October 28, 2009

1. Clinical Information Call on Antiviral Treatment Options in Critically Ill 2009 Influenza H1N1 Patients Clinician Outreach and Communication Activity (COCA) Conference Call October 28, 2009

2. Continuing Education Disclaimer In compliance with continuing education requirements, all presenters must disclose any financial or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters as well as any use of unlabeled product(s) or product(s) under investigational use. CDC, our planners, and our presenters wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters with the exception of Dr. Gaur who wishes to disclose that he serves as a site investigator for a Gilead clinical trial and of Dr. Maroushek who wishes to disclose being on Merck’s speaker’s bureau. Presentations will not include any discussion of the unlabeled use of a product or a product under investigational use with the exception of Dr. Gaur’s discussion of use of intravenous zanamivir in a patient, this medication was given under an emergency IND approval for its use for this patient and Dr. Maroushek’s discussion of use of IV peramivir in treatment of Novel H1N1 influenza. There is no commercial support.

3. Accrediting Statements CME: The Centers for Disease Control and Prevention is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The Centers for Disease Control and Prevention designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. CNE: The Centers for Disease Control and Prevention is accredited as a provider of Continuing Nursing Education by the American Nurses Credentialing Center's Commission on Accreditation. This activity provides 1 contact hour. CEU: The CDC has been approved as an Authorized Provider by the International Association for Continuing Education and Training (IACET), 8405 Greensboro Drive, Suite 800, McLean, VA 22102. The CDC is authorized by IACET to offer 0.1 CEU's for this program. CECH: The Centers for Disease Control and Prevention is a designated provider of continuing education contact hours (CECH) in health education by the National Commission for Health Education Credentialing, Inc. This program is a designated event for the CHES to receive 1 Category I contact hour in health education, CDC provider number GA0082.

4. H1N1 Case Presentation Stacene Maroushek MD, PhD, MPH

5. HPI/PMH/SH • 17 yo previously healthy male presents to UC with ST, fever, cough and worsening SOB x 3 days • Diagnosed with pneumonia and referred to our hospital for further treatment • Initially admitted from ED to pediatric ward, but sent to PICU within hours due to increased WOB • Intubated within 12 hours of admission • High Frequency Oscillatory Ventilation within 4 hours • PMH/SH • 2 ppd smoker x 2 years • BMI 31 (97%) • Otherwise healthy • Visited State Fair ~1 week prior to illness • Lives with friends, some also ill with ILI

6. Physical Exam • VS:T=42.1, BP=90/43, HR=174, R=58 • HEENT-Sclera clear, ETT, NG in place • Lungs-Coarse BS decreased air entry R base, pink frothy sputum from ETT • CV-Tachycardic, cool extremities, perfusion poor, good pulses • GI-blood from NG and grossly bloody diarrhea, soft, ND, +BS, No HSM • Skin-No rashes • Neuro-intubated, sedated • Lymph- No adenopathy

7. ABG-7.22/58/76/23/-6 WBC-2.8 Plts-23 Hgb-16.811.5 INR-1.7 APTT-71.5 Lactate-4.3 BUN-62 CR-3.1 Bacterial Cultures from blood, urine, sputum, stool all negative Troponin 32 ng/ml (<.09) ALT-814 AST-2432 TBili-1.7 CRP-202.8 mg/l CXR-Cons RUL, RLL infiltrates, patchy ground glass opacities throughout ECHO-unable Sputum and Nasal Aspirate with PCR confirmed H1N1 Influenza A Laboratory Findings

8. Assessment • Previously healthy 17 year old with suspected H1N1 influenza and associated: • Systemic Inflammatory Response Syndrome • Hypotension • Pancytopenia • Myocarditis • Coagulopathy • Acute Renal Failure with Oligouria • Acute GI bleed due to Bowel Ischemia • Hepatitis • Pancreatitis

