Pandemic

Influenza A 2009 (H1N1):

What You Need to Know

Paul F. Kamitsuka, M.D., D.T.M.&H.

Hospital Epidemiologist, NHHN
Infectious Disease Consultant, WHA
Clinical Associate Professor, UNC
 Antigenic Drift: Error in Copying
RNA Strand
Why We Need a New Seasonal
Flu Vaccine Each Year

Viral Replication x
with Errors x

No editing capability –
“designed” to mutate

Initial Influenza Strain “Drifted” Influenza Strain

 Antigenic Shift:
Genetic Reassortment

Influenza Strain 1 Influenza Strain 2

Reassortant
Influenza Virus:
PANDEMIC
 Eurasian
Swine H1N1
N. American
Classical Swine
H1N1
Avian influenza genes
Triple-
Reassortant PANDEMIC
Swine H1N2 2009 H1N1

Avian
Influenza A 1918 Human X Seasonal
Gene Pool H1N1 H1N1
“Spanish Flu”

Avian influenza genes

1957 Human X
H2N2
“Asian Flu”

Avian influenza genes Seasonal

1968 Human
H3N2
H3N2
“Hong Kong Flu”

Morens DM, Taubenberger JK, Fauci AS. N Engl J Med 2009;361:225-229; Shinde V, et al. N Engl J Med 2009; 360:2616-25;
Zimmer SM, Burke DS. N Engl J Med 2009; 361:279-85; Brockwell-Staats C, et al. Influenza and Other Respiratory Viruses
2009; 3:207-213
History of Human and Swine Influenza Lineages

Zimmer S, Burke D. N Engl J Med 2009;361:279-285

 Groups Affected by 2009 A (H1N1)
As of 7/31/09
– median age of hospitalized persons = 20 years
– Hospitalization rates highest in children < 5 years
– Median age of death = 37 years
– Only 5% of hospitalizations and 8% of deaths occurred
among persons aged ≥ 65 years
In Chicago, attack rate highest in children 5-14 years
(147/100K), 14 X higher than adults aged ≥ 60 years
Overall case-fatality rates similar to seasonal flu so far
– The young are disproportionately affected
As of 10/1/09, 28 pregnant women have died of H1N1

Dawood FS et al. N Engl J Med 2009; 360:2605-15; CDC. Flu activity and surveillance. Atlanta, GA. Available at
http://www.cdc.gov/flu/weekly/fluactivity.htm; CDC. MMWR 58(33);913-918, August 28, 2009; Chowell G, et al. N Engl
J Med 2009;361:674-9; Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. N Engl J Med 2009;360:2605-15.
 Who Has Immunity Against
Pandemic Influenza A (H1N1)?
Among persons 18-64 years, only 6-9% have cross-
reactive antibody levels to 2009 influenza A (H1N1) at
titers correlating with protection from illness in seasonal
flu
– Most children and young or middle-aged adults are
susceptible to infection
For those > 60 years, 33% had cross-reactive antibodies

Garten RJ, et al. Science 2009; 325:197-201; CDC. MMWR 2009; 58:521-4.
“Flu Season” Never Left Us This Year
What Happened in the Southern
Hemisphere This Summer?
 Diagnosis of Pandemic Influenza A
(H1N1) Infection
Requires specific testing using real-time reverse
transcriptase PCR or viral culture
– Confirmatory test currently available only at the State
Lab for those in the ICU
Rapid influenza diagnostic tests (RIDTs) can detect
novel influenza A (H1N1) only 40-70% of the time
– Proper sample acquisition technique and early testing
may increase RIDT sensitivity
– A negative RIDT result does NOT exclude the
diagnosis of 2009 influenza A (H1N1)

CDC. MMWR 58(RR10); 1-8, August 28, 2009; Hurt AC, et al. Influenza and Other Respiratory Viruses 2009; 3:171-6.
 H1N1 May Be More Pathogenic Than
Seasonal Influenza
In animal models, pandemic H1N1 replicates faster
and damages lungs more than seasonal influenza
– In mice, ferrets, and non-human primates
greater expression of viral antigen in peri-bronchial
glands (more exuberant viral replication)
caused more severe bronchopneumonia than
seasonal influenza
Severe influenza pneumonia and respiratory failure
reported in patients
– Mortality among patient requiring mechanical
ventilation – 58% in Mexico

Itoh Y et al. Nature 2009; 460:1021-5; Perez-Padilla R, et al. N Engl J Med 2009; 361:680-9
Admission CXR
8/22/09
 ██████████████

CXR
Four Days
Later
 Use Tamiflu Selectively!!!!
Give Tamiflu or Relenza to patients with influenza-like
illness only if:
– They are sick enough to be hospitalized
– They have risk factors for flu-associated complications
Instruct patients to call if they develop:
Difficulty breathing or shortness of breath
Pain or pressure in the chest or abdomen
Sudden dizziness
Confusion
Severe or persistent vomiting
Flu symptoms that improve but return with fever, worse cough
In babies, bluish gray skin color, lack of responsiveness, or
extreme irritation
Do NOT give prophylactic therapy unless:
– Exposed person is at high risk for flu-associated complications
– Healthcare workers exposed without precautions
CDC. MMWR 58(35): 969-72, September 11, 2009
Resistance of 2009 H1N1 to Tamiflu
So far, sporadic resistance
2 cases in North Carolina, epidemiologically linked, both
on Tamiflu prophylaxis at a summer camp.
Resistance due to H255Y mutation; second mutation
(I223V)
– H255Y mutation = same mutation that has caused
virtually all seasonal H1N1 influenza to be Tamiflu-
resistant over the past two years
– 2009 H1N1 is resistant to amantidine and rimantidine
We will run out of effective influenza drugs -- MUST
NOT OVERUSE Tamiflu!

WHO. http://www.who.int/csr/don/2009_09_11/en/print.html ; CDC. MMWR 2009; 58(35):969-72

Swine Flu Infection Control
 Vaccinate!!!!!
People look to you for guidance
This is not a drill
PROMOTE VACCINATION!
Vaccine Skepticism Grows in US
(Oct. 2) - As the United States awaits the arrival of the
H1N1 vaccine next week, growing skepticism over the
overall safety and importance of vaccinations of all types
is worrying health officials.
"I don't trust that the pharmaceutical industry is looking
out for my child's best interest," said Eileen Karpfinger, a
licensed chiropractor and co-founder of the Upaya
Center for Wellbeing in Alameda, Calif. She says she
does not plan to have her own infant daughter
vaccinated against any disease. "It's ludicrous to me that
I have to put my child through this," she said of vaccines
in general. "As a mother I don't find vaccines to be
effective."
Source: AOL News
 ██████████████

CXR
Four Days
Later
 Concern About Vaccine-Associated
Guillian-Barre Syndrome in Perspective
1976 swine flu vaccine: 1 additional case of GBS per
100,000 persons vaccinated, 32 deaths.
No clear evidence of increased risk associated with
seasonal flu vaccine – if risk exists, 1 additional case per
million doses given
Influenza illness itself is a trigger: risk of GBS is 4-7
times higher with influenza illness than influenza vaccine
– GBS risk from 2009 H1N1 illness expected to be
higher than potential risk of vaccine-associated GBS

Sivadon-Tardy V, et al. Clin Infect Dis 2009;48:48-56; Haber P et al. JAMA 2004; 292:2478-81;
Lasky T et al. N Engl J Med 1998; 339:1797-802; CDC. MMWR 58(RR-8): 1-56, 2009.
 Priority Groups
To Receive 2009 H1N1 Vaccine
1. Pregnant women
2. Persons who live with or provide care for infants
aged < 6 months (parents, siblings, daycare staff)
3. Health-care and EMS personnel who have direct
contact with patients or infectious material
4. Children aged 6 months-4 years
5. Children and adolescents aged 5-18 years with
medical conditions that put them at higher risk for
flu-related complications
6. All persons aged 5 – 24 years
7. Persons 25-64 years with medical conditions
increasing the risk of flu complications (chronic lung
disease including asthma, chronic heart conditions except
hypertension, immunocompromised persons)
CDC. MMWR 58(RR10); 1-8, August 28, 2009
Surgical Mask vs. N95 Controversy
Loeb et al, JAMA 10/1/09:
– Noninferiority RCT of 446 nurses in ER, medical units,
pediatric units in 8 tertiary care Ontario hospitals
– Fit-tested N95 (n = 221) vs. surgical mask (n = 225) when
caring for patients with AFRI during 2008-2009 flu season
– Lab confirmed influenza occurred in 50 nurses (23.6%) in
the surgical mask group vs. 48 (22.9%) in N95 group
ASM Meeting, SF, 9/09
– Study in Beijing, 2000 staff
– N95 reduced risk of respiratory illness by 60% and risk of
confirmed influenza by 75%, surgical masks had no effect
– Fit testing made no difference in protection
CDC and IOM continue to recommend N95
Loeb M, et al. JAMA 2009; 302(17);(doi:10.1001/jama.2009.1466)
 Personal Protective Measures to Prevent
Catching 2009 H1N1 in Healthcare Settings
Droplet precautions when caring for patients: standard
masks, handwashing, private room, door closed
Droplet precautions for obtaining rapid flu test
N95 masks for aerosol generating procedures
– bronchoscopy, open suctioning of airway secretions,
intubation
Healthcare workers with acute febrile respiratory illness
should stay home until afebrile x 24 hours
– 70% of health-care workers with influenza work
Spread influenza to co-workers and to patients
Presenteeism: less work efficiency, increased
errors
Seasonal Flu Vaccine: Vaccinate NOW

Get seasonal flu shots out of the way now

Current ACIP recommendations for seasonal flu
shots encompass 83% of the population
– Only group for whom vaccine contraindicated = those
< 6 months and those with egg allergy
– Only group for whom vaccine not specifically
recommended = healthy persons age 19-49
But recommended for any person wishing to avoid
influenza
Vaccinate all persons without egg allergy age 6
months and older
CDC. MMWR 58(RR-8): 1-56, 2009.
Seasonal Flu Vaccine: Pregnant Women
Since 2004, ACIP and ACOG has recommended that all
pregnant women receive trivalent influenza vaccine during
any trimester of pregnancy.
Vaccine uptake has been extremely low: in Georgia, only
10.4% and 15.5% in 2004, 2007; in Rhode Island, 21.9%
and 33.4% in 2004, 2007
In 2006 in Georgia, most common reasons for not being
vaccinated:
– “I don’t normally get the flu vaccination” (69.4%)
– “My physician did not mention anything about a flu vaccine during my
pregnancy (44.4%)
Importance of vaccinating in pregnancy: protects the
mother, but also protects the infant
CDC. MMWR 58(35): 972-5, 2009; Zaman K, et al. N Engl J Med 2008; 359:1555-64
Tuberculosis
Update
Paul F. Kamitsuka, M.D.,
D.T.M.&H.
Hospital Epidemiologist, NHRMC
ID, Wilmington Health Associates
Clinical Associate Professor, UNC
 Reported TB Cases*
United States, 1982–2007
28,000
26,000
No. of Cases

24,000
22,000
20,000
18,000
16,000
14,000
12,000
10,000
1983 1986 1989 1992 1995 1998 2001 2004 2007

Year
*Updated as of April 23, 2008.
 TB Morbidity
United States, 2002–2007

Year No. Rate*

2002 15,056 5.2
2003 14,837 5.1
2004 14,501 4.9
2005 14,065 4.7
2006 13,754 4.6
2007 13,299 4.4
*Cases per 100,000, updated as of April 23, 2008.
Reported TB Cases by Age
Group, United States, 2007
<15
yrs
>65 yrs (6%)
(19%) 15–24 yrs
(12%)

45–64 yrs 25–44 yrs

(30%) (32%)
 Number of TB Cases in
U.S.-born vs. Foreign-born Persons
United States, 1993–2007*

20000
No. of Cases

15000
10000
5000
0
1993 1995 1997 1999 2001 2003 2005 2007
U.S.-born Foreign-born

*Updated as of April 23, 2008.

 Trends in TB Cases in Foreign-born
Persons, United States, 1987–2007*
No. of Cases Percentage
10,000 70
60
8,000
50
6,000 40
4,000 30
20
2,000
10
0 0
1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007

No. of Cases Percentage of Total Cases

*Updated as of April 23, 2008.

First-Line Treatment of TB
for Drug-Sensitive TB
 Primary Anti-TB Drug Resistance
United States, 1993–2007*
10
% Resistant

0
1993 1995 1997 1999 2001 2003 2005 2007

Isoniazid MDR TB

*Updated as of April 23, 2008.

Note: Based on initial isolates from persons with no prior history of TB.
Multidrug resistant TB (MDR TB) is defined as resistance to at least
isoniazid and rifampin.
 Primary MDR TB
United States, 1993–2007*
No. of Cases Percentage
500 3
400
300 2
200 1
100
0 0
1993 1995 1997 1999 2001 2003 2005 2007
No. of Cases Percentage

*Updated as of April 23, 2008. Based on initial isolates from persons with no prior history of TB.

MDR TB: resistant to at least

isoniazid + rifampin.
 Primary MDR TB in
U.S.-born vs. Foreign-born Persons,
United States, 1993–2007*
3
% Resistant

0
1993 1995 1997 1999 2001 2003 2005 2007

U.S.-born Foreign-born
*Updated as of April 23, 2008.
Note: Based on initial isolates from persons with no prior history of TB.
MDR TB defined as resistance to at least
isoniazid and rifampin.
Extensively Drug-Resistant Tuberculosis (XDR TB)
Diminishing Options for Treatment
 XDR TB Case Count defined on
†
Initial DST by Year, 1993–2007*
12
10
Case Count

8
6
4
2
0
1993 1995 1997 1999 2001 2003 2005 2007
Year of Diagnosis
†
Drug susceptibility test.
*Reported incident cases as of April 23, 2008.
Extensively drug-resistant TB (XDR TB) is defined as resistance to isoniazid and rifampin,
plus resistance to any fluoroquinolone and at least one of three injectable second-line anti-TB drugs.
New Tuberculosis (TB) Drugs Under Development
 Current Approach to the Clinical
Management of Tuberculosis
Clinical Guidelines for TB: www.cdc.gov
More aggressive approach with goal of TB
eradication from U.S.
Key Components:
– Targeted tuberculin testing to identify those with
latent TB infection (LTBI) = reservoir for new
cases
– Treating persons with LTBI regardless of age
– Uniform definition of skin test conversion
– Revised regimens for treating tuberculosis
ATS, CDC, IDSA. Controlling tuberculosis in the United States. MMWR 2005; 54(RR-12): 1-81; Mazurek GH et al.
Clin Infect Dis 2007; 45: 837-45.
 Latent Infection (LTBI)
vs. Active TB Disease
10% with intact immunity develop disease
Risk not uniform through life: recent converters at high risk
Certain conditions increase the risk of disease progression:
– Lifetime risk of reactivation is 20% or more for those with
evidence of old, healed tuberculosis
– Some co-morbid conditions increase the risk of
progressing to active disease
HIV infection
Others: silicosis, diabetes mellitus, chronic renal
failure, gastrectomy, cancer of head or neck
Disease-modifying anti-rheumatic drugs (RR 1.5)

Horsburgh Jr, CR. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004; 350:2060-2067;
Brassard P, Kezouh A, Suissa S. Clin Infect Dis 2006; 43:717-22.
 Mantoux Tuberculin Skin Test
(TST)

Method of choice to screen for TB infection. Heaf or Tine
tests should not be used.

