key: cord-0759364-vcth2reg
authors: Gwenzi, Willis
title: Leaving no stone unturned in light of the COVID-19 faecal-oral hypothesis? A water, sanitation and hygiene (WASH) perspective targeting low-income countries
date: 2020-08-20
journal: Sci Total Environ
DOI: 10.1016/j.scitotenv.2020.141751
sha: 91050eb84276e0dff0764d25c950f4e4c06bb4e5
doc_id: 759364
cord_uid: vcth2reg

Abstract The human coronavirus disease (COVID-19) is now a global pandemic. Social distancing, hand hygiene and the use of personal protective equipment dominate the current fight against COVID-19. In developing countries, the need for clean water provision, sanitation and hygiene have only received limited attention. The current perspective examines the latest evidence, on the occurrence, persistence and faecal-oral transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent for COVID-19. Evidence shows that SARS-CoV-2 proliferate in the human gastrointestinal system, and is shed via faeces. SARS-CoV-2 can survive and remain viable for up to 6 to 9 days on surfaces. Recent wastewater-based epidemiological studies from several countries also detected SARS-CoV-2 RNA in raw wastewaters. Shell disorder analysis show that SARS-CoV-2 has a rigid outer shell conferring resilience, and a low shell disorder conferring moderate potential for faecal-oral transmission. Taken together, these findings point to potential faecal-oral transmission of SARS-CoV-2, which may partly explain its rapid transmission. Three potential mechanisms may account for SARS-CoV-2 faecal-oral transmission: (1) untreated contaminated drinking water, (2) raw and poorly cooked marine and aquatic foods from contaminated sources, and also raw wastewater-based irrigation (e.g., salads) and aquaculture, and (3) vector-mediated transmission from faecal sources to foods, particularly those from open markets and street vending. SARS-CoV-2 faecal-oral transmission could be particularly high in developing countries due to several risk factors, including; (1) poor drinking water, wastewater and sanitation infrastructure, (2) poor hygiene and food handling practices, (3) unhygienic and rudimentary funeral practices, including home burials close to drinking water sources, and (4) poor social and health care systems with low capacity to cope with disease outbreaks. Hence, clean drinking water provision, proper sanitation, food safety and hygiene could be critical in the current fight against COVID-19. Future research directions on COVID-19 faecal-oral transmission are highlighted.

presents a summary of the focus of the current perspective. First, the various lines of evidence pointing to potential faecal-oral transmission of COVID-19 are presented.

Then, the potential human exposure pathways via the faecal-oral route are discussed. Risk factors and risky practices potentially predisposing human health to COVID-19 via the faecaloral route are then highlighted. The potential critical role of clean water provision, proper sanitation, food safety and hygiene, and solid waste management systems in the fight against COVID-19 and future pandemics is discussed. Finally, key knowledge gaps pertaining to COVID-19 faecal-oral transmission in developing countries are highlighted.

To address the study objectives three sequential steps were followed: (1) searching and retrieval of articles, (2) verification of articles for relevance, and (3) review of articles and synthesis of results. Literature searches and retrieval were conducted using Boolean search techniques, which are regarded as efficient for searching and retrieving literature from a large pool in scholarly scientific databases. A detailed description of the generic search procedures is presented in recent reviews by the current author (Gwenzi, 2020a, b) . Online scholarly databases included in the literature search were: (1) ScienceDirect ® , (2) Clarivate's Web of Science ® , (3)

Researchgate ® , (4) Scopus ® , and (5) Google Scholar ® , among others. The Boolean search techniques were used to search for a combination of keywords/words using, among others;

showed that SARS-CoV-2 infected the rectal, duodenal and gastric epithelial cells, which in turn, release infectious SARS-CoV-2 virions into the human gastrointestinal tract.

A coronavirus virion is a complete virus particles comprising of the following: (1) several structural proteins or glycoproteins, (2) a phospholipid membrane, and (3) a viral RNA (Ashour et al., 2020; Race et al., 2020) . A detailed description of the structure and functions of the various components of SARS-CoV-2 is presented in earlier papers (Ashour et al., 2020; Race et al., 2020) .

Briefly, the structural proteins consists of: (1) the spike (S), (2) membrane (M), and (3) envelope (E), while the nucleocapsid (N) protein occurs inside the virus particle, and interacts with the virus RNA (Race et al., 2020) . The E protein is critical in the virus production or replication. The S glycoprotein is responsible for the formation of the spikes on the surface of viral particle, which mediates viral entry into the host cells (Race et al., 2020) . The binding capacity of the coronavirus S proteins to cellular receptors thought to be promoted by: (1) angiotensinconverting enzyme 2 (ACE2), which facilitate entry into host cell, and (2) serine protease enzymes (e.g., TMPRSS2 and TMPRSS4), responsible for S protein priming (Race et al., 2020; Hoffmann et al., 2020; Zang et al., 2020) . Collectively, the outer structural proteins (shell) confers protein binding specificity or promiscuity, while the RNA confers infectivity or virulence (Goh et al., 2020b) . As discussed later, the structural proteins, also referred to as the shell, also confer environmental stability or resilience (Goh et al., 2020) .

A COVID-19 infected person sheds SARS-CoV-2 RNA for a mean period of approximately 14 to 21 days, and the magnitude of shedding range between 10 2 and 10 8 RNA copies per gram, but these vary among patients (Lescure et al., 2020; Pan et al., 2020; Woelfel et al., 2020) . A high shedding period of 33 days was reported in one patient after respiratory J o u r n a l P r e -p r o o f

Journal Pre-proof samples tested negative, while faecal samples from another patient tested positive for 47 days following the first onset of symptoms (Wu et al., 2020a) . Wu et al. (2020a) also report the longer shedding of SARS-CoV-2 RNA in faecal samples than in respiratory samples. further report that faecal samples in their study tested positive for SARS-CoV-2 RNA for a mean of 11.2 days after respiratory tract samples became negative for SARS-CoV-2 RNA. Two inferences can be made from 's finding: (1) SARS-CoV-2 could have been actively replicating in the patient's gastrointestinal tract, and/or, (2) SARS-CoV-2 persisted for a longer period in the gastrointestinal tract than in the respiratory tract. Faecal shedding of SARS-CoV-2 occur during incubation period before manifestation of symptoms, during illness and after recovery, independent of diarrhoea and intestinal infections (Holshue et al., 2020; Woelfel et al., 2019; Wu et al., 2020a; Xiao et al., 2020; Zhang et al., 2020b) . Therefore, depending on the nature of sanitation, faecal shedding may release SARS-CoV-2 RNA: (1) via open defaecation,

(2) into on-site sanitation systems (i.e., pit latrines, septic tanks), and (3) into municipal wastewater systems.

