RESPIRATORY VIRAL INFECTIONS

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1 RESPIRATORY VIRAL INFECTIONS Infectious Diseases in Clinical Practice February 2015 Jennifer Babik, MD, PhD Division of Infectious Diseases University of California, San Francisco Disclosures NONE 1

2 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. 2

3 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 3

4 Influenza Types Influenza A Influenza B 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 Humans No subtypes No reassortment (b/c few related viruses in animals) ~25% of circulating influenza but wide variation year-to-year <1% in to 30% in 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 ) Quadruple Gene Reassortment Neumann et al, Nature 2009, 459:931. 4

5 Influenza A (H2N2) is Predominant This Year FluView, CDC, Week ending February 7, Influenza Hospitalizations H3N2 + ph1n1 H3N2 ph1n1 H3N2 FluView, CDC, Week ending February 7,

6 Influenza Hospitalizations by Age >65 yr yr FluView, CDC, Week ending February 7, 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,

7 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 7

8 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:

9 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) ICH non-ich Memoli et al, Clin Infect Dis 2014, 58:214. Ison, Influenza and Other Respir Viruses 2013, 7 Suppl 3: 60. Back to the case She starts requiring more oxygen while in the ED and so gets a CT scan. 9

10 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:

11 Chest CT Findings in Influenza PNA Abnormalities: GGO 90% Consolidations 66% Centrilobular nodules 60% Tree-in-bud 22% 3 main patterns: GGO predominant Consolidations+GGO Centrilobular nodules+ggo Kang et al, J Comput Assist Tomogr 2012, 36:285. 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. 11

12 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 Tests Point-of-care tests Widely available in clinics and ERs ~50-70% sensitive >90% specific Molecular PCR Assays ~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,

13 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, Case #2 Continued He gets an lower tract sample (BAL) and the sample is positive for influenza A. 13

14 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 Antivirals Matrix proteins (M1 and M2) X M2 Inhibitors Amantadine, rimantidine Influenza A only Widespread resistance Neuraminidase Inhibitors Oseltamivir, Zanamivir, Peramivir Influenza A and B Drugs of choice 14

15 Neurominidase Inhibitors Drug Adult dosage Renally dose? Can use if intubated? Contraindications 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.: CD Kelley and Cowling, Lancet 2015, Jan 29. Dobson et al, Lancet 2015, Jan

16 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 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:

17 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, 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:

18 Timing of Rx: Better Late than Never % patients who survived Rx No Rx Days after symptom onset Treatment " mortality, even up to 5 days after symptom onset Louie et al, Clin Infect Dis 2012, 55:1198. 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,

19 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,

20 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:e

21 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 Who to treat? All inpatients 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? 21

22 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%, peripartum 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. 22

23 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 ( : 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 FDA 23

24 Antiviral Resistance CDC, Influenza Season FluView, Week ending February 7, 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. 24

25 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:

26 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. 26

27 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:

28 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:

29 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:

30 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 30

31 Avian Flu: H5N1 694 cases in Asia, Africa, the Pacific, Europe, the Near East! 402 deaths (~60% case fatality rate) Jan 8, 2014: 1 st 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, WHO, Influenza, January

32 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

33 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 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

34 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 WHO, MERS-CoV Summary Updates, June 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

35 Thank you! 35