Lecture 4-Infectious Diarrhea, UTI, STDs 2

Lecture 5-HIV, TB, and Immunocompromising Infections 64

Lecture 2-Strept Infections 115
Lecture 3-Staph Infections_Meningitis_Endocarditis 174
DLA_Notes on Miscellaneous Infections 218
DLA_Notes on Sepsis and Septic Shock 243
DLA_Notes on Viral Hepatitis 255
DLA_Notes on Anaerobic Infections 273
DLA_Notes on Infectious Diarrhea 275
DLA_Notes on Microbial Algorithms 280
 Pathophysiology Lecture 4:
Infectious Diarrhea, UTI, STDs
Dr. Charles Opperman

1
Gram Negative Bacteria: Algorithm

2
 Diarrhea
• 3 loose/liquid bowel movements/day
• Causes: viral, bacterial, parasite,
inflammatory/autoimmune, thyroid, medications,
lactose intolerance, celiac, chronic pancreatitis, etc.
• Duration:
– Acute (<14 days duration) – infectious
– Chronic (>1 month) – noninfectious
• Types:
– Secretory
– Osmotic
– Exudative/Inflammatory
3
4
 Secretory Diarrhea
• Active secretion or inhibition of absorption
– Cholera → Causes over secretion of chloride ions, no blood
• To maintain charge within lumen – Na follows with H2O
• Persistent despite fasting
• Occurs day and night
• Often >1L of output per day (total circulating blood volume = 5L)
– Osmotic Gap – differentiate between secretory and osmotic
diarrhea
• 290 - 2 ({Na+} + {K+})
– <50 mOsm/kg = Secretory
– >125 mOsm/kg = Osmotic
– Causes: Vibrio cholerae, Zollinger-Ellison (gastrinoma),
Carcinoid syndrome, laxatives (luminal secretagogues) Celiac
and Short bowel syndrome (reduced absorption)
• By far – most common type of diarrhea
5
 Vibrio cholerae
• Travel to area with poor drinking
water (monsoon season)
• Gram negative, oxidase- positive,
curved, flagellated rod
• “Shooting star” motility
• “Rice water stools”
– Massive amounts
– Mucous/white flecks within stool
• Increase cAMP within intestinal
mucosa = increased chloride
secretion, decreased Na
absorption
• Risk increases with PPI
– Grows on highly alkaline media
– Stomach pH = 2
6
Mechanism of secretory diarrhea: Vibrio

7
 Mechanism of secretory diarrhea
• Enterotoxigenic E. coli (ETEC)
– Heat-labile toxin (LT)
• Overactivates adenylate cyclase → increase cAMP
• Similar action to cholera toxin
– Heat-stable toxin (ST)
– Has pili that allow attachment to intestinal epithelial cells
• Vibrio cholerae
– Cholera toxin
• Activates Gs protein →Overactivates adenylate cyclase →↑
cAMP
• Activation of cAMP causes chloride efflux and sodium
and H2O follow 8
9
 Osmotic diarrhea
• Osmotically active, poorly absorbed solutes in the
bowel lumen that inhibit normal water and
electrolyte absorption
– Certain laxatives, lactose intolerance
• USMLE loves to compare lactose intolerance MOA to
laxatives
– Ingestion of high fructose corn syrup, sorbitol (Candy,
gum, and fruit juices) →poor absorption.
– Antibiotic-related → loss of gut flora and carb
digestion
• Treatment – find and remove offending agent
10
 Exudative/Inflammatory Diarrhea
• Blood or pus present
• Deeper disease invasion
• UC or Crohns
• Could be infectious if severe

11
 Infectious gastroenteritis
• Viruses • Most gastroenteritis is viral
– Norovirus – most common – Bacterial culture + = 1-5%
– Rotavirus – Usually self-limited
– Adenoviruses
• Look for bacterial cause if:
• Bacteria
– Profuse watery diarrhea with signs of
– Enterotoxigenic E. coli hypovolemia
– Shigella
– Passage of many small volume stools
– Enterohemorrhagic E. coli containing blood and mucus
– Salmonella
– Bloody diarrhea
– Campylobacter
– Temperature ≥38.5ºC (101.3ºF)
– Yersinia enterocolitica
– C. difficile – Passage of ≥6 unformed stools per 24
hours or a duration of illness >48 hours
– C. perfringens
– B. cereus – Severe abdominal pain
– Listeria – Hospitalized patients or recent use of
antibiotics
• Protozoa
– Cryptosporidium
– Diarrhea in the elderly (≥70 years of
age) or the immunocompromised
– Giardia
– Entamoeba
– Severe and Pregnant - Listeria 12
 Food-borne pathogens
• Symptoms begin within 6 hours:
– Think that the cause has to already be present: a pre-
formed toxin
– Staph aureus (mayo) or Bacillus cereus (rice)
• 8-16 hours:
– Clostridium perfringens (reheated meat)
• C. perfringens also causes gas gangrene – lecithinase
• Lecithinase → Catalyzes splitting of phospholipids
• After 16 hours:
– Viral or Enterotoxigenic or Enterohemorrhagic E.coli 13
 Bloody diarrhea
• Causes:
– Shiga-toxin (Verotoxin) producing E.coli (EHEC)
• AKA = E. coli O157:H7
• Responsible for Hemolytic-uremic Syndrome (HUS)
– Campylobacter jejuni
• Major cause in children. Domestic animal exposure.
• Can precede Guillain-Barre and reactive arthritis
– Yersinia enterocolitica
• Transmitted from pet feces (puppies). Mimics Crohn disease.
– Shigella
• Outbreak amongst preschool
• No Hydrogen Sulfide production on triple sugar iron (TSI) agar
– Salmonella – undercooked poultry, eggs, produce
• ZEBRA alert: look for the kids playing with pet reptiles
• + Hydrogen Sulfide on TSI agar (turns black) 14
 Shiga and Shiga-like toxin
• Produced by Shigella and • Only difference:
EHEC, respectively – SLT (from EHEC) does not
– E. coli O157:H7 is a strain of cause host cell invasion
EHEC – Shiga toxin invades
• Undercooked ground beef intestinal mucosa
• Inactivates 60s ribosome – Needs only a very small
– Blocks tRNA binding inoculum (50-100 cells)
inhibiting protein synthesis
and causing cell death • HUS
• Hemolytic-Uremic Syndrome – Microangiopathic hemolytic
(HUS) is most common cause anemia (MAHA)
of pediatric renal failure in US – Thrombocytopenia
– Caused by cytokine release – Renal Failure
15
Schistocyte

Schistocyte

16
 Salmonella typhii
• Gram-negative rod, facultative anaerobes
• Fecal-oral transmission, poor sanitation
• Oxidase negative, lactose nonfermenter, flagella
• Produce Hydrogen Sulfide
• Encapsulted with Vi antigen – beware asplenics!

• Salmon-colored rose spots on chest/abdomen

• As an aside: Sickle cell and osteomyelitis
17
 Campylobacter
• Originally confused with Vibrio until 1973
• Gram negative, comma shaped
• Combination of spiral shape and long polar
flagella leads to rapid motility
– Allows organism to "corkscrew" their way through
mucus membranes.
– Very similar morphology to Helicobacter pylori
• Grows best at 42 degrees Celcius
• Can precede Guillain-Barré Syndrome (10-30%)
18
Clostridium dificile
• Loss of healthy intestinal microbiome
• Toxin A (enterotoxin) – binds brush
border of intestines
– Results in inflammation and
increased fluid secretion
• Toxin B – Cytotoxic
– Results in pseudomembrane
– Exotoxin kills enterocytes
• Will always have a history of
antibiotic use!
– PPI also increase risk
• Gram positive, spore-forming
• Toxic megacolon association
• Fecal transplant anyone?
19
20
http://zdoggmd.com/dawn-of-the-
cdiff/

21
 Diarrhea quick hits!
• B. cereus – Diarrhea after reheating rice
• Listeria – Consumption of unpasteurized foods or deli
meats in pregnant woman
• Norovirus – diarrhea affecting a cruise ship
• ROTAvirus – infant diarrhea which can quickly
dehydrate and lead to death
• Cryptosporidium – Acid-fast oocytes. In water. AIDS
pts.
• Giardia – Camping/hiking. Foul smelling, fatty
diarrhea.
• Entamoeba – bloody diarrhea, liver abscess.
“Anchovy paste” exudate.
22
 Parasitic diarrhea
• Recent contaminated water
exposure
• Giardia
– “Smiley face” trophozoites
• Entamoeba
– Similar symptoms/story
but bloody diarrhea, liver
abscess
• Cryptosporidium
– Similar symptoms/story
but acid-fast oocytes, HIV
23
Urinary Tract Infections

24
 Symptoms
• Dysuria
• Suprapubic pain
• Urinary frequency
• Urgency
• Hematuria
• Bedwetting (peds)

• Pyelonephritis
– Fever
– CVA tenderness
– WBC casts in urine 25
 Sorry ladies!!!
• Women 10x more likely to
suffer
– Shorter urethra
– Proximity of urethra to
anus
– Colonization of fecal flora
in vagina

• Risk factors:
– Foley catheter
– Pregnancy
– BPH
– Kidney
surgery/malformation
26
 Making the diagnosis
• Urinalysis (UA) not indicated if typical symptoms
• UA with microscopy
– Need mid-stream, clean catch specimen
• ? Diagnostic accuracy if you see epithelial cells
– Looking for infection:
• Leukocyte esterase – enzyme released by leukocytes which
reflects pyuria (neutrophils in urine)
– Sensitivity = 75-96%; Specificity = 94-98%
• Nitrite – Converted from nitrate by Enterobacteriaceae
– Sensitivity not as good. Some false negative results at lower
colony counts
– Phenazopyridine – turns urine red. False positive nitrite test.
• Culture – Need >100K colony forming units/mL
27
Understanding the dipstick

28
 Bugs that cause UTI
• E. coli (80%)
• E. coli
• E. coli
• S. saprophyticus (10-20%)
• K. pneumoniae (8-10%)
• Proteus mirabilis
• Pseudomonas – Catheter associated
• Other organisms – think contamination
29
 E. coli
• Virulence – pili (fimbriae)
– Allows travel up urethra via adhesion to uroepithelium
• Gram negative
– Nitrite positive on UA
• Urease negative
• Fast lactose fermenter
– EMB agar – “green, metallic sheen”
• Also ferments glucose
• Indole positive
– Turns tyrptophan into indole
30
 Staph Saprophyticus
• Nitrite negative on UA – gram positive org
• Coagulase negative, novobiocin-resistant
• Tends to occur more in young, sexually active
women
– Tends to occur within 24 hours of sex
– “Honeymoon cystitis”
• Urease positive

31
 Proteus mirabilis
• Urease positive
– Splits Urea into CO2 and
NH3 (ammonia)
– (NH2)2CO + H2O → CO2
+ 2NH3
– Results in an alkaline pH
(>6.5)
– Struvite crystals

32
Staghorn calculi

33
 Unique situations

• Bacteria present on microscopy but no symptoms

– Usually leukocyte esterase is negative
– Suggests asymptomatic bacteriuria with
colonization
– No treatment necessary!
– Unless….
– Pregnant, urologic intervention, hip arthroplasty

34
Sexually transmitted infections

35
 Where are you from?

• http://www.topmastersinhealthcare.com/state-
risks/

36
 Symptoms

• Most STI’s do not initially cause symptoms

• When they do:
– Vaginal or penile discharge
– Ulcers around the genitals
– Pelvic pain
– Inguinal rash or lymphadenopathy
• Risk factors:
– Young age at first intercourse
– Unprotected sex
– Multiple sexual partners
37
 Etiology
• Bacterial:
– Syphillis
– Chlamydia
– Gonorrhea
• Viral:
– Herpes
– HPV
– HIV
– Hepatitis
• Protozoal:
– Trichomonas
38
 Treponema pallidum (Syphillis)
• Risk factors
– Men who have sex with men (MSM)
• 1/3 of contact with chancre or open lesion will contract
– HIV infection
– Recent sexual partners from the internet
– Highest prevalence:
• Men
• African American race

