Worldwide Evolution of COVID-19

The SARS-CoV-2 causing COVID-19 has reached pandemic levels since March 2020. ^{Reference Cucinotta and Vanelli43} In the absence of vaccines or curative medical treatment, COVID-19 exerts a huge global impact on public health and health-care delivery. SARS-CoV-2 not only causes viral pneumonia but has major implications for the cardiovascular CV system. ^{Reference Zheng, Ma and Zhang44} Patients with CV risk factors, including male sex, advanced age, diabetes, hypertension, and obesity, as well as patients with established CV and cerebrovascular disease, have been identified as particularly vulnerable populations with increased morbidity and mortality when suffering from COVID-19. ^{Reference Driggin, Madhavan and Bikdeli45}

Viral respiratory infections represent a very significant part of the morbidity observed in the patient and remain the main cause of death from infectious agents. This route of transmission remains a major source of global pandemics due to rapid human-to-human transmission through the respiratory tract. ^{Reference Lina46} The myocardial damage by means of the receptor for the angiotensin converting enzyme 2 (ACE2), which cardiomyocytes express in a significant amount. This could be the cause of true myocarditis; according to Ruan et al., ^{Reference Ruan, Yang and Wang47} the SARS-CoV viral RNA was detected in 35% of human hearts autopsied during the SARS epidemic. This shows that SARS-CoV can cause ACE2-dependent myocardial infarction.

ACE2 is an enzyme of the renin angiotensin system (RAS) that is expressed on the cell surface of many tissues including brain, heart, kidney, and type 2 alveolar epithelial cells in the lungs. It is defined as the receptor for the SARS-CoV-2 spike protein, and affect to host cells, however, the affinity of SARS-CoV-2 for ACE2 is 10- to 20-fold higher than that of SARS-CoV, and induce a high transmissibility. ^{Reference Hoffmann, Kleine-Weber and Schroeder48}

ACE2 converts angiotensin II (Ang II) into Ang-1 to -7, that lowers blood pressure with vasodilation and by promoting kidney sodium and water excretion. ^{Reference South, Shaltout and Washburn49} ACE2 shares approximately 60% homology with ACE. ACE converts Ang I into Ang II, which acts at the type 1 angiotensin receptor (AT1R) by increasing blood pressure and inducing vasoconstriction, increasing kidney reabsorption of sodium and water, and increasing oxidative stress to promote inflammation and fibrosis. ^{Reference Sparks, Crowley and Gurley50}

Although clinical manifestations are dominated by respiratory symptoms up to acute respiratory distress syndrome (ARDS), the virus has a double cardiovascular impact: on the one hand, the infection will be more intense if the host has comorbidities (cardiovascular disease) and, on the other hand, the virus can by itself cause life-threatening cardiovascular damage. Several data had shown that Middle East respiratory syndrome coronavirus (MERS-CoV) could be the cause of acute myocarditis. ^{Reference Alhogbani51} Data obtained from patients infected with SARS-CoV and monitored over a 12-y period argue in favor of a deregulation of lipid metabolism induced by the virus, which could be at the origin of an increase in events long-term cardiovascular disease in survivors without the mechanism being identified at this time. ^{Reference Wu, Zhou and Sun52}

People with diabetes have impaired immune-response to infection both in relation to cytokine profile and to changes in immune-responses, including T-cell and macrophage activation, ^{Reference Ferlita, Yegiazaryan and Noori53} and are at increased risk of infections, including influenza, and for related complications, such as secondary bacterial pneumonia, many patients with diabetes can be in poor metabolic control when infected by COVID-19. Poor glycemic control impairs many aspects of the immune response to viral infection that lead to infection in the lungs. ^{Reference Critchley, Carey and Harris54} In most cases, diabetes is associated with obesity that is a risk factor for severe infection. ^{Reference Huttunen and Syrjänen55} During the influenza A H1N1 epidemic in 2009, the disease was more critical and had a 2-fold longer duration in the patients with obesity who were then treated in intensive care units compared with the background population. ^{Reference Honce and Schultz-Cherry56} People with obesity also have mechanical respiratory problems, with reduced ventilation of the basal lung sections increasing the risk of pneumonia as well as reduced oxygen saturation of blood. ^{Reference Dixon and Peters57}

