The Apicomplexans
Babesia: Describe the presentation of Babesia
-1-4 wks incubation with malaise, occasional hemolytic anemia and renal failure -Asplenia, immuosuppression and advanced age are risks for severe disease
Plasmodium falciparum: How many cases every year? In some countries, what does it account for?
-1-5 hundred million clinical cases every year In some countries it accounts for: -40% of public health expenditure -30-50% of inpatient admissions -50% of outpatient visits
Plasmodium falciparum: How many Plasmodium species are there? What kinds of species?
-170 Plasmodium species -Avian, reptillian, and mammalian Plasmodium species
Plasmodium falciparum: What is the prevalence of malaria?
-2.3 billion people live in risk areas (40% of the world) -WHO estimated that in 2015 malaria caused 214 million clinical episodes & 400,000 deaths. -90% of malaria deaths are in Africa -The majority of deaths are children -Things are getting better: between 2000 and 2015 incidence rates fell by 37%, mortality rates by 60% -Malaria is the 5th cause of death from infectious diseases worldwide (after respiratory infections, HIV/AIDS, diarrheal diseases & Tbc. -Malaria is the 2nd leading cause of death from infectious diseases in Africa after HIV/AIDS).
Plasmodium falciparum: Describe the vector of the parasite
-Anopheline mosquito (Anopheles spp.) -Approximately 400 Anopheles spp, only 30-40 can transmit malaria -Female feeds on blood -Nighttime feeders
Plasmodium falciparum: Who does malaria kill?
-As child grow chances of severe malaria are less: a case of acquired immunity. -But can still get normal malaria: immunity to the disease manifestation not the microbe! -Reason: Specific P. falciparum 'strains' cause specific complications
Toxoplasma gondii: Describe the rates of Congenital Toxoplasmosis
-Between 400 and 4,000 cases annually in the US -Between 1 to 10 in every 10,000 live births -Mandatory testing during pregnancy in many European countries but not in the US
Plasmodium falciparum: Describe Chloroquine
-Disrupts hmg digestion and heme detoxification -Ok in pregnancy -Only sensitive strains in Central America
Plasmodium falciparum: Describe the disease when X-chromosome linked gene G6PD produces ubiquitous enzyme
-Erythrocytes unable to adequately respond to oxidative stress, which leads to premature hemolysis of RBC and anemia -Primaquine depletes erythrocyte of reduced glutathione and potentiates the underlying hemolytic anemia Favism ==> oxidative stress
Describe effect of Plasmodium falciparum
-Fevers and symptoms spike every 48 hours, but can seem more constant -Incubation time 7-12 days -No relapse -Prevalent in all continents -Most severe and responsible for almost all deaths
Describe effect of Plasmodium vivax
-Fevers every 48 hr -Incubation time 15 days to 9 months -Relapses -Mild disease -Infects only Duffy + reticulocytes, so Duffy - individuals are immune -Most widespread
Describe effect of Plasmodium ovale
-Fevers every 48 hrs -Incubation time 15 days - 4 years -Relapses (up to 5 years) -Least prevalent (mostly in W. Africa)
Describe effect of Plasmodium malariae
-Fevers every 72 hrs -Incubation over 3 weeks -Incomplete treatment can lead to a low persistent parasitimia -Can survive in peripheral blood up to 20 years in low numbers -Most persistent but least severe -World wide distribution
Cryptosporidium parvum: What are the clinical manifestations in healthy individuals?
