Tag Archives: Gastroesophageal Reflux

Clinical Features of 22q11.2 Deletion Syndrome

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Since I participate in the 22q Specialty Clinic in Atlanta, I am interested in relevant clinical studies.  A recent study provides more information on clinical features and follow-up (J Pediatr 2014; 164: 1475-80).

This retrospective and prospective multicenter study involved 228 patients.  The median age at diagnosis was 4 months.  In 71% the diagnosis was made before age 2 years and predominantly related to congenital heart disease and neonatal hypocalcemia.

Key findings:

  • The survival probability was 0.92 at 15 years from diagnosis, most commonly from severe cardiovascular complications.  Two subjects died without cardiac defects, one with severe autoimmune anemia and the second with lymphoproliferative disease.
  • Congenital heart disease was confirmed in 79% of the entire cohort.
  • Neonatal hypocalcemia was noted in 43%
  • ENT manifestations were present in 59% and included most commonly velopharyngeal insufficiency
  • GI manifestations were noted in 41%, particularly feeding difficulties in infancy.  Anorectal malformations were identified in 5% and esophageal atresia was noted in 1%.  GI problems tended to improve during followup, particularly gastroesophageal reflux.  During followup, three children with abdominal pain (along with leg pain) had mild hypocalcemia.
  • Autoimmune manifestations developed in 11%, most commonly autoimmune thrombocytopenia.

Related blog posts:

Link: Practice guidelines for 22 q (from UC Davis Website and J Pediatr. 2011 Aug;159(2):332-9.e1. doi: 10.1016/j.jpeds.2011.02.039).

How Proton Pump Inhibitors Can Cause Infections

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In yesterday’s blog, the editorial on “Acid-reducing agents in infants and children: friend or foe?” also commented on an additional study (JAMA Pediatr. 2014. doi: 10.1001/jamapediatrics.2014.696) which addresses the issue of how proton pump inhibitors (PPIs) may contribute to an increased risk of infections.  It is well-known that use of PPIs (and to a lesser extent histamine-2 receptor antagonists) contribute to a significant increased risk of community-acquired pneumonias and gastrointestinal infections (probably including necrotizing enterocolitis in infants).

In this study, (from the editorial) “acid suppression was associated with a positive gastric culture (P =.003) and increased median concentration of gastric bacteria (P<.001). Full-column nonacid reflux was associated with higher concentrations of bacteria in the lung.”

In this era of pioneering microbiome research, it is not surprising that chronic changes in gastric acid production could cause these results.  This is something to consider when calculating risks and benefits, particularly in situations where the benefits are quite minimal.

Here’s the abstract:

Importance  The use of acid suppression has been associated with an increased risk of upper and lower respiratory tract infections in the outpatient setting but the mechanism behind this increased risk is unknown. We hypothesize that this infection risk results from gastric bacterial overgrowth with subsequent seeding of the lungs.

Objectives  To determine if acid-suppression use results in gastric bacterial overgrowth, if there are changes in lung microflora associated with the use of acid suppression, and if changes in lung microflora are related to full-column nonacid gastroesophageal reflux.

Design, Setting, and Participants  A 5-year prospective cohort study at a tertiary care center where children ages 1 to 18 years were undergoing bronchoscopy and endoscopy for the evaluation of chronic cough. Acid-suppression use was assessed through questionnaires with confirmation using an electronic medical record review.

Main Outcomes and Measures  Our primary outcome was to compare differences in concentration and prevalence of gastric and lung bacteria between patients who were and were not receiving acid-suppression therapy. We compared medians using the Wilcoxon signed rank test and determined prevalence ratios using asymptotic standard errors and 95% confidence intervals. We determined correlations between continuous variables using Pearson correlation coefficients and compared categorical variables using the Fisher exact test.