Diabetic complications, such as ischemic heart disease and diabetic kidney disease, may complicate the situation for people with diabetes, cuasing an increase of the severity of COVID-19 disease and the need for special care such as acute dialysis. Some studies show that COVID-19 could induce acute cardiac injury with heart failure, leading to deterioration of systemic circulation. ^{Reference Li, Yang and Zhao58}

Furthermore, inflammation plays a critical role in the progression of crystal-caused disease and can be seen in patients with particle-induced lung disease. ^{Reference Mossman and Glenn59} A study from Dostert et al. has shown that exogenous particles such as asbestos (asbestosis) or crystalline silica (silicosis), activate the NLRP3 inflammasome. ^{Reference Dostert, Petrilli and Van Bruggen60} The NLRP3 inflammasome detects crystalline warning signs that can occur during autoinflammatory diseases, and environmental diseases, such as silicosis or asbestosis. ^{Reference Hornung, Bauernfeind and Halle61} Interleukin (IL) -1 cytokines are potent mediators of innate immunity in response to exposure to crystalline silica ^{Reference Driscoll and Maurer62} and have been implicated in the pathophysiology of human and experimental diseases. ^{Reference Huaux63}

Damby demonstrated the propensity of volcanic cristobalite to activate the NLRP3 inflammasome, following a series of conclusive toxicological investigations of ash from recent major eruptions. The NLRP3 inflammasome has become a central mechanism in mediating cellular responses to various endogenous and exogenous signals and particles related to environmental and lifestyle diseases, given the established danger posed by respirable crystalline silica in occupational settings, the ability of volcanic ash to stimulate the release of IL-1β by macrophages in vitro, and the observation that the instigation of chronic crystalline silica disease depends on NLRP3. ^{Reference Mossman and Glenn59,Reference Damby, Horwell and Baxter64}

The researchers demonstrate that SARS-CoV-2 causes severe lung pathology by inducing pyroptosis, ^{Reference Yang65} a highly inflammatory form of programmed cell death. ^{Reference Cookson and Brennan66} This type of cell death is carried out by macrophages and other immune cells of the immune system causing symptoms such as lymphopenia ^{Reference Panesar67} that blocks an effective immune response to the virus.

As the molecular biology of SARS-CoV-2 is still being studied, inflammatory mechanisms similar to SARS-CoV-1 are known. A viral protein encoded by ORF8b interacts directly with the inflamasome NLRP3 (leucine-rich repeat of the nucleotide binding domain [NLR] and receptor 3 containing the pyrin domain), ^{Reference Shi, Nabar and Huang68} which activates the adapter protein ASC and caspases 4, 5, and 11. Simultaneously, it induces proinflammatory cytokines (eg, IL-1β and IL-18), ^{Reference Man, Karki and Kanneganti69} Therefore, it is necessary to inhibit pyroptosis by acting on NLRP3 in the lungs. The mechanisms of inhibition of NLRP3 have been studied, ^{Reference Zahid, Li and Kombe70} and melatonin acts as an inflammasome inhibitor of NLRP3. ^{Reference Ma, Chen and Feng71} In the bacterial pneumonia model, lipopolysaccharide (LPS) -induced mouse model, melatonin was shown to successfully inhibit pneumonia by interfering with the NLRP3 inflammasome, protecting macrophages from pyroptosis. ^{Reference Zhang, Li and Grailer72} Other publications also demonstrate that melatonin can be an effective inhibitor of pyroptosis and associated pathologies. ^{Reference Wang, Bian and Zhang73}

Chong-Shan Shi et al. demonstrate that SARS-CoV can activate the NLRP3 inflammasome in macrophages through ORF8b. Although SARS-CoV abortively infects macrophages/monocytes, there may be enough ORF8b to affect the integrity of the lysosome, autophagy pathways, and NLRP3 inflammasomes. Unlike macrophages, SARS-CoV productively replicates in lung epithelial cells. These cells also express NLRP3 and can assemble NLRP3 inflammasomes. In humans infected with SARS-CoV, the full impact of ORF-8b on the pathways we delineated in this study is likely on the pulmonary epithelium. ORF8b may contribute to cytokine storm and inflammation activation that occurs during severe SARS-CoV infection. ^{Reference Shi, Nabar and Huang74} In the future, live virus clearance studies are required to assess the effects of ORF8b-mediated intracellular aggregates and ORF8b-mediated activation of NLRP3. However, here we identify novel mechanisms through which ORF8b can contribute to the pathogenesis of SARS.