-Frequent, watery diarrhea (10 l of feces a day in severe cases) -Nausea and Vomiting -Abdominal cramps -Low-grade fever -Lasts 1-2 weeks
Plasmodium falciparum: Describe Artemisinin (given in combo as ACT)
-From the shrub Artemisia annua -Newest anti-malarial -"Resistance" starting to show up in South east Asia
Plasmodium falciparum: Describe the diagnosis of malaria
-In US travel history of patient is important 1. If malaria is suspected giemsa-stained thin or thick blood smears should be examined: -Repeated blood smears might be needed to see parasites -P. vivax and P. ovale infect reticulocytes (young RBCs), so fewer infected cells in circulation 2. Antigen tests: one immunochromatographic dip-stick test in USA (BinaxNOW Malaria) FDA cleared for P. falciparum & P. vivax testing to be used only in hospital & commercial labs; microscopic confirmation required - test lacks sensitivity 3. Speciation can be important (Can be done with certain stains, PCR most accurate (done only at CDC and a few labs))
Plasmodium falciparum: Describe Erythrocytic schizogony
-In red blood cells -Early form known as 'ring stage' -Undergoes "trophic" (growth) phase (Ingestion of host hemoglobin - As the trophozoite grows, dark malarial pigment may collect within the cytoplasm as the Hgb is converted into insoluble hematin) -Division by schizogony -Erythrocyte is lysed to release merozoites -4-36 merozoites are released
Plasmodium falciparum: Describe Malaria as a disease
-Initially flu-like symptoms (fever, headache, vomiting) -Symptoms are sudden and can be severe (malarial paroxysm) General malaria: -Intermittent fevers -Anemia -Jaundice -Enlarged spleen
Plasmodium falciparum: Describe Malaria, the disease - what are the symptoms?
-Initially flu-like symptoms (fever, headache, vomiting) -Symptoms are sudden and can be severe (malarial paroxysm) -Intermittent fevers -Anemia -Jaundice -Enlarged spleen *Note: Symptoms can go up and down in a very specific pattern!!!
Plasmodium falciparum: Describe Malaria during pregnancy
-Malaria can occur in pregnant women, even those clinically immune before pregnancy -Can result in maternal anemia, increase risk of miscarriage, still birth and low birth weight -Most common in first pregnancies, infection during subsequent pregnancies not as dangerous
Plasmodium falciparum: Describe Cerebral malaria
-Manifests as impaired state of consciousness with or without seizures -Rapidly progresses to coma and death -Universally fatal if untreated -With treatment 15 percent of children and 20 percent of adults die -Over 10% of those who survive have persistent neurologic abnormalities -Associated with retinal whitening
Plasmodium falciparum: Describe Mefloquine (aka Lariam)
-OK for pregnant woman
Cryptosporidium parvum: What are the clinical manifestations in immunocompromised/AIDS patients at risk for severe disease:
-Persistent infection leads to life-threatening diarrhea. -Dissemination from gut to hepatobiliary and pancreatic ducts. Results in cholangiohepatitis, cholecystitis (gallbladder), choledochitis (bile duct), or pancreatitis
Toxoplasma gondii: Describe the effect of Toxoplasma gondii in the immunocompromised host
-Reactivation of cysts or primary infection in immunocompromised (AIDS) patients can lead to encephalitis -Toxoplasmic encephalitis in 25-50% of AIDS patients seropositive for Toxoplasma and with CD4+ T cell counts of less than 100/l -Clinical features of TE: headache, confusion, ataxia, hemiparesis and blurred vision -Development of brain lesions that can be detected by CT scan -Toxoplasmosis can be seen in lymphoma and leukemia patients Encephalopathy, menigoencephalitis and cerebral mass lesions *95% of toxoplasmic encephalitis cases in AIDS patients are due to reactivation of existing cysts. TE is usually a multifocal process that arises spontaneously Although Toxoplasma can infect any organ the brain is the most common focus of disease in AIDS patients. This is likely due because of the immunological properties of the brain and not a true tissue tropism of the parasite. Other organs at risk are heart and eyes.
Plasmodium falciparum: Describe Malaria relapse
-Relapse can occur years after primary infection -Only in P. vivax and P. ovale -The sporozoite stays in liver cell and does not divide -Latent form: hypnozoite (in liver cell)
Plasmodium falciparum: Describe Doxycycline
-Related to tetracycline, make sure not allergic
Plasmodium falciparum: Describe the complications caused by P. falciparum
-Severe anemia -Cerebral Malaria (Coma) -Renal and hepatic disease -Blackwater fever -Enlargement of spleen (Tropical Splenomegaly Syndrome) -Dysenteric Malaria -Can cause severe disease during pregnancy (placental malaria)
Plasmodium falciparum: Describe the complications of malaria?