Results  Forty-six percent of patients taking acid-suppression medication had gastric bacterial growth compared with 18% of untreated patients (P = .003). Staphylococcus (prevalence ratio, 12.75 [95% CI, 1.72-94.36]), Streptococcus (prevalence ratio, 6.91 [95% CI, 1.64-29.02]), Veillonella (prevalence ratio, 9.56 [95% CI, 1.26-72.67]), Dermabacter (prevalence ratio, 4.78 [95% CI, 1.09-21.02]), and Rothia (prevalence ratio, 6.38 [95% CI, 1.50-27.02]) were found more commonly in the gastric fluid of treated patients. The median bacterial concentration was higher in treated patients than in untreated patients (P = .001). There was no difference in the prevalence (P > .23) of different bacterial genera or the median concentration of total bacteria (P = .85) in the lungs between treated and untreated patients. There were significant positive correlations between proximal nonacid reflux burden and lung concentrations of Bacillus (r = 0.47, P = .005), Dermabacter (r = 0.37, P = .008), Lactobacillus (r = 0.45, P = .001), Peptostreptococcus (r = 0.37,P = .008), and Capnocytophagia (r = 0.37, P = .008).

Conclusions and Relevance  Acid-suppression use results in gastric bacterial overgrowth of genera including Staphylococcus and Streptococcus. Full-column nonacid reflux is associated with greater concentrations of bacteria in the lung. Additional studies are needed to determine if acid suppression–related microflora changes predict clinical infection risk; these results suggest that acid suppression use may need to be limited in patients at risk for infections.

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GERD Treatment in Infants: “Friend or Foe”

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From a recent JAMA Peds editorial: (JAMA Pediatr. Published online August 18, 2014. doi:10.1001/jamapediatrics.2014.1263)

An excerpt:

Gastroesophageal reflux disease (GERD) is common in infants and children and has been estimated to affect as much as 3.3% of the pediatric population.1 Despite this, we still struggle with the management of GERD. With a growing body of literature that illustrates a lack of efficacy and alarming adverse effects, there is increasing reason to limit the empirical use of acid suppression therapy in children.

Other points highlighted in this editorial:

  • 36% of pediatricians prescribe PPIs for infants with uncomplicated regurgitation -“despite evidence and recommendations against this approach.”
  • 39% of pediatricians prescribed proton pump inhibitors (PPIs) for infants with unexplained crying
  • Conditions predisposing a child for severe GERD include those with neurological impairment, repaired esophageal atresia, cystic fibrosis, hiatal hernia, repaired achalasia, and lung transplantation.
  • In the related article ((JAMA Pediatr. doi: 10.10001/jamapediatrics.2014.1273), the authors reviewed 8 studies of histamine-2 receptor antagonists (H2RAs) and noted no improvement in overall symptoms infants.  In older age groups, H2RAs were more effective than placebo in symptom reduction, and histological healing.

Take-home message: “It is becoming clearer that in many circumstances, prescribing acid-reducing medication to infants is doing no good and increasing the risk of harm.”

Related blog posts:

 

Will This Change ALTE-GERD Practice?

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This blog has highlighted several publications which have shown the lack of benefit and potential harm of pharmaceutical agents for gastroesophageal reflux “disease” (GERD) in infancy (see links below). However, in current practice, proton pump inhibitors and histamine receptor antagonists are used frequently.  Now, another influential study (J Pediatr 2014; 165: 250-5) has shown the lack of GERD as a causal mechanism in acute life-threatening events (ALTEs) and demonstrated other pathophysiologic mechanisms. However, changing physicians’ practice in this regard may prove to be as difficult as avoiding overprescribing antibiotics, or convincing reluctant parents to vaccinate their children.

So what did this study show?

This study of 20 infants (10 with proven ALTE and 10 healthy controls) had pharyngoesophageal manometry.  Key findings:

  • Infants with ALTE (vs controls) had delays in restoring aerodigestive normalcy (P=.03).  This was indicated by more frequent and prolonged spontaneous respiratory events (SREs)
  • Infants with ALTE had a lower magnitude of protective upper esophageal sphincter contractile reflexes (P=.01)
  • Infants with ALTE had swallowing as the most frequent esophageal event associated with SREs (84%), a higher proportion of failed esophageal propagation (10% vs 0%, P=.02), an more frequent mixed apnea mechanisms (P=<.01) along with gasping breaths (P=.04)

The associated editorial (pg 225-26) explains some of the limitations of the study, including the fact that the patients had a mean gestational age of 28 weeks.

