Clinical Virology Jeopardy Weve Got a Cure for

Clinical Virology Jeopardy We’ve Got a Cure for That What Do You Make of This? “Out of Control” Diagnostic Dilemmas What’s New With YOU? 100 100 100 200 200 200 300 300 300 400 400 400 500 500 500

Sofosbuvir has been approved for use in the treatment of chronic infection by which virus? A. Hepatitis B virus B. Hepatitis C virus C. HIV-1 D. HIV-2

B. Hepatitis C virus • Sofosbuvir = Nucleotide inhibitor HCV polymerase – Binds active site – Inhibits chain elongation – High barrier to resistance • Mutations in the active site impair viral fitness – Broad genotypic coverage (gt 1 -6) • Approved for Gt 1, 4 Sofosbuvir (UTP analog) Gerber, L. et al. Liver Intl. 2013; 33 Suppl 1: 85 -92.

Which of the following drugs inhibits a viral protease? A. Adefovir B. Dolutegrevir C. Maraviroc D. Simeprevir

D. Simeprevir • Non-covalently binds/inhibits HCV NS 3 -4 A protease • Low barrier for resistance – never used as monotherapy • Broader genotypic coverage than 1 st gen HCV PI’s – Activity against Gt 1, 2, 4, 5, 6 – Approved for use in Gt 1 • Better tolerability than 1 st gen HCV PI’s www. chemspider. com

Rituximab is effective for the treatment of disease caused by which virus? A. Adenovirus B. BK virus C. Enterovirus D. Epstein Barr virus E. JC virus

D. Epstein Barr virus Rituximab is an anti-CD 20 monoclonal antibody • Activity: depletes CD 20+ B cells via – Antibody-dependent cellular cytotoxicity – Complement-dependent cytotoxicity – Apoptosis • Effective against B cell proliferative disorders – Post-transplant lymphoproliferative disease – Non-Hodgkin’s lymphoma – Chronic lymphocytic leukemia

Which activity of ritonivir, in its current formulation, makes it useful for the treatment of HIV-1? : A. Cytochrome P 450 inducer B. Cytochrome P 450 inhibitor C. Integrase inhibitor D. Protease inhibitor E. Reverse transcriptase inhibitor

B. Cytochrome P 450 inhibitor • Ritonavir activities – Protease inhibitor – Cytochrome P 450 inhibitor • CYP 3 A 4 and CYP 2 D 6 • Originally introduced as PI • Now used in low dosage coadministered with other drugs Plasma atazanavir -/+ ritonavir • Boosts plasma concentrations of drugs metabolized by cyp • Results in improved antiviral activity compared to single agent • Allows for decreased dosing http: //dailymed. nlm. nih. gov/dailymed/archives/fda. Drug. Info. cfm? archiveid=4548

In patients co-infected with HIV-1 and HBV, which drug is useful for the treatment of both infections? A. Atazanavir B. Pritelivir C. Raltegrevir D. Tenofovir

D. Tenofovir Drug Mechanism of Activity Action against HIV-1 Atazanavir Protease inhibitor Yes Pritelivir Helicase inhibitor No (HSV-2) Raltegrevir Integrase strand Yes transfer inhibitor Tenofovir Nucleoside reverse Yes transcriptase inhibitor Activity against HBV No No No Yes

HIV and HBV have reverse transcription in common HBV Replication Crowther R Phil. Trans. R. Soc. B © 2008 by The Royal Society 2008; 363: 2441 -2451 HIV Replication

In the process of completing her Results Verification Report, your Ace Lead Technologist notes a positive enterovirus reverse transcription real-time PCR result for Patient A-68 from your laboratory’s LDT. As part of her report, she checks the raw data and notes the following curve.

Given this result, which of the following is the most appropriate action? A. B. C. D. Verify A-68’s result as positive at Ct of 36 and sign off on the run. Amend A-86’s result to indeterminate and sign off on the run. Perform competency assessment. Call the real-time PCR instrument manufacturer to request service.

C. Perform competency assessment. • When interpreting amplification plots, shape and Ct value should be assessed. • Successive doubling should result in a sigmoidal curve. Walker NJ. Science. 296: 557 -559, 2002.

