Acute chest syndrome in adult patients with sickle cell disease: The relationship with the time to onset after hospital admission

INTRODUCTION

Acute chest syndrome (ACS) is one of the most severe complications observed in adult patients with sickle cell disease (SCD) and is associated with high morbidity and mortality rates.¹ The syndrome is conventionally defined in France as a combination of one or more respiratory symptoms (chest pain, dyspnoea, cough, expectoration, fever) or abnormal auscultation findings and a new pulmonary infiltrate on imaging.² Although ACS commonly occurs after a bone vaso-occlusive crisis (VOC), it may also be inaugural.³ Relative to a VOC alone, ACS is associated with a significantly longer length of hospital stay, a greater likelihood of admission to an intensive care unit (ICU), and a greater frequency of red blood cell (RBC) transfusion.^3-6 Hence, ACS is a major cause of death in people with SCD^{1, 7-11}; the mortality rate ranges from 1.6% to 4.6% in hospitalized patients not admitted to the ICU^{12, 13} and can be as high as 13% in patients admitted to the ICU.^{14, 15}

Despite its severity, precise epidemiological data on ACS are scarce. The prevalence of ACS after a VOC (i.e. secondary ACS) ranges from 12.5% to 42%, and the median time to onset is usually between 2–4 days.^{3, 4, 16-20} However, data on early-onset ACS (i.e. onset less than 24 hours (h) after the VOC) are particularly scarce, and it is not known whether early-onset ACS and secondary ACS have different characteristics. Indeed, the pathophysiology of ACS is complex, and one can hypothesize that early-onset ACS often has an infectious trigger.

Thus, the objectives of the present study were to (i) describe the clinical, laboratory and imaging characteristics of consecutive episodes of ACS, and (ii) compare early-onset ACS with secondary ACS after hospital admission for a VOC.

MATERIALS AND METHODS

RESULTS

Characteristics of the study population

In all, 117 ACS episodes were recorded prospectively (Figure 1). After the application of our exclusion criteria, 105 of the 117 episodes (in 81 patients) were selected for analysis. Forty-four of the 105 episodes of ACS (42%) were classified as early-onset, and 61 (58%) as secondary.

At the time of the first ACS episode, the median [IQR] age of the 81 patients was 27 [22–34] years (Table S1). There were 48 males (59%), and 72 patients (89%) had an S/S or S/β⁰ thalassaemia genotype. Sixty-six patients (81%) had a history of ACS, with a median of 3 [2–5] episodes per patient (of which 1 [0–2] led to ICU admission). A history of pulmonary embolism (PE) was noted for 4 patients (6%). The “early-onset” and “secondary” groups of patients did not differ significantly with regard to the prevalence of chronic complications of SCD.

DISCUSSION

We comprehensively described 105 consecutive ACS episodes in adult patients with SCD and compared the characteristics as a function of the time to onset after hospital admission. No major differences between early-onset and secondary episodes were found.

The French definition of ACS is slightly different from the definition of the Cooperative Study for Sickle Cell Disease (CSSCD) and National Acute Chest Syndrome Study Group (NACSSG) (new infiltrate on imaging and any of 5 clinical criteria between chest pain, fever >38.5°C, tachypnea, wheezing, or cough).²⁴ These American criteria derive from studies mainly conducted on paediatric patients. The French definition includes detailed auscultatory abnormalities (crackles, bronchial breathing and decreased sounds) that we believe are critical in the early detection of ACS in adults and probably more accurate than chest pain, which may be due to rib VOC without lung involvement. Six episodes in our study did not perfectly match with the clinical CSSCD and NACSSG criteria, but all presented dyspnea, crackles or bronchial breathing and all had lung condensation on imaging, in the absence of other cause, making the diagnosis of ACS reliable. The British definition (fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on chest X-ray) is even less detailed.²⁵ An international consensus for the definition of ACS would be useful.

