Hantavirus pulmonary syndrome

Introduction to Hantavirus Pulmonary Syndrome Since May 1993, in the southwestern United States, New Mexico, Colorado, Utah, and Arizona, the four corners of the border area of the four continents of the United States have been suffering from acute respiratory failure (Hantavirus pulmonary syndrome, HPS), currently 30 states in the United States Some cases have been found. In addition to Canada in the United States, Brazil, Paraguay, Argentina, Chile, Bolivia, and Europe, Germany, the former Yugoslavia, Sweden, Belgium and other countries have reported cases of HPS. With the increase in HPS cases, countries have conducted some research on this disease with extremely high mortality. In view of this disease, heart failure can occur in addition to pulmonary edema, so North America and other countries also known as the disease is Hantavirus cardiopulmonary syndrome (HCPS). China is a high-risk area for Hantavirus infection, and it is worthy of caution whether this disease exists. The situation of foreign research in recent years is briefly described. basic knowledge The proportion of illness: 0.001% Susceptible people: no specific population Mode of infection: contact spread Complications: hypotension, shock, heart failure, sinus bradycardia, sinus tachycardia, arrhythmia, edema

Cause of Hantavirus lung syndrome

(1) Causes of the disease

Researchers in the US CDC and other units use IFA and ELISA to detect IgM and IgG antibodies that can react with Hantavirus antigens from patient sera, followed by Puumala virus and Hantavirus. A nucleotide sequence designed primer, using reverse transcription polymerase chain reaction (RT-PCR), to amplify the nucleotide sequence of Hantavirus from the lungs and other organs of the patient, confirming that the pathogen of the disease is A new Hantavirus, which was later isolated from the patient's autopsy specimen using Vero-E6 cells. The virus was named Four Corners virus based on the region where the virus was first discovered, and later renamed Xin. Sin Nombre virus (SNV), also known as the anonymous virus, SNV electron microscopy is a rough spherical shape with an average diameter of 112 nm, a dense envelope and fine surface protrusions, and a 7 nm long filamentous nucleus. The shell is present in the viral particle and the viral inclusion body is present in the infected cytoplasm.

Further studies on SNV have revealed that gene rearrangements are also common in SNV. Therefore, there are different subtypes of SNV. The transcription of L, M, and S fragments of SNV is determined by quantitative PCR. Different time, peak value and duration are different. According to the determination of viral nucleotide sequence, it is believed that the pathogen causing Hantavirus lung syndrome has at least type 6 Hantavirus-related virus, in addition to sinobacillus virus. Including New York virus (NYV), New York type 1 virus (NYV-1), Bayou virus (BAYV), black creek canal virus (BCCV) and Andes Virus Wait.

The immunogenicity of the above six Hantavirus Pulmonary Syndrome-associated viruses has a weak neutralizing reaction with the Pumara virus and the Hope Mountain virus causing hemorrhagic fever with renal syndrome, but with Hantavirus (HTNV) and Seoul virus. (SEOV) has few cross-neutralization reactions.

(two) pathogenesis

The pathogenesis of Hantavirus lung syndrome has not been studied in depth. It is currently believed that the lung is the primary target organ of the disease, and the pulmonary capillary endothelial cells are the main target cells of HPS-associated virus infection. These endothelial cells are seriously infected, although Does not cause cell necrosis, but the effects of various cytokines caused by infection lead to increased capillary capillary permeability, causing a large amount of plasma extravasation, into the pulmonary interstitial and alveolar, causing non-cardiogenic pulmonary edema, clinical Respiratory distress syndrome appears on the body. The histological examination revealed that the viral antigen is widely distributed in the pulmonary capillary endothelial cells and in the cells of the heart, kidney, pancreas, adrenal gland and skeletal muscle. Therefore, the pathogenesis is generally considered to be the direct damage of the virus to the cells. Or virus-mediated immune responses lead to cell damage. In addition, a variety of cytokines and chemical factors also play an important role in the occurrence of HPS.

