Since the world came to a near economic and social standstill at the beginning of 2020 due to COVID-19, scientists, researchers, epidemiologists and microbiologists turned to wastewater for answers. Scientific reports indicated that the concentration of SARS-CoV-2 in wastewater was proportional to the number of COVID-19 patients in a sewerhed and thus, numerous cities, regions and countries turned to wastewater-based epidemiology (WBE). Nearly a year later, we had the chance to speak with Dr Christian Daughton, formerly with the US EPA National Exposure Research Laboratory, on the progress of this type of testing.
Before diving into answering our questions, Daughton pointed out: “Given the sheer magnitude of this pandemic - and the certainty of more in the future - the failure to make WBE a central and integral tool in what promises to be a long (perhaps perpetual) challenge will only diminish progress in fighting COVID-19. Ignoring WBE as an important tool in the armamentarium of epidemiology would greatly hamper the fight. For all the scientists and engineers who've advanced the capabilities of WBE over the last 2 decades (primarily focusing on the many steps involved with the analytical methodology, including sampling), those who pivoted their WBE expertise to COVID-19 a year ago, and those planning to join this broad international effort, their contributions could prove critical to controlling this pandemic.”
Ignoring WBE as an important tool in the armamentarium of epidemiology would greatly hamper the fight
Question: What is the current status of environmental surveillance for SARS-CoV-2?
Answer: The utility of WBE for monitoring the incidence and spread of community-wide infectious disease (such as Covid-19) is currently much more limited that the application of WBE for determining community-wide usage of anthropogenic chemicals (such as drugs) or exposure to naturally occurring xenobiotics.
Currently, WBE for monitoring community-wide COVID-19 (via markers for SARS-CoV-2) is usually implemented in a "binary" mode - detecting whether infections are present or not within a sewershed. Determining the absolute numbers of infections is far more challenging. As such, WBE has been most commonly deployed for monitoring the emergence or presence of COVID-19 in well-defined populations that share a working or living space over a period of time, thereby facilitating contact tracing. One notable example is college dormitories but others including long-term care facilities, prisons, manufacturing and warehouse facilities, meat processors, maritime ships, and naval vessels (critical for maintaining national security and military personnel readiness).
WBE for surveilling a pandemic would be most useful to identify communities where infections are just emerging or to get an early warning
Beyond its binary mode, WBE can currently be used for estimating the relative change in the numbers of infections - for example, whether infection trends are rapidly increasing or decreasing for a particular community; but significantly, relative comparisons among different communities cannot currently be easily done. To spot trends, sewage samples need to be analyzed over a period of time sufficient to establish the background variability and signal noise. For this reason, WBE for surveilling a pandemic would be most useful to identify communities where infections are just emerging or to get an early warning (or verify) that community spread is dramatically increasing or declining. WBE essentially could serve as a fast way in which to perform, en masse, population-wide random diagnostic testing at much lower cost. The overall objective is to guide (and conserve) the use of more expensive clinical diagnostic testing of individuals and to provide early warning to healthcare providers and public health officials.
Q: Could you explain what are the difficulties involved?
A: The current use of WBE is its most rudimentary - as a tool that gives a binary answer, determining whether COVID-19 is present or absent in a sewershed community. With this simple capability, WBE is most useful before disease has widely spread or is newly spreading. But to reach its full capability for tracking the incidence of infectious diseases, WBE will need to be able to estimate the actual number of infected cases in the sewershed. This is currently not possible. Infected cases cannot be inferred with measures of virus excreted because of very large inter- and intra-individual variability in virus shedding via stool (and to a lesser extent urine). WBE cannot reach its full potential until an approach is developed to properly "calibrate" WBE. Other measures will be required to benchmark WBE data to the actual number of COVID-19 cases. Furthermore, the lower-limit of detection of infected-case numbers via PCR is currently difficult to determine, especially because of the variable half-lives of targeted fragments of virus RNA in sewage. The biggest impediment to expanding the development of useful applications for WBE is the lack of government involvement. Federal (and state) support and leadership is essential for making WBE a widespread, widely accepted tool in fighting pandemics. The federal government needs to embrace WBE and take the lead in shepherding and funding its further development, refinement, standardization, and nationwide implementation. WBE should become part of the White House 2021 "National Strategy for the Covid-19 Response and Pandemic Preparedness" and perhaps be overseen by the COVID-19 Pandemic Testing Board or the NSC Directorate on Global Health Security and Biodefense; the WHO also needs to get more involved with WBE. This would ensure that WBE becomes an integral part of an overall approach to testing and surveillance; the U.S. CDC and EPA would be logical federal agencies to lead and coordinate a national WBE research effort.
The biggest impediment to expanding the development of useful applications for WBE is the lack of government involvement
Ultimately needed will be a continual effort to harmonize disparate methods and to create internationally standardized methodology. This is essential for assuring the inter-comparability of data. WBE also needs to be extremely cost-effective and easily implemented with little operator training required. The method should have options for the use of inexpensive detection methods (in addition to PCR). This will be especially important in poorer areas and developing countries.
Federal and state governments will be essential to gaining universal acceptance of WBE at local levels and embraced by the public as a cost-effective, non-intrusive way to help control virus spread. Historically, local city officials have sometimes felt that WBE data could tarnish or stain their cities' reputations (causing a loss of tourists and visitors, and harming property values), thereby alarming some residents. This is often because of misunderstandings of how WBE works, what it can do (and can't do), and what the data actually mean. Another frequently cited concern is the violation of citizens' privacy (a frequently discussed problem when WBE is used for illicit drug monitoring). And specifically, with respect to WBE used for Covid-19 monitoring, some of the public errantly think this means that infectious SARS-CoV-2 is rampant in sewage and therefore poses an imminent threat to public health. All of these misperceptions and problems need to be addressed with greatly improved explanations of how WBE works and with improved risk communication.
WBE also needs to be extremely cost-effective and easily implemented with little operator training required
Q: What do you see as future research directions in this area?
A: It will be a daunting task to achieve the full potential of WBE for measuring the incidence of infections in a community because of the very high inter- and intra-individual variability in shedding of virion, virus particles (and antigens), or RNA. Virus-based detection methods also cannot discern whether the virus originates from asymptomatic infected cases or from moderate or severe cases. Moreover, the incidence of post-Covid sequelae (e.g., long covid; long-haulers) would be completely missed. Long COVID appears to be developing into a major long-term public health problem, especially for those lacking access to affordable health care. The spread, geographic incidence, and severity of long COVID will be important to track.
The future of WBE for infectious disease monitoring, therefore, needs to also focus on measures of the disease that target biomarkers produced by infected individuals as a result of the multifaceted disease itself (including long-term, persistent sequelae). Many advantages could derive from targeting endogenous biomarkers of disease. One major advantage of endogenous biomarkers is that they would also probably be excreted during infection by any virus escape variants, so the need to wait for genomic sequence tracking in order to update PCR primers for use in WBE could be avoided. Importantly, endogenous biomarkers might have more predictive ability of the absolute numbers of infected cases and serve as more faithful measures of disease severity than direct measures of virus loads in sewage. This is because real-world reference ranges could be tighter for biomarker excretion from individuals than they would be for detection of virus shedding. WBE could, therefore, be more accurately calibrated against infected cases by using biomarkers than with viral load.
Comparatively very little R&D has been done to reveal potential endogenous biomarkers that would be useful to target with WBE.
With this said, comparatively very little R&D has been done to reveal potential endogenous biomarkers that would be useful to target with WBE. This research field needs more engagement by researchers versed in uncovering biomarkers of disease that meet the criteria for use with WBE - in contrast to clinical needs; in particular, suitable biomarkers must be highly excreted (preferably in urine) and also have sufficiently long half-lives in sewage. Suitable examples could include markers of specific disease states on one extreme, and on the other extreme those markers that serve to integrate many conditions resulting from multi-organ stress. Some examples of biomarkers that could be elevated during (and after) SARS-CoV-2 infection and perhaps worthy of examination include: markers of systemic inflammation (e.g., isoprostanes, neopterin, and proteins associated with the kinin system), markers of gut inflammation (e.g., calprotectin), and markers of gut dysfunction due to excessive paracellular permeability (e.g., zonulin). Biomarkers excreted from the critical Integrated Stress Response (ISR) could be particularly useful.
With selection of an optimal suite of endogenous biomarkers, in concert with PCR, WBE's capabilities could be greatly expanded. Not only could the incidence of infection cases be more far more accurately estimated, but other parameters or conditions could be revealed. Possible scenarios include: (i) When the incidence of COVID-19 is reduced to low levels in particular populations, the monitoring of certain biomarkers could serve to identify populations with high incidence of long-haulers who may be relegated to home-care and can't afford health care. (ii) Likewise, identifying communities suffering from health disparities and income inequities could be identified. An example would be communities where hospitalization rates (as well as outpatient treatment rates) are low but increasing numbers of recovering cases become longhaulers and suffer through their disabilities at home. And (iii) possibly detecting the rapid emergence of new escape variants if disease biomarkers increase but PCR testing does not indicate rising levels. WBE based on non-virus biomarkers could reveal where genomic sequencing efforts should be targeted to promote earlier discovery of emergence of escape variants having more transmissibility or virulence, resulting in increased morbidity and mortality or perhaps reducing the effectiveness of therapeutics or vaccines. Many other aspects of WBE will require advancements, one being the need for real-time remote sensors capable of operating in sewage.
Q: Can you comment on the success of efforts to implement SARS-CoV-2 monitoring in wastewater in support of public health responses? To what extent do you think wastewater surveillance can contribute to disease prevention and control during the remainder of this pandemic and any future ones?
A: With the exception of mass vaccination, the development of truly effective therapeutics (or drug repurposing), improved medical protocols, and society-wide acceptance of personal control measures (with improved PPE), WBE stands out as the single most important missing tool in the armamentarium to control COVID-19, escape variants (preventing the development of herd immunity via vaccination), and future pandemics. Its value becomes even greater should the development or modification of vaccines for future novel viruses or escape variants become problematic.
The utility of WBE in disease prevention, mitigation, and control is many faceted - and probably still not fully appreciated. WBE has the potential to improve the trajectory of fighting epidemics or pandemics in the following areas (among others):
- Modifying public behavior. Non-compliant public behavior will continue to play a major role in suppressing effective responses to controlling Covid-19. But the ever-growing infodemic is an information crisis fueled by mis/dis-information and leading to widespread public denialism, scepticism, polarization, and politicization. WBE could improve public willingness to comply with control measures simply because it would be overseen and performed at the local level. WBE programs could be a powerful tool because the public tends to be more accepting and trusting of local officials; there's also only one version of WBE data for any sewershed. The public might be more willing to accept data generated, interpreted, and reported by local officials and therefore be more receptive to its authenticity. Local WBE monitoring programs could foster a more cohesive, collective community consciousness and greatly improve the daily awareness of the pandemic at a local level. This could lead to better engagement and willingness to abide by simple control measures. WBE would still be useful for mass surveillance even once a very inexpensive, fast, highly sensitive and specific over-the-counter point-of-use self-test is developed. Even though this would allow anyone to self-test multiple times a day, many people would not see any reason to self-test (even though they might be asymptomatic spreaders), and some would elect to keep their personal results confidential.
- Aiding public health responses. An obvious strength of WBE is that it can quickly identify communities where public health officials need to focus more attention and guide the deployment of contact tracing and individual diagnostic testing. The best-known current example is for monitoring buildings shared by well-defined populations, such as college dormitories. But WBE's use could extend beyond guiding and conserving the use of diagnostic testing. It could also prove useful for identifying populations having difficulty with accessing healthcare (because of racial or economic disparities). WBE could indefinitely continue to be necessary once Covid-19 becomes endemic because of recurrent epidemic cycles and promotion of new variants. Once Covid-19 is well controlled and its incidence enters a long tail of prevalence, it will be critical for identifying outbreaks of clusters as soon as possible.
- Improving the odds of adequate healthcare responses. If WBE can consistently provide several-day early warning of emerging or accelerating spread of Covid-19, healthcare workers can then perform more appropriate preparations for surges, and public health professionals can better target individual diagnostic testing.
- Improving healthcare administration. Early detection can be important by facilitating early therapeutic treatment. And morbidity and mortality can be reduced. For example, in vulnerable populations with risk factors, diagnosing infections as early as possible can be important for the optimal timing of certain therapeutics (e.g., monoclonal antibodies).
- Protecting national security. Early detection of Covid-19 outbreaks on navy vessels and military bases is critical for maintaining military personnel readiness. For example, an onboard WBE program may have greatly lessened the impact of the Covid-19 outbreak that resulted in the incapacitation of the crew of the USS Theodore Roosevelt; and this was followed by outbreaks on dozens of other Naval ships.
- Adopting WBE for international sentinel surveillance for future zoonotic spillover events. Applied to human wastewater, domestic animal waste, and open waters, WBE could play an invaluable role as another tool in the range of approaches still evolving for the early detection of zoonotic spillover events; this could be coordinated under the CDC's One Health Office. Clearly, preventing pandemics is immeasurably more effective than mitigation in terms of economic damage and human suffering.
