"Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has."

Margaret Mead

Original article
peer-reviewed

Does Fecal-Oral Transmission of SARS-CoV-2 Due to Low Sanitation Conditions Contribute to Low Mortality Rates From COVID-19



Abstract

Background: The novel coronavirus disease 2019 (COVID-19) is a global pandemic generated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary infection site is mucosal surfaces, mainly the lungs and the intestine, where epithelial cells can be infected. COVID-19 has spread throughout the world, causing millions of deaths and hundreds of millions of confirmed infections. Despite the global spread of SARS-CoV-2, there are extreme differences between countries in mortality rates and confirmed infections.

Methods: Pearson correlations and a t-test were performed on data from 137 countries in order to test the correlation between number of deaths from diarrheal diseases (pre-COVID-19 pandemic data) as a marker for countries’ sanitation level, and the number of confirmed COVID-19 cases and deaths per million.

Results: It was found that countries’ prevalence of confirmed COVID-19 cases and deaths per million are statistically correlated with their sanitation level.

Conclusions: The hypothesis proposed in this article is that the low mortality rates from COVID-19 in countries where the level of sanitation is low are due to fecal-oral infection of the population by SARS-CoV-2, rather than infection of the respiratory system. This hypothesis is supported by the protective effect of the low sanitation level presented in this work and the fact that lung infection by SARS-CoV-2 can cause severe pathology, while infection in the intestine generally causes minor or no symptoms.

Introduction

Coronaviruses constitute a large family of enveloped, positive-sense, single-stranded RNA viruses that cause diseases in mammals and birds [1]. There are seven coronavirus strains known to infect humans and cause respiratory diseases. Of these, four strains are endemic globally and cause only mild upper respiratory tract diseases, and three result in severe infections. These strains include the Middle East respiratory syndrome coronavirus (MERS-CoV), the severe acute respiratory syndrome coronavirus (SARS-CoV), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2]. SARS-CoV-2 is a novel coronavirus that emerged in late 2019 in China and quickly spread throughout the world, causing the novel coronavirus disease 2019 (COVID-19). This virus has to date resulted in the confirmed infection of hundreds of millions and in the death of millions worldwide [3].

SARS-CoV-2 enters cells via attachment of its spike protein to the angiotensin-converting enzyme (ACE2), which is particularly abundant on the epithelial cells of the lungs and the small intestine. This indicates that not only the respiratory system, but also the digestive system, are potential routes of infection [4].

Respiratory symptoms, including common cold, cough, shortness of breath, runny nose and sore throat, are the most common. However, nearly half of the patients who were confirmed as having COVID-19 exhibited detectable SARS-CoV-2 RNA in their fecal samples [5]. The characteristics of gastrointestinal symptoms in COVID-19, such as lack of appetite, diarrhea, vomiting, and abdominal pain, are more insidious than the respiratory symptoms and are easily overlooked. However, some patients might have only gastrointestinal symptoms during the entire course of this disease, and some continue to shed the virus in feces, despite testing negative for respiratory samples. It has been suggested that further investigation is necessary in order to determine whether these patients represent a potentially overlooked means of transmission of SARS-CoV-2 [6].

Despite the global spread of SARS-CoV-2, mortality rates differ greatly between countries, and range from less than one death to more than 1800 deaths per million confirmed COVID-19 cases [3]. Several explanations have been suggested for these differences in mortality rates between countries, including the differences in the vitamin D level of the population [7], the age distribution of the population [8], the degree of exposure to air pollution [9], the variability in genetic polymorphisms [10-11], the vaccination policy [12], the microbiome composition [13], and cross-immunity [14]. It is, therefore, reasonable to assume that the geographical variations in COVID-19 cases are multifactorial. However, some explanations were only partially supported by statistical evidence or dealt mainly with a limited geographical area and did not examine their hypothesis globally.

