STUDY - Technical - New Dacian's Medicine
Pathological
Changes of Granulocytes and Monocytes (2)
Translation Draft
We continue, as we announce, with neutrophil anomalies.
We continue, as we announce, with neutrophil anomalies.
A malfunction occurring at
any time in the evolution of neutrophils can lead to malfunction
and compromise of the host's defense. Inflammation is often
suppressed, the clinical result being frequently recurrent
bacterial and fungal infections, which make it difficult to
approach the therapeutic. Diagnosis of phagocytic cell disorder
is suggested by clinical evaluation. Foot-and-mouth ulcers of
the mucous membranes (grey ulcerations without pus), gingivitis
and periodontal diseases are common.
Patients with congenital phagocytic defects may experience infections from the first days of life. Skin infections in the ear, respiratory and lower tract and bones are common. Septicemia and meningitis are rare. In some disorders, the frequency of infections is variable and patients may experience periods of months or even years without a major infection. People with birth defects rarely lived more than 30 years in the past. However, the aggressive therapeutic approach extended life expectancy in these patients.
The consequences of the lack of neutrophils (neutropenia) constitute dramatic proof of their importance in defending the host. A large number of clinical data indicate that susceptibility to infections increases significantly when the number of neutrophils drops below 1,000 cells per cubic millimeter. When the total number of neutrophils (NTN - young forms and associated mature neutrophils) decreases below 500 cells per cubic millimeter, the control of endogenous microbial flora (e.g. oral, intestinal, etc.) is disturbed and when there are less than 200 cells per cubic millimeter the inflammatory process is absent.
The causes of neutropenia are related to decreased production, increased peripheral destruction or excessive enlargement of the peripheral compartment. A collapse in or significant decrease in the number of neutrophils below stability levels, together with an inability to increase the number of neutrophils at the onset of infection or at another request of bone marrow reserve should be investigated. Acute neutropenia, that caused by chemotherapy in neoplasm, is more likely to be associated with an increased risk of infection than long-term neutropenia (months or years) which disappears in response to infection or after carefully controlled endotoxin administration.
Some of the causes of inherited or acquired neutropenia are represented by: 1. low production (a. medicinally induced by alkilants such as nitrogen mustard, busulfan, chlorambucil or cyclophosphamide, antimetabolites like methotrexate, 6-mercaptopurin or 5-flucytosine, noncytotoxic agents such as chloramphenicol, penicillinor or sulfonamide, phenothiazine, tranquilizers like meprobat, anticonvulsants such as carbazepin, antipsychotics such as clozapine, some diuretics, anti-inflammatory agents, antithyroid drugs and many, many others, b. haematological diseases such as idiopathic ones, cyclic neutropenia, Chediak-Higashi syndrome, aplastic anaemia or infantile disorder, c. tumor invasions and myelofibrosis, d. nutritional deficiencies such as vitamin B12 and folates, especially in alcoholics and e. infections such as tuberculosis , typhoid fever, brucellosis, tularemia, measles, infectious mononucleosis, malaria, viral hepatitis, leishmaniosis or AIDS), 2. peripheral destruction (with a. anti-neutrophil antibodies and/ or sequestration in the spleen or lungs - alveolar macrophages, b. autoimmune diseases such as Felty syndrome, rheumatoid arthritis and lupus erythematosus, c. drugs like haptenes - aminopiridine, alpha-methyl dopa, phenylbutazone, mercuarial diuretics and some phenothiazides, and d. granulomatosis Wegener) and 3. peripheral accumulation/ transient neutropenia (with a. generalised bacterial infection - acute endotoxemia, b. hemodialysis and c. cardiopulmonary bypass). The most common neutropenias are iatrogenic, caused by the widespread use of immunosuppressive therapy in neoplasm or for the control of autoimmune diseases.
