Viruses and Fungi Flashcards

Question

Grouping of Most Frequently Encountered Pathogenic Fungi (for Man) in the U.S., with respect to Tissue Involved and Dimorphism. Type of Mycotic Disease: Subcutaneous A. Representative Fungus (1) and MORPHOLOGY IN (Infected Tissue Room / Temperature Culture) and Life Cycle.

Answer 1

Sporothrix schenckii; Yeast; Mycelia; Dimorphism

Answer 2

1. Microsporum species; Mycelia; Mycelia; No Dimorphism*** 2. Trichophyton species; Mycelia; Mycelia: No Dimorphism*** 3. Epidermophyton floccosum; Mycelia; Mycelia; No Dimorphism*** (Diamond) Except during sexual phase. * Spherules and mold ** Different from classical temperature dimorphism ***The fungi that parasitize epidermis, nails and hair (dermatophytes) all appear alike in infected skin, but in culture may develop a variety of specialized hyphae and spore structures that differentiate diverse genera and species.

Answer 3

Dermatophytoses - localized fungal infections of the keratinized tissues (hairs, skin, nails). Infecting fungi secrete proteases that can degrade this insoluble protein. Organisms are usually saprobes and keratinized tissue is not alive. - Ringworms or Tineas.

Answer 4

1. Tinea pedis - Athlete’s foot - T. mentagrophytes 2. Tinea capitis - Ringworm of the scalp - Microsporum audouini, T. Tonsurans 3. Tinea cruris - jock itch, groin – E. floccosum, T. mentogrophytes, T. rubrum 4. Tinea unguium- onychomycosis - nails - T. rubrum, T. mentogrophytes 5. Tinea corporis - Ringworm of the body - Microsporum sp., Trychophyton sp. 6. Tinea barbi – beard- Trychophyton sp. Note: bearded areas of the face and neck

Answer 5

macrocondia called aleurospores

Answer 6

1. Found in soil 2. Usually transferred from man to man 3. Occasionally from dogs and cats, e.g. M. canis D. Severity 1. Mildest infections, typical-redness, exudate, vesicles, scales 2. Increasing severity a. Mycotic folliculitis b. Temporary baldness c. Suppuration and kerion d. Connective tissue involvement 3. Nail infections cause nail degradation, hyperkeratosis in seniors

Answer 7

1. Tinea versicolor a. Skin discoloration – inhibits melanin synthesis b. Malessezia globosa and furfur (old name: Pityrosporum orbiculaire) c. Dimorphic, normal flora 2. Tinea favosa (favus) a. Localized to hair and torso b. Scales, hyperkeratosis c. Trichophyton schoeneinii 3. Piedra a. Localized to the hair b. Piedrai hortai (black) – binds very tightly to hair (tropical) c. Trichosporon beigelii (white) – looser association (subtropical) 4. Tinea nigra a. Black palms b. Tropical regions c. Exophiala werneckii

Answer 8

1. KOH prep of infected tissue shows mycelia 2. Slide culture, plate culture (slow growth, only for epidemiology) 3. Wood’s Lamp, UV light, some fungi fluoresce when infecting hair or skin

Answer 9

1. T cell reaction 2. Soluble antibodies raised but have little or no role in elimination infection 3. Secondary allergic response to many dermatophytes (dermtophytid response or id response)-itchy lesions devoid of organism Note: Id reactions (also known as "Disseminated eczema,"and "Generalized eczema") present with a variety of infectious disorders, often occurring in response to an inflammatory tinea of the feet, resulting in an eczematous dermatitis. The pruritic rash that characterizes the id reaction, which is considered immunologic in origin, has been referred to as dermatophytic. 1. 80-90% of population has an infection some time in their lifetime 2. Outbreaks common in college, army barracks, kindergartens

Answer 10

1. Skin a. Topical i. Terbinafin-Lamisil® ii. Clotrimazole-Lotrimin® iii. Desenex , Tinactin (Tolnaftate) - detergent iv. Whitfield’s ointment - salicylate and benzoate; old remedy v. Use combinations b. Systemic i. Terbinafin – for nails, long term ii. Ketoconazole 2. Hair a. Cut hair b. Griseofulvin - three to four weeks 3. Nails - Surgical removal of nail and/or systemic drug treatment a. Terbinafin - Lamisil® - several months b. Thiobendazole or itraconazole - several months c. Griseofulvin - one year

Answer 11

A. Causative Agent: Sporothrix (Sporotrichum) schenkii B. Ecology: Soil, thorns, tree bark, timber, decaying vegetables C. Pathogenesis: infection by direct inoculation below skin 1. Lymphocutaneous 2. Fixed cutaneous 3. Pulmonary 4. Systemic D. Laboratory Diagnosis: 1. Culture shows temperature dimorphism 2. Serology 3. Skin test E. Treatment: 1. Potassium iodide for surface lesions; inhibits yeast, not mold 2. Amphotericin B

Answer 12

A. Ecology: Causative agents are soil organisms: 1. Pseudoallescheria boydii, Madurella, Exophiala and Aspergillus 2. Nocardia braziliensis - actinomyces, a procaryote 3. Streptomyces sp. - actinomyces, a procaryote B. Pathogenesis: 1. Break in skin -> subcutaneous tissue-> fascia-> bone 2. Draining sinuses C. Laboratory diagnosis requires culture of organism. D. Treatment is difficult 1. thiabendazole or 5-fluorocytosine may be effective for Pseudoallescheria. 2. Sulfa and Penicillin for treating Actinomyces 3. Surgical removal of infected tissue

Answer 13

A. Causative Agents: Highly pigmented molds 1. Phialophora 2. Cladosporium 3. Fonsecea B. Ecology: soil organisms C. Pathogenesis: 1. Break in skin 2. Infection usually involves skin and subcutaneous tissue 3. Occasionally obstructs lymph channels 4. Dissemination is very rare 5. Can be complicated by more serious secondary infections D. Diagnosed by observing fungal materials in biopsy samples, sclerotic bodies. Laboratory diagnosis requires culture of organism to distinguish prokaryotic vs eukaryotic etiology E. Treatment: 1. Surgical removal of infected tissue 2. Topical administration with Amphotericin B, Thiabendazole or Terbinafine

Answer 14

A. Causative Agent: Histoplasma capsulatum - (a/k/a Emmonsiella capsulatum), ascomycete B. Ecology: Found in soil 1. Midwestern river valleys 2. High concentration in bird’s droppings C. Pathogenesis: Inhalation of spores: 1. Mild or asymptomatic in 95% of cases (approximately 40 million people are thought to be infected in U.S.) 2. Pulmonary: a. Acute: malaise, fever, respiratory problems b. Chronic infections can recur c. Healed infection gives calcified and fibrotic nodules that resemble tuberculosis 3. Disseminated throughout body: a. Lymph nodes b. Liver, spleen, heart, etc. 4. Skin involvement, eruptions D. Macrophages: Grows inside of macrophages. Mutants isolated that do not survive in macrophages and have an altered glucan on the cell surface. E. Laboratory Diagnosis: 1. Biopsy of infected tissue shows macrophages filled with yeast cells - Methaneamine silver stain 2. Culture: a. Dimorphic - 37 yeast, 25 slow growing mycelia b. Tuberculate chlamydospore 3. Serology: a. Latex agglutination b. Complement fixation c. Hypersensitivity to histoplasmin (an antigen from culture medium), Skin tests are unreliable because many people have been exposed d. Soluble antibodies have little or no role in eliminating infections F. Treatment: 1. Amphotericin B 2. Itraconazole

Answer 15

North American Blastomycosis A. Causative Agent: Blastomyces dermatitidis (a/k/a Ajelomyces dermatitidis), ascomycete B. Ecology: 1. Not known, may be soil organism related to particular vegetation 2. Mississippi Valley and Southeastern U.S., can occasionally be found further north C. Pathogenesis: 1. Inhalation or broken skin 2. Cutaneous - primary or systemic 3. Pulmonary - primary then hematogenously to bones, skin, other viscera D. Laboratory Diagnosis: 1. Direct microscopic examination of infected tissue gives thick-walled, single budded, yeast-like organisms 2. Culture on Sabouraud’s medium shows temperature dimorphism a. 37 yeast like b. 25 mycelia c. Growth inhibited by cycloheximide and chloramphenicol 3. Serology - Latex agglutination and complement fixation tests E. Treatment: 1. Amphotericin B 2. Itraconazole 3. Stilbamidine, antiprotozoal-less toxic

Answer 16

South American Blastomycosis A. Causative Agent: Paracoccidioides brazilliensis B. Ecology: Found in soil, South Texas and below C. Pathogenesis: Inhalation 1. Pulmonary - causes a mild respiratory tract infection not unlike Histoplasmosis 2. First lesions of infection are in the mucous membranes of the nose or mouth and can spread to the face 3. Lymphangetic 4. Disseminated to wide variety of tissues D. Laboratory Diagnosis: 1. Direct microscopic observation shows thick walled, yeast like organisms with multiple buds 2. Cultures show temperature dimorphism, requires rich medium for yeast phase 3. Serology - Latex agglutination and complement fixation tests 4. Skin test to hypersensitivity to secreted antigen E. Treatment: 1. Amphotericin B 2. Sulfonamides (not curative)

Answer 17

Valley fever, California fever, desert rheumatism A. Causative Agent: Coccidioides immitis B. Exhibit different dimorphism - spherule and mold C. Ecology: Found in desert soil 1. Southwestern U.S. 2. Mexico 3. Central and South America D. Pathogenesis: 1. Inhalation of arthrospores 2. Often asymptomatic 3. Primary pulmonary infections resemble tuberculosis 4. Dissemination to skin, bone and viscera is rare E. Laboratory Diagnosis: 1. Direct examination of sputum shows: a. Spherules, thick walled cells filled with ~100 endospores b. Sometimes hyphae are observed in infected lung tissue 2. Culture on medium enriched with ascites fluids gives mixture of hyphae and spherules: a. Temperature dimorphism b. Arthrospores on hyphae have unique morphology c. Serology -Latex agglutination and complement fixation d. Skin test: hypersensitivity to coccidioidin (an antigen from culture fluid) F. Treatment: 1. Amphotericin B 2. Ketoconazole

Answer 18

A. Causative Agent: Cryptococcus neoformans (a/k/a Filobasidiella neoformans), basidiomycete B. Usually a small yeast, but also has a sexual mold stage and therefore is actually dimorphic, but not classical temperature dimorphism. C. Ecology: Found in soil and especially pigeon droppings; Cryptococcus grows poorly at 42C. Organism is resistant to drying D. Pathogenesis: 1. Inhalation of urban dust 2. Causes pulmonary infections and meningitis 3. Capsules thought involved in resistance to immune response E. Diagnosis: 1. India ink to centrifuged CSF 2. Culture on Sabouraud’s agar a. Urease positive b. Other cryptococci (albidus, laurentii, terreus, etc.) c. Mycelium only during sexual stage 3. Cryptococcal antigen in CSF by latex agglutination 4. Cryptococcal antibody appearance-good prognosis 5. Additional assimilation and fermentation reactions used to identify different species F. Treatment: 1. Amphotericin B 2. Fluoconazole 3. 5-Fluorocytosine 4. Ketoconazole

