Professional Documents
Culture Documents
1. What is Schistosomiasis?
• Schistosomiasis (called bilharziasis in non-English speaking world) is a disease syndrome caused by infection
from one of several species of parasitic trematodes of the genus Schistosoma.
• Disease develops from the host’s immune response to the shistosome eggs >>> granuloma formation >>> fibrosis
(amount of fibrosis correlates to intensity of infection).
• Most granulomas develop at sites of maximal egg accumulation in the intestine and liver (if S. mansoni or S.
japonicum), or in the GU tract (if S. haematobium).
• Granulomas destroy the ova, but result in fibrotic deposition in host tissues. Eggs trapped in tissues release
enzymes and other antigenic substances that sensitize local host lymphocytes >>> secretion of lymphokines >>>
recruits macrophages, lymphocytes, eosinophils and fibroblasts >>> forms compact cellular infiltrate.
• Early acute granulomas are usually composed of eosinophils and neutrophils as well as mononuclear cells.
• Chronic granulomas are primarily macrophages, lymphocytes, fibroblasts, and multinucleated giant cells.
Collagen deposition and fibrosis cause irreversible pathology.
• Schistosomiasis is a major source of M&M for developing countries in Africa, South America, the Caribbean, the
Middle East, and Asia.
• Three types of clinical disease:
1. Swimmer’s Itch: Kabure,
Clamdigger’s itch
2. Katayama Syndrome: acute
schitosomiasis
3. Chronic Schistosomiasis:
a. Intestinal tract
b. Urogential tract
Eggs are eliminated with feces or urine . Under optimal conditions the eggs hatch and release miracidia , which swim
and penetrate specific snail intermediate hosts . The stages in the snail include 2 generations of sporocysts and the
production of cercariae . Upon release from the snail, the infective cercariae swim, penetrate the skin of the human host
, and shed their forked tail, becoming schistosomulae . The schistosomulae migrate through several tissues and stages
to their residence in the veins ( , ). Adult worms in humans reside in the mesenteric venules in various locations,
which at times seem to be specific for each species . For instance, S. japonicum is more frequently found in the superior
mesenteric veins draining the small intestine , and S. mansoni occurs more often in the superior mesenteric veins
draining the large intestine . However, both species can occupy either location, and they are capable of moving between
sites, so it is not possible to state unequivocally that one species only occurs in one location. S. haematobium most often
occurs in the venous plexus of bladder , but it can also be found in the rectal venules. The females (size 7 to 20 mm;
males slightly smaller) deposit eggs in the small venules of the portal and perivesical systems. The eggs are moved
progressively toward the lumen of the intestine (S. mansoni and S. japonicum) and of the bladder and ureters (S.
haematobium), and are eliminated with feces or urine, respectively . Pathology of S. mansoni and S. japonicum
schistosomiasis includes: Katayama fever, hepatic perisinusoidal egg granulomas, Symmers’ pipe stem periportal fibrosis,
portal hypertension, and occasional embolic egg granulomas in brain or spinal cord. Pathology of S. haematobium
schistosomiasis includes: hematuria, scarring, calcification, squamous cell carcinoma, and occasional embolic egg
granulomas in brain or spinal cord.
Human contact with water is thus necessary for infection by schistosomes. Various animals, such as dogs, cats, rodents,
pigs, hourse and goats, serve as reservoirs for S. japonicum, and dogs for S. mekongi.
Left image: forked-tailed cercaria of Schistosoma mansoni (body 185-230 x 75-110; tail trunk 185-300 x 60-75;fork 90-
130mM). This is the infective larva that emerges from the snail intermediate host. Right image: Miracidium; emerges
from the egg in freshwater. They are ovoid and about 160mM long, possessing cilia on four rows of epidermal plates. They
have four flame cells functioning as the excretory system and their activity serves to indicate the viability of the ovum.
Schistosoma mansoni in intestinal tissue, acid fast staining of the egg shell is highly characteristic.
11. What are the differences between immunity to different strains of Schistosomiasis?
• There is a difference in development of immunity between SM and SJ
• Early: blocking antibodies (IgG2, IgG4, IgM) that block binding of protective IgE and IgG2a, thereby stopping
killing of infectious agents
• Later: IgE and IgG4 compete for binding sites and attack invading larvae >>> humoral immunity of host then has
upper hand
• Eosinophils and macs bind via Fc receptors to specific IgE, IgA and IgG2a on Schistosomium >>> eosinophils
degranulate
1. Major Basic Protein (MBP)
2. Eosinophilic Cationic Protein (ECP)
3. Eosinophil Peroxidase (EPO)
4. Reactive Oxygen Intermediates (ROI)
• C3 also acts with antibodies to enhance response
12. Discuss the involvement of cell mediated immunity in response to Schistosoma infection.
• Early: large volume granulomas form with Eosinophils, PMNs, and monocytes
• Later: modulation occurs with macs, lymphocytes, Giant cells and fibroblasts
• Increase in antibodies acts to trap eggs and egg antigens
• Granulomas is TH2 dominated
• Increased eosinophils levels driven by IL-4, IL-5, IL-13 secretion
Chlornorchis in bile ducts. Note periductal fibrosis, hyperplasia of biliary epithelium, and bile capillary
proliferation.
Life Cycle:
Embryonated eggs are discharged in the biliary ducts and in the stool . Eggs are ingested by a suitable snail intermediate
host ; there are more than 100 species of snails that can serve as intermediate hosts. Each egg releases a miracidia ,
which go through several developmental stages (sporocysts , rediae , and cercariae ). The cercariae are released
from the snail and after a short period of free-swimming time in water, they come in contact and penetrate the flesh of
freshwater fish, where they encyst as metacercariae . Infection of humans occurs by ingestion of undercooked, salted,
pickled, or smoked freshwater fish . After ingestion, the metacercariae excyst in the duodenum and ascend the biliary
tract through the ampulla of Vater . Maturation takes approximately 1 month. The adult flukes (measuring 10 to 25 mm
by 3 to 5 mm) reside in small and medium sized biliary ducts. In addition to humans, carnivorous animals can serve as
reservoir hosts. (www.cdc.gov)
Clonorchis sinensis ova in uterus of worm.
Image: Clonorchis sinensis egg (20-30 x 15-17µm), note the operculum or lid.
This structure opens to permit the miracidium to escape.
• Ectopic sites: brain & spinal cord, intestinal wall, lymph nodes,
and subQ
• Cerebral & Spinal Paragonimiasis: some mature flukes migrate
from the lungs through the juguluar or carotid foramen to the
temporal or occipital lobes of the brain >>> necrosis and
eosinophilic granulomatous reactions. Most common in children and males. Patients can die if left untreated,
if not, remission occurs in 1-2 months, but can recur. Patients present with:
1. headache
2. vomiting
3. fever
4. visual disturbances
5. rarely, transverse myelitis
6. spinal tap shows eosinophilic pleocytosis
7. CT shows cysts
Left image: stained Fasciola hepatica. Right image: unstained specimen of F. hepatica, a moderately fleshy fluke
up to 30mm in length by 13mm wide.
Life Cycle:
Immature eggs are discharged in the biliary ducts and in the stool . Eggs become embryonated in water , eggs release
miracidia , which invade a suitable snail intermediate host , including many species of the genus Lymnae. In the snail
the parasites undergo several developmental stages (sporocysts , rediae , and cercariae ). The cercariae are released
from the snail and encyst as metacercariae on aquatic vegetation or other surfaces. Mammals acquire the infection by
eating vegetation containing metacercariae. Humans can become infected by ingesting metacercariae-containing freshwater
plants, especially watercress . After ingestion, the metacercariae excyst in the duodenum and migrate through the
intestinal wall, the peritoneal cavity, and the liver parenchyma into the biliary ducts, where they develop into adults . In
humans, maturation from metacercariae into adult flukes takes
approximately 3 to 4 months. The adult flukes (Fasciola
hepatica: up to 30 mm by 13 mm; F. gigantica: up to 75 mm)
reside in the large biliary ducts of the mammalian host.
Fasciola hepatica infect various animal species, mostly
herbivores. (www.cdc.gov)
Life Cycle:
Immature eggs are passed in feces . Under appropriate conditions, the eggs mature (approximately 18 to 20 days) and
yield oncospheres which develop into a coracidia . After ingestion by a suitable freshwater crustacean (the copepod first
intermediate host) the coracidia develop into procercoid larvae . Following ingestion of the copepod by a suitable
second intermediate host, typically minnows and other small freshwater fish, the procercoid larvae are released from the
crustacean and migrate into the fish flesh where they develop into a plerocercoid larvae (sparganum) . The plerocercoid
larvae are the infective stage for humans. Because humans do not generally eat undercooked minnows and similar small
freshwater fish, these do not represent an important source of infection. Nevertheless, these small second intermediate
hosts can be eaten by larger predator species, e.g., trout, perch, walleyed pike . In this case, the sparganum can migrate
to the musculature of the larger predator fish and humans can acquire the disease by eating these later intermediate infected
host fish raw or undercooked . After ingestion of the infected fish, the plerocercoid develop into immature adults and
then into mature adult tapeworms which will reside in the small intestine. The adults of D. latum attach to the intestinal
mucosa by means of the two bilateral groves (bothria) of their scolex . The adults can reach more than 10 m in length,
with more than 3,000 proglottids. Immature eggs are discharged from the proglottids (up to 1,000,000 eggs per day per
worm) and are passed in the feces . Eggs appear in the feces 5 to 6 weeks after infection. In addition to humans,
many other mammals can also serve as definitive hosts for D. latum.
7. Discuss the pernicious anemia-like syndrome that can be associated with D. latum infection?
• D. latum has a high affinity for Vitamin B12 >>> producing a hyperchromatic macrocytic megaloblastic
anemia without thrombocytopenia, that resembles pernicious anemia both clinically and hematologically.
• The anemia is usually moderate, but can be severe, and is characterized by pallor, glossitis, dyspnea,
paresthesia, disturbance of movement and coordination, and impairment of deep senses, subacute combined
degeneration >>> decreased hemoglobin and decreased oxygen in blood.