39
 Syphillis
• Treponema pallidum
– Spirochete seen under darkfield microscopy
• Serological tests:
– VDRL (Venereal disease research laboratory test)
• High sensitivity
• Detects anti-cardiolipin antibodies (ox heart)
• False positives common
– Virus (Mono, hep)
– Drugs (IVDA)
– Rheumatic Fever/Rickettsial
– Lupus
– Also pregnancy, endocarditis
– RPR (Rapid plasma reagin)
• Similar to VDRL test
• Easier to use – initial screening test
• No microscope needed
• High false positive
• Mix serum with cardiolipin. Anti-cardiolipin Ab present will result in “flocculation”
– FTA-ABS (Fluorescent treponemal antibody-absorption test)
• Confirmatory test
40
 Syphillis

1° syphillis 2° syphillis

Maculopapular rash

Also condylomata lata

(google it)
41
Painless chancre
 Primary syphillis
• Incubation period of 2-3 weeks then chancre
– Painless ulcer with inguinal lymphadenopathy
– Spontaneously heal within 3-6 weeks without Rx.
– Lesions on penis, posterior pharynx, anus, vagina
– Why would you seek treatment for that????
• No treatment – enhances transmission
– 25% go on to systemic illness – secondary syphillis
– Patients may miss original chancre if in area they can’t
see
• Jarisch-Herxheimer Reaction: Reaction resembling
sepsis after antibiotics due to endotoxin-like release.
42
 Not to be confused with chancroid…
• Cause:
– Haemophilus ducreyi
• PAINFUL, ulcer
– You “do cry” from them
• Ragged, irregular edges
• Necrotic, purulent base
• Bleeds easily
• Multiple lesions
• Curved gram neg rods clump
in long parallel strands
– “School of fish” 43
 Secondary syphillis
• Rash: Diffuse, symmetric macular or papular eruption
involving the entire trunk and extremities including the
palms and soles
– Rash on palms and soles Ddx for USMLE 1:
• Rocky Mtn Spotted Fever – wrists.
– NC, TN, MO, OK, AR – not Colorado
– Headache, Fever, tick bite, rash
• Hand, foot and mouth disease (Coxsackie virus)
• Meningiococcemia
• Condyloma lata - Large, raised, gray to white lesions on
warm moist surfaces (mucosa)
– Appear near primary area of previous chancre
• Systemic symptoms – fever, HA, malaise, sore throat,
weight loss, myalgia, anorexia
44
 Tertiary syphillis
• Gummas (chronic granulomas)
• Aortitis (small vessel vasculitis) – Aortic regurg
– 15-30 years after initial infection
• Neurosyphillis
• May occur 1 to 25 years after initial infection
– Dementia, personality change
– Test CSF for VDRL or RPR
– + Romberg sign, broad-based ataxia (tabes dorsalis)
• Argyll Robertson pupil – Constricts with
accommodation, not responsive to light
45
Tertiary syphillis

46
 Congenital syphillis
• Cause of hydrops fetalis
– Stillbirth due to fluid accumulation in fetus
• If survives:
– Hutchinson incisors
– Mulberry molars
– Saddle nose
– Frontal bossing
– Recurrent ear infections
– Interstitial keratitis – vision problems
47
 Congenital syphillis

Hutchinson incisors Mulberry molars

48
 Chlamydia trachomatis
• Several serotypes:
– A,B,C – Africa, blindness, chronic (trachoma)
– D-K – Urethritis/ PID, neonatal conjunctivitis, Reactive
arthritis
• Most prevalent STD in United States
• Symptoms indistinguishable from Gonorrhea infection
– L1,L2, L3 – Lymphogranuloma venereum (LGV)
• Small painless genital ulcers which change to swollen painful
inguinal lymph nodes which can ulcerate (buboes)
• Obligate intracellular organisms, gram negative
– Elementary body→Reticulate body→Elementary body
49
 Symptoms of Chlamydia
• Women:
– Most are asymptomatic (85%)
– Cervical infection ascends to cause PID
• Chronic pelvic pain, inability to become pregnant
• Mucopurulent cervical discharge, easily cervical bleeding with
PAP
– Pelvic inflammatory disease (PID) – cervical motion
tenderness. Tubal infertility, ectopic pregnancy, chronic
pelvic/abdominal pain.
– Pyuria but no bacteruria on urine studies
• Men:
– Also can be asymptomatic
– Mucoid or watery penile discharge (seen with milking urethra)
– Dysuria
– Epididymitis – unilateral testicle pain, swelling
– 1% will develop reactive arthritis – arthritis, uveitis, urethritis 50
Chlamydia

51
 Chlamydia

Use Giemsa stain to see inclusion bodies of chlamydia

52
 Neisseria gonorrhea
• Gram - , kidney-shaped diplococci within PML’s, No capsule
• Not as common as Chlamydia, but still common
• Again, most asymptomatic
• Women:
– Vaginal itching, mucopurulent discharge, dysuria
– Bleeding between periods
– Cervix often friable
– Can lead to PID
• Men:
– Copious discharge that doesn’t need to be expressed
• Disseminated gonococcal infection (DGI) → migratory
polyarthritis, tenosynovitis (wrists, fingers, ankles, toes), dermatitis
(pustular lesions)
• Grows on Thayer-Martin Agar
53
 Herpes viruses
• Double standed and linear
• Types of herpesviruses:
– HSV-1 – Oral lesions, keratoconjunctivitis,
encephalitis
– HSV-2 – Genital lesions
– VZV – Chickenpox, Zoster (shingles)
– EBV – Mono, Burkitt lymphoma, Hodgkin lymphoma
– CMV – Diarrhea, retinitis, esophagitis in AIDS
– HHV-6 - Roseola
– HHV-7 - Roseola
– HHV-8 – Kaposi sarcoma 54
 HSV-1 and HSV-2
• Conventionally:
– HSV-1 = cold sores
– HSV-2 = genital sores
• Rates of genital HSV-1 soaring
• Sexually transmitted
• Painful vesicles, tender LAD
• Giant cells on Tzanck smear with
eosinophilic inclusions (Cowdry A)
• PCR testing best; Tzanck outdated
• 80% of patients asymptomatic
• Latent in sacral ganglia
– Stress triggers reactivation
55
 Human Papilloma Virus (HPV)
• Double stranded DNA viruses
• Most common STI in US
– 53% of men are HPV carriers. 1/3 of them are oncogenic strains.
– Causes inactivation of p53 and Rb genes
• More than 100 types of HPV
• USMLE focuses mostly on:
– Types 6 and 11 – Genital warts (Condyloma acuminatum)
– Type 16 (50%) and 18 (20%) – Squamous cell CA involving:
• Vagina
• Vulva
• Cervix
• Anus – MSM. Incidence rising significantly over past 30 years
• Penis
• Prevalence decreasing dramatically with HPV vaccine.
• Type 16 and 18 mechanism of cancer:
– E6 and E7 are viral oncogenes which deactivate and destroy p53 56
HPV

Pap Smear – “aka cervical cytology”

57
58
 Trichomonas vaginalis
• Profuse, yellow-green, frothy
discharge
• Itching, tenderness, burning
• Vulva, Vagina inflammed
• Cervix – “strawberry” appearance
– Small, punctate red lesions
– Known as colpitis macularis
• Wet mount→ aka saline microscopy
– Pear-shaped, flagellated, protozoan
– Elevated vaginal pH >4.5
59
 Bacterial Vaginosis
• Loss of acidic lactobacillus (normal flora)
• Overgrowth Gardnerella vaginalis (anaerobic)
• “Clue cells” – gram-variable rods coating epithelial cells
• Thin, gray-white discharge
• No vaginal inflammation
• Pain, itching, burning
• Fish-like odor
• KOH “Whiff Test”
• pH > 4.5
• Risk factors – multiple sexual partners, douching
60
Clue Cells

61
62
 Pathophysiology Lecture 5:
HIV/AIDS and Immunocompromised
Infections
Charles Opperman

1
 HIV/AIDS
• Lentivirus, single strand, positive sense, enveloped RNA virus
• HIV turns into AIDS when CD4 count drops below 200 or
infection with opportunistic org
• CD4 cells are T-helper cells responsible for cell-mediated
immunity
– No antibodies involved
– Rather, activation of phagocytes and cytotoxic T-lymphocytes
– Without CD4 cells (helper), cannot signal B cells to produce
antibodies or Cytotoxic T cells to kill infected cells as well.
– Defend against fungi, protozoans, cancers, and intracellular
bacteria. All viruses need intracellular host for reproduction.

2
 HIV facts
• Most often sexually
transmitted
– Second most common is
blood-to-blood (needle)
• Unlikely as transmission low
– Saliva, tears, urine, feces,
vomit, mosquitos – no
transmission
– Mother-to-child (Give ART)
• 3rd most common worldwide
• Pregnancy, delivery, or
breastfeeding 3
 More than just a virus
• NEJM - 1986
– Risk of transmission is
"minimal to nonexistent,"
even when contact
included sharing:
• Toothbrushes
• Razors
• Clothing
• Combs
• Drinking glasses
• Sleeping in the same
bed
• Hugging and kissing 4
 History and Society HIV/AIDS
• Many proposed mechanisms:
– Mutation from Simian
Immunodeficiency Virus (SIV) –
Hunters/Bushmeat vendors
– Colonialism/prostitution in early
1900’s Africa
– Unsafe vaccination with reuse of
syringes in post WWII Africa
• Initially called 4H disease
– Heroin, Homosexuals,
Hemophiliacs, and Haitians
• Heavily stigmatized
– Ostracism, Rejection, Violence,
Quarantines
– Ryan White - hemophiliac
5
The US culture in 1991

6
HIV transmission risk

7
8
9
10
Quick immunity review

11
 HIV structure
• Diploid RNA genome (2 RNA molecules)
• Reverse transciptase
– Retrovirus – changes RNA into DNA
– Synthesizes dsDNA from the RNA
– dsDNA integrates into host genome
• Envelope proteins (env gene)
– gp120 – attachment to host CD4 cells.
– gp41 – Anchors gp120 and mediates fusion/entry
• CCR5 – Area of binding on CD4 lymphocytes.
– CCR5 mutation
• Homozygote – Immunity
• Heterozygote – Slower course 12
HIV structure

13
14
Pol gene – HAART resistance 15
16
Joseph Juene (Partners in Health)

17
 CD4 T-helper lymphocyte destruction
• Pyroptosis – Non-HIV
infected CD4 cells die
secondary to
overwhelming
inflammation
– 90-95% are killed this
way
• Direct viral killing of CD4
cells by HIV
• Apoptosis by CD4 cells
• Killing by CD8 cytotoxic
lymphocytes 18
Timeline of HIV infection

19
Acute HIV Syndrome
• Symptoms begin around 1
month after exposure
• Rarely accurately diagnosed
• If fever, young and have
significant risk - consider HIV
– Primary infection:
• Check HIV-RNA or p24
antigen (capsid antigen)
– After seroconversion:
• Check HIV PCR
• For the USMLE – Confirm
with Western blot
• USPTF: screen ages 15-65
• Screen in presence of STI20
Opportunistic Infections

21
 Monitoring and Prevention
• Condom use – 80% risk reduction in
transmission
• Circumcision
• Post-exposure prophylaxis (PEP)
– Triple drug therapy for 4 weeks
– Given within first 72 hours
• Monitor:
– Viral load
– CD4 count
– Antibiotic prophylaxis
• CD4 <200 = PCP, Histo (TMP-SMX)
• CD4<50 = MAC (Azithro)
22
The following conditions are placed in
order of decreasing CD4 counts