The authors conclusion: “In infants with ALTE, prolonged SREs are associated with ineffective esophageal motility ,,,suggestive of dysfunctional regulation of swallow-respiratory junction interactions.  Hence, treatment should not target gastroesophageal reflux, but rather the proximal aerodigestive tract.”

Take-home message: (from the editorial): “Far too many low birth weight (and term) infants are being unnecessarily treated with a variety of antireflux medications that have serious side effects and few, if any, demonstrable benefits.”

Related blog posts:

“If all you have is a hammer…”

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In my training, one of my mentors would be critical of the mentality “scope first, think second.”  He was concerned that too many gastroenterologists/pediatric gastroenterologists used endoscopy as a tool simply “because if all you have is a hammer, the world looks like a nail.”

A recent publication (Clin Gastroenterol Hepatol 2014; 12: 963-69) on first glance, however, provides ammunition to the “scope first” gastroenterologists and undermines the concept that “functional” GI disorders vastly outnumber “organic” GI disorders.  The key finding was that esophagogastroduodenoscopy (EGD) provided an “accurate” diagnosis in 38%.  This included reflux esophagitis in 21%, eosinophilic esophagitis (EoE) in 5%, eosinophilic gastroenteritis (EGE) in 4%, H pylori in 2%, celiac disease 0.6%, and Crohn’s disease 0.4%. This finding is dramatically higher than previous studies.  In fact, in a recent published study (Understanding Idiopathic Nausea | gutsandgrowth) on idiopathic nausea, a control group of patients with chronic abdominal pain had a normal endoscopy in 100%!

In this prospective study of 290 children (ages 4-18 years with a mean age of 11.9 years), the primary indication for upper endoscopy was chronic abdominal pain.  Of this 290, 216 had at least 1 alarm feature and 125 had at least 2 alarm features.  Alarm features were considered to be the following:

  • Nighttime awakening 33.3%
  • Weight loss 15.6%
  • Family history of IBD 8.4%
  • Vomiting 7.8%
  • Dysphagia 6.9%
  • Nocturnal diarrhea 6.7%
  • Gastrointestinal bleed 5.8%
  • Chronic diarrhea 5.8%
  • Unexplained fever 4.4%
  • Arthralgia 4.0%
  • Growth failure 2.4%
  • Perirectal disease 0.7%
  • Delayed puberty 0.2%

There is little debate that abdominal pain in combination with true alarm symptoms (True red flags in recurrent abdominal pain | gutsandgrowth) merits further evaluation.  The aspect of this report that is worthy of close inspection is the diagnostic yield in the 74 patients without alarm symptoms.  The authors note that 25 (33.7%) had a diagnosis established with EGD including 16 with reflux esophagitis, 4 with EGE, 2 with EoE, 1 with erosive esophagitis, 1 with celiac and 1 with H pylori.  The diagnostic criteria for EGE included ≥10 eosinophils per hpf in the stomach and ≥20 eosinophils per hpf in the duodenum.

The authors note that the diagnostic yield was based on gross endoscopic findings in procedure notes or histologic changes in biopsy reports; “final pathology report on biopsies provided the data source for histologic diagnosis.”

In my opinion there are multiple flaws of this prospective study.

1. There is a very high rate of reflux esophagitis in both the alarm group and the non-alarm group patients with chronic abdominal pain.  Of the entire cohort (n=290), the authors identified reflux esophagitis in 21% and this was “primarily histologic esophagitis.”  Furthermore, the authors state that “the presence or response to PPI therapy was not predictive of esophagitis or GERD.”  So, the obvious problems:

  • Presence of histologic reflux esophagitis varies widely based on the interpreting pathologist.  In a prospective study, more than one pathologist interpreting the histology would be useful.
  • Presence of histologic reflux esophagitis does not exclude the likelihood of coexisting functional disorders (related blog post: Why didn’t patient with documented reflux get better with PPI …).  As a practical matter, “slight” or “focal” esophagitis on histology has questionable real-world relevance in pediatric gastroenterology.
  • The authors acknowledge, “current expert consensus indicates that histology has limited value in evaluating pediatric GERD.”  Yet this diagnostic finding is one of the reasons why the authors claim that EGD is so valuable.

