The Challenge of Creating an Evidence-Based Guideline for Sickle Cell Disease

In this issueof JAMA, Yawnandcolleagues1publish themuchanticipatedNationalHeart, Lung, andBlood Institute (NHLBI) guideline for the management of sickle cell disease (SCD) in the United States. The last SCD guideline sponsored by the NHLBI was published a decadeago.Thechallengesassociatedwithdevelopingguidelines for individualswithanuncommondisease areunique and formidable becauseof the relianceonevidenceother thanclinical trials, inparticularexpert opinion.Given the importanceofevidence-derivedguidelines, particularly formanagementof anuncommondisease, adherence to rigorousmethodology iscritical for their credibility.The InstituteofMedicine (IOM)publishedguidelines2 toaddress the most importantcomponentsofanyguideline thatwill allowfor primary care clinicians, specialists, and payers to have confidence in its content.For the foreseeable future, the recommendations fromthe IOMrepresent thecriterionstandardbywhich guidelines should be assessed. The SCD guideline1 has numerous strengths. In reviewing more than 12 000 articles, the NHLBI guideline committee explicitly followed3of thekey recommendations fromthe IOMfor guideline creation including: (1) performanceof a systematic review of the existing evidence; (2) using an explicit and transparent process that minimized distortion, bias, and conflicts of interests; and (3) providing a clear explanation of the logical relationships betweenalternative care options and health outcomes. Ratings of both the quality of evidence and the strength of recommendations are included. Inaddition, theguideline iswellorganized,withnumerous tables that summarize thequalityof theevidenceandstrength of the recommendations in specific areas including: a consensus treatmentprotocol for the implementationofhydroxyurea therapyandevidence-basedsummariesformedicalmanagement ofhealthmaintenanceandacutecomplications.Yawnetal1 also includedatable thathighlights thestrongest recommendations with thehighest-qualityevidence.Theauthorsemphasize that themajorityof the recommendationsarebasedonmoderateor weakevidenceandshouldnotbeusedasquality indicators.An additionalstrengthoftheSCDguidelineis theprovisionofaclear roadmapforestablishingfundingprioritiesinwhichtheevidence tosupport recommendationsforclinicalcare is lowormoderate. Despite these many strengths, the creators of the guideline did not follow all of the IOM recommendations. Amultidisciplinary panel of experts and representatives fromkey affectedgroupswerenot includedandpatient preferenceswere not solicited. The absence of representation of patients with SCD and their affected familymembers is an important omission, particularly given the possible differences between the perspectives of the adult with or parent of a child with SCD and the membersof the committee. Listening to theperspectiveof the families and understanding which of these recommendations are important to them and how they may be implemented is critically important. In the new era of patientcenteredoutcomes research, a rare opportunitywasmissed in shaping this SCDguidelinebynot obtaining input from the individuals most affected by the disease. The guideline did undergo extensive review and revision and ultimately was endorsed by the American Society of Hematology, the American Academy of Pediatrics, and the American Society of Pediatric Hematology/Oncology, representing an attempt to build consensus prior to the release. Notably absent was endorsement from other professional organizations that have expertise in themanagement of chronic kidneydisease,pulmonaryhypertension,obstructive lungdisease, and stroke, which are the 4 most common comorbidities that occur in individualswith SCDandare associatedwith earlier death. However, it may be increasingly difficult for guidelines to be endorsed by all relevant societies, particularlywhen recommendations are based onweak ormoderate evidence. Thereareanumberofclinicalareas inwhichtheSCDguideline couldhaveprovided additional information. Chronic kidney disease ismore common in patients with SCD than in the general population and is associatedwith earlier death.3However, the recommendationsdonot includesuggestions forhow often to screen and when to screen for kidney disease, only to refer those with proteinuria of greater than 300 mg for 24 hours to a nephrologist. A common clinical problem for children with SCD is asthma. The presence of asthma or asthma symptom(recurrentwheezing), significantly increases the risk ofSCD-relatedmorbidity4andmortality.5-7However, theguidelinedoesnotprovide anyapproach to screenand treat asthma orasthma-like symptoms. InSCD, standard therapy for asthma treatment, such as steroids, has short-termSCD-specific8 and long-term nondisease consequences.9 Themanagement of and screening for pulmonary hypertensionorat leastelevated tricuspid regurgitantvelocity (TRV), a risk factor for earlier death in patients with SCD,was absent from the guideline, along with the absence of the endorsement from the American Thoracic Society (ATS). Most recently, theATShaspublished its guidelineonscreening for and managementof pulmonaryhypertension.10However, the recRelated article page 1033 Opinion