Antiviral Treatment

ANTIVIRAL TREATMENT:

HERPESVIRUSES, INFLUENZA author by

eLibrary Prof. Mojca Matičič, MD, PhD

Clinic for Infectious Diseases and Febrile Illnesses ESCMIDUniversity Medical Centre Ljubljana © Faculty of Medicine, University of Ljubljana Ljubljana: April 15, 2019 The extent of the pipelines

Antibioticsauthor Antibioticsby

eLibrary

AntiviralsESCMID ©

Antifungals Viral infections

• Clinical course depends on: author by virus patogenity

patienteLibrary immunity

• Infection: acuteESCMID ©chronic latent (clinically inactive) → reactivation Treatment of viral infections

• Usually symptomatic author by Antivirals used for:

• Treatment: for clinically overteLibrary disease

• Pre-emptive treatment: for prevention of disease in increased replication of latent viruses ESCMID • Supressive© treatment: for prevention of reactivation of latent viruses Antiviral drugs

Viruses: author • replicate intracellulary by • to synthesize viral particles they employ: - host cell enzymes - host cell macromolecules eLibrary - host cell organelles

Antiviral drugs:

• discriminationESCMID between host functions© and viral functions Antiviral drugs

NO “MAGIC BULLET” author by Main problems:

• toxicity eLibrary

• efficacy ESCMID • resistance© Medications against viral infections

• Antivirals: author prevent viral replication intracellularly nucleos(t)ide analogues, protease inhibitors, integraseby inhibitors etc

• Immunomodulators:

enhance or change host immuneeLibrary response to viruses immunoglobulins, interferons, biological therapy (anti TNF, anti-CD20, anti-CD52 etc)

• In 2019: over 50 antivirals for systemic use newESCMID or updated giudelines for their use © VIRAL INFECTIONS treated with SYSTEMIC ANTIVIRALS

Against: HIV (33) author herpesviruses: HSV-1, HSV-2, VZV, CMVby influenza viruses hepatitis B virus (HBV), hepatitis C virus (HCV) respiratory syntitialeLibrary virus (RSV) other viruses: EBV, HHV-6 parvo B19, enteroviruses, adenoviruses, ESCMIDhuman polioma viruses BK, JC © HPV Human herpesviruses Common characteristics: lifelong infection latency reactivation author oncogeneity by NOT curable! Clinical sindromes related to herpesvirus infections: Syndrome HSV-1 HSV-2 VZV CMV EBV HHV-6 HHV-7 HHV-8 Gingivostomatitis + + eLibrary------Genital lesions + + ------Keratokonjuktivitis + + + - - - - - Retinitis + + + + - - - - Skin lesions + + + + + + + + Ezophagitis + + + + - - - - Pneumonitis + + + + + + - - Hepatitis ESCMID+ + + + + + - - Meningitis + + + - + + - - Encephalitis © + + + + + + + - Mononucleosis - - - + + + - +? Hemolytical anemia - - + + + -

Peripartal infection + + + + - + - + Antiviral drugs used for herpesvirus infections VIRUS Antivirals aciclovir valaciclovir penciauthorclovir* byfamci clovir HSV and VZV brivudin inhibitors idoksuridin* trifluridin* eLibrary vidarabin* ganciclovir CMV inhibitors valganciclovir ESCMID foscarnet © cidofovir fomiversen**

HSV = virus herpes simplex; VZV = virus varicella-zoster; CMV = citomegalovirus *: topical; **intravitreal Aciclovir

• Guanozine derivative • Patented in 1974; approved for medical use in 1981 author • Oral/intravenous/topical administration by • In vitro: most potent against HSV-1 half as potent against HSV-2 10th as potent against VZV • Most commonly used in HSV infectionseLibrary • Very well tolerated • Favourable safety profile AE: renal disfunction

• Pregnancy: atESCMID high doses chromosomal breakage © NO fetal abnormalities NO MORE abnormalities compared to the newborns in general population Valaciclovir

• L-valine ester of aciclovir (prodrug form of aciclovir) author • Oral administration by

• Enhanced absorbtion after oral administration eLibrary • Bioavailability: 3-5x ↑ compared to acyclovir