23
 Mycobacterium tuberculosis
• If culturing – grow on Löwenstein-Jensen agar
• Obligate aerobe – mainly affects the lung
– Which part of the lung has the highest oxygen?
• Cord factor – Found in virulent strains of TB
– Induces Tumor Necrosis Factor-α (TNF-α) which causes
systemic inflammation
– Serpentine pattern – Two mycolic acid molecules bounded
• Tuberculin - responsible for delayed hypersensitivity
reaction (Type IV reaction)

24
 Acid-fast TB
• Acid-fast on staining
– Only Mycobacterium and Nocardia are acid-fast
• ***Note: Mycoplasma and Mycobacterium are
different!
– Has thick lipid wall (mycolic acid) which is not
destroyed when alcohol used in staining as a wash →
Isoniazid inhibits mycolic acid synthesis
– Ziehl-Neelson stain (acid-fast staining)
• Carbolfuchsin (red stain)→Alcohol→methylene
blue
• Acid fast organisms stain red, all others take on blue
• Cell wall makes it resistant to gram staining. 25
Tuberculosis (TB) – Acid fast stain

26
 Tuberculosis
• “Consumption”
– Refers to weight loss
• Symptoms:
– Fever
– Night sweats
– Bloody sputum (hemoptysis)
• Forms caseating granulomas
– Macrophages engulf bacteria and
attempt to remove via phagocytosis
– Forms phagolysosome to try to kill
with ROS
– Other macrophages fuse to form a
giant multinucleated cell
– Then TH1 (T-helper cells, CD4)
recruit other inflammatory cytokines
to form walled off granuloma
27
 TB
• Most of the time, TB is latent (90%)
– 10% of latent TB become reactivated into infection
– Latent TB is not infectious
– Latent TB is asymptomatic
• Spread via respiratory droplets
• Risk factors:
– HIV, Imprisonment, Poverty, Homelessness, IVDA,
Healthcare

28
Primary TB
• Usually asymptomatic
• Often seen in lower lobes of
lung
– Ghon Foci – walled off,
calcified caseated granuloma
– Ghon Complex – lymph node
involvement
• Positive PPD, Positive cultures
and stain
• If found, need to treat for 6
months with multi-drug regimen
– However, 95% of cases, the
symptoms self-resolve with
normal immune system →
latent
29
 TB testing
• Tuberculin (Purified protein derivative, PPD) Skin Testing (TST)
– AKA Mantoux testing
– AKA PPD testing
– Injected intradermally → check in 48-72 hrs to see if immune response
(Type IV Hypersens Rx)
• If positive without symptoms = LTBI
– False positive – Bacillus Calmette–Guérin (BCG) vaccine
• Weakened (attenuated) strain of M. bovis
• Need chest X-ray always
• Ignore prior BCG vaccine when interpreting PPD
• Overtreating?
• Newer better test (but more expensive)
– Interferon gamma release assay (IGRA)
• Measures amount of interferon gamma released by T-lymphocytes when
exposed to Mycobacterium tuberculosis antigens
– AKA QuantiFERON-TB Gold.
– No BCG interference, easier, more accurate 30
PPD testing

31
 Latent TB (LTBI)
• Infected with
Mycobacterium
tuberculosis but NO
active infection
• Not contagious
• 10% go onto active
infection
• Should be treated –
9 months INH

32
 Reactivation TB (secondary)
• 10% lifetime risk of
reactivation from primary
TB
– Usually caused by event
which causes weakening
of the immune system
– HIV patients have 10%
chance per year of
reactivation
• Upper lobe cavitary
lesion
33
34
 Extrapulmonary TB
• TB pleurisy – affecting pleural space
• Scrofula – TB affecting lymph nodes of the neck
• TB osteomyelitis – Pott Disease
• TB meningitis looks like bacterial meningitis on CSF
– High opening pressure, high protein, low glucose
– Only difference: Many lymphocytes instead of PMN
– Appears the same as fungal meningitis
• Miliary TB – Disseminated spread via blood in small lesions
• USMLE wants you to know the common side effects of anti-TB
meds

35
Miliary TB

36
• Oral candidiasis Thrush (Candida albicans)
– Leaves red, bleeding base when
scraped
– <400 CD4
• Esophageal candidiasis – think HIV
– Odynophagia
– <100 CD4
• KOH mount (potassium hydroxide)
– Pseudohyphae and budding yeast
– Germ tube test – true hyphae at 37°
• Often presenting symptom of HIV/AIDS
– Can occur at higher CD4 counts (400)
• Oral hairy leukoplakia = Ebstein-Barr
– Not removed with tongue depressor
– Lateral surface
– Tobacco use 37
Candida albicans

38
 Kaposi Sarcoma

• Human Herpesvirus-8
• Purple nodules – tumor
• Can appear on gums and
in mouth
• Can be limited to only
skin or affect all organs

39
Pneumocystis jirovecii (PJP or PCP)
• CD4 = 100-200
• Fungal (yeast)
• Causes severe pneumonia
– Ground glass interstitial
infiltrates
– Hypoxia out of proportion to
CXR findings
– Dry cough and dyspnea
• Most often cause of death from
AIDS
– 80% of AIDS patients will get
this unless treated with
prophylactic Abx
• Dx - Silver stain of lung tissue
demonstrates cysts (sporozoites)
• TMP-SMX prophylaxis <200 CD4 40
The Dimorphic Fungi – Histo, Cocci,
and Blasto (and Sporothrix)
Changing from yeast at body temps to
molds (have hyphae) in ambient temps

41
• CD4 = 100-200
• Common soil fungus Histoplasmosis
– Found in bird and bat droppings
– Spelunkers or cave exploration
– Inhaled in spore form
• Symptoms:
– Mostly asymptomatic unless
immunocompromised
– Low grade fever
– Cough
– Hepatosplenomegaly
– Tongue ulcer
• Geographic region
– Ohio river valley
– Lung granulomas, calcifications
• Need lung tissue for Dx
– Oval yeast cells within macrophages @
body temps (37)
– Branching hyphae at 25 degrees C
(Sabouraud Agar) 42
 Histoplasmosis
• Oval yeasts within macrophages

Typically, smaller than the size of RBCs

Coccidiodomycosis – Larger than surrounding RBCs

43
• CD4 = 100-200 Coccidiodomycosis (Valley Fever)
• Common soil fungus
– Inhaled in spore form
– Spores are airborne after soil disruption
(construction, farming, earthquake)
• Mild bronchitis unless immunocompromised
• “Desert Rheumatism” – flu like illness
– Fever
– Joint pain
– Erythema nodosum
• Red, painful nodules on shins
• Need lung tissue for Dx
– Thick-walled spherules containing
endospores at body temperature
– Hyphae when grown at 25C
• Geographic region - Southwest (AZ, NM, CA)
44
 Blastomycosis
• Single Big, Broad-based, Budding yeast
• Found in Mississippi River/Ohio Valley region
– Oh no!!! USMLE asked me a question about someone
from Kentucky that traveled to New Mexico!!!
• Manifests as primary lung infection (pneumonia)
– Ulcerated dermal lesions (which “start out as a pimple”)
also occur
• Most rare of the mycoses
• Found in soil and rotting wood
• Large, round yeast with doubly retractile wall - 37°C
• Branching hyphae at 25°C
45
Blastomycosis

46
 Toxoplasmosis • Parasite infection
– Toxoplasma gondii
• CD4 = 50-100 – Latent infection → reactivation
• Main reservoir is cat feces
• Causes encephalitis
– HA
– Seizure
– Focal neurologic sign
• Multiple ring enhancing lesion(s) on
imaging
– DDx: Primary CNS Lymphoma,
cryptococcus, GBMs, neurocysticercosis
and TB all can cause ring-enhancing
lesions…know how to differentiate!
• Congenital Triad (avoid cat litter):
– Chorioretinitis – yellow/white scar
– Hydrocephalus
– Intracranial calcifications
47
 Cryptococcus neoformans
• Encapsulated fungal infection • CD4 = 50-100
• Usually starts as asymptomatic • Tissue – mucicarmine stain
lung infection → meningitis in • Culture with Sabouraud agar
AIDS patients
• India ink staining on CSF
– Headache
– “Yeast with narrow-based
– Nuchal rigidity budding and large capsule”
– Fever
– However, because of decreased
immune response – meningeal
signs may be absent
• Rapidly fatal
• “Soap bubble lesions in brain”
• Pigeon droppings
48
 Cryptosporidiosis
• CD4 = 50 – 100
• Protozoan parasite
• Chronic, severe diarrhea in
AIDS pts
• Weight loss
• Abdominal pain
• Some mucous stools, but no
bloody stools
• Contaminated water
• Acid-fast oocysts (red) in
stool
49
• CD4 = 50 – 100
• Herpesvirus (HHV-5)
Cytomegalovirus (CMV)
– All herpes virus = double strand linear DNA
• Common to have latent carriers (80%)
– Mononucleosis-like syndrome
• Reactivation can result in:
– Chorioretinitis – blindness
• Cotton wool spots
• Antigen-antibody complex
– Esophagitis – odynophagia
• Shallow, linear ulcerations
• Differentiate from Candida, HSV
– Colitis (diarrhea)
– Hepatitis
• Association with transplant patients
– Pneumonia
– AIDS patients rarely get pneumonia from CMV
• “Owl eyes” inclusion bodies - enveloped
• Congenital: Deafness and MR
50
 Mycobacterium Avium Complex (MAC)
• CD4 count < 50
– Azithro prophylaxis
• Intracellular bacteria
present throughout our
environment
• Acid-fast, non-branching
bacilli
• Rapidly fatal
– Systemic symptoms:
• Fever
• Weight loss
• Night sweats
• Diarrhea
• Elevated LFTs 51
Pathophysiology Lecture2:
Streptococcus infections

Dr. Charles Opperman, MD

Dept. of Internal Medicine,
Kettering Medical Center,
Kettering, OH.

1
• Streptococcal infections
– Complications of Group A Strep infections
• Sinusitis and Otitis media
• Pneumonia
– Strep
– Other causes

2
 Streptococcus
• Beta-hemolytic
– Completely lyse RBC
– Group A and B (Lancefield
classification)
• Alpha-hemolytic
– Partially lyse RBC
– Strep pneumo & viridans
• Gamma-hemolytic
– Not hemolytic at all!

• Mostly:
– Catalase negative
– Oxidase negative 3
Pyrrolidonyl
arylamidase
(PYR) positive

4
PYR

5
 Beta-hemolytic Strep
– A= pyogenes
• M protein – virulence factor
– Inhibits activation of complement by binding factor H
and protects organism against phagocytosis
• Streptolysin O – Destroys RBC and WBC
– Anti-steprolysin O (ASO) Ab – confirms recent Strep
infection
• Pyrogenic exotoxin – stimulate T cells to pour out
inflammatory cytokines
– Scarlett Fever, Strep toxic shock syndrome
• DNase B – used in detection (ASO more common)
• Streptokinase – breaks up fibrin clots
– B= agalactiae
6
 Beta-hemolytic Strep

(Group A only - Strep pyogenes)

7
 Beta-hemolytic Strep
5 diseases:
• Streptococcal skin
infections
• Streptococcal
pharyngitis
• Scarlet fever
• Rheumatic Fever
• Streptococcal toxic
shock syndrome
8
Erysipelas Cellulitis

9
 Erysipelas vs. Cellulitis
Erysipelas Cellulitis
• Upper dermis only • Deeper dermis and SQ fat
• Children and elderly • Middle age and older
• Well-demarcated • Unclear borders
• Raised • Flat
• Acute onset – sick
• Slow moving course
• No pus, bright red
• Can produce pus
• Beta-hemolytic Strep
• Milian’s ear sign • Beta-hemolytic Strep and Staph

10
11
12
Lymphangitis – Pick S. pyogenes!

