Breaking down lung defenses in Cystic Fibrosis

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Cystic fibrosis patients develop chronic neutrophilic inflammation of the airways.  Neutrophils which help fight off bacterial infections also release peroxidases and proteases which can damage the lung tissues.  Neutrophil elastase which is one of the proteases elaborated by neutrophils can digest elastin; this is prevented by α-1-antitrypsin.  However, when there is excessive free neutrophil elastase this can overwhelm this protection.  A recent study has shown that neutrophil elastase activity in bronchoalveolar lavage (BAL) at 3 months of age was associated with early bronchiectasis (NEJM 2013; 368: 1963-70).

Design: 127 consecutive infants (from region of Western Australia) who were diagnosed with cystic fibrosis after newborn screening were recruited; however, 10 were too young and 3 were lost to followup due to relocation.  Most were followed for 3 years; 78 remained in the study at 36 months. Chest CT scans and BAL were performed at 3 months, 1 year, 2 years, and 3 years when patients were in stable clinical condition.

Bronchiectasis was identified by CT scan findings: “defined as a bronchus-to-artery ratio of more than 1.0 or the presence of a non tapering bronchus in the transverse plane.”

Key findings:

  • Point prevalence of bronchiectasis: 29.3% at 3 months, 31.5% at 1 year, 44.0% at 2 years and 61.5% at 3 years.
  • Free (unbound) neutrophil elastase activity in BAL fluid was a risk factor for bronchiectasis with an odds ratio of 3.02.  At 3 months of age, 23.3% had detectable neutrophil elastase activity in BAL fluid.
  • Other risk factors for bronchiectasis included meconium ileum (OR 3.17), and respiratory symptoms at time of CT (OR 2.27).

Take-home message: Damage happens to the lungs early in life. The related editorial (pg 2026) states “early cystic fibrosis lung disease is not ‘silent’ if you listen carefully.” To improve long-term outcome, early intervention will be necessary.

Related blog posts:

Natural History of EoE -Journal Club (Part 3)

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This posting reviews the final article for our eosinophilic esophagitis (EoE) journal club: Aliment Pharmacol Ther 2013; 37: 114-21.

Design: Cross-sectional study of adult EoE patients (≥ 18 years) who were diagnosed at the Children’s Hospital of Philadelphia.  Patients underwent dysphagia questionnaire, Mayo Dysphagia Questionnaire (MDQ-30), and a patient assessment of upper gastrointestinal disorders quality of life questionnaire (PAGI-QOL). Of 140 eligible patients, 53 completed the questionnaires, 66 were unable to be contacted, and 21 refused to participate.

The MDQ-30 has been validated as a tool for esophageal strictures of 15 mm or smaller.  It has not been confirmed as a EoE dysphagia tool.

Diagnosis: According to the authors, a diagnosis of EoE required a >20 eosinohils/hpf after a 2-month therapeutic trial of proton pump inhibitors.

Results:

  • Mean age 20.5 years.  98% were caucasian and 75% were male.  15% had a history of esophageal dilatation.
  • 6/53 had positive dysphagia scores.  However, 18/47 with negative scores reported ongoing difficulty swallowing.
  • 26 (49.1%) of subjects were receiving proton pump inhibitor therapy and 40 (76%) were following allergy-directed dietary elimination.  Most common allergy in this cohort was dairy (49%) followed by peanuts/tree nuts (23%), eggs (9%), wheat (9%), soy (8%), and seafood (2%).**
  • Overall, dietary QOL scores, but not overall QOL scores, were adversely affected by ongoing EoE.

**With regard to dietary therapy, there is a significant discrepancy in reported allergy avoidance in this cohort compared with some previous data published by this center. For example, Liacouras et al (Clin Gastro Hepatol 2006; 3: 1198) reported a  98% improvement with diet treatment (n=351) (2/3rds were treated with elemental diet, mostly NG, with food reintroduction).  Their protocol included rebiopsy after introduction of last new food.  75/242 responded to elimination of specific foods.  Overall pattern of food avoidance after biopsy: milk 45%, eggs 45%, soy 38%, corn 38%, wheat 30%, beef 30%, chicken 20%, potato /oats/peanuts 15%, turkey/barley 11%, pork 8%, rice 5%, green beans 3%, apples /pineapple 1%.*  The reported allergens in this study match up much more closely to a highly-selected group of patients that was more recently reported from their database and is reviewed separately (Picking the right diet for EoE | gutsandgrowth).  In this group, the authors stated that the most common foods by biopsy were the following: milk (35%), egg (13%), wheat (12%), soy (9%), corn (6%).