In general, SARS-CoV-2 infection can be transmitted through respiratory droplets, which are 5-10 microns (µm) in diameter. ⁵ According to the available data, the COVID-19 virus is transmitted mainly through contact with respiratory droplets ^{Reference Liu, Liao and Qian75} from a person with respiratory symptoms (eg, cough or sneeze), the droplets gaining access through mucous membranes (mouth and nose) or conjunctiva (eyes). In addition, transmission can occur through fomites droplets in the immediate environment of a person infected. ^{Reference Ng, Lee and Yang76} Airborne transmission of the COVID-19 virus may be possible in specific circumstances and locations where procedures are performed or treatments that can generate aerosols, such as endotracheal intubation, bronchoscopy, open aspiration, administration of a drug by nebulization, manual ventilation before intubation. However, there has been some evidence that the COVID-19 virus can cause intestinal infection and be present in feces, ^{Reference Zhang, Chen and Zhu77} although no fecal-oral transmission has been reported.

Measures to avoid a contagion involve the following: correct, frequent hand washing with soap and water or with an alcohol-based hand sanitizer of at least 70%; keeping a distance of at least 2 meters (6 feet) from other persons, especially those who cough, sneeze, and have a fever; and disinfecting inanimate surfaces with disinfectants as often as possible.

The World Health Organization (WHO) has received reports of the existence of variants of SARS-CoV-2 that cause changes in transmissibility, clinical presentation, and severity, causing concern as to if there is an impact on the diagnosis, therapeutics, and protection from vaccines. Reports mentioning virus variants from the Kingdom of Denmark, the United Kingdom of Great Britain and Northern Ireland, and the Republic of South Africa have raised interest and concern about the impact of viral changes (Table 2).

Table 2. Variants of the SARS-CoV-2 virus

These 4 variants share a specific mutation called D614G. ^{Reference Korber, Fischer and Gnanakaran78,Reference Zhang, Jackson and Mou79} This mutation provides the variants the ability to spread more rapidly than the prevailing viruses. ^{Reference Zhou, Thao and Hoffmann80,Reference Volz, Hill and McCrone81} As of December 30, 2020, variations have been reported in another 31 countries. Therefore, it is important that genomic surveillance be conducted to identify and characterize the variants of the virus and how these variants influence the severity of COVID 19 cases and the efficacy of vaccines and treatments. This is still being evaluated by the scientific community. ^{Reference Hartley, Tillett and AuCoin82–Reference Quéromès, Destras and Bal84}

Volcanism and the Distribution of Volcanic Ash in Ecuador

Ecuador is a country with an extremely high density of volcanoes in its continental as well as insular territory. ^{Reference Toulkeridis85–Reference Toulkeridis and Angermeyer87} The Galapagos archipelago, as a result of hot spot geodynamics, possesses more than 3000 mostly extinct volcanoes, while the Ecuadorian mainland has more than 250 volcanoes due to the subduction of the Nazca Plate below the South American continent. ^{Reference Toulkeridis85,Reference Toulkeridis86} From the Galapagos, an aseismic ridge of extinct volcanoes, called Carnegie, is transported above the oceanic Nazca Plate toward the continent, where its subduction gives rise to the striking NNE-SSW volcanic chains of Ecuador. ^{Reference Lonsdale88–Reference Coltorti and Ollier90} In both environments, only a minor amount of the existing volcanoes are active, but their activity contemplates with a variety of volcanic hazards, including the massive emission of fine-grained volcanic ash, among other threats. ^{Reference Toulkeridis, Buchwald and Addison91–Reference Echegaray-Aveiga, Rodríguez and Toulkeridis101} In continental Ecuador, there are 19 active volcanoes, of which 5 have been erupting in several occasions during the past 22 y. ¹⁰² (Smithsonian Institution Global Volcanism Program, 2021). These 5 erupting volcanoes have been Sangay, Tungurahua, Guagua Pichincha, Reventador, and Cotopaxi (Figure 3). Sangay has a permanent activity with higher intensities in 2004-2011, 2013, and 2016 as well as strong intensities in 2018-2021. ¹⁰³ Tungurahua erupted after 80 y of tranquility in 1999 and continued erupting with minor interruptions until 2016. ¹⁰⁴ Guagua Pichincha has been occasionally erupting between 1999 and 2001 and again in 2009. ¹⁰⁵ The Reventador volcano erupted in 1976 and 2002 and continued with major interruptions until 2021, while Cotopaxi has been very active only in 2015. ^106,107