• Vitamin B12 absorption based on Intrinsic Factor
• binds to ileal receptor (Ca2+)
• pancreatic factor also increases absorption
• 40% of infected have low B12, 2% develop anemia, worm uptake of B12 is 1000:1
Top image: T. solium with armed scolex. Bottom image: T. saginita with unarmed scolex
14. What are the life cycles of Taenia solia and Taenia saginatum?
• Cattle or pigs become infected by ingesting eggs while grazing in low-lying pastures or barnyards that are
contaminated with human feces >>> eggs hatching inside the animal >>> embryos then penetrate the
intestinal mucosa >>> enter animal’s circulation and are transported throughout the body >>> embryos encyst
in animal’s striated muscle >>> develop into larvae called cysticercus cellulosae (in pigs) or cystericus bovis
(in cattle), which are infectious if ingested by definitive host.
• Upon consumption of infected meet that is improperly cooked, the cystericus is activated by gastric juices and
the scolex evaginates and attaches to a person’s jejunal wall >>> becomes a mature tapeworm.
Life Cycle:
19. What is the significance of, and causative agents of, Cysticercosis?
• Cysticercosis is an infection of human tissues with the larvae of the pork tapeworm, Taenia solium.
• The symptoms of cysticercosis are caused by the development of cysticerci in various sites. Of greatest
concern is cerebral cysticercosis (or neurocysticercosis), which can cause diverse manifestations including
seizures, mental disturbances, focal neurologic deficits, and signs of space-occupying intracerebral lesions.
Death can occur suddenly. Extracerebral cysticercosis can cause ocular, cardiac, or spinal lesions with
associated symptoms. Asymptomatic subcutaneous nodules and calcified intramuscular nodules can be
encountered.
• Humans can be both intermediate host and main host for T. solia, not for T. saginata.
Echinococcus granulosus, the entire adult tapeworm consists of a scolex and 3 segments: an immature, mature and
gravid proglottid.
Left image: Protoscolices are formed by the germinal membrane of the hydatid cyst and together with internal daughter
cysts, brood capsules are the hydatid sand all of which are suspended in the hydatid fluid. Right image: Echinococcus
granulosus, protoscolex note double row of hooks.
9. How do you diagnose Echinococcus infection?
• Geographic history important
• History of canine (and also possibly sheep)
• Serological tests (immunoblot)
• MRI, CT, X-ray, US
The adult Echinococcus granulosus (3 to 6 mm long) resides in the small bowel of the definitive hosts, dogs or other
canids. Gravid proglottids release eggs that are passed in the feces. After ingestion by a suitable intermediate host
(under natural conditions: sheep, goat, swine, cattle, horses, camel), the egg hatches in the small bowel and releases an
oncosphere that penetrates the intestinal wall and migrates through the circulatory system into various organs, especially
the liver and lungs. In these organs, the oncosphere develops into a cyst that enlarges gradually, producing protoscolices
and daughter cysts that fill the cyst interior. The definitive host becomes infected by ingesting the cyst-containing organs
of the infected intermediate host. After ingestion, the protoscolices evaginate, attach to the intestinal mucosa , and
develop into adult stages in 32 to 80 days. The same life cycle occurs with E. multilocularis (1.2 to 3.7 mm), with the
following differences: the definitive hosts are foxes, and to a lesser extent dogs, cats, coyotes and wolves; the intermediate
host are small rodents; and larval growth (in the liver) remains indefinitely in the proliferative stage, resulting in invasion of
the surrounding tissues. With E. vogeli (up to 5.6 mm long), the definitive hosts are bush dogs and dogs; the intermediate
hosts are rodents; and the larval stage (in the liver, lungs and other organs) develops both externally and internally,
resulting in multiple vesicles. E. oligarthrus (up to 2.9 mm long) has a life cycle that involves wild felids as definitive
hosts and rodents as intermediate hosts. Humans become infected by ingesting eggs , with resulting release of
oncospheres in the intestine and the development of cysts , , , , , in various organs.
Eggs of Hymenolepis diminuta are passed out in the feces of the infected definitive host (rodents, man) . The mature
eggs are ingested by an intermediate host (various arthropod adults or larvae) , and oncospheres are released from the
eggs and penetrate the intestinal wall of the host , which develop into cysticercoid larvae. Species from the genus
Tribolium are common intermediate hosts for H. diminuta. The cysticercoid larvae persist through the arthropod's
morphogenesis to adulthood. H. diminuta infection is acquired by the mammalian host after ingestion of an intermediate
host carrying the cysticercoid larvae . Humans can be accidentally infected through the ingestion of insects in precooked
cereals, or other food items, and directly from the environment (e.g., oral exploration of the environment by children).
After ingestion, the tissue of the infected arthropod is digested releasing the cysticercoid larvae in the stomach and small
intestine. Eversion of the scoleces occurs shortly after the cysticercoid larvae are released. Using the four suckers on the
scolex, the parasite attaches to the small intestine wall. Maturation of the parasites occurs within 20 days and the adult
worms can reach an average of 30 cm in length . Eggs are released in the small intestine from gravid proglottids that
disintegrate after breaking off from the adult worms. The eggs are expelled to the environment in the mammalian host's
feces. (www.cdc.gov)
23. What is the clinical presentation of infection with H. nana?
• If patient only has a few tapeworms probably will be asymptomatic, but if they have a lot of worms, will have the
following symptoms:
• Headaches
• Dizziness
• Anorexia
• Pruritis ani
• Periodic diarrhea
• Abdominal pain (85%)
• Restlessness and irritability (65%)
• Eosinophilia (<5%)
• Seizures (<1%)
Hookworm egg
6. What are the clinical manifestations of infection with N. americanus or A. duodenale?
• Infections last 5-10 years, but no auto-infectious cycle (infection continuous even outside of endemic area)
Adult worms live in the lumen of the small intestine. A female may produce approximately 200,000 eggs per day, which
are passed with the feces . Unfertilized eggs may be ingested but are not infective. Fertile eggs embryonate and become
infective after 18 days to several weeks , depending on the environmental conditions (optimum: moist, warm, shaded
soil). After infective eggs are swallowed , the larvae hatch , invade the intestinal mucosa, and are carried via the
portal, then systemic circulation to the lungs . The larvae mature further in the lungs (10 to 14 days), penetrate the
alveolar walls, ascend the bronchial tree to the throat, and are swallowed . Upon reaching the small intestine, they
develop into adult worms . Between 2 and 3 months are required from ingestion of the infective eggs to oviposition by
the adult female. Adult worms can live 1 to 2 years. (www.cdc.gov)
Toxocara canis accomplishes its life cycle in dogs, with humans acquiring the infection as accidental hosts. Infective eggs
are excreted by dogs. Humans are paratenic hosts who become infected by ingesting infective eggs in contaminated soil.
After ingestion, the eggs yield larvae that penetrate the intestinal wall and are carried by the circulation to a wide variety of
tissues (liver, heart, lungs, brain, muscle, eyes). While the larvae do not undergo any further development in these sites,
they can cause severe local reactions that are the basis of toxocariasis.
17. Compare and contrast the clinical presentations of VLM with those of OLM.
A. VLM
• VLM is usually found in toddlers (ages 2-4) who eat soil
• Marked inflammatory immune response to numerous migrating larvae in liver and other tissues.
• Get febrile systemic illnesses manifested by fever and chills, fleeting infiltrates in chest, may have seizures,
myocarditis, or hepatitis
• Very high levels of eosinophils (30-50%), leukocytosis, fever, hepatomegaly, hypergammaglobulinemia,
Isohemagglutinins are elevated, ery high IgE
• + ELISA test, serology is only way to make definitive diagnosis, because human is not host, won’t see eggs in
stool.
• High dose may end up as VLM, low dose of eggs ingested more likely to have OLM.
B. OLM
• School-age children and adults
• Sitting in school has to strain eyes to see
• Ocular lesions, strabismus, retinal scar on opthalmoscopic exam
• Diagnosis: + ELISA test
• Won’t have eosinophilia, isohemagglutinins or systemic
manifestations
Intestinal Nematodes
• Oral-fecal: Enterobius vermicularis (pinworm), Trichuris trichuria (whipworm), no migration in the lung
• Oral-fecal with migration to lungs: Ascaris lumbricoides
• Soil-migration to lungs: N. americanis and A. duodenales (hookworm), and Strongyloides sterocoralis, patients
can get them from walking barefoot
• All are treated with Albendazole
Infection with Enterobius vermicularis (Pinworm)
• Common worldwide: including temperate and colder climates, particularly noted in cooler climates b/c worms are
more unusual in N. America, found in all socio-economic groups.
• Transmission: hand to mouth transmission; egg is excreted in fairly mature form and can be passed from person-
to-person, rather than requiring incubation in warm, moist soil. Humans are only host.
• Distribution: most common helminthic infection in US and W. Europe. Greatest prevalence amongst school-aged
children, high population density, indoor conditions.
• Pinworm season is typically in middle of winter, b/c kids are cuddling together or sleeping together more often
Pinworm Morphology
• Female 8-13 mm in length (can be seen with naked
eye) much larger than male, female has pin tail, male
does not
• So as physician look for eggs on perineal skin, rather
than checking stool sample
• Pinworms have ala or ventral wings
• Round = nematode
• Eggs are flattened on one side and convex on other
side, have thick albuminous layer that can get
attached to dust, they mature and are infective within
6 hours, and remain infective for several days,
infectious egg contains first stage larvae. Look like
coffee bean.
Top image: Enterobius vermicularis (pinworm) adult male demonstrating cephalic alae. Lower images: Enterobius
vermicularis (pinworm) eggs on scotch tape test. The eggs are elongate-ovoidal, compressed laterally, flattened on one
side and measure 50-60 x 20-30µm.
Life Cycle:
Eggs are deposited on perianal folds . Self-infection occurs by transferring infective eggs to the mouth with hands that
have scratched the perianal area . Person-to-person transmission can also occur through handling of contaminated
clothes or bed linens. Enterobiasis may also be acquired through surfaces in the environment that are contaminated with
pinworm eggs (e.g., curtains, carpeting). Some small number of eggs may become airborne and inhaled. These would be
swallowed and follow the same development as ingested eggs. Following ingestion of infective eggs, the larvae hatch in
the small intestine and the adults establish themselves in the colon . The time interval from ingestion of infective eggs
to oviposition by the adult females is about one month. The life span of the adults is about two months. Gravid females
migrate nocturnally outside the anus and oviposit while crawling on the skin of the perianal area . The larvae contained
inside the eggs develop (the eggs become infective) in 4 to 6 hours under optimal conditions . Retroinfection, or the
migration of newly hatched larvae from the anal skin back into the rectum, may occur but the frequency with which this
happens is unknown.
