Risk-score based strategy to minimize antibiotic exposure in children with sickle cell disease and fever

Abstract Severe bacterial infections (SBI) have become less frequent in children with sickle cell disease (SCD) in the last decades. However, because of their potential risk of SBI, they usually receive empirical therapy with broad-spectrum antibiotics when they develop fever and are hospitalized in many cases. We performed a prospective study including 79 SCD patients with fever [median age 4.1 (1.7–7.5) years, 78.5% males; 17 of the episodes were diagnosed with SBI and 4 of them were confirmed] and developed a risk score for the prediction of SBI. The optimal score included CRP > 3 mg/dl, IL-6 > 125 pg/ml and hypoxemia, with an AUC of 0.91 (0.83–0.96) for the prediction of confirmed SBI and 0.86 (0.77–0.93) for possible SBI. We classified the patients in 3 groups: low, intermediate and high risk of SBI. Our risk-score based management proposal could help to safely minimize antibiotic treatments and hospital admissions in children with SCD at low risk of SBI.

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Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease

Blood ◽

10.1182/blood.2020005687 ◽

2020 ◽

Vol 136 (5) ◽

pp. 623-626 ◽

Cited By ~ 3

Author(s):

Ruta Brazauskas ◽

Graziana M. Scigliuolo ◽

Hai-Lin Wang ◽

Barbara Cappelli ◽

Annalisa Ruggeri ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Risk Score ◽

Unrelated Donor ◽

Cell Disease ◽

Event Free Survival ◽

Matched Unrelated Donor ◽

Free Survival ◽

Matched Sibling

Abstract We developed a risk score to predict event-free survival (EFS) after allogeneic hematopoietic cell transplantation for sickle cell disease. The study population (n = 1425) was randomly split into training (n = 1070) and validation (n = 355) cohorts. Risk factors were identified and validated via Cox regression models. Two risk factors of 9 evaluated were predictive for EFS: age at transplantation and donor type. On the basis of the training cohort, patients age 12 years or younger with an HLA-matched sibling donor were at the lowest risk with a 3-year EFS of 92% (score, 0). Patients age 13 years or older with an HLA-matched sibling donor or age 12 years or younger with an HLA-matched unrelated donor were at intermediate risk (3-year EFS, 87%; score, 1). All other groups, including patients of any age with a haploidentical relative or HLA-mismatched unrelated donor and patients age 13 years or older with an HLA-matched unrelated donor were high risk (3-year EFS, 57%; score, 2 or 3). These findings were confirmed in the validation cohort. This simple risk score may guide patients with sickle cell disease and hematologists who are considering allogeneic transplantation as a curative treatment relative to other available contemporary treatments.

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Procalcitonin to Reduce Antibiotic Exposure during Acute Chest Syndrome in Adult Patients with Sickle-Cell Disease

Journal of Clinical Medicine ◽

10.3390/jcm9113718 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3718

Author(s):

Keyvan Razazi ◽

Ségolène Gendreau ◽

Elise Cuquemelle ◽

Mehdi Khellaf ◽

Constance Guillaud ◽

...

Keyword(s):

Sickle Cell Disease ◽

Bacterial Infection ◽

Sickle Cell ◽

Major Complication ◽

Adverse Outcomes ◽

Acute Chest Syndrome ◽

Antibiotic Exposure ◽

Cell Disease ◽

Intervention Phase ◽

Entire Cohort

Acute chest syndrome (ACS) is a major complication of sickle-cell disease. Bacterial infection is one cause of ACS, so current guidelines recommend the routine use of antibiotics. We performed a prospective before–after study in medical wards and an intensive-care unit (ICU). During the control phase, clinicians were blinded to procalcitonin concentration results. We built an algorithm using the obtained measurements to hasten antibiotic cessation after three days of treatment if bacterial infection was not documented, and procalcitonin concentrations were all <0.5 μg/L. During the intervention period, the procalcitonin algorithm was suggested to physicians as a guide for antibiotic therapy. The primary endpoint was the number of days alive without antibiotics at Day 21. One-hundred patients were analyzed (103 ACS episodes, 60 in intervention phase). Possible or proven lung infection was diagnosed during 13% of all ACS episodes. The number of days alive without antibiotics at Day 21 was higher during the intervention phase: 15 [14–18] vs. 13 [13,14] days (p = 0.001). More patients had a short (≤3 days) antibiotic course during intervention phase: 31% vs 9% (p = 0.01). There was neither infection relapse nor pulmonary superinfection in the entire cohort. A procalcitonin-guided strategy to prescribe antibiotics in patients with ACS may reduce antibiotic exposure with no apparent adverse outcomes.

