The overall purpose of this project is to provide information on the epidemiological and clinical characteristics of the COVID-19 disease in Kazakhstan, contributing to clarify the uncertainties regarding the determinants of the infection, the differences in the progression, and the overall population impact. These main aims will be met providing a scientific response to the following research questions:1. Why some people develop the COVID-19 infection and others not:a. What are the risks and protective factors associated with developing COVID-19 infection, with a special focus to determine the protective effect BCG vaccination?2. Why some people develop symptomatic COVID-19 disease while others remain asymptomatic:a. What is the population extension that the COVID-19 epidemic has had in the country?b. What are the determinants of symptomatic and asymptomatic disease?3. Why some people develop mild, moderate, or severe types of infection:a. What are the characteristics of patients diagnosed with COVID-19?b. What are the determinants of the different progression of those patients?Since SARS-CoV-2, the novel virus that causes coronavirus disease 2019 (COVID-19), was first detectedin December 2019, approximately 5,5 million cases have been reported worldwide, including more than8,500 in Kazakhstan1. The global death tolls exceed 347,000. Kazakhstan has taken a very proactivestrategy to control this infection, conducting population-based surveillance, identifying cases and tracingcontacts, testing and providing healthcare to those patients. Only 35 deaths have been reported in thecountry. Analyzing the epidemiological and clinical characteristics outcomes of COVID-19 patients willbe critical to better understand the evolving epidemiology of this disease, the spectrum of cases, and toguide plan and prioritize health care resources. Cases of pneumonia of unknown cause detected in Wuhan, China were first reported to the WHO Officein China on December 31, 2019. The outbreak was declared a Public Health Emergency of InternationalConcern on January 30, 2020. On February 11 WHO announced a name for the new coronavirus disease:COVID-19, and on March 11 WHO Director-General characterized COVID-19 as a pandemic2.Although in Kazakhstan the impact of COVID-19 has been less severe than in other countries, with a lowCFR of <0.5%, more than 8,500 cases have been diagnosed and 35 patients have died. The first diagnoseson March 13 were imported cases, involving Kazakh citizens who returned from other countries. OnMarch 15, the state of emergency was introduced, and on March 19 a lockdown was placed on the citiesof Nur-Sultan and Almaty where the highest number of cases were occurring. Lockdowns and blockadeswere later extended to other cities and regions.Given the absence of a vaccine and the lack of antiviral treatment, together with the high infectiousnessand significant fatality, Government measures have confined millions of people to prevent infections andlimit the extension of the epidemic: schools have been closed, most of the enterprises cannot operate,people have lost their jobs and income. The social and economic impact of those measures is difficult toestimate. At the same time, confirmed cases have been requiring medical care, and more than 300,000 tests have been performed, adding significant costs to the public budgets.These measures were taken with a significant level of uncertainty regarding COVID-19. In the last fewmonths, the main biological and clinical characteristics of this virus are beginning to be unraveled, but asthe experience with this virus is less than 5 months, it is yet very limited3. What we know reflects thecomplexity faced with both its public health control as well as with its clinical management.Understanding of the transmission risk is incomplete. Epidemiologic investigation in Wuhan identified aninitial association with a seafood market that sold live animals, however, as the outbreak progressed,person-to-person spread became the main mode of transmission, which is thought to occur mainly viarespiratory droplets. The period of contagiousness is long and variable, from 2-14 days, with a mean of 5-6 days between contact and onset of symptoms4. Viral RNA levels from upper respiratory specimensappear to be higher soon after symptom onset, suggesting infectiousness starts 1-2 days before symptomonset, and that patients might be more infectious in the earlier stage of infection5. Contact tracing suggeststhat most secondary infections are among household contacts. Clusters of cases have been reported whereclose, personal contact can occur. The risk of transmission with more indirect contact is not wellestablished. Viruses present on contaminated surfaces may be another source of infection. Also, whetherSARS-CoV-2 can be transmitted through the airborne route is still a controversial issue. It is not clear thefrequency and relative importance of these types of transmission, as is the role that host response has,what are the factors that may explain differences in terms of being or not infected are not well known. COVID-19-is usually considered a respiratory condition, although a variable but significant proportion ofcases do not have respiratory symptoms. However, cases with no respiratory symptoms are as infectiousas the more severe case, as they may show high levels of viral loads6. Data from the Diamond PrinceCruise ship indicates that asymptomatic cases represent 17.9% (15.5–20.2%), which overlaps with anestimate of 33.3% (8.3–58.3%) from citizens evacuated from Wuhan. CEBM Oxford has concluded that5%-80% of people testing positive for SARS-CoV-2 may be asymptomatic. The public health implicationis that symptom-based screening will miss cases, perhaps a lot of them7.As well as from patients with no respiratory symptoms, the transmission of SARS-CoV-2 within theincubation period also is documented. The extent to which pre-asymptomatic or asymptomatictransmission occurs and how much it contributes to the pandemic remains unknown but has obviouspublic health implications.Identifying cases and tracing contacts is a key public health function to curb further transmission, controlthe extension of infectious outbreaks, and safeguarding the broader population. Delayed and ineffectivecontact tracing contributes to extensive transmission. Understanding and addressing the challenges ofimplementing and managing contact tracing is essential to stopping SARS-CoV-2 transmission. To beeffective or controlling the extension of the infection at least 80% of contacts have to be identified andquarantined8. An elevated number of cases and the above-mentioned disease characteristics make thiscontact tracing in COVID-19 incredibly difficult. Some local studies are beginning to determine the real extension of the infection and the number ofasymptomatic cases9. But that data will have relevance on the specific contexts where it will be obtained.Population sero-prevalence studies may provide a better sense of the scope of asymptomatic infections,inform epidemiologic analysis, and allow to understand three major questions: 1) what is the true extent ofthe infection at the population level; 2) whether there are differences among patients who showed positiveantibodies and have had or not respiratory symptomatic disease, and 3) what is the capacity of the public health systems to be able to identify positive cases. Another uncertainty is what determines the susceptibility to develop the infection among those exposed tothe virus and what is the role of the immune system in defending from the infection. Significantdifferences in National Immunization Programs have been found in countries hit by COVID-19 and it hasbeen identified that countries with a mandatory BCG vaccination10 have a lower incidence of cases anddeaths by COVID-19. One of the possible explanations might be immunity of the population againstCOVID-19 related to BCG vaccination. BCG vaccination has been found to reduce mortality in childrenbecause of non-specific cross-protection against other unrelated pathogens, and to protect against thedevelopment of community acquired pneumonia, sepsis or deaths1112 Recently the heterologous protectiveeffect of BCG was confirmed in experimental viral infection in humans13. Clinical trials have been startedto evaluate the possible protective effect of BCG vaccination14. In the absence of protective specificvaccine against a new coronavirus use of heterologous protection achieved with BCG vaccination canbecome an important alternative. Regarding investigating a possible protective effect of BCG vaccine, vaccination rate is quite high inKazakhstan. According to the Ministry of Health it is about 98%-99%. BCG is one of the first vaccinesadministered to children. Thus, it may be unlikely to find a large enough group of cases or controlswithout BCG for comparison. Also, collecting medical history of vaccination could be challenging, as alldocumentation is not yet digitalized. Therefore we will be investigated to evaluate specific post-BCG scar.The presence or absence of a BCG scar is used as an indicator of BCG vaccination in clinical contexts aswell as in health surveys to assess vaccine coverage and its effectiveness15.The extended contact tracing conducted in Kazakhstan provides a valuable opportunity to explore whypersons with high-risk exposure did or did not develop the infection. A case-control study, including thosewho tested positive and those who did not as controls, would provide with valid evidence in an efficientway to identify whether past exposure to diverse factors, including post BCG vaccination scar, mayrepresent an increased risk or have a protective effect for the development of COVID-19 infection. Case-control studies have certain characteristics that make it useful for diseases of low prevalence, likeCOVID-1916: they are less costly and less time-consuming, offer valid estimates with low samples, andallow to asses the protective or risk effect of multiple factors. One the major potential biases of casecontrolstudies is the selection of control groups. The best option is to select population based controls. Asmentioned, the extended contact tracing in the country provides a unique opportunity to work withcommunity controls, reducing therefore the inherent bias of this type of study design.Once infected, uncertainty remains regarding the course of the disease17. It is still not well determinedwhich factors predict the severity and resource needs of patients diagnosed with COVID-19 or the risk ofdeath: whether patients were admitted to ICU; how many days patients stayed on ICU; how many dayspatients stayed in hospital; whether patients needed higher level support (e.g. non-invasive ventilation);whether patients experienced organ failure; and whether patients were referred required mechanicalventilation or other specialized ICU services, like ECMO.The spectrum of symptomatic infection ranges from mild to critical. The Chinese CDC reported thatconfirmed infections reported that most of cases, around 80% are mild. Severe case (coursing withdyspnea, hypoxia, or >50 % lung involvement on imaging) represent around 15%, while only 5% arecritical disease (eg, with respiratory failure, shock, or multiorgan dysfunction). But the proportion of severe or fatal infections has shown variation, even in China, where CFR rangedfrom 5.8% in Wuhan to 0.7% in the rest of China, although later the adjusted CFR in mainland China wascalculated around 1.4%. There is no clear explanation of the determinants of those differences.Age seems one of the factors with the highest effect on mortality: older people are particularly vulnerableto COVID-19 and are less likely to benefit from intensive medical treatment if they become unwell. InItaly, 12% of all cases and 16% of all hospitalized patients were admitted to the ICU; the estimated CFRwas 7.2%. In contrast, the estimated CFR in South Korea was 0.9%. This may be related to distinctdemographics of infection; in Italy, the median age of patients was 64 years, whereas in Korea was in the40s, but there is no clear explanation yet of those differences.Countries with massive testing have found that younger age groups tend to show higher rates of infection,however, more severe cases and deaths occur at advanced ages. In Kazakhstan, people >= 60 representless than 10% of cases, while most of the deaths occur in this age group.Comorbidities and other conditions have been also associated with severe illness and mortality18:cardiovascular disease, diabetes, hypertension, COPD, cancer, (in particular hematologic malignancies,lung cancer, and metastatic disease), CKD, obesity and smoking. The specific mechanisms associatedwith worse outcomes are not yet fully elucidated. Males have comprised a disproportionately high numberof deaths, as well as black individuals in the United States, but it may possible be due to underlyingsocioeconomic disparities. In the UK ethnic differences in mortality have also been identified, with ahigher risk of death in black and Asian populations19. Particular laboratory features associated with worse outcomes are: Lymphopenia and elevated levels ofliver enzymes, LDH, inflammatory markers (eg, C-reactive protein, ferritin), D-dimer, prothrombin time,troponin, and CPK20.Acute respiratory distress syndrome is a major complication in patients with severe disease and canmanifest shortly after the onset of dyspnea. Other complications have included arrhythmias, acute cardiacinjury, acute kidney injury and shock. Information from autopsies has shown the high frequency of microcapilaraffectation with the presence of thrombi, a finding link with the incidence of thromboembolicevents, including pulmonary embolism and acute stroke (even in patients young patients without riskfactors)21. Some patients with severe COVID-19 have laboratory evidence of an exuberant inflammatoryresponse, similar to cytokine release syndrome, with persistent fevers, elevated inflammatory markers (eg,D-dimer, ferritin), and elevated proinflammatory cytokines; these laboratory abnormalities have beenassociated with critical and fatal illnesses. Guillain-Barré syndrome has also been reported22.Common abnormal X Ray findings were consolidation and ground glass opacities, with bilateral,peripheral, and lower lung zone distributions; lung involvement increased over the course of illness, witha peak in severity at 10-12 days after symptom onset. Chest CT most commonly demonstrates groundglassopacification with or without consolidative abnormalities, consistent with viral pneumonia. Thoseabnormalities are more likely to be bilateral, have a peripheral distribution, and involve the lower lobes.Less common findings include pleural thickening, pleural effusion, and lymphadenopathy.WHO has launched SOLIDARITY clinical trial to test some of treatments that have been proposed(Chloroquine or Hydroxychloroquine, Azithromycin, Remdesivir, Lopinavir / Ritonavir) to treat patientswith COVID-1923. Also, in patients with advanced and complex status, Tocilizumab, a biologicmedication that blocks IL-6 is being tested. The role and timing of indicating corticosteroids and anticoagulants are also controversial and under discussion. The possibilities to use of convalescent plasmaor hyper-immune immunoglobulin are also being explored. Other drugs like camostat or anakinra are alsobeing evaluated. ACE inhibitors or angiotensin receptor blockers (ARB) have been also under scrutiny,given that SARS-CoV-2 links to ACE2 receptors, but recent evidence indicates that although hypertensionis a risk factor, no higher risk or benefit has been found with the use of either ACE-inhibitors or ARB24.Although those drugs do not provide clear benefit, should be continued for patients who are already takingthem for cardiovascular and other conditions.A retrospective cohort study of COVID-19 hospitalized patients, exploring data already collected duringroutine clinical care, will contribute to define the clinical characteristics of COVID-19 patients inKazakhstan, understand which of them indicate an increased risk or which treatments may be effective,and allow the prediction of a variety of adverse outcomes in an individual patient. Improving ourunderstanding of the course of the disease may, in the future, inform targeting of treatments at those mostlikely to benefit from them, and may assist with prediction of the hospital resources required for caring forCOVID-19 patients, as well as plan accordingly if necessary in the future. Several analytic methods willhave to be applied in such a study to overcome the inherent limitations of observational data and toproduce robust unbiased estimates to offer a valid image to define COVID-19 process and trajectory.COVID-19 infection has shown very specific features also in children, reflecting relevant biological andclinical dimensions that also have relevant public health implications. The specificities of the childrenpopulation would require to be explored in depth in a specific project. This proposal is only focusing inthe adult population. The impact of the results on the development of science and technologyThe integrated perspective adopted by this proposal, combining data from different sources,methodological approaches, and researchers from diverse backgrounds, will create an integrated platformfor analyzing the complexity of the COVID-19 infection with a population health perspective. This datalakewill provide the basis for gaining our understanding of the biological characteristics of the virus,individual responses, as well as to support health care and public health decision-making.Expected social and economic impactsThe social and economic impact of the COVID-19 is still not being appropriately measure, but it will bein the range of 3% of global GDP. It is necessary to improve our understanding of SARS-CoV-2 toprovide valuable information to strengthen the Public Health response in case other waves of COVID-19may arrive or in case of similar infectious diseases outbreaks. Developing more precise information on theinfective patterns of the virus may allow to health national authorities to implement more or less selectiveconfinement or quarantined strategies, as well as to improve the quality and efficiency of the delivery ofhealthcare services.
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