Infectious Disease Pathology p56-75

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India Ink: C. neoformans (latex agglutination +): Cryptococcus in glomerulus:

Encapsulated, narrow-based bud. Latex particles are coated w/antibodies. If there Budding yeast, huge size variation. is capsular antigen present, they will clump.

C. neoformans (GMS):

Narrow-based bud, capsule, size variation. Mucicarmine stain (same as for adenocarcinomas)

Cryptosporidium and Cyclospora:

• Protozoans (like Giardia) that adhere to the brush border of the small intestine and cause malabsorption (diarrhea)

• Direct morphologic identification in tissue or stool • Cryptosporidium oocysts: 4-5µm, acid-fast (AF)+ Cyclospora oocysts: 8-10µm, AF+

• Source: contaminated water

Little round bodies coating small intestine  malabsorption. Can do immunologic testing or can take stool and do modified acid-fast stain on it. If round oocysts present = cryptosporidium.

Toxoplasmosis: Toxoplasma gondii • Intracellular protozoan • Cat feces, lamb, pork

• Encephalitis, myocarditis, chorioretinitis, lymphadenopathy, pneumonia (usually, first infection involves lung)

• Direct morphologic identification – bradyzoites and free tachyzoites in necrotic RING-ENHANCING foci

• Tissue culture or animal (mouse) inoculation

Toxoplasma: Large structures w/little bodies inside  How to tell apart from coccidioides? T is in the brain, occasionally heart. C would be

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Toxoplasma in the tachyzoite stage  I f you get a pulmonary infection, these organisms will be

free-living. Look like banana w/a nucleus.

HTLV-1:

• T-cell leukemia/lymphoma – retrovirus • Japan and Caribbean

• Strongiloidiasis

• Autoinfection (entire life cycle can occur within the host  huge numbers of strongiloides, larvae)

3. Humoral Defects (Predispose to Infection):

• Primary antibody defects - X-linked agammaglobulinemia (failure of B-cell precursors to differentiate) • Secondary antibody defects - CLL (chronic lymphocytic leukemia), other leukemias

4. Splenectomy: • Trauma

• Sickle cell disease with autoinfarction • Encapsulated bacteria:

Streptococcus pneumoniae (sepsis) Salmonella typhi (osteomyelitis)

S. pneumoniae – Gram+ diplococci w/capsule  Test q: A 36F w/sickle cell anemia and recurrent crises presents w/fever, cough, and shortness of breath. She has infiltrates on chest x-ray. The most likely etiology of her pneumonia is: Streptococcus pneumoniae.

5. Obstruction:

• Lung cancer - pneumonia (bacterial)

• Prostate hyperplasia or Carcinoma - urinary tract (E. coli, others) • Cystic Fibrosis (Pseudomonas) – with necrotizing vasulitis

Pseudomonas aeruginosa:

• GNR (Gram negative rod/bacillus) • Culture – green pigment – pyocyanin

• Numerous enzymes and exotoxins; mucoid coating on bacteria resists phagocytosis

• Necrotizing inflammation and vasculitis • Cystic fibrosis, burn patients

Can see rods in blood vessel walls   Sputum sample – strongiloidiases. Get pneumonia, cough, productive sputum that MOVES (worms).

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6. CNS (Central Nervous System):

• Catheters (coagulase-negative staphylococci; attach by glycocalyx outside the cell wall) • Unconsciousness/decreased gag reflex

• aspiration pneumonia- infections by microbiota

7. Medical Procedures:

• Catheters: urinary bladder and vascular • Prosthetic devices- valves, joints

• Bacteria – Viridans streptococci; Coagulase-negative staphylococci (CNS) – biofilms

Viridans – If you’ve had rheumatic fever and you have abnormal mitral valve, and you go to the dentist and get burst of alpha-strep into your bloodstream, will latch on and grow on your heart valve  endocarditis. Same for artificial joint/valve. If you have artificial knee or heart valve, need antibiotics before you go to the dentist.

Yeast - Candida

Premature newborn with multiple catheters 

8. Changes in Microbiota:

Environment (hospital) - Legionella – hyperchlorinate and superheat water to prevent

• MRSA and Clostridium difficile – organisms resistance to oxa?cillin are common in the hospital bc we use beta-lactams on everyone. Predispose to these methilicillin-resistant organisms.

• Antibiotic (broad spectrum) - overgrowth of surviving microbiota

eg. After tetracycline for acne, a patient develops thrush (Candida)

Every time we clear one microorganism (ex: with antibiotics), we create a spot for another.

Test q: A 32F is treated w/tetracyclines for severe acne for several weeks. She develops vaginal itching and a creamy white vaginal discharge. Yeasts and pseudohyphae are present. The patient is infected by: Candida albicans.

