IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

IMMUNOTOXIC IMPACT OF ENVIRONMENTAL FACTORS ON THE HUMAN BODY

The Influence of Environmental Factors on Chronic Fatigue Syndrome

Chronic Fatigue Syndrome (CFS) (ICD-10 code D86.9) is a condition still insufficiently recognized by the broader medical community. It was first described under this name by A. Lloyd et al. in 1984 in the article "Immunological abnormalities in the chronic fatigue syndrome," and subsequently by D. Buchwald in 1989 in "The post-infectious chronic fatigue syndrome: laboratory abnormalities." Over the past 15 years, this syndrome has been studied in detail abroad, establishing that The Development of CFS is accompanied by immune dysfunction leading to secondary immunodeficiency. In the USA, the National Center for CFS Research (CFIDS Association) has been established, and a dedicated journal is published: The CFIDS Chronicle. J. CFIDS Association.

Clinically, CFS is characterized by a combination of polymorphic asthenic, subdepressive, neurasthenic, and neurocirculatory disorders. It frequently follows a viral or viral-bacterial infection (such as ARVI or tonsillitis), which is why in the Cytology/cytology/16.html">Early stages of research it was often termed "post-infectious chronic fatigue syndrome." The most characteristic feature of CFS is chronic fatigue that does not resolve with rest and eventually leads to a significant decrease in both mental and physical performance.

In the etiopathogenesis of CFS, infection with Viruses of the family Herpesviridae plays a notable role, particularly the persistence of the Epstein-Barr virus, as patients have exhibited elevated antibody titers to this virus, including the IgM Class. However, attempts to treat CFS with antiviral drugs, such as acyclovir, proved ineffective; consequently, A number of researchers have argued against the viral Etiology of the syndrome. Other researchers attribute a decisive role in CFS development to persistent viral infection, specifically those caused by lymphotropic Herpesviruses, Retroviruses, and enteroviruses. This is because the progression of CFS is accompanied by pronounced alterations in Immunity, including elevated antinuclear antibody titers, decreased levels of IMMUNOGLOBULINS A and G, suppressed NK Cell activity, reduced T-lymphocyte counts, and other changes characteristic of chronic viral pathology.

From a psychiatric perspective, classifying CFS as a distinct disease reflects the ongoing search for a somatic ("biological") basis for many non-specific non-psychotic (neurotic, borderline) disorders that are accompanied by pronounced shifts in immunological parameters. This approach opens up possibilities for developing pathogenetically grounded therapies, primarily The Use of immunotropic agents combined with antidepressants and other psychotropic medications.

Currently, several theories explain the ETIOLOGY AND Pathogenesis of CFS. According to Professor J.Goldstein (California, USA), the disease is caused by a yet unidentified virus capable of prolonged persistence within the patient's body. This researcher suggests it may be one of the herpesviruses, specifically Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus types 1 and 2 (HHV-1, 2), human herpesvirus type 6 (HHV-6), Coxsackie A or B viruses, enteroviruses, among others—a view supported by several other investigators.

The most substantiated theory at present is the reactivation of a persistent viral infection, with herpesviruses (Herpesviridae)—particularly the lymphotropic Epstein-Barr virus—implicated as the etiological agent of CFS. It is believed that in individuals with a genetic predisposition, exposure to external factors (radiation, toxins, psychogenic stressors, or a combination thereof) triggers immune system depression, against the Background of which viral agents (such as herpesviruses) become activated. These viruses, acting alongside immune disorders, initiate neuroimmune mechanisms that lead to Central Nervous system dysregulation and the development of clinically manifest neuropsychiatric symptoms in patients.

