penetrate

Skin  Lung  GI

Lose lots of blood; ANEMIA

Make anticoagulant

Whipworms (Trichuris trichiura) Strongyloidiasis Pinworm (Enterobious vermicularis)

GI (local damage/rectal prolapse) Local GI damage

Ingest egg

All in gut

Mostly Asx Heavy infection in children: GI problems (abd. pain, bloody diarrhea, prolapse; growth retardation) Hyperinfection into tissues in transplant patients Initial infection  migration to brain, muscle, other organs with gut flora sepsis (after immune suppression)

Think: bloody stools & rectal prolapse!

SKIN: Larva penetrate

Skin  Lung  GI

Think: Vietnam vet getting a transplant

Perianal pruritus

Ingest egg

All in gut

Itchy butt at night; adults migrate to anus to lay eggs (E.g. kids)

Scotch tape test to see st eggs! (1 thing in morning)


Tissue Roundworms: Filaria
Insect vectors blood = microfilia; tissues = adult worms Organism
Filiarasis (Wucheria & Brugia spp)

Mug shot

Damage lymph vessels (elephantiasis) Migrate to, across sclera of eye Chronic inflammation of eye


Life Cycle
Mosquito/ human

Clinical presentation
Spectrum of disease: 1. Asymptomatic 2. Night fevers (when microfiliare circulate) 3. Chronic: elephantiasis Calabar swelling; can migrate to eye! Doesn’t cause blindness!

Microfiliare circulate at night when mosquitos feed!

Loa loa


Fly /human




RIVER BLINDNESS (whole towns sometimes in Africa) Subcutaneous nodules

Inflammatory reaction due to bacterial co-infection (LPS) brought in by parasite


Mug shot

Granuloma reaction to eggs Nutritional deprivation; big worm in intestine

Cercariae penetrate skin after release from snail Ingest larvae (via raw meat)

Life Cycle
Snail / human

Clinical presentation
Liver/bladder fibrosis; cancer S. mansoni: GI disease (in portal veins): cirrhosis, etc. S. haematobium: (in bladder)  ureter obstruction, bladder cancer Can go to CNS, inflame  paralysis! Swimmer’s itch in Great Lakes: from bird schisto (penetrates only) Taenia solium: pork/pigs Taenia saginata: beef/cows Cysticercosis (T. solium ONLY) – can go to all kinds of tissues Neurocysticercosis is most serious  3-5y incubation  Psychiatric syndromes; epilepsy, cysts, rarely SC involved/eye Dx: CT+ELISA or Western Tx: steroids/albendazole +/- surgery

Ingest RBC to eat Hb Eggs have characteristic shapes / spines : see slide

Pigs or cows / humans

Make & excrete adults

Cestodes (Tapeworms)

Larval forms in tissues (cysticercus in brain, etc.)

Ingest egg (fecal/oral)

Pigs or cows / humans

Note EGG not larva ingested Make larvae; can go all around!


Worms, wheezes & weird diseases  Asthma, IBD, cancer, rheum stuff, drugs, etc. Helminth eosinophilia: Usually higher in acute infection o Chronic, high eosinophilia – think helminth! o Differs among species (often absent or lower in adult forms)  Ascariasis: often absent with adult worms  Hookworm can be low too in adult worms Eosinophilia & Helminths  Not caused by protozoa  Higher in short-term visitors  Often highest before eggs form  Infections with eosinophilia often Asx (sx months to years later)  Absence doesn’t exclude helminth  Malaria, other bacterial infections can suppress eosinophilia  Chronic: can cause endomycardial fibrosis

Life cycle vocabulary for eukaryotic parasites
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


Other Protozoa
Organism Mug shot Pathology Transmission Life Cycle Clinical presentation
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 (Leishmaniasis) Lives in Mϕ and other RES cells


Sandfly bites; IV drug use

Dogs / Sandfly / Humans

2. Mucosal: (Central/South America); metastatic from skin; extensive non-healing ulcers on mucosa (nose, oral cavity, pharynx, larynx) 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”) 1. Immune-competent: primary infection usually subclinical; can produce mononucleosis-like syndrome with painless lyphadenitis (esp. cervical)

Cutaneous: think vet from Iraq or tourist from /to South/Central America

Toxoplasma (Toxoplasmosis)

Forms cysts (latent; bradyzoites) if immune reaction; otherswise proliferates in lots of tissues as tachyzoites

Think: Primary in healthy patient = mono HIV patient reactivates & gets brain lesions / neuro problems Pregnant woman changes litterbox for the first time (primary) & fetus gets birth defects Leading curable STI in US (7.3M new cases/yr) Theoretically survives up to 45m on clothes, washcloths, bath water

Undercooked beef/pork; eggs in cat feces

Cat/rat, Cat-feceshuman

2. Immunocompromised: reactivation of dormant infection (encephalitis, brain lesions, chorioretinitis, myocarditis, pneumonitis) 3. Pregnant: Primary infection  transinfection of fetus  CNS sequelae, chorioretinitis, severe disease.

Trichomonas vaginalis (Trichomoniasis)

Pear-shaped Motile Flagella

Sexual intercourse

Human / Sex / Human

Women: 50% Asx  PID & severe complications Men: 75% Asx  severe infection, epidiymitis / prostatitis


Diarrheal Protozoa
Organism Mug shot Pathology
Cyst active trophozoite in GI tract; can invade (flask abcess) & spread to liver, brain Oocyst outside / troph inside


Life Cycle

Clinical presentation
Developing countries mostly (also immigrants, travelers, MSM in US) 1. 2. 3. Diarrhea (severe & bloody – dysentery) Liver abscesses Brain abscesses

Cyst outside host; trophozite (active) inside – see pictures Dx: stool o+p (about 50%)

Entamoeba histolytica (Amebiasis)

Ingest cyst (water, soil, food)

Human: ingestGI liver / brain


Contaminated water (shallow wells, other)

GI only

Worldwide: epidemic diarrhea (contaminated water) AIDS pts: severe diarrhea if low CD4 ct Sporadic: day care, child care, travelers, backpacker/hiker/swimmer Large volume secretory diarrhea with nausea/cramps/vomiting/wt loss Self limited (2-3wks; >2mo in AIDS) #1 fecal parasite for diarrhea in USA Day care, travel to endemic areas, ingestion of unfiltered water while camping; fecal-oral sex contact (esp. MSM), well water on farms Acute diarrhea, abdominal cramping, bloating, flatulence, Stools become NASTY SMELLING & GREASY over time (malabsorptive) No blood/pus/mucous

Need special stains (Stool O+P with AFB)

Giardia lamblia

Cyst outside Troph inside

Contaminated water (mountain streams)

Think: hiker who drank the water; smelly stool Both trophs & cysts shed in stool; only cyst survives Dx: Stool O&P; antigen

GI only


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