3/15/18

1

Bryn A Boslett, MDDivision of Infectious DiseasesUniversity of California, San Francisco

Respiratory Viral Infections: Focus on InfluenzaAdvances in Infectious DiseasesMarch 2018

1

Disclosures

• Roche Molecular Diagnostics • Spouse is consultant

Outline

• Respiratory viral illness overview • Influenza

• Clinical presentation• Diagnostics• Treatment• Prevention

• Respiratory syncytial virus• If there is time!

3

Case 134yo woman with history of migraine presents to clinic in June with “cold symptoms” for 2 days – runny nose, watery eyes, mild cough and sore throat. Exam remarkable for temp 100.4F (38C), rhinorrhea, clear lungs. What is the most likely etiology?

1. Group A Strep (GAS)2. Influenza3. Respiratory syncytial virus (RSV)4. Rhinovirus5. Seasonal allergies

3/15/18

2

Epidemiology of Respiratory Viruses

0

2

4

6

8

10

12

14

16

18

20

# o

f Pa

tien

ts

Adenovirus

Influenza

PIV

RSV

Rhinovirus

Couch et al. Am J Med. 1997;102:2. (MDACC); slide courtesy of Michael Ison, MD and Catherine Liu, MD

Respiratory Viral Comparison

* = immunocompromisedTeichtahl et al. Chest.1997;112:591-596.; Marx et al. Clin Infect Dis.1999;29:134-140.; Ruuskanen et al.Lancet. 2011 Apr 9;377(9773):1264-75.

Winter Spring Summer Fall RxInfluenza NAIs

RSV Ribavirin + IVIG*

Parainfluenza None

Adenovirus Cidofovir*

Rhinovirus None

Coronavirus None

Case 1 continued…What is your next step?

1. Obtain a CXR2. Obtain respiratory virus testing3. Obtain a rapid strep test for GAS4. Start antibiotics (azithro, doxycycline, etc)5. Supportive care recommendations

The Case for antibiotic stewardship

• Overuse of antibiotics is the single most important driver in antibiotic resistance

• Most antibiotics prescribed in the US are for acute respiratory tract infections – many of which do not require antibiotics

• Physician and patient education, computerized clinical decision support, and financial incentives have historically produced only modest reductions in prescription rates

JAMA. 2009;302(7):758-766; JAMA Intern Med. 2013;173(4):273-275.

3/15/18

3

Outpatient antibiotic use, 2000 - 2010

Shapiro DJ et al. J Antimicro Chemotherapy, 2013.

• Broad-spectrum antibiotic prescriptions doubled, 2000 – 2010

• 30% of prescriptions deemed unnecessary

Case 268yo man with history of diabetes presents to clinic in January complaining of fever, cough and malaise. Temp of 102.2F (39C), HR 100, other VS normal. His lungs are clear. What is your next step?

1. Obtain respiratory virus testing2. Obtain a CXR3. Start oseltamivir (Tamiflu®)4. Start antibiotics (azithro, doxycycline, etc)5. All of the above6. Some combination of the above

Epidemiology of Respiratory Viruses

0

2

4

6

8

10

12

14

16

18

20

# o

f Pa

tien

ts

Adenovirus

Influenza

PIV

RSV

Rhinovirus

Couch et al. Am J Med. 1997;102:2. (MDACC); slide courtesy of Michael Ison, MD and Catherine Liu, MD

You decide to order a diagnostic assay for viral infection.The best possible test would be:

1. Direct fluorescence antibody (DFA)2. Rapid antigen detection3. Respiratory viral PCR4. Viral culture

3/15/18

4

Diagnostics Comparison

Viral Culture PCR DFA Rapid Ag

Sensitivity +++ +++ ++ +

Turn-around Slowest Fast Fast Fastest

Case 2 continued…

You send an NP swab for rapid antigen detection AND a respiratory viral PCR, which will take two days. You also obtain a CXR, shown here.

Case 2 continued…The rapid antigen test is negative for influenza A and B. Your next step:

1. Azithromycin x 5 days2. Oseltamivir while awaiting full PCR result3. Send home with strict return instructions4. Send to the ED for admission

68M, DM2cough + fever in January

Two days later, respiratory PCR (+) for influenza

Based on what we know about this current influenza season, what is the most likely influenza subtype in our patient?