Since SARS-CoV-2 can be transmitted not only through the respiratory system, but also through the fecal-oral route, it was suggested that sanitation may be an important factor in preventing the COVID-19 pandemic [15]. The COVID-19 pandemic was suggested to be more serious in developing and least developed countries struggling with the problem of ineffective waste disposal, open defecation, poor sanitation, and limited access to clean drinking water [15-16]. Surprisingly, the death toll from COVID-19 in developing and least developed countries is extremely low [17]. The hypothesis examined in this work is that a lower level of COVID-19 cases and mortality occurs in countries with a low sanitation level.

Materials & Methods

Pearson correlations (SPSS) were performed on data from 134 countries in order to test the correlation between the number of deaths from diarrheal diseases (pre-COVID-19 pandemic data) per 100,000 individuals and the number of confirmed COVID-19 cases per million. Pearson correlations were also performed in order to test the correlation between the number of deaths from diarrheal diseases per 100,000 individuals and the number of confirmed COVID-19 deaths per million. A comparative analysis between countries with less than 10 deaths and those with more than 10 deaths from diarrheal diseases per 100,000 individuals and the number of confirmed COVID-19 cases and confirmed deaths per million was conducted using a two-tailed t-test performed on mean values. COVID-19 related statistical data were extracted from Our World in Data (https://ourworldindata.org/coronavirus-source-data) according to an update from April 11, 2021. Statistical data on mortality rates from diarrhea in each country were taken from Our World in Data (https://ourworldindata.org/diarrheal-diseases) according to an update from 2018. Data for 14 countries with fewer than 600 confirmed COVID-19 cases per million were not included, in order to avoid countries in which COVID-19 did not spread in the population due to radical government intervention and avoid countries in which COVID-19 cases may not be monitored satisfactorily due to lack of test kits for SARS-CoV-2.

Results

Analysis of data from 134 countries was performed in order to test the correlation between the number of deaths from diarrheal diseases (pre-COVID-19 pandemic data) and the number of confirmed COVID-19 cases and mortality (Table 1).

