Avigdor Mandelberg

Association between Common Toll-Like Receptor 4 Mutations and Severe Respiratory Syncytial Virus Disease

BACKGROUND The clinical spectrum of respiratory syncytial virus (RSV) bronchiolitis in previously healthy infants is extremely variable. Thus, it is likely that factors such as genetic heterogeneity contribute to disease severity. Toll-like receptor 4 (TLR4) and CD14 are part of a receptor complex involved in the innate immune response to RSV. METHODS The association of the TLR4 mutations (Asp299Gly and Thr399Ile) and the CD14/-159 polymorphism were analyzed in 99 infants hospitalized with severe RSV bronchiolitis (group I). Eighty-two ambulatory infants with mild RSV bronchiolitis (group II) and 90 healthy adults (group III) composed the 2 control groups. The TLR4 mutations and the CD14/-159 polymorphism were genotyped by use of reverse-transcriptase polymerase chain reaction and restriction fragment-length polymorphism analysis, respectively. RESULTS Each of the TLR4 mutations, either alone or in cosegregation, were associated with severe RSV bronchiolitis: the Asp299Gly and Thr399Ile mutations were significantly overrepresented in group I, compared with groups II and III. No association between the CD14/-159 polymorphism and RSV bronchiolitis was found. CONCLUSIONS These findings suggest that TLR4 mutations, but not the CD14/-159 polymorphism, are associated with an increased risk of severe RSV bronchiolitis in previously healthy infants.

Hypertonic saline or high volume normal saline for viral bronchiolitis: Mechanisms and rationale

In recent years and particularly in the last 5 years, there have been substantial advances in our understanding of the mechanisms governing mucus clearance (MC) in health and disease. These have demonstrated the role of hydration of the airway surface liquid (ASL) and the importance of inhaled hypertonic saline for rehyadration and have been recently reviewed. Briefly, it was suggested that MC failure is a dominant factor not only in CF but in most airway diseases and that hydration is the dominant variable governing MC in all airway diseases. This was also found to be true even in normal subjects and furthermore, it has been noted, that exacerbations in many airway diseases result from intermittent catastrophic failures of MC due to dehydration of ASL often triggered by viral infections. Thus, therapy to maintain ASL hydration is probably important during viral exacerbations not only in CF patients but in all chronic airway diseases. Issues crucial to understanding the postulated mechanism involving hypertonic saline inhalation treatment in RSV bronchiolitis will be described in more detail here.

A Double-Blind, Placebo-Controlled, Randomized Trial of Montelukast for Acute Bronchiolitis

BACKGROUND. Cysteinyl leukotrienes are implicated in the inflammation of bronchiolitis. Recently, a specific cysteinyl leukotriene receptor antagonist, montelukast (Singulair [MSD, Haarlem, Netherlands]), has been approved for infants in granule sachets. OBJECTIVE. Our goal was to evaluate the effect of montelukast on clinical progress and on cytokines in acute bronchiolitis. METHODS. This was a randomized, placebo-controlled, double-blind, parallel-group study in 2 medical centers. Fifty-three infants (mean age: 3.8 ± 3.5 months) with a first episode of acute bronchiolitis were randomly assigned to receive either 4-mg montelukast sachets or placebo, every day, from hospital admission until discharge. The primary outcome was length of stay, and secondary outcomes included clinical severity score (maximum of 12) and changes in type 1 and 2 cytokine levels (including interleukin4/IFN-γ ratio as a surrogate for the T-helper 2/T-helper 1 ratio) in nasal lavage. RESULTS. Both groups were comparable at baseline, and cytokine levels correlated positively with disease severity. There were neither differences in length of stay (4.63 ± 1.88 [placebo group] vs 4.65 ± 1.97 days [montelukast group]) nor in clinical severity score and cytokine levels between the 2 groups. No differences in interleukin 4/IFN-γ ratio between the 2 groups were seen. There was a slight tendency for infants in the montelukast group to recover more slowly than those in the placebo group (clinical severity score at discharge: 6.1 ± 2.4 vs 4.8 ± 2.2, respectively). CONCLUSIONS. Montelukast did not improve the clinical course in acute bronchiolitis. No significant effect of montelukast on the T-helper 2/T-helper 1 cytokine ratio when given in the early acute phase could be demonstrated.

