IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\n
Designed to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\n
After a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\n
Our innovative Book Series format brings you:
\n\n
\n\t
Topic Focused Publications - Each topic showcases high impact subject areas
\n\t
Renowned Editorial Expertise - Series Editors, Topic Editors, and a team of international Board Members that permanently support each Book Series
\n\t
Fast Publishing - quick turnaround which is unique for book publishing
\n\t
The benefit of ISSN and ISBN for increased citation and indexing possibilities
\n
\n\n\n\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
We invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\n
Note: Edited in October 2021
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1. Introduction
Obesity in children is the most serious public health problem globally [1], as children are more likely to become obese adults in their future lives. Currently, childhood obesity represents a significant public health challenge in both developed and developing countries by increasing the burden of noncommunicable diseases (NCDs) [2]. Recent estimates suggest that over 38 million children younger than 5 years of age were overweight or obese in 2019 [3]. Over 340 million children and adolescents aged 5–19 years were overweight or obese in 2016 [3]. The prevention of diabetes mellitus and obesity in adults and children was one of the goals set by the World Health Assembly in 2013 [4]. The rapid increase worldwide in obesity is also analyzed in association with the economic causes because some differences were observed between high- and low-income settings. In high-income settings, the higher prevalence of obesity is observed in disadvantaged and marginalized communities. In contrast, in low- and middle-income settings, the prevalence of obesity is higher in groups with higher socioeconomic status. This trend can be explained by socioeconomic inequalities, because in the high-income countries, commonly, the socioeconomic disparities improve the consumption by the poor people of inexpensive, energy-dense foods and beverages.
Furthermore, the increment of obesity prevalence by 23–33% was recorded for children in low-education, low-income, and higher-unemployment households. The family with low-income demonstrates a lower awareness that their children are overweight and then face a host of barriers to improving the diet, the activity behaviors, and the general health status [5]. Many economic consequences for public health strategies are related to the epidemic trend of childhood obesity.
The problem of childhood obesity has become a global public health concern, and the fight for its prevention is a commitment that involves all institutions. The prevention of obesity requires the implementation of surveys to monitor its evolution over time, the knowledge of its determinants, and the research and implementation of interventions, necessarily in a multisectoral and multidisciplinary context, as well as a continuous evaluation process. These actions are necessary for the implementation of evidence-based interventions, which must be supported by appropriate nutritional policies. Overweight and obesity at a young age are associated with various health or economic consequences, therefore it is important to analyze the causes and risk factors and identify the best prevention and treatment strategies. On the prevention of childhood obesity, the promotion of teamwork and the dissemination of information related to childhood obesity is one of the vital strategies to fight against childhood and adolescent obesity. Therefore, teamwork in health care is a crucial strategy for promoting public health and preventing childhood chronic diseases such as childhood obesity.
In Europe, childhood obesity remains a significant health challenge and is distributed disparately across and between countries and population groups [6]. Approximately, 398, 000 children aged 6–9 years were severely obese in Europe in 2019 [7]. Obesity in children is associated with immediate adverse consequences such as psychological problems [8] and lower educational attainment [9]. Also, it is associated with negative health effects later in life or adulthood, such as type 2 diabetes mellitus, hypertension, obstructive sleep apnea, dyslipidemia, and other noncommunicable diseases [10]. Childhood obesity is the outcome of an interaction between a complex series of factors related to environmental, genetic, and ecological effects [10]. Due to the speedily increasing prevalence of childhood obesity in Europe, various initiatives and actions have been launched in recent years in response to this alarming trend. As a result, the WHO European Childhood Obesity Surveillance Initiative has measured the trends in childhood obesity for over a decade [11]. It provides data to inform policy and practice to respond to the problem of childhood obesity [11, 12]. Also, the EU developed an action plan to tackle childhood obesity (EU Action Plan on Childhood Obesity 2014–2020) on February 24, 2014 [13]. However, the progress on combating obesity in children has been slow and inconsistent across the region. For instance, the latest data have shown that southern European countries such as Greece, Italy, Malta, Cyprus, San Marino, and Spain have the highest rate of childhood obesity (nearly one in five children are obese) [14]. On the other hand, Denmark, France, Ireland, and Norway are among countries with the lowest rates of obesity in children in either sex [14]. Hence, childhood obesity is still a so-called time bomb [15] for future demands for health services and could jeopardize the progress toward achieving the Sustainable Development Goals (SDGs) [16].
The present chapter is aimed at (1) illustrating the prevalence of obesity in children and adolescents aged 5—19 years by the WHO European Region and (2) analyzing the effectiveness of the prevention strategies adopted in EU countries to combat childhood obesity from a social and legal point of view and pointing out the best strategies to reduce the prevalence of obesity in children and adolescents.
2. Epidemiology
2.1 Prevalence
Data on the prevalence of obesity in children and adolescents aged 5—19 years in the WHO European Region were taken from the Global Health Observatory (GHO) data [17]. By geographic area, the highest crude prevalence of childhood obesity was observed in Mediterranean countries in 2016, ranging from 7.6% to 13.8% for either sex. In particular, Greece, Malta, Italy, Cyprus, Andorra, Turkey, and Israel among the Mediterranean countries had the highest prevalence of childhood and adolescent obesity in 2016 (Table 1). In 1980, Oriental European countries had a prevalence of less than 2%, ranging from 0.3 to 1.9%. However, in 2016, it changed completely, and the prevalence was more than 4%, ranging from 4.2 to 11.1% (Table 1). The prevalence in all northern European countries, except Iceland, increased by over 100% between 1980 and 2016, but in Iceland, it increased by 94% in the same period (5.1% in 1980 and 9.9% in 2016). In 2016, among the Western European countries, the United Kingdom (UK) and Germany had the highest childhood obesity. In contrast, Armenia, Azerbaijan, and the Republic of Moldova among Eastern European countries with relatively low prevalence levels (Table 1). The prevalence distribution in Oriental Europe countries showed relatively small when compared to the other areas in Europe in 2016. However, EU member states (Bulgaria, Czechia, Hungary, Lithuania, Poland, Slovakia) among Oriental countries had higher prevalence levels (Table 1).
1980
1990
2000
2010
2016
M (%)
F (%)
T (%)
M (%)
F (%)
T (%)
M (%)
F (%)
T (%)
M (%)
F (%)
T (%)
M (%)
F (%)
T (%)
Mediterran ean Region
Turkey
0.7
0.8
0.7
2.3
2.5
2.4
5.2
5.3
5.2