Legionnaire’s Disease:

• Pontiac fever 1968; American Legion convention in Philadelphia 1976 • Pneumonia with varied appearance

• Elderly with chronic lung disease, organ transplant particularly susceptible • Mortality up to 50% in immunocompromised patients

• Heavy aerosol exposure (shower, A/C)

• Prevent by chlorination or superheating of water Legionella Diagnosis:

Legionella pneumophila

• GNR (Gram negative rod/bacillus); intracellular; silver stain (GMS) +

• Direct fluorescent antibody on sputum • Culture on special media:

• Opalescent colonies on Buffered Charcoal Yeast Extract (BCYE) supplemented with L-cysteine • Urine antigen detection in disseminated cases • DNA probe

Legionella cultured  Can do fluorescent test or molecular test to ID it.

Test q: A 52M who is a heavy smoker presents w/fever, cough, and shortness of breath. He has been working on the cooling tower and water

distribution system in a nearby building. A Gram stain of his sputum reveals intracellular Gram negative bacilli. White-gray opalescent colonies grew on buffered charcoal yeast extract agar (BCYE) but not on blood agar. (One year, said “Opalescent colonies grow on special medium supplemented w/L-cysteine.”) The most likely diagnosis is infection with: Legionella pneumophila. REPEATED x2

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MRSA:

• HA-MRSA (Hospital-acquired or Healthcare-associated)

• Nasal carrier rates in hospitals approach 20%; infection rate much lower (Rx is vancomycin) • CA-MRSA (community-acquired)

Athletes, gyms. 80%+ of S. aureus infections in kids are MRSA (Rx is septra or clindamycin) • Easier to treat

MSSA – methicillin-susceptible – can give a beta lactam

Clostridium difficile:

• Pseudomembranous enterocolitis – most common cause of nosocomial diarrhea • Proton pump inhibitors (Prilosec, Prevacid)

• Clindamycin

• 3rd generation Quinolones (Gatifloxacin, Moxifloxacin etc.); quinolone-resistant C. difficile • Rx is Vancomycin or Flagyl

Test q: A 30F is being treated w/proton pump inhibitors for Zollinger-Ellison syndrome. She develops a urinary tract infection during hospitalization and is treated w/a Quinolone antibiotic. She develops diarrhea 3 days later and you order a stool: Assay for Clostridium difficile toxin.

Test q: The most common cause of nosocomial (hospital-acquired) diarrhea is: Clostridium difficile.

Candidiasis:

Candida albicans most virulent and most common Budding yeasts and sausage-like pseudohyphae

• Patients with catheters (venous, arterial, bladder, CSF); neutropenia • Broad spectrum antibiotics – if all flora is gone

• Thrush and esophagitis in AIDS; kidney microabcesses in other immsupp. • Morphologic ID or culture (germ tube +)

Test q: A 54M w/HIV presents w/a white coating on his tongue and pharynx. A GMS (Gomori’s methenamine silver) stain of an oral mucosal biopsy reveals yeast w/narrow-necked budding and

pseudohyphae. The cells are of uniform size and do not appear encapsulated. The most likely diagnosis is infection with: Candida albicans.

Test q: A 39M renal transplant patient develops fever and his neutrophil count drops below 400/µL. CT scan reveals a liver abscess which is biopsied showing abundant pseudohyphae and a few yeast-like organisms. Diagnosis? Candida albicans.

Candidiasis of Distal Esophagus:

Can grow down the esophagus. Very poor prognosis for AIDS patients. Important note:

Candida glabrata – does not make pseudohyphae. UTIs

C. albicans – Rx: fluconazole. C. glabrata is resistant to it, so it’s important to identify.

Thrush – mucocutaneous candidiasis

Below: Candida in the blood – RBCs, WBCs, and pseudohyphae of candida – like bowling pins strung end-to-end

Candida species pseudohyphae:

Eee budding yeasts, pseudohyphae. Constriction points – not parallel

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9. Diabetics:

• High glucose – good culture medium for organisms • Poor oxygenation

• Peripheral nerve defects – dysfxnl bladder emptying • Neutrophil dysfunction – don’t phyagocytose well • Cystitis, pyelonephritis, soft tissues

Mucormycosis:

Mucor or Rhizopus (also see Aspergillus in these patients) N US – Mucor. S US – Rhizo.

• Diabetic ketoacidosis (DKA), transplant/heme-onc • Nasal sinuses, lung, GI tract, brain

• Rhinocerebral mucormycosis – extends into brain • Morphologic identification or culture

Broad irregular ribbon-like hyphae, no septae (aseptate), right-angle branching

Test q: A 56M w/poorly controlled diabetes presents w/severe headache and sinusitis. A GMS (Gomori’s Methenamine Silver) stain of a sinonasal mucosal biopsy reveals broad ribbon-like aseptate hyphae w/right-angle branching. The most likely diagnosis is infection with: Mucor. REPEATED x2 (Once, was a 73F)

Test q: A 62M renal transplant patient develops fever and pneumonia. He is noted to be neutropenic. A fine needle aspiration of lung shows broad, aseptate hyphae that branch at 90 degree angles. Brownish grey colonies grow on agar plates luxuriously. Identity: Mucor rouxii.

Test q: A lung biopsy reveals aseptate, ribbony hyphae that branch at right angles. Diagnosis? Rhizopus stolonifer.