Does the size of nasogastric tubes affect gastroesophageal reflux in children

BACKGROUND To evaluate the effects of nasogastric tube insertion and different nasogastric tube sizes on gastroesophageal reflux in children. METHODS During a prospective randomized study, 29 patients aged 1 month to 4 years (median, 9 months) underwent 24 hours of continuous esophageal pH monitoring to rule out gastroesophageal reflux as the cause of severe pulmonary problems. Each patient was monitored without nasogastric tube for 16 hours (baseline), and thereafter the first nasogastric tube, small (8-Fr) or large (10-Fr or 12-Fr), was placed. Four hours later, the original nasogastric tube was replaced by a new one of large (instead of small) size or of small (instead of large) size. We selected the times of wakefulness in these study periods and compared the number of reflux episodes (NREs), the number of reflux episodes that lasted more than 5 minutes (NRE>5), and the percentage of time with esophageal pH less than 4 (PTP<4). RESULTS The 12-Fr group in comparison with the 8-Fr group and baseline showed significant difference (P<0.05) in the NRE>5 and PTP<4 parameters. No significant differences were found when comparing 8-Fr versus 10-Fr groups and baseline. In children with (n = 20) and without (n = 9) gastroesophageal reflux, comparison of the various reflux parameters between baseline and the different sizes of nasogastric tubes showed the same results. CONCLUSIONS Size of the nasogastric tubes is a significant factor in predisposing the child to gastroesophageal reflux. Large nasogastric tubes interfere with the clearance of the refluxed acid from the esophagus.

Dorsal penile nerve block in children under- going circumcision in a day-care surgery

PurposeCircumcision is performed under general anaesthesia (GA) with dorsal penile nerve block (DPNB) as an analgesic technique for postoperative pain. The purpose of this study was to compare DPNB as the sole anaesthetic procedure vs GA and DPNB for circumcision in children as an outpatient procedure.MethodsIn a six-month prospective study, 250 boys aged 6 to 17 yr (mean age 11.5 ± 3.5 yr) were randomized into two groups. Group A (n = 122) received DPNB only prior to circumcision, and Group B (n = 128) received GA + DPNB. The groups were compared for complications of the block, effectiveness of anaesthesia, operating room time, postoperative time and ease of recovery.ResultsThere were no major operative complications in the two groups. Minor block complications, including oedema and haematoma, occurred in 16 (13.1%) boys in Group A and 27 (21.10%) boys in Group B (NS). At surgery, 3 (2.6%) from Group A received additional GA and 1 (0.8%) received additional local anaesthesia. They represent a DPNB failure rate of 3.3%. Mean operating room time was 11 ± 2.5 min in Group A and 19 ± 3.5 min in Group B, and post-anaesthesia care unit (PACU) time was 51 ± 10 min in Group A and 101 ± 14.5 min in Group B (P < 0.001). Nausea and vomiting in the PACU were noted in one patient in Group A and in 15 in Group B (P < 0.05). Only patients in Group B required additional analgesia and tranquilizers in the PACU (0 versus 20; P < 0.05).ConclusionsThese data confirm that DPNB has advantages over GA + DPNB for paediatric circumcision in day-care surgery.RésuméObjectifLa circoncision est réalisée sous anesthésie générale (AG) associée au bloc du nerf dorsal de la verge (BNDV) pour l’analgésie postopératoire. Cette étude visait à comparer chez des enfant opérés en chirurgie ambulatoire le BNDV seul et l’anesthésie générale avec BNDV.MéthodesPendant une étude prospective de six mois, 250 garçons âgés de 6 à 17 ans (âge moyen 11,5 ± 3,5 ans) avaient été répartis au hasard entre deux groupes. Le groupe A (n = 122) recevait un BNDV seul avant la circoncision et le groupe B (n = 128) recevait AG + BNDV. Les groupes étaient comparés au regard des complications du bloc, de l’efficacité de l’anesthésie, de la durée de l’intervention, de la durée de la période postopératoire et du confort du patient.RésultatsIl n’y a pas eu de complication opératoires majeures dans aucun des groupes. Des complications mineures dues au bloc, dont l’oedéme et l’hématome sont survenues chez 16 (13,3%) des garçons du groupe A et chez 27 (21,10%) du groupe B (NS). Au moment de la chirurgie, dans le groupe A, on a complété avec de l’anesthésie générale chez trois enfants (2,6%) et avec un anesthésique local chez un enfant (0,8%). Ce qui établi le taux d’échec du BNDV à 3,3%. La durée moyenne de l’utilisation de la salle d’opération était de 11 ± 2,5 min pour le groupe A et de 19 ± 3,5 min pour le groupe B. La durée du séjour à l’unité de soins postanesthésiques (USPA) était 51 ± 10 min pour le groupe A et de 101 ±14,5 min pour le groupe B (P < 0,001). À l’USPA, des nausées et vomissements sont survenus chez un patient du groupe A et chez 15 du groupe B (P < 0,05). À l’USPA, seuls les patients du groupe B ont eu besoin d’analgésie additionnelle et de tranquillisants (0 vs 20; P < 0,05).ConclusionCes données confirment certains avantages de BNDV sur AG + BNDV pour la circoncision en chirurgie ambulatoire.

