| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
* From Gastrointestinal Pathophysiology and Gastroenterology (Drs. Ravelli, Verdoni, and Consolati, and Ms. Bolognini), University Department of Pediatrics, Children’s Hospital; and Service of Nuclear Medicine (Ms. Panarotto), Spedali Civili, Brescia, Italy.
Correspondence to: Alberto M. Ravelli, MD, Gastrointestinal Pathophysiology and Gastroenterology, University Department of Pediatrics, Children’s Hospital, Spedali Civili, 25123 Brescia, Italy; e-mail: alberto_ravelli{at}yahoo.com
Abstract
Objectives: Gastroesophageal reflux (GER) may underlie respiratory manifestations via vagally mediated airway hyperresponsiveness or microaspiration, and intraesophageal pH monitoring is generally used to identify GER in patients with such manifestations. We aimed to establish the frequency of retrograde pulmonary aspiration in patients with unexplained respiratory manifestations.
Methods: Fifty-one patients with refractory respiratory symptoms (cough, n = 18; pneumonia, n = 14; apnea, n = 8; asthma, n = 7; and laryngitis, n = 4) were prospectively evaluated. They underwent 24-h intraesophageal pH monitoring and gastroesophageal 99Tc scintigraphy with lung scan 18 to 20 h after the test meal.
Results: Thirteen of 51 patients (25.5%) had abnormal intraesophageal pH study results (mean reflux index, 11.3%; range, 6.5 to 50%); and in 25 of 51 patients (49%), overnight scintigraphy showed pulmonary aspiration. Nineteen of these 25 patients had entirely normal pH study results, whereas 6 of 13 patients with abnormal pH study results had aspiration. Pulmonary aspiration was demonstrated in all patients with apnea and 61.5% of patients with recurrent pneumonia. Nine of 25 patients (36%) with aspiration had histologic evidence of esophagitis, whereas histologic esophagitis was present in 5 of 13 patients (38.4%) with pathologic GER as shown by intraesophageal pH monitoring.
Conclusions: Pulmonary aspiration as demonstrated by overnight scintigraphy is common in children with unexplained and refractory respiratory manifestations, suggesting that GER could be the underlying cause of these manifestations. Since only a few children with chronic or recurrent respiratory symptoms have a pathologic gastroesophageal acid reflux, a normal intraesophageal pH study result does not rule out GER in these children.
Key Words: aspiration • gastroesophageal reflux • scintigraphy
Gastroesophageal reflux (GER) is considered a possible pathogenetic factor in a variety of respiratory manifestations, such as recurrent pneumonia, chronic cough, apnea, laryngitis, asthma, and wheezing.12 A causal relationship between GER and pulmonary disease has never been clearly demonstrated,3 but it is commonly accepted that two major mechanisms related to GER may underlie such manifestations, ie, microaspiration of refluxed material, and a vagally mediated reflex triggered by acid within the esophagus leading to bronchial or laryngeal constriction and hyperresponsiveness.4 Therefore, in patients with uncontrolled or equivocal respiratory manifestations, the possibility of GER as an underlying cause should be considered. In clinical practice, 24-h intraesophageal pH monitoring is mostly used to identify pathologic GER in patients with atypical manifestations, particularly unexplained or refractory respiratory symptoms.56 Studies78 using simultaneous pH monitoring and intraluminal impedance—a technique that does not depend on pH of the refluxate for the detection of a GER episode—have shown that only a minority of refluxes are acidic and up to 90% of reflux episodes can be missed by intraesophageal pH studies, since in most cases the refluxate is neutral or slightly alkaline and may not be detected by pH study. These findings suggest that in patients with unexplained or refractory respiratory symptoms, a normal pH study result may not be sufficient to rule out GER as a pathogenetic factor. Gastroesophageal scintigraphy can be used to detect pulmonary aspiration during the postprandial period. Although this technique is expensive, not widely available, and its reported sensitivity for the detection of aspiration is rather low,910 in patients with unexplained respiratory symptoms the demonstration of retrograde aspiration would be a strong evidence in favor of GER as a pathogenetic factor.
Aim of the Study
Episodes of GER with aspiration of refluxed material are more likely to occur during the nocturnal period, when the esophagus and stomach are leveled and the swallowing response to reflux and airway protection mechanisms are blunted by sleep. Therefore, we wanted to verify the impact of a gastroesophageal radionuclide study followed by overnight scan on the lung fields on the identification of an underlying GER in children with unexplained or refractory respiratory symptoms. We also wanted to verify the correlation—if any—between the radionuclide study and 24-h intraesophageal pH monitoring in these children.
