AGRANULOCYTOSIS (agranulocytosis; Greek negative a-prefix, lat. granulum — a kernel and Greek kytos — a cell; former names — an aleukia, aneytrofilez, a granulophthisis) — the syndrome which is characterized by sharp reduction of quantity or lack of neutrocytes in peripheral blood. And. has no clear borders with a granulocytopenia — clinically asymptomatic state therefore for And. conditionally less than 750 granulocytes in 1 mkl [Andrews, 1969] or total number of leukocytes less than 1000 in 1 mkl accept the content in blood.
For the first time And. it was described in 1922 by W. Schultz. At the same time Fridemann (Friedemann) described agranulocytic quinsy. With broad use of tsntotoksichesky therapy (medicinal and beam), and also a big arsenal of new means frequency And. considerably increased.
Etiology and pathogeny. On origins And. can be myelotoxic and immune.
Myelotoxic And. suppression of growth of prestages of granulocytes in marrow result, including also stem cells. In this regard in blood reduction not only of granulocytes, but also thrombocytes, reticulocytes and lymphocytes is noted. Myelotoxic And. can develop as a result of impact on an organism of ionizing radiation, chemical connections having cytostatic properties (antineoplastic drugs, benzene, etc.), waste products of a fungus like Fusarium breeding in the wintered grain (see the Aleukia alimentary and toxic).
Immune And. develops as a result of the accelerated death of granulocytes under the influence of antileukocytic antibodies; stem cells do not suffer. Antileukocytic antibodies are formed under the influence of the medicines able to play a role of haptens (see Haptens). At repeated introduction of such medicine agglutination of leukocytes appears.
Development of an immune agranulocytosis depends on a dose of drug a little, an important role in its emergence is played by unusual sensitivity of an organism. On the contrary, at myelotoxic And. the crucial role belongs to the size of the damaging influence. Among the drugs causing immune And., the main place belongs to pyramidon. Immune And., besides, can cause Butadionum, acetphenetidiene, quinophan, analginum, Diacarbum, barbamyl, streptocides, PASK, Tubazidum, an Aethoksidum, streptomycin, Pipolphenum and some other drugs. Long reception of drug-hapten can cause destruction not only mature granulocytes, but also myelocytes and promyelocytes. Development autoimmune And., leukopenias are more often, it is observed at collagenoses (especially scattered lupus erythematosus, rhematoid polyarthritis), and also at some infections.
A specific place is held And. at systemic lesions of the hemopoietic device — leukoses (see), hypoplastic anemia (see), and also at metastasises in marrow of a cancer tumor and sarcoma.
Pathological anatomy. Pathoanatomical signs of an agranulocytosis are necrotic - the ulcer changes which are most often found in oral cavities and throats. The almonds increased, friable, a gray and dirty look, with fibrinous imposings and ulcerations. In a soft and hard palate the centers of a necrosis, sometimes with perforation of a soft palate are found. Necrotic changes come to light in skin, in places of injections, in a crotch, around an anus. The centers of a necrosis are described in a conjunctival sac, in slime cost to a cover of a throat, gullet and stomach. At development of a necrosis in a mucous membrane of a small or large intestine, including a worm-shaped shoot, intestinal bleedings, perforation are observed. Necrotic ulcers can be in a wall of a bladder, in generative organs, especially in a wall of a vagina, and also in tissue of a liver and other bodies. Microscopic examination shows that in sites of a necrosis there are no neutrophilic leukocytes. The demarcation strip around a necrosis does not come to light, near sites of a necrosis it is possible to see lympho-histiocytic and plazmokletochny accumulations. Pneumonia has character of fibrinous and hemorrhagic. At the same time fibrinous imposings are located also on a pleura. In a zone of pneumonia sites of disintegration of fabric (gangrene) can come to light. Microscopically in gleams of alveoluses desquamated cells of an epithelium, a bacterium, yeast cells and their mycelium are visible. Limf. nodes are usually not increased. At necrotic changes in an oral cavity small increase cervical and submaxillary limf can be observed. nodes. Their microscopic structure is rather kept. In a bast layer and especially in the field of brain tyazhy a large number of plasmocytes comes to light. Proliferation and swelling of cells of a reticuloendothelium in sine is sharply expressed. The spleen is not changed a thicket. Tissue of a spleen of a softish consistence, on a section — a pulp of pink-gray color with big scraping. At microscopic examination uniform reduction of quantity of cells of a red pulp of a spleen attracts attention. Marrow of flat bones it is macroscopic more often than a usual look, it is a little dryish, but there can be various centers of hemorrhage — from small to extensive; in the lower and average third of tubular bones marrow fatty.
