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Viral Infections in the Immunocompetent Host

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1 Viral Infections in the Immunocompetent Host
Corey Casper, M.D., M.P.H. Departments of Medicine, Epidemiology and Global Health The University of Washington Vaccine and Infectious Disease, Clinical Research, and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center

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

3 Classification of Viruses

4 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

5 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

6 Viral Structures

7 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 patient’s 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

8 Diagnosis of Viral Infections - Direct

9 Diagnosis of Viral Infections - Indirect

10 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 viruses

11 Diagnostic Virology: DFA
Fluorescent label Antibody to Viral Protein Clinical Specimen

12 Diagnostic Virology: EIA
Viral Protein Sera Containing Antibodies to Viral Protein Antibody to Human Antibodies Fluorescent label

13 Diagnostic Virology: PCR
Advantages: Rapid Sensitive Quantitative Disadvantages Too sensitive? Specificity Costly Source:

14 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 labs/studies: Normal CBC, SMA-7, negative UA, negative CXR and KUB AST 110, ALT 124, nml INR, GGT, Amylase, Alk Phos Hospital Course: Subsequent multiple blood and urine cultures negative 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

15 Case 1: Hepatic Lesions

16 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

17 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: Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) Clinical: KS, multicentric Castleman’s disease, primary effusion lymphoma

18 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

19 Herpesvirus Therapy: DNA Synthesis Inhibitors
Source: Naesens and de Clercq Herpes 2001 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

20 Case 2 34 y.o. nurse presents with 3 weeks of coughing, post-tussive emesis, sinus congestion and malaise in January

21 Respiratory Viruses: Clinical
Heterogeneous group of viruses DNA and RNA, enveloped and “naked” Similar clinical presentations Seasonality is important

22 What goes around comes around…

23 Viruses in Health Care Workers, 2007-2008
Switch to PCR from DFA

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

25 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

26 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 LRTI Wheezing is a common initial presentation Treatment is supportive

27 Respiratory Viruses: Coronaviruses
Large family of viruses with multiple animal hosts 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 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

28 PCR for Respiratory Virus Detection
Problem of inadequate specimens for immunoblot or DFA PCR is more sensitive and perhaps equally as specific Molecular Virology Lab now offers multiplex PCR for detection of 12 viruses Kuypers, et al 2006

29 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

30 Case 3: Continued Physical examination revealed the following:

31 Enteroviruses 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 agammaglobulinemia Diagnosis PCR of stool, oropharynx or CSF

32 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 palate) Group B Myopericarditis EV71 has been associated with large outbreaks in China, and is frequently complicated by cardiovascular collapse and neurologic injury

33 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)

34 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

35 FLAVIVIRUSES 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 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!) PCR Less sensitive, but useful in immunocompromised hosts

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

37 West Nile Distribution, 2010

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

39 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

40 Other Flaviviruses Japanese Encephalitis St. Louis 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.

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

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

43 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 malaise. 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

44 Poxviruses: Parapox Molluscum contagiousum Umbilicated firm cutaneous
May be more persistent in immunocompromised adults Typically is treated with curettage or cryotherapy.

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

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

47 Filoviridae 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

48 Bunyaviridae Rift Valley Fever Crimean-Congo Hemorrhagic Fever
Transmitted by Aedes mosquitos in sub-Saharan Africa 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

49 Arenaviruses 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

50 Case 7 You are called in the middle of the night because sibling’s child has high fevers and an unusual rash

51 PARVOVIRUS Smallest DNA virus Epidemiology Clinical
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 miscarriage 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 disease Consider IVIG in non-immune, exposed pregnant women Diagnosis Plasma PCR Low reticulocyte count in presence of anemia could be an early diagnostic clue

52 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

53 Measles (Rubeola) Virology Symptoms Complications Diagnosis
Extremely infectious paramyxovirus spread through contact with respiratory droplets Nearly 2 week incubation period followed by Symptoms Constitutional symptoms “Classic”: cough, coryza and Koplik’s spots (small, bluish granules on erythematous buccal mucosa) 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

54 Measles: Koplik’s Spots

55 Mumps 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

56 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


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