Fifty-eight percent of the ACS episodes were diagnosed after more than 24 h in hospital (median [IQR]: 2 [2–3] days); these values are in line with the literature data.^{3, 4} With a median [IQR] duration of stay of 9 [7–11] days, ACS is responsible for prolonged hospitalizations (average of 4.4 days in our centre in case of non-complicated VOC). ²⁶ We noted a history of ACS for 81% of the patients, with a median [IQR] number of 3 [2–5] previous episodes. This is similar to the value of 76% for 128 SCD patients aged 20 or over in Vichinsky et al. US study (published in 2000) of ACS in a population of adults and children.²⁴ In a previous study of our centre's cohort, 162/231 patients (70.1%) had a history of ACS with a median of 1 [0–3] episodes in their lifetime.²³ In the present study, the proportion of patients with an S/S or S/β⁰-thalassaemia genotype was higher (89%) than in our previous study (79%), although the median ages were equivalent. These findings emphasize that the vaso-occlusive phenotype is more severe for S/S and S/β⁰-thalassaemia patients than for S/C patients, and that ACS may be a recurrent complication. Here, it is noteworthy that 19 patients experienced two or more episodes of ACS during the 2.5-year study period, highlighting the risk of subsequent ACS when a first episode has occurred. This observation should prompt physicians to carefully monitor these patients as soon as they arrive at the emergency department after a VOC. Some patients are more susceptible to ACS than others, and whether this is due to genetic or environmental factors is unclear. Moreover, secondary-onset ACS occurred despite the systematic use in our centre of incentive spirometry for every inpatient with VOC. While this study was conducted in an expert centre with careful attention to regular adaptation of disease modifying therapy to severity, only 61% of our patients were taking HU at the time of hospital admission (median [IQR] daily dose: 20.3 [16.5–25] mg/kg/day), even though this treatment is recommended in patients with a history of ACS. Ongoing disease-modifying treatment was noted only for 63% (17/27) of the recurrences. Moreover, the median mean corpuscular volume (MCV) in the 60 patients on chronic HU therapy was 87 [81.5–93] fL, and only 4 of them (7%) had a median MCV > 100 fL. These real-life data highlight the problem of patients sometimes refusing disease modifying therapy or having poor therapeutic compliance as suggested by MCV data collected in our study, despite systematic revaluation of treatment plan at discharge and proposal of therapeutic education sessions. However, our results seem better than those of the recent study by Minniti et al. in American SCD centres where 42% (28/66) of patients were on HU despite 62% (41/66) having a history of ACS.²⁷

Overall, fever was noted at least once for 54% of the episodes; this proportion is lower than in the literature (from 64% to 81%).^{6, 13, 24, 28, 29} This difference might be due to the small proportion of episodes with an infectious cause. As previously discussed, the standardized definition of ACS by the CSSCD and NACSSG does not require fever as clinical sign; temperature measurement is of course important, but this cannot be used as much of a medical decision-making criterion. In contrast, the prevalence of chest pain (73%) and crackles (64%) is consistent with the literature data.^{6, 13, 28} Interestingly, bronchial breathing was observed in 32% of episodes; to the best of our knowledge, this phenomenon has not previously been described in the literature on ACS. Although bronchial breathing is a classical lung auscultation finding in case of pulmonary consolidation,³⁰ it is sometimes difficult to recognize in the absence of training.³¹ These physical examination signs are very useful in low-resources countries (e.g. in Africa), where there is little access to chest imaging, and this clinical approach could also decrease the use of radiations in SCD patients (at least by avoiding systematic chest imaging in case of simple VOC), who are exposed from an early age.³²

Twenty-one of the 105 microbiological samples (20%) were positive. Sputum samples were most frequently collected (38%, 40/105) and mostly evidenced oral flora. It should be noted that our study was performed before the coronavirus disease 2019 pandemic. Furthermore, our microbiological work-up was guided by the patient's symptoms and was not systematic; hence, the positivity rate was probably overestimated. However, our present findings are similar to those of a recent French study of 61 adult patients with SCD and febrile ACS; microbiological samples were collected in all cases, and pathogens were documented in 12 of these (19.7%).³³ Our findings are also consistent with other literature reports, in which the microbial positivity rate ranged from 1% to 25%.^{13, 24, 34, 35} Overall, the microbiological characteristics of ACS are poorly documented, even when systematic, in-depth microbiological work-up is performed.¹³ In contrast, antibiotics were prescribed for 91% of the episodes of ACS: all febrile episodes and 84% (44/52) of the initially non-febrile episodes. Considering the low overall frequency of samples with a single documented bacterial species (9/105, 8.5%), these data may correspond to an overuse of antibiotics. Indeed, in adult patients with SCD, antibiotic therapy should be restricted to febrile and/or severe episodes of ACS and should be fine-tuned as a function of the bacteria detected.³³ Moreover, and as emphasized by the glomerular hyperfiltration observed in our patients at the time of ACS (median [IQR] eGFR: 136 [127–146] mL/min/1.73 m²), elevated doses of antibiotic might be required to achieve a sufficient plasma concentration and thus avoid treatment failure.³⁶ Specific clinical and pharmacokinetic studies are therefore needed to determine how best to manage empirical antibiotic therapy and optimize the corresponding dosage regimens (especially for beta-lactams), as well as randomized studies to address a key question about the indication of antibiotics in afebrile ACS, or about the duration of antibiotics in febrile and non-severe ACS.

Although a higher serum CRP concentration was significantly more frequent in secondary ACS, this result was not totally unexpected. Indeed, Veil et al. showed that a rapid increase in serum CRP (up to 60 mg/L) during the first 2 days was a normal trajectory for a non-complicated VOC.²⁶

RBC transfusion was performed in 50% of the episodes, which is similar to other observational studies of adult patients with SCD in non-ICU hospital wards,^{4, 13} but lower than the proportion reported in adults by Vichinsky et al. (61%).²⁴ Moreover, transfusion was required in 67% (29/43) of the severe cases; this proportion can be as high as 83% in the ICU.¹⁴ In France, an RBC transfusion sparing policy has been implemented for the past 10 years at least to limit iron overload and allo-immunization²; therefore, transfusions are discussed in case of ACS with severity criteria, or in patients in chronic transfusion program (indicated for various reasons, i.e. stroke, repeated VOC, multiple ACS, pulmonary arterial hypertension, etc.), countering potentially severe secondary allo-immunization and delayed hemolytic transfusion reaction. We did not note the reason of transfusion for each episode, but this transfusion policy did not appear to have an impact on mortality in our series. Indeed, in-hospital mortality rate was 0.95% (1/105), which is much lower than the value of 7% reported by Vichinsky et al.,²⁴ or the 1.6% noted by Allareddy et al. for over 24 000 hospitalizations for ACS in the USA.¹²

The most frequent radiological findings in our series are consistent with the literature data.^{6, 13, 37} Lung CT data were available for 57% of the episodes of ACS but only 2 of the 60 (3%) evidenced PE. This prevalence of PE is lower than 12%–17% observed in two recent French studies of ICU patients with severe ACS,^{38, 39} although the discrepancy might be due to differences in severity. This prevalence is also lower than the value of 9.8% reported by Vichinsky et al., although the researchers did not have CT data for all episodes.²⁴ It should be borne in mind that a causal relationship between PE and ACS (occurrence or severity) has not been clearly established. Despite these high prevalence rates (especially in ICU studies), we note that the ACS-specific mortality rate among adult with SCD has fallen over the last few decades, although PE may not always be looked for, especially in non-ICU wards, and therefore undertreated. Furthermore, ACS-specific mortality is more attributable to acute respiratory distress syndrome and multiorgan failure than to pulmonary arterial thrombosis.¹⁴ Lastly, imaging cannot show whether the PE is caused by blood clots or is linked to sickled RBC aggregates, and definitive diagnoses cannot be made for the older post-mortem studies.^{40, 41}

The main strengths of our study were the comprehensive, time-of-onset-based description of a large series of consecutive ACS episodes in adult patients with SCD and the homogeneous application of diagnostic criteria in a national SCD referral centre (previous prospective studies of ACS, especially those performed in emergency departments (which can complicate data collection and interpretation), might have included a small, selected subgroup of the potentially eligible patients). In contrast, retrospective collection (with missing data) and the absence of comparison of ACS episodes as a function of the time since the start of the VOC (which was not part of our dataset collection) constitute study limitations.

CONCLUSION

We found that most cases of ACS occurred a few days after hospital admission for a VOC but that it was sometimes already present on admission. Secondary and early-onset forms of ACS do not appear to differ significantly. Disease-modifying treatments should be revaluated after each ACS episode because the recurrence rate is high. Moreover, in order to counter the rise in antibiotic resistance, evidence-based antimicrobial stewardship and optimized dosage regimens are needed; although fever is frequent in ACS, infectious triggers are rare and the prognosis is good.

AUTHOR CONTRIBUTIONS

G. Cheminet and J.-B. Arlet designed the study and wrote the manuscript. G. Cheminet and D. Khimoud collected the data. A. Brunetti and A.-S. Jannot performed the analyses. J.-B. Arlet, B. Ranque, J. Pouchot, A. Michon and E. Flamarion cared for patients. All authors contributed to data interpretation, revised the manuscript for critical content and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

None of the authors report any conflicts of interest with regard to the present study.