LACTOFERRIN IN PEDIATRIC PRACTICE

INDICATIONS FOR PRESCRIPTION OF LACTOFERRIN FOR PREMATURE AND LOW-WEIGHT CHILDREN

PREMATURE BIRTH

Premature birth is indeed a significant contributor to perinatal morbidity and mortality. Premature babies are most at risk of developing infectious pathology, disorders of the nervous system, respiratory organs and gastrointestinal tract, metabolic disorders.

Children born with very low and extremely low body weight often have osteopenia and retinopathy of prematurity, periventricular leukomalacia, peri- and intraventricular hemorrhages, early anemia. They have a number of both organic and functional features associated with hypoxia and impaired intrauterine nutrition as a result of uteroplacental dysfunction.

The overall morbidity of prematurely born children increases inversely with gestational age. The clinical prognosis improves with both increasing gestational age and increasing birth weight [12]. Successful nursing of children, including children with extremely low birth weight, in addition to therapeutic measures, largely depends on the creation of optimal external conditions and adequate nutrition.

HIGH VULNERABILITY

Lability of metabolic processes and morphofunctional immaturity of almost all organs and systems in premature infants extremely complicate the course of the neonatal period, causing their high vulnerability to various damaging factors of the external environment, including in specialized intensive care units and neonatal resuscitation units and departments for nursing premature infants.

This group of children often has:
• generalized and severe localized forms of intrauterine infections (18%) — sepsis, meningoencephalitis, pneumonia, gastroenterocolitis;
• localized infectious processes of moderate severity (12%) — vesiculopustulosis, conjunctivitis, dacryocystitis, rhinitis, omphalitis, vulvovaginitis, local forms of candidiasis;
• morphological changes in the central nervous system and internal organs detected by ultrasound examination suggest a history of intrauterine infection (10%);
• hypoxic lesions of the central nervous system of varying severity (12%);
• intrauterine growth retardation (12%).

NEWBORNS AND INFECTIOUS DISEASES

In newborns at risk for developing infectious diseases, the frequency of isolation of aerobic microflora in smears from the mucous membrane of the nasopharynx, skin, and anus at the time of birth ranges from 40% in clinically healthy newborns to 62% in children with severe forms of intrauterine infection, which is consistent with the data of other researchers on the limited diagnostic significance of these pathogens in intrauterine infections. There is a statistically significant relationship between severe forms of intrauterine infections and the isolation of gram-negative enterobacteria from the mucous membrane of the pharynx and anus.

Combined isolation of herpes simplex virus 1,2 and cytomegalovirus antigens from the umbilical cord blood of newborns and simultaneously from other loci at the time of birth is a prognostic and early diagnostic criterion for severe forms of intrauterine infection.

Severe forms of intrauterine infection are characterized by a high frequency of contamination of newborns with pathogens, including sexually transmitted ones: herpes simplex virus - 43.6%, cytomegalovirus - 58.2%, chlamydia - 41.8%, ureaplasma - 52.7%, mycoplasma - 32.7%.

Treatment of infectious pathology in newborns, especially in extremely premature babies, should include anti-infective drugs. Promising for this category of children, taking into account the unique anti-infective properties of the biologically active protein lactoferrin, is its use in a complex of therapeutic measures.

RATIONALE FOR PRESCRIPTION OF LACTOFERRIN IN CHILDREN WITH MALNUTRITION

 The presence of malnutrition in children with chronic diseases is closely associated with immunological deficiencies and negatively affects the process of treatment and recovery, increasing the duration of hospitalization and treatment costs.

With malnutrition, especially chronic, in young children, non-specific dystrophic changes occur, caused by quantitative or qualitative deficiency of nutrients and energy, or a significant decrease in food tolerance.

They manifest themselves in the form of general metabolic disorders, occur simultaneously in all organs and tissues and lead to disturbances in cellular differentiation of tissues.

The prevalence of acute and chronic malnutrition in children admitted to hospitals in Europe and the United States is 6–14%, in Turkey it reaches 40%. The prevalence of chronic malnutrition is high in children with heart disease (24–44%) and kidney disease (63–64%).