Microscopically the small centers of a rassasyvaniye of bone beams with formation of small lacunas come to light. In zones of a rassasyvaniye of a bone proliferation of osteoblasts can be observed. Ratio of fatty and hemopoietic tissue variously. More often reduction of number of the hemopoietic cells and increase in quantity of lipoblasts of marrow takes place. In cellular structure sharp reduction of number of young, band and segmentoyaderny granulocytes attracts attention. Dominance of young forms of granulocytes can be observed a nek-swarm. Megakarpotsita and a cell of a red row, as a rule, remain. At the heaviest current And. a picture of marrow the same, as at it on plastic anemia (see).
Clinical picture. Myelotoxic And. begins gradually: without any subjective signs. Immune And. can clinically have various options depending on the factor which caused it. And. against the background of collagenose develops gradually and differs in persistence of a current. Beginning medicamentous immune And. in most cases acute.
First manifestations of any And. fever, stomatitis, quinsy are. At a myelotoxic syndrome also usually moderately expressed hemorrhagic syndrome (bruises and bleeding of gums, nasal bleedings) is noted: the expressed hemorrhagic syndrome — an infrequent complication And. Damage of mucous membranes (necroses and the milkwoman) oral cavities also went. - kish. a path — the most constant sign And. At myelotoxic And. it is caused by the fact that, on the one hand, disappearance of granulocytes does possible a microbic invasion, with another — suppression of mitoses of epithelial cells of a mucous membrane cytostatic factors breaks its integrity.
In peripheral blood the quantity of all forms of leukocytes (quite often to hundreds of cells in 1 mkl), and also thrombocytes and reticulocytes decreases. The number of plasmocytes is usually increased. There can be anemia. Sometimes granulocytes disappear completely. A leukopenia at immune And. has moderate character — 1000 — 2000 cells in 1 mkl, but the quantity of granulocytes, as a rule, decreases to zero; thrombocytopenia is absent. In serum antileukocytic antibodies are found.
At height myelotoxic And. in marrow both granulotsitarny elements, and erythronormoblasts, megacaryocytes almost completely disappear; lymphoid, reticular and plasmocytes remain. In 2 — 3 days prior to escaping of a state And. in marrow promyelocytes and single normoblasts appear in a huge number. In peripheral blood the first sign of activation of a hemopoiesis is detection of young elements — myelocytes and metamyelocytes, sometimes plasmocytes. Often in 2 — 3 days prior to emergence of granulocytes the number of thrombocytes and reticulocytes increases.
In marrow at immune And. reduction of cellular elements only at the expense of a granulotsitarny sprout is noted. Escaping immune And. it is characterized by emergence in peripheral blood of young cells — myelocytes, metamyelocytes, sometimes promyelocytes.
Duration And. it is various and depends both on extent of damage of marrow, and on specific features of an organism of the patient.
Complications. The most frequent — sepsis (quite often staphylococcal), a perforation of intestines (is more often than an ileal gut since it is more sensitive to cytostatic influence), a mediastinitis, pneumonia, a noma; more rare — heavy hypostasis of a mucous membrane of a gut with formation of impassability, peritonitis. A serious complication is acute epithelial hepatitis which often develops after A. Otsutstviye's elimination of granulocytes gives an originality to a current of infectious complications — lack of abscesses, dominance of necroses. Pneumonia proceeds against the background of scanty physical data: obtusion is hardly noticeable, rattles, the expressed bronchial breath can not be, only crepitation over area of defeat is listened. Radiological changes very scanty.
The diagnosis is made on the basis of anamnestic data, a characteristic clinical picture, data of a research of peripheral blood and punctate of marrow. Diagnosis immune And. it can be confirmed with serological researches: detection of antileukocytic antibodies (see Blood groups, leukocytic groups). And. it is necessary to differentiate from an acute leukosis in an aleukemic stage and hypoplastic anemia. In the first case in diagnosis studying of punctate of marrow, the second — the indication of a pas suddenness of development is decisive And. at its immune nature or data on long administration of drugs of myelotoxic action (sometimes interrupted several weeks prior to development And.). Overseeing by the patient allows to come to final conclusion about character of devastation of marrow.
Forecast in most cases myelotoxic And. In the conditions of an asepsis and timely powerful antibiotic therapy favorable. Sharply the necrotic enteropathy, and also heavy septic complications worsen the forecast. The forecast at immune And. a medicamentous origin in the conditions of timely cancellation of drug-hapten, therapy by steroid hormones and at observance of all rules of maintaining such patients in most cases favorable.
Treatment And. any origin demands immediate elimination of the reason which caused it: cytostatic drug, ionizing radiation, the medicine hapten provoking an immune game flikt, etc. Therapy And., the pseudorheumatism complicating a current or a scattered lupus erythematosus, first of all it has to be directed against a basic disease.
At myelotoxic And. steroid hormones are not shown. At decrease in number of leukocytes to 50 — 200 cells in 1 mkl replacement therapy — transfusion of a leukocyte concentrate is necessary. In one step pour more than 15 — 20 billion cells. At oncological patients the good effect is noted during the use of the leukocyte weight received from patients with hron. a myeloleukemia in the developed stage of a disease. Bone marrow transplantation is used only at acute total exposition in the doses exceeding 600 I am glad on marrow. Along with use of pathogenetic means use pisimptomatichesky therapy: in case of a persistent hyperthermia to 39 — 40 ° at miyelotokspchesky And. (but not immune!) patients are given analginum to 2 — 3 g a day or acetilsalicylic to - they are 2 g a day.
