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      COVID-19 in Latin America: Novel transmission dynamics for a global pandemic?

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          Abstract

          The COVID-19 virus expanded from China into Western Asia, Europe, and North America, impacting many of the world’s wealthiest countries. Brazil reported Latin America’s first case in late February 2020, and in less than a month, over 7,000 COVID-19 cases have been confirmed among nearly every country and territory in Latin America and the Caribbean (LAC). The LAC outbreak appears to be about two weeks behind the United States and Canada and about three to four weeks behind Western Europe. Thus, the global COVID-19 pandemic is entering a new phase, not only expanding beyond primarily temperate Northern Hemisphere countries into the tropics but also spreading to a geopolitical region marked by significantly worse poverty, water access and sanitation, and distrust in public governance (Fig 1). We believe that these aspects of the Latin American context are likely to substantially affect the transmission dynamics and scope of the COVID-19 outbreak in LAC, with potential implications for the trajectory of the global pandemic. 10.1371/journal.pntd.0008265.g001 Fig 1 Socioeconomic differences between “First 15” COVID-19 countries and LAC. Significant differences are found in the HDI [23], WPI [24], and CPI [25] between the first 15 (“First 15”) countries where COVID-19 was recorded to have expanded rapidly out of China (blue) and the 15 most populous countries in LAC (red). HDI: (Welch-corrected t test; AverageFirst 15 = 0.907; AverageLAC = 0.721; P < 0.0001); WASH: (Welch-corrected t-test; AverageFirst 15 = 95.11; AverageLAC = 49.17; P < 0.0001); CPI: (Welch-corrected t-test, AverageFirst 15 = 70.9; AverageLAC = 33.87; P < 0.0001). We classified “First 15” countries as the 15 non-Chinese countries with the highest reported number of COVID-19 cases in the March 8, 2020 COVID-19 Situation Report [26]. CPI, Corruption Perceptions Index; HDI, Human Development Index; LAC, Latin America and the Caribbean; WASH, Water, Sanitation, and Hygiene; WPI, Water Poverty Index. COVID-19, temperature and humidity, and transmission One of the most important questions in COVID-19 global epidemiology is whether warmer temperature and higher humidity impedes transmission. The initial countries to experience the largest increase in day over day new COVID-19 cases experienced cold and dry conditions typical for wintertime in temperate Northern Hemisphere. Among Chinese cities, the COVID-19 basic reproductive number (R) appears to be inversely related with temperature and relative humidity, albeit with substantial variation [1]. One early travel-based model of COVID-19 global spread predicted that several southeastern Asian countries should have been the first non-Chinese countries to experience substantial COVID-19 outbreaks [2]. Instead, substantial outbreaks outside China occurred first in Western Asia and Europe. Additional support for the hypothesis that higher temperature and humidity dampens COVID-19 transmission comes from laboratory experiments on the severe acute respiratory syndrome (SARS) virus and other coronaviruses, which found that increasing temperature and humidity decreases the virulence of dried virus on smooth surfaces [3]. Some commentators have suggested that COVID-19 transmission may decline as the Northern Hemisphere transitions to summer, as happens with seasonal influenza. However, as demonstrated by 2009 H1N1 influenza, novel pandemic respiratory virus transmission dynamics are often decoupled from the climatic conditions that drive the seasonality of influenza [4]. While seasonal influenza does vary with temperature and humidity in LAC, the region’s environmental heterogeneity causes peaks in influenza transmission to be asynchronous across the region [5]. Thus, although environmental conditions in March 2020 appear to be less favorable for COVID-19 transmission across most of LAC, by July 2020 many South American cities have climatic conditions that would appear more favorable for rapid COVID-19 transmission [1], coinciding with a strong peak of seasonal influenza transmission in subtropical South America between May and October [6]. Therefore, while the environmental models suggest that LAC’s higher temperature and humidity may slow the initial COVID-19 transmission, this effect may be ephemeral for much of the region. Any tropical climate effect may also be limited by the ubiquity of indoor air conditioning, which creates indoor environments with temperature and humidity ranges favorable to coronavirus persistence [3]. Most importantly, climate-based transmission models assume COVID-19 spreads primarily via indirect surface contact transmission. We believe that other transmission models (especially fecal–oral) may be as or more important for COVID-19 transmission in LAC, making predictions from climate models premature. The potential for increased fecal–oral COVID-19 transmission in LAC Although a respiratory disease, COVID-19 is likely transmissible via fecal–oral contamination. While only a portion of Wuhan patients experienced gastrointestinal symptoms, these generally presented prior to respiratory symptoms [7]. Fecal swabs test positive using reverse transcription PCR (RT-PCR) for COVID-19 virus in slightly more than half of sampled patients [8], and stool samples remained positive for an average of 11 days after respiratory swabs turned negative [8]. During the Middle East respiratory syndrome (MERS) and SARS (and now COVID-19) coronavirus epidemics, patients often experienced gastrointestinal symptoms, and these viruses were detected in stool samples and shown to infect and replicate in intestinal tissues [9]. A large SARS outbreak in a Hong Kong apartment complex is believed to be due to virus particles that were aerosolized from improperly installed wastewater pipes [10]. Finally, molecular modeling suggests that the COVID-19 (like MERS and SARS) uses the angiotensin-converting enzyme II (ACE2), which is highly expressed in both lung and some intestinal epithelial tissues [11] as its host receptor. Collectively, this suggests that fecal–oral transmission will probably be important for COVID-19 spread [9]. Thus, LAC will be the first region where water scarcity and poor sanitation may substantially impact COVID-19 spread. The World Bank estimates that 36 million people in LAC lack access to improved drinking water, and 110 million lack access to improved sanitation [12]. In LAC urban slums, the lack of in-house water delivery results in reduced water usage, limited handwashing, and poor family hygiene, leading to widespread fecal contamination [13]. In LAC households without clean water delivery, drinking water is often boiled and stored; yet this water often becomes fecally contaminated [13]. Importantly, coronaviruses can remain infectious for weeks in room temperature water [14]. Like poor clean water access, inadequate sewage disposal causes chronic fecal contamination and disease in LAC, even when improved water is available [15]. Many LAC countries score poorly on the WASH index, which is a measure of access to abundant clean water and improved sanitation. If increased transmission due to fecal contamination is combined with climatically reduced contact transmission, the epidemiological dynamics of COVID-19 in LAC may be fundamentally distinct from the dynamics currently observed in the Northern Hemisphere. We can look to the epidemiological characteristics of norovirus and cholera in LAC for insights. In LAC slums with poor water access and sanitation, over 80% of children are infected with at least one strain of norovirus in their first year of life [16]; adults are only infected when novel genotypes enter the community. Cholera is a disease of poverty exacerbated by poor access to clean water. During the 1991 cholera epidemic in Peru, cholera spread nearby instantaneously from a single town to nearly communities along the Peruvian coast with attack rates over 2% in just the first month of the epidemic [17]. Because cholera is often transmitted via contaminated stored water and food, up to half of all family members show signs of infection within two days of the presentation of an index case [18]. If COVID-19 spreads in a similar fashion, we can expect increased intrafamily and intraneighborhood infection rates. Like norovirus, this may result in rapid herd immunity within infected communities [16]; however, with a large peak of simultaneous infections, local health centers will almost certainly be overwhelmed. Extreme rates of local infection can cause complex metapopulation dynamics that could favor rapid local eradication while at the same time facilitating long-term regional viral persistence [19]. In the face of this, LAC will need to implement widespread population surveillance of both active cases (using RT-PCR) and prior exposure and potential immunity via serology. COVID-19, weak infrastructure, and poverty COVID-19 expanded from China into some of the world’s richest countries (Fig 1), perhaps masking socio-economic factors in the outbreak’s spread. During recent epidemics, LAC’s poor were more likely to become infected with Zika and more likely bear children with microcephaly [20], suggesting that the burden of COVID-19 may be disproportionately borne by LAC’s poorest and most marginalized. Health infrastructure is weak and inadequate in LAC, where epidemics routinely overwhelm a public health system that suffers from chronic understaffing and a lack of modern medical equipment and diagnostic and therapeutic consumables, including personal protective equipment. If the COVID-19 epidemic in LAC is severe, it is probable that the region will come out of the epidemic even more inequitable than it is now. Thus, the imperative to “flatten the curve” is even greater for LAC than Western Europe and the United States. Not surprisingly, several LAC countries rapidly implemented strict social restrictions (“lockdowns”) to curb transmission, including complete border closures, restricted daytime movements, night-time curfews, and the cessation of intraprovincial travel. Evidence from China suggests that such extreme restrictions should reduce transmission and blunt COVID epidemics. But will LAC citizens comply? Public distrust of government is significantly higher in LAC than in the first countries to experience COVID-19 spread out of China (Fig 1), and this distrust has been shown to erode compliance with public health societal restrictions [21]. Collectively, the interactions between climate, WASH conditions, and other socioeconomic factors suggest that the impacts of COVID-19 in LAC will be more extreme than even that experienced by Western Europe and the United States. Experimental studies and modeling efforts should focus on alternative COVID-19 transmission dynamics, and LAC’s leaders must continue to take immediate and decisive actions to slow the spread of COVID-19. Extreme regulation of social distancing may be required. Fortunately, several commercial ELISA tests predict neutralizing antibody levels for COVID-19 [22]. Widespread serological testing will allow citizens with developed immunity to return back into society and the economy.

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          Most cited references14

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          Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

          In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
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            Prolonged presence of SARS-CoV-2 viral RNA in faecal samples

            We present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time RT-PCR results of all respiratory and faecal samples from patients with coronavirus disease 2019 (COVID-19) at the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China, throughout the course of their illness and obligated quarantine period. Real-time RT-PCR was used to detect COVID-19 following the recommended protocol (appendix p 1). Patients with suspected SARS-CoV-2 were confirmed after two sequential positive respiratory tract sample results. Respiratory and faecal samples were collected every 1–2 days (depending on the availability of faecal samples) until two sequential negative results were obtained. We reviewed patients' demographic information, underlying diseases, clinical indices, and treatments from their official medical records. The study was approved by the Medical Ethical Committee of The Fifth Affiliated Hospital of Sun Yat-sen University (approval number K162-1) and informed consent was obtained from participants. Notably, patients who met discharge criteria were allowed to stay in hospital for extended observation and health care. Between Jan 16 and March 15, 2020, we enrolled 98 patients. Both respiratory and faecal samples were collected from 74 (76%) patients. Faecal samples from 33 (45%) of 74 patients were negative for SARS CoV-2 RNA, while their respiratory swabs remained positive for a mean of 15·4 days (SD 6·7) from first symptom onset. Of the 41 (55%) of 74 patients with faecal samples that were positive for SARS-CoV-2 RNA, respiratory samples remained positive for SARS-CoV-2 RNA for a mean of 16·7 days (SD 6·7) and faecal samples remained positive for a mean of 27·9 days (10·7) after first symptom onset (ie, for a mean of 11·2 days [9·2] longer than for respiratory samples). The full disease course of the 41 patients with faecal samples that were positive for SARS-CoV-2 RNA is shown in the figure . Notably, patient 1 had positive faecal samples for 33 days continuously after the respiratory samples became negative, and patient 4 tested positive for SARS-CoV-2 RNA in their faecal sample for 47 days after first symptom onset (appendix pp 4–5). Figure Timeline of results from throat swabs and faecal samples through the course of disease for 41 patients with SARS-CoV-2 RNA positive faecal samples, January to March, 2020 A summary of clinical symptoms and medical treatments is shown in the appendix (pp 2–3, 6–8). The presence of gastrointestinal symptoms was not associated with faecal sample viral RNA positivity (p=0·45); disease severity was not associated with extended duration of faecal sample viral RNA positivity (p=0·60); however, antiviral treatment was positively associated with the presence of viral RNA in faecal samples (p=0·025; appendix pp 2–3). These associations should be interpreted with caution because of the possibility of confounding. Additionally, the Ct values of all three targeted genes (RdRp, N, E) in the first faecal sample that was positive for viral RNA were negatively associated with the duration of faecal viral RNA positivity (RdRp gene r= –0·34; N gene r= –0·02; and E gene r= –0·16), whereas the correlation of the Ct values with duration of faecal sample positivity was only significant for RdRp (p=0·033; N gene p=0·91; E gene p=0·33). Our data suggest the possibility of extended duration of viral shedding in faeces, for nearly 5 weeks after the patients' respiratory samples tested negative for SARS-CoV-2 RNA. Although knowledge about the viability of SARS-CoV-2 is limited, 1 the virus could remain viable in the environment for days, which could lead to faecal–oral transmission, as seen with severe acute respiratory virus CoV and Middle East respiratory syndrome CoV. 2 Therefore, routine stool sample testing with real-time RT-PCR is highly recommended after the clearance of viral RNA in a patient's respiratory samples. Strict precautions to prevent transmission should be taken for patients who are in hospital or self-quarantined if their faecal samples test positive. As with any new infectious disease, case definition evolves rapidly as knowledge of the disease accrues. Our data suggest that faecal sample positivity for SARS-CoV-2 RNA normally lags behind that of respiratory tract samples; therefore, we do not suggest the addition of testing of faecal samples to the existing diagnostic procedures for COVID-19. However, the decision on when to discontinue precautions to prevent transmission in patients who have recovered from COVID-19 is crucial for management of medical resources. We would suggest the addition of faecal testing for SARS-CoV-2. 3 Presently, the decision to discharge a patient is made if they show no relevant symptoms and at least two sequential negative results by real-time RT-PCR of sputum or respiratory tract samples collected more than 24 h apart. Here, we observed that for over half of patients, their faecal samples remained positive for SARS-CoV-2 RNA for a mean of 11·2 days after respiratory tract samples became negative for SARS-CoV-2 RNA, implying that the virus is actively replicating in the patient's gastrointestinal tract and that faecal–oral transmission could occur after viral clearance in the respiratory tract. Determining whether a virus is viable using nucleic acid detection is difficult; further research using fresh stool samples at later timepoints in patients with extended duration of faecal sample positivity is required to define transmission potential. Additionally, we found patients normally had no or very mild symptoms after respiratory tract sample results became negative (data not shown); however, asymptomatic transmission has been reported. 4 No cases of transmission via the faecal–oral route have yet been reported for SARS-CoV-2, which might suggest that infection via this route is unlikely in quarantine facilities, in hospital, or while under self-isolation. However, potential faecal–oral transmission might pose an increased risk in contained living premises such as hostels, dormitories, trains, buses, and cruise ships. Respiratory transmission is still the primary route for SARS-CoV-2 and evidence is not yet sufficient to develop practical measures for the group of patients with negative respiratory tract sample results but positive faecal samples. Further research into the viability and infectivity of SARS-CoV-2 in faeces is required.
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              COVID-19: Gastrointestinal Manifestations and Potential Fecal–Oral Transmission

              The outbreak of novel coronavirus (2019-nCoV) pneumonia initially developed in one of the largest cities, Wuhan, Hubei province of China, in early December 2019 and has been declared the sixth public health emergency of international concern by the World Health Organization, and subsequently named coronavirus disease 2019 (COVID-19). As of February 20, 2020, a total of >75,000 cumulative confirmed cases and 2130 deaths have been documented globally in 26 countries across 5 continents. Current studies reveal that respiratory symptoms of COVID-19 such as fever, dry cough, and even dyspnea represent the most common manifestations at presentation similar to severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome in 2012, which is firmly indicative of droplet transmission and contact transmission. However, the incidence of less common features like diarrhea, nausea, vomiting, and abdominal discomfort varies significantly among different study populations, along with an early and mild onset frequently followed by typical respiratory symptoms. 1 Mounting evidence from former studies of SARS indicated that the gastrointestinal tract (intestine) tropism of SARS coronavirus (SARS-CoV) was verified by the viral detection in biopsy specimens and stool even in discharged patients, which may partially provide explanations for the gastrointestinal symptoms, potential recurrence, and transmission of SARS from persistently shedding human as well. 2 Notably, the first case of 2019-nCoV infection confirmed in the United States reported a 2-day history of nausea and vomiting on admission, and then passed a loose bowel movement on hospital day 2. The viral nucleic acids of loose stool and both respiratory specimens later tested positive. 3 In addition, 2019-nCoV sequence could be also detected in the self-collected saliva of most infected patients even not in nasopharyngeal aspirate, and serial saliva specimens monitoring showed declines of salivary viral load after hospitalization. 4 Given that extrapulmonary detection of viral RNA does not mean infectious virus is present, further positive viral culture suggests the possibility of salivary gland infection and possible transmission. 4 More recently, 2 independent laboratories from China declared that they have successfully isolated live 2019-nCoV from the stool of patients (unpublished). Taken together, a growing number of clinical evidence reminds us that digestive system other than respiratory system may serve as an alternative route of infection when people are in contact with infected wild animals or sufferers, and asymptomatic carriers or individuals with mild enteric symptoms at an early stage must have been neglected or underestimated in previous investigations. Clinicians should be careful to promptly identify the patients with initial gastrointestinal symptoms and explore the duration of infectivity with delayed viral conversion. To date, molecular modelling has revealed by the next-generation sequencing technology that 2019-nCoV shares about 79% sequence identify with SARS-CoV, indicative of these 2 lineage B β-coronaviruses highly homologous, and angiotensin-converting enzyme II (ACE2), previously known as an entry receptor for SARS-CoV, was exclusively confirmed in 2019-nCoV infection despite amino acid mutations at some key receptor-binding domains. 5 , 6 It is widely accepted that coronavirus human transmissibility and pathogenesis mainly depend on the interactions, including virus attachment, receptor recognition, protease cleaving and membrane fusion, of its transmembrane spike glycoprotein (S-protein) receptor-binding domain, specific cell receptors (ACE2), and host cellular transmembrane serine protease (TMPRSS), with binding affinity of 2019-nCoV about 73% of SARS-CoV. 7 Recent bioinformatics analysis on available single-cell transcriptomes data of normal human lung and gastrointestinal system was carried out to identify the ACE2-expressing cell composition and proportion, and revealed that ACE2 was not only highly expressed in the lung AT2 cells, but also in esophagus upper and stratified epithelial cells and absorptive enterocytes from ileum and colon. 8 With the increasing gastrointestinal wall permeability to foreign pathogens once virus infected, enteric symptoms like diarrhea will occur by the invaded enterocytes malabsorption, which in theory indicated the digestive system might be vulnerable to COVID-19 infection. In contrast, because ACE2 and TMPRSS especially TMPRSS2 are co-localized in the same host cells and the latter exerts hydrolytic effects responsible for S-protein priming and viral entry into target cells, further bioinformatics investigation renders additional evidence for enteric infectivity of COVID-19 in that the high co-expression ratio was found in absorptive enterocytes and upper epithelial cells of esophagus besides lung AT2 cells. However, the exact mechanism of COVID-19–induced gastrointestinal symptom largely remains elusive. Based on these considerations, ACE2-based strategies against COVID-19 such as ACE2 fusion proteins and TMPRSS2 inhibitors should be accelerated into clinical research and development for diagnosis, prophylaxis, or treatment. Last, mild to moderate liver injury, including elevated aminotransferases, hypoproteinemia, and prothrombin time prolongation, has been reported in the existing clinical investigations of COVID-19, whereas up to 60% of patients suffering from SARS had liver impairment. The presence of viral nucleic acids of SARS in liver tissue confirmed the coronavirus direct infection in liver, and percutaneous liver biopsies of SARS showed conspicuous mitoses and apoptosis along with atypical features such as acidophilic bodies, ballooning of hepatocytes, and lobular activities without fibrin deposition or fibrosis. 9 It is believed that SARS-associated hepatotoxicity may be likely with viral hepatitis or a secondary effect associated with drug toxicity owing to high-dose consumption of antiviral medications, antibiotics, and steroids, as well as immune system overreaction. However, little is known about 2019-nCoV infection in liver. Surprisingly, recent single cell RNA sequencing data from 2 independent cohorts revealed a significant enrichment of ACE2 expression in cholangiocytes (59.7% of cells) instead of hepatocytes (2.6% of cells), suggesting that 2019-nCoV might lead to direct damage to the intrahepatic bile ducts. 10 Altogether, substantial effort should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation, and early intervention.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                7 May 2020
                May 2020
                : 14
                : 5
                : e0008265
                Affiliations
                [1 ] University of Oklahoma, Norman, Oklahoma, United States of America
                [2 ] University of Alaska Fairbanks, Fairbanks, Alaska, United States of America
                [3 ] INDICASAT-AIP, City of Knowledge, Republic of Panama
                [4 ] Smithsonian Tropical Research Institute, Balboa, Republic of Panama
                [5 ] John Hopkins University, Baltimore, Maryland, United States of America
                London School of Hygiene & Tropical Medicine, UNITED KINGDOM
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-2939-0239
                http://orcid.org/0000-0001-5195-8540
                http://orcid.org/0000-0001-7991-9164
                http://orcid.org/0000-0002-9037-0712
                Article
                PNTD-D-20-00503
                10.1371/journal.pntd.0008265
                7205198
                32379757
                9f043f1c-a239-4b78-a6c3-b34ec4a0f8d6
                © 2020 Miller et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                The author(s) received no specific funding for this work.
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