Coronavirus disease (COVID-19) technical guidance: The Unity Studies: Early Investigations Protocols

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The emergence of a new virus means that understanding transmission patterns, severity, clinical features and risk factors for infection will be limited at the start of an outbreak. To address these unknowns, WHO has provided Four Early Investigation Protocols (rebranded the WHO Unity Studies).

These protocols are designed to rapidly and systematically collect and share data in a format that facilitates aggregation, tabulation and analysis across different settings globally. One additional study to evaluate environmental contamination of COVID-19 is also provided.

Data collected using these investigation protocols will be critical to refine recommendations for case definitions and surveillance, characterize key epidemiological features of COVID-19, help understand spread, severity, spectrum of disease, and impact on the community and to inform guidance for application of countermeasures such as case isolation and contact tracing.

The Unity Studies: WHO Early Investigations Protocols

Why Unity Studies?	Study focus	Objectives
The First Few COVID-19 X cases and contacts transmission investigation protocol (FFX)	Cases and close contacts in the general population or can be restricted to close settings (like households, health care settings, schools).	The primary objectives are to provide descriptions or estimates of : clinical presentation of COVID-19 infection and course of associated disease; secondary infection rate (SIR) and secondary clinical attack rate of COVID-19 infection among close contacts (overall, and by key factors such as setting, age and sex, for various end-points); serial interval of COVID-19 infection; symptomatic proportion of COVID-19 cases (through contact tracing and laboratory testing); and identification of possible routes of transmission. The secondary objectives are to support the estimation of: the basic reproduction number (R0) of COVID-19 virus; the incubation period of COVID-19; and the preliminary COVID-19 infection and disease-severity ratios (for example, case‑hospitalization ratio [CHR] and case-fatality ratio [CFR]).
Household transmission of COVID-19 investigation protocol (HH)	Cases and close contacts in household setting	Primary objectives To better understand the extent of transmission within a household by estimating the secondary infection rate for household contacts at an individual level, and factors associated with any variation in the secondary infection risk. To characterize secondary cases including the range of clinical presentation, risk factors for infection, and the extent and fraction of asymptomatic infections To characterize serologic response following confirmed COVID-19 infection
Assessment of COVID-19 risk factors among Health workers (HW) protocol (prospective study of a cohort of health workers)	Health workers in a health care setting in which patient(s) with a laboratory-confirmed COVID-19 infection are receiving care	Primary objectives To better understand the extent of human-to-human transmission among health workers by estimating the secondary infection rate[1] for health worker contacts at the individual level. To characterize the range of clinical presentations of infection and the risk factors for infection among health workers. To evaluate the effectiveness of infection prevention and control measures among health workers. To evaluate the effectiveness of infection prevention and control programmes at health facility and national level. Secondary objectives such as, but not limited to: To determine the serological response of health workers with symptomatic and possibly asymptomatic COVID-19 infection; To characterize the duration and severity of COVID-19-associated disease among health workers.
Assessment of risk factors for COVID-19 in health workers: protocol for a case-control study	Health workers at occupational risk for COVID-19	Nested case-control study of health workers exposed to confirmed COVID-19 patients. Similar objectives to the cohort study but case-control studies may be cheaper and provide more robust evidence to characterize and assess the risk factors for SARS-CoV-2 infection in health workers exposed to COVID-19 patients. Health workers with confirmed COVID-19 will be recruited as cases and other health workers in the same health care setting without infection will be recruited as controls (incidence density sampling). Secondary objectives are similar to the cohort study. WHO is coordinating an international multi-centre study that will undoubtedly lead to a more robust analysis of potential factors affecting the secondary infection risk, and to a more detailed characterization of serological responses following infection. A Go.Data data collection template is available upon request.
Population-based age-stratified seroepidemiological investigation protocol for COVID-19 infection	Virus infection in the general population	Primary objectives: To measure the seroprevalence of antibodies to COVID-19 in the general population by sex and age group, in order to ascertain the cumulative population immunity; and To estimate the fraction of asymptomatic, pre-symptomatic or subclinical infections in the population and by sex and age group. Secondary objectives, such as, but not limited to: To determine risk factors for infection by comparing the exposures of infected and non-infected individuals; To contribute to determine the case fatality ratio; and To contribute to an improved understanding of antibody kinetics following COVID-19 infection.
Surface sampling of COVID-19 virus: A practical “how to” protocol for health care and public health professionals	For environmental surfaces	Primary objectives: To assess the extent and persistence of surface contamination of COVID-19; and To identify environmental surfaces and fomites that may play a role in onward transmission of COVID-19. Secondary objectives such as, but not limited to: To characterize of the sequence diversity of COVID-19 in environmental samples, as capacity and resources permit.

For more information, please contact: EarlyInvestigations-2019-nCoV@who.int

A one-pager summarizing on all early investigations is available in several languages

- Access the one-pager summary

More details and web links to the five early investigations protocols and forms are given below:

1 - The First Few X (FFX) Cases and contact investigation protocol for COVID-19 infection

- Access the investigation protocol (08 May 2020)

The following protocol has been designed to investigate the First Few X number of cases and their close contacts (FFX). It is envisioned that the FFX -COVID-19 investigation will be conducted across several countries or sites with geographical and demographical diversity. Using a standardized protocol such as the protocol provided here, epidemiological exposure data and biological samples can be systematically collected and shared rapidly in a format that can be easily aggregated, tabulated and analyzed across many different settings globally for timely estimates of COVID-19 infection . FFX is the primary investigation protocol to be initiated upon identification of the initial laboratory-confirmed cases of COVID-19 in a country.

For a more targeted approach on specific groups and more precise estimation of epidemiological parameters, two other investigation protocols are available:

2 - Household transmission investigation protocol for COVID-19 infection

- Access the investigation protocol (09 May 2020)

The household transmission investigation is a case-ascertained prospective study of all identified household contacts of a laboratory confirmed COVID-19 infection. It is intended to provide rapid and early information on the clinical, epidemiological and virological characteristics of COVID-19.

3 - Assessment of risk factors for COVID-19 in health workers: protocol for a prospective study of a cohort of Health workers

- Access the assessment protocol (17 March 2020)

The extent of -COVID-19 infection in health care settings is not clear, nor whether there are certain risk factors associated with infection in health care workers. The following protocol has been designed to investigate the extent of infection and risk factors for infection among health care workers. Follow-up and testing of respiratory specimens and serum of health care workers within a facility in which a confirmed case of COVID-19 infection is receiving care can provide useful information on transmissibility and routes of transmission and are important for limiting amplification events in health care facilities.

For more information, please contact: EarlyInvestigations-2019-nCoV@who.int.

4 - Assessment of risk factors for COVID-19 in health workers: protocol for a case-control study

- Access the assessment protocol

Aiming at assessing risk factors for COVID-19 in health workers, the current protocol consists of a nested case-control study of health workers involved in the care of any confirmed COVID-19 cases. The study is based upon the use of incidence density sampling. The study is to be initiated as soon as a case of SARS-CoV-2 infection is confirmed among health workers in a health care setting. Health workers with confirmed COVID-19 will be recruited as cases. Health workers exposed to COVID-19 patients in the same setting but without infection will be recruited as controls with a target of at least 2–4 controls for every case.

For countries or health care facilities willing and able to participate, WHO is proposing to conduct an international multi-centre case-control study. For more information, please contact: EarlyInvestigations-2019-nCoV@who.int. Upon request, WHO will provide a Go.Data template for data collection to local investigators.

5 - Population-based age-stratified seroepidemiological investigation protocol for COVID-19 virus infection

- Access the protocol (18 February 2020)

This protocol is a population-based, age-stratified prospective study for assessing COVID-19 virus infection. It is intended to provide key epidemiological and serologic characteristics of COVID-19 virus in the general population. This includes the extent of infection in the general population and age-specific infection cumulative incidence, as determined by seropositivity, and the fraction of asymptomatic or subclinical infection

For more information, please contact: EarlyInvestigations-2019-nCoV@who.int

6 - Surface sampling of coronavirus disease COVID-19 virus: A practical “how to” protocol for health care and public health professionals

- Access the protocol

The role of environmental contamination in transmission of COVID-19 virus is currently not clear. This protocol has been designed to determine (viable) virus presence and persistence on fomites in various locations where a patient infected with COVID-19 is currently receiving care or being isolated, and to understand how this may relate to COVID-19 transmission events in these settings. It is therefore important that it is done as part of a comprehensive outbreak investigation and that information obtained by environmental studies is combined with the results of epidemiological, laboratory and sequence data from COVID-19 patient investigations.