october 31, 2011 anaheim, ca health watch and the glrce ...•β-thalassemia patients under...
TRANSCRIPT
Health Watch
and the GLRCE Emergency Response
An investigation of a fatal case of
laboratory-acquired septicemic plague.
ABSA
The 54th Annual Biological Safety Conference October 31, 2011
Anaheim, CA
Scope of Research Program
Two Campuses:
1. Howard T. Ricketts Regional Biocontainment
Laboratory
– On the DOE campus of Argonne National
Laboratories
2. University of Chicago-Hyde Park
2
Ricketts RBL
• Home of UC Select Agent Program
– Since January, 2010
• 5 Principal Investigators/~50 staff/1 ABSO
• Houses BSL2, BSL3 and ABSL3
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Yersinia sp. (SA and non-SA) Rickettsia sp. (SA and non-SA)
Bacillus sp. (SA and non-SA)
Coxiella sp. (non-SA)
Brucella sp. (SA)
Staphylococcus sp. (non-SA)
UC Hyde Park
• ~ 220 Principal Investigators
• ~ 350 protocols
• IBC annual workload
– ~50 new protocol submissions
– ~80 protocol re-submissions
– ~200 amendments
• Three IBC staff/One ABSO
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UC Hyde Park
• One ABSL3 (Prion Disease)
• Remainder: BSL2, BSL2-enhanced, ABSL2
• Prior to January 2010, three of the BSL3/
ABSL3 programs now housed at Ricketts were
conducted in one BSL3 suite and two ABSL3
suites.
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UC Hyde Park Agents
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Viral Vectors Viruses (Replication-
competent)
Viruses
(Replication-
competent
Adenovirus (Replication-
defective) Herpes Simplex Virus 1 Dengue Virus
Adeno-Associated Virus
(Replication-defective) Epstein-Barr Virus Reovirus
Murine retroviruses
(Replication-
defective/amphotropic)
Influenza A Vaccinia Virus
(Attenuated)
Lentivirus (Replication-
defective) Influenza B Rotavirus
UC Hyde Park Agents
Bacteria
Salmonella
typhimurium
Coxiella burnettii
(vaccine strain)
Yersinia
pseudotuberculosis
Mycobacterium
avium
Staphylococcus
aureus
Yersinia
pseudotuberculosis
Listeria
monocytogenes
Enteropathogenic
E. coli
Listeria
monocytogenes
Bacteroides fragilis
Vibrio cholerae Serratia
marcescens
Yersinia
enterocolitica
Legionella
pneumophila
Shigella flexneri Klebsiella
pneumoniae
Pseudomonas
aeruginosa
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Fungi
Aspergillus fumigatus Candida albicans
Agent Profile Forms
• Required for any pathogen or molecular vector
managed at BSL2/ABSL2 or above.
• Describe biological features of pathogen,
including source, susceptibility to disinfectants,
drug sensitivity, environmental stability, routes of
infection, BSL/PPE, treatment paradigm.
– Accompanies investigator to UCOM in the event of
an exposure
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Agent Profile Forms
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Agent Profile Forms
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Occupational Health/Medical Assessment (pre-employment for BSL3/ABSL3)
• Occupational Medicine
– Health Questionnaire
– PFT as needed; Clearance for use of respiratory
protection (PAPR)
– Vaccination (e.g. influenza, AVA)
– Serological surveillance (very limited)
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Occupational Exposure
• Examples
– Needle stick, bite or scratch
– PIM splash into mucus membrane/exposed skin
– Aerosol exposure
– Medical Emergency within primary containment
– Disease symptoms exhibited by investigator
– Confirmed LAI
Occupational Exposure First Aid
Skin Contamination
• Proceed to Ante Room
• Disinfect by submersing or exposing the area with 70% alcohol for 10 minutes.
