Tag Archives: cystic fibrosis

How Commonly Does Cystic Fibrosis Present as Rectal Prolapse?

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Since residency, I have understood that patients with cystic fibrosis patients could present with rectal prolapse.  Yet, I can recollect only one instance in which a family told me that rectal prolapse was a presenting feature in the diagnosis of their child.  It turns out that rectal prolapse is a little less common as a presenting feature, at least these days, and that the majority of cases occur in individuals with cystic fibrosis who have already been diagnosed (JPGN 2015; 60: 110-12).

In this retrospective study (2000-2010), there were 262 patients with rectal prolapse identified: 65% were male and mean age was 4 years 8 months.  Newborn screening for cystic fibrosis(1994 in Wisconsin) had preceded the study period.

The most common reason for rectal prolapse was constipation (52.1%), and then acute diarrhea (12%).  Only 3.6% had cystic fibrosis. Two patients were diagnosed with cystic fibrosis based on testing performed due to rectal prolapse; the remaining five had already been diagnosed.

The authors note that among their cystic fibrosis population that 3.5% also had rectal prolapse.

Take-home message: In patients with rectal prolapse, testing for cystic fibrosis has a low yield in the era of newborn screening but is probably still necessary.

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Boat in Chicago Marina –Like the Name?

“Origins of Cystic Fibrosis Lung Disease”

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Origins of Cystic Fibrosis Lung Disease — NEJM (NEJM 2015; 372: 351-62) is a good read.  The authors note that the basic defect in Cystic Fibrosis (CF), the loss of the cystic fibrosis transmembrane conductance regulator (CFTR), has been recognized for a long time.  However, the connection between this defect and the progressive lung disease/inflammation has remained uncertain.

Now, new animal models have provided a wealth of information that closes the knowledge gap.

Here are the key points:

  • CF affects the lungs very early: Bronchiectasis is present in nearly one in three children with CF by 3 years of age and CT scans are abnormal in most babies with CF as early as 3 months of age.
  • Infection precedes inflammation: “During the first hours after birth, piglets with CF show no evidence of inflammation in their airways…yet,…they fail to eradicate bacteria as well…[which] can initiate a cascade of airway inflammation and airway remodeling.”
  • There are multiple “hits” on the airways.  While many have suggested that increased sodium leads to a ‘dehydrated’ state, this does not seem to be correct.
  • More recent studies point to loss of bicarbonate secretion as a crucial factor.  This results in a reduced pH which in turn leaves the lungs more vulnerable to infection.  Lower acidity reduces the effectiveness of a “complex soup of antimicrobial peptides, proteins, and lipids in airway-surface liquid.”
  • Poor mucociliary transport, “which guards the lungs by trapping invading pathogens and particulates in mucus,” is another important “hit” on the lungs.

Implications:

  • CF needs to be diagnosed early and treated early
  • Improving even one of these defects in host defenses is likely to be beneficial.
  • Animal models remain important in understanding pathophysiology.  They allow “investigating the disease at its genesis and before the onset of secondary manifestations.”

Related blog posts:

Progress in Cystic Fibrosis over 18 Years

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A recent study (J Pediatr 2014; 165: 1091-7) showed significant improvement in lung function among 6-year-olds with Cystic Fibrosis (CF) between 1994-2012.

Using the Cystic Fibrosis Foundation Patient Registry with a total of 11,670 children, the authors found that the mean FEV1 and FVC z-scores increased significantly over the period in the entire cohort.  In addition, the height-for-age (HFA) also improved.  These results are easy to see graphically in Figures 1 & Figure 2.  The authors note that in 2012, children who were identified by screening had improved HFA, FEV1, and FVC compared to children who were not identified by screening.

Take-home points:

  • These data show impressive improvement in lung function and growth over the past two decades
  • These values are going to improve further now that all 50 states mandate newborn screening for CF
  • While there is improvement, 6-year-olds with CF still have measurable pulmonary dysfunction; thus, more work is needed, perhaps with novel therapies.

Related blog posts:

Briefly Noted…Scoliosis, Cystic Fibrosis, Specific Carbohydrate Diet, GGT, Surgeon General

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“Net effect of scoliosis surgery on gastric emptying, upper gastrointestinal symptoms, and clinical nutritional status was minimal”  according to this prospective study of 31 children: JPGN 2014; 58: 38-45.

Lactobacillus reuteri ATCC55730 was associated with reduced pulmonary exacerbations (but not improved FEV1) in 61 patients with cystic fibrosis who were enrolled in a prospective randomized, double-blind, placebo-controlled study over 6 months between 2007-2009 (JPGN 2014; 58: 81-86).

A retrospective chart review of seven children with Crohn disease who were treated with the specific carbohydrate diet with an average diet duration of 14.6 months showed that all symptoms resolved and laboratory studies improved or normalized.  (JPGN 2014; 58: 87-91). More studies on this diet are expected to be published soon.

Data from 200 preterm infants and 383 term infants help provide updated GGT (gamma-glutamyl transferase) reference values.  In preterm infants during 1st 7 days: 141 ± 89 U/L, then between days 8-28: 131 ± 85 U/L.  In term infants the values were similar 140 ±86 U/L and 145 ± 87 U/L respectively. (JPGN 2014; 58: 99-101).

And from NEJM twitter feed, Congress may allow the NRA veto power in the selection the next surgeon general: http://nej.md/1nECFlM.

