Why Pertusis is resurgent –it’s not what you think

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What are the reasons why pertusis, a vaccine-preventable disease, is epidemic?

According to an editorial by James Cherry (NEJM 2012; 367: 785-87), there are four main reasons.

  • 1) Increased awareness
  • 2) Easier detection with PCR assays
  • 3) Increased use of less potent vaccines, mainly DTaP
  • 4) Possible genetic changes in B pertusis

Useful epidemiology information:

  • 13-20% of adolescents and adults with prolonged cough have B pertusis.
  • Lowest incidence was reported in 1973: 1 per 100,000.
  • In prevaccine era, B pertusis had pattern of epidemics every 2 to 5 years, with peak incidence of 157 per 100,000.
  • In 2010, incidence was 9 per 100,000
  • Neither infection or immunization provides lifelong immunity

His recommendations/conclusions:

  • We need to use the vaccines we have.  This is necessary to avoid the ‘frightening rates of complications and death’ associated with pertusis in infants.
  • Consider starting immunization at an earlier age –1st three doses could be completed by 3 months of age
  • Improved vaccines are needed

Related blog entries:

Protecting the most vulnerable

Hepatitis A vaccine immunity –will it last?

How to stop HBV vertical transmission

Epidemic of Prescription Drug Overdoses

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More information on the epidemic of drug overdoses: MMWR 2012: 61: 10-13.

In 2007, in U.S. one death due to unintentional drug overdose occurred every 19 minutes (27,000 cases), primarily due to opioid analgesics.  In addition, for every death, there were nine persons admitted for drug treatment, and 35 emergency room visits.

The escalating drug use can be quantified.  In 1997, drug distribution through pharmacies delivered the equivalent of 96 mg of morphine per person whereas in 2007 the amount was 700 mg per person; 700 mg is enough for every person in U.S. to receive a three-week course of Vicodin (hydrocodone/acetaminophen 5mg q4 hours).

Only 10% of these patients were seeking care from multiple doctors; yet this 10% accounted for 40% of the cases of overdosage.

Prevention strategies:

  • Prescription data to prevent doctor shopping & reduce inappropriate use of opioids/selling excessive opioid prescriptions
  • Enforcing laws against ‘pill mills’
  • Improve medical practice in prescribing opioids

Additional references/previous blog entries:

Epidemic: Responding to America’s Prescription Drug Abuse Crisis  Whitehouse plan

Pediatric pharmaceutical poisoning

Deadly consequences of pain management

Why “therapeutic dose” of codeine can kill

Vedolizumab -another new IBD treatment

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Occasionally a parent will express concern that their child may run out of effective treatments for inflammatory bowel.  At this time, there are a limited number of effective therapies. If a patient develops reactions or antibodies to medications and/or does not have a clinical response, then the options become quite limited.

Against this backdrop, it is encouraging that new medical treatments are being tested, including Vedolizumab (Inflamm Bowel Dis 2012; 18: 1470-79).

The cited study reports the experience of using Vedolizumab in a randomized controlled phase 2 dose-ranging study in 46 patients (9 placebo, 37 vedolizumab).

Vedolizumab is “a gut-selective monoclonal antibody that antagonizes α4β7 integrin on select subsets of leukocytes binding to MAdCAM-1 on gut vascular endothelium.”  Many have considered vedolizumab to be similar to natalizumab, except it is considered  gut-specific and therefore should not increase the risk of progressive multifocal leukoencephalopathy (PML).  By altering the immune surveillance/lymphocyte tracking of the GI tract and not the brain, theoretically there should not be an increased risk of PML.

Another previous limitation of vedolizumab in small studies was the development of human antihuman antibodies (HAHA) –no joke!  HAHA occurred in up to 44% of patients in previous studies and were associated with reduced efficacy.  As a consequence, a new formulation of vedolizumab has been developed with presumably reduced  immunogenicity.

In the cited study, patients between 18-70 were recruited to receive one to three doses of vedolizumab (2, 6, or 10 mg/kg) or placebo.

Results:

  • Over 50% of vedolizumab-treated patients maintained a clinical response between days 29-253 whereas placebo response ranged between 22-33%.
  • This study was not powered for efficacy; however, the treated patients did have reduced fecal calprotectin.  At baseline, the calprotectin in the treatment groups averaged 405 μg/g and by day 113 had reduced to 54 μg/g.  In contrast, placebo group started with calprotectin of 310 μg/g and dropped to 192 μg/g during same time period.
  • HAHA were detected in 4 (11%)

According to a presentation at DDW (GEMINI I trial), more than 2500 patients have been treated in trials with vedolizumab.  None has developed PML. Encouraging results for efficacy (dosing 300mg IV q4weeks) were also noted; 1 year clinical remission noted in 45% of treated patients compared with 14% of placebo group. Digestive Disease Week 2012 – Vedolizumab Scores on Safety …)

Results of vedolizumab for Crohn’s disease are expected soon as well.

Related blog entries:

Quantifying Risk of PML with Natalizumab

Tofacitinib –a JAK Inhibitor for UC

Effects of pegylated interferon on growth

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Besides examining the effectiveness of pegylated interferon for hepatitis C virus (HCV) in children, the PEDS-C (Pediatric Study of Hepatitis C) trial data has been studied to determine the effects of pegylated interferon (PEG) on growth and body composition (Hepatology 2012; 56: 523-31).

In this study of 114 children who were treated with PEG along with ribavirin (RBV), anthropometric measurements, dual-energy X-ray absorptiometry, dietary intakes, and activity assessments were performed.  Of the initial 114 children (5-18 years), 107 received treatment for more than 24 weeks: 14 for 24 weeks, 82 for 48 weeks, and 11 for 72 weeks.

In the group treated for 48 weeks, 29 (33%) had more than a 0.5 unit decrement in height-for-age score (HAZ).  Based on figure 2 in the study, most of the HAZ decrement at 48 weeks and resolved at 144 weeks (time after treatment initiation).  In contrast, weight-for-age and BMI scores returned to baseline after stopping HCV therapy.  The authors note that while most growth parameters generally were “reversible with cessation of therapy…HAZ scores had not returned to baseline after 2 years of observation in many.”

Another observation from the study was that weight and height decreased in tandem.  In contrast to sequential change, this type of change indicates that other mechanisms besides poor intake are likely affecting linear growth.  These HAZ effects were noted in adolescents; there was no difference in HAZ scores in preadolescent patients.

The potential effects on growth may influence the timing of therapy.  At the same time, as new HCV treatments are studied in pediatric patients, the effects of interferon may become a moot point.

Related blog entries

Pediatric HCV Guidelines

Understanding IL28B

Increased ferritin predicts poor response in Hepatitis C

Unknown unknowns for Hepatitis C

CHOOSE TNF TRIAL

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While most physicians consider drug efficacy as the most important factor in choosing therapy, this is not always the determinant factor in patient choice.

The “CHOOSE TNF TRIAL” (Inflamm Bowel Dis 2012; 18: 1523-30) was a prospective survey of 100 adult patients with Crohn’s disease who were naive to anti-TNF therapy (infliximab, adalimumab, certolizumab).

Most important to patients:

  • Ease of use 69%
  • Time for therapy 34%
  • Time between applications 31%
  • Evidence for efficacy 19%
  • Fear of syringes 10%

Patient choice: Adalimumab preferred in 36%, certolizumab in 28%, and infliximab in 25%

While patient concerns need to be considered, others have shown that physician opinion is an important factor for patient decisions (J Rhemumatol 2008; 35: 618-24).  The discussion notes that “three anti-TNF drugs used in inflammatory bowel disease treatment have not been compared side-by-side in clinical trials.”  Thus far in pediatrics, infliximab is the only TNF approved for clinical use; as such, the other anti-TNF agents have been used primarily when infliximab loses effectiveness.

One drawback with injectable medications has been reduced adherence; up to 50% of patients fail to maintain regular injection interval; in addition, in patients who have had intravenous infusions (rather than patients who are naive) it is preferred over injections (Jay Popp, medical director of Janssen pharmaceuticals–personal communication).

As such, when patients receive infusions (eg. infliximab), closer followup and better adherence are more likely in comparison to injections.  This certainly improves efficacy.

Related blog entries:

TNF-α antagonists and infections

Disease modifying treatment in IBD

Only one chance to make first impression

Impedance recommendations from PIG

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The ESPGHAN Pediatric Impedance Group (PIG) has published a review/consensus statement on the use of pH-Impedance monitoring (MII-pH) in children (JPGN 2012; 55: 230-34).

