Viral Infections in the Immunocompetent Host

Corey Casper, M.D., M.P.H.Corey Casper, M.D., M.P.H.Division of Infectious Disease, Department of Medicine Division of Infectious Disease, Department of Medicine

The University of WashingtonThe University of WashingtonVaccine and Infectious Disease Institute, Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center Fred Hutchinson Cancer Research Center

Outline Classification of VirusesClassification of Viruses

o Classical vs. Other SchemesClassical vs. Other Schemes Diagnosis of Viral Diagnosis of Viral

InfectionsInfections Common Viral Infections Common Viral Infections

for the Infectious Disease for the Infectious Disease ConsultantConsultant

Classification of Viruses

Classification of Viruses Classic TaxonomyClassic Taxonomy

o Nucleic Acid StructureNucleic Acid Structure• DNA vs. RNADNA vs. RNA• Single vs. Double StrandedSingle vs. Double Stranded

o EnvelopeEnvelope• Presence or absencePresence or absence

o Organization of genomeOrganization of genome• Example: ParamyxovirusesExample: Paramyxoviruses

o Mode of transcriptionMode of transcription• Example: RetrovirusesExample: Retroviruses

““Functional Taxonomy”Functional Taxonomy”o Group viruses by primary organ system Group viruses by primary organ system

involved in the pathology of diseaseinvolved in the pathology of disease• Example: Respiratory VirusesExample: Respiratory Viruses

o Group viruses with similar treatmentsGroup viruses with similar treatments• Example: HerpesvirusesExample: Herpesviruses

Your Mother Knows Best? Which of the following Which of the following

viruses would you be most viruses would you be most likely to acquire from likely to acquire from touching a toilet seat? touching a toilet seat? True MedCon Call!True MedCon Call!

1.1. HIVHIV

2.2. CalicivirusCalicivirus

3.3. Herpes Simplex Virus-2Herpes Simplex Virus-2

4.4. ParainfluenzaParainfluenza

Viral Structure

Player or Bystander? A 63 y.o. man presents from an A 63 y.o. man presents from an

outside hospital with fever and outside hospital with fever and headache for 2 weeks. Multiple headache for 2 weeks. Multiple blood, urine, CSF, and sputum blood, urine, CSF, and sputum cultures have been negative. Chest cultures have been negative. Chest X-ray, full body CT and peripheral X-ray, full body CT and peripheral smear are all unremarkable. You smear are all unremarkable. You are consulted by the medical team are consulted by the medical team to assess whether the patient’s to assess whether the patient’s symptoms could be attributable to symptoms could be attributable to infection with CMV. Which of the infection with CMV. Which of the following studies would support following studies would support that diagnosis?that diagnosis?

1.1. 1,000 copies of CMV DNA by PCR from 1,000 copies of CMV DNA by PCR from the peripheral bloodthe peripheral blood

2.2. Positive CMV IgMPositive CMV IgM3.3. Positive urine CMV shell-vial culturePositive urine CMV shell-vial culture4.4. None of the aboveNone of the above

Diagnosis of Viral Infections - Direct

Diagnosis of Viral Infections - Indirect

Diagnostic Virology: Culture Clinical specimen collected and Clinical specimen collected and

either sent directly to lab or placed either sent directly to lab or placed in viral culture mediumin viral culture medium

Specimens then grown on number Specimens then grown on number of different cell lines depending on of different cell lines depending on type of virus suspectedtype of virus suspected

o Diagnosis either by looking for CPE, or Diagnosis either by looking for CPE, or adding fluorescently-tagged antibodies adding fluorescently-tagged antibodies to viral antigensto viral antigens

• ““Shell vial” culture: Diagnosis of CMV or Shell vial” culture: Diagnosis of CMV or BKBK

Advantages: Specific, sensitivity Advantages: Specific, sensitivity testing?testing?

Disadvantages: Slow, not as Disadvantages: Slow, not as sensitive as molecular diagnostics, sensitive as molecular diagnostics, not possible for all virusesnot possible for all viruses

Diagnostic Virology: DFA

Clinical Specimen

Antibody to Viral Protein

Fluorescent label

Diagnostic Virology: EIA

Viral Protein

Sera Containing Antibodies to Viral Protein

Antibody to Human Antibodies

Fluorescent label

Source: http://www.nupedia.com/newsystem/upload_file/678/pcr.png

Diagnostic Virology: PCR

Advantages:Advantages:o RapidRapido SensitiveSensitiveo QuantitativeQuantitative

DisadvantagDisadvantageses

o Too Too sensitive?sensitive?

o SpecificitySpecificityo CostlyCostly

Case 1: HPI 18 y.o. woman from Sitka, Alaska who presents 18 y.o. woman from Sitka, Alaska who presents

with fevers and abdominal pain for 2 weekswith fevers and abdominal pain for 2 weeks Initially presented to ED in AK 2 weeks PTA with Initially presented to ED in AK 2 weeks PTA with

dysuria and mild abdominal paindysuria and mild abdominal paino Treated with TMP-SMX without improvementTreated with TMP-SMX without improvement

Re-presented 3 days later with severe Re-presented 3 days later with severe abdominal pain, headache and temperature to abdominal pain, headache and temperature to 102F. Had diffuse vesicular rash102F. Had diffuse vesicular rash

