MID Test II Viruses and TB Kit Delgado [email protected]

Herpesviruses and Smallpox General Stuff

Common Features of Herpesviruses Replicative Cycle •Morphology 1. Enveloped viral particle invades clss by utilizing receptors on the cell surface (HSV binds to members of Ig, TNF family and • Basic mode of replication VSV to mannose-6 phosphate and heparan sulfate) • Primary followed by latency 2. Glycoproteins (B, D, H, I) on virion – enable attachment of virus to cell (also used by the • Ubiquitous 3. Virus uncoats, DNA goes to nucleus and replicates • Ability to cause recurrent (reactivation of latent virus), reinfections • Transcription of viral genome and protein synthesis (cascade of gene expression), essential and luxury (with a new virus), persistent infections – 1. immediate early (IE): regulation of gene expression, DNA binding (chronic low grade virus multiplication) – 2. early (E): more transcription factors, enzymes, DNA polymerase immortalizing infections (EBV only). The other form of infection is latent, and there is little viral – 3. late (L): structural proteins gene expression, so the host cell survives. 4. Nuclecaspids are formed there, which extrude into the perinuclear space with an early envelope 5. Fuses with the RER naked nuclecaspid goes into cytosol 6. Nucleocaspid become enveloped by tegument proteins and glycoprotiens in the trans Golgi Network (TGN) 8 Human Herpesviruses, 3 categories 7. Enveloped virion incorporated into endosomes (HSV resists the acidic environment) released extracellularly • Alpha: short reproductive cycle,variable host range, latent in sensory neurons 8. virus in cell to cell spread). They are components of a new HSV2 vaccine. – Herpes simplex virus (HSV 1, 2) 9. Lytic infection cell death – Varicella- zoster virus (VZV) 10. Latency occurs when the cascade is interrupted 11. Latent infection occurs in sensory neurons • Beta: long reproductive cycle, narrow host range, latent in lymphoid cells & others – Latency associated transcripts (LATS) (salivary glands, kidney) – Minimal transcription of DNA, no translation – Cytomegalovirus (CMV) – HHV6, HHV 7 Because of cell cell spread, CMI is crucial in host response; Ab’s usually inefective (except for VSV infection. . • Gamma: narrow host range; latent in lymphoid cells, associated with tumors Herpesviruses can also spread as a free enveloped particle. – Epstein Barr Virus (EBV) – Kaposi Sarcoma Virus (KSH, HHV8) • Encode targets for antiviral therapy – Thymidine kinase (TK), DNA polymerase

Clinical Presentation Pathogenesis Predisposing Factors/ Likely Definitive Diagnosis Complications Treatment / Prevention Epidemiology Pathogens Genital Ulcers: Transmitted via sexual Virus can be shed by symptomatic Herpes Simplex Clinical: Associated with Acyclovir (ACV), famicylovirm, contact and asymptomatic individuals Virus 2 mostly, ulcerate leaving a primary disease: valacylovir Multiple, bilateral grouped umbilicated Invades local cell causes HSV-1 rarely shaggy ulcer Aseptic meningitis vesicles which become postular and local inflammatory Most common STD in higher (from oral lymph node Transverse coalece into large PAINFUL ulcers response socioeconomic groups genital involvement myelitis (“shaggy”) Spreads to other cells locally transmission) Sacral severe painful vulvovaginits or balantis Moves aliong sensory nervers Microscopic: radiculopathy with or without urthritis (Schawn cells) to ganglia Wright-stained or Can be pain, itching, dysuria with or without Becomes latent, reactivates Tzank stained: transmitted to urethral discharge see newborn tender inguinal lymphadenopathy multinucleated resulting in giant cell in serious organ In 1/3 of patients, symptomatic complaints: Herpes damage headache, , malaise, and myalgia (cytopathic involvement)

Serology: Rise in anitbody titers

Rule out , chancroid, LGV.

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Baby with: Saliva transmission Usually transmitted by saliva HSV-I May lead to poor No antiviral therapy Ulcers in oral mucosa nutrition and (gingivostomatatitis) Examiners should wear gloves, dehydration of a Swollen friable gums highly infectious at this point few days Secondary infection on the thumb from sucking on it (whitlow of the finger) Baby may have fever or be irratable Although infection looks severe, it’s self limited

Corneal ucers Mouth Hand eye May lead to Lesions of the conjunctival epithelium transmission scarring or (karatitis or keratoconjunctivitis) blindness

Severe infection of the skin Person with underlying eczema

Headache Focal Encephalitis Primary or recurrent HSV- 1 . Differential Treat with ACV if suspect disease; Fever diagnosis: TB prognosis better in children than Personality change, Most common form of focal meningitis, arbovirus, adults; early therapy is best Focal seizures, ncephalitis in USA - about 1000 enterovirus, flavivirus, Skin lesions may be present (not helpful cases of encephalitis annually mycoplasma, tumor, for diagnosis) toxoplasmosis, aneurysm Test findings: Abnormal EEG, CT, MR Diagnosis: CSF culture is usually negative, but PCR is often positive for HSV

Newborn with: Perinatal HSV Usually HSV-2; Immunofluorescence Skin, mucous • Treat all newborn infants with • Usually the mother is HSV-1 in very culture, membrane possible HSV • Skin, eye, mucous membrane (40%) Perinatal HSV is usually due to asymptomatic cases PCR infection • Recurrent skin vesicles are – Skin vesicles Type 2 virus Antibody titers are untreated associated with a poorer prognosis – Good prognosis with early treatment • 95% neonatal, 5% congenital • Attack rate >10 times higher in not useful disseminated – may re- treat with ACV Untreated 75% develop disseminated maternal primary infection – May give 6 weeks of oral ACV infection infection than recurrence; attack rate about 50% CNS Infection (35%) – Fever, lethargy, seizures, abnormal CSF 1600 cases annually – 50% mortality; major sequelae if survive

• Disseminated disease (25%) Hepatosplenomegaly, jaundice, hepatitis, – 2/3 develop skin vesicles – 70% mortality

Fever and malaise (prodromal symptoms) In the body VZV spreads • Varicella is likely to be severe Varicella Zoster • Culture, DFA, PCR, After primary Treatment Papulovesicular rash appears in crops on from cell-to-cell in the Immunocompromised Virus (VZV) cytology on skin infection: the trunk and then spreads to head (lack of TH1 response) rash bacterial ACV (but not as useful as for HSV and extremities (centripiltal) Varicella (Chickepox) –Can distinguish the superinfectio infections) Papules vesicles pustules crusts • VZV respiratory mucosa – Prevent or modify with pre- Oka virus from wild n, Itching blood (viremia) T cells (long formed antibodies just after type virus encephalitis, famicylovirm, valacylovir for Mild in chilren, severe in adults incubation period – 2 weeks exposure pneumonia, elderly patients with zoster from cell-cell spread) • Antibody titers, IgG congenital Years later.... – Slow spread prevents host – Treat most patients immediately –Acute serum, early in syndrome, Prevention: from being with illness Reye’s syndrome. Live, attenuated, infectious virus Painful vesicles along the course of a overwhelmed before the acyclovir –Convalescent serum, (Oka strain) sensory nerve of the head or trunk immune response • The frequency of zoster is 10- 14 days after Contraindications: pregnancy, Pain can last for weeks develops increased onset Post-herpetic immunocompromised, allergy to Postzoster neuralgia can be debilitating – Probably related to low CMI nerualgia (elderly vaccine Zoster (Shingles) response • Antibody titers, IgM and components • Latent infection in dorsal root – Likely to suffer post- herpetic –False positives and immunocompromi ganglia (DRG) neuralgia false negatives can be sed) Major complaint afterwards: mild • 6 of 68 genes (also RNA and (PHN) (also elderly) a problem rash in 5% proteins) • This vaccine is extremely safe 80% expressed during latency Rule out smallpox completely protected; 20% partial • Proteins of regulatory genes immunity. Little evidence for waning are expressed in immunity. 3

cell cytoplasm, not nucleus • Suggests regulatory proteins are blocked from normal action, leading to inhibition of cascade of gene expression preventing lytic infection from occurring (latency) • Latency is established when cell- free VZV in skin vesicles invades neurons