C B A Country C B A Country C B A Country
342 32899 1.1 Oman 24 2937 34.8 Ghana 65 1468 11.8 Afghanistan
70 3264 46.8 Pakistan 847 28184 0.1 Greece 803 44532 0.3 Albania
556 52122 1.1 Palestine 391 11311 21.3 Guatemala 71 2700 1.1 Algeria
1427 83058 4.6 Panama 10 1584 62.0 Guinea 17 710 98.5 Angola
8 932 74.4 Papua New Guinea 34 1869 110.9 Guinea-Bissau 1275 55698 1.3 Argentina
666 32772 3.1 Paraguay 22 1126 30.9 Haiti 1255 68225 0.5 Armenia
1658 49732 3.7 Peru 482 19741 18.1 Honduras 36 1153 0.4 Australia
135 7786 8.4 Philippines 2403 73897 1.3 Hungary 1073 63816 0.5 Austria
1537 67454 0.4 Poland 123 9680 85.5 India 383 27969 2.4 Azerbaijan
1658 81098 0.6 Portugal 155 5714 46.0 Indonesia 326 91328 1.5 Bahrain
115 65623 0.4 Qatar 765 24396 1.3 Iran 59 4123 30.0 Bangladesh
1300 52130 0.6 Romania 365 22827 1.4 Iraq 248 35438 0.1 Belarus
692 31388 0.3 Russia 969 48735 0.5 Ireland 2021 79596 2.4 Belgium
24 1802 50.1 Rwanda 727 96564 2.2 Israel 8 620 79.2 Benin
194 11422 1.8 Saudi Arabia 1884 62090 0.5 Italy 1066 24121 5.6 Bolivia
64 2351 72.1 Senegal 226 14224 1.2 Jamaica 2224 55452 0.3 Bosnia-Herzegovina
838 93977 0.5 Serbia 74 3981 0.7 Japan 270 18147 38.1 Botswana
5 10364 0.2 Singapore 755 64921 0.8 Jordan 1653 63253 3.5 Brazil
1921 67857 0.4 Slovakia 174 17089 0.5 Kazakhstan 2065 53470 0.4 Bulgaria
1978 1E+05 0.2 Slovenia 43 2700 76.9 Kenya 7 620 78.7 Burkina Faso
38 772 89.5 Somalia 329 57534 0.3 Kuwait 35 2325 62.6 Cameroon
898 26261 32.8 South Africa 233 13798 1.9 Kyrgyzstan 617 28087 2.0 Canada
34 2137 1.2 South Korea 1053 56855 0.2 Latvia 1267 55896 1.8 Chile
10 925 138.6 South Sudan 971 72469 1.2 Lebanon 1289 49500 1.8 Colombia
1633 71597 0.8 Spain 147 4998 90.0 Lesotho 25 1827 79.9 Congo
28 4429 3.7 Sri Lanka 409 24288 1.5 Libya 592 43687 2.2 Costa Rica
47 726 17.9 Sudan 1349 82764 0.3 Lithuania 10 1709 58.2 Cote d'Ivoire
1349 84897 2.3 Sweden 18 995 114.8 Madagascar 1527 70860 0.4 Croatia
1208 71354 1.0 Switzerland 59 1767 70.1 Malawi 40 7555 1.6 Cuba
78 1150 0.4 Syria 41 11096 3.3 Malaysia 311 58266 1.3 Cyprus
9 1395 15.2 Tajikistan 97 3874 55.6 Mauritania 2590 147350 1.3 Czechia
14 1443 65.8 Togo 9 936 2.3 Mauritius 421 41054 2.6 Denmark
104 5989 1.9 Trinidad-Tobago 1623 17671 4.2 Mexico 312 23708 4.3 Dominican Republic
781 22870 1.2 Tunisia 1331 59714 0.4 Moldova 979 19547 2.5 Ecuador
400 45036 0.7 Turkey 6 4326 0.9 Mongolia 121 2049 7.8 Egypt
7 899 57.8 Uganda 241 13592 3.6 Morocco 316 10097 5.5 El Salvador
880 43289 0.2 Ukraine 25 2194 69.1 Mozambique 76 5145 31.8 Equatorial Guinea
155 48728 3.4 United Arab Emirates 59 2620 21.9 Myanmar 3 972 121.5 Eritrea
1876 64562 0.8 United Kingdom 222 17837 46.2 Namibia 769 85739 0.1 Estonia
1697 94113 1.7 United States 104 9600 63.7 Nepal 27 1977 89.0 Ethiopia
407 40700 2.6 Uruguay 989 79722 1.0 Netherlands 157 14747 0.3 Finland
19 2531 0.7 Uzbekistan 27 1015 3.4 Nicaragua 1441 73395 0.7 France
62 6111 4.7 Venezuela 10 794 73.7 Nigeria 57 9272 33.4 Gabon
67 4891 78.2 Zambia 2007 67754 0.4 North Macedonia 70 2318 44.4 Gambia
103 2508 44.9 Zimbabwe 126 18995 2.7 Norway 970 72117 0.5 Georgia
. . . . 24 947 50.5 Oceania 936 35919 1.7 Germany

The findings of this work (see Figure 1) show a significant correlation between the level of sanitation in the various countries as reflected in the population’s mortality rate from diarrhea (pre-COVID-19 pandemic) and confirmed COVID-19 cases (p < 0.000, r=-0.524). In addition, a significant correlation was obtained (Figure 2) between the level of sanitation in the various countries as reflected in the population’s mortality rate from diarrhea (pre-COVID-19 pandemic) and the mortality rate from COVID-19 (p < 0.000, r=-0.471). Division of the countries into two groups according to their mortality rate from diarrheal diseases shows that the mortality rate from COVID-19 is significantly lower in countries with a low level of sanitation and a high mortality rate from diarrhea (more than 10 deaths from diarrheal diseases per 100,000 individuals) in countries with a high level of sanitation (less than 10 deaths from diarrheal diseases per 100,000 individuals) (p=3, E-13). Similar significant results were obtained when examining the effect of the mortality level from diarrheal diseases in different countries on the average number of confirmed cases of COVID-19 per million (p=7, E-21) (Figure 3).