2. In the entire cohort, the authors try to validate their findings by indicating that identification of a diagnosis led to medical therapy that was “effective in approximately 67%” of children with short-term followup. (Only 81% had short-term followup outcomes available).  Yet, there is no control group.  How many children with chronic abdominal pain will improve for a short period without an EGD-based diagnosis?  The answer: a lot of them.

3. Limitations include selection bias toward those with more severe symptoms or alarm symptoms.  In addition, this study included only a small number who were considered to have no alarm symptoms.  Finally, the short-term followup makes conclusions about the response to therapy questionable.

This study will be a useful reference for any pediatric gastroenterologist who wants to justify the need for an endoscopy.  The authors note “the majority of children in our study (93%) met criteria for functional gastrointestinal disorders, and a significant proportion (38%) still had significant histologic findings.  Therefore, we conclude the Rome III criteria alone are not sufficient to identify children who require upper endoscopy, and screening for alarm symptoms has limited utility.”

In my opinion, the reliance on histology as well as selection bias weaken the findings of this study.  If a patient with a histologic diagnosis of reflux (or several other entities) and a presentation of chronic abdominal pain does not improve, the pediatric gastroenterologist should remember that only “a poor carpenter blames his tools.”

Bottomline: EGD remains an important tool in evaluating abdominal pain.  However, I think this study substantially overestimates its utility.

Related blog posts:

 

 

 

 

“If You Never Give Up, You Cannot Possibly Lose”

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Recently I was reviewing the “Black Knight scene” from Monty Python’s Holy Grail.  This scene in which the Black Knight continues to insist on fighting King Arthur even after losing all of his limbs came to mind as I was reading a recent study (JPGN 2014; 58: 226-36).  The blog title comes from an explanation of the scene from John Cleese who intended the scene to mock this philosophy. (Wikipedia link: Black Knight (Monty Python) – Wikipedia, the free encyclopedia)

The study is another trial of a proton pump inhibitor (rabeprazole) for 1- to 11-month old infants with symptomatic GERD.  In the discussion the authors note that this is the “fourth DB randomized placebo-controlled study published in the last 4 years that fails to show the efficacy of PPIs to treat symptomatic GERD in infants younger than 1 year.”

If anything, the design of this study should have allowed a therapeutic effect to be witnessed if present.  Infants selected for participation (n=268 in the double-blind phase) had been responsive to a 10 mg open-label usage of rabeprazole before randomization.  Yet, those infants who continued to receive 5 mg or 10 mg daily fared no better than placebo-treated patients.

The good news: no new safety signals in those who were treated compared to placebo.

The findings of this study are in marked distinction to clinical practice which has embraced PPIs in all age groups. In the same issue of JPGN, using a national database, De Bruyne et al (JPGN 2014; 58: 220-25) show a huge increase in PPI usage over the past decade in the Netherlands, especially in children ages 2 years and younger.  From 2004 to 2008, use of PPIs nearly doubled in this population.

The rabeprazole study manuscript which had nearly as many pediatric GI investigators as enrolled patients discusses the potential drawbacks of PPI therapy in infants including enteric infections like Clostridium difficile, lower respiratory infections (e.g.. pneumonia), and “perhaps even an increased incidence of necrotizing enterocolitis in premature infants.”  Unlike the Black Knight, after four blows to the PPI cause, the authors recommend yielding on PPIs except under much more stringent criteria (1 of 3):

  • Nonimproving symptoms at 1 year of age & resistant to conservative measures
  • Presence of underlying conditions that predispose to a natural history of severe chronic unremitting reflux
  • Erosive reflux esophagitis proven on endoscopy

Take-home message: PPIs have not been shown to be effective in infants…again!

Related blog posts:

Even the Experts Agree: pH-MII is a “Flawed Test”

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A recent study (JPGN 2014; 58: 22-26) reports on the combination of a new technique of intraesophageal pressure recording (IEPR) along with multichannel intraluminal impedance with pH (pH-MII).  While this prospective study is small with only 20 children who had a history of chronic intractable cough, some of its observations are important, especially for those who have embraced pH-MII.