A 47 year old woman is undergoing chemotherapy for breast cancer. 3 weeks into treatment she develops a low grade fever, a sensation of burning in her chest, and dysphagia which has worsened over the past three days. Endoscopy demonstrated numerous erythematous ulcers throughout the esophagus. Biopsies were taken and histology is shown. Which drug should be prescribed as first line therapy?

A. B. C. D. E. Acyclovir Ganciclovir Cidofovir Foscarnet Leflunomide

A. Acyclovir • HSV and VZV are indistinguishable by histopathology. • Acyclovir can be used for treatment of both viruses. HSV, VZV CMV, VZV • Nuclear changes in HSV/VZV infections • Molding • Ground glass appearance • Multinucleation • Cowdry A eosinophilic inclusions Normal skin

A 10 -year old boy is taken to the emergency department by his mother. He has a low grade fever, is achy, congested, has a dry cough, and is refusing to go outside and play despite the fact that he only has a week of summer vacation left. • Mom reports that he was very excited about winning the blue ribbon for his sow at the state fair 3 days ago. • A multiplex NAAT for respiratory viruses is ordered from a nasopharyngeal swab sample. • Given the indicated mean fluorescence intensity (MFI) cutoffs, which of the following results would most motivate you to initiate an epidemiologic investigation?

HIV VL (cp/m. L) 125, 000 (ARVs initiated) Given the indicated mean fluorescence intensity (MFI) cutoffs, which of the following results would most motivate you to initiate an epidemiologic investigation? Flu. A Result 1 H 1 2009 H 3 Flu. B RSV h. MPV Rhino Adeno 73 45 33 87 54 47 96 16 90 95 12 Result 2 32 101 129 Result 3 69 55 37 89 67 108 Result 4 15 71 59 77 38 87 MFI<150, no analyte detected MFI >150<300, indeterminate MFI >300, analyte detected A. Result 1 B. Result 2 C. Result 3 D. Result 4 78 91

A. Result 1 Flu. A Result 1 H 1 2009 95 H 3 Flu. B RSV h. MPV Rhino Adeno 12 73 45 33 87 MFI<150, no analyte detected; MFI >150<300, indeterminate; MFI >300, analyte detected Viral load “blips” • Meets criteria for probable Influenza A H 3 N 2 v case. • Probable case: swine exposure and one of the following results by molecular test: • Influenza A, not subtyped • Influenza A, unsubtypeable • Influenza A, H 3 • Probable cases should be referred to state health labs for confirmation with CDC’s r. RT-PCR Influenza Subtyping assay

H 3 N 2 v • First identified 2011 • 9 July-7 Sept ‘ 12: 306 cases in 10 states • >80% cases in Ohio and Indiana • >95% attended agricultural fairs or had swine contact – 5% human-human transmission, unsustained • Symptoms: fever, cough, fatigue after ~3 d incubation period • Serosurveys suggest young children are most susceptible • Median age of cases, 7 yrs • Median age of hospitalized cases, 5 yrs • Candidate vaccine identified (A/Minnesota/11/2010) • Inactivated vaccine trials in progress Jhung, MA etal. Clin. Infect. Dis. 57: 1703 -12, 2013.

Data from a clinical trial for a NAAT for the qualitative detection of HSV-2 are shown below. NAAT results were compared to conventional culture using mucocutaneous specimens. What data support the conclusion that the NAAT is more sensitive than culture? A. B. C. D. Negative agreement Positive agreement Total agreement None – a different calculation is necessary Negative Positive HSV-2 NAT Conventional Culture Positive Negative 146 28 2 883 Total Agreement 97% Positive Agreement 99% Negative Agreement 97%

A. Negative agreement Conventional Culture Negative Positive HSV-2 NAT Positive Negative A 146 B 28 C D 883 2 Total Agreement 97% Positive Agreement 99% Negative Agreement 97% • Negative agreement: • % agreement of NAT with negative culture result • [D/(D+B)] x 100 • Positive agreement • % agreement of NAT with positive culture result • [A/(A+C)] x 100 • Total agreement • Proportion of all results that are in agreement • [(A+D)/(A+B+C+D)] x 100