Answer 19

``` OPPORTUNISTIC FUNGAL INFECTIONS I. Predisposing factors for opportunistic infections: A. AIDS B. Pregnancy C. Trauma D. Endocrine disorders E. Malnutrition F. Malignancy G. Anemias H. Post-operative state I. Antibacterial therapy J. Immunosuppressive drugs K. Oral contraceptives L. Heroin addiction ```

Answer 20

A. Most frequent causative agent - Candida albicans B. Pleiomorphic - yeast, pseudohypha or hypha C. Ecology - C. albicans ubiquitous - part of the normal flora of man (mouth, GI tract, vaginal) D. Pathogenesis - transmitted in birth canal, produces a secreted protease that is an important virulence factor E. Types of infections: 1. Thrush (oral candidiasis) 2. Skin 3. Nails 4. Vaginitis 5. Esophagitis 6. Gunshot wounds 7. Endocarditis 8. Pulmonary 9. Burns 10. Eye 11. Balanoposthitis 12. Urinary tract 13. Chronic mucocutaneous

Answer 21

1. Microscopy of stained specimens show yeast and pseudo mycelium 2. Sabouraud’s medium culture - Yeast cells with some pseudomycelia, some blastospores, a few chlamydospores. Ferments and assimilates specific sugars 3. C. albicans yeast cells or chlamydospores incubated at 37C in serum grow a germ tube 4. Other pathogenic Candida species do not give rise to germ tubes when put in serum at 37C a. C. stellatoidea b. C. parapsilosis c. C. krusei d. C. tropoicalis e. C. guillermondii f. C. glabrata

Answer 22

Treatment: 1. Clotrimazole (Lotramin®) – topical 2. Amphotericin B - systemic 3. Ketoconazole - systemic

Answer 23

A. Recently identified as a fungus rather than a protozoa based on RNA homology. Not yet possible to culture in liquid media B. Considered normal flora C. Most people infected asymptomatically and show Ab by age 3 D. Early clinical manifestation of AIDS E. Ecology - airborne pathogen F. Pathogenesis 1. Reaction of dormant organism 2. 30 day incubation period 3. Pulmonary 4. Extrapulmonary infections have been found in AIDS patients F. Diagnosis 1. Identification of organism from BAL (bronchoalveolar lavage- bronchoalveolar irrigation) 2. Silver, Calcofluor or Giemsa stain useful G. Treatment and prophylaxis- organism does not contain ergosterol 1. Trimethaprin - Sulfamethoxazole 2. Echinocandins - experimental 3. Pentamidine – rarely used H. rRNA contains self-splicing introns - potential chemotherapeutic target

Answer 24

A. Most common causative agents (not dimorphic) 1. Aspergillus fumigatus 2. Aspergillus niger 3. Aspergillus flavus B. Ecology - soil, dust, decaying food C. Pathogenesis 1. Immuno-compromised host 2. Allergic rhinitis 3. Burns 4. Otitis externa 5. Diabetics 6. Invasive infections in immunocompromised patients - poor prognosis D. Laboratory diagnosis 1. Septate hyphae (not dimorphic) 2. Serology - Aspergillus galactomannan antigen in blood is a good indicator of invasive infection (newly approved diagnostic) 3. Culture on Sabouraud’s agar produces a typical mold A common lab contaminant so finding it is unreliable. In addition, culture takes too long to be an effective diagnostic. E. Treatment 1. Amphotericin B 2. Echinocandins (Caspofungin-Cancidas®)

Answer 25

A. Causative agents - Mucor sp. and Rhizopus (not dimorphic) B. Ecology - soil, decaying food (Rhizopus is a common black bread mold) C. Pathogenesis 1. Severely immunocompromised individuals a. Uncontrolled diabetics, steroid treatment, leukemia, lymphoma, etc. - rhinocerebral, pulmonary, systemic b. Burn patients - infection in wounds 2. Extremely fast growing D. Laboratory Diagnosis 1. Non-septate hyphae on smear 2. Culture on Sabouraud’s medium E. Treatment 1. Amphotericin B 2. Surgery 3. Mortality rate > 50%

Answer 26

I. Poisoning by by-products of fungi – fungi produce antibiotics/poisons as a way of protecting themselves from predation. II. Aflatoxins: A. Produced by Aspergillis flavus B. Found in foods, especially peanuts C. Arcinogenic, causes liver cancer and liver necrosis ``` III. Other toxins: A. Ochrotoxin 1. Produced by Aspergillis sp. 2. Causes liver necrosis B. Amanita mushroom 1. Phalloidin - binds to microtubules 2.  amanitin - binds to RNA polymerase and other proteins; also a neurotoxin ``` ACTINOMYCETES - filamentous bacteria related to mycobacter that produce colonies that resemble molds.

Answer 27

Rhodotorula and Torulopsis

Answer 28

Location of the infection 1. Systemic mycoses caused by: Blastomyces Coccidioides Aspergillus Histoplasma Cryptococcus Candida Sporothrix Paracoccidioides 2. Cutaneous Candidiasis Candida albicans - mucocutaneous infections : nose, pharynx, vagina, areas of bowel. Easier to treat than systemic and not as bad as systemic 3. Dermatophytic infections Microsporum Trichophyton Epidermophyton - E.g typical ringworm. Usually not life threatening. Athletes foot, jock itch. Enjoy areas warm, dark, and moist. Note: Histoplasma usually associated with lungs, Cryptococcus may cause meningitis in immunocompromised patients, Candida is the most common causative agent of septicemia after bacteria.

Answer 29

1. Systemic mycoses Amphotericin B (IV) Flu cytosine - restricted use Azoles (oral) 2. Cutaneous Candidiasis - Nystatin (topical, suppository, suspension ) - Azoles (topical/oral) 3. Dermatophytic infections Azoles (topical/oral) Griseofulvin

Answer 30

- Fungicidal - amphipathic - Amphotericin B - Nyastin -only for topical Tx. Never given systemically

Answer 31

8 molecules of Amphotericin B interacts hydrophobically with 8 molecules of ergosterol in the fungal cell membrane forming a pore. Potassium leaves first, and the follow other small molecules leading to the death of the cell. Note: Selective because the pores are transient. Half time of pores in Fungi cells is longer than in human cells. The affinity of Amphotericin B for ergosterol is a litter better for ergosterol than the predominant cholesterol in human cells.

Answer 32

Very poor oral absorption - requires parenteral administration •Sequestered in tissue membranes very low serum levels * App. Vd ≈ 4 L/kg * Half-life ≈ 15 days •Administered as a freshly prepared suspension - Liposomal preparations Note: Vd and half life are high because the Amphotericin B is lodge in the cell membrane of fungi.

Answer 33

* Chills, fever and vomiting * Renal toxicity (decreased renal blood flow and direct toxicity to tubule cells) * Normocytic, normochromic anemia (high doses may cause hemolysis) * Hypokalemia * Arrhythmias- hypokalemia can lead to arrythmias. Further complications can occur with Rx e.g. digitalis. * Pain, headache, impaired vision and chemical meningitis when given intrathecally. E.g Ex. patient may become combative * Thrombophlebitis * Anaphylaxis- anaphylactoid- not allergenic in origin but will cause similar symptoms. (anaphylactoid reaction a reaction resembling generalized anaphylaxis but not caused by IgE-mediated allergic reaction but rather by a nonimmunologic mechanism.) -Renal Toxicity is the worst issue. Note: Chills and fever are part of the infusion reaction and thus may coadminister steroids or acetaminophen

Answer 34

ABD - Micelles, $76, yes, yes ABLC - Ribbons, $740, - , less common than ABD ABCD - Disks, $360, ++ , less common than ABD LAMB - Spheres $1099, - - , less common than ABD Note: Prescrive liposomal prep for immunocompromised patients. Otherwise prescribe Na+ deoxycholate prep ABD. Note: Amphotericin has a very small TI and cannot be excreted rapidly and long half life.

Answer 35

- Cancer drug - Pyrimidine derivative •Narrow spectrum of activity - For most strains of Cryptococcus neoformans •Usually used in combination with amphotericin B Note: Cryptococcus can cause meningitis

Answer 36

Flucytosine is more highly permeable to fungi membrane compared to human membrane. Flucytosine becomes more permeable with the addition of Amphotericin B. The Flucytosine enters via a permease within the fungal plasma membrane and intracellular converted to 5-Flurouracil ---> 5-FdUMP. 5-FdUMP inhibits* dUMP --- *Thymdylate synthase* ---> dTMP --> DNA Decrease of dTMP leads to inhibition of DNA synthesis and cell division

Answer 37

Antifungal and anticancer drug. * Well absorbed orally * Dependent upon renal function for elimination * Penetrates well into the CNS ≈ 70% of serum levels Note: With combination Tx of Amphotericin B the major excretion method may be a problem since an adverse effect of Amphotericin B is renal toxicity.

Answer 38

Induction Tx because it kills the organism without administration major toxic agents. * 25% exhibit nausea, vomiting, severe diarrhea and enterocolitis * 25% exhibit elevation of hepatic enzymes- Damage to liver. Above more than 3x the normal amount of enzyme consider reducing dosage. * 15% exhibit bone marrow depression: anemia, leukopenia, thrombocytopenia

Answer 39

Imidazole's (5 membered ring with 2 N) - KETOCONAZOLE - CLOTRIMAZOLE - miconazole - econazole Triazoles (5 membered ring with 3 N) - FLUCONAZOLE - ITRACONAZOLE - terconazole

Answer 40

All azoles have the same mechanism of inhibiting the cyt P-450 dependent 14-a-demethylation of sterols. This leads to decreased ergosterol synthesis and the accumulation of 14-methyl sterols in the fungal membrane. Selective toxicity is based on the higher affinity of the triazole or imidazole group for the heme iron of cyt P-450 of fungi when compare human cyt P-450. In addition, humans can use preformed, exogenous sterols while Fungi must make there sterols. - All azoles are FUNGISTATIC due to the DECREASE of ergosterol synthesis - Ketoconazole is a really good inhibitor of CytP450 dependent enzymes. Has lots of drug interactions - Fluconazole also and inhibitor of CytP450 dependent enzymes, but not as good and has lots of drug interactions a well. - Normally steroid biosynthesis is in the mitochondria. High doses of ketoconazole affect production of sex steroids.

Answer 41

Ketoconazole and Itraconazole have to be in an acidic environment so that they will dissolve. We have to absorb the dissolutes. Thus don't take antiacid with it. - Once dissolved there is good bioavailability (more than 70%) - Fluconazole is more than 70, Ketoconazole is less than 10, Itraconazole is less than 1 Fluconazole does not require acidic environment. -Fluconazole should be given because at the point of urinary excretion there is more than 80% of the drug active. Ketoconazole and Itraconazole are greatly metabolized and thus 2-4 and less than 1%, respectively, are active at the point of urinary excretion.

Answer 42

All azoles have a TERATOGENIC POTENTIAL during pregnancy. Ketoconazole * Gastrointestinal distress * Rash, pruritis * Elevated hepatic enzymes * Decreased sex steroid synthesis- gynecomastia, change in menses, decreased libido * Decreased cortisol synthesis * Severe hepatotoxicity Fluconazole * Gastrointestinal distress * Rash * Elevated hepatic enzymes * No effect on host steroid synthesis

Answer 43

Only 1 to 2 % of patients must discontinue fluconazole because of adverse effects. Ketoconazole - increase in dose leads to a higher % of patients discontinuing the Rx. 0.4g/day: 4% to 1.6g/day: 60%

Answer 44

Azoles inhibit hepatic microsomal drug metabolizing enzymes to varying extents. The following interactions have been reported. Note: caused by the inhibition of CytP450 dependent enzymes. ``` Arrhythmias with terfenadine & astemizole Increased levels of cyclosporine Increased bleeding time with warfarin Hypoglycemia with oral hypoglycemics Increased serum levels of phenytoin Increased serum levels of digoxin ``` The following two Rx decrease blood levels of azoles because they induce CytP450 dependent metabolizing enzymes, thus increases the metabolism of azoles. 1. Rifampin decreases blood levels of azoles 2. Phenytoin decreases INTRACONAZOLE blood levels by > 10x

Answer 45

``` Candidiasis Coccidioidomycosis Cryptococcus chronic suppression Blastomycosis Histoplasmosis Sporotrichosis Pseudallescheriasis Aspergillosis ```

Answer 46

Infections of the mucosa of the oropharynx, esophagus, bowel or vagina caused by Candida albicans May be treated with nystatin suspensions or creams. Topical azoles are also efficacious. Not absorbed orally Systemic administration may also be employed for when there is an extensive area of tissue infection. Note: Never parenterally. Swallow a little not a big deal because does not get absorbed in GI tract. If given parenterally more toxic properties than amphotericin. Note: Clotrimazole - suppository for Candida vagina infections

Answer 47

Fungicidal synthetic allylamine Inhibits squalene epoxidase leading to the accumulation of toxic levels of squalene in the organism. Normally Squalene is converted to Ergosterol by Squalene epoxidase. No Ergosterol also leads to death. Mammalian enzyme is 4,000 times less sensitive. Effective in the treatment of dermatophytic infections: - Topical - Oral for onychomycosis; once a day therapy for 12 weeks is 90% effective (better than griseofulvin or itraconazole) Adverse Effects: Headache and GI symptoms (diarrhea, abdominal pain, nausea) are most common. Rarely, hepatotoxicity & severe skin allergy Note: Headache occurs usually when route is ORAL

Answer 48

* Chitin synthesis – nikkomycins * Glucan synthase – Caspofungin (echinocandins) * Mannoproteins – pradimicin - Used for more severe issues and for substitution of Rx that not as sensitive to the infection. - These potentially useful drugs are derived from naturally occurring substances

Answer 49

Most parasitic infections cause non-specific and non-identifying symptoms, predictions of infectious agent must be confirmed by direct observation of the parasite using light microscopy.

