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Viral Bronchiolitis in Children H. Cody Meissner, M. Address reprint requests to Dr. N Engl J Med ; DOI: In addition, guidelines from the American Academy of Pediatrics regarding the diagnosis, management, and prevention of bronchiolitis are summarized. Cl inic a l Fe at ur e s A young child with bronchiolitis typically presents to a health professional during the winter months after 2 to 4 days of low-grade fever, nasal congestion, and rhinorrhea with symptoms of lower respiratory tract illness that include cough, tachypnea, and increased respiratory effort as manifested by grunting, nasal flaring, and intercostal, subcostal, or supraclavicular retractions.

Various definitions of bronchiolitis have been proposed, but the term is generally applied to a first episode of wheezing in infants younger than 12 months of age. Apnea, especially in preterm infants in the first 2 months of life, may be an early manifestation of viral bronchiolitis. The variable course of bronchiolitis and the inability of medical personnel to predict whether supportive care will be needed often results in hospital admission even when symptoms are not severe.

A variety of potential clinical markers have been proposed for use in identifying infants who are at risk for severe disease. Unfortunately, current scoring systems have low power to predict whether illness will progress to severe complications that would necessitate intensive care or mechanical ventilation. For personal use only. No other uses without permission. Copyright Massachusetts Medical Society. All rights reserved.

Table 1. Late winter and early spring; season typically peaks 12 mo later than RSV peak. Human bocavirus has been detected as a copathogen in bronchiolitis, but it is isolated infrequently as a single agent in hospitalized children, leading to speculation that this virus is more likely to be an innocent bystander than a true pathogen.

No evidence has been found for a primary role of bacteria as a cause of bronchiolitis, although Bordetella pertussis, Chlamydia trachomatis, or Mycoplasma pneumoniae may be included in the differential diagnosis of a lower respiratory tract infection in a young child. Coinfection with viral and bacterial pathogens such as Haemophilus influenzae type b or Streptococcus pneumoniae is uncommon, mainly because of the widespread use of conjugate polysaccharide vaccines.

RSV denotes respiratory syncytial virus. V ir a l C ause s The availability of molecular-detection techniques has made it possible to identify a diverse group of viruses that are capable of causing bronchiolitis Table1. Although the reported proportion of hospitalizations that are attributable to each virus differs according to the geographic area and the year, the most common pathogen is RSV, followed by human rhinovirus.

For example, it has been observed that rhinovirus-associated bronchiolitis may result in a shorter length of hospitalization than bronchiolitis that is attributable to RSV. The epidemiologic and clinical importance of. Patho gene sis The immune response elicited by RSV may be both protective and pathogenic, and there appear to be functional differences between an initial infection in a seronegative infant and reinfection in an older child or adult Fig.

RSV reinfections occur throughout life, despite the induction of both antibody and T-cell responses after a primary infection and the absence of a detectable antigenic change in RSV surface glycoproteins. How RSV evades or inhibits host defenses is not fully understood. In addition, evidence suggests that both the relative balance between type 1 and type 2 helper T cells that respond to antigenic stimulation by the virus and the profile of evoked chemokines and cytokines determines the extent of RSV disease expression.

These findings are not consistent with a pathologic inflammatory response. The fact that a more effective, adaptive cytotoxic Figure 1 facing page. After an incubation period of 4 to 6 days, viral replication in the nasal epithelium results in congestion, rhinorrhea, irritability, and poor feeding. Once in the lower respiratory tract, the virus infects the ciliated epithelial cells of the mucosa of the bronchioles and pneumocytes in the alveoli.

Two RSV surface glycoproteins, F and G, mediate viral attachment to the glyco calyx of the target cell. Viral attachment initiates a conformational change in F protein to a postfusion structure that facilitates fusion of the viral envelope and the plasma membrane of the host cell, resulting in viral entry into the cell.