Regarding how Hantavirus enters human-related cells, Gavrilovskaya et al. experimented with human umbilical vein epithelial cells and Vero-E6 cells as target cells, cultured in vitro and infected with Hantavirus, and they found that if the culture medium was added with 3 Integrins are antibodies that cannot be infected and enter cells. They use murine-human hybrid 3 integrin-specific Fab fragments to inhibit both HTNV, SEOV and PUUV infections, as well as SNV and HPS that cause HPS. Type 1 virus (NYV-1) affects cells, and thus Hanta virus is thought to enter the cell through 3 integrin present on the surface of platelets, endothelial cells and macrophages. Mackow et al also believe that 3 integrin is present in Tissue surfaces such as platelets and endothelial cells act to regulate platelet function and maintain capillary integrity, and are also adhesion receptors. Hantavirus binds to these receptors before entering the cell.

As for the role of HPS-associated virus in the pathogenesis of HPS, there are few studies. Recently, Terajima et al. used to understand the role of viral load in the pathogenesis of HPS. They used quantitative RT-PCR to detect the amount of SNV in peripheral blood of 26 patients with HPS. The primers were S fragments, and the RT-PCR products were verified by Southern blot. Among the 26 cases, 20 were positive for viral RNA, 9 of which were dying and 7 of them were positive, and 13 of the 17 survivors were positive. The patient's virus was quantified at 106.7 ± 1.4 Copies/ml, and the surviving patient was 105.8 ± 1.3 Copies/ml. The authors believe that the level of viremia is related to the level of viral antigens in lung cell infections. This high level of viremia can also Triggering the pathogenesis of immunopathology, the results suggest that death patients have higher levels of viral RNA copy than survivors, and they also found that the amount of viral RNA copies is related to the degree of thrombocytopenia and blood concentration in patients.

Regarding the immune pathogenesis, Koster et al. noted that anti-SNV IgM and IgG antibodies were present in the blood circulation before pulmonary edema in patients with Hantavirus lung syndrome. For this reason, they examined blood circulation immune complexes in 11 cases, but all Negative, only one case detected anti-platelet glycoprotein IgG, plasma C3a, C4a and C5a and other complement components were normal or slightly higher, while in different stages of peripheral blood smear for lymphocyte count, indicating that most are CD3, CD8 And CD4 lymphocytes, indicating that the patient's lesion is a T cell-mediated immune response, not B cell-mediated, Ennis et al. isolated mononuclear cells from peripheral blood of patients with Hantavirus Pulmonary Syndrome, using interleukin-2 ( IL-2) or recombinant vaccinia virus capable of expressing SNV protein was stimulated and cultured. It was found that CD8 and CD4 T lymphocyte clones of these patients can recognize highly conserved regions of Hantavirus in different isolates, and some can be identified by The target cell is expressed, and its genetic distance is far from the sequence of the virus strain. Therefore, it is considered that the cross-reaction of T cell epitopes may be important in the pathogenesis of Hantavirus lung syndrome. Van Epps and others believe that the pathogenesis of HPS, like many other viral infectious diseases, CTL response has both the role of clearing the virus and inducing immunopathology. In addition, Koster et al detected HLA typing in HPS patients and found HLA- The tissue typing of B35 is associated with severe HPS caused by SNV, suggesting the role of T lymphocytes in aggravating the disease and supporting the role of cellular immune responses in the pathogenesis of HPS.

To understand the role of cytokines in the pathogenesis of HPS, Mori et al. used immunohistochemical staining to observe and calculate cytokine-producing cells from autopsy tissues, including mononuclear factors IL-1, IL-1, IL-6 and TNF. Lymphokines IFN, IL-1, IL-4 and TNF, found that there are a large number of cytokine-producing cells in the lung and spleen tissues of HPS patients, while the liver and kidneys are small, dying from non-HPS acute respiratory distress syndrome ( In patients with ARDS, the cytokine-producing cells in the lungs only increase moderately, while the lungs that die in non-ARDS patients have little or no detectable cells, so local cytokine production may play an important role in the pathogenesis of HPS. .

