Plasmapheresis for the Treatment of Idiopathic Pulmonary Fibrosis

This disease of unknown nature, often occurring with autoimmune disorders, refers to the idiopathic interstitial pneumonias. It is characterized by an isolated lesion of the lungs (Idiopathic Pulmonary Fibrosis or IPF) or in the form of pulmonary syndrome in other, usually systemic, diseases (systemic vasculitis, granulomatosis, rheumatoid polyarthritis, systemic lupus erythematosus, etc.). IPF occurs in 9.0-41.8 per 100,000 population, and worldwide in about 3 million people with a significant increase in the number of cases in recent years [1-3].

It is supposed that as a result of influence of unknown still etiological factor of the exo or endogenous nature there is an initial damage of alveolar structures (both an endothelium of vessels and alveolocytis) to development of interstitial edema.

These processes are followed by attraction of alveolar macrophages, neutrophils, lymphocytes with an infiltration them alveolar partitions that defines a stage of an alveolitis. Activation of T-helpers promotes allocation of the cytokines of the Th-2 type (interleukins 4, 5, 10, 13) stimulating proliferation of fibroblast and processes of a fibrosing [4,5]. The excited macrophages and neutrophils are sources of proteolytic enzymes that finally the interstitium conducts to hyper production of collagen and formation of pulmonary fibrosis. The fibrosing alveolitis is a characteristic sign substantial increase of level of the circulasting immune complexes (CIC), immunoglobulins A, G and M, antipulmonary autoantibodies against the increased proteolytic activity of blood [4]. IPF are quite often combined with cardiovascular diseases, a gastro-oesophageal reflux, pulmonary hypertension, an obstructive sleep apnoea, that ultimately lead to disease progression and death [6,7].

The illness proceeds extremely severe, is followed by the increasing respiratory insufficiency and comes to an end with a lethal outcome within 2-3 years from the moment of emergence of the first symptoms [8-11]. As the illness develops gradually and with indistinct symptoms, it is late diagnosed and patients during rather long time don't receive treatment [12]. The analysis of deadly outcomes at group of children with the same chronic interstitial pulmonary diseases showed that opportunity to live 24, 48 and 60 months had 83%, 72% or 64% of these children respectively [13].

Considering autoimmune character of a disease corticosteroids and cytostatics find application, however many authors consider them dangerous and don't recommend them [14,15]. However, such therapy does not lack a large number of adverse reactions. Corticosteroids cause Cushingoid syndrome and hypertriglyceridemia, which predisposes to mitochondrial dysfunction and damage to cardiomyocytes, accompanied by free radicals generation [16]. Steroid therapy predisposes to the development of diabetes mellitus, especially in older patients with pre-diabetes mellitus, exacerbating vascular disorders [17]. Moreover, there are certificates on higher risk of development of lung cancer at this disease which isn't depending even on the smoking fact [18], that it is possible to connect also with deeper immunosuppression during glucocorticoid therapy.

As the fibrosing is the main process in formation of all group of these diseases, also antifibrotic preparations, such as pirfenidon and nintedanib are used [19-21]. However they render only temporary medical effect at an mild to moderate forms of diseases, and in severe form they not only inefficient, but also are toxic [22]. In particular, they have high hepato-gastrointestinal toxicity [23], skin phototoxic reactions, up to a leukomelanoderma [24-26]. Besides, neither nintedanib, nor pirfenidon not at all patients prevent progressing of fibrosis [27,28]. Thus it is necessary to use only on a long-term oxygen therapy and overall lung transplantation [27]. Besides, it is necessary to consider also rather high cost of such treatment- from 1000 to 2700 Euro a month.

It is difficult to expect essential return development of already come organic damages of lungs, in particular fibrosis, however impact on initial stages of a disease is quite possible- alveolitis and interstitial swelled. At removal from an organism as primary agents, toxic for alveolar structures, and, obviously, by-products of the immune response it is possible to expect an improvement or, at least, stabilization of pathological processes in the lungs parenchyma. Nevertheless, such approach is used only at development of a pulmonary fibrosis against other autoimmune diseases, such as ANCA-vasculitis or microscopic angiitis [29,30], and also at a acute exacerbations of a fibrosing alveolitis in cases of inefficiency of usual glucocorticoid therapy [31].

In our clinic a plasma exchange at the fibrosing alveolitis began to be applied since 1986. Studied patients with IPF were divided into 2 groups: the main and comparative. The main group included 52 patients, and the control group was made by 25 patients. At 52 surveyed patients with a group basis treatment was carried out by basic drugs (corticosteroids) and PA. 25 patients of comparative group received only corticosteroids. Efficiency of carried-out therapy in both groups estimated on the basis of dynamics of clinical and immunological indicators. As markers of activity of an inflammation the following indicators were used: circulating immune complexes (CIC) (there levels were measured using nephelometric method in polyethylene glycol precipitation reaction). Pro-inflammatory (IL-1β, IL-2, IFNγ) and anti-inflammatory (IL-ra, IL-10) cytokines (test systems of the Protein CounterCompany, St. Petersburg), in peripheral blood serum of patients with IPF were investigated before and after each course PA and in 6 months after it.