These drugs cause neutropenia because they are toxic and lead to decreased production of rapidly growing precursor (stem) cells in the bone marrow. Cytotoxic chemotherapies fall into this category, but also a number of antibiotics such as chloramphenicol, trimetoprim-sulfamethoxazole, flucytosine, vidarabine and the antiretroviral drug zidovudine can cause neutropenia by inhibiting myeloid precursors. The suppression of the marrow is generally dependent on the dose and continuous administration of the drug. The human recombinant granulocytes colony stimulation factor (G-CSF) is an important medicine for the improvement of this form of neutropenia and is particularly useful in cancer chemotherapy.
Another important mechanism of iatrogen-inducing neutropenia is the effect of drugs that serve as immune haptenes, sensitizing peripheral neutrophils or neutrophil precursors to immune-mediated peripheral destruction. This form of drug-induced neutropenia can be observed after 7 days of administration of the drug (when there is a previous exposure to this drug, which caused the formation of antibodies, neutropenia may occur within a few hours).
Although any drug can cause this form of neutropenia, the most common are widely used antibiotics such as sulfamides, penicillins and cephalosporins. Fever and eosinophilia may also be associated with the reaction to medications, but these signs are usually missing. Drug-induced neutropenia can be severe, but discontinuation of the sensitizing drug is sufficient for recovery, which generally occurs after 5-7 days and is complete after 10 days.
Readministration of the sensitising drug should be avoided, since acute neutropenia may occur. For this reason, diagnostic sensitivity testing should be avoided in most cases. Autoimmune neutropenias caused by circulating antineutrophil antibodies are another form of acquired neutropenia leading to mass destruction of neutrophils. Acquired neutropenia can also be found in viral infections, including human immunodeficiency virus. Rarely, acquired neutropenia can be cyclical in nature, occurring every few weeks. Acquired cyclic neutropenia may be associated with an increase in NK cells and may respond to corticosteroid therapy.
Syndromes have been described in which the expansion of large granulocytes (LGL) is associated with neutropenia. Patients with LGL lymphocytosis may have moderate blood and medullary lymphocytosis, neutropenia, polyclonal hypergamaglobulinemia, splenomegaly and the absence of adenopathy. These patients may have a chronic and relatively stable development. Recurrent bacterial infections are relatively common. There are both malignant and benign forms of this syndrome. In some patients, spontaneous regression occurred even after 11 years, suggesting that at the base of at least one form of this disease is an immunoregulation defect.
Hereditary neutropenias are rare and manifest in early childhood, as a deep and constant agranulocytosis or neutropenia. Examples of congenital forms of neutropenia are Kostmann syndrome, which is commonly fatal (less than 100 neutrophils per microlitre), chronic idiopathic neutropenia, less serious (300 - 1,500 neutrophils per microlitre), hypoplasia-cartilage-hair syndrome, Shwachman syndrome associated with pancreatic insufficiency and neutropenias associated with other immune defects (X-linked agamaglobulinemia, telcalitangian ataxia, IgA deficiency).
Recently, severe forms of congenital neutropenia have been identified, in which a mutation of the G-CSF receptor, encoded on chromosome 1, appears, which causes a low response of G-CSF and apparently predisposes to the development of myeloid myeloplasm. Cyclical hereditary neutropenia, transmitted autosomal dominantly, can occur in childhood and is characterized by a remarkably regular 3-week cycle. Cyclical hereditary neutropenia is, in fact, a cyclic hematopoiesis. Although the mechanism of congenital cyclic neutropenia is unknown, corticosteroids and G-CSF strengthen cycles in some patients. Maternal factors may be associated with neutropenia in newborns.
Transplaneceal transfer of IdG against fetal neutrophil antigens may lead to peripheral destruction. Medications (e.g. thiazides) ingested during pregnancy can cause neutropenia in the newborn either by suppressing production or by peripheral destruction. The presence of anti-neutrophil immunoglobulins is found in Felty syndrome (rheumatoid arthritis-splenomegaly-neutropenia triad). Patients responding to splenectomy by increasing the number of neutrophils present postoperative and lower serum levels of IgG-neutrophil complexes, suggesting that one of the beneficial effects of splenectomy is the decrease of anti-neutrophil antibodies. Splenomegaly with the seizure and peripheral destruction of neutrophils is also found in lysosome deposit disease and portal hypertension.