Admitted to hospital where she had the Admitted to hospital where she had the following labs/studies:following labs/studies:

o Normal CBC, SMA-7, negative UA, negative CXR Normal CBC, SMA-7, negative UA, negative CXR and KUBand KUB

o AST 110, ALT 124, nml INR, GGT, Amylase, Alk PhosAST 110, ALT 124, nml INR, GGT, Amylase, Alk Phos Hospital Course:Hospital Course:

o Subsequent multiple blood and urine cultures Subsequent multiple blood and urine cultures negativenegative

o CT of chest, abdomen and pelvis negativeCT of chest, abdomen and pelvis negativeo Exploratory laparotomy found lesions on the liver Exploratory laparotomy found lesions on the liver

as on the following slideas on the following slideo Persistent fevers and abdominal pain despite Persistent fevers and abdominal pain despite

Cefotetan, Doxycycline and MetronidazoleCefotetan, Doxycycline and Metronidazoleo Transferred to UWMCTransferred to UWMC

Case 1: Hepatic Lesions

Case 1: Physical Exam on Transfer to UWMC

T 38.9, HR T 38.9, HR 110, RR 22, 110, RR 22, BP 118/72BP 118/72

Abd: Diffuse Abd: Diffuse TTP, no TTP, no rebound or rebound or guardingguarding

Skin: Skin: Adjacent Adjacent rashrash

GU: Nml GU: Nml genitaliagenitalia

The Herpesvirus Family HHV-1 : Herpes Simplex 1 (HSV-1)HHV-1 : Herpes Simplex 1 (HSV-1)

o Clinical: Oral HerpesClinical: Oral Herpes HHV-2 : Herpes Simplex 2 (HSV-2)HHV-2 : Herpes Simplex 2 (HSV-2)

o Clinical: Genital HerpesClinical: Genital Herpes

HHV-3 : Varicella Zoster Virus (VZV)HHV-3 : Varicella Zoster Virus (VZV) o Clinical: Chickenpox, ZosterClinical: Chickenpox, Zoster

HHV-4 : Epstein Barr Virus (EBV)HHV-4 : Epstein Barr Virus (EBV)o Clinical: Mono, lymphomaClinical: Mono, lymphoma

HHV-5: Cytomegalovirus (CMV)HHV-5: Cytomegalovirus (CMV)o Clinical: Retinitis, Pneumonitis, etcClinical: Retinitis, Pneumonitis, etc

HHV-6/7: RoseolavirusHHV-6/7: Roseolaviruso Clinical: Exanthem subitumClinical: Exanthem subitum

HHV-8: Kaposi’s Sarcoma-Associated HHV-8: Kaposi’s Sarcoma-Associated Herpesvirus (KSHV)Herpesvirus (KSHV)o Clinical: KS, multicentric Castleman’s disease, primary Clinical: KS, multicentric Castleman’s disease, primary

effusion lymphomaeffusion lymphoma

Herpesvirus Family Characteristics Large, Enveloped DNA-virusesLarge, Enveloped DNA-viruses

o Envelope:Envelope:• Transmission via mucosal surfacesTransmission via mucosal surfaces• Fomite acquisition is uncommonFomite acquisition is uncommon

o LargeLarge• Smart!Smart!

Evolved many complex mechanisms for immune evasion Evolved many complex mechanisms for immune evasion and pathogenesisand pathogenesis

o DNADNA• Use similar cellular machinery to human DNA, so Use similar cellular machinery to human DNA, so

therapy must find novel areas of difference (in therapy must find novel areas of difference (in contrast to HIV)contrast to HIV)

UbiquitousUbiquitouso Except for HSV-2 and HHV-8, all infect more than Except for HSV-2 and HHV-8, all infect more than

50% of most populations worldwide50% of most populations worldwide Latency allows for life-long infectionLatency allows for life-long infection

o Intermittent reactivation and lifelong shedding can Intermittent reactivation and lifelong shedding can make understanding clinical symptoms and make understanding clinical symptoms and diagnostic tests challengingdiagnostic tests challenging

o Long term infection with some herpesvirus can Long term infection with some herpesvirus can lead to cancerlead to cancer

Herpesvirus Therapy: DNA Synthesis Inhibitors

Aciclovir and ganciclovir require viral TK Aciclovir and ganciclovir require viral TK to make dGMP, then cellular kinases make to make dGMP, then cellular kinases make dGTP which terminates DNA synthesisdGTP which terminates DNA synthesis

Cidofovir and foscarnet do not require TKCidofovir and foscarnet do not require TK Ribavirin depletes intracelluar GTPRibavirin depletes intracelluar GTP

Source: Naesens and de Clercq Herpes 2001

Case 2 34 y.o. nurse presents 34 y.o. nurse presents

with 3 weeks of coughing, with 3 weeks of coughing, post-tussive emesis, sinus post-tussive emesis, sinus congestion and malaise in congestion and malaise in JanuaryJanuary

Respiratory Viruses: Clinical Heterogeneous group of viruses Heterogeneous group of viruses

o DNA and RNA, enveloped and DNA and RNA, enveloped and “naked”“naked”

Similar clinical presentationsSimilar clinical presentations Seasonality is importantSeasonality is important

J F M A M J J A S O N D

Influenza

Corona

Metapneumo

Adenovirus

Paraflu

Rhino

RSV

What goes around comes around…

http://depts.washington.edu/rspvirus/http://depts.washington.edu/rspvirus/respiratory.htmrespiratory.htm

Viruses in Health Care Workers, 2007-2008

Respiratory Viruses: Pearls

Influenza: Virus Strains Type AType A - moderate to severe illness- moderate to severe illness

- all age groups- all age groups- - humans and other animalshumans and other animals

- Subtypes of type A determined by hemagglutinin and neuraminidase

Type BType B - milder epidemics- milder epidemics- humans only- humans only- primarily affects children- primarily affects children

Type CType C - rarely reported in humans- rarely reported in humans- no epidemics- no epidemics

Neuraminidase•Antigenic Determinant•Confer virulence•Allow viral mobility throughRespiratory tract

Hemagglutinin•Binds virus to cell•Confers target specificity

RNA

M2 protein•only on type A•Allows H+ ions to enter virus to lower pH for viral uncoating

Influenza Virus

Influenza Antigenic Changes Hemagglutinin and Hemagglutinin and

neuraminidase antigens change neuraminidase antigens change with timewith time

Changes occur as a result of Changes occur as a result of point mutations in the virus gene point mutations in the virus gene (“antigenic drift”), (“antigenic drift”), or due to or due to exchange of a gene segment with exchange of a gene segment with another subtype of influenza another subtype of influenza virus (“antigenic shift”)virus (“antigenic shift”)

Impact of antigenic changes Impact of antigenic changes depend on extent of change depend on extent of change (more change usually means (more change usually means larger impact)larger impact)

Making a Global Influenza Pandemic

OR

Influenza Clinical Features Incubation Incubation

period 2 days period 2 days (range 1-4 days)(range 1-4 days)

Severity of Severity of illness depends illness depends on prior on prior experience with experience with related variantsrelated variants

Abrupt onset of Abrupt onset of fever, myalgia, fever, myalgia, sore throat, sore throat, nonproductive nonproductive cough, cough, headacheheadache

2 3 4 5 6 71

Incubation Period

Day

Infe

ctio

n

Ons

et o

f S

ympt

oms

Contagious

Highest Risk of Infection

The incubation period is from 1 to 2 days. Persons who become ill may shed virus and can transmit infection for up to one day before the onset of illness. Viral shedding and the risk of transmission will be greatest during the first 2 days of illness.

Infected persons are contagious for about a week, although children and immunocompromised patients are contagious for a longer period of time.

Influenza Contagious Period

Influenza Complications PneumoniaPneumonia

o primary influenzaprimary influenza

o secondary bacterialsecondary bacterial

Reye syndromeReye syndrome MyocarditisMyocarditis Death 0.5-1 per 1,000 Death 0.5-1 per 1,000

casescases

Influenza: Treatment & Prophylaxis

M2 InhibitorsM2 Inhibitorso Amantadine and rimantidineAmantadine and rimantidineo ““Effective” against Influenza AEffective” against Influenza A

• 2007, >97% of influenza was resistant2007, >97% of influenza was resistant• SWINE FLU IS RESISTANTSWINE FLU IS RESISTANT

o Inhibit viral replicationInhibit viral replicationo Single mutation confers resistance, occurs Single mutation confers resistance, occurs

with every 1,000-10,000 replicationswith every 1,000-10,000 replications Neuraminidase inhibitorsNeuraminidase inhibitors

o Oseltamivir (oral pill) and Zanamivir Oseltamivir (oral pill) and Zanamivir (inhaled)(inhaled)

o Effective against Influenza A and BEffective against Influenza A and Bo 98% of H1N1 strains (except SWINE FLU) 98% of H1N1 strains (except SWINE FLU)

were resistant in 2008-9!were resistant in 2008-9! Combination therapy?Combination therapy?

o Oseltamavir, rimantidine and ribavirin have Oseltamavir, rimantidine and ribavirin have been shown to have combined efficacybeen shown to have combined efficacy

Respiratory Viruses: Adenovirus

o Common cause of URI and Common cause of URI and keratoconjuntivitis. Has been keratoconjuntivitis. Has been occasionally associated with occasionally associated with pneumonia in community pneumonia in community outbreaks, diarrhea in outbreaks, diarrhea in children, and hepatitis.children, and hepatitis.

o May cause cystitis or May cause cystitis or nephritis in transplant nephritis in transplant patientspatients

o Treatment: Supportive. IV Treatment: Supportive. IV cidofovir may be effective in cidofovir may be effective in the immunocompromisedthe immunocompromised

Respiratory Viruses: Parainfluenza

o Four subtypesFour subtypes• PIV3 seen most commonly in PIV3 seen most commonly in

severe infectionssevere infections

o In children, leading cause of In children, leading cause of croup. Can be a cause of croup. Can be a cause of severe lower respiratory severe lower respiratory tract illness in some children tract illness in some children or transplant patientsor transplant patients

o Treatment is supportive, but Treatment is supportive, but aerosolized ribavirin may be aerosolized ribavirin may be used in life-threatening used in life-threatening casescases

Respiratory Viruses: Metapneumovirus

o Recently identified from Recently identified from retrospective series of retrospective series of unidentified respiratory unidentified respiratory illnesses.illnesses.

o Serologic studies suggest Serologic studies suggest most are infected by 5 years most are infected by 5 years of age, peak 6-12 monthsof age, peak 6-12 months

o Mild URI in most, with rare Mild URI in most, with rare progression to severe LRTIprogression to severe LRTI

o WheezingWheezing is a common initial is a common initial presentationpresentation

o Treatment is supportiveTreatment is supportive

Respiratory Viruses: Coronaviruseso Large family of viruses with Large family of viruses with

multiple animal hostsmultiple animal hostso Generally cause non-specific Generally cause non-specific

symptoms such as fevers, symptoms such as fevers, myalgias, fatigue. May progresses myalgias, fatigue. May progresses to non-productive cough and to non-productive cough and dyspnea.dyspnea.

o Diagnosis is by PCR, and treatment Diagnosis is by PCR, and treatment is supportiveis supportive

o SARSSARS• Newly identified virus associated with Newly identified virus associated with

severe LRTI in Asia in 2003. Thought to severe LRTI in Asia in 2003. Thought to be transmitted by contact with small be transmitted by contact with small mammals (civets) in Asia, spread mammals (civets) in Asia, spread between humans through respiratory between humans through respiratory droplets and fecesdroplets and feces

• Development of respiratory failure Development of respiratory failure occurs in minority of cases, but may be occurs in minority of cases, but may be more common in Asian personsmore common in Asian persons

PCR for Respiratory Virus Detection

Problem of Problem of inadequate inadequate specimens for specimens for immunoblot or immunoblot or DFADFA

PCR is more PCR is more sensitive and sensitive and perhaps equally perhaps equally as specificas specific

Molecular Molecular Virology Lab Virology Lab now offers now offers multiplex PCR multiplex PCR for detection of for detection of 12 viruses12 viruses Kuypers, et al 2006

Gastrointestinal Viruses Most common viruses to cause Most common viruses to cause

gastrointestinal illnesses are gastrointestinal illnesses are Norovirus, calicivirus, rotavirus, Norovirus, calicivirus, rotavirus, astrovirus, and adenovirus astrovirus, and adenovirus

Present with diarrhea, fever Present with diarrhea, fever and/or abdominal pain. Children and/or abdominal pain. Children more often affected, although more often affected, although incidence high in institutional or incidence high in institutional or “closed” settings (i.e. cruise “closed” settings (i.e. cruise ships)ships)

Transmission via fecal-oral routeTransmission via fecal-oral route Diagnosis: Diagnosis:

o PCR of stool, or plasma PCR if PCR of stool, or plasma PCR if disseminated disease suspected disseminated disease suspected (adenovirus)(adenovirus)

Case 3 21 year old UW student 21 year old UW student

presents with fever to 39, presents with fever to 39, headache, stiff neck and headache, stiff neck and photophobia shortly after photophobia shortly after returning for Fall Quarterreturning for Fall Quarter

Student health service Student health service concerned about risk of concerned about risk of meningitis epidemicmeningitis epidemic

Case 3: Continued Physical Physical

examination examination revealed the revealed the following:following:

Enteroviruses Large group of viruses Large group of viruses

including the subgroups: including the subgroups: poliovirus, echovirus, and poliovirus, echovirus, and coxsackievirusescoxsackieviruses

Worldwide pathogens with Worldwide pathogens with most infections in summer and most infections in summer and fallfall

Chronic meningoencephalitis Chronic meningoencephalitis among persons with among persons with agammaglobulinemiaagammaglobulinemia

DiagnosisDiagnosiso PCR of stool, oropharynx or CSF PCR of stool, oropharynx or CSF

Enteroviruses: Coxsackievirus Common causes of aseptic Common causes of aseptic

meningitismeningitis Heterogeneous and non-Heterogeneous and non-

distinct exanthems (skin distinct exanthems (skin rashes). Exception: Hand-Foot-rashes). Exception: Hand-Foot-Mouth (Coxsackievirus A16) Mouth (Coxsackievirus A16) with oral vesicles and with oral vesicles and papules/vesicles on palms and papules/vesicles on palms and soles.soles.

Complications: Complications: o Group AGroup A

• herpangina (dysphagia with lesions herpangina (dysphagia with lesions on soft palate)on soft palate)

o Group B Group B • MyopericarditisMyopericarditis

Case 4 62 y.o. man taken to HMC 62 y.o. man taken to HMC

from cruise ship docked at from cruise ship docked at Pier 66 with fevers, altered Pier 66 with fevers, altered mental status, and mental status, and weakness in the left legweakness in the left leg

FLAVIVIRUSESo Heterogeneous group of zoonotic / arthropod Heterogeneous group of zoonotic / arthropod

transmitted virusestransmitted viruses• West Nile VirusWest Nile Virus• DengueDengue• Yellow FeverYellow Fever• Japanese EncephalitisJapanese Encephalitis• St. Louis EncephalitisSt. Louis Encephalitis• Tick-Borne EncephalitisTick-Borne Encephalitis

o DiagnosisDiagnosis• Serology Serology

IgM during acute illness or IgG in convalescenceIgM during acute illness or IgG in convalescence Serum should be collected 8-10 days after illness

onset. Follow up with a convalescent serum specimen

obtained at least 2 weeks after the first specimen. CSF should be collected within 8 days of illness

onset. IgM may appear in CSF earlier than in serum.

IgM does not cross the blood brain barrier: its presence in CSF indicates neuroinvasive disease.

IgM antibody can persist for more than Non-specific (but this may be a good thing!)Non-specific (but this may be a good thing!)

