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Clinical Lessons Learned
During the H1N1
Pandemic
Jonathan A. McCullers, M.D.
Associate Member
Department of Infectious Diseases
St. Jude Children’s Research Hospital
Memphis, Tennessee
The ecology of influenza viruses
H1
H2
H3
H4
H5
H6
H7
H8
H9
H10
H11
H12
H13
H14
H15
H16
Timeline of viruses in humans and pigs
Novel
Novel
H1N1
H1N1
H1N1
H1N1
H2N2
H2N2
H3N2
H3N2
H1N1
H1N1
H1N2
H1N2
H1N1
H3N2
H3N2
H1N1
H1N1
H1N1
1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
H3N2
Emergence of a pandemic strain
N.A. Avian
“Classic” or
Eurasian Swine
Human
“Triple reassortant” novel pandemic H1N1 influenza virus
Segments
1
2
3
4
5
6
7
8
PB2
PB1
PA
HA
NP
NA
M
NS
Pandemics in the last century
1918 – fully avian H1N1 virus enters humans and pigs
simultaneously, 40-50 million deaths worldwide, endemic in pigs
1957 – reassortant virus takes H2N2 surface proteins and PB1
from avian sources, other genes from human H1N1, ~ 2 million
deaths worldwide
1968 – reassortant virus takes H3 and PB1 from avian sources,
other genes from human H2N2, ~ 1 million deaths worldwide
[1977 – H1N1 related to 1950 strain “re-emerges” from frozen
source, has circulated together with H3N2 since]
2009 – “triple” reassortant H1N1 emerges from pigs, “novel H1N1”
Clinical features of influenza
- Sudden onset of symptoms
- Incubation period 1 to 7 days, typically 2-3 days
- Infectious period varies by age:
- Adults shed virus typically 1 day before through
4-5 days after onset of symptoms
- Children shed virus longer, typically 2-3 days
before (and up to 6) through 7-10 days
(and up to 21) after onset of symptoms
ACIP (Advisory Committee on Immunization Practices). MMWR 2004 Vol. 53.
Kavet J. Am J Public Health 1977; 67: 1063.
Nicholson K Human Influenza In: Textbook of Influenza, 1998.
Clinical manifestations of influenza
_________________________________________________
Infants Children Adults Novel H1N1 *
_________________________________________________
Fever
++
+++
+++
+++
Cough
+
++
+++
+++
Myalgias
+
++
++
Sore throat
+
++
++
Headache
++
++
++
Diarrhea
++
+
+
Vomiting
++
+
+
Rhinitis
++
+
+
+
Maliase
++
+
+
+
/ lethargy
Neurologic
+
+
symptoms
_________________________________________________
- rare, + uncommon, ++ common, +++ very common
*Represents children and adult data combined
McCullers JA. Infect in Med, November 2009.
Each episode of influenza may result in:
7 to 15 days
of illness
5 to 6 days
of restricted activity
3 to 4 days
of bed rest
3 days
Monto AS. Am J Med. 1987;82(suppl 6A):20-25.
Kavet J. Am J Public Health. 1977;67:1063-1070.
of missed work or school
Toll of disease from influenza in the U.S.
Deaths
~41,0001
Hospitalizations
~334,0001
(primarily in the elderly)
Physician visits
~31 million1
Infections and illnesses*
~95 million2
Economic costs
~$87.1 billion1
1. Molinari NM, Ortega-Sanchez IR, Messonier ML, et al. Vaccine 2007;25:5086-96.
2. Adams PF, Hendershot GE, Marano MA. Vital Health Stat. 1999;10:200.
Complications occur at extremes of age
Hospitalizations
per 100,000
persons
2000
Not High Risk
High Risk
1500
1000
500
0
<1
1-2
3-4
5-14 15-44
45-64 >65
Age in Years
MMWR 2001, 50:RR4
Patient groups at risk for complications
- Children < 2 years old
ACIP, MMWR, 2007;56:1-54.
Patient groups at risk for complications
- Children < 2 years old
- Children and adults with chronic conditions
- chronic pulmonary, renal, metabolic, or CV
disorders
- neurological or neuromuscular disorders
- hemoglobinopathies
- immunosuppression, including HIV infection
ACIP, MMWR, 2007;56:1-54.
Patient groups at risk for complications
- Children < 2 years old
- Children and adults with chronic conditions
- chronic pulmonary, renal, metabolic, or CV
disorders
- neurological or neuromuscular disorders
- hemoglobinopathies
- immunosuppression, including HIV infection
- Pregnant women
ACIP, MMWR, 2007;56:1-54.