Cellular infiltration of the peribronchiolar tissue, edema, increased mucous secretion, sloughing of infected epithelial cells, and impaired ciliary beating cause varying degrees of intraluminal obstruction. During inspiration, negative intrapleural pressure is generated and air flows past the obstruction. The positive pressure of expiration further narrows the airways, producing greater obstruction, which causes wheezing.

Innate and adaptive immune responses are involved in viral clearance, and most hospitalized children are discharged after 2 to 3 days. Regeneration of the bronchiolar epithelium begins within 3 to 4 days after the resolution of symptoms. ICU denotes intensive care unit. T-cell response does not develop in such infants is supported by reports of a direct correlation between RSV load, as measured in nasopharyngeal aspirates obtained from children who have been hospitalized with bronchiolitis, and more severe disease, defined as a higher risk of apnea, a longer hospital stay, and a greater need for intensive care.

Resolution of this issue will determine whether a potent antiviral agent administered early in the course of bronchiolitis can reduce the duration and severity of illness without the need for immune modulation.

Virus replication results in epithelial-cell sloughing, inflammatory cell infiltration, edema, increased mucous secretion, and impaired ciliary action Sloughed cells.

After day incubation period, fever, congestion, rhinorrhea, irritability, and poor feeding develop. Cough, tachypnea, wheezing, grunting, nasal flaring, and thoracic retractions may be present. Hyperinflation of the lung develops as air is trapped behind occluded bronchioles. Air trapped in the alveoli is absorbed, resulting in localized atelectasis distal to obstruction. Increased work of breathing and decline in lung function occur owing to mismatching of ventilation and perfusion, resulting in increasing hypoxemia.

Intraluminal obstruction and air trapping Migrating white cells and sloughed cells. Sloughing of RSV-infected epithelial cells into the lumen accelerates viral elimination but also contributes to obstruction of the airway.

Loss of integrity of alveoli Absorption of trapped air in the alveoli distal to the obstruction leads to localized atelectasis. R isk Fac t or s Most infants who are hospitalized with RSV bronchiolitis were born at full term with no known risk factors. Because of the use of antenatal glucocorticoids and surfactant replacement, improvements in methods of ventilatory support, and a better understanding of neonatal nutrition, many preterm infants are healthier at discharge today than in the past.

Infants born with certain types of hemodynamically important congenital heart disease, However, most data defining the relative risk of bronchiolitis among children born with congenital heart disease are more than 10 years old and may not reflect recent advances in corrective cardiac surgery that is undergone early in life.

The extent of the possible increase in the risk of severe bronchiolitis that can be attributed to other conditions e. Most reported host and environmental factors are associated with only a small increase in the risk of hospitalization for RSV infection and thus have a limited contribution to the overall burden of RSV disease.

In temperate climates in the Northern Hemisphere, such as that in the United States, outbreaks of bronchiolitis typically begin in November, peak in January or February, and end by early spring. Lower serum concentrations of maternal RSV antibody resulting from waning maternal immunity from infection during the previous season may account for the more severe disease that is observed among infants born early in the RSV season, as compared with those who are born later.

Rainy seasons and cold weather prompt indoor crowding, which may facilitate viral transmission, especially in areas with high population density. A complex interaction has been identified among latitude, temperature, wind, humidity, rainfall, ultraviolet B radiation, cloud cover, and RSV activity.

Rates of hospitalization for RSV infection among Alaska Native children living in the YukonKuskokwim Delta in southwestern Alaska and in certain indigenous Canadian populations are reported to be five times as high as the rate among agematched children in the continental United States.

Data from several population-based CDC-sponsored reports indicate no disparity in the rates of hospitalization for RSV infection between black children and white children. Some studies have indicated that boys may be at greater risk for severe RSV bronchiolitis than girls; this finding is similar to the sex difference observed with other respiratory viral infections.

Bronchiol i t is a nd A s thm a Severe bronchiolitis early in life is associated with an increased risk of asthma, especially after rhinovirus or RSV bronchiolitis, and an increased risk of asthma may persist into early adulthood. This finding suggests that preexisting pulmonary abnormalities are separate from bronchiolitis and not a complication of it.