1. Influenza A (H1N1)pdm092. Influenza A (H3N2)3. Influenza A (H7N9)4. Influenza B

3/15/18

5

FluView, CDC, accessed MAR 14, 2018.

H3N2

FluView, CDC, accessed MAR 14, 2018.

Questions I’ve been asked about influenza this year…

1) I heard that the flu shot didn’t work this year. Should I still be vaccinated?

25

Vaccine Effectiveness (VE), 2017-18 season • Interim VE estimates of 17% from Canada, 10% from Australia• In US, 4,562 children and adults with acute respiratory illness enrolled

during November 2, 2017–February 3, 2018, at five outpatient study sites • Overall interim vaccine effectiveness of the 2017–18 seasonal influenza

vaccine for preventing medically attended, laboratory-confirmed influenza virus infection was 36%– 25% for A(H3N2)– 67% for A(H1N1)pdm09– 42% for influenza B virus

• Protection rates higher for children 6mo – 8yo (VE = 59%)• Data limited to outpatient setting (ie, less severe cases)

Flannery B, Chung JR, Belongia EA, et al. Interim Estimates of 2017–18 Seasonal Influenza Vaccine Effectiveness — United States, February 2018. MMWR Morb Mortal Wkly Rep 2018;67:180–185.

3/15/18

6

Questions I’ve been asked about influenza this year…

1) I heard that the flu shot didn’t work this year. Should I still be vaccinated?

28

YES!!!!!

Questions I’ve been asked about influenza this year…

2) Besides the vaccine, what else can I do to avoid getting sick?

29

How is influenza spread?

• 142 confirmed cases of influenza in college students

• Examined 30 mins of natural breathing, prompted speech, spontaneous coughing and sneezing on day 1, 2 and 3 after symptom onset

• Assessed the infectivity of detected influenza RNA in aerosols

30Yan J, et al. Proc Natl Acad Sci U S A. 2018 Jan 30; 115(5): 1081–1086.

Results - Aerosolized transmission may be a risk

• Infectious virus detected in 39% of fine-aerosol samples collected during 30 min of normal tidal breathing

• Cough was NOT necessary for infectious aerosol generation (culturable virus found in half of all cough-free samplings).

31Yan J, et al. Proc Natl Acad Sci U S A. 2018 Jan 30; 115(5): 1081–1086.

3/15/18

7

Questions I’ve been asked about influenza this year…

2) Besides the vaccine, what else can I do to avoid getting sick?

32

-Tell friends/family/colleagues to STAY HOME when ill-Avoid sick contacts-Wash hands frequently-Wear N95 mask?-Consider NAI prophylaxis if clear exposure history AND high-risk patient (more later…)

Case 3You are paged regarding a patient of yours who was admitted overnight to the ICU. He is a 72M with COPD who had fevers and cough x 1 week, now positive for influenza A by rapid testing. In addition to broad-spectrum antibiotics, you would recommend:

1. No antiviral treatment – he is outside of the treatment window

2. Oseltamivir 75 mg PO BID x 5 days3. Oseltamivir 75 mg PO BID x 10 days4. Peramivir 600 mg IV x15. Zanamivir 10 mg inhaled BID x 5 days

Complications of Influenza

• Influenza viral pneumonia• Common in those hospitalized with influenza• Severe! Up to 20% mortality

• Secondary bacterial pneumonia • Difficult to distinguish clinically• Influenza “primes” lung tissues for bacterial superinfectionà direct viral damage, disrupts mucus barrier, upregulates adherence receptors • S. pneumoniae, S. aureus > S. pyogenes > H. influenzae, gram (-) rods

Chertow and Memoli, JAMA 2013, 309:275. MMWR 2009, 58:1. Jain et al, Clin Infect Dis 2012, 54:1221.

Available treatments for Influenza

• Adamantanes: amantadine, rimantidine

• M2 ion channel blockers – prevents viral uncoating

• Influenza A only

• Resistance widespread = Not Reliable

• Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir

• Drugs of choice

• Active against A + B

• Resistance low (~1%) since 2009

3/15/18

8

Neuraminidase comparison

Drug Adult dose Renallyadjust?