While performing lot-lot verification of reagents for HIV-1 quantification, your QA lead runs into a bit of a problem. – Results for previously tested samples are concordant between lots – To verify the AMR (1. 0 – 7. 0 log 10 IU/m. L), a commercial panel was used • The internal control failed when the highest concentration panel member was tested; no value is reported by the assay. - What do you advise? AMR log 10 IU/m. L – commercial panel Previous result Correlation (log 10 IU/m. L) – plasma specimen Expected TND Observed TND 2. 0 1. 8 3. 0 3. 2 4. 0 3. 9 5. 0 5. 1 6. 0 6. 2 7. 0 IC failure 2. 2 2. 0 4. 3 4. 4 5. 8 5. 6

AMR log 10 IU/m. L – commercial panel Previous result Correlation (log 10 IU/m. L) – plasma specimen Expected TND Observed TND 2. 0 1. 8 3. 0 3. 2 4. 0 3. 9 5. 0 5. 1 6. 0 6. 2 7. 0 IC failure 2. 2 2. 0 4. 3 4. 4 5. 8 5. 6 A. Purchase and test a different commercial panel. B. Repeat the AMR with another set of the same commercial panel. C. The available data are sufficient to qualify the lot for use. D. Test a previous sample near the upper limit of quantification. E. Peter Rabbit.

A. B. C. D. E. Purchase and test a different commercial panel. Repeat the AMR with another set of the same commercial panel. The available data are sufficient to qualify the lot for use. Test a previous sample near the upper limit of quantification. Peter Rabbit. Discuss

Your Aunt Mabel (age 75) is going on a humanitarian mission to the Democratic Republic of Congo. She is generally fearless, but has heard that the area has a high rate of monkeypox and is afraid of contracting it. Your advice to her is not to worry unless she does which of the following: A. Drinks water from a local water hole B. Goes hunting and filets bush meat C. Has unprotected sex at a truck stop D. Sleeps under the stars without mosquito netting

A. Drinks water from a local water hole B. Goes hunting and filets bush meat C. Has unprotected sex at a truck stop D. Sleeps under the stars without mosquito netting • Monkeypox is a zoonosis – Animal species that harbor virus are unknown – Rodents are likely an important source • Transmission via contact with contaminated saliva/respiratory secretions, lesion/crust material, feces – “…precise exposure of a human case can be difficult to pinpoint in areas where contact with animals via household rodent infestations and the hunting and preparation of bushmeat from a variety of species is common. ” Mc. Collum AM and Damon IK. Clin. Infect. Dis. 58: 260 -7, 2014.

Don Juan, a 46 year old man, divorced his wife of 20 years last year. He has ventured out into the dating scene (Good news! He has a 23 year old girlfriend!), has read about genital warts and the transmission of HPV, and has come for advice on protection via the quadrivalent HPV vaccine. His specific question is whether he and his “new love” should get vaccinated. What is your reply? A. Yes, definitely, Mr. Juan and his hottie should get vaccinated. B. Only Mr. Juan should get vaccinated. C. Neither should get vaccinated. D. Vaccination should be considered for his gal pal only.

D. Vaccination should be considered for his gal pal only. Quadrivalent HPV vaccine is approved for use in people from 11 -26 years of age • Why vaccinate a 23 year old? – If not yet sexually active, will receive full benefit of vaccination – Even after debut: • Very few have been infected with all four types • If previously infected with one or more, will still benefit from protection from remaining types in vaccine MMWR 2007; 56(RR 2): 1 -32. MMWR 2011; 60: 1705 -08.

Which of the following sentences describes HSV-2 incidence? A. The estimated number of new HSV-2 infections among 15– 49 year olds worldwide in 2003 is 23. 6 million. . B. The estimated total number of people aged 15– 49 years who were living with HSV-2 worldwide in 2003 is 536 million. is n. C. The number infected increased with age, most markedly in the younger ages, until it peaked in the age stratum 35– 39 years of age… D. The risk factors associated with HSV-2 seropositives were multiple sex partners (AOR 2. 5, p = 0. 04), condom non-user's (AOR 4. 7, p <0. 001)…

A. The estimated number of new HSV-2 infections among 15– 49 year olds worldwide in 2003 is 23. 6 million. . B. The estimated total number of people aged 15– 49 years who were living with HSV-2 worldwide in 2003. (Prevalence)is n. C. The number infected increased with age, most markedly in the younger ages, until it peaked in the age stratum 35– 39 years of Limited reaction constituents age… (Prevalence) D. The risk factors associated with HSV-2 seropositives were Maximal efficiency multiple sex partners (AOR 2. 5, p = 0. 04), condom non-user's (AOR 4. 7, p <0. 001)… Limited target Incidence – The rate at which a certain event occurs, as a number of new cases of a specific disease occurring during a certain period in a population at risk. Prevalence – The number of cases of a specific disease present in a given population at a certain time. Dorlands Medical Dictionary

A 29 year old woman who is a nurse in a pediatric inpatient unit of your hospital presents to Occupational Health complaining of itchy red eyes that have been bothering her for one day. On exam, she is noted to have injected sclerae bilaterally. Conjunctival swabs were submitted for viral culture. Three days later cytopathic effect (CPE) was noted.

Of the following CPEs, which would make you consider furloughing the nurse in order to prevent a nosocomial outbreak of conjunctivitis? B A C

A Adenovirus-associated Epidemic Keratoconjunctivitis – Highly contagious, severe ocular infection – Common serotypes: Ad. V 8, 19, 37 – Incubation period: up to 14 days – Symptoms: redness, gritty sensation, watery discharge, photophobia – Duration: 7 -21 days, usually self-limited – Sequelae: infection can spreadily to cornea • can persist for months and cause decreased visual acuity

Ad. V EKC – Infection Control • Prolonged severe healthcareassociated outbreaks occur due to: – Transmissibility prior to symptom onset – Long period of infectiousness – Prolonged survival of virus in environment – Late outbreak investigation • Clinic and unit closure often necessary for outbreak containment • JHH EKC Control Policy – All employees with eye complaints evaluated by Occ Health – Practioners trained in basic ophtho exam – Swabs for Ad. V PCR obtained • Same day result (5/7 days) – Ad. V PCR+: 7 day furlough w re-evaluation required – Referral to Ophtho as necessary

A 27 year old pregnant woman from Tanzania, who arrived in the US 5 weeks ago, presents in premature labor at 35 weeks of gestation. A male infant is born who is jaundiced, has hepatosplenomegaly, cataracts, multiple cardiac defects (including patent ductus arteriosus and pulmonary artery stenosis), is hypotonic, and fails a newborn hearing screening test. On further questioning, the mother recalls a few days of fever and a week or so of bumpy red rash about the time of her first missed period. Vaccination against which virus could have prevented the most likely cause of this baby’s infection? A. B. C. D. E. Hepatitis B virus Measles virus Polio virus Rubella virus VZV

A. B. C. D. E. Hepatitis B virus Measles virus Polio virus Rubella virus VZV

Horstmann DM. Yale J Biol Med. 42: 99 -112, 1969

A 42 year old man developed aphasia and right-sided weakness/numbness 12 months after completing a course of chemotherapy for lymphoma. MRI showed white matter lesions in the left frontal cortex and left parietotemporal region consistent with demyelination. Which of the following tests should be requested to diagnose JC virus infection? A. B. C. D. E. Brain biopsy with SV 40 T antigen stain CSF culture Ig. M from CSF Viral DNA detection from CSF CDC. gov Viral DNA quantification from plasma

D. Viral DNA detection from CSF Berger J R et al. Neurology 2013; 80: 1430 -1438

A 3 year old boy with hereditary spherocytosis complained of cough, abdominal pain, and headache. His mother reports that he had low grade fever and vomited several times at home. In the ED, the following blood count results are obtained: WBC 8. 2 K/cu mm (5. 5 -15. 5) RBC 1. 28 m/cu mm (3. 9 -5. 3) Hemoglobin 2. 9 g/d. L (11. 7 -13. 8) Hematocrit 7. 4% (34 -40) Platelets: 240 k/cu mm Which of the following tests would be most useful in identifying the etiology of his illness?

WBC 8. 2 K/cu mm (5. 5 -15. 5) RBC 1. 28 m/cu mm (3. 9 -5. 3) Hemoglobin 2. 9 g/d. L (11. 7 -13. 8) Hematocrit 7. 4% (34 -40) Platelets: 240 K/cu mm (150 -350 K) Which of the following tests would be most useful in identifying the etiology of his illness? A. Monospot B. Periodic acid/Schiff stain of bone marrow C. Qualitative NAAT for parvovirus B 19 from plasma D. Quantitative NAAT for CMV from plasma

A. B. C. D. Monospot Periodic acid/Schiff stain of bone marrow Qualitative NAAT for parvovirus B 19 from plasma Quantitative NAAT for CMV from plasma Pathogenesis of Anemia Production Destruction Peripheral blood smear Hereditary Spherocytosis Sequestration Splenomegaly Hereditary Spherocytosis

AV’s Diff Dx List: Causes of Severe Anemia in Destructive/Consumptive Anemia 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Parvovirus B 19 Parvovirus B 19 Parvovirus B 19 Everything else A. Monospot B. Periodic acid/Schiff stain of bone marrow C. Qualitative NAAT for parvovirus B 19 from plasma D. Quantitative NAT for CMV from plasma • Diagnostics for parvovirus B 19 virus infection – Serology (Ig. M/Ig. G) – NAAT of peripheral blood

A 13 year old girl wanders into the living room one Sunday evening to show her mother, a physician and clinical virologist, some painful lesions on the back of her right thigh. Mom asks about a hundred questions, and the most pertinent history includes: she has had them for about three weeks, they appeared roughly three weeks after a travel swim meet when she spent three days in a wet suit sitting on risers on a pool deck, they itch and burn and they appear umbilicated. As her mother, what diagnostic test would you request? A. B. C. D. E. DFA from lesion Culture of lesion fluid NAAT of lesion fluid Serology None, I’m good.

E. None. I’m good. Molluscum Contagiosum – Poxvirus – Transmitted via close contact with skin or skin trauma • Now evidence of sexual transmission with genital lesions – Diagnosis: usually clinical • EM diagnostic - shows brick-shaped particles

A 25 year old woman who is 20 weeks pregnant undergoes ultrasound because her uterus is too small by dates. The ultrasound demonstrates an enlarged placenta, and a fetus that is small for dates. The obstetrician orders serologies for CMV; Ig. M and Ig. G results are positive, just above the assay cutoff. What CMV test would you recommend next be performed? A. B. C. D. E. F. Ig. G avidity testing – maternal serum Ig. G avidity testing – fetal blood Repeat maternal Ig. M and Ig. G in 2 weeks Qualitative NAAT on amniotic fluid Quantitative NAAT on maternal plasma Peter Rabbit

A. B. C. D. E. F. Ig. G avidity testing – maternal serum Ig. G avidity testing – fetal blood Repeat maternal Ig. M and Ig. G in 2 weeks Qualitative NAAT on amniotic fluid Quantitative NAAT on maternal plasma Peter Rabbit Discuss.

A 19 year old college student presents to The Health and Wellness Center on campus complaining of a fever, sore throat, myalgias, and arthralgias. On physical exam, cervical lymphadenopathy and a fine erythematous papular rash are noted. A variety of tests are ordered and the results are shown. What test would you order next? A. EBV VCA Ig. M B. Measles Ig. M C. 4 th Gen HIV serology D. Mumps RT-PCR from gingival fluid E. Quantitative CMV NAAT from plasma Test Result Influenza A + B NAAT No RNA detected Monospot Negative CMV Ig. M Negative CMV Ig. G Positive Measles Ig. G Positive Mumps Ig. G Positive Rubella Ig. G Positive

A. EBV VCA Ig. M B. Measles Ig. M C. 4 th Gen HIV serology D. Mumps RT-PCR from gingival fluid E. Quantitative CMV NAAT from plasma Test Result Influenza A + B NAAT No RNA detected Monospot Negative CMV Ig. M Negative CMV Ig. G Positive Measles Ig. G Positive Mumps Ig. G Positive Rubella Ig. G Positive

Acute HIV • Symptoms: fever, lymphadenopathy, pharyngitis, rash, myalgias, arthralgias – Can be asymptomatic – Often not considered in differential due to symptom overlap with other diseases (mononucleosis, influenza) • Absence of history of high risk behavior does not preclude the diagnosis • Diagnostic testing: multiple serologic/NAAT algorithms used

4 th Generation HIV-1/2 immunoassay Reactive Repeat in duplicate Repeatedly Reactive 2/3 result reactive HIV-1/HIV-2 discriminatory immunoassay Not Reactive NAAT Positive Acute Infection Negative False Positive 4 th Gen Result or acute HIV-2

The hypothesis that MERS is a zoonosis has been bolstered by the recent isolation of MERS Co. V from which type of pet? A. Dog B. Guinea pig C. Rabbit D. Sand lizard E. Camel