Needle Sticks, Contaminated Cuts and Animal Bites/Scratches
• If bleeding, squeeze out blood, spray with 70% alcohol
• Proceed to Ante Room
• Disinfect with iodine solution (povidone-idone) or peroxide for 20 minutes
• Wipe surrounding tissue with iodine solution or peroxide
Eye Contamination
• Proceed to nearest Eye Wash
• Flush eyes in eye wash for 15 minutes.
Aerosol Exposure
• Exit lab under normal SOP
Occupational Exposure First Aid
Exit under normal SOP
• Immediately after exiting, contact the University of Chicago
Occupational Medicine (UCOM) Bloodborne Pathogen/Needle
Stick hotline at ###-###-####, enter pager number ####,
followed by #.
• Notify PI, BSO, RO/ARO (SA) and supervisor
For Life Threatening Situations call 911.
Health Watch SOP
BSL3/ABSL3
Independent of known exposure event
If fever develops (oral temp 101.5o F) with or without
respiratory complaints or other disease symptoms
employee shall report the illness
Within 14 days of last entry into containment
Contact UCOM BBP/ID Hotline
Contact RO/ARO/PI
Assessment and Treatment provided by UCOM as
needed
Wallet Cards
Notification Name: Joe Kanabrocki
Biosafety Level 3 Agent(s):
Anthrax (Bacillus anthracis AMES strain)
Plague (Yersinia pestis CO92 and/or KIM strain)
Rickettsia (Rickettsia rickettsii)
Vaccinations Received: None
University Emergency Contact Number:
Outside Medical Center: ###-###-####, enter ####, followed by #
Medical Center: ###, enter ####, followed by #
Agent/Treatment Information:
www.phac-aspc.gc.ca/msds-ftss
Health Watch SOP
BSL2/ABSL2
Monitor health for disease symptoms;
Employee shall report the illness if disease symptoms
suggest LAI
Contact UCOM BBP/ID Hotline
Contact BSO/PI
Assessment and Treatment provided by UCOM as
needed
GLRCE Emergency Response:
An investigation of a fatal case of
laboratory-acquired septicemic plague.
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Septicemic plague –
sequence of events
September 13, 2009
• researcher dies in the Emergency Room of the University of Chicago
September 15, 2009
• blood cultures positive for Gram-negative rods and Gram-positive cocci
September 16, 2009
• memorial service at Bond Chapel
September 18, 2009
• Autopsy report by the University of Chicago: no obvious cause of death,
including no pulmonary pathology.
• Clinical microbiology reports Gram-negative rod preliminarily identified
as Yersinia pesudotuberculosis.
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Septicemic plague –
sequence of events
September 18, 2009 (con’t):
• Case review determines that Deceased worked with Y.p. KIM D27, an attenuated, non-SA strain of Y.p. approved for work at BSL2. The Deceased’s lab bench, all research materials quarantined immediately.
• Finding reported to UC Admin, CDC, IDPH (Illinois), CDPH (Chicago), CDC SAP, NIH-NIAID, NIH-RAC, DOE, ANL (Argonne National Laboratories);
• UC Public Affairs issues press release;
• GLRCE Emergency Response Core identifies Gram-negative rods as the non-pigmented Yersinia pestis isolate UC91309 (PCR, Western blots); the Gram-positive cocci were identified as Streptococcus defecticus
20
Septicemic plague –
sequence of events
September 18-19, 2009
• Infectious Diseases and UC Hospital Infection Control, together with CDPH, contact all lab contacts and patient contacts of the Deceased to offer tetracycline prophylaxis; approximately 100 persons offered antibiotics.
September 19, 2009:
• 8:00 AM conference call/data review with the CDC, IDPH, CDPH, UC Hospital IC, ID, ES, Risk Mgmt, GC, Microbiology and UC Administration.
• CDPH decision to close down lab bench pending data review & inspection of laboratory, scheduled for Monday, Sept. 21 at 1:00 PM.
21
Septicemic plague –
sequence of events September 21, 2009
• CDC, CHPH, IDPH, County PH, OSHA, NIOSH, Chicago Police
Department arrive on-site for investigations, which continue through
Thurs., Sept 24. OSHA leaves after first day, returning Oct. 5. CPD
leaves after the first day.