Conclusions from this group:

  • MII-pH provides more information than conventional pH probe.  Whether this information will “inform prognosis, or predict response to therapy in pediatric patients has yet to be determined”
  • ‘As long as there is no effective medical therapy for weakly acid and nonacid reflux, the clinical relevance of MII-pH remains debatable’
  • “There are no data on the results of antireflux surgery based solely on the detection of weakly acid and nonacid reflux”
  • MII-pH is investigational technique needing standardization before routine diagnostic use can be recommended.
  • Major indications: need to identify weakly acid and nonacid reflux, persisting symptoms during antireflux treatment, use in identifying rumination syndrome, and research
  • Limitations of MII-pH: high cost, limited contribution to change in medical care, lack of evidence-based parameters for assessment of GER

Related blog entries:

Gastroesophageal Reflux: I know it when I see it

Treating reflux does not help asthma

The Medical Pendulum and Gastroesophageal Reflux

How sensitive is Calprotectin?

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A recent article suggests that fecal calprotectin, while good, is not as good as endoscopy at detecting mucosal disease in pediatric Crohn’s disease (Inflamm Bowel Dis 2012; 18: 1493-97).

In this study, 60 consecutive children with new onset untreated Crohn’s disease (diagnosis based on Porto criteria -JPGN 2005; 41: 1-7) were enrolled in ESPGHAN growth study.  The data for this study was collected prospectively (21 investigators from multiple sites).  The calprotectin values were obtained prior to treatment.

Median fecal calprotectin values were 2198 μg/g in patients with isolated small bowel disease; this did not differ significantly from the value of 2400 μg/g in patients with colonic disease (with or without small bowel disease).

Fecal calprotectin was elevated in 95% of patients; this outperformed CRP (86%) and ESR (83%) as a marker for Crohn’s disease.  In the three children with normal calprotectin values, the serum inflammatory markers were normal in all three and two had minimal endoscopic findings.  The histology findings for these three children were not reported.

In my experience, fecal calprotectin has been very useful as a marker for Crohn’s disease and has helped identify some atypical cases by increasing my clinical suspicion.  I have had two patients with high calprotectin values who had normal-appearing mucosa with panendoscopy; they both had small bowel (jejunal) Crohn’s disease; one of these patients did have granulomas identified histologically.

While I realize that no test is perfect, I think additional studies are warranted to determine the actual sensitivity of this test for Crohn’s disease.  The sensitivity of calprotectin may yet be higher than the 95% reported in this study.

Related posts:

Biomarkers identify patients who benefit and how  Multiple additional calprotectin references with this link

n-3 Fatty Acids and Cardiovascular Outcomes

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A recent study has cast doubt on the benefit of n-3 fatty acids for preventing cardiovascular complications in patients with type 2 diabetes (NEJM 2012; 367: 309-18).

While previous studies have indicated that persons who consume fish regularly or take supplements with n-3 fatty acids have a reduced risk of cardiovascular events, there are many potential confounding variables.  This “ORIGIN” study (Outcome Reduction with an Initial Glargine Intervention) which had 12,611 patients undergo randomization looked at a high risk group (type 2 diabetes patients) but did not find any change in cardiovascular events, including death over a median followup of 6.2 years.  The treatment group received 1 gram of n-3 fatty acids which did result in a lower triglyceride level (by 14.5 mg/dL).

How do the authors explain the results of this negative study in comparison to previous reports?

  • Two of the largest trials had recruited patients with recent myocardial infarction –these patients may have been more likely to benefit
  • In ORIGIN study, more concomitant cardioprotective therapies were being used which could have reduced the potential benefit of n-3 fatty acids
  • Other study populations may have had a lower dietary intake of n-3 and therefore benefitted more from supplementation

While the results of this study may reduce the enthusiasm for n-3 fatty acids, several additional large studies (ASCEND/NCT00135226, VITAL/NCT01169259) are underway which should give additional information on this topic, including in participants at lower risk for cardiovascular events. In addition, the authors conclude that while their findings do not show a reduction in cardiovascular events, they state that dietary recommendations of increased fish consumption should not change; increased fish consumption not only increases n-3 fatty acids but results in lower intakes of red meats which may be harmful.

Related posts:

TODAY is worrisome for a lot of tomorrows

Who needs aspirin?

Cardiovascular disease for the entire family

Treating diabetes with surgery

Abatacept for IBD?

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Doesn’t work (Gastroenterology 2012; 143: 62-69).  While this study indicates that Abatacept was not effect for either Crohn’s disease (CD) or ulcerative colitis (UC), it was useful nevertheless.

In brief, the study examined four placebo-controlled trials of abatacept for induction and maintenance therapy in both CD and UC.  The induction studies included 451 CD patients and 490 UC patients.  The maintenance studies had 90 CD and 131 UC patients.