Anti-inflammatory effect

Disturbances in protein metabolism lead to a decrease in the effectiveness of immunity due to changes in the synthesis of immunoglobulins, as well as antioxidant activity, accompanied by damage to cell membranes, a decrease in the secretion of transport proteins, intracellular energy deficiency and a violation of the transport of micronutrients. The activity of enzymes and the secretion of insulin, as well as insulin-like growth factor, decreases, insulin resistance decreases, and the synthesis of fibrinogen and blood clotting factors is disrupted.
Insufficient nutrition and the resulting stress lead to a sharp increase in cortisol production and an increase in catabolism. Under conditions of catabolic metabolic processes, glucose as the main energy carrier is directed primarily to the brain, insulin-dependent tissue growth is disrupted, body weight decreases and linear growth slows down.

Changes that occur with malnutrition cannot but affect the digestive system. Atrophy of the intestinal mucosa develops, which is accompanied by a decrease in enzymatic activity and deterioration in the processes of digestion and absorption of food. Motility of the gastrointestinal tract is impaired, the barrier function and local immunity suffer.

The development of malnutrition gradually leads to disruption of all types of metabolism. The first to be depleted are glycogen and fat depots, later protein breakdown increases, mainly in muscle tissue; the utilization of amino acids increases, which are actively used for the synthesis of essential transport, immune, acute-phase and some other proteins, and are also spent on energy needs.

In recent years, studies have convincingly proven the connection between malnutrition and inflammatory changes in the child's body. Inflammation contributes to the destruction of skeletal muscles due to a cytokine-mediated mechanism, limits the effectiveness of nutritional support. Of the inflammation markers currently used in children with malnutrition, C-reactive protein, orosomucoid, , α1-antitrypsin.

Immune markers of malnutrition include lymphopenia, decreased CD4/CD8 ratio and delayed hypersensitivity tests (indicators of cellular immunity), as well as decreased concentrations of immunoglobulins as indicators of humoral immunity. These indicators have an important prognostic value, since they can reflect the possibility of infectious complications against the background of immunodeficiency in children with malnutrition. It seems quite reasonable to use lactoferrin in complex therapy for malnutrition in order to correct inflammatory changes in the child's body and prevent infectious diseases.

Malnutrition and inflammation

Lactoferrin in therapy

Supporting Healing: Lactoferrin for Children Undergoing Surgery

In surgical practice, it is advisable to use hLF to reduce the severity of the acute proinflammatory response that developed against the background of surgical intervention, as well as to prevent infectious complications, especially after abdominal surgeries. This applies to children suffering from organic diseases of the digestive organs (malformations, Hirschsprung's disease, biliary atresia, etc.), which lead to serious changes in the processes of digestion and absorption of nutrients entering the body with food. Previous surgical interventions exacerbate existing disorders. The most severe changes are noted in children with short bowel syndrome, they are accompanied by intestinal insufficiency.

STUDY RESULTS

Nutritional deficiency and associated metabolic disorders significantly complicate the preoperative preparation of these patients, reduce the effectiveness of surgical treatment and, most importantly, have a negative impact on the course of the postoperative period, increasing the percentage of complications and mortality, increasing the length of hospital stay, the rehabilitation period and the consumption of expensive drugs, reducing the quality of life of patients. The study of hemodynamic, immunological, metabolic disorders in patients in critical condition showed that regardless of their cause (trauma, burn, surgery, sepsis, etc.), they proceed similarly and are regulated by the same mediators. In response to stress or trauma, the patient experiences significant changes in the intensity of metabolism.

SIRS CONDITIONS

Since 1992, the inflammation that develops in response to traumatic stress has been called "systemic inflammatory response syndrome" (SIRS). Under SIRS conditions, muscle tissue catabolism accelerates. One of the most important factors in the formation of multiple organ damage in critical conditions is the rapid development of hypermetabolism syndrome - hypercatabolism caused by mediators of the systemic inflammatory response (cytokines, eicosanoids, lipid peroxidation products). Activated phagocytes release metabolically active peptides, which leads to the accumulation of prostaglandin E2 in the brain, liver, muscles and adipose tissue, resulting in increased protein breakdown in muscles, synthesis of acute phase proteins in the liver, fat mobilization.

Simultaneously with metabolic changes, ischemia and atrophy of the intestinal mucosa are observed in the body. This is why damage to the gastrointestinal tract is the most common organ dysfunction in children in extreme conditions. The intestine is an organ responsible for providing the body with nutrients, performing endocrine, immune, metabolic and barrier functions. The intestinal wall is rich in lymphoid tissue, which interacts with bacterial flora. In critical conditions, the permeability of the intestinal mucosa changes, which leads to the translocation of bacteria and toxins into the lymph and hemocirculation system.

Supporting Recovery: Lactoferrin for Acute Respiratory and Intestinal Infections

Acute respiratory and intestinal infections are among the most common infectious diseases in early childhood. Acute respiratory infections account for up to 70-80% of all infectious morbidity. Cytopathic effects in viral infections are varied, they are determined by the interaction of the virus and the cell, and are reduced to its destruction (cytolytic effect), coexistence of the virus and the cell without the death of the latter (latent and persistent infection) and transformation of the cel. The involvement of the body in the infectious process depends on a number of circumstances: the number of dead cells, the toxicity of viruses and the products of cell decay from the body's reactions, ranging from reflexes to immune disorders.

Acute period of infection

As is known, the majority of people with acute intestinal infections are children under 5 years of age. This age is characterized by the most significant shifts in the immune system. There is still no consensus on the role of the humoral link of the immune system in acute intestinal infections in children. In the acute period of infection, both a decrease in the content of IgA and M and an increase in the concentration of IgM are possible. The interaction of pathogenic enterobacteria with cells of the immune system leads to stimulation of the secretion of cytokines, which are regulators of their interaction with each other. In connection with the above, taking into account the data on the antiviral and bacterial activity of lactoferrin, its use as an additional corrective agent in the treatment of acute respiratory infections and intestinal infections in children seems promising.

Acure respiratory infections

In acute respiratory infections, various immune shifts occur in the child's body: insufficiency of the functional activity of phagocytes, secondary immunodeficiency of the hypersuppressor type, consisting in a decrease in the number of the main subpopulations of T lymphocytes (T helpers/inducers, T suppressors) develop. On the contrary, in acute intestinal infections, some researchers note an increase in the population of cytotoxic T lymphocytes. Despite the introduction of modern methods of diagnosis, prevention and treatment, a significant decrease in the incidence of acute intestinal infections is not observed. At the same time, in early childhood acute intestinal infections of bacterial etiology are often accompanied by complications and are characterized by a protracted course.

RATIONALE FOR THE USE OF LACTOFERRIN IN CHILDREN WITH SEPSIS AND MULTIPLE ORGAN FAILURE

Sepsis is a severe generalized infectious process caused by pathogenic and opportunistic microflora. Massive entry of the infectious agent into the bloodstream is associated with disruption of tissue barriers. The most common causative agents of sepsis are streptococci, staphylococci, Haemophilus influenzae, Proteus, Pseudomonas aeruginosa and Escherichia coli. Constant or recurrent, but long-term bacteremia and/or microbial toxemia are one of the most significant pathogenetic links in sepsis, regardless of the etiology of the pathological process. In sepsis, the specific response of cellular factors of innate immunity plays an important role. This is inextricably linked with inflammation as a typical adaptive, and under certain conditions, pathogenic reaction.

In conditions of bacteremia and microbial toxemia accompanying sepsis, the cells that provide the body's natural resistance to infectious agents are excessively activated: the mechanisms of anti-infective immunity are triggered. As a result of the body's non-specific reaction to infection during sepsis, a severe pathological condition may arise and progress - multiple organ failure, which is manifested by the transition of dysfunction of two or more organs to their failure.
The main causes of the development of multiple organ failure are considered to be the insufficiency of specific and non-specific factors of immune defense, impaired protein metabolism, increased pulmonary vascular resistance with increased pressure in the pulmonary artery and overload of the right half of the heart.

It is typical that multiple organ failure in its course always goes through the stage of pulmonary failure, then cardiac and renal failure usually join it, and subsequently - failure of the hemostasis system and general depression of the immune system. In the genesis of these disorders, a large role belongs to the effects of mediators capable of initiating necrobiosis and apoptosis processes in cells, as well as to the factors and mechanisms of immune autoaggression.

The identified general immunodepression as a component of the pathogenesis of multiple organ dysfunction allows us to assume the effectiveness of substitution immunocorrection and the advisability of including immunoactive drugs in the composition of complex treatment for severe sepsis and septic shock. In this regard, the use of natural biologically active protein lactoferrin in the complex treatment of children with severe generalized infection and multiple organ failure that developed against its background to strengthen anti-infective immunity seems promising.

PREVENTION OF NOSOCOMIAL INFECTIONS IN CHILDREN'S HOSPITALS

HOSPITAL-ACQUIRED INFECTION

A hospital-acquired infection is any infectious disease (condition) that occurs in a medical institution. An infection is considered hospital-acquired if it was absent in the patient before admission to the hospital, even during the incubation period, and appeared in its conditions or after the patient's discharge during the incubation period. According to statistics, nosocomial infections develop in 10–35.5% of newborns. All hospital-acquired infections can be divided into 2 groups depending on the route of infection: endo- and exogenous infections.

In endogenous infections, infection is associated with the patient's own (normal, permanent) microflora or flora acquired in a medical institution and colonizing it for a long time. An example is the occurrence of an infection in the area of ​​​​surgical intervention when microorganisms that colonize the patient's skin or intestines enter the wound. Exogenous infections are most often associated with the implementation of natural transmission routes (food, water, contact-household, airborne, airborne dust, etc.).

MOST COMMON TYPE OF PNEUMONIA

The highest incidence of hospital-acquired infections is registered in patients in neonatal intensive care units, where it ranges from 9.3 to 25.6%, and among patients weighing less than 1500 g it reaches 50%. The high incidence of hospital-acquired infections is reflected in the morbidity of patients in neonatal intensive care units. The incidence of hospital-acquired infections in these departments is 10 times higher than in other departments. Almost any microorganism can lead to the development of hospital-acquired infections.

Multicenter studies conducted in the United States and European countries have shown that over the past 20 years there have been changes in the incidence, localization and distribution of etiologic factors of nosocomial infections. Hospital-acquired pneumonia has become the most common type of pneumonia, and the most common etiological factors worldwide are coagulase-negative staphylococci, enterococci, Escherichia coli and Pseudomonas aeruginosa, Klebsiella, Enterobacteriaceae and Candida fungi.

Hospital-acquired infections are caused by a complex of reasons, therefore, when comparing morbidity, internal and external risk factors should be taken into account. Internal risk factors are associated with the patient's condition. Thus, for newborns, first of all, this is birth weight. The risk of developing clinically expressed forms of hospital infections increases in direct proportion with a decrease in birth weight. External risk factors include factors associated with the treatment and diagnostic process (invasive manipulations, artificial ventilation, venous catheterization, parenteral nutrition). The addition of HAI to the underlying disease increases the costs of nursing newborns, negatively affects the results of surgical treatment, increases postoperative mortality, increases the length of the patient's stay in the hospital.

Newborns with symptoms of intrauterine infection are prescribed antibacterial therapy early, and fluconazole is used to prevent candidiasis. Also, taking into account the immune status and features of interferonogenesis, intravenous immunoglobulins and interferon preparations are included in the treatment regimen. At the same time, any antibacterial therapy promotes the selection of highly resistant strains, which can subsequently cause nosocomial infection. Etiopathogenetic therapy of infectious and inflammatory diseases in newborns requires a comprehensive approach taking into account the immunological reactivity of the newborn's body, especially an immature premature baby.

The search for preventive measures to prevent the development of hospital infections is being conducted in almost all countries of the world. One of the innovative findings is the use of the multifunctional protein hLF with its antimicrobial, antiviral, antifungal and antiparasitic activity, the ability to stimulate natural immunity, and synergistic action with other antimicrobial peptides, in particular lysozyme and secretory leukoprotease inhibitor.

Treatment regimen

Prevention