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What Is Epidemiology?

For many people, the COVID-19 pandemic was the first time they’ve been exposed to the idea of an uncontrolled disease—introducing phrases like “transmission,” “incubation period,” “contact tracing,” and “herd immunity” into the public vernacular. But for those in the field of epidemiology, these ideas are at the core of their careers, and a pandemic is exactly what they’ve been preparing for. Epidemiologists have historically performed vital work to protect and improve the health of populations, whether it is neighborhoods, cities, countries, or continents.

Epidemiologists are crucial in mapping and understanding the effects of the coronavirus, but their work extends beyond novel viruses and pandemics. So, what is this unique field? And how do epidemiologists approach issues in public health?

What is epidemiology?

Epidemiology is the foundation of public health and is defined as the study of the “ distribution and determinants ” of diseases or disorders within groups of people, and the development of knowledge on how to prevent and control them. Epidemiological research helps us understand not only who has a disorder or disease but why and how it was brought to this individual or region. One of the earliest instances of modern epidemiology can be found during an 1854 cholera outbreak in London . Doctors believed the widespread illness must have been airborne, but Dr. John Snow, widely considered to be the father of epidemiology, employed a different kind of thinking. By carefully mapping the outbreak and analyzing those who were infected, Snow was able to link every cholera case to a single water pump at the intersection of Broad and Cambridge Streets (now Lexington Street) in London’s Soho neighborhood. The removal of the pump stopped the disease in its tracks—laying the basis of today’s epidemiological practices.

Today, epidemiologists use the insights gathered in their research to determine how illness within a population affects our society and systems on a larger scale, and in turn, provide recommendations for interventions, such as removing a fatal water pump.

As the novel coronavirus became widespread, epidemiologists around the world worked to control the spread. Our research spans work to better understand the virus and how it is transmitted; to project its spread and identify vulnerable communities; to develop diagnostic tests and therapies; and, to assess the U.S. and global health systems’ preparedness.  See examples of our faculty's work with COVID .

Types of epidemiology

Epidemiology can cover a wide range of issues, from unintentional injuries to psychosocial stress. Here are a few areas in which Columbia Mailman faculty and students work:

Infectious Disease Epidemiology for Public Health  This type of epidemiology is at the forefront of today’s world—as epidemiologists work on the front lines to track and trace the spread of COVID-19. In this concentration, infectious disease epidemiologists work to detect pathogens or viruses, understand their development and spread, and devise effective interventions for their prevention and control.

Chronic Disease Epidemiology Chronic disease epidemiologists  battle day-to-day chronic conditions such as cancers, diabetes, obesity, and more. Epidemiologists in this fieldwork to research the origins, treatment, and health outcomes of these diseases in the fight towards prevention.

Environmental Epidemiology Environmental epidemiology focuses on how an individual’s external factors affect health outcomes. This includes physical factors like pollution or housing, as well as social factors like stress and nutrition. Environmental epidemiologists work to understand how different environments may result in physical or neurological outcomes, ranging from psychiatric to cardiovascular disorders. 

Violence and Injury Epidemiology This epidemiological focus aims to address unintentional and intentional injuries across a lifespan. For example, epidemiologists in this field might focus their research on car accidents and work to identify the associated risk factors. Armed with extensive research, the goal of violence and injury epidemiology is to improve a population’s health by reducing the morbidity and mortality rate from unintentional and intentional injuries.

How epidemiologists track diseases

Epidemiology centers around the idea that disease and illness do not exist randomly or in a bubble. Epidemiologists conduct research to establish the factors that lead to public health issues, the appropriate responses, interventions, and solutions.

By using research—from the field and in the lab—and statistical analysis, epidemiologists can track disease and predict its future outcomes. In the case of COVID-19, this analysis requires heavy data surveillance, collection, and interpretation. 

Due to the scale and threat of the coronavirus pandemic, testing centers, and healthcare systems are required to report all related data, providing epidemiologists with a wealth of information upon which to base their studies. With this information, epidemiologists will track data including :

Number of Incidences (how many cases over time?)

Disease Prevalence (how many cases at a specific time?)

Number of Hospitalizations

Number of Cases Resulting in Death

Epidemiological Modeling

Using this data and more, epidemiologists create models that help predict the spread of the disease in the future—including where and when the spread may occur. They may also be able to discern the most vulnerable populations likely to contract a disease and provide recommendations for intervention. See examples of our faculty's work modeling COVID data .

Contact Tracing

In an attempt to stop the spread of disease and understand where it might go next, many public health workers use contact tracing to determine the connections of an infected person. See what some of our students have been doing:  Students take the lead on the COVID-19 response .

Degrees in epidemiology

By achieving a degree in epidemiology, you are poised to work in places such as local health departments, nonprofits, government organizations, academia, the pharmaceutical industry, and more. 

With Columbia Public Health programs ranging from MPH , MS , DrPH , and  PhD , students at all levels can gain the necessary knowledge to drive public health initiatives and conduct independent epidemiological research. Our graduates go on to work in roles at companies and organizations ranging in size, scope, and mission, such as:

Data and Informatics Analysts at medical technology firms, hospitals, and universities 

Research Scientists at statewide health departments 

Fellows at the Centers for Disease Control and Prevention (CDC) 

Clinical Trial Associates at international research laboratories

Research and Evaluation Manager at nonprofit organizations

Other areas of employment among our graduates include:

Consulting firms

Health insurance companies

Marketing and strategic communications firms

Pharmaceutical and biotechnology or medical device companies

The Department of Epidemiology at Columbia University Mailman School of Public Health is committed to producing world-class science with real-world impact while training the next generation of epidemiologists to improve the health and lives of communities around the world. Apply today or explore our overview book  for more info.

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• Published: 07 May 2018

Epidemiology is a science of high importance

Nature Communications volume  9 , Article number:  1703 ( 2018 ) Cite this article

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Epidemiology dates back to the Age of Pericles in 5th Century B.C., but its standing as a ‘true’ science in 21st century is often questioned. This is unexpected, given that epidemiology directly impacts lives and our reliance on it will only increase in a changing world.

Epidemiology identifies the distribution of diseases, factors underlying their source and cause, and methods for their control; this requires an understanding of how political, social and scientific factors intersect to exacerbate disease risk, which makes epidemiology a unique science. Nevertheless, its definition as a science is debated; among the criticisms of the field are that epidemiology is an inexact science that it is simply a set of tools used by other disciplines, and that its dependence on observational data makes it a form of journalism rather than a science 1 , 2 . Nature Communications editors have visited established epidemiologists and also found, to our surprise, that their impression from the rest of the scientific community is often that epidemiology is not viewed as a ‘true’ science.

Among the many reasons why its scientific significance is sometimes trivialised is its intersection with the so-called ‘soft’ sciences, which have traditionally been thought of as less exact than other disciplines because of their focus on variables that are complex and difficult to quantify, such as human behaviours and interactions. But socioeconomic and lifestyle factors, and features of the built environment, are known to affect health outcomes, including in individuals with cardiovascular 3 and genetic diseases 4 , and so they cannot be overlooked in studies of human health 5 .

Furthermore, there are tangible results from epidemiological research. It is unquestionable that the discipline has saved millions of lives, from both infectious and non-communicable diseases, through interventions and preventative programs that have been implemented as a result of study findings. In fact, the CDC credits medical epidemiologists with adding 25 years to the average life expectancy of people living in the United States since 1947 6 .

While the exact number of people whose lives have been saved by epidemiological research may not be possible to calculate, its importance in enhancing life quality and longevity cannot be overlooked. Even more significantly, despite the uncertainty, the incompleteness of models and the imperfections of data, epidemiology continues to be at the forefront of saving lives today through forecasting epidemics and pandemics, and identifying diseases likely to cause outbreaks in the future and implementing forward-planning, targeted and collaborative interventions to minimise fatalities 7 , 8 .