Slow injection of local anaesthetic will decrease pain during dorsal penile nerve block

Purpose: To evaluate whether a very slow injection of local anaesthetics during dorsal penile nerve block for circumcision causes less pain than a more rapid injection.

Epidemiologic, Socioeconomic, and Clinical Factors Associated with Severity of Respiratory Syncytial Virus Infection in Previously Healthy Infants

We prospectively quantified disease severity associated with epidemiologic and socioeconomic parameters as well as the clinical factors in 195 previously healthy infants with confirmed respiratory syncytial virus (RSV) infection. Infants were enrolled into three subgroups according to disease severity: outpatients (82 patients), inpatients (100 patients), and intensive care unit patients (13 patients). Epidemiologic parameters such as gestational age, birth weight, chronologic age at presentation, and gender as well as socioeconomic factors such as ethnic origin, family history of asthma, exposure to cigarette smoke, number of family members, presence of pets at home, breast-feeding, and day-care attendance were not found to predict the severity of RSV illness in previously healthy infants. Our results emphasize the complexity of predicting disease severity in previously healthy infants with RSV infection and suggest that other parameters such as host genetic background might explain the clinical variability.

Giardiasis with protein-losing enteropathy: diagnosis by fecal α1-antitrypsin determination.

: Giardia lamblia infection was documented by jejunal biopsy in a previously healthy 2-year-old boy with acute onset of hypoproteinemia due to protein-losing enteropathy. All symptoms and abnormal laboratory findings resolved with anti-Giardia therapy. This is only the second case report of giardiasis with documented protein-losing enteropathy. Further application of the fecal alpha 1-antitrypsin assay may help to clarify the relationship between Giardia infection and protein-losing enteropathy and its role in development of malnutrition.

Efficacy of EMLA® cream prior to dorsal penile nerve block for circumcision in children

Background: While circumcision may be performed solely with dorsal penile nerve block (DPNB), some painful steps in its use are skin needle penetration and infiltration of the anesthetic product. The objective of this study was to evaluate the efficacy of EML® cream, prior to DPNB for circumcision in children.

Effect of Natural Oxygen Enrichment at Low Altitude on Oxygen-Dependent Patients with End-Stage Lung Disease