Answer 50

1. They are eukaryotes. 2. Many have complex life cycles that cannot be completed without transmission to several hosts. 3. They are widely dispersed throughout the world and do not occur solely in “tropical” areas.

Answer 51

1. Parasites are: a. Eukaryotes, and can be single cells (protozoa), or multicellular organisms (helminths) b. Larger than bacteria and viruses c. In some cases, able to change their antigenic surface proteins d. Able to use a variety of mechanism to avoid mammalian host defenses 2. Infectious parasites fall into two main groups: a. Protozoans: for example: plasmodium (malaria), trypanosomes b. Helminths: for example: Cestodes, Trematodes, Nematodes

Answer 52

Informational

Answer 53

Parasite control is complex. For example, malaria control relies heavily on vector elimination and prevention of mosquito bites, as well as drug prophylaxis.

Answer 54

Bacteria and viruses may be cultured, and antibodies against them may be measured. Diagnosis of malaria currently requires direct demonstration of the organism in the blood of an infected patient. However, ELISA tests are currently in use for some parasites.

Answer 55

Parasite immunity is complex. For example, immunity to malaria is difficult to acquire because of serological differences of the infectious agent. Parasites cause disease at a wide variety of sites in the body. They cause disease in many organ systems.

Answer 56

1. Physical barriers Bacteria: Intact skin usually impenetrable. Fatty acids of skin toxic to bacteria. Vaginal flora normally produce acid pH. Parasites: (Special modes of entry) Insect bite, Ingestion, STD, Direct invasion 2. Innate immunity Bacteria: Recognition of bacterial LPS activates complement, TNF, IL-1. Chemotaxis, cell adhesion. NK cells activated. Parasite: Host response varies. Parasite may coexist with host. Initial response depends on macrophages. Macrophages secrete cytokines such as TNFa, IL1; respiratory burst produces reactive O2 metabolites, NO for parasite killing. 3. Antibody responses Bacteria: Lymphocytes activated, Specific antibodies pro- duced and targeted cells attached to complement. Parasites: TH2 response is necessary for expulsion of GI worms. 4. Killing Bacteria: Phagocyte attaches to organism, which is then ingested. Killing occurs via: NO, O2-, lysosome formation. Parasite: Macrophage killing mechanisms activated

Answer 57

Definitive host- where the parasite reproduces sexually. Often where the adult stage resides. Intermediate host-larval stage develops

Answer 58

ROUND WORMS-also called Nematodes 1. Ascaris lumbricoides-over half of the world carries one or more of theses worms. Infection causes a decrease in allergies since the worms recruit IgE. World-wide, mainly in tropics. a. Disease- worms in upper part of small intestine. b. Life cycle- complex. Accidentally ingest eggs, larvae hatch in small intestine and are carried to liver. Larvae migrate to heart, then to lungs. They then break out of lungs and migrate up trachea, are swallowed and finally reside in the gut. Adults mature in the gut and lay eggs which are then passed in feces. Acquire infection by ingestion of eggs found in soil. Often an infection in children. c. Pathogenesis-obstruction of GI tract, malabsorption of nutrients in infection children, peritonitis, Loeffler’s syndrome (type of pneumonia associated with high eosinophils). Fatal cases of Ascarisis caused by aberrant migration of adult worms to the liver. d. Diagnosis- eggs in stool. Adults can be vomited up when they are migrating. Symptoms include: No symptoms, palpable abdominal mass, obstruction (biliary or intestinal), migration associated problems. e. Treatment-mebendazole (a vermafuge), paralyzes worms that are then expelled. Surgical intervention is a last resort. Mebendazole is the treatment for most roundworms, including whipworm, hookworms, strongyloides, pinworm. f. Prevention and control- Eggs survive well in soil under a wide variety of conditions. ii. Eradicate reservoir hosts. iii Sanitary disposal of feces. iv. Avoidance of eating uncooked vegetables in epidemic areas.

Answer 59

Trichuris trichiura - Whipworm a. Disease - i. Light worm load-usually no symptoms ii. Heavy worm load - prolapse of rectum, diarrhea, weight loss iii. Acquire- fecal-oral root- eating embryonated eggs from soil or vegetables contaminated with feces. iv. Epidemiology - world wide, greatest incidence in tropics and southern United States v. Reservoir – only humans b. Life cycle: humans ingest eggs in soil. Larvae migrate to colon. Adult female releases eggs into human feces. Fecal-oral passage. Humans are definitive host. c. Pathogenesis - prolapse of rectum, diarrhea, weight loss d. Diagnosis - Eggs in stools. Football shaped eggs. e. Prevention, control i. Sanitary disposal of feces ii. Avoidance of eating uncooked vegetables in epidemic area iii. Personal cleanliness

Answer 60

Hookworm- Necator americanus (new world) and Ancylostoma duodenale (old world) a. Disease - i. Depends on worm load, mainly causes anemia due to significant blood loss. ii. Acquire - Feces in soil, infective filariform larva enter through skin (usually children) iii. Epidemiology - Most common in tropics and subtropics b. Life cycle: infection is via burrowing larva that develop in soil that has been contaminated with infected stool. Definitive host – humans c. Pathogenesis - Symptoms - depends upon worm load Heavy - anemia, cardiac damage, ‘pica’ (desire to eat dirt) d. Diagnosis i. Eggs in patient’s feces ii. Rhabditiform larva in stool in constipated individuals or in fecal samples that have been left unexamined for hours e. Prevention, control i. Sanitary disposal of feces ii. Wearing of shoes

Answer 61

a. Disease - diarrhea i. Definitive host – humans ii. Acquisition- Feces in soil, infective filariform larva enter through skin (usually children). As in Hookworm except disease can last many years due to autoinfection, even after individual has left an endemic area. iii. Epidemiology - tropics, Southeast Asia, Appalachia b. Life cycle- larvae migrate from bloodstream to lungs, then swallowed and live in human small intestine. Autoinfection occurs in humans. There is also a free-living soil cycle. Larvae infect humans by penetrating unbroken skin. c. Pathogenesis i. Many individuals asymptomatic ii. Moderate to heavy load - diarrhea or constipation, anemia, weight loss iii. Hyperinfection syndrome in immunocompromised hosts d. Diagnosis i. Rhabditiform larva in stool or duodenal aspirate ii. Mucosol biopsy, string test, ELISA. e. Prevention and control - same as in Hookworm i. Sanitary disposal of feces ii. Wearing of shoes

Answer 62

Enterobius vermicularis a. Disease- itchy anal area i. Definitive host – humans ii. Epidemiology – world wide. b. Life cycle: eggs expelled from gravid female pinworm in perianal area of human. Eggs are infectious to other individuals. c. Pathogenesis i. Pruritus ani (irritation of anus), insomnia ii. Internal - adults may migrate to genital tract and become imbedded and result in granuloma formation. iii. Psychic trauma to parents when their children become infected. d. Diagnosis i. Sticky plastic paddle pressed on perianal region on rising in the morning ii. Three consecutive days if first and second results are negative iii. Stools are not examined e. Prevention and control i. Personal cleanliness and cleanliness of living quarters - Eggs survive on inanimate objects in the home. Entire household gets contaminated, difficult to eradicate

Answer 63

Trichinella spiralis a. Disease - calcified larvae in muscle Definitive host -pigs, rats, bears, humans (dead end) b. Life cycle: larva, infected meat is mode of entry into the human host. Adults mature in small intestine; newborn larvae carried through blood stream and enter skeletal muscle cells. Reside in muscle cell in human/animal tissue. c. Pathogenesis – Symptoms i. Few ingested larva - no symptoms ii. 50 larvae/gram - diaphragm, extraocular, deltoid, gastrocnemius, etc. iii. Fever, muscular pain, weakness, diarrhea in acute phase iv. Periorbital edema, splinter hemorrhages v. Prognosis - dose related d. Diagnosis i. Early diagnosis difficult ii. History iii. High eosinophilia iv. Biopsy of striated muscle e. Treatment-None, supportive therapy. f. Prevention, control i. Feed hogs cooked garbage ii. Cook pork and pork products well

Answer 64

A cause of parasitic tissue disease a. Disease – elephantiasis, filariasis. The organism is a thread-like worm that locates in the lymphatic vessels and lymph nodes. There are male and female worms and the females produce sheath-covered microfilaria (~200 M long). b. Life cycle - transmitted by the bit of a mosquito that has previously acquired microfilaria with a blood meal. The cycle is complete when infective larva in the mosquito pass into the mammalian host where they make their way into the lymph nodes and develop into adult worms in a few months. There is a periodicity to the emergence of microfilaria in the bloodstream- the timing (nocturnal or diurnal, during the day) is indicative of the geographic source of infection. c. Pathogenesis- adult worms live in lymphatics and cause blockages. d. Diagnosis - periodicity of microflaria in bloodstream requires care in sampling time. Thick blood smears are also used. e. Treatment - Diethylcarbamazine (Heteraza) is effective against the microfilaria. f. Prevention - control of mosquitoes.

Answer 65

another important filarial worm that causes tissue disease. Close related to Wuchereria. There are primate reservoirs for this worm and infection to humans is zoonotic.

Answer 66

This filariae parasite is transmitted by the bite of the black fly. a. Disease - It was the major cause of blindness in Africa before the drug Ivermectin was available. The distinguishing trait of this filarium is that it is found in the skin and not the blood. Eye infection by microfilarial – human immune reaction contributes to blindness. b. Diagnosis is via microfilaria in ear skin snip.

Answer 67

Aberrant nematode infections in humans -Visceral and cutaneous larva migrans. Normally infections of dogs and cats. Numerous nematodes cause these aberrant human infections. Since these worms infect us accidentally and they cannot complete their life cycles in the human host. Infection acquired- mainly when children eat dirt with eggs in it or when the body comes in contact with a larval form (cutaneous). a. Visceral larval migrans (i.e. Toxocara canis) - i. Affects liver, heart and CNS. ii. Eosinophila - 30% iii. Diagnosis- CSF examination, biopsy. b. Cutanous larval migrans (i.e., Ancylostoma braziliense) - i. Skin lesion, abscess formation ii. Diagnosis-biopsy

Answer 68

Diphyllobothrium latum- fish tapeworm. a. “Jewish house wives’ disease”. Infection from eating larva in raw fish. Adult attaches to the human gut and reaches full length in 3 months. b. Achieves 10 meters in length in the human gut! Causes anemia- B12 deficiency.