September 22-24, 2009
• Investigations continue. Protocols and training records examined,
approx. 30 lab staff and maintenance workers interviewed by CDPH.
September 23, 2009
• Emergency Response Core animal experiments with non-pigmented
plague isolate indicate attenuation
22
Septicemic plague –
sequence of events September 24, 2009
• On-site investigation ends.
October-November, 2009: Investigation continues:
• Genome sequence for the plague isolate UC91309
• Genetic information for the deceased becomes available
• Genome sequence for the parent strain KIM D27 and laboratory records indicate that the deceased had constructed UC91309
October 16, 2009
• Formal incident report filed with NIH-OBA
August 2, 2010
• University of Chicago IRB, legal counsel, CDC as well as City and State Public Health Departments endorse submission case report
23
Septicemic plague –
sequence of events November 23, 2010
• UC provides an update report to the NIH Office of Biotechnology Activities
December 30, 2010
• Chicago Dept. of Public Health issues final investigation report.
February 25, 2011
• CDC publishes case report in Morbidity and Mortality Weekly
March 14, 2011
• U.S. Occupational Safety and Health Administration (OSHA) provides a final report to the UC, with recommendations but no citations.
– Incorporates December 18, 2009 final report and findings of NIOSH investigation
April 8, 2011
• NIH Office of Biotechnology Activities provides a report to the UC with a request for additional documentation.
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Investigation Findings: University of Chicago
• Characterization of clinical isolate:
– Microbial analysis
– Molecular analysis
– Virulence assessment
• Characterization of post-mortem specimens
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Wright-Giemsa staining of peripheral blood Safety-pin stained bacteria and leukemoid reaction
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Liver – hereditary hemochromatosis H&E and iron staining reveal intracellular iron deposits
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Lung -
intravascular Y. pestis Lillie-Twort Gram and HE stains
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Spleen Necrosis and immuno-histochemical
identification of Y. pestis
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UC91309 non-pigmented Y. pestis (V+, F1+)
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UC91309 genome sequence pgm and HPI are absent
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Yersiniabactin,
the iron scavenger of transferrin
Crosa and Walsh (2007) MMBR
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UC91309 harbors cat primers define the cat insertion site
on the chromosome
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Attenuation and iron-dependence of
UC91309 in Swiss -Webster mice
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Pathology of UC91309 infection
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Hereditary hemochromatosis
N.D. Andrews (2008) Blood 112:219
36
Antemortem iron load in a patient with
septicemic plague
• serum ferritin 392,530 ng/ml (20-300) – a measure for liver iron storage
• total iron binding capacity 648 µg/dl (230-430) – a measure for the abundance of transferrin
• iron 541 μg/dl (40-160) – the amount of iron in the serum
• iron saturation 83.5% (14-50%) – the % amount of transferrin charged with iron
• liver iron 14,672 µg/g dry weight
Frank et al. (2010)
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Yersiniosis and hemochromatosis
• β-thalassemia patients under deferoxamine therapy (streptomyces siderophore) are highly susceptible to Y. enterocolitica infection
• Patients with iron overload or secondary hemochromatosis due to blood transfusions receive deferoxamine treatment and this increases their susceptibility to Y. enterocolitica infection
• Hereditary hemochromatosis patients (HFE C282Y) display increased susceptibility towards Y. enterocolitica infection and liver abscesses even without deferoxamine
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Investigation Findings: Chicago Dept. of Public Health/CDC
• Case Report
• Epidemiological and Environmental
Investigation
• Laboratory and Pathologic Testing
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Investigation Findings: Chicago Dept. of Public Health/CDC
• Case Report
– Deceased researcher was a 60 y/o, insulin-dependent
diabetic. Last day in lab was Sept. 4.
– Seen in outpatient clinic on Sept. 10, three days prior to
ER admission for fever, body aches and cough (3 days
duration).
– Subsequently seen in ER (Sept. 13) for fever, cough,
worsening shortness of breath.
– Patient expired in ER.
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Investigation Findings: Chicago Dept. of Public Health/CDC
• Case Report
– Blood cultures yielded:
• Gram negative bacilli: ultimately determined to be Yersinia pestis
KIM D27 derivative (attenuated, non-SA)
• Gram positive cocci: ultimately determined to be a nutritionally
variant Streptocci (NVS).
– Autopsy:
• No signs of pneumonia, bowel perforation or endocarditis.
• Preliminary diagnosis of hereditary hemochromatosis.
– Later confirmed through genetic testing.
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Investigation Findings: Chicago Dept. of Public Health/CDC
• Epidemiological and Environmental Investigation
– Antibiotic prophylaxis offered to close contacts
• Inhalation exposure not ruled out at this time.
– Lab environment assessment revealed no deficiencies in lab
engineering controls; no history of work-related injuries or
illnesses.
– Training records revealed deficiencies in attendance of
required of some lab staff (including deceased)
– No reports of exposure incidents.
– Interviews with co-workers revealed inconsistent compliance
by deceased with lab PPE policies.
42
Investigation Findings: Chicago Dept. of Public Health/CDC
• Laboratory and Pathologic Testing
– PCR and microbiological testing confirmed pgm- genotype
and colony pigmentation (CDC).
– Antibiotic resistance testing confirmed presence of
chloramphenicol resistance gene.
– Virulence testing in mouse in vivo model confirmed “that
the strain with which the patient was infected was attenuated and
that no new virulence mechanisms were acquired by or engineered into
the infecting strain.”
43
Investigation Findings: Chicago Dept. of Public Health/CDC
• Laboratory and Pathologic Testing
– Histopathological examination ruled out pneumonic
plague as a cause of death; consistent with diagnosis of
septicemic plague.
– Histologic staining revealed abnormal iron deposits in the
liver.
– Post-mortem blood chemistries were consistent with UC
findings regarding elevated serum iron content.
44
Investigation Findings: Chicago Dept. of Public Health/CDC
• Conclusions:
– First known fatality from a lab-acquired infection with an
attenuated Y.p. strain.
– Findings are consistent with cause of death being septic shock
from Y.p. infection and inconsistent with pneumonic plague.
• Suggestive of a trans-dermal or mucosal route of infection.
• Inconsistent use of gloves could have resulted in an inadvertent
transdermal exposure.
– Severe outcome of infection with Y.p. (pgm-) was unexpected.
45
Investigation Findings: Chicago Dept. of Public Health/CDC
• Conclusions:
– NVS bacteremia cannot be excluded as a contributing factor
in the patient’s death.
– Animal studies have shown that virulence of Y.p. KIM D27
can be enhanced by simultaneous injection of iron into
experimental animals.
• Hemochromatosis-induced iron overload might have a similar effect.
– Diabetes is a known risk factor for increased severity and
complications from bacterial infections.
46
Investigation Findings: Chicago Dept. of Public Health/CDC
• Conclusions:
– Researchers working with attenuated Y. pestis and other
potentially infectious materials should always use at least BSL2
practices.
– Lab managers should ensure that staff adhere to
recommended biosafety practices.
– Institutional safety committees should implement and
maintain effective surveillance programs to identify and
monitor acute illness among lab workers.
– Health-care providers should routinely inquire about
occupational exposures when evaluating patients.
47
Investigation Findings: OSHA: Major Finding and Conclusion
“Apparent violations warranting citations
were not found during the inspection period.”
48
Investigation Findings: OSHA: Recommendations
1. Prior to start of work on an attenuated pathogen, identify all
know factors that could potentially enhance virulence and
be hazardous to workers. The principal investigator should
ensure that the attenuated strain remains attenuated.”
2. Implement a medical surveillance program to provide
confidential screening for personnel for the presence of, or
potential predisposition to, these factors.
3. Train laboratory personnel and supervisors to recognize the
signs and symptoms of the virulent form of the pathogen
being studied.
