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Infectious Diseases in Clinical Practice February 2015

Jennifer Babik, MD, PhD Division of Infectious Diseases University of California, San Francisco

RESPIRATORY VIRAL INFECTIONS

Disclosures

• NONE

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Outline •  Influenza •  Epidemiology •  Clinical Presentation •  Diagnosis •  Antivirals

•  Other respiratory viruses: •  RSV •  Parainfluenza •  Metapneumovirus •  Adenovirus •  Avian and Swine Flu •  MERS

Case #1

63 y/o woman with h/o breast cancer is admitted January 2015 with fever, cough, and shortness of breath. A nasopharyngeal swab rapid influenza PCR is positive for influenza.

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What is the most likely influenza subtype?

1.  Influenza B

2.  Influenza A (H3N2)

3.  Influenza A(H1N1)pdm09

Influenza

•  From the Italian word meaning “influence” because it was thought that the stars and planets caused and controlled diseases

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Influenza Types

Influenza A

•  Humans, mammals, birds

•  Multiple subtypes (e.g. H1N1) •  H1 to H18, N1 to N11

•  Gene reassortment ! drastic changes in H +/- N ! pandemic

•  Currently circulating are 2 seasonal subtypes (H1N1 and H3N2) and pandemic H1N1

Influenza B

•  Humans

•  No subtypes

•  No reassortment (b/c few related viruses in animals)

•  ~25% of circulating influenza but wide variation year-to-year •  <1% in 2009-10 to 30% in 2012-13

•  Clinically indistinguishable from influenza A

Su et al, Clin Infect Dis 2014, 59:252. Glezen, Clin Infect Dis 2014, 59:1525.

Pandemic H1N1 (“Swine Flu”)

Neumann et al, Nature 2009, 459:931.

Quadruple Gene Reassortment

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Influenza A (H2N2) is Predominant This Year

FluView, CDC, Week ending February 7, 2015.

Influenza Hospitalizations

2011-12 2012-13 2013-14 2014-15

H3N2 + pH1N1 H3N2 H3N2 pH1N1

FluView, CDC, Week ending February 7, 2015.

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Influenza Hospitalizations by Age

18-64 yr

2012-13 2013-14 2014-15 2011-12

>65 yr

FluView, CDC, Week ending February 7, 2015.

Vaccine Match and Efficacy

•  This year, most (67%) of isolated H3N2 viruses are antigenically drifted compared to the vaccine strain

•  Early estimate of vaccine efficacy is 23% overall, and 12-14% for adults

•  CDC still recommends vaccination since: •  It still has some effectiveness – CDC modeling predicts that an efficacy of

only 10% in older adults can prevent ~13,000 hospitalizations •  There may be an effect in preventing severe illness/complications •  The vaccine is likely effective against other influenza strains (eg influenza

B) that could predominate later in the season

Flannery et al, MMWR January 16, 2015.

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Back to the Case…

63 y/o woman with a h/o breast cancer admitted with fever, cough, and shortness of breath and found to have influenza A H2N3.

Which is the most predictive of influenza?

1.  Sudden onset fever + myalgias

2.  Sudden onset fever + headache

3.  Sudden onset fever + cough

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Influenza: Are any Symptoms Predictive?

•  In studies without age restriction: •  There were no strong positive predictors •  Absence of fever, cough, congestion were negative predictors (LR<0.5)

•  In studies looking at pts ≥ 60 yrs old, strongest predictors: •  Acute onset of both fever and cough (LR 5.4) •  Fever (LR 3.8) •  Malaise (LR 2.6) •  Myalgias (LR 2.4)

Call et al, JAMA 2005, 293:987.

Influenza: Clinical

•  Fever 95% •  Cough 93% •  SOB 73% •  Chills 61% •  Fatigue/weakness 54% •  Myalgias 51% •  Rhinorrhea 32% •  Sore throat 31% •  Vomiting 26% •  Wheezing 27% •  Diarrhea 25%

Lee et al, J Infect Dis 2011, 203:1739. Jain et al, N Engl J Med 2009, 361:1935.