• PCRPCR Less sensitive, but useful in immunocompromised Less sensitive, but useful in immunocompromised

hostshosts

Flaviviruses: West Nile Virus Rapidly emerging virus across Rapidly emerging virus across

U.S. since 1999U.S. since 1999o WA one of the few states without WA one of the few states without

any documented infectionsany documented infections Transmitted from reservoirs in Transmitted from reservoirs in

birds to human via mosquitoesbirds to human via mosquitoes Majority of infections are Majority of infections are

without symptoms or only with without symptoms or only with fever and malaise, but most fever and malaise, but most severe complication is severe complication is neurological (encephalitis and neurological (encephalitis and muscle weaknessmuscle weakness))

West Nile Distribution, 2008

Flaviviruses: Dengue Tropical virus transmitted by Tropical virus transmitted by

Aedes aegypti Aedes aegypti (day biting) (day biting) mosquitomosquito

Illness characterized by high Illness characterized by high fever, headache (often retro-fever, headache (often retro-orbital), myalgias/arthralgias orbital), myalgias/arthralgias and rashand rash

Hemorrhagic fever or shock Hemorrhagic fever or shock may occur shortly after may occur shortly after resolution of fever. May be resolution of fever. May be more common in persons more common in persons previously exposed.previously exposed.

Flaviviruses: Yellow Fever Endemic to sub-Saharan Africa Endemic to sub-Saharan Africa

and South Americaand South America Transmitted by mosquito bitesTransmitted by mosquito bites Symptoms range from Symptoms range from

constitutional to severe. constitutional to severe. Symptomatic patients likely to Symptomatic patients likely to experience headache, altered experience headache, altered mental status, icterus, and mental status, icterus, and many have diffuse hemorrhagemany have diffuse hemorrhage

Preventable by vaccine, which Preventable by vaccine, which may cause vaccine-induced may cause vaccine-induced encephalitis among young encephalitis among young infants or the elderlyinfants or the elderly

Other Flaviviruses Japanese Encephalitis Japanese Encephalitis

o High fevers and altered mental status High fevers and altered mental status o Endemic to regions in Asia where Endemic to regions in Asia where

mosquitoes interact with pigs and birdsmosquitoes interact with pigs and birds St. Louis EncephalitisSt. Louis Encephalitis

o Fevers and altered mental status, Fevers and altered mental status, especially among the elderly. especially among the elderly.

o Seen in North, Central and South Seen in North, Central and South America as well as the Caribbean. America as well as the Caribbean.

Tick-Borne EncephalitisTick-Borne Encephalitiso Infection via Infection via IxodesIxodes species ticks species tickso Europe and Asia Europe and Asia o History: persons with outdoor exposure. History: persons with outdoor exposure. o Presents with fever, but may progress to Presents with fever, but may progress to

altered mental status and paralysis.altered mental status and paralysis.

Case 5 28 year old 28 year old

latina sheep-latina sheep-sheerer from sheerer from Oregon Oregon presents to presents to UWMC with UWMC with increasing increasing lesion on lesion on hand hand

Poxviruses: Orthopox Monkeypox: recently spread Monkeypox: recently spread

by prairie dogs by prairie dogs Cowpox: cause “milkers Cowpox: cause “milkers

nodules” on hands of dairy nodules” on hands of dairy workersworkers

ORF: nodule on hands, arms or ORF: nodule on hands, arms or face after exposure to face after exposure to ruminantsruminants

SmallpoxSmallpox DiagnosisDiagnosis

o Electron MicroscopyElectron Microscopy

Poxviruses: Smallpoxo Smallpox is the only infectious disease Smallpox is the only infectious disease

eradicated with vaccination, now threatening eradicated with vaccination, now threatening to return in the setting of bioterrorismto return in the setting of bioterrorism

o Infection via respiratory droplets or contact Infection via respiratory droplets or contact with infected lesions. Acquisition is largely with infected lesions. Acquisition is largely asymptomatic for first 7-10 days, followed by asymptomatic for first 7-10 days, followed by a non-specific prodrome consisting of fevers a non-specific prodrome consisting of fevers and malaise. and malaise.

o Patient becomes infectious upon Patient becomes infectious upon development of rash. Typically, rash is development of rash. Typically, rash is maculopapular, starts in the maculopapular, starts in the oropoharynx/head/neck/upper extremities, oropoharynx/head/neck/upper extremities, and moves caudally. Lesions are usually and moves caudally. Lesions are usually in in the same stagethe same stage (i.e. vesicular, pustular, (i.e. vesicular, pustular, crusted), which differentiates the lesion from crusted), which differentiates the lesion from varicella.varicella.

o Diagnosis is by PCR or electron microscopy of Diagnosis is by PCR or electron microscopy of vesicular fluidvesicular fluid

o Treatment is supportive, although cidofovir Treatment is supportive, although cidofovir may be effective if given early after may be effective if given early after infection. Vaccination within 4 days of infection. Vaccination within 4 days of exposure may mitigate course of infectionexposure may mitigate course of infection

Poxviruses: Parapox Molluscum contagiousumMolluscum contagiousum

o Umbilicated firm cutaneous Umbilicated firm cutaneous o May be more persistent in May be more persistent in

immunocompromised adultsimmunocompromised adultso Typically is treated with Typically is treated with

curettage or cryotherapy.curettage or cryotherapy.

Case 6 26 year old medical 26 year old medical

student wanders on to student wanders on to general medical ward with general medical ward with conjunctival hemorrhages, conjunctival hemorrhages, fever, and confusionfever, and confusion

HEMORRHAGIC VIRUSES FiloviridaeFiloviridae

o EbolaEbolao MarburgMarburg

Bunyaviridae Bunyaviridae o HantavirusHantaviruso Rift Valley FeverRift Valley Fevero Crimean-Congo Hemorrhagic FeverCrimean-Congo Hemorrhagic Fever

Arenaviridae Arenaviridae o Lassa virusLassa virus

DiagnosisDiagnosiso Serology from CDC or PCRSerology from CDC or PCR

Filoviridae Ebola and Ebola and

MarburgMarburg Acquired Acquired

through contact through contact with non-human with non-human primates in primates in AfricaAfrica

Fevers and Fevers and myalgias are myalgias are followed by followed by maculopapular maculopapular rash, after rash, after which between which between 10 and 50% will 10 and 50% will develop develop disseminated disseminated intravascular intravascular coagulationcoagulation

Bunyaviridae Rift Valley FeverRift Valley Fever

o Transmitted by Transmitted by AedesAedes mosquitos in sub- mosquitos in sub-Saharan AfricaSaharan Africa

o Three clinical syndromesThree clinical syndromes• Non-specific febrile illness (~90%)Non-specific febrile illness (~90%)• Macular Retinitis / Vasculitis (10%)Macular Retinitis / Vasculitis (10%)• Fulminant disease: hepatic failure / Fulminant disease: hepatic failure /

hemorrhagehemorrhage Crimean-Congo Hemorrhagic FeverCrimean-Congo Hemorrhagic Fever

o Transmitted by ticks in Southwest Asia, Transmitted by ticks in Southwest Asia, Middle East and AfricaMiddle East and Africa

• Hemorrhagic fever / DIC in 20-50%Hemorrhagic fever / DIC in 20-50% HantavirusHantavirus

o Transmitted by wild rodentsTransmitted by wild rodentso Two typesTwo types

• Asian strains: fever and renal failureAsian strains: fever and renal failure• North American strains: fever and North American strains: fever and

pulmonary edemapulmonary edema

Arenaviruses Transmitted to humans via Transmitted to humans via

contact with rodentscontact with rodents Endemic to Africa and South Endemic to Africa and South

AmericaAmerica Lassa feverLassa fever

o Severe systemic illness with Severe systemic illness with shockshock

o ~20% mortality~20% mortality

Lymphocytic Choriormeningitis Lymphocytic Choriormeningitis Virus (LCMV)Virus (LCMV)

o Aseptic meningitis with low Aseptic meningitis with low mortalitymortality

Case 7 You are You are

called in the called in the middle of the middle of the night night because because sibling’s sibling’s child has child has high fevers high fevers and an and an unusual rashunusual rash

PARVOVIRUS Smallest DNA virusSmallest DNA virus EpidemiologyEpidemiology

o Widespread infectionWidespread infection• 50% of adolescents and nearly all elderly persons have 50% of adolescents and nearly all elderly persons have

serum antibodies to Parvovirus B19serum antibodies to Parvovirus B19o Spread among close contacts by respiratory droplets Spread among close contacts by respiratory droplets

or bloodor blood ClinicalClinical

o Cause of erhythema infectiousum (“slapped cheek” or Cause of erhythema infectiousum (“slapped cheek” or 55thth disease), arthritis, red cell aplasia or aplastic crisis, disease), arthritis, red cell aplasia or aplastic crisis, and hemophagocytic syndromeand hemophagocytic syndrome

o Fetal infection may lead to hydrops fetalis or Fetal infection may lead to hydrops fetalis or miscarriage miscarriage

• 10% fetal loss in 110% fetal loss in 1stst trimester pregnancies trimester pregnancies• Risk of hydrops greatest in 3Risk of hydrops greatest in 3rdrd trimester trimester

o Immunocompromised patients may have chronic low-Immunocompromised patients may have chronic low-level viremia which is not associated with diseaselevel viremia which is not associated with disease

Consider IVIG in non-immune, exposed pregnant Consider IVIG in non-immune, exposed pregnant womenwomen

DiagnosisDiagnosiso Plasma PCRPlasma PCRo Low reticulocyte count in presence of anemia could be Low reticulocyte count in presence of anemia could be

an early diagnostic cluean early diagnostic clue

Case 8 7 year old boy 7 year old boy

presents with presents with fever and rash fever and rash after visiting after visiting Hunan Province Hunan Province of Chinaof China

Also traveled to Also traveled to Hong Kong and Hong Kong and San FranciscoSan Francisco

11 other 11 other children had children had fever and fever and similar rash similar rash

Measles (Rubeola) VirologyVirology

o Extremely infectious paramyxovirus spread Extremely infectious paramyxovirus spread through contact with respiratory dropletsthrough contact with respiratory droplets

o Nearly 2 week incubation period followed by Nearly 2 week incubation period followed by SymptomsSymptoms

o Constitutional symptomsConstitutional symptomso ““Classic”: cough, coryza and Koplik’s spots Classic”: cough, coryza and Koplik’s spots

(small, bluish granules on erythematous (small, bluish granules on erythematous buccal mucosa)buccal mucosa)

o Erythematous maculopapular rash spread Erythematous maculopapular rash spread cranio-caudally and may desquamate and cranio-caudally and may desquamate and involve palms / soles.involve palms / soles.

ComplicationsComplicationso Pneumonia with secondary bacterial Pneumonia with secondary bacterial

superinfectionsuperinfectiono Encephalitis (may be chronic in subacute Encephalitis (may be chronic in subacute

sclerosing panencephalitis)sclerosing panencephalitis) DiagnosisDiagnosis

o SerologySerology

Measles: Koplik’s Spots

Mumps Paramyxovirus acquired through Paramyxovirus acquired through

nasopharyngeal contact with nasopharyngeal contact with respiratory droplets or fomitesrespiratory droplets or fomites

Extended (2-4 week) incubation Extended (2-4 week) incubation periodperiod

Clinical illness heralded by Clinical illness heralded by otalgia and parotid hypertrophy otalgia and parotid hypertrophy and sialadenitis, and may be and sialadenitis, and may be followed by meningitis, followed by meningitis, encephalitis or orchitisencephalitis or orchitis

Diagnosis:Diagnosis:o SerologySerology

Rubella (German Measles) Benign viral infection Benign viral infection

characterized by fever and characterized by fever and maculopapular non-maculopapular non-confluent craniocaudal confluent craniocaudal rash. rash.

May occasionally be May occasionally be complicated by arthralgiacomplicated by arthralgia

Congenital infectionCongenital infectiono May lead to fetal death and May lead to fetal death and

congenital abnormalities, congenital abnormalities, including hearing loss, heart including hearing loss, heart disease, cognitive delaydisease, cognitive delay

  

                                                 

                     

HSV-1: EpidemiologyPrevalencePrevalence

o Worldwide, 90% of people Worldwide, 90% of people seropositive for HSV-1 by age seropositive for HSV-1 by age 4040

o In US, approximately 50% and In US, approximately 50% and declining, but closer to 90% in declining, but closer to 90% in groups with low SESgroups with low SES

TransmissionTransmissiono Via salivaVia salivao Vesicles>Ulcers>AsymptomaticVesicles>Ulcers>Asymptomatic

• Culture positivity: 80%, 33% and Culture positivity: 80%, 33% and <25% respectively<25% respectively

HSV-1: Primary Infection AsymptomaticAsymptomatic

o 47% of people with positive HSV-1 serology 47% of people with positive HSV-1 serology do not recall history of oral / genital ulcersdo not recall history of oral / genital ulcers

Oral or Genital UlcersOral or Genital Ulcerso Fever / pharyngitis in first 12-24 hours (oral)Fever / pharyngitis in first 12-24 hours (oral)o Vesicles by median of 7 daysVesicles by median of 7 dayso Resolved by 14 daysResolved by 14 days

Skin InfectionsSkin Infectionso Herpetic WhitlowHerpetic Whitlow

Ocular DiseaseOcular Diseaseo Leading cause of blindness worldwide is Leading cause of blindness worldwide is

Herpes Keratitis!Herpes Keratitis! EncephalitisEncephalitis

o Neonates or immunocompromisedNeonates or immunocompromised PneumonitisPneumonitis

o Neonates or immunocompromisedNeonates or immunocompromised HepatitisHepatitis

o Fulminant and fatal in 80%Fulminant and fatal in 80%

HSV-1: Recurrences Oral / Genital Ulcer DiseaseOral / Genital Ulcer Disease

o Recurrence rates vary greatly by individualRecurrence rates vary greatly by individualo 85% with prodrome 24h prior to lesion, 85% with prodrome 24h prior to lesion,

then lesion x 8dthen lesion x 8do HSV-1 recurs infrequently at genital sites HSV-1 recurs infrequently at genital sites

(average once per year)(average once per year) EncephalitisEncephalitis

o Recurrences after primary encephalitis not Recurrences after primary encephalitis not uncommon (in contrast to HSV-2)uncommon (in contrast to HSV-2)

o First episode of encephalitis may result First episode of encephalitis may result from reactivation of HSV-1 from oral from reactivation of HSV-1 from oral primary in trigeminal ganglionprimary in trigeminal ganglion

PneumonitisPneumonitiso First episode of pneumonitis may result First episode of pneumonitis may result

from aspirating reactivated oral HSV-1 from aspirating reactivated oral HSV-1 during intubation or AMSduring intubation or AMS

HSV-1: Diagnosis SerologicSerologic

o Detect IgG antibodies to HSV-1 and 2 gG (envelope Detect IgG antibodies to HSV-1 and 2 gG (envelope glycoprotein)glycoprotein)

o Develop within 7-21 daysDevelop within 7-21 days• May be delayed by use of antiviralsMay be delayed by use of antivirals

o Some antibody assays have difficulty Some antibody assays have difficulty differentiating between HSV-1 and 2differentiating between HSV-1 and 2

o IgM testing is unreliableIgM testing is unreliable VirologicVirologic

o ““Looking” for the virusLooking” for the virus• TzanckTzanck

Insensitive and not specificInsensitive and not specific• DFADFA

Rapid, specific and pretty sensitive for persons with active Rapid, specific and pretty sensitive for persons with active lesionslesions

o Growing the virusGrowing the virus• CultureCulture

Sensitive, specific, time consuming (3-7 days)Sensitive, specific, time consuming (3-7 days)

o Amplifying viral DNAAmplifying viral DNA• PCRPCR

Sensitive, specific, rapidSensitive, specific, rapid Prone to contaminationProne to contamination Not widely availableNot widely available

VZV – Natural History

Source: Gilden DH, et. al. N Engl J Med 2000 342: 635-645

Varicella Zoster Virus – Clinical Syndromes

Varicella (Primary Infection)Varicella (Primary Infection)o 90-95% of persons by the age of 18 90-95% of persons by the age of 18

have had chickenpoxhave had chickenpox Zoster (Recurrent)Zoster (Recurrent)

o Common: 30-50 cases per 1000 Common: 30-50 cases per 1000 person yearsperson years

o 20-30% of patients with HIV will 20-30% of patients with HIV will develop Zosterdevelop Zoster

• More likely to be multi-dermatomalMore likely to be multi-dermatomal• Associated with Immune Associated with Immune

ReconstitutionReconstitution 8% in one study8% in one study

Domingo P, Am J Med 2001; 110:605-9

Chronic encephalitisChronic encephalitiso Seen rarely outside Seen rarely outside

immunocompromised personsimmunocompromised personso Subacute headache, fever, altered Subacute headache, fever, altered

mental statusmental status Acute Retinal NecrosisAcute Retinal Necrosis

o Weeks to months after varicella or Weeks to months after varicella or zosterzoster

o Likely due to hematogenous spread, Likely due to hematogenous spread, so initial lesion at site distant to eye so initial lesion at site distant to eye does not rule out ARNdoes not rule out ARN

o 75-85% chance of detachment 75-85% chance of detachment leading to blindness, with little leading to blindness, with little benefit from antiviralsbenefit from antivirals

• May prevent spread to contralateral May prevent spread to contralateral eyeeye

Source: http://www.dermis.net/bilder/CD18/img0054.jpg

EBV: Primary Infection AsymptomaticAsymptomatic

o Common in kids under 2Common in kids under 2o May have negative MonospotMay have negative Monospot

Infectious MonoInfectious Monoo Fever, malaise, pharyngitis, Fever, malaise, pharyngitis,

lymphadenopathy, atypical lymphadenopathy, atypical lymphocytosis, splenomegaly lymphocytosis, splenomegaly without jaundice or hepatomegalywithout jaundice or hepatomegaly

Hemophagocytic syndromeHemophagocytic syndrome

EBV: Malignancies after Chronic Infection

MechanismMechanismo Persistent infection / activation of B cells Persistent infection / activation of B cells

coupled with viral immune evasion and coupled with viral immune evasion and control of cell cyclecontrol of cell cycle

Burkitt’sBurkitt’so Most common malignancy in childhood in Most common malignancy in childhood in

Africa, along malaria beltAfrica, along malaria belt HIV Associated LymphomasHIV Associated Lymphomas

o Primary CNSPrimary CNSo NHLNHL

Nasopharyngeal CarcinomaNasopharyngeal Carcinoma Post-Transplant Lymphoproliferative Post-Transplant Lymphoproliferative

DisorderDisordero Associated with degree of Associated with degree of

immunosuppression after SOTimmunosuppression after SOTo Lung (up to 9%)>Heart>Kidney>Liver (1-2%)Lung (up to 9%)>Heart>Kidney>Liver (1-2%)o Risk Factors: Lymphocyte depletion (OKT3 or Risk Factors: Lymphocyte depletion (OKT3 or

ATG), D+/R-ATG), D+/R-

EBV: Diagnostic Tools and Cautions

SerologicSerologico Heterophile Test (MonoSpot)Heterophile Test (MonoSpot)

• Antibodies to sheep erythrocytesAntibodies to sheep erythrocytes• Develop in up to 70% of patients and may persist for Develop in up to 70% of patients and may persist for

> 1 year> 1 yearo Antibodies to EBV ProteinsAntibodies to EBV Proteins

• Viral Capsid Antigen (VCA)Viral Capsid Antigen (VCA) IgM develop immediately and rapidly fall, but laboratory IgM develop immediately and rapidly fall, but laboratory

test is difficult and prone to inaccuracytest is difficult and prone to inaccuracy IgG develop rapidly and persist (not useful for diagnosis)IgG develop rapidly and persist (not useful for diagnosis)

• Epstein Barr Nuclear Antigen (EBNA)Epstein Barr Nuclear Antigen (EBNA) Appears at the end of course of IM and persists for lifeAppears at the end of course of IM and persists for life Allows for viral latencyAllows for viral latency

• Early Antigen (EA)Early Antigen (EA) Develop within 2-4 weeks and disappearDevelop within 2-4 weeks and disappear

Virologic (PCR)Virologic (PCR)o PCR for EBV from blood should be interpreted with PCR for EBV from blood should be interpreted with

cautioncaution• May be found in blood from asymptomatic individuals May be found in blood from asymptomatic individuals

Possibly due to B-cell stimulationPossibly due to B-cell stimulation• Quantity does NOT predict development of malignancyQuantity does NOT predict development of malignancy

o Helpful from CSF to predict CNS lymphomaHelpful from CSF to predict CNS lymphoma

HHV-8 DiseasesDiseases

o Kaposi SarcomaKaposi Sarcomao Primary Effusion LymphomaPrimary Effusion Lymphomao Multicentric Castleman DiseaseMulticentric Castleman Diseaseo Prostate Cancer?Prostate Cancer?o Multiple Myeloma – NOMultiple Myeloma – NOo Pulmonary Hypertension - NOPulmonary Hypertension - NO

PrevalencePrevalenceo General PopulationGeneral Population

• Random Blood Donors: US 5%, Italy 20-30%, Random Blood Donors: US 5%, Italy 20-30%, Middle East 20-30%, Africa 20-100%, South Middle East 20-30%, Africa 20-100%, South America 3-70%, Asia 5-30%America 3-70%, Asia 5-30%

o High Risk GroupsHigh Risk Groups• MSM: 20-30% HIV-negative in US, 30-50% HIV-MSM: 20-30% HIV-negative in US, 30-50% HIV-

pospos• Recent study suggests that women in the Recent study suggests that women in the

United States may also have high rates of United States may also have high rates of infection (16%)infection (16%)

HHV-8: Pictures