preparedness for emerging infectious threats : escmid

Preparedness for Emerging Infectious Threats : Avoiding Outbreaks in Europe

MARSEILLE 19-21 march 2012

Laboratory accidents as source of outbreaks : impact on lab worker surveillance.

Dominique VIDAL Biodefense advisor Ministry of Defense

FRANCE ESCMID Online Lectu

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Introduction

1/ BioSafety laboratories (BSL) BSL principles Laboratory accidents in BSL

2/ Laboratory acquired infections (LAIs)

LAIs Definition, Surveys, Prevention Specific laboratory acquired infections : bacteria and viruses

3/ Lab-workers surveillance

BioSafety regulations, Health surveillance of lab-workers and occupational medicine

BioSecurity surveillance of lab-workers

ESCMID Online Lecture Library

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Part 1. Biosafety Principles Principal investigators and laboratory directors are

responsible for biosafety compliance in their institutions to avoid laboratory acquired infections and outbreaks development in the community and in the environment

Pathogenicity of microorganisms Classification of pathogens Group 1 : unlikely to cause human disease/Lactobacillus

acidophilus Group 2 : Can cause HD, Salmonella Group 3 : Can cause severe HD, risk of spreading to the

community, prophylaxis or treatment available/Yersinia pestis

Group 4 : Severe HD, serious hazard, risk of spreading, no prophylaxis nor treatment/Ebola virus

Host-pathogen interactions :

immunology status, underlying diseases, immunodepression, Immunizations

Routes of transmission : cutanous Pulmonary Ocular Digestive


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Risk assessment : What ? How ? Who ?

Personnel

Laboratory material and devices Biologic samples

Dangerous pathogens and Microorganisms Waste

Air

Water

Activities ESCMID Online Lecture Library

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Biosafety Principles : biocontainment

BioContainment : BSL1, 2, 3, 4

Primary barriers : equipment Biosafety cabinets, isolators PPE : clothes, gloves, mask, glass,

coat

Secondary barriers : architecture Liquid effluents (chemical or heat

inactivation) Wastes (double-ended autoclave) Airlock entrance Air treatment (HEPA filters)


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Biosafety education Comprehensive initial courses for

microbiologists and scientists Basic microbiology and infectious diseases

education Good microbiology practices Biosafety

practice and management (level 1) Specialized education

Biosafety professionals (level 2) and engineers

BSL 3 course and BSL 4 course Biosafety and biosecurity for principal

investigators and laboratory directors Biosafety for occupational medicine

practitioners Continuing education

Training workers Regularly organize drills of emergency

procedures Biosafety and biosecurity Associations

Guidelines and Journals Courses and Conferences


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Laboratory accidents and Lab incidents

Fire, thermal burns, clothing fire Cold liquid frostbite Electric shock Gaseous leak Chemical spills or dispersion (acid, base burns) Poisoning (ingestion, inhalation) Liquid splashes to the eye Contamination to the body Aerosols, droplets Needlestick, syringe or sharps injury Animal bites Broken device BSlaboratory dysfunction : electric supply or air

treatment failure LabWorker fall down Medical emergency : collapse, heart failure,

unconsciousness, discomfort


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Laboratory accidents and origin of bio-contaminations

Inhalation 50 % : infectious aerosols, droplets

Ingestion : mouth pipetting; eating, drinking

Percutaneous inoculation : Needle and syringe, contaminated sharps animal bites exposure to previously broken or damaged skin

Mucous membrane exposure : infectious materials in contact with eyes, nose, mouth (splashes,

contact from contaminated surfaces)

Accidental origin or failure to comply with safety instructions ESCMID Online Lecture Library

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Part 2. Laboratory acquired infections (LAIs)

Definition : LAI is an infection obtained through laboratory or laboratory-related activities as a result of work with infectious biological agents, which may be either symptomatic or asymptomatic

No systematic collection of data

Difficulty of precise evaluation ESCMID Online Lecture Library

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Survey of Laboratory acquired infections (LAIs)

1893 France : tetanus-syringe 1915 Germany : 50 typhoid fever 1947 NIH : 47 Q fever 1949-1951 : Sulkin and Pike

5000 laboratories 1342 LAIs 39 deadly cases 16% of known origin

Many more LAIs likely unreported during this period of time 17% in clinical diagnostic laboratory 59% in research laboratory


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Microorganisms responsible for LAIs (Pike, 1978)

Microorganisms cases (% ) dead

Bacteria 1704 41,8 71 Virus 1179 28,9 55 Rickettsiae 598 14,7 25 Fungi 354 8,7 5 Chlamydia 128 3,1 10 Parasites 116 2,8 2

TOTAL 4079 100 168 ESCMID Online Lectu

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Most frequent infections (Pike, 1978)

