swine origin h1n1 2009: clinical aspects

Swine Origin H1N1 2009

Clinical Aspects

Javeed Siddiqui M.D.,M.P.HDivision of Infectious and Immunologic Diseases

Center for Health and TechnologySchool of Medicine

University of California, Davis

Clinical Case

September 2009

Clinical Case

Clinical Presentation

• The symptoms of pandemic H1N1 influenza of 2009 are essentially the same as the seasonal flu, although some have noted an increased frequency of gastrointestinal symptoms, including vomiting and diarrhea.

• It has been noted some have observed the absence of fever in a significant number with virologically proven cases.

CDC. Interim guidance for clinicians on identifying and caring for patients with swine-origin influenza A (H1N1) virus infection. June 2009. Available at: http://www.cdc.gov/h1n1flu/identifyingpatients.htm Accessed September 16, 2009.)

S-OIV H1N1 Clinical Findings

• Incubation: mean of 3-9 days Range 1-7 days

• Symptoms:– Fever (90%)– Cough (100%)– Headache (60%)– Diarrhea (30%)

Shinde V et al NEJM May 7 2009

Clinical Features of S-OIV H1N1

• The incubation period for H1N1 influenza is 1-4 days, possibly as long as 7 days.

• clinical features of influenza:• Sudden onset of fever (usually high)• Headache• Extreme tiredness• Dry cough• Sore throat• Runny nose• Muscle aches • and stomach symptoms -- more common in children.

• (CDC. Interim guidance for clinicians on identifying and caring for patients with swine-origin influenza A (H1N1) virus infection. June 2009. Available at: http://www.cdc.gov/h1n1flu/identifyingpatients.htm Accessed September 16, 2009.)

Symptoms in virologically confirmed cases

• Cough (98%)• Subjective fever (96%)

• Fatigue (89%)• Headache (82%)• Sore throat (82%)• Abdominal pain (50%)

• Diarrhea (48%)• Dyspnea (48%)• Joint pain (46%)• The measured mean peak fever in this group was 102.2 F.

•During an outbreak of H1N1 in a New York City high school, a sample of New York City school students (median age, 15 years) with virologically confirmed cases.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0430a1.htm Accessed November 7, 2009 MMWR Morb Mortal Wkly Rep Dispatch. 2009;58:1-3..

The CDC Definitions influenza-like illness (ILI)

• fever of ≥100 F (37.8 C) plus cough and/or sore throat in the absence of a known cause other than influenza.

• acute respiratory illness (ARI), defined by the presence of 2 of the following 4 symptoms: fever, cough, sore throat, or rhinorrhea.

•http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0430a1.htm Accessed November 7, 2009)

Symptomatology Associated with pandemic influenza in New York

City April - May 2009

• In the outbreak of pandemic influenza in New York City, 95% of virologically proven cases satisfied the ILI definition.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0430a1.htm Accessed November 7, 2009 MMWR Morb Mortal Wkly Rep Dispatch. 2009;58:1-3..

Case Definitions for S-OIV H1N1

• Confirmed case: Patient with ILI plus laboratory evidence confirmed by real-time RT-PCR or viral culture.

• Probable case: ILI plus laboratory test positive for influenza A and negative for human H1 and H3 by RT-PCR; and

•Interim guidance for clinicians on identifying and caring for patients with swine-origin influenza A (H1N1) virus infection. June 2009.• http://www.cdc.gov/h1n1flu/identifyingpatients.htm Accessed November 7, 2009.

Case Definitions for S-OIV H1N1

• Probable case [Optional]: ILI without negative H1N1 test and

(1) previously healthy person > 65 years hospitalized for ILI;

(2) epidemiologic link to confirmed or probable case in past 7 days; or

(3) ILI plus travel to a state or country with confirmed or probable cases.

•Interim guidance for clinicians on identifying and caring for patients with swine-origin influenza A (H1N1) virus infection. June 2009.• http://www.cdc.gov/h1n1flu/identifyingpatients.htm Accessed November 7, 2009.

Complications of S-OIV H1N1

Related Risk for Infection, Hospitalization, and Lethal Outcome

Age-related risk. Rates for H1N1 for May-July 2009 by Age

Age Cases/100,000 Hospitalization/100,000 Death %0-4 yrs 23 4.5 7 (2%)a5-24 yrs 27 2.1 48 (16%)25-49 yrs 7 1.1 124 (41%)50-64 yrs 4 1.2 71 (24%)65 yrs 1.3 1.7 26 (2%)

a % of total deaths. Age data not available for 15%. Rate expressed /100,000 population

US age data

(Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team; Dawood FS, Jain S, Finelli L, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009;360:2605-2

Complications of S-OIV H1N1

• Exacerbation of underlying chronic disease;• Complications related to the upper airways,

including sinusitis or otitis;• Pulmonary complications, including bronchitis,

asthma (sometimes with status asthmaticus), and acute exacerbations of chronic bronchitis;

• Miscellaneous conditions, including cardiac (myocarditis and pericarditis), myositis, rhabdomyolysis, central nervous system complications (encephalopathy, encephalitis, seizures), toxic shock syndrome, and secondary bacterial pneumonia.

