Download 3/15/2017 1 Respiratory Viral Infections: Focus on Influenza

3/15/2017
Disclosures
Respiratory Viral Infections:
Focus on Influenza
• None
Advances in Infectious Diseases
March 2017
Bryn A Boslett, MD
Division of Infectious Diseases
University of California, San Francisco
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Outline
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?
• Influenza
• Epidemiology & Pathogenesis
• Clinical presentation
• Diagnostics
• Treatment
1. Group A Strep (GAS)
• Prevention
2. Influenza
• Non-influenza respiratory viruses
3. Respiratory syncytial virus (RSV)
• Focus on RSV
4. Rhinovirus
5. Seasonal allergies
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Epidemiology of Respiratory Viruses
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Respiratory Viral Comparison
Winter
Adenovirus
Spring
Summer
Fall
Rx
RSV
Influenza
Ribavirin + IVIG *
16
PIV
Parainfluenza
14
# of Patients
RSV
None
12
Rhinovirus
Adenovirus
10
Cidofovir*
8
Rhinovirus
6
None
4
Coronavirus
2
None
0
* = immunocompromised
Couch et al. Am J Med. 1997;102:2. (MDACC); slide courtesy of Michael Ison, MD and Catherine Liu, MD Case 1 continued…
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.
The Case for antibiotic stewardship
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
•
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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Outpatient antibiotic use, 2000 - 2010
• Broad-spectrum antibiotic
prescriptions doubled,
2000 – 2010
• 30% of prescriptions
deemed unnecessary
Shapiro DJ et al. J Antimicro Chemotherapy, 2013.
Nature 472, 32 (07 April 2011); doi:10.1038/472032a
Procalcitonin (PCT)
PCT effect on antibiotic prescribing
• Peptide released from cell during
bacterial infections
Setting
– 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 infections
Abx initiation
Abx duration, days
median (IQR)
Overall
64% vs 84%
7 (4–10) vs 10 (7–13)
Outpatient*
23% vs 63%
7 (5–8) vs 7 (6–8)
ED
ICU
73% vs 88%
100% vs 100%
7 (4–10) vs 10 (7–12)
8 (5–15) vs 12 (8–18)
*Mainly trials of URI, bronchitis, COPD exacerbation
J. 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. Mitsuma SF et al. Clin Infect Dis 2013; 56(7):996-1002
Schuetz P etal. Arch Int Med 2011; 171(15):1322-31
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Case 2
Epidemiology of Respiratory Viruses
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?
20
Adenovirus
18
Influenza
16
PIV
14
2. Obtain a CXR
# of Patients
RSV
1. Obtain respiratory virus testing
12
Rhinovirus
10
8
6
3. Start oseltamivir (Tamiflu®)
4
4. Start antibiotics (azithro, doxycycline, etc)
2
0
5. All of the above
6. Some combination of the above
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.
Diagnostics Comparison
The best possible test would be:
1. Direct fluorescence antibody (DFA)
2. Rapid antigen detection
3. Respiratory viral PCR
Viral Culture
PCR
DFA
Rapid Ag
Sensitivity
+++
+++
++
+
Turn‐around
Slowest
Fast
Fast
Fastest
4. Viral culture
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Diagnostic sampling
• Upper tract samples:
-NP aspirates or swab > nasal swab > throat swab
-Collect samples preferably within 5 days of onset (shedding is
Case 2 continued…
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
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.
Case 2 continued…
Radiology Findings
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
Viral infections come with diverse CXR possibilities:
normal, consolidation, diffuse infiltrates, etc
www.radiology.vcu.edu
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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
H3N2
FluView, CDC, accessed March 6, 2017.
Pandemic H1N1 Influenza A
Ages 65+
•
2009: novel influenza A strain pandemic
•
Swine presumed “mixing vessel”
•
Pregnancy (4x risk), obesity, and
comorbid medical conditions emerged as
main associations
Ages 50‐64 FluView, CDC, accessed March 6, 2017.
Trifonov et al, New Engl J Med, 2009;361:115-119
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Hospitalized 2009 - Influenza A (pH1N1)
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?
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
1.
Influenza viral pneumonia
2.
H. influenzae
3.
S. aureus
4.
S. pneumoniae
5.
S. pyogenes
MMWR, August 28, 2009;58(RR10):1-8. Slide courtesy of Lisa Winston.
Complications of Influenza
• Influenza viral pneumonia
Microbiologic diagnosis (EPIC study)
•
2488 adults
hospitalized with
community acquired
pneumonia
•
No microbiologic dx
found in 62% of cases
•
Viruses +/- bacterial
co-infection in 27%
• 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.
Jain S et al. N Engl J Med 2015;373:415-427.
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Treatment
In addition to broad-spectrum antibiotics, you would recommend:
Available treatments for Influenza
• Adamantanes: amantadine, rimantidine
• M2 ion channel blockers – prevents viral uncoating
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
• 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
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
Slide courtesy of Jen Babik, MD, PhD
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
Timing, Duration, Dose
• 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.
• 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
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%)
Jefferson et al, Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965.
Dobson et al, Lancet 2015, Jan 29.; Kelley and Cowling, Lancet 2015, Jan 29.; Kaiser et al, Arch Intern Med 2003, 163:1667.
Survival by Time of Antiviral Initiation, 2009
H1N1 Pandemic, California
Kumar AJT 2009; Casper Blood 2010; SE Asian CID Network BMJ 2013; Lee CID 2013
Timing, Duration, Dose
•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
Start Rx while awaiting test results!
•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
*p <.05
Louie J CID 2012; 55: 1198-204
Noel et al, J Intens Care Med. 2016 Mar 18. Welch et al, Intens Care Med 2015; 41:1365.; SE Asian CID Network BMJ 2013; Lee CID 2013
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Influenza Treatment Summary
•
High risk of complications:
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
Influenza Vaccine
• 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
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CDC, Influenza Antiviral Medications: Summary for Clinicians, January 9, 2015.
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
Case 3
28yo 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.
• 2015–16 influenza season:
50% of pregnant women
vaccinated
• Recommendation and offer of
vaccine by a primary provider
significantly increased uptake
How should she be treated?
1. Supportive care
2. Inhaled ribavirin
3. IV ribavirin + IVIG
4. Oral ribavirin
5. Oral ribavirin + IVIG
• 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.
RSV in Adults
Treatment of RSV: Ribavirin
• Clinical:
• 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
• 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
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. 43
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Outcomes with RSV therapy
Prevent URTI  LRTI
Progression URTI  LRTI in RSV
100%
80%
60%
40%
20%
0%
68%
32%
Prevent Mortality in LRTI
Mortality in RSV LRTI
100%
80%
80%
60%
40%
27%
20%
0%
Khanna et al, CID 2008. Kim et al Seminars in Respiratory and Critical Care Medicine 2007 RSV Treatment Summary
Other RSV therapies
• 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
Hirsch et al CID 2013
Respiratory Viral Summary
• 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)
• 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
• 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)
• Ways to Dx:
• Resp Viral PCR > DFA > Rapid test
• High suspicion = don’t trust (-) test result or normal CXR
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Respiratory Viral Summary
Thank You!
• 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
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