9.3
8.7
9
12.1
10.9
11.5
Cyprus
3.7
1.8
2.7
8.5
4.2
6.4
11.9
6.1
9.1
14.1
7.6
10.9
15.5
8.7
12.2
Israel
7.5
5.9
6.7
9.8
7
8.4
11.8
8.1
10
13.4
9
11.3
14.2
9.5
11.9
Andorra
8.8
7
7.9
11.9
8.6
10.3
13.4
9.3
11.4
14.5
10
12.3
15
10.4
12.8
Malta
8.6
7.2
7.9
11.2
8.2
9.8
13.2
9.4
11.4
14.9
10.5
12.7
15.7
11.1
13.4
Portugal
2
1.7
1.9
4.4
3.5
3.9
7.9
6.4
7.2
10.4
9.2
9.8
10.7
10.2
10.4
Spain
4.7
2.8
3.8
7
3.8
5.4
9.3
5.1
7.3
11.8
7.2
9.5
13.1
8.4
10.8
Albania
0.4
0.2
0.3
1
0.6
0.8
2.6
1.5
2.1
6.1
3.6
4.9
9.5
5.5
7.6
Croatia
1.3
0.7
1
3.1
1.7
2.4
5.9
3.2
4.6
10.3
5.7
8.1
13.8
7.9
10.9
France
3.2
2.9
3
4.5
3.7
4.1
6.2
5
5.6
7.9
6.3
7.1
8.9
7.2
8.1
Greece
5.8
3.6
4.7
8.5
4.9
6.7
11.2
6.6
9
14.8
9.1
12
16.8
10.7
13.8
Italy
6.2
4.2
5.2
8.2
5.1
6.7
12.2
7.2
9.3
13.3
9.3
11.4
14.5
10.4
12.5
Montenegro
0.4
0.2
0.3
1.3
0.7
1
3.7
2
2.9
7.2
3.9
5.6
9.7
5.3
7.6
Northern Region
Iceland
5.8
4.4
5.1
8.2
5.5
6.9
10.2
6.3
8.1
11.5
6.7
9.1
12.5
7.2
9.9
Ireland
1.4
1.5
1.5
3
3.1
3.1
5.3
5.6
5.4
8.5
8
8.3
10.4
9.1
9.8
Denmark
3.7
3.3
3.5
6
4.5
5.3
8.1
5.2
6.7
8.8
4.9
6.9
9.4
4.9
7.2
Estonia
1.7
1.7
1.7
2.6
2.3
2.5
3.6
2.8
3.2
5.6
3.7
4.7
7.8
4.7
6.3
Finland
3.4
1.5
2.5
6.7
3
4.9
9.3
4.2
6.8
11.1
4.9
8.1
12.4
5.6
9.1
Netherlands
1.4
1.2
1.3
2.5
2
2.3
4.5
3.4
3.9
6.9
4.8
5.9
8.4
5.6
7
Norway
2.7
2.5
2.6
4.7
3.9
4.3
7.2
5.6
6.4
9.1
6.8
8
10.4
7.7
9.1
Sweden
3.3
2.5
2.9
4.7
2.9
3.9
6.5
3.6
5
7.4
4
5.7
8.6
4.7
6.7
Oriental Region
Hungary
2
1.4
1.7
3.5
2.3
2.9
5.8
3.7
4.8
9.9
6.2
8.1
13.7
8.4
11.1
Kazakhstan
1.5
0.8
1.2
2.4
1.4
1.9
3.7
2.1
2.9
5.6
3.4
4.6
8.1
4.9
6.5
Lithuania
1.3
1.1
1.2
2.7
2.1
2.4
4.3
2.8
3.6
6.3
3.7
5
8.7
4.8
6.8
Armenia
1.3
1.2
1.3
2.2
1.9
2
2.8
2.3
2.6
3.8
3.2
3.5
5.3
4.2
4.8
Azerbaijan
0.9
0.7
0.8
1.5
1.2
1.3
2.2
1.8
2
3.5
2.9
3.2
5.3
4.4
4.9
Bosnia and Herzegovina
0.3
0.2
0.3
1
0.6
0.8
2.2
1.3
1.8
4.5
2.9
3.7
6.5
4.3
5.4
Bulgaria
1.6
1
1.3
3.4
2
2.7
5.9
3.5
4.7
10.1
5.8
8
13.6
7.8
10.8
Czech Republic
2.3
1.5
1.9
3.7
2.2
3
5.8
3.1
4.5
9.1
4.8
7
12.6
6.6
9.7
Poland
1.4
0.6
1
2.9
1.3
2.1
4.9
2.1
3.6
8.8
3.6
6.3
12.7
5.3
9.1
Republic of Macedonia
1.3
0.7
1
2.8
1.4
2.1
5.3
2.7
4
8.7
4.5
6.7
11.9
6.4
9.3
Republic of Moldova
0.4
0.3
0.4
1.1
0.8
1
2
1.4
1.7
3.2
2.1
2.7
5.1
3.3
4.2
Romania
0.8
0.4
0.6
1.7
1
1.4
3.6
1.9
2.8
7.1
3.7
5.4
10.7
5.4
8.1
Russian Federation
1.7
1.4
1.5
3.1
2.2
2.6
4.1
2.4
3.2
6.6
3.3
5
9.5
4.4
7.1
Serbia
1
0.5
0.8
2.5
1.2
1.9
5.1
2.5
3.8
9.2
4.9
7.1
12.4
7
9.8
Slovakia
0.8
0.4
0.6
1.8
1
1.4
3.5
1.9
2.7
6.8
3.7
5.3
10.4
5.7
8.1
Occidental Region
Switzerland
1.1
0.9
1
3.1
2.1
2.6
5
3.1
4.1
6
3.8
5
6.9
4.6
5.8
United Kingdom
3
3.8
3.4
5.2
6
5.6
8.3
8.6
8.5
10.3
9.6
9.9
10.9
9.4
10.2
Luxembourg
3.6
2.7
3.2
5.7
3.8
4.8
7.8
4.9
6.4
9.5
5.7
7.6
10.4
6.2
8.3
Belgium
4.5
4.6
4.6
6.3
5.2
5.8
7.5
5.6
6.6
7.8
5.5
6.7
8.2
5.8
7
Austria
3.5
1.8
2.6
5.6
2.6
4.1
7.9
3.6
5.8
9.8
4.8
7.4
11.2
6
8.6
Germany
3.8
2.7
3.3
5.9
3.7
4.9
8
4.8
6.4
9.7
5.8
7.8
11
6.8
8.9
Table 1.
Prevalence (%) of obesity in children aged 5–19 years by the WHO European region from 1980 to 2016.
Data source: Global Health Observatory (GHO) data [17]; M, male; F, female; and T, total.
2.2 Trends
Obesity in children aged 5–19 years in almost all European regions have increased rapidly from 1980 to 2016. Mainly EU member states have shown increasing trends in the prevalence of obesity in children and adolescents during the study period. Notably, Greece and Croatia have shown secular trends in the prevalence of childhood obesity among EU countries in the Mediterranean Region (Figure 1). Besides, the prevalence in the United Kingdom tripled for either sex from 1980 to 2016, ranging from 3.4 to 10.2%, respectively (Table 1). Similarly, in France and Spain, the prevalence almost tripled from 1980 to 2016: for example, in France, it ranged from 3% in 1980 to 8.1% in 2016 and in Spain, passing from 3.8% in 1980 to 10.8% in 2016 (Table 1). In Slovakia, the prevalence of obesity in children has increased from 0.6% in 1980 to 8.1% in 2016 (Table 1). On the other hand, in Cyprus, Lithuania, Portugal, and the Netherlands, the prevalence has increased more than five times over 36 years in each country (Table 1). In contrast, in Italy, Malta, and Belgium, the magnitude of childhood obesity has doubled from 1980 to 2016. As shown in Table 1, in Poland, the prevalence has increased from 1% in 1980 to 9.1% in 2016, while in Bulgaria, it grew by more than eight times in the same period (1.3% in 1980 and 10.8% in 2016). In Ireland, the prevalence of obesity in children and adolescents has steadily increased over 36 years (1.5% in 1980 and 9.8% in 2016) (Figure 2). Mainly the prevalence level increased from 1.5 and 1.4%, respectively, for girls and boys in 1980 to 9.1 and 10.4% for girls and boys in 2016 (Table 1). Furthermore, the Oriental EU member states except for Lithuania all have shown consistently increased trends in the prevalence over 16 years (from 2000 to 2016) (Figure 3). Trends in the prevalence of obesity in children and adolescents aged 5–19 years have been presented in EU countries by geographic areas (Figures 1–4).
Figure 1.
Trends in the prevalence of obesity in children and adolescents aged between 5 and 19 years in the Mediterranean region EU countries from 1980 to 2016.
Figure 2.
Trends in the prevalence of obesity in children and adolescents aged between 5 and 19 years in the northern EU countries from 1980 to 2016.
Figure 3.
Trends in the prevalence of obesity in children and adolescents aged between 5 and 19 years in the oriental EU countries from 1980 to 2016.
Figure 4.
Trends in the prevalence of obesity in children and adolescents aged between 5 and 19 years in the occidental EU countries from 1980 to 2016.
3. Policies
The alarming proportions reached by childhood obesity in many countries pose an urgent and serious challenge, also concerning the most serious consequences of obesity on health. Obesity can produce effects immediately on a child’s health, educational performance, and quality of life, or chronic illnesses in adults, which are very likely to remain obese. The policy to tack childhood obesity is slow and inconsistent and then to review and resolve this gap, in 2014, the Commission on Ending Childhood obesity has been established. Moreover, the “Strengthening Nutrition Action of Food and Agriculture Organization of the United Nations and World Health Organization-United Nations decade of Action on Nutrition 2016-2025,” describes that in the same year (2014). The Second International Conference on Nutrition (ICN2) listed obesity and overweight among the malnutrition forms. It focused the attention of 164 member States of FAO and WHO, about the need to change the choices of the food systems for better diets and a healthier planet. The unhealthy diets, maternal and child malnutrition, are considered as the current top risk factors for one-quarter of global deaths.
Furthermore, the number of people of all ages who are affected by diet-related noncommunicable diseases (NCDs) has increased. The documents produced by ICN2 make up the roadmap for the governments of the world to eradicate hunger and prevent all forms of malnutrition such as undernutrition, micronutrient deficiency, overweight, and obesity. One year later, has been adopted the 2030 Agenda for Sustainable Development (“2023 Agenda”) and its Sustainable Development Goals (SDGs) at the United Nations (UN) General Assembly. In 2015, the United Nations mentioned the prevention and control of noncommunicable diseases as a top priority in the Sustainable Development Goals, and obesity listed as a risk factor for noncommunicable diseases [18]. The Global Action Plan for the Prevention and Control of Non-communicable Diseases 2013–2020 assess policy options for member states per their legislation for the selection and for undertaking actions from among the policy options about the monitoring, the disease registries, and the surveillance of NCDs.