Materials and Methods
Patients
Fifty-one neurologically normal children (34 boys and 17 girls) aged 1 month to 11.5 years (median, 6.5 years) who had been referred to our unit were prospectively studied during a 3-year period. They suffered from chronic or recurrent respiratory problems (chronic cough, n = 18; recurrent pneumonia, n = 14; apnea episodes, n = 8; asthma/wheezing, n = 7; posterior laryngitis, n = 4) that were hitherto unexplained and/or had not responded satisfactorily to medical treatment such as antibiotics, inhaled or oral steroids, and ß2-agonists. Sixteen of 51 patients had mild and occasional GI symptoms (regurgitation, n = 14; abdominal pain, n = 2) that had never caused medical consultation or self-medication, whereas none had dysphagia or other symptoms suggesting swallowing problems (ie, gagging or choking with feeds, excessive salivation, globus sensation in the throat) or failure to thrive. Patients with recurrent pneumonia had no laboratory evidence of humoral or cellular immune deficiency. All patients had been tested for total IgE (paper radioimmunosorbent test) and specific IgE (radioimmunosorbent test) for aeroallergens and major food allergens (cow’s milk, egg, wheat, maize, rice, soy, fish, shellfish, and peanut), All but two patients had normal IgE levels (paper radioallergosorbent test); and one of these two patients, who had cow’s milk-sensitive eczema in the first few months of life, had mildly raised levels of IgE to wheat, rice, and maize but had not responded to an exclusion diet. Sweat test results were normal in all 27 patients tested. Cardiac, neurologic, and metabolic abnormalities were excluded by appropriate investigation in all infants with apnea episodes. No patient had a history or clinical examination suggesting congenital or acquired anatomic abnormalities of the cardiopulmonary system such as bronchopulmonary dysplasia, bronchiectasia, or congenital heart disease; and in all patients, respiratory symptoms had begun after the first 2 weeks of life. Assuming that pulmonary aspiration of material refluxing from the stomach does not occur in normal individuals, we considered it unethical to subject healthy infants and children to a radionuclide investigation in order to obtain a normal control group. The parents of recruited patients gave written informed consent to all investigations, according to the protocols previously established by the Department of Pediatrics and approved by the hospital Ethics Committee.
Methods
All children underwent 24-h intraesophageal pH study and gastroesophageal scintigraphy followed by later study of the lung fields. Prior to these investigations, 16 of 51 patients (those who had regurgitation and/or whose symptoms had begun in early infancy) underwent barium meal and follow-through in order to rule out tracheoesophageal fistula and upper-GI malformations such as hiatus hernia or malrotation, whereas 23 of 51 patients also underwent upper-GI endoscopy with biopsy. Whenever the intraesophageal pH study had abnormal results (abnormal reflux index ± abnormality of any other pH parameter, see below) and/or there was endoscopic/histologic evidence of peptic esophagitis, the diagnosis of GER disease (GERD) was made.
Intraesophageal pH Monitoring: Irrespective of the respiratory manifestations, pH studies were performed when patients were well or relatively well (ie, not hospitalized for acute respiratory manifestations). Those who were already being treated with antibiotics, ß2-agonists, and/or steroids were allowed to continue their therapy during the pH study (14 patients), whereas any antireflux medication previously prescribed by the general practitioner was stopped at least 1 week prior to the study (11 patients). A 2.1-mm, dual-channel probe with monocrystant antimony sensors spaced 10 cm apart was passed via the nostrils and positioned with the tip at the level of T9-T10, under fluoroscopic control. After 24 h, the recording was stopped and subsequently analyzed using dedicated software (Flexilog 2020; Oakfield Instruments; Eynsham/Witney/Oxon, UK). All conventional pH parameters were considered, ie reflux index (percentage of time spent with intraesophageal pH < 4), number of acid reflux episodes, number of acid reflux episodes lasting > 5 min, and duration of longest acid reflux. Intraesophageal pH study results were considered abnormal whenever the reflux index recorded from the lower pH sensor exceeded the mean + 3 SD of the published reference values in > 500 healthy infants11 and our previously published normative values in 26 control children12 (Table 1 ).
