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Viral Infections in the Immunocompetent Host


Viral Infections in the Immunocompetent Host Corey Casper, M.D., M.P.H. Division of Infectious Disease, Department of Medicine The University of Washington – PowerPoint PPT presentation

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Title: Viral Infections in the Immunocompetent Host

Viral Infections in the Immunocompetent Host
  • Corey Casper, M.D., M.P.H.
  • Division of Infectious Disease, Department of
  • The University of Washington
  • Vaccine and Infectious Disease Institute,
  • Fred Hutchinson Cancer Research Center

  • Classification of Viruses
  • Classical vs. Other Schemes
  • Diagnosis of Viral Infections
  • Common Viral Infections for the Infectious
    Disease Consultant

Classification of Viruses
Classification of Viruses
  • Classic Taxonomy
  • Nucleic Acid Structure
  • DNA vs. RNA
  • Single vs. Double Stranded
  • Envelope
  • Presence or absence
  • Organization of genome
  • Example Paramyxoviruses
  • Mode of transcription
  • Example Retroviruses
  • Functional Taxonomy
  • Group viruses by primary organ system involved in
    the pathology of disease
  • Example Respiratory Viruses
  • Group viruses with similar treatments
  • Example Herpesviruses

Your Mother Knows Best?
  • Which of the following viruses would you be most
    likely to acquire from touching a toilet seat?
    True MedCon Call!
  • HIV
  • Calicivirus
  • Herpes Simplex Virus-2
  • Parainfluenza

Viral Structure
Player or Bystander?
  • A 63 y.o. man presents from an outside hospital
    with fever and headache for 2 weeks. Multiple
    blood, urine, CSF, and sputum cultures have been
    negative. Chest X-ray, full body CT and
    peripheral smear are all unremarkable. You are
    consulted by the medical team to assess whether
    the patients symptoms could be attributable to
    infection with CMV. Which of the following
    studies would support that diagnosis?
  • 1,000 copies of CMV DNA by PCR from the
    peripheral blood
  • Positive CMV IgM
  • Positive urine CMV shell-vial culture
  • None of the above

Diagnosis of Viral Infections - Direct
Diagnosis of Viral Infections - Indirect
Diagnostic Virology Culture
  • Clinical specimen collected and either sent
    directly to lab or placed in viral culture medium
  • Specimens then grown on number of different cell
    lines depending on type of virus suspected
  • Diagnosis either by looking for CPE, or adding
    fluorescently-tagged antibodies to viral antigens
  • Shell vial culture Diagnosis of CMV or BK
  • Advantages Specific, sensitivity testing?
  • Disadvantages Slow, not as sensitive as
    molecular diagnostics, not possible for all

Diagnostic Virology DFA
Fluorescent label
Antibody to Viral Protein
Clinical Specimen
Diagnostic Virology EIA
Diagnostic Virology PCR
  • Advantages
  • Rapid
  • Sensitive
  • Quantitative
  • Disadvantages
  • Too sensitive?
  • Specificity
  • Costly

Source http//
Case 1 HPI
  • 18 y.o. woman from Sitka, Alaska who presents
    with fevers and abdominal pain for 2 weeks
  • Initially presented to ED in AK 2 weeks PTA with
    dysuria and mild abdominal pain
  • Treated with TMP-SMX without improvement
  • Re-presented 3 days later with severe abdominal
    pain, headache and temperature to 102F. Had
    diffuse vesicular rash
  • Admitted to hospital where she had the following
  • Normal CBC, SMA-7, negative UA, negative CXR and
  • AST 110, ALT 124, nml INR, GGT, Amylase, Alk Phos
  • Hospital Course
  • Subsequent multiple blood and urine cultures
  • CT of chest, abdomen and pelvis negative
  • Exploratory laparotomy found lesions on the liver
    as on the following slide
  • Persistent fevers and abdominal pain despite
    Cefotetan, Doxycycline and Metronidazole
  • Transferred to UWMC

Case 1 Hepatic Lesions
Case 1 Physical Exam on Transfer to UWMC
  • T 38.9, HR 110, RR 22, BP 118/72
  • Abd Diffuse TTP, no rebound or guarding
  • Skin Adjacent rash
  • GU Nml genitalia

The Herpesvirus Family
  • HHV-1 Herpes Simplex 1 (HSV-1)
  • Clinical Oral Herpes
  • HHV-2 Herpes Simplex 2 (HSV-2)
  • Clinical Genital Herpes
  • HHV-3 Varicella Zoster Virus (VZV)
  • Clinical Chickenpox, Zoster
  • HHV-4 Epstein Barr Virus (EBV)
  • Clinical Mono, lymphoma
  • HHV-5 Cytomegalovirus (CMV)
  • Clinical Retinitis, Pneumonitis, etc
  • HHV-6/7 Roseolavirus
  • Clinical Exanthem subitum
  • HHV-8 Kaposis Sarcoma-Associated Herpesvirus
  • Clinical KS, multicentric Castlemans disease,
    primary effusion lymphoma

Herpesvirus Family Characteristics
  • Large, Enveloped DNA-viruses
  • Envelope
  • Transmission via mucosal surfaces
  • Fomite acquisition is uncommon
  • Large
  • Smart!
  • Evolved many complex mechanisms for immune
    evasion and pathogenesis
  • DNA
  • Use similar cellular machinery to human DNA, so
    therapy must find novel areas of difference (in
    contrast to HIV)
  • Ubiquitous
  • Except for HSV-2 and HHV-8, all infect more than
    50 of most populations worldwide
  • Latency allows for life-long infection
  • Intermittent reactivation and lifelong shedding
    can make understanding clinical symptoms and
    diagnostic tests challenging
  • Long term infection with some herpesvirus can
    lead to cancer

Herpesvirus Therapy DNA Synthesis Inhibitors
  • Aciclovir and ganciclovir require viral TK to
    make dGMP, then cellular kinases make dGTP which
    terminates DNA synthesis
  • Cidofovir and foscarnet do not require TK
  • Ribavirin depletes intracelluar GTP

Source Naesens and de Clercq Herpes 2001
Case 2
  • 34 y.o. nurse presents with 3 weeks of coughing,
    post-tussive emesis, sinus congestion and malaise
    in January

Respiratory Viruses Clinical
  • Heterogeneous group of viruses
  • DNA and RNA, enveloped and naked
  • Similar clinical presentations
  • Seasonality is important

What goes around comes around
  • http//

Viruses in Health Care Workers, 2007-2008
Respiratory Viruses Pearls
Influenza Virus Strains
  • Type A - moderate to severe illness - all age
    groups - humans and other animals
  • - Subtypes of type A determined by hemagglutinin
    and neuraminidase
  • Type B - milder epidemics - humans only -
    primarily affects children
  • Type C - rarely reported in humans - no

Influenza Virus
  • Neuraminidase
  • Antigenic Determinant
  • Confer virulence
  • Allow viral mobility through
  • Respiratory tract
  • Hemagglutinin
  • Binds virus to cell
  • Confers target specificity

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

Influenza Antigenic Changes
  • Hemagglutinin and neuraminidase antigens change
    with time
  • Changes occur as a result of point mutations in
    the virus gene (antigenic drift), or due to
    exchange of a gene segment with another subtype
    of influenza virus (antigenic shift)
  • Impact of antigenic changes depend on extent of
    change (more change usually means larger impact)

Making a Global Influenza Pandemic
Influenza Clinical Features
  • Incubation period 2 days (range 1-4 days)
  • Severity of illness depends on prior experience
    with related variants
  • Abrupt onset of fever, myalgia, sore throat,
    nonproductive cough, headache

Influenza Complications
  • Pneumonia
  • primary influenza
  • secondary bacterial
  • Reye syndrome
  • Myocarditis
  • Death 0.5-1 per 1,000 cases

Influenza Treatment Prophylaxis
  • M2 Inhibitors
  • Amantadine and rimantidine
  • Effective against Influenza A
  • 2007, gt97 of influenza was resistant
  • Inhibit viral replication
  • Single mutation confers resistance, occurs with
    every 1,000-10,000 replications
  • Neuraminidase inhibitors
  • Oseltamivir (oral pill) and Zanamivir (inhaled)
  • Effective against Influenza A and B
  • 98 of H1N1 strains (except SWINE FLU) were
    resistant in 2008-9!
  • Combination therapy?
  • Oseltamavir, rimantidine and ribavirin have been
    shown to have combined efficacy

Respiratory Viruses Adenovirus
  • Common cause of URI and keratoconjuntivitis. Has
    been occasionally associated with pneumonia in
    community outbreaks, diarrhea in children, and
  • May cause cystitis or nephritis in transplant
  • Treatment Supportive. IV cidofovir may be
    effective in the immunocompromised

Respiratory Viruses Parainfluenza
  • Four subtypes
  • PIV3 seen most commonly in severe infections
  • In children, leading cause of croup. Can be a
    cause of severe lower respiratory tract illness
    in some children or transplant patients
  • Treatment is supportive, but aerosolized
    ribavirin may be used in life-threatening cases

Respiratory Viruses Metapneumovirus
  • Recently identified from retrospective series of
    unidentified respiratory illnesses.
  • Serologic studies suggest most are infected by 5
    years of age, peak 6-12 months
  • Mild URI in most, with rare progression to severe
  • Wheezing is a common initial presentation
  • Treatment is supportive

Respiratory Viruses Coronaviruses
  • Large family of viruses with multiple animal
  • Generally cause non-specific symptoms such as
    fevers, myalgias, fatigue. May progresses to
    non-productive cough and dyspnea.
  • Diagnosis is by PCR, and treatment is supportive
  • SARS
  • Newly identified virus associated with severe
    LRTI in Asia in 2003. Thought to be transmitted
    by contact with small mammals (civets) in Asia,
    spread between humans through respiratory
    droplets and feces
  • Development of respiratory failure occurs in
    minority of cases, but may be more common in
    Asian persons

PCR for Respiratory Virus Detection
  • Problem of inadequate specimens for immunoblot or
  • PCR is more sensitive and perhaps equally as
  • Molecular Virology Lab now offers multiplex PCR
    for detection of 12 viruses

Kuypers, et al 2006
Gastrointestinal Viruses
  • Most common viruses to cause gastrointestinal
    illnesses are Norovirus, calicivirus, rotavirus,
    astrovirus, and adenovirus
  • Present with diarrhea, fever and/or abdominal
    pain. Children more often affected, although
    incidence high in institutional or closed
    settings (i.e. cruise ships)
  • Transmission via fecal-oral route
  • Diagnosis
  • PCR of stool, or plasma PCR if disseminated
    disease suspected (adenovirus)

Case 3
  • 21 year old UW student presents with fever to 39,
    headache, stiff neck and photophobia shortly
    after returning for Fall Quarter
  • Student health service concerned about risk of
    meningitis epidemic

Case 3 Continued
  • Physical examination revealed the following

  • Large group of viruses including the subgroups
    poliovirus, echovirus, and coxsackieviruses
  • Worldwide pathogens with most infections in
    summer and fall
  • Chronic meningoencephalitis among persons with
  • Diagnosis
  • PCR of stool, oropharynx or CSF

Enteroviruses Coxsackievirus
  • Common causes of aseptic meningitis
  • Heterogeneous and non-distinct exanthems (skin
    rashes). Exception Hand-Foot-Mouth
    (Coxsackievirus A16) with oral vesicles and
    papules/vesicles on palms and soles.
  • Complications
  • Group A
  • herpangina (dysphagia with lesions on soft
  • Group B
  • Myopericarditis

Case 4
  • 62 y.o. man taken to HMC from cruise ship docked
    at Pier 66 with fevers, altered mental status,
    and weakness in the left leg

  • Heterogeneous group of zoonotic / arthropod
    transmitted viruses
  • West Nile Virus
  • Dengue
  • Yellow Fever
  • Japanese Encephalitis
  • St. Louis Encephalitis
  • Tick-Borne Encephalitis
  • Diagnosis
  • Serology
  • IgM during acute illness or IgG in convalescence
  • Serum should be collected 8-10 days after illness
  • Follow up with a convalescent serum specimen
    obtained at least 2 weeks after the first
  • CSF should be collected within 8 days of illness
    onset. IgM may appear in CSF earlier than in
  • 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!)
  • PCR
  • Less sensitive, but useful in immunocompromised

Flaviviruses West Nile Virus
  • Rapidly emerging virus across U.S. since 1999
  • WA one of the few states without any documented
  • Transmitted from reservoirs in birds to human via
  • Majority of infections are without symptoms or
    only with fever and malaise, but most severe
    complication is neurological (encephalitis and
    muscle weakness)

West Nile Distribution, 2008
Flaviviruses Dengue
  • Tropical virus transmitted by Aedes aegypti (day
    biting) mosquito
  • Illness characterized by high fever, headache
    (often retro-orbital), myalgias/arthralgias and
  • Hemorrhagic fever or shock may occur shortly
    after resolution of fever. May be more common in
    persons previously exposed.

Flaviviruses Yellow Fever
  • Endemic to sub-Saharan Africa and South America
  • Transmitted by mosquito bites
  • Symptoms range from constitutional to severe.
    Symptomatic patients likely to experience
    headache, altered mental status, icterus, and
    many have diffuse hemorrhage
  • Preventable by vaccine, which may cause
    vaccine-induced encephalitis among young infants
    or the elderly

Other Flaviviruses
  • Japanese Encephalitis
  • High fevers and altered mental status
  • Endemic to regions in Asia where mosquitoes
    interact with pigs and birds
  • St. Louis Encephalitis
  • Fevers and altered mental status, especially
    among the elderly.
  • Seen in North, Central and South America as well
    as the Caribbean.
  • Tick-Borne Encephalitis
  • Infection via Ixodes species ticks
  • Europe and Asia
  • History persons with outdoor exposure.
  • Presents with fever, but may progress to altered
    mental status and paralysis.

Case 5
  • 28 year old latina sheep-sheerer from Oregon
    presents to UWMC with increasing lesion on hand

Poxviruses Orthopox
  • Monkeypox recently spread by prairie dogs
  • Cowpox cause milkers nodules on hands of dairy
  • ORF nodule on hands, arms or face after exposure
    to ruminants
  • Smallpox
  • Diagnosis
  • Electron Microscopy

Poxviruses Smallpox
  • Smallpox is the only infectious disease
    eradicated with vaccination, now threatening to
    return in the setting of bioterrorism
  • Infection via respiratory droplets or contact
    with infected lesions. Acquisition is largely
    asymptomatic for first 7-10 days, followed by a
    non-specific prodrome consisting of fevers and
  • Patient becomes infectious upon development of
    rash. Typically, rash is maculopapular, starts in
    the oropoharynx/head/neck/upper extremities, and
    moves caudally. Lesions are usually in the same
    stage (i.e. vesicular, pustular, crusted), which
    differentiates the lesion from varicella.
  • Diagnosis is by PCR or electron microscopy of
    vesicular fluid
  • Treatment is supportive, although cidofovir may
    be effective if given early after infection.
    Vaccination within 4 days of exposure may
    mitigate course of infection

Poxviruses Parapox
  • Molluscum contagiousum
  • Umbilicated firm cutaneous
  • May be more persistent in immunocompromised
  • Typically is treated with curettage or

Case 6
  • 26 year old medical student wanders on to general
    medical ward with conjunctival hemorrhages,
    fever, and confusion

  • Filoviridae
  • Ebola
  • Marburg
  • Bunyaviridae
  • Hantavirus
  • Rift Valley Fever
  • Crimean-Congo Hemorrhagic Fever
  • Arenaviridae
  • Lassa virus
  • Diagnosis
  • Serology from CDC or PCR

  • Ebola and Marburg
  • Acquired through contact with non-human primates
    in Africa
  • Fevers and myalgias are followed by maculopapular
    rash, after which between 10 and 50 will develop
    disseminated intravascular coagulation

  • Rift Valley Fever
  • Transmitted by Aedes mosquitos in sub-Saharan
  • Three clinical syndromes
  • Non-specific febrile illness (90)
  • Macular Retinitis / Vasculitis (10)
  • Fulminant disease hepatic failure / hemorrhage
  • Crimean-Congo Hemorrhagic Fever
  • Transmitted by ticks in Southwest Asia, Middle
    East and Africa
  • Hemorrhagic fever / DIC in 20-50
  • Hantavirus
  • Transmitted by wild rodents
  • Two types
  • Asian strains fever and renal failure
  • North American strains fever and pulmonary edema

  • Transmitted to humans via contact with rodents
  • Endemic to Africa and South America
  • Lassa fever
  • Severe systemic illness with shock
  • 20 mortality
  • Lymphocytic Choriormeningitis Virus (LCMV)
  • Aseptic meningitis with low mortality

Case 7
  • You are called in the middle of the night because
    siblings child has high fevers and an unusual

  • Smallest DNA virus
  • Epidemiology
  • Widespread infection
  • 50 of adolescents and nearly all elderly persons
    have serum antibodies to Parvovirus B19
  • Spread among close contacts by respiratory
    droplets or blood
  • Clinical
  • Cause of erhythema infectiousum (slapped cheek
    or 5th disease), arthritis, red cell aplasia or
    aplastic crisis, and hemophagocytic syndrome
  • Fetal infection may lead to hydrops fetalis or
  • 10 fetal loss in 1st trimester pregnancies
  • Risk of hydrops greatest in 3rd trimester
  • Immunocompromised patients may have chronic
    low-level viremia which is not associated with
  • Consider IVIG in non-immune, exposed pregnant
  • Diagnosis
  • Plasma PCR
  • Low reticulocyte count in presence of anemia
    could be an early diagnostic clue

Case 8
  • 7 year old boy presents with fever and rash after
    visiting Hunan Province of China
  • Also traveled to Hong Kong and San Francisco
  • 11 other children had fever and similar rash

Measles (Rubeola)
  • Virology
  • Extremely infectious paramyxovirus spread through
    contact with respiratory droplets
  • Nearly 2 week incubation period followed by
  • Symptoms
  • Constitutional symptoms
  • Classic cough, coryza and Kopliks spots
    (small, bluish granules on erythematous buccal
  • Erythematous maculopapular rash spread
    cranio-caudally and may desquamate and involve
    palms / soles.
  • Complications
  • Pneumonia with secondary bacterial superinfection
  • Encephalitis (may be chronic in subacute
    sclerosing panencephalitis)
  • Diagnosis
  • Serology

Measles Kopliks Spots
  • Paramyxovirus acquired through nasopharyngeal
    contact with respiratory droplets or fomites
  • Extended (2-4 week) incubation period
  • Clinical illness heralded by otalgia and parotid
    hypertrophy and sialadenitis, and may be followed
    by meningitis, encephalitis or orchitis
  • Diagnosis
  • Serology

Rubella (German Measles)
  • Benign viral infection characterized by fever and
    maculopapular non-confluent craniocaudal rash.
  • May occasionally be complicated by arthralgia
  • Congenital infection
  • May lead to fetal death and congenital
    abnormalities, including hearing loss, heart
    disease, cognitive delay


HSV-1 Epidemiology
  • Prevalence
  • Worldwide, 90 of people seropositive for HSV-1
    by age 40
  • In US, approximately 50 and declining, but
    closer to 90 in groups with low SES
  • Transmission
  • Via saliva
  • VesiclesgtUlcersgtAsymptomatic
  • Culture positivity 80, 33 and lt25 respectively

HSV-1 Primary Infection
  • Asymptomatic
  • 47 of people with positive HSV-1 serology do not
    recall history of oral / genital ulcers
  • Oral or Genital Ulcers
  • Fever / pharyngitis in first 12-24 hours (oral)
  • Vesicles by median of 7 days
  • Resolved by 14 days
  • Skin Infections
  • Herpetic Whitlow
  • Ocular Disease
  • Leading cause of blindness worldwide is Herpes
  • Encephalitis
  • Neonates or immunocompromised
  • Pneumonitis
  • Neonates or immunocompromised
  • Hepatitis
  • Fulminant and fatal in 80

HSV-1 Recurrences
  • Oral / Genital Ulcer Disease
  • Recurrence rates vary greatly by individual
  • 85 with prodrome 24h prior to lesion, then
    lesion x 8d
  • HSV-1 recurs infrequently at genital sites
    (average once per year)
  • Encephalitis
  • Recurrences after primary encephalitis not
    uncommon (in contrast to HSV-2)
  • First episode of encephalitis may result from
    reactivation of HSV-1 from oral primary in
    trigeminal ganglion
  • Pneumonitis
  • First episode of pneumonitis may result from
    aspirating reactivated oral HSV-1 during
    intubation or AMS

HSV-1 Diagnosis
  • Serologic
  • Detect IgG antibodies to HSV-1 and 2 gG (envelope
  • Develop within 7-21 days
  • May be delayed by use of antivirals
  • Some antibody assays have difficulty
    differentiating between HSV-1 and 2
  • IgM testing is unreliable
  • Virologic
  • Looking for the virus
  • Tzanck
  • Insensitive and not specific
  • DFA
  • Rapid, specific and pretty sensitive for persons
    with active lesions
  • Growing the virus
  • Culture
  • Sensitive, specific, time consuming (3-7 days)
  • Amplifying viral DNA
  • PCR
  • Sensitive, specific, rapid
  • Prone to contamination

VZV Natural History

Source Gilden DH, et. al. N Engl J Med 2000
342 635-645
Varicella Zoster Virus Clinical Syndromes
  • Varicella (Primary Infection)
  • 90-95 of persons by the age of 18 have had
  • Zoster (Recurrent)
  • Common 30-50 cases per 1000 person years
  • 20-30 of patients with HIV will develop Zoster
  • More likely to be multi-dermatomal
  • Associated with Immune Reconstitution
  • 8 in one study
  • Domingo P, Am J Med 2001 110605-9
  • Chronic encephalitis
  • Seen rarely outside immunocompromised persons
  • Subacute headache, fever, altered mental status
  • Acute Retinal Necrosis
  • Weeks to months after varicella or zoster
  • Likely due to hematogenous spread, so initial
    lesion at site distant to eye does not rule out
  • 75-85 chance of detachment leading to blindness,
    with little benefit from antivirals
  • May prevent spread to contralateral eye

Source http//
EBV Primary Infection
  • Asymptomatic
  • Common in kids under 2
  • May have negative Monospot
  • Infectious Mono
  • Fever, malaise, pharyngitis, lymphadenopathy,
    atypical lymphocytosis, splenomegaly without
    jaundice or hepatomegaly
  • Hemophagocytic syndrome

EBV Malignancies after Chronic Infection
  • Mechanism
  • Persistent infection / activation of B cells
    coupled with viral immune evasion and control of
    cell cycle
  • Burkitts
  • Most common malignancy in childhood in Africa,
    along malaria belt
  • HIV Associated Lymphomas
  • Primary CNS
  • NHL
  • Nasopharyngeal Carcinoma
  • Post-Transplant Lymphoproliferative Disorder
  • Associated with degree of immunosuppression after
  • Lung (up to 9)gtHeartgtKidneygtLiver (1-2)
  • Risk Factors Lymphocyte depletion (OKT3 or ATG),

EBV Diagnostic Tools and Cautions
  • Serologic
  • Heterophile Test (MonoSpot)
  • Antibodies to sheep erythrocytes
  • Develop in up to 70 of patients and may persist
    for gt 1 year
  • Antibodies to EBV Proteins
  • Viral Capsid Antigen (VCA)
  • IgM develop immediately and rapidly fall, but
    laboratory test is difficult and prone to
  • IgG develop rapidly and persist (not useful for
  • Epstein Barr Nuclear Antigen (EBNA)
  • Appears at the end of course of IM and persists
    for life
  • Allows for viral latency
  • Early Antigen (EA)
  • Develop within 2-4 weeks and disappear
  • Virologic (PCR)
  • PCR for EBV from blood should be interpreted with
  • May be found in blood from asymptomatic
  • Possibly due to B-cell stimulation
  • Quantity does NOT predict development of
  • Helpful from CSF to predict CNS lymphoma

  • Diseases
  • Kaposi Sarcoma
  • Primary Effusion Lymphoma
  • Multicentric Castleman Disease
  • Prostate Cancer?
  • Multiple Myeloma NO
  • Pulmonary Hypertension - NO
  • Prevalence
  • General Population
  • Random Blood Donors US 5, Italy 20-30, Middle
    East 20-30, Africa 20-100, South America 3-70,
    Asia 5-30
  • High Risk Groups
  • MSM 20-30 HIV-negative in US, 30-50 HIV-pos
  • Recent study suggests that women in the United
    States may also have high rates of infection (16)

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