12-14 days afer exposure: Bioterrorist Agent (currently Smallpox virus Rule out VCV Tx Resp mucosa LN viremia eradicated around the world) (incubation similar, No known treatment Exanthema (asymptomatic) secondary difference is Strict quarantine Muculpapular rash (face mucosa trunk viremia (rash) Transmission prodome where trunks and legs) vesicles Infectious via aerosol (droplet rash starts pustules (can become confluent on face) nuclei or aerosol) (smallpox = Prev Severe looking rash gets progressively Rapid person person centrifugal), Live virus vaccine, worse Most at risk = household contacts erythmema Admin: poke with a needle (old Secondary spread 1-10 new mutliforme school) stab skin 3X for cases Swab of vesicular unvaccinated, 15X for previously High rates of transmission in fluid PCR assay at vaccinated; draw blood hospitals CDC See vacule pustule scab (if this less contagious than doesn’t happen, didn’t work) /varicella Lasts for a while, best for three years Patients not contagious until rash afterwards, but steadily decline begins Can see normal extra reactions (extra lesions, LN swelling etc) Contra: immunodeficiency, skin Immunity diseases (exema, or atopi Worldwide immunity waned dermatitis), preg women, cardiac 30% mortality problems Vaccine after exposure still Adverse event: infecting your eye prevents illness by touching; generalized vaccinia Severe: someone with excema given vaccine, or progressive vaccinia in immunocompromised patient Old vaccine can be diluted Tx for complications Ab for vaccinia First responders ought to be pre- vaccinated So far complication rate has been low with pre-screening New complication myopericarditis

Healthy Adult Host: – immune evasion Congenital Cytomegalovirus • Distinguish between Treatment of CMV • usually subclinical • Down regulation of MHC Most common congenital viral (CMV) congenital and • Ganciclovir Mononucleosis- like syndrome occurs but class I expression infection in US • Largest of the perinatal – Phosphorylation by viral enzymes is rare to reduce effectiveness of • Risk to the infant is highest in first herpesviruses – In congenital urine is causes inhibition of viral DNA cytotoxic T cells trimester (13 weeks) maternal culture +for CMV in polymerase (related to acyclovir); Immunocompromised: • Host defense: cellular not infection first 3 weeks of toxicity: bone marrow suppression Fever humoral immunity - primary maternal infection poses life • Foscarnet Pneumonia • Latency in bone marrow greatest risk – Inhibits viral DNA polymerase; Retinitis precursors of - the fetus is not always protected Diagnosis of CMV renal, metabolic toxicity Colitis monocytic peripheral blood when an “immune” mother • Histology: has • Cidofovir Lymphadenopathy cells is re-infected with a different strain limitations (not – Inhibits viral DNA polymerase Rash – Differentiation of monocytes of CMV specific) • Very toxic (renal, uric acid increase) Encephalitis into macrophages – Basophilic inclusion Pre- emptive approach Neutropenia, etc. due to antigenic stimulation bodies Identify infection before the illness reactivates CMV Transmission – H&E, Pap staining Treatment used mostly for • Fetal (congenital) infections: can be • Adverse effects on •Close personal contact • Cell culture immunocompromised severe ransplantation – Sexual, day care, saliva, tears, – Cytopathic effect, patients - 40,000 annual cases (1% of all infants) urine immunofluorescence - 3,000 symptomatic at birth (jaundice, – Virus is not usually airborne • Serology: acute and Control of CMV petechiae, • Cell-associated virus, no skin convalescent antibody • Hand washing (eg, after diapering) microcephaly, prematurity) lesions titers are of limited • Condoms, abstinence - 8,000 with sequelae (deafness, • Spread from secretions, on hands value • Beware of blood 4

retardation) • intrauterine/ – False positive and – Use seronegative, irradiated, birth/breast milk false negative IgM filtered • Perinatal infections: of little consequence •Transfusion titers blood for high risk patients •Transplantation • In situ hybridization • Testing for CMV in transplantation • PCR (donor, recipeint) • Vaccine still not available

Young adults adult with: Attachment – Patients with x- linked Epstein-Barr • Positive heterophile Infectious • In mononucleosis, give steroids if Fever Major glycoprotein is gp 350 agammaglobuinemia can’t be Virus (EBV) antobody (monospot) mononucleosi airway obstruction, Adenopathy which binds to CD21 on B cells infected s, hemolytic anemia, severe cardiac, exudative pharyngitis (C3d complement receptor) • EBV specific nasopharyngeal neurologic disease rash (ampicillin) • Virus practices immune Transmission: antibodies carcinoma, (no specific antiviral therapy) hepatosplenomegaly evasion • saliva (lytic) lymphomas fatigue – Genes that mimic IL 10 and – Anti VCA (develops (including • Experimental therapy decrease IF response, inhibit early, persists) Burkitt’s), forimmunocompromised apoptosis oral hairy patients with severe – Anti EBNA leukoplakia infections/tumors Latency (develops late (lytic – Decrease immunosuppressive • B cells are latently infected in persists) infection), therapy if possible mononucleosis; T cells X- linked – Monoclonal antibodies (rituximab) (atypical lymphocytes) are the proliferative – Infusion of leukocytes host response disease • Latency persists in memory B (males only) cells • EBV is not related to chronic fatigue syndrome, but rarely severe chronic illness follows mononucleosis

Normal Hosts: • Encodes for human proteins • Infections are rare in children Herpesvirus 8 No effective antiviral treatment. Can cause non- specific fever and rash (piracy) (KHSV) illness – IL- 6, Bcl- 2, cheomkines and • Closely related receptor to EBV Elderly, HIV- infected • Causes Kaposi’s Sarcoma • Causes primary-effusion lymphoma • Castleman’s disease

5 Enteroviruses and GI Viruses Clinical Presentation Pathogenesis Predisposing Factors/ Likely Pathogens Definitive Diagnosis Treatment Prevention Epidemiology Asymptomatic infection most common (95%) Infection Polioviruses Isolation of the Symptomatic relief 2 vaccines: Enters via gut Used to be common virus: and support. Abortive poliomyelitis (4-8%) (Sx last a few days): Replicates in childhood infection Picornavirus from throat Oral Polio Vaccine Fever submucosal but then later onset of Small secretions in No antiviral therapy. (OPV): Headache lyphoid tissue disease as populations Non-enveloped first week of Live attenuated vaccine Sore throat Spreads to had better nutrition ssRNA (+) illness = mainstay of vaccination Listlessness reticuloendothelial Vaccine introduced in 1955 icosohedral neucleocapsid from feces for programs across world. Anorexia system has helped eliminate several weeks Excreted in feces Vomiting From there blood polio in Westernized unlike other allowed for futher spread Abdominal pain replicates in gray countries enteroviruses, to unvaccinated Normal neuro exam matter of motor rarely isolated individuals (if ya can’t neurons in brain, from CSF beat em, join em). Nonparlytic poliomyelitis spinal cord cuases cytopathic Rarely, vaccine led to Systemic symptoms more severe than above extensive necrosis effect paralytic disease. See meningeal signs Therefore: Full recovery is norm Immunity: Serologies IgA, IgG response rise in Ab titer Inactivated Polio Spinal paralytic poliomyelitis (0.1% of cases) – biphasic Infection provides life- Vaccine (IPV) – used, course w/ major, minor illnesses. Patient recovers after 1- long type specific now just as 3 days of mild illness, remains well for 2-5 days but then immunity immunogenic, and safer. becomes abruptly ill with: Headache Fever Vomiting Neck stiffness This lasts for 1-2 days before: Weakness Flaccid paralysis ensue (on range of single muscle quadriplegia)

