Immunologic Distinction between Infectious and Serum Hepatitis.

Serums from patients with acute viral hepatitis were tested for the presence of the serum-hepatitis (SH) antigen to determine whether this would permit distinction between the two major types of viral hepatitis. None of four patients with short-incubation MS-1 infection (Willowbrook) had detectable antigen, whereas this antigen was identified in all eight cases of long-incubation MS-2 infection (Willowbrook). Correspondingly, only one out of 74 cases associated with four epidemics of infectious hepatitis, and none of 19 sporadic cases occurring in children under the age of 14 showed presence of detectable antigen, whereas 76 of 116 cases (66 per cent) that followed exposure to contaminated needles and 25 of 43 post-transfusion cases (58 per cent) were positive.

SH antigen was also detected in 71 of 129 patients (55 per cent) with viral hepatitis who gave no history of parenteral exposure.

Serum-hepatitis virus thus appears to be the major cause of sporadic hepatitis in urban adults regardless of the presence or absence of parenteral exposure to blood or blood products.

Source: NEJM


Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial..


On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48-72 h with slow rewarming improved mortality in children after brain injury.


In this phase 3, multicenter, multinational, randomised controlled trial, we included patients with severe traumatic brain injury who were younger than 18 years and could be enrolled within 6 h of injury. We used a computer-generated randomisation sequence to randomly allocate patients (1:1; stratified by site and age [<6 years, 6-15 years, 16-17 years]) to either hypothermia (rapidly cooled to 32-33°C for 48-72 h, then rewarmed by 0·5-1·0°C every 12-24 h) or normothermia (maintained at 36·5-37·5°C). The primary outcome was mortality at 3 months, assessed by intention-to-treat analysis; secondary outcomes were global function at 3 months after injury using the Glasgow outcome scale (GOS) and the GOS-extended pediatrics, and the occurrence of serious adverse events. Investigators assessing outcomes were masked to treatment. This trial is registered with, number NCT00222742.


The study was terminated early for futility after an interim data analysis on data for 77 patients (enrolled between Nov 1, 2007, and Feb 28, 2011): 39 in the hypothermia group and 38 in the normothermia group. We detected no between-group difference in mortality 3 months after injury (6 [15%] of 39 patients in the hypothermia group vs two [5%] of 38 patients in the normothermia group; p=0·15). Poor outcomes did not differ between groups (in the hypothermia group, 16 [42%] patients had a poor outcome by GOS and 18 [47%] had a poor outcome by GOS-extended paediatrics; in the normothermia group, 16 [42%] patients had a poor outcome by GOS and 19 [51%] of 37 patients had a poor outcome by GOS-extended paediatrics). We recorded no between-group differences in the occurrence of adverse events or serious adverse events.


Hypothermia for 48 h with slow rewarming does not reduce mortality of improve global functional outcome after paediatric severe traumatic brain injury.

Source: Pubmed

Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage.


Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known.


We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician’s choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups.


Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively.


In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure.

Source: NEJM


FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death.

The U.S. Food and Drug Administration (FDA) is reviewing reports of children who developed serious adverse effects or died after taking codeine for pain relief after tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. Recently, three pediatric deaths and one non-fatal but life-threatening case of respiratory depression were documented in the medical literature1,2 (see Data Summary below). These children (ages two to five) had evidence of an inherited (genetic) ability to convert codeine into life-threatening or fatal amounts of morphine in the body. All children had received doses of codeine that were within the typical dose range.

Facts about codeine



  • An opioid pain reliever used to treat mild to moderately severe pain
  • Also used, usually in combination with other medications, to reduce coughing
  • Available as a single-ingredient product, or in combination with acetaminophen or  aspirin, and in some cough and cold medications


When codeine is ingested, it is converted to morphine in the liver by an enzyme called cytochrome P450 2D6 (CYP2D6). Some people have DNA variations that make this enzyme more active, causing codeine to be converted to morphine faster and more completely than in other people. These “ultra-rapid metabolizers” are more likely to have higher than normal amounts of morphine in their blood after taking codeine. High levels of morphine can result in breathing difficulty, which may be fatal. Taking codeine after tonsillectomy and/or adenoidectomy may increase the risk for breathing problems and death in children who are “ultra-rapid metabolizers.” The estimated number of “ultra-rapid metabolizers” is generally 1 to 7 per 100 people, but may be as high as 28 per 100 people in some ethnic groups (see Table 1 below).