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Developing a risk-based composite neurologic outcome for a trial of hydroxyurea in young children with sickle cell disease

Clinical Trials ◽

10.1177/1740774518807160 ◽

2018 ◽

Vol 16 (1) ◽

pp. 20-31

Author(s):

James F Casella ◽

Robert J Adams ◽

Donald J Brambilla ◽

John J Strouse ◽

Pia Maier ◽

...

Keyword(s):

Relative Risk ◽

Sickle Cell Disease ◽

Risk Reduction ◽

Sickle Cell ◽

Risk Score ◽

Relative Risk Reduction ◽

Phase Iii ◽

Motor Deficit ◽

Composite Outcome ◽

Cell Disease

Background Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial. Methods In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the “Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial” (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome. Results In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well. Conclusion This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study.

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A clinical risk score for pulmonary artery thrombosis during acute chest syndrome in adult patients with sickle cell disease

British Journal of Haematology ◽

10.1111/bjh.14914 ◽

2017 ◽

Vol 179 (4) ◽

pp. 627-634 ◽

Cited By ~ 2

Author(s):

Anaïs Winchenne ◽

Jérôme Cecchini ◽

Jean-François Deux ◽

Nicolas De Prost ◽

Keyvan Razazi ◽

...

Keyword(s):

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Risk Score ◽

Adult Patients ◽

Acute Chest Syndrome ◽

Clinical Risk Score ◽

Cell Disease ◽

Clinical Risk ◽

Artery Thrombosis

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Incentive Spirometry to Prevent Acute Chest Syndrome in Adults with Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-117450 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3660-3660

Author(s):

Bart J. Biemond ◽

Charlotte F.J. Van Tuijn ◽

Aafke E. Gaartman ◽

Erfan Nur ◽

A. W. Rijneveld

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Risk Score ◽

Predictive Value ◽

Plasma Levels ◽

Adult Patients ◽

Acute Chest Syndrome ◽

Control Group ◽

Cell Disease ◽

Incentive Spirometry

Abstract Introduction: Amongst patients with sickle cell disease (SCD) the leading cause of death is the acute chest syndrome (ACS). This pneumonia-like complication frequently occurs during or shortly after a vaso-occlusive crisis (VOC). In pediatric patients hospitalized for VOC, incentive spirometry has demonstrated to prevent the development of ACS. This study was designed to determine if a comparable effect of incentive spirometry can be demonstrated in adult patients with SCD. Furthermore, we aimed to validate the ability of the Bartolucci score to identify patients at risk of ACS and assessed the value of procalcitonin as a potential biomarker for ACS . In addition, clinical characteristics and laboratory results were determined to identify potential risk factors. Methods: In this multicenter prospective randomized trial, we included consecutive adult patients (≥18 yr) admitted for VOC presenting with chest or back pain above the diaphragm. Patients were randomly assigned to spirometry or control group. Patients presenting with ACS were excluded. A chest radiograph was performed 5 days after admission, or sooner when clinically indicated, in order to diagnose pulmonary abnormalities. ACS was defined as a new infiltrate/atelectasis combined with pulmonary symptoms. At presentation, procalcitonin plasma levels were assessed and the Bartolucci risk score was calculated to determine to the risk of developing ACS for each patient. In addition, clinical and laboratory parameters were compared between patients with and without ACS during admission. Results: In total 66 episodes of hospitalization for VOC in 48 patients were included. Median age was 26 years and 46 of the hospitalizations concerned patients with a severe genotype (HbSS/HbSβ0 thalassemia) versus 20 hospitalization with a mild genotype (HbSC/HbSβ+thalassemia). The overall incidence of ACS in this study cohort was 19.7%. In the spirometry group, ACS was diagnosed in 5/34 (14.7%) hospitalizations compared to 8/32 (25%) hospitalizations in the control group (OR 0.5 [0.15-1.8]; P=.293). Twelve of the 13 ACS episodes occurred in patients with a severe genotype. The Bartolucci risk score could be calculated for 50 hospitalizations. The scores area under the curve (AUC) was 0.747 (P=.013), with a negative predictive value (NPV) of 94% and a positive predictive value (PPV) of 31%. No difference in procalcitonin plasma levels were found between patients with and patients without ACS (0.52 ± 1.56 μg/ml versus 0.56 ± 1.44 μg/ml, respectively). At baseline, hemoglobin levels were significantly lower while LDH plasma levels, leukocyte and platelet counts were significantly higher in ACS hospitalizations as compared to non-ACS hospitalizations. Patients who developed ACS showed significantly more documented fever during admission (61.5% vs 17.0%) and a longer length of hospital stay (median 10.0 days vs 4.5 days). Conclusion: Incentive spirometry did not significantly reduce the development of ACS in this prospective study in adult patients with SCD admitted with VOC and pain above the diaphragm. Procalcitonin plasma levels and the Bartolucci score could not accurately identify patients that at risk to develop ACS, but a low score appeared to be a reliable tool to identify patients with a low risk of ACS. Disclosures No relevant conflicts of interest to declare.