Bulbar paralytic poliomyelitis (paralysis of muscles innervated by CN): Dsyphagia Nasal speech Dyspnea with (CN 9, 10 – most affected) Vasomotor, respiratory centers may be involved

Polioencephalitis: Confusion Changes in mental status Uncommon and occurs primarily in infacnts

Do not usually cause symptomatic Distributed worldwide “Other enteroviruses”: Therapy is supportive infections of the gastrointestinal system • More prevalent in summer Coxsackieviruses, and autumn in temperate echoviruses, newer climates (June-October) enteroviruses • Most infections occur in DON”T NEED TO KNOW children < 1 year SPECIFIC VIRUSES Central Nervous System PCR of spinal fluid usually reveals cause

Aseptic meningitis 90% of viral aseptic Prodrome- fever, chills, malaise, URI meningitis in the Headache, fever, stiff neck, photophobia community due to group B coxsackieviruses – CSF: 10-500 WBC, lymphocytes, nl to slightly and echoviruses elevated protein, nl glucose

Encephalitis Accounts for 11-22% of viral Unusual manifestation of CNS infection encephalitis when you include echovirus and polioviruses coxsackievirus

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Prognosis, except in infants, is excellent Chronic meningoencephalitis Seen in patients with Echoviruses Echoviruses can be Try to prevent with acquired or congenital recovered from CSF monthly IG defects in B cell function for months-years

Paralytic Infections Occasionally associated Usually less severe than poliomyelitis with coxsackie and Paresis not permanent echovirus infections Outbreaks of flaccid paralysis associated with coxsackievirus A7 and enterovirus 71

Exanthems Morbilliform rashes Common in summer Associated with Fine, erythematous, months echovirus 9 maculopapular rashes Rash appears simultaneously with fever and starts on face

Roseoliform rashes Contagious especially Echovirus 16 most Discrete, nonpruritic, amongst young children commonly associated salmon-pink macules and papules on the face and upper chest Prodrome of fever and pharyngitis Rash appears after defervescence and lasts1-5 days

Hand-foot-and-mouth disease Most common in children Coxsackie A16 or Distinctive vesicular eruption under age 10 enterovirus 71 Fever and vesicles in the mouth and on the hands and feet Can look like chickenpox but illness is generally milder

Generalized vesicular eruptions Most frequently caused by Lesions look like those of hand-foot-and-mouth but occur coxsackievirus A9 and in crops on the head, trunk and echovirus 11 extremities Do not evolve into pustules or scabs (unlike chickenpox)

Herpangina Summer outbreaks Group A coxsackievirus Vesicular rash involving pharynx and soft palate Fever, vomiting, myalgia and headache associated with prodrome

Respiratory Disease Cause majority of summer Coxsackieviruses A21 and Upper respiratory infections colds in children A24; echovirus 11 Fever with sore throat, cough and coryza

Epidemic pleurodynia Acute disease with fever and sharp, spasmodic pain in chest/upper abdomen muscles Fever peaks one after onset of pain spasm Lasts 4-6 days usually but can persist for months

Myopericarditis Virus appears to Special predilection for Enteroviruses, especially Inflammation of the myocardium and replicate in the myofibers physically active group B pericardium leading to myofiber adolescents and young coxsackieviruses, group A and necrosis and local adults types 4 and 16 inflammation Symptoms Males outnumber females Echoviruses 9 and 22 URI in 70% followed by Dyspnea, chest pain- precordial, 2:1 account for 50% dull of all cases of acute 7

Fever, Malaise myopericarditis

EKGs usually abnormal, cardiac enzymes elevated

Complications: Can lead to chronic congestive heart failure

Enterovirus infection of the newborn Neonates are especially Echovirus 11 Diagnosis by PCR of Treatment is Biphasic illness susceptible to severe urine, feces, blood, supportive; pleconaril Mild non-specific symptoms between 3 and 7 days of life enterovirus infection Group B CSF disappointing followed by 1-7 days of well-being Coxsackieviruses Most serious infections appear Generalized disease follows Myocarditis with encephalitis- to occur perinatally and Fulminant hepatitis- hypotension, bleeding, multiple organ probably are acquired from the failure mother

Lack of macrophage activity in the neonate is probably responsible for seriousness of infections Acute hemorrhagic conjunctivitis Highly contagious Enterovirus 70 associated Epidemic outbreaks of eye pain, swelling and subconjunctival hemorrhage Usually bilateral Most cases resolve spontaneously

Range from asymptomatic to severe diarrhea Infection Geography Rotavirus – Clinical- febrile – Replace fluids and – Wash your hands Spread by fecal-oral – Worldwide distribution infant with diarrhea in electrolytes (oral or – Chlorine containing • First infection more severe than subsequent route • Reovirus family the IV) disinfectants • Maximal disease incidence in infants 6-24 mos – Virus enters and Epidemiology – Wheel-like appearance winter – Early feeding- – Vaccine • Up to 30% of adult cases are symptomatic replicates in mature villus – Most common cause of – Large, non-enveloped – ELISA- detect promote enterocyte • Rotashield® – Symptoms include cells diarrhea requiring RNA viruses rotavirus antigen in regeneration – Live, oral vaccine • Fever of the small intestine hospitalization in the world – Eleven segments of stool sample – Do NOT give – Rhesus-human • Nausea/vomiting – Infection kills cells and • Account for 10-20% of double stranded RNA – PCR antidiarrheal agents recombinant • Watery diarrhea without blood/mucous loss of absorptive area diarrhea-related deaths in » Reassortment occurs – Electron microscopy – 15 cases of ensues children » Require RNA polymerase – Serology- intussusception in first 10 Dehydration/electrolyte imbalance lead to • Up to 120,000 to make mRNA epidemiological tool months after licensure hospitalization and death Disease hospitalizations in US/year • Seven antigenic groups led to withdrawal • Lactose intolerance named A-G common following Season – groups A-C cause disease infection – Seasonal in temperate in humans • Enterotoxin may also climates – group A viruses account contribute to diarrhea • Occur in winter months in for most human disease – Highly infectious and North America worldwide. hardy • Outbreaks start in the south • 1 pfu can cause west and move up to the north disease east by spring • Not killed by many disinfectants Host Everyone infected by age 3

• Incubation period 24-48 hours followed by • Spread through oral- Geography Caliciviruses • Diagnosis clinical • Treatment is abrupt onset of vomiting and diarrhea with fever fecal route • Widespread and common and epidemiologic supportive- may • Survive stomach acid throughout the • Non-enveloped, single • Can’t grow in tissue require IV hydration • Lasts 24-72 hours and move to jejunum world stranded, positive culture sense RNA viruses • EM of stool (in Diarrhea associated with transient Incredibly hardy • RNA encodes 4 proteins research settings) malabsorption and decreased enzyme – Survives routine Season – Helicase- unwinds double activity chlorination • No seasonal variation helical regions in – Difficult to eradicate • Affects all age groups RNA during replication • Viral shedding highest in first 24-48 hours of illness – Can persist for weeks • Important causes of – Protease- cleaves single • Secondary and tertiary outbreaks of polypeptide into cases common gastroenteritis proteins – RNA polymerase- • Blunting of villi in replicates RNA jejunum seen on – Capsid- covers RNA pathologic specimens genome