FDA is currently conducting a safety review of codeine to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as post-operative pain following other types of surgery or procedures.

Health care professionals should be aware of the risks of using codeine in children, particularly in those who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. If prescribing codeine-containing drugs, the lowest effective dose for the shortest period of time should be used on an as-needed basis (i.e., not scheduled around the clock).

Parents and caregivers who observe unusual sleepiness, confusion, or difficult or noisy breathing in their child should stop giving their child codeine and seek medical attention immediately, as these are signs of overdose.

FDA will update the public with more information once it has completed its review.

Additional Information for Parents and Caregivers

  • Certain children may be at risk for life-threatening side effects, such as breathing difficulty, or death when taking codeine for pain relief after tonsillectomy or adenoidectomy. This can occur even with use of codeine at recommended doses.
  • Codeine is usually prescribed on an “AS NEEDED” basis. Do not administer codeine to the child on a regular basis UNLESS the child requires the drug. Do not administer more than six (6) doses per day.
  • Signs of serious side effects of codeine in children can include unusual sleepiness, confusion, and difficult or noisy breathing. If your child shows these signs, stop giving your child codeine and seek medical attention immediately by taking your child to the emergency room or calling 911.
  • Talk to your child’s health care professional if you have any questions or concerns about codeine.
  • Report side effects from codeine to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page.

Additional Information for Health Care Professionals 

  • Life-threatening adverse events and death have occurred in certain children who received codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. These children had evidence of being “ultra-rapid metabolizers” of substrates of cytochrome P450 2D6 (CYP2D6), including codeine.
  • If prescribing codeine-containing drugs, use the lowest effective dose for the shortest period of time on an as-needed basis (i.e., not scheduled around the clock).
  • Counsel parents and caregivers on how to recognize the signs of morphine toxicity, and advise them to stop giving the child codeine and to seek medical attention immediately if their child is exhibiting these signs.
  • FDA-cleared tests are available for determining a patient’s CYP2D6 genotype.
  • The estimated number of ultra-rapid metabolizers varies among different racial/ethnic groups (see Table 1below).
  • Consider prescribing alternative analgesics for children undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome.
  • Report adverse events involving codeine to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of this page.

Data Summary

Recently, three deaths and one case of severe respiratory depression were reported in children who received codeine after undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. The children ranged in age from two to five years old. The three deaths occurred in children who had evidence of being “ultra-rapid metabolizers” of substrates of the cytochrome P450 isoenzyme 2D6 (including codeine), and the life-threatening case occurred in a child who was an extensive metabolizer. All children received doses of codeine that were within the typical dose range. In these cases, signs of morphine toxicity developed within one to two days after starting codeine. The post-mortem morphine concentrations in the three children who died1,2 were substantially higher than the typical therapeutic range.3

FDA is conducting a review to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occurred during treatment of other kinds of pain such as post-operative pain following other types of surgery or procedures. FDA will update the public when more information is available.
Table 1. Prevalence of Ultra-rapid Metabolizers in Different Populations

Population UM Genotypes/Phenotypes
(↑ Activity)
Prevalence %
(UM/Total n)
African/Ethiopian4 UM (active duplicate genes) 29% (35/122)
African American5, 6 UM (three active duplicate genes) 3.4% (3/87)
6.5% (60/919)
Asian7, 8, 9 UM (active duplicate genes) 1.2% (5/400)
Caucasian5, 6 UM (three active duplicate genes) 3.6% (33/919) 6.5% (18/275)
Greek10 CYP2D6*2xN/UM 6.0% (17/283)
Hungarian11 UM (active duplicate genes) 1.9%
Northern European10, 12 UM (active duplicate genes) 1-2%