Long-term home oxygen therapy is the standard of care for patients with chronic obstructive pulmonary disease and end-stage lung disease with chronic hypoxemia [1-6]. Oxygen therapy improves functional and exercise capacity [4-7], reduces pulmonary hypertension, and improves right ventricular function [8, 9] and survival [10, 11]. This important tool in pulmonary medicine involves substantial cost and requires continuous maintenance of equipment and patient cooperation. Further, despite the major advances in portable oxygen devices, quality of life for patients receiving long-term oxygen therapy is substantially impaired because of the constant dependence on an oxygen source and equipment. An alternative to portable oxygen therapy is the natural oxygen enrichment resulting from high barometric pressure at altitudes below sea level, but this has not been investigated and is not routinely recommended by pulmonary physicians or in any major textbook in pulmonary medicine. To assess this therapeutic option, we took advantage of the natural topography of the Dead Sea and its holiday resorts that lie at the lowest natural altitude on earth (402 m below sea level), a short distance (40 km) from Jerusalem, which lies 800 m above sea level. This yields a 1200-m difference in altitude between the two locations. The alveolar oxygen concentration can be calculated using the following equations: PAO2 = (barometric pressure 47) x Fio 2 Pa CO2/0.8 PAO2 Dead Sea = (800 47) 0.21 Paco 2/0.8 = 158.1 - Paco 2/0.8 PAO2 Jerusalem = (696 47) 0.21 Paco 2/0.8 = 136.3 - Paco 2/0.8 Additional inspired Po 2 = 21.8 mm Hg Delta Paco 2/0.8, where PAO2 is the partial pressure of alveolar oxygen; Fio 2 is the fractional concentration of oxygen in inspired gas; Paco 2 is the partial pressure of arterial carbon dioxide; and Po 2 is the oxygen pressure. We investigated the short-term effect of lowering altitude in 10 patients with various lung diseases who used oxygen on a long-term basis and compared arterial oxygenation, spirometry, exercise tolerance, and oxygen saturation values during sleep at high and low altitudes. Methods We studied 10 oxygen-dependent patients attending the pulmonary clinic at Hadassah University Hospital in Jerusalem, Israel. Table 1 summarizes demographic data and diagnoses. The five males and five females, 12 to 77 years of age, had severe obstructive or restrictive lung disease, as indicated by their lung function results (Table 2). Table 1. Demographic Data of Patients with End-Stage Lung Disease* Table 2. Pulmonary Function of Patients* Barometric pressure was measured daily during the study. In Jerusalem it was between 696 and 697 mm Hg and at the Dead Sea it was between 797 and 800 mm Hg. We studied patients in Jerusalem 7 to 10 days before their descent to the Dead Sea resort area, on day 6 of their stay at the Dead Sea, and 7 to 14 days after returning to Jerusalem. The equipment and staff were the same at both locations. Each patient had the following studies on each examining day. Blood Gas Analysis Using radial arterial puncture and topical anesthesia, we obtained arterial blood while patients breathed room air. We used a Corning 175 gas analyzer (Corning, New York) to do blood gas analyses. Spirometry We measured spirometry and maximal voluntary ventilation for 12 seconds using an electronic spirometer (Vitalograph, Ltd., Buckingham, United Kingdom). The predicted values we used were European Coal Conference Standard 1983. In Jerusalem, we also measured lung volumes by whole-body plethysmography and carbon monoxide diffusion capacity by the single-breath method using MedGraphics equipment (Medical Graphics Corp., St. Paul, Minnesota). Data were corrected for body temperature and ambient pressure, saturated with water vapor (BTPS). Exercise Testing Patients performed incremental exercise tests using an electronically braked cycle ergometer (MedGraphics CPE 2000, Medical Graphics Corp.) and a breath-by-breath analyzing system (MedGraphics CPX, Medical Graphics Corp.). After a rest period of 2 minutes, the patients peddled at 60 rpm without added load for 2 minutes. The work load was then increased gradually in a ramp pattern at a rate calculated so each patient would complete the exercise in 6 to 10 minutes. The patients continued the test to their symptom-limited maximum capacity [12]. Data were corrected for BTPS or STPD (the gas volume at standard temperature and pressure, free of water vapor) at both locations. Sleep Oximetric Study Continuous nocturnal sleep oximetry was studied in Jerusalem and at the Dead Sea in six patients (patients 1, 2, 3, 4, 5, and 8). We used a Nonin 8600 finger oximeter and 8586 printer interface module (Nonin Medical, Plymouth, Minnesota). Minute-by-minute data and histograms were printed each morning after the night study was completed. Statistical Analysis Data are expressed as medians and observed paired differences with corresponding 95% confidence intervals of the median