|
), and this was considered delayed when > 90 min. The following morning, 18 to 20 h after the ingestion of the test meal, static planar anteroposterior and posteroanterior images of the thorax were obtained (overnight scan) in order to study the lung fields, which were defined by the markers drawn around the thorax (Fig 1
). Parents were always requested to carefully wash their children and change their children’s clothes prior to such overnight scan, in order to avoid external contamination in case of vomiting or regurgitation. The presence of detectable radioactivity within the lung fields was considered as evidence of aspiration of refluxed material. Incorrect labeling in vitro may cause breakdown of the 99mTc-Hepatate bond in vivo, leading to intestinal absorption of the radioisotope, which in turn may result in significant and widespread background noise with early or late intense radioactivity detectable within the thyroid or the urinary bladder (Fig 2
). If such radioactivity was detected, the study was discarded and repeated on another occasion.
|
|
Results
No anatomic abnormality was detected during the contrast study of the upper-GI tract. All 23 children subjected to upper-GI endoscopy had normal macroscopic findings, but 21 of 23 children had histologic evidence of mild (grade 1 or G1) esophageal damage, and all had an eosinophil count < 10/high-power field, so that allergic eosinophilic esophagitis could be excluded. Intraesophageal pH study results were abnormal in 13 of 51 patients (25.5%), showing a mean reflux index of 11.3% (range, 6.5 to 50%) as recorded by the distal pH probe. In the remaining 38 patients, reflux index and the other pH parameters were all within the normal limits for age. During the 2-h postprandial scintigraphic study, one or more reflux episodes reaching the upper third of the esophagus were detected in 14 patients (Fig 3
) and early pulmonary aspiration was seen in 2 patients (Fig 4, 5
). The number of reflux episodes detected by scintigraphy was not significantly different between patients with normal and abnormal pH study results. Furthermore, gastroesophageal scintigraphy showed delayed gastric emptying—a T > 90 min—in 27 of 51 patients (52.9%), with a mean T of 154 min (range, 106 to 540 min), and one patient had a T > 12 h. The overnight scan, however, showed evidence of unilateral (5 patients) or bilateral (20 patients) pulmonary aspiration in 25 of 51 patients (49%) [Fig 6
], 10 of whom also had delayed gastric emptying and 10 of whom had had refluxes reaching the upper esophagus during the postprandial study. Two of these 25 patients had shown pulmonary aspiration also during the postprandial study. One radionuclide study was repeated due to the appearance of significant diffuse background radioactivity associated to thyroid uptake of the isotope (Fig 1). Six of 13 patients with abnormal pH study results had aspiration, and 6 of 25 patients with aspiration had abnormal pH study results, which means that 50% of patients with normal pH study results had evidence of aspiration (Table 2
).
|
|
|
|
|
|
Although GER is regarded as a possible cause of respiratory manifestations such as recurrent pneumonia, apnea, asthma, wheezing, chronic cough, and laryngitis,12 its causal role in lung disease has never been clearly established.3 Indeed, one of the very few controlled pediatric studies15 to date showed that over a 1-year follow-up period, infants with regurgitation do not acquire GERD or respiratory symptoms more often than infants without regurgitation. Furthermore, the precise correlation between GER and respiratory symptoms is not easy to define, and the majority of patients with GER-associated respiratory manifestations do not have esophagitis at endoscopy.12351617 Controlled trials181920 of antireflux therapy essentially failed to demonstrate significant benefits on adult patients with asthma, whereas one study21 showed that in children with asthma and pathologic GER, an adequate antireflux therapy resulted in a significant reduction of asthma medications. The demonstration of pathologic acid reflux by prolonged intraesophageal pH monitoring suggests that GER may underlie respiratory symptoms or is at least a contributory factor.6181922 However, studies using intraluminal impedance have shown that sensitivity of pH monitoring for the detection of retrograde bolus reflux is only 8%,78 and up to 90% of refluxes may be missed since they are neutral or slightly alkaline.78 In infants, only 16% of all reflux episodes associated with breathing abnormalities and oxygen desaturation were detected by pH monitoring,23 and only 22% of apnea-associated reflux episodes were acidic and thus detected by pH monitoring.24 However, aspiration may result in damage to the airway even if the refluxate is not acidic.25 Taken together, these findings suggest that nonacidic reflux could be even more relevant than acidic reflux in the pathogenesis of respiratory manifestations.
