Acid-fast Stain of M. tuberculosis:
Above: “Cording” – virulent strains will cord (organisms wrap around each other)
– Primary TB – mid-lung fields, involvement of lymph nodes (Ghon complex)
– Reactivation/Secondary TB – apices of lungs. Exaggerated – more cavitation, necrosis, lymph node involvement (because all the destruction is due to the immune response, and the patient has already been exposed)
Ghon Complex or Primary Complex: Reactivation TB:
Ghon Complex: LN and peripheral lesion
Miliary tuberculosis (hematogenous spread): Granuloma with necrotic center:
Above (left): If organism gains entry into pulmonary artery, will shower into the lungs – will get small affected areas everywhere = Miliary TB. Everything that has been shown for TB can also be said for Histo – can have Miliary Histoplasmosis. Major difference is that TB is spread from person-to-person (communicable), Histo is not. Above (right): Necotizing granuloma – seen in TB and Histo. If you have non-necrotizing granuloma, could be sarcoidosis.
Figure: Primary pulmonary TB. In granulomatous infections, IFN-γ is important in producing/maintaining granulomas. Made by lymphocytes. Current best method to test for Mycobacterium TB infection is IFN-γ test. Still do PPD test because it is cheaper, however. QuantiFERON for TB Diagnosis:
– Measure of cell-mediated response
– Pt. whole blood incubated in tubes coated with TB Ags – Gamma-interferon production is measured by ELISA – More sensitive and more specific than TB skin test
Mycoplasma pneumoniae:
– Defective cell wall; membrane with cholesterol – Fried-egg look on hyperosmolar agar
– Cold agglutinins+
– Erythromycin or tetracycline
– Example: Young pneumonia patient; CXR looks awful; pt. feels pretty good; cold agglutinins present
Mycoplasmas are obligate parasites that grow inside other cells – cause infection that looks like viral infection. They are bacteria but don’t incite production of neutrophils. They incite lymphocytes and will see infection in alveolar walls (not alveoli). If you see interstitial infection pattern – think M. pneumoniae – also if you see cold agglutinins (RBCs agglutinate at lower temperature).
Chlamydia:
– C. trachomatis- urethritis, conjunctivitis, arthritis; azithromycin – Tetracycline plus ceftriaxone if GC suspected also
– C. pneumoniae (TWAR) and C. psittaci (bird feces)- atypical pneumonias – Molecular ID
– Tetracycline/doxycycline Rickettsia:
– R. rickettsii- Rocky Mt Spotted Fever; wood or dog ticks (Dermacentor sp); rash spreads from palms and soles; Weil-Felix+; doxycycline
– R. prowazekii- epidemic typhus; rash spares palms and soles; Weil-Felix+
– Coxiella burneti- cough, fevercattle and milk; Weil-Felix(-); NOT spread by arthropods; NO rash Rash on palms and soles: RMSF or Secondary Syphilis.
RMSF rash Spirochete diseases:
– Borrelia burgdorferi – Giemsa+; deer, Ixodes tick; erythema chronicum migrans “bull’s eye rash” in NE U.S.A. – Lyme disease (can get arthritis,
myocarditis, arrhythmias)
– T. pallidum- syphilis; darkfield exam or Warthin-Starry stain; VDRL
– T. pertenue- yaws; non-STD
Erythema chronicum migrans Classic rash of Lyme disease
Syphilis:
– Primary – painless chancre
– Secondary – rash on palms and soles; condyloma lata
– Tertiary – aortitis, tabes dorsalis (broad-based ataxia), gummas
– Argyll Robertson pupil – not reactive to light but constricts with accomodation – Thoracic aorta aneurism
In all stages of syphilis, see endarteritis – inflammation of blood vessels, surrounded by plasma cells
Aneurysm in the ascending aorta Many plasma cells present Spirochetes Can see spirochetes at any stage of the disease if you do the right serology.
Syphilis serology:
• FTA- treponemal test is more specific, is positive earlier and persists for life • VDRL- non-treponemal test- fades
• VDRL+/FTA+ is infection
• VDRL+/FTA- is probably a false+ - see lots of this in pregnancy • VDRL-/FTA+ is successful treatment
Candida:
• C. albicans - #1 pathogen in Candida infections; thrush (overgrowth in mouth or vagina); esophagitis; sepsis. Yeasts and pseudohyphae in tissue and on cornmeal agar; germ tube+; chlamydoconidia+
• C. tropicalis - yeast and pseudohyphae in tissue; fungemia • C. glabrata - yeast ONLY, no pseudohyphae
• Fluconizole, caspofungin
• *ALL Candidas FERMENT some sugars
Candida budding yeasts and pseudohyphae: C. albicans positive germ tube test:
Yeasts continue to bud and elongate.
