Plasmapheresis for the treatment of idiopathic pulmonary fibrosis

The interstitial pulmonary diseases are made by 10–15% in structure of all diseases of lungs. More than 130 diseases of a known and unknown etiology concern to them. One of the most widespread and predictively adverse diseases is the idiopathic pulmonary fibrosis (IPF) [3].
IPF – a disease in which development the main role is played by immune mechanisms to what presence of the activated lymphocytes and macrophages in lungs testifies. Essential deviations from norm are defined and in system of humoral immunity. Immunoglobulins of three main classes (A, G and M) and the circulating immune complexes (CIC) serve as criterion of intensity of autoimmune processes in an organism [3, 5]. Therefore research of changes of indicators of the immunological status at IPF is important in the solution of questions of medical tactics.
Basis of treatment of IPF are corticosteroids, sometimes in combination with immunosupressants and anti-fibrous drugs (D-penicillamin, etc.), along with medicines are used also efferent methods of treatment, mainly, a plasmapheresis (PA). The positive effect of PA consists in elimination autoantibodies (AB) and immune complexes circulating in blood which play an important role in IPA development. PA increases sensitivity to corticosteroids [4], deleting AB and CIC, improves microcirculation, promotes normalization of the main metabolic processes [1, 6]. However and so far efficiency of separate efferent methods at IPF raised doubts, pathogenetic mechanisms of action of PA aren't proved at this disease.
The purpose of the real research was to estimate efficiency of PA at patients with IPF.
Materials and methods.
In clinic of pulmonology 77 patients with IPF (from them 70% of women and 30% of men) are surveyed. Average age of patients made 55,6±2,1 years, disease duration – 5,3±1,2 years, treatment duration – 4,4±1,8 years. At all investigation phases for an assessment of a clinical condition the 6-minute walking test was carried out. As markers of activity of an inflammation the following indicators were used: CIC, immunoglobulins A, G, M, E, pro-inflammatory (IL-1β, IL-2, IFNγ) and anti-inflammatory (IL-ra, IL-10) cytokines, in peripheral blood of patients with IPF  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.
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.
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 volumes of circulating plasma). RepeatedcoursesPAwereperformedin 6-12 months [2].
The main group of patients (52 patients) was divided into 2 subgroups, depending on extent of decrease in indicators of VLC.
16 patients (30,7%) at whom VLC made <50% from due sizes (<50% D) entered into the I subgroup, and at the time of the inspection beginning the average value of VLC was 49,44%.
In the II subgroup made 36 patients (69,3%) who had initial VLC ≥ 50% from due size and the average value of VLC was 67,7%.
In comparative group (25 patients) the initial average value of VLC was 55,2% from due size.
Results and discussion
Results of researches of humoral immunity – levels of immunoglobulins A, G, M and the maintenance of CIC in peripheral blood at patients with IPF (before and after course PA and in 6 months after it) are given in table 1.                   
Levels of immunoglobulins and CIC in peripheral blood of patients with IPF

Group Period IgA
Mkg/ml
IgG
Mkg/ml
IgM
Mkg/ml
CIC
%
Donors
n=20
1.9±0.09 9.8±0.7 1.3±0.1 80.0±7.7
Main
n=41
Initial 2.10±0.11 10.68±0.86 1.60±0.12 146.6±13.8
After PA 1.82±0.09 7.03±0.71 0.83±0.08 96.7±8.8
In 6 month 1.92±0.12 9.02±0.82 1.33±0.09 122.8±9.3
Comparative
n=22
Initial 3.4±1.3 12.1±1.9 1.3±0.09 110.3±10.8
In 6 month 3.7±1.6 14.1±1.6 1.5±0.4 116.7±11.2