If aspiration is demonstrated in a patient who has chronic or recurrent respiratory symptoms (and no evidence of swallowing problems), GER could be one—if not the only—cause of such symptoms. A number of investigations have been used to document aspiration. Tracheal pepsin has been reported in 84% of children with GERD and respiratory symptoms.26 The finding of lipid-laden macrophages in the fluid obtained by tracheobronchial lavage has been claimed to demonstrate that bronchial aspiration of gastric contents occurred. The sensitivity and specificity of this test are not very high, however, varying from 57 to 69% and from 75 to 79%, respectively, in different studies.2728 Furthermore, tracheobronchial intubation is an invasive procedure and may itself cause reflux.
Gastroesophageal 99Tc radionuclide scanning can detect GER episodes and aspiration occurring during or shortly after meals, but its reported sensitivity for microaspiration is relatively low.910 When using this technique with late imaging, however, it was found that 52% of adult patients with posterior laryngitis had proximal GER and 15% also had pulmonary aspiration.29 Although the procedure is expensive, it is noninvasive and allows the simultaneous measurement of gastric-emptying time, which can be a pathogenetic factor in GER. GER-related aspiration is most likely to occur during meals and at nighttime, which is why we used an overnight radionuclide scan in this study. We detected microaspiration in nearly 50% of our patients with unexplained or refractory respiratory manifestations. Although swallowing problems may cause aspiration irrespective of GER, none of our patients had oropharyngeal dysphagia or evidence of direct aspiration at the beginning of the radionuclide study. We based our observations on the assumption that retrograde pulmonary aspiration (ie, aspiration of gastroesophageal refluxate) does not occur in normal individuals. This could be a limitation, since anterograde aspiration (ie, aspiration of nasopharyngeal secretions) can occur in healthy adult individuals during sleep.30 There is no evidence, however, that in the absence of upper respiratory infection, such anterograde aspiration may lead to bronchopulmonary disease or dysfunction.
An early or late breakdown of the 99Tc-Hepatate bond may lead to intestinal absorption of the radioisotope, which can result in significant background noise. Such background noise may not be mistaken for pulmonary aspiration, however, since it is widespread (unlike the distinctly focal radioactivity produced by pulmonary aspiration) and is typically associated with early or late radioactivity detectable within the thyroid or the urinary bladder. The major limitation of the overnight scan is related to the radioisotope decay, which may reduce the sensitivity of the test if aspiration occurs shortly after the postprandial study. In fact 99Tc has a decay of approximately 6 h, so that after 6 h the radioactivity of 99Tc is reduced by 50%, and after 18 h it is further reduced to 1/8. Should higher radioactivity or an isotope with slower decay be used, it is possible that the overnight scan would detect aspiration in a higher number of patients.
In conclusion, our study shows that pulmonary aspiration, most likely nocturnal, is present in one half of the patients with unexplained or refractory respiratory symptoms. Assuming that retrograde pulmonary aspiration does not occur in normal individuals, this finding could be the only evidence relating these symptoms to GER. It should be emphasized that in > 75% of patients who had scintigraphic evidence of aspiration, intraesophageal pH study results were normal. Furthermore, only a minority of patients with aspiration and pathologic intraesophageal pH study results had histologic esophagitis. Should pH monitoring and/or upper-GI endoscopy be performed as the sole investigation, GER would be missed in most of these patients. We therefore recommend that, whenever possible, an overnight 99Tc radionuclide scan be performed in patients with respiratory symptoms possibly related to GER, especially if intraesophageal pH study and/or endoscopy results are normal. In patients with respiratory manifestations and normal pH study results, the finding of aspiration has also potential therapeutic implications, since prokinetic drugs could be equally—if not more—important and effective than acid-suppressant drugs.
Footnotes
Abbreviations: GER = gastroesophageal reflux; GERD = gastroesophageal reflux disease; T = time to gastric half-emptying
The authors have no conflicts of interest to disclose.
Received for publication December 9, 2005. Accepted for publication May 7, 2006.
References
This article has been cited by other articles:
|
|
 |
|
  V. Starosta, R. Kitz, D. Hartl, V. Marcos, D. Reinhardt, and M. Griese Bronchoalveolar Pepsin, Bile Acids, Oxidation, and Inflammation in Children With Gastroesophageal Reflux Disease Chest, November 1, 2007; 132(5): 1557 - 1564. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
