Liječenje infekcija donjeg dijela dišnog sustava uzrokovanih respiratornim sincicijskim virusom

Respiratorni sincicijski virus (RSV) najčešći je uzročnik teških infekcija donjeg dijela respiratornog trakta (DRTI) u dječjoj dobi. U terapiji se uz potpornu terapiju kisikom i rehidratacijom uglavnom rabe bronhodilatatori i kortikosteroidi. U posljednjih deset godina antibiotska se terapija također provodila dosta često i nekritički. Specifični antivirusni lijek je ribavirin, čija je primjena dosta ograničena i sporna. U novije vrijeme moguća je terapija specifičnim RSV-imunoglobulinom. Kako djelotvorno cjepivo protiv RSV-infekcija još ne postoji, moguće je provoditi samo pasivnu profilaksu RSV-imunoglobulinom (RSV-IG) ili humaniziranim monoklonskim protutijelima.
Praćenjem provedene terapije u RSV-pozitivnih bolesnika, uglavnom dojenčadi s RSV-DRTI, u Zagrebu 1988-94, nađeno je da su bronhodilatatori davani u 75,6%, a kortikosteroidi u 20% bolesnika. U 5% bolesnika provedena je umjetna respiracija, dok specifična terapija ribavirinom nije provođena. Antibiotici su upotrijebljeni u 92,4% bolesnika s RSV-DRTI
The application of bronchodilators in the treatment of patients with bronchiolitis and wheezy bronchitis in small children is controversial (7). Some recent papers have indicated that bronchodilators may be used in the treatment of bronchiolitis in some patients (7, 11). Those patients, in the first place, would be children, mainly above the age of 1 year where wheezing is a significant symptom (8). Derish et al (12) found beneficial effects of bronchodilators in infants with severe RSV infection. Out of 88 centres represented in the European Society for Paediatric Infectious Diseases (ESPID), bronchodilator treatment was applied universally in various combinations in all patients in 54 centres (13). Another study, the Pediatric Investigators Collaborative Network on Infections in Canada, has indicated that bronchodilators were applied in 77-95% of patients (14). During RSV outbreaks from 1988 to 1994, RSV-LRTI was followed in 201 hospitalized children, mostly infants, at the childrens wards of two Zagreb hospitals. Bronchodilators were applied in 152 (75.6%) cases (Figure 1). They were applied for 1 day (the shortest) to 56 days (the longest) (Figure 2) (15). In a less severe clinical picture (when ventilation disorders and bronchial hypersecretion are not severe), beta-2 selective bronchodilators are sufficient (e.g. salbutamol). The most appropriate application is an inhalation of a liquid or an oral spray by the so called babyhaler.
Newly racemic epinephrine (micronephrine) inhalations are recommended. Micronephrine is a sympathomimetic amine with topical effect within the respiratory tract. It has a vasoconstrictor property through alpha-receptor stimulation which results in the reduction of mucosal and submucosal oedema, and also a beta-2 receptor stimulating effect with the reduction of airway smooth muscle spasm. Administration: inhalation by micronebulizer or inhalator with individual control of reactions. Adverse reaction: increased heart rate greater than 20-40/min. Epinephrine showed its efficiency in 63% of infants aged less than 12 months and in 92% of children aged between 12 and 24 months according to clinical criteria based on elevated respiratory rate, wheezing and retractions (16).
In case the inhalation therapy by salbutamol or micronephrine is insufficient and the respiratory distress is increasing, continuous intravenous infusion of aminophiline may be used in addition but blood concentrations should be monitored.
According to the American Academy of Pediatrics, corticosteroids in previously healthy infants with RSV bronchiolitis are not indicated (10). However, corticosteroids were administered by more than 80% of ESPID colleagues in various combinations of administration routes. They may be effective in accelerating the clinical recovery of children admitted to hospital with RSV bronchiolitis (13). More than one half of the centres has administered corticosteroids by a combination of inhalation, parenteral and/or oral route. Corticosteroids used in oral and parenteral applications are prednisolone and hydrocortisone (17), and beclomethasone for inhalation (18).
Lukić et al (15) found the application of corticosteroids in 40/201 (20%) Zagreb RSV-LRTI patients (Figure 1). Corticosteroids were applied for 1 day (the shortest) to 14 days (the longest) (Figure 3). They were applied in cases of bronchiolitis (19), bronchitis (16), and pneumonia (5). Corticosteroids were administered parenterally, and only in 1 infant aged less than 6 months locally (15).