Confirmation of this possibility would make it possible to identify infants who would be most likely to benefit from active or passive prophylaxis. A genetic predisposition to severe bronchiolitis early in life and to the subsequent development of asthma is supported by reported associations between polymorphisms in genes involved in the innate immune response and genes mediating allergic responses, surfactant proteins, and inflammatory cytokines.

Results from a Danish study involving twins suggested that severe RSV bronchiolitis is an indicator of a genetic predisposition to asthma and that, in the absence of this predisposition, asthma is less likely to develop even if they had previously had bronchiolitis. A randomized, doubleblind, placebo-controlled trial conducted in the Netherlands involving preterm infants born at 33 to 35 weeks of gestation addressed the possible benefit of prophylaxis with palivizumab ahumanized anti-RSV antibody in preventing wheezing during the first year of life.

Because the viral cause of wheezing episodes was determined inconsistently and the primary end point of the study was audible wheezing as reported by a parent, rather than a medically verified event, the small reduction in the number of days with wheezing is of uncertain clinical significance. A prospective randomized, placebo-controlled trial with motavizumab a second-generation monoclonal antibody with greater potency against RSV than palivizumab that involved healthy, full-term Native American infants showed a significant between-group difference in favor of motavizumab in both inpatient and outpatient medically attended RSV lower tract disease.

This result is consistent with the concept that prevention of RSV infection with immunoprophylaxis does not have a measurable effect on subsequent episodes of wheezing. No available treatment shortens the course of bronchiolitis or hastens the resolution of symptoms.

Therapy is supportive, and the vast majority of children with bronchiolitis do well regardless of how it is managed. The intensity of therapy among hospitalized children has been shown to have little relationship to the severity of illness.

Short-acting 2-agonists, epinephrine, and systemic glucocorticoids are not recommended for the treatment of children with bronchiolitis. Intravenous or nasogastric fluids may be used for children with bronchiolitis who cannot maintain hydration orally. A complete discussion regarding the management of bronchiolitis is available in the clinical practice guidelines. Palivizumab, a humanized mouse IgG1 monoclonal antibody directed against a conserved epitope on the surface fusion protein of RSV, was licensed by the Food and Drug Administration in June for monthly prophylaxis for infants at high risk for RSV infection.

Table 2. Poor correlation with severity of disease or risk of progression; studies show increase in inappropriate use of antimicrobial therapy owing to similar radiographic appearance of atelectasis and infiltrate. May influence isolation of symptomatic patients, but infection-control procedures are similar for most respiratory viruses. Randomized trials have not shown a consistent beneficial effect on disease resolution, need for hospitalization, or length of stay. Large, multicenter, randomized trials have not shown improvement in outcome among outpatients with bronchiolitis or hospitalized children.

Oxygen saturation is a poor predictor of respiratory distress; routine use correlates with prolonged stays in the emergency department and hospital Deep suctioning is associated with a prolonged hospital stay; removal of obstructive secretions by suctioning the nasopharynx may provide temporary relief.

Hospitalization for observation of hydration and nutritional status may be needed for infants with respiratory distress. Risk of serious bacterial infection is low; routine screening is not warranted, especially among infants 30 to 90 days of age Intravenous or nasogastric hydration may be used. Guidance from the American Academy of Pediatrics regarding the use of palivizumab is stratified according to risk, targeting the infants who are most likely to benefit from prophylaxis.

F u t ur e Dir ec t ions RSV is one of the last viruses to cause annual worldwide outbreaks of disease against which no safe and effective vaccine is available. Several approaches to vaccine development are being investigated. Efforts to date have been hampered by the difficulty of achieving.

Table 3. Maximum five monthly doses or Rate of hospitalization for RSV infection is higher than until end of RSV season, whichamong infants born at 29 wk of gestation3,34,35 ever comes first. No significant difference, as compared with full-term infants, in rate of hospitalization for bronchiolitis3,34, No significant reduction in rates of hospitalization for RSV 7.

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