Politics and Limiting Physician Speech

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A concise review/commentary (WE Parmet et al. NEJM 2016; 374: 2304-7) of Wollschlaeger v Governor of Florida explains how attempts to support the gun lobby are likely imposing unconstitutional limits on the free speech of physicians as well as undermining good health policy.

This law “prohibits physicians from intentionally entering into a patient’s record information about firearm ownership that ‘is not relevant to the patient’s medical care or safety, or the safety of others’; prohibits physicians from asking patients (or for minors, patients’ parents) about firearm ownership unless they believe ‘in good faith’ that ‘information is relevant to patient’s medical care or safety.'”

There are good reasons for physicians to inquire about guns in the homes as there is definitive evidence that a gun in the home increases the risk of death, especially by suicide.  The odds, on average from studies, is a 3-fold risk in homes with guns, but even higher for children and adolescents.

The law is counter productive as well. “Studies to date, as limited as they are, suggest that gun owners so counseled are more likely to change storage practices than to remove guns from their homes.”

While the politics with firearms is heavily influenced by well-funded lobbyists, there are other areas in which there are laws regulating physician speech, including abortion and fracking.

My take: I think it is outrageous that there are laws curtailing a physician’s free speech and efforts to dictate practice based on political philosophy. I hope they will not be upheld.

Related blog post: Can the FDA prohibit free speech? | gutsandgrowth

MosqitoWarninig

Elafibranor Study & “My compliments to the photographer”

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A while back, I remember seeing a cartoon with a dissatisfied patron leaving a restaurant and saying “my compliments to the photographer.”

Sometimes reading journal titles has the same feel.  The title does not always indicate what you are really going to get.  A recent study (V Ratziu et al. Gastroenterol 2016; 150: 1147-59) has the following title: “Elafibranor, an Agonist of the Peroxisome Proliferator –Activated Receptor –α and –β, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening.”  Sounds great –a new effective treatment for NASH, right?

Here’s are the results:

  • “In intention-to-treat analysis, there was no significant difference between elafibranor and placebo groups in the protocol-defined primary outcome.”
  • However, based on a post-hoc analysis with a modified definition, the treatment group had  a 19% NASH resolution compared with 12% of the placebo group.

This study examined 276 patients in a randomized double-blind placebo-controlled trial.

To me these results are not impressive.  The associated editorial (pg 1073) expresses more optimism and indicates that there have been evolving outcome measures in NASH studies to look for the combination of NASH resolution without worsening fibrosis.  Thus, prior studies that used only NASH resolution, such as pioglitazone (47%), vitamin E (36%) and obeticholic acid (22%) cannot be compared to his current study.

My take: Pretty picture or not, what this really means -is that we need more studies, including the outcome of phase III studies of this medication.

Georgia Terrace

The Georgian Terrace

More than Two Years of Constipation Before Specialty Help

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A recent article (S Malowitz et al. JPGN 2016; 62: 600-02) examined the age of onset of constipation in a retrospective review of 538 children with functional constipation between 2012-2014.

Key findings:

  • Median age of onset was 2.3 years
  • On average, “2.7 years pass between the onset of functional constipation and a referral to a specialist.”  In the oldest quartile, the lapse between onset and referral was shorter, 1.8 years.  This may reflect the social consequences of soiling in school-aged children.

The authors note: “encouraging clinicians and parents to think of constipation as a chronic problem with physical and mental health implications may improve outcomes and quality of life for affected children.”

My take: The suffering and burden of constipation is easily overlooked in a busy primary care visit.  This is a shame because this is one area where inexpensive specialty care (i.e. minimal testing) can truly make a big difference.

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Atlanta Zoo 2016

Atlanta Zoo 2016

 

 

What to Make of Post-op Treatment for Crohn’s Disease

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In 2009, Regueiro and colleagues published an influential paper “Infliximab prevents Crohn’s disease recurrence after ill resection” (Gastroenterol 2009; 136: 441-50). However, this was a small study with only 24 patients.  In this study, only 1 of 11 patients on infliximab had endoscopic recurrence compared with 11 of 13 of placebo patients at 1 year.  Besides the promising result that infliximab may prevent recurrent Crohn’s disease, this study confirmed that there is poor correlation between endoscopic recurrence and clinical activity scores.  In addition, the implication was that early treatment could be very important.