Increasingly, epidemiology is the key to understanding the impact of climate change on disease burden through the effect of temperature, humidity and seasonality on infectious disease dynamics, and the expansion of the ranges of disease vectors. Unlikely to be an isolated case, the State of Texas has reported transmission or outbreaks of Ebola, chikungunya, West Nile, and Zika virus infections within the past 5 years, and this is believed to be attributed to both climate change and rapid population expansion and urbanisation 9 .

Along with increased inequality, and urbanisation, climate change presents new challenges for global health programmes; in light of these, epidemiological research is sure to remain a cornerstone in guiding public health policies in the near future 10 .

So, epidemiology is important but is it a science? Yes, it is. While it may not be helpful to compare it with, say, mathematics, it is a bona fide multidisciplinary approach to the study of human health and disease that follows the scientific method of systematic observation, and the formulation, testing, and modification of hypotheses. If anything, epidemiology is a highly complex science because it needs to consider multiple variables associated with human diseases, such as pathogens, human social or travel dynamics, and the climate. This can mean that the results obtained for a disease and/or outbreak may not always be replicable for the same disease in a different environment.

Nature Communications editors appreciate the importance of epidemiology and would like to encourage submissions from the field, especially when applied to tackling issues of public health.

Perkins, P. Epidemiology, real science vs journalism. https://www.linkedin.com/pulse/epidemiology-real-science-vs-journalism-patty-perkins

Branas, C. The future of epidemiology: world class science, real world impact. https://www.mailman.columbia.edu/become-student/departments/epidemiology/who-we-are/message-chair/future-epidemiology-world-class-science-real-world-impact

Framingham Heart Study. https://www.framinghamheartstudy.org/

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Epidemiology is a science of high importance. Nat Commun 9 , 1703 (2018). https://doi.org/10.1038/s41467-018-04243-3

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Epidemiology Of Study Design

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• 1 Nassau University Medical Center
• 2 Penn State College of Medicine
• PMID: 29262004
• Bookshelf ID: NBK470342

In epidemiology, researchers are interested in measuring or assessing the relationship of exposure with a disease or an outcome. As a first step, they define the hypothesis based on the research question and then decide which study design will be best suited to answer that question. How the researcher conducts the investigation is directed by the chosen study design. The study designs can be broadly classified as experimental or observational based on the approach used to assess whether exposure and an outcome are associated. In an experimental study design, researchers assign patients to intervention and control/comparison groups in an attempt to isolate the effects of the intervention. Being able to control various aspects of the experimental study design enables the researchers to identify causal links between interventions and outcomes of interest. In several instances, an experimental study design may not be feasible or suitable; observational studies are conducted in such situations. As the name indicates, observational studies involve merely observing the patients in a non-controlled environment without actually interfering or manipulating with other aspects of the study and therefore are non-experimental. The observation can be prospective, retrospective, or current, depending on the subtype of an observational study.

Observational Studies

Case-Control Studies

Case-control studies are used to determine the degree of associations between various risk factors and outcomes. The factors that affect the risk of a disease are called exposures. Case-control studies can help identify beneficial or harmful exposures. As the name suggests, there are two groups of patient cases and controls in a case-control study. Cases are patients who have a particular disease, condition, or disability. Controls are those patients that do not have the disease. Typically, researchers identify appropriate representative controls for the cases that they are studying from the general population. Then they retrospectively look in the past for the possible exposures these patients might have had to a risk factor. Selecting the patients for the control group is a very critical component of research based on case-control studies. Due to the retrospective nature of the study design, case-control studies are subject to recall bias. Case-control studies are inexpensive, efficient, and often less time-consuming to conduct. This study design is especially suitable for rare diseases that have long latency periods.

Case-Crossover Studies

Case-crossover studies are helpful to study triggers within an individual. When the researcher is studying a transient exposure or risk factor, the case-crossover design is useful. This is a relatively new study design where there is a case and a control component, both of which come from the same individual. Each case is self-matched by serving as its own control. Determining the control and case components period is a critical and difficult aspect of a case-crossover study.

Cohort Studies

Cohort studies initially classify patients into two groups based on their exposure status. Cohorts are followed over time to see who develops the disease in the exposed and non-exposed groups. Cohort studies can be retrospective or prospective. Incidence can be directly calculated from a cohort study as you begin with exposed and unexposed patients, unlike a case-control study where you start with diseased and non-diseased patients. Relative risk is the measure of effect for a cohort study. Cohort studies are subject to very low recall bias, and multiple outcomes can be studied simultaneously. One of the disadvantages of cohort studies is that they are more prone to selection bias. Studying rare diseases and outcomes that have long follow-up periods can be very expensive and time-consuming using cohort studies.

Cross-Sectional Studies

Cross-sectional studies are observational in nature and give a snapshot of the characteristics of study subjects in a single point of time. Unlike cohort studies, cross-sectional studies do not have a follow-up period and therefore are relatively simple to conduct. As the exposure status/outcome of interest information is collected in a single moment in time, often by surveys, cross-sectional study design cannot provide a cause-effect relationship and is the weakest of the observational designs. This study design is generally used to assess the prevalence of a disease in a population.

Ecological Studies

Ecological studies are used when data at an individual level is unavailable, or large-scale comparisons are needed to study the population-level effect of exposures on a disease condition. Therefore, ecological study results are applicable only at the population level. The types of measures in ecological studies are aggregates of individual-level data. These studies, therefore, are subject to a type of confounding called an ecological fallacy, which occurs when relationships identified at group level data are assumed to be true for individuals. Ecological studies are generally used in public health research.

Experimental Studies

Randomized Clinical Trials

Randomized clinical trials or randomized control trials (RCT) are considered the gold standard of study design. In an RCT, the researcher randomly assigns the subjects to a control group and an experimental group. Randomization in RCT avoids confounding and minimizes selection bias. This enables the researcher to have similar experimental and control groups, thereby enabling them to isolate the effect of an intervention. The experimental group gets the exposure/treatment, which can be an agent involved in causation, prevention, or treatment of a disease. The control group receives no treatment, a placebo treatment, or another standard of care treatment depending on the study's objective. The groups are then followed prospectively to see who develops the outcome of interest. RCT’s are expensive, and researchers using this study design often face issues with the integrity of randomization due to refusals, drops outs, crossovers, and non-compliance.

Copyright © 2024, StatPearls Publishing LLC.

• Introduction
• Issues of Concern
• Clinical Significance
• Other Issues
• Enhancing Healthcare Team Outcomes
• Review Questions

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• Study Guide

• Chapter 1. What is epidemiology?
• Chapter 2. Quantifying disease in populations
• Chapter 3. Comparing disease rates
• Chapter 4. Measurement error and bias
• Chapter 5. Planning and conducting a survey
• Chapter 6. Ecological studies
• Chapter 7. Longitudinal studies
• Chapter 8. Case-control and cross sectional studies
• Chapter 9. Experimental studies
• Chapter 10. Screening
• Chapter 11. Outbreaks of disease
• Chapter 12. Reading epidemiological reports
• Chapter 13. Further reading

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Epidemiology Design in Clinical Research

• First Online: 17 December 2023

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• Yi Wang 3  

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In previous chapters, we introduced different types of epidemiological study designs and discussed their strengths and weaknesses. The overall strategy of clinical research is the same as that utilized in other areas of epidemiology: observation of incidences between groups and then extrapolation based on any differences. In clinical research studies, the defining characteristics of groups can be symptoms, signs, diseases, diagnostic procedures, or disease treatment. The discussion that follows in this chapter will consequently summarize and integrate the core epidemiological topics involved in the previous chapters. We will concentrate mainly on observational studies, diagnostic/prognostic studies, clinical trials, and systematic reviews looking for the general principles frequently applied in clinical research. Clinical epidemiological studies prefer randomized groups to epidemiological studies. Firstly, the “exposure” in clinical research is usually a treatment approach that tends to be more randomized than the exposures considered in most epidemiological studies (e.g., tobacco or alcohol consumption, diet, or personal or environmental characteristics). Secondly, the results uncovered in clinical epidemiological studies, such as disease progression, complications, or mortality, are comparatively frequently found in the patient groups being compared, making randomized studies more feasible. Thirdly, the potential for confounding is particularly high in clinical epidemiological studies where there is no randomized grouping. In a large number of nonrandomized treatment studies in which a correlation has been detected, it is unclear whether changes in patients’ risk of disease progression, complications, or death are related to the type of treatment they receive.