Regarding the surveillance, the WHO indicates the surveillance of the key risk for the NCDs considering behavioral and metabolic risk factors as for example the use of alcohol, the physical inactivity, tobacco use, unhealthy diet, overweight, and obesity, raised blood pressure, raised blood glucose, and hyperlipidemia, and determinants of risk exposure such as marketing of food, tobacco, and alcohol [19]. Moreover, to accelerate the actions on nutrition, the UN General Assembly, in 2016, proposed that the period from 2016 to 2020 should be a UN Decade of Action on Nutrition (Nutrition Decade), providing a clearly defined, time-bound, and cohesive framework for all countries and stakeholders to increase nutrition investments and implement policies and programs to improve food security and nutrition, reach the six global nutrition targets 2025, and the diet-related global noncommunicable disease (NCD) targets. Modifying possible risk factors as the reduction of an unhealthy diet is one of the “best buys” for the prevention and control of noncommunicable diseases (NCDs) proposed by the World Health Organization [20].
All reports proposed by the international organization of public health proposed a no single intervention to resolve childhood obesity and overweight but analyses and interventions about the environmental context and three critical periods in the life-course. The first is the preconception and pregnancy, infancy and early childhood, and finally, older childhood and adolescence. Therefore, the prevention and the treatment of obesity require a whole-of-government approach in which the policies of all sectors are across the same target, which the health, the eradication of harmful health impacts, and thus improve population health and health equity. The Commission on Ending Childhood Obesity collected and an organic package of recommendations to address childhood obesity and achieve strategic objectives. As a result, the first object is tacking the obesogenic environment because the major negative elements are the unhealthy diet and physical activity of children. The second goal is the reduction of the risk to develop the obesity development factors able to change the biology and behavior of children before birth and through infancy. The last is the treatment and cure of children or young people with notified obesity. Consequently, the areas identified by the commission to define the preventive actions are the promotion of healthy foods intake, physical activity, the cure preconception, and pregnancy care, the early childhood diet, and physical activity, the health, nutrition, and physical activity for school-age children and finally the weight management. The first recommendation concerns the promotion of healthy food intake and the reduction of sugar-sweetened beverages by children and adolescents. Among the actions promoted are listed the development and diffusion of appropriate and context-specific nutrition guidelines for adults and children, the implementation of a tax on sugar-sweetened beverages, and the marketing of foods and nonalcoholic beverages to children. Besides, the description of the nutrient-profiles to identify unhealthy foods and beverages associated with a standardized global nutrient labeling system. The Codex Alimentarius Commission proposes a standardized system of food labeling for all packaged foods and beverages, which can support the nutrition and health education [21]. In association with the correct labeling system could be improved, also, the public education of both adults and children about nutrition literacy and the interpretation of front-of-pack. This recommendation is included in the recommendation 14 of United Nations decade of Action on Nutrition 2016–2025, concerning saturated fat, sugars, salt, and trans-fat reduction has been focused on the promotion of a healthy diet to stop the consumption and sale of highly processed foods, growing fastest in lower-middle-income countries. The actions to prevent and control NCDs include the reduction of salt intake, and the setting of target levels for the amount of salt, reformulating food products. Furthermore, the action plan has been indicated the elimination of industrial trans-fats and the reduction of sugar consumption through taxation on sugar-sweetened beverages. The availability, and consequently, the high consumption of these products, is the principal cause of health problems such as obesity and other diet related NCDs. The reduction of sedentary behaviors in children and adolescents, focusing on physical activity programs, is the second recommendation and includes the definition of advice to children, adolescents, parents, caregivers, teachers, and health professionals on healthy body size, physical activity, sleep behaviors and appropriate use of screen-based entertainment. The same recommendation promotes the improvement, during the recreational time, for all children (including the children with disabilities), of physical activity favoring adequate facilities at school or in public areas. Recent epidemiologic data show a decline from the age of school about physical activity. About 81% of adolescents have insufficient physical activity lower than 60 minutes each day. Obesity is more linked with physical activity because it creates a vicious cycle, which increases body fat levels and decreases physical activity. The recommendation about the prevention of childhood overweight and obesity regarding all guidelines promoted introduces the protection of the diet in women during pregnancy, the improvement of child nutrition status and growth, and finally, the promotion of physical activity to address sedentary lifestyle from the early stages of life. The best keys to these recommendations are breastfeeding promotion and protection because they have a crucial role in the reduction of childhood obesity risk. Indeed, the diagnosis and management of hyperglycemia and gestational hypertension, the monitoring of gestational weight gain, the correct diet, and lifestyles during pregnancy are key preventive factors against childhood overweight and obesity. To ensure healthy child development, policies should provide advice not only on healthy eating but also on appropriate sleep time, sedentary or screen time, physical activity, or active play for the age group of 2–5 years. The school is also a fundamental environment to promote the correct lifestyles, especially about the diet. Two aspects can be improved at school, the promotion of standardized meals, in accordance with guidelines, without unhealthy foods with sugar, sweetened beverages or energy-dense, nutrient-poor foods etc. but characterized by the introduction of fresh fruits, vegetables, and safe drinking water. The secondary aspect is the improvement of knowledge’s on children about health education within the core curriculum of schools and practical experiences of food preparation available to children, their parents, and caregivers.
Finally, the six recommendations of the commission are the correct weight management in children and young people suffering from obesity and overweight, developing multicomponent services concerning physical activity, nutrition, and psychological support. These supports are delivered by professional and treated teams, as part of Universal health coverage. The responsibilities of these actions are divided by different structures at different levels. The first is the WHO and concerns the institutionalization of each measure across all technical areas of WHO, and regional and country offices. Furthermore, it provides the consultation and technical support for action at global, regional, and national levels, with international agencies, and the governments of each Member States. Each Member States are supported by International organizations, and define political commitment against childhood obesity, coordinate all sectors and institutions engaged for policies about nutrition, food, agriculture, sport and recreation, urban planning etc. Collect and record all data on BMI-for-age of children and define the national targets for childhood obesity. The other structures are represented by nongovernmental organizations (NGOs), the private sector, the philanthropic foundations, and academic institutions [22].
In Europe, the EU Action Plan on Childhood Obesity 2014–2020 translates the international guidelines with the purpose of demonstrating the shared of EU Member States to addressing childhood obesity; set out priority areas for action and a possible toolbox of measures for consideration and finally propose ways of collectively keeping track of progress. The EU Action Plan considers the presence of three types of stakeholders which are: the 28 EU Member States, the European Commission, and international organizations such as the WHO and finally civil society (e.g., nongovernmental organizations (NGOs), industry, research institutes, and associations). The national, regional, and local level was represented by the specific authorities. Each area defined in the EU action plan is in agreement with the areas proposed by the Global Action Plan, and to evaluate the efficacy of the intervention for each region were defined as specific indicators. Regarding the area for action 1: Support a healthy start in life the first operational objective is, for example, increase the prevalence of children that are breastfed, the indicator is the % of children breastfed and the final target the achievement of 20% in 2020 of children with adequate periods of exclusive breastfeeding according to national recommendations. The area of action 2 is about the promotion of healthier environments, especially at schools and preschools, and the main priority is the establishment of children’s health as a priority at schools, and for example, the first operational objective is to “provide the healthy option and increase daily consumption of fresh fruit and vegetables, healthy food and water intake in schools (with a targeted focus on schools in underprivileged districts).” The action is the development of preschool and school meals with fruits, vegetables, and drinking milk following the existing EU guidelines. The indicators are, for example, the number of member states implementing frameworks on preschool and school meals, and the target to achieve in 2020 is 90% of the member states participating in the program. The other areas are the improvement of healthy options regarding the availability of healthy food choices to children and the target of restriction related to vending machines. Area number 4 has the goal to limit the exposure of children to advertisements for food/drinks high in fat, sugars, and salt. The improvement of family knowledge and information’s on the daily food and health choices of children of action number 5. The last two areas of action are number 6 to encourage physical activity, and number 7 is related to the monitoring and evaluation of children’s nutritional status and behaviors. At this moment, the assessment of the effectiveness of the Action Plan that can be analyzed is referred to in 2018, because the final assessment will be defined at the end of 2020. The initial results compare the activities improved before 2014 with the activities promoted with the EU Action Plan in each action area [23]. The results show an improvement of actions relatively the guidance around the pregnancy, the policies on vending machines, energy drinks, and reformulation of food and especially the concentration of salt.
4. Prevention strategies adopted by European states
Despite the important engagement of the European countries in reversing the progress of obesity, the incidence of overweight subjects remains alarming, particularly if considering the young population. Childhood weight gain has, in fact, a severe impact on health and psychosocial outcomes, deeply affecting individual and family’s quality of life. Research shows that overweight children are more likely if compared to normal weight ones, to become obese adults and so to develop chronic conditions. The recent increment of hours dedicated to “screen time” and the associated damaging effects on eating habits, together with little safe spaces to be active in, are essential factors influencing the level of physical activity and health among young. Also, cheaper and larger-portioned fast food, as well as the massive consumption of high-sugar products, must be taken into consideration. In 2014, in EU, the 7% of yearly national health budgets were spent on diseases correlated to obesity, and investigations showed how policies addressed to children obesity control would repay on investment of 6–10%.
