*6.1.1 Cognitive-behavioral psychotherapy*

In this therapy applied to psychoneuroimmunology, the way of thinking on the immune response is explained to the person. A variety of cognitive strategies have helped identify the unhealthy beliefs that affect the individual's health condition. In general, the following process is followed:


*Psychological Intervention Based on Psychoneuroimmunology in Children and Adults DOI: http://dx.doi.org/10.5772/intechopen.99501*


#### *6.1.2 Relaxation techniques*

Relaxation techniques commonly used in psychoneuroimmunology usually include muscle relaxation and deep breathing to decrease neurovegetative activation. The training is the same as those used in clinical contexts, only adapting the procedure to health conditions.

#### *6.1.3 Guided imagery techniques*

The body does not discriminate between what we imagine and the actual events, which is why people who carry out a treatment based on psychoneuroimmunology must become aware of the power of their mind, and the care they must have at the time to worry in advance or imagine catastrophic events that alter their physical conditions.

Guided imagination in PNI includes 2 phases. Initially, the patient is guided through a relaxation process, and then he is induced to imagine the activation of his nervous, endocrine and immune systems to regulate his disease. This imagination can be general or specific according to his illness.

#### *6.1.4 Psychoeducation*

• Information about the disease:

In PNI, the patient must know all the details related to his disease. For example, if he has a tumor in any part of the body, it is essential that he can see the exams, know where it is located, its size, shape, texture, everything that allows him to imagine it or even draw it later.

#### • Treatment information:

In psychoneuroimmunology, the patient has an active role in his clinical condition and recovery of health; that is why he must know all the treatment details, the approximate time that he will receive them and the side effects. It is relevant that the patient can mentally potentiate or reject these treatments; that is why it is necessary to verify the distracted or catastrophic thoughts that can alter him emotionally and affect the immune response.

In children, it is very important to foster a collaborative attitude towards treatment, which stems from the understanding that some treatments, although painful, are promoting their health. Also, strengthening communication with their parents and health professionals.

• Information on the Immune System

The patient is required to recognize the main authors of the immune system to develop greater control over his physical symptoms and disease.

The content provided implies understanding the defense system, represented by white blood cells, and its function is to defend the person from viruses, bacteria, and any invading agent, such as tumor cells.

In psychoeducation, the different types of cells must be present, and their characteristics and general functions are explained according to the age group and cognitive level. Among the actors that stand out are T Lymphocyte, B Lymphocyte, Macrophage, Natural Killer Cell or NK and Neutrophil Polymorphonuclear.

### **7. Psychoneuroimmunology research in adults**

There are several reasons to investigate whether a psychological intervention, in patients or healthy subjects, alters immunity: 1) Because it is possible to know if there is a causal relationship between psychological factors and the functioning of the immune system 2) because the improvement of the immunity obtained after the psychological intervention would be an added benefit (eg. Some stressors can cause a decrease in some forms of immunity. The psychological intervention would reduce stress and increase the multidisciplinary treatment of patients affected by organic diseases [5].

In this sense, any psychological variable can influence the appearance or the course and outcome of a certain disease in which the immune system is involved. As the psychological determinants that influence behavior can come directly from the CNS or indirectly through the stress response (hormonal mechanisms), any change in behavior that is associated with personality characteristics or coping styles in emergencies (stressful), as well as negative emotional states, could affect the immune system (for example, people who smoke or overeat when stressed or people who generate more stress than necessary in everyday situations by evaluating them exaggeratedly threatening). It also happens that, on some occasions, individuals see a threat where there is none (or they exaggerate it), resulting in the acquisition of a phobia; either they do not have adequate coping resources at a given moment (they do not know how to solve problems), or they have wrong ideas about how the world should work (irrational ideas or cognitive distortions) [10].

This can be evidence in a in work carried out by Antoni in 2003 [12], through a 10-week group program based on cognitive stress control and relaxation strategies, the results show that there are effects of psychological intervention on mood, as well as neuroendocrine changes in the HHC, HHG (Hypothalamic–Pituitary– Gonadal) axis as well as in the hormones of the Sympathetic Nervous System and the state of the Immune System in people infected with HIV. The changes produced by the effects of relaxation and cognitive coping strategies, and social support can mediate mood changes. In turn, these changes affect the regulation of adrenal hormones evaluated through changes in urinary cortisol, norepinephrine, and testosterone levels. As suggested by Antoni, the changes in these hormones as a result of the intervention could also explain, in part, the short-term changes in IgG antibodies and the longer-term changes in CD4 lymphocytes.