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Chongjian Wang

Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China

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Wang, Y. (2023). Epidemiology Design in Clinical Research. In: Wang, C., Liu, F. (eds) Textbook of Clinical Epidemiology. Springer, Singapore. https://doi.org/10.1007/978-981-99-3622-9_19

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What Is Epidemiology?

Epidemiology is the branch of medical science that investigates all the factors that determine the presence or absence of diseases and disorders. Epidemiological research helps us to understand how many people have a disease or disorder, if those numbers are changing, and how the disorder affects our society and our economy.

The epidemiology of human communication is a rewarding and challenging field. Much of the data that epidemiologists collect comes from self-report—from answers provided by people participating in a study. For instance, an epidemiological study may collect data on the number of people who answer, “Yes” when asked if someone in their household has trouble hearing. Each person providing such an answer may interpret “trouble hearing” differently. This means that the results of such a study may be quite different from a study in which actual hearing (audiometric) tests are administered to each person in a household.

Also, many epidemiological estimates try to determine how the number of people affected by a disorder changes over time. The definition of a disorder also tends to change over time, however, making estimates more difficult. Even scientists working in the same field at the same time may not agree on the best way to measure or define a particular disorder.

Key terms to know in this field are: 

• Incidence: The number of new cases of a disease or disorder in a population over a period of time.
• Prevalence: The number of existing cases of a disease in a population at a given time.
• Cost of illness: Many reports use expenditures on medical care (i.e., actual money spent) as the cost of illness. Ideally, the cost of illness would also take into account factors that are more difficult to measure, such as work-related costs, educational costs, the cost of support services required by the medical condition, and the amount individuals would pay to avoid health risks. (Adapted from the Environmental Protection Agency’s Cost of Illness Handbook )
• Burden of disease: The total significance of disease for society, beyond the immediate cost of treatment. It is measured in years of life lost to ill health, or the difference between total life expectancy and disability-adjusted life expectancy (DALY). (Adapted from the World Health Organization .)
• DALY (Disability-Adjusted Life Year): A summary measure of the health of a population. One DALY represents one lost year of healthy life and is used to estimate the gap between the current health of a population and an ideal situation in which everyone in that population would live into old age in full health. (Adapted from the World Health Organization .)

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Researchers know that populations vary in their susceptibility to and resilience against heart, lung, blood, and sleep disorders, as well as in disease course and outcomes. These differences sometimes are caused by age, sex, race, ancestry or genetic factors that cannot be changed. In other cases, these differences are due to factors that can be changed or modified, such as lifestyle choices or environment, and some biological factors. Future research will help to better understand the causes of population health differences and to identify strategies that effectively address these differences before they become health disparities. Health disparities are differences in the risk, burden of diseases, and adverse health conditions that exist among specific population groups.

KEY ACCOMPLISHMENTS

• The multi-generational Framingham Heart Study helped discover risk factors and interventions to prevent heart disease, and continues to drive discovery.
• The landmark Women’s Health Initiative (WHI) found that hormone replacement therapy did not prevent heart disease as thought in post-menopausal women.
• The long-term Jackson Heart Study revealed that African Americans who took certain health measures had a lower risk for heart disease.
• The Trans-Omics for Precision Medicine (TOPMed) program is leveraging data from participants in NHLBI’s population and epidemiology studies.

OPPORTUNITIES & CHALLENGES

In 2016, the NHLBI released its Strategic Vision , which will guide the Institute’s research activities for the coming decade. Many of the objectives and compelling questions identified in the plan focus on factors that account for differences in health among populations. For example, researchers are looking at the factors that make individuals or populations resistant or prone to diseases, despite having experienced the same exposures such as diet, smoking, environmental and social factors. Part of NHLBI’s priorities include recruiting and retaining researchers who are interested in epidemiology research and developing a diverse scientific workforce.

More Information - Population and Epidemiology Studies

Age, sex, race, genes and biology may account for some differences in health among different populations.Lifestyle choices, behaviors, and socioeconomic status may also play a role in creating differences in health. Our research seeks to better understand the causes of health differences and to identify ways to improve public health and health outcomes.

Population studies have entered an exciting period when advances in assay methods, imaging technologies, and electronic data are creating new scientific opportunities. These tools make it possible for large epidemiology studies to explore what makes individuals susceptible to disease. To capitalize on these opportunities, NHLBI established an Advisory Council Working Group on Epidemiology and Population Science to look at the current landscape, emerging tools, and future opportunities in population science and  make important recommendations that contributed to the Institute’s strategic thinking in this area.

The NHLBI’s large-population cohort studies have been major generators of new knowledge that has informed the molecular basis for disease and identified targets for new treatments. For example, NHLBI research has transformed the way the public approaches cardiovascular disease by conducting numerous studies that focus on diverse populations. The  Women’s Health Initiative (WHI)  continues to yield new insights that advance our understanding of heart disease and other diseases in women.  

It is important that the NHLBI continue to build on its legacy of excellence in population studies research. Our population studies have led to a wide range of discoveries and initiatives that will reduce health disparities and improve health outcomes in  heart and vascular diseases ,  obesity ,  women’s health , and  precision medicine .

Learn about some of NHLBI’s efforts to support and advance population and epidemiology research.

We Perform Research

NHLBI’s  Division of Intramural Research , including its  Epidemiology and Community Health Branch and  Population Sciences Branch , is actively engaged in studying thousands of population cohort study participants to formulate a global view of both the natural history and future trends related to heart, lung, blood, and sleep disorders.

We Fund Research

The research we fund today will help improve our future health. Our  Division of Cardiovascular Sciences ’  Program in Prevention & Population Sciences , including its Epidemiology Branch and Clinical Application & Prevention Branch, supports population and epidemiology research including population studies, disease risk and outcome studies, and clinical trials to prevent disease and improve clinical care and public health. Other  NHLBI Divisions  also fund population and epidemiology research specific to their disease areas.

The Promise of Precision Medicine

Through NHLBI’s  Trans-Omics for Precision Medicine (TOPMed) program , researchers will use data from studies focused on heart, lung, blood and sleep disorders to better predict, prevent, diagnose, and treat diseases based on a patient’s unique genes, environment, and molecular signatures. Learn more about NHLBI  precision medicine activities .

Following Cardiovascular Disease in Generations of Families

The  Framingham Heart Study (FHS)  is a long-term study designed to identify genetic and environmental factors influencing the development of cardiovascular and other diseases in generations of families. Through the FHS, scientists learned of the risk factors for heart disease that are now checked in all routine physicals. This study has contributed discoveries that led to major changes in the prevention and treatment of heart disease.

Leading Women’s Health Research

The  Women's Health Initiative (WHI)  is a long-term study focusing on strategies to prevent the major causes of death and disability among postmenopausal women. Although the original WHI study completed data collection in 2005, the WHI continues to advance women’s health through extension studies and ancillary studies, such as the Women’s Health Initiative Strong and Healthy Study (WHISH) and the Women's Health Initiative Sleep Hypoxia Effects on Resilience (WHISPER).

Informing Improvements to Clinical Care and Public Health

The  Systolic Blood Pressure Intervention Trial (SPRINT)  demonstrated that managing high blood pressure more intensely than recommended significantly lowers the rate of cardiovascular disease and risk of death in a group of high-risk adults who are 50 years or older with high blood pressure. The SPRINT Memory and Cognition in Decreased Hypertension (SPRINT-MIND) Trial is examining whether intensive high blood pressure treatment can reduce the rate of dementia or slow the decline in cognitive function.

Investigating Atherosclerosis Causes and Outcomes

NHLBI’s  Atherosclerosis Risk in Communities Study (ARIC)  study is investigating the causes of atherosclerosis, a disease in which plaque builds up in the arteries, and the clinical outcomes from four U.S. communities. ARIC is also measuring how cardiovascular risk factors, medical care, and outcomes vary by race, sex, place, and time.

Examining Cardiovascular Disease Beginning in Young Adulthood

The  Coronary Artery Risk Development in Young Adults (CARDIA)  study examines the causes, risk factors, and natural history of cardiovascular disease that begin in young adulthood. For over 30 years, CARDIA has followed over 5,000 black and white young adults who were recruited from four centers in 1985 to 1986. The study has helped researchers better understand the importance of early adulthood factors that increase the risk of cardiovascular disease later in life.

Studying Cardiovascular Disease Outcomes

The  Cardiovascular Health Study (CHS)  is a long-term, population-based study of risk factors for the development of coronary heart disease and stroke in men and women aged 65 and older. Annual exams included measures of possible and proven cardiovascular disease risk, including subclinical disease.

Understanding How Diseases Impact Diverse Populations and People who love in Rural South

The NHLBI supports research to better understand the impact of diseases on minorities and to improve health outcomes in diverse populations. Studies include  Hispanic Community Health Study/Study of Latinos (HCHS/SOL) ;  Jackson Heart Study (JHS) ;  Multi-Ethnic Study of Atherosclerosis (MESA) ;  Strong Heart Study (SHS) ;  The Rural Cohort Study ; the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium; Consortium on Asthma among African-Ancestry Populations in the Americas (CAAPA); Healthy Communities Study: How Communities Shape Children’s Health (HCS). 

Providing Access to NHLBI Biologic Specimens and Data

The  Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC)  centralizes and integrates biospecimens and clinical data that were once stored in separate repositories. Researchers can find and request available resources on BioLINCC's secure website, which maximizes the value of these resources and advances heart, lung, blood, and sleep research.

Advancing Research on Conditions in People Living with HIV

In 2019, the NHLBI became the primary steward of the new  Men’s AIDS Cohort Study (MACS) / Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MACS/WIHS-CSS) . This study is a trans-NIH collaborative research effort that aims to understand and reduce the impact of chronic health conditions that affect people living with HIV. The MACS/WIHS Combined Cohort Study will build on decades of research in thousands of men and women who are living with and without HIV to further our understanding of chronic heart, lung, blood, sleep, and other disorders in people living with HIV.

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Research Gaps Around Type 1 Diabetes

A large body of research on Type 2 diabetes has helped to develop guidance, informing how patients are diagnosed, treated, and manage their lifestyle. In contrast, Type 1 diabetes, often mistakenly associated only with childhood, has received less attention.

In this Q&A, adapted from the  April 17 episode of Public Health On Call , Stephanie Desmon speaks to Johns Hopkins epidemiologists  Elizabeth Selvin , PhD '04, MPH, and  Michael Fang , PhD, professor and assistant professor, respectively, in the Department of Epidemiology, about recent findings that challenge common beliefs about type 1 diabetes. Their conversation touches on the misconception that it’s solely a childhood condition, the rise of adult-onset cases linked to obesity, and the necessity for tailored approaches to diagnosis and care. They also discuss insulin prices and why further research is needed on medications like Ozempic in treating Type 1 diabetes.

I want to hear about some of your research that challenges what we have long understood about Type 1 diabetes, which is no longer called childhood diabetes. 

MF: Type 1 diabetes was called juvenile diabetes for the longest time, and it was thought to be a disease that had a childhood onset. When diabetes occurred in adulthood it would be type 2 diabetes. But it turns out that approximately half of the cases of Type 1 diabetes may occur during adulthood right past the age of 20 or past the age of 30.

The limitations of these initial studies are that they've been in small clinics or one health system. So, it's unclear whether it's just that particular clinic or whether it applies to the general population more broadly. 

We were fortunate because the CDC has collected new data that explores Type 1 diabetes in the U.S. Some of the questions they included in their national data were, “Do you have diabetes? If you do, do you have Type 1 or Type 2? And, at what age were you diagnosed?”

With these pieces of information, we were able to characterize how the age of diagnosis of Type 1 diabetes differs in the entire U.S. population.

Are Type 1 and Type 2 diabetes different diseases?

ES:  They are very different diseases and have a very different burden. My whole career I have been a Type 2 diabetes epidemiologist, and I’ve been very excited to expand work with Type 1 diabetes.

There are about 1.5 million adults with Type 1 diabetes in the U.S., compared to 21 million adults with Type 2 diabetes. In terms of the total cases of diabetes, only 5 to 10 percent have Type 1 diabetes. Even in our largest epidemiologic cohorts, only a small percentage of people have Type 1 diabetes. So, we just don't have the same national data, the same epidemiologic evidence for Type 1 diabetes that we have for Type 2. The focus of our research has been trying to understand and characterize the general epidemiology and the population burden of Type 1 diabetes.

What is it about Type 1 that makes it so hard to diagnose?

MF: The presentation of symptoms varies by age of diagnosis. When it occurs in children, it tends to have a very acute presentation and the diagnosis is easier to make. When it happens in adulthood, the symptoms are often milder and it’s often misconstrued as Type 2 diabetes. 

Some studies have suggested that when Type 1 diabetes occurs in adulthood, about 40% of those cases are misdiagnosed initially as Type 2 cases. Understanding how often people get diagnosed later in life is important to correctly diagnose and treat patients. 

Can you talk about the different treatments?

MF:  Patients with Type 1 diabetes are going to require insulin. Type 2 diabetes patients can require insulin, but that often occurs later in the disease, as oral medications become less and less effective.

ES: Because of the epidemic of overweight and obese in the general population, we’re seeing a lot of people with Type 1 diabetes who are overweight and have obesity. This can contribute to issues around misdiagnosis because people with Type 1 diabetes will have signs and will present similarly to Type 2 diabetes. They'll have insulin resistance potentially as a result of weight gain metabolic syndrome. Some people call it double diabetes—I don't like that term—but it’s this idea that if you have Type 1 diabetes, you can also have characteristics of Type 2 diabetes as well.

I understand that Type 1 used to be considered a thin person's disease, but that’s not the case anymore.  MF:  In a separate paper, we also explored the issue of overweight and obesity in persons with Type 1 diabetes. We found that approximately 62% of adults with Type 1 diabetes were either overweight or obese, which is comparable to the general U.S. population.

But an important disclaimer is that weight management in this population [with Type 1 diabetes] is very different. They can't just decide to go on a diet, start jogging, or engage in rigorous exercise. It can be a very, very dangerous thing to do.

Everybody's talking about Ozempic and Mounjaro—the GLP-1 drugs—for diabetes or people who are overweight to lose weight and to solve their diabetes. Where does that fit in with this population?

ES: These medications are used to treat Type 2 diabetes in the setting of obesity. Ozempic and Mounjaro are incretin hormones. They mediate satiation, reduce appetite, slow gastric emptying, and lower energy intake. They're really powerful drugs that may be helpful in Type 1 diabetes, but they're  not approved for the management of obesity and Type 1 diabetes. At the moment, there aren't data to help guide their use in people with Type 1 diabetes, but I suspect they're going to be increasingly used in people with Type 1 diabetes.

MF:   The other piece of managing weight—and it's thought to be foundational for Type 1 or Type 2—is dieting and exercising. However, there isn’t good guidance on how to do this in persons with Type 1 diabetes, whereas there are large and rigorous trials in Type 2 patients. We’re really just starting to figure out how to safely and effectively manage weight with lifestyle changes for Type 1 diabetics, and I think that's an important area of research that should continue moving forward.

ES: Weight management in Type 1 diabetes is complicated by insulin use and the risk of hypoglycemia, or your glucose going too low, which can be an acute complication of exercise. In people with Type 2 diabetes, we have a strong evidence base for what works. We know modest weight loss can help prevent the progression and development of Type 2 diabetes, as well as weight gain. In Type 1, we just don't have that evidence base.

Is there a concern about misdiagnosis and mistreatment? Is it possible to think a patient has Type 2 but they actually have Type 1? 

