Association and Causation: Early Life Risk Factors for Eosinophilic Esophagitis

A recent case-control study (CP Witmer et al. JPGN 2018; 610-5) using the Military Health System Database examined 1410 cases of eosinophilic esophagitis (EoE) and matched them with 2820 controls; the study period was 2008-2015.

  • The authors found that early exposure to proton pump inhibitors (PPIs), histamine-2 receptors (H2RAs), and antibiotics were all associated with an increased risk of developing EoE with adjusted odds ratios of 2.73, 1.64, and 1.31.
  • In addition, among atopic problems, milk protein allergy had an adjusted odds ratio of 2.37 and eczema 1.97. –for developing EoE.

My take: This study does not determine whether the use of PPIs, H2RAs or antibiotics are involved in causation of EoE or whether patients with EoE simply receive these medications more frequently.  Nevertheless, the findings reinforce the idea that these medications should be used less frequently in infants.

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Somewhere near Banff

#NASPGHAN18 -Our Poster on Antibiotic Stewardship and PEG Placement

Thanks to Chelly Dykes for presenting poster later today and to co-authors for collaborating on this project: Jeffery Lewis, Bonney Reed-Knight and Cate Crenson.

Full abstract below.

ABSTRACT:

 Background: While there is general agreement that antibiotic prophylaxis for percutaneous gastrostomy (PEG) tube insertion reduces the risk of infection at the site of placement (Lipp A, Cochrane Review 2013), optimal antibiotic selection and regimen remain unclear; as a result, there is widespread practice variation.  In addition, in order to limit the development of bacterial resistance and complications from antibiotic use (eg. Clostridium difficile infection), antibiotic stewardship programs have aimed to limit antibiotic usage, particularly broad-spectrum antibiotics.

Methods: From December 1, 2016 through May 1, 2018, the charts of all patients who underwent PEG tube placement in our children’s hospital were reviewed.  This period coincided with an optional practice change in antibiotic prophylaxis.  Prior to the study period, the typical patient received prophylaxis with a three-dose regimen of cefoxitin.  During the study period, at the discretion of the gastroenterologist, patients received either a three-dose regimen of cefoxitin (n=38) or treatment with cefazolin (n=109); 73 patients received a single dose of cefazolin prior to PEG placement and 36 received multiple doses.  The initial dose of either regimen was given within thirty minutes of placement.  All patients were observed for at least 24 hours.  In patients with PEG tube site infections based on clinical assessment, rescue antibiotic treatment was prescribed.

Results: In total, 144 subjects had PEG placement. The main indications for PEG placement were swallow dysfunction (56.2%), poor growth (17.6%), feeding aversions (18.9%) and malignancy (6%).  In the cefoxitin group, clinical infection occurred in 3 of 35 (8.6%).  In the cefazolin group, clinical infection occurred in 20 of 109 (18.3%). In the subset of patients who received multiple doses of cefazolin, the clinical infection rate was 6 of 36 (16.7%). Patients in the cefazolin group had a 2.39 times higher odds (95% CI  0.667-8.612) of infection compared to the cefoxitin group. Although rates of infection were more than twice as high in the cefazolin group compared to the cefoxitin group, this association did not differ statistically using a chi square test (x^2 = 1.89, p = 0.20).

Conclusion: This study highlights the ongoing uncertainty regarding optimal antibiotic prophylaxis for PEG tube placement.  The difference in the clinical infection rate between cefazolin and cefoxitin was not statistically significant; however, the absolute rate of infection in the cefazolin group was more than twice as high as the cefoxitin group and this may influence selection of antibiotic prophylaxis for PEG tube insertion.