For these reasons, in 2007, after analyzing the report by the WHO European Childhood Obesity Surveillance Initiative (COSI), the European Commission adopted the White Paper on a Strategy for Europe on Nutrition, Overweight and Obesity-related Health issues, composed of six major goals: better-informed subjects, physical activity, and healthier options promotion, supporting low socioeconomic groups and developing evidence and monitoring systems to support the program. The High-Level Group on Nutrition and Physical Activity and the EU Platform for Action on Diet, Physical Activity, and Health are the main instruments set up for implementation of the strategy. The first one enables governments to share health and economic analysis and enhances contact between governments and the EU platform for action on a diet, physical activity, and health. It also works on some priorities such as reducing children’s exposure to marketing of foods high in fat, salt and sugars, physical activity, labeling, and public procurement of food, reducing health inequalities. The EU Platform is a forum for European level organizations, including Food business and consumer organizations, scientific associations, and NGOs. The high-level group can also be asked by the commission to prepare the groundwork for relevant prevention and promotion initiatives agreed by the steering group on promotion and prevention.
In 2013 the strategy went through an external evaluation to test its efficiency: the results were positive. However, they suggested a greater commitment to promoting physical activity. Besides, an Action Plan on Childhood Obesity addressed to a Europe-wide context was redacted, to lower young overweight by 2020. One of its main goals is to support a healthy start in life, encouraging breastfeeding and promoting the adoption of a healthy lifestyle both during the early stage of life and preconception period. Developing healthier school environments is the sequel, providing wholesome meals, with the proper nutritional intake, and also allowing adequate time to consume it. Making the healthy option more available in addition, both in schools and in the working environment, would encourage good eating behavior to be part of the routine. The fourth point is about making families informed in order to empower parents in planning a correct meal plan and schedule regular active leisure activities, which is also linked to the significant focus on the promotion of the physical activity. Last, the increase in monitoring and research, would, in the end, test the nutritional quality of food, health status, and habits of children, together with the collection of systematic data.
The main actors of the plan are 28 EU Member States, the European Commission, and a variety of civil society stakeholders such as NGOs, industry and agricultural sectors, University and research institutes. Another project, the Joint Action on Nutrition and Physical Activity (JANPA), was proposed as a contribution to the EU action plan on childhood obesity 2014–2020, focusing on specific outcomes that can effectively contribute to nutritional and physical activity policies during childhood. It has the following objectives: economic evaluation of the cost of overweight and obesity in children with the aim to encourage public actions, promoting healthy nutrition and physical activity to pregnant women and families with young children, promoting healthier environments in schools and preschools, efforts at a local or at a national level regarding nutrition and physical activities, promoting healthy eating and drinking practices, and improving the information addressed to the consumer at the national level [13]. At the national level, many policies and programs have been adopted in recent years in Europe, aiming to prevent child obesity and improve its treatment and management.
4.1 Italy
Data from the Childhood Obesity Surveillance Initiative (2015 – 17) show that Italy is ranked first in Europe for child obesity, with 21% of children obese or overweight: taking into account this evidence, Italy has turned its attention not only to monitoring, but also to the population approach, using media, brochures, and education in schools and health-care facilities. These actions are part of the Italian Health Plan on Prevention. One of the objectives of this program is to reduce the preventable and avoidable burden of morbidity, mortality, and disability of noncommunicable diseases. Another initiative adopted in Italy is the program named “OKKIO all Salute,” launched in 2007 as a part of the COSI initiative, to monitor children’s weight, eating behaviors, physical activity habits, and their related risk factors among children of 6–10 years. From 2008, around 45.000 families took part in this project. Italy is also part of the international program HBSC (Health Behavior in School-aged Children), showing commitment to understanding factors influencing children’s eating behaviors [24].
4.2 Malta
The increasing prevalence of overweight and obesity, especially among children, is a significant public health problem in Malta, as it has been estimated that 40% of school-aged children are overweight or obese. Different actions have been put in place to tackle this problem since the Maltese Presidency of the Council of the EU selected childhood obesity as one of its priority areas during its European Presidency in the first half of 2017. Considering the fact that children spend much time in school, particular attention was put to the school environment. In 2016, the government of Malta enacted the “Healthy Lifestyle Promotion and Care of Non-Communicable Diseases Act,” which aimed to promote physical activity and balanced diets to achieve healthy lifestyles and reduce the noncommunicable diseases in all age groups. An intersectoral Advisory Council was set up, and one of its major initiatives was outlining a legislative tool for schools: there was a clear need for improving the school environment to help the whole school community to adopt healthier dietary patterns and lifestyle. The consumption of healthy foods and restrictions on products high in salt, sugar, and fats were encouraged, following nutritional criteria based on the WHO nutrient profiling model and carrying random inspections by specifically trained health practitioners.
In August 2018, the Maltese government issued subsidiary legislation to regulate the food being sold and provided by schools, implement programs for healthy eating, ban advertising or sponsorship of unhealthy foods, and ensure the provision of drinking water in schools. One of the divergences identified across EU states was in planning food procurement tenders for schools that promoted healthy eating and to allow their smooth implementation. It has been important to set clear specifications, with support from the Joint Research Centre and experts [24].
4.3 Poland
In Poland, a 2016 Regulation by the Minister of Health addressed groups of food intended for sale to children and adolescents in the education system. Besides, the School Program Strategy 2017/18 – 2022/23 has, as one of its goals, the promotion of a healthy, balanced diet among children and parents. In particular, it aims to change the eating habits of children by increasing the share of fruit and vegetables and the intake of milk. In Poland, the food industry is one of the most influential lobby groups, with well-organized representation and significant financial resources. Poland is also one of the participating countries in the Choices Program, an initiative introduced in the Netherlands in 2006 in response to WHO’s call for the food industry to take an active voluntary role in tackling obesity. To reduce the consumption of salt, there has been an important consumer awareness initiative through media, schools, and health-care facilities, as well as 16% of salt reduction in bread by 2012. Concerning physical activity, it is mandatory in primary and secondary schools, and it is included in general teaching training [25].
4.4 United Kingdom (UK)
In some countries, reducing childhood obesity is a task shared by the Ministry of Health with the Ministry of Finance (responsible for taxes on food high in saturated fat and sugary soft drinks), the Ministry of Education (for school curricula, healthy nutrition education, and physical activity), and the Ministry of Agriculture and Food Industry (for free school fruit and vegetable schemes and sustainable healthy food supplies) [24]. This is the case of England, opposed to the approach of the Republic of Moldova, where a lack of multisectoral collaboration has been found. The UK Childhood Obesity Plan introduces for the first time a soft drink industry levy and the revenue will be invested in programs to reduce obesity and encourage physical activity, in addition to substantial restrictions for sailing and promoting high sugars and fat drinks or snacks, after the introduction of a tax on sugary drinks was announced in March 2016 and came into force in April 2018.
In some countries, television (TV), radio, and Internet services are regulated with some set standards for advertising to protect children from the overconsumption of unhealthy foods, and this is the case of England, where, the National Office of Communications since 2006, does not allow TV advertisements for such foods to be shown during or close to children TV programs. They also launched a sugar reduction program intending to remove sugar from the food’s children frequently eat, paying attention that it is followed by a calorie restriction and not by compensation with extra fats. Also, supporting agricultural innovation by bringing together food business and researchers is part of the project. Support is also given to disadvantaged families, with the distribution of 60 million worth of vouchers that can be exchanged for fresh fruit and vegetables or vitamins. Of course, also physical activity is considered, and it is included in each day at school for at least 30 minutes. It should also be taken into consideration the GREAT commitment of the UK Government in enabling health professionals to support families’ diet, as well as training them to face eating behaviors changes and promoting wellbeing [26].
4.5 Moldova
Concerning Moldova, concrete actions to face childhood obesity were only undertaken in 2012. The National Health Policy (2007–2021) was the first policy document that addressed obesity as a priority, involving the society and government, but it was in 2014 when the Moldovan government endorsed the first National Food and Nutrition Program for 2014–2020 and the Action Plan for 2014–2016, with the specific objective to halt the rise of obesity prevalence among children and adults. The 31 July 2007, the Ministry of Health Decision forbids the marketing of energy-dense food with high-fat content and reduced nutritional value in institutions for children. In 2009, new laws prohibited marketing pressure on children to consume healthy drinks. After the Food Law was amended, selling and distribution of unhealthy food within 100 m by schools were banned. The Republic of Moldova became part of COSI from 2013 and participated in the third and fourth rounds of this initiative. Further in 2014, the government adopted the first National Food and Nutrition Programmed for 2014 – 2020 (NFNP) and its Action Plan with the aim of zero increase in obesity prevalence, employing compulsory nutritional labeling, limitations on advertising, together with the elimination of trans-fats and reduction of sugar and salt [24].