Aseptate hyphae of Mucor (H&E): Mucor in GMS/silver stain

Broad hyphae – 90 degree branching. Aseptate hyphae. Can look like a mess when cut in 2D.

10. Medical Immune Supression: • Remicade (Imixiflab)

• Crohn’s and Rheumatoid arthritis • Inhibits TNF-alpha and macrophages • Crohn’s – Tuberculosis + fungal infection • Histoplasmosis

• Coccidioidomycosis

• RA – predisposes to lymphoma and fungal infections.

If you want to give Remicade, need to do a PPD first (skin reaction test to TB) to make sure they don’t have TB – if in their body, will reactivate.

TB chart  Test q: A 29F w/severe rheumatoid arthritis is a candidate for Remicade (Imixaflab) treatment. Before beginning treatment, it is mandatory to: Perform a PPD.

Rhinocerebral mucormycosis: Nasal sinus infection. Left – clear, black. Right – filled w/organisms, inflammatory cells

Rhinocerebral Mucormycosis Extended into brain  fatal case.

 Ribbony appearance of

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TB: M. tuberculosis in a gastric biopsy:

Remember the difference between 1° and 2° TB. Acid-fast stain; blue organisms are Candida Giemsa – H. capsulatum: GMS – H. capsulatum:

Could see in Remicade patient. Macrophage, Yeast inside macrophages. Pneumocystis

budding yeast. is NEVER inside macrophages.

Coccidioides: Coccioidomycosis:

Spherules w/endospores. Numerous spherules, all w/endospores.

Opportunistic Infection Treatment:

• Trimethoprim-sulfamethoxazole = Septra (used to tx CA-MRSA, UTIs [E.coli], pneumocystic pneumoniae, shigellosis) • Acyclovir – herpes • Isoniazid – TB • Fluconazole – Candidas • Gancyclovir – CMV • Rifabutin – MAI • Other  Cording – wraps around itself, looks like cords of rope. TB w/cord factor (more virulent).

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Infections in the Compromised Host—Quiz: Buzzwords that you have to know Matching I

1. Owl's Eye Nuclear Inclusions A. CMV

2. Septate hyphae invade blood vessels B. Pseudomonas aeruginosa 3. Lymph node stuffed with acid-fast bacilli C. Legionella

4. Budding yeast and pseudohyphae D. Candida albicans

5. Showers and non-chlorinated water E. Cryptococcus neoformans 6. Broad hyphae with no septae F. Aspergillus fumigatus 7. Severe diarrhea G. Rhizopus

8. Cat’s litter box H. Pneumocystis jirovecii 9. Cysts with 8 trophozoites I. Cryptosporidium 10.Cystic fibrosis J. Toxoplasma gondii

K. Mycobacterium avium-intracellulare Answers:

1. A; 2. F; 3. K; 4. D; 5. C; 6. G; 7. I; 8. J; 9. H; 10. B

Infections in the Compromised Host—Quiz 2: Matching II

11. Splenectomy or Sickle Cell A. Coagulase negative staphylococci

12. AIDS B. Streptococcus pneumoniae

13. Ketoacidosis and sinusitis C. Pneumocystis jirovecii

14. Neutropenia D. Mucor

15. Arterial and CNS catheters E. Aspergillus

16. Failure to immunize normal children F. Bordetella pertussis 17. Giant cell pneumonia G. Measles virus 18. Quinlones and PPIs H. Clostridium difficile Answers:

11. B; 12. C; 13. D; 14. E; 15. A; 16. F; 17. G; 18. H

SEXUALLY TRANSMITTED DISEASES: 11/15/10

OBJECTIVES:

1. Understand the pathology of the STDs common in the U.S. 2. Know the diagnostic tests available for STDs

3. Recognize gross and microscopic images of the STDs presented in lecture Sample Question:

State-of-the-art laboratory testing for Neisseria gonorrhoeae and Chlamydia trachomatis includes: A. Culture on chocolate blood agar

B. Growth in McCoy cells (tissue culture) C. Gram or Giemsa stain

D. DNA probe or amplified DNA probe E. Electron microscopy

Test q: The state-of-the-art lab test recommended to diagnose both Neisseria gonorrhoeae and Chlamydia trachomatis in a urine or Thin Prep specimen from a 20y/o sexually active female is: Amplified DNA probe. REPEATED x2

STDs TODAY:

• Over the past 50 years STDs have increased worldwide

• STDs are both infectious diseases and communicable diseases • 1/3 of sexually active people in the U.S. will acquire a STD by age 24 • The prevalences of Herpes and HIV-1 increase annually

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STDs in the U.S.:

• 45 million have Herpes • 15 million new STDs per year

• 10+ million have HPV or Trichomonas • 3-5 million Chlamydia cases annually • 1-3 million GC cases annually • 20-30,000 new HIV cases annually

• # 1 in curable STDs of all western countries Highest INCIDENCE (new cases) reported = Chlamydia Highest incidence (new cases) not reported = Trichomonas

Highest PREVALENCE (how many people in the entire population are infected) – Herpes The Silent Epidemic:

• Women infected more than men

• Asymptomatic females with severe complications • M-to-F transmission of GC is 4X greater than F-to-M • M-to-F transmission of HIV is 8X greater than F-to-M Why have STDs Increased in the U.S.?