UM = ultra-rapid metabolizer; CYP2D6 = cytochrome P450 2D6

  1. Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med 2009;361:827-8.
  2. Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012;129:e1343-7.
  3. Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br J Anaesth 2002;89:839-45.
  4. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M. Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996;278:441-6.
  5. Kohlrausch FB, Gama CS, Lobato MI, Belmonte-de-Abreu P, Gesteira A, Barros F, et al. Molecular diversity at the CYP2D6 locus in healthy and schizophrenic southern Brazilians. Pharmacogenomics 2009;10:1457-66.
  6. Gaedigk A, Fuhr U, Johnson C, Bérard LA, Bradford D, Leeder JS. CYP2D7-2D6 hybrid tandems: identification of novel CYP2D6 duplication arrangements and implications for phenotype prediction. Pharmacogenomics 2010;11:43-53.
  7. Ji L, Pan S, Marti-Jaun J, Hänseler E, Rentsch K, Hersberger M. Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel *14B allele in mainland Chinese. Clin Chem 2002;48:983-8.
  8. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjöqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452-9.
  9. Lee SY, Sohn KM, Ryu JY, Yoon YR, Shin JG, Kim JW. Sequence-based CYP2D6 genotyping in the Korean population. Ther Drug Monit 2006;28:382-7.
  10. Arvanitidis K, Ragia G, Iordanidou M, Kyriaki S, Xanthi A, Tavridou A, Manolopoulos VG. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Fundam Clin Pharmacol 2007;21:419-26.
  11. Rideg O, Háber A, Botz L, Szücs F, Várnai R, Miseta A, Kovács GL. Pilot study for the characterization of pharmacogenetically relevant CYP2D6, CYP2C19 and ABCB1 gene polymorphisms in the Hungarian population. Cell Biochem Funct 2011;29:562-8.
  12. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5:6-13.





New Evidence about an Old Drug — Risk with Codeine after Adenotonsillectomy.

During the past 10 years, efforts in pharmacogenomics have generated insights into the efficacy and safety of drugs, enhancing our understanding of the safety profile of even some of the oldest drugs, such as codeine sulfate, an opioid analgesic first approved in 1950 for relief of mild or moderate pain. Simultaneously, an increased awareness of the value of both personalized medicine and the reporting of rare adverse outcomes has resulted in the publication of information on adverse events that previously might not have been reported. These developments, in turn, led the Food and Drug Administration (FDA) to reanalyze the safety of — and ultimately restrict — codeine use in patients after adenotonsillectomy.

The activity of codeine depends on its conversion to morphine by the cytochrome P-450 isoenzyme 2D6 (CYP2D6); morphine is subsequently metabolized to the active morphine-6-glucuronide by means of UDP-glucuronosyltransferase 2B7 .The gene encoding CYP2D6 has many genetic variations that affect the amount of codeine that is converted to an active form and that result in the drug’s variable effect. Patients with a normal range of CYP2D6 activity represent 75 to 92% of the population and are called extensive metabolizers. At the low end of the activity spectrum are poor metabolizers (approximately 5 to 10% of the population), who have no functional alleles and therefore receive little to no morphine or analgesia from codeine. At the high end of the CYP2D6 activity spectrum, ultrarapid metabolizers have two or more functional alleles, and their bodies can convert codeine into large amounts of morphine. The prevalence of ultrarapid metabolism varies by ethnic group: it is lower than 1% among Chinese and Japanese patients but potentially higher than 15% among Middle Eastern and North African patients. Clinically significant toxic effects related to opioid excess have been reported in ultrarapid metabolizers, which suggests that the risk of toxic effects from codeine depends, in part, on genotype.1

In April 2012, a case series was published reporting two deaths and one case of respiratory depression in children 3 to 5 years of age who had received typical doses of codeine after tonsillectomy, adenoidectomy, or both performed because of obstructive sleep apnea.2 The two deaths occurred in children who had evidence of being ultrarapid metabolizers, and the postmortem morphine levels in these children were substantially higher than the therapeutic range. The third child was an extensive metabolizer. Signs of morphine toxicity developed within 1 to 2 days after codeine treatment began.