Life Cycle:
The unembryonated eggs are passed with the stool . In the soil, the eggs develop into a 2-cell stage , an advanced
cleavage stage , and then they embryonate ; eggs become infective in 15 to 30 days. After ingestion (soil-
contaminated hands or food), the eggs hatch in the small intestine, and release larvae that mature and establish
themselves as adults in the colon . The adult worms (approximately 4 cm in length) live in the cecum and ascending
colon. The adult worms are fixed in that location, with the anterior portions threaded into the mucosa. The females begin
to oviposit 60 to 70 days after infection. Female worms in the cecum shed between 3,000 and 20,000 eggs per day. The
life span of the adults is about 1 year.
Diagnosis of Trichuriasis
• Take 3 stool samples from 3 different days and look for eggs
under microscope.
Treatment of Trichuriasis
• Put the rectum back in place, does not require surgery
• Albendazole
• Mebendazole
Diagnosis of Strongyloidiasis
• Rhabtidiform larvae in stool, obtain several stool samples.
• String test (outdated) / duodenal aspirate.
• Serology – IgG4 to strongyloides, if see patient with slight eosinophilia get serology.
• Check sputum and stool for possible Hyper-infection.
Treatment of Strongyloidisis
• Thiabendazole – 95% cure rate
• Ivermectin – cidal
1. What is Dracunculosis?
• Dracunculosis (also called Guinea Worm disease) is a painful, incapacitating disease caused by Dracunculosis
medinensis.
• Transmission: by drinking water containing cyclopoid copepods, freshwater microcrustaceans that harbor
infective larvae.
• This nematode lives in connective and subcutaneous tissue of humans.
• The female worm emerges through the skin to discharge its larvae into water.
• The clinical course is characterized by allergic prodromal symptoms and cutaneous ulceration.
• Most infections are limited to a single worm.
Humans become infected by drinking unfiltered water containing copepods (small crustaceans) which are infected with
larvae of D. medinensis . Following ingestion, the copepods die and release the larvae, which penetrate the host stomach
and intestinal wall and enter the abdominal cavity and retroperitoneal space . After maturation into adults and
copulation, the male worms die and the females (length: 70 to 120 cm) migrate in the subcutaneous tissues towards the skin
surface . Approximately one year after infection, the female worm induces a blister on the skin, generally on the distal
lower extremity, which ruptures. When this lesion comes into contact with water, a contact that the patient seeks to relieve
the local discomfort, the female worm emerges and releases larvae . The larvae are ingested by a copepod and after
two weeks (and two molts) have developed into infective larvae . Ingestion of the copepods closes the cycle .
4. What is the distribution of Dracunculus medinensis?
• Africa, Asia, Yemen and Saudi Arabia
8. What is Loiasis?
• Loiasis is caused by infection with the filarial (“thread-like”)” nematode Loa loa.
• The adult worms migrate through the subQ tissue causing intermittent “calaber swellings” and sometimes
beneath the conjunctiva (eye worm).
• Microfilariae are found in the peripheral blood during the day.
• Distribution: endemic to rain forests of Central and West Africa; in some parts 100% infection rates.
• Transmission: flies of genus Chrysops or Deer Fly, which bites in shaded areas during the day.
• L3 larvae are infective form.
Onchocerca volvulus microfilaria in subcutaneous tissue. The microfilaria are unsheathed in the tissues and depending on
how they are prepared for measurement are 315-360µm long by 6µm. The anterior and posterior ends are nuclei-free.
During a blood meal, an infected blackfly (genus Simulium) introduces third-stage filarial larvae onto the skin of the human
host, where they penetrate into the bite wound . In subcutaneous tissues the larvae develop into adult filariae, which
commonly reside in nodules in subcutaneous connective tissues . Adults can live in the nodules for approximately 15
years. Some nodules may contain numerous male and female worms. Females measure 33 to 50 cm in length and 270 to
400 μm in diameter, while males measure 19 to 42 mm by 130 to 210 μm. In the subcutaneous nodules, the female worms
are capable of producing microfilariae for approximately 9 years. The microfilariae, measuring 220 to 360 µm by 5 to 9
µm and unsheathed, have a life span that may reach 2 years. They are occasionally found in peripheral blood, urine, and
sputum but are typically found in the skin and in the lymphatics of connective tissues . A blackfly ingests the
microfilariae during a blood meal . After ingestion, the microfilariae migrate from the blackfly's midgut through the
hemocoel to the thoracic muscles . There the microfilariae develop into first-stage larvae and subsequently into third-
stage infective larvae . The third-stage infective larvae migrate to the blackfly's proboscis and can infect another
human when the fly takes a blood meal .
Different species of the following genera of mosquitoes are vectors of W. bancrofti filariasis depending on geographical
distribution. Among them are: Culex (C. annulirostris, C. bitaeniorhynchus, C. quinquefasciatus, and C. pipiens);
Anopheles (A. arabinensis, A. bancroftii, A. farauti, A. funestus, A. gambiae, A. koliensis, A. melas, A. merus, A.
punctulatus and A. wellcomei); Aedes (A. aegypti, A. aquasalis, A. bellator, A. cooki, A. darlingi, A. kochi, A. polynesiensis,
A. pseudoscutellaris, A. rotumae, A. scapularis, and A. vigilax); Mansonia (M. pseudotitillans, M. uniformis); Coquillettidia
(C. juxtamansonia). During a blood meal, an infected mosquito introduces third-stage filarial larvae onto the skin of the
human host, where they penetrate into the bite wound . They develop in adults that commonly reside in the lymphatics
. The female worms measure 80 to 100 mm in length and 0.24 to 0.30 mm in diameter, while the males measure about
40 mm by .1 mm. Adults produce microfilariae measuring 244 to 296 μm by 7.5 to 10 μm, which are sheathed and have
nocturnal periodicity, except the South Pacific microfilariae which have the absence of marked periodicity. The
microfilariae migrate into lymph and blood channels moving actively through lymph and blood . A mosquito ingests the
microfilariae during a blood meal . After ingestion, the microfilariae lose their sheaths and some of them work their way
through the wall of the proventriculus and cardiac portion of the mosquito's midgut and reach the thoracic muscles .
There the microfilariae develop into first-stage larvae and subsequently into third-stage infective larvae . The third-
stage infective larvae migrate through the hemocoel to the mosquito's prosbocis and can infect another human when the
mosquito takes a blood meal .
23. What are the clinical manifestations of Bancroftian Filariasis?
• Signs and symptoms of Bancroftian filariasis vary widely form one endemic area to another. Differences may be
due to relative intensities of different vectors in different regions.
• Asymptomatic individuals are seen in endemic areas.
• Early on in disease, patients will experience acute attacks of retrograde lymphangitis, accompanied by fever,
chills, and malaise lasting 3-15 days. Can occur several times per year.
• Patients give history of: pain, erythema, tenderness in area of affected lymphnodes for hours or 1 day prior to
onset of lymphangitis.
• Acute filariasis: microfilariae in blood, eosinophilia, and increased IgE. Some individuals may only have a few
attacks in a lifetime. Months to years of acute episodes ranging from very mild to severe are followed by
development of chronic obstructive disease due to lymphatic insufficiency.
• Chronic filariasis: recurrent episodes of lymphedema of the extremeties will progress to elephantiasis (Focal
Point of O’Connor: point of lymphagenic spread in scrotum). The lower extremities are more commonly
affected. In many areas, most common chronic manifestation is a hydrocele. As a result of blockage of draining
lymph, straw colored hydrocele fluid accumulates (sometimes in huge volumes). Can have edema in any region
containing lymphatics.
1. Elephantiasis
2. NO IgE & NO Eosinophilia
3. Chyluria: lymphatic varices in bladder burst >>> lymphatic fluid in bladder & urine.
Tropical Pulmonary Eosinophilia: is an allergic reaction to microfilaria (Wuchereria bancrofti) which occurs
particularly in the Asian subcontinent (also Eastern Europe?). Presentation is with cough & asthma, fever,
lassitude, and weight loss. Chest X-ray shows bilateral hazy mottling that is equally distributed throughout both
lung fields. This condition is commonly accompanied by false positive serological tests for syphilis. There are
high titres of cold agglutinins. Treat w/ DEC.
Trichinosis
• Trichinosis caused by Trichinella and is acquired by eating muscles of wild or domestic animals.
• Severity is related to number of larvae ingested, and characterized by:
1. fever
2. GI symptoms
3. myositis
4. swollen eyelids
5. Eosinophilia - very high
• Transmission: through eating pork, bear, or horse meat
• Number of infections is declining. General drop in reported cases, but
probably milder so more cases than reported.
• Zoonosis: swine, rats
• Distribution: Occurs all over the US and the world.
• Any muscle mass can get involved: masseters, exta-ocular, nuccal, intercostals, gluteus, biceps, triceps, lower
extremities
• Larvae can go through CNS and myocardium, but won’t encyst there
• Nurse cell larva complex
• Trichinella pseudospiralis: does not form cysts
Laboratory Findings
• High eosinphilia (40-60% typically)
• Leukocytosis
• Elevated muscle enzymes (CPK, Aldolase, SGOT)
• Elevated IgE
• Positive serology: shows up 2-3 weeks later
Treatment
• Mebendazole
• Albendazole
• Corticosteroids for severe disease: if neuro or myocarditis, problem is that people think you might be interfering
with natural immunological response of the host, but this is only a theoretical problem
Prevention
• Cook meat to 160 degrees F is best
• Banning of feeding garbage including animal carcasses to swine and other barnyard animals.
Amebiasis
• Amebiasis: Should always be in your differential diagnosis, seen frequently in the US (4%), also very common in
Mexico
• Worldwide distribution, due to unclean water and poor sanitation, 10% of world infected, and up to 50% in some
developing countries.