Regarding whether the humoral immune response mediates the clearance of the virus and promotes the recovery of the body, Bharadwa et al. detected the IgG, IgA and IgM of the recombinant virus nucleocapsid protein (NP) and glycoprotein G antigen in a series of 26 samples of SNV-infected patients. The neutralization antibody of SNV was determined, and it was found that the IgG and neutralizing antibodies were significantly lower in the lighter patients at the time of admission. Therefore, the neutralizing antibody was considered to be an effective antibody for clearing SNV, and it was predicted that neutralizing antibodies against SNV could be used. Passive immunotherapy for HPS.

The pathological changes of Hantavirus lung syndrome caused by different viruses are different. The HPS caused by SNV has severe pulmonary edema and pleural effusion, but there is no peritoneal exudation. Microscopic examination shows alveolar edema, with few to moderate The transparent membrane, edema of the interstitial lung and less infiltration of lymphocytes, a small number of patients with mild swelling of the spleen, atypical lymphocytes in the spleen arterioles and red pulp, most patients in the lungs, bone marrow, lymph nodes, liver The spleen can find a large number of immunoblastic cells, the naked eye, the heart and the brain are normal, no abnormalities in microscopic examination, a small number of patients have gastrointestinal bleeding, and HPS pathological examination caused by long marsh virus, except pulmonary edema and atelectasis In addition, severe pleural effusion, peritoneal and pericardial effusion and cerebral edema were observed. Microscopic examination showed interstitial pneumonia. Monocytes and neutrophils infiltrated inside and outside the alveoli. A large amount of edema fluid and cellulose were observed in the alveoli. Alveolar type II cell proliferation was observed, and renal lesions were consistent with early tubular necrosis.

Hantavirus lung syndrome prevention

1. Anti-rat and rodent control: Use rats such as drugs or machinery to kill rats, and establish anti-rat facilities in the family.

The main methods for preventing and treating mice are as follows:

(1) Place the trench net: Add the wire mesh at the exit and entrance of the sewer. The diameter of the mesh should not be larger than 0.6×0.6cm to prevent the rats in the sewer from going up and down the pipeline. The open ditch in the operation of the catering industry should be covered or covered with other items and should not be exposed.

(2) Set the anti-mouse door: The lower part of the door (frame) is inlaid with a 40 cm high iron sheet to prevent the rat from smashing the door panel (box).

(3), narrow the various gaps: repair the door and the ground, the door and the door, the window and the window sill, so that the gap is not more than 0.6 cm, in order to prevent the house mouse from entering. Set the mouseboard; add a 60cm height door at the bottom of the door to keep the mouse out of the door.

(4) Hardened ground: repair the damaged, unhardened ground in time, or harden the road surface to prevent the mouse from stealing holes.

2. Pay attention to personal hygiene

Zoologists and on-site biologists try not to touch the rodents and their excreta with their hands. When medical staff contact patients, care should be taken to isolate them.

3. Vaccine

The Hantan virus Hantan and Seoul vaccines currently developed have no cross-immunization effect on various viruses of Hantavirus lung syndrome. Therefore, it is necessary to continue to develop effective vaccines.

Recently, Crowleg et al reported that three patients with severe cardiopulmonary failure were treated with extracorporeal membrane oxygenation (ECMO). These 3 patients met at least two of the criteria for difficult survival and were the patients who failed the best conventional treatment. In the first case, ECMO treatment was applied when the heartbeat was stopped, and the result was death. The other 2 patients survived after ECMO treatment and no complications occurred. ECMO is considered to be an effective treatment for patients with extreme Hantavirus pulmonary syndrome. Conditional units can be tried. Due to the outbreak of the disease in Argentina, epidemiological studies have suggested that there is human-to-human transmission, so patients should be closely isolated.

In view of the rapid progress of the disease and the high mortality rate, the clinically diagnosed cases should be carefully monitored and carefully observed for breathing, heart rate and blood pressure. After the onset, you should rest in bed early, properly add water, intravenous infusion of balanced salt injection and glucose saline, high fever patients with physical cooling, can also be given intravenous infusion of glucocorticoids.