9. Aggressive critical care support Norepinephrine Milrinone Pantoprazole HFOV, considered ECMO Multiple FFP, Plts, pRBC transfusions Antibiotics for pneumonia Initial Levofloxacin, Vancomycin Later Piperacillin/Tazobactam, Meropenem Antivirals for H1N1 Influenza Oseltamivir 75 mg x 1 dose Oseltamivir 150 mg suspension down NG x 6 days (?absorption due to GI bleed and ongoing diarrhea) Zanamivir inhalation ordered, but unable to be given due to oscillator Peramivir 600 mg IV x 5 days starting early on PAD #2 Treatment Plan

10. Outcome • Patient Ventilated for total 16 days • 4 days HFOV, 12 days conventional ventilator • Improvement seen after 2 days of IV Peramivir • Hospitalized for total of 25 days (~$300K) • Gradual return to normal lab values and functioning of all organ systems • No secondary bacterial infections ever identified • Left hospital walking and talking with parents, but in weakened state with some mental slowing. • Plan for additional outpatient rehabilitation with Occupational and Physical Therapy.

11. Case 2: Oseltamvir resistant pandemic A (H1N1) influenza respiratory disease in an immunocompromised child

12. Timeline of events • Day one: 10 year old with pre B acute lymphoblastic leukemia admitted with cough, rhinorhea and fever and is found influenza A positive based on rapid antigen test. Absolute lymphocyte count (ALC) 576 mm3; Absolute neutrophil count (ANC) 860 mm3 • Day five: patient discharged after 5 days of PO oseltamivir (75mg BID). • Patient remains afebrile but continues to have some residual cough and rhinnorhea over the next twelve days • Day 16: Presents with increasing cough, fever, hypoxia, neutropenia, lymphopenia and right lower lobe pneumonia; rapid antigen test for influenza A comes back negative

13. Timeline of events • Day 17-20: Respiratory status worsens despite broad spectrum antibiotics prompting intubation and transfer to a referral hospital. Oseltamivir through NG (75mg q12) re-initiated. • Day 21: Tracheal aspirate secretions influenza A positive by DFA and PCR • Day 22 – 26: High frequency oscillator support, neutrophil count recovery, bilateral lung disease – intravenous methylprednisolone initiated. Tracheal aspirate and blood cultures show no growth • Day 29: oseltamivir resistant (H275Y) pandemic H1N1 virus population confirmed by PCR in nasal aspirate specimen collected on Day 27; assessments done later show presence of this resistant virus in the day 21 specimen as well.

14. Timeline of events • Day 29 (continued): A request to GlaxoSmithKline (Research Triangle Park, NC, USA) for emergency use of intravenous zanamivir is made under an emergency IND approved by the FDA for this patient • Day 30: Patient started on 600 mg intravenous zanamivir q12 after IRB approval and consent of parents • Patient treated for a total of 15 days with IV zanamivir with gradual improvement of respiratory status; iv zanamivir tolerated well

15. Timeline of events • Respiratory specimens collected in the interim remain PCR positive but cycle threshold (Ct) values suggest decreasing viral load • Day 45: With the patient improved and on minimal ventilator support on a conventional ventilator, IV zanamivir and methylprednisolone stopped. • Day 53: Tracheal aspirate specimen PCR negative for influenza A • Day 55: Patient extubated

16. Continuing Education Credit/Contact Hours for COCA Conference Calls Continuing Education guidelines require that the attendance of all who participate in COCA Conference Calls be properly documented. ALL Continuing Education credits/contact hours (CME, CNE, CEU and CECH) for COCA Conference Calls are issued online through the CDC Training & Continuing Education Online system http://www2a.cdc.gov/TCEOnline/.   Those who participate in the COCA Conference Calls and who wish to receive CE credit/contact hours and will complete the online evaluation by November 27, 2009 will use the course code EC1265. Those who wish to receive CE credits/contact hours and will complete the online evaluation between November 28, 2009 and October 28, 2010 will use course code WD1265. CE certificates can be printed immediately upon completion of your online evaluation. A cumulative transcript of all CDC/ATSDR CE’s obtained through the CDC Training & Continuing Education Online System will be maintained for each user.