SARS-COV-2, and other coronaviruses may survive for up to 6 to 9 days on surfaces (van Doremalen et al., 2020; Kampf et al., 2020) . In one study, SARS-CoV-2 was incubated at various temperatures for up to 14 days in a virus transport medium, and then tested for infectivity (Chin et al., 2020) . The results showed that the virus was still infective even on day 14 when incubated at 4oC, but was inactivated in 5 min when incubated at 70 o C. The study also investigated the stability of the virus on various surfaces by dropping the cultured virus onto the surfaces under room temperature of 22 o C and relative humidity of 65%. The infective virus persisted longer on treated or artificial smooth surfaces specifically plastic and steel than on rough surfaces such as wood, cloth and tissue paper (Chin et al., 2020) . However, the J o u r n a l P r e -p r o o f Journal Pre-proof mechanisms account for the differences in stability between smooth and rough surface are unclear. Goh et al. (2020b) also showed that, unlike other coronaviruses, SARS-CoV-2 has a strange structural featurea hard or rigid shell that confers high persistence or stability outside the human body and body fluids (Section 2.3) . The survival times depend on viral strain and environmental conditions, including nature of surface, air humidity and temperature (Kampf et al., 2020) . Survival times could be potentially longer in contaminated aquatic systems, including wastewaters due to the conducive environment and occurrence of organisms that may serve as putative alternative host for SARS-CoV-2. However, further research is required to determine survival times in wastewaters, possible host organisms in aquatic systems, drinking water sources and potential vectors such as houseflies.

Wastewater and on-site sanitation systems receive, and act as a reservoirs of SARS-CoV-2 from multiple point and non-point sources in a catchment Zhang et al., 2020a) . These sources include; (1) faeces released via the toilet system, (2) household wastewaters from bathing of infected persons, (3) laundry wastewater from washing of infectious materials such as contaminated clothes and personal protective equipment, and (3) wastewaters from health care, autopsy and thanatopraxy/embalming facilities, including funeral homes (Gwenzi, 2020a, b; Zhang et al., 2020a) . The occurrence of SARS-CoV-2 and other human pathogens in wastewater forms the basis for wastewater-based epidemiology (WBE). WBE is emerging field entailing surveillance of wastewater systems for the presence of pathogens including SARS-CoV-2 to gain clues on the occurrence of human infections such as COVID-19 within a catchment (Choi et al., 2018; Lorenzo and Pico et al., 2019; Ahmed et al., 2020; Mallapaty, 2020) .

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An increasing body of literature drawn from developed countries including Australia, Spain, France, Netherlands, the USA, and Italy, among others, has detected SARS-CoV-2 RNA in raw wastewater systems Lodder et al., 2020; Medema et al., 2020) . Lodder and de Roda Husman (2020) reported the presence of SARS-CoV-2 RNA in raw wastewater samples. Moreover, the potential to use WBE for COVID-19 surveillance in Africa has been discussed in an earlier perspective (Street el al., 2020) . However, unlike in developed countries, the use of diverse sanitation systems in Africa, including centralized sewer systems, and onsite sanitation systems such as pit latrines, pit latrines and septic tanks could present significant challenges to WBE.

One WBE study conducted in Australia using reverse transcriptase quantitative polymerase chain (RT-qPCR) showed two positive detections of SARS-CoV-2 RNA in untreated wastewater within a 6-day sampling period. Using Monte Carlo simulation modelling, the same authors estimated that a median range of between 171 to 1090 infected persons occurred in the catchment. Further studies are required to evaluate the global validity of WBE as a tool for estimating COVID-19 prevalence, especially in developing countries where severe shortages of diagnostic equipment constrain comprehensive testing. An independent study of six wastewater treatment plants in a low COVID-19 prevalence area in Murcia (Spain) detected 5.29 log genomic copies/L of SARS-CoV-2 RNA in untreated wastewaters (Randazzo et al., 2020) . The same authors showed that, SARS-CoV-2 circulation among the population occurred before the negative for SARS-CoV-2 RNA, indicating the effectiveness of the disinfection processes used (Randazzo et al., 2020) . Contrary, in Wuchang Fangcang Hospital, China, SARS-CoV-2 RNA were detected in medical wastewater from septic tanks after disinfection with 800 g/m 3 sodium hypochlorite (Zhang et al., 2020a) . The detection of SARS-CoV-2 RNA after chlorination of raw wastewater in septic tanks of a hospital could be attributed to the fact that free chlorine was not detected in the effluent. Thus one may expect even higher concentrations and persistence period in raw wastewaters in on-site sanitation systems in developing countries, where no chlorination is practised. Further evidence on the occurrence of SARS-CoV-2 and other coronaviruses in the wastewater system has been reported in Paris (France) and Hong Kong, among others (Gormley et al., 2020; Lodder et al., 2020) . Due to the interconnectedness of the wastewater system, airborne transmission of coronaviruses via the wastewater system, including the widely reported 2003 super-spreading SARS event in Hong Kong has been reported (WHO, 2003; Gormley et al., 2020) .