Similarly, Robinson in 2002 [13] showed encouraging results with an 8-week program to reduce stress in people infected with HIV. Subjects who received this treatment showed increased activity in the killer (NK) cells and their number. The same measurements were taken three months after completing the intervention, noting that the increases in NK cells and decreases in tension, anger or depression also remained, thus showing the subjects a much-improved state of mind.

In any case, the psychological influence of the mind on the body, and more specifically in the field of PNI since the mid-70s, have been treated from multidisciplinary approaches that include medicine, psychology, sociology, social work and even religion [3].

For this reason, and as far as psychologists are concerned, psychotherapies are usually directed towards two final objectives: to reduce or eliminate levels of stress

#### *Psychological Intervention Based on Psychoneuroimmunology in Children and Adults DOI: http://dx.doi.org/10.5772/intechopen.99501*

and/or depression. Although stressors can be physical or psychological, the disparity between them is a mere illusion when it comes to the emission of a stress response [3]. Therefore, any treatment aimed at eliminating or reducing the stress response will be favoring the improvement of depression, this being, in this way, considered a dependent variable.

How an individual interprets and responds to a certain stressor determines its reaction (flight, freeze or flight) and the immune system's response and disease behaviors [14]. Therefore, any intervention from health psychology, designed to modulate stress, provides problem-solving strategies, identifies both phobic stimuli and real or potentially dangerous stimuli, adopts healthy behaviors, and interprets life events from a perspective adaptive (not a perfectionist or tremendous), will walk in the direction sought.

It has been scientifically proven that there are significant decreases in hormones related to stress, such as thyroxine or GH, decreases in Cortisol, THS, and prolactin have also been described during relaxation. Visualization produces increases in IgA levels in saliva. Decreases in the sensitivity of beta-adrenergic receptors measured in circulating lymphocytes have also been described without variations in the number of receptors or catecholamines' plasma concentration [15].

It has also been demonstrated that loneliness, social support, stressful situations such as exams, personality variables, etc., have been studied. The treatments carried out have shown certain effectiveness, these being mainly: Visualization techniques, Directed Imagination, Relaxation, Cognitive-Behavioral Stress Control Techniques, as well as Meditation, Shamanic Techniques, Prayers, etc. Any of these techniques can be useful if it is practised with the necessary rigor, whatever the psychological approach used. However, relaxation produces physiological states that, combined with the representation of images (imagination), can become so-called meditation techniques, positive visualization, directed imagination, etc. That is to say, positive emotion, in this case pleasant, would be the combination of the body state with a mental representation in the form of an image and thought [15].

Furthermore, Bower in 2003 [16], developed a handy tool that achieved more significant control of emotions and cognitive processes called guided imagination. To develop desired changes in behavior, guided imagery can be used to relieve muscle tension, reduce or eliminate pain, and facilitate the process of managing stressful situations through behavioral change. In this technique, it is important to describe the positive physiological and psychological effects of imagining scenes.

Understanding the communications between the brain and the immune system at their most intimate levels will also help health professionals believe in their patients when they tell them that their beliefs in the recovery process, hope, and laughter make you feel good.

### **8. Psychoneuroimmunology in children**

There are very few studies on interventions based on psychoneuroimmunology (PNI) in pediatric patients. Studies reported that inappropriate clinical settings, knowledge of PNI could improve outcomes for pediatric surgical patients. Additionally, parents who receive these same services may also experience better psychological health, allowing them to be more available and prepared to support their children's recovery [17].

