See related article, p 14 . Gastroesophageal reflux disease (GERD) has been the whipping boy of gastroenterologic diagnoses for a decade or more. Although the mantra “reflux is responsible” emanating from primary care offices as well as gastroenterology, otolaryngology, and pulmonary clinics is deafening, attention from it can be easily diverted by the nighttime wailing of a single colicky baby. The management of excessive crying in infants remains a medical imbroglio. Call the symptom what you will—colic, fussiness, distress, or irritability—the nonverbal but far–from–silent infant poses a challenge to which few clinicians and no parents clamor. The article by Heine et al1Heine RG Cameron DJS Chow CW Hill DJ Catto-Smith AG. Esophagitis in distressed infants: poor diagnostic agreement between esophageal pH monitoring and histopathologic findings.J Pediatr. 2002; 140: 14-19Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar in this issue of The Journal offers a retrospective analysis of 125 infants referred to pediatric gastroenterologists in a tertiary medical center for persistent distress attributed to GERD.1Heine RG Cameron DJS Chow CW Hill DJ Catto-Smith AG. Esophagitis in distressed infants: poor diagnostic agreement between esophageal pH monitoring and histopathologic findings.J Pediatr. 2002; 140: 14-19Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar The infants had cried more than 3 hours per day for at least 3 weeks. Other symptoms not uniformly present included regurgitation, feeding difficulties, failure to thrive, atopic dermatitis, diarrhea, respiratory symptoms, and constipation. Half of the study population was examined beyond the age of 4 months. Before they were referred, 104 of the 125 infants received empiric therapy for reflux, although none of the infants received a proton–pump inhibitor. The formula-fed infants had multiple formula changes, and 33% of the infants were receiving a formula whose protein was extensively hydrolyzed at the time of referral. No infant received an amino–acid-based formula. Intraluminal pH monitoring and endoscopic esophageal biopsies were performed in all the babies and revealed that remarkably few of the infants had evidence of GERD. Thirteen percent of the infants had both esophagitis seen in biopsy specimens and esophageal acidification exceeding 10% of the pH monitoring time. Another 13% of the infants had esophagitis but a normal pH study. Statistically, esophagitis correlated poorly with feeding difficulties, failure to thrive, regurgitation, and hematemesis. The results of pH monitoring corresponded to the observed regurgitation, but little else. Nonspecific inflammation was present in the stomach and duodenum in 20% of the infants. This inflammation may be immune-mediated, because it failed to improve with previous acid suppression, although the cause remains enigmatic. Pain, vomiting, nausea, or anorexia from this inflammation might well be expected to promote feeding difficulties or failure to thrive. Esophageal biopsy specimens taken from 22% of the infants with esophagitis revealed an increase in eosinophils beyond the range expected with simple GERD.2Ruchelli E Wenner W Voytek T Brown K Liacouras C. Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy.Pediatr Dev Pathol. 1999; 2: 15-18Crossref PubMed Scopus (178) Google Scholar It is not clear whether any of the infants with esophageal eosinophilia were fed a hydrolysate formula or if they had been evaluated for dietary protein intolerance.3Kelly KJ Lazenby AJ Rowe PC Yardley JH Perman JA Sampson HA. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino–acid-based formula.Gastroenterology. 1995; 109: 1503-1512Abstract Full Text PDF PubMed Scopus (882) Google Scholar The study does not comment on the cause of the irritability in the infants without evidence for GERD, nor does it document resolution of the irritability with antireflux treatment after the diagnosis of GERD was confirmed in the remainder of the infants. Without that information, any diagnosis must remain provisional. What should we take away from this study? There are messages that need to be heard by primary care physicians and gastroenterologists, although few overt conclusions can be drawn. The retrospective nature of the study, referral bias, and selection bias make inference unavailable. A special group of infants was studied. We simply do not know how many infants were taken to their primary care physician with the same symptoms and were successfully, if empirically, treated. The latter group forms the essential denominator to the current patients, who are the numerator. In the future, that fraction must be calculated by prospective longitudinal study of unselected irritable infants from presentation to diagnosis and successful therapy. The treatment of these infants before their referral is as much an issue as the lack of a final diagnosis and the failure of pH monitoring to aid in the diagnostic process. Unfortunately, the clinician faced with the irritable