13
Strep Pharyngitis (Strep throat)

14
15
16
• Centor criteria
– Exudate
– Cervical adenopathy Strep pharyngitis
– Fever history
– Lack of cough
• Typically last 5 days
• Important to treat with penicillin (PCN)
– Suppurative complications – abscess
– Nonsuppurative complications
• Rheumatic fever – only in pharyngitis and not skin infect
• Glomerulonephritis (skin and pharyngitis) & Scarlett Fever
• Far more common in kids than adults
– Check rapid antigen detection test (RADT)
• Detects A-carbohydrate antigen
• Send for throat culture 17
 Sore throat
Viral pharyngitis – 50% of cases Bacterial pharyngitis
• 15% Strep
• Influenza • 5% other
• Parainfluenza • Treat with PCN
– Rheumatic fever
• Coronavirus – Acute GN
– Scarlett Fever
• Rhinovirus – Abscess
• Adenovirus – Hasten symptoms
• No fever, with cough – no
• Enterovirus testing!
• RSV
• HSV • 30% not identified
• EBV – Allergies
– Smoke exposure
• CMV
– Dry air
• HIV • NO ANTIBIOTICS NEEDED
18
 USMLE loves rare conditions!
• Epiglottitis: “hot potato”/muffled voice
– Drooling
– “Thumb sign”
– Respiratory distress & stridor
– Haemophilus influenza (HiB vaccination?)
• Peritonsilar abscess
– “hot potato”/muffled voice
– Drooling
– Pain on one side of throat
– Untreated bacterial pharyngitis: Strep pyogenes,
Fusobacterium necrophorum
• Ludwig’s Angina: Life-threatening infection of submandibular
space
– Usually from dental infections with Viridans strep 19
 I can’t breathe!!!

H. Influenza virulence factor:

polyribosylribitol phosphate (PRP)
capsule

Protects against lysis by binding factor H

(circulating complement)
20
 Necrotizing Fasciitis
• S. pyogenes
– M-protein
• Inhibits opsonization by
complement
• Blocks phagocytosis
• Bacteria moves rapidly
through fascia
• Type I – polymicrobial
• Type II – one bug
• Strep Toxic Shock
– Hypotension
– Multiorgan failure
– Usually Nec Fasc
– M1 and M3 protein strains
• Clinically:
– Changing appearance
– Pain out of proportion
– No time to waste!
• Debridement
• Antibiotics
– Untreated mortality =
73%
• Fournier’s gangrene
– Involves penis
– Google picture if you’d
like.
21
Necrotizing Fasciitis

22
• Streptococcal infections
– Complications of Group A Strep infections
• Sinusitis and Otitis media
• Pneumonias
– Strep
– Other causes

23
• Complication of Group A (S.
pyogenes) strep infection Scarlet Fever
– Pyrogenic/Erythrogenic exotoxin
• “Pyro” – causes fever
• “Erythro” – red
• Clinical course:
– Fever, sore throat,
lymphadenopathy
– Sandpaper Rash:
• Begins on the neck, armpits
and groin
• Spreads to trunk, extremities
• 1-2 mm papules, Blanches
with pressure (Boiled lobster)
• Spares the face (but flushing)
• Desquamation (after 1 week) 24
 Scarlet Fever
• Late complications:
– Endocarditis
– Glomerulonephritis
• Dx: clinical + ASO titer
• Treatment - PCN
• DDx:
– Kawasaki’s disease
• Autoimmune vasculitis
• Conjunctivitis, swollen erythematous hands and feet
• Coronary artery aneurysm
• IVIG and Aspirin (Reye’s syndrome?)

25
 I have it narrowed down to two!
Scarlet Fever Kawasaki Disease

26
 Rheumatic Fever
• Complication of Group A (S. pyogenes) strep infection (pharyngitis only)
– Typically symptoms appear 2-4 weeks after infection
• Clinical manifestations:
– Fever
– Myocarditis
• 10-20 years later- mitral valve disease
• Occurs in 3% of untreated patients
– Joint swelling
– Chorea (Syndenham’s or St. Vitus Dance)
– Subcutaneous nodules
– Erythema marginatum - Red margin which spreads out from center
• Antibody-mediated
– Antigens in heart similar to antigens of Group A Strep
– Type II hypersensitivity reaction – molecular mimicry
• Dx: Jones Criteria
27
 Jones Criteria – Rheumatic Fever
• Major:
– Carditis
– Migratory polyarthritis
– Erythema marginatum
– Subcutaneous nodules
– Chorea
• Minor:
– Fever
– Arthralgia (excluded if polyarthritis major)
– ESR or CRP elevation
– Leukocytosis
– PR prolongation (AV block)
– Previous rheumatic fever
28
 Mitral stenosis

Erythema marginatum

29
30
Other Strep infections

31
 Group B strep (Strep agalactiae)
• Group B → think (B)aby!
• Also beta-hemolytic, but bacitracin resistant
• Causes:
– Neonatal (<3months) meningitis
– Pneumonia
• 25% of women have as vaginal flora
– Vaginal and rectal cultures at 35-37 weeks gestation for screening
– Intrapartum PCN is recommended - Kills GBS for approximately 4 weeks after given.
• Preterm labor and PROM are risks factors.

32
 USMLE question
• 1 month old baby born prematurely at 36 weeks with fever, poor feeding
and irritability. Uncomplicated pregnancy except for prolonged rupture of
membranes (PROM). Mother GBS status was unknown. What could have
prevented this meningitis?
a) Intrapartum penicillin to mother prior to delivery
b) Use of polysaccharide vaccine at time of + preg test
c) IM penicillin injection to baby after birth
d) Prophylactic penicillin to mother at 18 weeks gestation
e) Unfortunately, this was not a preventable circumstance

33
 Strep Viridans
• Think mouth, teeth and dental
• Recognize the group names, but DO NOT memorize individual
bacteria in group.
– Mitis group, Salivarius group, Mutans group
• Dental infections/endocarditis
– Anginosus group – abscess (brain or GI)
• Strep InterMeDius and AnginoSus IMeDiately ASsess for
ABSCESS
• Alpha-hemolytic
• Subacute Bacterial Endocarditis (SBE)
– Slower moving endocarditis
– After dental procedure – fever, new murmur, history of valve
problem
– Give prophylactic antibiotics if valve history 34
 Enterococcus species
• Vancomycin-resistant
enterococcus (VRE)
– VanA gene
– Encodes peptidoglycan
cell wall change:
• D-ala-D-ala → D-ala D-
lactate
• Gene can transfer to
MRSA
• Strep bovis think colon
CA
– Grows in 40% bile

35
• Streptococcal infections
– Complications of Group A Strep infections
• Sinusitis and Otitis media
• Pneumonias
– Strep
– Other causes

36
• Most cases viral
Sinusitis
– Resolves <10 days
– Rhinovirus and others
• Bacterial pathogens:
1. Strep pneumoniae
2. H. influenza
3. Moraxella catarrhalis
– >10 days
– Fever, purulent
discharge, pain in
sinuses

37
 Mucormycosis
• Type I DM with DKA and sinusitis
• Periorbital pain, headache and purulent nasal discharge
– Think mucormycosis (Rhizopus, Mucor, or Absidia
species)
– Necrotic tissue, Black pus discharge (eschar)
– Broad, nonseptate hyphae at right angles (90 degrees)
• If 45 degrees and septated, think Aspergillus species in
neutropenic patients

• Can also see with immunocompromised hosts

38
 Branching hyphae

Mucormycosis Aspergillus

39
Acute maxillary sinusitis

40
 Complications of sinusitis
• Untreated bacterial sinusitis:
– Brain abscess
– Osteomyelitis of facial bones
– Orbital cellulitis
– Cavernous sinus thrombosis
– All of the above very, very rare.

41
• Acute Otitis Media
– Middle ear
– Usually 2/2 obstructed
Eustachian tube.

42
 Acute Otitis Media
• Usually due to S. pneumoniae (most common)
– USMLE: also H. influenza, M. catarrhalis, RSV
• Typically preceded by viral URI
• Ear pain and hearing loss common
• Fever not necessary
• Perforation = pain relief

OM with effusion OM with perforation

43
 Clinically – OM
• Child too young to speak pulling on ear. Poor
bottle feeding. Not been vaccinated. Irritability.
There has been second hand smoke exposure.
Recently had viral URI.
– Tympanic membrane bulging and no light reflex

• Which organism is most common?

– They could give all bugs as choices = know S. pneumo
• Always give Abx if less than 2 years old
44
• Streptococcal infections
– Complications of Group A Strep infections
• Sinusitis and Otitis media
• Pneumonias
– Strep
– Other causes

45
 Strep pneumoniae
• Most common in very
young and very old.
• Middle aged = think
atypical bugs
– Mycoplasma
– Chlamydial
– Legionella
• Physical exam key!
– Rales
– E-to-A egophony
– Dullness to percussion
– Tactile fremitus
• Increased with
consolidation
• Decreased with pleural
effusion
46
 Strep pneumoniae
• Encapsulated
– Virulence due to polysachharide
capsule
– Inhibits phagocytosis
– >90 known capsule types
• “Lancet shaped diplococci”
• Optochin sensitive
– VROPS
• “Viridans Resistant Optochin,
Pneumoniae Sensitive”
• Quelling reaction +
– Swelling of capsule when mixed
antibodies to capsule
– Remember: capsule = virulence 47
 Clinical scenario
• A 72 year old male presents with cough, productive
brownish (rust)-colored sputum, fevers and chills at home.
He was in a car accident last week and suffered an injury to
the chest wall. Since that time he has had dull pain but
states this pain is different. He describes chest pain which is
sharp and worsened with inspiration. He has had some
mild blood mixed in with his sputum. Vital signs are:
– Temp – 103 F
– RR – 22
– HR – 121
– BP – 133/78
• PE reveals increased tactile fremitus and rales in upper lobe
• CXR obtained shows:

48
49
 What is most likely diagnosis?

• Know the distractors!