It is well established that all members of the Herpesviridae family exhibit pronounced immunosuppressive effects: they suppress cellular immune responses, generate infectious circulating immune complexes (CICs) that circulate in the bloodstream for extended periods and inflict damage on various Tissues and Organs (especially the central nervous system and immunocompetent Cells), and promote the activation of immune-complex and autoallergic reactions. In economically developed countries (where regular virological monitoring is conducted), the Epstein-Barr virus infects up to 75–80% of the entire population, facilitated by high viral concentrations in saliva and efficient droplet transmission. Like other members of Herpesviridae, this pathogen is capable of persisting in The Human Body, establishing latent and transforming types of infection, with the Epstein-Barr virus predominantly targeting B lymphocytes, a subset of T helpers, and macrophages. A recognized chronic active viral infection caused by the Epstein-Barr virus manifests clinically as fever, lymphadenopathy, Splenomegaly, interstitial Pneumonia, and high antibody titers against the virus, reaching up to 163,840 units for viral capsid antigen. Thus, the clinical manifestations of chronic Epstein-Barr infection resemble those of CFS to a certain extent. Latent transforming infection associated with Epstein-Barr virus persistence in lymphocytes and macrophages is characterized by the integration of viral DNA into The Genome of these immunocompetent cells, which constitutes one of the primary Mechanisms for the persistence of this viral agent. When immunocompetent cells (lymphocytes and macrophages) are infected with persistent viruses, the cooperative interactions among various Links of the body's immune system become disorganized. The chronic pathological process develops both As a result of the tissue fixation of macromolecular immune complexes containing the persistent virus and through the activation of these viral agents.

Factors triggering the activation of herpesviruses include immunosuppression of various origins, superinfection with other viruses (such as Influenza types A and B), and psycho-emotional stress. Clinically, the presence of an active viral infection in CFS patients is confirmed by symptoms typical of infectious pathology (fever, myalgia, arthralgia, enlargement of peripheral Lymph Nodes AND the Spleen, recurrent chills, and loss of appetite). In the pathogenesis of CFS, alongside chronic infection and associated intoxication, genetic predisposition is also considered significant, potentially linked to defects in The Immune System and innate anti-infectious resistance factors.

A high incidence of CFS is characteristic not only of Kyiv but also of Ukrainian regions with elevated levels of radioactive environmental contamination resulting from the Chornobyl disaster. It is believed that the continuous intake of even small doses of radionuclides leads to immune system dysfunction, facilitating the reactivation of persistent viral agents and the subsequent potential development of CFS in a subset of individuals. CFS is frequently observed among individuals relocated from radioactively contaminated zones (particularly children), as well as among residents of the industrial Donbas region living in close proximity to sources of atmospheric pollution—metallurgical plants, chemical and coking plants, and coal spoil heaps.

Thus, in Ukraine, a high incidence of CFS is noted in areas with elevated environmental pollution from industrial emissions and waste, as well as in high-radiation zones affected by the Chornobyl nuclear accident. Furthermore, a clear correlation is traceable between environmental pollution levels from major metallurgical, chemical, and coal-mining enterprises, the immune status of the population (especially children), and the morbidity rate of CFS.

The pathogenesis of CFS is defined by J.Goldstein as a multi-causal disorder of neuroimmune mechanisms that manifests in genetically predisposed individuals as a result of the immune system's activation by infectious (viral) agents and central nervous system dysregulation, predominantly affecting the functional activity of its temporolimbic region. The limbic system, as is well known, not only participates in The regulation of autonomic Functions but largely determines an individual's "profile," general emotional and behavioral background, work capacity, and memory, ensuring a tight functional Integration of the somatic and autonomic nervous systems. Latent viral infection, characterized by periodic exacerbations, can precipitate disease under METABOLISM/18.html">The Influence of various adverse factors, notably severe emotional stress, harmful environmental exposures, intoxications, trauma, surgical interventions, and Pregnancy, among others.

Another theory assigns the primary role in CFS pathogenesis to psychological factors accompanied by predominant immune dysregulation. In this context, neuropsychological disorders are recognized as one of the diagnostic criteria for CFS. G. Taerk et al. noted a significant increase in the incidence of depressive states among CFS patients compared to a control group. Indeed, many researchers, particularly neuropsychiatrists, consider depression as a premorbid state to occur significantly more often in CFS patients than in patients with other pathologies lacking signs of chronic fatigue. However, The Role of depression in the development of CFS is difficult to evaluate because many somatic signs of primary depression overlap with the clinical symptomatology of CFS. Therefore, in each specific case, the attending physician must determine whether the psychological disorder is a primary cause or a component of the CFS clinical picture. At the same time, it can be hypothesized that immunological shifts in CFS may be, at least in part, due to concomitant depression. Conversely, according to a group of leading CFS researchers from the University of Washington (USA), depressive states and other psychological Problems associated with chronic fatigue are either the result of this fatigue or caused by underlying immunological and psychological dysfunctions.

Clinical manifestations. The onset of symptoms is usually linked to a preceding ARVI, influenza, tonsillitis, or psycho-emotional stress. Initially, CFS patients are diagnosed with "post-infectious asthenia" and prescribed general supportive therapy. However, the patient's condition fails to improve over several weeks; low-grade fever persists, lymph nodes enlarge, and general weakness intensifies. Differential Diagnosis is performed to rule out chronic infections (such as Toxoplasmosis, tuberculosis, brucellosis, or HIV). In more severe cases, diagnoses such as "chronosepsis" or "fever of unknown origin" are considered. Clinically, chronic fatigue syndrome manifests as pronounced fatigue and Muscle weakness that do not resolve following night Sleep; nighttime insomnia and daytime sleepiness; marked sleep disturbances; memory impairment; mood swings and unmotivated anxiety; depression; and loss of appetite. Weight loss ranging from 2-3 to 10-12 kg is common, along with myalgia, arthralgia, intermittent low-grade fever (37.3–37.8 °C), increased frequency of recurrent herpes, splenomegaly, and generalized lymphadenopathy. All authors report that the majority of CFS patients (85%) experience allergic Reactions of the food or drug allergy type, most frequently manifesting as Skin and mucosal lesions such as papular, maculopapular, or hemorrhagic rashes. Among food products triggering urticarial skin lesions, chicken eggs, milk, citrus fruits, strawberries, seafood, and honey are the most common. During the course of CFS development, many patients (more frequently women) develop allergic reactions to house pet dander, presenting as bronchial obstruction syndrome. Most women with CFS are intolerant to perfumes (deodorants, lotions, aftershave creams). Drug allergies manifest predominantly toward Antibiotics, sulfonamides, nonsteroidal anti-inflammatory drugs, B-group Vitamins, and ascorbic acid. Because CFS patients frequently suffer from recurrent tonsillitis and acute exacerbations of chronic bronchopulmonary pathology, they are forced to take numerous medications, which in turn provoke allergic reactions. Over time, in more than 15% of patients with a disease duration exceeding 5 years, polyvalent allergy to a wide range of medications is identified.

Objective clinical signs of CFS: First and foremost, one should highlight the enlargement, tenderness, or mild pain upon Palpation of certain lymph node groups—predominantly the posterior cervical, followed by the anterior cervical and submandibular nodes (the Drannik-Frolov sign). Less frequently, palpation reveals enlarged and tender axillary lymph nodes, and even more rarely, inguinal ones. The lymph nodes are moderately firm, not fused to surrounding tissues, and roll easily beneath the fingers. Their enlargement is never excessive, nor is the tenderness intense. Some patients note spontaneous, moderate pain in the neck region corresponding to the anterior and posterior cervical lymph nodes. In such CFS patients, lymph node enlargement is typically more pronounced (up to 1.5–2 cm in diameter), and chills and fever are more prominent. The spleen is frequently enlarged in CFS patients; it is soft, elastic, and sensitive or moderately sensitive upon palpation. The Liver is typically palpable at the costal margin or projects 1–2 cm below it. Occasionally, discrepancies arise between ultrasound findings regarding spleen size and palpatory exam results, whereas in other cases, splenic enlargement in CFS is confirmed by ultrasound.

The presence of lymphadenopathy and splenomegaly, combined with persistent low-grade fever, undoubtedly indicates the infectious nature of this syndrome, as these are typical signs of chronic pathogen persistence. Clinically, these exact signs distinguish CFS from ordinary asthenia that may follow respiratory viral infections (so-called post-infectious asthenia). CFS patients, especially women, often possess a characteristic appearance—they tend to have an asthenic body type, pale skin, thin extremities, and chronic digestive disorders (hypoacid gastritis, gastroptosis, chronic colitis, pancreatitis). However, this does not apply to Chornobyl cleanup workers, among whom strong, healthy young men predominated prior to entering the Chornobyl zone.

A subset of individuals suffering from CFS also exhibit significant weight loss (ranging from 2–3 kg in individuals with low initial body weight to 10–12 kg in patients with high baseline weight); the skin is typically pale, and skin turgor is reduced.

Clinical and immunological features of CFS. CFS patients demonstrate pronounced disturbances in immune Homeostasis, manifested as T-lymphocytopenia, a marked decrease in functional T-cell activity, and a reduction in circulating T-helper cells (on average by a factor of 2.3–3) and T-suppressor cells (by 1.5–1.8 times). The T-helper/T-suppressor immunoregulatory index is significantly decreased, indicating The formation of a relative suppressor-type immunodeficiency. CFS is characterized by suppressed phagocytic activity of peripheral Blood neutrophils—particularly the Digestion phase—along with a 1.6- to 2.2-fold decrease in serum IgB concentration and elevated levels of circulating immune complexes. A significant decrease in blood IgA levels is also observed in a subset of CFS patients.

Quite frequently, CFS patients exhibit elevated serum IgE levels; clinically, these exact patients manifest food and drug allergies, pollinosis, and other allergic pathologies.

Thus, immunological disorders are highly characteristic of individuals suffering from CFS. Manifestations of immune system dysfunction in this syndrome also include reduced cytolytic activity and decreased counts of natural killer (NK) cells, elevated levels of interleukins 1-alpha, 2, and 6, and alterations in the number and functional activity of T AND B lymphocytes. Evidence also indicates a reduced synthesis of IgG and its subclasses alongside elevated CIC levels in CFS patients.

Many researchers note the development of lymphopenia in CFS, a sharp suppression of the T-cell arm of immunity, and suppressed phagocytic activity of peripheral blood neutrophils, expressed both as a decrease in the number of phagocytosing cells and an Impairment of the digestive phase, i.e., reduced capacity for complete phagocytosis.

A specially conducted study in CFS revealed a statistically significant decrease in both the absolute count of NK cells and their functional activity, as well as serum alpha-interferon concentrations; an imbalance in the helper-suppressor ratio and a decreased IgG concentration were also noted.

Diagnosis of CFS. Clinically, the diagnosis of chronic fatigue syndrome is established taking into account the following criteria:

- onset of the disease immediately following an episode of influenza, adenoviral infection, or acute respiratory viral infection (ARVI) of unspecified etiology;

- presence of chills or a chilliness sensation; persistent or periodically recurring low-grade fever (subfebrile Temperature), marked and persistent general weakness, malaise, and severe fatigue lasting 6 months or longer that are not relieved by nocturnal rest and vacation;

- poor, superficial sleep, difficulty falling asleep, early awakening, nightmares, and a persistent feeling of body-wide exhaustion after a night's sleep;

- constant general weakness and emotional instability, with an urge to lie down and rest during the day;

- low emotional tone, depressed and unstable mood, increased irritability, with periodic episodes of depression, most commonly presenting as astheno-depressive syndrome;

- enlargement and tenderness of certain lymph node groups, primarily the anterior and posterior cervical and submandibular nodes (Drannik-Frolov sign); development of splenomegaly as a manifestation of chronic persistent infection;

- presence of diffuse myalgia and arthralgia;

- frequent recurrent ARVI, tonsillitis, Bronchitis, and other "cold-related" illnesses;

- throat pain and a scratchy throat caused by chronic non-exudative pharyngitis (granulose, later progressing to atrophic);

- increased physical fatigability with prolonged (exceeding 24 hours) persistence of fatigue, even after minor exertion;

- impaired memory for recent events, inability to concentrate, and a gradual decline in intellect noted by the patients themselves;

- residence in ecologically disadvantaged regions with high environmental pollution by harmful chemicals, including waste from chemical and byproduct-coke production, metallurgical plants, and emissions from large thermal power plants, as well as contact with pesticides and toxic chemicals, or exposure to adverse radiation settings.

Diagnostic criteria that exclude CFS include:

- iatrogenic causes;

- presence of malignant neoplasms;

- history of Chemotherapy;

- psychiatric disorders;

- alcohol abuse;

- chronic infectious diseases (tuberculosis, toxoplasmosis, brucellosis, AIDS, etc.);

- morbid obesity.

If CFS is suspected, an immunological evaluation should be performed, which must include at least the following parameters:

- total peripheral blood T-lymphocyte count (CD3+), their major subpopulations—T-helper/inducer cells (CD4) and T-suppressor/cytotoxic cells (CD8)—with calculation of the CD4/CD8 immunoregulatory index;

- serum immunoglobulin levels of the major classes—IgA, IgM, IgG; and when necessary (tendency toward allergic reactions), also IgE;

- phagocytic activity of peripheral blood neutrophil granulocytes (PAN) and monocytes (PAM), with mandatory Assessment of the completeness of phagocytosis (digestion index - DI), since in CFS it is primarily the digestion phase of microorganisms by phagocytes that is impaired;

- serum concentration of circulating immune complexes (CIC), particularly the levels of the most pathogenic medium-sized (11S–19S) and small-molecular (<11S) immune complex fractions, which are primarily responsible for the elevated CIC levels observed in CFS.

A characteristic feature of CFS is considered to be a decrease in the total number of T-lymphocytes (CD3+), as well as in the count of circulating T-helper cells (CD4+), along with an imbalance in the helper-to-suppressor ratio, dropping the CD4/CD8 coefficient to 1.5 or lower in the majority of examined patients. An exception is found in 20–25% of CFS patients who exhibit a relative hypersuppressor variant of secondary immunodeficiency, manifested by an elevated CD4/CD8 ratio (up to 3.0 and higher). These patients typically show increased IgE levels and frequently present with allergic reactions (food and drug allergies). When an immunodeficiency state is detected in a patient with suspected CFS, it is advisable to assess serum alpha-interferon levels and NK-cell functional activity. It is also useful to determine the levels of anti-herpetic Antibodies and antibodies to the Epstein-Barr virus using enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay Methods.

Thus, the laboratory parameters confirming a CFS diagnosis include the following immunological examination data from patients:

- a decrease in the total number of T-lymphocytes (persistent lymphopenia);

- a reduction in the count of T-helper cells (by a factor of 2.3–3) and T-suppressor cells (by 1.5–1.8 times);

- a decreased immunoregulatory index (indicating the development of a relative suppressor variant of immunodeficiency);

- reduced proliferative activity of T-lymphocytes;

- decreased phagocytic activity of neutrophils;

- a reduction in both the absolute count and functional activity of NK cells (cellular immunity);

- dysimmunoglobulinemia (decreased IgG and its subclasses, as well as IgA);

- elevated circulating immune complexes (CIC) in blood serum;

- elevated serum IgE;

- ELISA testing reveals the presence of antibodies to herpes simplex viruses and Epstein-Barr virus in high titers.

Given the polymorphism of CFS clinical presentations and the insufficient Specificity of its symptoms, it is necessary to perform differential Diagnostics of this pathological condition to rule out a number of chronic infections and the following disorders:

- chronic infectious diseases: AIDS, toxoplasmosis, brucellosis, cytomegalovirus infection, infectious mononucleosis, chronic Sepsis;

- sarcoidosis, lymphogranulomatosis, lymphoma;

- chronic radiation sickness;

- systemic Connective Tissue diseases (systemic lupus erythematosus, rheumatoid Arthritis);

- cerebral arachnoiditis;

- chronic alcoholism and drug addiction;

- low-dose heavy metal poisoning;

- iatrogenic causes (chemotherapy);

- morbid obesity.

Treatment. Without rational treatment, CFS frequently tends to progress and can lead to disability in patients. Treatment for CFS should aim to enhance the body's adaptive capacity against adverse environmental factors and emotional stress, while stimulating natural anti-infectious resistance and immunity. The administration of adaptogens and certain antiviral agents (interferons and interferon Inducers) is indicated; non-pharmacological treatment methods (acupuncture, diet therapy, rational psychotherapy) are also recommended. Given the identified disorders of The Nervous System and immune homeostasis in CFS patients, the question naturally arises as to the expediency of simultaneously administering psychotropic medications and implementing immunocorrective measures—in other words, the immunological rehabilitation of these patients. In this regard, ongoing CFS therapy should be directed at bolstering the resistance of individuals with maladaptive disorders against stress and other adverse environmental factors, which is achieved through the administration of low doses of psychotropic drugs, acupuncture, manual therapy, and dietary therapy. A combination of these nonspecific agents with immunotherapy targeting latent viral infection is indicated.

As immunocorrectors for CFS, the drugs kemantan and bromantane are used; they activate the body's energy reserves while possessing antiviral and neuroimmunoregulatory activity. The antiviral effect of kemantan and bromantane is driven by both their membranotropic activity and immunomodulatory properties; it is noted that these drugs significantly improve the emotional and physical state of patients. Kemantan and bromantane are noted to simultaneously exert neurotropic, immunomodulatory, and antiviral effects. The Mechanism of the neurotropic action of these drugs is associated with The stimulation of central dopaminergic systems. The immunotropic activity of kemantan and bromantane involves the Regulation of Cell-mediated and humoral responses, stimulation of effector functions alongside limitation of suppressor functions of T-lymphocytes, acceleration of the maturation of T-cell precursors into mature, active cells, enhancement of the migration of B-lymphocyte precursors into the spleen, and increased functional activity of antibody-producing splenic cells. If the impairment of the immune system's functional activity occurs against a background of depression, prolonged physical overexertion, and is combined with profound muscular or mental fatigue, the prescription of bromantane is advisable. When immunological parameters are reduced as a result of Radiation therapy, age-related changes, or in patients with heightened excitability, kemantan is indicated.

There is evidence indicating a positive effect of herbal preparations with adaptogenic action on immune parameters and the General condition of CFS patients. For instance, the administration of the dietary Supplement Una de Gato—which is an extract of the bark of the wild-growing vine Uncaria Tomentosa (cat's claw) originating from the tropical rainforests of South America—helps reduce the sensation of fatigue, improves sleep, and increases work capacity in CFS patients. This preparation also exerts a beneficial effect on the state of the immune system, specifically promoting the normalization of T-lymphocyte counts and the ratio between their distinct subpopulations, an increase in IgG concentration, and a decrease in CIC levels. Such a preparation has been registered under the brand name "Manax" by the Pharmacological Committee of Ukraine.

Along with immunocorrective drugs, plant-based adaptogens are prescribed, typically consisting of licorice ROOT and golden root (Rhodiola rosea) extracts, 15 drops 3 times a day 15–20 minutes before meals for 30–40 days, as well as purple coneflower (Echinacea purpurea) at 20–30 drops 3 times a day orally for 15–20 days.

Since patients with CFS frequently present with allergic reactions against the background of pronounced immunodeficiency, for the immunocorrection and immunorehabilitation of individuals with such pathology, it is advisable to use immunoactive drugs that stimulate the T-cell link of immunity and phagocytic responses, while at the same time not causing exacerbations of allergic conditions, but rather helping to reduce their development during the treatment process. One such drug is polyoxidonium, a novel synthetic immunomodulating agent belonging to the class of Water-soluble derivatives of hetero-chain aliphatic Polyamines. The main pharmacological action of polyoxidonium consists in the activation of phagocytosis processes and the stimulation of natural killer cells, the enhancement of antibody formation and cytokine production. Practically immediately after the administration of polyoxidonium, a sharp increase in the body's anti-infective resistance occurs. The drug is prescribed for immunodeficiencies, particularly those associated with viral, bacterial, and fungal infections. Importantly, polyoxidonium not only promotes the restoration of immunological homeostasis in CFS patients, but also possesses a distinct detoxifying effect, specifically reducing the severity of endogenous "metabolic" Intoxication syndrome. The drug is administered intramuscularly or intravenously (by drip) to adults for acute inflammatory processes at 6 mg for 3 days, then every other day, for a total of 5–10 injections; for chronic diseases at the same dose every other day with a course of 5 injections, then twice a week with a course of 10 injections; to children for acute Inflammatory Diseases at 0.1 mg/kg of body weight every other day, and for chronic conditions at 0.1–0.15 mg/kg of body weight twice a week (for a course of 7–10 injections).

Table 95. Recommended treatment for various CFS subtypes