• Young people are more sexually active • Earlier sexual experience

• More partners

• BCP and decreased condom use • Drugs/sex; sex/drugs

• Increased travel

• More sensitive diagnostic tests –

• Although, Chlamydia has gone from culture to antigen-antibody tests to direct DNA probes to amplified DNA probes to real-time PCR probes – rate hasn’t changed at all.

Herpesvirus Infections:

• DS DNA virus with capsule

alpha-group (neurotropic)- HSV-1, HSV-2 and VZV

beta-group (lymphotropic)- CMV gamma-group- EBV

All can be sexually transmitted, but 1&2 are most commonly.

HSV-1 and HSV-2:

• Replication in skin and mucous membranes • Vesicular lesions of epidermis and infection of

nerves where the virus is latent

• Reactivation with spread of virus to skin and mucous membranes

Herpes Complications: • Corneal lesions

Encephalitis (temporal lobe) • Herpes esophagitis

• Bronchopneumonia, hepatitis • HHV-8- Kaposi sarcoma

Herpes Simplex Pathology:

Cowdry type A inclusions- pink/purple bodies that push host chromatin to the edges of the nucleus. (Center of nucleus will be clear, rim will be dark)

• Inclusion = enough viral particles to actually see w/a microscope.

• Syncytia or multinucleated giant cells • Intraepithelial vesicles and ulcers

Test q: The classic pathology seen in herpes infected cells is: Cowdry type A inclusions.

Test q: A 25y/o AIDS patient develops esophagitis. A biopsy shows focal ulcers. Several epithelial cells show viral inclusions w/increased chromatin around the nuclear membrane in infected cells. Giant cells are present. Identity: HSV.

Pap Smear – Herpes Giant Cells:

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Cowdry A Inclusions of Herpes (H&E)  Herpes Simplex: Multinucleated cells – center of nucleus is clear, rim of nucleus is dark. Genital Herpes:

• Vesicles on mucous membranes and external genitalia with ulcers • Very painful bc have a preference for nervous tissue. • Neonatal Herpes- necrosis of lungs, liver adrenals and CNS;

C-section required if active Herpes infection is present • If mom has active herpes

Painless ulcers – suspect syphilis Painful – herpes, chanchroid

Herpes – vesicles. Vesicles can be on any number of H&E: epidermis lifted by edema fluid, if you look inside, can see inclusions. mucous membrane locations (genitals, mouth).

Temporal lobe infection: think herpes. HHV-8 + HIV = Kaposi’s sarcoma Diagnosis of Herpes:

• Giemsa or Pap stains on blister contents exhibit poor sensitivity

Culture in standard tissue cultures or shell vial tissue culture (48 hrs.) is most sensitive

• Direct Fluorescent AB stain (DFA) is specific but lacks sensitivity – not done on ulcers, maybe on brain lesion • In situ DNA probe is specific but also lacks sensitivity

• PCR also available Herpes Culture:

Need intact vesicle, unroof ulcer, swab contents  tube  lab culture.

Herpes DFA:

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Chlamydia: Most common reportable STD

• Obligate intracellular parasite; gram-negative rod • Elementary bodies are infectious but do not divide

Reticulate bodies multiply in host cells but are not infectious Chlamydia Infections:

Chlamydia trachomatis causes: urethritis and cervicitis; PID complications, etc. LGV (serotypes L1,L2,L3) and Trachoma (eye infection)

• LGV – lymphogranuloma venereum – seen in tropics

C. pneumoniae (newborns) and C. psittaci (parrots, parakeets) cause pneumonia Pathology of Chlamydia:

• Urethritis, cervicitis and salpingitis • Usually mild symptoms

• Epididymitis

Symptomatic or asymptomatic females may develop Pelvic Inflammatory Disease (PID) – inflammation/infection of fallopian tubes and ovary

• Tubo-ovarian abscess (could perforate) or ectopic pregnancy • Inclusion conjunctivitis in newborns

Chlamydia and Gonorrhea both cause urethritis, cervicitis, salpingitis, epididymitis, PID.

Pathology of LGV:

Stellate abscess- irregular-shaped or stellate abscess in genital area; stellate sheets of PMNs surrounded by granulomatous inflammation- the center is often necrotic

Stellate Abscess of LGV  Irregular-shaped lesion, may have neutrophils in the middle, histiocytes around the edge. Diagnosis of Chlamydia Urethritis:

• Why do we screen for the disease? • Most common STD in the U.S. • Curable disease

• Communicable disease

• Asymptomatic females suffer serious complications Gonorrhea:

• Neisseria gonorrhoeae • GNC – gram negative coccus • Urethritis, pharyngitis, proctitis

• Salpingitis with sterility and ectopic pregnancy

Bacteremia with arthritis and dermatitis (arthritis in ONE joint)

Same symptoms as chlamydia except more virulent – more inflammation/tissue damage. G is capable of growing outside cells. C is an obligate intracellular parasite. Since G can live outside cells, can cause additional

symptoms – pharyngitis, proctitis.

