Sirolimus and transplant mortality

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A surprise to me was a recent study which identified sirolimus as a risk factor for increased mortality and graft loss in HCV-positive liver transplant patients (Liver Transpl 2012; 18: 1029-36, commentary 1003-1004).

Sirolimus mechanism of action: inhibits mammalian target of rapamycin (mTOR) which is a phosphoinositide 3-kinase which affects cell proliferation, angiogenesis, and immune function.  For transplant patients, sirolimus blocks interleukin-2-induced stimulation of T lymphocytes.

Black box warnings for sirolimus: FDA warns that sirolimus can increase risk of hepatic artery thrombosis, graft loss, and death with de novo sirolimus-based treatment.

What’s different about HCV transplants? HCV reinfection occurs immediately during liver transplantation and “unlike all other indications, graft survival and patient survival have not improved” (between 1991-2001).  HCV transplant survival continues to be 10-15% lower than non-HCV transplant survival.  Immunosuppression allows more rapid progression of HCV; this allows ~20% of recipients to develop cirrhosis within 5 years of transplantation.

The authors of the study analyzed 26,414 patients (12,589 with hepatitis C virus) from the Scientific Registry of Transplant Recipients (SRTR) database; all recipients were >18 years.  Among this database, 1685 liver transplant recipients received sirolimus; in the majority, it was administered along with a calcineurin inhibitor.  A multivariate analysis of patient mortality showed the following were risk factors for increased mortality:

  • recipient age
  • donor age
  • hepatocellular carcinoma
  • diabetes
  • creatinine

Tacrolimus-based immunosuppression was associated with superior survival. Whereas, the use of sirolimus was associated with increased mortality in patients with HCV, even when adjusting for confounding variables (eg. renal function, and cancer).  In patients who received sirolimus at baseline, the adjusted HR for mortality at 3 years was 1.29 (p=0.0053).  In non-HCV patients, the adjusted HR for the sirolimus group was 1.09  (p=0.40).  Also, duration of exposure to sirolimus was directly correlated with worse outcomes.  Why?

This is not clear.  It is recognized that the study has several limitations.  Due to the nature of the SRTR database, there is not adequate information on how sirolimus may have affected viral load, histologic progression or causes of death.  Despite attempts to control for risk factors, it is possible that the sirolimus group did have higher disease severity.  Nevertheless, sirolimus effects on multiple cellular functions may have deleterious consequences in certain subsets of patients.

GI & Nutrition Problems in Rett Syndrome

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A nationwide survey of 983 patients with Rett syndrome identifies a high prevalence of GI and nutritional problems (Motil KJ et al. JPGN 2012; 55: 292-98).

Parents from 983 female patients with Rett syndrome responded to the study questionnaire; this was a 59% response rate from the 1666 families in the North American Rett Database.  Patients included those who fulfilled clinical criteria for diagnosis or who had MECP2 gene (methyl-CpG-binding-protein).

Prevalence of GI problems were listed in article’s Table 2 and included the following:

  • Gastrointestinal problems 92%
  • Feeding problems 81%
  • Constipation 80%
  • Poor weight gain 38%
  • Gastroesophageal reflux 39%

Z-scores for height-for-age, weight-for-age, and BMI are presented for ages 0-40 (see Table 1) -these are all significantly lower than age-matched healthy children.

Important findings:

  • Surgical interventions were common: 11% had fundoplication, 28% gastrostomy, 3% and cholecystectomy
  • Many gastrointestinal symptoms improved with age.  However, short stature, gastrostomy tube, and bone health issues were more common in older patients.
  • Bone fractures are 3- to 4-fold higher than in healthy children

Addtional references:

  • -J Pediatr 2010; 156: 135.  Longevity in Rett syndrome –about 1/2 survive to age 40.
  • -Ann Neurol 2010; 68: 944-50.  Rett diagnostic criteria
  • -JPGN 2007; 45: 582-90.  Growth/feeding issues in Rett syndrome

Lessons on Stature from Asthma Treated with Steroids

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A study of the effects of budesonide for the treatment of asthma should be carefully considered by those of us who treat eosinophilic esophagitis with “topical” steroids; also, this study has applicability to Crohn’s disease patients receiving chronic glucocorticoids.  Mean adult height was 1.2 cm lower in the budesonide-treated asthmatics than in the placebo group (NEJM 2012; 367: 904-12).