Systemic Mycoses: • Dimorphic
• Mold phase in nature and in lab at 23C
• Yeast or yeast-like phase in human tissue and at 37C (except cox) • Some are endemic
• Infect ALL people
Most of the organisms that cause life-threatening infections in NORMAL people are dimorphic fungi – molds in nature, yeasts in the body.
Systemic Mycoses (cont’d):
• Coccidioides immitis (cox)- endemic in desert SW, esp. SJ Valley in Ca. and in Az.; SPHERULES in tissue; mold with arthroconidia in lab at room temperature
• Histoplasma capsulatum- intracellular small, budding yeast in tissue; mold with tuberculate/spiny macroconidia in lab; blackbird, chicken and bat roosts
Grows in soil as a mold, makes arthroconidia (inhale), grows in body as a spherule w/endospores inside.
Spherules of C. immitis: Arthroconidia of C. immitis:
Endospores inside spherule Empty spherules – endospores have broken out. H. capsulatum yeasts in macrophage: H. capsulatum spiny/tuberculate macroconidia
About ~1/3 size of RBCs (uniquely small).
• Mississippi River Valley – endemic area for Histo • Blasto – endemic area is more SE.
• Pneumocystis – everywhere.
– Histoplasma – black birds, chickens, bats. Get it from soil contaminated w/bird and bat material.
– Cryptococcus – pigeon dung (but people who are around pigeons don’t get infected) – seen everywhere. Don’t really know where people get it.
Coccidioidomycosis endemic area:
Grows as mold in lab – big, spiny macroconidia. Identify w/DNA probe, though, because growing takes too long.
Systemic Mycoses (cont’d):
• Blastomyces dermatitidis- large yeast with Broad-Based-Buds and thick cell wall in tissue; southeastern U.S.; skin hyperplasia (pseudoepitheliomatous
hyperplasia) mimics carcinoma of skin and larynx. o Blastomycosis skin lesions
Pseudoepitheliomatous hyperplasia. Blastomycosis always starts as a pulmonary infection. Will see broad-based buds and thick cell walls in sputum or lung biopsy.
o “Broad-based” buds of Blastomyces dermatitidis • Paracoccidioides brasiliensis- “mariner’s wheel” in tissue; South
America only
• Treatment- AZOLES (eg. Fluconazole) prevents ergosterol synthesis; AMPHOTERICIN B destroys ergosterol in the cell membrane;
Echinocandin/CASPOFUNGIN inhibits glucan synthetase Opportunistic fungi:
Candida- yeasts and pseudohyphae
Seen in people who are immune-suppressed or getting therapy for malignancies.
Aspergillus – septate hyphae; 45 degree branching; transplants Mucor – aseptate hyphae; 90 degree branching; diabetic ketoacidosis
Cryptococcus neoformans – capsule (India Ink+, latex+); melanin+ ??pigeons??
Cryptococcus neoformans: Latex agglutination test: Septate hyphae of Aspergillus:
Use serum or spinal fluid. Sensitive and specific.
Neutropenic patients get Aspergillus infections. Also happens to diabetics. Septate hyphae, acute angle branching. Aseptate hyphae of Mucor or Rhizopus: Rhizopus:
Above (left): Aspergillus appearance if grown in the lab. Fist-shaped structure w/bowling pins on top – conidia on top. Hyphae are septate.
Above (middle): Mucor – primarily in diabetics. See broader hyphae. If you saw it in a smear, would see how ribbony they are (curl up). Branch at 90 degrees; no cross-walls.
Above (right): Rhizopus. Hyphae do not have septate, produce bags of sporangia. If it makes root-like structures, it’s Rhizopus. If the roots are off to the side, it’s Absidia (rare). No roots = Mucor.
Candida and Cryptococcus – opportunistic yeasts. Aspergillus, Mucor – opporutnistic hyphal fungi. More fungi:
• Pneumocystis- fungus that cannot be cultured; trophozoites on Giemsa and cysts on GMS (silver); TMP-SMX, pentamadine
• Sporothrix- dimorphic; thorn or rose prick; nodules along lymphatics; “cigar/pencil-shaped yeast” is classic; potassium iodide
Pneumocystis fills alveoli on H&E stain: Pneumocystis cysts:
Bubbly pink filling in alveoli. Cysts show up on GMS stain. Trophozoites show up on Giemsa. Pneumocystis cysts = round bodies that may have targets (bulls-eyes) on GMS. Sometimes see grooves, can look like tea-cups.
