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Assessment of potential risk factors of infection of Middle East respiratory syndrome coronavirus (MERS-CoV) among health care personnel in a health care setting, Version 1 (WHO, edited)

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  • Assessment of potential risk factors of infection of Middle East respiratory syndrome coronavirus (MERS-CoV) among health care personnel in a health care setting, Version 1 (WHO, edited)

    [Source: World Health Organization, full PDF document: (LINK). Edited.]


    Assessment of potential risk factors of infection of Middle East respiratory syndrome coronavirus (MERS-CoV) among health care personnel in a health care setting, Version 1

    Date: Version 1 / 27 January 2014 / Contact: mountsa@who.int


    Acknowledgement

    This document was adapted from a protocol developed by the Consortium for the Standardization for Influenza Seroepidemiology (CONSISE), a global partnership aiming to develop influenza investigation protocols and standardize seroepidemiology to inform public health policy for pandemic, zoonotic and seasonal influenza. This international partnership was created out of a need, identified during the 2009 H1N1 pandemic, for standardized seroepidemiological data to estimate infection attack rates and severity of the pandemic virus and to inform policy decisions. More information on the CONSISE network can be found on their website: www.CONSISE.tghn.org.

    See acknowledgements at the end for individual reviewers.


    PROTOCOL SUMMARY

    Comprehensive investigations of health care personnel (HCP) who may have been exposed to patients infected with Middle East respiratory syndrome coronavirus (MERS-CoV), diagnosed either prospectively or retrospectively, are essential to understand the risk factors of infection within health care facilities. The risk factors identified from such investigations may provide insights into the potential modes of transmission to inform guidance and policy in infection control in health care facilities, and in directing national and international public health response.

    The epidemiological methods to guide data collection for the comprehensive assessment of the HCP are set out in this document. This protocol outlines methods of an analytical epidemiological, virological and serological study involving staff working at the health care facility(ies) where an index patient infected with MERS-CoV virus is being or had been treated.

    Comments for the user?s consideration are provided in purple text throughout the document as the user may need to modify methods slightly because of the local context in which this study will be carried out.


    1.0 SCIENTIFIC BACKGROUND & RATIONALE FOR STUDY

    The Middle East respiratory syndrome coronavirus (MERS-CoV) was first detected in a patient living in Saudi Arabia in September of 2012 [1]. The virus is thought to be zoonotic in origin although the reservoir(s) and route of transmission to humans remains unclear. Sporadic cases and clusters in health care facilities have been reported in several countries [2-5]. Indeed, the largest proportion of secondary transmission currently appears to have occurred in a health care facility. Identification of the factors that facilitate transmission in health care settings will inform measures to interrupt transmission. Experience with Severe Acute Respiratory Syndrome (SARS) demonstrated that studies of transmission in health care settings were critical to the development of control measures [6].

    This investigation, as outlined in this document, will provide data to evaluate risk factors and prevention methods for MERS-CoV infection by comparing exposures of infected (as provided by virologic or serologic confirmation) with HCP not infected (sero-negative study subjects).

    Current information on the MERS-CoV and interim guidance on infection prevention and control can be found on the WHO website: http://www.who.int/csr/disease/coronavirus_infections/en/index.html.


    1.1 OBJECTIVES

    The data collected from this study will be used to characterize the key epidemiological transmission features of MERS-CoV virus and inform strategies for control of transmission, particularly in health care settings.


    PRIMARY OBJECTIVES

    The primary objectives of this study are to:
    • Determine the risk factors for MERS CoV transmission and infection in health care settings
    • Assess the extent of MERS-CoV secondary transmission to HCP caring for probable and confirmed patients


    SECONDARY OBJECTIVES

    Seroepidemiologic investigations, such as the one described below, can provide rich data to assess secondary objectives, including, but not limited to:
    • Description of the spectrum of illness and clinical course of disease with MERS-CoV infection
    • Quantification of the proportion of asymptomatic to sub-clinical MERS-CoV infections
    • Quantification of the proportion of individuals who seroconvert
    • Assessment of the effectiveness of infection control measures


    2.0 STUDY PROCEDURES

    This study uses epidemiological, virological and serological methods applied to HCP exposed to a patient infected with MERS-CoV virus to assess the risk factors for human-to-human transmission of MERS-CoV.

    In this study, the exposures of laboratory-confirmed (by RT-PCR) or serologically confirmed health care workers will be compared with those of laboratory- and serologically negative HCP to determine risk factors associated with infection.

    It is recommended to start the study with a general interview of HCP, including supervisors and colleagues, to have a better understanding of the potential exposures and existing infection control practices (their proxies, such as direct supervisors/colleagues in the same team, may respond if the affected HCP is unable to participate as a result of critical illness or death), and a visit to the medical facilities to learn more about the management, infrastructure and policies of infection control to develop more concrete hypotheses about the possible exposures HCP may have had to the MERS-CoV (Appendix A). The interview should be used in conjunction with a data collection form to identify all potential study subjects (Appendix B).

    A full questionnaire can then be developed. A sample questionnaire has been provided in Appendix C as a starting point.


    COMMENT:

    The timing of this study is critical. Ideally, this study should be conducted as soon a patient with MERS-CoV (the index case) is identified. The current protocol is based on the assumption that the patient with MERS-CoV infection was identified while still in the hospital.



    2.1 ETHICAL CONSIDERATIONS

    Ethical approval must be sought in accordance with local, regional and national authorities.


    COMMENT:

    It is strongly recommended that ethical approval is obtained in advance from relevant ethical or institutional review boards (e.g. national Ministries of Health, Agriculture, etc.) using a generic protocol such as this one before an outbreak occurs. Once an outbreak occurs, the study design, questionnaires, sampling and consent forms can be modified rapidly to the actual situation. This may still have to be resubmitted for ethical approval, but as the generic protocol including this final step has already been approved, this could be a very rapid process, without substantial delay in the investigations.



    2.2 STUDY SUBJECT IDENTIFICATION AND SELECTION

    2.2.1 SELECTION OF HEALTH CARE PERSONNEL

    Every effort will be made to include all HCP who may have come in contact with the MERS-CoV confirmed patients (e.g. by means of going through the duty roster, contact tracing, interviews) from the time of first contact with the patient (or patient materials) to 14 days after the last contact.


    COMMENT:

    For the purposes of this protocol specifically designed for MERS-CoV, we recommend that the definition of a contact not be too restrictive so that a large number of potentially exposed HCP are included in the study. Contacts should include, for example, cleaners, clerks, and others who may not have provided care to the patient but who would have been in the general environment.


    COMMENT:

    If the patient was transferred from another health care facility, then the HCP from that facility would need to be recruited for this study.

    Health care personnel with potential exposure to the patient should be identified initially by hospital infection control staff. These will include all staff involved in provision of care for an infected patient, including those who may have been present in the same area as the infected patient for other purposes and those who may have had contact with patient body fluids, potentially contaminated items or environmental surfaces. For practical reasons, the study population may comprise all staff working in all hospital facilities involved in provision of care to the infected patient during all or part of the time of potential exposure, including reception area/admission facilities, specialized and supporting services. All categories of potentially exposed staff should be selected, including health care workers, allied health professionals, auxiliary health workers (e.g. cleaning and laundry personnel, x-ray physicians and technicians, clerks, phlebotomists, respiratory therapists, nutritionists, social workers, physical therapists, lab personnel, cleaners, clerks, patient transporters, catering staff, etc.).


    COMMENT:

    The concept of ?protected exposure? should be avoided when selecting the study subjects. In particular, wearing personal protective equipment (PPE) should not be considered an exclusion criterion as one of the risk factors to be studied by this protocol is the effectiveness of PPE.


    COMMENT:

    Recommendations are provided for the definition of a HCP contact in terms of space and duration; however, the specific definition of a contact in terms of duration and distance may vary depending on the characteristics of the novel virus, if the protocol is used for viruses other than MERS-CoV. Any variation in the definition of HCP contacts between studies will result in reduced comparability. Definition of a contact in terms of space and time in reporting of the results of this study will aid in comparability between studies.


    COMMENT:

    Background information about the health care setting and those potentially exposed to the patient will be required to be collected before sampling to understand the likely contacts of the MERS-CoV patients. A data collection tool to help in formulating hypotheses about the exposure and to identify potential subjects for this study is provided in Appendix A.



    2.2.2 RECRUITMENT AND FOLLOW UP

    After identification of potential participants, informed consent from subjects will be obtained (see 2.2.4 below). At the time of recruitment, combined nasopharyngeal and throat swabs, and, ideally, specimens from the lower respiratory tract (highly recommended, if possible) will be collected for virological confirmation, blood for serological confirmation and a questionnaire will be administered (Appendix C). The recommended clinical specimens may change in the future as more information is learned about the optimal specimens and appropriate timing after exposure to detect MERS-CoV infection.

    Subjects will be monitored for symptoms for 14 days after last contact with MERS-CoV patient or patient materials. If symptoms occur, virological testing will be carried out at that time. Specimens to be collected for virological testing include combined nasopharyngeal and throat swabs, and, ideally, specimens from the lower respiratory tract, if possible. Repeat blood collection will be carried out at least 14 days after the last contact with the MERS-CoV patient or patient materials.


    2.2.3 INFORMED CONSENT

    All potentially exposed HCP will be asked to provide consent by a trained member of the investigation team.


    2.2.4 DATA COLLECTION

    After enrolment, a brief questionnaire will be administered to those consenting, which will be piloted in advance (Appendix C). Information will be collected on demographics, job duties, symptoms of respiratory disease, use of PPE, and specific exposures to the MERS-CoV confirmed patient.

    Additional exposure (including exposures to confirmed or suspected human cases in the community and to other potential sources such as animals) questions will be included for all study subjects in the questionnaire.

    A template of the study questionnaire for the use of all cases and contacts is provided in Appendix C.


    2.2.5 RISKS AND BENEFITS FOR SUBJECTS

    This investigation poses minimal risk to participants, involving collection of a small amount of blood and upper (and lower) respiratory tract specimens. The direct benefit to the participant is the early detection of infection to allow appropriate monitoring and early treatment. The primary benefit of the study is indirect in that data collected will help improve and guide efforts to prevent further spread of MERS-CoV to HCP.


    2.2.6 CONFIDENTIALITY

    HCP and controls will be assigned a study identification number by hospital staff for labelling of study questionnaires and clinical specimens. The link to specific individuals will be maintained by the hospital and the Ministry of Health (or equivalent) and will not be disclosed to any other research personnel.


    COMMENT:

    If shared by the implementing organization, data provided to WHO or any agency supporting data analysis will include only the study identification number.


    2.2.7 PREVENTION OF MERS-COV TRANSMISSION IN FRONT-LINE STAFF

    Before study implementation, front-line staff, including all study personnel, will be trained in infection control procedures (standard, contact, droplet or airborne precautions). These procedures include proper hand hygiene and the correct use of surgical or respiratory face masks, if necessary, not only to minimize their own risk of infection when in close contact with patients in a health care setting, during home visits and elsewhere, but also to minimize the risk of spread among other HCP and their household members.


    2.3 SAMPLE SIZE CONSIDERATIONS

    For this study, the overall sample size will be determined by the number of HCP in contact with the confirmed MERS-CoV patient(s). Every effort will be made to include all HCP who have been and are in contact with confirmed MERS-CoV patients.


    2.4 SPECIMEN COLLECTION AND LABORATORY EVALUATIONS

    2.4.1 SPECIMEN COLLECTION, TRANSPORTATION

    WHO lab guidance on specimen collection and transportation can be found at: http://www.who.int/csr/disease/coronavirus_infections/LaboratoryTestingNovelCoronavirus_21Dec12.pdf

    Additional records will be kept for each biological sample, including the time of collection, the conditions for transportation and the time of arrival at the study laboratory.


    2.4.2 LABORATORY PROCEDURES

    VIROLOGIC TESTING

    MERS-CoV case definitions can be found at: http://www.who.int/csr/disease/coronavirus_infections/case_definition/en/MERS-CoVconfirmed.html.

    As of 3 July 2013, one of the following conditions must be met to consider a case as laboratory-confirmed:
    • positive RT-PCR or other validated molecular assays for at least two different specific targets on the MERS-CoV genome
      • OR

    • one positive RT-PCR assay for a specific target on the MERS-CoV genome and an additional different PCR product sequenced, confirming identity to known sequences of the new virus.

    A positive PCR assay for a single specific target without further testing is considered presumptive evidence of MERS-CoV infection. Final classification of cases will depend on clinical and epidemiological information combined with laboratory data. Member States are requested to immediately notify WHO.

    See full details for virologic laboratory testing of MERS-CoV can be found here: http://www.who.int/csr/disease/coronavirus_infections/LaboratoryTestingNovelCoronavirus_21Dec12.pdf.


    SEROLOGIC TESTING

    COMMENT:

    Serologic assays for MERS-CoV are currently in development by a small number of laboratories around the world. Here we provide details of the only published serologic testing available for MERS-CoV [7,8]. Investigators are encouraged to check current scientific literature for newer information on serological testing.


    COMMENT:

    Only a limited number of laboratories have the facilities for MERS-CoV serologic testing and therefore collaboration between countries without current capacity and designated reference laboratories is possible.

    Collaboration is up to the discretion of Member States carrying out the research, but WHO strongly supports such collaborations and will facilitate this collaboration and possible shipment for testing, if required.

    The following laboratory assay results are currently available for defining a case as MERS-CoV antibody positive (full details can be found in [7,8]).

    However, as more research findings on the improvement of serological assay become available, guidance will be updated accordingly.
    • Screening for antibodies reactive to MERS-CoV by indirect immunofluorescence assay (IFA) described in [7,8]
    • More specific secondary serologic testing should be done using microneutralization or ELISA-based assays using appropriately timed sera (ideally, paired acute and convalescent sera)[7,8]

    COMMENT:

    Although a four-fold rise in titre is generally thought to be indicative of seroconversion for most standardized serological assays for other pathogens, MERS-CoV assays have not yet been standardized. However, the analysis of data from this study will compare rates of seropositivity or presumptive seroconversion to those without. The relationship will depend on a statistical association to determine potential risk factors rather than the absolute value of an individual test. Therefore, for the purposes of this study, a positive test will be determined by the specific laboratory doing the assay. It will likely depend on a combination of results from multiple tests and cut-off values designating a ?positive? result set by the laboratory based on the results of experience with the particular assay.


    3.0 STUDY ENDPOINTS & STATISTICAL ANALYSES

    The following section discusses the endpoints ? that is, what can be measured and calculated using the data collected in this study ? for the primary objectives, including statistical advice.


    3.1 STUDY OUTCOME MEASURES

    3.1.1 PRIMARY ENDPOINTS

    The following will be assessed as study endpoints corresponding to the study?s primary objectives as outlined above.


    3.2 STATISTICAL ANALYSES

    3.2.1 FOR PRIMARY OBJECTIVES

    The primary objective of this study is to assess the frequency of infection (virological and serological) among exposed HCP
    • Virologic infection = % of total subjects included in study who are RT-PCR positive
    • Immunologic infection = % of total subjects included in study who are seropositive (see section 2.4.2 for definition of seropositivity)

    COMMENT:

    Depending on your study sample size, reporting of these rates may be done by reporting overall infection rates or by subtype (e.g. by occupational group or job duty, by age, gender, etc.).


    RISK FACTORS FOR INFECTION

    One way to measure risk factors for infection is to compare the exposures (e.g. characteristics, behaviours, practices) of subjects who are seropositive or virologically positive (combining the two into a ?infected? group) versus study subjects who are negative serologically and virologically.

    The reported practices among seropositive and seronegative subjects will be compared using appropriate statistical tests, e.g. bivariate associations between risk factors being infected will be determined by chi-square statistics or 2-sided Fisher?s exact test and expressed as odds ratios with 95% confidence intervals. Multivariate logistic regression will be used to further analyse the associations.


    COMMENT:

    Univariate statistical analysis by logistic regression could be used to test the significance of each predictor on the outcome of infection. Multivariate logistic regression can be used to identify independent risk factors (after adjusting for known or potential confounders) or a combination of risk factors associated with the odds of infection.


    COMMENT:

    Alternatively, Mantel-Haenszel matched-pair analysis (McNemar test) can be used to estimate the strength and statistical significance of associations between exposures and infection.


    4.0 REPORTING OF FINDINGS

    COMMENT:

    Any deviation from the study methodology should be reported to aid in the interpretation of findings. The timely dissemination of results of this study are critical in understanding transmission of the MERS-CoV virus to inform guidance for policy to direct national and international public health response.


    REFERENCES
    1. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA (2012) Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367: 1814-1820.
    2. Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, et al. (2013) Hospital Outbreak of Middle East Respiratory Syndrome Coronavirus. New England Journal of Medicine 2013 Jun 19. [Epub ahead of print].
    3. Guery B, Poissy J, el Mansouf L, S?journ? C, Ettahar N, et al. (2013) Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. The Lancet 381: 2265-2272. doi: 2210.1016/S0140-6736(2213)60982-60984. Epub 62013 May 60930.
    4. Hijawi B, Abdallat M, Sayaydeh A, Alqasrawi S, Haddadin A, et al. (2013) Novel coronavirus infections in Jordan, April 2012: epidemiological findings from a retrospective investigation. Eastern Mediterranean Health Journal 19: S12-S18.
    5. The WHO MERS-CoV Research Group. State of Knowledge and Data Gaps of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Humans. PLOS Currents Outbreaks. 2013 Nov 12. Edition 1. doi: 10.1371/currents.outbreaks.0bf719e352e7478f8ad85fa30127ddb 8
    6. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J (2012) Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One 7: e35797. doi: 35710.31371/journal.pone.0035797. Epub 0032012 Apr 0035726.
    7. Buchholz U, M?ller MA, Nitsche A, Sanewski A, Wevering N, et al. (2013) Contact investigation of a case of human novel coronavirus infection treated in a German hospital, October-November 2012. Euro Surveill 2013;18(8):pii=20406 Available online: http://wwweurosurveillanceorg/ViewArticleaspx?ArticleId=20406
    8. Corman VM, M?ller MA, Costabel U, Timm J, Binger T, et al. (2012) Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections. Euro Surveill 2012;17(49):pii=20334 Available from: <http://wwweurosurveillanceorg/ViewArticleaspx?ArticleId=20334>.


    ACKNOWLEDGEMENTS

    Many people were involved in the creation and revision of this protocol. These include: Maria D Van Kerkhove, Anthony W Mounts, Sergey Eremin, Cota Vallenas, Julia Fitzner, Tim Uyeki, John Wood, Othmar Engelhardt, Jeffery Cutter, Salah Al Awaidi, Susan I Gerber, Pasi Penttinen, Julien Baute and Elizabeth Bancroft.

    (...)


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