Intubation OK?

Contraindictions Adverse effects

Oseltamivir 75mg PO Q12x 5d

Yes Yes None N/V (10%), headache

Zanamivir 10mg INH Q12 x 5d

No No Resp disease (COPD, asthma)

Cough, bronchospasm

Peramivir 600mg IV x1 Yes Yes None Diarrhea (8%), neuropsych

Conflicting Data• Multiple observational trials show ê illness duration, hospitalizations and

pneumonia for all groups with NAIs• 2014 Cochrane meta-analysis: No impact on hospitalization, not enough data

on complications. Excluded many high-risk groups.

However…• 2015 meta-analysis (most complete data from manufacturer):

• ê duration of illness by ~24 hrs for laboratory-confirmed infection• ê antibiotic prescription for lower respiratory tract infection (8.7 vs 4.9%)• ê risk of hospital admission for any cause (1.7 vs 0.6%)

Dobson et al, Lancet 2015, Jan 29.; Kelley and Cowling, Lancet 2015, Jan 29.; Kaiser et al, Arch Intern Med 2003, 163:1667. Jefferson et al, Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965.

Timing, Duration, Dose

• Greatest benefit ≤ 48 hrs, but potential benefit > 48 hrs• 48 hrs chosen based on healthy outpatient data• Observational studies: Antivirals improved outcomes up to 5 days after

symptom onset

Kumar AJT 2009; Casper Blood 2010; SE Asian CID Network BMJ 2013; Lee CID 2013

Influenza Treatment Summary

41

• Who to treat?– All inpatients, and outpatients at high risk of complications– For these high risk groups, treat irrespective of duration of symptoms, as early as

possible, and do not delay therapy while awaiting lab confirmation

• Which drug?– Oseltamivir: drug of choice for most patients– Zanamivir: only if no COPD/asthma and not intubated– Peramivir: if need an IV option

• How long?– 5 days for most– Consider 10 days based on severity of illness

3/15/18

9

• All inpatients • Outpatients with severe disease, or at risk for complications:

• Ages <2 or >65• Chronic disease (cardiopulmonary, diabetes, liver or kidney

disease, etc)• Immunocompromised• Pregnant or recent post-partum • American Indians/Native Alaskans• Morbidly obese (BMI ≥40)• Residents of chronic care facilities

High risk of complications

CDC, Influenza Antiviral Medications: Summary for Clinicians, January 9, 2015.

Adjunctive treatments for influenza• Prospective open-label, randomized, controlled

trial of clarithromycin-naproxen-oseltamivircombination vs usual course of oseltamivir in confirmed influenza A(H3N2) infection

• Patients also received 5 days Amox/clavulenate• Primary end point: 30-day mortality• Secondary end points:

– 90-day mortality– Serial nasopharyngeal aspirate virus titer– Percentage of NAI resistant quasispecies– Pneumonia severity index (PSI)– Duration of hospital stay– Admission to ICU

Hung IFN et al. Chest. 2017 May;151(5):1069-1080. doi: 10.1016/j.chest.2016.11.012.

Hung IFN et al. Chest. 2017 May;151(5):1069-1080. doi: 10.1016/j.chest.2016.11.012.

Mean Viral Titer

Pneumonia Severity Index

30-day Mortality

Days After First Dose

• Combo rx associated with lower 30d and 90d mortality, lower PSI, fewer resistant viral quasispecies, shorter hospital stay

• No change in ICU admission, 30d re-admission, or d/c to skilled nursing unit• No significant adverse effects reported• Limitations: single center, elderly, hospitalized, onset <72h prior, small sample

Hung IFN et al. Chest. 2017 May;151(5):1069-1080. doi: 10.1016/j.chest.2016.11.012.

Outcome Event Rate RRR (95% CI) NNT (CI)Triple Rx Oseltamivir

30-dayMortality

0.9% 8.2% 89% (32-98) 14 (8-49)

90-day Mortality

1.9% 10% 81% (27-95) 13 (7-48)

ICUadmission

1.9% 6.4% 71% (-21-93) Not significant

Results and Limitations

3/15/18

10

Questions I’ve been asked about influenza this year…

3) I know I’ve been / will be in contact with someone with influenza. Can I take something preventative? Scary!