Figure 3. Main direction of volcanic ash distribution within a rose-diagram of the volcanoes Tungurahua (4412 satellite images), Reventador (2744), Sangay (1641), Cotopaxi (151), and Guagua Pichincha (31). All data are normalized to 100%, for each evaluated volcano.

In all these periods, all 5 volcanoes have emitted fine-grained volcanic ash in a variety of amounts and reach. ^{Reference Vaca Mora, Arroyo Rodriguez and Debut97,Reference Toulkeridis and Zach98,Reference Toulkeridis, Seqqat and Torres108,Reference Aviles-Campoverde, Chunga and Ortiz-Hernández109} Since September 1999, these eruptive phases have been observed from space due to the satellite imagery of the Satellite Services Division of the National Environmental Satellite, Data, and Information Service (NESDIS). Using the available data, the distribution of the volcanic ash has been traced in the corresponding areas of Ecuador, allowing evaluation of the areas experiencing the fallout of this volcanic hazard. Some 8703 satellite images gathered between September 1999 and January of 2021 have been evaluated, allowing characterization of the areas influenced by the volcanic ash precipitation. It is well known that vocanic ash fallout is the cause of a high amount of previously described health vulnerabilities and damage or interruptions of strategic infrastructure. ^{Reference Toulkeridis and Zach98,Reference Echegaray-Aveiga, Rodríguez and Toulkeridis101,Reference Toulkeridis, Seqqat and Torres108,Reference Aguilera, Viteri and Seqqat110}

Such fine-grained volcanic materials have a wide range of composition as well as morphologies due to a variety of processes during the rise of the magma and its subsequent fractionalization prior eruption. ^{Reference Eichelberger111–Reference Karbowska and Zembrzuski113} We have taken samples at different, regular time periods of all active volcanoes of which some results have been published elsewhere. ^{Reference Toulkeridis, Arroyo and Cruz D’Howitt95,Reference Vaca Mora, Arroyo Rodriguez and Debut97,Reference Aguilera, Viteri and Seqqat110}

A field emission gun scanning electron microscope (FEG-SEM), brand TESCAN model MIRA3, was used to characterize all the samples. Chemical analysis was performed using the EDX technique with a BRUKER detector XFlash 6130, resolution 123 eV for Mn alpha. This was done using a double adhesive layer of carbon tape on SEM stubs. To ensure conductivity of the samples, morphology analysis was done applying a gold coating of around 20 nanometers using the sputter coater QUORUM Q150R. The main elements analyzed were Na, Mg, Al, Si, P, K, Ca, Ti, Mn, Fe. Other elements are present but at lower than the limit of detection. The compositions of ashes of Pichincha, Cotopaxi, Reventador, Sangay, and Tungurahua volcanoes are listed in Table 3. The elements Ti, P, and Mn have a percentage weight concentration lower than 1.5%.

Table 3. Average weight percentages of each analyzed element in wt %, of all ash samples of the studied active volcanoes (Mn<1%, Ti and P<1.5%)

All of the volcanic ashes had an Si composition greater than 40% wt; Si is an aggressive element for human lungs. SEM pictures showed that ashes are quite inhomogeneous in their morphology. The size of the particle determines the distance it travels, and the particles sampled ranged in size from nanometers to millimeters. As an example, from the most recent Cotopaxi eruption, particles ranged in size from 10 nm to 300 µm at 20 km distance from the crater, and a mean size 113.5 µm. Except of the Cotopaxi volcano, all other fine-grained pyroclastic material have been juvenile. The 101 days in 2015 of expulsion of volcanic ash from the Cotopaxi volcano has been exclusively of reworked material due to the fact that it has been originated by hydrothermal processes. ^{Reference Toulkeridis, Arroyo and Cruz D’Howitt95,Reference Vaca Mora, Arroyo Rodriguez and Debut97} Therefore, the reworked fine-grained pyroclastic material of the Cotopaxi volcano was of angular to sub-angular morphologies, while the predominant material of Sangay, Reventador, Guagua Pichincha, and Tungurahua volcanoes has been varied from rounded to sub-angular shapes.