4.6 France
EPODE, or Ensemble, Prévenons L’Obésité Des Enfants (Together, Let us Prevent Childhood Obesity) was established in January 2004, based on the guidelines from the National Health Program recommendations. This program was developed based on the effectiveness observed from the Fleurbaix-Laventie Ville Santé Study, which started in 1992 and continuing, which showed a decrease in childhood obesity rate after the nutritional and physical activity initiatives were implemented in the two towns. The project is supported by the French Ministry of Health, in collaboration with more than five other Ministry, the French National Academy of Medicine, together with some partners like Nestle and Ferrero, financing half of the costs of the program. EPODE now extends to nearly 1.8 million inhabitants in 167 French cities, 20 cities in Spain, and eight cities in Belgium. The project aims to reduce BMI in overweight or obese children promoting physical activity and a healthy diet through three major steps: (1) informing community and families about the obesity problem, using meetings and brochures; (2) Training participants (teachers and professionals); (3) starting the action in schools, distributing educational materials, improving school catering, and hosting food workshop [27].
4.7 Germany
Understanding the importance of obesity as a health issue, and recognizing the worrying increase of overweight adolescences, a range of federal policies were established in Germany to face the issue since, public health services in Germany have played a great role in putting obesity on the political agenda, and they focused on dealing with obesity from child and adolescent health services perspective. The Robert Koch Institute has launched the German Health Interview and Examination Survey for Children and Adolescents (KiGGS-Study), with a baseline study in 2003–2006 and a follow-up study in 2014–2017. The results of the second study were published in March 2018. They pointed to a strong social gradient, with the prevalence of overweight reaching 27.0% and 24.2% in girls and boys respectively, aged 3–17 years with low socioeconomic status compared to 6.5% in girls and 8.9% in boys with high socioeconomic status.
Some of the other vital initiatives in response to the Survey are the National Cycling Plan 2020, which promotes cycling, walking, and the use of public transport and the two programs of the Federal Centre for Health Education (FCHE): Gut Drauf (Feeling Well), which aims to improve the health of children and adolescents aged 12–18 years, and Tutmirgut (Good For Me), aimed at children aged 5-11 years. In 2007, there were 708 programs for overweight or obese children and adolescents in Germany, reaching approximately 44,000 persons [24]. In Germany, policies are implementing a salt reduction in bread and many consumer awareness initiatives regarding a healthy lifestyle, promoted in schools, and via media and Internet [28].
4.8 Denmark
The Danish National Action Plan against Obesity was written to improve awareness in the Danish population and generally reduce high BMI. Children and adolescents are one of their main targets. Concerning nutrition, the aim concerning children’s diet is to reduce the number of subjects who consume more energy from fat and sugar and, at the same time, pay attention to the correct fiber intake. Also, life outside the home was provided with healthy food, and parents were supported in taking proper diet choices. Of course, also physical activity is considered, and new guidelines were established, increasing the hours to it dedicated to schools and strengthening the competences of teachers. Suitable playground and outdoor areas were provided, as well as car-free areas near schools and safe foot and cycle paths [29].
5. Conclusion
Handling childhood obesity is undoubtedly challenging despite the substantial progress made concerning healthy nutrition, early life, and increased physical activity. It has also been essential to restrict advertising on TV actively. Still, it should also be taken into consideration to control video games, mobile phones, tablets, and social media since, nowadays, there is no more efficient way to address kids than getting in touch with them through the Internet. Monitoring childhood obesity is, for sure, more rewarding if compared to adults but, initially, for the complexity of relating to young subjects, it can be very onerous.
Consequently and taking into account the role played by multinational food industries in supporting French policies should be considered to further involve in obesity control plans, food, and sports industries. Doing so will make it possible to boost the research resources and, at the same time, allow the markets’ sectors, that would possibly be affected by the latest policies and guidelines, to adapt their selling to the new consumer type. It should also be mentioned that some European countries are still not facing the childhood obesity problem, primarily due to inadequate resources and a lack of interface between the health institutions and industries.
In Malta, for example, the requirement of precise definitions for food procurement that tenders on how to set a healthy meal plan in schools was given by the Advisory Council with the support from the EU Joint Research Centre, a proper example of a strategy controlling balance and micronutrient intake of at least one meal per day of all school kids. This strategy, together with the Healthy Weight for Life strategy for 2012–2020 and the Food and Nutrition Policy and Action Plan for Malta 2015–2020, makes Malta one of the most committed European countries in the battle against childhood obesity. The Maltese case is one of the first to be taken into consideration when evaluating the situation.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"obesity, overweight, childhood, adolescents, prevalence, epidemiology, policies, prevention",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73241.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73241.xml",downloadPdfUrl:"/chapter/pdf-download/73241",previewPdfUrl:"/chapter/pdf-preview/73241",totalDownloads:736,totalViews:0,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,introChapter:null,impactScore:2,impactScorePercentile:76,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"May 29th 2020",dateReviewed:"August 16th 2020",datePrePublished:"September 17th 2020",datePublished:"April 21st 2021",dateFinished:"September 17th 2020",readingETA:"0",abstract:"The childhood overweight and obesity epidemic has become a global emergency in public health and a crucial challenge of the twenty-first century. Nowadays, childhood and adolescent obesity represent a significant public health problem both in developing and developed countries. Globally, above 340 million children and adolescents aged 5–19 years were overweight or obese in 2016. Childhood obesity is a critical burden because it can be associated with a higher possibility of obesity, premature death, and disability in adults, as well as early markers of cardiovascular disease. In Europe, childhood obesity remains a significant health challenge and is distributed disparately across and between countries and population groups. In 2019, over 398,000 children aged 6–9 years were severely obese in Europe. Particularly, Southern European countries such as Greece, Italy, Malta, San Marino, and Spain had one in five children obese in 2018. In Europe, different initiatives and actions have been launched in recent years to fight childhood obesity. However, the progress on combating obesity in children has been slow and inconsistent across the region. In this chapter, we have discussed the prevalence of obesity in children and existing policies to combat childhood obesity in the World Health Organization (WHO) European Region.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73241",risUrl:"/chapter/ris/73241",book:{id:"9559",slug:"teamwork-in-healthcare"},signatures:"Giulio Nittari, Stefania Scuri, Getu Gamo Sagaro, Fabio Petrelli and Iolanda Grappasonni",authors:[{id:"322429",title:"Dr.",name:"Giulio",middleName:null,surname:"Nittari",fullName:"Giulio Nittari",slug:"giulio-nittari",email:"giulio.nittari@unicam.it",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Camerino",institutionURL:null,country:{name:"Italy"}}},{id:"322447",title:"Prof.",name:"Iolanda",middleName:null,surname:"Grappasonni",fullName:"Iolanda Grappasonni",slug:"iolanda-grappasonni",email:"iolanda.grappasonni@unicam.it",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Camerino",institutionURL:null,country:{name:"Italy"}}},{id:"322448",title:"Dr.",name:"Stefania",middleName:null,surname:"Scuri",fullName:"Stefania Scuri",slug:"stefania-scuri",email:"stefania.scuri@unicam.it",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Camerino",institutionURL:null,country:{name:"Italy"}}},{id:"323556",title:"Prof.",name:"Fabio",middleName:null,surname:"Petrelli",fullName:"Fabio Petrelli",slug:"fabio-petrelli",email:"fabio.petrelli@unicam.it",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Camerino",institutionURL:null,country:{name:"Italy"}}},{id:"323558",title:"Dr.",name:"Getu Gamo",middleName:null,surname:"Sagaro",fullName:"Getu Gamo Sagaro",slug:"getu-gamo-sagaro",email:"getugamo.sagaro@unicam.it",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Camerino",institutionURL:null,country:{name:"Italy"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Epidemiology",level:"1"},{id:"sec_2_2",title:"2.1 Prevalence",level:"2"},{id:"sec_3_2",title:"2.2 Trends",level:"2"},{id:"sec_5",title:"3. Policies",level:"1"},{id:"sec_6",title:"4. Prevention strategies adopted by European states",level:"1"},{id:"sec_6_2",title:"4.1 Italy",level:"2"},{id:"sec_7_2",title:"4.2 Malta",level:"2"},{id:"sec_8_2",title:"4.3 Poland",level:"2"},{id:"sec_9_2",title:"4.4 United Kingdom (UK)",level:"2"},{id:"sec_10_2",title:"4.5 Moldova",level:"2"},{id:"sec_11_2",title:"4.6 France",level:"2"},{id:"sec_12_2",title:"4.7 Germany",level:"2"},{id:"sec_13_2",title:"4.8 Denmark",level:"2"},{id:"sec_15",title:"5. Conclusion",level:"1"},{id:"sec_19",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'WHO | Childhood Overweight and Obesity. Available from: https://www.who.int/dietphysicalactivity/childhood/en/ [Accessed: 24 June 2020]'},{id:"B2",body:'Poskitt EME. Obesity: Childhood obesity. 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Available from: https://www.who.int/end-childhood-obesity/publications/echo-plan-executive-summary/en/'},{id:"B24",body:'World Health Organization. European observatory on health systems and policies: Digital health systems. Eurohealth (Lond). 2019;25(1) [Online]. Available from: https://apps.who.int/iris/handle/10665/326127'},{id:"B25",body:'WHO and Regional Office for Europe. Nutrition, Physical Activity and Obesity Poland [Online]. 2013. Available from: http://www.euro.who.int/en/nutrition-country-profiles [Accessed: 18 July 2020]'},{id:"B26",body:'Childhood Obesity: Applying All Our Health–GOV.UK. 2020. Available from: https://www.gov.uk/government/publications/childhood-obesity-applying-all-our-health/childhood-obesity-applying-all-our-health [Accessed: 18 July 2020]'},{id:"B27",body:'EPODE Tackles Childhood Obesity in France | CYP Now. 2019. Available from: https://www.cypnow.co.uk/best-practice/article/epode-tackles-childhood-obesity-in-france [Accessed: 18 July 2020]'},{id:"B28",body:'World Health Organization and Regional Office for Europe. Nutrition, Physical Activity and Obesity Germany [Online]. 2013. Available from: http://www.euro.who.int/en/nutrition-country-profiles [Accessed: 18 July 2020]'},{id:"B29",body:'National Board of Health. Center for Health Promotion and Prevention National Action Plan against Obesity [Online]. 2003. Available from: https://www.sst.dk/~/media/681E3288F0A14C2EAA71ED9C4866D01F.ashx'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Giulio Nittari",address:"giulio.nittari@unicam.it",affiliation:'
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1. Introduction
Chronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
2. Chronic myeloproliferative disorders
2.1 Polycythemia vera
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the European Medicines Agency (EMA) for the treatment of patients is ropeginterferon. It is human recombinant interferon alpha-2b. Ropeginterferon is a monopegylated form of interferon alpha-2b. Ropeginterferon is conjugated with a two-arm methoxypolyethylene glycol (mPEG).