MF: I think so. Insulin is the overriding concern. In the obesity paper, we looked at the percentage of people who said their doctors recommended engaging in more exercise and dieting. We found that people with Type 1 diabetes were less likely to receive the same guidance from their doctor. I think providers may be hesitant to say, “Look, just go engage in an active lifestyle.”

This is why it's important to have those studies and have that guidance so that patients and providers can be comfortable in improving lifestyle management.

Where is this research going next?

ES:  What's clear from these studies is that the burden of overweight and obesity is substantial in people with Type 1 diabetes and it's not adequately managed. Going forward, I think we're going to need clinical trials, clear clinical guidelines, and patient education that addresses how best to tackle obesity in the setting of Type 1 diabetes.

It must be confusing for people with Type 1 diabetes who are   hearing about people losing all this weight on these drugs, but they go to their doctor who says, “Yeah, but that's not for you.”

ES: I hope it's being handled more sensitively. These drugs are being used by all sorts of people for whom they are not indicated, and I'm sure that people with Type 1 diabetes are accessing these drugs. I think the question is, are there real safety issues? We need thoughtful discussion about this and some real evidence to make sure that we're doing more good than harm.

MF:  Dr. Selvin’s group has published a paper, estimating that about 15% of people with Type 1 diabetes are on a GLP-1. But we don't have great data on what potentially can happen to individuals.

The other big part of diabetes that we hear a lot about is insulin and its price. Can you talk about your research on this topic?

MF:  There was a survey that asked, “Has there been a point during the year when you were not using insulin because you couldn’t afford it?” About 20% of adults under the age of 65 said that at some point during the year, they couldn't afford their insulin and that they did engage in what sometimes is called “cost-saving rationing” [of insulin].

Medicare is now covering cheaper insulin for those over 65, but there are a lot of people for whom affordability is an issue. Can you talk more about that? 

MF:  The fight is not over. Just because there are national and state policies, and now manufacturers have been implementing price caps, doesn't necessarily mean that the people who need insulin the most are now able to afford it. 

A recent study in the  Annals of Internal Medicine looked at states that adopted or implemented out-of-pocket cost caps for insulin versus those that didn't and how that affected insulin use over time. They found that people were paying less for insulin, but the use of insulin didn't change over time. The $35 cap is an improvement, but we need to do more.

ES: There are still a lot of formulations of insulin that are very expensive. $35 a month is not cheap for someone who is on insulin for the rest of their lives.

• Overweight and Obesity in People With Type 1 Diabetes Nearly Same as General Population
• The Impacts of COVID-19 on Diabetes and Insulin
• Why Eli Lilly’s Insulin Price Cap Announcement Matters

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Epidemiology of COVID-19: An updated review

Mehrdad halaji.

1 Department of Microbiology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran

Mohammad Heiat

2 Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran

Niloofar Faraji

3 Department of Medical Laboratory Sciences, School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran

Reza Ranjbar

4 Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a zoonotic infection, is responsible for COVID-19 pandemic and also is known as a public health concern. However, so far, the origin of the causative virus and its intermediate hosts is yet to be fully determined. SARS-CoV-2 contains nearly 30,000 letters of RNA that allows the virus to infect cells and hijack them to make new viruses. On the other hand, among 14 detected mutations in the SARS-CoV-2 S protein that provide advantages to virus for transmission and evasion form treatment, the D614G mutation (substitution of aspartic acid [D] with glycine [G] in codon 614 was particular which could provide the facilitation of the transmission of the virus and virulence. To date, in contrary to the global effort to come up with various aspects of SARS-CoV-2, there are still great pitfalls in the knowledge of this disease and many angles remain unclear. That's why, the monitoring and periodical investigation of this emerging infection in an epidemiological study seems to be essential. The present study characterizes the current epidemiological status (i.e., possible transmission route, mortality and morbidity risk, emerging SARS-CoV-2 variants, and clinical feature) of the SARS-CoV-2 in the world during these pandemic.

INTRODUCTION

In late December 2019, hospital physicians in Wuhan, China, reported unusual cases of pneumonia. Subsequent studies have shown that the origin of this disease is from the food market in Wuhan City, Hubei Province, in Central China. By confirmation of the Chinese section of the Centers for Disease Control and Prevention (CDC), on January 2, 2020, the cause of the disease was announced to be a new coronavirus called nCoV-2019. The World Health Organization (WHO) approved the results of isolation of genome and genomic sequencing of the nCoV-2019 on February 11, 2020.[ 1 ] The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an enveloped, positive single-stranded RNA virus, belongs to the Riboviria Realm, Orthornavirae Kingdom, Pisuviricota Phylum, Pisoniviricetes class, Nidovirales order, Coronaviridae family, Coronavirinae subfamily and beta-coronavirus (β-CoV) genus, Sarbecovirus subgenus, and SARS-related coronavirus species.[ 2 ]

SARS-CoV-2 contains nearly 30,000 letters of RNA (29,903) (GenBank: {"type":"entrez-nucleotide","attrs":{"text":"MN908947.3","term_id":"1798172431","term_text":"MN908947.3"}} MN908947.3 )[ 3 ] that allows the virus to infect cells and hijack them to make new viruses. Studies have shown that this virus applies its spike protein to bind to cell receptors such as the angiotensin-converting enzyme 2 (ACE2) receptor protein and transmembrane serine protease 2 (TMPRSS2) protease, to enter cells. Findings confirmed that the spike protein structure with 3822 nucleotides is the main reason for higher infectivity of SARS-CoV-2 than its ancestors.[ 4 , 5 ]

The most common clinical symptoms of the COVID-19 patients are fever, cough, shortness of breath, and other breathing difficulties in addition to other nonspecific symptoms including headache, dyspnea, fatigue, and muscle pain and digestive symptoms such as diarrhea and vomiting.[ 6 ] The incidence of COVID-19 continues to increase. Globally, up to February 10, 2021, 106,797,721 infected cases, including 2,341,145 deaths, have been reported.

To date, in contrary to the global effort to come up with various aspects of SARS-CoV-2, including clinical manifestations, epidemiology, mortality and morbidity, and diagnosis, there are still great pitfalls in the knowledge of this disease and many angles remain unclear. That's why, the monitoring and periodical investigation of this emerging infection is an essential issue. The present study characterizes the current epidemiological status (i.e., possible transmission route, mortality and morbidity risk, emerging SARS-CoV-2 variants, and clinical feature) of the SARS-CoV-2 in the world in 2020–2021.

DOMINANT TRANSMISSION ROUTES

SARS-CoV-2 can be transmitted directly from human to human and indirectly via contaminated objects.[ 7 ] Person-to-person transmission of SARS-CoV-2 occurs mainly via respiratory droplets spread by coughs, sneezes, or even talking. Droplets usually cannot proceed more than six feet. SARS-CoV-2 remains contagious in droplets and suspends in the air for maximum 3 h.[ 8 ] However, the WHO demonstrated that airborne transmission is not a significant route in disease transmission on 75,465 confirmed COVID-19 cases in China as of March 27, 2020.[ 9 ] In order to prevent aerosol spread of SARS-CoV-2, room ventilation and airborne isolation can be useful.[ 10 ]

Direct contact of a contaminated hand with mucous membranes such as the eyes, nose, or mouth can also transmit the virus.[ 11 ] Therefore, handwashing with soap and water or using sanitizers can be helpful. Transmission of SARS-CoV-2 from asymptomatic cases without any paraclinical findings may also occur.[ 12 , 13 , 14 ] Hence, there is an urgent need for sensitive and fast diagnosis of suspected individuals.

In a multicenter study while each patient showed at least two nonpolymerase chain reaction (PCR) negative tests, the reverse transcription-PCR remained still positive up to 13 days after discharge.[ 15 ] Viral shedding in the stool takes place up to 5 weeks[ 16 ] with a mean of 11.2 days after a negative respiratory test.[ 17 ]

Although positive blood and stool samples for SARS-CoV-2 RNA have been reported and some COVID-19 patients had positive stool cultures for living SARS-CoV-2,[ 18 ] a WHO-China report showed that fecal-oral transmission is not a major route.[ 11 ] However, a recent study in China with 1070 specimens collected from 205 COVID-19 patients showed that 29% of positive COVID-19 individuals have been infected by transmission via feces.[ 18 ]

Based on studies of semen and testicular samples of COVID-19 patients, SARS-CoV-2 is not sexually transmitted.[ 19 ] In a recent case report, an infant delivered from a COVID-19-positive mother was tested negative for 7 samples of pharynx, blood, and stool;[ 20 ] on the other hand, some studies demonstrated that immunoglobulin M against SARS-CoV-2 was detected in blood samples of newborns; therefore, vertical transmission of SARS-CoV-2 is still a matter of conflict.[ 21 , 22 ]

Although it is not clear that SARS-CoV-2 can be transmitted from infected animals to humans, this phenomenon needs to be considered as a possibility.[ 23 ] SARS-CoV-2 is able to infect dogs, cats, and some other animals.[ 24 ] A German shepherd dog was reported dead (with unclear cause of death and no autopsy) 2 days after quarantining the pet owner because of COVID-19. Cat-to-cat transmission of SARS-CoV-2 has been reported, but it is not clear if cat-to-human transmission is possible.[ 9 ]

FACTORS CONTRIBUTING TO RISK OF THE DISEASE

SARS-CoV-2 can spread through direct and indirect contact (human-to-human and contaminated objects). Meantime personal protective equipment could also be considered as the possible source of airborne infections.[ 7 ] Transmission factors are varied from environmental, behavioral, and physical to virological (viral loading, location of virus receptor, etc.) features which can infected individuals and cause serious problems.[ 25 ] SARS-CoV-2 aerosol spread can occur when a person touches a contaminated surface, and then, the hands contact with mucous membranes such as the mouth, nose, or eyes. Therefore, proper sanitizers or washing hands with soap and water is recommended.[ 25 ] Despite RNA of SARS-CoV-2 has been detected in blood and stool sample, a joint WHO-China report indicated that fecal-oral transmission did not seem to be an important spread factor.[ 25 , 26 ] Consequently, Xiao et al . documented evidence of gastrointestinal SARS-CoV-2 infection and represented the risk of virus transmission via the fecal-oral route, which can be as a possible route for SARS-CoV-2 transmission.[ 27 ] It seems that the risk of virus transmission is greater than what we think. Vivanti et al . reported a case of SARS-CoV-2 transplacental transmission from a pregnant woman infected by COVID-19 during late pregnancy to her fetus. The load of virus was much more higher in the placental tissue than in the amniotic fluid or maternal blood which based on the European Centre for Disease Control ( https://www.ecdc.europa.eu/en/all-topicsz/coronavirus/threatsand-outbreaks/covid19/laboratory-support/questions ) detecting both “E” and “S” genes of SARS-CoV-2 is confirming positive result. The viral load in the placental tissue was much higher than in amniotic fluid or maternal blood.[ 28 ] Furthermore, some systematic reviews demonstrated vertical transmission of SARS-CoV-2, vaginal delivery from mother to neonate 9.6%–21%,[ 29 , 30 ] and maternal immune cells. Nevertheless, vertical transmission of mother-to-infant hypothesis requires further investigation. One of the major problems of SARS CoV-2 pandemic is decreasing transplant rate which leads to increasing mortality on the waiting list, for instance, in Spain as a great pandemic area for SARS-CoV-2, on March 13, 2020, the mean number of donors has declined from 7.2 to 1.2 per day, and the mean number of transplants from 16.1 to 2.1 per day.[ 31 ]

NOSOCOMIAL TRANSMISSION

Nosocomial transmission of SARS-CoV-2 is a serious health center problem which is facilitated by mobile phones of health-care workers and hospital equipment.[ 32 ] One case report study showed a person-to-person transmission between health-care workers and patients. Of forty-eight study cases, six out of twelve patients had SARS-CoV-2-positive results by RT-PCR and had shown symptoms at the time of examination.[ 33 ] Among high-risk professionals at SARS-CoV-2 outbreak, dental professionals are at the top of the nosocomial transmission and infection list that make them to become as a disease potential carriers.[ 34 ] The previous studies showed the existence of SARS-CoV-2 in patient's face and saliva,[ 35 , 36 ] in which SARS-CoV-2 was able to bind to the receptors of ACE2 indicating a remarkable reason for the existence of COVID-19 in the secretory saliva.[ 1 , 37 ] Consequently, the transmission of SARS-CoV-2 via aerosol or fomites and health-care facilities is plausible, which may be related to person-to-person transmission in the dental clinics.[ 38 ] The Epidemiology Team of Coronavirus Pneumonia Emergency Response (2020) represented that COVID-19 nosocomial coughing transmission is still imprecise, but in China, around 1716 hospital staff have been infected by February 2020 during their makeshift. Those huge infections numbers probably have been occurred by the person-to-person transmission of viral-loaded aerosol.

The CDC has declared that till April 2020, in the USA, around 9000 medical center staff have been identified with SARS-CoV-2-positive results, which could be related to airborne aerosol cloud nosocomial transmission.[ 39 ] Therefore, combination of handwashing and surgical face mask effectively decreases the rate of nosocomial transmission.[ 40 ] Among patients who were hospitalized or admitted, about 15 individuals (4.9%) were identified as a COVID-19 nosocomial infected patients.[ 41 ]

MORBIDITY AND MORTALITY

According to the WHO, by February 2021, there have been 109,068,745 confirmed cases of SARS-CoV-19, including 2,409,011 deaths.[ 9 ] The mortality of COVID-19 is associated with some health conditions including older age (>60 years), gender, smoking history, preexisting pneumonia, and significant comorbid illnesses (such as immunocompromised states, chronic cardiovascular, cerebrovascular, pulmonary, kidney disease, diabetes mellitus, fulminant inflammation, lactic acid accumulation, and thrombotic events).[ 42 , 43 , 44 ] A meta-regression study has reported that hypertension is considered as a risk factor for both mortality and severity.[ 45 ] Although there is no sufficient documentation to display the association of this fatality with fever in SARS-CoV-2, fever and cough are the most frequent symptoms which have been related to death or sever acute condition in infected patients.[ 44 ] Children are less affected than adults, and clinical attack rates in the 0–19 age group are low and usually present as a mild disease.[ 46 ] Zhao et al . investigated association between the blood group and the SARS-CoV-2 among 2173 patients and compared them with normal patients in Wuhan and Shenzhen, China. The results showed that the proportion of blood group A in SARS-CoV-2 patients was significantly higher indicating it as a risk factor for the individuals.[ 47 ] SARS-CoV-2 has the ability to infect neurons in vitro and leads to neuronal death, but the data from CSF and autopsy examinations do not show consistent evidence of direct CNS invasion. Nevertheless, effects on the median eminence and other circumventricular organs cannot be prevented and may play an important role in the disease systemic expression.[ 2 ]

Furthermore, according to some case-cohort studies, there are some blood markers which can be related to mortality of SARS-CoV-2 in hospitalized patients, including lower oxygenation index, serum urea nitrogen, total bilirubin, lactate dehydrogenase (LDH(, aspartate aminotransferase/alanine aminotransferase ratio, C-reactive protein (CRP), D-dimer, fibrin/fibrinogen (FIB) degradation products, FIB, erythrocyte sedimentation rate, and prolactin.[ 48 , 49 , 50 ] In a meta-analysis, Lippi et al . showed the remarkably lower level of platelet in patients with more severe COVID-19. Consequently, thrombocytopenia could be a clinical indicator and is also considered as a risk for severe disease and mortality in COVID-19 patients.[ 51 ]

Furthermore, some molecular investigations on SARS-CoV-2-infected patients have revealed a significant role of some molecular features and gene expression in susceptibility of infection and symptoms indication, such as ACE2, ACE1/ACE2, ACE2/TMPRSS2, renin–angiotensin system pathway, CD147, CD26-related molecules, and IFITM3.[ 52 , 53 ] Shi et al . represented that IFITM3 plasma membrane localization increases SARS-CoV-2 infection, while IFITM3 endocytosis successfully restricts the virus.[ 54 ] FITM3 with IFITM2 was shown to enhance SARS-CoV-2 infection, quite than restrict it, both in the absence and presence of interferon.[ 55 ] Zhang et al . suggested that rs12252:G is the risk allele of COVID-19 in Chinese patients.[ 56 ] Devarajan et al . studied the single-nucleotide polymorphism rs12252-C/C in the gene IFITM3 as a risk factor that is associated with severe influenza in patients with COVID-19. However, they have suggested that further investigation of the IFITM3-rs12252-C/C allele in a large population is needed.

Although there are few reports of studies investigating the association of human leukocyte antigen (HLA) genetic variation and the immune response against SARS-CoV-2, Lin et al . represented that the HLA-B*46:01 has been significantly related to the severity of SARS in Asian populations.[ 57 ] Another study showed that HLA-A*24:02 is associated with SARS-CoV-2 susceptibility after noticing this allele in four of five patients from Wuhan.[ 58 ] The severity of SARS-CoV-2 disease is associated with elevation of IL-2R, IL-6, IL-10, and TNF- due to “cytokine storming”. It is related to the development of severe alveolar damage and lung inflammation as a distinctive pathological picture of the acute respiratory distress syndrome.[ 59 ] Among all previously mentioned risk factors, male gender, diabetes, age, and chronic heart and pulmonary conditions show higher morbidity or mortality associated by SARS-CoV-2.[ 60 , 61 ]

NOTABLE FEATURES OF POSSIBLE ORIGINS, SOURCES, AND RESERVOIRS OF THE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2

Zoonotic diseases are type of illnesses which normally exist in animals and could infect humans. Understanding the source of a zoonosis infection is very critical for health authorities to separate humans from infected animals, in the outbreaks or pandemics of zoonotic agents. SARS-CoV-2 as a zoonotic infection is responsible for COVID-19 pandemic and also is known as a public health concern. However, so far, the origin of the causative virus and its intermediate hosts is yet to be fully determined.[ 62 ]

Commonly, the SARS-CoV, MERS-CoV, and SARS-CoV-2 are known as highly zoonotic pathogenic β-CoVs with bat origin which caused tree pandemics in the 21 th century.[ 20 ]

Previous reports have revealed that SARS-CoV and MERS-CoV have been spread from the source origin (bats) to the intermediate host (palm civets for SARS-CoV and camels for MERS-CoV) and then transmission circle has been completed by the transmission of the virus from the interface hosts to the humans. Most likely, it seems that the SARS-CoV-2 may have been transmitted to subjects via the intermediate host.

Phylogenetic analysis is one of the good approaches to finding the possible sources and reservoirs of zoonotic agents. Phylogenetic data have shown that genomes of SARS-CoV-2, SARS-CoV, and MERS-CoV share noticeable similarities with each other.[ 63 ] To date, a large number of phylogenomic analysis investigations have reported that the complete genome sequence (~29.9 kb size) of SARS-CoV-2 had almost 80% and 96% similarity with human SARS-CoV and bat coronavirus at nucleic acid level, respectively, suggesting that the bats’ CoV and SARS-CoV-2 might be generated from the common ancestor.[ 64 , 65 ] Furthermore, the recent studies have confirmed that bats are the primary reservoir of SARS-CoV and MERS-CoV.[ 66 , 67 , 68 ] Another report has introduced the pangolins as natural reservoirs for SARS-CoV-2-like CoVs, but there is no conclusive document that SARS-CoV-2 has a specific wildlife host as a virus reservoir.[ 69 , 70 ]

Besides bats, CoVs have been isolated from various animals such as snakes, minks, and pangolins and these animals have considered as a possible intermediate host for SARS-CoV-2.[ 71 ] Anyway, there is no experimental data to support the hypothesis of being of snakes and minks as interface hosts of the SARS-CoV-2. At the front, more advanced molecular analysis and virological studies suggested that pangolins are the most likely candidate for intermediate hosts and this suggestion is supported by phylogenetic analysis studies. For example, original papers have identified 99% and 85.5%–92.4% similarity in complete genome sequence of pangolin-CoV and SARS-CoV-2.[ 72 ] Meanwhile, another research has identified that S protein in receptor-binding domain (RDB) of isolated Malayan pangolin-CoV was almost the same as that of SARS-CoV-2.[ 73 ] The current main suggestion is that the CoVs derived from bat have infected the pangolins and then some genetical variations such as mutations and recombination phenomena evolved this pathogen for transmission to human.[ 24 ] Figure 1 represents the potential and possible transmission routs of SARS-CoV-2.

Potential and possible transmission routs of severe acute respiratory syndrome coronavirus 2

The S protein of SARS-CoV-2 is responsible for virus entry into the cells and beginning the infection in human. This viral protein shares approximately 80% similarity with the SARS-CoV ones in amino acid level, however, there are some difference in amino acid residues of the RBD-S protein between SARS-CoV and SARS-CoV2.[ 74 ] It seems that humans are infected with the virus directly from intermediate animal hosts through contact.[ 75 ] Now, it is obvious that the animals are main intermediate hosts for the evolution of SARS-CoV-2 via recombination and mutation events. Nevertheless, further investigation and analysis may be needed to find the intermediate hosts and other sources.[ 76 ]

INCUBATION PERIOD AND CLINICAL CHARACTERIZATION

The incubation period of an infectious disease is the time interval between the exposures to an infectious agent until signs and symptoms of the disease appear.[ 77 ] The incubation period of a disease can widely vary from one person to another. Understanding the incubation period data of a novel infectious agent is useful to estimating the size of the transmission potential and the pandemic, finding the active cases, assessing the effectiveness of entry screening and contact tracing, and relative infectiousness of a pathogen.[ 63 , 78 ]

The reported estimate of the novel coronavirus incubation time is based on limited case data. Using the data from many online publishes, the incubation period for the novel coronavirus is estimated to be in the range of 2–14 days;[ 78 ] however, two cases with an incubation period of 19 and 27 days have been reported in other public reports.[ 14 ] Although the median incubation period of COVID-19 is variable, many public studies have estimated approximately 5-day incubation time for this viral infection.[ 78 , 79 , 80 ] It has been shown that the median time to confirm the virus infection after first doctor's visit is around 1 (ranged from 1 to 2 days) day.[ 81 , 82 ] Further studies have reported that the median time from start of manifestation to dyspnea and hospitalization was 5 and 7 days, respectively. Furthermore, the median time for ARDS was 8 days.[ 25 ] Hence, applying at least 14-day quarantine, which is longer than incubation time of virus, is a very effective policy to avoid the risk of COVID-19 transmission from active clusters to other subjects.[ 83 ] Studies that compare the average incubation time in SARS-CoV-2, SARS-CoV, and MERS infections, statistically remarkable differences in the incubation periods between these three coronaviruses have not reported, 3 while, some studies have suggested that new emerged COVID-19 had long incubation time than MERS and SARS-CoV[ 84 ] however, most studies with large sample size around the world are needed to find this issues.

The clinical outcomes of COVID-19 are variable, and there is no complete study on its true clinical features. Although SARS-CoV-2 is a respiratory tract virus, because the presence of cellular receptors (ACE2) for virus entry into host cell in the most organs, infection does not limit to lungs and it could be considered as a multi-organ infection with pulmonary and extrapulmonary outcomes.[ 85 ] Adults infected by COVID-19 can develop a spectrum of disease and illness severity, from asymptomatic to mild, moderate, or severe disease. In approximately 80% of patients, infection is asymptomatic or mild,[ 86 , 87 ] and unfortunately, in the 20% of infected patients, the disease progresses to severe stage with severe respiratory manifestations.[ 87 , 88 ] The major presenting manifestations of COVID-19 are fever, cough, headache, fatigue, myalgia, malaise, and shortness of breath or difficulty breathing. On the other hand, sore throat, muscle ache, confusion, sputum production, rhinorrhea, chest pain, conjunctivitis, diarrhea, nausea, and vomiting are less frequently seen in these patients.[ 89 , 90 ] Therefore, this disease cannot be distinguished from other respiratory diseases.

COVID-19 can be divided into four levels including mild, moderate, severe, and critical, based on the severity of clinical manifestations. The details of each level are represented in Table 1 .

The clinical details of four levels of COVID-19

Analysis of clinical features in the young, middle-aged, and elderly SARS-CoV-2-sufferings from Hainan (China) indicated that fever was the common symptom in the all age groups and infection also followed by dry cough and sputum. Overall, the elderly and immunocompromised patients are more susceptible to the severe forms of COVID-19 and also the mortality rate in these patients is higher than young and middle-aged individuals.[ 20 , 82 ] Meanwhile, SARS-CoV-2 infection in neonates, infants, and children is markedly milder than their patients.[ 25 ] There are little data from SARS-CoV-2-perinatal infection, and previous studies indicated no evidence of perinatal infection during the pregnancy.[ 90 , 91 ] Furthermore, this virus has not been detected in the milk of mothers; however, mothers with ARS-CoV-2 infection are encouraged to use personal protective equipment during breastfeeding their babies.[ 92 , 93 ]

According to published reports, complications observed in these patients included ARDS, shock, coagulation dysfunction, metabolic acidosis, acute lung injury, acute cardiac injury, and acute kidney injury. The disease in critical patients can quickly progress to multiple organ functional failure.[ 25 , 94 ] Furthermore, clinical complications such as ARDS and acute heart, liver, and kidney dysfunctions in elderly patients are largely higher than young and middle-aged ones.[ 68 ] The conducted studies have found a distinct positive correlation between age and peak viral load in clinical samples; all these suggest that viral replication can lead to clinical manifestations and death among the elderly group.[ 35 ] Although 4%–11% case fatality rate was recorded for the hospitalized ARS-CoV-2-positive patients,[ 25 ] the overall case fatality rates are truly different among different countries around the world. For example, it is 4.2% in China, 7.7% in Italy, 5.7% in Iran, 3.6% in the United Kingdom, and 6.2% in the United States of America. This is may be because of differences in medical care systems, number of undiagnosed cases with mild or asymptomatic stages of illness, sensitivity of laboratory detection methods, and population heterogeneity.[ 95 , 96 ] Hence, precise estimation of overall case fatality rates is impossible at now.[ 97 ] Figure 2 shows the main complication and comorbidity related to coronavirus disease.

Main complication and comorbidity related to coronavirus disease

Similar to SARS and MERS, COVID-19 led to the extreme enhance in the level of inflammatory cytokines such as IL-2, IL-6, IL-7, IL-10, interferon-inducible protein 10 (IP-10), granulocyte colony-stimulating factor, monocyte chemotactic protein 1, TNF-α, and macrophage inflammatory protein 1A (especially in intensive care unit patients) which is named cytokine storm[ 25 ] and is responsible for severe symptoms in the pulmonary tract.[ 98 , 99 ] Higher viral loads in the serum and stool are associated with drastically elevated IL-6 level and diarrhea, respectively.[ 18 ] The viral load in the salivary is reached to the maximum level during the 1 st week after symptom onset and then decreased over time. The viral loads in some specimens indicate that extrapulmonary viral replication contributes to clinical manifestations. The most common laboratory findings of COVID-19 are included neutrophilia, lymphopenia, enhanced LDH, prolonged prothrombin time, increased alanine transaminase, enhanced D-dimer, creatinine kinase, and CRP.[ 35 ]

EMERGING SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 NOTABLE VARIANTS

The genome mutation of the SARS-CoV-2 during reproducing by infected cell is one of the ways of the virus evolution and the variability of the genome, thus allowing viruses to escape from the host immune system and cause drug resistance and also have an effect on the virus transmission and the disease severity.[ 100 ]

A group of viruses that share the same distinct inherited mutations is called a variant. Most of the reported mutations in this virus is related to mutations in its spike glycoproteins.[ 101 ] Among 14 detected mutations in the SARS-CoV-2 S protein that provide advantages to virus for transmission and evasion form treatment, the D614G mutation (substitution of aspartic acid [D] with glycine [G] in codon 614 was particular important since enables the virus to be at least 36% more transmissible than other variants.[ 102 ]

SARS-CoV-2 spike D614G variant, also called lineage B.1.1.7 or Variant of Concern 202012/01 which has emerged in the United Kingdom (UK variant), may be associated with an increased risk of death compared to the other variants.

This variant has an unusually large number of mutations such as nonsynonymous mutations, deletions, and synonymous mutations that some of them resulted in amino acid changes in the spike protein including ΔH69/V70, ΔY144, D614G, N501Y, A570D, P681H, T716I, S982A, and D1118H. These mutations are important. For instance, the spike protein with N501Y mutation that is located in the receptor-binding site (spike protein's RDB) binds more tightly to its cellular receptor, ACE-2.

The other variant 501Y.V2 that has been identified in South Africa was called B.1.351 lineage. The last three changes are located within the RBD which is estimated to cause 50% more transmissibility than previously circulating variants in South Africa.[ 103 ]

One novel variant which was described in Brazil, P. 1 variant (VOC202101/02, 20J/501Y.V3), is not tightly related to VOC 202012/01 or 501Y.V2 and has eleven amino acid alterations, L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, H655Y, T1027I, and V1176F. Three of them (K417T, E484K, and N501Y) are located in the RBD. Due to the presence of N501Y, the increased transmissibility is assumed for this variant.[ 104 ] Another variant has been also reported in Brazil that was called as VUI202101/01, P. 2 which owns less mutation than P. 1 variants. Figure 3 reveals the global distribution of emerging variants of SARS-CoV-2. Another variant, an Indian type, Delta SARS-CoV-2 (B.1.617.2. AY.1, AY.2, AY.3 lineage), was detected in October 2020[ 105 ], and spread drastically in many countries. A study demonstrated that the spread ability of variant delta (55% more transmittable than variant Alpha, said WHO) is due to its potency to scape to antibodies targeting non-RBD and RBD Spike epitopes[ 106 ].

The global distribution of emerging variants of severe acute respiratory syndrome coronavirus 2

At the beginning of the COVID-19, numerous scientists and biopharmaceutical manufacturers have attended in research collaboration for developing medications, vaccine discovery, and manufacturing. To the best of our knowledge, about 100 vaccines reached the final testing stages. Most of the vaccine designs are based on two different variants of SARS-CoV-2 genomes, called L and S.[ 105 ] Some antiviral medications are prepared for clinical trials.[ 61 , 105 ]

Tracking the novel variants of SARS-CoV-2 is one of the important global issues. Some variants including 501Y.V2, B.1.351 and P. 1 could represent more transmissibility and impact on incidence of this pandemic.[ 107 ] Moreover, some concerns are growing about the impact of introduced vaccines and medications on newly discovered variants. For example, E484K in 501Y.V2 and P. 1 variants could cause a reduction in neutralization by the anti-RBD monoclonal antibodies.[ 108 ] There are also some evidences that this mutation has significant effects on viral sustainability and adaptive evolution which could decline vaccines efficiency.[ 109 ] Fortunately, almost all vaccines have maintained their efficacy to acceptable levels, but not favorable. However, it requires more evidences and studies to confirm their efficiencies against new variants.

CONCLUSIONS

This article is an overview of the current researches on epidemiology in response to the outbreak of COVID-19. In the present review, we summarized the latest reports of transmission route and risk of transmission, mortality and morbidity risk factor, possible origins and reservoirs, and clinical outcomes of SARS-CoV-2 infection. On the other hand, notable variants of SARS-CoV-2 that are the important challenge were investigated. However, further investigations on all aspects of the illness are urgently needed to overcome this viral infectious pandemic.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

Acknowledgments

We would like to thank to guidance and advice from the Clinical Research Development Unit of Baqiyatallah Hospital, Tehran, Iran.