Mechanical ventilation
Mechanical ventilation is also used as a support and non-specific therapy in extremely severe cases of RSV infection (8). An indication for the utilization of mechanical ventilation is hypoxia which does not respond to oxygen therapy and recurrent prolonged apnoea (19, 20, 21, 22). According to data from literature, around 20% of RSV positive patients with congenital heart disease (CHD) were supported by mechanical ventilation (14, 23). A group of Canadian authors found that mechanical ventilation was used in 20.6% of children with CHD, in 20.9% of children with chronic pulmonary disease, in 15.5% of infants aged less than 6 weeks, in 15.2% of premature children (gestation <36 weeks), and in 13.3% of children with early hypoxia (in the first 28 hours upon admission) (24). In the Zagreb study, there was only one patient with CHD who suffered RSV-LRTI, and although he was supported by mechanical ventilation, he died (15).
According to data from literature, antibiotics are to a high percentage used in the therapy of bronchiolitis caused by RSV although such patients rarely develop secondary bacterial infections and produce negative hemocultures (11). Hall et al (25) have noted that severe bacterial infections in children with bronchiolitis were rarely observed. Adcock et al (26) have given the figure of 42% patients with bronchiolitis who were treated by antibiotics. The study done in Canada (14) has shown that 60% of previously healthy children with bronchiolitis were treated by antibiotics. Lukić et al (15) have found the application of antibiotics in 185/201 (92.4%) of patients with RSV-LRTI (Figure 1). In that study, positive bacterial tests for throat and nasopharyngeal swabs were observed in 45 (54.2%), 24 (48%), and 30 (58.8%) cases of bronchitis, bronchiolitis and pneumonia, respectively. Haemophilus influenzae was isolated in 19.6% of patients with RSV pneumonia and Streptococcus pneumoniae in 27.4% (15). Hall et al (25) have emphasized that as a risk of secondary bacterial infection, with Streptococcus pneumoniae and Haemophilus influenzae, pneumonia was suggested to have been developed in 1.2% of children with RSV infection. Korppi et al (27) found coinfection with bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, in children with RSV pneumonia in about 40%. Some RSV-LRTI patients, beside the underlying syndrome for which they had been hospitalised and treated, also had the symptoms and findings of another respiratory tract infection. Since children with bronchiolitis show a high prevalence of otitis media, it certainly may be the reason for introducing antibiotics in the therapy (28). In Zagreb study beside bronchitis, the RSV-positive patients most frequently showed the signs of otitis media (19 patients) (15). Those who had pneumonia as the first diagnosis showed most frequently otitis media as the secondary diagnosis (9 patients) (15).
It is recommended that antibiotics in previously healthy children with bronchiolitis should not be routinely administered since severe bacterial infections are rare (septicaemia and pneumonia) but are indicated if bacterial pneumonia is suspected (high temperature, lobar infiltration, high erythrocyte sedimentation level (ESL), white blood cell count (WBC) >15000, high C-reactive protein value (CRP) (11, 15). Since otitis media is frequent in children with RSV infection, it is treated by antibiotics orally, and the recommendation is not to interrupt the antibiotics therapy if bacteria are not found and viral etiology is confirmed (11).
Ribavirin (1-D-ribofuranosyl-1,2,4-tri-azol-3-carboxamine) is a synthetic nucleoside (analogue to guanosine and inosine) that interferes with viral synthesis of guanosine triphosphate (GTP) (7). Three possible mechanisms of action for ribavirin have been proposed: 1. a decrease in the intracellular concentration of GTP due to competitive inhibition of inosine monophosphate dehydrogenase and to virus-specific actions, 2. inhibition of 5'-cap formation of mRNAs and 3. inhibition of the function of virus-coded RNA polymerases necessary to prime (initiate) and elongate viral mRNAs (29). Its effectiveness has been proven in vitro for RSV, measles virus, parainfluenza and influenza viruses (29).
Various investigations were carried out with the aim of determining the effectiveness of ribavirin (22, 30, 31, 32). Those were mostly studies with placebo control in previously healthy children and in children with bronchopulmonary dysplasia (BPD) or CHD. Hall et al (30, 31) have shown that in previously healthy children infected by RSV, ribavirin therapy shortened the duration of virus secretion. Smith et al have noted a decreased need for mechanical ventilation in children with BPD and CHD (22). Edell et al (33) have also shown the positive effect of ribavirin in the prevention of repeated wheezing caused by RSV.