• ConcentrationESCMID-time curve: 1g tid© PO valcyclovir = 5 mg/kg tid IV acyclovir

• Very well tolerated Famciclovir

• Guanosine analogue author • Prodrug form of penciclovir with improved oral bybioavailability (77%↑) • Oral administration

• Intracellular concentrations of eLibrarypenciclovir triphosphate are higher than acyclovir triphosphate

• Penciclovir is not metabolized, but is eliminated unchanged in urine ESCMID • Adjustment© of the famciclovir dose is required in patients with creatinine clearance of <60 ml/min. Brivudin

• Bromovinildeoksiuridin • Competitive inhibitor of viral DNA polymerase IC50 activity in vitro author • Oral administration by • Once daily

• In vitro: BVD 200-1000 times more potenteLibraryin inhibition of VZV replication compared to ACV

• Indication: ESCMIDShingles in immunocompetent© patients Brivudin • Bromovinildeoksiuridin • Competitive inhibitor of viral IC activity in vitro DNA polymerase 50 author • Oral administration by • Once daily

• In vitro: eLibrary BVD 200-1000 times more potent in inhibition of VZV replicationESCMID compared to ACV © • Indication: Shingles in immunocompetent patients author by

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ESCMID © HSV infections Systemic treatment options

• acyclovir author • valacyclovir by • famciclovir

Rescue treatment: eLibrary • foscarnet • cidofovir ESCMID © HSV-1, HSV-2 Systemic antiviral treatment efficacy

• Primary: acyclovir IV/PO speeds healing of lesions valacyclovir PO reduces virus shedding author

• Recurrent: by acyclovir PO speeds healing of lesions valacyclovir PO

• Immunocompromised: eLibrary speeds healing of lesions acyclovir IV reduces virus shedding • Labial herpes:ESCMID valacyclovir© 2g bid, 1 day reduces duration by 1 day

Fife KH. Sex Transm Dis 1997; 24: 481-6. Bodsworth NJ. Genitourin Med 1997: 73: 110-6. CDC. MMWR 2010; 59(RR-12): 15-6. HSV-1, HSV-2 Indications for systemic TREATMENT

author • genitalni herpes: primary infection recurrences by GPs • orofacialni herpes  • ophtalmic herpes • herpes encephalitis • neonatal herpes eLibrary • mucocutaneous herpes in immunocompromised • Other herpetic syndromes eccema herpeticum, erythema multiforme hepatitis,ESCMID proctitis, esophagitis, pneumonitis systemic© infection HSV-1, HSV-2 Indications for systemic TREATMENT

author • genitalni herpes: primary infection recurrences by • orofacialni herpes  • ophtalmic herpes • herpes encephalitis • neonatal herpes eLibrary • mucocutaneous herpes in immunocompromised • Other herpetic syndromes eccema herpeticum, erythema multiforme hepatitis,ESCMID proctitis, esophagitis, pneumonitis systemic© infection Genital herpes Indications for CHEMOPROPHYLAXIS

• Immunocompetent patients: author by recurrent herpes (≥6 recurrences per year) • Immunodefficient patients:eLibrary