Hantavirus pulmonary syndrome complications Complications hypotension shock heart failure sinus bradycardia sinus tachycardia arrhythmia edema

Severe patients may have hypotension, shock, heart failure and arrhythmia such as sinus bradycardia or sinus tachycardia. Only a few patients found conjunctival hyperemia, bulbar conjunctival edema, skin mucosal bleeding spots or bleeding spots.

Hantavirus lung syndrome symptoms common symptoms fatigue nausea kidney damage tachycardia diarrhea abdominal pain heart failure hypotension low fever blood pressure is low

The incubation period of HPS is 9 to 33 days, with an average of 14 to 17 days. The course of the disease is divided into three phases, namely, the prodromal phase, the respiratory failure phase and the recovery phase. The patient has more rapid onset, and there are symptoms of prodromal symptoms such as chills, fever, myalgia, headache, and fatigue. It can also be accompanied by gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain. The fever is usually 38 ~ 40 ° C, the above symptoms last for 12 hours, the elderly for several days, most of the 2 to 3 days after the rapid cough, shortness of breath and respiratory distress and into the respiratory failure period is non-cardiogenic pulmonary edema. Physical examination: visible breathing increased, often up to 20 ~ 28 times / min or more, heart rate increased, up to 120 beats / min, the lungs can be heard with coarse or small wet voice, a small number of patients with pleural effusion or pericardial effusion. In severe cases, arrhythmias such as hypotension, shock, heart failure, and sinus bradycardia or sinus tachycardia may occur. Only a small number of patients found conjunctival hyperemia, conjunctival edema, skin mucosal bleeding spots or bleeding spots.

Men who are caused by Sin Nob virus, New York virus, and New York type 1 virus generally have no kidney damage. However, those caused by the long marsh virus and the black port virus are accompanied by kidney damage, so oliguria can occur. General respiratory failure lasts for about 1 week, and patients who can survive the respiratory failure gradually enter the recovery period. At this time, the breathing is stable and the hypoxia is corrected. However, a small number of patients still have sustained low fever, and the physical strength has recovered for some time. However, some patients have no pulmonary syndrome.

Hantavirus lung syndrome examination

1, most patients with this disease increased white blood cell count, up to (30 ~ 65) × 10 ⁹ / L, neutrophils increased significantly, nuclear left shift, immunoglobulin-type lymphocytes, promyelocytes And (or) myelocytes, atypical lymphocytes are also common, platelets are significantly reduced, some patients have blood concentration, red blood cells and hemoglobin increase, hematocrit increases.

2, patients with renal damage, urine protein and microscopic hematuria, urine protein is generally, blood biochemical examination of ALT and AST and hypoproteinemia, in addition LDH and creatine kinase are often significantly elevated, with renal damage Urea nitrogen and creatinine increased, a small number of patients have metabolic acidosis, Hallin et al found that patients with blood gas analysis arterial oxygen partial pressure is often <7.98kPa, alveolar arterial oxygen pressure > 3.19kPa or more, arterial catheter examination pulmonary artery wedge pressure is low The cardiac index was significantly reduced, suggesting non-cardiogenic pulmonary edema, X-ray examination, infiltration of the interstitial lungs or interstitial and alveolar infiltrates, and pleural effusion and pericardial effusion were observed in some patients.

Bustamanta et al. examined the pleural effusion of patients with HPS and found that the early stage was leakage, and the later stage was exudate, pleural effusion protein/serum protein>0.5, microscopic examination, nucleated cells <170×106/L, mainly mononuclear. Cells, cultured without bacterial growth, increased pleural effusion protein and capillary damage, protein leakage.

Khan et al. performed bronchoscopy on patients with HPS who were admitted to the hospital for 12 days. The airway was normal and no bronchial mucosal damage was found. A few patients showed erythema in the airway, total protein in the endotracheal aspirate, albumin and lactate dehydrogenase. Increase or even reach or exceed serum levels.