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Influenza in Immunocompromised Hosts

•  Less likely to have classic flu symptoms: •  Fever •  Cough, SOB •  Chills/sweats

•  More likely to have: •  Decreased appetite •  Abnormal pulmonary exam/CXR •  Need for hospitalization •  Need for mechanical ventilation •  Higher mortality •  Longer viral shedding

(median 8 vs 5d, mean 19 vs 6 d)

Memoli et al, Clin Infect Dis 2014, 58:214. Ison, Influenza and Other Respir Viruses 2013, 7 Suppl 3: 60.

ICH non-ICH

Back to the case… She starts requiring more oxygen while in the ED and so gets a CT scan.

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Centilobular nodules indicate:

1.  Influenza PNA

2.  Secondary bacterial PNA

3.  Either

CXR Findings in Influenza PNA

•  Infiltrates are: •  Bilateral 60-70%, unilateral 30-40% •  Consolidations in 75-90% •  Interstitial thickening 60%

•  8% of patients with PNA by CT scan have a normal CXR

Jain et al, Clin Infect Dis 2012, 54:1221. Jartti et al, Acta Radiologica 2011, 52: 297. Jain et al, N Engl J Med 2009, 361:1935. Agarwal et al, AJR 2009, 193: 1488.

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Chest CT Findings in Influenza PNA •  Abnormalities: •  GGO 90% •  Consolidations 66% •  Centrilobular nodules 60% •  Tree-in-bud 22%

•  3 main patterns:

Kang et al, J Comput Assist Tomogr 2012, 36:285.

GGO predominant Consolidations+GGO Centrilobular nodules+GGO

Case #2

A 35 year old man is admitted with 5 days of fever and cough and progressive respiratory distress. He rapidly deteriorates and is intubated. Rapid influenza PCR from an NP swab is negative.

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What is the next appropriate test?

1.  Rapid influenza antigen test

2.  Repeat NP swab for influenza PCR

3.  Nasal wash for influenza PCR

4.  Lower tract sampling for influenza PCR

Diagnostic Tests for Influenza

Rapid Antigen Testing

•  Point-of-care tests • Widely available in clinics

and ERs •  ~50-70% sensitive •  >90% specific

PCR

•  ~95% sensitive and specific •  Test of choice •  Some assays can determine: •  Influenza A vs B •  Influenza A subtypes (seasonal

H1N1, seasonal H3N2, pandemic H1N1)

Harper et al, Clin Infect Dis 2009, 48:1003. CDC, Influenza Symptoms and the Role of Laboratory Diagnostics, 2011.

Rapid Antigen Tests Molecular Assays

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Diagnosis: Samples

•  Upper tract samples: •  NP swabs or aspirates •  Collect samples preferably within 5 days (as shedding is "" after 5d)

•  In critically ill patients: collect both upper and lower tract specimens •  Lower tract samples can be positive even if viral shedding is no longer

detectable in the upper tract •  If suspicion is high, do not stop empiric therapy until lower tract sample

is negative

Harper et al, Clin Infect Dis 2009, 48:1003. CDC, Influenza Symptoms and the Role of Laboratory Diagnostics, 2011.

Case #2 Continued

He gets an lower tract sample (BAL) and the sample is positive for influenza A.

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Would you give him antivirals?

1.  No antivirals (he is out of the treatment window)

2.  Oseltamivir 75mg PO bid x 5 days

3.  Oseltamivir 150mg PO bid x 10 days

4.  Zanamavir 10mg inhaled bid x 5 days

M2 Inhibitors •  Amantadine, rimantidine •  Influenza A only •  Widespread resistance

Matrix proteins (M1 and M2)

Antivirals

Neuraminidase Inhibitors •  Oseltamivir, Zanamivir, Peramivir •  Influenza A and B •  Drugs of choice X

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Neurominidase Inhibitors

Drug Adult dosage

Renally dose?