This was the main finding at the end of the Childhood Asthma Management Program (CAMP) clinical trial.  This report examined 943 of 1041 (90.6%) participants  who had received either 0.4 mg of budesonide, 16 mg of nedocromil or placebo daily for 4 to 6 years.  Treatment with these agents began between ages 5 to 13.

The reduction in adult height was to similar in adulthood as it was after 2 years of treatment; there was not catch up growth.  With regard to the adult measurements, 96.8% of the adult women were at least 18 years and the adult men were at least 20 years of age.

Other findings:

  • Larger daily dose: each microgram per kilogram was associated with -0.1 cm drop
  • Other risk groups: Hispanic ethnic group, female sex, greater body mass index, longer duration of asthma, and higher Tanner stage at initiation

The authors note that 0.2 mg dosage of budesonide has been shown to be effective to control asthma symptoms in children 5-11 years.  The “lowest effective dose” should be used; “the effect on adult height must be balance against the large and well-established benefit of these drugs in controlling persistent asthma.”

Related links:

Looking better or feeling better in EoE?

Guidelines for Eosinophilic Esophagitis

Choosing topical therapy for EoE

The undiscovered country

What is the risk of colon cancer in IBD?

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Some recent studies have shown that colorectal cancer complicating IBD may not be as common as previously thought or may be decreasing in incidence (Gastroenterology 2012; 143: 375-81 & Gastroenterology 2012; 143: 382-89 ).

The first study used a nationwide cohort of 47,374 Danish patients with IBD over a 30-year period.  During a 178 million person-years of follow-up evaluation, 268 patients with ulcerative colitis (UC) and 70 patients with Crohn’s disease (CD) developed colorectal cancer (CRC).  The risk was comparable to the general population (RR 1.07)!  Furthermore, the relative risk for CRC decreased over sequential time periods: 1.34  (1979-88) to 0.57 (1999-2008).

Increased risk:

  • UC diagnosed in childhood or adolescence
  • longer disease duration
  • patients with primary sclerosing cholangitis

Their conclusion, ‘the overall risk of CRC in patients with UC has decreased markedly over time and no longer exceeds that of the general population, at least in the first decade after diagnosis.”  And, based on their data, patients with Crohn’s disease are not at increased risk for CRC.

The second study from California used a large Kaiser Permanente database from 1998-June 2010.  29 cancers were identified in CD (n=5603) and 53 in UC (n=10,895) patients.  The incidence per 100,000 for CRC was 75 for CD, 76 for UC, and 47 for general population.

These authors conclude that there is an increased risk of CRC in a community-based IBD population between 1998-2010 despite advances in medical treatment.

To understand the discrepancy of these reports, the same issue provides an editorial (page 288).  My take is that the current incidence of CRC is lower than in previous reports but that the risk factors identified in the Danish cohort (see above) likely remain important.

Additional references:

  • -Gastroenterol 2009; 136: 718. 22% of cancers occurred before recommended surveillance in adults (only 9% if exclusion of patients who had IBD and cancers diagnosed at same time).
  • Colon Cancer Survival Calculator http://www.mayoclinic.com/calcs-Gastro 2010; 138: 207-2177 (entire issue)
  • -JAMA 2009; 302: 649. Aspirin use likely increases survival after dx of colon cancer. Commentary-Gastro 2010;138: 2012.
  • -NEJM 2009; 361: 2449. molecular basis of colorectal cancer
  • -Gut 2008; 57: 1246. IBD and colon cancer
  • -IBD 2007; 4: 367. 5ASA Rx did not reduce rate of cancer in large study of UC/CD -review of 18,000 colorectal cancer cases. IBD increased risk of CRC 6-7-fold..
  • -Clin Gastro & Hep 2006; 4: 1346. aminosalicylates reduce CRC.
  • -Gastroenterol 2006; 130: 1030, 1039, 1350. 600 patients followed for 35 yrs: CRC by colitis duration: 2.5% @ 20yrs, 7.6% @ 30yrs, 10.8% @ 40yrs. 5 year survival was 73% among those with cancer. 2nd study showed main CRC risk in UC pts is among those with extensive colitis.
  • -Clin Gastro & Hepatol 2004; 2: 1088. Lower cancer risk in this cohort, n=1460. CRC 0.4 @10yrs, 1.1% @ 20yrs, 2.1% @ 30yrs. Lower CRC may be due to more surgery in Rx failures & use of 5-ASA.
  • -Clinical perspectives in Gastro 1999; 2: 9 & 25. (review) surveillance/ overview take 4 bx q10cm. start p 8yrs in pancolitis & 15yrs for left-sided dz. Cancer risk: ~5% at 20yrs + 1%/yr p 20yrs in pancolitis.
  • -Gastroenterol 2003; 125: 1311. Advancement of dysplasia to cancer in UC.

