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

Respiratory Viral Infections: Focus on InfluenzaAdvances in Infectious DiseasesMarch 2017

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Disclosures

• None

Outline

• Influenza

• Epidemiology & Pathogenesis

• Clinical presentation

• Diagnostics

• Treatment

• Prevention

• Non-influenza respiratory viruses

• Focus on RSV

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Case 1

34yo 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. Influenza

3. Respiratory syncytial virus (RSV)

4. Rhinovirus

5. Seasonal allergies

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Epidemiology of Respiratory Viruses

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# o

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tien

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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

* = immunocompromised

Teichtahl 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 Rx

RSV Ribavirin + IVIG *

Parainfluenza None

Adenovirus Cidofovir*

Rhinovirus None

Coronavirus None

Case 1 continued…

What is your next step?

1. Obtain a CXR

2. Obtain respiratory virus testing

3. Obtain a rapid strep test for GAS

4. 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.

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Nature 472, 32 (07 April 2011); doi:10.1038/472032a

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

Procalcitonin (PCT)

• Peptide released from cell during bacterial infections– Correlated with infection severity– Assay takes ~30 min to run

• Two main uses found to be effective in studies:– Prevention of initiation of

antibiotics (outpatient/ED)– Shortened duration of antibiotics

(ICU)– Most data exists for respiratory

tract infectionsJ. Clin. Endocrinol. Metab. 79 (6): 1605–8.

Lindscheid P et al. Endocrinology 2003; 144:5578‐84.Christ‐Crain M, Mueller B. Swiss Med Wkly 2005; 135: 451‐460. 

PCT effect on antibiotic prescribing

Setting Abx initiation Abx duration, daysmedian (IQR)

Overall 64% vs 84% 7 (4–10) vs 10 (7–13)

Outpatient* 23% vs 63% 7 (5–8) vs 7 (6–8)

ED 73% vs 88% 7 (4–10) vs 10 (7–12)

ICU 100% vs 100% 8 (5–15) vs 12 (8–18)

*Mainly trials of URI, bronchitis, COPD exacerbation

Mitsuma SF et al. Clin Infect Dis 2013; 56(7):996-1002Schuetz P etal. Arch Int Med 2011; 171(15):1322-31

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Case 2

68yo man with history of diabetes presents to clinic in January with 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 testing

2. Obtain a CXR

3. Start oseltamivir (Tamiflu®)

4. Start antibiotics (azithro, doxycycline, etc)

5. All of the above

6. Some combination of the above

Epidemiology of Respiratory Viruses

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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 detection

3. Respiratory viral PCR

4. Viral culture

Diagnostics Comparison

Viral Culture PCR DFA Rapid Ag

Sensitivity +++ +++ ++ +

Turn‐around Slowest Fast Fast Fastest

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• Upper tract samples:-NP aspirates or swab > nasal swab > throat swab-Collect samples preferably within 5 days of onset (shedding is after 5d)

• Lower tract samples: -Collect both upper and lower tract specimens in critically ill patients!-Lower tract can be (+) even if viral shedding is no longer detectable in the upper tract

Diagnostic sampling Case 2 continued…

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

Radiology Findings

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Viral infections come with diverse CXR possibilities: normal, consolidation, diffuse infiltrates, etc

www.radiology.vcu.edu

Case 2 continued…

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

1. Azithromycin x 5 days

2. Oseltamivir while awaiting PCR

3. Send home with strict return instructions

4. Send to the ED for admission

Two days later, respiratory PCR (+) for influenza

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

1. Influenza A (H1N1)pdm09

2. Influenza A (H3N2)

3. Influenza A (H7N9)

4. Influenza B

FluView, CDC, accessed March 6, 2017.

H3N2

Ages 65+

Ages 50‐64 

FluView, CDC, accessed March 6, 2017.

Pandemic H1N1 Influenza A

• 2009: novel influenza A strain pandemic

• Swine presumed “mixing vessel”

• Pregnancy (4x risk), obesity, and comorbid medical conditions emerged as main associations

Trifonov et al, New Engl J Med, 2009;361:115-119

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Hospitalized 2009 - Influenza A (pH1N1)

FIGURE. Distribution by age group of persons hospitalized with laboratory‐confirmed influenza,* ‐‐‐ United States, 2007‐‐08 winter influenza season and April 15‐‐August 11, 2009

MMWR, August 28, 2009;58(RR10):1-8. Slide courtesy of Lisa Winston.