Can use if intubated?

Contra-indications

Adverse Effects

Oseltamivir 75mg PO bid x 5 d

Yes Yes None N/V in ~10%

Zanamivir 10mg INH bid x 5 d

No No Underlying resp disease (eg, asthma, COPD)

Bronchospasm, cough

Peramivir 600mg IV x 1

Yes Yes None Diarrhea (8%), neuropscyh

Efficacy of Oseltamivir in Outpatients

• " symptoms by ~17-24 hours

•  Conflicting data on the effect on influenza complications: PNA, hospitalizations, and mortality •  Multiple observational studies show a " in PNA and hospitalizations in

healthy and high-risk patients •  2014 Cochrane review: no benefit on rates of PNA, hospitalization, or

death (all RCT data, many high-risk patients excluded) •  2015 meta-analysis: " in PNA and hospitalizations (most complete

data, based on individual patient data from trials)

•  Very similar results for zanamivir

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

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Timing of Oseltamivir in Outpatients

• Most trial participants had symptoms for ≤ 48h •  48h cutoff chosen because replication is largely controlled by most

healthy outpts by this point •  The earlier therapy is started ! the greater the effect

•  Treatment up to 72 hours? •  One RCT showed Rx for up to 72 h after illness onset " sx by ~1 d and " viral shedding (mostly children)

Jefferson et al, Cochrane Database Syst Rev 2012. Fry et al, Lancet Infect Dis, 2014, 14:109. Aoki et al, J Antimicrob Chemother 2003, 51:123.

Is Outpatient Oseltamivir Cost-Effective?

•  Yes…but this is assuming there is a benefit in preventing influenza complications and hospitalizations

•  Cost-effective in all groups: high risk adults > children > elderly > healthy adults

Talbird et al, Am J Health-Syst Pharm. 2009; 66:469.

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CDC Guidelines in Outpatients: Who to Treat?

•  Treat as early as possible (but even >48 hrs) •  All patients with severe, complicated disease •  All outpatients at risk for complications •  Ages <2 or >65 •  Chronic disease (cardiopulmonary, diabetes, kidney disease, etc) •  Immunocompromised •  Pregnant or post-partum (within 2 weeks) •  American Indians/Native Alaskans •  Morbidly obese (BMI ≥40) •  Residents of chronic care facilities

•  Can consider in healthy outpatients if <48h

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

Timing of Oseltamivir in Inpatients

•  Treatment within 48hrs " mortality by 50-65%

•  But >40% of patients hospitalized with influenza present at >48 hrs after symptom onset

• Multiple studies have shown a mortality benefit for treating inpatients at >48hrs: •  Treatment seems to be effective even out to 5 days •  But earlier is better: each day in delay increases risk of death by 20%

Lee and Ison, Clin Infect Dis 2012, 55:1205. Viasus et al, Chest 2011, 140:1025. Muthuri et al, J Infect Dis 2013, 207:553.

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Timing of Rx: Better Late than Never Treatment " mortality, even up to 5 days after symptom onset

Louie et al, Clin Infect Dis 2012, 55:1198.

% p

atie

nts

who

sur

vive

d Rx No Rx

Days after symptom onset 0 1

2 3 4 5

Empiric Antivirals

•  If influenza is suspected: start treatment empirically while awaiting test results

•  The earlier treatment is started the better, so DO NOT DELAY

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

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Treatment: High Dose Oseltamivir?

•  Some experts recommend using high dose oseltamivir (150mg PO bid x 5-10 days) in immunocompromised or critically ill patients

•  2 RCTs in 2013 of high vs regular dose oseltamivir x 5d: •  Hospitalized patients (adults in 1 study, kids in the other) •  Mostly immunocompetent, non-ventilated patients •  Results: No difference in viral clearance, mortality, duration of fever,

use of O2, ICU admission or intubation, LOS •  High dose oseltamivir was well tolerated

South East Asia ID Clinical Research Network, BMJ 2013, 346:f3039. Lee et al, Clin Infect Dis 2013, 57:1511.