• Causes a fair amount of mortality
Left image: Entamoeba histolytica trophozoite, note: fine uniform granules of peripheral chromatin and small central
karyosome in nucleus, size over 12 uM. Right image: Entamoeba histolytica trophozoite (8-30µm), note: ingested red
blood cells.
Life Cycle
• E. histolytica is an enteric protozoa that exists as either trophozoite or cyst.
• Infection acquired from ingestion of cysts (quadranucleate and resistive to low stomach pH) from environment
>>> excysts in intestine >>> forms 8 trophozoites >>> invade large intestine feeds on bacteria and cellular debris.
• Trophozoites may then encyst
• Upon excretion, cysts remain viable for weeks to months depending on environmental conditions.
• Cyst infectious, trophozoite invades
Cysts and trophozoites are passed in feces . Cysts are typically found in formed stool, whereas trophozoites are typically
found in diarrheal stool. Infection by Entamoeba histolytica occurs by ingestion of mature cysts in fecally contaminated
food, water, or hands. Excystation occurs in the small intestine and trophozoites are released, which migrate to the
large intestine. The trophozoites multiply by binary fission and produce cysts , and both stages are passed in the feces
. Because of the protection conferred by their walls, the cysts can survive days to weeks in the external environment and
are responsible for transmission. Trophozoites passed in the stool are rapidly destroyed once outside the body, and if
ingested would not survive exposure to the gastric environment. In many cases, the trophozoites remain confined to the
intestinal lumen ( : noninvasive infection) of individuals who are asymptomatic carriers, passing cysts in their stool. In
some patients the trophozoites invade the intestinal mucosa ( : intestinal disease), or, through the bloodstream,
extraintestinal sites such as the liver, brain, and lungs ( : extraintestinal disease), with resultant pathologic manifestations.
It has been established that the invasive and noninvasive forms represent two separate species, respectively E. histolytica
and E. dispar. These two species are morphologically indistinguishable unless E. histolytica is observed with ingested red
blood cells (erythrophagocystosis). Transmission can also occur through exposure to fecal matter during sexual contact (in
which case not only cysts, but also trophozoites could prove infective).
Cysts
• Never see cysts in tissue, only trophozoites
• Very hardy
• Killed by boiling over 100 degrees Celsius, lives in ice
• Resistant to chlorine
• Survives for days on salads, cheeses and yogurt (20-25 degrees)
• In the stool, you see round cysts with peripheral chromatin with thick hyaline cell wall that looks like a halo (not
able to differentiate from ED).
• Stacking of ribosomal RNA used as an apparatus for cell division
Trophozooite
• Pathogenesis: lysis
• Non-inflammatory disease
• Amoeboid trophozoite nucleus with peripheral chromatin
• Can invade, and on contact can lyse host tissue or cause host apoptosis, can ingest debris in intestine and RBCs
and WBCs due to lectin (wouldn’t see RBCs in E. dispar).
• Unidirectional motion of trophozoite
Pathogenesis of Amebiasis
• Initial lesion is cecal and then extends down to rectum.
• Can get extra-intestinal disease
1. hepatic: pretty common
2. pleuropulmonary
3. pericarditis
4. cerebral
5. other
• adherence of trophozoites to the mucus lining of large bowel – vital role in pathogenesis
• adhere to colonic mucins, epithelial cells and leukocytes >>> Galactose-inhibitable adherence lectin has
difficulty adhering but easier if malnourished have thinner layer of protective mucin.
• Bantu tribe lives primarily on corn, poor nutritional status >>> higher infection rates
• If in bowel can get into blood vessels and then disseminate into portal blood vessels and travel to liver
• Contact-dependent cytolysis: EM of cells pre and post infection of EH. After, see autolysis >>> release of
enzymes >>> causing destruction of local tissue. So organism invades by causing host cells to autolyse >>> then
organism can move easily through dead tissue.
• Phagocytoizes PMNS and other cells >>> release of lysosomal agents >>> more necrosis
• Foci of necrosis coalesce to form classic flask-shaped amebic ulcers.
• Deeper tissue invasion >>> vasculitis and thrombosis >>> transmural disease and tissue death
• Virulence: depends both on amoeba and host factors (someone who is healthy and gets low dose of pathogen less
likely to develop disease). Nutritional status very important: immunocompromised, corticosteroids, malignancies,
and malnutrition predispose to infection.
Entamoeba histolytica infection of rectum, note: ulcerative lesion, usually described as flask shaped ulcer.
Intestinal Disease
• Asymptomatic: majority pass cysts in stool with no symptoms, but cysts are infectious so it is a public health
issue. Carries a low, but definite possibility of invasion.
• Mucosal Disease:
1. acute rectocolitis (dysentery): bloody diarrhea and tenesmus
2. chronic non-dysenteric colitis: person has diarrhea for months on and off, can look like
inflammatory bowel disease (AI disease of colon presents with bloody diarrhea that lasts for months)
• Transmural Disease:
1. fulminant colitis with perforation due to coalescence of ulcers >>> high M&M
2. Toxic Megacolon: much more common in children, very bad complication due to transmural
disease and thinning of the bowel >>> huge cecum (may require a cecostomy otherwise will burst
and life-threatening illness).
• Ulcerative post-dysenteric colitis
Amoebic Colitis
• Does not have rapid onset like Salmonella and Shigella (normally associated with high fever).
• Gradual onset of 1-3 weeks, weight loss common due to gradual onset
• Abdominal pain and tenderness
• Bloody stools and tenesmus
• Fever 1/3 patients
• Path: flask-shaped ulcers with necrotic debris in the middle, on the edge trophozoites
• Differential diagnosis:
1. Infectious: amebiasis, Shigella, Salmonella, Campylobacter, Enteroinvasive and Enterohemorrhagic
E. coli
2. Non-infectious: ischemic colitis, AV malformation, Diverticulitis, inflammatory bowel disease
• Treatment for IBD is steroids. Must consider amoebic colitis, b/c if patient has that and you misdiagnose and give
steroids you will make patient sicker.
• Amoebic serology directed at 170 kD lectin will become positive with 1-2 weeks of infection, quite specific, but
can remain positive for up to 10 years.
• Complications:
1. appendicitis
2. perforation & peritonitis
3. ameboma: pain and tenderness, can present as an apple-core lesion on CT, usually secondary to
malignancy
4. amebic stricture: fibrosis secondary to healing transmural disease
5. cutaneous amebiasis
Treatment
• Tissue-cidal: Flagyl=Metronidazole (not good for cysts, but good for invasive disease)
• Luminicidal: Iodoquinol, Paromomycin, Diloxanide Furoate (in other countries), good for asymptomatic cyst
characteristics
Conclusion
• Dispar never invasive >>> don’t need to treat
• Cyst doesn’t invade (it is infective stage); trophozoite is invasive stage
• Amoebiasis: ring enhancing lesion in brain, space-occupying cystic lesions can develop in brain, lung, or liver.
Hepatic Amebiasis
• Hepatic infection results from trophozoites ascending portal venous system.
• Predilection for right lobe, usually singular, but can be multiple. Trophozoites cause cells to self destruct >>> get
a lot of necrotic debris. Also, lysis of PMNs >>> release of destructive host enzymes. Only see Trophs in edge of
lesion. This is called a “liver abscess,” but misnomer (no pus, not an abscess). If grows can get elevation of
hemidiaphragm. Can rupture into lung or peritoneum. If on right can rupture into heart.
• If you put a needle into an amoebic abscess, you see Anchovy paste or chocolate-like paste, vs. regular abscess
see sheets of PMNs.
• Males are 10x more likely to get invasive Amebiasis than females.
• Patient presentation: RUQ tenderness and fever. Patients look really ill and toxic. (In amoebic colitis many don’t
have fever). On chest x-ray see elevated right hemi-diaphragm >>> something is going on in right sub-phrenic
space. Typically seen in patients who have traveled to endemic location. Normally, not acute onset (4 weeks). A
history of diarrhea is only present in 1/3 of patients, vs. amebic colitis where patients have bloody diarrhea.
Cough present in 1/3 of patients.
• See + amebic serology, but can remain + for up to 10 years.
• Path: collapse of stroma of liver, with necrotic debris. See invasive trophozoites on edge of lesion.
Lab Tests
• Leukocytosis (12,000-20,000 mm^3)
• ESR is elevated (non-specific marker of inflammation)
• Normocytic-normochromic anemia
• Alkaline phosphatase elevated
• Partial immunity develops
General Notes
• Most intestinal protozoa have cyst >>> excyst in intestine >>> amplify in intestinal lumen >>> trophozoites
invade >>> trophozoites can then encyst and go out into environment.
What is Dientamoebiasis?
• Dientamoebiasis is caused by Dientomoeba fragilis, an ameba-like flagellate closely related to the genera
Histomonas and Trichomonas.
• D. fragilis has a worldwide distribution
• Transmission: unknown. May be water borne and person-to-person transmission. Close relationship between
Enterobius vermicularis and D. fragilis infections.
• Non-invasive in large intestine.
• It doesn’t have cyst phase, and it is a trophozoite >>> not sure how it gets around. It has been postulated that
pinworm eggs or larvae may be transmitting agent for D. fragilis.
What is Trichomoniasis?
• It is a specific GU tract infection with Trichomonas vaginalis.
• The organism is highly site specific >>> vaginitis in women and urethritis in men (both sexes are equally
susceptible, but women symptomatic and men tend not to be, so treat both men and women, if woman presents).
• Distribution: occurs worldwide, in both rural and urban settings.
• Transmission: it is a common STD and patients should be screened for other STDs if positive. Perinatal
transmission occurs rarely in vaginal births. No cyst forms! Transmission requires intimate contact with actively
motile organism. So, if find in a child, be concerned about child abuse.
• At risk groups: professional sex workers, young people who are more sexually active
Trichomonas vaginalis typically infects the vagina in women and the prostate and urethra in males.
Trichomonas vaginalis resides in the female lower genital tract and the male urethra and prostate , where it replicates by
binary fission . The parasite does not appear to have a cyst form, and does not survive well in the external environment.
Trichomonas vaginalis is transmitted among humans, its only known host, primarily by sexual intercourse .
What is Giardiasis?