Answer 69

Beef and Pork Tapeworms a. Taenia saginata (beef tapeworm) i. Definitive host - humans ii. Life cycle: cystecerci (larvae) are ingested when we ingest infected beef. These larvae are released in the stomach and adults remain in the small intestines. Eggs from female adult are deposed with human feces. Cows ingest eggs which then hatch in their muscle. iii. Symptoms (a) Vague complaints of abdominal discomfort (b) Awareness of movement of proglottids that emerge from anus. Taenia solium (pork tapeworm) i. Definitive host – humans ii. Life cycle: as for the beef tape worm, except the eggs mature into larvae in the pig. iii. Symptoms – same as beef tapeworm. If we ingest the tapeworm eggs, and not the larva in the meat muscle, we get aberrant parasite migration as larva develop in our brains and eyes. This disease is called cysticercosis. c. Laboratory diagnosis for Both beef and pork tapeworms i. Eggs in stool, identical in appearance for both species ii. Differentiating T. solium and T. saginata by pressing proglottid between slide and counting main lateral branches (a) T. solium - 7 to 12 pairs (b) T. saginata - 15 to 30 pairs iii. For Cysticercosis (pork tapeworm)-find larva/cysticercus in brain/muscle/eye by (a) CAT scan or MRI (b) ELISA test d. Epidemiology i. Incidence less than 2% in U.S. iii. Spread by eating undercooked beef and pork iv. Cysticercosis more common in Mexico, Central and South America

Answer 70

``` Echinococcus granulosus (HYDATID DISEASE) a. Definitive host – dog, wolf, sheep. Infection in humans leads to cyst development in liver, lung or brain. ``` b. Symptoms i. Slowly growing tumor in liver (60%), lung (25%), other (15%) ii. Rupture of cyst - possible anaphylactic shock - spread of daughter cysts throughout body c. Diagnosis - History i. X-ray, CAT scan, Serology ii. No stool examination for ova d. Epidemiology i. Sheep raising areas - man obtains eggs in soil or from dog fur ii. Very prevalent in China also native American Indians. iii. Infected Australian sheep dogs brought the disease to California, Utah, etc. e. Prevention i. Do not feed dogs raw refuse from slaughter ii. Treatment for dogs that have eggs in stools f. Treatment i. Careful surgical removal of cyst ii. Multiorgan involvement – praziquantel

Answer 71

1. Most medically important flukes are Schistosoma mansoni, japonicum and hematobium. a. Definitive host - humans b. Have separate sexes (all schistosomes have 2 sexes, other trematodes are hermaphroditic.) c. Life cycle: cycle through both humans and snails to complete their complex life cycle. d. Immune Reactions i. Production of specific IgE antibodies and eosinophilia (a) Due to stimulation of CD4+ helper T cells that secrete IL-4 and IL-5 (b) IgE antibody binds to helminths, eosinophils attach to these opsonized organisms by Fc receptors specific for IgE. The eosinophils are activated, secrete major basic proteins which lyse the parasites. ii. Activated macrophages directly kill schistosome larva through action of nitric oxides and TNF iii. S. mansoni eggs in liver stimulate CD4+ T cells, which activate macrophages, result in granulomas, severe fibrosis. Leads to disruption of venous blood flow, portal hypertension and cirrhosis.

Answer 72

e. Symptoms of S. mansoni infection i. Acute stage fever, malaise, diarrhea, weight loss ii. Chronic (a) Weight loss, anemia, splenomegaly, periportal fibrosis, ascites (b) Intestinal structures and polyps (c) Portal hypertension f. Laboratory diagnosis and treatment i. Eggs in feces (S. hematobium in urine) Multiple stools must be examined ii. Rectal biopsy iii. Cercarial slide agglutination test iv. treat with praziquantel g. Epidemiology i. Defecation (S. mansoni and S. japonicum) and urination (S. hematobium) by infected persons contaminates water ii. Untreated sewage into ditches, streams and lakes in endemic areas iii. Not acquired in continental U.S. due to lack of correct snail vector, only certain fresh water snails are intermediate hosts iv. Walking, swimming or washing clothes in contaminated water allows cercaria to penetrate skin h. Prevention and control i. Sanitary disposal of feces ii Control snail population iii. Education of people

Answer 73

Amebiasis - Entamoeba histolytica- ameba a. Disease – can be asymptomic, diarrhea, acute rectocolitis (dysentery), If untreated, fulminant colitis with perforation, perianal ulceration liver abscess. b. Epidemiology: i. Institutional outbreaks ii. Breakdown in sewer lines iii Homosexuals iv. Migrant workers v. Travelers and immigrants from endemic areas vi. Communal living c. Life cycle- cyst and trophozoite forms. Exist in gut after ingestion of cysts from soil. Divide by binary fission. d. Pathogenesis- migration to liver preceded by ulceration of gut. e. Diagnosis- eggs and ameba in stool.

Answer 74

``` Amebic Dysentery Few cells Charcot-Leyden crystals RBC in clumps or rouleaux Eosinophils (2-5%) Epithelial cells undamaged and damaged ``` ``` Bacillary Dysentery Many cells (polys) Absent RBC - scattered Rare eosinophil Epithelial cells are bile-stained ``` ``` E. histolytic Nuclei: 1-4 Karyosome: center Chromatin: regular Chromatoidal bar: large, thick ``` ``` E. coli ( non-pathogenic) Nuclei: 1-8 Karyosome: off center Chromatin: irregular Chromatoidal bar: splinter ``` Prevention i. Personal hygiene ii. Environmental sanitation (a) Water - 8 ppm iodine - cysticidal (b) No human waste for fertilizer (c) Sanitary disposal of feces Bacillary dysentery is a type of dysentery, and is a severe form of shigellosis. Bacillary dysentery is associated with species of bacteria from the Enterobacteriaceae family.

Answer 75

Giardiasis - Giardia lamblia – flagellate a. Disease-can be asymptomic, diarrhea, Epidemiology: i. Children (especially day care nurseries) ii. Travel iii. High risk sexual activities b. Pathogenesis - ingestion of cysts, Trophozoites attach to duodenal wall c. Excystation in duodenum and the trophozoites attach to mucosa. Pathogenesis and symptoms-diarrhea, Malabsorption d. Diagnosis i. Direct and concentrated examination of feces ii. Antigen detection test Entero-string test e. Prevention - same as in amebiasis. i. Personal hygiene ii. Environmental sanitation (a) Water - 8 ppm iodine - cysticidal (b) No human waste for fertilizer (c) Sanitary disposal of feces

Answer 76

Cryptosporidium a. Disease - severe diarrhea in compromised host, self-limiting diarrhea in normal host Epidemiology- world wide, appears in severely compromised patients-AIDS i. Transient diarrhea in normal host in the tropics ii. Major outbreak in Milwaukee (1993), water supply contaminated, 500,000 cases, other outbreaks reported. iii. Found in wave pools b. Life cycle- see slide. Is a coccidia (related to malaria). Constant host reinfection. c. Diagnosis - intestinal biopsy, observe a minute coccidian about 2-4 microns spherical bodies on the mucosal surface or free in the crypts. Modified acid-fast stain of diarrheic feces. d. Resistant to chlorine – need Clorox to kill it.

Answer 77

1. Disease- vaginitas, urethritis. Considered a STD. 2. Life cycle- human to human transmission. Lives in anaerobic environments. 3. Diagnosis -wet prep - No cyst form occurs 4. Treatment - flagyl - both sexual partners should be treated.

Answer 78

Blood borne infections- caused by Plasmodium species (malaria), Babesia species (Babesiasis), Trypanosoma b. gambiense and rhodensiense (African sleeping sickness).

Answer 79

1. Malaria: a. Estimated numbers: People infected with plasmodium: 800 million Cases annually: 300 million Annual mortality: 2 million Countries affected: 103 Number of people at risk: 2,500 million Major risk to travelers! i. Malaria is the most common tropical disease. Malaria means “bad air” in Italian. Thought to be caused by the marsh gas in hot, low areas with stagnant water. We now know that these are mosquito breading grounds and mosquitoes pass malaria from person to person. ii. Increase in malaria infection recently due to rise in insecticide- resistant mosquitoes and drug-resistant parasites! iii. Causative agent of malaria: Protozoan (unicellular) organism of the sporozoa family. Sporozoa are intracellular protozoa with alternating sexual and asexual reproduction. The Sporozoa that cause malaria are four types of Plasmodium: P. falciparum, P. vivax, P. ovale, P. malariae iv. All species cause recrudescence - which is reinfection of RBC's by blood stage parasites for up to two years. Only P. vivax and P. ovale cause relapse malaria- when hypnozoites develop from a persistent infection in the liver after many years. Each species looks different enough while it is growing in the red cell to allow for its identification in blood smears. Diagnosis is via looking for parasites inside thin and thick blood smears.

Answer 80

Life cycle: very complex life cycle. i. Mating of male and female gametes that are produced in human blood infection occurs in the mosquito. Because of this mating cycle, drug resistance among parasites is rapidly spread. In malaria, the taking up of a blood meal by a female Anopheles mosquito is where the life cycles “begins”. ii. In the insect, the gametocytes (which are the male and female gametes taken up in the blood meal) fuse, and oocytes form in the stomach wall of the insect. The parasites emerge as sporozoites and migrate to the salivary gland. These infective forms are injected into humans when the mosquito takes a second blood meal. iii. In the human host- the sporozoites enter the blood stream and travel to the liver where they change into schizonts when they rapidly divide. They emerge as merozoites. The merozoites infect red cells. They grow here as they did in the hepatic cells, feeding as trophozoites and dividing as schizonts until they emerge as merozoites. The merozoites can reinfect more red cells or transform into gametocytes. The gametocytes are what are taken up by the mosquito. iv. The ‘shape’ of parasites inside the red cells is diagnostic of species. The grown stages here (erythrocytic phase) are: (a) Ring-like, early trophozoites (feeding forms) (b) Schizonts-eat hemoglobin,divide and produce a characteristic pigment, hemazoin. (c) Merozoites released from RBCs and reinfect other RBCs or become gametocytes. (d) Some merozoites differentiate into sexual forms- macrogametes and microgametes. The uptake of the gametes by the mosquito completes the life cycle.

Answer 81

4 main species: Plasmodium malariae-quartan malaria; mild, worldwide. Only infection that causes fever spikes 3 days apart. (fever recurs on the fourth day) Plasmodium ovale- like vivax, but less severe. Plasmodium vivax-benign tertian malaria, through tropical regions and in some temperate zones. Ovale and vivax can lie dormant for years in liver, as hypnozoites. Their maturation and reinfection of RBCs is called relapse. The liver forms that lie dormant are called hypnozoites. Plasmodium falciparum- malignant tertian; in Africa, Asia & Latin America. Life threatening! Only one that causes mortality. The names tertian/quartan refer to the periodicity of fever cycles- tertian malaria is when the fever spikes are 48 hrs apart, thus fever occurs on the third day. Periodicity of fever, when synchronous after a few weeks, is characteristic of each plasmodium type.

Answer 82

fever spike day 1 day 2 day 3 day 4 P. vivax + + P. falciparum + + P. malariae + +

Answer 83

Pathogenesis: invasion, alteration and destruction of RBCs. Rupture of RBCs and release of pyrogens are accompanied by fever, chills and sweating. d. Diagnosis: Symptoms are such that malaria is called "The Great Masquerader" – difficult to identify. All types have chills, fever, headache, muscle pain, splenomegaly and anemia. Hallmark of disease is malaria paroxysm: i. Severe chill (20-60 min in duration)-cold stage ii. Fever 104-107F (3-6 hrs)-hot stage iii. Exhaustion but no other symptoms. Drop in polys and rise in monos Thick and thin smear- Wright or giemsa stain. Perform smear 4 consecutive days; always before a fever spike (before cells lyse). Observe rings, gametocytes, Schuffner’s dots. Each species has different characteristics in infected red cells. Polymerase chain reaction-based assay to identify each of the 4 species. Also useful (using PCR) to identify drug-resistant parasites. Hepatomegaly, jaundice and edema often observed.