Discussion

In this work, it is suggested that fecal-oral infection with SARS-CoV-2 is more common under low sanitation conditions than respiratory infection, and that a high proportion of those who are infected with the virus via the fecal-oral route are asymptomatic. The wide range of COVID-19 cases and mortality rates for countries with a good level of sanitation, as evident from the very small number of deaths from diarrheal diseases, indicates that factors other than sanitation level may affect the number of COVID-19 cases and mortality rates in the absence of the protective effect of a low level of sanitation.

This hypothesis is supported by the following finding: SARS-CoV-2 can cause severe pathology in the lungs driven by an exaggerated immune response, whereas infection in the intestine generally seems to cause minor or no symptoms [5, 18-19]. Nonetheless, the results of a meta-analysis of the prevalence and mortality of COVID-19 patients with gastrointestinal symptoms indicate that the mortality among patients with gastrointestinal symptoms is similar to the overall mortality [20]. Another meta-analysis found conflicting results and reported that diarrhea is associated with increased severity of disease for COVID-19 [21]. Since this meta-analysis data was obtained from patients of countries presenting a high level of sanitation, it is likely that in most cases, the initial site of infection of COVID-19 patients was the respiratory system and that the infection of the digestive system was a secondary event and therefore may not contribute to lowering the severity of the disease. The reduced mortality reported in patients with COVID-19 who present gastrointestinal symptoms may be linked to the absence of a pro-inflammatory response in the gastrointestinal tract despite detection of SARS-CoV-2 [19]. In addition, SARS-CoV-2 neutralization is more closely correlated with IgA than IgM or IgG in the first weeks after symptom onset [22]. Furthermore, in humans, intestinal IgA are mostly dimeric, and dimeric IgA was reported to be 15 times more potent against SARS-CoV-2 than IgA monomers [23-24]. Analysis of the structural component of the corona viruses family suggested that members of this group persist in the environment for a longer period and possess the highest fecal-oral components but relatively low respiratory transmission components [25]. Indeed, immunofluorescence and polymerase chain reaction (PCR) analyses of intestinal biopsies obtained from asymptomatic individuals at four months after the onset of COVID-19 revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small intestine of 7 out of 14 individuals [26].

The well-established Syrian hamster model was recently used to experimentally delineate the relative contribution of fomite and airborne transmission and to study the impact of the SARS-CoV-2 transmission route on disease severity [27]. SARS-CoV-2 disease severity and transmission efficiency were increased for airborne compared to fomite exposure in Syrian hamsters and fomite SARS-CoV-2 exposure displayed delayed replication kinetics in the respiratory tract and led to less severe lung pathology. Since fomite exposure partially resembles the fecal-oral route of exposure in that the virus is attached to particulate material, these reports support the hypotheses that the fecal-oral route of infection by SARS-CoV-2 results in decreased severity compared to primary infection of the respiratory system.

In order to further test this hypothesis, the populations of countries suffering from a low level of sanitation as well as a low level of COVID-19 cases and mortality must be tested for the presence of SARS-CoV-2 in both feces and nasal cavity samples, in addition to determining the blood antibodies composition. This will enable increasing the population’s exposure to COVID-19, the extent to which those infected with the disease are asymptomatic, and the prevalence of the fecal-oral infection pathway. Determining the SARS-CoV-2 viral RNA sequence in these countries for individuals suffering solely from gastrointestinal symptoms will allow clarification of whether there is a mutation that improves the effectiveness of the fecal-oral infection pathway. Because the microbiome is a key part of the intestinal mucosal barrier sites and plays a major role in shaping the immune system, it may also play an important role in infection by SARS-CoV-2 and subsequent immune responses [5, 13, 28]. It is therefore suggested that the intestinal microbiome of asymptomatic and symptomatic individuals should be analyzed and compared.

Conclusions

A new hypothesis, which can partially explain differences between countries regarding their confirmed COVID-19 cases and mortality rates, is proposed in this article. The proposed hypothesis is that the low confirmed number of COVID-19 cases and mortality rates found in countries with low levels of sanitation are due to fecal-oral infection of the population by SARS-CoV-2, rather than infection of the respiratory system.

Given that intestinal immune responses to infection with SARS-CoV-2 appear to be highly regulated, while those in the lung are exaggerated, understanding the similarities and differences between the two sites will help unravel the different immune responses in individuals suffering from mild and severe COVID-19 symptoms. This will enable better treatment of COVID-19 and the development of improved and more available vaccination techniques. This study highlights the need for developing oral vaccines which may present better immunity outcomes for the COVID-19 pandemic.


References

  1. Cui J, Li F, Shi ZL: Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019, 17:181-192. 10.1038/s41579-018-0118-9
  2. Ahn DG, Shin HJ, Kim MH, et al.: Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-19). J Microbiol Biotechnol. 2020, 28:313-324. 10.4014/jmb.2003.03011
  3. Hasell J, Mathieu E, Beltekian D, Macdonald B, Giattino C, Ortiz-Ospina E, Roser M, Ritchie H: A cross-country database of COVID-19 testing. Sci Data. 2020, 8:345. 10.1038/s41597-020-00688-8
  4. Zhang X, Tan Y, Ling Y, et al.: Viral and host factors related to the clinical outcome of COVID-19. Nature. 2020, 583:437-440. 10.1038/s41586-020-2355-0
  5. Pearson CF, Jeffery R; Oxford-Cardiff COVID-19 Literature Consortium, Thornton EE: Mucosal immune responses in COVID 19 - a living review. Oxf Open Immunol. 2021, 2:iqab002. 10.1093/oxfimm/iqab002
  6. Yang L, Tu L: Implications of gastrointestinal manifestations of COVID-19. Lancet Gastroenterol Hepatol. 2020, 5:629-630. 10.1016/S2468-1253(20)30132-1
  7. Merzon E, Tworowski D, Gorohovski A, et al.: Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. FEBS J. 2020, 287:3693-3702. 10.1111/febs.15495
  8. Musa HH, Musa TH, Musa IH, Musa IH, Ranciaro A, Campbell MC: Addressing Africa's pandemic puzzle: perspectives on COVID-19 transmission and mortality in sub-Saharan Africa. Int J Infect Dis. 2021, 102:483-488. 10.1016/j.ijid.2020.09.1456
  9. Travaglio M, Yu Y, Popovic R, Selley L, Leal NS, Martins LM: Links between air pollution and COVID-19 in England. Environ Pollut. 2021, 268:115859. 10.1016/j.envpol.2020.115859
  10. Debnath M, Banerjee M, Berk M: Genetic gateways to COVID-19 infection: Implications for risk, severity, and outcomes. FASEB J. 2020, 34:8787-8795. 10.1096/fj.202001115R
  11. Shapira G, Shomron N, Gurwitz D: Ethnic differences in alpha-1 antitrypsin deficiency allele frequencies may partially explain national differences in COVID-19 fatality rates. FASEB J. 2020, 34:14160-14165. 10.1096/fj.202002097
  12. Escobar LE, Molina-Cruz A, Barillas-Mury C: BCG vaccine protection from severe coronavirus disease 2019 (COVID-19) [published correction appears in Proc Natl Acad Sci USA. 2020 Nov 3;117(44):27741-27742].. Proc Natl Acad Sci USA. 2020, 117:17720-17726. 10.1073/pnas.2008410117
  13. Janda L, Mihalčin M, Šťastná M: Is a healthy microbiome responsible for lower mortality in COVID-19? [published online ahead of print, 2020 Oct 15]. Biologia (Bratisl). 2020, 1-11. 10.2478/s11756-020-00614-8
  14. Yaqinuddin A: Cross-immunity between respiratory coronaviruses may limit COVID-19 fatalities. Med Hypotheses. 2020, 144:110049. 10.1016/j.mehy.2020.110049
  15. Pandey D, Verma S, Verma P, et al.: SARS-CoV-2 in wastewater: challenges for developing countries. Int J Hyg Environ Health. 2021, 231:113634. 10.1016/j.ijheh.2020.113634
  16. Heller L, Mota CR, Greco DB: COVID-19 faecal-oral transmission: are we asking the right questions?. Sci Total Environ. 2020, 10:138919. 10.1016/j.scitotenv.2020.138919
  17. Tcheutchoua DN, Tankeu AT, Angong DLW, et al.: Unexpected low burden of coronavirus disease 2019 (COVID-19) in sub-Saharan Africa region despite disastrous predictions: reasons and perspectives. Pan Afr Med J. 2020, 37:352. 10.11604/pamj.2020.37.352.25254
  18. Livanos AE, Jha D, Cossarini F, et al.: Gastrointestinal involvement attenuates COVID-19 severity and mortality. Preprint medRxiv. 2020, 10.1101/2020.09.07.20187666
  19. Livanos AE, Jha D, Cossarini F, et al.: Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms [published online ahead of print, 2021 Mar 4]. Gastroenterology. 2021, 10.1053/j.gastro.2021.02.056
  20. Tariq R, Saha S, Furqan F, Hassett L, Pardi D, Khanna S: Prevalence and mortality of COVID-19 patients with gastrointestinal symptoms: a systematic review and meta-analysis. Mayo Clin Proc. 2020, 95:1632-1648. 10.1016/j.mayocp.2020.06.003
  21. Ghimire S, Sharma S, Patel A, et al.: Diarrhea is associated with increased severity of disease in COVID- 19: systemic review and metaanalysis. SN Compr Clin Med. 2021, 1-8. 10.1007/s42399-020-00662-w
  22. Sterlin D, Mathian A, Miyara M, et al.: IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med. 2021, 13:eabd2223. 10.1126/scitranslmed.abd2223
  23. Chen K, Magri G, Grasset EK, Cerutti A: Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA. Nat Rev Immunol. 2020, 20:427-441. 10.1038/s41577-019-0261-1
  24. Wang Z, Lorenzi JCC, Muecksch F, et al.: Enhanced SARS-CoV-2 neutralization by dimeric IgA. Sci Transl Med. 2021, 13:1555. 10.1126/scitranslmed.abf1555
  25. Goh GK, Dunker AK, Uversky V: Prediction of intrinsic disorder in MERS-CoV/HCoV-EMC supports a high oral-fecal transmission. PLoS Curr. 2013, 5:
  26. Gaebler C, Wang Z, Lorenzi JCC, et al.: Evolution of antibody immunity to SARS-CoV-2. Nature. 2021, 591:639-644. 10.1038/s41586-021-03207-w
  27. Port JR, Yinda CK, Owusu IO, et al.: SARS-CoV-2 disease severity and transmission efficiency is increased for airborne compared to fomite exposure in Syrian hamsters. Nat Commun. 2021, 12:4985. 10.1038/s41467-021-25156-8
  28. Powell N, MacDonald TT: Recent advances in gut immunology. Parasite Immunol. 2017, 39:10.1111/pim.12430

Original article
peer-reviewed

Does Fecal-Oral Transmission of SARS-CoV-2 Due to Low Sanitation Conditions Contribute to Low Mortality Rates From COVID-19


Author Information

Nathan Rothschild Corresponding Author

Biotechnology, Tel-Hai College, Tel-Hai, ISR


Ethics Statement and Conflict of Interest Disclosures

Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.



Original article
peer-reviewed

Does Fecal-Oral Transmission of SARS-CoV-2 Due to Low Sanitation Conditions Contribute to Low Mortality Rates From COVID-19


Figures etc.

SIQ
8.9
RATED BY 2 READERS
CONTRIBUTE RATING

Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. Learn more here.