Test q: A 25F becomes infected w/an STD. She has a cervical discharge and later is found to have a left tubo-ovarian abscess. On workup before surgery to remove the left tube and ovary, she is noted to have a swollen, painful, and warm left elbow. The rest of her joints are normal. Her infection is most likely due to: Neisseria gonorrhoeae.

Test q: A 19F develops pelvic pain, fever, and vaginal discharge for 3wk. She has lower abdominal adnexal tenderness and a painful, swollen left knee. Lab studies show WBC count of 11,875/mm3 with 68% segmented neutrophils. The patient receives antibiotic therapy and recovers, but 5 years later she undergoes a workup for infertility. Which of the following infectious agents is most likely to produce these findings? Neisseria gonorrhoeae.

Virulence Factors of GC:

• Adhesins or pili bind epithelial cells • Capsule inhibits phagocytosis • Protease cleaves IgA

• Endotoxin and peptidoglycan cause secretion of tumor necrosis factor- alpha which induces shock • TNF-alpha also damages fallopian tubes

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Pathology of GC:

• Purulent (PMNs) inflammation with later granulation tissue and fibrosis • Urethral stricture and epidydimitis in males

• Acute inflammation with abscess in submucosal glands of females- subsequent spread to fallopian tubes with fibrosis(scar) or tubo-ovarian abscess; sterility or ectopic pregnancy

Purulent Discharge: Tubo – Ovarian Abscess: Abdominal adhesions:

Tubo-Ovarian Abscess: Ultimate result of either C or G infection. Used to be ovary-fallopian tube, but now is useless mass of fibrotic tissue. If just the tube is the problem, can get ectopic pregnancy  rupture.

Abdominal Adhesions: With G and esp C, will see adhesions – thin filaments of fibrous connective tissue and edema that form between fallopian tubes and ovaries and cause them to stick together. Sometimes can extend out to intestines.

Neonatal N. gonorrhoeae infection of the eyes 

All newborns are treated w/antibiotics to prevent this disorder – prophylax. Diagnosis of GC and Chlamydia:

• Gram stain is diagnostic for GC in males only • Culture for GC and Chlamydia lacks sensitivity • DFA, ELISA, EIA (antibody tests) are poor • Direct DNA probe tests on discharge swab

** “Amplified” DNA Probe test on discharge swab, urine or Thin Prep

Test q: A 22F w/a cervical discharge is thought to have a Chlamydia trachomatis infection. The most sensitive and specific test for diagnosis on a cervical sqab is: Amplified DNA probe.

Amplified Nucleic Acid Tests:

Polymerase Chain Reaction (PCR) Ligase Chain Reaction (LCR)

*Transcription Mediated Amplification (TMA) Strand Displacement Assay (SDA)

*RNA target- the others target DNA

Take very small piece of the DNA (yellow piece) – Can do cervical swab for G and C. Urine is only slightly less

make lots of copies of it, easier to diagnose. sensitive than swab (9998%)

Can also do Thin Prep Pap smears.

Gram Stain:

Rarely performed in clinical labs and diagnostic for males only. Cannot make the diagnosis from female discharge – could be many other things.

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Syphilis:

caused by Treponema pallidum

• spirochete with flagellum – too thin to see on gram stain • visualize with darkfield, silver stains or DFA

no culture available

no molecular test available • Epidemic in Indianapolis (again) Clinical Features of Syphilis:

Primary- chancre in 3-4 weeks at the site of invasion (usually genital location) Secondary- rash, fever, lymphadenopathy in 10 weeks (esp. palms and soles) Tertiary- aorta, heart, CNS, etc. (years)

Syphilis Pathology:

The characteristic pathology at all stages is: OBLITERATIVE ENDARTERITIS and PLASMA CELL INFILTRATE. OE = inflammation of artery wall that destroys the artery

• Spirochetes bind endothelial cells via fibronectin

• Abs prevent more chancres, but fail to clear spirochetes (protein-poor outer membrane)

Test q: A 25y/o HIV-infected male is seen in a dental clinic and complains about a copper-colored, macular (bumpy) rash that covers his entire body including palms and soles. He reports that four weeks ago he had a painless ulcer on his upper lip. A biopsy of the rash would most likely show: Obliterative endarteritis and plasma cell infiltrate. REPEATED x2

Test q: A 30M who has had multiple sexual partners and does not use barrier precautions comes to the physician complaining of a nontender ulcer on the penis that has been present for 1 week. The lesion is scraped, and darkfield examination is positive for spirochetes consistent w/Treponema pallidum Which of the following is most likely to be seen microscopically in the biopsy specimen? Obliterative endarteritis.