Answer 84

i. Asymptomic- infection causes immune response that can limit multiplication and lead to partial immunity. ii. Recrudescence- periodic rise in parasitemia. Parasites stay in RBCs. Periodic rise may be due to antigenic variation. Can occur after one year (P. falciparum) or 50 years (P. malariae). iii. Relapse - hypnozoites forms stay in liver- remerge several years later. iv. Blackwater fever- brown-black urine due to hemolysis of RBC that is greater that just lysis of infected cells (unknown reasons). Kidney affected and accumulate hemoglobin. Can also occur if you treat disease too aggressively. v. Death- usually from falciparum’s resulting cerebral malaria. Falciparum malaria can lead to cerebral malaria- infected RBCs stick to cerebral capillaries. (If initial infection is not cured, recrudescence and relapse (after a long latency time) can occur.)

Answer 85

Plasmodium falciparum and antigenic variation: - Infected RBCs stick to lumen of capillaries because the intracellular parasites places ‘docking’ proteins on the infected cell surface. These ‘docking’ proteins are antigenic and the host mounts an immune response. The parasite has an arsenal of ‘docking’ proteins (called ‘var’ genes) and changes them to avoid the host immune response. Immunity: i. T and B-cell mediated. Need constant exposure to maintain resistance. Vaccines are under study. ii. Individuals with sickle cell trait or glucose-6-phosphate deficiency are more resistant to malaria than individuals without these traits. iii. Individuals without duffy antigens on their RBCs are protected. iv. Thalessemia and hemoglobin C- difficult for parasites to use these hemoglobins.

Answer 86

Treatment: i. Prophylaxis- chloroquine; there is a major resistance problem currently and thus mefloquine is the recommended drug for travelers to P. falciparium areas. If origin of infection is from a chloroquine sensitive area, then chloroquine is given. If unknown origin, assume resistance and use pyrimethamine- sulfadoxine -- for 3 days. ii. Relapse from P. vivax or ovale is preventable by a course of primaquine. This is a gametocidal drug. iii. Chloroquine-resistant infection - pyrimethamine (folic acid antagonist works because the parasites synthesize folates de novo), mefloquine ( starting to see resistance to this, too) iv. Note- original treatment was quinine- from the bark of the cinchoa tree. Gin and tonics! Prevention and Control: i. Malaria can be acquired via bite of mosquito, congenital malaria-placenta, injury, blood transfusion, hypodermic injection. ii. Malaria can potentially be controlled by: (a) Eradication of mosquito- resistance problem (b) Elimination of parasites by mass prophylaxis not practical). (c) Vaccines are being developed; vaccines against parasites are difficult since parasites are very clever!

Answer 87

a. Disease- similar to malaria. Caused by intracellular blood parasite, Babesia sp., that infect RBCs. Very severe in humans without spleens. b. Life cycle- Transmitted by the same deer ticks that transmit Lyme disease in Northeastern US. Found in travelers to Nantucket and Block Island. c. Pathogenesis- Unlike Plasmodium, Babesia does not produce pigment (hemozoin) within RBCs. d. Diagnosis -blood smear (see “Maltese cross” in infected RBCs). Mimics malaria in appearance but absence of pigment is characteristic. Characterized by fever, chills, lethargy; also splenomegaly and hepatomegaly. e. Treatment- clindamycin and quinine.

Answer 88

African trypanosomiasis- Trypanosoma brucei gambiense (Western Africa) and T. b.rhodesianse (East Africa) a. Diseases: African sleeping sickness b. Life cycle: African trypanosomes-A human or domestic animal (cattle) acquires the parasite via the bite of an infected Tsetse fly. These flies are found only in sub-Saharan Africa and the disease is limited to this area. The parasites reside in the blood stream and tissue spaces, eventually migrating to the brain to cause "sleeping" symptoms and eventual coma and death. The parasites are transmitted to uninfected Tsetse when the fly takes a blood meal from an infected mammal.

Answer 89

Diagnosis: African trypanosomes-blood or CNS smear. Only trypomastigote form is present. South American trypanosomes- Blood smear or biopsy- see both trypomastigote and amastigote forms. Xenodiagnosis- feed bug on infected individual and look for parasites in insect feces. PCR methods are being developed. e. Treatment: African trypanosomes- Diamidines, arsenicals; DFMO at later stages. f. Prevention and control---insect vector control, identification of biochemical targets for chemotherapy. Animal reservoirs- some animals are asymptomatical but serve as reservoirs. The animal reservoir is different for different trypanosomatids- bush buck for African trypanosomes.

Answer 90

Leishmaniasis -- a. Diseases- different forms of Leishmaniasis. Leishmania donovani- Kala-azar, Visceral leishmaniasis Occurs in South and Central America, Middle east, Mediterranean areas. Leishmania major or L. tropica- old world cutaneous (self healing) Leishmania braziliensis- mucocutaneous or cutaneous leishmaniasis (chronic and debilitating) All leishmania transmitted by the bite of a sandfly Most common in South and Central America, the Middle East and India. All 3 species outlined here are carried by the sand fly vector (Phlebotomus). Note: Leishmania are close ‘cousins’ of the Trypanosoma spp

Answer 91

b. Life cycle: The extracellular promastigote is injected into the host by the sandfly and invades the macrophages, changing into an amastigote (‘a’= without flagella).The amastigotes multiply in the macrophages and enter the blood stream where they are taken up by a sand fly as it takes a blood meal. c. Pathogenesis-varied, depending on species. i. Cutaneous-self-healing lesion. Leishmania major or L. tropica- old world cutaneous (a) Localized to skin (b) Permanent scarring (c) Secondary infections are problematic ii. Visceral-all organs affected, splenomegaly and hepatomegaly occur, bone marrow is involved and anemia ensues; if untreated it is fatal. iii. Leishmania braziliensis- mucocutaneous or cutaneous leishmaniasis (a) Occurs around nose- attacks cartilage-may break through to the brain (b) Diagnosis-depending upon location in body- i. Blood and bone marrow, only see promastigote form, lymph culture. ii. Biopsy lesion-only find amastogote form

Answer 92

Immunity associated with production of IFN gamma and TNF by CD4+ cells-exacerbation of lesions associated with high levels of IL-4 which inhibits activation of macrophages by TNF; blocked production of cytokines. e. Treatment--pentavalent antimonials including Pentostam and Glucantime. Pentamidine and amphotericin B are second line of defense because these drugs are rather toxic. Strains are becoming resistant to pentavalent antimonials. f. Prevention and control: i. Prophylaxis - no available preventative drugs (a) Minimize contact with sand flies, wear protective clothing, destruction of mammalian reservoirs such as dogs and rodents. (b) Immunity by previous exposure with cutaneous leishmaniasis. ii. Relevance to clinical medicine in US- leishmaniasis and Chagas disease can be transmitted by blood transfusions. "Desert Storm" personnel were prohibited from donating blood due to the appearance of leishmaniasis in troops.

Answer 93

American trypanosomiasis- a. Trypanosoma cruzi- flagellated parasitic protozoa that lose their flagella and live inside many human cell types as intracellular parasites. b. Chagas Disease or American trypanosomiasis. Infection via the bite of a reduviid bug or ‘kissing bug’. c. Parasites have several forms, morphologically and biochemically distinguishable: trypomastigote - found in man and animals epimastigote - found in insect vector, is infectious promastigote - found in insect vector and easiest to culture amastigote - intracellular form found in man. Has no flagella. All the Leishmanias and the American trypanosomes (T. cruzi) have this form.

Answer 94

South American trypanosomes: A human is infected by the bite of the kissing bug, or Reduviid bug, which lives in the thatched roofs of huts in South and Central America. These bugs bite and defecate near the mouth and the parasites, deposited in the feces, are scratched into the wound by the soon to-be infected person. The trypomastigotes infect the cells of many organs and develop into unflagellated, intracellular amastigotes. Trypomastigotes, circulating in the blood, are taken up by a Reduviid bug when it feeds. There is no antigenic variation in T. cruz. e. Pathogenesis: South American trypanosomes- initial infection is acute, especially in the young. Many organs are affected. In the adult, the disease initially is less severe, but leads to chronic myocarditis and megacolon. Chagas disease is characterized by cardiomegaly, enlarged esophagus and/ or colon. Symptoms due to invasion of smooth muscle cells by parasites. Autoimmunity may play a role as well.

Answer 95

f. Diagnosis: South American trypanosomes- Blood smear or biopsy- see both trypomastigote and amastigote forms. Xenodiagnosis- feed bug on infected individual and look for parasites in insect feces. PCR methods are being developed. g. Treatment: Flagyl in acute phase; gamma interferon stimulates macrophages to kill amastigotes. h. Prevention and control-(for both types of trypanosomes) insect vector control, identification of biochemical targets for chemotherapy. Animal reservoirs- some animals are asymptomatical but serve as reservoirs. The animal reservoir is different for American trypanosomiasis is the armadillo.

Answer 96

Toxoplasma gondii. Cause of brain, liver and congenital eye /neurological infections. a. This is a very common infection in US and in Europe (10-80% of population). It is a serious disease in newborns who have acquired infection in utero and in immunocompromised patients. b. Causative agent is Toxoplasma gondii, which is an intracellular parasite. Parasites live in reticuloendothelial and parenchymal cells. c. Morphology and life cycle: T. gondii lives in man and animals. The definitive host is the cat. Infected cats pass oocysts in feces of cattle, pig, and sheep. Cats become infected when they consume mice that received parasites from these animals. Human acquires infection when they eat uncooked infected meat or when they accidentally ingest oocysts from cat feces (i.e., when cleaning out litter boxes). Parasites initially infect macrophages, replicating as intracellular tachyzoites. These infected cells rupture and parasites infect many types of host cells. Growth is limited by cellular immunity (T cell). Eventually, tissue cysts form, many tissue cysts reside in the brain. These remain dormant as long as host cellular defenses remain active. Immunosuppression reactivates disease with possible fatal dissemination.

Answer 97

d. In adults, infections are asymptomatic, or mild mononucleosis - like symptoms. Serious disease is caused by congenital infection- major CNS and respiratory problems. e. Congenital infection:- when mother receives a primary infection when pregnant, she will transmit disease to fetus with grave consequences: mental retardation, etc. Infection of the CNS is responsible for the pathology of the disease. Congenital infection may show up many years after birth.

Answer 98

f. Diagnosis: Lymph node biopsy. Initially perform antibody titers. Rise in antibody titer over time-- variable titers at any one time indicate past exposure or early disease, medium titers indicate recent exposure or present disease, high titers indicate active disease. g. Therapy: Combination of pyrimethamine and sulfadiazine for newborns and immunocompromised patients. During pregnancy spiramycin is used. h. Prevention and control: i. Avoid uncooked or rare meat ii. For pregnant women, do not change cat litter boxes, avoid rare/uncooked meat iii. Indoor cats - feed can or dry food to eliminate problem.

