Plasmapheresis in allergies

In recentyears there has beena continuousincrease in the frequencyof allergicdiseases with damage of skin, mucousof the upper respiratorytract and bronchi. 
The greatest danger isbronchial asthma. Attemptsonlymedical treatmentis notalways effective. There is pathogenetically more justificatedthe use ofplasmapheresis. 
Key words: allergy, atopic dermatitis, asthma, plasmapheresis.   
Increased incidence of allergic diseases (up to 20% of the population) is the result of human contact with the growing number of allergens: industrial (turpentine, nickel, chromium, tar, varnishes, resins, tannins, etc.), food (eggs, citrus fruits, tomatoes and chemical additives), vegetable (ragweed pollen, timothy grass, etc.), household (house dust, perfumes, detergents, synthetic fabrics), agricultural (insecticides, pesticides, defoliants, fertilizers), medicines (penicillin, sulfonamides, aspirin, etc.).
Occurrence of allergic diseases there are due to imperfection of the biotransformation allergens in the microsomal liver unit (appearance of secondary reactive compounds) and with defects of the immune response (atopic forms), biotransformation and elimination of immune complexes.

Atopy seems as overreaction of the immune system against common and harmless environmental substances. Allergic antibodies are immunoglobulin E (IgE). IgE production by B-lymphocytes is stimulated by cytokines IL-4, IL-5 and IL-13 secreted by T-helper lymphocytes influenced allergens [1, 2]. Communication IgE-antibodies to allergens (antigens) generates involving complement persistent immune complexes, the elimination of which is difficult in allergy. Some of them are still in circulation (circulating immune complexes or CIC), and the rest are fixed in the interstitium of target organs, stimulating there the immune or allergic inflammation. Among these target organs occupies the leading place bronchial tree, skin and mucous membranes of the nasal cavity. 

Allergy is a disorder characterized by immune system hypersensitivityas the first (immediate) type, which develops when the IgE-response is directed against a normally harmless environmental antigens such as pollen, house dust mites or animal dander. IgE-sensitized mast cells excreted wherein the bioactive mediators that causes an acute inflammatory reaction with symptoms of asthma or rhinitis.
Triggers or provoking factors of allergic reactions exacerbation, act above allergens, among which the pollen of trees such as birch, alder, hazel, oak, hornbeam. Leading role among them belongs to the pollen of white birch (Betula verrucosa), containing the major allergen Bet v 1, which can be detected in 60% of patients with IgE reactions [3, 4].

 In atopic dermatitis and asthma forms can connection IgE-antibodies and autoantigens with the activation of allergic effector cells – mast cells and basophils. IgE-autoimmunity thus explains exacerbation for severe atopy even in the absence of exogenous allergens [5]. This may cause sensitization and against self antigens. Special studies have shown that antigens Aspergillis fumigatus can be close to the antigenic structure of the human body's own proteins, so if sensitization to this microorganism, and even in its absence, can be maintained autoreactivity and allergic reactions [6].

IgE-dependent activation of mast cells plays a leading role in the development of immediate allergic reaction [7]. Moreover mast cells can produce various mediators, including tumor necrosis factor (TNF-a) and many other cytokines (interleukins IL-1, IL-2, etc.). Furthermore, mast cells stimulate the formation of a large number of highly active surface receptors for IgE, and enhance the level of IgE-dependent secretion of neurotransmitters in response to increasing concentrations of IgE. Mast cells (and in some cases released fr om them cytokines) may play an important role in triggering acute, subacute and chronic components of IgE-dependent allergic inflammation that can affect the development of important functional consequences of these reactions – airway hyperresponsiveness [8].

In allergic inflammation plays a role also eosinophils which increased release of stimulatory cytokines IL-4 and IL-5 of T-helper cells [2]. Eosinophils, in turn, release the enzymes in large amounts, which have high proteolytic activity, and contribute to eosinophil infiltration. Basic proteins of eosinophils promote to the release of histamine from mast cells, suggesting their close cooperation [9].

Significant incidence of allergic diseases in infants and even newborns suggests the possibility of their perinatal sensitization, especially in the presence of allergy in their mothers. Contributing factors are disorders of pregnancy (toxemia, preterm labor) and used in significant quantities in this medication. In such cases, increased concentrations of immunoglobulins, including IgE, found in newborns and even in a few months after birth [10].