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2396. Clostridium difficile Infection is Children with Sickle Cell Disease: An Uncommon Entity

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2074 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S827-S828

Author(s):

Philip Lee ◽

Vijaya L Soma ◽

Carlos Cruz ◽

Deepa Manwani ◽

David L Goldman

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Positive Test ◽

Cell Transplant ◽

Antibiotic Exposure ◽

Cell Disease ◽

Chi Square ◽

Intestinal Dysbiosis ◽

Penicillin Prophylaxis

Abstract Background Children with sickle cell disease (SCD) have numerous risk factors for intestinal dysbiosis, including frequent hospitalization, iron overload, antibiotic exposure including penicillin prophylaxis, hypoxia, and altered gut permeability. Many of these conditions are also established risk factors for C. difficile infection (CDI); however, the incidence of CDI in children with SCD has not been characterized. Methods We performed a 10-year retrospective review from 1/2008–December 2017. Patients who qualified with CDI were either admitted or within 2 weeks of discharge from our site and had a positive test. A positive test was defined as a positive glutamate dehydrogenase 1 test in conjunction with either a positive ELISA or a positive PCR for toxin. Three investigators independently reviewed if patients had active diarrhea during the time of their positivity. Patients excluded were <2 years old and patients undergoing a stem cell transplant (SCT) or irritable bowel disease (IBD) at the time of a positive test. Chi-square test with Yates correction, descriptive statistics were used when comparing groups<./p> Results Over a 10-year period (2008–2017), there were 5666 admissions for children with SCD, corresponding to 25,915 hospitalization days and 957 unique patients. The average age of this cohort at the time of admission was 10.6 ± 6.7 years; 51.7% were male. One patient qualified; a 12-year-old who developed diarrhea and abdominal pain after recent hospitalization for pneumonia (Figure 1). This yielded a CDI incidence of 0.39/10,000 patient-days or 0.18 cases per 1000 admissions (Table 1). There were 208 cases of CDI in non-SCD children, with an incidence of 5.53/10,000 patient-days (P < 0.001) or 2.77 cases per 1000 admissions (P < 0.001) (Table 2) during the study period. In 2015–2017, there were no cases of CDI in 957 SCD patients, of which 218 were on penicillin prophylaxis. Conclusion There is a very low incidence of CDI in children with SCD despite significant antibiotic exposure and other risk factors for intestinal dysbiosis. These findings are consistent with recent studies in adults (N Engl J Med 2019; 380:887–888) and suggest that sickle cell patients are somehow protected against CDI. Additional studies are needed to define the host and biome factors that confer this protection. Disclosures All authors: No reported disclosures.

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