Answer 99

Details of Diagnostic methods: A. Blood smear 1. Malaria 2. Trypanosomes 3. Babesia 4. Lymph Filarial worms

Answer 100

Stool samples 1. Cysts of amoeba 2. Giardia trophozoites or cysts 3. Cryptosporidia - cysts 4. Tapeworm eggs and proglottids that crawl out of anus 5. Ascaris eggs 6. Fluke eggs - Schistosoma eggs 7. Anal area-pinworm 8. Whip worm- eggs 9. Hookworm eggs

Answer 101

Tissue biopsy 1. Trichinella in muscle 2. Hydatic cyst- dog tapeworm-Echinococcus 3. Strongyloides - worms 4. Adult Acaris in liver 5. Free living amoeba- Naegleria 6. Amebic liver abscess 7. Meagcolon, cardiomyopathies- Trypanosoma cruzi - amastigotes 8. Visceral Leishmaniasis – amastigoes

Answer 102

Skin observation and biopsy 1. Cutanous leishmaniasis 2. Dracuncules- fire worm E. Immunological techniques 1. Toxoplasma- antibody test for IgM and IgG antibodies 2. Cryptosporidium- ELISA antibody test

Answer 103

Modes of infection A. Direct 1. Hookworm 2. Schistosomes 3. Strongyloides

Answer 104

Arthropod-borne 1. Plasmodium 2. Trypanosomes 3. Onchocherca 4. Wucheria

Answer 105

Fecal –oral 1. Direct-feces to mouth: Amoeba Pinworm Hookworm 2. Water borne- Schistosomes

Answer 106

Ingestion from food 1. Tapeworms 2. Anisekiasis 3. Toxoplasma 4. Trichonella

Answer 107

Informational

Answer 108

Most diseases are associated with either poor hygiene, immunosuppression (either disease-induced or drug-induced) or diabetes mellitus.

Answer 109

Eosinophilic component is classical with hypersensitivity response. The invasive parasites are usually chronic and pathological in state.

Answer 110

* Common cause of disease/death in developing countries and are widely present in U.S. but usually not fatal. * Reproductive life cycles are more complex than bacteria or fungi. * Lumenal: Giardia, Cryptosporidia, Entameba * Bloodstream: Plasmodium sp, Trypanosoma sp. * Tissue: E. histolytica, T. cruzi, Leishmania, Toxoplasma, Trichomonas Note: Entameba has the ability to be in the lumen and be invasive to be in the tissue.

Answer 111

causes disease by interfering with absorption - diarrhea - malabsorption Surface parasite of small intestines: Two eyes looking at you

Answer 112

Immunocompromised patients presenting with diarrhea - Diarrhea - Malabsorption Surface parasite: Dot like smuts on the surface of villi - Parasite displace the microvilli --> malabsorption, diarrhea

Answer 113

Entemabe histolytic 1. Iliocecal bowel ulcer 2. erythrophagocytosis - the protozoan ingests RBCs 3. liver abscess "amebic abscess" - Organisms gain access from GI into vasculature --> get into vein --> portal vein --> liver disease Note: Less common but after liver abscess the protozoan may travel to the brain

Answer 114

- Tsetse fly (Glossina) "Arthropod-borne" - Trypanosomiasis- Ultimately disease is due to the infiltration of Trypanosomes into brain tissue. Sleeping disease is characterized by macrophage engulfed trypanosomes in the brain and inflammatory response. - Trypanosomes in blood and not inside RBCs. Extracellular organism that will eventually invade tissue.

Answer 115

Trypanosome cruz Organism is intracelullar and does not cause much of an inflammatory response. Likes to get into striated muscle - e.g. the HEART; patients will develop heart disease. Also likes to get into the esophagus.

Answer 116

Leishmaniasis, also spelled leishmaniosis, is a disease caused by protozoan parasites of the genus Leishmania and spread by the bite of certain types of sandflies. Prevalent in the Middle East - Esp. Iran and Iraq Cutaneous and Visceral (systemic) Found in macrophages

Answer 117

Toxoplasmosis is a parasitic disease caused by Toxoplasma gondii. Prevalent in immunocompromised patients e.g. AIDS and women cleaning cat litter box. Toxoplasma gondii can cross placenta Reservoir : domesticated animals; "Filet American" in Belgium TORCH - acronym for congenital infections TO- Toxoplasmosis

Answer 118

Some of these only cause disease because of malabsorption. Increased severity may increase upon consumption of larva. Larva penetrates small bowel wall gets into circulation and returns into small bowel into its mature form. Ascaris in particular the larva penetrate the small bowel and makes its ways into the lung. This causes an inflammatory response, we cough and some of the larva we swallow back up where the larva mature into adult and remain in GI not being pathological.

Answer 119

Necrotizing pneumonia with exudate within alveola spaces and inflammatory cells. In the alveolar spaces cyst are seen with Taxozoates

Answer 120

The bumpy shaped ova in feces.

Answer 121

Normally : Eggs excreted into feces and becomes larva once picked up by something else SI is different because: Ova changes into larva state before excreted. The larva has potential to penetrate tissue before excretion. Larva can be seen in the small bowel mucosal wall.

Answer 122

Larva form circulates in the tissues encysts in striated muscle causing aocalized inflammatory response with increased eosinophils. Dx: increased eosinophil count. Trichinella spiralis is a nematode parasite, occurring in rodents, pigs, horses, bears, and humans, and is responsible for the disease trichinosis. It is sometimes referred to as the "pork worm" due to it being found commonly in undercooked pork products.

Answer 123

Predilection of winding up in lymphatics and clogs ----> chronic edema. Long standing edema ---> lymphaedema ---> skin thickens (hyperkeratonic) Elephantiasis (Wuchereria)

Answer 124

Majorly found in Middle East. Persists as larval stage and the liver is greatly affected. Large cystic lesions may be mistaken for a cystic tumor Absolute alcohol will first be injected into cyst

Answer 125

Onchocerciasis: Major cause of blindness in developing countries "River blindness" Organism can be found circulating the eye. Tx: Ivermectin

Answer 126

Can also cyst in the brain particularly pork and beef tape warms

Answer 127

Cystic echinococcosis (CE) is the larval cystic stage (called echinococcal cysts) of a small taeniid-type tapeworm (Echinococcus granulosus) that may cause illness in intermediate hosts, generally herbivorous animals and people who are infected accidentally. By eating contaminated animals. Humans become the accidental second part of the life cycle; larval stage (cyst). Liver is greatly affected by these large space occupying cysts. Can be confused for a cystic tumor. Hydatid cyst in liver. Tx: If Dx prior to operation as echinococcal cysts provide absolute alcohol treatment. It kills off the organism and now can be surgically removed. If rupture a cyst then the daughter cyst will spread out and enter into peritoneal surface.

Answer 128

schistosomiasis mansoni Generally a middle east and Asian disease but has a prevalence in Puerto Rico. Schistosomiasis is found in fresh water found in snails in larval form. Larval form Cercaria can penetrate intact skin. Depending on type of Schistosomiasis determine where they migrate. Schistosoma mansoni (ME -Egypt and PR) - Adults live in inferior mesentric venous plexus Schistosoma japonicum (Asia)- larva in liver migrate down portal vein and the adults develop in inferior or superior mesenteric vein Left side of bowel (Inf) or rest of colon and most of small bowel (Sup). Adult found in small bowel or right side of colon. Schistosoma haematobium- larva get into liver but push into the hepatic venous side and end up in circulation perivesical plexus (veins surrounding bladder)

Answer 129

larva live in inferior mesenteric vein --> portal vein ---> liver ---> focal eosinophils surrounding ovum Leads into portal fibrosis ---> edema and ascites Granulomatous reaction to present ovum with eosinophilic presence. Granulomas heal by fibrosis. Shriveled ovum with giant nucleated cell. Liver: Schistosome fibrosis Portal hypertension with Ascites

Answer 130

Schistosoma haematobium ova (calcified) Bladder: S. haematobium-induced squamous metaplasia Transmitted through the wall of the bladder and eventually pass through the urine after the chronic cystitis nature. Chronic disease we get metaplasia, i.e. the change of one type of tissue type to another Chronic cystitis ---> leads change of transitional epithelium to squamous epithelium (metaplasia) --> leading to squamous cell carcinoma of bladder Metaplasia predisposes person to cancer.

Answer 131

•Schistosoma haematobium: Squamous cell carcinoma of urinary bladder Liver flukes • Clonorchis sinensis: Adenocarcinoma of biliary ductal system (cholangiocarcinoma)

Answer 132

•Generally don’t cause lesions! - Don't cause chronic inflammatory disease -Live only in the keratin liver. Non invasive.

Answer 133

- Mainly live in skin. * Generally do not cause systemic disease. * Scaly lesions * In epidermis, fungi release factors that are chemotactic for PMNs; One exception to the chronic inflammation rule * In dermis, fungi cause a chronic inflammation

Answer 134

- Spongiosis, neutrophils, septate hyphae. Edema separating the cell layers. Neutrophils within the epidermis

Answer 135

Inoculated into the dermis and subcutis - get in through pricks in the skin and may enter the lymphatics (e.g. Sporotrichosis) •Cause abscesses, suppurative granulomas, reactive thickening of the epidermis and ulcers, lymphangitis - Invasive, get into subcutaneuos tissue, cause chronic inflammation and leads to secondary change to skin overlying Sporotrichosis- Can tract the lymphatics because of the overlying inflammation

Answer 136

•Disseminate in the body but can also cause skin lesions A) True pathogenic fungi: –Associated with specific geographic locations –Form necrotizing granulomas—mimic Tb –Major ones are Histoplasmosis, N.A. Blastomycosis, S.A. Blastomycosis, Coccidiomycosis. True- intrinsically pathologically causing disease in anyone. Immuno- competent/compromised.

Answer 137

Histoplasmosis: Caseating granuloma + Silver stain Necrotizing caseating granuloma in lung cannot differentiate from TB Bat dropping spore inhalation may be a cause.

Answer 138

B) Opportunistic Fungi : We are more concerned about these in this part of the country * “only” cause disease in immunocompromised/diabetic individuals * Candida sp.: most common. Unique in that it usually causes abscesses, not granulomas * Aspergillus sp.: may cause hypersensitivity (without entering the body) or grow in pulmonary cavities (“fungus ball”) or  pneumonia and grow into blood vessels  infarction (as does Mucor); This leads into thrombosis --> MI Note: These are very common normally causing issue for immunocompromised or DM patients. Note: Aspergillus sp found on bread mold Note: Mucor is an organisms seen predominately in DM patients. Aspergillus and Mucor both cause pneumonia, gets into blood vessels --> MI (same thing with blood vessel can occur in other areas of body e.g. body and cause an infarction

Answer 139

Fungus ball Mucor sp. in cerebral blood vessel

Answer 140

* B) Opportunistic Fungi: * Cryptococcus neoformans: both a true pathogen and an opportunistic yeast, forms granulomas or grows in sub-arachnoid space  meningitis * Pneumocystis jiroveci: mainly in immuno-suppressed patientsintra-alveolar eosinophilic exudate + interstitial chronic pneumonia (requires special stains to be seen) Note: Cryptococcus neoformans found in pigeon droppings. Note: Pneumocystis jiroveci- became one of the major infections diseases for AIDS patients Prophylaxis: vactrum for AIDS/HIV/Cancer patients to prevent Pneumocystis

Answer 141

mucicarnin stains. Stain mucin (mucopolysaccharide) Has a mucoid capsule Pneumocystis pneumonia (eosinophilic exudate) Pneumocystis is not routinely visualized with H&E Pneumocystis juroveci (GMS stain); Silver stain. Reclassified as fungal because of this staining. Before was considered parasitic

Answer 142

•Silver stain aka GMS (Grocott's methenamine silver stain) or Grocott stain •PAS stain (Periodic acid–Schiff stain) (Unlike most bacteria, most fungi can usually be seen on H & E stain but special stains make them appear more prominent).

Answer 143

a. Phagocytosis (protozoa) b. Secretion of cytotoxic substances (Helminths) c. Produce cytokines that regulate inflammation e.g. IL- 1, TNF, d. NO - involved in kill of Leishmania e. Granuloma formation – wall-off parasites f. Presentation of antigen to T cells. However, many parasites are effective in resisting these mechanisms and persist in the host, sometimes replicating within macrophages.