In industrialized countries, up to 20% of the population suffered from allergic symptoms of type I – rhinitis, conjunctivitis, asthma [3]. The earliest manifestations of allergy, often from the very first days of life, are skin – so-called diathesis, with undulating course, passing at a later age in common, persistent, recurrent continuously neurodermatitis.

Atopic dermatitis is often accompanied by bronchial asthma and allergic rhinitis. Studies indicate activation of cytokines IL-3, IL-4, IL-5, IL-15. Clinical manifestations largely depend on the reactions to exogenous allergens [11]. However, as antigens there may play a role not only products of external origin but also bacterial, in particular – Staphylococcus aureus, which can be identified in 95% of patients with atopic dermatitis. Such bacterial superantigens can activate both local T-cell mechanisms and produce IgE [12].

Duration course neurodermatitis indirect evidence of the ineffectiveness of traditional treatments designed usually to local places of skin lesions. Even hormonal ointments cause only temporary effects.

The most reasonable pathogenetic approach to the treatment of this skin, only to localize lesions, disease seems efferent therapy aimed at removing allergens from the body, autoantibodies, immune complexes and other pathological metabolites, create a series of vicious circles that break neither the body nor any medications not be able to. That is, treatment should be directed not so much at the local sites of lesions as to eliminate the conditions of their occurrence and chronicity. And the best way it can be achieved by plasmapheresis. From our own experience the best results are achieved by adding to the rate of 4 operations plasmapheresis also hemosorption with simultaneous ultraviolet or laser beams blood irradiation and subsequent enterosorption [41].

Allergic dermatitis poses also a risk of pregnancy, when many allergy medications pose a risk to the developing fetus and preferred in such cases are also courses of plasmapheresis [13]. 
Described the so-called "hyper-IgE syndrome" when needed to conduct 60 (!) sessions of plasmapheresis for two years to eliminate manifestations of severe dermatitis, which lasted eight years [14].

Local eczema-like dermatitis also has an allergic nature. In particular, periorbital eczema and eyelids dermatitis are a variety of allergic contact dermatitis. The reasons could be eye ointments, creams, eye shadows and makeup, shampoos and even nail polish [15].

Urticaria is episodic and transient allergic skin lesions, although described and chronic urticaria, in which are found in the blood of patients with IgG-antibodies against highly IgE-receptors. Removing them using plasmapheresis leads to clinical remission [16, 17, 18]. Application of the IgG-antibody immunosorbent provided almost complete disappearance of autoantibodies with regressive disease within 8 months. X. Jiang et al. [19] have achieved the considerable success using cascade plasmapheresis in the case of chronic urticaria resistant to treatment of dexamethasone and gamma globulin.

Given the greater frequency of detection of parasites in these patients (giardiasis, opistorhosis, toxocariasis), it is advisable to carry out additional inspection and detection of parasites prescribe appropriate therapy (tiberal, flag, biltritsid, dekaris). Chronic urticaria may be accompanied by diseases caused by hepatitis B and C, HIV, Epstein- Barr virus, coxsackie A and B, infectious mononucleosis. While acute urticaria can become chronic. Chronic urticaria often develops on the background of other autoimmune diseases – chronic hepatitis C, autoimmune thyroiditis [20].

Same episodic angioedema clearly limited skin and subcutaneous tissue, usually affects the lips, tongue, throat, tissues of the orbit. Nevertheless, it is sometimes a danger to life in the propagation of the larynx edema on the development of severe dyspnea. This swelling usually idiopathic, but may be triggered also some drugs administration, including nonsteroidal anti-inflammatory drugs. Pathogenetic mechanism may be the accumulation of bradykinin by inhibiting its degradation mechanisms [21].

Another factor in the pathogenesis of this edema is the appearance of autoantibodies against specific protein that inhibits the complement component C1 (C1- inhibitor), the lack of which contributes to suddenly increased vascular permeability of certain local areas of the vascular bed, most often on the face, abdomen and extremities. Until recently, such a sudden edema accompanying upper airway obstruction could be lethal to 50% of patients. Permitting trigger such a reaction may be an increase in the content of vasoactive peptides of kinin cascade, in particular the already mentioned above bradykinin at allergic reactions [22].