High Dose Oseltamivir: When to use?

•  There is no benefit in hospitalized patients who are immunocompetent, non-ICU patients

• What about critically ill or immunocompromised patients?

•  At UCSF we are using oseltamivir 150mg PO bid x 10 days in all critically ill patients

WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) 2009 and other Influenza Viruses, 2010.

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Duration of Therapy

•  5 days in uncomplicated cases

•  Consider 10 days in critically ill and immunocompromised because of longer shedding (UCSF guidelines)

•  Can consider prolonging the treatment duration beyond this depending on clinical response and follow-up testing (although no data for this)

Peramivir (IV)

•  FDA approved on Dec 19, 2014 as a single IV dose for use in adults with acute uncomplicated influenza and symptom onset <48hrs

•  What is the evidence? •  Outpatients with uncomplicated influenza, <48hr of symptoms ! single

dose " symptom duration by 21h compared to placebo •  Inpatients with influenza, <72 hours of symptoms ! daily dose x 5 days did

not offer a benefit in addition to SOC (only 1/3 of study did not get NAI)

•  Well tolerated

Whitley et al, Antivir Ther 2014, Oct 15 Epub. Kohno et al, Antimicrob Agents Chemother 2010, 54:4568. de Jong et al, Clin Infect Dis 2014, 59:e172.

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Peramivir: Guidelines for Use

• When to use? •  Any concerns for GI absorption of oseltamivir (note: limited data shows

that oseltamivir is well absorbed in obese and critically ill patients icluding those on CRRT and ECMO)

•  Patients not responding to oseltamivir? Patients critically ill?

• How to dose? •  FDA approved for a single dose in uncomplicated influenza •  Under the EUA in 2009: was given as a daily dose for 5-10 days •  UCSF guidelines: 5 days

Influenza Treatment Summary

Outpatients

•  Who to treat? •  Severe, complicated disease •  High risk for complications •  Start as soon as possible but

treat even if >48 hours

•  Which drug? •  Oseltamivir •  Zanamivir (if no COPD/asthma)

•  How long? •  5 days

Inpatients

•  Who to treat? •  All inpatients

•  Which drug? •  Oseltamivir (high dose if critically ill,

immunocompromised?) •  Zanamivir (if no COPD/asthma and

not intubated) •  Peramivir if need an IV option

•  How long? •  10 d if critically ill,

immunocompromised? •  5 days for everyone else •  Peramivir: 1 day or 5 days?

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ECMO for Severe Influenza

• Why ECMO? •  Young patients, low comorbidities, likelihood of reversible ALI

• Meta-analysis of 8 case series with 266 patients who received ECMO for severe H1N1: •  Average age 36 y/o •  Co-morbidities: Obesity in 40%, DM or asthma/COPD in 10%, peri-

partum in 20% •  Mortality 8-65%

•  Bottom line: it is feasible and effective although mortality benefit is unclear

Zangrillo et al, Critical Care 2013, 17:R30.

Case #2 Continued

After 10 days his influenza PCR is still positive. You decide, although there is no data one way or another, to treat him for an additional 7 days since he is critically ill. However, he remains critically ill and his PCR continues to be positive.

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What is your next step?

1.  Change to IV oseltamivir

2.  Start vancomycin and cefepime

3.  Change to inhaled zanamavir

4.  Send to the DPH for resistance testing

What If My Patient Doesn’t Get Better?