-Severe anemia -Cerebral Malaria (Coma) -Renal and hepatic disease -Blackwater fever (dark urine due to kidney damage) -Enlargement of spleen (Tropical Splenomegaly Syndrome) -Dysenteric Malaria -Can cause severe disease during pregnancy (placental malaria)
Plasmodium falciparum: Describe the recurrent fevers
-The cycle of fevers and symptoms is coincident with the erythrocytic cycle -Fever onset coincides with lysis of red blood cells -If infection is not synchronous the fevers can occur at 24 hours intervals
Toxoplasma gondii: Describe toxoplasma in the immunosuppressed host
-Transplant patients on immuno suppressors are at risk for Toxoplasmosis -Infection can come from the host or the transplanted organ
Toxoplasma gondii: Describe the treatment of toxoplasmosis
1. Approved drug: sulfadiazine + pyrimethamine: -Pyrimethamine inhibits folate synthesis and DNA and RNA synthesis in the parasite -Not effective against encysted form -Poorly tolerated, patient might require folinic acid 2. Alternative treatment clindamycin and pyrimethamine 3. Atovaquone can also be used 4. In France spiramycin is prescribed during pregnancy to prevent transmission in utero *Notes: Sulfadiazine and pyrimethamine = Fansidar a drug commonly used in Malaria treatment. Although resistance in plasmodium is now rampant. Toxoplasma (and plasmodium) cannot use preformed pyrimidines (U, C and Ts for DNA and RNA) and thus needs to synthesize them de novo. The dihydrofolate cycle is essential for the synthesis of pyrimidines. Pyrimethamine acts by inhibiting the enzyme dihydrofolate reductase and as a consequence it affects folate synthesis and the synthesis of DNA and RNA. Sulfadiazine also inhibits folate synthesis. Since folate synthesis is not a essential to the host for DNA and RNA synthesis (it can salvage pyrimidines) the effect is more or less specific. Nonetheless, pyrimethamine can cause bone marrow depression and therefore folinic acid might have to be administered to patient. Spiramycine is available in the US on a case by case basis for the treatment of congenital toxoplasmosis. In Plasmodium resistance to pyrimethamine comes about from mutations in the dihydrofolate reductase gene. Since human to human (adult) transmission of Toxoplasma is not possible (unless you are a cannibal) drug resistance is not common. Nevertheless, resistant strains can arise in farm animals treated with sulfa drugs and these can then be passed on to humans in food.
Plasmodium falciparum: What are the 7 main anti-malarial drugs?
1. Chloroquine 2. Pyrimethamine and sulfadiazine (AKA Fansidar) 3. Artemisinin 4. c (aka malarone) 5. Doxycycline 6. Mefloquine (aka Lariam) 7. Primaquine
Cryptosporidium parvum: Describe the diagnosis
1. Detection of oocysts in feces. -Modified Kinyoun acid fast stain -Direct/indirect immunofluorescence microscopy 2. Serology not readily available and not good in immunocompromised
Toxoplasma gondii: Describe the diagnosis of toxoplasmosis
1. Direct identification is difficult and culture is rarely done 2. Serology -IFA or ELISA -Single high IgM or very high IgG level -Test not reliable in AIDS 3. PCR test from amniotic fluid available 4. Clinical features and response to treatment
Cryptosporidium parvum: Describe the modes of transmission
1. Human-Human: -Nosocomial: hospital acquired -Daycares (fecal-oral route) 2. Animal-Human: -Primarily from cattle -Other reservoirs include deers, swine, cats and dogs 3. Waterborne -Swimming pools -Oocysts are highly resistant to chlorine. 4. Food borne -Uncooked contaminated food *Note: Cysts are resistant to chlorine, treatment of water is insufficient. Filtration is the best way to control but it can fail. New water treatment methods are needed. Major underreported disease. Children and adults living in U.S. have 30% positive antibody test.
Toxoplasma gondii: What are the sources of human infections?
1. Ingesting cysts in undercooked or raw meat: most common in pork, lamb and goat - not as common in beef 2. Ingesting unwashed vegetables contaminated with oocysts 3. Contaminated water 4. Inhaling or ingesting oocysts in cat litter or gardens 5. Congenital (mom to fetus)
Plasmodium falciparum: Describe Malaria prevention
1. Insecticides and larvicides -DTT most successful insecticide but now banned -Newer "greener" ones are too expensive and not as effective 2. Mosquito nets -Net creates barriers between human and mosquito -If soaked in insect repellent or killer effectiveness is increased -Cost estimate $10-20 per year of life saved
Cryptosporidium parvum: Describe the treatment
1. Lack of effective anticryptosporidial drugs: -Supportive therapy only -Rehydration -Nutritional supplementation 2. AIDS patients: -Nitazoxanide (also used with children) -Paromomycin (inhibits protein synthesis and binds to 16s rRNA) -HAART (Antiretroviral therapy treatment in AIDS patients; treatment shows complete clinical, microbiological and histological recovery) Treatment is dependent upon CD4+ cell counts: <180 cells/mm3 treated aggressively >180 cells/mm3 spontaneous recovery
Plasmodium falciparum: What are the 4 human Plasmodium spp:
1. P. vivax 2. P. malariae 3. P. ovale 4. P. falciparum
Plasmodium falciparum: What is the host range for genetic factors in malaria?