The findings of WBE are significant in our understanding of the occurrence, transmission and control of COVID-19 especially in developing countries. First, this evidence point to the fact that SARS-CoV-2 RNA occur and persist in the wastewater system and on-site sanitation systems, which could in turn act as potential reservoirs of SARS-CoV-2. Subsequently, hydrological processes, including; direct discharges, spillages, runoff/erosion, infiltration, groundwater recharge, and surface water-groundwater exchanges may disseminate SARS-CoV-2 from various faecal sources into other environmental compartments, including drinking water sources. In this regard, the untreated wastewater could play key role in the faecal-oral transmission of SARS-CoV-2, yet its role has not be fully investigated. In turn, effective wastewater treatment, entailing advanced treatment processes may act as a barrier for preventing J o u r n a l P r e -p r o o f Journal Pre-proof faecal-oral transmission of COVID-19. Second, the fact that SARS-CoV-2 RNA are detected in wastewater systems ahead of official reports of COVID-19 cases indicates that WBE may act as an early warning system (Randazzo et al., 2020) . Hence, WBE constitute an under-utilized critical tool for COVID-19 surveillance especially in developing countries lacking comprehensive diagnostic systems for SARS-CoV-2. In such regions, surveillance data from WBE can be used to trigger emergency preparedness and response systems.

Besides literature reporting SARS-CoV-2 RNA in wastewater, to date, only one study has documented SARS-CoV-2 in river water impacted by raw sewage wastewater in a low-income country (Guerrero-Latorre et al., 2020) . Guerrero-Latorre et al. (2020) investigated the occurrence of SARS-CoV-2 at three locations along the urban rivers in Quito (Ecuador) during the peak of COVID-19 cases. In the same study, the SARS-CoV-2 and the human adenovirus, a human viral indicator were concentrated using the skimmed milk flocculation method, and subsequently using the N1 and N2 target regions. SARS-CoV-2 RNA was detected in all water samples, ranging from 2,91E+05 to 3,19E+06 GC/L for N1, and from 2,07E+05 to 2,22E+06 GC/L for N2. The human Adenovirus were detected in high concentrations ranging between 1,13E+04 and 2,60E+05 GC/L (Guerrero-Latorre et al., 2020) . The high concentration of human adenovirus are indicative of a high microbial contamination of aquatic systems via human excreta (Rusiñol et al., 2014; Guerrero-Latorre et al. 2020 Literature on the occurrence and persistence of SARS-CoV-2 and bacteriophages used as surrogates or models of coronaviruses in water and wastewater matrices has been reviewed elsewhere (Barcelo et al., 2020; Nghiem et al., 2020 : Race et al., 2020 . Recent reviews also exist on the occurrence and persistence of SARS-COv-2 in faces, urine, raw wastewater and sewage sludge based on studies drawn from various countries (Collivignarelli et al., 2020; Kitajima et al., 2020) . In summary, some studies reported that enveloped coronaviruses in wastewater are relatively short-lived, as evidenced by 3-log10 reduction in virus titre occurring within 2-3 days (Gundy et al., 2009) . Other studies suggest longer survival periods in water and wastewater matrices. For example, SARS-CoV-1 survived in sewage for 14 days at 4°C, and for partly reflect the fact that, the evidence were under different environmental conditions using different viruses or their surrogates rather than SARS-CoV-2. Consequently, scientific opinion remain divided on whether or not to consider the faecal-oral transmission: (1) due to this perceived rapid degradation in water, some authors suggest that, human infections from waterborne coronaviruses, including SARS-CoV-2 are unlikely (e.g., Farkas et al., 2020) , while, (2) based on data suggesting longer survival periods, coupled with the positive detection of SARS-

CoV-2 in stool samples, some authors suggest that facial transmission routes should be considered (e.g., Barcelo et al., 2020) .

Analysis of literature reporting SARS-CoV-2 in wastewaters (e.g., Ahmed et al., 2020; Medema et al., 2020; Naddeo and Liu, 2020; further revealed the following: (1) none of the available studies investigating the survival of coronaviruses in water and wastewater matrices were conducted in developing countries, (2) no data is available on the survival of coronaviruses in sewage and wastewaters from on-site sanitation systems common used in Goh and colleagues pioneered shell disorder analysis of viruses using artificial intelligence and molecular techniques to gain insights into the persistence, transmission mode and virulence of viruses and coronaviruses (Goh, 2017; Goh et al., 2015 Goh et al., , 2016 Goh et al., , 2019 Goh et al., , 2020a .

Using shell disorder analysis, Goh et al. (2020b) showed that, SARS-CoV-2 is very strange and unique relative to other coronaviruses, because it has the hardest or most rigid outer shell among the coronaviruses. A hard or rigid outer is indicative of a resilient or persistent coronavirus outside and within the body and body fluids, while a soft shell reflects low resilience or persistence (Goh et al., 2020a, b) . SARS-CoV-2 also has the lowest shell disorder measured using percentage intrinsic disorder (PID) among the coronaviruses (Goh et al., 2020b) . The degree of shell disorder is related to the mode of infection and virulence (Goh et al., 2015 , Goh et al., 2020a . Low PID values typical of SARS-CoV-2 are indicative of both moderate respiratory and faecal-oral transmission potentials (Goh et al., 2020b) . Higher PID values are often associated with higher infectivity via respiratory transmission, because high disorders point to greater promiscuity of the virus with respect to binding to host proteins (Goh et al., 2013; Goh. 2017) . Therefore, the potential persistence or stability of SARS-CoV-2, coupled with its low shell disorder of SARS-CoV-2 appears to give further credence to the faecal-oral transmission hypothesis. The link between shell disorder analysis and persistence of viruses is interesting, as it points to a possibility to develop predictive tools for estimating the stability of virus in environmental media. However, further work is required to develop and validate such predictive tools.

Further evidence shows that the versatility of SARS-CoV-2 is not only limited to its persistence and transmission modes, but also the point of infection (i.e., lung versus gut).