baby still has no evidence-based guidelines upon which to initiate consistent evaluation and treatment. Empiric antireflux medications, formula changes, and diagnostic testing are all viable options in the absence of a clear clinical diagnosis, but the application of each must be individualized depending on the nature of the complaint. When it is used properly, empiric therapy for GERD or formula protein intolerance is generally safe and is clearly less expensive than formal testing. Histamine receptor blockers are commonly used, although often not as effectively as possible because the dose used is too low to induce sustained acid suppression.4Khan S Orenstein SR Shalaby TM. The effects of increasing doses of ranitidine on intragastric pH in children.Gastroenterology. 2001; 120: A212Abstract Full Text PDF Google Scholar Parents become frustrated and believe that GERD cannot be the problem, not recognizing that the trial was destined to fail regardless of the diagnosis. What should fussy babies be fed? Again, evidence-based advice is lacking. “Formula roulette” is played with abandon by parents and primary care physicians, with few rules and no strategy. The array of available formulas has created the opportunity to fine-tune an infant's intake and exposures, with options to reduce or eliminate iron, lactose, cow's milk protein, soy protein, and even polypeptides. At the same time, there appears to be considerable confusion as to potential therapeutic efficacy and indications for the specialized formulas. In a study of 100 infants with GERD, infants had been subjected to up to 9 different formulas before referral. More than 30% of the formula changes were determined to be “illogical” when they were analyzed.5Kosmack SN Shalaby TM Frankel EA Orenstein SR. Formula changes for 100 infants with symptoms of gastroesophageal reflux disease.J Pediatr Gastroenterol Nutr. 2001; 33: 423Google Scholar The study by Heine et al1Heine RG Cameron DJS Chow CW Hill DJ Catto-Smith AG. Esophagitis in distressed infants: poor diagnostic agreement between esophageal pH monitoring and histopathologic findings.J Pediatr. 2002; 140: 14-19Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar notes multiple formula changes without benefit in all their formula-fed patients.1Heine RG Cameron DJS Chow CW Hill DJ Catto-Smith AG. Esophagitis in distressed infants: poor diagnostic agreement between esophageal pH monitoring and histopathologic findings.J Pediatr. 2002; 140: 14-19Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar However, none of the infants is reported to have received an amino-acid based formula, which may be required in some infants with significant dietary protein intolerance who do not respond to a hydrolysate formula.6Vanderhoof JA Murray ND Kaufman SS Mack DR Antonson DL Corkins MR et al.Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants.J Pediatr. 1997; 131: 741-747Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar Once again, an inadequate trial does not erase a potential cause from consideration. We should be able to agree that babies with excessive crying constitute a heterogeneous population at presentation. As such, each irritable infant deserves individualized attention to determine the cause of the irritability. Therapeutic trials must be timely. The response to formula change or empiric acid suppression is prompt, such that failure within 2 weeks demands renewed attention and perhaps a new approach. Parents cannot be left to fend for themselves for weeks and months with unremitting irritability in their child, waiting for some mystical event to resolve the symptom. The remaining challenge is to establish the practical, efficient, and effective schemes to evaluate and treat these babies from their first presentation of symptoms rather than after referral to the subspecialist. Although many of us decry the creation of politically correct recipes for the management of common problems, such as GERD and constipation, it can be argued that one of the benefits of such documents is the attempt to eliminate ineffective practice. The chaos that surrounds the contribution of GERD to crying in infants cries out for such clarification. Esophagitis in distressed infants: Poor diagnostic agreement between esophageal pH monitoring and histopathologic findingsThe Journal of PediatricsVol. 140Issue 1PreviewObjectives: Our purpose was to study the relation between gastroesophageal reflux (GER) and esophagitis in infants with persistent distress. Study design: Infants (n = 125, 79 boys; median age, 4.2 months) with persistent distress and clinical symptoms suggestive of GER and esophagitis were retrospectively studied. All had undergone esophageal 24-hour pH monitoring and had upper gastrointestinal biopsy specimens taken. Results: There were 65 (48%) infants with inflammatory changes found in at least one upper gastrointestinal biopsy specimen, of whom 32 (25.6%) had esophagitis; 11 infants with esophagitis also had gastritis or duodenitis. Full-Text PDF