recurrent herpes solid organ/bone marrow Tx HIV/aidsESCMID haematological© malignances Treatment regimens for HSV infection encephalitis aciclovir intravenous 10-15 mg/kg x 3; 14-21 days immunocompromised– aciclovir intravenous 10-15 mg/kg x 3; 14-21 days systemic infections neonatal herpes aciclovir intravenous 10-15 mg/kg x 3; 14-21 days intravenous 5 mg/kg x 3; 5-10 days primary aciclovir or oral 200 mg x 5; 7-10 days (treatment) valaciclovir or oral 500 mg x 2; 7-10 days famciclovir oral 250 mg x 3; 7-10 days genital herpes aciclovir or oral 200 mg x 5; 5 days or recurrent 800 mg xauthor 2; 5 days (treatment) valaciclovir or oral 500 mg x 2; 3 days famciclovir oral 1000 mg x 2; 1 days by200 mg x 1-5 or aciclovir or oral recurrent 400 mg x 2; several months (chemo- valaciclovir or oral 500-1000 mg x 1; several months HSV prophylaxis) famciclovir oral 125-250 mg x 2; several months intravenous 5 mg/kg x 3; 7 days aciclovir or oral 500 mg x 5; 10 days immuno- treatment valaciclovir or oral 1000 mg x 3; 7 days compromised – mucocutaneous famciclovireLibraryoral 500 mg x 2; 4 days oral 200 mg x 2; prolonged herpes aciclovir or chemo- intravenous 5 mg/kg x 2; prolonged prophylaxis valaciclovir or oral 1000 mg x 3; prolonged famciclovir oral 500 mg x 2; prolonged labial herpes penciclovir or topical 1% ointment: for 2h in the morning; 4 days (recurrent) valaciclovir or oral 2000 mg x 2; 1 day famciclovir oral 500 mg x 3; 5 days ESCMIDaciclovir or oral 200 mg x 5; 7-10 days valaciclovir oral 500 mg x 2; 10 days © + herpetic keratitis aciclovir or topical 3% ointment: 5x daily 1 gtt, 1% ocular solution:every 2 h during trifluridin or topical daytime vidarabin topical 3% ointment: 5xdaily Tomažič J, Strle F, et al. Infekcijske bolezni. 2nd ed. Ljubljana, SZD 2017; p. 76-7. HSV-1, HSV-2 Resistance to acyclovir

Prevalence: • immunocompetent patients: 0,3 % (USA) - 0,7 %(UK)author 0,19 % (11 large trials)by • herpes keratitis patients: 6,4 % • HIV/aids patients: 3,5-7 % • solid organ Tx patients: eLibrary2,5-10% • allogenic bone marrow Tx patients: 30%

Treatment options: RESCUE ONLY! • foscarnet IVESCMID • cidofovir© IV (not well controlled studies)

Morfin F, Trouvenet J. J Clin Virol 2003; 26: 29-37. Chilukuri S, Rosen T. Dermatol Clin 2003; 21: 311-20. Pirat J, Boivin S. Antimicrobial Agents Chemother 2011; 55: 459-72. author by

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ESCMID © VZV Chickenpox

Serious compications in: author by • adults (50x ↑ than children) • newborns • immunocompromised eLibrary • pregnancy • chronic pulmonary diseases • chronic skinESCMID diseases © Chickenpox Systemic treatment options

VZV HSVauthor • acyclovir : 5x800 mg PO 5-7 days by5x200mg • acyclovir : 3x10 mg/kg IV 10 days 3x 5 mg/kg • valacyclovir : 3x1000 mg PO 5-7 days 2x500 mg • famciclovir eLibrary

Aciclovir : VZV vs HSV higher doses and more frequent dosing for VZV than for HSV (VZV less sensitive) ESCMID © Chickenpox Systemic treatment efficacy

Immunocompetent host:

- children: ↓ fever duration temperature author ↓ no. of lesions (247 vs. 347) by speeds healing (2.7 days vs. 3.2 days) - adolescents: ↓ fever duration ↓ time of new lesion development (for 0.5 days) - adults: ↓ fever duration (for 1.8eLibrary days) speeds healing ↓ general symptoms ImmunocompromisedESCMID host: - Systemic© treatment prevents dissemination of the disease

Balfour HH, 1990; Dunkle LM, 1991; Wallace MR, 1992; Walsh JB,1996; Dunkle LM, 2001; Balfour HH, 2001. CHICKENPOX Avtiviral treatment guidelines

• Indications: >18 years secondary contacts 12-17 years pregnant women patients with complications author immunocompromised by • Treatment should be started within 48 hours of the onset of skin lesions (except for immunocompromised patients)

• Pregnant women should eLibrarybe warned on Category 3 treatment recommendation

• Acyclovir IV in highly impaired immunity: HIV/aids, haematological malignanciesESCMID, high dose citostatic treatment, TX © • Acyclovir PO or valacyclovir PO in moderately impaired immunity: solid tumors, corticosteroid therapy, low dose citostatic treatment Treatment regimens for CHICKENPOX