Coronaviruses are also versatile with respect to their capacity to preferentially infect the J o u r n a l P r e -p r o o f gastrointestinal (gut tropism) or the respiratory system (lung tropism) (Song et al., 2005) . Some studies suggest that, the lung tropism causes severe adverse health effects, while the gut version is relatively less harmful (Holshue et al., 2020) . Anecdotal evidence reported in a pre-print based on a modelling study of the Wuhan City COVID-19 outbreak pointed to the existence of a second transmission route (Danchin et al., 2020) . Although the work is not peer-reviewed, Danchin and co-workers (2020) showed that a model that did not account for a second propagation route based on environment-human transmission vial faecal-oral route cannot explain the Wuhan COVID-19 outbreak compared to a similar model accounting for the second transmission route. The same authors also concluded that sub-groups of SARS-CoV-2 existed, an observation which appears consistent with the existence of the lung and gut tropisms. This further suggest that coronaviruses, including SARS-CoV-2 could be amenable to multiple transmission via respiratory droplets, direct contact with contaminated surfaces and faecal-oral

route. Yet several opinions may exist on the mechanisms accounting for such behaviours, thus this is subject to further research.

In summary, to this point, it is evident that: (1) SARS-CoV-2 colonizes and proliferates in the human gastrointestinal tract, (2) symptomatic and asymptomatic infected persons shed SARS-CoV-2 via faeces, and (3) SARS-CoV-2 RNA have been detected in wastewaters and onsite sanitation systems (pit latrines, septic tanks). Finally, the hard outer shell of SARS-CoV-2 and low shell disorder, point to potential persistence and moderate potential for faecal-oral transmission. Taken together, these findings suggest that faecal-oral transmission of SARS-CoV-2 cannot be totally discounted especially in developing countries due to several risk factors (Section 3.2).

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The bulk of literature reporting SARS-CoV-2 in environmental and human media, including wastewaters, saliva, sputum, faeces and human gut samples rely on the detection of SARS-CoV-2 RNA Kitajima et al., 2020) . Yet consensus exists that SARS- SARS-CoV-2 from human stools (Zang et al., 2020) . The study showed that serine protease enzymes (TMPRSS2 and TMPRSS4) enhance the SARS-CoV-2 infection of enterocytes in the human small intestines. However, rapid inactivation of SARS-CoV-2 was observed in simulated colonic fluid. Barring the study by Zang et al. (2020) , it remains unclear whether the shedding, and subsequent detection of SARS-CoV-2 RNA in both environmental (e.g., wastewaters) and human media (e.g., stools) is a true indicator of viable and infective viruses. In addition, currently, no established technique exists for estimating infectious virus particles from data on the occurrence and persistence of SARS-CoV-2 RNA in environmental media. Due to person-toperson variations, coupled with knowledge gaps in the virulence and pathogenicity of SARS-CoV-2, the quantitative estimation of the human health risks such as transmission and fatality rates from SARS-CoV-2 RNA data is even more complicated. Therefore, drawing accurate inferences of potential human health risks based on the detection of SARS-CoV-2 RNA in environmental media still presents significant challenges.

The possibility of novel transmission of SARS-CoV-2 via multiple faecal-oral route pathways further complicates the estimation of human health risks. Moreover, the potential for human exposure to viruses, including SARS-CoV-2 via bioaerosols and wastewater aerosols has been highlighted (Carducci et al., 2018; Fears et al., 2020; Kitajima et al., 2020; Meng et al., 2020) . For example, anecdotal evidence based on a laboratory study investigating the persistence of SARS-CoV-2 in aerosols showed that the virus retain its viability and infectivity in aerosols for up to 16 hours (Fears et al., 2020) . This raises the possibility for human exposure to SARS-CoV-2 through bioaerosols and wastewater aerosols. Human exposure to SARS-CoV-2 via bioaerosols could be particularly important in crowded environments. Similarly, human exposure to SARS-CoV-2 via wastewater aerosols could be significant in shared sanitation systems especially in crowded informal settlements in developing countries (Gwenzi, 2020) . However, as Kitajima et al. (2020) pointed out, studies investigating human exposure to SARS-CoV-2 via bioaerosols and wastewater aerosols are scarce. Therefore, further research is required to better understand the human exposure and health risks associated with wastewater aerosols. This calls for further research on the development, validation and application of tools and models based on quantitative microbial risk assessment (QMRA).

QMRA relies on quantitative dose-response models or relationships between human exposure, and probability of occurrence of human health outcomes or endpoints such as infection or illness . QMRA requires data on the nature, concentrations, behaviour and fate of a biohazard (i.e., SARS-CoV-2) in environmental media as well as the multiple human exposure pathways. Yet quantitative dose-response models are not yet available for 

The evidence pointing to faecal-oral transmission of COVID-19 is still characterized by high uncertainties. These uncertainties are associated with knowledge gaps, untested assumptions, analytical techniques, and data inconsistencies. To some extent, such a high uncertainty is understandable, given that COVID-19 is an emerging human infectious disease Uncertainties also arise from the sampling and analytical techniques (i.e., RT-qPCR) and

proxy indicators (i.e., SARS-CoV-2 RNA) currently used to evaluate the occurrence and persistence of SARS-CoV-2 in environmental media. The limitations associated with current extraction and analytical methods have been discussed in a few recent studies . These limitations include: (1) low capacity of current techniques to extract RNA from enveloped coronaviruses such as SARS-CoV-2, and (2) the possibility of false-positive and negative results. Anecdotal evidence shows that false-negative results are more common than false-positive ones Wikramaratna et al., 2020; . False-negative results under-estimate the COVID-19 cases, which in turn, has significant adverse implications for the subsequent diagnosis, transmission and control of COVID-19.

Some contradictory results also exist: on one hand, some studies suggest that SARS-CoV-2 is unstable in the environment because it has a delicate envelope Nghiem et al., 2020) . On the other hand, work by Goh and co-workers (2020a, b) based on shell disorder analysis suggested that SARS-CoV-2 has a very rigid shell conferring persistence.

