INFLUENZA, ANTIVIRAL THERAPY AND THE HIGH RISK PATIENT

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INFLUENZA, ANTIVIRAL THERAPY AND THE HIGH RISK
PATIENT
Janet A. Englund, M.D. Pediatric Infectious Disea
se
University of Washington
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PATIENTS RECOMMENDED TO RECEIVE INFLUENZA
VACCINE ARE NOT NECESSARILY AT HIGH RISK FOR
SERIOUS INFLUENZA DISEASE

• Those groups traditionally recommended for
  influenza vaccine
  
• Elderly
• Chronic Care Facility residents
• Those with chronic underlying diseases
• Children taking daily aspirin
• 6-23 month old children
• Pregnant women
• Caregivers of risk groups
• Healthcare workers
• NOTE These are not all at risk for serious
  sequelae from influenza disease.
  
• THEREFORE Antiviral drug priorities need
  special consideration

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INDIVIDUALS AT HIGHEST RISK FOR SEVERE DISEASE
DUE TO INFLUENZA

• Patients at high risk for serious/fatal influenza
  disease and unable to respond well to vaccine,
  even if vaccine were available
  
• Immunocompromised
• Elderly (Very old, debilitated)
• Very young (
• Egg allergic

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INDIVIDUALS AT HIGH RISK FOR INFLUENZA DISEASE
AND SPREADING FLU

• Individuals at increased risk for spreading or
  shedding influenza
  
• Children infants, toddler, school age
• Immunocompromised
• Caretakers of children and immunocompromised
• Hospitalized and institutionalized patients
• ?Health care workers with direct patient care
  contact
  

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INFLUENZA VIRAL SHEDDING

• Normal infants up to 14 days
• Nosocomial infection in infants up to 21
  days1
  
• HIV-infected child up to 63 days2
• SCID patient 5 months3
• Rapid development of antiviral resistance to
  rimantadine noted in both HIV-infected child and
  SCID patient note that rimantadine-resistant
  virus can be spread to other patients

1. Hall Douglas, Pediatarics 197555673
2. Evans Kline PIDJ, 199514 332 3.
Klimov et al. JID 19951721352
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WHAT DO WE KNOW ABOUT INFLUENZA IN THE
IMMUNOCOMPROMISED HOST?

• Highest rates of frequency of pneumonia and death
  of any population
  
• Persistence of viral infection prolonged
  shedding for up to 3 months with symptoms at
  least intermittently present
  
• High rate of nosocomial acquisition- especially
  in hospital outpatient settings
  
• Immune response in immunocompromised host not
  well understood

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Pneumonia and Death during Influenza Infection of
Adults and Children with Hematological Malignancy
or Organ TX
Adapted from Human Influenza , KG Nicholson,
Textbook of Influenza, 1998, page229- review of
literature thru 1998
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Reported Overall Mortality of Respiratory Virus
Infections in Stem Cell/ BMT Recipients
1. Bowden Am J Med 1997102 (3A)22 4.
Nichols et al Blood 2001 98573
2. Couch et al. Am J Med 1997102 (3A)3 5.
Lewis et al CID 1996231033 3a. Ljungman Am J Me
d 1997102 (3A)45 6. Ghosh et al CID
199929528 3. Ljungman et al, BMT 200128479
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Influenza Infections in the Hospital Reflects the
Community Epidemiology FHCRC and Seattle Data,
1989-2002
Influenza Attack rate 62/4797 (1.3)
Parainfluenza attack rate 7
Nichols WG, Blood 2001
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Influenza Virus and Pneumonia at FHCRCPossible
Effect of treatment for URI

• 51 influenza cases initially diagnosed as URI
• No treatment 34 (67) 17 had influenza B
• 6 progressed to pneumonia (18)
• M2 inhibitor 1/8 (13) progressed to pneumonia
• NAI treatment 0/9 progressed to pneumonia

Nichols et al CID 2004391300
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Influenza Shedding after SCTPredictors and
effect of therapy

• Flu shed median 7 days (range 2-37)