• DDx pleuritic chest pain:
– Pneumonia
– Pulmonary embolism
– Pleural effusion
– Pericarditis
– Pneumothorax
– TB

50
• Streptococcal infections
– Complications of Group A Strep infections
• Sinusitis and Otitis media
• Pneumonias
– Strep
– Other causes

51
 That’s SO typical…
Typical (Strep) PNA Atypical PNA
• Sudden onset • Gradual onset
– High fever – Myalgia
– Productive cough – Dry cough
– Dyspnea – Headache
– Pleuritic chest pain – Sore throat
• Very young and old • Ages 18-65
• Most common cause • Have provide risk factors in
• Not walking, barely moving! stem
• “Walking pneumonia”

52
• Age 0-6 weeks A pneumonia for the ages
– Group B strep (S. agalactiae)
– E. coli
• 6 weeks – 18 years
– RSV
– Parainfluenza
– Mycoplasma
– Chlamydia pneumoniae
– Strep pneumoniae
• 18 – 65 years
– Mycoplasma
– Chlamydia
– Strep pneumo A normal CT chest for reference

• >65 years: Strep pneumo 53

 Atypical pneumonias
• Mycoplasma
– Young adults, college
– Imaging looks bad!
– No cell wall
– Require cholesterol to grow
– Virulence factor – Protein P1
– + cold agglutinins
• Blood clumping at cold temps
• Due to Ab against Mycoplasma
• Similar antigen to RBCs and can
cause hemolytic anemia
– “fried egg” appearance on
Eaton’s agar
54
55
Atypical pneumonias
• Chlamydia pneumoniae
– “Adult-onset” asthma
• Chlamydia psittaci
– Inhaling dried bird feces
– Elementary body
• Not a virulence factor but helps survival
outside host

• Legionella
– Silver stain and Buffered charcoal
yeast extract
– Outbreak - Air conditioners/water
reservoir
– Check urine antigen (real-life)
– Hyponatremia, diarrhea, transaminitis

56
• Klebsiella Gram negative pneumonias
– Lactose-fermenting
– Polysachharide capsule (O antigen)
– Four A’s:
• Aspiration PNA (affects upper lobe)
• Abscess (DDx: TB)
• Alcoholics
• Di-A-betics
– Currant jelly sputum
• Pseudomonas aeruginosa
– Common hospital acquired
– Ventilators, water (hot tub folliculitis)
– Burn patients, cystic fibrosis (forms slime layer – difficult
phagocytosis)
– Resistant organism – piperacillin, cefepime, carbapenems
– Blue-green pigment with “grape-like odor”
– Non-lactose fermenting; Oxidase positive & Capsulated 57
 Pseudomonas
Ecthyma gangrenosum (EG)
- Necrosis, ulceration
- Febrile neutropenia

Hot tub folliculitis

- Self limited

58
 MRSA pneumonia
• After influenza
• Causes empyema
• Noscomial - vents
• Necrotizing
• CAP vs HCAP
– HCAP – cover Abx for
MRSA and Pseudomonas
– Risk factors determine
HCAP coverage

59
Pathophysiology Lecture3:

Staphylococcal infections

Dr. Charles Opperman

1
 Difference between Staph and Strep
Staph Strep
• Gram stain • Gram Stain
– Grape-like clusters – Cocci in lines
– Both gram + – Both gram +
• Catalase test • Catalase test
– All have enzyme – Catalase negative
– Produce O2 when exposed to
H2O2 • Culture
• Culture – Pigment varies on
blood agar
– Characteristic golden pigment
– Can also be B-
– Beta-hemolytic
hemolytic
2
 Comparing Staph
Staph aureus
• Coagulase positive
– Converts fibrinogen to
fibrin
– Protects from phagocytosis
• Always a pathogen
• Most of the time, the
causative organism
Staph saprophyticus
• Coagulase negative
• 2nd most common UTI bug
• Novobiocin resistant
Staph epidermidis
• Coagulase negative
• Often a contaminant
– Draw blood from two sites
• Can form biofilm
– Biofilm: extracellular
polysaccharide matrix
– Indwelling devices
• Joints
• Catheters
• Valves
– Biofilm protects from Abx
• Novobiocin sensitive 3
4
 Staphylococcus aureus
• Has microcapsule surrounding cell wall
from which many powerful proteins extend
– Protein A
• Binds the Fc region of IgG which helps prevent
opsonization and phagocytosis
– Coagulase
• Fibrin formation around bacteria which protects
from phagocytosis
– Hemolysins
• Destroy RBCs, neutrophils, platelets
– Leukocidins
• Destoys leukocytes
– Panton-Valentine Leukocidin (PVL) – forms abscesses
5
6
 Staphylococcus aureus (cont)
• Staph exotoxins
– Exfoliatin
• Exotoxin which causes skin to slough off
– Nikolsky’s sign – skin slipping off with gentle pressure
• Responsible for scalded skin syndrome
• Affects neonates usually after severing of
umbilicus
• Disrupts desmosomes in skin which are
responsible for epithelial cell adhesion
– Enterotoxins
• Cause food poisoning – think mayonnaise
• Heat stable exotoxin
• Occurs because of ingestion of food with pre-
formed toxin
7
 S. aureus
• Toxic shock syndrome
– Exotoxin = TSST-1 is a “superantigen”
– Massive T-cell response and outpouring of cytokines
– Foreign body packing or tampon use
– Desquamating rash (palms and soles), septic shock,
multiorgan failure
– DDx:
• Stevens-Johnson (TEN) → will be new medication use
• Scalded Skin Syndrome → infant, body desquamation
• Pemphigus vulgaris → Flacid blister formation which
can desquamate
• Kawasaki/Scarlett Fever → Strawberry tongue,
maculopapular rash

8
Symptoms of Toxic Shock
Syndrome

9
Staph exotoxins

10
 Staphylococcus aureus (cont)
• All other infections caused by direct
tissue invasion
– Pneumonia, Meningitis, Osteomyelitis,
Endocarditis, Septic arthritis, Skin
infections, UTI
– Discussed separately
– MRSA nasal colonization common
• Multiple proteins involved but remember:
hyaluronidase
– Hyaluronidase – “spreading factor”
• Breaks down proteoglycans in connective
tissue 11
 Staph skin infections
• Cellulitis
– Typically either due to S. pyogenes or
Staph
– Appear similar, but Staph is suppurative
• Impetigo
– “Honey-crusted” facial lesions
– Due to coagulase, exfoliatins
• Abscess, furuncle, carbuncle
– Abscess – collection of pus,
– Furuncle – deep infected hair follicle
– Carbuncle – Cluster of furuncles 12
 Impetigo

Classically, from S. aureus. WILL NOT CAUSE post-strep GN.

However, this is now too easy for USMLE. Think about post-strep GN from S. pyogenes

13
 Staph skin infections

Abscess Furuncle Carbuncle

14
Methicillin-Resistant S. aureus (MRSA)
• Most Staph are resistant to penicillin at
baseline
– Possess penicillinase enzyme – secreted
form of B-lactamase
– However, methicillin and nafcillin are not
broken down by penicillinase
• MRSA – acquired resistance to
methicillin and nafcillin
– Colonizes in the nostrils
– Penicillin Binding Protein 2A – responsible
for resistance, encoded by mecA gene
– Although others exist → think Vancomycin
for Rx. 15
Osteomyelitis
• Staph is most common
• 3 mechanisms of spread
– Hematogenous seeding
• Bacteremia
• Young boys
• Affects tibia, fibula, femur
– Contiguous focus of infection
• Diabetic foot wound
– Direct bone inoculation
• Compound fracture

• Osteomyelitis hints:
– Sickle cell→ Salmonella
– Pott disease
– Diabetic → Polymicrobial
– IVDA → Vertebral column 16
MENINGITIS

17
 Meningitis
• Fever (sudden, high)
• Headache
• Altered mental status
• LOC, Seizures
• Nuchal rigidity – Inability to move neck forward
passively
• Photophobia, Phonophobia
• Kernig’s and Brudzinski sign +
– Kernig – supine, flex hip and knee to 90 degrees. Pain?
– Brudzinski – flexion of neck causes involuntary flexion
of the knee and hip.
• KIDS – Can just look drowsy and be irritable.
Bulging fontanelle.
18
 Meningitis

NOT nuchal rigidity →

19
 Causes of Meningitis
• Bacterial
– Strep pneumo: Old and young (most common)
– Neisseria meningitidis: middle age, college
– Group B Strep: newborns – most common
– Listeria monocytogenes – Old, newborn
– E. coli - newborn
– H. influenza – unvaccinated
– TB – AIDS, endemic country
• Viral (aseptic)
– HSV2 – Mollaret’s meningitis
– Enterovirus – most common
– Varicella
20
 Causes of Meningitis
• Fungal
– Cryptococcus
– Coccidioides, Blastomycosis,
Histoplasma – location, location,
location
– Candida
• Parasitic – unlikely tested and
extremely rare
(neurocysticercosis)
• Non-infectious
– Malignancy, Neurosarcoidosis, SLE 21
 Strep Pneumoniae
• Most common cause
• Encapsulated
– Protects from
phagocytosis
– Asplenic patients
• IgA protease
• Lancet-shaped
diplococci
• Optochin sensitive
• Pus formation –
Increased CSF
pressure

22
•
Neisseria
Common amongst:
meningitidis
– College students living in dorm
– Army recruits in close quarters
– Infants 6 months to 2 years
• Window period where maternal Ab wane
• Similar with H. influenza
– S. pneumo is still the MOST COMMON
• Gram negative diplococci
– Converts acid to maltose
– N. gonorrhoeae – non-maltose fermenter
• Grows on chocolate agar
– Heated blood agar turns it brown
• Thayer-Martin VCN
– Chocolate agar with Abx
– Vanco, Colistin, Nystatin
– Selectively kills competing bacteria 23
24
 N. Meningitidis virulence
• Virulence factors:
– Polysaccharide capsule (vaccine against)
• Prevents phagocytosis
• Asplenic patients
– Endotoxin (LOS)
• Cause blood vessel hemorrhage (petechiae) and
sepsis
– IgA Protease
• Cleaves IgA antibody (mucous membrane Ab)
– Pili
• Allow attachment to nasopharynx
• Transmission: Respiratory

• Pharynx → Blood → Choroid plexus → Meninges

25
 Neisseria meningitidis

Classic petechial rash Waterhouse-Friderichsen

26
 Neonatal meningitis
• Contracted during delivery through birth
canal or through placenta
• Poor prenatal care
• Group B strep (gram + cocci) – strep lecture
– Most common cause in neonates
• Other two causes:
– Listeria monocytogenes (gram pos bacilli)
• Ampicillin! (altered penicillin binding protein)
– E. coli (gram neg bacilli)
• Pink (lactose fermenting) on MacConkey
• Virulence factor: K1 capsular antigen
– Prevents phagocytosis and complement-mediated lysis
27
 E. coli virulence factors
• K1 capsule – meningitis
• Fimbriae – UTI
• LPS – Septic shock
• Verotoxin (shiga-like) - EHEC

28
 Listeria monocytogenes
• Facultative intracellular
• Gram positive with LPS
• “Tumbling motility”
• Causes:
– Deli meat
– Unpasteurized dairy
• Can multiply at cold temp
• Newborns, immuno-
compromised, and elderly
• Outbreaks Tumbling motility:

https://www.youtube.com/watc
h?v=bV_Wd7JCo6A
29
 Viral meningitis
• Milder disease
• Normal glucose on CSF, lymphocytes
• Know how to differentiate the CSF findings!
• Often etiology can never be determined, so
we lump all etiology into “viral” meningitis
– Can check PCR for enterovirus (coxsackie),
HSV, West Nile, etc if its really important to
you
• Think about West Nile if history of mosquito bite –
flacid paralysis
• Single-stranded RNA flavivirus
30
•
Fungal meningitis
CSF findings very similar to bacterial
– Lymphocytic pleocytosis in fungal (similar to viral)
• High opening pressure >250 mm H20
– Cryptococcus neoformans:
• Yeast (oval, encapsulated, budding) found in pigeon droppings
• Virulence factor: Thick polysaccharide capsule
• Inhalation transmission
• No geographic distribution
• AIDS (CD4 <50) and meningitis → think cryptococcus!
• Hematologic cancers (Hodgkin’s) and immunosupp.
– “Soap bubble” lesions in the brain
• India ink stain → Negative stain. Capsule doesn’t stain, but
everything surrounding it does.
– Better test is cryptococcal antigen test followed by culture
– Latex agglutination in CSF
– Culture: Use Sabouraud agar

31
 Cryptococcus neoformans: Diagnosis

India ink stain – Oval yeast “Soap bubble” lesions on MRI

with capsule
32
CSF: Meningitis

• If the thought, “this

could be meningitis”
even crosses your
mind
– LP→empiric Abx
– No time to waste!

33
CSF findings: Meningitis

34
 Haemophilus influenza - Meningitis
• Unvaccinated
– Think Haemophilus influenza, type B (HiB)
– Most common cause of meningitis in the pre-
vaccine era
– HiB vaccine against PRP capsule
• Polyribosyl Ribitol Phosphate (PRP)
• Allows for invasion

35
INFECTIOUS ENDOCARDITIS

36
 Infectious Endocarditis (IE)
• Infection of heart valves
• Vegetations → “globs” of bacteria,
platelets, fibrin
• Symptoms:
– Duke criteria:
• 2 major
• 1 major and 3 minor
• 5 minor

37
38
 Vascular phenomena
• Major arterial emboli
• Septic pulmonary
infarcts
• Mycotic aneurysm
– Infected aneurysm
• Intracranial hemorrhage
• Conjunctival
hemorrhage
• Janeway lesions
– Jane would never hurt Janeway lesions
anyone!