8 Viral Respiratory Infections, Anthrax, and TB Clinical Presentation Test Findings Pathogenesis Predisposing Factors/ Likely Pathogens Definitive Diagnosis Complications Treatment Prevention Epidemiology Classic presentation Chest X-ray: Infection is limited primarily to Season: Influenza Virus Clinical Complications Rest and fluids: Vaccine (nasty, self-limited): epithelium of the respiratory tract. Winter months 3 types: A, B presentation: are very Most people In severe cases (i.e. disease; C = Adequate for common: Inactivated Required: pandemic) see Key virulence factors: Transmission: sublclinical diagnosing most Antivirals (do not virus (reduces Fever above 101 F bilateral, rapidly Respiratory droplets enveloped individuals Pneumonia: prevent hospitalization, At least one progressing Neuraminidase protein (NA): ssRNA (-) (most common) complications, but death). Lower systemic pneumonia Surface protein (antigenic) Hosts: C type – lacks Rapid Ag test: Primary viral, or may be used): efficacy in symptom (primary viral) Allows virus to escape the host cell Healthy young adults: Neuraminidase Nasopharyngeal Secondary immuno- (myalgia, chills, and move through mucous deaths during protein (key swab bacterial (S. Amantadine, suppressed. malaise) Can also see lobar pandemics most virulence Test of choice areus, S. Rimantadine: And, at least one infiltrate Hemagglutinin protein (HA): often caused by factor) Highly sensitive, pneumo, H. Interfere with M2 in For: individuals respiratory (secondary Surface proteint (also antigenic) primary viral specific influenza, Influenza A. > 50, cardiac, symptom bacterial: S. Attachment site pneuomina Nomenclature: Group A Limitations: pulmonary, (cough, nasal pneumonia) Also, mediates fusion of viral Older adults, Others: strep). resistance, CNS side renal diseases, discharge) envelope to endosome chronically ill: A/Texas/1/77/H3N2 Viral culture: used to effects, elderly with diabetes, Incubation period = 1- Necrotizing allowing virus to get into cell bacterial pneumonia = monitor Myositis: renal insufficiency. immuno- 2 days pneumonia = major cause of Type A outbreaks Inflammation of suppressed, Hb Sx can persist for 2 (secondary Immune evasion: mortality Isolated in Texas PCR: not in the muscles Neuraminidase disorders, weeks bacterial: S. Antigenic Drift: ongoing mutation Children: more In 1977 widespread use (legs in inhibitors (zanamivir nursing home areus) of RNA segments of NA,HA susceptible to 1 = strain children) and oselatamivir): residents, Rarely: GI Sx (this is why the vaccine needs myositis, Reye’s designation decrease duration of health care Complications are to be changed every year) syndrome H3N2 = subtype Neurologic: Sx, prevent providers. quite common: Antigenic Shift: ressortment of Post-infectious infections. Milder Admin: 1/ yr. (pneumonia, RNA segments (accounts for Review session: encephalitis side effects. 5% low myositis, pandemics caused by type A Binds to sialic acid Guillain-Barre grade fever (not neurological, virus). Influenza A virus of residues, enters cell syndrome the flu) Reyes animals = new source of RNA through receptor syndrome) new HA or NA segments mediated Reyes Antivirals: being introduced into human endocytosis, syndrome: Can be used for pop. No immunity mechanism of viral Changes in people who’ve epidemics. uncoating is well mental been exposed. worked out. status, liver function Other viral proteins: when given RNA polymerase (PB1, PB2, PA) aspirin for replication Mortality from NP = nucleocaspid. Covers the increased genome ICP M1 protein: provides stability for type A, B viruses M2: acts as ion channel within endosome for type A (allows the DNA to get out; also a drug target) NS: nonstructural, function unknown

2 – 7 days after Chest X-ray SARS (not well characterized yet) Emerging Infection SARS - • Clinical suspicion Treatment is exposure to normal focal Evolving pathogen and Coronaviruses – Particularly in a supportive someone who has interstitial infiltrates It is hypothesized that there is an new disease. traveler from an been in Asia or more generalized Asian susceptibility based on HLA • Member of the endemic region or Toronto recently infiltrates type, one type being very common in The outbreak of SARS has Coronaviridae family someone exposed to with: consolidation ARDS Hong Kong. been traced from a single • Pleomorphic 100- a possible/probable prodrome of fever individual from Southern 150 nm particle with case – Chills, headache, Labs There is also the hypothesized China. The patient characteristic surface – Still investigational malaise, myalgia, • Lymphopenia, phenomenon of “super spreaders” traveled to Hotel Metropol projections – Sputum, blood and diarrhea may also be thrombocytopenia, that have a greater capacity to spread in Hong Kong infecting – Single stranded, body fluids for viral present elevated CPK and the virus. other travelers there, who (+) sense RNA cultures and PCR • Next phase: dry hepatic enzymes may subsequently went back to genome (27-32 kb) • May not be positive cough and/or be seen There have also been PCR studies their own countries and – Cytoplasmic for up to 28 days shortness of breath that show that the virus’ peak infected persons there. replication • In 10-20% disease excretion occurs 10 days after – Viral assembly in may be rapidly infection, which differs greatly from Mortailty Golgi apparatus and progressive and other viruses that cause respiratory To date there have been endoplasmic require mechanical symptoms. 8,427 cases in 29 reticulum 9

ventilation countries, and 813 deaths. • Infect multiple species

Young health person Chest X-ray: Hantavirus Pulmonary Syndrome Emerging infection Hantaviruses (Sin PCR of viral RNA in Hemorrhagic fever Treatments is No vaccine 14-17 days after Bilateral interstitial New agent and disease Nombre viruses)_ lung with renal supportive exposure to rodents infiltrates (moderate to Deposition in terminal respiratory First described in 1993 in Bunyaviridae family, syndrome (HFRS) with: rapid progression), bronchiole or alveolus Four Corners area, New segmented RNA, Serologically b. Hantavirus myalgia, malaise, and bilateral alveolar • Local replication with viremia Mexico. enveloped viruses. pulmonary fever (mild flu-like infiltrates, and pleural • Widespread infection of pulmonary syndrome symptoms). effusion endothelium Epidemiology: (HPS)—emerging General GI – Cell invasion may be mediated by Basically localized to the infection. disturbances B3 integrins western hemisphere all (anorexia, nausea, Labs: • Infiltration by CD4 and CD8 cells over the U.S. but less than vomiting, and a. elevated • Loss of vascular integrity in lungs 50 cases a year. However, abdominal pain) and hemoconcentration • Capillary leak syndrome when it does infect a non-specific (Hct) • Myocardial depression also seen patient, it is usually a respiratory b. leukocytosis with left young healthy person, and complaints (cough, shift; atypical it is usually fatal. tachypnea, and lymphocytes seen ) may be c. thrombocytopenia Resevoirs: observed. Symptoms d. elevated liver rodents (deer mice) may rapidly progress enzymes, proteinuria, to respiratory failure. elevated creatinine may Transmission be seen To humans via inhalation of contaminated aerosolized excreta, especially urine.

Infant presents with: Chest X-ray: Infection involves primarily lower Host: Respiratory Cell culture: Pneumonia Supportive care: Passive Pneumonia “Peribronchial cuffing”: respiratory tract in infants with Virtually all children Syncytial Virus multinucleated mainstay for sick Immunity: Bronchiolitis infiltrate with without systemic spread (although infected by age 2. (RSV) giant cells infants Monoclonal Ab edema of may just be upper tract infection). Premature infants Paramyxoviridae (syncytia cells) Epinephrine, supple- (palivisum History: bronchial walls Immune response probably (esp. w/ family immuno- mental 02 for ab) Sx start with contributes to pathogenesis. bronchopulmonary Enveloped flourescence hypoxic infants Immune Nasal congestion dysplasis, congenital ssRNA (-) serology not useful globulin Sore throat Infection: heart disease, Antiviral (Ribivirin): Given Fever Innoculation: through eyes and nose pulmonary disease) Aerosol for very sick 1X/month Cough develops in Lyphocytic peribronchiolar infiltrate and those from low infants for at-risk first few days with edema of bronchial walls SES are at greater Interferes with RNA infants and becomes Later proliferation and necrosis of risk for serious polymerase, Doesn’t benefit deeper and more bronchioles develops disease and depletes patients prominent as Collections of sloughed epithelium Imunnocompromised: intracellular with infection obstruction of small (CMI esp.) nucleotide congenital proceeds bronchioles air trapping pools heart Viral infection may lead to Season: disease Physical: pneumonia Winter bug: outbreaks No vaccine Increased RR, begin in Nov., peak retraction of Immune Response in Jan, continue until Hand washing lower Most sever infections: when Ab titer April intercostals high, CMI low (e.g. early infancy (indicates lower when maternal Ab present; Transmission: resp. tract vaccinated infants had worse Respiratory droplets involvement) outcomes) CMI key for protecting against Geography: Adults: serious lower tract infections everywhere Common cold-like symptoms May be worse depending on immune status Viral proteins: Attachment: F, G, SH Nucleocaspid: N, L, P RNA polymerase: NS1, NS2