Answer 144

a. T cells: T helper, cytotoxic, cytokine production (Th1 vs. Th2). Th1 cells deal better with intracellular parasites by activating the macrophages and parenchymal cells; Th2 deal with extracellular organisms. b. Antibody: Eosinophils and high levels of IgE are associated with parasitic worms. Other antibody classes are associated with opsonization, complement lysis, blocking of invasion, etc. c. Effective immune strategies can vary: - Different stages of the parasite life cycle. For example, in malaria infection, at the liver stage, cytotoxic T cells can contribute to parasite control, but at the bloodstage, since RBC do not express MHC Class I, other mechanisms are more important (antibody, free radicals, phagocytosis). - VECTOR also effects Immune response. ``` -Host Immune status: –Immunocompetence –Age –Nutrition –Coinfection ```

Answer 145

Th2 responses are particularly important in helminthic infections. IL-3, IL-4, IL-5 production by activated T cells leads to increased eosinophil killing of schistosome larvae (Schistosomes "helminths". Eosinophils kill these parasitic worms by oxygen dependent and independent means. They can degranulate in antigen specific or non-specific manner. They function most efficiently in an antigen-dependent manner by binding the Fc portions of IgG or IgE antibody to their surfaces, while the Fab domains bind to the worm. This results in the release of major basic protein, which is toxic to the worm. This is a form of ADCC. The eosinophils work together with the mast cells, and their killing is enhanced by mast cell products that are released following IgE-dependent degranulation. Smooth muscle contraction, for example, helps expel the parasites from the gut. Th2 cytokines are important for these responses: IL-4 results in class switching to IgE production and IL-5 is a growth and activation factor for eosinophils. It should be noted that the protective response is mixed, with some contribution of Th1 responses as well. Note: ADCC = Antibody‐dependent Cellular Cytotoxicity

Answer 146

Th1 cytokines are important in resistance to protozoan parasites. IFN-required for macrophage destruction of leishmania and Toxoplasma. Th2 cytokines predominate (IL-4, IL-10), then the macrophages are unable to eliminate the parasite. Other Th1-inducing cytokines play a role in this resistance: IL-12 produced by macrophages will up-regulate the IFN-production by the Th1 and NK cells, but IL-10 is later expressed to prevent immunopathology.

Answer 147

1. Site sequestration 2. Complement resistance 3. Avoidance of intra-phagocytic digestion - protozoa 4. Antigenic variation - Trypanosomes 5. Avoidance of recognition: schistosomes cloak themselves with hostmolecules. 6. Suppression of host response - very common - Immunopathology: over-zealous immune response can have damaging consequences for the host.

Answer 148

Th1: Dendritic cells will be induced by small parasites e.g. protozoans to release IL-12. The IL-12 will induce NK to secrete INF-gamma. IL-12 and INF-gamma activate naive CD4 T cells to commit to differentiate into Th1. Th1 cells secrete INF-gamma, TNF, and IL-2. Th2: Pathogens such as worms (helminths) will induce NK1.1+ T cells to secrete IL-4. Naive CD4 T cells are activated in the presence of IL-4 and commit to differentiate into Th2. Th2 cells secrete IL-4, IL-5, IL-13.

Answer 149

Th1 produces IL-2, TNF, IFN-gamma. IL-2 is positively feedback to Th1 to continue induction. TNF and IFN-gamma cause increased induction to express IL-12 and thus loop back to Th1. IL-2, TNG, IFN-gamma serve to activate macrophage. Th-2 produces IL-4 which antagonizes (inhibits) the effect of IFN-gamma on the macrophage and thus we get no macrophage activation.

Answer 150

Chronic controlled infection: Young Th1 produces IL-2. As positive proliferation feedback occurs with IL-2 the Th1 becomes very active. Th1 then starts to produce IL-10 and along with IFN-gamma, the two antagonize their effects. IFN-gamma on the macrophage increased the NO-mediated parasite killing. IL-10 inhibits the macrophage and its production of IL-12, which serves as positive proliferation feedback for Th1. Unchecked lethal infection: Necrotizing disease without IFN-gamma. The parasite proliferates. Without the activation of macrophage there is also no production of IL-12. Controlled infection/uncontrolled inflammation: Parasite cleared but IFN-gamma and IL-12 will continue to stimulate Th1 to make IFN-gamma. Overexpression of IFN-gamma, IL-12, and production of TNF will cause multi-organ damage due to Hyperinflammation. Quicker self destruction than the lack of IFN-gamma (persistance of parasite)

Answer 151

* Parasitic worms * Induce IL-4 (class switch to IgE), IL-5 (promotes generation and activation of eosinophils) * Favors Th2 response, IgE expression * IgE binds to high affinity Fc-EpsilonRI receptors on eosinophils * ADCC against the Schistosome larva; release of major basic protein; mostly by IgE, but also IgA * Other allergic mediators involved in gut hyperactivity * CTL, macrophages also involved

Answer 152

GI - increased fluid secretion, increased peristalsis --> expulsion of GI tract contents (diarrhea, vomiting) Airway - decreased diameter, increased mucus secretion --> expulsion of airway contents (phlegm, coughing) Blood vessels - increased blood flow, increased permeability -->Edema, inflammation, increased lymph flowing carriage of antigen to lymph nodes. Note: In type I hypersensitivity, anaphylaxis

Answer 153

Sporozoites enter the capillaries an Abs are produced against it. The sporozoites enter the liver. They invade a hepatocyte, harbor a vacuole and get released as merozoite into the blood stream. The merozoite now enter RBCs or reticulocytes and undergo asexual reproduction. Then the RBCs is burst open--> hemolytic anemia --> and now their is the development of gametocytes. Note: with the uptake of Ab by the mosquito prevention of the maturation of gametocytes into pathogen is possible thus reducing the incidence of population disease. Note: their is also host defense with the involvement of CTL, free radicals, Abs, and cytokines.

Answer 154

Sporozoites enter the lymph vessel and make their way into the lymph node. In the lymph node the dendritic cell picks up the Sporozoites and presents it a naive T cell via MHC complex. In the liver the activated T cells both CTL and Th cells will have their role in eradicating hepatocyte infected cells and prime neighboring hepatocytes not yet infected. CTL release perforin which poke holes in the cell. Granzymes are the excutioner; does the killing. In a Th1 response IFN-gamma will activate JAK-STAT. Turns on the genes to serve to kill pathogen. The IFN-gamma will spill over to the other cells and prime them even though they have not been infected yet; making them antimicrobial.

Answer 155

A hepatic stage immune response is unrelated to immune response in the blood stage. The antigens expressed are different for both in the case of antigens expressed from an infected RBC and an infected hepatocyte. Cell mediated Response: From an infected RBC a dendritic cell primes a Naive T cell to become a Th1 cell. In the sinus of the liver the Th1 cell expressed INF-gamme to activated a macrophage in the red pulp of the liver. With an activated macrophage can now kill the infected RBCs. Later the response switches over to a more Ab dominated immune response.

Answer 156

Cercaria can penetrate intact skin. Adult worm have very thick follicular tissue and able to resist immune response. The adult worm can live for decades in the body. Female worm will lay hundreds of eggs/day and excreted in feces. Some of the eggs will be swept up into the portal vein and cause a granulomatous response.

Answer 157

Early Th1 cell but with the production of eggs there is a switch to Th2 cell response. Eggs are the cause of this switch. With the persistence of the worm we go into a Regulatory T cell phase. Immunomodulatory or immunosuppressant cytokines IL-10 and TGF-beta.

Answer 158

Sudden loss of an co-evolved immunomodulating internal environment due to eradication of worm infections in populations leading to increased incidence in autoimmunity and allergy. Our immune system was evolved under the conditions of these now non influential pathogens. Regulatory T cell helps in dampening the long term effects of Th1/Th17 and Th2 responses. Without the exposure to these pathogens we may be lacking in the T regulatory response and achieving more organ specific autoimmune diseases or allergies due to over expression of Th1/Th17 and Th2, respectively.

Answer 159

Informational

Answer 160

A. All contain a protein shell (capsid) which protects a nucleic acid genome 1. Protein Shell - Protects and packages the viral genome Can be cubic, helical or complex 2. Nucleic Acid – Contains all genetic information for the virus B. Some viruses may be enveloped by a lipid membrane derived from the host cell

Answer 161

A. Determined by International Committee on Taxonomy of Viruses B. Based on morphology, genome properties, genomic organization (segmented vs non-segmented), antigens and biological issues C. Viruses are organized into orders, families, subfamilies, genera and species 1. Will discuss 23 families in this course 2. DNA viruses: Parvoviridae, Adenoviridae, Herpesviridae, Poxviridae, Polyomaviridae, Papillomaviridae, Hepadnaviridae 3. RNA viruses a. Single Stranded i. Positive sense:Picornaviridae, Flaviviridae, Togaviridae, Astroviridae, Caliciviridae, Coronaviridae, Hepeviridae, Retroviridae ii. Negative sense: (a) Non-segmented: Paramyxoviridae, Rhabdoviridae, Filoviridae, Bornaviridae (b) Segmented: Orthomyxoviridae iii. Ambisense: Segmented: Bunyaviridae, Arenaviridae b. Double Stranded: Reoviridae

Answer 162

A. Viruses can be cultured using: 1. Animal models: test therapies and vaccines 2. Embryonated eggs: High titers, used for vaccine production 3. Cell culture: extensively used by virologists - economical and accessible B. Viral detection and quantitation 1. Cytopathic effects: Rounding, fusion, inclusion bodies, lysis etc 2. Lysis is the basis of the Plaque Assay which is an effective biological method for detecting and quantitating several viruses C. Viruses can also be detected and quantitated using a variety of physical methods 1. Particle count in EM 2. Hemagglutination assay – virus must express hemagluttinin 3. ELISAs 4. Immunofluorescence 5. Molecular Diagnostics

Answer 163

A. The ability to culture viruses in cells allows for detailed molecular analysis of life cycles B. Early events – adsorption, penetration and uncoating – apply to all viruses

Answer 164

a. DNA Viruses: Generally go to nucleus where they transcribe the genome to make viral proteins necessary for replication b. RNA Viruses: i. Positive Sense – Stay in cytoplasm where they directly translate the genome to make proteins necessary for replication. Replicate the genome using a negative sense replication intermediate. ii. Negative Sense - Stay in cytoplasm – Must replicate before translation therefore must package the polymerase in the vision. iii. Retroviruses: Two stage replication occurring in both cytoplasm and nucleus. Require reverse transcriptase to convert RNA genome into a DNA genome. iv. Double Stranded RNA viruses: Replicate in the cytoplasm using a positive sense replication intermediate. Package their polymerase in the virion.

Answer 165

Viruses must shift from early expression to late expression a. DNA viruses: Selective promoter usage b. Retroviruses: Splicing/polyproteins c. RNA viruses: Many strategies i. Positive Sense (a) One polyprotein – post translational regulation through protease i.e. picornaviridae (b) Several polyproteins – regulation through protease plus production of subgenomic mRNAs i.e. Togaviridae (c) Polyproteins plus individual ORFs – regulation through protease and production of subgenomic mRNAs i.e. Coronaviridae ii. Negative Sense: Single polymerase initiation site – regulation determined by the action of the polymerase – produces subgenomic mRNAs iii. Segmented: Regulatory elements present in individual segments

Answer 166

1. Viral packaging – self assembly of capsids and insertion of nucleic acid 2. Viral release – non-enveloped generally exit by lysis enveloped exit by budding

Answer 167

A. Host Susceptibility i. Genetics: Surprisingly few good examples in humans ii. Age: Clear differences related to immune status, status of alimentary canal and respiratory muscles. iii. Gender: Differences not well understood. Males generally more susceptible. iv. Immunity: Vaccination, previous exposure, immunodeficiency v. Nutrition: Not as obvious in developed countries but good examples in undeveloped countries (measles) B. Transmission i. Human-Human: Horizontal, vertical, germ-line, iatrogenic, nosocomial ii. Animal-Human: Humans are not always a productive reservoir

Answer 168

A. Typically a successful infection requires large quantities of virus, accessible cells, and an ineffective defense system by the host. B. There are five points of entry for viruses 1. Skin – Depth of inoculation often determines spread 2. Respiratory tract – Most common site of infection 3. Alimentary tract – either by ingestion or sexual contact 4. GU tract – transmission generally by sexual contact 5. Conjunctiva – generally associated with localized infections

Answer 169

C. Infections can be either localized or disseminated 1. Localized infections generally involve entry and exit through the same cell surface (apical). a. Allows for the rapid dispersal of enteric viruses in feces 2. In disseminated infections viral exit is more typically through the basolateral surface. a. Virus must cross the basement membrane so infections are often associated with localized inflammation. b. Once through the membrane viruses can enter the lymphatic system, the circulatory system or neurons. D. Shedding: Viruses generally exit using the same routes as entry: respiratory secretions, saliva, feces, blood, breast milk, skin lesions etc.