• Effect of antiviral therapy after controlling for
  steroid dose
  
• Nichols CID 2004

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Influenza Disease in BMT/Leukemia Patients at
MDACC Treated with Rimantadine
P LaRosa et al. CID Abstract
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Other Immunocompromised Patients

• HIV HIV Adults HIV not increased susceptible
  BUT high rate of hospitalization or ILI14 days.
  Vaccine most effective for CD4 100. HIV
  children hospitalized in South Africa with LRTI
  and influenza were HIV-infected had similar
  outcome (duration hospitalization, mortality
  rate).
• Rheumatoid Arthritis case report of serious
  disease in patient on cyclosporine (NEJM
  20013451558)
  
• COPD most common chronic underlying disease in
  Glezen study, with frequent use of steroids- most
  common respiratory virus in hospitalized patients
  based on serology culture. Impact of steroids
  and influenza on this population unclear (Glezen
  JAMA 1991)
• Children receiving steroids little data

Fine et al, CID 1996201 1784
Madhi SA et al PIDJ 200221291-7
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SUMMARY IMMUNOCOMPROMISED PATIENTS

• Appear to have substantially higher rates of
  influenza-related disease and prolonged viral
  shedding
  
• Appear to benefit from antiviral therapy
• Are not major source of viral shedding/ spreading
  EXCEPT in the hospital/clinic setting
  

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INFLUENZA IN THE ELDERLY

• High risk for serious sequelae
• Benefit of vaccine less in debilitated elderly or
  nursing home patients
  
• Spread of influenza increased in institutional
  setting
  
• HOWEVER important benefit attained by
  preventing influenza in health care providers

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INFLUENZA RISKS DURING PREGNANCY Historical
Reports

• 1918 Mortality associated with infection during
  pregnancy 51, with highest rates in later
  stages of pregnancy
  
• 1957 Half of women of childbearing age who died
  of influenza were pregnant 10 of all influenza
  deaths that season were in pregnant women (most
  in latter half of pregnancy )
• Case reports of complications since then many
  in later stages of pregnancy

Harris. JAMA 191914978 Freeman and Bar
no, Am J Ob Gyn 1959781172 Greenberg et al.
Am J Ob Gyn 195876897 Neuzil et al Inf Dis
Clin N Am 200115123
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PREGNANCY IS STILL A HIGH RISK CONDITION DURING
INFLUENZA SEASON
Cardio-pulmonary hospitalizations per 10,000
Neuzil, et al. NEJM 1996
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APPROACH TO INFLUENZA
BEWARE OF KID
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CHILDREN AS A HIGH RISK GROUP Hospitalizations
Per 10,000 Persons Attributable to Influenza
Number
Low Risk High Risk
Age in Years
Glezen et al Am Rev Respir Dis 1987
Neuzil et al. NEJM 2000, J Peds 2000
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PEDIATRIC ANTIVIRAL RESISTANCE

• To Rimantadine
• Commonly develops after 4-5 days rimantadine
  therapy at a time when viral load is generally
  greatly decreased in the normal host.
  
• Develops within 24-48hours in the IC host
• To Oseltamivir
• Has only been rarely documented to be associated
  with prolonged shedding in IC hosts.
  
• Resistance reported at variable rates in
  children, generally after 4-5 days of therapy at
  a time when viral load is generally greatly
  reduced in the normal host.

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RESISTANCE TO OSELTAMIVIR IN CHILDREN US vs.
JAPAN
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FINAL QUESTIONS

• What high risk conditions need to be given
  priority during times of limited drug supply?
  Should risk of sequelae from influenza as well as
  risk of spread be considered?
• Is prophylaxis vs. treatment to be advocated
  during periods of limited supply?
  
• Do we need to make different recommendations
  depending on availability or lack of vaccine?
  

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INFLUENZA IN HOSPITALIZED BMT RECIPIENTS AND
ADULTS WITH LEUKEMIA AT MDACC
La Rosa et al. Clin Infect Dis 2001331160,
abstr418