3, coagulation function test: whole blood partial thromboplastin time (WBPTT) and prolonged prothrombin time, a small number of patients with fibrin degradation, but fibrinogen is normal.

Diagnosis and identification of Hantavirus lung syndrome

Diagnostic criteria

1. Mainly based on fever, myalgia, headache, fatigue and other symptoms of poisoning and rapid cough, shortness of breath, respiratory rate and heart rate significantly increased, hypoxia and other respiratory distress, may also have low blood pressure or shock, laboratory Examination of white blood cell count increased, nuclear left shift, and visible atypical lymphocytes, hemoglobin and red blood cells increased, hematocrit increased, blood gas analysis of arterial oxygen partial pressure decreased, X-ray chest showed interstitial pulmonary edema.

2. Specific diagnosis

Currently, HPS-associated virus-infected Vero-E6 cells are used to detect patient-specific IgM and IgG. To understand the appearance of various antibodies, recent Bostik performed SNV antibody detection on serum samples from 22 patients with acute HPS. SNV-specific IgM is 100% positive, while the specific IgA positive rate is 67%. As for the recovery-specific IgG, the highest is IgG3 (97%), followed by IgG1 (70%), IgG2 is 30% and IgG4. It is 3%.

In order to quickly and accurately diagnose HPS, Pudula et al. used the recombinant nucleocapsid protein of Andes virus, the main pathogen of Argentine HPS, as antigen, and detected specific IgG and IgA by solid phase enzyme immunoassay. IgM was detected by capture ELISA, and 135 cases were RT- PCR-approved HPS cases, 77 cases of other respiratory infections, and 957 healthy residents from infected and non-epidemic areas were examined. As a result, early HPS patients had strong specific IgM, IgG and IgA responses, and IgM was the earliest. On the first day after the onset of symptoms, IgG was on day 7, IgA was on day 1, IgM antibody was positive in all patients' first specimens, and IgM and IgG were 100% specific and sensitive. IgA antibodies are also detected in the saliva of acute HPS patients.

3. Viral RNA examination: RT-PCR can detect viral RNA in serum, plasma and mononuclear cells of acute phase patients. In the recovery period, the general blood RNA can no longer be detected, but there are also reports that the disease is still in the patient for 23 days. A person who detects viral RNA in the blood.

Differential diagnosis

Early disease needs to be differentiated from influenza, sepsis, leptospirosis, etc., when respiratory distress occurs, with cardiogenic pulmonary edema, primary acute respiratory distress syndrome, bacterial and viral pneumonia, SARS and Leptospira Hemorrhagic pneumonia and other identification.

Moolenaart et al compared 24 patients with HPS and 33 patients with influenza. It was found that sore throat and cough were the most common symptoms of influenza patients, which were significantly higher than HPS, while HPS increased white blood cell count and left shift of the lung to identify the flu. Both sepsis and leptospirosis can have fever, headache, myalgia and white blood cell count, but routine examination of HPS often shows blood concentration, and hematocrit and thrombocytopenia can be distinguished.

The difference between this disease and cardiogenic pulmonary edema is that the former is pulmonary edema caused by increased vascular permeability, so the pulmonary wedge pressure is low. The early chest X-ray examination is mainly pulmonary interstitial exudation, and the latter is pulmonary vein. Due to congestion, the wedge pressure of the pulmonary artery is increased. The upper part of the pulmonary artery and the shadow of the hilar are enlarged on the chest radiograph. The laboratory examination shows that the blood is concentrated, the thrombocytopenia, the white blood cells are increased, the nucleus is shifted to the left, and the late granules appear. Cells and atypical lymphocytes, particularly thrombocytopenia, are not found in cardiogenic pulmonary edema and primary respiratory distress syndrome.

The identification of bacterial or viral pneumonia is that the latter is oocyst exudation, so X-ray examination is a lesion of the lung lobe, and the disease is a diffuse lesion of the lung.

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