Gluten avoidance -quite common

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In a pediatric Boston cohort of 579 patients presenting for celiac evaluation but no previous diagnosis, 7.4% had previous gluten avoidance (J Pediatr 2012; 161: 471-5). In this cohort, the mean age at presentation was 8.7 years.

Independent predictors of gluten avoidance and the odds ratio (OR) included the following:

  • Irritability OR 3.2
  • Family history of celiac OR 2.2
  • Diarrhea OR 2.5
  • Pervasive developmental disorder OR 5.3

From my perspective, many families and sometimes referring physicians are convinced that their child has celiac disease before subspecialty evaluation. While a gluten-free diet may reduce some gastrointestinal symptoms even in the absence of celiac disease, it is probably helpful for families to complete diagnostic testing and to obtain dietary counseling prior to implementing a gluten-free diet.

Previous related blog entries:

“There is More to Life Than Death”

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This commentary helps explain some of the reasons for recent recommendations to drop PSA screening for prostate cancer and to stop mammograms for women ages 40 to 49 while at the same time showing how these decisions are not in fact ‘no-brainers.’ (NEJM 2012; 987-89).

With both decisions, the U.S. preventive services task force (USPSTF) focused on mortality data.  For prostate cancer, the pivotal trial was the U.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) that showed no difference in mortality between a PSA-screened group and a control group.  Besides detailing a few limitations of the study, the authors note that separate epidemiologic data show a 75% decrease in men presenting with advanced prostate cancer since the introduction of PSA screening. Furthermore, a European study showed advanced cancers were 40% more likely in the control group as well.

Patients with more advanced prostate cancer are prone to bone pain and urinary obstruction; whereas, patients who undergo unnecessary surgery (b/c prostate cancer was not going to kill them) may develop incontinence and impotence.

For breast cancer, similarly, identifying smaller breast cancers may allow more conservative therapy. This has to be weighed against increased anxiety, discomfort, and biopsies for those with false-positive mammograms.

Conclusions:

“Basing decisions on the outcome of death ignores vital dimensions of life that are not easily quantified…It is neither ignorant nor irrational to question the wisdom of expert recommendations that are sweeping and generic.  There is more to life than death.”

On a side note, one of the authors (Jerome Groopman) has written several books.  My favorite of his: “The Measure of Our Days.”

Why call it botulinum?

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“Clostridium botulinum is a neurotoxigenic, anaerobic, gram-positive, spore-forming bacillus named after an outbreak of sausage poisoning in the late 1700s.” Botulus is latin for sausage.  Hence the name.

This and other facts about foodborne botulism are presented in a clinical problem-solving case (NEJM 2012; 367: 938-43).

Key information:

  • For foodborne botulism to develop neurotoxins must be absorbed from the gastrointestinal tract.
  • Fewer than 35 cases are reported annually in U.S.
  • Initial GI symptoms typically occur 12-72 hours after spore ingestion and can include constipation, cramps, vomiting, and less commonly diarrhea.
  • Biggest risk factors: home-canned foods or injecting black-tar heroin
  • Prolonged ventilatory support and antitoxin are cornerstones of treatment
  • Typical features: “Dozen D’s” dry mouth, diploplia, dilated pupils, droopy eyelids, droopy face, diminished gag reflex, dysphagia, dysphonia, difficulty lifting head, descending paralysis, and dyspnea.