Imunity Patients Antivirals Mode of Dosing Treatment application duration <12 years symptomatic / / / primary contact symptomatic / / / 12-18 years secondary aciclovir p.o. 5x800mg 5-7days normal contact valaciclovir or p.o. author3x1000mg 5-7days >18 years famciclovir or p.o. by 3x500mg 5-7days aciclovir p.o. 5x800mg 5-7days newborns aciclovir i.v. 10mg/kg/8h 5-7days pregnant women aciclovir p.o. 5x800mg 5-7days complications aciclovir i.v. 10mg/kg/8h 10 days Immune deficiency: mild / valaciclovir or p.o. 3x1000mg ≥7days moderate: eLibraryfamciclovir or p.o 3x500mg ≥7days •solid tumor in remission, aciclovir p.o 5x800mg ≥7days deficient •corticoid treatment •moderate dosing of citostatics

Immune deficiency: severe ESCMID• HIV/aids, aciclovir i.v. 10mg/kg/8h 7-10days •stemcell carcinoma, © •high dosing of citostatics, •treansplant recipients complications aciclovir i.v. 10mg/kg/8h aciclovir resistant viral strains foscarnet i.v. 40-60mg/kg/8h ≥14days Tomažič J, Strle F, et al. Infekcijske bolezni. 2nd ed. Ljubljana, SZD 2017; p. 76-7. VZV Shingles (Herpes zoster)

Complications: • Dissemination: skin author pneumonitis, hepatitis by meningo/encephalitis • Dermatological: bacterial superinfection granulomatous dermatitiseLibrary erythema multiforme • Due to localisation: otic ophtalmic ESCMIDanogenital • Postherpetic© neuralgia Shingles Systemic antiviral treatment efficacy

• Shortens healing process of acute disease author • Alleviates pain by

• Alleviates/prevents acute and chronic complications (postherpetic neuralgia!)eLibrary

ESCMID ©

Am J Clin Dermatol 2005; 6: 317-25. Dworkin RH. Clin Infect Dis 2007; 44: S1-26. Shingles Systemic antiviral treatment

Indications: >50 years of age severe pain/several vesicles at anyauthor age zoster on head/neck by immunocompromised atopic dermatitis eccema eLibrary Effective: given within 48-72 hours by rash onset >72 hours: ophtalmic HZ ESCMIDimmunocompromised © severe acute pain

Am J Clin Dermatol 2005; 6: 317-25. Dworkin RH. Clin Infect Dis 2007; 44: S1-26. Treatment regimens for ZOSTER Mode of Treatment Imunity Patients Antivirals application Dosing duration Pain: no / mild symptomatic / / / valaciclovir or p.o. 3x1000mg 7days <50 years Pain: moderate / severe famciclovir or p.o. 3x500mg 7days brivudin or p.o. 1x125mg 7days preserved aciclovir p.o. 5x800mg 7days valaciclovir or p.o. 3x1000mg 7days >50 years famciclovir or p.o. author3x500mg 7days brivudin or p.o. 1x125mm 7days aciclovir byp.o. 5x800mg 7days valaciclovir or p.o. 3x1000mg 7days Zoster ophtalmicus / zoster oticus (any age) famciclovir or p.o. 3x500mg 7days aciclovir p.o. 5x800mg 7days Immune deficiency: mild / moderate: aciclovir or p.o. 5x800mg 7days •solid tumor in remission, valaciclovir or p.o. 3x1000mg 7days •after immunosupressive treatment eLibraryfamciclovir p.o 3x500mg 7days Immune deficiency: severe deficient •leukemia / lymphome aciclovir i.v. 10mg/kg/8h 7-10days •immunosupressive therapy •trensplant recipients HIV/aids: aciclovirali p.o. 5x800mg 7-10days •zoster in one dermatoma valaciclovir p.o. 3x1000mg 7-10days (notESCMID face) ©• zoster with complications aciclovir i.v. 10mg/kg/8h 10- (face, multiple dermatomas, etc) 14(21)days disseminated disease aciclovir i.v. 10mg/kg/8h 10- 14(21)days aciclovir resistant viral strains foscarnet i.v. 40-60 ≥14days Tomažič J, Strle F, et al. Infekcijskemg/kg/8h bolezni. 2nd ed. Ljubljana, SZD 2017; p. 76-7. CMV Antiviral treatment DNA polymerase inhibitors: • Ganciclovir author • Valganciclovir by • Foscarnet • Cidofovir • Brincidofovir eLibrary

Viral terminaseESCMID inhibitor: NEW! • Letermovir© Ganciclovir • synthetic analogue of 2′-deoxy-guanosine • DNA polymerase inhibitor • absorption of the oral form is very limited • 90% of plasma ganciclovir is eliminated unchanged in theauthorurine • a half-life of 2–6 hours by

Indication: primarily CMV (symptomatic immunocompromised pts)

Administration: eLibrary - IV - slow-release formulations (implantate) – intravitreous - topical ophthalmicESCMID gel (acute HSV keratitis) AE: bone marrow© supression (↓ Leu, ↓Tr) Resistant strains: rarely occur (genes: DNA polymerase, UL97) usually sensitive for foscarnet and cidofovir Valganciclovir

• L-valyln ester of gancyclovir • Good resorbtion • 60% bioavailability author by • Oral administartion

• Indications: CMV infection

- treatment (900 mg/day bid) eLibrary symptomatic immunocompromised pts - pre-emptive treatment (900 mg/day bid) - chemoprophylaxis (900 mg/day qd) ESCMID © Foscarnet

• phosphonoformic acid • DNA polymerase inhibitor author • only IV • efficacy: same as ganciclovir by

• Indication: CMV retinitis in HIV/aids pts CMV - failure of ganciclovireLibrary(resistant virus, neutropenia) HSV, VZV - ONLY rescue treatment !

• MAJOR TOXICITY: renal impairmentESCMID!!! (Ca, K, P, Mg) • Cross-resistance© with gancyclovir possible Cidofovir

• citosyne derivate • DNA polymerase inhibitor • only IV author • long half-life time: 5mg/kg once a week for 2 weeksby followed by maintainance 5mg/kg /2 wks • MAJOR TOXICITY: renal impairment !!! Indications: • Primarily CMV eLibrary • HSV, VZV - ONLY rescue treatment

BRINCIDOFOVIR: lyposomal prodrug of CIDOFOVIR ESCMID1000x more potent than cidofovir against CMV © oral, high blood levels, NOT nephrotoxic Treatment regimens for CMV infection

prophylaxis valganciclovir oral 900 mg once daily; 3-6 mths

valganciclovir oral 900 mg x 2; untill 2 x negative viremia pre-emptive or treatment ganciclovir intravenous 5 mg/kg xauthor 2; untill 2 x negative viremia

5 mg/kg x 2; at least 14 d; CMV ganciclovir intravenous by Followed by maintainance 5 mg/kg/d infection or treatment 900 mg x 2; at least 14 d; valganciclovir or oral Followed by maintainance 900 mg/d

90 mg/kg x 2 or 60 mg/kg x 3; at least 14 d; foscarnet intravenous eLibrary Followed by maintainance: 90-120 mg/d or

5 mg/kg, 1 x weekly; 2 weeks; cidofovir intravenous Followed by 1x per 2 weeks Good hidration ESCMID Add probenecid

1. day and 15. day: 330 mg; © fomivirsen intravitreal Followed by maintainance 330 mg /mth

Tomažič J, Strle F, et al. Infekcijske bolezni. 2nd ed. Ljubljana, SZD 2017; p. 76-7. • Existing CMV antivirals & brincidofovir are inhibitors of viral DNA polymerase • inhibits the synthesis of viral DNA • act early in the virus lifecycle

• Letermovir is a novel viral terminase inhibitor • prevents proper DNA cleavage into unit-length genome and packaging of these genomes into procapsids author • blocks viral replication without inhibiting the synthesis of HCMV DNA or viral proteins • prevents the formation of infectious virions by • acts late in the virus lifecycle

Existing CMV eLibrary antivirals

letermovir letermovir ESCMID © EBV Antiviral treatment

• Indication: PTLD author HPS by

• Treatment: ganciclovir?eLibrary rituximab? ESCMIDother? © INFLUENZA pandemics

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ESCMID © 151.700 – 575.400

ECDC, 2009. INFLUENZA pandemics

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European Centre for Disease Prevention and Control. Seasonal influenza vaccination andantiviral use in EU/EEA Member States – Overview of vaccine recommendations for 2017–2018 and vaccination coverage rates for 2015–2016 and 2016–2017 influenza seasons. Stockholm: ECDC; 2018. INFLUENZA Antiviral agents