1. P. vivax uses the Duffy blood group antigen as its receptor to attach to & invade RBCs -RBCs of most West Africans, in contrast to RBCs of Europeans, lack the Duffy Ag. -Thus, West Africans are resistant to P. vivax infections. 2. Sickle hemoglobin (heterozygotes) protects against death & severe life-threatening P. falciparum malaria 3. Erythrocyte glucose-6-phosphate dehydrogenase deficiency is associated with resistance to P. falciparum infection
What are the Apicomplexans?
1. Plasmodium falciparum 2. Toxoplasma gondii 3. Cryptosporidium
What are the 2 sub-groups with important human pathogens?
1.Insect vector borne: -Plasmodium falciparum -Babesia spp 2. Coccidians (shed in feces of definitive host) -Toxoplasma gondii -Cryptosporidium spp
Cryptosporidium parvum: How long is incubation?
3-10 days
Babesia: How is it transmitted?
A zoonosis infecting deer, cattle & rodents....man an accidental host. Lxodes dammini (tick) transmits Babesia microti (also transfusion-related infections)
Cryptosporidium parvum: Who are at risk?
AIDS patients at risk for severe disease
Plasmodium falciparum: Describe the life cycle of Plasmodium falciparum
After liver cell stage ==> RBC and can't go back to liver stage ==> repeat cycle *Mosquitoes = definitive host
Babesia: Where is Babesia endemic?
Babesia microti is endemic in NE seaboard of US and occasionally infects humans
Toxoplasma gondii: Describe the chronic form and acute form
Bradyzoites can establish the chronic form and the other can establish the acute form
Toxoplasma gondii: Can invade what types of cells?
Can invade almost any nucleated cell (gets everywhere!!!)
Plasmodium falciparum: Describe primaquine
Can't use if deficient in G6PD
Plasmodium falciparum: Describe the P. falciparum mechanism of pathogenesis for "cerebral and placental malaria"
Cerebral and placental malaria: -Erythrocytes containing parasites adhere to endothelial cells (aka cytoadherence or sequestration) -The adhered erythrocytes can block flow cause damage -Induction of cytokines in brain, placenta and other organs -Damage of blood vessel in brain (hemorrhages) -Infected erythrocytes adhere to placental endothelium and slows blood flow in placenta
Toxoplasma gondii: Describe Congenital Toxoplasmosis
Congenital Toxoplasmosis: -Result of a primary infection during pregnancy -Infection during 1st and 2nd trimester can lead to fetal death -Children asymptomatic at birth might later develop neurological problems, chorioretinitis or mental retardation Clinical manifestations: hydrocephalus, calcification in the brain, hepatosplenomegaly, jaundice, fever, anemia, pneumonia, blindness
Toxoplasma gondii: Keeping cats?
Considerations: -Inside cats are rarely infected -Don't feed cat raw meat -A cat can only shed oocysts once for 2 weeks during its lifetime -Get help in changing cat litter -Gardening is a bigger risk. Use gloves and mask to garden.
Cryptosporidium parvum: Causes what type of disease?
Cryptosporidia causes a zoonosis first discovered among veterinary students and animal handlers who acquired it from calves they were treating for diarrhea.
Plasmodium falciparum: Diagnose when you have Erythrocytic schizogony
Early on when parasite gets in, form ring stage ==> starts growing as an early trophozoite ==> many nuclei put into one parasite and it bursts out!! This cycle takes ~48 hours
Toxoplasma gondii: Describes its host range?
Exceptionally broad host-range: all warm blooded animals (hawks, chickens, bears, cats, deer, humans...)
Plasmodium falciparum: Why test for Glucose 6-Phosphate-Dehydrogenase Deficiency?