Severe complications of S-OIV H1N1

• In June 2009, the University of Michigan reported severe pulmonary complications of 2009 H1N1 influenza infection in 10 patients with a median age of 49 years.

• All 10 patients were referred for severe hypoxemia, ARDS, and inability to oxygenate with conventional ventilation methods. All had severe multilobar pneumonia on x-ray, none had evidence of bacterial pneumonia, and 4 had CT scan-confirmed pulmonary embolism.

CDC. Intensive care patients with severe novel influenza A (H1N1) virus infection -- Michigan, June, 2009. MMWR Morb Mortal Wkly Rep. 2009;58:749-752)


• Lab findings included leukocytosis in 5 (median WBC 9500/mm3), elevated AST levels (41-109 IU/L) in all 10, and elevated CPK levels (51-6572 IU/L) in 6; none had evidence of disseminated intravascular coagulation.



• The major risk factor was obesity in 9 and morbid obesity (BMI > 40) in 7.

• All 10 required advanced mechanical ventilation with high-frequency oscillatory or bilevel ventilation with mean airway pressures of 32-55 cm H2O.

• Two required veno-venous extracorporeal membrane oxygenation (ECMO) support and 6 required dialysis.

• At the time of the report, 3 had died, 1 was still on ECMO, 1 was still on mechanical ventilation, and 5 had been transferred back to referring institutions.


Neurologic complications

• Neurologic complications were reported in 4 children ages 7-17 years with 2009 H1N1 influenza A.

• Findings included seizures in 2 children, encephalitis in 2, and ataxia in 1.

• All recovered without neurologic sequelae. • The editorial comment in this report noted that

the neurologic disease in these 4 patients was less severe than what has been described in previous reports of seasonal flu.

•CDC. Neurological complications associated with novel influenza A (H1N1) infection in children -- Dallas, Texas, •May 2009. MMWR Morb Mortal Wkly Rep. 2009;58:773-778.; •Maricich SM, Neuf JL, Lotze TE, et al. Neurologic complications association with influenza A in children during the 2003-2004• influenza season in Houston, Texas. Pediatrics. 2004;114:e626-e633.; •Morishima T, Togashi T, Yokota S, et al. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis. 2002;35:512-517.)

Severe Cases

• 10 Cases across Michigan– BMI >30 for 9/10– All with high level rescue ventilation

– MAP 32-55 cm H2O– 6/10 CRRT– 2/10 ECMO– 3 deaths– Post: severe ALI with hemorrhage

MMWR July 17, 2009 / 58(27);749-752

PREGNANCY AND S-OIV H1N1

Risks for serious disease requiring hospitalization or causing death: Pregnancy and 2009 influenza A

(H1N1)• One hundred pregnant women with swine flu have

been hospitalized in ICUs.• 28 of these women have died• Pregnancy: A review of 34 confirmed cases of

2009 H1N1 influenza in pregnant women, reported to the CDC from 13 states, showed that 11 women were hospitalized and 6 died.

• All 6 deaths were in previously healthy women who developed viral pneumonia and ARDS requiring mechanical ventilation.

• None of the 5 infants born to these women had evidence of influenza.

CDC Press Briefing Transcripts. Weekly 2009 H1N1 Flu Media Briefing. October 1, 2009.

Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. 2009;374:451-458.)

Acute Respiratory Distress Syndrome and S-OIV H1N1

The PB1-F2 protein of Influenza A virus: increasing pathogenicity by disrupting

alveolar macrophagesJ Robert Coleman

Virol J. 2007; 4: 9.Published online 2007 January

Influenza A virus and the PB1-F2 protein

• Mechanisms of host defense manipulation and avoidance by Influenza A virus exist including a novel alternate reading frame recently discovered in the PB1 polymerase gene segment.

• This reading frame is found in select Influenza A viruses and has been shown to impact host defense mechanisms and in turn enhance pathogenicity in vivo.

Influenza A virus and the PB1-F2 protein

• This protein, named PB1-F2, has an apoptotic induction effect on macrophages, thus reducing their ability to contribute to an immune response.

• It has been previously suggested that this PB1-F2 protein contributes to viral pathogenicity solely because of it causes an inhibition of viral clearance, thus increasing cytoxicity.

Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory

Distress SyndromeThe Australia and New Zealand

Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators

JAMA. 2009;302(17):1888-1895. Published online October 12, 2009

ARDS/ECMO and SO-H1N1

Design, Setting, and Patients:

• An observational study of all patients (n = 68) with 2009 influenza A(H1N1) associated ARDS treated with ECMO in 15 intensive care units (ICUs) in Australia and New Zealand

• June 1 and August 31, 2009


Main Outcome Measures:

• Incidence, clinical features, degree of pulmonary dysfunction, technical characteristics, duration of ECMO, complications, and survival.