Castes in 1999 [18], carried out an investigation in the Isla de Coche, Venezuela, entitled: "Clinical, immunological changes associated with a psychosocial support program based on psychoneuroimmunology in asthmatic children", the authors state that anatomical evidence is presented, physiological and functional that

demonstrate the interaction between the central nervous system (CNS), the endocrine system and the immune system. Likewise, it is shown that this communication is bidirectional, and the scientific bases that establish communication between the immune system and the CNS are provided. Likewise, the relationship between stress and the immune response is pointed out. We also present the results of our group that show that a psychosocial intervention based on psychoneuroimmunology (PNI) produced a significant decrease (p < 0.05) in the number of asthmatic attacks and the consumption of inhaled b2 agonist, together with a significant improvement (p < 0.05) of lung function (FEV1), when compared before the PNI intervention. A significant decrease was also found in specific IgE antibodies against Ascaris lumbricoides and in the marker CD23 (low-affinity receptor for IgE) postintervention. In contrast, a significant increase (p < 0.001) of NK cells (CD56) and T cells with the receptor for IL-2 (CD25) was found after PNI intervention. None of these significant changes was found in children in the non-operated control group. These results demonstrate that the PNI intervention induces immunological alterations that are probably responsible for the clinical and physiological improvements observed in the group under study.

In summary, these studies were able to demonstrate that the disease process and the quality of life of a child can present favorable changes as a result of the application of a psychological intervention protocol based on psychoneuroimmunology, which systematically contains activities that allow the patient to work on the awareness of their disease and exercise active participation in their self-healing.

#### **8.1 Psychoneuroimmunology intervention protocol for children with cancer**

The authors developed a psychological intervention protocol based on psychoneuroimmunology principles for children with leukemia, and it was published in 2019 [19]; given its proven effectiveness at the research level, we allow ourselves to show its structure in detail.

It is a structured programme aimed at children between 5 and 15 years of age diagnosed with leukemia. A total of 30 pediatric patients with the diagnosis of acute lymphoblastic leukemia were evaluated. The BFM chemotherapy treatment protocol (Berlin-Frankfurt-Münster, 2009) was applied to the entire sample. From the sample, 18 patients were assigned to the experimental group. The psychoneuroimmunology-based psychological intervention protocol was applied during the remission induction period, and 12 children who belonged to the control group did not receive said protocol.

This protocol consists of different activities grouped together to psycho-educate the child and achieve learning about his illness, medical treatment and the influence of her emotions on his Immune System. The protocol has a printed and digital didactic story (audiobook) called "A Battle Won, My Fight Against Leukemia". It is made up of four chapters: Knowing my body, now I know what is happening to me, my treatment and the power of my mind. Likewise, an activities notebook is included to verify the knowledge that the child has acquired, including the development of activities that motivate and reinforce the knowledge that the patient must have to face their disease and complete their oncology treatment successfully physically and mentally.

Play therapy in psychoneuroimmunology aims to give the child the opportunity to become familiar with stimuli or objects of interest in the disease process or interact with objects symbolically loaded with medical content to stimulate thoughts and fantasies about the procedures be performed, which will be submitted.

Among the playful techniques used is drawing, since it allows the individual to externally represent how he imagines his disease, the immune system and its

*Psychological Intervention Based on Psychoneuroimmunology in Children and Adults DOI: http://dx.doi.org/10.5772/intechopen.99501*

treatment, among others. These actions allow the therapist to evaluate the perception that he is having in a conscious or unconscious way of the disease and treatment experience.

For this reason the Program is complemented with playful strategies, employing puppets representing the immune system, a memory game referring to the psychoeducational story "A Battle Won, My Fight Against Leukaemia." These strategies seek to maintain the child's attention and interest in learning and know more about her body and consolidate the story's informative content and the manual (see table by phases).



At the end of the Psychoeducation, the phase of guided imagination based on psychoneuroimmunology continues, which is programmed in an important phase of the child's medical treatment protocol for day 33 for patients with Acute Lymphoid Leukemia according to the ALL Protocol. IC-BFM 2009.

*Psychological Intervention Based on Psychoneuroimmunology in Children and Adults DOI: http://dx.doi.org/10.5772/intechopen.99501*

For the guided imagination phase, the authors created audio, intending to relax and take an imaginary journey in your body to activate your immune system and thus activate your healing process. These exercises were carried out in the hospital and at home. A record was made daily and was complemented with didactic activities where the child could capture visualizations of her within her body through drawing.

This phase is accompanied by an information session for parents that reinforces the importance of psychoneuroimmunology techniques and the importance of them being involved in the treatment of the child and motivating them to carry out relaxation sessions at home.