Brucellosis 426 cases 5 dead Q fever 280 1 Hepatitis 268 3 Typhoid fever 258 20 Tularemia 225 2 Tuberculosis 194 4 Dermatomycosis 162 0 Venezuelian Equine Encephalitis 146 1 Psittacosis 116 10 Coccidioidomycosis 93 2

TOTAL 2 168 48


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Recent surveys of LAIs in UK and US Harding and Byers literature

search of LAIs for 20 years : 1,267 declared infections with 22 deaths Only 7 documented secondary

infections from LAIs ClinMicroNet survey of 2002-

2004 (ASM) 33 % of laboratories reported at

least 1 LAI Most common : shigellosis,

brucellosis, salmonellosis Highest incidence : Brucella and

Neisseria meningitidis

Incidence of infection

General population

Laboratory workers

population

Brucella species

0.08/100.000 641/100.000

Neisseria meningitidis

0.62/100.000 25.3/100.000


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Thank to Biosafety LAIs decrease but despite Controls LAIs continue

Since 1965 : decrease of annual number of LAIs,

1979 Pike concluded “the knowledge, the techniques, and the equipment to prevent most laboratory infections are available”

Yet, laboratory acquired infections continue to occur…(even today)


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Specific Laboratory acquired infections (LAIs)

Bacterial infections Viral infections Fungi and parasites infections (not

treated here)


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Bacterial LAIs : brucellosis

The most frequent reported LAI In the US 24 % LAI and 11 % of deaths due to LAI Transmission

Aerosol is the major source Direct contact

Post-exposure prophylaxis Doxycycline 100 mg/day and rifampicin 600 mg/day for 3 weeks Serologic tests monthly for all exposed workers for 6-9 months


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Bacterial LAIs : Neisseria meningitidis

In a study of LAI meningococcal disease worldwide 16 cases were identified and 8 (50 %) were fatal.

Probably due to aerosol exposure of clinical microbiologists.

Attack rate : 13/100.000 microbiologists 0.3/100.000 persons among general population

Post-exposure prophylaxis Doxycycline a single dose of 500 mg or rifampicin 600 mg/twice daily for 2 days


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Bacterial LAIs : Mycobacterium tuberculosis

Incidence of tuberculosis among laboratory workers : 3 to 9 times greater than in the general population

High infectivity of M. tuberculosis by aerosol exposure of clinical microbiologists

50 % infective dose : 10 bacilli Use of laminar-flow Biosafety cabinet in BSL3 Annual skin test (Mantoux) If positive test, chest radiography If accidental exposure worker should be tested 3 and 6

months after the accident ESCMID Online Lectu

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Bacterial LAI : Bacillus anthracis After 2001 outbreak of bioterrorism related anthrax

in the US Bacillus anthracis became a major source of concern in laboratories

Increased importance with biodefense emergence programs

In march 2002 a labworker was diagnosed with cutaneous anthrax One day after he had cut himself over the right jaw Handled without gloves vials of B. anthracis from

Biosafety cabinet to freezer Three days later he developed fever, cervical

lymhadenopathy and black eschar on neck Culture were positive with B. anthracis

The tops of the vials were tested positive for B. anthracis

Storage vials were sprayed with 70 % isopropyl unless 10 % bleach

Treated with intravenous doxycycline and ciprofloxacin ESCMID Online Lectu

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Sverdlovsk Incident 1979 Sverdlovsk (Ekaterinburg) : 2 April 1979 Release of anthrax spores from a military

facility 94 people affected, at least 64 deaths of

pulmonary anthrax Anthrax aerosol leak due to forgetting to

replace an exhaust filter


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The Bruce Ivins case and the anthrax attacks in the USA

Bruce Ivins : scientist working on anthrax vaccine, biodefense expert at USAMRIID

September 2001 : intentional release of anthrax in mail

FBI investigate : Ivins participate to the sample expertise 2002, a person of interest : Steven Hatfill march 2008, Steven Hatfill exonerated 5,8 M$ 2006 investigation against Ivins

July 2008 : Ivins kill himself FBI declared he was the sole culprit and he suffered

from psychiatric disorders


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Bacterial infections : Francisella tularensis

Fastidious Gram-negative coccobacillus, infrequently encountered in clinical laboratory

Incresed importance with biodefense emergence programs In 2002 12 labworkers were exposed after a suspected case of

pneumonic tularemia in a man who died Clinicians failed to notify the laboratory about the suspicion Culture were initially misidentified as Hemophilus Post-exposure prophylaxis with doxycycline was given : 100 mg

twice daily for 14 days


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Bacterial infections : Yersinia pestis

Y. pestis, the agent of plague, a class 3 pathogen A scientist at University of Chicago had been working with a

pigmentation-negative attenuated strain of Y. pestis (KIM D27) This strain is excluded from the National Select Agent Registry

Septicemic plague with KIM D27 strain On September 10 the researcher was evaluated at an outpatient clinic

for fever and cough On September 13 he was admitted to the Chicago hospital because of

worsening breath, fever and cough, and died 12 hours after presentation

On September 18 the clinical laboratory identified Y. pestis in blood cultures

30 co-workers and 64 other close contact were prescribed a 7-days course of doxycycline for prophylaxis

The 60-year old patient had insulin-dependant diabetes and hereditary hemochromatosis

Hemochromatosis is an iron-overload disease and patients are especially susceptible to infection. This disease and iron storage in multiple organs might have enhanced the virulence of the KIM D27 strain of Y. pestis.


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Another kind of plague “infection” : the Dr Thomas Butler case

Thomas Butler is a scientist at Texas Tech University specialized in infectious diseases

170 papers on cholera, plague, He made oral hydration the standard treatment of

diarrheas In 2000 he initiated a research program on plague

prevention and treatment with Tanzania co-workers In January 2003 he reported 30 vials of Y. pestis were

missing from his laboratory This triggered a bioterrorism investigation by FBI and

Butler was arrested and accused of illegal transportation of plague samples, tax evasion, fraud.


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Illegal transportation of plague samples and Y. pestis strains


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Thomas Butler prosecution Thomas Butler pleaded not

guilty Despite support of scientists,

Nobel Prizes, National Academy of Sciences, and the Federation of American Scientists

He was convicted of 47 charges for improper shipment of plague samples and “shadow contracts”


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Viral LAIs Viral agents transmitted through blood

and bodily fluids Viral hemorrhagic fevers in Germany in

1967 31 workers infected while handling

tissue specimens from African green monkeys

7 deaths resulting : Marburg virus Hepatitis B virus

Incidence four times higher in healthcare workers

Hepatitis B vaccine should be offered to lab workers

In unvaccinated exposed workers PEP with hepatitis B, they should received immunoglobulin and vaccine

HIV infections a great concern for healthcare workers and laboratory workers (25 % of HCW-HIV) In case of laboratory-based exposure,

immediate referral to employee health and PEP


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Severe acute respiratory syndrome SARS is respiratory disease that infected over 8 000 people in 37 countries

from late 2003 through 2004, with high mortality rate of 9 to 14 %. Started in November 2002 in South of China (Guangdong). Highly contagious patients infected customers at Metropole Hotel in Hong

Kong in February 2003 and spead in their countries In March WHO trigger a “Global Alert”. On 21 of march 2003 the coronavirus responsible of SRAS was identified by

electron microscope and PCR.


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SARS LAI in Singapore

4 months after the end of SARS epidemic, a graduate student in Singapore working on a non-attenuated strain of West Nile virus, was evaluated for flu-like symptoms

The patient denied exposure to SARS and had no travel history

5 days later due to persistent fever and because Singapore remained in SARS alert, a PCR test was done and revealed to be positive

Epidemiologic investigation revealed that the laboratory worked on SARS and that a culture of West Nile virus was contaminated with the same strain of SARS coronavirus ESCMID Online Lectu

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Left eye and right ear of a man with laboratory-acquired

vaccinia virus infection --- Virginia, 2008, MMWR, 58,

797, 2009.

LAI Vaccinia virus infection in Virginia Vaccinia virus (VACV) is the live viral component of smallpox vaccine Severe complications can occur in person with underlying risk factors

Pregnancy, Immunodeficiencies, Dermatologic pathologies

On July 5, 2008 a 20-year man working in a laboratory went to a local urgent care clinic reporting swelling of cervical lymph nodes and pain and inflammation of his right earlobe

On July 7 : he return to emergency department with increasing eye pain ; he was treated with intravenous vancomycin/ceftriaxone

Investigation revealed that he worked on mice infected with VACV On July 10 he was administered 800 mg acyclovir then was improving and full

recovered after.


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Part 3. Lab-worker surveillance

French Legislation : décret 2008-244 Code du travail, protection des travailleurs article R 4425 : formation et information

risques biologiques pour la santé procédures à suivre en cas d’accident gestes de secours déclaration

article R 4426-9 : surveillance médicale renforcée liste des travailleurs exposés à des agents biologiques des groupes 3 et 4 conservation au moins 10 ans du dossier médical individuel après la fin de

l’exposition (Burkholderia : 40 ans) article R 4624-19

dossier médical spécial information conservation de l’information

European Community Directive : 2000/54/CE/18 September 2000

Protection of workers from risks related to exposure to biological agents at work Article 9 Information and training of workers Article 10 Worker information in particular cases Article 11 List of exposed workers Article 14 Health surveillance


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2000/54/CE/18 September 2000 Protection of workers from risks related to

exposure to biological agents at work Hygiene and individual protection

Workers do not eat or drink in working areas Workers are provided appropriate protective clothing and equipment Workers are provided appropriate washing and toilet facilities, including eye

washes and skin antiseptics Article 9 Information and training workers Article 10 Worker information in particular cases

Procedure in case of serious accident or incident Workers shall immediately report any accident or incident involving the

handling of biological agent to the person responsible for safety and health at work

Employers shall inform the workers of any accident or incident with biological agent

Article 11 List of exposed workers Workers exposed to class 3 or 4 biological agents List kept at least 10 years, up to 40 years

Article 14 Health surveillance


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2000/54/CE/18 September 2000 Protection of workers from risks related to

exposure to biological agents at work

Article 14 Health surveillance

Done prior to exposure, and at regular interval there after When necessary effective vaccine When a worker is suffering from occupational infection, all co-workers shall

be offered medical surveillance if similarly exposed Medical reports kept for at least 10 years Information and advice must be given to workers regarding health

surveillance and results which concern them


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Strengthened medical surveillance Article R4426

Employer obligation Obligatory Occupational medicine specialist

must have a good knowledge of biosafety, biological agents and of the laboratory where are handled agents

Must record medical and professional history of workers Preplacement Examination (PPE)

To reveal any medical condition that might put the worker at risk Recommendations for job restriction or denial of employment should be carefully

considered Laboratory testing Obligatory vaccinations : tuberculosis, tetanus, polio, diphteria, typhoid Circumstantial vaccinations : HVC, HVA, influenza, anthrax, tularemia, leptospirosis,

rabies, rubella Periodic Monitoring Examination (PME)

List of biological agents handled In the medical file of the worker Blood sample : renal, hepatic, inflammatory and hematologic functions Pulmonary radiography

Postemployment Evaluation (PEE)


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Strengthened medical surveillance Article R4624

Employer obligation Contra-indications of working in BSL3 BSL4 laboratories

Deficiency of host defenses asplenia, complement defects, antibody defects, T-cell defects, PMN defects chronic dermatitis, eczema, psoriasis immunosuppressive treatment, corticosteroid

Pregnancy Deep wound Recent surgery Underlying diseases :

cancer, diabetes mellitus, hemochromatosis, alccolism allergy

Viral disease, influenza Psychiatric disorders : depression, schizophrenia… For space suit : claustrophobia, obesity.

Medical consultation after recovery before returning at work


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Medical surveillance of lab-workers after an incident or accident

Technical incident : material failure, centrifuge, broken tube, air ventilation system failure… Medical examination Biological or medical surveillance Post exposure prophylaxis or treatment ? Declaration Investigation occupational physician

Accident : needlestick injury, spills or splash of biologic fluids, animal bite Immediate decontamination/disinfection, antiseptics, undressing, shower Medical examination , medical support, by referent infectious disease specialist Biological or medical surveillance Post exposure prophylaxis or treatment ? Declaration Investigation


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Security surveillance of BSL3-BSL4 lab-workers : to be considered

New approaches Always working in pairs (two-person rule) Video-monitoring in BSL3 and BSL4 laboratories Inspections and controls :

strain collection stock and movements Compliance inspections

Security investigation and risk assessment (SRA) For biodefense laboratories working with Biological Select Agents & Toxins

(BSAT) and MOT (micro-organisms & toxins) Defense secret habilitation or Security clearance

at employment at 5-years frequency

Reliability of workers Personal Reliability Program : in discussion Judiciary history Psychiatric disorders, mentally impaired Personal conflicts (woks colleagues, institution, wife/husband) Behaviorial surveillance Credit difficulties Drug use

Biosafety committees Project evaluation (new virus construct, synthetic biology…) Dual-use publications (unexpected or controversial results)


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Conclusion : laboratory accidents and lab worker surveillance to avoid of outbreaks

Laboratory acquired infections represent an occupational hazard unique to laboratory workers

With transmissible agents it represents also the possibility of outbreak among population with public health consequences

Moreover exists the risk of misuse, illegal activities, non compliance to regulations or intentional malevolence

Medical surveillance is essential As is aptitude selection and security investigation before and along the

professional carrier of workers


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A thirty years experience in BSL3 laboratory

A technician suffering obesity willing enter space suite A labworker suffering claustrophobia A technician suffering deep depression who attempted to kill herself with

toxic substances Laboratory Liquid splashes to the eye of a technician, the filtered liquid

supposed to be sterile was not and contained Burkholderia pseudomallei A scientist who inadvertently inoculated him with vaccinia virus A scientist who dissimulated that he injected him with live spore

suspension when handling mouse and treated himself with antibiotics A electric fire in autoclave with thick smoke and the BSL3 lab to evacuate

Thank you for attention ! ESCMID Online Lecture Library

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