To avoid being the next case report, if you like to can your own food, follow the guidelines in the link below:

National Center for Home Food Preservation | USDA Publications

More intriguing than helpful

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A recent study reports that a pH-impedance (pH-MII) may help identify children with allergen-induced gastroesophageal reflux disease (GERD) after exposure to cow’s milk (J Pediatr 2012; 161: 476-81).  The study population included 17 children (average age 14 months) with a clinical diagnosis of cow’s milk allergy (CMA) who had responded to an elemental diet.

Given the limitations of the study, it is hard to take seriously the conclusions of the authors that in “selected cases of children with CMA in whom GERD is suspected” pH-MII “should be considered as part of diagnostic workup.”

The limitations:

  • CMA diagnosed clinically based on response to dietary therapy
  • GERD diagnosed based on Infant GER Questionnaire, though authors acknowledge that “we are aware that no symptom or cluster of symptoms have been shown to reliably predict the diagnosis of GERD”
  • Statistically-significant findings only for weakly acidic reflux which was induced on second day after switching from elemental formula to cow’s milk
  • No endoscopic correlation of mucosal disease or exclusion of eosinophilic esophagitis
  • Small number of patients

I cannot see how obtaining a pH-MII study would offer a meaningful benefit to these patients; though, it is intriguing that one potential measure of clinical deterioration like increased weakly acid episodes can be detected when these patients are challenged with cow’s milk.

Some related blog entries:

Impedance recommendations from PIG

Gastroesophageal Reflux: I know it when I see it

Guidelines for Eosinophilic Esophagitis

Hepatitis A vaccine immunity –will it last?

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In a previous post (HAV vaccination: how long will it take?), it was noted that U.S. HAV immunization rates are poor but much better in states that have employed a strategy of implementing universal vaccination for a longer period.  Another article provides reassurance that once patients are vaccinated that the immunity is quite durable (Hepatology 2012; 56: 516-22).

197 infants and children were followed after HAV immunization; these patients were divided into three groups; two dose immunization at 6 & 12 months (group 1), at 12 & 18 months (group 2), and at 15 & 21 months(group 3).  Anti-HAV serology was followed sequentially. At 10 years, almost all children retained seroprotection (>10 mIU/mL) levels, >95% of group 2 & 3.  In group 1,  7% of infants born to anti-HAV negative mothers and 11% of infants born to anti-HAV positive mothers did not have protective antibody levels.

Conclusion: Seropositivity for HAV persists for at least 10 years after vaccination with two-dose regimen when administered to children 12 months of age and older.

Something to think about (unrelated to blog post):

A Zen master was once asked, “What is the key to happiness?”

He answered, “Good judgment.”

“How do I gain good judgment?” he was questioned.

“Experience,” was the reply.

“How then do I get experience?” the student further probed.

“Bad judgment,” were his final words.

(quoted previously in Pediatrics and from the following link QUOTATIONS AND PASSAGES ON EXPERIENCE)

Better growth charts for preterm children

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A community-based cohort study from the Netherlands involving 1690 preterm infants (25-36 weeks) and a random sample of 634 full term infants provides a more precise tool for monitoring growth over the first four years of life (J Pediatr 2012; 161: 460-5).

Key findings:

  • The lower the gestational age, the lower the median value for both weight and height.  A quick glance at their tables indicate that infants born at 25 weeks gestation remained on average about 2 kg and 4 cm smaller than full term infants.  Infants born at 32 weeks gestation were on average about 1 kg and 2 cm smaller through the study period.
  • The absolute differences in weight and height were nearly constant, indicating that there was a lack of ‘catch-up’ growth.  At the same time, a child ‘following his own curve’ parallel to growth curve is likely a normal pattern
  • Head circumference at the end of the first year was similar between preterm and term infants
  • Greater variability was noted in boys

While this study did not adjust for maternal height, it is known that short maternal height does correlate with increased likelihood of short offspring.  This is partly mediated by having a small for gestational age birth.  Other limitations of the study included that the cohort was >90% Caucasian, and there was no adjustment for multiple births.

Useful links/references:

  • Growth Charts – Homepage -CDC growth charts
  • Pediatrics 2011; 128: e1187-94.  Growth and predictors of growth restraint in moderately preterm-born children.
  • Pediatrics 2003; 112: e30-8.  Growth of preterm infants during 1st 20 years.