39
 Vascular phenomena

Splinter hemorrhage Conjunctival hemorrhage

40
Immunologic phenomena
• Glomerulonephritis
• Osler’s nodes – Ouch!
• Roth’s Spots
– Retinal hemorrhages
• Rheumatoid Factor

Osler’s nodes

41
Roth’s spots
• Duration
Classifying
• Culture
IE
– Negative: HACEK
– Acute
• Haemophilus,
• Fulminant illness in days Aggregatibacter,
to weeks Cardiobacterium,
• Most often Staph species Eikenella and Kingella
• Embolic events – Positive: Most common

– Subacute • Staph, Strep

• Valve type
• Illness lasts weeks to – Native valve
months – Prosthetic valve
• Most often Strep species • 16-30% of all cases

• Side of the heart

– Left-sided → Most common
– Right-sided → think IVDA

* Forms of endocarditis exist called marantic and Libman-Sacks which

are non-infectious 42
43
 USMLE Pearls
• IVDA – Staph aureus; Tricuspid valve
• Dental procedure – Viridans Strep (dextrans)
• Prosthetic valves – Staph epi (Coag neg Staph)
• Colon cancer – Strep gallolyticus (Strep bovis)
• Mitral valve prolapse – predisposes to IE
– Rheumatic heart disease if clinical scenario right
• Multiple areas of stroke/PE → shower emboli
• Glomerulonephritis → Immune-complex deposition
• Prosthetic valve → Dental prophylactic antibiotics

44
 Directed Learning Activity in
Infectious Diseases
Topic: Miscellaneous infections

1
 1. Lyme Disease
• Spirochete Borrelia burgdorferi
– First discovered as unique condition in Old Lyme, Connecticut
in 1975
– Causative bacterium discovered by Willy Burgdorfer
– Transmitted by the Ixodes tick, natural reservoir is the mouse,
deer preferred host
– Most bites are from ticks at nymph stage (poppy seed)
– Saliva of tick has anesthetic properties
– Adults ticks are discovered and removed more easily
• Tick must be attached for at least 36 hours
• To remove: Pinch with tweezers and lift straight up

2
Lyme disease

3
 Early localized infection (Days 3-30)
• Fever
• Headache
• Arthralgias
• Erythema Migrans (EM)
– Occurs 70-80% of time
– Pathognomonic of Lyme
– Appears on average at day 7,
worse at day 12
– Not painful
– Hot to the touch
• Can have atypical rash but not
classic (USMLE would give
classic)
• Serum testing will be negative
early
4
Early disseminated infection (weeks-
months after)
• Bell’s palsy
– Most common but can have
any palsy/neuropathy
• Lymphocytic meningitis
• Carditis
– Typically manifesting as AV
node block
– USMLE love this! Testing
cardiology (EKG) and ID at
the same time!
• Migratory arthalgias

5
 Late Lyme disease (months-years)
• “Chronic lyme disease”
• Large joint arthritis, headache, fatigue
• Lyme encephalopathy
– Mild cognitive decline

6
7
Diagnosis of Lyme
Do not check any labs in early
localized

ELISA – initial screening test

Western Blot – confirmatory test

Other tick-borne diseases:

Babesia – hemolytic anemia, Maltese
cross (intraerythrocytic inclusions)
Erlichiosis/Anaplasmosis – no rash,
neutropenia

American dog tick

(Dermacentor variabilis):
Rocky mountain Spotted Fever:
--- Southeastern US (despite name),
Fever, HA, rash on the wrists,
palms and soles 8
 2. Botulism
• Clostridium botulinum
– Gram +, spore-forming
– Bacilli found in soil
– Obligate anaerobe
– Heat-resistant
• Botulism neurotoxin (BoNT)
– Exotoxin – botulinum toxin
– Blocks release of acetylcholine presynaptically into
neuromuscular junction
– Irreversible binding
• Takes 3-6 months for new synapses to form (repeat BoTox)
– Paralysis is symmetric and descending
9
 Botulism
• Adult – Bacteria must be
ingested (preformed toxin)
– Poorly canned food
(vegetables)
• Infant – Toxin produced by
the gut. Consumption of
spores.
– Honey is classic

• Prevention of binding and

fusion of Ach synaptic
vesicles with plasma
membrane of NMJ
10
Botulism → inhibits Ach release
from presynaptic nerve terminal

11
 Botulism
• Adult
– Symptoms:
• Diplopia (ptosis), Dysphagia, Dysphonia, dry mouth, nausea
• Death from paralysis of diaphragm – respiratory failure
• Infant
– Symptoms:
• Constipation, weak cry, limpness (floppy baby), difficulty feeding
(dysphagia)
– Colonization of spores in gut.
– After infants have been eating regular food, the acid in the
gut inhibits bacterial growth and toxin formation
– Can consume honey > ~ 1 year old
• Wound
– Commonly from injection of contaminated black tar heroin
• Therapeutic uses
– Cerebral palsy, blepharospasm, achalasia, cosmetic 12
3. Tetanus
• Clostridium tetani
– Found in soil
– Enter system through cut,
puncture or wound
– A rusty nail provides the optimal
environment (large surface area)
for endospores to penetrate deep
into wound
• Affects only skeletal muscles
– Exotoxin - tetanospsmin
– Inhibits release of glycine and
gamma-aminobutyric acid
(GABA)
– These are inhibitory
neurotransmitters
13
 Tetanus
• Muscle spasms typically
begin in the jaw – trismus
(lockjaw)
• Wounds, bites, burns
– Likely need booster or tetanus
IVIG
– See next slide
• Routine Td booster given
every 10 years through
adulthood for waning
immunity
• Neonatal tetanus
– More common in developing Opisthotonus
world
– Vaccinate during pregnancy
• Transplacental IgG 14
15
 4. Gas Gangrene
• Clostridium perfringens
– Gram +, spore forming Anti-alpha toxin present

– Obligate anaerobe
– Forms alpha toxin
• Lecithinase – enzyme which
can destroy tissue
• Disrupts cellular membranes
by hydrolyzing phospholipids
• Nagler reaction
– Half of plate is egg yolk
– Alpha toxin destroys one
side of plate
– Other side has anti-alpha
toxin built into agar 16
Gas gangrene

17
 5. Aspergillosis
• Septate hyphae branch at acute
angles (45° angle)
• Invasive form - opportunistic
infection
– “Recent steroid use”
– Hemoptysis, upper resp infection
• Chronic Granulomatous disease
– “Fungus ball” or aspergilloma
• Circular, mobile mass within
preexisting cavitary lung lesions
(think TB)
18
 Aspergillus
• Asthma history
– Allergic bronchopulmonary aspergillosis
(ABPA)
• IgE mediated hypersensitivity reaction to
Aspergillus spores
• Causes bronchospasm and pneumonitis
• Produces aflotoxin
– Causes increased risk of hepatocellular
carcinoma

19
 Figure 1. Posteroanterior view of the chest film showed a round mass with surrounding
crescent air shadow in the upper left lung field (arrows), a finding compatible with fungus ball.

Kwang Kon Koh et al. Circulation. 2006;114:e551-e552

20
Copyright © American Heart Association, Inc. All rights reserved.
 6. Psittacosis
• “Parrot fever”
• Chlamydia psittaci
• Inhalation of dried bird feces
• High fevers, pneumonia, headache, nuchal
rigidity
• Diagnosis by PCR

21
 7. Leprosy
• Mycobacterium leprae
• Tuberculoid leprosy
– Confined to the skin and peripheral nerves
– Hypopigmented macules
– Cell-mediated immunity is intact
• Lepromatous leprosy
– “Leonine facies”
• Collapse of nasal bone
• Loss of eyebrows
– Failed cell-mediated immunity
• Lepromin skin test negative
– Skin lesions and peripheral nerve involvement more severe
– Can involve testes, respiratory tract, anterior chamber of eye
– Contagious (but not very virulent)
22
– Potential association with armadillo exposure in southwestern US
 Tuberculoid Leprosy
Tuberculoid Leprosy

Esfandbod M. N Engl J Med 2011;364:1657-1657.

 Leonine Facies: Lepromatous Leprosy
Lepromatous Leprosy

Salgado CG, Barreto JG. N Engl J Med 2012;366:1433-1433.

 8. Leptospirosis
• Spirochete, Leptospira.
• Headache, Fever,
conjunctivitis (red eye)
• Severe – Weil’s disease
– Liver failure (jaundice)
– Kidney failure
– Bleeding
• Contact with animal urine
(rodents)
• Exposure to sewer water
• High incidence in Hawaii
25
Directed Learning Activity in
Infectious Diseases

Topic: Sepsis and Septic

Shock

1
 Systemic Inflammatory Response Syndrome
(SIRS)
• Criteria:
– Body temp <36°C or >38°C (100.4°F)
– HR >90 bpm
– Tachypnea > 20 breaths/min or PaCO2 <32 (normal 40)
– WBC count <4K or >12K or >10% bands (left shift)
• Sepsis definition (old, but may show up on USMLE)
– 2 or more SIRS criteria with presence of infection
• NEJM (May, 2015) – this criteria missed 1 in 8 cases of
severe sepsis (Elderly - fever response, BB therapy, etc)
• Led to the “3rd international consensus definitions for
sepsis and septic shock” – JAMA Feb 2016

2
Sepsis-related Organ Failure Assessment score
(SOFA)

3
 Quick SOFA (qSOFA)
• While calculating a SOFA score provides
significant mortality data, it is
burdensome to determine the criteria for
sepsis
• qSOFA score:
–New or worsened altered mentation
(Neuro)
–RR >22 (Respiratory)
–Systolic BP <100 (Cardiovascular)
• 2/3 criteria of the qSOFA = sepsis 4
 Septic Shock
• Sepsis with hypotension • Type of distributive shock
• Septic shock definition: – Endothelial cells
• Become less sensitive to
– Requires vasopressors to
vasoconstrictive agents
maintain mean arterial
• Become leaky
pressure >65mm Hg
• Cause overexpression of NO
despite adequate
volume resuscitation – Increased cardiac output
– Lactic acid >2mmol/L

*Procalcitonin – Typically elevated by >2 times in sepsis. Not elevated in viral.