Bronchiolitis in Infection and death of respiratory Transmission Parainfluenza Virus Isolation of virus in Supportive. No vaccine. infants epithelium without systemic spread of Respiratory Droplets enveloped cell culture virus. Multinucleated giant cells helical immunoflourescence Croup in young caused by the giant cell fusion protein nucleocapsid 10

children are a hallmark. one piece of ssRNA Serology: four-flod (-) rise in titer Common cold in RNA polymerase in adults virion STABLE hemaglutinin and neuraminidase

Common-cold Virus can be detected Infection is limited to mucosa of High rate of community Rhinoviruses: Clinical diagnosis Paranasal Symptomatic Tx: avoidance symptoms (for about in nasal secretions as upper respiratory tract and infection: Small, noneveloped sinuses Decongestants a week): early as 10 hours after conjunctiva. Due to multiple serotypes ssRNA (+) Antihistamines Rhinorrhea inoculation (but not Antigenic drift picornaviridiae Exacerbation of Anticholinergics Congestion usually done) Infection: reinfection 100’s of serotypes chronic NSAIDS Sneezing Innoculation: nasal, ophthalmic bronchitis Paranasal sinuses may mucosa Host: Don’t prescribe Also: be seen in CT scan Optimal growth at temp of nose Infants < 1 y.o. have antibiotics for URI Sore throat (33 degrees) why doesn’t highest rate of Asthma attacks (pharyngitis can infect lower resp. tract (37 illness (mediator be severe, can degrees). Although, lower tract related) be exudative) infection may happen in some Season: Hoarseness, cough infants. peaks in early fall and (less common, Replication: in nonciliated spring but more lymphoepithelical cells of persistent – nasopharynx; primary infection Geography: lasting up to in adenoidal tissues Worldwide several weeks) Attachment: binds to ICAM-1 Yellow-green receptor Transmission: sputum may be Respiratory droplets seen Immune response: Homes, schools Leads Sx May survive on High , Cytokines (esp. IL-8) elevated and environmental myalgias, and shown to cause Sx (release surfaces for hours chills NOT dependent on interaction of Killed with lysol usually seen virus with ICAM and (should prompt proportional to severity of other diagnoses) symptoms)

Upper and lower Virus primarily infects epithelium of Transmission Adenovirus Viral cell culture – see No antiviral therapy Live vaccine respiratory tract respiratory tract and eyes. After Respiratory droplets; Nonenveloped cytopathic effect available. used in the disease, especially acute infection, persisten, low-grade iatrogenic in eye disease; Icosohedral military to phrayngitis and virus production without symptoms in fecal-oral with enteric neucleocapsid Serology: Ab titer rise prevent pneumonia the pharynx. strains Linear dsDNS pneumonia No virion (against types polymerase 3, 4,7) 41 serotypes

Measles (serious Infects upper respiratory tract LN Transmission Measles Virus Subacute No antiviral therapy Live disease) blood other organs (including Respiratory droplets enveloped sclerosing available. attenuated skin). Giant cell pneumonia and helical panencephalitis virus vaccine Maculopapular rash encephalitis can occur. Significant degree of neucleocapsid is a rare (given with mortality ssRNA (-) complication mumps, rubella) RNA polymerase in virion

Congenital Infects nasopharynx LN skin Transmission: Rubella Virus To determine No antiviral therapy See above malformations, Respiratory droplets, Enveloped whether woman is available. cardiovascular, and If occurs during 1st trimester cross-placental Icosohedral immune – single CNS congenital abnormalities nucleocapsid serum specimen to One piece of detect IgG ssRNA (+) No viral polymerase To see if infection Single serotype has occurred, look for IgM

Inhalational Anthrax Chest X-ray Anthrax Bioterrorist Agent Bacillus anthracis Inhalational Dx Antibiotics are Vaccine After 1-6 day Non-specific clinical Non-motile, Non-specific clinical effective against Attenuated form incubation period CXR – widened Inhalational (more lethal) Cutaneous goal to get gram positive, rod, CXR – widened vegetative form, non Good at (closer to 1 day, but mediastinum, pleural Hemorrhagic mediastinitis into the blood stream spore former, not mediastinum, pleural spore form preventing skin could be much longer): effusions malignant edema with regional Inhalational –> more contagious effusions (key) Empiric – cipro or anthrax Flu-like symptoms lymphadentis toxic induced dangerous Does occur naturally doxy 6 doses – 11

Septic untreated septicemia Spores are viable for Gm stain.culture, PCR Plus one or two difficult to get necrotizing years of blood CSF others: clindamycin, limited supplies mediastinitis death Cutaneous Large gram pos rods, rifampin imipenem Necrotic lesion malignant edema • Produces three rough, grayish Prevention Cutaneous w/ or w/o reional lymphadenitis exotoxins: colonize, non- After identification, Primary- 1-7 days up to 14 septicemia – Edema factor nemolytic non-motile 60 day course vaccination at after being exposed – Lethal factor risk (military) to white powdery – Protective antigen Usually penicillin Secondar substance: Path susceptible Pruitic macule Alveolar mac regional LN Send culture to CDC vesicle round ulcer Inf Dose = 1 or more spores NYCDOH black eschar over 1-2 weeks Surrounding Cutaneous Dx edema/erythema Vesicular fluid or (pretty profound), but border of skin lesion painless (gram stain, culture, +/- painful regional sensitivity, PCR) lynphadenopathy untreated 5%-20% Skin biopsy (culture, fatality rate PCR, special CDC If treated, do well immuno test)

Serologies – take wihile to develop

History, commonly: Lab findings: Primary Infection: uimpeded Transmission: Mycobacterium Clinical Exposure, no risk of Fever Mild anemia replication and dissemination Inhalation of respiratory Tuberculosis PPD test infection: need to get Fatigue Normal WBC, normal secondary to lack of host droplets Interferon repeated testing Night sweats differential immune response GI (contaminated milk), production by Weight loss Elevated ESR Development of immune response: skin exposure unsual WBC’s PPD (+), Anorexia CD4 cytokines recruit exposed to asymptomatic: Chills Chest X-ray: Mac’s kill MTB, cause tissue Risk of infection: MTB Ag’s monitor Sx, chest X- Suggestive –apical damage (form Langhans giant Directly proportional to AFB culture ray. Indications for Pulmonary Sx (non- infiltrates or cells, granulomas) length of exposure to PCR, DNA probes Tx in this population: specific): cavities, hilar Clinical events – primary infection organisms Recent development Productive Cough adenopathy. mild viral like syndrome, PPD of PPD (2 yrs) Hemoptysis Different X-rays comes out positive. If not Risk of disease: Close contacts of Pleuritic chest pain for HIV patients. progressive, resolves into Ghon Greatest in infants <6 mo known cases of complex. Time: highest after 1st infectious TB Physical: If meningeal Progressive primary disease: (in year following Persons in hospitals, Fever involvement lubar immunocompromised, young primary infection prisons, Cachexia tap: children): military, CNS Decreased nutritional, shelters, Perhaps pulmonary Glucose: normal, or involvement, pleural disease (in immune status nursing homes consolidation low absence of parenchymal increase risk Children < 5 y.o. Protein: up involvement) = more common Extrapulmonary: Lymphocytic Persistence of viable organisms: at Those with increased Lymph predominance secondary sites (lung apices, risk for progression: Bone/joint LNs, meninges, bones, Fibrotic changes, Miliary Biopsies: kidneys). 85-90% of apical scarring GU LN: cervical node immunocompetent individuals Immunosupresseced CNS (meningeal) Miliary: granulomas do not progress further… Underlying disease Pleural: AFB staining Reactivation (remaining 10-15%; Immigration within 5 often negative for weeks to decades later) often years from area some reason depends of weak host immune with high TB status can’t contain infection. rate 85% located in apical-posterior Underweight lungs, rest extrapulmonary. Get persons caseating necrosis of lungs IDUs Exogenous reinfection: occurs in People less than 35 developing countries, homeless y.o. shelters. Postive PPD convers some protection. Isoniazid Rifampin

