Therapeutic apheresis for infectious diseases

According to WHO in the world of infectious diseases killed every day, up to 16 million people. 30-50 million infections annually registered in Russia. Of these, 10-12% of patients requiring intensive care as a result of infectious toxic shock, toxic encephalopathy and damage other vital organs. The best results are achieved in the presence of intensive treatment before the onset of the critical state [Pokrovsky V.I., 2005].

Virtually no infectious diseases that would not be accompanied by significant intoxication, the latter usually determine the severity of the state, as the main mechanism tanatogenesis significantly affecting the overall outcome. The structure consists of endotoxemia bacterial endo- and exotoxins, products of inflammation and tissue destruction from primary foci of inflammation entering the circulation, secondary metabolic disorders such as, as mentioned above in the description of septic complications.

Clinical manifestations of a variety of infections in many guises, as well as diverse and selective tropism of organ damage as a result of endotoxemia. In some cases the most severe toxic myocardial lesions (diphtheria), in others – the liver (hepatitis, leptospirosis), kidneys (hemorrhagic fever with renal syndrome), brain (encephalitis, botulism, typhoid, paratyphoid infection). Intestinal infections are often accompanied by dehydration syndrome with disorders of the central and peripheral hemodynamics. However, in most cases combined lesions observed in many organs and systems

In particular, the development of acute liver failure in viral hepatitis contributes to not only the direct impact of viruses that damage the hepatocytes as a cascade of metabolic disorders with accumulation of highly toxic products. Thus, activation of prooxidant and oppression of antioxidant systems is accompanied by accumulation of free radicals and toxic end products of lipid peroxidation [Shuvalova E.P., Antonova T.V., 1996]. Disturbances of hepatocyte membrane permeability contribute to the development of swelling last with intracellular acidosis and hypoxia. Damage of intracellular organelles, including lysosomes, is accompanied by the release of powerful proteolytic enzymes (hydrolases) from necrobiosis of hepatocytes.

However, viral infection, particularly hepatitis B-virus, triggers a cascade of successive immunopathological reactions [Sorinson S.N., 1998]. Namely cytotoxic T-cells, forming the immune response are those effectors that perform cytolysis and death of the infected hepatocytes, mainly those which are contained in the virus antigen. Rapid immune cytolysis of hepatocytes often becomes the dominant factor in the pathogenesis of viral hepatitis. Furthermore, circulating immune complexes formed (antibody + antigen + C3 complement component) also causes adverse immunopathological reactions.

Especially dangerous is the fulminant form of hepatitis with massive liver necrosis, which was previously called "acute yellow atrophy of the liver" [Sorinson S.N., 1998]. Cytotoxic agents while maintaining the active autolysis hepatocytes with suppression of all regeneration processes [Ohnishi H., Nagaki N., 1993]. Developing an "explosion of lysosomes" with the release of active cyto- and proteolytic enzymes causes progressive autolysis and necrosis of hepatocytes with the transition of liver failure in hepato-lenticular form. Accumulation wherein is confirmed endotoxins and "paramecium test" accelerated in 4-6 times of death protozoa time in serum of these patients. This explains naturally developing acute renal failure (hepato-renal syndrome), accelerating the onset of multiple organ failure complete. In the genesis of neurological disorders in the course of acute hepatitis leading role played by endotoxins that accumulate with the increase of liver failure. However, we can not exclude the direct damaging effects of hepatitis viruses on elements of the central nervous system, especially as found in the cerebrospinal fluid antibodies against hepatitis C-virus and RNA of the virus, which can be traced as far back as during the year [Caudai C. et al., 1997].

Severe endotoxemia causes toxic secondary immunodeficiency, which further weakens the patient's resistance to infection, inhibits the production of specific antibodies. There is evidence that intensive therapy of acute hepatitis C with intravenous high-dose immunoglobulin promotes development in the later period (up to two years) hypogammaglobulinemia, is a predisposing factor for chronic viral infection [Christie J.M. et al., 1997].

All this is particularly acute determines the need for detoxification and therapeutic apheresis at the height of the manifestations of endogenous intoxication, along with measures to immunostimulation by photo-hemotherapy, using indirect electrochemical oxidation of the blood, in addition to having more detoxification and bactericidal action. In particular, A.D.Safonov et al. (2003) was performed in 148 patients with plasmapheresis, which amounted to 72.5% of all patients with acute viral hepatitis B and B+C, treated in the intensive care unit. At the same time noted the clarification of consciousness, the disappearance of euphoria, weakness, headaches, drowsiness, tremor, tachycardia, normalize the level of middle weight molecules, increased life expectancy paramecium. In the absence of positive dynamics was carried out repeated sessions of plasmapheresis. L.J. Li et al. (2005) positive results achieved also during of membrane plasmapheres is the removal plasma volume up to 3500 ml.