Precursor to calcitonin released when bacterial toxin exposure. Downregulated
in viral infections. 5
Physical exam findings: Septic Shock
• “Warm shock” - early
– Bounding pulses, tachycardia
– Altered mental status
– High CO2 and decreased systemic vascular
resistance (SVR)
– Decreased urine output
– Hyperglycemia
• “Cold shock” – late
– Cyanosis
– Cold, clammy skin
– Leads to multi-organ dysfunction (MODS)

6
 Pathophysiology of Gram neg Shock
• Gram negative
– Lipopolysaccharide (LPS)
• Endotoxin
• Binds to CD14 on WBC
– Intracellular signaling through
toll-like receptor 4 (TLR-4)
• Recognizes Lipid A of LPS
– The subsequent cytokine and
inflammatory response
causes:
• Systemic vasodilation
• Decreased myocardial
contractility
• Widespread endothelial
injury
– DIC
– Inflammatory response is
mediated by TNF-α
7
Pathophysiology of Gram neg Shock

8
 Pathophysiology of Gram pos Shock
• Immune response to
lipoteichoic acid
• Superantigens (SAgs)
– S. aureus
• Staph enterotoxins (A-E)
• Toxic shock syndrome
toxin (TSST-1)
• S. pyogenes
• Strep pyrogenic exotoxin
A and C (SPEA and SPEC)
9
 Gram positive Superantigens
–Bypass antigen presenting cells (APC) by
binding directly to major
histocompatability complex-II (MHC-II)
–Also bind to CD28 which activates T-cell
response
–Leads to massive induction of cytokines:
• TNF-α
• Interferon-ϒ
• IL-2
10
 Neonatal sepsis and shock
• Neonate – first 28 days after birth
• May not mount sufficient immune response
to have “typical symptoms.”
• Must have very high suspicion if fever
– Blood cultures
– Urine cultures
– Urinalysis
– CBC
– Lumbar Puncture
• Can also present with jaundice
11
 Treatment of Septic Shock
• Mortality = 40% even with optimal care
• Early goal-directed therapy
– ISOTONIC, Crystaloid fluids
• 0.9% NaCl or Lactated Ringers
• Given in boluses
– Antibiotics
– Securing airway and avoiding hypoxemia
– Targets:
• MAP >65mm Hg
• >0.5 ml/kg/hr of urine output
• Pressors
– Norepinephrine – 1st line
• Immediately remove possible infected devices
– Catheters or lines
• Glucocorticoids? (Stress-dose steroids)
– Maybe, but too controversial for USMLE 12
Directed Learning Activity in
Infectious Diseases
Topic: Viral Hepatitis

1
 Hepatitis
• Inflammation of the liver
– Can be caused by:
• Viral hepatitis: A, B, C, D, E
• Tylenol and other meds
• Alcohol
• Autoimmune, Hemochromatosis, HELLP, NASH, Wilson’s,
malignancy, and many others
– Marked by elevation of transaminases (ALT, AST)
• Important to distinguish between:
– Hepatocellular damage (transaminases only, mild
elevation of others)
– Cholestatic damage (AST, ALT- mild elevation;
Alkalline phosphatase, and bilirubin much higher)
– Utility of GGT in elevated alkaline phosphatase?
2
 Symptoms of hepatitis
• Fever • Normal bilirubin <1.0
• Headache, malaise • Jaundice cannot be
• Jaundice (icterus) = detected unless >2
bilirubin elevation • First place it shows up:
– Conjunctiva
– Under the tongue
• Dark urine
• Pale stools
• Hepatomegaly

3
 Hepatitis B: Features
• Double-stranded DNA, hepadnavirus
• Sexual, Parental (IVDA), maternal-fetal
transmission
• Hepatocellular CA risk
– Acts as an oncogene
• Acute and chronic phases
– Acute phase
• The sicker the patient, the more likely to clear virus
spontaneously
– Asymptomatic in most
• Vaccination – 95% successful
– Series starting at first day of life.
– Anti-HBs positive only
4
 Hepatitis B: Features
• Associated with other weird
conditions
– Polyarteritis nodosa, MPGN,
Cryoglobulinemia
• Two phases:
– Proliferative
• Host CD8 cells destroy
hepatocytes (virus not cytotoxic)
– Integrative
• HBV integrated into host genome
• Only hepatitis virus to have DNA-
dependent DNA polymerase
• Double-stranded DNA →
RNA template→ Double-
stranded progeny
– Reverse transcription like HIV
5
(DNA to RNA)
 Hepatitis B serology
• Hepatitis B surface antigen (HBsAg)
– First to appear in serum
– Often used as screening test
– Observed in: Acute HBV, Chronic HBV
• Hepatitis B surface antibody (Anti-HBs)
– Successfully responded to vaccine or recovered from
acute hepatitis B in the past
– Observed in: Immunized patients, Recovery
• Hepatitis B core antigen (HBcAg)
– Not circulated in the blood and cannot be checked
• Hepatitis B core antibody (Anti-HBc IgM)
– Immune response to the inner core of the virus
– IgM form observed in: Acute HBV and window
phase
– IgG form observed in: Chronic HBV and recovery 6
 Hepatitis B serology
• Hepatitis B e Antigen (HBeAg)
– Associated with high rates of viral replication
– Observed in: Acute HBV, Chronic HBV with
high infectivity
• Hepatitis B e Antibody (Anti-HBe)
– Associated with decreased rates of viral
replication
– Remains positive for several years after acute
HBV infection
– Observed in: Window phase, Chronic HBV
with low infectivity, and recovery
7
Hepatitis B serology

8
Hepatitis B serology: Interpretations

9
 Hepatitis C
• RNA, positive stranded, flavivirus
• 10-30% of those affected will develop
cirrhosis
– 1-5% of these patient will develop HCC
• Transmitted mostly parentally (blood, IVDA)
– Rarely transmitted via sexual contact (Hep B)
• Chronic. Acute Hep C is rarely symptomatic
• Screening test: Anti-HCV Ab
• Diagnosis: HCV RNA viral load
• Lacks 3’ → 5’ exonuclease = no proofreading
– Multiple genetic mutations of Hep C 10
 Hepatitis C treatment
• Pivotal, game-changing new
medications
• RNA-dependent polymerase
inhibitors
– “uvir’s”
– Sofosbuvir, dasabuvir
– Inhibit enzymes needed for
Hep C RNA synthesis
• If you have an old book,
cross out interferon-based
therapies!

11
 Hepatitis A
• Hepatitis A
– RNA, picornavirus, + single stranded
– Fecal-oral transmission
• Overcrowding, poor sanitation – risks
• Raw or steamed shellfish (within United States)
– No hepatocellular carcinoma risk (HCC)
– IgM antibody to HAV – active
• Acute only. Self resolves in 3-6 weeks. Not chronic.
• Vaccinate international travelers.

12
• Hepatitis D
– RNA delta virus, defective
• No independent survival Hepatitis D
without B
• Requires Hep B Surface Ag
– Coats Hep D and allows
hepatocyte entry

– Parenteral (IVDA in USA), sexual

or maternal-fetal transmission
– Has risk of HCC
– Dependent upon Hep B presence for
infection
• Coinfection – simultaneous
infection
• Superinfection –
superimposed on chronic Hep
B
– 20% fatality rate. Highest of all
Hepatitis. 13
 Hepatitis E
• Hepatitis E
– Unenveloped, single-stranded RNA
– Fecal-oral transmission, waterborne epidemics
• Typically doesn’t occur in the United States
• Check HEV Ag or RNA in the stool first
– Similar clinically to HAV
– Susceptible individuals:
• Expectant mothers – high mortality
• Immunosuppression after organ transplant.

14
 Hepatitis: Comparison
HAV HBV HCV HDV HEV
Family Picornavirus Hepadnavirus Flavivirus Defective Hepevirus
Characteristics Naked RNA Enveloped DNA Enveloped RNA Enveloped RNA Naked RNA
(circular)
Disease Mild acute Acute Acute Co-infection or Mild acute
No chronic Chronic (~20%) Chronic (70%) superinfection No chronic
Cirrhosis Cirrhosis (worse) with
Carcinoma Carcinoma HBV

Transmission Fecal-oral Parenteral or Parenteral or Parenteral or Fecal-oral

sex sex sex
Mortality <0.5% 1-2% 0.5-1% High 1-2% or 25% if
pregnant 3rd
trimester
Incubation period Short (3 wks) Long (3 mo) Short (6-12 wks) -- --
Carriers No Yes Yes Yes No
No (in clinical
Vaccine available Yes No (in clinical No
Yes trials)
trials)

Remember! A is Acute only B is Bad (many C is Chronic D is Dependent E is Enteric in

diseases, high (leading cause (needs HBV to the far East
mortality), Big for liver infect -- HBsAg (seen in Asia,
like a "great transplant) must coat not U.S.)
dane" HDAg)
15
Hepatitis: Comparison

16
Clicker question-Hepatitis

17
A 24-year old medical student from St. George's
University presents to her family physician for routine
blood work. Based on her extensive traveling history
and her humanitarian work in rural Haiti, her physician
checks a viral hepatitis profile. The results are:
HBsAg – Negative; HB IgM core – Negative;
HBeAg – Negative; Anti-HBs - Positive
The above report most likely mean?

A. She has chronic Hepatitis B

B. She has chronic Hepatitis B with
immunity
C. She had vaccination against Hepatitis B
D. She has acute Hepatitis B 0% 0% 0% 0%

A. B. C. 18
D.
 Notes on Anaerobic Infections

Following anaerobic pathogens will be discussed:

Clostridia: Anaerobic spore forming gram positive rods that include C. botulinum, C.
tetani, C. perfringens and C. difficile.
Bacteroides fragilis: Important gram-negative anaerobe in gut that produces beta
lactamase.
Finegoldia magna (formerly Peptostreptococcus): Important gram-positive anaerobic
coccus in respiratory and intra-abdominal and pelvic infection, complicated skin and
soft tissue infection.

Clostridium perfringens:

A soil organism.
Produce gas gangrene and myonecrosis usually in devitalized tissue (vascular
compromise). Myonecrosis and gas gangrene associated with invasion of infection
into normal muscle and tissue.
Crush injury, knife or gunshot wounds.
Ischemic limbs result in anaerobic cellulitis without destruction or invasion of normal
tissue.
C. septicum causes similar infection in normal tissue without injury but host often
immunocompromised or has underlying bowel cancer.
Pathogenesis: Spores are introduced into deep tissue at time of injury. If devitalized,
anaerobic environment promotes growth of organism and myonecrosis or gas
gangrene occurs within 24 to 36 hours. Alpha toxin released by the pathogens has
sphyngomyelinase and phospholipase C, both have a cytolysin activity. White cells
are absent from infected tissue. Shock is secondary to effects of alpha and theta
toxins (Decreased cardiac output by alpha toxin. Decreased systemic vascular
resistance by theta toxin).
Signs and symptoms: Acute onset of severe pain at site of injury. Skin initially pale
but then becomes bronzed then red or purple. Bullae may form. Followed by
tachycardia, shock, multiorgan failure. Bacteremia occurs in 15% and is associated
with intravascular hemolysis.
Diagnosis by high index of suspicion: Gas palpable in tissue (crepitus), also seen on
CT or MRI.
Surgical exploration essential for removal all dead tissue. Infected muscle does not
bleed.
Therapy: penicillin + clindamycin + surgery.
Mortality rate 20%.

1
Clostridium botulinum:

Causes botulism, a toxin mediated food borne illness from contaminated food.
Can also colonize newborn GI tract, wounds and adult GI tract and produce toxin.
Pathogenesis: Botulinum toxin causes flaccid paralysis by binding to presynaptic
neurons and irreversibly disrupting acetylcholine release. One gram of aerosolized
botulinum toxin could kill 1.5 million people.
Epidemiology: 72% of cases occur in newborns, 25% are food borne, 3% wound
related. 110 cases/year in USA. May be associated with IVDU and cocaine inhalation.
Home-made canning and food storage if undercooked during preparation.
Spores can survive 100o C at 1 atmosphere for 5 hours but die at 120 o C in 5 minutes
(pressure cooking).
Symptoms: Bilateral cranial neuropathies with descending symmetrical motor
weakness. No fever, sensory deficits, loss of consciousness, tachycardia or
hypotension.
Diagnosis: High index of suspicion based on history and physical exam. Isolation of
botulinum spores from stools in infants. Serum analysis for toxin in bioassay in mice.
EMG with characteristic findings.
Therapy: Supportive care including ventilation, Antitoxin administration, Hospitalization
required for 1 to 3 months.

Clostridium tetani:

Soil organism causing tetanus.