Neutrophilia occurs by increasing production, release from the marrow or insufficient margin of neutrophils. The most "known" causes of neutrophilia are represented by: 1. increased production (with a. idiopathic, b. drug-induced - glucocorticoids, c. infections - bacterial, fungal, rarely viral, d. inflammation - thermal lesion, tissue necrosis, pulmonary or myocardial infarction, hypersensitivity states, vascular collagen diseases and e. myeloproliferative diseases - myeloid leukemia, myeloid metaplasia and polycytemia vera), 2. increased mobilization of the marrow (glucocorticoids, acute infection - endotoxins, inflammation - thermal lesion), 3. insufficient margin (with a. drugs - epinephrine, glucocorticoids, nonsteroidal anti-inflammatory agents, b. stress, emotions, marked physical exertion, c. leukocytic adhesion deficiency type 1 - beta chain of integrins, CD18, leukocytic adhesion deficiency type 2 - ligand selectin, CD15s, sialyl-Lewis) and 4. other causes (with a. metabolic disorders - ketoacidosis, acute renal failure, eclampsia, acute intoxication, b. drugs - lithium and c. others - metastatic carcinoma, hemolysis or acute hemorrhage).
The most important acute cause of neutrophilia, requiring prompt medical attention, is infection. Neutrophilia from infection occurs both by increasing production and release from the marrow. Increased production is also associated with chronic inflammation and some myeloproliferative diseases. Increased release from the marrow and mobilisation of bordered leukocytes is induced by glucocorticoids. The release of norepinephrine in sustained physical exertion, emotion or stress will mobilize the bordered neutrophils in the spleen and lungs and double their number. Leukocytosis of 10,000-25,000 cells per microlitre occurs in response to infection and other forms of acute inflammation and is determined by both the mobilization of medullary reserves and the release of bordered leukocytes. Persistent neutrophilia of 30,000-50,000 cells per microlitre or more is called leucemoid reaction, a term that distinguishes between this type of neutrophilia and leukemia. In a leucemoid reaction, circulating neutrophils are usually mature and not clonal derivatives.
We'll continue to the next post with the functional anomalies of the neutrophils...
Patients with congenital phagocytic defects may experience infections from the first days of life. Skin infections in the ear, respiratory and lower tract and bones are common. Septicemia and meningitis are rare. In some disorders, the frequency of infections is variable and patients may experience periods of months or even years without a major infection. People with birth defects rarely lived more than 30 years in the past. However, the aggressive therapeutic approach extended life expectancy in these patients.
The consequences of the lack of neutrophils (neutropenia) constitute dramatic proof of their importance in defending the host. A large number of clinical data indicate that susceptibility to infections increases significantly when the number of neutrophils drops below 1,000 cells per cubic millimeter. When the total number of neutrophils (NTN - young forms and associated mature neutrophils) decreases below 500 cells per cubic millimeter, the control of endogenous microbial flora (e.g. oral, intestinal, etc.) is disturbed and when there are less than 200 cells per cubic millimeter the inflammatory process is absent.
The causes of neutropenia are related to decreased production, increased peripheral destruction or excessive enlargement of the peripheral compartment. A collapse in or significant decrease in the number of neutrophils below stability levels, together with an inability to increase the number of neutrophils at the onset of infection or at another request of bone marrow reserve should be investigated. Acute neutropenia, that caused by chemotherapy in neoplasm, is more likely to be associated with an increased risk of infection than long-term neutropenia (months or years) which disappears in response to infection or after carefully controlled endotoxin administration.
Some of the causes of inherited or acquired neutropenia are represented by: 1. low production (a. medicinally induced by alkilants such as nitrogen mustard, busulfan, chlorambucil or cyclophosphamide, antimetabolites like methotrexate, 6-mercaptopurin or 5-flucytosine, noncytotoxic agents such as chloramphenicol, penicillinor or sulfonamide, phenothiazine, tranquilizers like meprobat, anticonvulsants such as carbazepin, antipsychotics such as clozapine, some diuretics, anti-inflammatory agents, antithyroid drugs and many, many others, b. haematological diseases such as idiopathic ones, cyclic neutropenia, Chediak-Higashi syndrome, aplastic anaemia or infantile disorder, c. tumor invasions and myelofibrosis, d. nutritional deficiencies such as vitamin B12 and folates, especially in alcoholics and e. infections such as tuberculosis , typhoid fever, brucellosis, tularemia, measles, infectious mononucleosis, malaria, viral hepatitis, leishmaniosis or AIDS), 2. peripheral destruction (with a. anti-neutrophil antibodies and/ or sequestration in the spleen or lungs - alveolar macrophages, b. autoimmune diseases such as Felty syndrome, rheumatoid arthritis and lupus erythematosus, c. drugs like haptenes - aminopiridine, alpha-methyl dopa, phenylbutazone, mercuarial diuretics and some phenothiazides, and d. granulomatosis Wegener) and 3. peripheral accumulation/ transient neutropenia (with a. generalised bacterial infection - acute endotoxemia, b. hemodialysis and c. cardiopulmonary bypass). The most common neutropenias are iatrogenic, caused by the widespread use of immunosuppressive therapy in neoplasm or for the control of autoimmune diseases.
These drugs cause neutropenia because they are toxic and lead to decreased production of rapidly growing precursor (stem) cells in the bone marrow. Cytotoxic chemotherapies fall into this category, but also a number of antibiotics such as chloramphenicol, trimetoprim-sulfamethoxazole, flucytosine, vidarabine and the antiretroviral drug zidovudine can cause neutropenia by inhibiting myeloid precursors. The suppression of the marrow is generally dependent on the dose and continuous administration of the drug. The human recombinant granulocytes colony stimulation factor (G-CSF) is an important medicine for the improvement of this form of neutropenia and is particularly useful in cancer chemotherapy.
Another important mechanism of iatrogen-inducing neutropenia is the effect of drugs that serve as immune haptenes, sensitizing peripheral neutrophils or neutrophil precursors to immune-mediated peripheral destruction. This form of drug-induced neutropenia can be observed after 7 days of administration of the drug (when there is a previous exposure to this drug, which caused the formation of antibodies, neutropenia may occur within a few hours).
Although any drug can cause this form of neutropenia, the most common are widely used antibiotics such as sulfamides, penicillins and cephalosporins. Fever and eosinophilia may also be associated with the reaction to medications, but these signs are usually missing. Drug-induced neutropenia can be severe, but discontinuation of the sensitizing drug is sufficient for recovery, which generally occurs after 5-7 days and is complete after 10 days.
Readministration of the sensitising drug should be avoided, since acute neutropenia may occur. For this reason, diagnostic sensitivity testing should be avoided in most cases. Autoimmune neutropenias caused by circulating antineutrophil antibodies are another form of acquired neutropenia leading to mass destruction of neutrophils. Acquired neutropenia can also be found in viral infections, including human immunodeficiency virus. Rarely, acquired neutropenia can be cyclical in nature, occurring every few weeks. Acquired cyclic neutropenia may be associated with an increase in NK cells and may respond to corticosteroid therapy.
Syndromes have been described in which the expansion of large granulocytes (LGL) is associated with neutropenia. Patients with LGL lymphocytosis may have moderate blood and medullary lymphocytosis, neutropenia, polyclonal hypergamaglobulinemia, splenomegaly and the absence of adenopathy. These patients may have a chronic and relatively stable development. Recurrent bacterial infections are relatively common. There are both malignant and benign forms of this syndrome. In some patients, spontaneous regression occurred even after 11 years, suggesting that at the base of at least one form of this disease is an immunoregulation defect.
Hereditary neutropenias are rare and manifest in early childhood, as a deep and constant agranulocytosis or neutropenia. Examples of congenital forms of neutropenia are Kostmann syndrome, which is commonly fatal (less than 100 neutrophils per microlitre), chronic idiopathic neutropenia, less serious (300 - 1,500 neutrophils per microlitre), hypoplasia-cartilage-hair syndrome, Shwachman syndrome associated with pancreatic insufficiency and neutropenias associated with other immune defects (X-linked agamaglobulinemia, telcalitangian ataxia, IgA deficiency).
Recently, severe forms of congenital neutropenia have been identified, in which a mutation of the G-CSF receptor, encoded on chromosome 1, appears, which causes a low response of G-CSF and apparently predisposes to the development of myeloid myeloplasm. Cyclical hereditary neutropenia, transmitted autosomal dominantly, can occur in childhood and is characterized by a remarkably regular 3-week cycle. Cyclical hereditary neutropenia is, in fact, a cyclic hematopoiesis. Although the mechanism of congenital cyclic neutropenia is unknown, corticosteroids and G-CSF strengthen cycles in some patients. Maternal factors may be associated with neutropenia in newborns.
Transplaneceal transfer of IdG against fetal neutrophil antigens may lead to peripheral destruction. Medications (e.g. thiazides) ingested during pregnancy can cause neutropenia in the newborn either by suppressing production or by peripheral destruction. The presence of anti-neutrophil immunoglobulins is found in Felty syndrome (rheumatoid arthritis-splenomegaly-neutropenia triad). Patients responding to splenectomy by increasing the number of neutrophils present postoperative and lower serum levels of IgG-neutrophil complexes, suggesting that one of the beneficial effects of splenectomy is the decrease of anti-neutrophil antibodies. Splenomegaly with the seizure and peripheral destruction of neutrophils is also found in lysosome deposit disease and portal hypertension.
Neutrophilia occurs by increasing production, release from the marrow or insufficient margin of neutrophils. The most "known" causes of neutrophilia are represented by: 1. increased production (with a. idiopathic, b. drug-induced - glucocorticoids, c. infections - bacterial, fungal, rarely viral, d. inflammation - thermal lesion, tissue necrosis, pulmonary or myocardial infarction, hypersensitivity states, vascular collagen diseases and e. myeloproliferative diseases - myeloid leukemia, myeloid metaplasia and polycytemia vera), 2. increased mobilization of the marrow (glucocorticoids, acute infection - endotoxins, inflammation - thermal lesion), 3. insufficient margin (with a. drugs - epinephrine, glucocorticoids, nonsteroidal anti-inflammatory agents, b. stress, emotions, marked physical exertion, c. leukocytic adhesion deficiency type 1 - beta chain of integrins, CD18, leukocytic adhesion deficiency type 2 - ligand selectin, CD15s, sialyl-Lewis) and 4. other causes (with a. metabolic disorders - ketoacidosis, acute renal failure, eclampsia, acute intoxication, b. drugs - lithium and c. others - metastatic carcinoma, hemolysis or acute hemorrhage).
The most important acute cause of neutrophilia, requiring prompt medical attention, is infection. Neutrophilia from infection occurs both by increasing production and release from the marrow. Increased production is also associated with chronic inflammation and some myeloproliferative diseases. Increased release from the marrow and mobilisation of bordered leukocytes is induced by glucocorticoids. The release of norepinephrine in sustained physical exertion, emotion or stress will mobilize the bordered neutrophils in the spleen and lungs and double their number. Leukocytosis of 10,000-25,000 cells per microlitre occurs in response to infection and other forms of acute inflammation and is determined by both the mobilization of medullary reserves and the release of bordered leukocytes. Persistent neutrophilia of 30,000-50,000 cells per microlitre or more is called leucemoid reaction, a term that distinguishes between this type of neutrophilia and leukemia. In a leucemoid reaction, circulating neutrophils are usually mature and not clonal derivatives.
We'll continue to the next post with the functional anomalies of the neutrophils...
Until then, understanding,
love and gratitude!
Dorin, Merticaru