• 68 patients with severe influenza-associated ARDS were treated with ECMO

• 61 had either confirmed 2009 influenza A(H1N1) (n = 53) or influenza A not subtyped (n = 8)


• An additional 133 patients with influenza A received mechanical ventilation but no ECMO in the same ICUs.


• The 68 patients who received ECMO had a median (interquartile range [IQR]) age of 34.4 (26.6-43.1) years and 34 patients (50%) were men.


• Before ECMO, patients had severe respiratory failure despite advanced mechanical ventilatory support with a median (IQR) PaO2/fraction of inspired oxygen (FIO2) ratio of 56 (48-63)

• positive end-expiratory pressure of 18 (15-20) cm H2O

• an acute lung injury score of 3.8 (3.5-4.0).


• The median (IQR) duration of ECMO support was 10 (7-15) days.


• At the time of reporting, 48 of the 68 patients (71%; 95% confidence interval [CI], 60%-82%) had survived to ICU discharge

• 32 had survived to hospital discharge and 16 remained as hospital inpatients

• Fourteen patients (21%; 95% CI, 11%-30%) had died and 6 remained in the ICU, 2 of whom were still receiving ECMO


Conclusions: During June to August 2009 in Australia and New Zealand,

The ECMO-treated patients were often young adults with severe hypoxemia and had a 21% mortality rate at the end of the study period.


• "Affected patients were often young adults, pregnant or postpartum, obese, had severe respiratory failure before ECMO, and received prolonged mechanical ventilation and ECMO support,"


• "Despite their illness severity and the prolonged use of life support, most of these patients survived,"

• "This information should facilitate health care planning and clinical management for these complex patients during the ongoing pandemic."

Bacterial co-infections


• CDC investigators reviewed clinical records and pathology reports from 77 lethal cases of pandemic H1N1 infection.

• The tissue specimens were examined by tissue Gram stain, Warthin-Starry silver stain, various microbe-specific immunohistochemical assays, and PCR that targeted the 16S ribosomal DNA in tissue blocks.

Morens DS, Taubenberger JK, Fauci AS. Prominent role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness J Infect Dis. 2008;198:962-970


• Bacteria were detected in 22 of 77 cases (29%)• Streptococcus pneumoniae (10)• Staphylococcus aureus (7)• Streptococcus pyogenes (6)• Streptococcus mitis (2)• Haemophilus influenzae (1)• 4 cases had more than 1 pathogen. • The study authors emphasize the importance of

bacterial superinfection in patients with influenza. During the 1918-19 pandemic, most deaths were associated with bacterial superinfection.

Morens DS, Taubenberger JK, Fauci AS. Prominent role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness J Infect Dis. 2008;198:962-970

MRSA Post-influenza Pneumonia

Treatment and Prevention

Summary of Antiviral Resistance, U.S. 2008-09

Influenza viruses

AntiviralSeasonal A

(H1N1) Seasonal A

(H3N2)Seasonal B Pandemic H1N1

Adamantanes Susceptible Resistant No activity Resistant

Oseltamivir Resistant Susceptible Susceptible Susceptible

Zanamivir Susceptible Susceptible Susceptible Susceptible

Oseltamivir-resistance among Pandemic H1N1 viruses

3 oseltamivir-resistant isolates of Pandemic H1N1 detected

- 2 cases found to have resistant strain while on oseltamivir chemoprophylaxis

- Japan and Denmark- 1 case detected by Hong Kong Department of Health

reported a resistant virus isolated from a 16 year-old girl who had a fever upon arrival at the Hong Kong International airport

- Illness began prior to boarding the plane in San Francisco

- No exposure to - No illness among close contacts - No sign of community transmission- Al recovered uneventfully

No change in recommendations for treatment or prophylaxis of persons with influenza

Antiviral Treatment Recommendations

http://www.cdc.gov/h1n1flu/recommendations.htm

Priority: Hospitalized Patients with suspected or confirmed pandemic H1N1 virus infection

- Treatment recommended with Oseltamivir or Zanamivir - Treat patients as soon as possible (duration: 5 days)

Antiviral Treatment Recommendations

http://www.cdc.gov/h1n1flu/recommendations.htm

Outpatients with suspected or confirmed pandemic H1N1 virus infection who are at high risk for complications

- Persons with chronic pulmonary, cardiac, renal, hepatic, metabolic, hematological disorders; immunosuppression, pregnant women, children <5 years; adults ≥65 years - Treatment recommended with Oseltamivir or Zanamivir- Treat patients as soon as possible (duration: 5 days)

Thank You

swine origin h1n1 2009: clinical aspects

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