paired differences. We used the Wilcoxon matched-pairs signed-rank test to determine the significance of differences. Probability values less than 0.05 were considered significant. We obtained informed consent from all patients, and the study was approved by the Helsinki Committee of Hadassah University Hospital. Patients were interviewed before each study and were asked about their general well-being, use of oxygen, daily activities, and exercise capacity. Results Spirometry There were no significant differences in spirometry values at the two locations. Arterial Blood Gases Results of analyses are shown in Figure 1 and Table 3. Arterial Po 2 increased from a median of 51.6 mm Hg in Jerusalem to 67.0 mm Hg at the Dead Sea, an increase of 15.2 mm Hg (CI, 4.1 to 20.4 mm Hg). The Paco 2 values also increased but to a lesser degree. The alveolar-arterial gradient did not change substantially, and pH remained unchanged. After the return to Jerusalem, the values returned to those found before descent to the Dead Sea. Table 3. Blood Gas Analysis in Jerusalem and at the Dead Sea* Figure 1. Blood gas analysis of 10 patients in Jerusalem (before traveling to the Dead Sea resort) and at the Dead Sea. Top left. o Top right. co Bottom left. o Bottom right. Exercise Performance Results of exercise testing are given in Table 4. Maximal oxygen uptake (VO2max) increased with the descent to the Dead Sea compared with the results obtained in Jerusalem. After the return to Jerusalem, VO2max returned to the previous level. The anaerobic threshold did not change significantly (median of 650 mL/min in Jerusalem and 710 mL/min at the Dead Sea; P = 0.5). We also found no significant differences in minute ventilation during rest and maximal exercise, although heart rate increased slightly. End tidal carbon dioxide and oxygen pulse (Vo 2/heart rate) increased during rest and maximal exercise at the Dead Sea compared with the values measured in Jerusalem. At peak exercise, oxygen saturation decreased at both locations to the same degree. Table 4. Progressive Exercise Testing in Jerusalem and at the Dead Sea* Nocturnal Oximetry Results of nocturnal oximetry are shown in Figure 2. Six patients had oximetric monitoring during the night. All reported usual sleep with a median duration of 5.5 hours in Jerusalem and 5.2 hours at the Dead Sea. Median oxygen saturation increased from 85% in Jerusalem to 90% at the Dead Sea, a change of 5% (CI, 2% to 7%; P = 0.005). The percentage of total sleep time with oxygen saturation greater than 90% increased from a median of 24% in Jerusalem to 73% at the Dead Sea, an increase of 49% (CI, 20% to 87%; P = 0.02). Median heart rate during sleep was 82 beats/min in Jerusalem and 76 beats/min at the Dead Sea (P = 0.25). When questioned, all patients reported an improvement in their general well-being, with less need for oxygen during simple daily activities compared with their usual activities in Jerusalem. Figure 2. Sleep oximetry in six patients in Jerusalem and at the Dead Sea. Left. Right. Discussion Our study clearly shows the increase in arterial oxygen tension with the relatively mild change in altitude of 1200 m. The increase of 10 to 12 mm Hg in Pao 2 is a substantial improvement for patients with hypoxemia, which can shift their percentage saturation on the oxygen dissociation curve from the low to mid-80s to the low 90s. This may reduce pulmonary vascular resistance and pulmonary hypertension. The improvement in oxygenation caused a mild increase in arterial carbon dioxide tension, as is commonly found with the application of external oxygen in patients with chronic obstructive pulmonary disease. The addition of approximately 21 mm Hg inspired Po 2 is equivalent to about a 4% increase in Fio 2 in the Jerusalem area or to a nasal cannula with continuous oxygen flow of about 1 L per/min. The major advantage, however, is elimination of the need for external devices and tubing and assurance that the patient receives oxygen 24 hours a day, thus improving quality of life and psychological well-being and increasing independence. Since early studies by Abraham and colleagues [13] and Petty and Finigan [14], oxygen therapy has been considered one of the basic modes of therapy in patients with chronic obstructive pulmonary disease and other end-stage lung diseases. Oxygen therapy reduced the mortality rate and increased survival in patients in several large-scale studies [2, 3]. Researchers think the mechanism by which oxygen improves survival is reduced pulmonary vascular resistance and pulmonary artery pressure [10, 13]. Exercise capacity improves after administration of oxygen in other studies [15, 16], probably by a similar mechanism. A study in Colorado [17] showed that survival of patients with emphysema was better at low altitudes compared with survival at high altitudes (the Denver area). Renzetti and coworkers [18] previously made a similar observation. Veterans with chronic obstructive pulmon