• A zoonotic infection (but most commonly person-to-person transmission) of the lumen of the small intestine with
the flagellate protozoan Giardia lamblia.
• Many patients have no symptoms (50% spontaneous cure w/o symptoms), but a smaller portion have diarrheal
disease that varies in its severity (can be acute or chronic diarrhea, usually 1+ week after exposure).
1. usually non-bloody, explosive diarrhea (it is an upper intestinal parasite, that is NOT invasive,
prevents absorption).
• Distribution: occurs worldwide in temperate and tropical areas. Essentially a disease of poverty where sanitation
is poor, fecal contamination of environment is common, and there is no clean drinking water. 200 million cases
annually.
• Transmission: infection follows ingestion of viable parasitic cysts from contaminated food or water. Cysts can
also be transmitted via fingers to mouth particularly in children (after touching ground contaminated with feces).
Person-to-person transmission also occurs in children.
1. US outbreaks: defective water treatment plants
2. beavers and dogs
3. tropics >>> high level of environmental contamination
4. can get it from drinking from mountain streams
• Symptomatic disease more common in children
• Mechanism of diarrhea with Giardia is unknown. Giardia contains viruses (mini Rotovirus) – may be involved in
diarrhea, but doesn’t seem to be.
Left image: Giardia lamblia cyst (8-12 long x 7-10µm wide) with 2 nuclei. The mature cyst has 4 nuclei. Right image:
Giardia lamblia trophozoite (9-21 long x 5-15µm wide). Typically found in the duodenum. It is binucleate and has 4 pairs
of flagella. Giardia is a Diploid organism with 2 1N nuclei.
Balantidium coli
• B. coli is a classic ciliate
• Invasive >>> bloody diarrhea
• Covered with rows of cilia
• Defining characteristic is nuclear dimorphism
• Sexual reproduction involving conjugation
• Primarily seen in people with exposure to pigs and other
animals.
• Treatment: Tetracycline or Iodoquinol
• Diagnosis: look for cysts or trophozoites in stool
Blastocystis hominis
• Life cycle unknown
• Previously called yeast, ameba, sporozoan, etc. Appears to be a Stramenophile.
• Pathology: on the border between commensal organism and pathogen >>> can lead to vague intestinal discomfort.
Fecal-oral transmission.
• Treatment: no real treatment. Can use Iodoquinol or Metronidazole, but only 50-60% effective.
Toxoplasmosis
• Major cause of M&M, caused by the protozoan parasite Toxoplasma gondii.
• Most infections are asymptomatic, with at most minor flu symptoms. Infections most severe in congenitally
infected infants and in immunocompromised.
• Transmission:
1. ingestion of tissue cysts containing bradyzoites in undercooked infected meat
2. ingestion of environmentally resistant sporulated oocytes in water, raw produce, or soil
3. transplacentally from mother to fetus
4. tissue transplantation
• Cats (particularly younger cats and kittens) and field animals are definitive hosts (adult forms and sexual
reproduction), and most warm-blooded animals can serve as intermediate hosts (immature forms and asexual
reproduction).
• 22.5% of people in US have antibodies to it – very common parasitic illness.
• Treatment: drugs can treat active infection, but none kill the tissue cyst stage of parasite.
• Oocysts are environmentally stable can survive in water, etc.
• Latent tissue cyst stage parasites can reactivate and cause development of new illness in immunocompromised
patients.
• Distribution: worldwide, widespread infections in mammals and birds.
Toxoplasma gondii stages; A) bradyzoite, B) tachyzoite, C) tachyzoites in tissue culture, D) oocyst [Nomarski optics].
Apicoplasts
• A class of parasites
• Apicoplast: organelle with 4 membranes, typical plastid has 2 membranes as do mitochondria (potentially b/c of
joining of 2 cells). Potentially ingestion of a fungi.
• Toxoplasmosis and Malaria have several plant-like metabolic pathways >>> major potential therapeutic target!!
• Unique mechanism of replication called endogeny. Form 2 daughter cells within eukaryotes.
Pathogenesis of Toxoplasmosis
• Tachyzoites (proliferative stage) can be found in any cell type in the body except RBCs.
• Hundreds to thousands of Bradyzoites are contained in tissue cysts (latent stages), and can be found in many
tissues including brain, eye, heart, kidney, liver, bone marrow and skeletal muscles.
• Domestic cats excrete the largest amount of T. gondii sporulated oocytes in their feces >>> humans can become
infected after ingesting infected water, food, etc.
• Ingestion of unwashed fruits and vegetables is associated with increased risk of maternal toxoplasmosis, as is
contact with soil.
• Cockroaches can pick up cysts and deposit them other places
• Pork is the most likely commercial food sources of tissue cysts in the US. Chicken (rarely), sheep, goat, deer, wild
pigs, turkeys, and bear are all possible sources of infection – found in mammals. Can ingest zoites in undercooked
meat.
• Cats are pivotal in transmission of parasite to herbivores and omnivores
• Only the bradyzoite stage from the tissue cyst can cause the enteroepithelial cycle in the cat’s enterocytes, which
terminates in occyst excretion in feces.
• Sporulation occurs in environment and depends on temp and moisture.
• Organ transplantation can transfer infection if latent cysts or bradyzoites in tissue of transplanted organ.
• Blood transfusions can transmit T. gondii only during acute stage of infection.
Diagnosis of Toxoplasmosis
• detection of anti-T. gondii antibodies by serological tests
• detection of tachyzoites or T. gondii-specific DNA in body fluids or tissue sample
• parallel testing of specimens 4 weeks apart
• seroconversion of a 4 fold rise in IgG titer is diagnostic of acute infection.
• In polymyositis or myocarditis biopsy can be useful (so low avidity antibody is seen during acute infection).
• IgG persists for life. Titer avidity increases with time, so low avidity IgG more likely to be acute infection.
• IgM appears earlier and declines more rapidly than IgG (usually within a few months) >>> presence of IgM
suggests acute infection.
• Low IgG titers in first trimester with negative IgM are consistent with chronic infection
• Positive IgM titers require further evaluation. 60% with + IgM have chronic infection.
• Amnio and US of fetus are recommended for acute infection with PCR. Fetal blood sampling does not increase
diagnostic yield.
Treatment of Toxoplasmosis
• Asymptomatic or latent infection:
1. immunocompetent individuals w/ latent disease do not require treatment
2. AIDS patients can get encephalitis >>> treat with TMP-SMX
3. cardiac transplantation treat prophylactically for 6 weeks with Pyrimethamine
• Acquired Toxoplasmosis:
1. if immunocompetent treatment probably not necessary
2. in cases of myocarditis, encephalitis, or sepsis, treat with Pyrimethamine + Sulfadiazine (or
Trisulfapyrimidine) + Folinic Acid (for 4-6 weeks)
• Acquired infection during pregnancy:
1. acutely infected pregnant women treat with Spiramycin
2. Amniocentesis, fetal blood monitoring and fetal US should also be used
3. If + fetal diagnosis >>> treat mother with Pyrimethamine + Sufladiazine + Folinic Acid. However,
Pyrimethamine should not be used during first 16 weeks of pregnancy.
• Congential Toxoplasmosis:
1. treat with Pyrimethamine + Sulfadiazine + Folinic Acid
2. corticosteroids should be added in patients with macular disease
• Toxoplasmosis infection in immunocompromised host:
1. Pyr + Sulfa + FA (Clindamycin can be substituted for Sulfa drugs)
2. Corticosteroids can be used to control intracranial HTN
• Alternative meds: Atovaquone, Azithromycin, Clindamycin, gamm-interferon (critical for almost all
intracellular parasites) recombinant form is experimental therapy, plant fatty acid pathway inhibitors like
Triclosan or Roundup
Prevention of Toxoplasmosis
• Don’t eat raw or poorly cooked meat
• Food preparers should wash hands and cooking surfaces with warm soapy water
• Change cats’ litter boxes regularly, but pregnant women and immunocompromised shouldn’t do this. Also, keep
cats indoors and feed only commercially prepared foods.
• Wear gloves when gardening
• Wash all fruits and vegetables
Pyrimethamine (PYR)/Daraprim
• Mechanism of Action: inhibits dihydrofolate reductase (Trimethoprim also inhibits this enzyme)
• Absorption: readily absorbed from GI tract
• Distribution: well distributed in most tissues, and found in CSF; t1/2= 35-175 hours
• Metabolism: hepatic
• Adverse Effects: dose-related bone marrow suppression w/ thrombocytopenia, neutropenia, and anemia. Folinic
Acid given to prevent these side effects.
Sulfonamides
• Mechanism of Action: inhibit dihydrofolic acid synthetase, which is another enzyme involved in folic acid
metabolism, so synergistic with PYR.
• Absorption: well-absorbed
• Distribution: good, with CSF
• Metabolism:
• Adverse Effects: are common (particularly in AIDS patients), bone marrow suppression (responsive to Folinic
Acid), hypersensitivity reactions with rash and Stevens-Johnson syndrome.
Pneumocystis Carinii
• Originally considered a protozoa, but it is actually an atypical fungus.
• However, doesn’t respond to anti-fungal drugs. Responds to Bactrim (TMP-SMX) and other anti-protozoal drugs.
• Host specific organism (rats and humans have 2 different species).
• Pneumocystis jirovecii is the species that infects humans, so P. carinii is not actually the infective agent in PCP
seen in AIDS patients.
• Symptoms: primarily infects the lungs >>> pneumonia, SOB, chronic cough, low-grade or no fever, decreased
PaO2 on room air, chest tightness or pain.
• Who does it affect?
1. Primarily disease of immunocompromised (AIDS CD4 >200) and lethal if untreated. Occurs at less
immunosuppression than other op. infections >>> bellweather of HIV epidemic.
2. Malnourished infants
3. Children with primary malignancies
4. solid tumor patients, neoplasms, hematologic malignancies
5. high dose corticosteroids !!!
6. transplant recipients
7. inflammatory or collagen-vascular diseases (esp. Wegener’s granulomatosis)
Pneumocystis carinii, Lung section stained with Gomori methenamine silver stain; cyst wall is stained black. Know this
slide!!! Classic pneumocystosis shown by silver stain. Know it isn’t yeast b/c no budding.
Diagnosis of Pneumocystis
• a non-cultivatable organism, but can look for it in sputum with special stains or monoclonal antibodies
• bronchopsy for deep lung specimen
• Gallium scan
• Diffuse, foamy infiltrate in the middle of the lung
• Life cycle is not completely figured out
• Person-to-person transmission
• PCP increasing in HIV+ people in developing countries
• HAART is decreasing incidence
• Evidence for transmission form symptomatic hosts; some
outbreaks in hospital settings >>> may want to isolate
pneumocystis patients
Cryptosporidium Species
• Intracellular GI parasites originally thought to cause disease in animals.
• Current methods of water purification do not remove Cryptosporidia.
• No effective therapy for it.
• Most cases self-limited, but can be devastating in immunocompromised, and to children in developing countries.
Immunocompromised with deficient cell-mediated immunity are particularly vulnerable.
• Types: 10 species, but Cryptosporum parvum infects humans.
• Infection is a zoonosis with mainly bovine and human reservoirs.
• Transmission: humans get infection by ingesting oocysts, which are shed in stool of animals or humans either
through water, food, and excreted fully infective so can be passed from person to person! Hardy cysts resistant to
chlorine, UV radiation, but killed by freezing or heating.
• Epidemiology:
1. Endemic in developing countries >>> one of most common causes of persistent diarrhea among children.
2. In developed world, mainly in outbreaks, usually due to contaminated drinking water.
3. Antibodies in 30% of US population.
4. Milwaukee & Nevada outbreaks
5. Water outbreaks
Sporulated oocysts, containing 4 sporozoites, are excreted by the infected host through feces and possibly other routes such
as respiratory secretions . Transmission of Cryptosporidium parvum occurs mainly through contact with contaminated
water (e.g., drinking or recreational water). Occasionally food sources, such as chicken salad, may serve as vehicles for
transmission. Many outbreaks in the United States have occurred in waterparks, community swimming pools, and day care
centers. Zoonotic transmission of C. parvum occurs through exposure to infected animals or exposure to water
contaminated by feces of infected animals . Following ingestion (and possibly inhalation) by a suitable host ,
excystation occurs. The sporozoites are released and parasitize epithelial cells ( , ) of the gastrointestinal tract or
other tissues such as the respiratory tract. In these cells, the parasites undergo asexual multiplication (schizogony or
merogony) ( , , ) and then sexual multiplication (gametogony) producing microgamonts (male) and
macrogamonts (female) . Upon fertilization of the macrogamonts by the microgametes ( ), oocysts ( , ) develop
that sporulate in the infected host. Two different types of oocysts are produced, the thick-walled, which is commonly
excreted from the host , and the thin-walled oocyst , which is primarily involved in autoinfection. Oocysts are
infective upon excretion, thus permitting direct and immediate fecal-oral transmission.
Note that oocysts of Cyclospora cayetanensis, another important coccidian parasite, are unsporulated at the time of
excretion and do not become infective until sporulation is completed. Refer to the life cycle of Cyclospora cayentanensis
for further details.
Pathogenesis of Cryptospordiosis
• Infection with Cryptosporidium begins when the ingested oocyst releases sporozoites >>> attach to and invade
intestinal epithelial cells (particularly jejunum and terminal ileum) >>> minimal inflammatory infiltrate (IFN-
gamma) and blunting of villus (more pronounced in immunocompromised) >>> malabsorption.
• Mechanism of diarrhea is unclear.
Diagnosis of Cryptosporidiosis
• biopsy w/ demonstration of intracellular parasite
• Acid-fast Kinyoun test to identify oocysts in stool – gold standard
Treatment of Cryptosporidiosis
• Nitazoxanide in children and HIV patients. HIV patients also need HAART.
• Azithromycin
Isospora
• Distribution: South America, Mexico, Carribean
• Symptoms: watery diarrhea, flatulence, malaise, anorexia, low fever, weight loss, Charcot-Leyden crystals in
stool, peripheral eosinophilia (exception to rule that protozoa don’t cause eosinophilia!).
• Transmission: sporulates outside of host – probably doesn’t have person to person transmission.
• Diagnosis: check stool for O&P. Acid Fast!
• Treatment: Bactrim; prophylax patients with low CD4
counts.
Left image:
Isospora belli
oocyst (20-33µm
x10-19µm)
containing 2
sporoblasts.
Right image:
Isospora belli
acid fast staining.
Cyclopsora
• Cyclospora is a genus in the phylum Apicomplexa. It is related to Cryptosporidium, Isospora, Toxoplasma, and
Sarcocystis.
• Like other Apicomplexans, sporozoites have an apical complex composed of a polar ring, conoid, rhoptries, and
other coccidian structures.
• Morphology: 8-10 microns in diameter.
• Life cycle: not known. Thought that sexual and asexual development occurs in human host. Cyclospora oocysts
in fresh stool are NOT infectious; oocysts require days to weeks outside host in favorable environmental
conditions to sporulate and become infectious.
• Transmission: through food (often fresh produce like raspberries), and water (highly chlorine resistant), human-
to-human unlikely.
• Distribution: common in tropical and subtropical areas worldwide; endemic to Nepal, Haiti & Peru. Rainy season
May to October, and in US May to July. Marked seasonality of infection – but with differing patterns in
different regions.
• Pathogenesis: intracellular organism that parasitizes enterocytes of upper small bowel. Inflammatory cell
infiltrates in lamina propria sometimes. Pathological changes are similar to tropical sprue.
• Histology: contain numerous refractile globules in membranes. Acid-fast staining variable.
Diagnosis of Cyclosporiasis
• Microscopic demonstration of oocysts in fecal specimens, duodenal or jejunal aspirates or biopsy specimens.
• Identify acid-fast organisms (variable) with modified Ziehl-Neelsen or Kinyoun stains.
• Oocysts autofluoresce and appear as neon blue circles under UV fluorescent microscope.
Treatment of Cyclosporiasis
• TMP-SMX
Microsporidiasis
• Microsporidia are obligate eukaryotic intracellular parasites.
• Ubiquitous in environment, infect most animal phyla.
• Probably zoonotic and/or waterborne infections.
• Produces a wide array of clinical diseases in immunocompromised hosts.
• Over 1000 species in the phylum Microsporidia.
• Morphology: form very hardy characteristic unicellular ovioid spores w/ chitin & protein (1-3 microns in size).
A defining characteristic of all Microsporida is an extrusion apparatus consisting of a polar tube attached to inside
of anterior spore by an anchoring disk. During germination, the polar tube everts forming a hollow tube that
serves as a bridge to deliver sporoplasm to the host cell.
• Distribution: everywhere except Antarctica.
• Cause diarrhea.
Types of Microsporidia
• over 1,000 species in the phylum Microsporidia. Some important pathogens are:
1. Vittaforma corneae
2. Brachiola algerae
3. Pleistophora
4. Trachipleistophora: associated with encephalitis and disseminated disease.
5. Encephalitozoon hellem: associated with superficial keratoconjunctivitis, sinusitis, respiratory disease,
prostatic abscesses, and disseminated infections.
6. Encephalitozoon cunicili: associated with Hepatitis, encephalitis, and disseminated disease.
7. Encephalitozoon (Septata) intestinalis: associated with diarrhea, disseminated disease and superficial
keratoconjunctivitis.
8. Nosema, Vittaforma, and Microsporidium have been associated with stromal keratinis due to trauma in
immunocompetent.
9. Pleistophora, Brachiola, and Trachipleistophora have been associated with myositis.
10. Enterocytozoon bieneusi: associated with malabsorption, diarrhea, and cholangitis.
Pathogenesis of Microsporidia
• Common enteric pathogens that are usually self-limited and asymptomatic.
• Self-limited diarrhea in normal hosts.
• If immunocompromised: diarrhea, wasting syndrome, and disseminated infection.
• Enterocytozoon bieneusi most common, hard to treat, seen in liver and heart-lung transplant patients.
• Encephalitozoon species infect patients with kidney, pancreas, liver or bone marrow transplants.
• Prior to HAART, Microsporidia responsible for 1/3 of cases of chronic diarrhea in HIV+.
Diagnosis of Microsporidiosis
• NOT acid fast – use Trichome Stain!!
• Examination of stool specimens with light microscopy
• If stool is negative after 2+ months diarrhea, do endoscopy
• Obtain urine specimens b/c shedding of spores in urine is common in all species of Microsporidia.
Treatment of Microsporidiosis
• Microsporida that disseminate (like Encephalitozoon) are usually sensitive to Albendazole.
• E. bieneusi resistant and often treated with Fumagillin.
• Effective HAART >>> patients with improved immune function can usually fight off infection on their own.
LECTURES #12-13: MALARIA
Malaria
• Malaria is an acute and chronic disease caused by obligate intracellular protozoa of the genus Plasmodium.
• Four species of Plasmodium can infect humans:
1. P. malariae
2. P. vivax: present in Mexico, Central & South America, India, SE Asia
3. P. falciparum: associated with severe and complicated disease; predominant species in Africa,
Haiti, Dominican Republic; present in Mexico, Central & South America, Indian subcontinent, SE
Asia, and Oceania.
4. P. ovale: mainly in Africa
• Transmission: parasites are transferred to humans via Anopheles mosquitoes.
• Clinical Presentation: illness is highly variable, but characterized by fever, chills, anemia, and splenomegaly.
Epidemiology of Malaria
• 100+ countries in Asia, Africa, Latin America, Caribbean and Pacific Islands.
• 300-500 million cases each year, 100 million annually in SSA
• 1 million death per year – mostly in infants and young children
Immunity to Malaria
• Merozoite of P. vivax needs Duffy antigen on surface of RBC >>> lack of Duffy antigen 100% protective against
PV infection.
• In West Africa, 98% of local population lacks Duffy antigen.
• P. Ovale also found in West Africa, but can invade regardless of Duffy antigen.
• Sickle cell trait provides 90-95% protection from malaria, b/c HbAS clears organisms from spleen more quickly
and inhospitable pH. Spleen key site of antibody production >>> phagocytosis of merozoites, infected RBCs, and
debris, and Cytotoxic killing of infected RBCs.
• HbF in newborns provides protection from malaria for 5-6 months.
• After a long, unbroken period of heavy exposure, strain-specific clinical immunity can develop in adults, but not
permanent.
• Malaria immunity: TH1 regulated (TNF-alpha & IFN-gamma) initially >> TNF causes fever which inhibits
parasite growth. Later antibody depedent TH2 regulated >>> opsonization of parasites and infected RBCs with
IL-4, IL-5, IL-6, IL-10.
Cerebral Malaria
• Life-threatening complication of P. falciparum infection.
• Coma or impaired neural status during malaria infection needs to be distinguished from other causes of neuro
deficits such as hyperpyrexia, hypoglycemia, and concurrent infection.
• Seizures >>> coma or decreased consciousness.
• Nuccal rigidity and photophobia do NOT occur, but patients can develop neck retraction, opishotonos, gaze
disorders and posturing.
• Pathogenesis: altered RBC rheology, upregulation of cytokines (TNF-alpha, IL-1), upregulation of endothelial
receptors (ICAM-1, CD36, ELAM-1, Thrombosondin), cytoadhesion (high sequestration in brain capillaries
correlates with high mortality).
• Corticosteroids can increase mortality.
• Antipyretics, antiemetics, and anticonvulsants can be used.
Blackwater Fever
• Etiology unknown, but may be the following:
1. G6PD deficient individuals with ingestion of oxidant drugs +/- malaria.
2. G6PD deficient + malaria + Quinine
3. severe quinine-treated malaria with normal G6PD
4. unknown how Quinine is involved.
• Hemoglobinuria
• Jaundice
• Dark urine
• Oliguria or anuria (typically <200 ml/day)
• Nausea & vomiting of bile
Diagnosis of Malaria
• Malaria is a lab diagnosis. Important to examine several sequential blood smears for presence of parasitized
erythrocytes. Initial smear may be negative, b/c symptoms can occur a few days before the appearance of infected
erythrocytes at detectable levels.
• Ideally, both thick & thin smears should be obtained and examined on multiple occasions over a 72-hour period
before diagnosis of malaria is excluded.
• New tests can detect parasites at lower levels.
• Rapid Diagnostic Tests (RDT), which are immunochromatographic, are based on capture of parasite antigen
from peripheral blood using monoclonal antibodies prepared against a malaria antigen target.
1. malaria antigens currently targeted by RDT are P. falciparum histidine-rich proteins
(HRP-2), pLDH, and Plasmodium aldolase.
• Thick blood smears are prepared with Giemsa stain in a manner that optimizes parasite detection, but is
unreliable for identification of species. Uses 30-40 microliters of blood >>> can’t see through it on microscope so
lyse RBCs and then stain.
• Thin blood smears are used for species identification, and prepared same as routine hematologic smears. Uses
about 10 microliters of blood, morphology of parasite in relation to RBC is preserved.
• In addition to species identification, the degree of parasitemia should be estimated >>> prognostic implications in
severe PF infections. At low levels of parasitemia, this can be done via thick smears, but at higher levels smears
should be examined at several oil immersion fields.
• Blood cultures should be obtained due to possible presence of coincidental bacterial infection (e.g. Typhoid).
• Should not have parasites in blood after 4-5 days of treatment >>> if there are, then organism is chloroquine
resistant.
Left image: Plasmodium falciparum, ring forms. Right image: Plasmodium falciparum diagnostic sausage or banana-
shaped gametocyte.
Initial Evaluation of Newly Diagnosed Case
• Percentage parasitemia
• Blood cell count
• Platelet count
• Electrolytes
• Creatinine levels
• Urea
• Ca2+
• Glucose
• Liver enzymes
• Coagulation tests
• In patients with severe malaria or symptoms of respiratory distress, lactate and blood gas analysis should be
obtained.
• After treatment or before travel, glucose 6-phosphate dehydrogenase levels should be determined.
Malaria Prophylaxis
• Doxycycline: problems is side effects like photosensitivity, Stevens-Johnson syndrome, and GI effects.
• Primaquine: good with minimal side effects, but not FDA approved yet.
• Malarone: most popular, few side effects, but very expensive.
• Mefloquine: very effective, but major problem with side effects – particularly in those with depression or anxiety
disorders >>> use Tetracylcine or Malarone instead. Also, severe nightmares.
Prevention of Malaria
• Sleep in screened rooms, and use permethrin-treated bed nets
• Pyrethrum insect spraysor repellents with N, N-diethyl-m-toluamide (exposure to high levels for prolonged
periods of time >>> neurotoxicity, particularly seizures in children, so use <35% DEET)
• Minimize exposed skin from dusk until dawn
• Use Mefloquine or Atovaquone-proguanil for prophylaxis (except in few areas where chloroquine resistant malaria
has not been described). Alternative: Doxycycline.
Anti-malarial Drugs
• Chloroquine phosphate (Aralen)
• Chloroquine sulfate (Nivaqine)
• Mefloquine (Larium)
• Quinine & Quinidine
• Primaquine phosphate
• Pyrimethamine-sulfadoxine (Fansidar)
• Tetracylcines: Tetracylcine, Doxycycline, Demeclocycline & Minocycline
• Macrolides: Erythromycin, Azithromycin, Clarithromycin
• Lincomycins: Clindamycin (Cleocin)
• Proguanil-Atovaquone (Malarone)
• Artemesinin (Artesunate & Artemether)
• Halofantrine (Halfan)
• Fluorquinolones
Chloroquine
• Chloroquine phosphate (Aralen) & Chloroquine sulfate (Nivaqine) are 4-aminoquinolones that act on the
erythrocytic stage of all species of Plasmodium.
• Drug of choice for treatment of susceptible strains of PF, PV, PO, and PM.
• Does not affect liver schizonts >>> doesn’t prevent relapse of P. vivax or P. ovale >>> subsequent treatment with
Primaquine should be used to avoid relapses.
• Primaquine should NOT be given to patients with G6PD deficiency.
• Adverse Effects: occur in 25%
1. GI upset
2. visual disturbances
3. headache
4. non-allergic pruritis
5. Via IV, hypotension and heart block can also occur, particularly if drug is administered rapidly.
Mefloquine
• Mefloquine/Larium is a r-quinolinemethanol that acts on the erythrocytic stage of all species of Plasmodium -
including most Chloroquine-resistant P. falciparum (CRPF). Does not affect liver schizonts.
• In US, recommended for prophylaxis not treatment, b/c effective treatment doses >>> CNS effects including
seizures and psychosis. Can be confused with Cerebral Malaria.
• Contraindicated in patients with history of:
1. epilepsy
2. psych disorders
3. cardiac conduction disorders (b/c can cause QT prolongation)
4. use with caution with patients on Beta blockers
• In theory, Quinine & Quinidine may exacerbate the cardiodepressant effects of Mefloquine >>> so loading doses
should not be given in patients who have recently taken Mefloquine.
• Teratogenic in rats, but has been taken in 2nd and 3rd trimesters w/o reported fetal malformations; 1st trimester
effects are unknown. Should be avoided in pregnancy.
• Due to long half life, patients should wait 3 months after stopping Mefloquine before getting pregnant.
Primaquine Phosphate
• Is an 8-aminoquinolone active against tissue schizonts and gametocytes
• Indication: prevent relapse of PV or PO
• Contraindicated in patients with G6PD deficiency (causes hemolysis), and in pregnancy
Pyrimethamine-sulfadoxine (Fansidar)
• Indication: treatment of CRPF malaria
• Not used for prophylaxis due to fatalities from serious cutaneous allergic reactions (Stevens-Johnson Syndrome)
occurs in 1/20,00 patients with 5 weeks
• Patients with G6PD deficiency can develop hemolysis
Tetracyclines
• Types: Tetracycline, Doxycycline, Demeclocycline, Minocycline
• Indication: active against CRPF malaria; some activity against schizonts, but not enough to be used to prevent
relapse.
• Doxycycline (Vibramycin) is used for prophylaxis in patients unable to take Mefloquine
• or in areas of Mefloquine resistance (Vietnam and Thai-Kampuchean border).
• Adverse Effects:
1. GI intolerance
2. photosensitivity
3. vaginal candidiasis >>> women can treat with Fluconazole
Proguanil-Atovaquone (Malarone)
• Indication: active against erythrocytic and extraerythrocytic schizonts. Atovaquone is highly effective against PF,
but high recrudescence rate with development of resistance when used as monotherapy. So used in combo with
Proguanil.
• Mechanism: inhibits mitochondrial electron transport.
• Adverse Effects: abdominal pain, diarrhea, nausea, coughing.
Artemisinin
• Derived from Chinese medicinal plant Qinghao (Artemisia annua)
• Rapidly acting anti-malarial effective against multidrug resistant P. falciparum malaria.
• Mode of delivery: IV, oral, suppository
• Not available in US
Halofantrine (Halfan)
• Is a phethrenemethanol derivative of an amine alcohol that requires fat for optimal absorption.
• Recrudescence is a reported problem after single dose treatment.
• Adverse effects: cough, pruritis, hemolytic anemia, QT prolongation, PR prolongation, Torsade de pointes. Use
limited by side effects and cardiotoxicity.
Fluoroquinolones
• Have anti-malarial activity in vitro, but not proven effective in vivo.
Babesiosis
• Distribution: localized to only NE US (particularly Cape Cod, Martha’s Vineyard, CT, & Long Island)
• Disease due to Babesia microti, which leads to infection of RBCs in wild and domestic animals with a malaria-
like organism.
• Transmitted by Ixodes ticks. A 3 host tick: hatches from egg >>> becomes larvae >>> feeds on animals such as
mice and birds >>> molts into nymph stage >>> becomes active the following year >>> looks for another host to
feed again >>> adult female feeds on deer and that’s where males and females copulate. Deer is not a host – just
site of mating and food.
• Hemolytic anemia, fever, hemoglobuinuria and malaria-like systems.
• Particularly problematic in people without spleens!
• Can have co-infection with AIDS, Ehrlichiosis & Lyme Disease.
• Diagnosiss: blood smear and PCR, look for Maltese Cross on blood smear – pathognomonic!
• Treatment: Clindamycin or Erythromycin + Quinine. Atovaquone + Azithromycin best treatement, particularly
in AIDS patients.
Image of Babesisos: with Maltese Cross!
Hemoflagellates/Kinetoplasts
• Have a single large organelle that is basically a mitochondria. Called a hemoflagellate because found in blood.
1. American Trypanosomiasis/Chagas’ Disease: Trypanosoma cruzi, vector is Reduvid bug
2. African Tropanosomiasis/African Sleeping Sickness Trypanosoma: Trypanosoma brucei gambiense,
vector is Tsetse fly
3. African Tropanosomiasis/African Sleeping Sickness: Trpanosoma brucei rhodesiense, vector Tsetse fly
4. Animal trypanosomiasis in Africa
5. Leishmania: cutaneous & visceral (vector is Sandfly)
Life Cycle:
An infected triatomine insect vector (or “kissing” bug) takes a blood meal and releases trypomastigotes in its feces near
the site of the bite wound (Chagoma forms around lips or eyes of child that was bitten). Trypomastigotes enter the host
through the wound or through intact mucosal membranes, such as the conjunctiva . Common triatomine vector species
for trypanosomiasis belong to the genera Triatoma, Rhodinius, and Panstrongylus. Inside the host, the trypomastigotes
invade cells, where they differentiate into intracellular amastigotes . The amastigotes multiply by binary fission and
differentiate into trypomastigotes, and then are released into the circulation as bloodstream trypomastigotes .
Trypomastigotes infect cells from a variety of tissues and transform into intracellular amastigotes in new infection sites.
Clinical manifestations can result from this infective cycle. The bloodstream trypomastigotes do not replicate (different
from the African trypanosomes). Replication resumes only when the parasites enter another cell or are ingested by another
vector. The “kissing” bug becomes infected by feeding on human or animal blood that contains circulating parasites .
The ingested trypomastigotes transform into epimastigotes in the vector’s midgut . The parasites multiply and
differentiate in the midgut and differentiate into infective metacyclic trypomastigotes in the hindgut .
Left image: Trypanosoma cruzi in blood smear; note "C" shape and large posterior kinetoplast. Right image:
Xenodiagnosis of Chagas' disease with Reduviid bug.
Specific Problems
• Transfusion Chagas’ Disease
• HIV/AIDS: acts as OI in AIDS patients, have necrotizing encephalitis and acute myocarditis.
• Congenital Chagas’ Disease
• Transplantation (organ and stem cell)
Prevention of Chagas’
• Avoid sleeping in dilapidated dwellings
• Insect repllents
• Mosquito nets
• Avoid blood transfusions in Latin America
Life Cycle:
During a blood meal on the mammalian host, an infected tsetse fly (genus Glossina) injects metacyclic trypomastigotes into
skin tissue. The parasites enter the lymphatic system and pass into the bloodstream . Inside the host, they transform into
bloodstream trypomastigotes , are carried to other sites throughout the body, reach other blood fluids (e.g., lymph, spinal
fluid), and continue the replication by binary fission . The entire life cycle of African Trypanosomes is represented by
extracellular stages. The tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal on an
infected mammalian host ( , ). In the fly’s midgut, the parasites transform into procyclic trypomastigotes, multiply by
binary fission , leave the midgut, and transform into epimastigotes . The epimastigotes reach the fly’s salivary glands
and continue multiplication by binary fission . The cycle in the fly takes approximately 3 weeks. Humans are the main
reservoir for Trypanosoma brucei gambiense, but this species can also be found in animals. Wild game animals are the
main reservoir of T. b. rhodesiense.
Diagnosis of Trypanosomiasis
• Serology and PCR – must use thick & thin smears and examine buffy coat!
Trypanosoma brucei rhodesiense in blood
Pentamidine
• 10 IM injections given on alternate days.
• Effective against early stage TBG, less so for TBR, and ineffective against later stage of both organisms.
• Does not kill organisms outright.
Suramin
• Early stage TBR
• Given in 5 IV injections
• Very long half life
• Binds to plasma proteins including LDL which trypanosomes avidly bind to and endocytose >>> slow decrease in
parasite numbers.
Eflornithine (DFMO)
• Enzyme-activated inhibitor of ornithine decarboxylase (ODC), the lead enzyme of polyamine biosynthesis.
• Give IV 4 doses every 6 hours for 2 weeks.
• Short half life
• Costly and lengthy treatment
• Not trypanocidal, but blocks bloodstream division of trypanosomes.
Types of Leishmaniasis
• Visceral Leishmaniasis (VL or Kala-Azar): fever, wasting, panctyopenia, HS, hyper-IgG
• Cutaneous Leishmaniasis (CL): skin ulcers
• Mucosal Leishmaniasis (ML or MCL): nasopharyngeal ulcers
Importance of Leishmaniasis
• Paradigm for studying cell mediated immunity, so important for scientific research.
Leishmaniasis
• Leishmania are hemoflagellates with a promastigote stage in insect vector and amastigote stage in
macrophages of vertebrate host (humans).
• Leishmaniasis is a disease caused by protozoa of the Leishmania species, which is transmitted by the bite of a
female sandfly. Clinically, Leishmaniasis is classified as:
Cutaneous Leishmaniasis (CL): skin ulcers
Mucocutaneous Leishmaniasis (ML or MCL): naso-pharyngeal ulcers.
Visceral Leishmaniasis (VL): fever, wasting, pancytopoenia, HS, hyper-IgG
• The prevalence of the disease is increasing, with estimates of 12 million people currently infected worldwide.
Once thought of as a disease affecting only rural areas, the disease remains common in the face of increasing
urbanization.
• Distribution: incidence is highest in tropical and subtropical regions where conditions are favorable for sandflies.
Leishmaniasis is found in some parts of 88 countries within Central America, South America, Africa, India, the
Middle East, Asia, southern Europe, and the Mediterranean.
Most Cutaneous leishmaniasis seen in Columbia, Brazil, Peru, Afghanistan, Iran, Iraq & Saudi Arabia
Visceral leishmaniasis is most common in Bangladesh, Brazil (epidemic in northeastern Brazil), India, Nepal,
and Sudan (on-going epidemic since 1992).
• Transmission: sandfly bite.
• Of great importance is the social burden placed by the morbidity of the disease, which can cause severe
deformities and disfigurment and lead to social isolation.
• Males are more commonly infected than females, with Visceral leishmaniasis in particular, having been shown to
be twice as common in males.
• Opportunistic infection in AIDS patients.
Causal Agent:
Leishmaniasis is a vector-borne disease that is transmitted by sandflies and caused by obligate intracellular protozoa of the
genus Leishmania. Human infection is caused by about 21 of 30 species that infect mammals. These include the L.
donovani complex with 3 species (L. donovani, L. infantum, and L. chagasi); the L. mexicana complex with 3 main species
(L. mexicana, L. amazonensis, and L. venezuelensis); L. tropica; L. major; L. aethiopica; and the subgenus Viannia with 4
main species (L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. (V.) peruviana). The different species are
morphologically indistinguishable, but they can be differentiated by isoenzyme analysis, molecular methods, or monoclonal
antibodies.
Leishmaniasis is transmitted by the bite of female phlebotomine sandflies. The sandflies inject the infective stage,
promastigotes, during blood meals . Promastigotes that reach the puncture wound are phagocytized by macrophages
and transform into amastigotes . Amastigotes multiply in infected cells and affect different tissues, depending in part on
the Leishmania species . This originates the clinical manifestations of leishmaniasis. Sandflies become infected during
blood meals on an infected host when they ingest macrophages infected with amastigotes ( , ). In the sandfly's midgut,
the parasites differentiate into promastigotes , which multiply and migrate to the proboscis .
Epidemiology of Leishmaniasis
• Canine: Dogs in South America, Mediterranean, China, Brazil; Dogs >>> Foxes in Brazil; Central Asia: Jackals
• Rodents in East Africa (rats, gerbels, squirrels)
• India no reservoir; human hosts
• Congential, lab, person-to-person
• Immunosuppression: co-factor in HIV/AIDS; steroids; chemo; transplants
Visceral Leishmaniasis
• Kala-azar
• Mild visceral disease which does not progress
• Visceral disease as a component of AIDS
• Sudanese disease “killing disease” is very virulent + PKDL
severe burning feet
gall bladder disease (Cholecystitis)
congenital transmission common
PKDL in 56% of cases within 56 days.
Clinical Presentation of VL
• Onset: gradual to abrupt
• Incubation: 3-8 months (can be years)
• Fever: double daily spikes that can be variable or intermittent, can be misdiagnosed as Malaria
• Anemia: very characteristic of this disease b/c RBCs are hemolysed, sequestration of RBCs by Spleen, hemorrhage,
and marrow replacement.
• Leukopenia: Eosinophils are almost always absent, and low number of neutrophils.
• Low Platelets >>> bleeding.
• Hyperglobulinemia: CIC, RF, GN
• Hepatosplenomegaly: spleen usually enlarges before liver, and Splenomegaly is almost always seen with this disease.
• sometimes Lymphadenopathy
• Grayish or blackish skin: in African form usually hyperpigmented skin, whereas in Indian form skin is
hypopigmented.
• VL, DCL & Lepromatous Leprosy all can look the same clinically >>> biopsy to differentiate.
Diagnosis of Leishmaniasis
• Kinetoplast makes diagnosis – have to see this, otherwise could be confused with Chagas, Toxoplasmosis or other
diseases!
• Formalin Gel Test: not specific diagnostic test, but used frequently in field in countries where this disease is
common.
• Demonstration of organism on Giemsa stained slides with bone marrow biopsy, splenic aspiration (diagnostic
procedure of choice but highest risk), liver biopsy, buffy coat in blood (sometimes). Culture specimen in NNN
medium. Do isozyme analysis, use species specific DNA probe and PCR, or Monoclonal antibodies.
• Serological Diagnosis
use antibodies with IFA, ELISA, DAT. Don’t see ABs in CL >>> so negative, but will be positive in VL.
DHR: will be positive with CL, and negative with VL.
American CL
• Zoonosis
• L. braziliensis: rodents, can metastasize to mucous membranes
• L. panamensis: sloths
• L. guyanensis: sloths and anteaters
• L. peruviana: dogs
• L. mexicana: rodents
• L. amazonensis: rodents and marsupials