12 HIV Infection Clinical Presentation Test Findings Pathogenesis Predisposing Factors/ HIV Structure / Replicative Epidemiology Cycle Early, Acute Stage a.k.a. Acute retroviral Blood test: In acute infection: Emerging Infection Structure: syndrome (mononucleosis like picture): luekopenia Virus encounters DC’s on mucosal New agent, new disease Retrovirus family 2-4 weeks after infection CD4 cells normal surface (DC-sign is a co-receptor ssRNA virus with an fever on DC) Determinants of Outcomes icosohedral nucleocapsid lethargy Serologies: Virus is delivered to LN where active and lipid envelope sore throat Ab’s appear 3-4 weeks replication takes place Viral Factors: two identical copies of RNA general lymphadenopathy after infection (so primary infection – R5 tropic Escape from immune response: under immune selective and carries a reverse macular popular rash on the trunk, arms, and legs prior testing (Mac’s) pressure (CMI, humoral), mutations in gag, pol, env transcriptase (but sparing palms and soles) results in false- high levels of viremia and viral Attenuation: nef deleted viruses associated with slow or long-term negatives) dissemination occur non progression in patients Replication: resolves spontaneously after 2 weeks HIV can still be Down regulation of the virus by CMI Tropism: R5 X4 virus conversions associated with increase in binding and infection transmitted during occurs pathogenicity (there may be mix of these) reverse transcription and only 20% of patients seek care for illness at this this period Viral set point reached after about Subtypes: a bunch of them. Subtype B in US. Potential for varied integration of viral DNA stage 6 months subtypes to exhibit differential transmissibility and virulence. transcription and translation Immune response, chemokine Potential for greater heterosexual. Modification and assembly increased severity of this symptoms indicate more receptor status and HLA type Budding and final assembly rapid progression of infection are important co determinants Host Factors: of outcome CMI: CTL’s: eliminate virus infected cells, play prominent roles in control Middle Stage (long latent period, measured in Blood tests: of viremia years, usually ensues): Progressive CD4+ Once HIV infection is established: T help: vital for CTLs Patient is usually asymptomatic at this time and depletion (pt. acute viral response present Humoral immunity: role unclear in prevention of transmission, without complications loses 50-75 CD4+ throughout course of the disease progression cells per year if major reservoirs of infection exist Chemokine receptors: Rarely, patients may have have AIDS-related RNA is above outside of blood CCR5-delta32: homozygosity associated with decreased complex (ARC) with persistent fevers, fatigue, 30,000) compartment: lymphoreticular succeptibility to R5 virus infection; heterozygosity delayed weight loss, and lymphadenopathy tissues (most important), CNS, disease progression PCR: Genital tract Other genetic factors: Average pt. has viral Virus exists as multiple Class I alleles: B35, … faster progression; …. slow load set point of quasispecies progression 30,000 copies of Mixtures of viruses with differential HIV RNA / ml phenotypic and genotypic characteristics may exist (drug Transmission Late stage HIV infection (AIDS) resistance mutations vary across Sexual: hetero; male to male most often manifested by Pneumocystis Pneumonia clones, compartments) Blood: transfusion; IV drug use; needle stick (PCP) or Kaposi’s sarcomas At least 10 * 10^9 virions produced Perinatal: intrapartum; breast feeding and destroyed each day (even Diseases or symptoms of other opportunistic in asymptomatic individual), and Epidemic infections include: combine this with: Stable in US (NYC, DC, Puerto Rico most affected) Lung: High turnover rate: t1/2 of HIV in Not stable in subsaharran Africa, developing regions Pneumonia plasma is <6 hr and may be as Tuberculosis short as 30 minutes (very Risk Factors: Male Mouth dynamic infection even in Male male (53%) Thrush asymptomatic individual) IDU (26%) Hairy leukoplakia Ulcerations Female Esophagus Heterosexual contact (64%) Thrush Esophagitis GI Diarrhea CNS Meningitis Brain abscess Progressive multifocal leukoencephalopathy Eye Retinitis Skin Kaposi’s sarcoma Zoster Subcutaneous nodules Reticularendothelial system Lymphadenopathy or splenomegaly

13 HIV Infection (cont.) Definitive Diagnosis / Prognosis Complications Treatment Prevention Diagnosis: Opportunistic disease Epitiope war: When do you start treatment? Prophylaxis (often in a cascade Patient’s disease stage: any symptomatic individual; CD4 count; plasma HIV-1 RNA level PCP – TMX (<200) ELISA: pattern with dropping Patients commitment to therapy in light of side effects Toxo – TMX or Dapsone + Pyrimethamine) (<100) HIV Ab detection (30 min – 1 hr) CD4+ levels) Philosophy of treatment MAC – Clarithro/Azithromycin (<50) <300 – TB (any level of TB – INH (9 months) (PPD+) – problems: high risk Western blot: CD4 count) Initiation of Retroviral Therapy individuals have lost skin reactivity (therefore Detects serum Ab’s to specific HIV proteins that Opportunistic infections Clinical outcome compromised if Tx begun when CD4 <200 compromise outcome PPD reaction set at lower level); also other are separated on a gel occur at CD4 <200 (worse than if you started above 200) problem – in developing countries INH and <200 – PCP No virologic or immunologic advantage to starting at CD4 >350 vs. 200-350 PPD skin test not used in may areas PCR: <100 – TE Usually start treating around 350 (would initiate earlier, but there are toxicities) RNA plasma levels (this would be positive in <75 – CMV, dMAC – acute infection, when ELISA and Western many people don’t Antiretroviral therapy Proof immune restoration is actually occurring: blot would be false negatives – but would survive until this point Markedly decreases rate of death from disease from protease inhibitors most effective Recommendations PCP: primary prophylais still do these together in acute infection to way to prevent OIs restore host immune function withdrawn after CD4 > 200 for 3 months rule out established infection). OI related events: Toxo: Primary >200 X 3 months; seconday, same MAC adenitis (may suddenly appear as inflammatory illness after retroviral therapy due for 6 months + asymptomatic Prognosis: to immune system recovery) MAC: >100 X 3 months; same pattern, secondary, Can develop prognosis based on CD4 and Inflammatory flare of CMV retinitis 100 X 6 months + asymptomatic viral load Previously stable hepatitis AIDS like impending train wreck: viral load = Development of cavitary TB speed of train, CD4 count = distance from site of crash Independent predictors of outcomes Pathogenesis after administration of retroviral therapy (measured in log of viral load More viral load, less CD4 AIDS over time): Absolute CD4 count: best established surrogate 1st phase: t1/2 = 1 day (productively infected CD4) marker to predict time to AIDS, risk of 2nd phase: t1/2 = 2-4weeks (mac’s, latenly infected CD4s, release of trapped virions from specific OIs (near term), or death LN’s) Combine with viral load can give very 3rd phase: t1/2 = 6-44 months (resting, memory CD4s): may not be a decline accurate prediction of time to AIDS in 5 irreducible reservoir. Can reemerge. years RNA above 30,000 copies 75 cell loss per Therapeutic Implications for 1st and 2nd phase declines: year: higher RNA, faster CD4 count will Can assess antiviral potency in first 7-14 days (should see 1-2 log decline in first two decline weeks of therapy) Gender specificity: after seroconversion – Trajectory over first 1-8 weeks can be predictive of subsequent response women have lower viral loads Treatment decisions should be individualized 3rd phase (Latent reservoir): Therapeutic implications Resting naïve CD4 cell activated by Ag gets exposed to HIV virus integrated into host cell rapid production kills most of cells some resting memory CD4 cells Non-progressors: remain (only 1 million to 10 million cells total) May last for 10+ years, but will eventually get Viral eradication not possible with current drugs AIDS Archive of replication competent history established Determined by host-factors primarily (chemokine Despite presence of reservoir, minimal degree of drug resistance over 2-3 years receptor co-receptors key (CCR5) heterozygous individuals just as infectable but not as progressive = lower viral load set point i.e. cells have less dense receptors Drug Resistance for HIV) Genetic variants are continuously produced as a result of high viral turnover and inherent Viral factors less so: nef deletion, non-clade B error rate of RT subtypes Viral replication 10^9-10^10 per day RT error rate 10^-4 base/cycle Emerge with drug selective pressure Need to look at person with 351-500 CD4 count Resistance emerges before exposure to drugs quickly afterwards if viral load over 100k get ready to start Single mutation drugs most dangerous treatment

