Hantavirus :The mode of communication to humans is by inhalation of aerosols from the saliva, urine, and feces of carrier rodents. Hands contaminated with the virus can infect the mucosa: ocular, nasal, and oral. Exceptionally, the infection can occur from ingesting contaminated food or water or from a mouse bite.
After a conglomerate of family or socially related cases, which occurred in southern Argentina, person-to-person transmission of the Andes virus was demonstrated. A third of the cases have occurred as family conglomerates, where more than one family member presented an HPS.
However, in the vast majority of them, those who fell ill shared the same risk environment. There are exceptional situations where the person-to-person transmission cannot be ruled out (23). Unlike in Argentina, the nosocomial transmission of the disease has not occurred in North America or Chile.
The first clinical case of SPH was diagnosed in a woman, resident in Cochamó, tenth region, in 1995. However, a retrospective investigation showed, serologically, that the disease had existed since at least 1993.
Between 1993 and August 2002, considering the confirmed retrospective clinical cases, 273 cases have been reported to date, which has occurred from the V to the XI region. The highest incidence rates in the country correspond to the XI region (4.1 x 100,000 inhabitants and the X region (3.1 x 100,000 inhabitants).
The disease occurs mainly in males (71%), in productive age ( 25 and 49 years); however, it should be noted that 15% corresponds to children under 15.
The vast majority of those who fall ill are agricultural or forestry workers. 60% are residents of the area in which the infection occurred, and 11% are tourists from other regions of the country, who were exposed to environments or situations of risk. Only two foreigners, a Frenchman and an American submitted an SPH.
Both were highly exposed to risky activities. One of them, a botanist, acquired the disease in the forests of southern Chile and / or Argentina, and the second, a zoology student, who was investigating a species of endangered foxes in the Nahuelbuta National Park.
The disease is currently endemic in our country. Although cases have been reported from V to XI regions of the country, the reservoir of the virus inhabits from III to XI regions of Chile, so cases could appear in all of them.
Epidemic outbreaks have shifted from south to north and predominate in the months between January and August.
In recent years, the number of diagnosed and confirmed cases has been increasing, reflecting the incidence, but at the same time, the early suspicion of the disease and its notification.
The clinical picture of SPH
Incubation period The incubation period is difficult to specify in the vast majority of cases. It can be as short as two days or last up to 45 days (on average, two to three weeks).
Viremia occurs even days before prodromal symptoms appear.
The virus, in humans, replicates in the pulmonary endothelium and the cardiac endothelium without causing cell destruction (Figure 3). Viremia triggers immune mechanisms, which can be defensive or deleterious.
Section of the human lung. Viral antigens are seen in red in the pulmonary endothelium, using the immunohistochemistry technique. Courtesy Dr. Pascale, Panama.
The production of IgM, IgG, or IgA antibodies, capable of neutralizing the virus and preventing it from infecting new cells, are called neutralizing antibodies. It is known that the earlier these antibodies develop and the higher the titers, the better the prognosis.
On the other hand, viral antigens activate cellular immunity mechanisms in the spleen, mediated by immunoblasts and T lymphocytes. Tumor necrosis factor (TNF-alpha) and interleukin (IL-8), increase in severe cases, and not thus in those of benign evolution.
Immune response in SPH according to severity. Source: Centers for Disease Control and Prevention.
As a consequence of this immune response, acute non-cardiogenic pulmonary edema, and myocardial depression occur.
It generally lasts from one to six days. However, it can be from 1 to 15 days. They appear suddenly: high fever, intense myalgias, and compromise of the general state. Nausea, vomiting, and abdominal pain occur in 50% of patients. Headache is frequent, and in 30% of cases, there is a dry cough. Many patients report polydipsia.
The conjunctival injection is found in 18% of cases of SPH from the Andes virus. Diarrhea is less frequent in our environment than in cases of the Sin Nombre virus. Although odynophagia may occur, it is not accompanied by pharyngo-tonsillar exudate. Less frequent symptoms are dizziness, polyarthralgias, and rushor redness.
The presence of coryza, dysphonia, and pharyngotonsillar exudate suggest other common upper respiratory infections. Differential diagnosis at this stage is difficult. The SPH presents with early hematological alterations and other alterations of the laboratory parameters, which are guiding in this stage of the disease.
Thrombocytopenia (less than 100,000 platelets) appears early on the blood count and immunoblasts, more than 10%, are seen on the smear.