Amantanes - target M2 ion channel protein of influenza A virus: - Amantadine and rimantadine - active against influenza A virus (not influenza B virus!) - high levels of resistance (>99% in H3N2 and H1N1) NOT recommended for antiviral treatment or chemoprophylaxis author by Neuraminidase inhibitors - active against both influenza A and B viruses: – oral oseltamivir phosphate (TamiflueLibrary®) – inhaled zanamivir (Relenza®) – intravenous peramivirESCMID(Rapivab ®) © Endonuclease inhibitor (cap-dependent): - oral baloxavir marboxil (Xofluza®) - approved 2018 in Japan, USA https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm INFLUENZA Antiviral agents

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Clinical trials and observational data: author • early antiviral treatment can shorten the duration of fever and illness symptoms by • may reduce the risk of some complications (e.g., otitis media in young children, pneumonia, and respiratory failure) • early treatment of hospitalized adult influenza patients with oseltamivir has been reported to reduce deatheLibrary in some observational studies • in hospitalized children, early antiviral treatment with oseltamivir has been reported to shorten the duration of hospitalization in observational studies. • Clinical benefitESCMID is greatest when antiviral treatment is administered early, especially© within 48 hours of influenza illness onset in clinical trials and observational studies.

https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm INFLUENZA Antiviral medications recommended for treatment and chemoprophylaxis

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https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm INFLUENZA Dosing of antiviral treatment and chemoprophylaxis

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https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm INFLUENZA Indications for treatment • hospitalized • severe, complicated, or progressive illness • at higher risk for influenza complications author • children <2 years • adults ≥65 years by • people with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematological (including sickle cell disease), and metabolic disorders (including diabetes mellitus), or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle, sucheLibrary as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury) • people with immunosuppression, including that caused by medications or by HIV infection • women who are pregnant or postpartum (within 2 weeks after delivery) • people youngerESCMID than 19 years old who are receiving long-term aspirin- or salicylate©-containing medications • people who are extremely obese • residents of nursing homes and other chronic care facilities. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm INFLUENZA Recommendations for treatment of suspected or laboratory confirmed influenza, season 2017/18 in Europe

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• Neuraminidase inhibitor s: 70 - 90% effective in preventing influenza

• Widespread or routine use of antiviral medications for pre-exposure or post- exposure chemoprophylaxis NOT recommended author • Indications for chemoprophylaxis for those not vaccinatedby and being exposed to person with influenza:

– people at high risk of influenza complications during the first two weeks following vaccination

– people at high risk for complications from influenza who cannot receive influenza vaccine due to a contraindication eLibrary

– people with severe immune deficiencies or others who might not respond to influenza vaccination, such as people receiving immunosuppressive medications • Indication to controlESCMID outbreaks among high risk people in institutional settings, such as long© term care facilities, is recommended. • Antiviral chemoprophylaxis generally is not recommended if more than 48 hours have elapsed since the first exposure to a person with influenza.

https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm INFLUENZA Recommendations for prophylaxis following exposure to of suspected or laboratory confirmed influenza, season 2017/18 in Europe

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Koszalka P et al. Influenza Other Respir Viruses 2017;11(3):240-246. doi: 10.1111/irv.12446. CONCLUSIONS

• Treatment of viral infections usually symptomatic

• Systemic antiviral treatment for: author HIV (31) by herpesviruses: HSV-1, HSV-2, VZV, CMV hepatitis B virus (HBV) hepatitis C virus (HCV) respiratory syntitial virus (RSV)eLibrary influenza A and B virus, H1N1

• Follow the indications

• https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm • https://www.ncbi.nlm.nih.gov/books/NBK47401/ author • http://www.idpublications.com/journals/pdfs/avres/avres_mostcited_1.p df by • https://journals.lww.com/transplantjournal/Fulltext/2018/06000/The_Thi rd_International_Consensus_Guidelines_on.13.aspx • http://www.bloodjournal.org/content/131/26/2899eLibrary • https://www.uptodate.com/contents/clinical-manifestations-diagnosis- and-treatment-of-human-herpesvirus-6-infection-in-adults • https://www.idsociety.org/globalassets/idsa/practice-guidelines/2018- seasonal-influenza.pdfESCMID ©