Results for induction:

  • CD: Clinical response: 17%, 10%, 15% for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 14%
  • UC: 21%, 19%, 20%  for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 29.5%

Results for maintenance:

  • CD: 24% abatacept vs 11% placebo
  • UC: 12.5% vs 14% placebo

The premise of this study was that T-cell activation requires co-stimulatory signaling via T cell CD28 and CD80 or CD86 on the antigen-presenting cell.  Abatacept (CTLA4-Ig) which is effective for psoriasis, rheumatoid arthritis, and juvenile idiopathic arthritis was thought to have potential; it blocks costimulation pathways involved in T-cell activation which was shown to be helpful in animal model of colitis.

So why did it not work?  The editorial in the same volume (pages 13-16) suggests the following possibilities:

  • Abatacept would be more likely to work when naive T cells are actively recruited into inflammation rather than memory T cells which are predominant in IBD
  • CD28-related pathways may not be important in IBD pathogenesis
  • Abatacept may have impeded Treg function in addition to preventing T-cell activation (explained in Fig 1D)
  • Blockade of CD28 pathways could have resulted in unfavorable changes in cytokine profiles from T-cell differentiation (Th1 vs Th2)

The implication of this study is that not all T-cell mediated inflammatory disease respond to the same treatment approaches.  The complexity of intestinal immune responses necessitates ongoing clinical studies to determine which promising therapies will be useful.

Alagille and liver transplantation

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Alagille syndrome (ALGS) is an autosomal dominant disorder which affects 1 in 30,000.  More information is available regarding the outcome of ALGS patients who have undergone liver transplantation (Liver Transpl 2012; 18: 940-48).

Using the SPLIT (studies of pediatric liver transplantation) database, the outcome of 91 ALGS patients was compared with 236 age-matched biliary atresia (BA) patients in a retrospective review (1995-2009).

  • 1-year survival was 87% for ALGS and 96% for BA (p=0.002).  Most of the ALGS deaths occurred in the initial 30 days.  No pretransplant factors could be identified which were associated with mortality.
  • Renal insufficiency worsened after liver transplantation in ALGS patients with 22% having glomerular filtration rate <90 mL/minute/1.73 meter squared; 8% of BA had similar renal insufficiency.
  • ALGS patients were more likely to receive special education: 50% compared to 30% for BA patients.
  • Increased mortality risk was not apparent after the 1st year following transplantation.  At 60 months post-transplantation, survival was 86% for ALGS group and 94.4% for BA group.
  • One other interesting finding was that 21% of ALGS group had undergone Kasai procedure prior to liver transplantation which may have a detrimental effect on liver outcome.

Since ALGS is a systemic disorder, it is not surprising that outcomes are inferior.  These patients frequently have a wide range of heart disease, renal dysfunction, and vascular disorders, including risk for intracranial hemorrhage.  In this series, intracranial hemorrhage occurred in one patient in each group.  It is noted that chidren with ALGS did have a vascular complication in 21% in the first 30 days after transplantation.

Information on Alagille:

There is family-oriented information on the ChiLDREN website.
http://childrennetwork.org/

There is also an Alagille Syndrome Alliance website.
http://www.alagille.org/

Additional Alagille references:

  • -JPGN 2010; 50: 11. Alagille Syndrome and Liver Transplantation
  • -JPGN 2011; 52: 84. King’s College experience.n=117.  HIDA scan w/o excretion in 60%.
  • -JPGN 2010;  51: 319.  Kasai procedure likely worsens outcome. N=19 out of 430 cohort.
  • -JPGN 2010; 50: 526.  TB >6.5, DB >4.5 & cholesterol >520 indicate likely severe liver dz in infancy & should be referred.
  • -JPGN 2010; 51:66.  Frequent bone fractures (esp LE), with peak age ~5yrs.
  • -Gastorenterol Clin N Am; 2003; 32: 857-75.  “Heritable disorders of the bile ducts” Kamath BM, Piccoli DA
  • -JPGN 2008; 47: 623. Urso may help c milder dz. n=42.
  • -JPGN 2005; 41: 676.  Increased risk of HCC.
  • -NASPGHAN 2003:  Can place peg-like tube in gallbladder for biliary diversion (done at CHOP)
  • -Pediatrics 2003; 111: 167-70.  Increased bleeding episodes, 38 of 174pts had bleeding complication; lethal in 4 pts
  • -Hepatology 2002; 35: 1501-6.  Review of partial biliary diversion for Alagille.
  • NASPGHAN 2009, Postgraduate course, pg 51.  95% c JAG1mutation identifiable with commercial lab (others c NOTCH2 mutation can be identified in research lab)