0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Editor's Correspondence |

Role of Toll-like Receptor 4 Mutations in Gram-Negative Septic Shock

Sachin Yende, MD
Arch Intern Med. 2002;162(21):2496. doi:.
Text Size: A A A
Published online

Extract

Genetic association studies related to septic shock have traditionally evaluated 2 end points: susceptibility to development of septic shock and mortality due to septic shock. Recently, Lorenz et al1 reported an association between toll-like receptor 4 (TLR4) mutations and susceptibility to gram-negative septic shock in the ARCHIVES. The C3H/HeJ mice, which are lipopolysaccharide hyporesponsive due to mutations within the Toll gene, were more susceptible to dissemination of gram-negative bacteria.2 In in vitro studies, when cells with the Asp299Gly mutation were exposed to lipopolysaccharide, they released less tumor necrosis factor α and interleukin 1, which are important mediators of septic shock.3 Although it is difficult to extrapolate these results to humans, one may hypothesize that patients who develop gram-negative infections and have the Asp299Gly mutation are more susceptible to bacteremia. However, whether these patients would be more or less susceptible to develop septic shock, which is mediated by proinflammatory cytokines, remains unknown. Therefore, the use of a 1-sided Fisher exact test cannot be justified.4 Furthermore, the same authors have demonstrated that patients with the Asp299Gly mutation have a trend for lower graft-vs-host reaction after stem cell transplantation.5 Although one may argue that the pathophysiologic mechanisms are different, the use of 1-sided statistical tests should be limited to conditions in which overwhelming evidence suggests that the effect will occur only in 1 direction. The authors report that 5 of 91 patients with septic shock had the mutation compared with 0 of 73 patients in the control group (P = .07 for a 2-sided Fisher test rather than P = .05 for a 1-sided test). The prevalence of the Asp299Gly mutation in control population is approximately 5%.6 The rationale of choosing only 73 patients in the control group remains unclear, especially when none of these patients had the Asp299Gly mutation. Although the authors report an important association, the validity of the study remains questionable because of these issues. I am also curious whether the authors evaluated other end points for increased risk of dissemination of gram-negative bacteria, such as the number of patients with positive blood cultures.

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

First Page Preview

View Large
First page PDF preview

Figures

Tables

References

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
brightcove.createExperiences();