To evaluate the disease process, the immunological, clinical, and pharmacological parameters in the child are considered during the induction phase of chemotherapy treatment by recording medical records during hospitalization and laboratory tests for Immunoglobulins Lymphocytes and subpopulation of Lymphocytes by cytometry (See below table).

To evaluate the Quality of Life: It is obtained by applying the Quality Questionnaire in Pediatric Oncology by Jordi Bernabeu, standardized in the applied child population (2014). The dimensions of the Questionnaire were


#### **8.2 Results to highlight from the research**

The results of the study indicate that the intervention protocol based on psychoneuroimmunology (PNI) positively modified the clinical evolution (symptoms and treatment) of the patients, substantially improved their immune parameters and significantly increased the quality of life of children with cancer, specifically in a sample of children with acute lymphoblastic leukemia.

Summary of the effects of the Psychological Intervention based on PNI



*Psychological Intervention Based on Psychoneuroimmunology in Children and Adults DOI: http://dx.doi.org/10.5772/intechopen.99501*


### **8.3 Some effects of the intervention protocol based on psychoneuroimmunology on clinical parameters**

#### *8.3.1 Symptoms and signs*

In this regard, the PNI-based intervention protocol's efficacy was directly appreciated in its clinical picture, especially the symptoms and signs compatible with infectious and inflammatory processes secondary to chemotherapy; Among these, statistically significant differences stand out on the days with fever during the induction process. The operated group had six days less fever than the control group. There was a lower frequency of vomiting, dyspnea and tachycardia in the operated patients than the controls; Although these differences did not reach statistical significance due to the values' variance, they could be taken as likely trends in a larger sample of patients.

#### *8.3.2 Complications during the induction phase*

The intervened group had a tendency (statistically not significant) to a lower frequency of complications during the induction phase, especially those of an infectious type such as febrile neutropenia, mucositis, septic shock, pneumonia, abscesses, chickenpox and enterocolitis. However, although there was no apparent effect on the duration of some symptoms of an infectious nature, the need to use antibiotics for fewer days in those treated - as described below - suggests that these processes were less severe or easier to manage.

#### **8.4 Effects of the intervention protocol based on psychoneuroimmunology on pharmacological parameters**

According to the results, although there was an improvement in the clinical evolution, it was not reflected in fewer days of hospitalization, if it was consistently associated with a lower frequency in the use of treatments to control fever and infectious and inflammatory processes: antibiotics, antipyretics, pain therapy and respiratory therapies in the intervened group compared to controls.

There was evidence to support the view that the lower use of antibiotics in operated patients was related to improved cellular immunity, although not humoral. The use of antibiotics was linearly and inversely correlated with a higher number of CD8 T lymphocytes and NK cells, mediators of cellular immunity, but not with the number of B lymphocytes, which participate in humoral immunity.

On the other hand, in the study, three variables estimated pain: directly, days with pain as a symptom (clinical parameter) and indirectly, days of pain therapy and days with analgesics (treatment parameters). A tendency to report pain for a smaller number of days was observed in those operated on than controls, although this difference did not reach statistical significance. However, the number of days during which pain therapy was administered was significantly lower in patients concerning controls. This suggests that the psychotherapeutic intervention markedly influenced the sensory function of leukemia patients during chemotherapy induction.

*Psychological Intervention Based on Psychoneuroimmunology in Children and Adults DOI: http://dx.doi.org/10.5772/intechopen.99501*

#### *8.4.1 Supportive therapy*

It was observed that the operated patients required respiratory therapy for 82% shorter periods than the controls. This smaller statistically significant difference in the intervened group may be due to a greater recurrence of infections that required this type of support for their recovery.

It was also evidenced that the intervened patients required colony growth factor therapies for periods 50% shorter than the controls. However, statistical significance was not reached due to the wide variability of the control group. However, this finding suggests that the intervened group presented a lower level of leukopenia during this period, as it required less use of this pharmacological agent.

#### **8.5 Effects of the intervention protocol based on psychoneuroimmunology on immune parameters**

Significant changes in the immune parameters' values, both cellular and humoral, were observed during the induction process in pediatric patients with acute lymphoblastic leukemia. These changes suggest that the better clinical evolution of the operated patients was linked to a substantial improvement in their immune function.