49
Investigation Findings: OSHA: Recommendations
4. Educate workers and supervisors about the hazards in the
workplace and any potential risks and personal risk factors that
may cause injury or illness.
5. Train workers how to obtain medical evaluations for suspected
occupational exposures and illness, including access to medical
evaluation after work hours.
6. Encourage laboratory personnel to report immediately to a
supervisor any signs and symptoms of illness.
7. Train supervisors to authorize and arrange for immediate
medical evaluation for workers reporting any signs and
symptoms of illness.
50
Investigation Findings: OSHA: Recommendations
8. Develop, implement and maintain an effective medical
evaluation program to identify, treat and track acute illness
among laboratory personnel.
9. Supervisors and managers should ensure that staff adheres
to recommended biosafety practices (Biosafety in
Microbiological and Biomedical Laboratories [BMBL], 5th Edition)
51
Investigation Outcomes
• CPD reports no evidence of criminal activity;
• CDC, CDPH, IDPH indicate that incident appears to be an isolated incident
with no threat to the public and no systemic issues identified;
• OSHA and NIOSH complete investigation issuing no citations or fines.
June 16, 2010
• NIH RAC debates applicability of NIH Guidelines Major Actions (III-A-1) clause
to attenuated Y. pestis strains.
– Lcr- are exempt
– Pgm- are NOT exempt, although CAM marker use is exempt.
52
Investigation Outcomes: UC Biosafety Program Enhancements
• Biosafety Office staffing increased from 2.0 to 3.5 FTE.
• Each investigator (PI, post-doc, student, tech) in the Dept. of
Microbiology has received a personalized biosafety manual:
– Agent Profile Forms for all pathogens present in work area.
• A written Code of Conduct has been established and each investigator
in the Dept. of Microbiology has signed this agreement.
• Includes provisions for peer reporting, self reporting.
• Includes commitment to adherence to established lab safety standards.
• Includes provisions for ethical conduct and scientific integrity.
• BSO/RO meets personally with all staff in SA program annually
53
Investigation Outcomes: UC Biosafety Program Enhancements
• Institutional BSL2 Biosafety Manual drafted. Will be distributed
during lab inspections and made available via web.
• Training module on peer reporting being developed for Biological
Sciences Division.
• Numerous biosafety training modules under development.
54
GLRCE
Emergency Response Core
• Mobilized immediately upon incident notification.
• Rapidly integrated and coordinated activities of institutional scientists and administration officials, local and Federal public health, law enforcement, regulatory and investigational agencies.
• Immediate and sustained communication with the public
• Evaluated institutional programs and implemented safety program enhancements.
• Performed incident review and response analysis; poised to share lessons learned.
55
Lessons Learned
• All investigators should inform their personal physician
about their work and hazardous materials, incl.
pathogens, with which they work.
• All investigators should be aware of their own health
status and about potential susceptibilities resulting
from illness, whether chronic or acute.
• All investigators should be aware of disease signs and
symptoms associated with pathogens with which they
work.
56
Lessons Learned
• All investigators should adhere to established biosafety
practices.
• Occupational Health Watch protocols should be
established to monitor for signs and symptoms of
disease, even in absence of known exposures.
• Mechanisms for reporting issues of non-compliance
should be established and training should be provided;
all investigators must commit to an ethical code of
conduct.
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CREDITS GLRCE EMERGENCY RESPONSE
Olaf Schneewind, Julie Bubeck-Wardenberg (UC Dept. of Microbiology)
John Bivona (U of C Biosafety)
Karen Frank, Peter Pytel, John Hart (U of C Pathology)
Helene Louvel, Bill Blaylock, Nate Miller (U o fC Microbiology)
Stephen Weber (U of C Medicine)
Elizabeth Marland Glass (ANL)
Lauriane Quenee, Tim Hermanas, John Schramm (HTRL)
Paul Keim, Jim Tschupp (Translational Genomics Research Institute)
William Nierman (JCVI)
Wun-ju Shieh , Sherif Zaki (CDC)
Rona Hirschberg, Michael Schaefer (NIAID RCE)
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