Answer 170

A. Vaccines are the most effective method for preventing viral infections. 1. Have virtually eradicated over a dozen diseases in the US 2. Three types of vaccine are currently in use a. Attenuated live viruses (Measles) b. Killed virus Vaccines (Polio, Rabies) c. Subunit vaccines (Hepatitis B)

Answer 171

B. A number of antibodies have also been approved for the prevention and treatment of viral diseases in the US: 1. Human immunoglobulins are used for pre- and post-exposure prophylaxis for Hepatitis A 2. Rabies immunoglobulins can be used for post-exposure prophylaxis C. There are currently over 85 antiviral drugs in use 1. Most drugs are for use against HIV, HBV, HCV, Influenza and Herpes 2. Targets include a. Viral proteases b. Viral uncoating c. Viral entry d. Viral release e. DNA synthesis f. Cellular enzymes involved in protein synthesis (interferon)

Answer 172

Informational list

Answer 173

* Trichomonas vaginalis - Administered to both sexes * Entameba histolytica * Giardia lamblia * Bacteroides fragilis * Clostridium spp. * Other anaerobic bacteria Route - Oral

Answer 174

Microaerophilic organisms—ameba—use ferredoxin-like low redox potential electron transport proteins in order to convert pyruvate to acetyl-CoA The nitro group of metronidazole can accept electrons from these proteins resulting in cytotoxic products which bind to DNA and proteins. Metronidazole is CIDAL Note: Microaerophilic organisms do not like lots of oxygen.

Answer 175

* Orally active * Well distributed: CSF, breast milk and alveolar bone * Half-life = 7.5 hours * Alkyl chain oxidation and glucuronidation * Parent (50%) and metabolites (50%) are excreted in urine

Answer 176

In susceptible organisms protozoans or anaerobes the reactive products favor areas of electron density e.g. DNA and possibly DNA. The reactive products bind irreversibly to these areas. Relative selectivity because the microbes have a perodoxin transport system to create these reactive products other than the amine product which is benign. Humans lack the perodoxin system, but we do make the amine product which is benign.

Answer 177

* Common: nausea, headache, dry mouth, metallic taste * Less frequent (12%): vomiting, diarrhea, insomnia, weakness, dizziness, stomatitis, rash, urethral burning, vertigo, paraesthesias * Disulfiram-like effects: No alcohol 24 hrs before or 48 hrs after last dose * Mutagenicity and carcinogenicity: Experimental evidence for these effects—Ames test and rodent model Humans—20 years of use with no increase in congenital defects, low birth weight or still births

Answer 178

* Potentiation (Enhancement) of oral anticoagulants * Phenytoin and phenobarbital increase rate of elimination * Cimetidine decreases metabolism * Increased risk of lithium toxicity (interferes with lithium excretion)

Answer 179

- Artemisinin, Chloroquine, Quinine, Mefloquine, Pyrimethamine - Primaquine - Primaquine

Answer 180

* Derived from Chinese medicine: * Artemisinin: oral only * Artemether: oral, rectal, IM * Artesunate: oral, IM and IV (only one) * All are endoperoxides that are non-enzymatically cleaved to dihydroartemisinin (oral only), a highly reactive substance that forms free radicals that rapidly kills blood schizonts of all 4 human malaria species * Combination therapy to improve efficacy and prevent selection of resistant parasites FDA approved: Coartem® - artemether + lumefantrine Note: Lumefantrine is normally given in combination

Answer 181

* Common: nausea, vomiting, diarrhea, dizziness * Rarely: neutropenia, anemia, hemolysis, liver enzyme elevations * Do not use in first trimester of pregvancy; can be used in the last two trimesters * Uses: Uncomplicated and complicated falciparum malaria. Standard of care for severe falciparum malaria (artesunate IV) Note: administered for Chloroquine resistant malaria

Answer 182

* 4-Aminoquinoline * Mechanism of antimalarial activity: Inhibits hemoglobin polymerase, plasmodial enzyme responsible for removing toxic heme break-down products * Only effective vs blood trophozoites & schizonts in non-chloroquine resistant falciparum malaria Other uses •Treatment of extraintestinal amebiasis •Anti-inflammatory: high doses relieve symptoms of rheumatoid arthritis and lupus erythmatosus

Answer 183

* Orally active * Protein binding about 55% * Vd = 115 L/kg; accumulates in tissues by binding to nucleoproteins (200-700 times plasma concentration in liver, spleen, kidney; less concentrated in brain) * Renal excretion: 70 % unchanged; N-dealkylated metabolites * Half-life = 7 days; long half life thus give a loading dose Note: as soon as it crosses the membrane it is bound.

Answer 184

The parasite digests the RBCs to obtain essential amino acids. Heme is released in the process and proves to be toxic to the parasite. The parasite polymerizes the heme ---> HEMOZOIN Chloroquine prevents polymerization to the hemozoin. The accumulation of heme results in the lysis of both the parasite and RBCs.

Answer 185

* Mild and transient GI discomfort, headache, dry skin, pruritus * Prolonged use (1 year) at high doses Diplopia T wave changes * Rare: loss of visual acuity; corneal opacities; “Bull’s eye” lesion (not reversible) * Acute toxicity: cardiac arrhythmias, death

Answer 186

•8-aminoquinoline •Effects on plasmodia: –**Tissue schizonticidal** –Gametocytocidal –Sporonticidal * No effect on erythrocytic forms of malaria; component of “radical cure”. Given after the treatment of malaria (erythrocytic form) to prevent reoccurrence from the tissue schizonts. * Mechanism is unknown

Answer 187

* Orally active * Distributed into tissues but not bound as is chloroquine * Completely metabolized * Urinary excretion * Half-life = 3–8 hours

Answer 188

* GI disturbances * Methemoglobinemia * Arrhythmias * Hemolytic anemia in G-6-P DH deficient individuals (symptoms: darkened urine; flank pain; weakness & fatigue)

Answer 189

Individuals with G6P DH deficiency there is a decrease in NADPH and GSH making the RBC more sensitive to oxidative agents such as Primaquine. Primaquine oxidizes GSH to GSSG. Less GSH is available to neutralize toxic compounds. Many drugs may cause hemolytic anemia including chloroquine, sulfonamides, etc

Answer 190

* Treatment of serious disease as an alternative to artemisinin-based therapy. All 4 blood schizonts are susceptible * Often combined with doxycycline to shorten therapy to 3 days. In children substitute with clindamycin * Cinchonism: cluster of side effects including tinnitus, headache, nausea, dizziness, flushing, visual disturbances Adverse effects * Severe hypotension if infused too rapidly * ECG abnormalities from high doses * Increased levels of warfarin & digoxin

Answer 191

* Treatment of chloroquine-resistant falciparum malaria * Recommended chemoprophylaxis in such areas * Oral only; long half-life; once a week dosing for prophylaxis * Nausea, vomiting, dizziness, sleep, behavioral changes * Avoid in patients with epilepsy, psychological disturbances and arrhythmias

Answer 192

* Effective against all 4 erythrocytic forms of human malaria * Only available combined with artemether (Coartem) * May be embryotoxic

Answer 193

1. Chloroquine 2. Chloroquine 3. Artemether + Lumefantrine (Coartem) 4. Artesunate (IV) follow with either full course of doxycycline or clindamycin --OR-- Quninidine

Answer 194

Informational

Answer 195

* Sodium stibogluconate—pentavalent antimony compound—interferes with glycosome, resulting in decrease in protozoal ATP and GTP * Administered parenterally; Vd = 0.22 L/kg; biphasic elimination: a) 2 hours; b) 33-76 hours; accumulates * Adverse effects: muscle & joint pain; fatigue; T-wave changes; transaminase elevations; shock/sudden death

Answer 196

* Therapeutic uses: Pneumocystis jiroveci pneumonia; leishmaniasis; African trypanosomiasis * Mechanism: unknown

Answer 197

•Parenteral administration only. Inhalation for pneumocystis prophylaxis * Rapidly distributed to liver, spleen & kidney * Does not cross blood-brain barrier but does cross the placenta * Excreted unchanged in urine

Answer 198

* Pain at injection site * Sympathoplegic (interfering with nervous system)—severe hypotension * Release histamine from mast cells (also causes hypotension) * Toxic to pancreatic islet cells: initially releases insulin causing hypoglycemia; later causes suppression of insulin release—diabetes * Renal toxicity: hyperkalemia, hypocalcemia * Rare: pancreatitis, toxic epidermal necrolysis thrombocytopenia

Answer 199

Mebendazole

Answer 200

Ivermectin Praziquantel Albendazole

Answer 201

* Mechanism: bind to helmintic tubulin preventing microtubule formation. Results in block of glucose uptake and depletion of ATP. Organism is immobilized and eventually dies * Selective toxicity: affinity of helmintic tubulin is two orders of magnitude greater than mammalian

Answer 202

* Only 10% absorbed after oral administration; tablets must be thoroughly chewed prior to swallowing * Rapidly metabolized and excreted in urine * Adverse effects: GI including nausea, vomiting & pain; headache, dizziness

Answer 203

* Rapidly absorbed * Active metabolite (sulfoxide) * Half-life 8–9 hours * Primarily renal excretion

Answer 204

* Low incidence (6%) of GI disturbance and CNS effects similar to mebendazole. Adverse effects: GI including nausea, vomiting & pain; headache, dizziness * Inflammatory response following death of organisms in the CNS leads to headache, vomiting, hyperthermia, mental changes. Administer corticosteroids to reduce or prevent the inflammatory response * Long-term therapy (3 months); hepatic enzyme elevations; rash, pruritus; alopecia; leukopenia

Answer 205

* Natural antihelmintic derived from soil actinomycete Streptomyces avermitilis * Activates glutamate-gated Cl– channels found only in invertebrates including nematodes and insects * Enhances GABA activated chloride channel activity also but pharmacological significance is not known

Answer 206

* Only given orally to humans * Vd = 0.7 L/kg * Does not penetrate into CNS * Slow distribution into the eye * Half-life - 28 hours * Excreted in the feces

Answer 207

•Most serious are Mazotti reaction— inflammatory response due to death of large numbers of microfilariae. In a small fraction (0.3%) can be life-threatening: high fever, hypotension and bronchospasm. - Give corticosteroids to prevent or reduce intensity * May cause corneal opacities; conjunctivitis, optic neuritis * Avoid co-administration of benzodiazepines, barbiturates and valproic acid

Answer 208

* Drug of choice for most trematode and cestode infestations * Target is a Ca++ channel of susceptible organisms. Enhances Ca++ influx which causes contraction followed by paralysis of the worm musculature. Vacuolization and disintegration of worm tegmen occurs and death ensues.

Answer 209

* Rapidly absorbed; 80% bioavailability. Swallow tablets immediately—bitter taste causes retching and vomiting * 80% protein bound * Distributes into CSF, bile, breast milk and feces * Short half-life: 0.8-1.5 hours * Metabolized to inactive hydroxy derivatives * Primarily renal excretion; some biliary

Answer 210

•Frequent –GI: abdominal pain; diarrhea –CNS: headache, dizziness –Malaise •Occasional –fever, sedation, sweating •Rare –Pruritus, rash; edema

Viruses and Fungi Flashcards

(234 cards)