46

• 1. Large tertiary university hospital – Outbreak of 97 cases of flu-like illness in 5 days (48 PCR confirmed)– All hospital workers received full-course NAI (3702 workers)– Mathematical modeling showed reduced infection rate (only 7 new cases)– Several other interventions occurred - isolation, mandatory leave, etc.

• 2. Systematic review: 4 meta-analyses examined– Included pre- and/or post-exposure prophylaxis– Settings varied (household transmission, long-term care facilities)– NAIs consistently lowered the odds or risk of symptomatic influenza in all

studies.

NAIs for Prevention?

1. Hagihara M, et al. Intern Med. 2018;57(4):497-501. doi: 10.2169/internalmedicine.8854-17.2. Doll MK, et al. Antimicrob Chemother. 2017 Nov 1;72(11):2990-3007. doi: 10.1093/jac/dkx271.

Systematic analysis of NAIs for prevention

1. Doll MK, et al. Antimicrob Chemother. 2017 Nov 1;72(11):2990-3007. doi: 10.1093/jac/dkx271.

• 3. Study of adverse effects of prophylaxis: – Single-center study – 540 medical staff received NAI post-exposure prophylaxis– Of 411 survey respondents, 22.5% reported adverse effects (GI

upset, headache most common)

• CDC guidelines: “In general, CDC does not recommend antiviral chemoprophylaxis, but antiviral medications (oseltamivir, zanamivir) may be to prevent influenza in certain situations”

NAIs for Prevention

3. Kato H, et al. J Infect Chemother. 2017 Oct;23(10):683-686. doi: 10.1016/j.jiac.2017.07.008. Epub 2017 Aug 3.

3/15/18

11

• Prophylaxis recommended if:

– Known exposure to case of influenza within past 48 hours, AND

– At high risk of complications during the first two weeks following vaccination

– Severe immune deficiencies who might not respond to influenza vaccination

– Unable to receive vaccination safely

– Dose is daily, not BID, for 7 days after last known exposure

• Institutional outbreaks (long-term care homes, hospitals):

– Continue antiviral chemoprophylaxis for a minimum of 2 weeks, and up to 1

week after the last known case was identified.

– Antiviral chemoprophylaxis is recommended for all residents, including those

who have received influenza vaccination.

CDC Guidance

https://www.cdc.gov/flu/professionals/antivirals/summary

-clinicians.htm. Accessed Feb 21, 2018.

Influenza Vaccine

Influenza vaccine in pregnant women• 2016–17 influenza season: 54% of pregnant women vaccinated• Recommendation AND offer of vaccine by a primary provider

significantly increased uptake • Refusal linked to concern about harmful effects of vaccine on the fetus

Ding H, Black CL, Ball S, et al. Influenza Vaccination Coverage Among Pregnant Women — United States, 2016–17 Influenza Season. MMWR Morb Mortal Wkly Rep 2017;66:1016–1022.

Vaccination in the first trimester?

• Vaccine Safety Datalink data, electronic records from ~9 million patients to examine 2010-11 and 2011-12 seasons

• Compared 485 women ages 18-44 who miscarried to 485 women ages 18-44 who didn't miscarry

• Women vaccinated in 1st trimester with vaccine containing pandemic H1N1, and who had also received the same component the previous year, had an increased risk for spontaneous abortion (SAB) within the 28 days after vaccination (aOR 7.7 vs 1.3)

• Median gestational age was 7 weeks

Donahue JG, et al. Vaccine. Volume 35, Issue 40, 25 September 2017, Pages 5314-5322

3/15/18

12

Limitations and Take-away• Case-control study (cannot determine causation), subset analysis• Small numbers overall • Rate of spontaneous abortion (SAB) closely follows typical observed rate in

1st trimester• Many cases were vaccinated within a few days of LMP• Many SAB may be missed, as very early pregnancy may not be recognized• SAB cases contained more high-risk women (Age ≥ 35 , ≥ 2 prior SAB)ACIP and ACOG continue to recommend vaccination given many other studies (including VSD data) demonstrating safety, and known complications of influenza infection in pregnancy