14

HIV Opportunistic Infections (Note: These are based on the information on the slides, see Lynn’s Chart for more info) Clinical Presentation Test Findings Pathogenesis Predisposing Factors/ HIV Structure / Definitive Diagnosis / Treatment Prevention Epidemiology Replicative Cycle Prognosis Pneumocystic pneumonia Diffuse interstitial Most common life Addition of Fully preventable Presents as subacute illness infiltrate on xray threatening infection corticosteroids to with (fever, cough, dyspnea) Predicted by CD4 count: of AIDS patients in US antimicrobials cuts trimethoprim- by time reach CD4 mortality of in sever sulfa (bactrin) <200 begin seeing disease of 50% (not PCP after 6 months intuitive: element of reaction to pathogen is not deficient, therefore reduce host response related disease)

CNS toxoplasmosis Reactivation in AIDS Transmission from cysts or Protozoan parasite; cats Serum IgG = reliable assocatiated with CD4 uncooked meat shed oocysts, markers (90% <100 (happens esp. in seroprevalence in tropical regions: DR, tropics) etc.) Most common CNS infections in AIDS

Cryptococcal Disease Spinal tap: good test for Ag Ubiquitous soil fungus Amphotericin = drug of Initial asymptomatic pneumonia Reactivation CD4 <100 choice Meningitis most common presentation, but wide dissemination frequent May see ulcers in skin (most commonly recognized sites)

CMV disease Reactivation at CD4 <50 Common viral Retinitis most common clinical Colonoscopy: colitis infections (50% form in AIDS population adult (pneumonia more common seroprevalence) for transplant pop) Other sites: colon, CNS

MAC Wide spread visceral Common in water Diagnosis: blood Local lung disease known prior dissemination in culture (b/c to AIDS AIDS mycobacteremia Non-specific features, liver, and becomes so spleen high) Absence of inflammation in tissue sites (hallmark of the disease – see enormous densities of organism, no WBCs)

15 Rabies/Prions Clinical Presentation Pathogenesis Predisposing Factors/ Likely Pathogens Definitive Diagnosis Treatment Prevention Epidemiology A week to a year after an animal Infection Rabies Viruses Spinal tap Once Active Vaccination (Pre bite: enters through break in skin Epidemiology Rhabdovirus family To determine which of the clinical and Post Exposure) Classical Rabies replicates in muscle cells muscle Usually imported into US; high Bullet-shaped differential diagnoses of GBS, symptoms The best is the human fever prodrome and spasm of spindles nerve that innervates in other areas of world - India Enveloped HIV, polio, and rabies your arise, diploid cell vaccine laryngeal muscle the spindle spinal cord Helical nuclueocapsid patient has. This comes up on there is Pre: for high risk groups leads to hydrophobia because it hurts moves throughout CNS, so every Exposure: One piece of ssRNA (-) boards. no (vets, Peace Corps to swallow; neuron is infected bites, inhalation, transplants RNA-dependent, RNA effective vol.) this also accounts for salivary encephalitis polymerase Find and observe animal for treatment Amdin: It’s painful, retention and drooling, During axonal transport to CNS, The distance from innoculation Codes for 5 proteins (L, P, N, ten days administered and eventually leads to coma and virus is hidden from immune site to the brain determines N, G) intradermally, and paralysis. response latency to the disease. For G: interacts with cellular Diagnosis give on days •Nonspecific Symptoms & Signs: High concentration of virus in saliva example, a bite on foot will receptor (Aceylcholine?) RT-PCR saliva, CSF, urine, nerve 0,3,7,14,28 post- These include itching, large pupils, from shedding in sensory nerve take longer to progress than a L: RNA polymerase tissue exposure. stiffness, hypersensitivity to sounds, endings in oral mucosa bite on the face. M: interacts with It is successful if given light, change in temperature. cytomplasmic tail of G Fluorescent rabies antibody in time, but once High Mutation Rate Reservoirs in US assembly and budding (FRA) test on brain tissue (more they’re in the Rarely presents as Gulliain Barre No proofreading activity of the RNA racoons- 44%, skunks- 28.5%, from PM for animals than for people) excitation stage, you Syndrome (ascending paralysis). polymerase. bats- 12.5, foxes- 5.5 Once in host, M and G not give it to them but • Prodromal Phase, 2-4 days. It’s This leads to a greater mutation rate of needed for spread in Animals, autopsies: without expectation of nonspecific so people have any kind of about 1 in 1000 that allows opportunity Mortality nervous system Presence of Negri bodies. any effect. viral complaint. It depends on whether for flexibility & enhanced fitness. 100% fatality rate if left Inverse correlation between G Specific for rabies but present in the virus is replicating in CNS or results in a quasi-species untreated levels and pathogenicity only 50% of cases. (Cytoplasmic Passive Vaccination. peripherally. (heterogeneous population of different 60K estimatedhuman inclusions in Infiltrates the wound site • Excitation Phase. Here they RNA molecules that has certain fatalities/y (30K in India) pyramidal neurons in and vicinity with antibodies develop weakness, weird ocular predominant consensus genotypes) hippocampus and Purkinje cells to prevent it from palsies, urinary retention and in cerebellum) propagating and spreading constipation. Basically you’re just centrifugally within CNS. documenting their demise because You can use human rabies you can’t save them. Ig and some people use • Paralysis Phase. You die of horse rabies Ig though that peripheral vascular collapse with can lead to serum sickness. flaccid paralysis if you don’t drown in Admin: it’s done just your own secretions first. once. After long incubation period: Hardy proteins: Kuru Prions Ususally, on basis of clinical No Resistant to heat, formaldehyde, UV Exposure to brain and syndrome and history. reasonable In New Guinea (Kuru): light mucous membranes of Proteinacious infectious treatments. Prodromal: headaches, arthralgias infected individuals particles associated with Definitive diagnosis is made by Neruologic: cerebellar ataxia, action • Role of PrPc may include synaptic transmissible spongiform taking a brain or lymphatic tremor, involuntary movement plasticity since knockout mice CJD encephalopathies (TSEs) biopsy, using antibodies to progressively worse dementia developed subtle sleep defects. What is Sporadic: most common in identify the proteins, then death certain is that it’s essential to TSE elderly PrPc (cellular) – protein digesting them with protease. pathogenesis. Hereditary: rare autosomal product thought to be target After digestion, only the PrPsc Creutzfield-Jakob Disease: KO mice are resistant to TSE. dominant of prion disease. signal has been preserved Lack of coordination, dementia, motor Iatrogenic: exposure to normal host protein encoded because of its protease weakness (Rule out Alzheimers in The key determinant of disease is growth hormone in by single exon of a single copy insensitivity whereas PrPc has elderly) the cellular gene itself and its pituitary, corneas, gene in chromosome 20. It is been chewed up. susceptibility of going through contaminated surgical attached to the neuronal Fatal familial insomnia conformational change as result of instruments surface by G proteins, are Autonomic dysfunction and sleep coming into contact with prion Variant: Ingestion of BSE *protease sensitive, and disturbances in middle late life protein in diet (i.e. PrPc exposure to infected meat or bone have a *α-helical secondary PrPsc changes it to PrPsc marrow (seen in structure. Gertsman-Straussler-Schneiker younger populations) Midlife progressive spinocerebellar Three phases: 1) first six • PrPsc (prion scrapie) is degeneration with associated months, little risk to humans; 2) *protease insensitive so they dementia, prion concentrated in CNS and accumulate in cytoplasmic animal is asymptomatic and vacuoles, eventually infectious; 3) animal blocking normal symptomatic and infectious physiological. They have a BSE = endemic in UK (“mad *β-sheet secondary cow”) structure.