G6PD functions in the reduction of glutathione, which is key in RBC to detoxify the peroxides that are formed during O2 loading and unloading X-chromosome linked gene G6PD produces ubiquitous enzyme: -Most common disease-producing enzyme defect of humans: 400 million worldwide, most prevalent in Africa and the Mediterranean -10% African American males are G6PD deficient
Toxoplasma gondii: Describe the prevalence
High prevalence: 15-30% US up to 80% in France -World-wide distribution -Add it all up ... most "successful" protozoan parasite on earth
Plasmodium falciparum: Describe the Erythrocytic cycle and pathogenesis
Lysis of red blood cells contributes to fevers: -Liberation of metabolites during lysis -Elevated levels of IL-1 & TNF consistently found in patients with malaria -High fever results in significant vasodilatation. Lysis of the red blood cell is one of the factors contributing to malarial anemia
Cryptosporidium parvum: Now recognized as a significant cause of __________ in otherwise healthy children
Now recognized as a significant cause of diarrhea in otherwise healthy children
Toxoplasma gondii: Describe the lifestyle
Oocysts taken up by humans/animals and in the stomach become tachyzoites (become fat - the repeating dividing cycle may cause damage), but we are good at recognizing! So parasites change into another form called "Bradyzoites" (can get it from other organisms now (from your cat, eating raw meat, etc.)
Plasmodium falciparum: Describe the distributions of P. falciparum and P. vivax
P. falciparum (above) P. vivax (below)
Babesia: Describe the diagnosis of Babesia
Parasites can be seen in blood smears and look like Plasmodium
Plasmodium falciparum: What is the parasite of Malaria?
Plasmodium
Plasmodium falciparum: Describe Pyrimethamine and sulfadiazine (AKA Fansidar)
Pyrimethamine and sulfadiazine (AKA Fansidar): anti-folate synthesis
Cryptosporidium parvum: Describe the life cycle
Reproduces asexually and sexually in GI tract. Oocysts are the products of sexual mating and are the infectious stage. Large numbers in feces. -Acid-fast oocysts containing 4 sporozoites ingested -Sporozoites released & attach to microvilli -Reproduce asexually (become schizonts that release merozoites) and sexually (merozoites become gametes that mate & fuse to form oocysts) -Thick-walled oocysts are source of spread & are infective when passed *Note: They live in brush-border: intracellular but extracytoplasmic
Plasmodium falciparum: Describe the P. falciparum mechanism of pathogenesis for "severe anemia"
Severe anemia: -Infected red blood cells clump with other infected and uninfected red blood cells -Clumping known as rosetting -When the infected cells lyse so do the uninfected cells *Note: Cytoadherence is unique to P. falciparum, this is why it is the most lethal of the Plasmodium species that infect humans.
Why are they called Apicomplexans?
So called because a unique complex of organelles at the apical (front) end of the parasites
Cryptosporidium parvum: Describe the largest waterborne outerbreak
The largest waterborne outbreak of Cryptosporidium in the United States occurred in Milwaukee, Wisconsin, in 1993: more than 400,000 persons were affected, and more than 4,000 people were hospitalized after contamination of the municipal water supply.
Toxoplasma gondii: Why is it so prevalent??
Toxoplasma has the remarkable ability to infect almost every warm blooded animal including humans, birds, whales and sea otters. As this wasn't impressive enough, Toxoplasma can invade any nucleated cell within the organisms it infects. In addition, is highly prevalent in all the species it infects. In humans the prevalence can go between 15% in the US to 85% in France. Toxoplasma is also found in all climates and parts of the world. When you take all this factors into account, Toxoplasma is the most successful parasite of warm blooded animals on earth. But besides being good at being a parasite, Toxoplasma is a good research system as you will see later on.
Plasmodium falciparum: What is Erythrocytic schizogony?
Type of asexual division of certain apicomplexans. Nucleus divides several times within the cell. The cell gets segmented, each segment getting a nucleus and a set of organelles.
Plasmodium falciparum: What kind of pathogen is apicomplexan?
Vector-borne
Plasmodium falciparum: Describe the rate of paroxysm and fevers
With p. falciparum, fevers can be more constant
Babesia: Describe the treatment of Babesia
clindamysin + quinine
Plasmodium falciparum: Describe the parasite: all are ______ ______ species
obligate intracellular