Patient groups at risk for complications
- Children < 2 years old
- Children and adults with chronic conditions
- chronic pulmonary, renal, metabolic, or CV
disorders
- neurological or neuromuscular disorders
- hemoglobinopathies
- immunosuppression, including HIV infection
- Pregnant women
- Persons > 50 years of age
ACIP, MMWR, 2007;56:1-54.
Patient groups at risk for complications
- Children < 2 years old
- Children and adults with chronic conditions
- chronic pulmonary, renal, metabolic, or CV
disorders
- neurological or neuromuscular disorders
- hemoglobinopathies
- immunosuppression, including HIV infection
- Pregnant women
- Persons > 50 years of age
- Residents of chronic care facilities
ACIP, MMWR, 2007;56:1-54.
ACIP vaccination recommendations
- Universal vaccination now recommended in the US
- Mandatory vaccination of health care workers should
be strongly considered
ACIP, MMWR, 2007;56:1-54. ACIP, Press release, 2/27/08.
Influenza is a disease of children
Age Specific Attack Rates
35
Attack Rate (%)
30
25
20
A
B
15
10
5
0
0-4
5-9
10-14
15-19
20-29 30-39 40-49 50-59
Age (years)
Monto & Sullivan, Epidemiol Infect 1993;110:145-60
60+
Burden for school-aged children
- For every 1000 children influenza accounts for an estimated:
- 280 primary illness episodes, 220 secondary
- 630 missed school days, 200 days missed work
- 50-95 outpatient clinic visits
- 0.9 hospitalizations
- 10-20% of outpatient clinic visits are due to influenza at peak
times of circulation
Neuzil KM, Hohlbein C, Zhu Y. Arch Pediatr Adolesc Med. 2002;156:986-991.
Poeling KA, et al. N Engl J Med. 2006;355:31-40.
Pediatric deaths 2003-2004
- CDC began collecting data on pediatric influenza-related deaths in
2003-2004
- 153 influenza-associated deaths among children <18 yo reported to
CDC from 9/03 to 5/04 (46-74 last 3 yrs)
- 37% of the children were 5 to 17 years of age
- 47% of the children had no high-risk medical conditions (only
33% had an ACIP-defined high risk condition)
- 24% died from secondary bacterial infections
Bhat N et al., N Engl J Med, 2005;353:2559-67.
Children transmit influenza
Other children
Family members
Daycare, preschool,
and school-age children
Community including
high risk populations
Mortality
Naïve immune systems = Higher replication = Increased transmission
Age Distribution of 2009 H1N1
Reichert TA…..McCullers JA. BMC Inf Dis 2010.
Rationale for universal vaccination
- Influenza is a vaccine-preventable disease
- influenza has not been brought under control using strategies
targeting high risk groups alone
- healthy school-age children are often major transmitters of
influenza
- substantial morbidity and some mortality in children
Rationale for universal vaccination
- Influenza is a vaccine-preventable disease
- influenza has not been brought under control using strategies
targeting high risk groups alone
- healthy school-age children are often major transmitters of
influenza
- substantial morbidity and some mortality in children
- Broader vaccination strategies are expected to reduce influenza
morbidity and mortality
- increased vaccination of preschool and school-age children may
provide benefits to their close contacts and the community at large
NA (neuraminidase)
HA (hemagglutinin)
M1 (matrix
protein)
Non-structural proteins
- NS1
- NEP
- PB1-F2
M2 (ion
channel)
RNP Complex
NP (nucleoprotein)
RNA (negative sense)
Polymerase complex (PA, PB1, PB2)
Lipid envelope
(host-derived)
11 proteins on 8 (-) strand RNA gene segments
(~ 14 kb)
Antivirals for influenza
M2 inhibitors
- block the M2 ion channel preventing viral uncoating
- Amantadine (Symmetrel) and Rimantadine (Flumadine)
- problems with resistance and side effects
Neuraminidase inhibitors
- block the neuraminidase enzyme and prevent viral
budding and spread through the respiratory tract
- Zanamivir (Relenza) and Oseltamivir (Tamiflu)
- may prevent secondary bacterial pneumonia and otitis media
Monto AS, Vaccine, 2004;21:1796-800.
Antivirals for influenza
- Significant resistance to M2 inhibitors last several years
(> 95% of all strains)
- Little resistance to oseltamivir now seen in the US
- There have been post-marketing reports of children taking
oseltamivir having delirium and abnormal behavior, sometimes
leading to injury, but unclear if from influenza itself or the drug FDA has recommended child warning label disclosing this
Treatment of novel H1N1
- Novel H1N1 viruses are susceptible to neuraminidase inhibitors
(NAIs; oseltamivir, zanamivir) but resistant to adamantanes
(amantadine, rimantadine) – limited published experience with
treatment outcomes
- Prophylaxis has been undertaken with NAIs to prevent spread to
close contacts
- Development of resistance in this clinical scenario has been
documented (H275Y mutation), but these strains have not spread
widely
WHO
Diagnosis of novel H1N1
- Currently used antigen tests have 40-60% sensitivity for novel
H1N1 compared to RT-PCR
- Most available RT-PCR assays cannot distinguish novel H1N1
from seasonal strains
- Targeted antiviral use will require development and widespread
utilization of PCR based assays that can distinguish type (A vs.
B), subtype (H3N2 vs. H1N1), and strain (seasonal vs. pandemic)
- Sequencing based methods for rapid antiviral resistance
determination could also be employed
MMWR 2009 / 58(30);826-829
Risk factors for severe disease
- Overall, similar to risk factors for seasonal influenza
- Chronic medical conditions including cardiopulmonary disease
and immunosuppression
- Pregnancy
- Neurodevelopmental delay
- Obesity (this is not recognized as a risk factor for seasonal
influenza)
- Extremes of age have not been a risk factor for novel H1N1
Complications of novel H1N1
- Viral pneumonia – most common cause of death
- Most severe disease in persons with no underlying risk factors
has been in older children and young adults – immunopathology?
- Bacterial super-infections – otitis media, pneumonia, sinusitis –
are being found more commonly with novel H1N1
Dawood FS, et al. NEJM 2009;360(25):2605-15.
Perez-Padilla R, et al. NEJM 2009;June 29th electronic publication.
Bacterial pneumonia and H1N1
- Few reports of bacterial superinfections in initial descriptions of
severe pandemic related disease
- However, most critically ill patients were treated with broad
spectrum antibiotics, and invasive assays (e.g., pleural taps) were
not commonly done
- Several pathology series have shown 30-50% of all fatal cases
had evidence of bacterial super-infection
(S. aureus, S. pneumoniae, Group A Streptococcus)
Dawood FS, et al. NEJM 2009;360(25):2605-15. Gill JR et al., Arch Pathol Lab Med 2010;134:235-43.
Mauad T et al., Am J Respir Crit Care Med 2010;181:72-9. CDC. MMWR 2009;58(38):1071-4.
Annual influenza vaccine composition
- All vaccines are trivalent and contain the same strains
- vaccine composition provides protection from the 3 most likely
wild-type virus infection in a given year
- vaccine strains are A (H3N2), A (H1N1), and B
- usually 1 or 2 vaccine strains are changed annually
- Recommendations are based on previous circulation
patterns, expert opinion, and last decade experience
Influenza type
Isolate number
Hemagglutinin subtype
A/Fujian/411/2002 (H3N2)
Geographic source
Year of isolation
Neuraminidase
subtype
Vaccines against H1N1 influenza
- Standard vaccines targeting H1N1 were made and tested by
same process we use every year
- The vaccines were extremely safe and no problems were
reported
- Although plenty of vaccine was made, distribution problems
limited access
- Children, young adults, pregnant women, first responders, and
persons with chronic illnesses were first priority
- Novel H1N1 has replaced seasonal H1N1 in the trivalent
vaccine for 2010-2011
Conclusions
The 2009 H1N1 pandemic shared several common features with
past pandemics, it:
- had a high clinical attack rate due to lack of
immunity
- transmitted easily enabling worldwide spread
- caused severe disease in some risk groups (but
fortunately was milder than was anticipated)
Children occupied a central role in the pandemic:
- highest clinical attack rate
- main vectors of transmission
- most severe disease in patients without chronic
medical conditions
Conclusions…continued
- All influenza strains predicted to circulate in the US in 20102011 are susceptible to oseltamivir but resistant to
adamantanes
- Antigen tests have low sensitivity – only trust PCR
- Universal vaccination is now recommended
- The vaccine is safe and the best means of protection against
severe outcomes such as pneumonitis and bacterial pneumonia
THANKS!