Gastrostomy Tubes for Children with Cystic Fibrosis

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A recent report indicates that gastrostomy tubes (Gtubes) can be safe and useful for supplemental nutrition in children with cystic fibrosis (CF) and portal hypertension (JPGN 2013; 57: 245-47).

This small study from Australia was a retrospective study of their CF database from 1991-2011.  During this timeframe, 60 CF patients had gastrostomy tubes.  7 children had CF and portal hypertension.  The mean age of insertion was 10.6 years and all of these patients were pancreatic insufficient. Six of these 7 patients had percutaneous endoscopic gastrostomy (PEG); one had open surgical placement due to preexisting varices.  The median length of followup was 4 years.

Results:

  • No patients developed stomal varices
  • One patient had minimal cellulitis in the perioperative period, otherwise no complications were noted.
  • Two patients died related to advanced pulmonary disease
  • Three patients developed varices during the course of their care
  • Overall, there was improvement in BMI z-score at 2 years from -1.07 ± 0.87 to -0.58 ± 0.81 (p=0.05) and also at w years there was improvement in pulmonary function in 6 patients with mean FEV-1 going from 49.5 ± 12.6 to 62.3 ± 20.3 (P=0.04)

Take-home message: in a select group of 7 patients with Cystic Fibrosis and portal hypertension, gtube placement was safe and associated with better nutrition and lung function.

Related blog links:

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:

Fluctuating Elastase Levels in Infants with Cystic Fibrosis

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A recent study sheds light on the variability of elastase levels in both pancreatic sufficient (PS) and pancreatic insufficient (PI) infants with cystic fibrosis (CF) (J Pediatr 2013; 162: 808-12).

After eliminating infants who did not have elastase values prior to 3.5 months and after 9 months, the study consisted of 61 formula-fed infants who had been diagnosed with CF.  Diagnosis was established based on either a positive sweat test or having two known CF mutations.

Background: Pancreatic elastase is produced by pancreatic acinar cells and is not degraded during intestinal transit.  It can be measured while on pancreatic enzyme replacement therapy (PERT) because it is specific for human elastase rather than porcine elastase.  In addition, samples are stable at room temperature for weeks.

Among this cohort, 28 (46%) were homozygous for the F508del mutation. Infants were part of a large docosahexaenoic acid (DHA) study; as such, they were randomized to receive either standard formula or formula supplemented with DHA.  Monthly stool samples were collected.

Results:

  • Of 29 infants with initial fecal elastase <50 mcg/g, all had a value <200 mcg/g at one year.  However, 3 had a value >200 mcg/g at some time during the first year of life.
  • Of 36 infants with initial elastase <100 mcg/g, 32 had a level <100 mcg/g at 1 year.  Only one infant in this group had a value consistent with PS and this infant had a mutation associated with increased likelihood of PS.
  • Of 12 infants with initial values between 100-200 mcg/g, more variability was noted in their multiple samples.  This group accounted for the majority of infants who were reclassified from PI initially to PS after one year of life.  Among all 48 with values <200 mcg/g, 4 were considered PS at final evaluation.  However, 13 had values >200 mcg/g at some point.
  • 13 infants were considered PS at initial evaluation with a value >200 mcg/g.  At the study conclusion, 3 had values <180 mcg/g.
  • The majority of fluctuation in elastase values occurred during the first 6 months of life.

These results lead to the following conclusions:

  1. Fluctuations in elastase levels during the first year of life indicate that some infants with PS become PI and vice versa.  Retesting at one year of life is important.
  2. The authors recommend that all CF patients with elastase values below 200 mcg/g receive PERT.
  3. One can extrapolate these findings to other populations.  A single normal or abnormal elastase value may not indicate ultimately whether a patient will remain pancreatic insufficient or sufficient. Though, values <50 mcg/g are more likely to indicate persistent PI status.

The authors do provide some speculation regarding these fluctuations.  They note that “a fecal elastase obtained very early in life might not reflect the child’s true functional pancreatic status.  Intestinal mucosal damage can cause secondary pancreatic insufficiency by decreasing signaling of the pancreas from enteroendocrine cells.”

Related blog links:

References:

  • -JPGN 2007; 44: 219.  Use of elastase in CF.  Pancreas secretes elastase; not degraded & does not cross react with porcine elastase, thus allowing measurement even in individuals on enzyme treatment.  Excellent sensitivity/specificity.
  • -J Pediatr 2004; 145: 322 & 285,  A fecal elastase-1   >100mcg/g has a 99% predictive value for excluding pancreatic insufficiency.
  • -JPGN 2003; 36: 314, 392.  Fecal elastase-1 is marker for exocrince pancreatic function & enteropathy.
  • J Peds 2009; 155: supplement. Clinical practice guidelines for infants/children <2 years of age with CF:
  1. -routinely give salt 1/8-1/4tsp/day
  2. -measure elastase & supplement if PI
  3. -Dose: 2000-5000 units lipase per feed –can go as high as 2500 units/kg (max daily 10000 units/kg/day)
  4. -monitor & supplement ADEK
  5. -consider 7% saline Rx & azithromycin in symptomatic

Ivacaftor for Cystic Fibrosis

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Recent FDA approval of Ivacaftor (Kalydeco) is a promising step for a subset of patients with cystic fibrosis who have the G551D mutation.  This drug enhances the cystic fibrosis transmembrane regulator (CFTR) gene in these patients; only ~4% of CF patients or about 1200 patients in the US have this genetic defect.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm

Additional references:

-NEJM 2011; 365: 1663. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 167 pts. (Ivacaftor).
-NEJM 2010; 363: 1991. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 39 adults.