Contrary to previous authors, in previously healthy children, Rodriguez et al (32) have observed no difference in the duration of virus secretion between children treated by ribavirin and those who were not treated by the drug. Long et al (34) have shown by measuring the pulmonary function of RSV-LRTI patients that there was no difference between children who were administered ribavirin and the control group, i.e. they have not found any significant effect of ribavirin therapy. So, the administration of ribavirin in previously healthy children, even when they show severe clinical signs, is controversial. In other words, it is considered that in those children, in spite of severe RSV-LRTI, the application of even non-specific therapy results decreases clinical symptoms within a few days (7). The Committee for Infectious Diseases of the Academy of Paediatrics has recommended ribavirin therapy in infants and small children who have a high risk of developing severe RSV disease (10). Those are, in the first place, children with complicated CHD, BPD, cystic fibrosis, and other chronic pulmonary diseases, previously healthy but premature children (gestation <37 weeks), and infants aged less than 6 months. Furthermore, ribavirin therapy is recommended also for all children with any immunosuppresive disease or those who receive immunosuppresive therapy (AIDS, severe combined immunodeficiency disease, organ transplantation) with a possible high mortality rate due to RSV infection or prolonged RSV disease. It is recommended for all children who develop severe clinical symptoms either supported or not by mechanical ventilation. Also, it is recommended for hospitalized patients with moderate RSV disease who have an increased risk of developing a severe disease. Those are patients either aged less than 6 weeks or having some other disease, such as multiple congenital anomaly or some neurological or metabolic diseases (10). Ribavirin is administered as an aerosol via an oxygen hood, tent or into a ventilator tubing mask. The therapy lasts 12 to 20 hours, 1 to 7 days (10). Oral administration of ribavirin may result in anaemia and elevated bilirubin levels (7). It is considered that the application of ribavirin may be toxic for health care personnel and requires wearing gloves and masks in order to reduce possible hazardous exposure. Also, the recommendation is for pregnant women to avoid caring for children on ribavirin therapy due to possible teratogenic drug effect (7).
Respiratory syncytial virus immunoglobulin (RSVIG)
RSV-IG is prepared from donors with high titre serum neutralizing RSV antibodies. In spite of all measures and controls such a product inevitably has to undergo, there is still the possibility of transferring an unexpected pathogen (35). Respiratory syncytial virus immunoglobulin may be an effective therapy but also an effective prevention of severe RSV infections (7). The therapeutic effectiveness of intravenous immunoglobulin was tested in infants and small children with RSV pneumonia and bronchiolitis (36). The results were similar to those obtained after ribavirin administration as an aerosol, i.e. the quantity of the secreted virus was significantly reduced within 48 hours, and the oxygenation was significantly increased within 24 hours. Rodriguez et al (37) have also shown the positive effect of RSV-IG infusions in previously healthy infants and small children, especially in those with a severe clinical picture of RSV infection but the duration of hospitalization and recovery in intensive care units was not shortened. Sandritter and Kraus (38), however, have observed that the prophylaxis by RSV-IG decreased the incidence (from 65% to 41%) and the duration of hospitalization for RSV-positive patients. Welliver has also found that passive prophylaxis in premature children with or without bronchopulmonary dysplasia reduced the severity of the clinical picture and shortened hospitalization by 40% (39). RSV-IG has been approved for application in the prevention of severe RSV infections in infants and children aged less than 24 months with BPD, and in premature children/gestation <35/ (39). It is to be administered once a month immediately before and at the time of the RSV season at a dosage of 15 mL/kg (750 mg/k). RSV-IG is not approved for application in children with CHD (10). The administration of RSV-IG in immunocompromised infants and children still has to be further investigated although it is considered that it may be efficient in patients with severe immunodeficiency (severe combined immunodeficiency or severe HIV infection) (10). RSV-IG prophylaxis should be started before the beginning of the RSV season and stopped at the end of the season. In children receiving RSV-IG prophylaxis, immunization with MMR (measles, mumps, rubella) vaccine should be postponed by 9 months (10).