UTIs:
o Community- E. coli 75%; Staphylococcus saprophyticus 20% (esp. sexually-active females) o Nosocomial- E. coli 40-50%; Proteus, Klebsiella
o UTI- dysuria, frequency; WBC in urine
o Pyelonephritis- fever, chills, flank pain; WBC “casts” in urine STDs:
o N. gonorrhoeae
o T. pallidum- painful chancre; condyloma lata and rash; gummas
o HSV2 (70%)/HSV1(30%)- giant cells with “glassy” cytoplasm and Cowdry A inclusions o LGV- C. trachomatis serovas L1-L3
o Trichomonas- vaginitis, “strawberry” mucosa o HPV 6, 11- condyloma accuminata; koilocytes
o HPV 16, 18 (and a dozen others) high risk for dysplasia/cervical cancer
o Haemophilus ducreyi- chancroid (soft chancre); painfull ulcer; “school of fish” on Gram stain o Gardnerella vaginalis- vaginosis; “clue” cells; +whiff test
Condyloma lata of T. pallidum: Herpes virus (H. simplex): CMV nuclear and cytoplasmic inclusions
Cowdry A inclusions
Above (left): Condyloma lata (syphilis). Remember condyloma accuminatum happens in HPV.
Above (middle): Herpes Cowdry A inclusions (chromatin darker around edge). This is a Pap smear specimen. Above (right): CMV. Owl’s eye inclusion – middle of nucleus. Outer part doesn’t have any chromatin left. Cowdry B type. Greatly enlarged cell.
Trichomonas vaginalis: Green smudges are T. vaginalis on Pap Stain: Condyloma accuminatum
Urethritis HPV
Koilocyte of HPV (usually low grade): Clue Cell of Gardnerella vaginalis:
Lower grade dysplasia (HPV 6, 11)
If patient has urethritis and you see epithelial cells coated w/bacilli (gram-negative rods) = Gardnerella vaginalis.
Nutrition Highlights: MARASMUS:
• < 60% body weight
• Diet lacks protein & carbohydrate
• Loss of muscle mass (somatic protein)- amino acids for energy • Serum proteins (visceral compartment) NORMAL
o Especially albumin
• Loss of subcutaneous fat (broomstick) • EMACIATION – loss of BOTH muscle and fat
Head looks too big, abdomen not protuberant (because no ascites), no periorbital edema SIGNS OF KWASHIORKOR – loss of protein
• Flaky Paint Skin- hypo- and hyper-pigment and desquamation • Hair loss or color change
• FATTY LIVER – due to loss of apolipoproteins; also small intestine atrophy/disaccharidase deficiency and diarrhea
• Apathetic with LOSS OF APPETITE • Multivitamin deficiencies**
• Immune defects and infections**
• Anemia- usually hypochromic/microcytic** • Cerebral atrophy**
• Pitting edema and ascites due to hypoalbuminemia
**both in MARASMUS AND KWASHIORKOR
ANOREXIA NERVOSA: • Self-induced starvation • Like PEM plus:
• Amenorrhea • Hypothyroidism
• Scaly, yellow skin and lanugo • Osteoporosis-like
• Anemia, lymphpenia, hypoalbuminemia • HYPOKALEMIA AND CARDIAC ARYTHMIA
VITAMIN A DEFICIENCY: • Night blindness
• Xerophthalmia (dry eye)- keratinized squamous epithelium replaces mucus-secreting epithelium • Bitot spots (keratin debris) and keratomalacia (destruction of the cornea)
• Squamous metaplasia in LUNG (infections) and BLADDER (stones) • Increased mortality in measles and diarrhea
• Also important in granulocyte maturation and in fallopian tubes.