Now, a much larger study has been published (M Regueiro et al. Gastroenterol 2016; 150: 1568-78) and has cast some doubt on these earlier findings. It may have “muddied the waters” regarding the optimal approach.  The authors conclude that infliximab reduces postoperative endoscopic, but not clinical, recurrence of Crohn’s disease. Furthermore, they recommend in their discussion: “it may be reasonable to approach low-risk patients undergoing their first resection for CD conservatively and initiate treatment only if there is endoscopic recurrence at 6 months” [post-op].  The associated editorial (1521-24), after highlighting some of the important clinical findings, also says, that it may be “difficult to convince payers and patients that >2-4 years of treating an asymptomatic patient with TNFi, with its potential risks of long-term adverse effects, will be required to prevent clinically meaningful endpoints.”

Before accepting these conclusions, a closer look at the study is important.  This randomized study evaluated 297 patients at 104 sites. The study was intended to stop at 200 weeks, but was prematurely terminated at 104 weeks. Infliximab dosing was 5 mg/kg every 8 weeks.  This study was called the PREVENT study:  Prospective, Multicenter, Randomized, Double-blind, Placebo-Controlled Trial Comparing Remade and Placebo in the Prevention of Surgical Resection Who Are at an Increased Risk of Recurrence.

Key findings:

  • At week 76, clinical recurrence was not statistically different, though favored infliximab group: 12.9% vs. 20.0%
  • At week 76, endoscopic recurrence was less in infliximab-treated: 30.6% vs 60.0%
  • Also, more severe endoscopic recurrence  (Rutgeerts scores of i3 or i4) was markedly lower: 22.4% vs 51.3%

Other points:

  • Infliximab effectiveness could have been even higher if there had been an opportunity to escalate dosing; this occurs in about half of patients in typical clinical care.
  • This study’s focus on the primary outcome of clinical recurrence winds up overshadowing the much improved endoscopic results.

My take: I think that most well-informed patients and physicians would prefer to be treated post-operatively if they look at the results of this study closely.

From AGA twitter feed

From AGA twitter feed

Recognizing Reactive Arthritis due to Clostridium difficile

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A recent study shows that reactive arthritis can occur in children with Clostridium difficile infection and that recognition of this problem will improve management.

From JAMA Online First, DB Horton et al JAMA Pediatr. Published online May 16, 2016. doi:10.1001/jamapediatrics.2016.0217 (thanks to Ben Gold for this reference):

Abstract:

Importance  The incidence of Clostridium difficile infection has increased among children. The epidemiology of pediatric C difficile infection–associated reactive arthritis is poorly understood.

Objective  To characterize the incidence, recognition, and distinguishing clinical features of pediatric C difficile infection–associated reactive arthritis among children with C difficile infection.

Design, Setting, and Participants  In this cohort and nested case-control study using electronic health records from January 1, 2004, to December 31, 2013, across 3 geographically diverse pediatric health care networks, we screened for reactive arthritis among 148 children between ages 2 and 21 years with diagnostic or procedural codes suggesting musculoskeletal disease associated with C difficile diagnosis or positive testing. We identified 26 cases with acute arthritis or tenosynovitis within 4 weeks before to 12 weeks after confirmed C difficile infection with (1) no alternative explanation for arthritis and (2) negative synovial cultures (if obtained). Network-matched C difficile–infected controls without arthritis were randomly selected at the time of cohort member C difficile infections.

Main Outcomes and Measures  Incidence of C difficile infection–associated reactive arthritis was calculated based on (1) pediatric source population and (2) children with C difficile infection. Characteristics of cases and controls were compared using conditional logistic regression.