E. Camel

MERS Co. V and Camels • Coronaviruses infect many different species • MERS Co. V is in b coronavirus family associated with bat infection – Closest relative of MERS Co. V found in vesper bats in Europe, Asia, and South Africa – MERS Co. V replicates in bat cell lines • Sequence data suggest human infections are due to independent zoonotic introductions in Middle East from unknown reservoir • Exposure history of patients suggests livestock exposure – including dromedary camels – Two MERS cases in individuals with exposure to a single camel farm prompted virologic investigation

MERS Co. V in Dromedary Camels • Flocked swabs from posterior nasopharynx and rectum of 14 camels were collected – Blood obtained for serology • Virus detection methods: – Multiple PCRs • Sequencing – Isolation • Results – NP swabs from 3 camels positive by 3 different RTPCRs – No virus detected in rectal/fecal samples – Virus isolation largely unsuccessful – All camels were seropositive

A new (and most unwelcome) viral tourist has come to visit multiple islands in the Caribbean. It is: A. Chikungunya virus B. Dengue virus C. O-nyong virus D. Semliki Forest virus E. Sindbis virus

A. Chikungunya virus • Transmitted by mosquitoes – Aedes aegypti and Aedes albopictus Island Suspected cases Confirmed cases Guadaloupe 2737 802 Martinique 11, 400 1284 St. Barts 432 135 St. Martin 2840 790 Dominica 558 81 PAHO – Updated 4/4/14 CDC

According to the latest CDC and USPHSTF Recommendations, you should be screened for hepatitis C virus by serology if you were born when which of the following songs topped the charts? A. “In the Mood” Glenn Miller (1940) B. “Itsy Bitsy Teenie Weenie Yellow Polka Dot Bikini” Bryan Hyland (1960) C. “Bridge over Troubled Water” Simon and Garfunkel (1970) D. “Another One Bites the Dust” Queen (1980)

B. “Itsy Bitsy Teenie Weenie Yellow Polka Dot Bikini” Bryan Hyland (1960)

CDC and USPHSTF HCV Screening Recommendations • Risk-based screening AND • One-time serologic testing for anyone born between 19451965 Why Screen the 1945 -1965 Birth Cohort? • Highest seroprevalence • Accounts for ~75% chronic HCV infections in US

Which of the following is a genome editing system that has enormous implications for gene therapy in humans but is actually a mechanism that lowly bacteria use to defend themselves from invading viruses? A. CASPR B. CHOPR C. CLASPR D. CLONR E. CRISPR

E. CRISPR Clustered Regularly Interspaced Palindromic Repeats PNAbio. com genscript. com

Disease caused by JC virus is a known complication of natalizumab therapy in patients with multiple sclerosis. What other viruses have recently been shown to cause central nervous system adverse events in patients treated with this drug? A. Echoviruses B. Enteroviruses 70 and 71 C. HSV and VZV D. Parechoviruses

C. HSV and VZV • a 4 b 7 integrins • Found on all leukocytes except PMNs • Interact with endothelial cell adhesion molecules –required for leukocyte transmigration Selewski DT etal. Am J Neuroradiol. 31: 1588 -90, 2010. • Natalizumab binds a 4 b 7 integrin • Inhibits leukocyte binding to endothelial cells • Impedes leukocyte transmigration • Leads to “compartmental immunosuppression” – localized CD 4 depletion • Gut: treatment for Crohn’s disease • CNS: treatment for multiple sclerosis • Increases susceptibility to JC reactivation in the CNS

Does natalizumab therapy increase the incidence of HSV and VZV CNS disease? • FDA Adverse Event Reporting System and published literature assessed for HSV and VZV CNS disease reports in NZA therapy • Reported incidence sporadic 20 Cases Worldwide, 2004 -2012 HSV encephalitis: 1: 250, 000 – 6 HSV NOS 10 encephalitis 1: 500, 000/yr 5 meningitis 5 HSV-1 • HSV encephalitis in NZA rx: 1 meningoencephalitis 5 HSV-2 1: 12, 446/yr 4 VZV 2 meningitis • 8 HSV encephalitis cases 1 meningoradiculitis in 8 years of 99, 571 1 meningomyelitis treated patients • Many potential confounders in this study…however, data suggest that HSV and VZV should be in the differential in individuals who develop CNS disease on NZA treatment Fine AJ etal. Clin Infect Dis. 57: 849 -52, 2013.