Extremely difficult course has idiosyncratic system syndrome of Lyellor Stephen-Jones – toxic epidermal necrolysis toxic-allergic nature with extensive lesions not only the skin but also the mucous membranes that occur in response to the reception of a number of drugs (sulfonamides, antibiotics). Sometimes play the role of viral infections and even the graft rejection. Mortality in this case reaches 25-75%. In particular, it describes death in a patient with Lyell's syndrome after administration of ciprofloxacin. Most of the hypotheses based on the autoimmune processes with skin infiltration by cytotoxic T-cells (CD8+), monocytes and macrophages, the deposition of a number of cytokines  (TNF-a), contributing to extensive apoptosis of keratinocytes [23]. 

  Efferent therapy quickly enough, sometimes already after the first session of plasmapheresis, interrupt such a reaction and lead to permanent cure [24, 25, 26]. G. Bamichas et al. [27] used a massive membrane plasma exchange remove 4.2 liters of plasma from 2 to 5 sessions carried out every other day or every day, replacing with fresh frozen plasma and albumin. In Japan, there are successfully used for the treatment of not only conventional, but also cascade plasmapheresis [28]. Isolated use of corticosteroids is fraught with increased septic manifestations, but in combination with plasmapheresis provides better results [29, 30, 31].

Intestinal allergies are characterized by sudden intestinal and biliary tract dyskinesia. In dentistry, characterized by the so-called prosthetic or medication stomatitis. In a separate form isolated eosinophilic esophagitis, characterized by the occurrence of transient dysphagias disorders. At esophagoscopy they find local narrowing of the esophagus, and biopsy in the mucosa determined high levels of eosinophils. It is often detected in the blood eosinophilia, as well as other manifestations of allergy, in particular – asthma [32, 33].   
Persistent course has vasomotor rhino-sinusopatiya, often accompanied by allergic conjunctivitis. Allergic rhinitis formed inflammatory infiltrates of various cells with the release of inflammatory mediators (histamine, leukotrienes, cytokines) that attract cells and promote their trans-endothelial migration that creates a vicious circle, which break the organism itself is no longer able. Outwardly innocuous running nose can last for many years, but they often attach and asthma also. This contributes to the restriction of nasal breathing. Inspiration of cold dry air and delay bacteria in the nasal cavity promote to the development and maintenance of catarrh in the bronchial tree, which also starts and establishes allergic inflammation in the airways. Therefore, the position to such rhinitis should be no less serious than asthma.   
The most serious manifestation of allergy is asthma, which represents the greatest danger and the greatest difficulties in the treatment.

According to U.S. statistics in the U.S. suffer from asthma for about 15 million people with the loss of up to 100 million training or working days per year [34]. However, even in such country with a highly developed medical care, wh ere the overall cost of treatment of patients with asthma are up to 6.2 billion dollars a year, the death rate from asthma increased from 13.4 per 1 million population in 1982 to 18.8 per 1 million population in 1992. Asthma is also an important cause of disability in adults and school days loss in children [35]. Occurrence of asthma there is often long preceded other manifestations of allergy, in particular – allergic rhinitis [Peters E. et al., 1999]. While 78% of patients with asthma have symptoms of rhinitis, and 38% of patients suffer both from rhinitis and asthma [34]. 

In asthma appear and persist clones of activated T-helper (CD4), sensitized allergens – from environmental antigens or viruses that stay on the lungs. Cytokines of these cells (IL-3, IL-5, and granulocyte-colony-stimulating factor) are activated eosinophils, which excite the eosinophilic inflammation of the mucous membranes and secrete IL-4, stimulates, in turn, produce IgE. Thiscauses damage to theepithelium, mucus hypersecretionand contractionmuscleof the bronchi(bronchospasm) [36]. In addition, with the development andaggravationof asthma there are occurand other homeostasis disorders, particularly depletedantioxidant activitysystem with accretionoflipidperoxidation productsand a high levelof free radicals.This furthersupportsallergicchronic inflammation andalso requiresspecial measures tocorrect suchdisorders.

Unfortunately, conventional therapeutic measures in these various manifestations of allergy are mainly symptomatic – various ointments to relieve the intolerable itching in skin manifestations, the vasoconstrictors  used in the form of droplets (galazolin, sanorin) with rhinitis, mucolytics and bronchodilators in asthma. At best, the effect sought appointment of hormonal preparations. It should be borne in mind and the potential dangers of hormone replacement therapy. Even seemingly innocuous with betamethasone nasal drops can, even before clinical manifestations of Cushing's syndrome, lead to stunted growth of children [37].