Results  Based on the cases identified within the source population of the 3 hospital networks, we estimated that C difficile infection–associated reactive arthritis incidence was 5.0 cases per million person-years (95% CI, 3.0-7.8). Reactive arthritis affected 1.4% of children with C difficile infection yearly (95% CI 0.8%-2.3%). Joint symptoms began a median of 10.5 days after initial gastrointestinal symptoms, often accompanied by fever (n = 15 [58%]) or rash (n = 14 [54%]). Only 35% of cases of C difficile infection–associated reactive arthritis were correctly diagnosed by treating health care professionals (range across centers, 0%-64%). Five affected children (19%) were treated for presumed culture-negative septic hip arthritis despite having prior postantibiotic diarrhea and/or other involved joints. Compared with controls, cases of C difficile infection–associated reactive arthritis were less likely to have underlying chronic conditions (odds ratio [OR], 0.3; 95% CI, 0.1-0.8). Although all cases had community-onset C difficileinfection and fewer comorbidities, they were more likely to be treated in emergency departments and/or hospitalized (OR, 7.1; 95% CI, 1.6-31.7).

Conclusions and Relevance  C difficile infection–associated reactive arthritis is an underdiagnosed, potentially morbid reactive arthritis associated with C difficile infection occasionally misdiagnosed as septic arthritis. Given the rising incidence of pediatric C difficile infections, better recognition of its associated reactive arthritis is needed.

Screenshot from JAMA website

Screenshot from JAMA website

Changing Approach to Neonatal Acute Liver Failure

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A recent review (SA Taylor, PF Whittington. Liver Transplantation 2016; 22: 677-85) provides several important concepts for practitioners who may need to manage neonatal acute liver failure.

The most common etiologies (in parenthesis the approximate percentage of cases in their experience):

  • Gestational alloimmune liver disease (GALD) (60-90%)
  • Viral hepatitis (20-30%)-particularly HSV, followed by HHV-6, and rarely CMV
  • Hemophagocytic lymphohistiocytosis (HLH) (<10%)
  • Mitochondrial hepatopathy (<5%)
  • Rare causes include galactosemia, hereditary tyrosinemia type 1, and hereditary fructose intolerance. (<1%)  In addition, bile acid synthetic defect 5-beta-reductase deficiency can cause neonatal liver failure.

While INR ≥2.0 was used in the PALF studies as a primary defining feature of liver failure, since an INR of 2.0 can occur in the normal newborn, the authors recommend using an INR≥ 3.0 for neonatal liver failure.

Their Table 1 helps provide some important differences, Distinguishing features:

  • With GALD, ALT values are typically <100 due to underdeveloped hepatic parenchyma and ferritin is typically >800 and <7000.  IUGR is frequent (70-90%) as is hypoglycemia. Hepatosplenomegaly is uncommon.
  • With viral infections and HLH, ALT values are typically high, ferritin often very high, hepatosplenomegaly is common. IUGR is rare.
  • With mitochondrial disorders, ALT typically is between 100-500, ferritin levels are variable, and IUGR occurs in 20-30%.  A distinguishing feature is lactate: pyruvate ratio and ketone body ratios.
  • By thinking carefully about the reasons for liver failure in the neonatal period and not trying to examine for every possible liver disease, the use of these variables can expedite the evaluation and decrease the cost.  Genetic testing is not recommended due to the slow turnaround time, “and many diseases that are prominent causes of cholestatic disease …just do not cause NALF.”

With regard to treatment, the authors advocate use of IVIG if suspicion for GALD.  If workup (lip biopsy and/or MRI) confirms GALD then exchange transfusion and repeat IVIG is recommended.

My take: This reference should be helpful when managing a neonate with severe liver disease.

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Set from the Musical "Beautiful"

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NPR: Getting Last-Ditch Experimental (Compassionate Use) Drugs

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NPR: It’s Still Not Easy to Get Last-Ditch Experimental Drugs

An excerpt:

The Food and Drug Administration has reduced an obstacle from its compassionate use policy, streamlining paperwork that physicians must submit to obtain experimental drugs for patients with life-threatening illnesses.

Doctors will now file an application for FDA approval that contains just 11 questions, 15 fewer than the old form. They should be able to complete this new version in 45 minutes, the FDA said. The new form is simpler because it was designed for individual patients, replacing an all-purpose format that had been used by doctors acting on behalf of individuals or groups of patients…

Doctors still must first obtain a letter of authorization from that drug’s manufacturer. The FDA can’t compel drugmakers to grant permission. Manufacturers might reject requests because they’re worried about liability if the drug causes harm or they might consider the drug unsuited for a particular patient.

In Case Someone Asks…Low FODMAP Maternal Diet May Help Colic

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According to a very small study, maternal ingestion of a low FODMAP diet reduced crying in colicy babies who were breastfed.  This report was presented at the recent United European Gastroenterology meeting (P0609).  The study consisted of a single-blind, open-label study of 18 infants.  The key finding was reduced crying from 142 minutes to 90 minutes over the 2 week study period.

A summary of this report is available at gastroendonews.com (May 2016, pg 8).

My take: A bigger study is needed to ascertain whether this intervention is worthwhile.  Many kids get better during a 2 week period without treatment.

Concise Review: Fatty Liver in Pediatrics

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A recent review (J Schwimmer. Hepatology 2016; 1718-25) provides a succinct up-to-date approach to the common problem of Nonalcoholic Fatty Liver Disease.

As this was a review, much of the material has been covered by this blog and previous publications.  The review discusses the upper limit of normal for alanine aminotransferase and its utility.  Liver imaging is discussed: “MRI is well suited for use in clinical research” whereas “ultrasound does not meet the standard clinical threshold required to be used to diagnose fatty liver…or used as an outcome measure.”

Dr. Schwimmer reviews a prospective study of 347 overweight or obese children with suspected NAFLD (blog review of this study: Screening for NAFLD).  He notes that 24% (n=61) of those who underwent liver biopsy ultimately had other diagnoses, especially autoimmune liver disease (n=11) and celiac disease (n=4). “The clinical challenge is to determine who needs how much of a workup. The greater potential for hepatotoxicity and the more advanced the disease is believed to be, the greater the need to be certain of the diagnosis and to properly grade and stage the disease.”  Currently, “no other diagnostic modality has shown sufficient accuracy to be appropriate for clinical use in the place of biopsy.”

He reviews associated health conditions with NAFLD including obesity, dyslipidemia, hypertension, cardiac dysfunction, and obstructive sleep apnea (~60% of NAFLD patients).

What about treatment? “There is not an available, proven, safe, and effective [pharmacologic] treatment for NAFLD in children…Current treatment is …focused on optimizing lifestyle, including nutrition, physical activity, and mental well-being.”

My take: Despite 20 years of clinical practice, the workup for NAFLD remains a vexing problem.  It is not practical to offer a liver biopsy to 10% of the pediatric population.  So determining who (besides those with more severe presentations) will benefit from an exhaustive workup remains unclear.  In the meanwhile, at a minimum, we need to keep looking for treatable liver conditions (eg. autoimmune hepatitis, celiac disease, Wilson’s disease, and viral hepatitis).

An article with a similar focus (Dr. Schwimmer is the corresponding author): J Pediatric 2016; 172: 9-13.  This report and Dr. Schwimmer’s review both tout the safety of liver biopsy.  Neither report presents much data on costs of either liver biopsies or MRI.

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Bring Out the Big Guns: Treating Infections with Cirrhosis

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A recent study (M Merli et al. Hepatology 2016; 1632-39) indicates that health-care associated infections (HCA) in the setting of cirrhosis respond more favorably to broad-spectrum antibiotics.  In this prospective study of 96 randomized patients, in-hospital mortality was improved in the broad-spectrum group (6%) compared to the standard group (25%).  There was a similar multidrug-resistnace rate (50% broad spectrum compared with 60% in standard group).

Table 1 lists the antibiotic selection.  In the broad spectrum treatment, this almost always included imipenem/cilastin (I/C); with spontaneous bacterial peritonitis (SBP), I/C was combined with vancomycin, and with pneumonia it was combined with both vancomycin and azithromycin.  In contrast, the standard group’s main medication was augmentin (with added azithromycin for pneumonia) or cefotaxime for SBP.

My take: Does this study show that infections in the setting of cirrhosis are becoming more difficult to treat? Probably. How much these findings can be extended to the pediatric population remains uncertain.

Somewhat related topic: Primary prophylaxis of Variceal Bleeding in Children –Summary of the Baveno VI Pediatric Satellite Symposium.  BL Shneider et al. Hepatology 2016; 63: 1368-80. Key point: “there are few pediatric data…therefore, no recommendations for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta-blockade in children was proposed.”

Silver Comet Trail

Silver Comet Trail