In determining whether the pH-MII studies were abnormal the authors relied on symptom index (SI) defined as the number of symptoms associated with reflux/total number of symptoms.  SI is considered positive if >50%.  In addition, the authors calculated the symptoms sensitivity index (SSI) which is defined as the total number of reflux episodes associated with symptoms/total number of reflux episodes; it is considered positive if it is >10%.  The authors note SAP and SI have a comparable positive predictive value and “our experience suggests that SAP calculation using software is unreliable.”

Key Results/Discussion:

  • IEPR changed the diagnosis in 15-20% of patients depending of scoring index used.  That is, IEPR assisted the detection of reflux-associated cough.
  • IEPR detected 106% more coughs than patient report alone.  Thus, this study, if accurate, indicates that “symptom reporting during pH or pH-MII testing is significantly flawed and, if possible, should not be used alone for clinical decision making.”
  • “We did not find a significant association between cough production and the height of the refluxate.”
  • The authors argue that since nonacid reflux can be associated with cough and is not always detected with pH-MII, that this could “explain why studies that have tried to use pH criteria to predict clinical outcome after acid suppression therapy have been negative.”  The two studies cited at that point by the authors were landmark studies (referenced below) showing that proton pump inhibitors are not effective in children or adults in improving asthma.  I think the authors’ comment misses the importance of these studies entirely.  There are no proven effective GERD (acid or nonacid) therapies that alter the course of asthma.

Take-home message from authors: “Studies are now needed to determine whether this increased detection improves therapeutic outcomes, but clearly, relying on symptom reporting by patients is flawed and clinical decision making based on patient report alone should be done with caution.”

Referenced studies:

  • JAMA 2012; 307: 373-81
  • NEJM 2009; 360: 1487-99

Related blog posts:

‘Little’ Knowledge Exists Regarding Medicines for Neonates

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Despite federal legislation encouraging the study of products used in the pediatric population, very little of these studies has translated into meaningful information regarding neonates (JAMA Pediatr 2014; 168: 130-36, thanks to Ben Gold for this reference).

This publication reviewed studies submitted to the FDA between 1997-2010.  The authors identified all drugs with pediatric studies that included neonates.  Subsequently, the use of these drugs was examined in a oohort of neonates admitted to 290 neonatal intensive care units (NICU) (Pediatrix Data Warehouse) in the U.S. form 2005-2010.

Key findings:

  • 28 drugs (in 41 studies) were examined in neonates. This led to 24 labeling changes.
  • 11 of 24 neonatal labeling changes included an approval for use in neonates, including 4 for HIV and 3 for anesthesia.
  • 13 of 24 labeling changes were the following: “safety and effectiveness have not been established.”  These drugs included several reflux medications: esomeprazole, lansoprazole, pantoprazole, and ranitidine.
  • In the Pediatrix database involving 446,335 hospitalized neonates, there were 399 different drugs identified that had been administered.  Of the 28 studied drugs, the gastroesophageal reflux medicines were used most frequently.  13 of the 28 studied drugs were not used at all in the NICUs.
  • Of the 11 drugs with a neonatal indication, 7 were never used in the Pediatrix neonatal population and the other 4 drugs were used infrequently.

Conclusions:

  • Neonates are a vulnerable and an understudied population
  • Most of the exposure to drugs was off-label for neonates.
  • Most often, off-label drugs were prescribed “despite studies indicating they were not effective…For example, ranitidine, lansoprazole, and inhaled nitric oxide (for the prevention of bronchpulmonary dysplasia) were the top 3 drugs used in neonates…none have FDA labelling for the indication studied because of lack of efficacy.”
  • Furthermore, drugs like ranitidine and lansoprazole” are associated with serious adverse effects in neonates.” (Clin Perinatol 2012; 39: 99-109)

Related blog entries:

Nexium versus Fluticasone for EoE

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As noted in previous blog posts (EoE: Drugs, Diets, Dilatation and PPI-REE | gutsandgrowth, EoE –Journal Club (Part 1) | gutsandgrowth, and EoE –Journal Club (Part 2) | gutsandgrowth), proton pump inhibitors are recommended as 1st line therapy in suspected eosinophilic esophagitis (EoE) for several reasons.  Besides the potential for gastroesophageal reflux to cause esophageal eosinophilia, there has been recognition of PPI-responsive eosinophilic esophagitis (PPI-REE).  In adults, the response to proton pump inhibitors, both clinically and histologically, is likely higher than in children; nevertheless, in children it is anticipated that 20-40% of patients with suspected EoE will have a histological remission with PPI therapy.