Generally, there is leukocytosis with left deviation, but without toxic granulation. Hemoconcentration (hematocrit greater than 45%) appears later. The tetrad of thrombocytopenia, leukocytosis, hemoconcentration, and the presence of immunoblasts strongly suggests an SPH.
It occurs in 95% of cases of benign evolution, in 100% of severe cases, and is seen only exceptionally in other pathologies ( Frederik Koster, personal communication). There is usually an increase in transaminases and creatine phosphokinase (CPK), which are attributed to rhabdomyolysis. LDH rises as a nonspecific response to lung injury. HSV is generally normal or slightly elevated.
Differential diagnosis in the prodromal stage The differential diagnosis includes:
Influenza and other systemic viruses (hepatitis, among others).
Adenovirus and other respiratory viruses.
Acute gastroenteritis and other acute abdominal conditions.
The epidemiological history of exposure to rodents or risk situations, the absence of coryza and pharyngeal exudate, and the presence of the hematological changes described, should guide the diagnosis of HPS.
Diagnostic algorithm during the prodromal phase of the SPH.
At this stage, the diagnosis is confirmed by serology: detection of specific IgM and IgG antibodies against hantaviruses present in the blood or serum using the ELISA technique. IgM detection allows confirmation of a case of acute hantavirus infection. Laguna Negra virus antigens are used to detect IgM, and Sin Nombre virus antigens are used to detect IgG since it has a cross-reaction with the Andes virus. Only for research purposes antigens of the Andes virus are used.
During the cardiopulmonary phase, fluid extravasation occurs from the intravascular to the extravascular space, especially to the pulmonary alveolar territory, due to severe alteration of capillary permeability. Secondarily occur hypotension and hemoconcentration. A group of patients also develops cardiogenic shock due to myocardial depression.
Very few patients progress slightly, without respiratory compromise. Diagnosis in them is extremely difficult and is confirmed by the presence of anti-hantavirus IgM antibodies.
Typically, between 2 to 15 days after the start of the prodromal phase, generally, on the fourth day, the patient suddenly worsens. They appear tachycardia, cough, and progressive dyspnea, secondary to non-cardiogenic pulmonary edema with or without hemodynamic compromise.
From the cardiovascular point of view, patients evolve in three ways:
Mild: patients who do not have hypotension throughout its evolution,
Moderate: patients who develop shock (BP less than 100/60 mm Hg or mean BP less than 70 mm Hg), but who respond quickly to the use of vasoactive drugs
Severe: patients who develop shock and despite having an initial response to the use of vasoactive drugs, remain unstable and die.
Massive pulmonary edema or cardiogenic shock can lead to death in 24 to 48 hours.
Hemorrhagic fever with renal syndrome characteristically evolves with impaired patency, hemorrhage, and renal compromise. Ocular, pancreatic, and hepatic involvement are also frequently described. This syndrome exceptionally leads to pulmonary edema or myocardial depression (1,34-35).
The SPH described in North America, caused by the Sin Nombre virus, does not present with bleeding disorders or kidney compromise, with exceptions (6-8).
30 to 70% of the cases of SPH due to the Andes virus, evolve with bleeding disorders of variable magnitude. The bleeding sites can be diverse and multiple. The most frequent are hematuria, hematemesis, hemoptysis, epistaxis, bleeding from puncture sites, gingivorrhagia, gynecological bleeding, and purpura. Less frequently, hemothorax, pulmonary hemorrhage, and subarachnoid hemorrhage occur.
The Andes virus also presents with renal compromise. The majority of patients (30% -50%) have an increase in creatininemia, and 6% develop kidney failure that requires temporary hemodialysis. Hematuria, proteinuria, and cylindric can be found on urinalysis.
Hyponatremia is frequent in our environment and is not related to the contribution of hypotonic solutions. Increased plasma amylase in the absence of clinical pancreatitis was observed in adults and children with SPH due to the Andes virus. The increase in lactic dehydrogenase (LDH) occurs in 100%. Elevation of creatine phosphokinase (CPK) and transaminase enzymes is highly frequent.
Disorders of consciousness have also been reported from drowsiness, excitement, to suggestive symptoms of meningitis in our country. In hemorrhagic fever with renal syndrome, alterations of the central nervous system, and even the appearance of Guillain Barré syndrome are described.