Study limitations:

  1. Small number of patients
  2. Low response rate/responder bias
  3. Retrospective cross-sectional study -does not provide longitudinal data
  4. Young age of subjects
  5. MDQ-30 not validated for dysphagia in EoE
  6. Tertiary children’s hospital with research focus on EoE
  7. No recent endoscopies in research cohort

Take-home message: EoE is a chronic disease with “little resolution of either symptoms or oesophageal eosinophilia without ongoing treatment.”

 

EoE -Journal Club (Part 2)

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The third article for our journal club: Aliment Pharmacol Ther 2013; 37: 1157-64.

This study involved a literature search which identified 10 articles which described the impact of proton pump inhibitor therapy for suspected eosinophilic esophagitis.  In total, these articles describe 258 patients (152 children and 106 adults).  Five of the studies were retrospective series.  The others included two randomized controlled trials, one randomized noncontrolled trial, and two prospective series.

Results: after PPI treatment, a clinical response was noted in 69% overall and histologic remission was evident in a mean of 44%.  Histologic remission was lower in children (23%-40%).  In two adult studies, both randomized controlled trials, PPI therapy (esomeprazole 40 mg/day) outperformed topical steroids (fluticasone 440 mcg bid); histologic remission was seen in 33% with PPI in both trials compared with 15% and 19% with fluticasone.

Key points in discussion:

  • PPI trial “is mandatory not only to confirm the presence of EoE, but to evaluate for PPI responsiveness.”  Yet, in surveys, …”only one-third of physicians thought it is necessary to initiate a PPI trial before diagnosing EoE.”
  • No clinical, endoscopic, histologic features nor pH testing “have demonstrated capacity to predict response to PPI therapy.”
  • PPI-REE “occurs in at least one-third of patients with suspected EoE, with response rates lower in children.”  Adults may have a higher response due to coexisting gastroesophageal reflux disease.

Related blog entry: gutsandgrowth | Pediatric Gastroenterology

EoE -Journal Club (Part 1)

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This week our Eosinophilic Esophagitis (EoE) journal club is meeting.  The first article had previously been reviewed on this blog: SFED works for EoE! | gutsandgrowth.

The second article examines the “Effect of Proton Pump Inhibitor on Esophageal Eosinophilia” (JPGN 2013; 56: 166-72). PPI responsive esophageal eosinophilia (PPI-REE) has also been discussed previously on this blog (EoE: Drugs, Diets, Dilatation and PPI–REE | gutsandgrowth); this article adds additional information to this subject and highlights the possibility of transient PPI-REE.

Design: retrospective review of 204 children with EoE (criteria included ≥15 dos/hpf) over an 11 year time span.  Only 35 subjects met the criteria of having an endoscopy before and after an exclusive 8-week trial of PPI (1-2 mg/kg/day).

Results: 8 of 35 subjects had clinical response and 7 had biopsy-confirmed response to PPIs ( 23%).  In five patients with durable response, mean eosinophil count decreased from 92 to 5 eos/hpf.  In addition, eosinophil peroxidase index (EPX) declined from 39.2 to 14.6.  Two patients experienced relapse despite initial PPI-responsiveness.  Clinical and histologic relapse occurred at 17 and 23 months respectively.  However, of the 5 subjects who did not experience relapse, average followup reported in study was only 8 months.

Study limitations: small number of patients, limited geographical area, tertiary medical center study, retrospective study, uncertain compliance with therapy, and variable dosing of PPIs

Take-home points:

  • No clinicopathologic features distinguished patients with PPI-REE from EoE patients or patients with transient PPI-REE. Yet, 23% (8/35) of initial cohort showed resolution of symptoms and 7/35 had resolution of esophageal inflammation after PPI treatment.
  • Potential explanations for transient PPI-REE: lack of PPI adherence, missed detection of EoE after PPI trial (patchy disease), variation in allergenic exposure, diminished effect of PPIs over time, fluctuation in EoE disease course unrelated to PPI usage

Related blog entries:

Also, for those of you who read all the way to the bottom, here’s a link to a culturally significant (aka viral video) advertisement that I thought was amusing (potty humor):

Kmart Big Gas Savings Ad (Video) – Daily Picks and Flicks

Anxiety and Functional Abdominal Pain

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A recent review highlights the importance of anxiety and functional abdominal pain (FAP) (JPGN 2013; 56: 469-74).

