Introduction to neutropenia

Introduction

Neutropenia(neutrophilic granuloaytopenia) is the absolute count of peripheral blood neutrophils (total number of white blood cells × percentage of neutrophils), less than 1.5 × 109 / L for children <10 years old, and less than 1.8 × 109 / L for children aged 10-14 years Adults are below 2.0 x 109/L. When granulocytes are severely reduced, below 0.5 × 109 / L, called agranulocytosis.

Cause

(1) Causes of the disease

There are many causes of neutropenia. According to the different parts of the action, it can be summarized into the following three aspects:

Act on the bone marrow

(1) bone marrow injury: 1 drug: including cytotoxic and non-cytotoxic drugs; 2 radiation; 3 chemical substances: such as benzene, DDT, dinitrophenol, arsenic acid, strontium, nitric oxide, etc.; 4 some congenital And hereditary neutropenia: such as Kostmann syndrome, reticular hypoplasia with congenital leukopenia, neutropenia with abnormal granulocyte production, etc.; 5 immune disorders: such as systemic lupus erythematosus,Rheumatoid arthritisEtc.; 6 infection: bacterial infections, such as typhoid fever, paratyphoid fever, brucellosis, miliary tuberculosis; viral infections, such as hepatitis, AIDS, etc.; 7 blood diseases: such as bone marrow metastasis,Myelofibrosis,LymphomaLeukocytosis, leukemia,Aplastic anemia,Multiple myelomaMalignant histiocytosis and the like.

(2) maturity disorders: 1 acquired: such as folic acid deficiency, vitamin B12 deficiency, pernicious anemia, severe iron deficiency anemia, etc.; 2 malignant and other clonal diseases: such asMyelodysplastic syndrome,Paroxysmal nocturnal hemoglobinuriaSymptoms, etc.

2. Acting on peripheral blood

(1) conversion of the neutrophil circulatory cell to the marginal pool (ie, pseudoneutropenia): 1 hereditary benign pseudoneutropenia; 2 acquired: such as severe bacterial infection, malignant nutrition Adverse diseases, malaria, etc.

(2) Intravascular detainment: such as detaining in the lung caused by complement-mediated leukocyte lectin, detaining in the spleen caused by hypersplenism.

3. Acting outside the blood vessels

(1) Increased use: such as serious bacteria, fungi, viruses or rickettsial infections, allergic diseases, etc.

(2) Increased damage: such as hypersplenism.

(two) pathogenesis

The pathogenesis of neutropenia is nothing more than: decreased or no production of granulocyte production; excessive loss of granulocyte destruction, shortened granulocyte lifespan; abnormal distribution of 3 granulocytes; 4 synthesis of the first three mechanisms.

symptom

Agranulocytopenia is a hematological abnormality, and if there is no infection, there is often no clinical manifestation. Such as long-term neutropenia, some patients can complain of fatigue, sleepiness. Once the infection is combined, the corresponding symptoms and signs appear depending on the infection site.

1. Leukopenia peripheral white blood cell count <4 × 109 / L. Children are determined by reference to normal values of different ages.

2. Apoptotic peripheral blood ANC < 1.5 × 109 / L.

3. Agranulocytosis peripheral blood ANC < 0.5 × 109 / L.

In short, after determining the above diagnosis, it is necessary to detect the primary disease according to the diagnostic criteria of various primary diseases. Patients with concurrent infections are clearly defined according to the diagnostic criteria for various infections.

Diagnostic evaluation: The diagnosis of neutropenia is usually without difficulty and can be determined according to the blood test. Because it is only a hematological abnormality in most cases, it is not an independent disease, so the difficulty in diagnosis is to find the primary disease.

After neutropenia is often combined with infection, it is still necessary to identify whether the infection is a primary disease, or a complication, sometimes difficult. Clinically secondary neutropenia is most common in viral infections. Because most patients do not have granulocytopenia, they usually do not have serious bacterial or fungal infections, so their clinical significance is limited and often requires no special treatment. What is really clinically significant is neutropenia, almost all of which are infected, requiring immediate emergency treatment. Among them, drugs are the first to be induced by immune mechanism, and most of them are determined by individual physique, so they cannot be prevented. Caused by cytotoxic drugs, it can be expected to take control dosage, medication time and prevention of G-CSF, which is easier to solve. In addition, some congenital agranulocytosis in infants and neonates is fierce and needs to be judged and dealt with in a timely manner.

diagnosis

The neutropenia needs to be identified from the following aspects.

1. The etiology of secondary agranulocytosis identifies the above eight categories of causes, which are generally not difficult to identify based on medical history and clinical manifestations. However, drug-induced, sometimes determined to be caused by a certain drug, will be difficult because the patient may use multiple drugs at the same time or in succession. The significance of identification is which drugs should be banned for life in the future.

2. Identification of various congenital neutropenia according to the degree of neutropenia, can be identified as benign or severe neutropenia; periodic regular author, the most easy to confirm the diagnosis; granulocytes associated with various syndromes Reduced, can be distinguished according to their clinical characteristics and laboratory results. In addition, the age of onset has a certain reference significance for diagnosis.

3. Identification of granulocytopenic infection and infection-induced neutropenia Non-infectious causes of neutropenia, neutropenia occurs before infection, and infection is concurrent; infection-induced neutropenia, vice versa. Non-infectious causes of neutropenia, such as concurrent infections, mostly have a clear primary disease.

4. Recovery period of agranulocytosis and acute leukemia identify patients with recovery of granulocytosis, mainly bone marrow (sometimes involving blood) can appear more early granulocyte, including primitive and promyelocytes, sometimes more than 30 %, resembles acute myeloid leukemia. Identification point:

1 The former has a history of agranulocytosis, and a history of primary disease or medication.

2 no signs of lymph node, liver, spleen and other leukemia infiltration.

3 usually without anemia and/or thrombocytopenia.

4 Short-term dynamic observation, early granulocyte in bone marrow and peripheral blood gradually decreased and disappeared.

complication

The main complication of neutropenia is infection, including lung infections, oral infections, skin infections, and the like. Such as agranulocytosis often sudden onset, patients have chills, high fever, the most prone to serious infections in the oral cavity, manifested as necrotizing ulcers, often covered by gray or black pseudomembrane, soft palate or pharyngeal arch can be perforated due to necrosis, ie The so-called walking. Infection in the perineum area is second only to the prone area of the oral cavity. Necrotic ulcers can occur in the rectum, perianal and vagina. If the infection of the above-mentioned parts is not treated in time, the lack of granulocytes often causes the infection to spread rapidly, progressing to sepsis, and the mortality rate is high.

treatment

(a) treatment

The treatment of neutropenia is mainly the treatment of etiologies, such as the withdrawal of suspicious drugs, the cessation of contact with suspected poisons, and the treatment of various primary diseases that cause neutropenia.

The main manifestation of neutropenia is infection, but the risk of infection is negatively correlated with the degree of neutropenia: patients with neutrophils (1.0 to 1.8) × 109 / L are less likely to develop infection. , (0.5 ~ 1.0) × 109 / L is centered, <0.5 × 109 / L patients are the most likely. In addition, the frequency and severity of infections are related to the cause and duration of neutropenia. In general, neutrophil production reduces disease, such as secondary to cytotoxic drugs, bone marrow radiotherapy, or early hematopoietic progenitor cells. Patients with neutropenia caused by defects, etc. have a greater chance of infection than patients with other causes; neutropenia is accompanied by mononuclear cell reduction, lymphopenia, hypogammaglobulinemia Patients with symptoms are more severe than those with only simple neutropenia. Therefore, the treatment of neutropenia should vary from person to person and from disease to disease.

1. Treatment of neutrophil count

(1) leukocyte-producing drugs: many of the current clinical applications, such asVitamin B6, vitamin B4, blood, inosine, deoxynucleotide, androgen, lithium carbonate, etc., but lack of affirmative and long-lasting effect, therefore, the initial treatment of patients can choose 1 to 2, every 4 to 6 weeks to replace A group, until it is valid, if it does not work for several months, you don't have to continue using it.

(2) immunosuppressive drug treatment: such as glucocorticoids,Azathioprine,CyclophosphamideHigh-dose human gamma globulin infusion, etc., is effective for some patients, such as anti-neutrophil antibody-positive or cytotoxic T-cell-mediated bone marrow failure patients.

(3) Colony stimulating factor therapy: mainly filgrastim (rhG-CSF) and rhGM-CSF. Phase III randomized controlled clinical trial of felstatin (rhG-CSF) in the treatment of severe chronic neutropenia (neutrophil count <0.5×109/L): 120 cases of idiopathic neutropenia Patients with dysplasia, periodic neutropenia, and congenital neutropenia, were treated with statin (rhG-CSF) 3.45 to 11.50 μg/(kg·d), subcutaneously, for 4 consecutive months, 108 of them The absolute value of the patient's neutrophils was ≥1.5×109/L. Other causes of neutropenia, such as Fehy syndrome, drug-induced agranulocytosis, intramedullary destruction of irregular neutropenia, Kostmann syndrome, Shwachmann syndrome, etc. Case report. The treatment not only increases the number of neutrophils by promoting the production and release of granulocytes in the bone marrow, but also activates mature neutrophils, thereby enhancing the phagocytic function and facilitating the control of infection.

2. Bone marrow transplantation in addition to some blood diseases that cause neutropenia, such as aplastic anemia, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, lymphoma, etc. successfully treated with bone marrow transplantation, congenital Neutropenia has also been reported to be successful in treatment. Due to the high mortality associated with the treatment of allogeneic bone marrow transplantation, the advantages and disadvantages should be weighed and the indications for the treatment should be absolutely mastered.

3. Treatment of patients with infectious neutropenia If patients with neutropenia have only fever and no sepsis, they can generally be treated in an outpatient clinic to avoid secondary infection in the hospital. For patients with severe neutropenia (especially those with neutropenia) who develop fever, they should be treated as emergency medical patients and immediately admitted to hospital for treatment. If conditions permit, they should be reversed. Immediately after the examination of the pathogens in the skin, throat, blood, urine, stool, etc., an empirical broad-spectrum antibiotic is given. If the pathogen clarifies the patient, then the targeted narrow-spectrum antibiotic is switched to the susceptibility test. If no pathogen is found, but the condition can be controlled after treatment, the oral antibiotic should continue to be given for 7 to 14 days after the condition is cured. If no pathogens are found, and the condition does not improve after 3 days of the above treatment, the patients with mild disease may stop using the empirical antibiotic treatment, and then carry out the pathogen culture again. If the disease is serious, the antifungal drug should be added on the basis of the original treatment. Such as amphotericin B and so on. For patients with severe infection, neutrophil infusion can also be given. Since neutrophils have a short survival time in peripheral blood and tissues, they can be effective at least once/d for 3 consecutive days.

(two) prognosis

It is related to the degree of neutropenia, the course of the disease, the cause, and the treatment method. When the absolute value of neutrophils is >1.0×109/L, the chance of infection is less. If the cause is removed, the prognosis is better. In the past, acute agranulocytosis caused a mortality rate of 70% to 90% due to secondary infection. At present, the enhancement of anti-bacterial drugs, hematopoietic growth factor (G-CSF, GM-CSF) and other means of infection control and widespread application make Most patients can pass the infection, the prognosis is good, and the mortality rate has dropped below 25%. However, elderly, systemic failure, jaundice or a combination of severe infections have a high mortality rate. Although the active treatment for 10 days, there is no obvious improvement, the prognosis is poor. A small amount of naive cells remained in the bone marrow and recovered faster than those who were completely deficient. Peripheral blood mononuclear cells persist and have an increasing trend, suggesting that the disease is improving.

prevention

A strict protection system should be established for close contact with radiation, benzene or other harmful substances, and regular blood tests should be carried out for timely diagnosis and treatment. For patients using cytotoxic drugs, the number of granulocytes should be measured every 1-2 days, and the dose of the drug should be reduced or discontinued in time. Avoid or limit the use of drugs that may cause neutropenia as much as possible. When taking drugs that may cause neutropenia (non-cytotoxic drugs), you should pay attention to check blood samples every week. Allergic to drugs