Highlights
– The PRESEV score (0–16) was prospectively validated in 393 adult sickle cell patients with vaso-occlusive crisis (VOC) across 13 centers in Africa and Europe.
– A PRESEV score ≤5 (low risk) had a negative predictive value (NPV) of 94.0% for subsequent acute chest syndrome (ACS); sensitivity for predicting ACS was 96.1%.
– Use of the score to guide outpatient management in 100 low-risk patients was associated with a single ACS event (1.0%), suggesting a potentially safe strategy to reduce unnecessary inpatient care.
Background
Acute chest syndrome (ACS) is one of the most serious and common pulmonary complications of sickle cell disease (SCD) and a leading cause of morbidity and mortality. ACS is characterized by a new pulmonary infiltrate on chest imaging accompanied by fever and/or respiratory symptoms. Multiple pathophysiologic mechanisms — pulmonary infarction from in situ sickling, infection, fat or marrow embolism, and hypoventilation — can precipitate ACS. Early recognition and prompt treatment are essential, but distinguishing which adults presenting with VOC are at low versus high risk of developing ACS within the next days is a frequent clinical dilemma.
Hospital admission for many VOC episodes is routine because clinicians worry about progression to ACS, yet unnecessary admissions increase costs, expose patients to nosocomial risks, and burden health systems, particularly in resource-limited settings. A validated, easy-to-use prognostic score that identifies adults with VOC at low risk for ACS could inform safe outpatient management and optimize resource allocation.
Study design
This prospective observational validation study was conducted in 13 centers across five countries in Africa and Europe. The investigators tested a previously developed PREdictive SEVerity (PRESEV) score designed to estimate the risk of ACS in adults hospitalized for VOC. The score ranges 0–16 and incorporates clinical and laboratory variables (the original derivation paper and component weights are preserved in the primary reference). A PRESEV value ≤5 was prespecified as a low-risk threshold.
Primary endpoint
– Occurrence of ACS during the index VOC episode.
Cohorts
– Validation cohort: 393 adult patients hospitalized for VOC (206 from Europe; 187 from Africa).
– Outpatient application cohort: 100 patients with VOC and PRESEV ≤5 managed with an outpatient strategy guided by the score.
Safety monitoring
– Deaths and ACS events were recorded. The study was registered (IRB 00003835; ClinicalTrials.gov NCT03032055) and funded by patient-advocacy and research organizations.
Key findings
Cohort characteristics and event rates
– The validation cohort included 393 adult patients with VOC; 76 patients (19.3%) developed ACS during their index presentation.
PRESEV score performance (validation cohort)
– Low-risk group (PRESEV ≤5): 50 patients (12.7% of cohort).
– Among low-risk patients, 3 developed ACS (6.0%), producing an NPV of 94.0% for ACS.
– Sensitivity: Of the 76 patients who developed ACS, 73 (96.1%) did not have a low-risk score (i.e., PRESEV >5), yielding a sensitivity of 96.1% for identifying those who ultimately developed ACS.
– Specificity and positive predictive value (PPV) are not explicitly reported here but can be inferred from full contingency tables in the original manuscript.
Mortality and safety
– Five deaths (1.3% of the validation cohort) occurred; none of the patients who died had a PRESEV score ≤5.
Geographic generalizability
– Score performance was similar across the African and European centers, supporting cross-continental generalizability in adult populations.
Application to outpatient management
– In an implementation cohort of 100 patients with VOC and PRESEV ≤5 managed as outpatients per the investigators’ protocol, one ACS event (1.0%) occurred.
Interpretation of prognostic metrics
– High sensitivity (96.1%) indicates the score is unlikely to miss most patients who will develop ACS when using the ≤5 cutpoint to define low risk.
– NPV (94.0%) depends on event prevalence (here ~19%); in populations with higher or lower baseline ACS incidence the NPV will change. Nevertheless, at the observed incidence the chance that a patient with PRESEV ≤5 will develop ACS was 6% in the validation cohort, and only 1% in the outpatient application cohort.
Clinical implications
– The PRESEV score appears to identify a subset of adults presenting with VOC who have a low short-term risk of ACS and who may be candidates for outpatient management with close follow-up.
– Use of the score could reduce unnecessary hospital admissions and their associated costs and risks, particularly relevant in settings with limited inpatient capacity.
Strengths
– Prospective, multicenter, international design with inclusion of centers in both Africa and Europe enhances external validity for adult SCD populations.
– Clinically relevant primary outcome (ACS) with standardized ascertainment.
– Pragmatic application cohort showing real-world utility and preliminary safety data when the score guides outpatient care.
Limitations
– The PRESEV score was validated in adults only; pediatric populations—who have different ACS epidemiology—were not studied.
– The outpatient implementation cohort was relatively small (n=100) and nonrandomized; selection bias (clinicians may have chosen lower-risk appearing patients beyond the score) could influence the low event rate.
– Full diagnostic adjudication details, interobserver variability in diagnosing ACS, and thresholds for imaging or admission decisions across sites are not detailed here and could affect observed event rates.
– Predictive values are contingent on local ACS prevalence; in centers with significantly different baseline rates, performance would differ.
Expert commentary
Why this matters
Acute chest syndrome remains a leading cause of hospitalization and death in adults with sickle cell disease. Clinicians often admit patients with VOC preemptively because early ACS can be subtle and progress rapidly. A validated, practical risk stratification tool that safely identifies low-risk patients could meaningfully reduce admissions and allow targeted allocation of monitoring and interventions to higher-risk patients.
How to use PRESEV in practice
– Consider PRESEV as one component of a broader clinical decision pathway rather than a standalone gatekeeper. Low PRESEV (≤5) suggests low short-term risk for ACS, but clinicians should still evaluate for concerning symptoms, comorbidities (e.g., severe cardiopulmonary disease), social factors that may impair outpatient follow-up, and local resources.
– For low-risk patients, structured outpatient pathways — including clear return precautions, scheduled follow-up within 24–48 hours, rapid-access clinic slots, and education about signs of respiratory deterioration — will be critical to maintain safety.
– For higher PRESEV scores (>5), the high sensitivity supports continued inpatient monitoring and proactive measures to prevent ACS progression (e.g., aggressive pain control, incentive spirometry, oxygen supplementation as needed, antibiotics if infection suspected, and transfusion thresholds per local protocols).
Research and policy implications
– A randomized controlled trial comparing PRESEV-guided outpatient management versus usual care would provide higher-quality evidence for safety and cost-effectiveness.
– Integration with electronic health records and clinical decision support could standardize application and facilitate real-time risk calculation.
– Health systems, especially in low-resource settings, should consider validating PRESEV locally and developing implementation protocols that include patient education and rapid re-evaluation mechanisms.
Conclusion
This prospective international validation demonstrates that the PRESEV score reliably stratifies adults presenting with VOC by short-term risk of ACS. A PRESEV threshold ≤5 identifies a group with low observed risk (NPV 94%) and in a pragmatic outpatient application cohort was associated with a very low ACS rate (1%). While promising, these results should be applied with clinical judgment, and larger, ideally randomized, implementation studies are warranted to confirm safety, define optimal outpatient pathways, and evaluate effects on utilization and outcomes across diverse health systems.
Funding and trial registration
The study was funded by the Support for Actions against Red Blood Cell Diseases Association and other sponsors (detailed in the primary publication). Institutional review board registration number IRB 00003835; ClinicalTrials.gov number NCT03032055.
References
1. Kassasseya C, Kéné S, Besse-Hammer T, et al. Validation and Application of a Predictive Score of Acute Chest Syndrome. NEJM Evidence. 2025 Dec 18:EVIDoa2500074. doi:10.1056/EVIDoa2500074. PMID: 41410575.
2. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. National Heart, Lung, and Blood Institute (NHLBI). (Available from: https://www.nhlbi.nih.gov/ )
3. World Health Organization. Sickle-cell disease: a strategy for the WHO African Region. WHO; 2020. (Available from: https://www.who.int/ )
(Note: Additional background literature and guideline documents should be consulted when applying PRESEV locally; the primary validation study cited above contains the detailed score components, derivation data, and supplementary analyses.)