 

IBD Reviews: Role of Antibiotics and Data on Biomarkers

A clinical review, “Antibiotics in IBD: Still a Role in the Biological Era?” (O Ledder, D Turner, Inflamm Bowel Dis 2018; 24: 1676-88).  While this article provides a detailed review of the use of antibiotics for Crohn’s (including perianal disease), Ulcerative colitis and the effects on the microbiome, the potential use for very early onset (VEO) IBD caught my attention:

“We have recently begun considering oral vancomycin and gentamicin as sole firstline therapy in the rare form of infantile (ie <2 years of age) mild to moderate IBD, with promising success…this is merely investigational” at this time.  (Ref: Lev-Tzion R et al. Digestion 2017; 95: 310-13).

My take: Antibiotics can be a helpful adjunct therapy in both Crohn’s disease and Ulcerative colitis. It is unclear what role antibiotics will have for VEO-IBD.

A recent commentary (R Khanna et al, Inflamm Bowel Dis 2018; 24: 1619-23) examines the role of biomarkers.  While much of this topic has been reviewed extensively, I found the part about calprotectin helpful.  One of the topics with discrepant data has been the negative predictive value of calprotectin for detecting inflammatory bowel disease.  The data in this review:

  • From a meta-analysis in patients with symptomatic ulcerative colitis, calprotectin had a sensitivity of 0.88 and specificity of 0.79 compared to endoscopic inflammation.  For Crohn’s disease, the respective values were 0.87 and 0.67.
  • For histologic remission in ulcerative colitis, a study found that with a threshold of 155 mcg/g, calprotectin had a sensitivity of 78% and specificity of 71%.
  • Another study suggested that values <100 mcg/g indicate quiescent disease, values 100-250 suggest possible active inflammation, and values >250 mcg/g suggest active inflammation.
  • A cross-sectional study indicated that calprotectin ≥57  mcg/g had a sensitivity of 91% and specificity of 90% to identify endoscopically-active disease (Gastroenterol 2016; 150: 96-102)

My take: Sensitivity/specificity vary greatly based on the likelihood of disease; in populations at lower risk for IBD, a calprotectin has a high level of excluding active inflammation/IBD. In populations with IBD, levels more than 250 mcg/g indicate a high likelihood of active inflammation whereas levels between 100-250 are indeterminate.

Related blog posts:

 

 

Antibiotics for Acute Uncomplicated Appendicitis in Children

A recent meta-analysis study (L Huang et al. JAMA Pediatr 2017; 17: 426-34 -thanks to Ben Gold for this reference) indicates that antibiotcis can be effective as treatment for acute uncomplicated appendicitis, particularly if no appendolith is present.

From the abstract:

Abstract

IMPORTANCE:

Antibiotic therapy for acute uncomplicated appendicitis is effective in adult patients, but its application in pediatric patients remains controversial.

OBJECTIVE:

To compare the safety and efficacy of antibiotic treatment vs appendectomy as the primary therapy for acute uncomplicated appendicitis in pediatric patients.

STUDY SELECTION:

Randomized clinical trials and prospective clinical controlled trials comparing antibiotic therapy with appendectomy for acute uncomplicated appendicitis in pediatric patients (aged 5-18 years) were included in the meta-analysis. The outcomes included at least 2 of the following terms: success rate of antibiotic treatment and appendectomy, complications, readmissions, length of stay, total cost, and disability days.

RESULTS:

A total of 527 articles were screened. In 5 unique studies, 404 unique patients with uncomplicated appendicitis (aged 5-15 years) were enrolled. Nonoperative treatment was successful in 152 of 168 patients (90.5%), with a Mantel-Haenszel fixed-effects risk ratio of 8.92 (95% CI, 2.67-29.79; heterogeneity, P = .99; I2 = 0%). Subgroup analysis showed that the risk for treatment failure in patients with appendicolith increased, with a Mantel-Haenszel fixed-effects risk ratio of 10.43 (95% CI, 1.46-74.26; heterogeneity, P = .91; I2 = 0%).

CONCLUSIONS AND RELEVANCE:

This meta-analysis shows that antibiotics as the initial treatment for pediatric patients with uncomplicated appendicitis may be feasible and effective without increasing the risk for complications. However, the failure rate, mainly caused by the presence of appendicolith, is higher than for appendectomy. Surgery is preferably suggested for uncomplicated appendicitis with appendicolith.