Results should be reported in mm of induration at 48-72
hours, NOT as “positive” or “negative”

Three different cut-off points for a “positive” TST
depending on

risk of exposure to TB

risk of progressing from latent infection to active
disease

No role for anergy testing (may even be misleading)
 An induration of 5 or An induration of 10 or An induration of 15 or
more mm is considered more mm is considered more mm is considered
positive in: positive in: positive in:

-HIV-infected persons -Recent immigrants (< 5 -Any person, including

-A recent contact of a years) from high- persons with no known
person with TB disease prevalence countries risk factors for TB.
-Persons with fibrotic -Injection drug users
changes on CXR -Residents and
consistent with prior TB employees of high-risk
-Patients with organ congregate settings
transplants -Mycobacteriology
-Persons who are laboratory personnel
immunosuppressed for -Persons with clinical
other reasons (e.g., conditions that place
taking the equivalent of them at high risk
>15 mg/day of -Children < 4 years of
prednisone for 1 month age
or longer, taking TNF-a - Infants, children, and
antagonists) adolescents exposed to
adults in high-risk
categories
 Clinical Approach to the
Patient With a Positive TST

All persons with positive TB tests are potential
candidates for treatment regardless of age.

implies latent infection (LTBI) or active disease

first task – assess whether active disease present

Signs and symptoms (cough, hemoptysis, fever,
night sweats, weight loss) + CXR

For those with latent TB infection but not active
disease:

9 months of INH (daily, or twice weekly)

Rifampin (daily) x 4 months = second-line alternative

Active TB therapy: multiple drugs
ATS, CDC, IDSA. Treatment of Tuberculosis. MMWR 52(RR11):1-77, 2003.
 Clinical Presentation
Of Tuberculosis

Reactivation TB
•Apical/Posterior Segments UL
•Superior segment LL

From: Heller: Chest, 2001; 120(2):

674-678
 Clinical
Presentation
Of Tuberculosis,
contd.

Superior Segment
Lower Lobe
Other Clinical Presentations
of Pulmonary TB
Progressive primary tuberculosis
– Seen in very debilitated patients with primary
tuberculosis – i.e., recent infection
– Immune system cannot contain the primary infection
as it does in most immunocompetent hosts
– Progressive lower lobe infiltrates unresponsive to
antibiotics
 Treatment of Active TB, contd.
Multi-drug Rx of TB due to Drug-Sensitive Isolate
– Initial Phase:
2 months of INH + RMP + PZA + EMB
If isolate is drug-sensitive, stop EMB
– Continuation Phase: 4 or 7 more months of INH + RMP
4 months if sputum culture at 2 months negative
7 months if culture-positive at 2 months and cavitary
disease or if the patient is HIV-positive
– Directly Observed Therapy (DOT)
– Laboratory Monitoring
Hold therapy if symptoms + transaminases exceed 3X
normal, or asymptomatic and exceeds 5X normal

ATS, CDC, IDSA. Treatment of Tuberculosis. MMWR 52(RR11):1-77, 2003.

 TB Infection Control Measures

Protocols to ensure appropriate respiratory isolation of
potentially contagious patients
– Think TB if apical/post. UL or superior segment LL
infiltrate or for unresponsive lower lobe infiltrates
– Proper isolation facilities (negative pressure, ≥ 6 air
exchanges/hr, ≥ 12 for new/renovated facility)

Keep pulmonary TB patient in isolation until clinically
improved + 3 consecutive smears negative at least 8
hours apart with at least one first AM specimen

N95 masks for staff and visitors; standard mask for
patient travel

Periodic skin testing of hospital personnel based on risk

Treat all converters, regardless of age

See: http://www.cdc.gov/tb