Back to our case…

You call your patient to inform him of the results, but his wife answers the phone and tells you that he was hospitalized last night, in the ICU. His latest CXR is shown. What is the most likely etiology?

1. Influenza viral pneumonia

2. H. influenzae

3. S. aureus

4. S. pneumoniae

5. S. pyogenes

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 superinfection

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.

Microbiologic diagnosis (EPIC study)

Jain S et al. N Engl J Med 2015;373:415-427.

• 2488 adults hospitalized with community acquired pneumonia

• No microbiologic dx found in 62% of cases

• Viruses +/- bacterial co-infection in 27%

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Treatment

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 days

3. Oseltamivir 150 mg PO BID x 10 days

4. Peramivir 600 mg IV x1

5. Zanamivir 10 mg inhaled BID x 5 days

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

Neuraminidase comparison

Slide courtesy of Jen Babik, MD, PhD

Peramivir

• Intravenous neuraminidase inhibitor (NAI), FDA approved Dec 2014

• Outpatients: Single dose duration of symptoms by 21 hrs

• Hospitalized patients: no advantage with daily dose x 5 days, in addition to standard of care (but included a NAI in two-thirds of patients)

• No adequately powered studies comparing outcomes of peramivir vs other NAIs

consider peramivir for use if malabsorption concern, or poor response to alternative NAI

Kohno et al, Antimicrob Agents Chemother 2010, 54:4568. de Jong et al, Clin Infect Dis 2014, 59:e172.

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Conflicting Data

• Multiple observational trials show 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):

• duration of illness by ~24 hrs for laboratory-confirmed infection

• antibiotic prescription for lower respiratory tract infection (8.7 vs 4.9%)

• 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

Louie J CID 2012; 55: 1198-204

*p <.05

Survival by Time of Antiviral Initiation, 2009 H1N1 Pandemic, California

Start Rx while awaiting test results!

Timing, Duration, Dose

Noel et al, J Intens Care Med. 2016Mar 18. Welch et al, Intens Care Med 2015; 41:1365.; SE Asian CID Network BMJ 2013; Lee CID 2013

•2 RCTs in 2013 of high vs regular dose oseltamivir x 5d:•Hospitalized kids or adults, immunocompetent, almost all non-ICU•Results: No difference in mortality, ICU admission or intubation, LOS

•2015 retrospective study in 124 ICU patients with influenza:•Patients in the high dose group were sicker at baseline •No benefit of high dose

•2016 retrospective study in 57 ICU patients with influenza: •Patients in high dose group were sicker•No difference in duration of ventilation, ICU or total hospital LOS

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Influenza Treatment Summary

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• 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

• 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.

Influenza Vaccine Uptake of influenza vaccine amongst healthcare workers (HCW)

• HCW influenza vaccination coverage estimate for the 2015–16 season was 79% 

• Rate of 96.5% attained when employers require vaccination – controversial policy

• Uptake lowest among medical assistants/aides (64%) and HCW in long‐term care settings (69%)

• Offering vaccination at the workplace at no cost was associated with higher vaccination coverage.

Black, et al. MMWR. September 30, 2016 / 65(38);1026–1031

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Influenza vaccine in pregnant women

• 2015–16 influenza season: 50% of pregnant women vaccinated

• Recommendation and offer of vaccine by a primary provider significantly increased uptake

• Main reason for refusal was concern about harmful effects of vaccine on the fetus

Ding H, Black CL, Ball S, et al. FluVaxView. Accessed March 6, 2017.

Case 328yo 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 care

2. Inhaled ribavirin

3. IV ribavirin + IVIG

4. Oral ribavirin

5. Oral ribavirin + IVIG

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• 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 hemolytic anemia, neutropenia, thrombocytopenia

• Oral: Now what we use at UCSF, watch for hemolytic anemia

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Outcomes with RSV therapy

Prevent URTI  LRTI Prevent Mortality in LRTI

32%

68%

0%20%40%60%80%100%

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

Progression URTI  LRTI in RSV

27%

80%

0%

20%

40%

60%

80%

100%Mortality in RSV LRTI

• 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

• 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

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• Treatment: For influenza, time = life!

In high-risk pts, don’t wait for results. Start a NAI (oseltamivir, others)

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 SummaryThank You!