•  Consider oseltamivir resistance •  Especially critically ill or immunocompromised pts who may shed for weeks •  Send to DPH or CDC •  Rare (2013-14: 1.8 % of pH1N1, 0% H3N2, 0% influenza B)

•  Consider whether PO absorption is adequate ! if not, use IV peramivir

•  If concerned for resistance ! IV zanamivir available via urgent EIND approval from GSK and the FDAhttp://www.cdc.gov/flu/professionals/antivirals/intravenous-antivirals.htm

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Antiviral Resistance 2014-15

CDC, 2014-2015 Influenza Season FluView, Week ending February 7, 2015.

Case #3

An otherwise healthy 39 year old man developed sudden onset of fever, myalgias, and HA.

He improved slightly after 2 days but then began to again have high fevers, developed a new cough, and started having progressive shortness of breath.

He presented to the ED and was found to have a large RLL pneumonia but vitals were stable. Rapid influenza PCR was negative.

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The most likely cause of his PNA is:

1.  Influenza

2.  S. pneumoniae

3.  S. aureus

4.  H. influenzae

Secondary Bacterial Pneumonia

• How common is it? •  <3% of all cases of influenza •  ~10% of all patients hospitalized for influenza •  20-30% of critically ill patients or deaths

•  Clinical: •  Classic: near resolution of influenza sxs and then 4-7 days later there

is recurrence of sx/development of PNA •  Reality: these patients can present on ~day 5 of illness with symptoms

that look like severe influenza (ie, without a period of improvement)

MMWR 2009, 58:1. Jain et al, Clin Infect Dis 2012, 54:1221. Jain et al, N Engl J Med 2009, 361:1935. Rice et al, Crit Care Med 2012, 40:1487.

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Secondary Bacterial Pneumonia

•  Viral infection leads to: •  Epithelial cell dysfunction and death ! #bacterial adhesion, invasion •  Impairment of mucociliary clearance of bacteria for the lungs

• Get infection by colonizers of the nasopharynx: •  S. pneumoniae ~40-50% •  S. aureus ~30-40% (# in critically ill) •  Group A Streptococcus 5-25% •  Others: H. influenzae, other GNRs

Chertow and Memoli, JAMA 2013, 309:275. MMWR 2009, 58:1. Jain et al, Clin Infect Dis 2012, 54:1221. Jain et al, N Engl J Med 2009, 361:1935. Rice et al, Crit Care Med 2012, 40:1487.

Case #4

84 y/o woman with ESRD on HD gets admitted with 2 days of fever and prominent wheezing in January. Her rapid influenza is negative.

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This is most likely to be:

1.  Adenovirus

2.  CMV

3.  RSV

4.  Parainfluenza

RSV in Adults

•  Epidemiology •  Winter seasonality – affects up to 10% of adults annually •  A common cause of CAP in adults (2.5-5%)

•  Clinical: •  Fever, cough, runny nose, wheeze •  Compared with influenza: •  More comorbidities •  Fever less common (but still in 75%) •  Wheezing and dyspnea more common

•  Bacterial co-infection in 12% •  Mortality rate 10% in elderly, >50% in HSCT patients

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

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RSV in Adults

•  CXR findings: •  Normal in 50% •  Consolidation 24% •  GGO 20% •  Unilateral 82%

•  Treatment only in immunocompromised: ribavirin + immunomodulator (IVIG or pavilizumab)

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

Parainfluenza

•  PIV-3 is most common type in adults (PIV-1 and PIV-2 cause croup in kids)

•  Seasonality is spring-summer

•  Clinical: •  Fever, cough, SOB, wheeze •  Causes URI, bronchiolitis, bronchitis, PNA •  Can be severe in immunocompromised

•  No treatment clearly effective (ribavirin, DAS-181)

Marx et al, Clin Infect Dis 1999, 29:134.

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Human Metapneumovirus •  Epidemiology:

•  First identified in 2001 •  ~4% of CAP •  Seasonality: winter-spring

•  Clinical: •  40-70% of infections are asymptomatic •  URI symptoms, cough, wheeze •  Usually afebrile •  CXR infiltrate in 27% •  Can be severe, especially in high risk populations

•  Treatment: case reports of using ribavirin + IVIG (like RSV) in transplant patients

Walsh et al, Arch Intern Med 2008, 168:2489.