A recent study in adults suggests that PPIs may in fact outperform topical steroids (Am J Gastroenterol 2013; 108: 366-72).  Thanks to Ben Gold and Seth Marcus for identifying this reference.  This study enrolled 42 patients: 90% male, 81% white, mean age 38 years. It was a prospective single-blinded, randomized controlled trial with newly suspected EoE; half of the patients received esomeprazole 40 mg daily and half fluticasone swallowed aerosol 440 mcg twice a day.  After 8 weeks, all patients had repeat endoscopy; a total of eight biopsies were obtained –four at two locations: 15 cm above LES and 3 cm above LES.  In addition, at the start of the study, patients also underwent 24-h pH/impedance monitoring.  4 of the 21 patients in each group had abnormal degrees of gastroesophageal reflux/gastroesophageal reflux disease (GERD).

Study characteristics note that 62% of patients had coexisting atopic disorders.

Results:

  • There was no significant difference in esophageal eosinophilia response with 19% of the fluticasone and 33% of the esomeprazole achieving an eosinophil count < 5/hpf (P=0.484)
  • In patients with coexisting GERD, all 4 esomeprazole patients achieved histologic remission  compared with none of the fluticasone-treated patients.
  • When the GERD patients were excluded, the histological remission was quite similar: 24% with fluticasone and 18% for esomeprazole.

Overall, this study population had a lower rate of response to topical steroids than in multiple previous studies.  More typically, response rates of ~50% have been reported; however, studies have shown lower responses in some adult studies.  Variability in response could be related to multiple factors included dosage, duration, delivery, and definition of response.  In addition, population characteristics included disease duration and frequency of underlying atopic disease and GERD play a role.

Take-home points: Although this is a small study, it reinforces the fact that PPIs induce a histological response and clinical response in some patients suspected of having EoE regardless of whether GERD is present.  PPIs are considered 1st line therapy.  Topical fluticasone had a lower response rate in this study.  However, in clinical pediatric practice, topical steroids are effective in about 50% of patients.

Additional related blog entries:

PPIs in Neonates –Helpful?

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Acid suppression in infants has not been proven to be effective in reducing gastroesophageal reflux (GER) symptoms. In a systemic review, this was thought to be either “because the symptoms are not caused by GER or if due to GER, because the symptoms are caused by volume reflux, rather than acidity.”  This quote is noted in the background information of another study which came to the same conclusion (J Pediatr 2013; 163: 692-8).

The pharmaceutical-supported study enrolled neonates (n=52) at 3 centers with gestational ages between 28-44 weeks.  Half of the participants were randomized to esomeprazole (0.5 mg/kg/day) and half placebo.  GER symptoms that were required for enrollment included any 2 of the following:

  • apnea with or without bradycardia
  • apnea with or without oxygen desaturations
  • irritability/pain
  • vomiting/gagging

Participants underwent extensive testing with video monitoring, esophageal pH & impedance testing, and cardiorespiratory monitoring.  They were followed for 14 days.

Findings:

  • There were no significant differences in any GERD-related signs and symptoms.
  • The esomeprazole group had improvement in acid reflux parameters on testing at 7 days, including number of reflux episodes (35 –>23) and mean percent time with pH<4.0.  The latter change was -10.7% was statistically significant (p= .0017) compared to placebo group which had an increase in time with pH<4.0 (2.2% increase).
  • No new safety signals were identified.

Despite its widespread usage, the authors had difficulty enrolling a larger cohort.  The small sample size was one of the study’s limitations along with the 14-day study period.  This limitation also precludes conclusions regarding the safety of these medications in neonates.

Bottomline: this study adds to the growing body of evidence that proton pump inhibitors (PPIs) are not effective in infants with so-called ‘signs and symptoms of reflux.’  PPIs are effective at reducing acid exposure and could be helpful in proven mucosal disease (eg. esophagitis and gastritis).

Related blog entries: