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Therapeutic Inertia in U.S Neonatal Units (vis-a-vis Probiotics)

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“More than 90% of very low birth weight (VLBW) infants receive substandard care” could be the headline of a recent article/editorial (J Pediatr 2014; 164: 980-5 & 959-60).  Instead they are titled: “Cohort Study of Probiotics in a North American Neonatal Intensive Care Unit” and “Probiotic Supplementation in Preterm Infants: It is Time to Change Practice.”

In the article introduction, the authors state: “In 2011, faced with overwhelming evidence that probiotics could decrease NEC in preterm infants, and because there were no significant risks described in the extensive literature, we decided to introduce probiotics as routine care for the prevention of NEC.”

Methods: Prospective cohort study of infants at a single center NICU.  Examined rates of necrotizing enterocolitis (NEC) and death for 17 months before and after introduction of a probiotic (FloraBABY).  This probiotic (0.5 g) was mixed with water and administered just before milk once a day.  It was started at the first feeding and continued until the infant reached 34 weeks postmenstrual age.

Key findings:

  • Probiotics reduced NEC from 9.8% to 5.4% (OR for NEC 0.51)
  • Probiotics reduced combined outcome for NEC or death from 17% to 10.5% (OR 0.56).  Reduction in death by itself did not meet statistical significance.

Why, in 2012, were probiotics only used in 8-9% of VLBW?

Potential profits for probiotics are small which has limited studies of specific strains.  The probiotic, FloraBABY, in this study cost 11 cents per day in amount used; however, since the probiotic came in a tub, the actual cost was $12.79 for a 60-g tub for each patient.  Thus, manufacturers are unlikely to support studies to garner FDA approval.

Yet, there have been 22 randomized controlled trials published which “showed substantial benefits of probiotics and no adverse events.” A recently completed ProPrems trial (Jacob S et al, presented at 2013 PAS Annual Meeting) used a probiotic called ABC Dophilus Probiotic Powder for Infants.  This trial showed “a significant, >50%, reduction in NEC despite an incidence in their control patients of only 4.4%” and despite the fact that >95% of infants received breast milk.

“Good quality control and confirmation of the contents of the preparation are essential…There seems to be no further reason to delay the introduction of this evidence-based therapy in the NICU.”  The adoption of probiotics could avoid 2500 cases of NEC every year in North America.

The editorial notes that the evidence for probiotics is much better than many other therapies used in NICUs.  They note that some have argued that “the evidence that probiotics reduce mortality rates is as conclusive as that for surfactant for respiratory distress syndrome.”  A recent Cochrane review of 17 trials and >4900 VLBW infants showed that the RR of severe NEC for probiotics versus control was 0.41.

If people really understood this issue, there would be outrage over this issue.  In the U.S., there was recently extensive coverage over inaction about a faulty ignition switch which has been linked to at least 13 deaths.  The potential reduction in NEC and deaths with probiotics is likely much greater.

While the editorial recommends involving parent representative groups, I recommend discussing this issue with your neonatology colleagues along with your “quality care” team to find out what they are going to do about it.  Given the enormous costs in most NICUs, it is likely that each unit could self-fund a quality project (with consented patients) to provide probiotics to this vulnerable population.

Bottomline: Probiotics have excellent evidence as prophylaxis for NEC in VLBW infants.  Physicians need to advocate for their usage to “avoid years of therapeutic inertia.”

Related blog post: One More Day Syndrome & Necrotizing Enterocolitis …

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Source Article: Methotrexate Safety

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A recent post (Monotherapy or Combination Therapy with Adalimumab) referenced an article indicating some potential concern for malignancy potential with methotrexate (Semin Arthritis Rheum 2014; 43: 489-97). Here’s a link to the source article/abstract:  Comparative cancer risk associated with methotrexate, other…

The authors conducted a comparative effectiveness study with cancer as an outcome in patients with rheumatoid arthritis (RA).  The final sample size was 6806 patients.  The most common drugs examined included methotrexate (n=1566) and TNF antagonists (n=3761). Other disease-modifying anti-rheumatic drugs (DMARDs) included other non-biologics (n=904), rituximab (n=167), and abatacept (n=408).

The authors note that with “the advent of newer DMARDs and combination therapy (this) has allowed more RA patients to lead more functional lives.  With this improvement in therapy, more attention is focused on the comparative risks and benefits of treatment.”

Key findings/discussion:

  • TNF antagonists were associated “with a reduced overall cancer risk versus methotrexate.” (HR 0.29).  Figure 2B, shows a plot with specific HR for various malignancies.  TNF antagonists had a HR of 0.15 for lymphoma.
  • Oncogenic potential of methotrexate was described almost 20 years ago, however, “its obvious clinical benefits have overshadowed malignancy concerns.”
  • “Our findings suggest that when examining the cancer risk associated with other DMARDs, combined methotrexate use must be factor into adjusted analyses.”

How does this translate to inflammatory bowel disease (IBD)?  While RA and IBD patients may have different risks for malignancy, this study suggests that patients receiving methotrexate therapy may have a low risk of malignancy.  The potential benefits of methotrexate therapy along with alternatives need to be weighed against this possible risk. Perhaps, this article may help reduce the concerns regarding anti-TNF therapy with regard to relative risk.

Related post:

Marriage, Divorce and Separation with Anti-TNF Therapy

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This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission.  This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married.  Once you committed, you stayed in that relationship indefinitely.  Of course, it is well-known that individuals get divorced.  In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions.  Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this?  The article examines nine studies with a little more than 500 patients.  “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval.  It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.  Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM.  Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.”

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56.  Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease.  This is a useful review with 103 references.

Superiority of Anti-TNF Therapy (Part 2)

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A recent blog (Superiority of Anti-TNF Therapy in Children | gutsandgrowth) described a recent article showing that kids treated with anti-TNF therapy at the time of diagnosis had improved outcomes compared to children who were treated with other medications.  In this day of multimedia, there is a video explaining the study which may be helpful for families and clinicians alike –here’s the link:  Dr. Michael Stephens discusses the research findings: .

An excerpt from the explanation with the video:

The current research study looks at outcomes and compares three different types of treatments. The first group receives anti-TNF therapy. The second group received immune modulating therapy. The third group received no treatment within the first three months. This study was an observational study and the choice of treatment was at the discretion of the physician. In order to correct for this factor, a statistical technique was used. Patients with similar characteristics were paired within the three groups . The results showed that patients who received the anti-TNF therapy had an improved outcome, such as a higher remission rate and some indications of improved growth, at one year. All three groups had improvements in weight and body mass index but only the anti-TNF group had improvements in linear growth.

Just the Beginning: Mutations in Very Early Onset Inflammatory Bowel Disease

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A recent study (Gastroenterol 2014; 146: 1028-39) indicates that mutations in tetratricopeptide repeat domain 7A (TTC7A) can result in a severe form of very early onset inflammatory bowel disease (VEOIBD).

After identifying a TTC7A heterozygote mutation in an infant by using whole exome sequencing of DNA, the authors subsequently identified 4 additional patients (2 siblings from 2 families) who also had loss of function mutations in VEOIBD.  Thus far, four of the five identified infants have died.

The manuscript has some terrific figures describing endoscopic/histologic characteristics, TTC7A genetic analysis, functional TTC7A enterocyte studies with immunofluorescence, impaired cell adhesion figure, tandem mass spectrometry, and a summary mechanistic figure (figure 6).  Hematopoietic stem cell transplantation has not been effective and might not work due to the enterocyte defect.

This study adds another VEOIBD gene mutation.  Previous mutations have involved in VEOIBD have included IL10RA/B, XIAP, ADAM17, NCF4, and NCF2/RAC2. The specific subtype matters as some defects may respond to stem cell transplantation.

Take-home message: there are a diverse number of pathways that can lead to VEOIBD.  Given the recent availability of whole exome sequencing, more mutations are sure to be identified soon.

Related blog post/link:

IL-10 and early onset IBD | gutsandgrowth In addition to the Toronto group (noted in this blog), a group in Boston with Harland Winter/CJ Moran is also interested in whole exome sequencing for VEOIBD patients.

Causes and Treatment of Very-Early Onset IBD –-this link is to the AGA Journals blog post on the same subject.

How Long Will Infliximab Work?

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Given the limited therapeutic options, the question of infliximab (IFX) durability in pediatrics is quite important.  One center has published its 10-year retrospective experience (Inflamm Bowel Dis 2014; 20: 606-13).

Inclusion criteria for the 188 patients included initiating IFX prior to age 21 years and patients who had a minimum of 1-year followup.

Demographics: Median age at diagnosis was 11 years for Crohn’s disease (CD) and 12 years for ulcerative colitis (UC). Indication for IFX due to steroid refractory disease was present in 42% of UC patients compared with 14% of CD patients.  Monotherapy was more common in UC patients, 65%, compared to 35% of CD patients.

Methotrexate was administered in 69 (44%) of CD patients at time of IFX with the majority (n=56) as oral treatment (low-dose <10 mg every week).  In addition, MTX was initiated after IFX induction in another 38 (24%).  Only 36 (23%) remained on IFX mono therapy throughout the duration of treatment in CD patients.

Key findings:

  • 88% of CD patients remained on IFX at 1 year, 80% at 2 years, and 72% at 5 years.
  • Only 7 of 157 CD patients were primary nonresponders.
  • 65 of 89 CD patients who did not achieve a sustained durable remission underwent dose escalation. 40 of 65 responded to dose escalation.
  • Of those who lost response to IFX, the majority were transitioned to adalimumab (ADA) and among this group, 82% remained on ADA treatment at last followup.
  • Among UC patients (n=31), 9 were primary nonresponders. At last followup, 41% (9) remained in a durable sustained response at last followup.
  • While the authors used MTX due to favorable effects on IFX pharmacokinetics (Arthritis Rheum 1998; 41: 1552-63), there was “not a significant difference in IFX durability or efficacy between this group and patients with CD on IFX monotherapy”
  • Availability of antibodies to infliximab (ATIs) and IFX trough levels were only assessed in a subset.  However, “we did see a significant difference in those that responded to dose intensification when ATIs were undetectable.”

Bottomline: The majority of CD patients can remain on IFX for >5 years.  Among those who lose response, adalimumab was a durable alternative.  A much lower durable response was evident with the subset of patients with UC.

Related blog post:

Also noted:

Inflamm Bowel Dis 2014; 20: 614-21. In this study of 78 youth with IBD, depressive symptoms warranting additional evaluation were present in 13% which was lower than in the community comparison group.  Disease severity was noted to be inactive in 63% and mild in another 18%.

Inflamm Bowel Dis 2014; 20: 495-501. This study showed that 25 children exposed to anti-TNFs prenatally for maternal IBD seemed to show good safety.  Immunologic investigation undertaken in 17 of the children was normal.  No control group limited the ability to determine if increased infections were present.

And, here’s a link to Mar-April Circle Newsletter from ImproveCareNow -topics include group medical appointments, parent working group, dieting with IBD, and includes link to self management handbook.

 

 

“Low quality of evidence; strong recommendation” for Probiotics in Gastroenteritis

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Recently a position paper on “Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN working group for probiotics and prebiotics” was published (JPGN 2014; 58: 531-39).

Two specific probiotics were recommended “strongly” but the working group describes the evidence for both as “low quality.”  This strikes me as odd.  The authors extensively reviewed previous studies and used the “GRADE” system to classify the quality of evidence and the category of recommendation.  There were 4 categories of quality of evidence: high, moderate, low and very low.  There were 2 possible recommendation categories: strong or weak.

The summary recommendations included the following:

  • Rehydration is the key treatment for AGE
  • Probiotics, overall, reduce diarrhea by approximately 1 day
  • However, probiotic effects are strain specific; findings from one probiotic cannot be extrapolated to another
  • The group recommends choosing probiotics with efficacy confirmed in well-conducted RCTs from a reputable manufacturer
  • Two specific recommended probiotics: Lactobacillus GG and Saccromyces boulardii

Take-home message: This article summarizes the available evidence for the use of probiotics in acute gastroenteritis.  Despite their classification as  “low quality of evidence,” the authors provide a strong recommendation for two probiotics (Lactobacillus GG and Saccromyces boulardii) as adjunctive therapy.

Related blog posts:

 

 

 

Something You Probably Have Not Seen with Celiac Disease and Headaches

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An “image of the month” in the NEJM shows the association between celiac disease and occipital calcifications in a 24 year-old with a 10 year history of headaches, here’s the link: 

The course and explanation: Treatment with a gluten-free diet, folic acid supplementation, and carbamazepine was initiated, and the patient’s condition improved, with remission of all symptoms. The combination of celiac disease, epilepsy, and cerebral calcification is a rare condition known as the CEC syndrome. Folate malabsorption is a suggested mechanism

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Also, there is a useful patient celiac education page from JAMA Pediatrics & University of Chicago: http://dlvr.it/55h6Rd 

Why is Celiac Disease Becoming More Prevalent?

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A recent editorial helps provide some answers and even explains the term “protopathic bias.”  Ostensibly, the editorial’s task is to explain the potential interaction of maternal serum iron ingestion and the risk of celiac disease (see previous blog post: Is There a Link Between Maternal Iron Supplementation and …).  However, the editorial provides an explanation for the Swedish epidemic and the ongoing slower, wider epidemic.

Here’s the link, http://ow.ly/vQGQ7, and here’s an excerpt:

The Swedish epidemic of CD of 1985–1994 has been extensively documented, and resulted in the development of hypotheses regarding environmental risk factors for this disorder.7 This epidemic was restricted to children younger than 2 years; in that age group, the incidence of diagnosed CD rose from 65 cases per 100,000 person-years to 198 cases per 100,000 person-years. In contrast, incidence data for older children were relatively flat during this period. The epidemic abruptly ended in 1995, although children born during the period of the epidemic have an ongoing increased risk of developing CD. Subsequent investigation led to the hypothesis that infant feeding practices affect the risk of CD in young children. The epidemic occurred during a period of relatively low rates of breastfeeding at the age of 6 months and during the same period of time, the quantity of gluten in infant formula greatly increased. Although it is difficult to separate the relative importance of each feeding practice, it seemed that high quantity of initial gluten intake without overlapping with breastfeeding was responsible for this epidemic. Although a systematic review of the issue has concluded that breastfeeding has not been definitively proved to be associated with risk of CD,8 subsequent research has indicated that the timing of gluten introduction is important in determining risk.9PreventCD, a prospective randomized trial of infants with a family history of CD, is testing specifically whether the introduction of small quantities of gluten beginning at age 4 months of age will induce tolerance to gluten in this high-risk group.

The second epidemic is more diffusely spread over time and space. Studies from the United States and elsewhere have shown that the seroprevalence of CD (as defined by positive tissue transglutaminase and endomysial antibodies) has increased markedly in recent decades. An analysis of stored serum from military recruits at the Warren Air Force Base in the years spanning 1948–1954 found a CD seroprevalence of 0.2%, whereas 2 recent cohorts from Olmsted County (spanning the years 2006–2008) matched by year of birth and age at sampling found a seroprevalence of 0.9% and 0.8%, respectively.11 An analysis of another cohort in this country found a doubling in seroprevalence during adulthood from 1974 (0.21%) to 1989 (0.45%).12 The mode of presentation of CD has changed in the past generation, with rising numbers of patients presenting without diarrhea.13 Patients presenting with anemia may have more severe disease expression (as measured by the degree of villous atrophy and the presence of metabolic bone disease) than patients presenting with diarrhea.14 Because most individuals in the United States with CD are undiagnosed,15 this is largely a hidden epidemic, but there is no reason to believe that the prevalence has peaked. In Finland, which had a higher prevalence of CD than the United States to begin with, the seroprevalence of CD doubled between the years 1978 (1.05%) and 2000 (1.99%).16 It is not known whether this epidemic will subside or if the prevalence of CD will continue to rise to a new set-point. But given the morbidity associated with CD17 and the cost and difficulty of the gluten-free diet18, 19 these data have sparked interest in identifying the cause of this less visible epidemic.

Certain infections (eg, rotavirus among infants20 and Campylobacter among adults21) have recently been shown to be associated with a increased risk of CD, but rates of these infections have not increased markedly, and so are not likely to be driving this epidemic. In contrast, a lack of exposure to certain microbes is a hallmark of modern times, and the increase in CD disease is congruent with the hygiene hypothesis, which states that decreased exposure to microbes may be driving the rise in autoimmune and atopic conditions. This hypothesis is particularly compelling in light of a recent study that found a dramatically different seroprevalence of CD in Finland (1.4%) and the Russian Karelia (0.6%), geographically proximate areas with a similar prevalence of HLA DQ2 and DQ8 but with major differences in economic development.22

Further evidence implicating the modern relationship with microbes is now accumulating. Children who were born by elective cesarean section are at increased risk of developing CD, whereas those born by emergent cesarean section (and may have had contact with the birth canal) are not.23 In addition, there seems to be an inverse relationship between Helicobacter pylori colonization and CD.24 Drugs are another modern innovation that may be affecting the CD epidemic. Population-based studies from Sweden have shown that prescription of antibiotics25 and proton pump inhibitors26 are each associated with an increased risk of the subsequent development of CD.

The associations identified in these studies are not necessarily causal. Studies of drug exposure in particular may be prone to protopathic bias, wherein early symptoms of the outcome of interest (CD) may lead to the prescription of the exposure (eg, antibiotics or proton pump inhibitors).

From the NY Times: Gluten-free, veggie snacks, vegan desserts, spring salads. They’re all in our new recipe finder.

Parenteral Omega-3 Lipid Emulsions and Risk of Bleeding

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A recent study indicates that patient’s placed on omega-3 lipid emulsions (eg. Omegaven) may be at risk for bleeding due to platelet dysfunction (J Pediatr 2014; 164: 652-4).

While omega-3 lipid emulsions have received a lot of attention due to improvements in intestinal failure associated liver disease (IFALD) (see previous links to prior posts below), the amount of data supporting their usage and potential advantages compared with standard lipids at similar dosing remains limited.

This case report describes a 9-month old who developed life-threatening hemorrhage following a standard central line placement.  Due to difficulty stopping the bleeding, the patient’s omegaven was discontinued.  Standard workup for bleeding disorders were negative.  Subsequently, the authors investigated clot formation and platelet function in a neonatal animal model.

Key Result: Piglets treated with omegaven had a doubling of time to clot formation and marked platelet agonist inhibition.

The discussion notes that “there is an acknowledged risk of high dose O3FA lipids [omegaven] increasing bleeding time because of competitive inhibition of AA [arachidonic acid] production, hence decreased TxA2 [thromboxane A2].  In addition, platelet-derived growth factor-like protein and endothelial platelet activation factor are decreased.”

Take home points (from the authors):

  • “the case report and piglet studies together demonstrate that there is potential for a significant antiplatelet effect and inhibition of the coagulation cascade with O3FA therapy…”
  • “We would suggest discontinuation of Omegaven therapy 72 hours preoperatively in high-risk cases where bleeding may be difficult to directly control.”
  • “Institutionally, we have abandoned the sole use of Omegaven therapy.”

Related blog posts: