A Thai woman was hospitalized with pneumonia and exposed healthcare workers to an unknown pathogen. Testing revealed the patient was infected with avian influenza H5N1, which resulted in her death. The exposure prompted monitoring of exposed healthcare workers and reinforced the need to consider avian influenza in differential diagnoses even with atypical presentations.

1. Post-Exposure Work Up:
What happen in reality?
Anucha Apisarnthanarak, M.D.
Division of Infectious Diseases
Thammasart University Hospital
Pratumthani, Thailand

2. Situation 1
• 45 year-old, Thai woman, with a history of
pulmonary fibrosis has been on prednisone and
endoxan for 6 months admitted to Thammasart
Hospital ICU because of CAP
• She was doing well on 10-days cefoperazone-
sulbactam and was subsequently extubated
• On HD day-11, she develop rash

4. Varicella Expose in ICU HCWs
(Epidemiology)
100,000-200,000 cases/yr post vaccine introduction (1995)
-4 million cases/yr pre-vaccine
-Cases in adult (>20 yr) <7%
Zoster 300,000 cases/yr
-Generally in patients >50 yr or immunocompromised
Mortality has been reduced post vaccine introduction
Atypical presentation could occur in patients who receive
vaccine
Nguyen, et al. Decline in mortality due to varicella after implementation of varicella vaccination in United States, N Engl J Med,
2005
Vazquez, et al. Varicella vaccine and infection with varicella zoter, N Engl J Med, 2005

5. Atypical presentation

6. What should be the most appropriate
management?
• A) Put the patient on airborne and contact isolation
• B) All exposed HCWs in ICU should off work from
day 5 to 21 after exposure
• C) Offer vaccine for all exposed HCWs
• D) Offer VZIG for all exposed HCWs
• E) All are correct

7. Varicella Exposure Among ICU HCW
• Transmission
Airborne and direct contact with lesions
• Transmission can occur from 2 days before to 5 days after rash appears
• Lesion non-infectious when crusted
Incubation period 10-16 days (range, 10-21 days)
Secondary attack rate ~90% in susceptible
contacts

8. Post-exposure management
• Establish susceptibility of HCWs
• Negative history of known susceptible
• Exclude from patient contact form day 10th-21st after last exposure or if
compatible symptom develop
• Offer VZV vaccine (2 doses separate by 4-8 wks)
-Effective in preventing illness or modifying severity, if use within 3-5 days after
post-exposure
-Vaccine contraindicated for pregnant female or those who become pregnant
• Previous vaccinated HCWs
• Retest for antibodies
• If negative, retest in 5-6 days to determine anamestic response
• If negative by 7 days post exposure, then furlough from work or monitor
• Risk of transmission of vaccine virus negligible unless vaccinee develop
rash

9. Case Scinario (cont)

10. Who should be the candidate for
vaccine?
• A) All HCWs in ICU
• B) All exposed HCWs in ICU
• C) All HCWs who reported previous
history of VZV
• D) All HCWs who reported no history of
VZV
• E) All are correct

11. Candidate for VZV vaccine
• Seroprevalence
• >90% adult seropositive (in general)
• History of varicella 97-99% predictive of
antibodies
• Negative or uncertain history 79-93%
seropositive

12. Exposed to Varicella zoster case
N = 140 HCWs
N = 18 ICU patients
Active disease No disease N = 130 HCWs N = 18 patients
N = 10 HCWs Cost: ACV to patients
Costs : Furlough HCWs occupational health protocol for continuing varicella risk:
ACV - Self-reported history
- IgG screen
- Counsel & vaccinate
Occupational health surveillance
No reported history of chicken pox Reported history of chicken pox
N = 77 N = 53
N Serology Vaccination
30 IgG+ NA Serologic testing Drop out
30 IgG- Yes 23/23 IgG+ N = 30
17 IgG- Declined