From a AHC Media synopsis of article:Although antibiotic treatment of acute appendicitis appears effective in many cases, there is a nearly nine-fold higher risk of treatment failure compared with appendectomy, with 26.8% of patients in the antibiotic treatment group requiring interval appendectomy.

My take: My opinion is that surgery is appropriate as first-line treatment for  acute uncomplicated appendicitis.

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View of Omaha Beach from Normandy American Cemetery 

Antibiotics Given Early in Life Linked to Childhood Obesity…Again

While yesterday’s post discussed quadruple therapy for H pylori/need for multiple antibiotics, today’s post will focus on one of the downsides of antibiotic usage. For several years, this blog has highlighted numerous studies which show a link between antibiotics and later obesity (see related blog posts below).  Another study (FI Scott et al. Gastroenterol 2016; 151: 120-29), using a large database, quantifies this risk further.

This retrospective study used prospectively collected data from The Health Improvement Network (THIN), using a cohort of 21,714 children from the UK.

Key findings:

  • In the cohort, 1306 (6.4%) were obese at age 4 years.
  • Antibiotic exposure was associated with an increased risk of obesity at 4 years, with odds ratio of 1.21. The OR went to 1.41 for 3-5 prescriptions.
  • Antifungal agents were not associated with an increased risk of obesity., OR 0.81

In the discussion the authors make a number of useful points:

  • In the U.S. between 2006-2008, there “were >10 million antibiotic prescriptions…annually for children without clear indication.” Thus, this is modifiable contributing factor to obesity.
  • The risk is modest with “approximately 1.2% absolute and 25% relative increase in the risk of early childhood obesity. This relationship is strongest when considering repeat exposures.”
  • Though this is a large study, the authors had many limitations, as expected in a retrospective study.  These included a lack of awareness of the indication for the antibiotic, potential selection bias, and difficulty adjusting for some confounders like breast feeding and physical activity.

The study is in agreement with data from agriculture.  Numerous studies have highlighted how antibiotics can improve weight gain in industry.  Here are some useful references:

  • Gaskins HR, et al. Antibiotics as growth promotants: mode of action. Animal Biotechnol 2002; 13: 29-42
  • Lassiter CA. Antibiotics as growth stimulants for dairy cattle: a review. J Dairy Sci 1955; 38: 1102-38.
  • Moore P, et al. Use of sulphasuccidine, streptothricin and streptomycin in nutrition studies with the chick. J Biol Chem 1946; 165: 437-41.
  • Cho I, et al. Antibiotics early in life alter the murine colonic microbiome and adiposity. Nature 2012; 488 (7413): 621-26.
  • Cox LM, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014; 158: 705-21.

My take: Farmers have understood that antibiotics fatten up young animals for 70 years.  Yet, this basic information is NOT commonly understood by parents and many physicians. If this risk for obesity were widely known, it would help limit the use of antibiotics for well-recognized indications.

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South Leads Obesity

Persistent Symptoms after Lyme Disease

A new study has shown that long-term antibiotic therapy for Lyme disease is not helpful.

Here’s a link to a quick summary (1:37 min): Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease

In the associated editorial (MT Melia, PG Auwaeter, NEJM 2016; 374: 1277-8), it is noted that 10-20% of treated patients (after initial antibiotics) “may have lingering symptoms of fatigue, musculoskeletal pains…The plausible idea that additional antimicrobial therapy for potentially persistent bacterial infection would foster improvement has been a touchstone of hope in the 40 years since discovery of the disease in the mid-1970s.”

My take (from editorial): “Prolonged antibiotic therapy is not the answer” for lingering symptoms after Lyme disease. “We do not know what is truly helpful”

Related blog post: Facts and fiction with Lyme disease gutsandgrowth

 

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