ASH sickle cell disease CPKD guidelines report Open Access

TO THE EDITOR:

The American Society of Hematology (ASH) Clinical Practice Guidelines for sickle cell disease (SCD) on cardiopulmonary and kidney disease (CPKD) were published in 2019¹ as part of a series on cerebrovascular disease, acute and chronic pain, transfusion support, and stem cell transplantation. The guidelines comprised 10 recommendations that focused on screening for cardiopulmonary disease (eg, pulmonary hypertension [PH], sickle lung disease, and sleep-disorder breathing) and managing cardiopulmonary and kidney complications (eg, PH, albuminuria, chronic KD, and venous thromboembolism).

ASH recognizes the importance of keeping guidelines contemporary and therefore implemented a rigorous process for monitoring and updating guidelines in 2021. An updated literature search was conducted for the guidelines on CPKD. Two assigned reviewers from a group of previous panel members scored each article’s abstract for inclusion in this update, further discussion, or rejection. Articles with discordant scores were discussed to determine the final category.

Following this review, the group determined that there was insufficient new evidence to change any of the previous recommendations. This article discusses the updated literature search and highlights key studies.

The 2019 ASH guidelines recommended against a routine screening echocardiogram (ECHO) to identify PH in asymptomatic children and adults with SCD. They also recommended against right-heart catheterization (RHC) for asymptomatic patients with a peak tricuspid regurgitant jet (TRJ) of ≥2.5 to 2.9 m/s but recommended RHC for patients with a TRJ of ≥2.5 and a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal pro-B-type natriuretic peptide (NT-BNP). The use of ECHO alone to identify patients with SCD at highest risk for PH remains unclear. Updated evidence suggests that higher TRJ thresholds, along with information from key ECHO parameters, can increase the positive predictive value for patients likely to have PH by RHC. Lilje et al² showed that among 91 children who underwent a screening ECHO, only 5.5% had ECHO evidence of a moderate risk for elevated pulmonary artery pressure suggestive of PH based on a TRJ of ≥ 2.9 and other ECHO data like right ventricular systolic pressure-to-systolic blood pressure ratio, systolic left ventricular eccentricity index, and right ventricular parameters. An ECHO remains imperfect for screening for PH, especially in children with SCD. Supplementing ECHO data with 6MWD and NT-BNP measurements requires further investigation.³ Studies that evaluate ECHO to screen for PH should also use the updated mean pulmonary artery pressure definition of >20 mm Hg.⁴ 

Confirmation by RHC remains the gold standard in patients with an abnormal ECHO suggestive of PH. Although computed tomography pulmonary angiography (CTPA) and ventilation-perfusion (V/Q) scanning are not standard for SCD in this setting, they may better define the causes of precapillary pulmonary arterial hypertension (PAH) in PH, like chronic thromboembolic PH. Among 142 adults with SCD who underwent a PH evaluation, including V/Q scanning, CTPA, and RHC, Mehari et al⁵ found that 45.8% and 26.7% had abnormal V/Q scanning and CTPA, respectively. For 33 patients with data from all 3 modalities, V/Q scanning had a sensitivity and specificity of 98.7% and 75%, respectively, for detecting RHC-confirmed PH as opposed to a sensitivity and specificity of 37.3% and 100%, respectively, for CTPA. Abnormal V/Q scanning was also associated with worse hemodynamics, a shorter 6MWD, and higher mortality.

For children and adults with SCD and RHC-confirmed PAH, the 2019 ASH guidelines suggest that PAH-specific therapies should be guided by a PH specialist. Recent evidence suggests that PAH-specific therapies, like phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, are safe for adults with SCD. Among 36 adults with SCD and RHC-confirmed PH, Cramer-Bour et al⁶ showed that treatment with sildenafil or tadalafil (median, 25 months) led to significant improvements in dyspnea and New York Heart Association functional class without increased hospitalizations or vaso-occlusive episodes during therapy. Although not specific for PH, a phase 1/2 randomized, placebo-controlled trial of riociguat in 130 adults with SCD and either a systolic blood pressure of 130 to 139 mm Hg and/or a diastolic blood pressure (BP) of 80 to 89 mm Hg or proteinuria showed no between-group differences in the treatment-related serious adverse events or safety outcomes, including vaso-occlusive episodes, pain severity, or pain interference.⁷ 

The 2019 ASH guidelines also emphasized initiation or optimization of hydroxyurea (HU) or chronic transfusions in patients with SCD and RHC-confirmed PAH. Among 110 adults with homozygous SCD, Garadah et al⁸ showed that patients on HU had a longer 6MWD, lower NT-BNP levels, and lower TRJ values. Moreover, fewer patients on HU when compared with those not on HU had a TRJ of >3.4 m/s, which is associated with a high probability of RHC-confirmed PH.

For asymptomatic children and adults with SCD, the ASH 2019 guidelines recommended against routine screening for sleep-disordered breathing using polysomnography. When combined with a comprehensive sleep history and review of systems, sleep questionnaires are valuable for identifying patients who should undergo formal sleep testing. Despite several validated tools in the general population (eg, Epworth Sleepiness Scale or the Pittsburgh Sleep Quality Index), future studies should further validate them in children and adults with SCD. Recent studies in children with SCD continue to be limited by small sample sizes, patient heterogeneity, and variability in the tool and study methodology.^9-11 

The 2019 ASH guidelines suggested the use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers to treat albuminuria in children and adults with SCD, which is further supported by recent evidence. Among 32 children and adults with sickle cell anemia, Quinn et al showed that losartan for 6 months led to a ≥ 25% reduction in the urinary albumin-to-creatinine (A:C) ratio in 83% of participants in the macroalbuminuria (>300 mg/g) group (median fold-change, −0.74) and in 58% of those in the microalbuminuria (30-300 mg/g) group (median fold-change, −0.46).¹² Urine osmolality and estimated glomerular filtration rate (GFR) did not change significantly. The similar benefits offered by ACEis and angiotensin II receptor blockers in patients with SCD from other small studies highlight the need for a phase 3 study. In the Haymann et al¹³ study of 42 patients with SCD and a urine A:C ratio of >10 mg/mmol who were treated for at least 6 months with an ACEi, a >30% decrease in the urine A:C ratio was observed in 62%, whereas the estimated GFR remained unchanged. In another study of 12 children and adults with SCD and persistent albuminuria on HU, reduced albumin excretion (microgram per minute) was observed with both short-term (1-2 months) (−134; 95% confidence interval [CI], −327 to −67; P = .0063) and long-term losartan treatment (≥12 months) (−90; 95% confidence interval, −431 to 19; P = .07).¹⁴ 

The 2019 ASH guidelines recommended a BP goal of <130/80 mm Hg over a goal of <140/90 mm Hg for adults with SCD. Recent data underscore the importance of optimizing BP targets given the association between hypertension and adverse events in children and adults with SCD. Roger et al¹⁵ found that a diastolic BP of >70 mm Hg was an independent risk factor for developing stage 2 chronic kidney disease after adjusting for the baseline estimated GFR and age. In a study of 42 children who underwent 24-hour ambulatory BP monitoring, Strumph et al¹⁶ found that nocturnal hypertension was more prevalent in children with than those without a history of silent cerebral infarct or stroke (55% vs 12%; P = .01).

The 2019 ASH SCD Guidelines on CPKD help to inform patients, clinicians, and other health professions on the decisions about screening, diagnosis, and management. A transparent systematic literature search and updated evidence review led to no changes in the recommendations or to their strength based on the quality of the new evidence. Ongoing monitoring using the current ASH guideline processes is warranted.

Contribution: R.I.L., M.V., T.W., and S.L. reviewed the abstracts and data from the updated literature search; R.I.L. wrote the initial manuscript draft; and M.V., T.W., and S.L. provided critical feedback and edits for the final manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Robert I. Liem, Division of Hematology, Oncology & Stem Cell Transplantation, Ann & Robert H. Lurie Children’s Hospital of Chicago; 225 East Chicago Ave, Box 30, Chicago, IL 60611; email: rliem@luriechildrens.org.