Besides, indicators of function of external breath, in particular the vital lung capacity (VLC), were investigated. The diagnosis was made collectively (multidisciplinary approach) with participation of pulmonologists and radiation diagnostics specialists. Patients with pulmonary fibrosis included both their idiopathic forms, as well as those arising against the background of other systemic autoimmune diseases (lupus, rheumatoid arthritis, scleroderma).

The patient of the main group conducted courses PA (4 sessions with intervals 2 days with removal of 700-900 ml of plasma and the general removal it up to 1-1.5 of circulating plasma volumes). Repeated courses PA were performed in 6-12 months [32]. Efficiency of carried-out therapy in both groups estimated on the basis of dynamics of clinical and immunological indicators. All the studied patients were selected randomly, but considering their comparability by the disease severity and the drug therapy type. All of them were observed for a year.

Dynamics of levels of the CIC is presented in table 1, and shifts of various cytokines are visible in table 2.

 

Plasmapheresis courses	The 1st course	In 6 months	In a year
Before course	252.3±12.2	221.2±12,5	198.8±10.3
After course	140.2±9.3*	131.4±8.3*	126.1±7.8*
*changes from initial level are reliable ( p<0.05)

Stages	TNF-α picogram/ml	INF-γ picogram/ml	IL-10  picogram/ml	IL-2 picogram/ml
Before plasmapheresis	35.3±3.36	103±8.45	16.2±1.97	45.6±3.6
After plasmapheresis	28.2±2.21*	41.5±3.98*	23.2±1.73*	40.3±3.6
In 6 months	29.85±2.32	77.48±5.4*	17.25±1.3	42.2±3.7
*changes from initial level are reliable ( p<0.05)

Table 1 shows that after 6 months, of course, there is a rise in the CIC content, but it does not reach the previous level. The same trend continues in the next 6 months. All this can significantly increase the life expectancy of such patients with even lower levels of drug support.

Thus levels and such toxic cytokine as TNF-α, IL-2, and IFN-γ (Table 2) decreased also. However the maintenance of IL-10 increased, but it also was positive shift as this cytokine oppresses activation of macrophages and inhibits production of cytokines by Th-1 lymphocytes. And, these shifts remained even in 6 months after the plasmapheresis course, especially it concerns level of INF-γ. 

The same can be told also about the vital capacity of lungs (Table 3). It is visible that in the course of a plasmapheresis there is an opportunity significantly to restore the vital capacity of lungs while only at medicamentous therapy of it practically doesn't occur.

Groups	Before treatment	In 6 months
Main (n=52)	58.82±1.3	65.13±2.4*
Control (n=25)	55.27±2.5	59.65±1.2
*changes from initial level are reliable ( p<0.05)

It is followed also by gas exchange improvement that is visible on increase of PaO2 after a plasmapheresis, keeping and after the subsequent courses of treatment while in control group there is only its insignificant stabilization (Table 4).

Groups	Before treatment	In 6 months	In the next 6 months
Main (n=52)	69.81±2.3	73.34±3. 9	75.62±2.1*
Control (n=25)	70.22±6.4	70.83±4.8	70.63±5.8
*changes from initial level are reliable ( p<0.05)

The results given above show that tactics accepted at us - plasma exchange courses (4 sessions with the full removal of plasma in volume of 1-1,5 CPV) with intervals between them of half a year lead to increase of the PaO2 level, stabilization of vital capacity of lungs which without this treatment tend to the permanent and progressing decrease. It allows to reduce doses of steroid preparations by 40% and almost completely to avoid purpose of cytostatics that in due time prevents aggravations and keeps the acceptable quality of life and even working capacity of patients within 7-15 years.

Thus it is necessary to consider that decrease in a dose of hormonal preparations can reduce also risk of accession of oncological diseases which meet at patients with a fibrosing alveolitis considerably more often than in the general population, and even bigger frequency, than at smokers [33]. In our previous studies it has already been established that the general life expectancy of these patients significantly increases-from 5.3±0.5 years at the isolated medicamentous therapy, to 9.3±1.1 years at the complex therapy including a plasma exchange [4,5,34].

Improvement of health of patients, though short-term is even surprising, at far come organic damages of lungs, speaking about existence and at a stage of fibrosis of some functional deteriorations. It is, obviously, about the accompanying edema of alveolar partitions of toxic genesis demanding a detoxification.

When fibrosing alveolitis proceeds against the other collagenosis manifestations, distinct clinical improvement is noted and these accompanying symptoms - characteristic skin deteriorations are softened at systemic lupus erythematosus, pains and constraint in a body disappear, mobility of joints at rheumatoid polyarthritis improves, progressing of organic disorders in joints is slowed down.