IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

ACQUIRED IMMUNODEFICIENCY STATES

Chronic Fatigue Syndrome

Class="center">(ICD-10 Code D86.9)

Chronic Fatigue Syndrome (CFS) is a post-viral (ARVI) chronic condition primarily characterized by unmotivated, profound generalized fatigue that incapacitates an individual from active daily life for a prolonged period. The Central Nervous system and The Immune System are the primary targets of the disease.

The prevalence of CFS is 10 to 37 cases per 100,000 population.

Diagnostic Criteria for CFS

Major diagnostic criteria: 1) persistent or relapsing fatigue and a reduction in performance capacity (by at least 50%) in previously healthy individuals lasting for the past six months; 2) exclusion of other clinical conditions or diseases that may cause chronic fatigue.

Minor symptomatic criteria: 1) sudden onset; 2) low-grade fever up to 38°C; 3) sore throat, pharyngeal discomfort or tickling; 4) mild enlargement (up to 0.3 - 0.5 cm) and tenderness of cervical, occipital, and inguinal Lymph Nodes; 5) unexplained generalized Muscle weakness; 6) tenderness of specific muscle groups (myalgia); 7) migratory joint pain (arthralgia); 8) recurrent headaches; 9) rapid physical fatigability followed by prolonged (exceeding 24 hours) exhaustion; 10) Sleep disturbances (hypo- or hypersomnia); 11) neuropsychological disorders (photophobia, memory impairment, irritability, mental confusion, cognitive decline, inability to concentrate, depression); 12) rapid development (within hours or days) of the entire symptom complex.

Objective (physical) criteria: 1) low-grade fever; 2) non-exudative pharyngitis; 3) palpable cervical or axillary lymph nodes (less than 2 cm in diameter).

A Diagnosis of CFS is established in the presence of both major criteria 1 and 2, along with the minor symptomatic criteria: 6 (or more) out of 11 symptomatic criteria and 2 (or more) out of 3 physical criteria; or alternatively, 8 (or more) out of 11 symptomatic criteria.

The disease affects individuals of all ages; however, it has been observed that women aged 25-49 are affected more frequently than men. In some cases, the disease develops 2 years after the initial acute episode. In the majority of patients, chronic fatigue and other accompanying symptoms—having begun during a flu-like illness—slightly subside after one to two weeks, but full recovery does not ensue. In the most severe cases, major depression may develop, accompanied by a loss of concentration and severe physical weakness. Cases of spontaneous recovery have been documented; however, the majority of patients continue to suffer from cyclic relapses for many months or years.

Etiology AND Pathogenesis. The most probable cause of CFS is a viral infection, the specific agent of which has not yet been definitively identified. This may include one of the Herpesviruses (Epstein-Barr virus [EBV], cytomegalovirus [CMV], Herpes simplex virus types 1 and 2 [HSV-1, 2], human herpesvirus type 6 [HSV-6]), varicella-zoster virus (HSV-4), Coxsackie Viruses A or B, enteroviruses, and others. CFS appears to be a multi-etiological neuroimmune disorder that manifests in genetically predisposed individuals As a result of immune system activation by infectious agents and central nervous system dysregulation. Latent infection can be triggered into active disease by a variety of potential stimuli: severe emotional stress, adverse environmental factors, intoxications, trauma, surgical interventions, Pregnancy, childbirth, and others.

Another theory assigns the primary role to neuropsychiatric factors with a predominance of immune dysregulation.

Immune Dysfunction. A wide array of "triggers" provoke immunological reactions involving various Blood Cell types and molecules, such as interferons and interleukins. It is believed that these mechanisms are impaired in CFS patients, exhibiting either an increase or a decrease in immunological parameters. For instance, leukocytosis is observed in 20% of CFS patients, and leukopenia in an equal percentage. Relative lymphocytosis is noted in 20% of cases, and lymphopenia in 30% of patients. A decrease in serum immunoglobulin classes A, D, G, and M levels is observed in 30% of patients, whereas immunoglobulin levels are conversely elevated in 30% of patients. Half of the patients (50%) present with low levels of circulating immune complexes, and 25% exhibit decreased Complement activity.

Immune system dysfunction in CFS patients is also manifested by a decrease in the cytotoxic activity of natural killer (NK) Cells; elevated levels of IL-1a, IL-2, and IL-6; decreased mitogen-stimulated lymphocyte proliferation; elevated levels of alpha-interferon and other cytokines; as well as alterations in the number and function of T- and B-lymphocytes.

Serological tests typically reveal no significant abnormalities. There is evidence of low-titer antinuclear Antibodies and rheumatoid factor presence, but without the clinical manifestations of systemic lupus erythematosus or rheumatoid Arthritis. Elevated levels of cryoglobulins and cold agglutinins have been found in a small subset (8%) of patients.

Taking into account The Nature of the etiological factor, the following variants of CFS are distinguished:

1. Intoxication variant - exposure to biologically active environmental factors leads to altered functioning of the immune and central nervous systems. Characteristic immune system disorders include decreased phagocytic activity of leukocytes, elevated toxic granularity of neutrophils (TGN), reduced NBT (nitroblue tetrazolium) test results, increased IgG levels, and an elevated count of circulating immune complexes, thereby reflecting the activation of the immune system's antitoxic function.

2. Endocrine variant of CFS - hormonal imbalances in both blood and Tissues, leading to impaired functioning of the central nervous system. The most significant factors include decreased thyroid hormone levels, sex hormone imbalance (particularly during menopause), and adrenal cortex dysfunction.

3. Infectious variant - persistence of "slow" viral infections, such as herpesvirus, CMV, and Epstein-Barr virus infections, leads to immune system dysfunction. It should be noted that A number of immunological alterations—specifically, the decreased functional activity of natural killer (NK) cells and macrophages, reduced lymphocyte response to mitogens, and impaired activation of CD4+ lymphocytes—are common to both CFS and various viral infections.

General Principles of CFS Treatment. Currently, no specific curative treatment for CFS has been developed. Management strategies are aimed at prolonging periods of remission and helping patients return to work. Tricyclic antidepressants and selective serotonin reuptake inhibitors (such as fluoxetine [Prozac]) are utilized to improve patients' energy levels, normalize sleep, and reduce muscle pain and tension. Comprehensive therapy with immunotropic agents is administered based on the results of immunological assessments. The Morphology/3.html">MAIN DIRECTIONS OF CFS therapy can be outlined as follows:

1. A nutritious, well-balanced diet rich in Proteins, Vitamins, and Trace Elements (Zn, Se, Cu, Co).

2. Antigen-sparing regimen: hypoallergenic diet; sanitation of chronic infection foci; avoidance of vaccination during the course of complex therapy; restoration of the microbiocenosis of the Skin and open/closed mucous membranes.

3. Antioxidant therapy.

4. Immunomodulatory therapy.

5. Adequate and rational antibacterial, antiviral, and antifungal therapy.

Principles of immunotropic (immunomodulatory) therapy for CFS (by sites of action):

1. Restoration of T-cell Immunity using thymic factors (tactivin, thymalin, thymogen, immunofan, gepon).

2. Restoration of interferon status (viferon, laferon).

3. Restoration of NK cell activity (immunomax, gepon, licopid, polyoxidonium).

4. Restoration of humoral immunity (myelopid).

When lymphocytic-type immunodeficiency is detected in a patient with CFS, the following are prescribed:

1) IL-2 synthesis stimulators (isoprinosine, groprinosine);

2) thymic Peptides: traditional (thymalin, tactivin, thymoptin) and novel (zadaxin, immunofan);

3) galavit.

Immunological criteria for therapy effectiveness include a decrease in:

✵ CD3, CD4, and CD25 levels;

✵ the CD4/CD8 immunoregulatory index;

✵ IL-2 and gamma-interferon production;

✵ alongside an increase in IL-4, 5, and 6 production.

When interferon-type immunodeficiency is detected in a patient with CFS, the following are prescribed:

1) interferons (viferon, laferon);

2) Inducers of endogenous interferon and NK cells: acridones (neovir, cycloferon); amiksin; antiplatelet agents (curantyl); and novel long-acting agents such as kagocel.

Immunological criteria for therapy effectiveness:

1. Decreased production of alpha- and gamma-interferons.

2. Reduced levels of CD4 and CD16.

3. Decreased CD4/CD8 immunoregulatory index.

4. Increased production of IL-4, 5, and 6.

When humoral-type immunodeficiency is detected in a patient with CFS

specific IMMUNOGLOBULINS are prescribed: anti-herpetic (type 1 or 2), anti-cytomegalovirus, anti-chlamydial, and in cases of an unidentified viral infection, normal human immunoglobulin.

Immunological criteria for therapy effectiveness:

1. Decrease in CD19 cell count.

2. Reduction in specific IgM and IgG levels, and normalization of the Polymerase Chain Reaction (PCR) assay.

3. In the seronegative form of the infection, normalization of IgA, IgM, and IgG titers is observed, along with a decrease in the levels of B-lymphocytes and plasmocytes, as well as a reduction in circulating immune complexes (CIC) and complement levels.

If a phagocytic-type immunodeficiency is detected in a patient with CFS, the following are prescribed:

1) polyoxidonium — 6 mg of the drug is dissolved prior to injection in 1–1.5 ml of saline, sterile Water, or a 0.25% novocaine solution, administered intramuscularly or subcutaneously every other day, with a course of 5 injections; then twice a week for a course of 10–15 injections;

2) methyluracil is used in 0.5 g tablets 3 times a day for 3–4 weeks or in longer courses.

Immunological criteria for therapy effectiveness:

1. Decrease in the phagocytic number and index.

2. Reduction in the NBT test values.

Etiotropic therapy — acyclovir preparations (zovirax, geviran, acic, herpivir), valacyclovir (valtrex), ganciclovir (cymevene), penciclovir (denavir), and famciclovir (famvir) are prescribed. The drugs are prescribed: 1) mandatorily during the acute phase (HSV-1, 2, 4, 6, CMV, EBV IgM+, DNA+); 2) preferably when specific organ lesions are detected, provided There is a progressive increase in the concentration of specific IgG (HSV-1, 2, 4, 6, CMV, EBV) over time; 3) as an option for virus-suppressive therapy (maintenance of remission) — at a lower dose and for a longer period. In cases of recurrent acute respiratory viral infections (ARVI), frequent exacerbations of Chronic Bronchitis, and other infections in the patient, antibiotic therapy is indicated using broad-spectrum drugs effective against intracellular infections: 1) macrolides (spiramycin, roxithromycin, clarithromycin, dirithromycin, azithromycin, josamycin, pristinamycin, minocycline); 2) fluoroquinolones (2nd, 4th generation — "non-respiratory": ciprofloxacin or gatifloxacin).

Criteria for therapy effectiveness: mandatory detection of infection (e.g., Chl-IgM+, Chl-DNA+, increasing concentration of Chl-IgG over time).

Clinical effects of CFS therapy:

1) regression of CFS manifestations, regression of chronic fatigue, restoration of working capacity, mental abilities, memory, and improvement of mood;

2) regression of chronic intoxication symptoms;

3) regression of signs of chronic pharyngitis and tonsillitis;

4) reduction in the frequency of ARVI from 15–24 per year to 1–3 per year;

5) reduction in HSV-1,2 episodes from 15–24 per year to 1–2 per year.

6) elimination of EBV, CMV, HHV-6, Chl (polymerase chain reaction — sub-diagnostic level).

The prognosis for CFS is favorable in most cases. Patients generally recover within 2–4 years, although complete restoration of physical activity does not occur. Approximately 15–20% of patients exhibit a progressive worsening of symptoms.

As an example of T-lymphocytopenic immunodeficiency in a chronic viral disease, we present the clinical case of female patient O., 48 years old, who was treated in the therapeutic department with a diagnosis of chronic fatigue syndrome, chronic recurrent herpesvirus infection localized to the labial area, HSV-1, acute phase.

Patient O., 48 years old, complains of severe fatigue over the past 6 months. Her medical history includes frequent stressful situations at work and a chronic recurrent herpetic infection with eruptions in the labial area. The last exacerbation occurred after hypothermia 2 weeks ago and was accompanied by increased general weakness, malaise, and depression, which forced the patient to consult a psychoneurotherapist, who referred her to a clinical immunologist (Table 77).

Immunogram of patient O., 48 years old: relative CTLocytosis, increased neutrophil engulfment activity (phagocytic index, phagocytic number), spontaneous bactericidal activity (spontaneous NBT test); decreased functional reserve of the oxidation-reduction potential of phagocytes (reserve NBT test); increased complement level.

Decreased relative and absolute counts of T-lymphocytes (CD3) with a reduced immunoregulatory index (IRI) skewed toward CD8 T-cytotoxic lymphocytes (suppressors); elevated levels of all classes of immunoglobulins (IgG, IgM, IgA), and slightly elevated levels of circulating immune complexes (CIC).

Conclusion: signs of T-cell immunodeficiency formation against the Background of high antigenic load (activation of phagocytosis, elevated immunoglobulin levels).

ELISA testing revealed elevated antibody titers in the patient: IgG HSV-1 1:550, IgM HSV-1 1:600, IgG CMV 1:550 (normal range up to 1:400).

Patient diagnosis: Chronic fatigue syndrome. Chronic recurrent herpesvirus infection with labial localization, HSV-1, acute phase. Immunodeficiency (D84.9), lymphocytic type, chronic course, II stage IS-1, PS.

Based on the immunological status of patient O., the following immunotropic therapy regimen was prescribed for the treatment of chronic fatigue syndrome:

1) specific Antiviral Therapy (replacement therapy – anti-herpetic immunoglobulin type 1, 1.5 ml i.m., 5 injections in total, twice a week, and anti-cytomegalovirus immunoglobulin (Cytotect), 1.5 ml i.m., 5 injections in total, twice a week);

2) etiotropic antiviral therapy – acyclovir 2 tablets 3 times a day for 7 days;

3) nonspecific antiviral therapy:

- laferon 1 million IU every other day i.m. for 10 days;

- interferon inducer – cyclferon – 12.5% injection solution – 2 ml, single dose 0.25 g i.m. on days 1, 2, 4, 6, 8, 11, 14, 17, 20, 23, 26, 29. Prescribed after Interferon Therapy;

4) galavit 0.2 g in 5 ml of saline i.m. every other day, 3 injections.

Immunorehabilitation:

5) galavit 0.1 g rectal suppositories every other day for 20 days;

6) sodium nucleinate 0.1 g twice a day for 40 days;

7) lucetam 1.2 g twice a day (morning and lunch) for a month.

Table 77. Immunogram of patient O., 48 years old