Results from contamination of wounds with spores.
Pathogenesis: Growth of organism releases toxin tetanospasmin, a metalloproteinase
that causes muscle spasms (trismus or lock jaw). Toxin binds irreversibly to receptors in
spinal cord and brain stem resulting in disinhibition of motor and autonomic impulses,
resulting in spasm and autonomic instability.
Epidemiology: Almost eliminated from developed world by vaccine and proper wound
care. Still problem in developing world.
Risk factors: Penetrating injury, Infection with other organisms, Devitalized tissue,
Foreign body, Ischemic tissue.
Incubation usually 1 to 8 days post injury.
Clinical presentation: Stiff neck, Rhisus sardonicus (grimace), Opisthotonus, Board like
rigid abdomen, Dysphagia, Generalized spasms with apneic spells.
Resolution requires growth of new axon terminals.
Treatment: Surgical debridement and antibiotic to decrease toxin production. Tetanus
immune globulin to neutralize unbound toxin. Supportive care to manage muscle
spasms and autonomic instability.
Prognosis: Mortality in developing world 8 to 50%. Shorter incubation time has worse
prognosis (more toxin).

2
 Notes on Infectious Diarrhea

What is Diarrhea?

• Excretion of more than 200 grams of stool / 24 hours with increased loss of
water and electrolytes.

• 3 or more loose or watery stools per day.

• Either due to increased water excretion or decreased water absorption.
• Acute diarrhea lasts less than 14 days and includes most infectious causes.
• Chronic diarrhea lasts more than 14 days and includes infectious and
noninfectious causes.

How Organisms Cause Diarrhea (1-5):

1. Non-inflammatory diarrhea due to Enterotoxin production that causes

intestinal cell dysfunction:
Non-inflammatory watery diarrhea.
Patient usually afebrile.
Dehydration particularly in infants and small children (rotavirus most common
cause world-wide).
Oral rehydration and anti-motility agents usually suffice.

Classical disease caused by enterotoxin production is cholera.

Cholera (Vibrio cholerae):
Severe watery diarrhea, epidemic, related to contaminated water supply
(developing world).
Caused by serotypes O1 and O139.
Curved gram-negative rod grown on selective media in the lab.
Infectious dose 104 to 1011 depending on stomach acidity, presence of food bolus.
Attachment and colonization of small bowel epithelium.
Cholera toxin produces persistent activation of adenylate cyclase. Increased
cAMP levels result in increased chloride excretion and decreased sodium
absorption and massive fluid loss. Enterotoxigenic E. coli “ETEC” (common
cause of travelers’ diarrhea) has same toxin. Dukoral oral vaccine provides
coverage against O1 strain and enterotoxigenic E. coli. Will prevent less than
7% of cases of travelers’ diarrhea.

Other organisms working by enterotoxins are:

S. aureus, Bacillus cereus: Food poisoning with rapid (1 to 6 hours to a day) onset of
vomiting due to preformed heat stabile toxin in food. Diarrhea and or fever occur in a
minority of patients with S. aureus enterotoxin. B. cereus also has a diarrheal syndrome
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- onset at 8 to 16 hours post ingestion and a Heat labile toxin.

2. Non-inflammatory diarrhea without an enterotoxin include:

• Viral: Rotavirus, Norwalk virus (nursing home outbreaks).

• Parasites: Giardia lamblia, Cryptosporidium, Cyclospora, Isospora belli.
3. By Cytotoxin Production and cell destruction:
Part of the causes of Inflammatory diarrhea.
May range from mild to severe diarrhea to frank dysentery.
Cramping, fever, bloody stools frequent.
Anti-motility agents contraindicated.
Antibiotics may or may not be indicated depending on organism and patient factors.

Examples of organisms that cause diarrhea by Cytotoxin Production and cell destruction
are: Clostridium difficle and E. coli O157:H7 (enterohemorrhagic E. coli “EHEC”).

Clostridium difficile diarrhea:

Anaerobic organism, gram positive spore former.
Associated with prior antibiotic use and usually hospital admission.
Picked up as spores in the environment. Noninvasive disease caused by intraluminal
toxin producing organisms.
Full gamut of self-limiting diarrhea that resolves with discontinuation of antibiotic, to
toxic megacolon with need for colectomy or to death.
Diagnosed by detecting C. difficile toxin in stool.
Treatment: oral metronidazole or oral vancomycin 10 -14 days. 10% to 25% relapse
rates with either treatment. Some may need long term vancomycin taper or “stool
transplant”.

E. coli O157:H7 (enterohemorrhagic E. coli “EHEC”) diarrhea:

Contaminated water or foods (apple cider, ground beef, food preparation surfaces).
Same toxin as Shigella (No cellular invasion).
May be complicated by hemolytic uremic syndrome (HUS).
Increased frequency of HUS with antibiotic therapy in children.

4. Inflammatory diarrheas caused by invasion of colonic cells:

Invasion of colonic cells by the pathogens produce inflammatory diarrhea.
Organisms include Salmonella enteritidis, Campylobacter jejuni, Shigella, Entamoeba
histolytica.
Salmonella enteritidis and Campylobacter jejuni are often associated with poultry and
have 2 – 3-day incubation. With Salmonella, the risk for dissemination to sites outside
GI tract increase with i) Age less than 1 or age over 50, ii) Presence of endovascular or
osseous prosthetic devices, iii) Immunosuppression with AIDS or organ transplantation
and iv) Sickle cell disease.
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Patients in these groups should receive antibiotic therapy.

Shigellosis: Gram negative rod in the Enterobacteriaceae family. Four species: S.

dysenteriae, S. flexneri, S. boydii, S. sonnei.
Caused by person to person spread or contaminated food or water.
Infectious dose very low. 101 to 102 organisms can cause disease.
Does not require incubation in food stuffs for transmission. Can occur directly from
contaminated hands.
Causes disease by both invasion and toxin production. Invades colonic cells then
produces cytotoxin (shigatoxin) that results in cell death (cleaves host cell RNA),
inflammation and bloody diarrhea.
Symptoms: Incubation 1 – 7 days, Uncommon in developed world, Fever and crampy
abdominal pain, Usually self-limited to 6 – 7-day course. Antibiotic of choice if used
depends on where disease contracted (North America Trimethoprim-sulfamethoxazole
(TMP-SMX) or quinolone ok. Outside of North America quinolone preferred).

Entamoeba histolytica (parasite):

Produces amoebic dysentery - Bloody diarrhea with fever.
Microscopically indistinct from E. dispar (non-pathogenic amoeba). Produces antibody
response while E. dispar does not.
Common in developing world but found world-wide.
Contaminated water or fecal/oral transmission. Ingestion of one cyst can cause disease.
Can occur as an STI depending on sexual practices. (common cause among some men
who have sex with men).
Complication: Organism can spread to liver and cause amoebic abscess.

Enteric Fever:
Causes: Salmonella typhi, Salmonella paratyphi, Yersinia enterocolitica, Vibrio
vulnificus, Campylobacter fetus.
Highly invasive organisms.
Penetrate distal small bowel and cause mesenteric adenitis, bacteremia, sepsis.
Diarrhea often a late sign with initial presentation of fever and abdominal pain,
constipation.
CBC, blood cultures, admission to hospital and antibiotics are indicated.

5. Diarrhea by viruses:
The major pathogens are Norwalk virus, Rota virus and other enteroviruses.
Norwalk virus:
Member of the Calcivirus family (Norovirus). Single stranded RNA genome.
Cause of up to 7% of admissions for gastroenteritis in USA.
Transmission - Fecal / oral person to person, airborne from emesis, food and water
contamination, contaminated surfaces, fomites. Shell fish (bottom feeders) implicated.
Secondary attack rates are high - Institutional outbreaks, cruise ships, restaurants. One
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of the common causes of traveler’s diarrhea.
Incubation is 24 to 48 hours. Symptoms last 12 to 60 hours. More prolonged and severe
in immune compromised.
Vomiting occurs in over 50%, fever and headache, malaise also common.
Diagnosis by PCR on stool.
Treatment is supportive.

Rotavirus:
Single most common cause of gastroenteritis in children under the age of 2.
Spectrum of illness ranging from asymptomatic to death. Vomiting, fever, non-bloody
diarrhea. May be accompanied by respiratory symptoms. Duration up to 8 days. Cases
in adults usually mild and occur with infected children in home.
Complications: Necrotizing enterocolitis in neonates, Intussusception (telescoping of
bowel on itself), Seizures and encephalopathy and Prolonged gastroenteritis.
Diagnosis is by PCR or immune based assays on stool.
Treatment is supportive (fluids).
Prevention: Rotavirus vaccine per specific schedules to decrease risk of
intussusception.

Other Enteroviruses causing diarrhea:

Includes polioviruses, coxsackieviruses, echoviruses and enteroviruses.
All members of picornavirus family (small RNA).
Enterically transmitted from person to person.
Transmission year round but higher in summer and fall in temperate climates.
Secondary attack rates up to 50%. Children in diapers efficient transmitters.
Incubation 3 to 5 days often with low grade fever. Polio associated with second fever
and onset paralysis 9 to 12 days after exposure. Initial replication in pharynx and
terminal ileum with viremia and spread to lymphoid tissue. Second viremia with spread
to CNS tissue.
Wide spectrum of diseases: Polioviruses cause paralytic polio (motor nuclei anterior
horn cells). Enterovirus 71 also causes paralytic disease. Enterovirus D68 Respiratory
illness with occasional acute motor neuron disease. Exanthems, “hand, foot and mouth
disease”, aseptic (viral) meningitis from many enteroviruses. Myocarditis and
pleurodynia from group B coxsackie viruses. Herpangina (vesicular enanthem soft
palate, tonsillar fossae in children 2 to 10) is possible with coxsackie A virus.
Diagnosis: Serology, viral isolation from stool or PCR of stool.
Treatment is supportive.
Prevention - Polio vaccine.

Approach to the Patient with Infectious Diarrhea:

History elements:
Duration of symptoms,
Exposure history (foods, preparation of same, water source, banquets, restaurants, pets
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etc.),
Travel history,
Other people with similar illness, Prior antibiotic use, hospitalization (think C. difficile),
Systemic symptoms (fever, dehydration, comorbidities),
Sources of Salmonella Outbreaks.

Diagnosis is by:
Stool culture for bacteria in following situations: Part of an outbreak situation, Food
handler, Severe acute disease, Underlying comorbidities, Returned traveler with
abdominal pain, fever or bloody diarrhea.
Stool examination for ova and parasites.

Treatment of Acute Diarrhea:

General guidelines: Rehydration and Alteration of diet.
Rehydration via oral route with water, salt and sugar solution: ½ teaspoon salt, ½
teaspoon baking soda, 4 tablespoons sugar to 1 liter of water.
Alteration of diet: Avoid milk products after viral gastroenteritis. Low roughage after
enteric fever.
Infectious Diarrhea: Antimicrobial Therapy is indicated.
General Principles - Most acute watery diarrhea is self-limiting and will resolve within a
week on its own and does not require antibiotics. Patients with acute diarrhea with the
following symptoms may require non pseudomonal quinolone for 3 – 5 days: Fever,
bloody diarrhea, fecal leukocytes, Diarrhea for more than a week, More than 8 stools a
day, Dehydration, Need to admit to hospital and Immunocompromised host.
Antimotility agents for watery diarrhea without fever. Never use for C. difficile or
dysentery (toxic megacolon). Do not use antibiotics for E. coli O157-H7 disease.

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 INFECTIOUS DISEASES SUPPLEMENT
SUPPLEMENT-1
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BACTERIOLOGY
Comparison of the thick cell wall of Gram
Gram-positive
positive bacteria with the comparatively
thin cell wall of Gram-negative
negative bacteria. Note the complexity of the Gram-negative
Gram
cell envelope (outer membrane, its hydrophobic lipoprotein anchor; periplasmic
space)

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Classification of clinically significant bacteria by genus

2
Differentiating aerobic Gram positive cocci

3
Differentiating aerobic Gram negative cocci

Differentiating aerobic Gram positive bacilli

4
Differentiating aerobic Gram negative bacilli

5
Differentiating aerobic Gram negative coccobacilli (including obligate
intracellular)

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Differentiating anaerobic bacteria