#### *8.5.1 Cellular immunity*

Specifically, there was a significant increase in the number of natural killers NK cells and CD8 and CD4 type T lymphocytes in the intervened group, especially at the end of the chemotherapy induction period (day 64), compared to the control group.

It is important to remember that both natural killer cells or NK cells and T lymphocytes are involved in cellular immunity mechanisms against neoplastic cells. Within the T lymphocytes population, there are two subpopulations of lymphocytes, CD4 and CD8, both of great clinical importance. CD4 lymphocytes act mainly against parasites, bacteria and fungi, and to a lesser degree, against viruses and tumor antigens, while CD8 lymphocytes will act mainly against tumor cells and viruses. Therefore, a more significant number of natural killer NK cells and CD8 lymphocytes, specialized in the destruction of malignant cells, in children treated with the protocol based on psychoneuroimmunology implied an improvement in their cellular immunity, and as a result, a lower frequency of infectious symptoms, which led to less need for antibiotics and antipyretics in the children treated in this study.

#### *8.5.2 Humoral immunity*

Serum levels of IgM and IgA antibodies were significantly higher in the intervened group in relation to the control group, which suggests that the PNI-based intervention increased humoral immunity. It is important to remember that B lymphocytes are immunocompetent cells whose primary function is to produce antibodies, a specific type of protein called immunoglobulins. Thus, it can be assumed that the higher serum antibody levels in the operated children were significantly related to the increase in the number of B lymphocytes.

#### **8.6 Effect of the intervention protocol based on psychoneuroimmunology on quality of life**

The recovery of quality of life was significantly greater in the operated patients than in the controls. This was linked to an improvement in both clinical symptoms and immunological parameters. It is important to highlight that this recovery of quality of life was linearly and positively correlated with the number of NK cells and CD8 lymphocytes, suggesting that an immunological substrate made this change possible.

#### **9. Psychoneuroimmunology: present and future in clinical and health practice**

The amount of research that reports the mind–body expresses that there is no longer any doubt about this relationship since its biochemical mechanism is recognized. That is why health professionals' objective is to encourage the promotion of developing health plans that incorporate psychoneuroimmunology techniques and promote the reduction of psychosocial risk factors.

On the other hand, it is exposed that Psychoneuroimmunology gives us the understanding of the mental factors that modulate the immune system, offering a transdisciplinary perspective of the way of understanding health and disease. This leads us to reflect on the need to incorporate public health measures considering these aspects and the challenges and opportunities for researchers and teachers in the health area to promote training and treatment programs oriented to these findings.

The consideration of Psychoneuroimmunology in understanding the disease is also of high impact in the prevention and proposals of public health policies, considering the high levels of stress to which children and adults are subjected in some harmful environments.

The information presented here wants to be a great incentive to promote mechanisms that integrate all disciplines within the academic, governmental, clinical and health sectors to generate policies and mutual support to develop plans that promote health and influence the healing of diseases on a physical and mental level.

#### **10. Conclusion**

Psychoneuroimmunology has provided a clear scientific insight into the mind– body relationship. This knowledge allows an integrative view of both prevention and treatment of diseases, representing a significant challenge. Research has shown the evident influence of stress and other psychological factors that can affect health through interactions with the immune, endocrine and nervous systems. This has provided a solid evidence base and has also improved our understanding of people's central role in their healing, both for adults and children, which implies both recovery of their physical condition and their quality of life.

#### **Acknowledgements**

Special thanks to Dr. Marianela Cástes, pioneer of psychoneuroimmunology in Latin America, researcher and main personal inspiration at the PNI level.

To Dr. Rosario Montilva, pediatric oncologist and Coordinator of the Pediatric Oncology Unit of the Pediatric Specialties Hospital, and to the entire team: Dr. Betty Urdaneta de Ramos (Hematologist), Dr. Fatima Viloria (Pediatric Oncologist), Dr. Yoleida Colmenares (Pediatric Oncologist), Lic. Leila Nouheid (Nutritionist), Lic Maira Alvarez and Mayra Vargas, both committed nurses.

*Psychological Intervention Based on Psychoneuroimmunology in Children and Adults DOI: http://dx.doi.org/10.5772/intechopen.99501*

Special thanks to the children and family members of the Pediatric Specialties Hospital, who participated in the research and who continue to be active in putting forth the greatest force to heal.