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
2.2 Essential thrombocythemia
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
2.2.1 Pregnancy
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
2.3 Myelofibrosis
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
2.4 Mastocytosis
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
2.5 Chronic neutrophilic leukemia
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented neutrophils in the bone marrow blast cells count below 5%), normal neutrophils maturation, and an increase of neutrophilopoiesis. Also the presence of the CSF3R gene mutation is required.
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
2.6 Another
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
\n',keywords:"chronic myeloproliferative disorders, polycythemia vera, essential thrombocythemia, myelofibrosis, ropeginterferon, pegylated interferon alpha",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81569.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81569.xml",downloadPdfUrl:"/chapter/pdf-download/81569",previewPdfUrl:"/chapter/pdf-preview/81569",totalDownloads:17,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 30th 2022",dateReviewed:"March 14th 2022",datePrePublished:"April 29th 2022",datePublished:null,dateFinished:"April 29th 2022",readingETA:"0",abstract:"It has been noted that interferon can exert an antiproliferative effect by stimulating cells of the immune system. Interferon has been shown to be effective in the treatment of chronic myeloproliferative neoplasms. Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. Studies have been showing the effectiveness of interferon alpha in reducing the number of platelets in essential thrombocythemia, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Additionally, it turned out to be effective in reducing the size of the spleen. Interferon has also been shown to be effective in inducing long-term molecular remissions. The introduction of new forms of interferon such as ropeginterferon and the combination of interferon alpha with newly introduced drugs from other groups causes that interferon remains an important drug in the field of chronic myeloproliferative disorders. The chapter presents the results of clinical trials and the experiences of various centers in its usage for mieloproliferative neoplasms.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81569",risUrl:"/chapter/ris/81569",signatures:"Anna Prochwicz and Dorota Krochmalczyk",book:{id:"11275",type:"book",title:"Interferon - Immune Metabolism",subtitle:null,fullTitle:"Interferon - Immune Metabolism",slug:null,publishedDate:null,bookSignature:"Prof. Hridayesh Prakash",coverURL:"https://cdn.intechopen.com/books/images_new/11275.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-886-8",printIsbn:"978-1-80355-885-1",pdfIsbn:"978-1-80355-887-5",isAvailableForWebshopOrdering:!0,editors:[{id:"287184",title:"Prof.",name:"Hridayesh",middleName:null,surname:"Prakash",slug:"hridayesh-prakash",fullName:"Hridayesh Prakash"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Chronic myeloproliferative disorders",level:"1"},{id:"sec_2_2",title:"2.1 Polycythemia vera",level:"2"},{id:"sec_2_3",title:"2.1.1 Ropeginterferon (monopegylated interferon alfa-2b)",level:"3"},{id:"sec_4_2",title:"2.2 Essential thrombocythemia",level:"2"},{id:"sec_4_3",title:"2.2.1 Pregnancy",level:"3"},{id:"sec_6_2",title:"2.3 Myelofibrosis",level:"2"},{id:"sec_7_2",title:"2.4 Mastocytosis",level:"2"},{id:"sec_8_2",title:"2.5 Chronic neutrophilic leukemia",level:"2"},{id:"sec_9_2",title:"2.6 Another",level:"2"},{id:"sec_11",title:"3. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391-2405. DOI: 10.1182/blood-2016-03-643544'},{id:"B2",body:'Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative disorders. Hematology. American Society of Hematology. 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British Journal of Haematology. 2010;149:352-375. DOI: 10.1111/j.1365-2141.2010.08122.x'},{id:"B31",body:'Edahiro Y, Yasuda H, Gotoh A, et al. Interferon therapy for pregnant patients with essential thrombocythemia in Japan. International Journal of Hematology. 2021;113:106-111. DOI: 10.1007/s12185-020-03001-w'},{id:"B32",body:'Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30:1701-1707. DOI: 10.1038/leu.2016.148'},{id:"B33",body:'Pizzi M, Silver RT, Barel A, Orazi A. Recombinant interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response. Modern Pathology. 2015;28:1315-1323. DOI: 10.1038/modpathol.2015.93'},{id:"B34",body:'Silver RT, Vandris K, Goldman JJ. Recombinant interferon-alpha may retard progression of early primary myelofibrosis: A preliminary report. Blood. 2011;117:6669-6672. DOI: 10.1182/blood-2010-11-320069'},{id:"B35",body:'Bachleitner-Hofmann T, Gisslinger H. The role of interferon-alpha in the treatment of idiopathic myelofibrosis. Annals of Hematology. 1999;78:533-538. DOI: 10.1007/s002770050554'},{id:"B36",body:'Sørensen AL, Mikkelsen SU, Knudsen TA, et al. Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: A phase II study. Haematologica. 2020;105:2262-2272. DOI: 10.3324/haematol.2019.235648'},{id:"B37",body:'Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27:1861-1869. DOI: 10.1038/leu.2013.119'},{id:"B38",body:'Silver RT, Barel AC, Lascu E, et al. The effect of initial molecular profile on response to recombinant interferon-α (rIFNα) treatment in early myelofibrosis. Cancer. 2017;123:2680-2687. DOI: 10.1002/cncr.30679'},{id:"B39",body:'Pardanani A. 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DOI: 10.1136/jcp.55.11.862'},{id:"B47",body:'Yassin MA, Kohla S, Al-Sabbagh A, et al. A case of chronic neutrophilic leukemia successfully treated with pegylated interferon alpha-2a. Clinical Medicine Insights: Case Reports. 2015;8:33-36. DOI: 10.4137/CCRep.S22820'},{id:"B48",body:'Wang R, Tong H, Wang H, et al. Nephrotic syndrome related to chronic neutrophilic leukemia. Internal Medicine. 2014;53:2505-2509. DOI: 10.2169/internalmedicine.53.2162'},{id:"B49",body:'Zhang X, Pan J, Guo J. Presence of the JAK2 V617F mutation in a patient with chronic neutrophilic leukemia and effective response to interferon α-2b. Acta Haematologica. 2013;130:44-46. DOI: 10.1159/000345851'},{id:"B50",body:'Meyer S, Feremans W, Cantiniaux B, et al. Successful alpha-2b-interferon therapy for chronic neutrophilic leukemia. American Journal of Hematology. 1993;43:307-309. DOI: 10.1002/ajh.2830430416'},{id:"B51",body:'Heibl S, Buxhofer-Ausch V, Schmidt S, et al. 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Some systems are highly affected by a small fraction of influential nodes. Number of fast and efficient spreaders in a network is much less compared to the number of ordinary members. Information about the influential spreaders is significant in the planning for the control of propagation of critical pieces of information in a social or information network. Identifying important members who act as the fastest and efficient spreaders is the focal theme of a large number of research papers. Researchers have identified approximately 10 different methods for this purpose. Degree centrality, closeness centrality, betweenness centrality, k‐core decomposition, mixed degree decomposition, improved k‐shell decomposition, etc., are some of these methods. In this expository article, we review all previous works done in the field of identifying potential spreaders in a network.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Reji Kumar Karunakaran, Shibu Manuel and Edamana Narayanan\nSatheesh",authors:[{id:"200190",title:"Dr.",name:"Reji Kumar",middleName:null,surname:"Karunakaran",slug:"reji-kumar-karunakaran",fullName:"Reji Kumar Karunakaran"},{id:"200193",title:"Mr.",name:"Manuel",middleName:null,surname:"Shibu",slug:"manuel-shibu",fullName:"Manuel Shibu"},{id:"200194",title:"Dr.",name:"E N",middleName:null,surname:"Satheesh",slug:"e-n-satheesh",fullName:"E N Satheesh"}]},{id:"57940",doi:"10.5772/intechopen.72145",title:"Graph-Based Decision Making in Industry",slug:"graph-based-decision-making-in-industry",totalDownloads:1724,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Decision-making in industry can be focused on different types of problems. Classification and prediction of decision problems can be solved with the use of a decision tree, which is a graph-based method of machine learning. In the presented approach, attribute-value system and quality function deployment (QFD) were used for decision problem analysis and training dataset preparation. A decision tree was applied for generating decision rules.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Izabela Kutschenreiter-Praszkiewicz",authors:[{id:"218951",title:"Associate Prof.",name:"Izabela",middleName:null,surname:"Kutschenreiter-Praszkiewicz",slug:"izabela-kutschenreiter-praszkiewicz",fullName:"Izabela Kutschenreiter-Praszkiewicz"}]},{id:"72140",doi:"10.5772/intechopen.91972",title:"Comparative Study of Algorithms Metaheuristics Based Applied to the Solution of the Capacitated Vehicle Routing Problem",slug:"comparative-study-of-algorithms-metaheuristics-based-applied-to-the-solution-of-the-capacitated-vehi",totalDownloads:685,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"This chapter presents the best-known heuristics and metaheuristics that are applied to solve the capacitated vehicle routing problem (CVRP), which is the generalization of the TSP, in which the nodes are visited by more than one route. To find out which algorithm obtains better results, there are 30 test instances used, which are grouped into 3 sets of problems according to the position of the nodes. The study begins with an economic impact analysis of the transportation sector in companies, which represents up to 20% of the final cost of the product. This case study focuses on the CVRP for its acronym capacitated vehicle routing problem, analyzing the best-known heuristics such as Clarke & Wright and sweep, and the algorithms GRASP and simulated annealing metaheuristics based.",book:{id:"8241",slug:"novel-trends-in-the-traveling-salesman-problem",title:"Novel Trends in the Traveling Salesman Problem",fullTitle:"Novel Trends in the Traveling Salesman Problem"},signatures:"Fernando Francisco Sandoya Sánchez, Carmen Andrea Letamendi Lazo and Fanny Yamel Sanabria Quiñónez",authors:[{id:"155426",title:"Ph.D.",name:"Fernando",middleName:"Francisco",surname:"Sandoya",slug:"fernando-sandoya",fullName:"Fernando Sandoya"},{id:"313162",title:"M.Sc.",name:"Carmen",middleName:null,surname:"Letamendi",slug:"carmen-letamendi",fullName:"Carmen Letamendi"},{id:"319376",title:"Dr.",name:"Fanny",middleName:null,surname:"Sanabria",slug:"fanny-sanabria",fullName:"Fanny Sanabria"}]},{id:"55541",doi:"10.5772/intechopen.68703",title:"Modeling Rooted in‐Trees by Finite p‐Groups",slug:"modeling-rooted-in-trees-by-finite-p-groups",totalDownloads:1148,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Graph theoretic foundations for a kind of infinite rooted in-trees T(R)=(V,E) with root R, weighted vertices v ∈ V, and weighted directed edges e∈E⊂V×V are described. Vertex degrees deg(v) are always finite but the trees contain infinite paths (vi)i≥0. A concrete group theoretic model of the rooted in-trees T(R) is introduced by representing vertices by isomorphism classes of finite p-groups G, for a fixed prime p, and directed edges by epimorphisms π: G → πG of finite p-groups with characteristic kernels ker(π). The weight of a vertex G is realized by its nuclear rank n(G) and the weight of a directed edge π is realized by its step size s(π)=logp(#ker(π)). These invariants are essential for understanding the phenomenon of multifurcation. Pattern recognition methods are used for finding finite subgraphs which repeat indefinitely. Several periodicities admit the reduction of the complete infinite graph to finite patterns. The proof is based on infinite limit groups and successive group extensions. It is underpinned by several explicit algorithms. As a final application, it is shown that fork topologies, arising from repeated multifurcations, provide a convenient description of complex navigation paths through the trees, which are of the greatest importance for recent progress in determining p-class field towers of algebraic number fields.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Daniel C. Mayer",authors:[{id:"198580",title:"Dr.",name:"Daniel C.",middleName:null,surname:"Mayer",slug:"daniel-c.-mayer",fullName:"Daniel C. Mayer"}]},{id:"57771",doi:"10.5772/intechopen.71774",title:"Governance Modeling: Dimensionality and Conjugacy",slug:"governance-modeling-dimensionality-and-conjugacy",totalDownloads:1347,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The Q-analysis governance approach and the use of simplicial complexes—type of hypergraph—allow to introduce the formal concepts of dimension and conjugacy between the network of entities involved in governance (typically organizations) and the networks of those attributes taken into account (e.g. their competences), which offer a specific angle of analysis. The different sources of existing data (e.g. textual corpora) to feed the analysis of governance—environmental in particular—are mentioned, their reliability is briefly discussed and the required pre-processing steps are identified in the perspective of evidence-based analyses. Various indices are constructed and evaluated to characterize the context of governance as a whole, at mesoscale, or locally, i.e. at the level of each of the entities and each of the attributes considered. The analysis of ideal-type stylizing boundary cases provides useful references to the analysis of concrete systems of governance and to the interpretation of their empirically observed properties. The use of this governance modeling approach is illustrated by the analysis of a health-environment governance system in Southeast Asia, in the context of a One Health approach.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Pierre Mazzega, Claire Lajaunie and Etienne Fieux",authors:[{id:"220099",title:"Dr.",name:"Pierre",middleName:null,surname:"Mazzega",slug:"pierre-mazzega",fullName:"Pierre Mazzega"},{id:"220102",title:"Dr.",name:"Claire",middleName:null,surname:"Lajaunie",slug:"claire-lajaunie",fullName:"Claire Lajaunie"},{id:"220103",title:"Prof.",name:"Etienne",middleName:null,surname:"Fieux",slug:"etienne-fieux",fullName:"Etienne Fieux"}]}],mostDownloadedChaptersLast30Days:[{id:"71899",title:"Moments of Catalan Triangle Numbers",slug:"moments-of-catalan-triangle-numbers",totalDownloads:562,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In this chapter, we consider the Catalan numbers, \n\n\nC\nn\n\n=\n\n1\n\nn\n+\n1\n\n\n\n\n\n\n2\nn\n\n\n\n\nn\n\n\n\n\n\n, and two of their generalizations, Catalan triangle numbers, \n\n\nB\n\nn\n,\nk\n\n\n\n and \n\n\nA\n\nn\n,\nk\n\n\n\n, for \n\nn\n,\nk\n∈\nN\n\n. They are combinatorial numbers and present interesting properties as recursive formulae, generating functions and combinatorial interpretations. We treat the moments of these Catalan triangle numbers, i.e., with the following sums: \n\n\n∑\n\nk\n=\n1\n\nn\n\n\nk\nm\n\n\nB\n\nn\n,\nk\n\nj\n\n,\n\n∑\n\nk\n=\n1\n\n\nn\n+\n1\n\n\n\n\n\n2\nk\n−\n1\n\n\nm\n\n\nA\n\nn\n,\nk\n\nj\n\n,\n\n for \n\nj\n,\nn\n∈\nN\n\n and \n\nm\n∈\nN\n∪\n\n0\n\n\n. We present their closed expressions for some values of \n\nm\n\n and \n\nj\n\n. Alternating sums are also considered for particular powers. Other famous integer sequences are studied in Section 3, and its connection with Catalan triangle numbers are given in Section 4. Finally we conjecture some properties of divisibility of moments and alternating sums of powers in the last section.",book:{id:"8142",slug:"number-theory-and-its-applications",title:"Number Theory and Its Applications",fullTitle:"Number Theory and Its Applications"},signatures:"Pedro J. Miana and Natalia Romero",authors:null},{id:"55642",title:"Monophonic Distance in Graphs",slug:"monophonic-distance-in-graphs",totalDownloads:1550,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"For any two vertices u and v in a connected graph G, a u − v path is a monophonic path if it contains no chords, and the monophonic distance dm(u, v) is the length of a longest u − v monophonic path in G. For any vertex v in G, the monophonic eccentricity of v is em(v) = max {dm(u, v) : u ∈ V}. The subgraph induced by the vertices of G having minimum monophonic eccentricity is the monophonic center of G, and it is proved that every graph is the monophonic center of some graph. Also it is proved that the monophonic center of every connected graph G lies in some block of G. With regard to convexity, this monophonic distance is the basis of some detour monophonic parameters such as detour monophonic number, upper detour monophonic number, forcing detour monophonic number, etc. The concept of detour monophonic sets and detour monophonic numbers by fixing a vertex of a graph would be introduced and discussed. Various interesting results based on these parameters are also discussed in this chapter.