Spots/lesions/destruction of cornea. See squamous metaplasia in kidney or lung. Corneal destruction. Marasmus:
Kwashiorkor swollen abdomen (due to fatty liver); periorbital edema
BULIMIA NERVOSA:
• < ½ have amenorrhea
o Major difference between bulimia and anorexia
• Weight and gonadotrophins near normal • Hypokalemia and CARDIAC ARYTHMIA • Aspiration of gastric contents
• Mallory-Weiss Syndrome- laceration of the esophagus or stomach
• Boerhaave’s Syndrome- rupture of esophagus or stomach
VITAMIN A TOXICITY:
• Increased intracranial pressure • Papilledema, headache, vomiting • Bone pain and hypercalcemia VITAMIN D DEFICIENCY:
• HYPOCALCEMIA and loss of bone: RICKETS (kids) or OSTEOMALACIA (adults)
• Robbins Figure 9-29 lists causes of Rickets and Osteomalacia:
1. < diet or sunlight
2. pancreatic insufficiency or obstruction 3. drugs, liver disease, renal disease 4. phosphate depletion
• In rickets and osteomalacia there is an excess of UNMINERALIZED matrix
• In children (rickets) endochondral bone growth is also disturbed
Problem is w/mineralization. Have plenty of osteoid (Vitamin C deficiency is opposite). RICKETS:
• Osteoid with inadequate mineralization • Disorganized fibroblasts and capillaries • Microfractures
• Deformed bones
• Abnormally-shaped (square) head, “rachitic” rosary (rib formation), pigeon breast, and bowed legs
OSTEOMALACIA:
• Abnormal bone remodeling
• Inadequate mineralization of new bone • Fractures and microfractures
• Vertebrae and femoral neck
• Note: osteoporosis is caused by inadequate osteoid protein and defective Vit D receptors w/ demineralization
Vitamin D Deficient Normal
Figure: Normal bone vs. Osteoporosis vs. Osteomalacia Osteomalacia – total volume is similar to normal bone.
Osteoporosis – lose volume of bone
Vitamin D Antimicrobial Effect: • Toll-like Receptors (TLRs) • Increase in Vitamin D receptor • Synthesis of Cathelicidin • Inhibition of M. tuberculosis VITAMIN K:
• Deficiency = Bleeding, especially intracranial in infants; also bleeding umbilical stump • Vitamin K factors: Factors II, VII, IX, X, Protein C and S
• Cryoprecipitate is not a good source of these Vitamin K factors. If patient is Vitamin K deficient, do not want to give cryo + Vitamin K. Want to give Vitamin K + FFP
– Vitamin A – important in lung (defense against viral and bacterial infections) – Vitamin D – defense against M. tuberculosis
– Vitamin C – important in wound healing, so deficiency improper collagen development/wound healing (especially in oral cavity)
THIAMINE:
• Not in polished rice, white flour or refined sugar
• TPP is a cofactor in oxidative decarboxylation and deficiency of thiamine results in DECREASED ATP
• Cardiovascular and nervous system problems • ¼ of all alcoholics are thiamine deficient THIAMINE DEFICIENCY:
• Dry beriberi (polyneuropathy)- myelin degeneration
• Wet beriberi (cardiovascular)- vasodilitation produces heart failure and edema
• Wernicke-Korsakoff Syndrome- Wernicke – ataxia/confusion; Korsakoff – amnesia, confabulation
NIACIN: Below: Skin lesions of pellagra.
• NAD and NADP are coenzymes for dehydrogenases • Grains, legumes and seed oils
• Deficiency- PELLAGRA (3 D’s): dermatitis, diarrhea (epithelial atrophy) and dementia (posterior column changes as in B-12 deficiency)
NIACIN AND HEART DISEASE: • High doses (1-6 grams per day) • Lowers LDL
• Lowers triglycerides • Increases HDL
VITAMIN C (ASCORBIC ACID): • (Citrus) fruits and vegetables • Bone disease in growing children
• Hemorrhage and poor wound healing in children and adults • Vitamin C is a cofactor in formation and maturation of procollagen • Hydroxylation is impaired and crosslinks are not formed
• Antioxidant??? VITAMIN C DEFICIENCY:
• SCURVY
• Capillary and venule walls are weak with hemorrages (purpura and ecchymoses) • Trauma – hematoma and hemarthrosis (joints – as in hemophilia)
• Child- too much cartilage and not enough osteoid protein); bowed legs and deformed chest • Bacterial infection associated with gingival hemorrhage
Remember, rickets is a problem with mineralization (osteoid is fine). Vitamin C deficiency is a problem with osteoid (mineralization is fine).
Dental problems in Vitamin C deficiency
FOLATE:
• Marginal body stores
• 20% of Americans have low Folate • Neural tube defects in the fetus • Macrocytic anemia
Zinc Deficiency:
• Acrodermatitis • Anorexia
• Growth retardation • Impaired wound healing • Hypogonadism
DONE!
Above: Vitamin C Deficiency. Scurvy – gum problems, bleeding problems, bony deformities, abnormal wound healing, corkscrew hair formation.