In response to that publication, the FDA initiated an evaluation of the safety of codeine in children. This assessment included a comprehensive review of the literature and case reports that were submitted to the FDA’s Adverse Event Reporting System (AERS, now known as FAERS) between 1969 and May 1, 2012. This search identified 13 cases, including 10 deaths and 3 cases of life-threatening respiratory depression associated with therapeutic codeine use. Seven of these 13 cases (including the 3 from the case series mentioned above) had been reported in the medical literature. Patients ranged in age from 21 months to 9 years. Most of the patients had undergone adenotonsillectomy (eight patients) or had a respiratory tract infection (three patients), and they appeared to receive appropriate doses of codeine. Of the seven children described in the published cases, three were characterized as ultrarapid metabolizers, three as extensive metabolizers, and one as a probable ultrarapid metabolizer. A search of the medical literature and AERS for cases of pediatric death or life-threatening respiratory depression with therapeutic use of hydrocodone, oxycodone, or morphine was also conducted and did not identify robust cases of unexplainable or unconfounded death or life-threatening respiratory depression after the use of these drugs.

In late 2011, the Patient Safety and Quality Improvement Committee of the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) was also becoming concerned about adverse events, particularly respiratory depression, after adenotonsillectomy. Such events have been described informally for decades but rarely reported. In 2012, the committee conducted a nationwide, anonymous survey of otolaryngologists to learn more about these events. When the FDA announced its investigation the committee reached out to share prepublication results with the agency. Limited information was available; however, two children (a 3-year-old and a 12-year-old) with obstructive sleep apnea who died after adenotonsillectomy were confirmed (by genotype) to be ultrarapid metabolizers or suspected (because of high postmortem blood morphine levels) of being ultrarapid metabolizers.3

The only well-documented cases of death or respiratory arrest after codeine treatment in ultrarapid-metabolizing children have involved patients who have just undergone adenotonsillectomy. That does not mean that the risk is not present in other situations, but currently available evidence suggests that the risk is most substantial in children after they have undergone tonsillectomy, adenoidectomy, or both. Many such children have sleep-disordered breathing, and children with sleep-disordered breathing are known to be more sensitive to opioids.4

Therefore, the FDA recently required that the manufacturers of all codeine-containing products add a boxed warning to the labeling of their product that describes the risk posed by codeine after a child has undergone tonsillectomy or adenoidectomy. A contraindication will be added to restrict codeine use in such patients. The “Warnings/Precautions,” “Pediatric Use,” and “Patient Counseling Information” sections of the labeling will also be updated.

Performing routine genotyping before prescribing codeine was not recommended for several reasons. Some of the patients who died or in whom respiratory depression developed were genetically extensive metabolizers, so patients with “normal” genotyping results may still be at risk. Also, since the number that would need to be screened to prevent such a rare toxic effect would be very high, and since preoperative laboratory assessments are not routine before adenotonsillectomy, the practicality of genotyping is questionable.

Although it did not participate in the FDA’s decision process, the AAO-HNS supported the labeling changes because of the increasing evidence that these extremely rare but catastrophic events can be related to codeine use, because codeine is ineffective in some patients (poor metabolizers), and because of emerging clarity that a variety of other drugs (e.g., some nonsteroidal antiinflammatory drugs) are safe to use and do not increase the risk of bleeding.5 The AAO-HNS informally surveyed opinion leaders in academic medicine, private practice, and pediatric otolaryngology and reached a consensus that the availability of other analgesic agents and the risk of catastrophic events outweighed the value of codeine.

Even old and commonly used drugs may cause rare but catastrophic events that will not be recognized without a vigorous effort by the profession to share information in the literature. In the case of codeine, a combination of case reporting and our evolving understanding of genetic influences on drug response has clarified the need to avoid this drug after adenotonsillectomy.

Source: NEJM



A Novel Channelopathy in Pulmonary Arterial Hypertension.


Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes.


We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis.


We identified a novel heterozygous missense variant c.608 G→A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082.


Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation.

Source: NEJM


Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension.


Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension.


In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro–brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety.