In our setting, 10% have a normal chest radiograph upon admission. Pulmonary edema in its initial stages is radiologically translated as interstitial infiltrates with Kerley B lines and loss of sharpness of the bronchovascular weft. In 24 to 48 hours, bilateral diffuse alveolar filling images appear, and in 10%, they are associated with Pleural effusion.
The pulmonary generally infiltrates bilateral (80.6%), and predominantly at baseline. In patients without underlying heart disease, the cardiac silhouette is normal in size. Atelectasis, flat or subsegmental, occurs in 5% of patients, regardless of whether they were connected to mechanical ventilation or not (Figure 7). Our findings correlate with those described in the North American literature (36,37).
Radiological evolution of pulmonary edema of the SPH since admission (a), cardiopulmonary phase (b and c), and resolution (d).
The electrocardiogram (ECG) shows sinus tachycardia with normal complexes. Relative bradycardia (40–60 per minute), nodal rhythm, and supraventricular arrhythmias may appear transiently. Ventricular arrhythmias (tachycardia and ventricular fibrillation), as well as electromechanical dissociation, are signs of poor prognosis (7,32).
Pathological anatomy The gross pathological anatomy in lethal cases shows congestive and edematous lungs. Histologically, alveolar edema is observed in the lung, with scarce focal hyaline membranes and mononuclear infiltrate (including immunoblasts). The virus is found within intact endothelial cells and occasionally in macrophages in the alveolar space. Cardiac histology shows no inflammation or necrosis (38).
Massive pulmonary edema in SPH.
Differential diagnosis in the cardiopulmonary phase
The diagnosis during the cardiopulmonary phase should be made before a patient with an epidemiological history of risk, with hematological alterations suggestive of SPH, respiratory distress, or chest radiography with bilateral diffuse infiltrates. Differential diagnosis includes community-acquired pneumonia and acute respiratory distress syndrome (ARDS).
The absence of the characteristic hematologic alterations of the SPH orient towards pneumonia or sepsis with ARDS. The presence of unilateral infiltrates does not rule out the possibility of an HPS, especially if the characteristic hematologic tetrad is present. Leptospirosis is another differential diagnosis when the disease presents with pulmonary involvement. However, the severe form (Weil’s disease) presents with jaundice, which does not happen in the SPH.
Diagnostic confirmation at this stage can be established using the following techniques:
Serology (the best sample that can be obtained from deceased patients, if the diagnosis has not been promptly suspected, is that of whole blood by cardiac puncture, post mortem). Detection of viral genetic material in infected cells present in clots and tissues (lung, liver, kidney, and spleen). It is only reserved for suspicious cases without serological confirmation or deceased patients.
Immunohistochemistry: detection of viral antigens in infected cells present in tissues. It is used in research and in a retrospective diagnosis where only formalin-fixed tissue is available (40).
Treatment Antiviral drugs, such as ribavirin, which is effective both in vitro and in vivo, have been used in FHSR. Antivirals have not been shown to be useful in the cardiopulmonary phase of SPH, possibly because the course is faster and they are administered late (41). It is possible that ribavirin given early during the prodromal phase is also effective in HPS; however, due to its adverse reactions, such as anemia requiring transfusions and pancreatitis, empirical use is not recommended.
As the severity of the clinical picture is mediated by immunological mechanisms, there is a certain rationale for administering systemic corticosteroids. Although a better evolution has been seen in patients who have received steroid therapy, there is currently insufficient evidence about its usefulness. A multicenter, double-blind, placebo-controlled study is underway to evaluate the efficacy of methylprednisolone in HPS.
The use of survivor serum has been used as a heroic and anecdotal measure without satisfactory results. The identification and production of mouse monoclonal neutralizing antibodies are in advanced stages in the United States, but the results of clinical studies should be awaited. Therefore the current treatment is symptomatic and depends on the patient’s condition.
Patients in the prodromal phase or with the mild disease should be hospitalized to monitor respiratory, hemodynamic, blood count, and routine laboratory function. Those patients with platelet disease, immunoblasts, with or without hematocrit elevation, (these findings precede the appearance of pulmonary edema) as well as those who begin with respiratory compromise (respiratory distress, low oxygen saturation, radiological infiltrates) and/or hypotension, should be transferred to a center that has an Intensive Care Unit (ICU) since the aggravation of pulmonary edema usually occurs in less than 24 hours and hypotension is rapidly progressive.
The contribution of volume should be avoided as much as possible, because fluids, both crystalloid and colloid, they contribute to increasing the severity of pulmonary edema due to the great alteration of the existing capillary permeability.
Those patients who develop severe respiratory failure (PaO2 / FiO2 <200) should be connected to invasive mechanical ventilation (MV), with protective MV techniques. Due to metabolic acidosis from severe lactacidemia, hypercarbia should not be allowed (10,32,42). Patients with SPH rarely have a compromise of consciousness by staying alert, experiencing great agitation. Their adaptation to the VM is difficult, and they require sedation and relaxation. Since they present tachycardia, relaxing, and sedative drugs that do not cause greater hypotension or tachycardia, such as tratracurium besilate and lorazepam in a continuous infusion, should be preferred.
It is recommended to use vasoactive drugs such as epinephrine, norepinephrine, phenylephrine, dopamine, and dobutamine early. In many patients, it is necessary to associate more than two drugs. Those patients who develop cardiogenic shock present with normal or low pulmonary capillary pressures, high levels of systemic vascular resistance, and low or normal cardiac index.
Patients who develop cardiogenic shock have a mortality of 100% unless they undergo extracorporeal circulation with a membrane oxygenator, a resource that has proven useful in shock. Cardiogenic by hantavirus refractory to vasoactive drugs (42). Patients who develop significant kidney failure require hemodialysis or hemodiafiltration, depending on their hemodynamic condition.
Because differential diagnosis with community pneumonia is extremely difficult, it is suggested to administer recommended antibiotics for empirical treatment of severe community pneumonia and to maintain antibiotics until diagnostic confirmation of SPH. In severe bleeding, blood products should be administered: platelets, cryoprecipitate, fresh plasma, and/or red blood cells.
Evolution and convalescence
The initial mortality of PFS in Chile was over 50% and has decreased to 26% in the last two years, probably due to early diagnosis, greater knowledge of the pathogenesis, and a better therapeutic approach in each of the stages of the disease.
Poor prognostic factors and associated with 100% mortality are:
PaO2/FiO2 < 50 mm Hg. Shock Cardiogenic with cardiac index (CI) <2.5 L / min / m2. Blood lactate> 4.0 mmol / L. The appearance of tachycardia or ventricular fibrillation and electromechanical dissociation.
A patient in cardiopulmonary phase who stabilizes after the first 48 hours generally recovers as quickly as aggravated unless complications of the disease occur, such as cardiogenic shock and severe arrhythmias, nosocomial infection, or iatrogenic complications.
Respiratory failure improves during the first week, on par with chest radiography. The normalization of laboratory tests occurs gradually over a period not exceeding 10 days. The recovery phase involves significant polyuria that can last up to 15 days. Full recovery is the rule. However, follow-up studies show that there may be fatigability, bradypsychia, dyspnea, peripheral airway obstruction, cognitive disorders, sensorineural hearing loss, and visual disturbances up to months and even years later.
Prevention of SPH
Hantavirus infection prevented by avoiding contact with wild mice, their excreta or urine, as well as by using adequate personal protection measures.
Prevent mice from entering the human habitat.
Prevent mice from entering the house.
Take precautions when entering rodent habitat.
Ventilate cellars or other uninhabited peasant buildings before entering.
Follow the recommended rules for camping.
Take precautions against possible nosocomial transmission.
In order to prevent mice from involving the human habitat, measures should be taken that decrease the possibility of nesting, breeding, and feeding the mouse near the human. It is recommended to keep the patio and the surroundings of the house free of garbage, debris, debris, and firewood.
Household garbage must be collected in closed, mouse-resistant containers, or it can be buried as well as burned in places far from home. Cut bushes and/or brush within a radius of 30 meters around the house, as well as seal houses, warehouses, and warehouses by covering the holes with steel cans or bolts.
Before entering any previously uninhabited building, it is recommended to ventilate before entering. Use a double HEPA filter mask, spray with chlorinated water (2 tablespoons of chlorine in 5 liters of water), and since the chlorine solution is not instantaneous, wait 15 minutes before cleaning.
Avoid camping in places where rodents are noted—camp in clear, debris-free locations and away from grassland. Use tents with a floor and do not sleep at ground level. Keep food in tightly closed containers—Wash kitchen utensils immediately after using them. Drink only clean, bottled, or boiled water.
In the clinical management of all hantavirus suspects, it is recommended to hospitalize the patient in an individual room (droplet isolation). During direct care: use thick masks, eye protection, gloves, apron, and bib. In the laboratory: wear a mask, eye protection, and manipulate tubes with fluids, using gauze when opening them.
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