For a long time been practiced specific immunotherapy increasing doses of allergens administered subcutaneously, orally, sublingually or intranasally. This process is also called hyposensitization or desensitization, because it is aimed at reducing the sensitivity of the target organ to these allergens. Typically, this is the inhaled allergens – house dust mites or minute Hymenoptera. Although this therapy has been used for about 80 years, but still not quite clear mechanisms of its action and its effectiveness is not constant [38].

Raise doubts and possibility of selective extracorporeal immunoadsorption, particularly to house dust antigen. And not just because of the risk of causing anaphylactic reactions as a result of massive basophil degranulation, carrier specific IgE, with the release of serotonin, histamine, slow reacting substance A, until the development of anaphylactic shock. Major objections cause allergy facts polyvalence. There are virtually no patients with asthma who were sensitized to one allergen only. Over time, their circle extends to several tens.

Despite the fact that the work of numerous researchers have proved the effectiveness of the introduction of efferent therapy in the range of therapeutic interventions, this tactic is still not widely used. In some cases, the diagnosis of asthma is set only after a few years of the disease under the guise of asthmatic bronchitis, bronchitis with asthmatic components, then preastma, and the final diagnosis is made only before the start of hormone therapy. Occurrence of asthma often occurs against a background of long flowing rhinosinusopathy or cutaneous manifestations Nevertheless, when all these listed types of allergies as pathogenetic treatment are present efferent therapy is aimed at removing from the body of antibodies – allergens blocking antibodies receptors, inhibitors, tissue degradation products, inflammatory mediators, leukotrienes and immune complexes. Reducing the concentration of biologically active substances leads to the restoration of b-adrenergic reception, reduces resistance to bronchodilators [39]. Deblocady and removal of inhibitors of receptors of T-suppressor activity in plasmapheresis leads to the restoration of T-lymphocyte activation and which promotes alveolar macrophages. Deblokady of phagocytereceptorspromotes more effectivenaturalelimination of allergens. Overall,this provides a morestable remission. Relatedphotohemotherapyalsohelps to normalize theprocessesof differentiationof T-lymphocyteswith increased activity ofT-suppressor anddecreased production ofIgE,the elimination ofbiochemicaldisorders.Usingphotohemotherapy of red lightevenin monotherapyhas a favorable effecton bronchialasthma[40].

Removingplasma atplasmapheresisstimulates the releaseinto the circulationof freshingredients andhelps to normalizemetabolism, particularly lipid peroxidationwith increased activity ofthe antioxidant system. Reducing the level ofbiologically active substanceshelps normalizemembrane phospholipids metabolism. All this leadsto the elimination ofimmunoallergicinflammationwith restorationof sensitivity andbronchial reactivityand eliminationof bronchial obstruction. Actionefferent therapycontinues in thelonger-term. Allnewly arrivingincirculationcomponentshomeostasis, young cell shape, which replaced theold,inrefreshedenvironmentfor the more longer periodretain theirgeneticallypredeterminedproperties and functionsthathelps breakmanypathologicalformedcircles, enter themorestable remission. Positive effectafter a courseof plasmapheresiscomes5-7daysafter the start oftreatment andlasts from a fewmonths to two years. Thisis also confirmedin our clinicalpractice [41]. 

Hemosorbtioninrecent years, increasinglygives way toplasmapheresis, as the mosteffective method ofremovingall pathologicalproducts, regardless of their abilityto adhereandbe adsorbed onthe surface ofactivatedsorbents.An exception is theso-called "aspirin" or "prostacyclin" form of bronchial asthma, in whichsorption methodsare quite efficient, as well as in cases ofconcomitantallergodermatitis [41].

Plasmapheresis, helps to eliminate pathologicalproducts, and also could eliminatethe reasons whichcauseimmune disorders, and create conditions fortheir gradualregression [42]. 

Bronchial asthmahas an adverse effecton pregnancy also, promoting to toxicity,with the threat oftermination of pregnancyand premature birth, abnormalitiesof labor, fetal hypoxia. All this makes theplasmapheresisnecessaryin these patients too [13].

Study ofbiochemical homeostasisdisordersshowed significantviolationsof lipid peroxidationwith the accumulation oftoxicend productsandsuppressionof antioxidant protection; determinedelevated concentrationsof histamine,serotonin, medium weightoligopeptides.It is therefore importantnot only tothe removal ofpathologicalimmunoglobulins, antibodies andimmune complexes, but also normalization ofbiochemical homeostasis.

Practically all of these types of allergies – as if not outwardly expressed rhinitis or skin forms, and in severe asthma, it is advisable to conduct a full course of efferent therapy and immune correction because there is never a guarantee that the lighter allergy can not be transformed into heavy. From this perspective, the unjustified delay in recognition that the diagnosis of asthma, registering only asthmatic bronchitis components and preasthma not allow timely eliminate background homeostasis disorders, helps to perpetuate pathological allergic reactions. There is much easier to prevent the progression of primary, yet functional disorders, than to achieve regression of organic disorders – severe obstructive suppurative endobronchitis, emphysema with destruction of the elastic framework of the lung parenchyma [41].

Use of plasmapheresis in the initial phases of formation of asthma often meets objections clinicians considering ample drugs prescriptions. However, A.K. Samotolkin [43] has made quite good results in patients with "Preasthma" using plasmapheresis, considering that the elimination of mediators of inflammation and bronchoconstriction stimulates macrophage system and complement. 

For all invasive techniques, plasmapheresis in these patients may well be applied even on an outpatient basis. This was confirmed by our own experience in the use of plasmapheresis in the early stages of asthma, including children, when they could almost completely interrupt the pathological process. In addition, the irradiation of blood in the extracorporeal circuit with laser beams on a helium-neon SHUTTLE device with the power density at the end of the fiber to 15-20 mW, quite sufficient for penetration through the wall of plastic tubeswithbloodflowingin them, located in a special spherical chamber [41].

Given the often concomitant allergic rhinosinusopathy, performed also an additional exposure of the nasal cavities in the same waveguide device SHUTTLE, as well as the maxillary, frontal sinuses and infrared laser penetrating the tissues up to 8 cm.  Expediency due to the need to eliminate the last points of chronic infection as one of the possible triggers excitation allergic reactions. Even in the absence of any symptoms of the rhino-sinus area, it can be considered one of the most influential reflex zones, promoting sensitization, area first contact with inhaled allergens. Thereforehealing of the nasal cavitiesandsinusespathogeneticallyjustified, as well as the possibleimpact onreflexthis sensitive zone. Furthermore, the improvement of the upper respiratory tractandpromotes greaterwarming ofinspirable air and humidification, delayallergens andblockade of nasal-bronchial reflex[34].Moreover, given thesignificant riskof asthma inconnectionwith allergic rhinitispatients, more intensive treatmentof the latter maybe one of themethods for the preventionof asthma.

Complete this complex of efferent therapy by enterosorption allowing to limits the entrance of enterogenous toxins that can support the allergic reactions, as well as for removal from circulation of middle weight endotoxins. Courses enterosorption can be repeated periodically also after plasmapheresis every 2-3 months for 2 weeks.

Unfortunately we must admit that completely cure patients with allergies is almost impossible and such patients will need later in life for repeated courses of efferent therapy, which is confirmed by clinical practice.   
Several stands out quite a rare disease – subsepsis Wissler-Fanconi ("allergosepsis"), characterized by articular syndrome (swelling, stiffness), hectic fever, ephemeral roseolous rash on the body, high leukocytosis with a left shift,  thrombocytosis (from 400-600x109 /l to 1000x109 /l), headaches and increased IgE levels by 3-4 times. It also helps the frequent repeat plasmapheresis sessions over time. At the patient with this disease who were treated in our department, it was observed the pattern of the lung spread infiltrates with the rapid development of refluence during the course of plasmapheresis .

There is in the same row also the Churg-Straus syndrome –allergic vasculitisandgranulomatosis. Oftendevelops on the backgroundof steroidtherapy for bronchialasthma.Eosinophiliclymphadenopathyoccurson a background ofblood eosinophiliawith severevasculitis, up to a fatal outcome. The use of highdosesof steroids, and sometimes of cyclophosphamide are not always successful.This underlines theneed forvigilancewhensteroid administrationto patientswith bronchial asthma[44]. In our practice in such cases helps plasmapheresis too. 

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