By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm–5 in the riociguat group and increased by 23 dyn·sec·cm–5 in the placebo group (least-squares mean difference, –246 dyn·sec·cm–5; 95% CI, –303 to –190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group).


Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension.

Source: NEJM


Therapies for Active Rheumatoid Arthritis after Methotrexate Failure.


Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate — a common scenario in the management of rheumatoid arthritis.


We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48.


Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (−2.1 with triple therapy and −2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications.


With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy.

Source: NEJM


Rationing Lung Transplants — Procedural Fairness in Allocation and Appeals.

Organ transplantation requires explicit rationing and relies on public trust and altruism to sustain the organ supply. The well-publicized cases of two pediatric candidates for lung transplants have shaken the transplant community with emergency legal injunctions arguing that current lung-allocation policy is “arbitrary and capricious.” Although the resulting transplantation seemingly provided an uplifting conclusion to an emotional public debate, this precedent may open the floodgates to litigation from patients seeking to improve their chances of obtaining organs. These cases questioned the potential disadvantaging of children and the procedural fairness in lung allocation. But legal appeals exacerbate inequities and undercut public trust in the organ-transplantation system.

The controversy began when the parents of Sarah Murnaghan, a critically ill 10-year-old awaiting a lung transplant for cystic fibrosis, appealed through her physicians to the Organ Procurement and Transplantation Network (OPTN) for an exception to the policy that restricts lung-transplant candidates younger than 12 years to receiving organs from donors younger than 12. When this appeal failed, the Murnaghans appealed to the media, politicians, and finally a federal judge to grant access to the larger pool of lungs from adult donors. They argued that mistreatment of pediatric candidates for transplants would probably result in Sarah’s death. The merits of the case were never argued, since during the 10-day temporary injunction, Murnaghan received two lung transplants from adult donors. She has had serious complications, including pneumonia, and required a tracheostomy.

In 2005, to improve equity and efficiency, the OPTN switched from prioritization based on waiting time, a first-come–first-served approach that often prioritized less-urgent cases for organs, to an approach that incorporated consideration of urgency. After a 5-year review, the OPTN had developed a lung allocation score (LAS) using medical factors that predict disease severity and the likelihood of dying on the waiting list.1 Such scores were assigned only to patients 12 or older, because there were insufficient data to support their applicability to younger populations, owing to their different diagnoses and limited outcomes data. Thus, patients younger than 12 were excluded from consideration for adolescent and adult donors’ lungs (which are allocated according to the LAS and geography) and limited to use of pediatric donors’ lungs, which are allocated according to two priority levels (different degrees of urgency based on medical criteria) and geography.

The LAS policy has increased lung-transplantation rates and reduced mortality on the waiting list among older patients.2 Pediatric patients, however, continue to have higher waiting-list mortality and are less likely to receive transplants.

Unadjusted Relative Risk of Dying While on the Waiting List or Becoming Too Sick to Receive a Lung Transplant (Panel A) and Relative Likelihood of Receiving a Lung Transplant (Panel B), According to Age Group, September 12, 2010 to March 11, 2013.), despite wider geographic sharing of pediatric organs and the use of urgency levels — primarily because there are few pediatric donors. The supporters of the “under-12 rule” argue that it promotes equity and efficiency because of its aggregate benefits. They also cite the problematic discrepancy in lung size between adult donors and pediatric recipients. Furthermore, as a treatment for cystic fibrosis (the most common diagnosis among pediatric candidates for lung transplants), transplantation has been shown in several retrospective studies to have only marginal benefit, owing to improvements in medical management (although some data suggest otherwise).3 Lung transplantation in pediatric patients is also associated with high postoperative morbidity and mortality, largely because of the recipients’ underlying diagnoses.