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"P. Titus and A.P. Santhakumaran",authors:[{id:"198301",title:"Dr.",name:"P.",middleName:null,surname:"Titus",slug:"p.-titus",fullName:"P. Titus"},{id:"199035",title:"Prof.",name:"A. P.",middleName:null,surname:"Santhakumaran",slug:"a.-p.-santhakumaran",fullName:"A. P. Santhakumaran"}]},{id:"71501",title:"Accelerating DNA Computing via PLP-qPCR Answer Read out to Solve Traveling Salesman Problems",slug:"accelerating-dna-computing-via-plp-qpcr-answer-read-out-to-solve-traveling-salesman-problems",totalDownloads:820,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"An asymmetric, fully-connected 8-city traveling salesman problem (TSP) was solved by DNA computing using the ordered node pair abundance (ONPA) approach through the use of pair ligation probe quantitative real time polymerase chain reaction (PLP-qPCR). The validity of using ONPA to derive the optimal answer was confirmed by in silico computing using a reverse-engineering method to reconstruct the complete tours in the feasible answer set from the measured ONPA. The high specificity of the sequence-tagged hybridization, and ligation that results from the use of PLPs significantly increased the accuracy of answer determination in DNA computing. When combined with the high throughput efficiency of qPCR, the time required to identify the optimal answer to the TSP was reduced from days to 25 min.",book:{id:"8241",slug:"novel-trends-in-the-traveling-salesman-problem",title:"Novel Trends in the Traveling Salesman Problem",fullTitle:"Novel Trends in the Traveling Salesman Problem"},signatures:"Fusheng Xiong, Michael Kuby and Wayne D. Frasch",authors:[{id:"14757",title:"Prof.",name:"Wayne",middleName:null,surname:"Frasch",slug:"wayne-frasch",fullName:"Wayne Frasch"},{id:"317054",title:"Prof.",name:"Michael",middleName:null,surname:"Kuby",slug:"michael-kuby",fullName:"Michael Kuby"},{id:"317055",title:"Dr.",name:"Fusheng",middleName:null,surname:"Xiong",slug:"fusheng-xiong",fullName:"Fusheng Xiong"}]},{id:"72027",title:"Identification of Eigen-Frequencies and Mode-Shapes of Beams with Continuous Distribution of Mass and Elasticity and for Various Conditions at Supports",slug:"identification-of-eigen-frequencies-and-mode-shapes-of-beams-with-continuous-distribution-of-mass-an",totalDownloads:939,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In the present article, an equivalent three degrees of freedom (DoF) system of two different cases of inverted pendulums is presented for each separated case. The first case of inverted pendulum refers to an amphi-hinge pendulum that possesses distributed mass and stiffness along its height, while the second case of inverted pendulum refers to an inverted pendulum with distributed mass and stiffness along its height. These vertical pendulums have infinity number of degree of freedoms. Based on the free vibration of the above-mentioned pendulums according to partial differential equation, a mathematically equivalent three-degree of freedom system is given for each case, where its equivalent mass matrix is analytically formulated with reference on specific mass locations along the pendulum height. Using the three DoF model, the first three fundamental frequencies of the real pendulum can be identified with very good accuracy. Furthermore, taking account the 3 × 3 mass matrix, it is possible to estimate the possible pendulum damages using a known technique of identification mode-shapes via records of response accelerations. Moreover, the way of instrumentation with a local network by three accelerometers is given via the above-mentioned three degrees of freedom.",book:{id:"8142",slug:"number-theory-and-its-applications",title:"Number Theory and Its Applications",fullTitle:"Number Theory and Its Applications"},signatures:"Triantafyllos K. Makarios",authors:[{id:"69418",title:"Prof.",name:"Triantafyllos",middleName:"Konstantinos",surname:"Makarios",slug:"triantafyllos-makarios",fullName:"Triantafyllos Makarios"}]},{id:"57940",title:"Graph-Based Decision Making in Industry",slug:"graph-based-decision-making-in-industry",totalDownloads:1723,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Decision-making in industry can be focused on different types of problems. Classification and prediction of decision problems can be solved with the use of a decision tree, which is a graph-based method of machine learning. In the presented approach, attribute-value system and quality function deployment (QFD) were used for decision problem analysis and training dataset preparation. A decision tree was applied for generating decision rules.",book:{id:"5842",slug:"graph-theory-advanced-algorithms-and-applications",title:"Graph Theory",fullTitle:"Graph Theory - Advanced Algorithms and Applications"},signatures:"Izabela Kutschenreiter-Praszkiewicz",authors:[{id:"218951",title:"Associate Prof.",name:"Izabela",middleName:null,surname:"Kutschenreiter-Praszkiewicz",slug:"izabela-kutschenreiter-praszkiewicz",fullName:"Izabela Kutschenreiter-Praszkiewicz"}]}],onlineFirstChaptersFilter:{topicId:"1399",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"August 16th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!0,editor:{id:"205604",title:"Dr.",name:"Tomas",middleName:null,surname:"Jarzembowski",slug:"tomas-jarzembowski",fullName:"Tomas Jarzembowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKriQAG/Profile_Picture_2022-06-16T11:01:31.jpg",biography:"Tomasz Jarzembowski was born in 1968 in Gdansk, Poland. He obtained his Ph.D. degree in 2000 from the Medical University of Gdańsk (UG). After specialization in clinical microbiology in 2003, he started studying biofilm formation and antibiotic resistance at the single-cell level. In 2015, he obtained his D.Sc. degree. His later study in cooperation with experts in nephrology and immunology resulted in the designation of the new diagnostic method of UTI, patented in 2017. He is currently working at the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. Since many years, he is a member of steering committee of Gdańsk branch of Polish Society of Microbiologists, a member of ESCMID. He is also a reviewer and a member of editorial boards of a number of international journals.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorTwo:{id:"484980",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Garbacz",slug:"katarzyna-garbacz",fullName:"Katarzyna Garbacz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003St8TAQAZ/Profile_Picture_2022-07-07T09:45:16.jpg",biography:"Katarzyna Maria Garbacz, MD, is an Associate Professor at the Medical University of Gdańsk, Poland and she is head of the Department of Oral Microbiology of the Medical University of Gdańsk. She has published more than 50 scientific publications in peer-reviewed journals. She has been a project leader funded by the National Science Centre of Poland. Prof. Garbacz is a microbiologist working on applied and fundamental questions in microbial epidemiology and pathogenesis. Her research interest is in antibiotic resistance, host-pathogen interaction, and therapeutics development for staphylococcal pathogens, mainly Staphylococcus aureus, which causes hospital-acquired infections. Currently, her research is mostly focused on the study of oral pathogens, particularly Staphylococcus spp.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:21,paginationItems:[{id:"83000",title:"Purine and Pyrimidine Pathways as Antimalarial Targets",doi:"10.5772/intechopen.106468",signatures:"Yacoba V.T. Minnow and Vern L. 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Saxena",hash:"105e347b2d5dbbe6b593aceffa051efa",volumeInSeries:1,fullTitle:"Influenza - Therapeutics and Challenges",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7064",title:"Current Perspectives in Human Papillomavirus",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7064.jpg",slug:"current-perspectives-in-human-papillomavirus",publishedDate:"May 2nd 2019",editedByType:"Edited by",bookSignature:"Shailendra K. Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. 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Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. 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He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"5",type:"subseries",title:"Parasitic Infectious Diseases",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. 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