Pathology of Primary Syphilis:

Chancre- shallow, painless ulcer with surrounding induration; plasma cells and endarteritis T. pallidum spirochetes visualized by silver stains on biopsy or dark field exam

• Lymphadenopathy

Chancre on Chest: Dark – Field Microscopy:

Not always on genital or oral mucosa – it’s wherever the organism first penetrated the integument.

Darkfield Microscopy: Specimen has to be fresh – organisms have to be alive, so don’t really offer it anymore. Pathology of Secondary Syphilis:

Rash- mucocutaneous, palms, soles; often macular (bumpy) and less than 5 mm; copper-colored Condyloma lata- 2 cm elevated plaques on penis or vulva; plasma cells and endarteritis

Condyloma accuminata – in HPV. Both are cauliflower-like proliferative lesions, usually on the genitalia.

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Pathology of Tertiary Syphilis:

Aorta- 80 % of cases (THORACIC or ASCENDING aorta);

aneurism with inflammation of media, incompetent aortic valve and narrowed coronary arteries

• Neurosyphilis- paresis, tabes dorsalis (involves dorsal columns) • Gummas- granuloma-like (but more destructive) lesions of liver,

bone and joints; also perforation of hard palate

Aneurysm in thoracic aorta – usually syphilis

Aneurysm in abdominal aorta – usually atherosclerosis

Test q: A 60M has had increasing exercise intolerance and difficulty breathing for the past year. His family has noted memory loss and decreased ability to perform activities of daily living for the past two years. On physical exam, his temp is 37.1C, pulse 70/min, resp 18/min, and BP 140/80 mmHg. On auscultation of the chest, rales are audible in the lung bases, and there is a diastolic murmur. He has a marked decrease in sensation to light tough and pinprick over the lower extremities. His gait is ataxic, with the feet widely spaced. He cannot name any of three objects after 3 minutes. An echocardiogram shows aortic regurgitation w/a widened aortic root and arch. MR imaging of the brain shows mild diffuse cortical atrophy and meningeal thickening. Infection w/which of the following organisms is most likely to produce these findings? Treponema pallidum.

Test q: An 81M who contracted syphilis while serving in WWII is now found to have a saccular aneurysm of the thoracic aorta. The pathogenesis of this lesion is best explained by which of the following? Endarteritis obliterans of the vasa vasorum.

Test q: Syphilitic aneurysms are characteristically located in the: Ascending aorta

Tabes Dorsalis in tertiary syphilis: Perforation of hard palate in 3° syphilis: Warthin – Starry (silver stain):

Lesions in palate or teeth. Congenital Syphilis:

• T. pallidum invades the placenta in the 5th month of gestation • Other diseases are usually 1st trimester, so syphilis is

unique because it’s 2nd trimester. • Stillbirth and late abortion

• Fibrosis of liver and lungs

• Latent disease in childhood- keratitis, Hutchinson teeth and 8th nerve deafness

Lab Tests for Syphilis:

VDRL/RPR- non-treponemal tests positive early but disappear – more sensitive

FTA/MHI- treponemal tests are positive lifelong but may be negative early – more specific

• Highly specific for syphilis in the serum – add anti-IgG • For neurosyphilis the only test available is the VDRL

(performed on CSF)

• All tests have biological false positives • Eg. (VDRL+/FTA-) is a false + • (VDRL+/FTA+) is a true +

Syphilitic Aortitis:

Thoracic aorta/aortic valve involvement in 3° syphilis.

Hutchison Teeth in congenital syphilis:

Hutchison (notched) teeth plus mentally challenged children (CNS destruction).

FTA (treponemal) Test:

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Diagnosis of Trichomonas, Candida and Gardnerella: • All 3 agents cause urethritis and vaginitis

• Culture slow and difficult

• Wet mount exams poorly sensitive (60% at best) • Method of choice is:

• a direct DNA probe assay for all 3 microorganisms (AFFIRM) • Or amplified DNA probe on Thin Prep for T. vaginalis

Trichomoniasis:

Trichomonas vaginalis is the causative agent • Anaerobic, flagellated protozoan

• trophozoites only

• rate at some Wishard clinics is 20-30%

• urethritis and vaginitis; superficial infection with itching and watery discharge

• strawberry mucosa- mixed inflammation • Premature birth, low birth weight, low birth rate • **NOT A REPORTABLE STD

Test q: Trichomonas vaginalis infection during pregnancy is associated with: Premature delivery and low birth weight.

Gardnerella: Candida on pap stain:

Cell is COVERED with bacteria = clue cell. Can see Pseudohyphae on Giemsa stain. If Gram stain, would be Gram neg.

More STDs:

HPV- condyloma accuminata (benign; types 6, 11) and dysplasia/CIS (premalignant; types 16, 18 and others) Haemophilus ducreyi- soft chancre (painful, tropical ulcer); school of fish on gram stain; culture on chocolate agar Painful “soft chancre” of Chancroid H. ducreyi – school of fish:

Clinically, look a lot like syphilis but is Direct smear – theoretically would see “school of softer – not fibrotic. Plus painful. fish” –Gram negatives swimming along together.

Above: Trichomonas vaginalis on Pap stain – green smudges.