Apparently from tab. 1, for patients with IPF the raised content in blood of immunoglobulins and CIC is characteristic. During carrying out PA gradual decrease in the maintenance of these indicators in peripheral blood was observed. In 6 months they increased again, however didn't reach initial level while in group of control all these indicators tended to increase.
Activity of cellular immunity is realized through cytokines, allocated by lymphocytes and defining intensity of a local immune inflammation in tissues of target organs (in this case – lungs). Results of these researches are given in table 2.
Levels of cytokines in peripheral blood of patients with  IPF before and after carrying out PA

Group Period IL-2
pg/ml
IL-1β
pg/ml
IFN-γ
pg/ml
IL-10
pg/ml
IL-ra
pg/ml
Donors
n=10
15.0±1.36 17.7±0.72 76.5±8.3 4.92±1.11 306.2±19.2
Main
n=15
Initial 34.69±3.5 23.51±2.1 183.9±15.4 5.90±0.81 187.65±14.6
After PA 26.44±2.8 14.66±1.3 127.05±10.2 6.48±0.5 331.5±29.5
In 6 month 31.2±2.9 20.8±1.7 168.6±14.3 10.8±1.3 294.0±24.9
Comparative
n=11
Initial  29.0 ± 1.9 38.6 ± 1.3     275.3 ± 11.8
In 6 month 27.9 ±2.2 41.2 ± 1.5     245.7 ± 9.7

Apparently from table 2, in the contents analysis pro- and anti-inflammatory cytokines during  PA similar regularity was observed. Before PA levels pro-inflammatory cytokines (IL-2, IL-1β, IFN-γ) were above normal values, the contents anti-inflammatory (IL-ra, IL-10) cytokines was in limits or norms are lower.
During carrying out PA the contents pro-inflammatory cytokines decreased, but also in 6 months yet didn't reach initial level. However the contents pro-inflammatory cytokines, mainly IL-ra, on the contrary, increased, remaining above initial level and in 6 months after treatment. On the other hand, in control group  the return picture was observed – the IL-1β level increased, and IL-ra continued to decrease.
All this found reflection and on dynamics of the main clinical indicators of severity of IPF. In particular, the analysis of results of research of such key indicator of function of external breath as the vital capacity of lungs it is presented in tab. 3.
VCL indicators at the patients with IPF during treatment.

Group Subgroup Initial level
(%)
VCL
after PA (%)
VCL
in 6 month (%)
Main
n=52
I
n = 16
49.44 ± 1.2 49.48 ± 0.9 52.67 ± 1.1
II
n = 36
67.72 ± 1.4 71.05 ± 1.6 78.5 ± 1.3
Comparative
n = 25
55.27 ± 2.1 _____________ 59.65 ± 1.2

Apparently from table 3, in the I subgroup directly after course PA and at control inspection in 6 months – VCL significantly didn't change, but, nevertheless, the tendency to increase was noted.
In the II subgroup already right after performance of PA the tendency to increase VCL which  proceeding  and  during  the  subsequent  period  and  has made  in 6 months  of 78.5%  (р <0.05) was observed.
In comparative group at control inspection in 6 months the average value of VCL was only 59.65%.
The analysis of gas composition of blood showed a tendency to increase of PaO2 in 6 months after PA (from 69.8±7.3 up to 73.3±6.9 mm Hg) while in control group the opposite picture was most often observed. Thus, in cases of regular repetition of courses PA through such intervals bigger increase of PaO2 to 75.6±7.1 mm Hg in a year from an initiation of treatment was observed still.
Stabilization of a condition of patients allowed them by whom course PA was performed, to lower doses of corticosteroids support. The average dose of corticosteroids in the main group before PA averaged 20 mg per day counting on Prednisolonum, and in 6 months the need for it decreased to 15 mg per day. Patients of comparative group initially received corticosteroids in the same daily dose of 20 mg, however in 6 months this dose should be increased to 25 mg per day due to the emergence of signs of progressing of an illness. Therefore, maintenance of a stable condition from patients with IPF when using PA demands much smaller doses of basic drugs, than from patients without PA.


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