FFI and GSS hereditary/genetic

16

Arboviral Infections / Encephalitides Clinical Presentation Pathogenesis Predisposing Factors/ Likely Pathogens Definitive Complications Treatment Prevention Epidemiology Diagnosis 4-10 day after insect bite (spectrum Aboviral Encephalitis Host Major US causes: Treatment is Aerial spraying, personal of severity): (post 1999) West Nile Serologically supportive with protective measures from mostly asymptomatic cases Asymptomatic Infections: Children are at greatest risk for JBV Encephalitis (WNE), (positive IgM or 4x IFN-α, ribavirin, bites. mild “flu-like” illness Arboviruses stay around by (30% mortality), TBE, WEE, VEE, Eastern Equine increase in IgG and other finding reservoirs of cells that and LAC, Encephalitis (EEE). titer), investigational Inactivated human to more sever cases: are resistant to its cytopathic LaCrosse (LAC). trials not proving vaccines are available for fever, effects, such as mosquito cells, Elderly are at greatest risk for SLE Others (don’t need to CSF PCR test. conclusive yet. JBE (also available for the headache, and muscle and neuronal cells and WNE. EEE (60% mortality) know): St. Louis amplifying hosts – pigs – to mental status changes, in humans. affects all ages with equal risk. Encephalitis (SLE), Western reduce reservoir) and TBE, and possibly focal neurologic Equine Encephalitis (WEE), and live attenuated equine signs. CNS Invasion and Powassan encephalitis vaccines are available for Encephalitis: Seasons (POW). VEE, EEE, and WEE (not Arboviruses invade the CNS for humans!). either through the vasculature Infections occur seasonally with from viremia or retrogradely peaks in late summer/early fall (Don’t need to know): through the olfactory nerves. correlating with mosquito activity. Japanese B Encephalitis Neuroinvasiveness and (JBE) predominates in neurovirulence is primarily Patterns of Infection South East Asia and determined the age of the host. There are two epidemiologic Australia, patterns: a more infrequent, Venezuelan Equine Perivascular inflammation: unpredictable epidemic like SLE and Encephalitis (VEE) in South A histologic hallmark of a more predictable annual caseload America, WNE in Northern arboviral encephalitis. of infections in a given region like Africa and the Middle East, The immune response can be JBE. and Tick-Borne Encephalitis damaging through excessive (TBE) in Eastern Europe cytokine release. and Russia. Arboviruses can also directly induce neuronal apoptotic death.

After mosquito bite: Emerging Infection West Nile Virus 1. CSF: Pleocytosis May see motor weakness in Previously described agent, in a new and positive IgM Most commonly an infection is encephalomyelitis (West Nile location now an established Flavivirus; reservoir = bird; asymptomatic. documented to affect infection vector = mosquito or anterior spinal cord an abrupt onset flu-like illness neurons). Incidence 2. Serum: 4x rise with: Largest recorded arboviral in IgG titer. or: moderate to high fever, encephalitis epidemic in US history, PCR for West Nile headache, with over 8,470 human cases in 45 in serum or CSF sore throat, states to date backache, are required for myalgia, Progression definitive arthralgia, 1 in 5 infections West Nile Fever diagnosis. fatigue, 1 in 150 West Nile rash, encephalomyelitis lymphadenopathy. Rule out: Host Bacteria, fungi, More serious cases: The more serious form of disease, and structural temperature above 38.0°C West Nile encephalomyelitis, lesions on brain and either focal neurologic signs, strikies mainly those over 50 imaging altered level of consciousness, and/or the immunocompromised. suggesting or diffuse profound motor another diagnosis weakness are also required. Negative for structural brain lesions.

Arboviral Encephalitis (see Geography: Eastern Equine Permanent brain above) Eastern US Encephalitis (EEE) damage

Season Alphavirus; vector = Summer/fall mosquito; reservoir = birds, horses Outbreaks Occasional in humans, frequent in 17

horses

Mortality 1/3 of cases are, fatal – regardless of age

Human Host Anybody

After mosquito bite: Mosquito bite replication in Geography Serology, Henorragic Treatment is Preventable with mosquito a regional lymph node Ssub-Saharan Africa and South Viral isolation, diathesis, supportive. controls, and improved 1 in 5-20 infections have clinical Viremia with infection of the America (never Asia) Flavivirus; vector = PCR circulatory sanitation/water systems, disease with jaundice. Kupfer cells and mosquito; reservoir = failure, and yet lapses in Africa has led hepatocytes. Two epidemiologic patterns: primates but NOT liver shock to increasing epidemics. 3 stages: The resulting liver biopsy because of The live attenuated Yellow 1) infection (viremia) with fever, degeneration causes Endemic bleeding diathesis. Fever 17D vaccine is chills, headache, back pain, release of inflammatory “Jungle yellow fever”:non-human effective and nausea, malaise, minor gingival mediators and the primate hosts and tree-hole breeding contraindicated in infants hemorrhages, epistaxis, and sequelae of hemorrhagic mosquito vector. less than 6 months of age, relative bradycardia (Faget sign) diathesis, circulatory in pregnant women, in the failure and shock. Epidemic immunosuppressed, and in 2) remission “Urban yellow fever”: human those with hypersensitivity hosts and urban mosquito vector reactions to eggs. 3) Intoxication with jaundice and (Aedes aegypti). black vomit, delirium, stupor, acidosis, and shock. Also present Mortality are leuko/throbocytopenias, liver High case-fatality rate of 20-50% in and kidney abnormalities, and patients with jaundice. coagulopathies.

2-7 days after mosquito bite: (Dengue fever is often called Incidence Dengue Fever DHF can Treatment with “breakbone fever”), 100 million cases annually in all progress (30%) supportive Biphasic disease… tropic and warm temperate zones. Flavivirus; vector = to Dengue measures can mosquito; reservoir = Shock lower the case Early phase: Immune enhancement Vector primates Syndrome fatality rate of major lumbosacral, joint, bone phenomenon (in DHF) Aedes aegypti and humans are the (DSS), defined DHF from >10% pain With Dengue virus antibodies primary hosts. as DHF with to <1%. fever, chills, headache, from a previous infection allow hypotension, transient maculopapular rash, and the new cross-reactive virus Transmission circulatory Faget sign over the first two days greater access to Air travel from viremic humans. failure and and macrophages (antibody- shock. Then anorexia, vomiting, and dependent enhancement) and Dengue Hemorrhagic Fever (DHF), a respiratory symptoms for cause increased T cell lysis more serious disease which occurs days two to six. of the infected macrophages, almost exclusively (>90%) in both of which cause greater those with prior immunity to a Late phase following: release of inflammatory heterotypic serotype, is on the defervescence results in fever, mediators. rise because there is increasing limb/face rash, endemicity and co-circulation of the lymphadenopathy, DSS 4 Dengue serotypes. and minor hemorrhages. Due to increased vascular Labs show leuko/ permiability Incidence of DHF is only 1 in 14,000 neutro/thrombocytopenia. with primary Dengue infections but 1 There are no fatalities. in 90 with secondary Dengue infections. DHF Dengue fever with thrombocytopenia and hemoconcentration (from diffuse capillary leakage and major hemorrhages). Can progress to DSS Other clinical signs are respiratory distress and neurologic symptoms.