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Over 100 DNA types for HPV: ~20 predispose to cancer.

Test for high-risk groups. Abnormal DNA not repaired  cells proliferate.

Pap Stain – Koilocytes: Condyloma accuminata: Cervical Cancer:

Normal sized nucleus – top left (very small comparitively). Compare to condyloma lata in HPV predisposes to Koilocyte nuclei – enlarged w/halo around them. 2° syphilis. cervical cancer. White =

Usually low-risk (6, 11). invasive carcinoma.

HPV Vaccines: • Gardasil

HPV 6,11 (condyloma, non-malignant forms) and 16,18 (high risk – predispose to malignancy) • Cervical (and anogenital) CA

• Works best in ages 9-12, less effective for ages 19-26 and older

• Women still need regular Pap exams- there are many more than 2 high risk HPV DNA types; and the vaccine is less effective in older ages

Test q: The Gardasil HPV vaccine is most effective in prevention of cervical cancer if given to females ages: 9-12. HPV and Oropharyngeal Cancer:

• 60% of oropharyngeal CA associated with HPV • 50% of tonsillar CA associated with HPV • 30% of oral cavity CA associated with HPV • 20% of head and neck CA associated with HPV

• HPV-associated CA has a better prognosis due to limited invasiveness – easier to treat, less likely to metastasize

Condylomas, probably associated w/Types 6, 11  Squamous cancer – associated w/HPV 16 

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Identification of High Risk HPV types by Hybrid capture (DIGENE):

Acquired Immunodeficiency Syndrome (AIDS): • Human Immunodeficiency Virus 1 (HIV-1)

• aka HTLV-3 • HIV-associated infections

Figure: Prevalence continues to increase  # of cases is dwindling, # of deaths dwindling,

but the number of people infected increasing.

Test q: The HIV-1 gene most associated w/cellular proliferation and neoplasia is: tax gene,  ThinPrep specimen collected w/paddle or spatula.

Pass thru machine that  pulls cells out, puts on slide, Pap smear made

Test q: A 25F has a pap smear that shows marked nuclear enlargement (high nucleus-to-cytoplasm ratio). A subsequent biopsy shows full-thickness dysplasia in the cervical epithelium. Invasion through the BM is not observed. The features described above are consistent with a diagnosis of: Squamous cell carcinoma-in-situ

The patient should be told: She should undergo cone biopsy for treatment and staging. (2006, #55. Other choices: She should have another pap smear in 12mo; She should have another pap smear within 3mo for HPV typing; She should receive radiation and hysterectomy; She requires no additional treatment)

Test q: In the US in 2006, describe the relationship between sqamous cell carcinoma-in-situ of the cervix and the death rate due to squamous cell carcinoma of the cervix: CIS increasing; death rate decreasing.

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Kaposi’s sarcoma w/colonies of Candida  Test q: A 25y/o white male reports for his annual dental checkup. Focally, his oral mucosa is raised and exhibits a purple-black color. Elsewhere, the mucosa and surface of the tongue exhibit white, raised areas that look a little like cottage cheese. You recommend that the patient have the following test as soon as possible: A rapid HIV test. (once, was Antibody test for HIV-1 and 2.) REPEATED x2

Test q: A 37y/o man who is HIV-positive has noticed multiple 0.5-1.2cm plaquelike, reddish purple skin lesions on his face, trunk, and extremities. Some of the larger lesions appear to be nodular. These lesions have appeared over the past 6 months and have slowly enlarged. Molecular analysis of the spindle cells found in these skin lesions is likely to reveal the genome of which of the following viruses? Human herpesvirus-8

And One More STD:

Mycoplasma genitalium- urethritis and cervicitis

Prevalence is higher than N. gonorrhoeae and lower than C. trachomatis There is no good test for it yet.

ID Lab Review 11/16/10

First, some non-ID review: Pediatric neoplasia – Most common pedriatic malignancies are lymphomas and leukemias. Of the solid tumors, the ones to differentiate (tumor mass in abdomen of child) are neuroblastoma, Wilm’s tumor, and Burkitt’s lymphoma.

Neuroblastoma: Wilms Tumor: Burkitt’s Lymphoma:

Neuroblastoma – small blue cells; neuropil (no nuclei in it; not stroma); Pseudorosettes (but may not see all the time). Overexpression of N-myc (Neuroblastoma). There is a special stage of neuroblastoma (S stage – S = special) – although these kids have widely metastatic disease, they do very well if the metastases are limited to certain sites (skin, liver, bone marrow).

Wilms: triphasic – blastema (blue cells); epithelium (tubules); stroma (with nuclei). The difference between stroma and neuropil is that stroma has a lot of nuclei in it. Wilm’s Tumor is associated w/tumor suppressor gene – WT.

Burkitt lymphoma – may seen in abdomen of small child. Lots of malignant cells – all the blue cells are lymphoblasts. The stars in the starry sky are benign macrophages. Translocation is t(8;14).