Nevertheless, appeals to list children for adult organs have merit. First, designating age 12 as the cutoff arbitrarily disadvantages some children because age is a poor proxy for size. Younger patients who meet the size requirements and could benefit from adult lungs should be considered eligible. Second, in allocating other organs, we often prioritize children, partly on the basis of “fair innings” considerations (equalizing people’s chances of living until a given age) and partly because of the unique importance for physical and cognitive development that a transplant may confer. These arguments also apply to lung transplantation. Third, transplanting lungs into children is similarly efficient to doing so in adults, since their graft-survival rates are similar. Lobar resection can facilitate transplantation of adult lungs into smaller pediatric patients — also with similar results.4 Finally, given the scarcity of pediatric lung transplants, the data necessary for optimal validation of the LAS in this population may never be available. Without conclusive data, we should err on the side of inclusion, not exclusion from access to a broader supply of lifesaving organs. Currently, only 30 children in the United States await lung transplants, and only 11 of them are 6 to 11 years of age. The change that would occur by allowing these children access would most likely have little effect on nonpediatric candidates.

In response to objections that children are unfairly disadvantaged, the OPTN will review its lung-allocation policy during the next year and allow expedited appeals to an expert lung-allocation board in the interim. Candidates approved during this period will gain access to the full pool of lungs on the basis of the LAS and geographic location, while maintaining their pediatric priority.

Are the organ-allocation and appeals processes fair? Despite this case, we believe they are. An ethical framework that is gaining traction in health policy, Accountability for Reasonableness (A4R), offers an approach for achieving fairness and legitimacy in allocating health resources.5 A4R requires transparency about the objectives of and evidence for decisions, consensus about the relevance of rationales used in resource allocation, a process for reevaluating and revising criteria in light of new evidence, and procedures for enforcing these conditions in the deliberative process. This approach claims that a fair deliberative process results in outcomes that are acceptable to all.

A4R has limitations in Murnaghan’s case, including those resulting from the limited data regarding lung-transplantation outcomes in the pediatric population. But generally, organ allocation follows A4R’s tenets: it is public, transparent, revisable, enforceable, and open to appeals, and it incorporates key stakeholders. Organ-allocation algorithms seek to balance equity and efficiency. Committees comprising medical and ethics experts, transplant recipients and donors, and other key stakeholders meet in a predictable and transparent way. They deliberate and issue reports and policy recommendations that are opened to public comment. Policies are enforced and revised regularly on the basis of new evidence.

Transplant candidates and their families go to great lengths to obtain lifesaving treatment. They should be assured of fair process and, in cases of error or newly available information, allowed to appeal decisions. Appeals waged through federal courts and the court of public opinion, however, undermine fairness. Judicial appeals grant discretionary access to wealthier people, exacerbating disparities and discrimination. Moreover, appeals are inefficient, complicating allocation and leading to longer allocation times, poorer matches due to expansion of criteria, and greater difficulty in managing the waiting list. Lawsuits also inappropriately saddle courts with decisions about health policy. Finally, appeals reduce transparency and predictability, undermining the public perception of fairness, which could reduce donation rates.

Although the OPTN’s allowance of appeals to an expert panel is preferable to judicial appeals, it is problematic. Relying on physicians to appeal on behalf of candidates leaves patients of lower socioeconomic status, those less informed about their options, and those lacking advocates vulnerable to worse treatment. Physicians may also fear that accepting the responsibility of mounting appeals means assuming greater risk of poor outcomes and subsequent audits, which may also result in disparities.

To prevent unequal treatment, absent better data, we believe the OPTN should expand its policy to automatically assign an LAS to pediatric candidates and put those meeting the size and LAS criteria for adult and adolescent organs on the waiting list. Lung transplants should be allocated on the basis of the LAS and size match, with consideration of lobar resection for small recipients of adult lungs. Children should retain preference for lungs from pediatric donors.

Overall, we believe that the organ-allocation process is fundamentally fair, in part because of procedures in place to revise and modify allocation. It is because of this fair process that errors can be discovered and addressed. Our proposed changes would provide more lifesaving lungs to children; they would also provide useful data for the 1-year policy review and could ensure equal treatment for all children awaiting lung transplants.


Source: NEJM



A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s Disease.


Alzheimer’s disease is characterized by the presence of cortical amyloid-beta () protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer’s disease.


We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer’s disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer’s Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used.


The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, −9.0 points in the placebo group, −10.5 points in the 100-mg group, and −12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated.


As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections.

Source: NEJM