The continental volcanoes of Ecuador are oriented perpendicular to the subduction zone along 4 NNE-SSW arcs, within the western volcanic cordillera, the Interandean Valley, the Cordillera Real, and the Subandean Basin. The evaluation of the distribution of fine-grained volcanic material of the 5 active volcanoes, based on 8979 satellite images (September 1999 – March 2021), indicates the predominant direction of travel to be mainly toward the west from their crater. Hereby, the predominant angle with above 60% of all possible directions of the ash distribution has been between 250 and 290 degrees (Figure 3). All other directions occur as well, but obviously to a minor degree, with the eastern directions being the very least of all. Volcanic ash fallout in southern regions and cities, such as Cuenca and Loja, or coastal cities, such as Guayaquil, occur occasionally, but less frequently; therefore, the areas are affected to a lesser extent (Figure 4).

Figure 4. Main direction and predominant reach of volcanic ashes (light gray colors) in Ecuador based on the activity of the volcanoes Tungurahua (TUN), Reventador (REV), Sangay (SAN), Cotopaxi (COT), and Guagua Pichincha (PIC), with the 3 most populated cities Quito (Q), Guayaquil (G), and Cuenca (C). Red triangles are further active volcanoes.

Not every contact with a coronavirus infected person leads to an infection, although the risk of transmitting the virus or its mutants, or even becoming infected, may vary due to a variety of situations. However, the dominant factor is the dose of the virus and certainly the closeness and time in contact with the an infected person. ^{Reference Ortiz-Prado, Simbaña-Rivera and Gomez-Barreno114} Therefore, it is a simple matter of time when in an area like Ecuador with very little or almost no preventive measures an increasing number of persons will be infected the coronavirus and its mutants. During a second or even third infection wave, the most vulnerable persons will have less and less opportunities to avoid contagions. The risk is particularly high if measures to reduce or limit the outbreak have been abandoned too early, due to countermeasures to avoid the increasing economic crisis as is occurring in Ecuador. ^{Reference Adams-Prassl, Boneva and Golin115,Reference Friedman, Friedman and Johnson116} Infection rates increase also because of a variety of reasons, such as fatigue, social and economic backgrounds, and a false sense of security among, many others. This phenomenon has been observed and documented worldwide. ^{Reference Dubey, Biswas and Ghosh117–Reference Islam, Bodrud-Doza and Khan119} Another fundamental aspect is based on the unsolved technical and economic issues in hospitals and their intensive care units, especially in Latin America. Such problems existed before the pandemic and have worsened since. ^{Reference Remuzzi and Remuzzi120–Reference Sasangohar, Jones and Masud122}

Based on the aforementioned data, a worsening of public health in areas in and close to volcanic ash emissions may be compared with that reported for air contaminated areas, which also increase vulnerability to the coronavirus. ^{Reference Wu, Nethery and Sabath123–Reference Urrutia-Pereira, Mello-da-Silva and Solé125} The most affected Ecuadorian population, however, will be the persons who are living and working in the shadow of the ash fallout westward of the main concentration of the active volcanoes, being within the Highlands, the Inter-Andean Valley, and the coastal regions, as indicated in the current study (Figures 3-5). For those persons, it is imperative to protect them fromCOVID-19, even more so than people in areas with less contamination due to the absence of volcanic ash emissions.

Figure 5. The maps represent the monthly death rates per 100,000 inhabitants that have been standardized taking the official data of deaths published as of March 13, and the population data taken from the projections to the year 2019-2021 made by the INEC, using data from the Census of Population and Housing in 2010. The lowest mortality rates are represented in green and the highest in red, with yellow representing the average values according to the color code of the traffic light adopted by the Ecuadorian authorities.