Special Stains for Microorganisms:

Gram Stain- G+ and G- bacteria; Candida

• (except some – like spirochetes and smaller organisms/cell-wall deficient organisms – Mycoplasma)

• Giemsa Stain- bacteria, fungi (all), viral inclusions, parasites • Silver Stain (GMS)- fungi and a few bacteria

(Modified)-Acid-Fast Stain- mycobacteria and Nocardia

GRAM STAIN: Gram negative bacilli 

Any fluid or tissue

• Screen for or identify bacteria • 30 minute turnaround

• GPC, GPR, GNC, GNR and yeastPoor sensitivity for filamentous

fungi, mycobacteria, parasites and viral inclusions Gram negatives stain red w/Gram stain. These look like small pairs of rods – could be H. influenzae.

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Gram positive cocci on blood smear: Rash of Toxic Shock Syndrome:

G+ in clumps = staph. Staph is catalase +. If also coagulase + = S. aureus.

Above: Hemolysis patterns. Strep is in chains. Catalase negative. Gram positive. If you have chains of G+ cocci that are catalase negative, put them on blood agar plate (above). If they completely destroy RBCs, they are beta hemolytic (group A – pyogenes and group B – agalactiae). If they turn it green, it’s alpha hemolysis (s. pneumoniae, viridans). If there is no change and they just grow as white colonies, it’s gamma hemolysis (Enterococci).

When dealing with patients that have endocarditis (staph/strep cause), organisms can flip off little septic emboli and go to different parts of the body. When they flip off and go to bottoms of toes/fingers, they are called Osler’s nodes. If they’re smaller and don’t hurt so much, they’re called Janeway lesions.

Splinter hemorrhages – under nails. Roth spots – hemorrhages in eye. ALL OF THESE ARE BUZZWORDS FOR ENDOCARDITIS.

 Patient suffering from Waterhouse-Friderichsen Syndrome – N. meningitidis or OCCASIONALLY H. influenzae – both G negative. Can get massive DIC and bleeding into the adrenal gland, adrenal failure. Adrenal glands FILLED w/RBCS.

 People w/TSS (usually due to Staph but occasionally Strep) get desquamating rash (skin falls off – palms and soles of feet). If woman comes in and is markedly hypotensive w/skin falling off palms and soles, it’s TSS – not syphilis.

Strep pneumoniae

– see pairs of organisms. Hard to see, but they have halo because they’re encapsulated.

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Gram (+) Clostridium perfringens:

GPR – sometimes can see spores as clear spaces within organism – sometimes cannot. C. perfringens causes gas gangrene.

Gram Stain of Candida albicans: Yeasts and Pseudohyphae of Candida Calcofluor stain:

Fungi on gram stain – sometimes can demonstrate yeast. GMS stain. Germ tubes formed by C. albicans Budding yeast, pseudohyphae. Candida albicans is the

most common one.

If you put organism in rabbit serum at 37 degrees, it will shoot out small structures called germ tubes = C. albicans. Giemsa Stain or Diff-Quick (rapid Giemsa) Stain:

• Any tissue or fluid

• Works best on peripheral blood smears • Bacteria, fungi, parasites, viral inclusions • Rapid preparation (1 minute)

Giemsa stain of a perispinal abscess: Giemsa stain: H. Capsulatum Giemsa stain of CMV:

Many intracellular cocci Note how much smaller the yeasts are than RBCs. MICROWAVE GMS (Silver) STAIN:

• Any tissue or fluid- 30 minutes

All fungi including Pneumocystis, Histoplasma, Cryptococcus,

Mucor, Aspergillus

• Most sensitive stain for fungi • Poor for bacteria and mycobacteria • O.K. for Nocardia and Actinomyces

Above: Erythema migrans. Targetoid rash (ring-shaped rash) that is seen in Lyme disease. Go on to develop arthritis and myocarditis, other complications. Other targetoid lesions: Erythema multiforme.

Above: Top left – normal respiratory epithelial cell – can see brush border on it. Then look at the starred cells – HUGE infected cells (cytomegaly). The stars are on the inclusions.

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Ribbony appearance of Mucor: Silver Stain of H. capsulatum: Cysts of Pneumocystis jiroveci:

Small budding yeasts.

ACID-FAST STAINS (Kinyoun, Ziel-Neelsen, etc.):

Carbolfucsin or fluorescent (more sensitive for Mycobacterium tuberculosis) “modified” AFB for Nocardia- weak acid wash

Mycobacterium, Nocardia, Rhodococcus, Cryptosporidium

• Cryptosporidium – parasite, can see oocysts in stool – use MODIFIED acid-fast stain. • Sputum must be decontaminated and concentrated for high sensitivity

M. tuberculosis in a gastric biopsy: Fluorescent Acid-Fast Stain of M. tuberculosis

TB shows “cording” (Mycobacteria wrapping More sensitive test – use for screening. around each other); blue organisms are Candida

Cording = VIRULENT.

Filamentous Nocardia on a Gram Stain (gram + filaments): Nocardia demonstrated by a modified-acid-fast stain: GMS (silver) stain: Dot form – sideways tea cup/groove-dot forms.

Figure

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References

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