Humanized monoclonal antibodies
Palivizumab are monoclonal antibodies to RSV. It is a biotechnologically produced molecule of immunoglobulin which, like RSV-IG, has the ability of neutralizing RSV but also has some differences and potential advantages over RSV-IG. The antibody was humanised by recombinant methods by inserting the complementary determining regions from an F-protein-specific neutralizing murine monoclonal antibody into a human IgG framework (40). Therefore a mouse monoclonal antibody which serves for production of polivizumab recognizes the protective epitopes on F glycoprotein of RSV (35). It has been determined earlier that antibodies to F protein neutralize the activity of RSV. Besides, F protein is highly conserved between A and B type of RSV (8). The advantages of this product over RSV-IG are: 1. the possibility of intramuscular administration (41); 2. the product is composed of pure RSV antibodies and the neutralization activity level is higher (42); and 3. there is no danger of introducing a pathogen (35). Human monoclonal antibodies are produced in a cell culture thus avoiding the possibility of transferring microorganisms. It is assumed that tolerance to this product should not present a problem since the majority of the original mouse monoclonal antibodies are replaced by human immunoglobulin (35).
RSV is spread worldwide, and has shown high proportions of infant morbidity and mortality. There are no precise therapeutic measures against RSV bronchiolitis at national and international levels around the world. These significant inconsistencies in therapy may be due to controversial reports of treatment of the disease in literature. The fact could be partly ascribed to the dramatic clinical picture of individual patients which requires rapid therapeutical action by all available resources that might be of assistance. The Zagreb study presented the actual situation of the treatment of RSV-LRTI in Croatia until 1994 (15). The treatment of patients in Croatia was in accordance with treatment applied elsewhere. Too frequent administration of antibiotics was observed in the support therapy, i.e. in as many as 92.4% of RSV-LRTI patients (15). In Croatia, children with bronchiolitis were not administered ribavirin because of its high cost and still dubious therapeutical effectiveness. The principal aims of the treatment of this disease are to avoid nosocomial infection and shorten treatment duration in children with bronchiolitis at intensive care units, to reduce the need for mechanical ventilation, and, of course, to reduce mortality. The application of specific therapy, and particularly the application of recent forms of prevention such as RSV-IG and humanised monoclonal antibodies, is seen as a great step forward in the prevention and treatment of such a severe disease of the respiratory system until an efficient vaccine is found.
As a support therapy, important are adequate hydration and oxygenation, respiratory tract toilette by frequent gentle aspirations using a soft tube, digitalization when necessary, and sedation in extreme cases.
Each child with bronchiolitis should be given treatment by bronchodilator. The therapy should be stopped only when the condition gets worse. Although salbutamol is found in different forms (syrup, tablets, inhalation liquids and oral spray (metered dose inhaler MDI)), it is recommended to be applied by inhalations using an inhalator or a babyhaler.
In the more severe clinical pictures, when lung auscultation shows crackles and wheezing, it is recommended to administer racemic epinephrine (micronephrine) to reduce mucosal edema along with bronchodilatation. If the above procedures do not yield any improvement, parenteral therapy by aminophiline should be applied.
We are of the opinion that corticosteroids have found their place in the treatment of the most severe forms of bronchiolitis when mechanical ventilation is already under consideration. Short parenteral therapy by methylprednisolone is applied. The immunopathogenesis of RSV bronchiolitis is known to be similar to that of asthma, hence the justified application of corticosteroids. Inhalatory corticosteroids (fluticasone-propionate) may have an impact on the course of a moderately severe disease. Although the risk of secondary bacterial infection in children with bronchiolitis is very low, sometimes it is necessary to introduce an antibiotic at the very beginning of the treatment. It applies to children with septic appearance, disease presented with apnoeas, and laboratory findings indicating bacterial infection. Double infections with RSV and bacteria should not be overlooked.
RSV-IG or ribavirin are reasonably administered to severely ill children or those at high risk. With an appropriate support therapy, mechanical ventilation is rarely needed. It is commonly applied in cases of frequent apnoeas with significant hypoxia, hypercapnia, acidosis, and respiratory failure despite the support of high oxygen doses.
Ključne riječi:
Kategorija: Pregled
Broj: Vol. 43, No 4, listopad - prosinac 1999
Autori: V. Hrešić - Kršulović, A. Baće, A. Lukić-Grlić, G. Mlinarić-Galinović, R. Lokar-Kolbas
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