Upon the occurrence of hepatic coma it was most effective membrane plasmapheresis with removal of up to 5 liters of plasma, thereby lowering levels of bilirubin up to 40%, ammonia 70%, methionine, phenylalanine and tyrosine on 60% and 20% of endotoxins. Unlike hemodialysis or hemosorption with membrane plasmapheresis more fully removed high-toxic products, including autoantibodies and immune complexes formed in severe hepatitis B and aggravating hepatocytes damage [Valbonesi V., 1986].

It should be noted that in acute liver failure metabolism and inactivation of the sodium citrate is difficult, however, for these procedures, in spite of its potential toxicity  this anticoagulant was used that nonetheless does not hinder the removal of patients from severe hepatic coma. The use of small doses of heparin allowed to dispense with the lower doses sodium citrate also. Sometimes requires removal of up to eight liters of plasma to adequately reduce the levels of ammonia, urea and amino acids, and cupping hepatic coma [Clemmesen J.O. et al., 2001].

Severe forms iktero-hemorrhagic leptospirosis is often accompanied by an infectious-toxic shock with hemorrhagic syndrome on 5-6th day of the disease. With plasmapheresis managed reduce the incidence of intoxication. In particular leukocyte index of intoxication after the first plasmapheresis decreased 2.4 times, an improvement of coagulation, especially when DIC under anticoagulation. Plasmapheresis also prevented the development of multiple organ failure [Gorodin V.N., 2003; Cerdas-Quesada C., 2011]. M.Valbonesi (1986) with the help of plasma exchange with removal of up to 2.8 liters of plasma was also able to stop acute renal-hepatic failure in 33 of 36 patients. Plasmapheresis was more effective than hemodiafiltration [Tse K.-C. et al., 2002].

With such viral disease such as hemorrhagic fever with renal syndrome is characterized by a development of hemorrhagic syndrome on the background of infectious-toxic shock and acute renal failure [Rabinowich V.I. et al., 2003]. When using plasmapheresis in the amount of 0.9 CPV with partial substitution of fresh frozen donor plasma achieved better results than in isolated dialysis [Matveeva I.B. et al., 2005]. Positive results also provide plasmapheresis before hemodialysis [Rabinovich V.I. et al., 2003].

In diphtheria with severe endotoxemia, toxic myocarditis and autoimmune poly-radiculopathy treatable with plasma exchange, held daily until stabilization of the patient’s condition against the background of indirect electrochemical oxidation of blood and the introduction of anti-diphtheria serum, which reduced the mortality rate from 66% to 6%. Plasma exchange allow not only prevent early, but later organ disorders [Vorobyev A.S., 1998]. A.S.Petruhin et al. (1998) also noted that the only way to influence the late neurological complications plasmapheresis is performed in the acute stage of the disease.

Of course, should be carried out and specific therapy with a special diphtheria antitoxic serum. However, the uncontrolled use of it may come a time when all the toxins in the blood, is completely bound and serum continues to be administered. This leads to accumulation of unbound antibodies which are deposited on the endothelium of small blood vessels, causing them damage and exacerbating manifestations of nephritis and myocarditis. Plasmapheresis can prevent such complications [Panchenkova N.R., Sokolov V.A., 1996].

Severe course of the disease develops as a result of infection caused by the Epstein-Barr virus, characterized by pancytopenia, coagulopathy, and liver failure. Besides immunosupressive therapy, in severe cases it needs to turn to plasmapheresis [Abe Y. et al., 2010].
Severe intoxication accompanied and tuberculosis patients for which is also characterized by immunosuppression, further exacerbated during startup and long-term course of the inflammatory process. Indications for therapeutic apheresis arise as in the period of preparation for surgery and in the postoperative period [Tityukhina M.V., 2012].

Intestinal infections have a definite value enterosorption preventing absorption from the intestinal lumen enterogenous and bacterial toxins. Severe poisoning was observed in some countries of Western Europe in the summer of 2011 caused by serotype O104:H4 Escherichia coli. Secreted with Shiga-toxin it causes severe enterocolitis with the development of hemolytic uremic syndrome, accompanied by high mortality. Antibiotics were powerless in this case or, on the contrary, contributed rise of endotoxemia. It became clear by the end of the epidemic, which forced to abandon antibiotics. Using plasma exchange the early stages of disease contributed to the rapid healing [Colic E. et al., 2011; Kreig L.S. et al., 2012; Ulrich S. et al., 2013]. J.T.Kielstein et al. (2012), summarizing the experience of treating 631 patients in 84 hospitals in Germany, Sweden and the Netherlands came to the same conclusion. I. Yildrim et al. (2010) have been successful in the treatment of multiple organ failure on background thrombocytopenia induced Salmonella enterica.

Plagued the people, especially in the regions of tropical climate, is malaria. This concerns mainly the tropical its shape, called Plasmodium falciparum, which gives 98% of deaths from malaria [Shkurba A.V., Ovcharenko P.A., 2010]. Its crises are accompanied by severe endotoxemia with coma, acute renal and respiratory failure due to infectious-toxic shock. It particularly affected with children and pregnant women [Dhingra N. et al., 2010; Eilese T.P. et al., 2010].

In recent years, not only in Africa but also in other parts of the world, the cases of the disease with fever caused by West Nile virus, which crosses the blood-brain barrier and causes severe encephalitis with frequent fatal consequences. There is even believed that Alexander the Great died in Babylon at the age of 32 in 2 weeks from such fever [Marr J.S., Calisher C.H., 2003]. Specific therapy has not yet been worked out. However, the pathogenesis of the disease plays a role not only direct viral damage to neural structures, but also a general toxic effects [Lim S.M. et al., 2011], that is an indication for extracorporeal detoxification, especially fatalities that precedes the development of severe respiratory distress syndrome [Morrey J.D., et al., 2012]. But after recovery remains quite severe neurological disorders by type of systemic autoimmune demyelinating disease with severe muscle weakness [Cook R.L. et al., 2010; Loeb M. et al., 2011; Leis A.A., Stokic D.S., 2012], which also raises the question about the use of efferent therapy .

In recent years, there were also many reports of severity for a number of hemorrhagic fevers caused by the Ebola, Marburg, Dengue viruses involving intoxication and severe shock with mortality up to 70-90% as the treatment of such infectious diseases remains almost symptomatic [Leong AS et al., 2007]. The pathogenesis of these complications is the release of a number of white blood cells of cytokines (TNF-α, IL-2, IL-6, IL-8) and other biologically active toxic compounds that disrupt the permeability of the vascular endothelium to the development of toxic edema, which contributes to the emergence of shock and multiple organ failure. It develops a toxic edema of the lungs that leads to respiratory distress with severe respiratory failure, in the liver - to toxic hepatopathy, in the brain - a toxic encephalopathy. Toxins damage the membranes of platelets, contributing to their increased adhesive activity with the formation of microaggregates, which is the first phase of development of disseminated intravascular clotting syndrome with thrombocytopenia and hemorrhagic manifestations (skin - hemorrhagic rash, stomach - vomiting blood, kidneys - oligouria and hematuria, etc.) [Feldmann H. et al., 1996; Carr J.M. et al., 2003; Aleksandrowicz P. et al., 2008].
As there is no specific treatment, and the disease is potentially fatal, especially for children, detoxification is virtually the only method of treatment. In this case, transfusion therapy alone is not able to withdraw all formed endotoxins. A fuller effect can be reached by the methods of therapeutic apheresis. 

I would like, however, to pay attention to much less studied problems postinfection rehabilitation as elimination of the main manifestations of infectious processes is still far from a full recovery of the affected organs and systems. In many cases, pathological toxic products that appeared during the main period of the disease, destroyed and removed simultaneously with the appearance of external signs of recovery. However, this does not always happen.

To the greatest extent it relates to viral hepatitis, when derivatives of bilirubin, bile acids, ammonia, products of lipid peroxidation and proteolysis continue to hold a "toxic press" hepatocytes, blocking them high enough potential to repair. This is the main prerequisite for the formation of chronic hepatitis and cirrhosis in the future with all the sad consequences.

Similarly, after the elimination of the main manifestations of diphtheria in the body are toxic products, autoantibodies and immune complexes, tropic to the myocardium, and toxic diphtheria autoimmune myocarditis completes eventually that did not have time at the height of diphtheria bacillus infection. In 50% of patients after diphtheria, observed neurological complications – late-type illness polyneuropathy like Guillain-Barre syndrome. Same rehabilitation may require also for patients who have suffered encephalitis.

In addition, after a series of infections formed almost real "acquired immunodeficiency syndrome" toxic origin with consequences no less serious than the particular viral AIDS.
Of course, the main method of treatment of infectious diseases remains causal treatment – antibiotics, but they do not always sufficiently effective. Therefore, to a large extent can assist hemosorption, which, in addition to effective detoxification, provides and capture pathogens from flowing blood to prevent their return to the body. However, only the decontamination and detoxification is not able to restore the immune capacity of the patient.  If the body itself is not able to resist infection, then no antibiotics will not help him.
And here comes to the fore plasma exchange, which in addition to removing all pathological and toxic compounds effectively restores the immune system due to the fill removed volume of donor fresh frozen plasma.

And this tactic of the primary detoxification and decontamination using hemosorption followed plasma exchange is completely justified [Voinov V.A., 2010].
Supporting role there are played by the methods of indirect electrochemical oxidation and ozonation of blood, potentiating detoxification, and photo-hemotherapy (UV- and laser irradiation of blood) having immunostimulatory effect. In general, significantly reduces the costs of expensive antibiotics and other medicines, the period when the patients in the ICU, the total duration and thefinal outcome of thedisease.

It must admit that at the present stage, these questions do not have significant differences and debate and only the weakness of the material base and the lack of trained professionals holding back wider adoption of methods of extracorporeal detoxification, plasma exchange and immune correction to the practice of infectious medical institutions [Swedov A.K., Gurevich K.J., 1995]..

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