Adenovirus •  Can cause severe PNA in ICH host, rarely in

immunocompetent

•  The classical features of adenoviral infection (pharyngitis, conjunctivitis, rash, diarrhea) may be absent

•  Diagnosis: •  Some respiratory viral panel PCR assays are

only ~60% sensitive for adenovirus (the primers miss some serotypes)

•  If high suspicion, also send the serum PCR (has # sensitivity)

•  Treatment: can consider cidofovir

Louie et al, Clin Infect Dis 2008, 46:421. Clark et al, J Med Case Rep 2011, 5:259. Pabbaraju et al, J Clin Microbiol 2008, 46:3056.

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Case #5

A 75 year old man just returned from a trip to China where he was visiting family. He was feeling unwell on his trip home and then next day is admitted with high fevers and a rapidly progressive pneumonia. He is intubated and requiring high levels of oxygen. His family in China sells chickens at stall at a local outdoor market.

You call the DPH asking them to check for:

1.  Influenza A (H3N2v)

2.  Influenza A (H5N1)

3.  MERS Coronavirus

4.  Human metapneumovirus

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Avian Flu: H5N1 •  694 cases in Asia, Africa, the Pacific,

Europe, the Near East ! 402 deaths (~60% case fatality rate)

•  Jan 8, 2014: 1st case in the Americas (Canada) in a traveler from China

•  Most cases are a result of direct or close contact with sick or dead infected poultry

•  Rare person-to-person spread, not sustained

CDC, Highly Pathogenic Avian Influenza A (H5N1), February 27, 2014. WHO, Influenza, January 6 2015.

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Factors Affecting Bird-Human Transmission

Poultry markets

Backyard flocks

Avian Flu: H7N9 •  453 cases reported in China since

March 2013 with 175 deaths (case fatality rate 38%)

•  1 case in Malaysia

•  Most cases are thought to be secondary to contact with infected poultry

•  Limited person-to-person spread in rare circumstances but not sustained

WHO, Avian influenza A(H7N9) virus, October 2014.

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Avian Flu: Evaluation

•  Consider avian influenza (H5N1 or H7N9) in patients with: •  Influenza-like illness AND •  Recent travel within 10 days to areas with avian influenza in poultry or

humans

• Diagnosis: •  Typical influenza tests may be positive for influenza A that is

“unsubtypable” but sensitivity unknown •  Arrange for testing via the DPH or CDC

CDC, Avian Influenza Case Definitions, Jaunary 2014.

Swine Flu •  When swine flu viruses sporadically

infect humans, they are called variant viruses (denoted by a “v” at the end of the subtype name)

•  H3N2v most common (343 cases since 2011, 1 death)

•  Most cases in Ohio and Indiana

•  Human infections usually occur in people with exposure to infected pigs (e.g., at agricultural fairs)

•  Limited person-to-person spread

CDC, Influenza A (H3N2) Variant Virus, September 2014.

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Middle East Respiratory Syndrome •  Caused by a coronavirus (MERS-CoV)

•  As of June 2014, 699 cases with 209 deaths (30% mortality rate)

•  Person-to-person spread through close contact

•  All cases linked to countries in the Arabian Peninsula

•  2 cases in the US in May 2014 (Indiana, Florida) in HCWs who had lived and worked in Saudi Arabia

CDC, MERS, July 2014. WHO, MERS-CoV Summary Updates, June 2014.

MERS: Evaluation

• Who to evaluate for MERS? •  Fever and respiratory symptoms AND •  A history of travel from countries in or near the Arabian Peninsula within 14

days before symptom onset

• Diagnosis •  Contact DPH or CDC to arrange for testing

CDC, MERS, July 2014.

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Thank you!