13. IgG
+ -
+ 23 0
Hx
- 30 47
Sensitivity = 23 / 53 = 43%
Specificity = 17 / 17 = 100%
PPV = 23 / 23 = 100%
NPV = 47 / 77 = 61%

14. Post-exposure management
Chemoprophylaxis
• No role for antivirus
Varicella-zoster immunoglobulin
• 400-500$ for maximum adult doses
• No role for routine use in post-exposure
in susceptible HCWs, unless HCWs
were know to be high risk for
complications or HCWs is not a
candidate for, or refuses vaccination

15. Will VZV vaccine be cost-effective to
provide for all HCWs in the hospital?
• A) Yes
• B) No
• C) Not sure

17. Cost Analysis
• Investment in future surveillance &
immunization next 300 HCWs
(cost 857,094.40 bath for ACV & furloughs)
NB: Attack rate = 21.1%
Seroprevalence = 55%
Apisarnthanarak A, et al. A Varicella zoster outbreak among Thai HCWs. Infect Control Hosp
Epidemiol, 06

18. Outbreak Investigation Steps
1. Confirm the outbreak 7. Formulate hypothesis
2. Prepare for 8. Execute additional
investigation studies
3. Initiate emergency 9. Implement control
measures measures
4. Create a case- 10. Share results
definition 11. Evaluate outbreak
5. Search for additional process
cases
6. Characterize outbreak

19. Quiz: A Thai student present with
fever, malaise and rash

20. What is the most appropriate action?
1. Start this patient on droplet isolation during the whole
admission period
2. Start this patient on droplet isolation during the first 24
hours
3. Start this patient on airborne isolation during the first 24
hours
4. Start this patient on airborne isolation during the whole
admission period
5. Provide ciprofloxacin to all HCWs for post-exposure
prophylaxis

21. Meningococcemia: Definition of Close Contact
• “Person who has had prolonged contact (>8
hours), while in close proximity (<3 ft) to index
patient or has been directly exposed to patient
secretion (intubation, mouth to mouth CPR)
within 1 week before onset until 24 hours after
received appropriate therapy”
• Classmate or coworkers who did not met the
close contact criteria were not included in
prophylaxis.
Garden P. Prevention of meningococcal disease. NEJM, 2006

23. Case 2
• On March 9, 2004 a 35 yo woman with no
underlying disease was transferred to Thammasat
University Hospital with rapidly progressive
pneumonia. At presentation to OSH, she reported
1 week of fever, N/V/D; no respiratory symptoms.
She received one dose of ceftazidime and
gentamicin prior to transfer.
• Social history: Lives in rural area of Ayudhaya
with family. Works in a factory; no travel history.

24. Additional data
• WBC 2,200 cells
– Neu 65%
– Lym 25%
– Mono 10%
• Hct 35%
• Plt 330,000 u/L
• BUN/Cr= 11/1.6
• AST/ALT = 474/106
• Alkaline phos = 546
• PT/PTT= 35/11.9
• LDH = 1,830

25. What should you do next?
• A) Obtain contact history
• B) Start broad spectrum antibiotics
• C) Perform rapid influenza test
• D) A-C
• E) A-B

26. Initial evaluation
• IC team notified and contact & air-borne
precautions initiated
• Rapid influenza test performed (negative)
• Local health department & hospital
administration notified
• Additional negative studies:
– HIV ELISA
– Chalmydia and mycoplasma titers
– Leptospira, melioid titer, dengue titer

27. What should be the diagnosis?
• A) Bacterial sepsis
• B) Avian influenza
• C) PCP
• D) SARS
• E) Influenza pneumonia H1N1

28. RT-PCR results
2 RT-PCR primers and 1 real-time RT-PCR positive
for H5 band and viral culture was negative.
Neighborhood chicken tested positive for H5N1.