“Preliminary evidence suggests that anxiety frequently co-occurs with FAP.  This is not to suggest that FAP is a manifestation of a psychological disorder, but rather that anxiety and FAP may frequently co-occur because of potentially shared etiological factors (eg. heightened physiological arousal) or as a consequence of coping with recurrent pain.”

“Anxiety disorders are estimated to affect 42-85% of youth with FAP.”

Proposed guidelines for assessment and treatment of youth with FAP and anxiety:

Initial evaluation: build rapport between family and medical provider, assess for red flags, perform standard testing, anticipate and predict normal testing results, validate the pain experience is real, educate regarding pain sensation via brain-gut axis, administer anxiety screener (see below)

Management: reassure family that FAP is not a failure to identify an organic condition, avoid extensive testing, consider a low-dose antidepressant when appropriate

Psychosocial: if elevated levels of anxiety, refer for assessment by a psychologist, educate families about cognitive-behavioral treatment

With regard to screening, the authors propose the Screen for Child Anxiety and Related Disorders (SCARED) tool.  From the University of Pittsburgh website,

http://www.psychiatry.pitt.edu/sites/default/files/Documents/assessments/SCARED%20Child.pdf:

  • Target Population: Children ages 8-18 years
  • Intended Users: Clinicians and psychiatrists
  • Time to Administer: 10 minutes
  • Completed By: Children and parents
  • Modalities Available: Handwritten
  • Scoring Information: Severity of symptoms for the past three months is rated using a 0 to 2-point rating scale with 0 meaning not true or hardly ever true, 1 meaning sometimes true, and 2 meaning true or often true.

Many other subspecialists joke about the need for a psychiatry degree to be an effective pediatric gastroenterologist; this review suggests that they are not far off the mark.

Take-home message: the review covers important aspects of this ubiquitous problem.  Trying to get patients (and their parents) to address anxiety will likely improve outcomes of children with FAP.

Related blog links:

Additional references:

  • -JPGN 2011; 53: 200. n=98. 79% of FAP responded to low dose tricyclics
  • -Gastroenterol 2009; 137: 1261, 1207– Editorial. Amitriptyline helped in 66% vs 58% w placebo. n=90. dose 10mg <35kg, 20mg >35kg. 89% had failed Rx prior to study. ‘inability to use placebo.. in practice may justify amitriptyline Rx. Consider hypnotherapy/CBT first.’
  • Distraction/ignoring important: Pain 2006; 122: 43-52. (Walker LS et al), J Pain 2006; 7: 319-26.
  • -J Peds 2009; 154: 313 (editorial), 322. Prospective school study. n=237. Weekly prevalence of abd pain was 38%. 18% with persistence for >12 weeks. FAP persists into adulthood in 1/3 to 1/2 of cases (Clin Gastro Hepatol 2008; 6: 329-32).
  • -Acta Paediatr 2007; 96: 697-701. Maternal anxiety is most consistent predictor of outcome.

LIU Score

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The LIU acronym interested me in part because I work with Steven Liu. The LIU score refers to a Liver Injury Unit scoring system which is used to predict survival in pediatric acute liver failure (J Pediatr 2013; 162: 1010-6).

The LIU score and admission value LIU (aLIU) were examined in individuals enrolled in the Pediatric Acute Liver Failure (PALF) Study group.  LIU score was determined in 461 patients and aLIU in 579 patients.

  • LIU =[3.584 x peak total bilirubin (mg/dL)] + [1.809 x peak prothrombin time (PT) (sec)] + [0.307 x peak ammonia (μmold/L)]

or alternatively, using INR instead of PT:

  • LIU =[3.507 x peak total bilirubin (mg/dL)] + [45.51  x peak INR] + [0.254 x peak ammonia (μmold/L)]

Results: The LIU score was shown to be strongly predictive of transplant-free survival with a c-index 0.81.  The aLIU score was less predictive with a c-index of 0.76.  In this population, the LIU score predicted the likelihood of receiving a liver transplant better than the risk of death.

Bottom-line: The LIU score may have similar utility as a MELD/PELD score but is easier to calculate.

Newsflash: constipation frequently causes abdominal pain

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From the following link (forwarded to me by Mike Hart) http://www.dailyrx.com/abdominal-pain-children-emergency-room-was-most-commonly-constipation:

A recent study found that constipation is the most common reason for abdominal pain among children going to one emergency room.

Appendicitis was diagnosed in only about 4 percent of children who went to the ER.

In addition, the researchers did not find any major differences in the treatment or outcomes of children based on their race.

“Call the pediatrician if your child has severe abdominal pain.”

The study, led by Kerry Caperell, MD, of the Department of Pediatrics at the University of Louisville in Kentucky, looked at the outcomes of children who went to the emergency room for abdominal pain.

The researchers investigated the medical records of 9,424 children, aged 1 to 18, who went to the Children’s Hospital of Pittsburgh emergency department for abdominal pain during a two-year period.

More than half of these children, a total of 5,493, ended up receiving multiple diagnoses for their complaints.

The researchers found that 1.9 percent of the African American children and 5.1 percent of the white children who visited the ER were diagnosed with appendicitis. Overall, 4.3 percent of the children had appendicitis.

Appendicitis was less common among younger children, but constipation was commonly diagnosed for all ages.

Almost 20 percent of the children were diagnosed with constipation, and more than 25 percent of the children aged 5 to 12 had constipation.

Constipation, gastroenteritis and urinary tract infections were more common among the African American patients than the white patients.

“Diagnosing causes of abdominal pain in children can often be difficult, especially the younger they are,” said Chris Galloway, MD, a dailyRx expert who specializes in emergency medicine.

“Fortunately common causes are still common and constipation is a frequent diagnosis we make in the ER, and can be quite distressing for your child,” Dr. Galloway said. “Consult your pediatrician if your child has abdominal pain.”

Older children were more likely to remain in the hospital and have an operation related to the reason they went to the ER.

The researchers did not find any differences in children’s outcomes related to their race. This finding means that all the children who went to the ER received similar evaluation and treatment and had similar outcomes regardless of their ethnicity.

The study was published May 20 in the journal Pediatrics. The research did not receive external funding, and the authors declared no conflicts of interest.

Comment: While constipation is a common entity, many of these children have underlying functional problems that are not addressed in the ER setting.

Related blog links:

Overcoming ATIs

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Usually, when antibodies to infliximab (ATI) develop in combination with a loss of clinical response in an individual with inflammatory bowel disease (IBD), this often indicates a need to switch treatments.  A recent study suggests that some patients can eliminate ATIs with the addition of immunomodulators (Clin Gastroenterol Hepatol 2013; 11: 444-47).

In this small retrospective study, 5 patients (18-37 years of age) who developed ATIs were able to continue infliximab therapy after instituting immunomodulator treatment (3 with thiopurines, and 2 with methotrexate).  What makes this report interesting, was that these ATIs (prior to immunomodulator use) were identified multiple times and were associated with undetectable infliximab levels.  None of these patients had dose intensification of infliximab.  After instituting immunomodulator therapy, detectable infliximab was evident and the ATIs disappeared.  According to Figure 1, the timeframe for return of response was about 10 weeks in some of these patients.

The authors note that the addition of immunomodulators can gradually eliminate a preformed memory response to infliximab antigen.  They also note that ATIs can sometimes disappear spontaneously, though this had not been noted to occur previously when mulitple ATIs levels have been identified.

While these observations are important, a larger prospective study is needed to inform how frequently this strategy could be successful.

Related blog links:

Anti-TNF Therapy for Eosinophilic Gastroenteritis

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A recent report highlights the use of anti-TNF therapy (eg. infliximab (IFX) and adalimumab [ADA])  for eosinophilic enterocolitis/eosinophilic gastroenteritis in eight patients who had not responded to other treatments (JPGN 2013; 56: 492-97).

The mean age of these patients was 8 years with a range of 1 to 14 years.  Prior to use of IFX therapy, multiple therapies had been used.  Four patients had been treated with complete elemental diet; medications that were used included montelukast, hydroxyzine, sodium cromogylcate, budesonide, amitriptyline, prednisone, ketotifen, cyproheptadine, thiopurines, and methotrexate (Table 1 in study).

Complete clinical remission was noted to occur in 6 (75%) with IFX induction treatment; this was associated with mucosal healing in 3, mucosal improvement in 2, and unknown in 1 patient.

The six responders were followed for a median of 7 years.  During that timeframe, four of six had secondary loss of response and were switched to ADA.  Three of these four maintained a clinical response with ADA using high doses (80 mg EOW).

Additional References:

  • -Clin Gastroenterol Hepatol 2011; 9: 950.  40% of Eosinophili gastroenteritis resolved.
  • -JPGN 2010; 51: 723. n=91.  Incidental gastric eosinophils does not predict a worse response to fluticasone then isolated EoE.
  • -NEJM 2009; 361: 1387.  Description of a case of eosinophilic gastroenteritis.
  • -Gut 2009; 58: 721-32. Review of primary Eos d/o of GI tract.
  • -JPGN 2008; 47: 234-8.  EGIDs.