Moreover, technical updates and briefs by WHO (2020a, c) suggest that 'no evidence' exists on the occurrence and persistence of SARS-CoV-2 in sewage, wastewater or drinking water. Yet some studies conducted in France, the USA, Italy, Netherlands, Australia and China have detected SARS-CoV-2 RNA in wastewaters Lodder and de Roda Husman, 2020; Medema et al., 2020; Wu et al., 2020a) even after disinfection (Zhang et al., 2020a) . Moreover, while some authors point to the potential faecal-oral transmission of SARS-Cov-2 Hindson, 2020; Wang et al., 2020; Yeo et al., 2020 , Goh et al., 2020 , WHO (2020b, c) is of the opinion that the human health risks are low. One also wonders, if data confirmed that SARS-CoV-2 may persist on surfaces for up to 9 J o u r n a l P r e -p r o o f 

Until these, and several questions are addressed, the faecal-oral transmission mechanism will remain a hypothesis that is yet to be validated. To this end, all the plausible routes that could potentially contribute to faecal-oral transmission are discussed. Subsequent in-depth research is expected to provide the evidence on the potential relative contribution to COVID-19

transmission. In view of these inconsistencies and uncertainties, it remains problematic to draw strong conclusions and recommendations. Notwithstanding these limitations, the significance and implications of the current evidence, and the need to consider precautionary measures are discussed.

occur via seepages from on-site sanitation systems such as pit latrines and septic tanks into surface and shallow groundwater systems serving as groundwater sources (Figure 2) . A study conducted on other coronaviruses reported that a 99.9% die-off occurred after 10 days in tap water at 23°C and over 100 days at 4°C (Gundy et al., 2009) . This finding suggest a longer survival time of coronaviruses in tap water than in wastewater. If these results are also valid for SARS-CoV-2, then this relatively long survival time in drinking water may increase the risk of human exposure.

The risk of contamination of drinking water via this route could be high in cases where drinking water sources are closely juxtaposed with wastewater and on-site sanitation systems.

Communities with potential high risks of COVID-19 transmission include: (1) densely populated informal settlements such as squatter camps, slums and refugee camps without access to centralized drinking water systems (Corburn et al., 2020; , and (2) Advanced water treatment systems have high initial and operating costs, hence are rarely used in water and wastewater treatment. Consequently, the discharge of raw and partially treated wastewaters into aquatic systems serving as drinking water sources is common (Angassa et al., 2020) . Vulnerable and low-income communities in rural urban and peri-urban areas often rely on shared community water points such as wells, boreholes and community water taps (Amin et al., 2016) . In such situations social distancing is problematic due to crowding. For example, in Zimbabwe, informal observations showed excessive crowding and queues of women and children at community water points such as boreholes. Moreover, shared water sources may transmit SARS-CoV-2 via fomite or contact with contaminated surfaces such as handles of water abstraction devices. This is because, frequent and regular cleaning of water extraction devices using sanitizers and disinfectants is not feasible on community water sources. Sanitizers and PPE such as disposal gloves are often expensive and beyond the reach of low-income communities.

Raw and partially treated wastewater discharges may contaminate marine and surface aquatic systems serving as human food sources (Angassa et al., 2020) . However, studies investigating SARS-CoV-2 contamination in the food value chain from farm to fork are still lacking. Similar to drinking water, the occurrence and persistence of SARS-CoV-2 on food warrant further investigating. Such studies will entail mimicking food contamination along the 

A number of vectors such as houseflies, cockroaches and rodents that frequent households and environments with faeces such as pit latrines and septic tanks are well-known reservoirs and vectors of pathogens (Akter et al., 2020; Al-Khalifa et al., 2020) . Vectors may harbour viruses in their intestinal tracts and on their bodies, and contaminate human food and surfaces (Dehghani and Kassiri, 2020; Heller et al., 2020) . 

To date, empirical evidence validating the faecal-oral hypothesis and its associated novel transmission pathways remain scarce. In developing countries, these novel transmission mechanisms could be negligible due to effective control barriers including effective waste, wastewater and water treatment, coupled with effective food quality and safety procedures. In contrast, given the several risk factors, and lack of effective barriers, these transmission mechanisms cannot be totally discounted in developing countries. While these novel transmission mechanisms could be currently regarded as insignificant relative to conventional transmission routes, only further research could confirm this notion. This perspective serves to stimulate further discussion and research on the subject, paying particular attention to developing countries. Such research may also provide insights into the transmission and control of future SARS.

Several potential risk factors and risky practices predisposing human health to risks in developing countries are discussed in reviews focussing on the funeral industry (Gwenzi, 2020a, b) . Figure 1 summarizes the factors and practices promoting COVID-19 faecal-oral transmission:

(1) Poor wastewater management: Overloaded and dilapidated conventional wastewater treatment systems are inefficient. Moreover, raw infectious wastewaters from health care systems and the funeral industry are directly discharged into the sewer system without any pre-treatment (Gwenzi, 2020a, b) . This contaminates marine and aquatic systems serving as drinking water and food sources. to the adverse health effects of COVID-19. Co-infections may synergistically interact with COVID-19, resulting in adverse human health outcomes (Lin et al., 2020; Park et al., 2020) .

(8) Weak social and health care systems: Social and health care systems are weak and poorly funded, thus have limited capacity to cope with large-scale outbreaks of infectious diseases including COVID-19 (Ji et al., 2020) . The high infection and mortality rates associated with outbreaks of cholera and typhoid in developing countries (e.g., Zimbabwe) (Ahmed et al., 2011) clearly demonstrate that such social and health care systems even fail to cope with outbreaks of treatable conventional or medieval diseases. In such settings, compulsory social distancing measures such as national quarantines or lockdowns may threaten, and even have adverse effects on livelihoods and food security of vulnerable communities. This may have long-lasting impacts, which may in turn, prolong or even constrain post-COVID-19 recovery. (10) Weak and poorly enforced policies and regulations: Environmental, occupational and public health policies and regulations are often weak, fragmented and poorly enforced (Gwenzi, 2020a, b) . In addition, public health and environmental regulatory agencies, and those responsible for disaster response are often poorly funded and equipped, and lack critical expertise in emerging infectious diseases such as COVID-19. Hence, developing J o u r n a l P r e -p r o o f Journal Pre-proof countries often strongly depend on the donor and international community for both resources and expertise, a scenario which may promote COVID-19 transmission and delay its control.

The need for in-depth research to confirm whether or not the faecal-oral route contributes to the transmission of COVID-19 has been discussed in a few earlier paper (Heller et al., 2020) .

However, until now, what has been missing is a comprehensive perspective discussing the hypothesis in the context of developing countries. Therefore, the current perspective addresses this gap, and adds to the growing voice calling for research to develop the scientific and empirical evidence base to confirm or dispel the faecal-oral hypothesis and its associated novel transmission pathways. Such empirical evidence will bring closure to the current speculation about the faecal-oral hypothesis. In addition, confirming or dispelling the hypothesis will provide key information on whether or not additional barriers are need to prevent novel transmission of practitioners, but the current perspectives paper argues that, the global research community, regional and national research institutions, think-tanks in public health and universities should play their role by providing evidence to inform policy and practice.

In its simplest form, such research entails testing for SARS-CoV-2 RNA in drinking water along the source, storage and distribution systems, including at the point of human consumption. Currently, no compelling data exist to enable the evaluation of the relative significance of the various potential faecal-oral pathways to COVID-19 transmission. However, based on experiential and inferential evidence, priority should be given to transmission via contaminated drinking water (Figure 1 ). This is because, compared to vector and food-mediated transmission, faecal contamination of drinking water sources is well-documented in developing countries (Ahmed et al., 2011) . Moreover, a significant population in developing countries also rely on untreated water from unsafe sources, creating opportunities for potential human exposure. Although not directly related to COVID-19, evidence also exists linking faecal J o u r n a l P r e -p r o o f Journal Pre-proof contamination of drinking water to human health risks including recurrent outbreaks of diarrhoeal infections, cholera and typhoid (Ahmed et al., 2011; Gwenzi and Sanganyado, 2019) .

Such research should also target and prioritize areas associated with putative faecal contamination such as informal settlements such as slums, squatter camps and refugee camps.

Communities in such informal settlements often rely on untreated raw water abstracted from shared and unsafe drinking water sources, which are often closely juxtaposed with on-site sanitation systems (Pujari et al., 2012 : Potgieter et al., 2020 . Developing countries with recurrent outbreaks of human infections transmitted via the faecal-oral route such as cholera and typhoid could constitute the ideal settings or 'worst-case scenario' to investigate the faecal-oral hypothesis.

The summary evidence on the occurrence of SARS-CoV-2 in human gastrointestinal system, faeces and wastewater systems, and the potential faecal-oral transmission of COVID-18 have potential implications on the control of COVID-19 especially in developing countries.

Clearly, the faecal-oral transmission route, is not a single pathway, but a set of multiple subpathways, including, drinking water, contaminated food and vector-mediated processes ( Figure   2 ). The current perspective raised the question whether or not clean water provision, sanitation and waste management are critical control points in the fight of COVID-19 in developing countries. Figure 1 and the following discussion partly address this question. However, evidence on the faecal-oral hypothesis remain weak and inconclusive, hence making strong recommendations based on weak evidence and uncertainty is problematic. Therefore, lacking strong evidence, the control measures premised on the faecal-oral transmission hypothesis J o u r n a l P r e -p r o o f Journal Pre-proof summarized here should be considered as precautionary measures. These measures seek to complement, rather than replace social distancing, hand hygiene and the use of PPE, which are premised on COVID-19 transmission via respiratory droplets and direct contact routes.

The fact that wastewater and on-sanitation systems are potential reservoirs of SARS-CoV-2, and the concept of wastewater-based epidemiology were discussed. Moreover, the dissemination of SARS-CoV-2 from faeces (in the case of open defaecation), wastewaters and on-site sanitation systems via hydrological processes may contaminate marine and aquatic systems serving as drinking water and food sources. Therefore, wastewater and sanitation-based barriers could be critical precautionary measures in preventing faecal-oral transmission arising from poor wastewater and sanitation (Figure 2 ). This include, proper sanitation entailing; (1) stopping open defaecation, and (2) safe and hygienic disposal of human excreta in properly sited and designed on-site sanitation or sewer systems. Proper wastewater management practices include: (1) stopping the discharge of raw or partially treated wastewaters into marine and aquatic systems, and (2) advanced wastewater treatment using ultra-violet irradiation and disinfection to effectively inactivate SARS-CoV-2 (Randazzo et al., 2020) . These control measures demonstrate the criticality of improved sanitation and wastewater treatment and disposal as potential barriers against faecal-oral transmission of COVID-19.

The risk factors and risky practices contributing to contamination of drinking water sources, communities most likely to be at risk were highlighted. Based on this understanding, potential precautionary barriers to prevent transmission via contaminated drinking include, reliable supply of clean and regularly tested drinking water via: (1) centralised drinking water J o u r n a l P r e -p r o o f Journal Pre-proof systems, where available, and/or (2) mobile systems such as water bowsers in the case of unconnected communities close to centralised drinking water systems. In the absence of centralised drinking water treatment systems, drinking water disinfection is recommended in communities with potential risk of transmission, where contamination is either suspected or confirmed (Figure 2) .

A number of generic guidelines exist on drinking water treatment in the case of disease outbreaks, and recent updates are available (WHO, 2019 . The World Health Organization recommends: (1) boiling, (2) high-performing ultrafiltration, and (3) nanomembrane filtration.

Solar disinfection (SODIS), ultra-violet (UV) irradiation and chlorination using an appropriate dosage of free chlorine are recommended for non-turbid waters (WHO, 2019). However, one study detecting SARS-CoV-2 RNA in wastewater following chlorination with 800 g/m 3 sodium hypochlorite (Zhang et al., 2020a) , raises concerns about the effectiveness of conventional dosages of chlorination. Notably, current recommendations are generic and largely based on inferential evidence for other viruses and coronaviruses. This is because data on the occurrence and removal of SARS-CoV-2 in drinking water using the stated methods are scarce. Several lowcost water treatment methods also exist, including; metallic iron filters, biosand filters, and ceramic filters (with or without silver nanoparticles), but their capacity to SARS-CoV-2 is also currently unknown. An exception is boiling, where some data exist. Coronaviruses such as SARS are highly sensitive to heat, and can be inactivated by heating at 56-60 o C for 30 min (Pastorino et al., 2020; Wu et al., 2020a) . Anecdotal evidence from a pre-print shows that, heating at 92°C for 15 min was more effective in achieving a 6 log reduction in SARS-CoV-2 than lower temperatures and longer heating times of 56°C for 30 min and 60°C for 60 min (Pastorino et al., 2020) . Thus, boiling for at least 15 min may effectively disinfect contaminated drinking water.

However, barring boiling, and probably solar disinfection, the technology (e.g., filters, chlorinating agents) and know-how to install and effectively operate ultrafiltration, nanomembrane filtration, UV irradiation and chlorination may not be readily available for most vulnerable communities in developing regions. In addition, unless such technologies are provided by the donor community or government, their appropriateness in developing countries could be questioned.

Several high risky practices in hygiene, food handling and preparation, and funeral promoting vectors such as rodents and houseflies, including regular spraying using insecticides.

Safeguarding human health against COVID-19 and future outbreaks of infectious diseases requires effective regulatory frameworks, coupled with well-funded and equipped institutions, and social and health care systems with relevant expertise. Effective and wellcoordinated policies, regulation and institutions are critical in developing resilience, early warning and response systems in developing countries. This aspect is cross-cutting, thus extends beyond infectious diseases to include environmental pollution and the associated health risks.

Earlier reviews present a detailed discussion of the need to develop better regulations, policies and institutions to safeguard human health in developing countries (Gwenzi, 2020a, b) .

Looking ahead: Decision scenarios and future directions

The world is current in the middle of the COVID-19 crisis, and inferential evidence summarised here and elsewhere (e.g., Heller et al., 2020; Hindson, 2020; Yeo et al., 2020) further highlights the possibility of a (1) Scenario 1 (' Business-as usual') and compromise the effectiveness of the mitigation strategy. Others may also argue that, changing a mitigation strategy in the middle of a global health crisis creates confusion and cause loss of confidence, resulting in disastrous health outcomes.

(2) Scenario 2 (WASH is critical pillar in fighting Clean water provision, hygiene and sanitation are critical pillars of the public health systems. Hence, WASH programmes should be according equal importance, and integrated into existing mitigation programmes. This decision scenario is consistent with the recommendations of an earlier communication targeting low-income countries (Adelodun et al., 2020) . Adelodun and co-workers (2020) recommended the following mitigation measures: (1) decentralized wastewater treatment, (2) community-wide monitoring of SARS-CoV-2 in wastewater, (3) improved sanitation, (4) developing point-of-use wastewater treatment devices. Those in support of this viewpoint may argue that, the health risks and impacts of COVID-19 are very high and far-reaching, hence in the face of imperfect knowledge, developing countries should assume the 'worst-case scenario' and take precautionary measures by integrating WASH in existing mitigation measures. Such proponents may also argue that WASH programs have the potential to bring long-lasting and far-reaching health benefits, not only for COVID-19, but for several other human infections, including future outbreaks of similar pandemics (Hyde et al., 2020) . In addition, strengthening the WASH pillar will complement the social distancing, hand hygiene and the use of PPE by reducing human interactions particularly among women and children due to their critical role in household water provision, including water fetching. Moreover, reliable clean water supplies are critical for the recommended frequent and regular hand washing (WHO, 2020c) . Hence, those in support of this viewpoint may propose that additional resources need to J o u r n a l P r e -p r o o f 

The scenarios highlighted here suggest that making decisions and specific recommendations in the middle of a crisis is a non-trivial task. The fact that the scientific evidence is rapidly changing, and still characterized by several unknowns and uncertainties further complicates the decision-making process. For similar reasons, the current perspective will not attempt to provide a 'yes' or 'no' answer to the question raised, nor make specific recommendations. Rather, the decision scenarios and their merits were highlighted to stimulate further debate on, and draw attention to the topic. Experts in the epidemiology of infectious viral diseases may provide a more authoritative evaluation of the weight of evidence, and make decisive recommendations. However, whether such decisions and recommendations will be made and implemented under the current COVID-19 pandemic or future similar outbreaks remains unknown. The need to further validate the evidence, and address gaps and uncertainties is apparent.

Future research in developing countries should address these knowledge gaps ( Figure 1 ):

(1) Validating the faecal-oral transmission hypothesis

Several lines of evidences pointing to the possibility of COVID-19 transmission via the faecal-oral route were highlighted, but evidence remain weak and inconclusive. Systematic epidemiological evidence are required to test this hypothesis in developing countries, where faecal contamination of water sources is well-pronounced due several risk factors. Such studies should also determine the relative contribution and significance of the various pathways (i.e., drinking water, vectors, food contamination) to faecal-oral transmission of COVID-19.

(2) Wastewater and drinking water-based epidemiology J o u r n a l P r e -p r o o f Journal Pre-proof WBE may provide cues and early insights on the occurrence of COVID-19 in developing countries where analytical equipment for comprehensive screening of humans are scarce. Given that wastewaters are closely coupled to drinking water systems through cross-connections and contamination, WBE can also be extended to drinking water sources. Such WBE studies can be coupled to spatial tools such as geographical information systems to map potential hotpots and hot moments.

(

Goh and co-workers (2020a, b) have pioneered a potentially interesting and promising tool based on shell order analysis for predicting the environmental stability of coronaviruses such as SARS-CoV-2 and other viruses. However, the predictive capacity of shell order analysis for SARS-CoV-2 and other viruses has not been fully explored. Thus, further work should investigate the following: (1) potential interactive effects between inherent shell structure of viruses and environmental conditions on the stability of viruses, and (2) validate the predictive capacity of shell order analysis for several other viruses of human health concern, including Ebola virus, Zika virus, Nipah, and HIV, among others. Once the predictive capacity of shell order analysis has been confirmed, this can act as a potential tool to estimate the stability of future coronaviruses.

The bulk of evidence of the occurrence and stability of SARS-CoV-2 are limited to developed countries, which experience predominantly temperate climates. Research is needed to investigate the occurrence, persistence and fate of SARS-CoV-2 in various environmental media J o u r n a l P r e -p r o o f Journal Pre-proof in tropical environments in developing regions such as Africa. Such media should include, aquatic and marine foods, wastewater, drinking water sources, and solid wastes from potential sources such as health care facilities, funeral homes, and isolation and quarantine centres.

(5) Tracking COVID-19 along the human gut-wastewater-human exposure pathway

Systematic studies are required to track the circulation of SARS-CoV-2 along the human gut-wastewater-human exposure pathways. Emerging tools such as genomics, coupled with in silico techniques and network analysis are ideal for analysis of complex networks. Such information is critical for the development of barriers to stop the transmission along the faecaloral route.

SARS-CoV-2 may preferentially colonize either the respiratory system (lung tropism) or the human gastrointestinal tract (gut tropism), resulting in different human health outcomes (Holshue et al., 2020) . This raises the question, 'Do the two tropisms reflect contrasting sources and human exposure mechanisms, and if not, what controls the differential distribution within the human body?'. Currently, it is unclear whether the lung and gut tropisms represent different SARS-CoV-2 sub-types, because RT-qPCR currently used for SARS-CoV-2 determination lack capacity to differentiate between SARS-CoV-2 sub-types. Further studies based on whole genome analysis are needed to address these knowledge gaps.

in contaminated drinking water. Low-cost drinking water methods are commonly used by vulnerable communities in developing countries and humanitarian disaster situations. These aspects warrant further research.

Modelling studies predominantly conducted in Asia have predicted COVID-19 outbreak using climatic/weather data, and showed that number of infections are negatively correlated with temperature (Shi et al., 2020; Wu et al., 2020b) . The bulk of these modelling studies were conducted after outbreaks (i.e., posterior). Therefore, it will be interesting to conduct similar anterior modelling studies using historical data or proxies from remote sensing in regions currently experiencing low infection outbreaks (e.g., Africa) to test the validity and universality of such modelling approaches. Such modelling efforts should focus on predicting areas ('hotspots') and periods ('hot moments') with exceptionally high outbreaks of COVID-19. Such modelling studies may entail using a combination of tools including internet, mobile technologies, spatial tools (GIS), and emerging tools including genomics and big data analytics (e.g., artificial intelligence).

Earth system dynamics and climatic phenomena (e.g., ENSO, La Niña) are often linked to vector and viral disease outbreaks (e.g., Chikungunya, dengue) in tropical Africa, Asia and South America through teleconnections (Anyamba et al., 2019) . Teleconnections occur when an earth system phenomenon triggers the outbreak of a disease at long distance away. Thus, understanding the earth system-disease inter-relationships and teleconnections with coronavirus such as COVID-19 is critical for better understanding, forecasting, prevention and control of future viral infections.

J o u r n a l P r e -p r o o f on the subject initiated and coordinated by foreign researchers may face strong resistance from governments in developing countries and rights activists. On the other hand, on their own, low income countries have limited capacity to implement comprehensive research to address the knowledge gaps highlighted. This is due to severe lack of funding, research infrastructure such as analytical equipment and expertise. In addition, research involving infective SARS-CoV-2 may require strict biosafety controls exceeding level 2, which are often lacking in developing countries. Hence, the best compromise could be collaborative projects bringing together foreign scientists, local scientists and international agencies such as WHO. In such joint projects, international scientists, developed countries and agencies may provide the bulk of resources including funding and expertise. To ensure transparency, and build trust among the various partners, the actual research should be designed and implemented jointly by local and foreign scientists with the participation of relevant institutions and regulatory agencies in developing countries. The research outputs from such joint projects should be shared fairly, and widely disseminated. Mechanisms also need to be developed on how any intellectual property rights, including vaccines, arising from such projects will be shared among the partners.

The current perspective examined current evidence to show that SARS-CoV-2 colonize and proliferate in the human gastrointestinal system, which as a reservoir of SARS-CoV-2. The SARS-CoV-2 is then shed into on-site sanitation and wastewater or sewer systems via faeces.

Wastewater-based epidemiological evidence confirm the occurrence and the persistence of SARS-CoV-2 RNA in wastewaters. The circulation of SARS-CoV-2 among the human population may even precede the manifestation of symptoms, and the first official reports of J o u r n a l P r e -p r o o f COVID-19 cases. This recent evidence points seem to support the COVID-19 faecal-oral transmission hypothesis particularly in developing countries. The notion of faecal-oral transmission seem to be further corroborated by results of shell disorder analysis and modelling, which indicate persistence and the potential for faecal-route transmission. The faecal-oral route is not a single pathway, but rather, consists of a multiple potential sub-pathways; (1) contaminated drinking water, (2) contaminated marine and aquatic foods, and (3) vectormediated transmission from faecal source to food. Collectively, these findings could be significant, and provide new insights on the potential transmission of COVID-19, the need for precautionary control measures in developing countries. Due to several risk factors and risky practices, the possibility for COVID-19 faecal-oral transmission and the corresponding adverse human health outcomes could be putatively higher in developing than developed countries.

Several precautionary barriers to prevent faecal-oral transmission were highlighted. Specifically, clean water provision, coupled with good sanitation, hygiene, and waste and waste practices could be potential critical control points, which can complement current efforts in the fight against COVID-19. Finally, decision scenarios and future directions were highlighted. 

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The research received no external funding, and was solely funded by the author's personal resources. I acknowledge with thanks the comments from the two anonymous reviewers that greatly improved the manuscript and its presentation.