29. Case outcome
• Exposures: Several recent chicken deaths in
the neighborhood.
• Given limited access to antiviral medication,
neuraminidase inhibitor was not prescribed;
prednisone was initiated.
• The patient died from severe ARDS with multi-
organ failure within 48 hours.
• All patient family members are well without
influenza-like illness.
Apisarnthanarak A, et al. Atypical avian influenza, 2004

30. Lesson Learned I
• Ask about occupation and exposure to ill
humans/animals during outbreaks. Inquire
about exposure history from multiple sources.
• Diff dx: Avian influenza in differential dx of
patients with only GI symptoms, especially if
there is exposure to poulty
• Design and coordinate a dynamic
interdisciplinary preparedness plan.
• A high index of suspicion will facilitate prompt
diagnosis and proper management.
Apisarnthanarak A, et al. Atypical avian influenza. Emerg Infect Dis
2004;10:1321-4.

31. • Clinical spectrum of H5N1 broader than we
thought.
• Surveillance definition should be adjusted to
include these presentations.
• Isolation of H5N1 from stool may have
implications for infection control.
deJong MD, et al. Fatal avian influenza A (H5N1) in a child presenting with diarrhea
followed by coma. New Engl J Med 2005.

32. Avian influenza (H5N1) replication sites.
Auewarakul P, et al. Emerg Infect Dis, 2005

33. Lesson Learned II
• The rapid influenza test is not the most
sensitive test, which may limit its usefulness
in correctly identifying H5N1, esp. when
patients present late in clinical course.
• Thus, clinical findings and history of
occupational exposure may be most helpful in
identifying patients with H5N1.

34. 48 hours post-transfer...
• Infectious disease
consultation
requested.
• 30 ICU HCWs
exposed to the
index case without
using appropriate
personal
protective
equipment.

35. Setting
• Level III, 8-bed MICU
equipped with central
air conditioning
• Two isolation rooms
• No negative pressure
room
• No special ventilation
system
• One Hospital
Epidemiologist
• Two ICNs

36. Personal Protective Equipment
AFTER CASE RECOGNITION:
• All HCWs wore surgical mask, gown, and
gloves.
• HCWs who were assigned for aerosol
producing procedures wore N95 mask,
cap/hood, and goggles.

37. IC protocol for HCWs at TU
Hospital
• All exposed HCWs monitored for 2 wks for
temperature and influenza-like illness (ILI)
• If any developed ILI, rapid influenza test done.
• If rapid test positive:
– Neuraminidase inhibitor prescribed.
– Influenza vaccine offered. Role??
• Paired acute and convalescent sera for anti-H5
antibody (microneutralization assay) collected.

40. Healthcare Workers and Avian
Influenza: Lesson Learned III
• Healthcare workers are at low risk of H5N1
acquisition, even unprotected.
• Continued precautions and monitoring are
essential in case viral mutations evolve to a
more virulent and readily-transmissible virus.
Apisarnthanarak A, et al. Seroprevalence of Anti-H5 antibody among Thai
HCWs after exposure to H5N1 in a tertiary care center. Clin Infect Dis,
2005

41. Avian Influenza (H5N1) Clinical Presentation
• Severe viral pneumonia • Mild influenza-like syndrome
Hong Kong: Yuen, et al Lancet 98
Yuen, et al. Lancet 98 Kandun, et al NEJM 06
Perris, et al. Lancet 04
Vietnam: • Difficulty for rapid diagnostic
Hien, et al. NEJM 04 Hong Kong:
Thailand: Yuen, et al. Lancet 98 (82%)
Chotepitayasunondh, et al. EID 05 Vietnam:
Turkey: De Jong, et al. Unpublished (20%)
Oner, et al. NEJM 06 Turkey:
Oner, et al. NEJM 06 (0%)
• Atypical presentation Indonesia:
De Jong, et al NEJM 05 Kandun, et al. NEJM 06 (0%)
Apisarnthanarak, et al EID 04 Thailand:
Apisarnthanarak, et al. CID 07 (29%)