In treatment immune And. the crucial role belongs to Prednisolonum in a dose of 1 — 1,5 mg on 1 kg of weight of a pla to its analogs in adequate doses, and in the absence of effect — is 2 — 3 times more. At severe damage of mucous membranes the drug is administered parenterally. A course — 7 — 10 days of a pla before elimination And. Replacement therapy by transfusions of leukocyte weight is shown only at infectious complications.
For prevention of an infection of patients it is necessary to place in boxes or isolation centers where aseptic conditions are created (see Chamber medical). Prevention of infectious complications antibiotics is necessary during the falling of number of granulocytes to 750 in 1 mkl. Inside appoint not absorbed antibiotic Neomycinum to 2 — 3 g a day (against colibacillus), polymyxin B on 150 — 200 mg a day (against a pyocyanic stick). Besides, appoint an antibiotic of a broad spectrum of activity — Garamycinum intramusculary on 40 — 80 mg 2 — 3 times a day, or Oxacillinum on 4 — 6 g a day inside, or Oletetrinum to 2 g a day inside. It is obligatory to accept nystatin to 10 000 000 — 15 000 000 PIECES a day. For systematic rinsing of a mouth use solution of levorinum 1: 500. Sores on a mucous membrane of a mouth and lips are oiled sea-buckthorn. At development of staphylococcal sepsis administration of anti-staphylococcal gamma-globulin, anti-staphylococcal plasma is shown. At emergence of ponos, abdominal distentions, persistent severe pains in a stomach of the patient it is necessary to translate on parenteral Nov food, there is necessary an observation of the surgeon. The perforation of ulcers of intestines which is characterized by weak signs of irritation of a peritoneum, the accruing abdominal distention, fading of a vermicular movement of intestines, emergence of an exudate in an abdominal cavity does necessary an urgent operative measure.
Prevention myelotoxic And. consists in careful hematologic control during therapy by cytostatic drugs. At reduction of quantity of leukocytes to 1000 — 1500 in 1 mkl or their bystry decrease it is necessary to stop cytostatic therapy or to take a break in treatment. At the same time at leykopenichesky options of an acute leukosis therapy should be carried out by small or average doses of cytostatic drugs, despite of low figures of leukocytes, being guided by their dynamics and level of thrombocytes. Persistent decrease in the last testifies to need of a break for cytostatic treatment. Prevention immune And. it is directed to an exception of repeated administration of drugs, earlier appeared the reason And. at this patient.
Agranulocytosis at children. In development And. at children the same mechanisms, as at adults play a role. Clinical picture myelotoxic and immune And. that corresponds at adults.
Children at early age rather seldom have peculiar neutropenias which on clinical features, in many respects remind complications a picture A. Two main types of neutropenias are known: constant and periodic.
The constant neutropenia described by Kostmann is characterized by emergence at early children's age of the repeating purulent diseases: abscesses on skin, in lungs, otitises, etc. With the advent of teeth develops amfodontoz, conducting to early dedentition. In blood the neutropenia at normal or a little reduced quantity of leukocytes is noted. Indicators of red blood and thrombocytes are not changed. This form of a disease is inherited on recessive type. Isolated cases of the similar disease proceeding more softly, inherited are described it is prepotent [Hittsig, 1959]. In marrow the stop of maturing of neutrophils on stages of promyelocytes, the increased percent of monocytes and eosinophils is noted.
The periodic neutropenia is characterized by regular rises in temperature, flashes of purulent processes, disappearance of mature neutrophils from blood and marrow. The Neytropenichesky period proceeds several days, then the normal picture of blood is recovered. In the period of a neutropenia the picture of blood and marrow corresponds that at a constant form. In most cases the disease is inherited on recessive type [Page with sotr., Videbek, is more rare on dominant.
Along with hereditary forms also the passing inborn neutropenia [Stefanini (M. of Stefanini)) at babies whose mothers suffer from a granulocytopenia is described.
Treatment of an agranulocytosis at children is carried out by the same rules, as at adults. In treatment of hereditary neutropenias the major role belongs to antibiotics which are appointed at a periodic form in 2 — 3 days prior to the expected crisis to the entire period of a neutropenia. At a constant neutropenia antibiotic therapy is carried out in connection with purulent complications. The leading place belongs to antistaphylococcal drugs, and also antibiotics of a broad spectrum of activity: to Oxacillinum, Methicillinum, tseporin, etc. With introduction of massive antibiotic therapy the lethality in the first years of life — the most dangerous period of a disease sharply decreased; further the disease proceeds slightly more softly, patients live up to mature age. Except the general therapy, systematic sanitation of an oral cavity, care of gingivas is carried out.
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