Irving et al. Obstet Gynecol. 2013 Jan;121(1):159-65; Bratton et al. Clin Infect Dis. 2015 Mar 1;60(5):e11-9; McMillan et al. Vaccine. 2015 Apr 27;33(18):2108-17; Chambers et al. Vaccine. 2013 Oct 17;31(44):5026-32; Moro et al. Am J Obstet Gynecol. 2011 Feb;204(2):146.e1-7; Moro et al. Am J Obstet Gynecol. 2011 Nov;205(5):473.e1-9; https://www.cdc.gov/vaccines/acip/meetings/downloads/min-archive/min-2015-06.pdf

• Timing:• Influenza and RSV – Oct through April, generally• Other resp viral illnesses vary by season – some active year-round• Resp viral infections play a significant role in community acquired pneumonia

• Ways to Dx: • Resp Viral PCR > DFA > Rapid test • High suspicion = don’t trust (-) test result or normal CXR

Respiratory Viral Summary

• Treatment: For influenza, time = life! à In high-risk pts, don’t wait for results. Start a NAI (oseltamivir, others) à Earlier is better, but Rx even >48hrs for inpatients, other high-risk pts

• For other resp viral illness, generally no Rx (unless immunocompromised)• Treat RSV in immunocompromised patients with oral ribavirin + IVIG

• Prevention: • Influenza vaccination for all (ages >6mo, no contraindication)• Especially important for healthcare workers, pregnant women

Respiratory Viral Summary Thank You!

3/15/18

13

Case 428yo woman with AML s/p alloSCT 3 months prior, now presents in January with cough and weakness. She is afebrile but hypoxic to 84% on RA, admitted for further care. Rapid PCR testing is positive for RSV.

How should she be treated? 1. Supportive care2. Inhaled ribavirin 3. IV ribavirin + IVIG4. Oral ribavirin5. Oral ribavirin + IVIG

60

• Clinical:• Similar active season as influenza• Wheezing and dyspnea more common

• Management:• Normal immune system – often URTI, supportive care only• In immunocompromised setting – LRTI more common, mortality

rates up to 80% (SCT > solid organ), need to consider Rx

RSV in Adults

Cesario, Clin Infect Dis 2012, 55:107. Lee et al, Clin Infect Dis 2013, 57:1069. Lee et al, Clin Infect Dis 2013, 57:1069.

Treatment of RSV: Ribavirin

• Synthetic guanosine nucleoside analogue that inhibits nucleic acid synthesis

• Available in 3 forms:

• Aerosolized: previously standard of care • Toxicity: Bronchospasm, cough, dyspnea• Isolation: Teratogenic, HCW precautions

• IV: toxicity à hemolytic anemia, neutropenia, thrombocytopenia• Oral: Now what we use at UCSF, watch for hemolytic anemia

Outcomes with RSV therapyPrevent URTI à LRTI Prevent Mortality in LRTI

32%

68%

0%20%40%60%80%

100%

Treatment

No Treatment

Khanna et al, CID 2008. Kim et al Seminars in Respiratory and Critical Care Medicine 2007

Progression URTI à LRTI in RSV

27%

80%

0%20%40%60%80%

100%

Treatment

No Treatment

Mortality in RSV LRTI

3/15/18

14

• Immunomodulatory therapies• IVIG: efficacy never evaluated by RCT; recommend in leukemia, per

European ECIL guidelines• RSV-IG: not available in US• Palivizumab: monoclonal Ab licensed to prevent RSV in high-risk

children – no benefit found for RSV treatment• Steroids

• Mixed data, generally not recommended

Other RSV therapies

Hirsch et al CID 2013

• Upper Respiratory Tract Infection• No treatment for most• Consider treatment for solid organ transplants or SCT with high risk

features (ie, prior to engraftment, <1 month post-transplant, etc)

• Lower Respiratory Tract Infection • Treatment for SOT or SCT patients requiring hospitalization for RSV• Can consider treating outpatient transplant patients with risk factors

(active GVHD, recently post-transplant, etc)

RSV Treatment Summary