In September 2021, a 6-year-old boy of Chadian descent, followed in our sickle cell disease (SCD) referral center for a severe form of homozygous SCD, was hospitalized in the Pediatrics department for a multifocal vaso-occlusive crisis (VOC) that started 24 h earlier. Prior medical history included subtotal splenectomy with cholecystectomy at age of 3 years due to recurrent splenic sequestrations, 20 episodes of VOC since the age of 9 months, including 4 in the previous year, and two episodes of acute chest syndrome (ACS) in 2019. Background treatment consisted of prophylactic penicillin, folic acid supplementation, and hydroxyurea (23 mg/kg/day) started at age 2 years. At admission, the patient presented no fever, no dyspnea, and oxygen saturation (SpO2) at 100%. He was treated with intravenous hydration and morphine, administered by patient-controlled analgesia. During the first day of hospitalization, he developed ACS characterized by fever with acute respiratory symptoms (superficial tachypnea, SpO2 at 88%, and decreased basal breath sounds) associated with bilateral pulmonary infiltrates on chest radiography. Antibiotic therapy with ceftriaxone was started and the patient was admitted to the intensive care unit (ICU) for noninvasive ventilation. Laboratory findings were: hemoglobin 6.7 g/dl, reticulocytes 389 × 109/L, leukocytes 8.6 × 109/L, platelets 245 × 109/L, C-reactive protein (CRP) 155 mg/L (normal range 0–6 mg/L), and lactate dehydrogenase 1269 U/L (normal range 192–321 U/L). Real-time reverse transcription-polymerase chain reaction (PCR) of nasopharyngeal swabs was negative for SARS-CoV-2 while respiratory multiplex PCR was positive for rhinovirus/enterovirus. PCR detection of Mycoplasma pneumoniae and urinary antigen test for Streptococcus pneumoniae were negative, as were blood and respiratory bacterial cultures. Despite initial red blood cell transfusion, the patient developed acute respiratory distress syndrome (ARDS) and was intubated on day 4 after undergoing a red cell exchange transfusion. Symptomatic treatment of ARDS included prone positioning and protective ventilation with tidal volume 5 ml/kg, respiratory rate 35 breaths per minute, PEEP 11 cmH2O, and maximal FiO2 90%. On day 5, inhaled nitric oxide (maximum 20 ppm, during 2 days) was introduced for isosystemic pulmonary hypertension (without pulmonary embolism on computed tomography pulmonary angiography) and norepinephrine was administered (0.08 μg/kg/min, during 5 days) for arterial hypotension. Interleukin (IL)-6 measurements in the golden tracheal secretions and in the pleural fluid on day 5 (pleural effusion puncture showing an exudate with negative bacterial culture) revealed dramatically high values (>40 000 pg/ml, normal range 0–10 pg/ml). In contrast, plasma IL-6 values were much lower but still increased at 204 pg/ml (normal range 0–10 pg/ml) with a CRP of 252 mg/L. On day 6, because of the severity of the disease and based on our previous experience of tocilizumab in an SCD child with ACS and COVID-19,1 intravenous tocilizumab (8 mg/kg) was administered. On day 7, a chest drainage was required for an increased right pleural effusion and allowed to discharge 300 ml of noninfected yellow-citrus liquid. On day 8, 36 h after tocilizumab administration, the patient was extubated and placed on noninvasive ventilation, which was stopped the next day due to a very rapid favorable respiratory evolution. Oxygen therapy was weaned on day 11 and the patient was discharged from the ICU (Figure 1).

Case timeline with key clinical events and levels of CRP. CRP, C-reactive protein; ICU, intensive care unit; iNO, inhaled nitric oxide; NIV, noninvasive ventilation; O2, oxygen

ACS is one of the most frequent and serious complications of SCD patients, representing the first cause of hospitalization and mortality in ICU. Several factors may contribute to its development, and include inflammation secondary to pulmonary infarction, viral and bacterial infections, hypoventilation secondary to pain during VOC, fat embolisms, and thrombosis. However, in the majority of cases, and particularly in severe forms with acute respiratory distress, the pathogenesis remains misunderstood. Therapeutic options are currently limited to oxygen and ventilation support, physiotherapy, analgesics, intravenous hydration, transfusion, empiric antibiotic treatment, and preventive anticoagulation. In the last years, a key role of inflammation induced by ischemia/reperfusion and hemolysis has been described in SCD pathophysiology, possibly mediated by activation of vascular endothelium and innate immune cells.2 We recently reported a major increase in IL-6, unlike other main pro-inflammatory cytokines, in the sputum and bronchoalveolar fluid from SCD children during ACS.3 These values were more than 150-fold higher than those observed in plasma, suggesting a predominant local inflammation over systemic inflammation. Furthermore, patients with the highest sputum IL-6 values had the most severe forms of ACS, suggesting a positive correlation between IL-6 concentrations and ACS severity. Our findings in this patient with an extremely severe form of ACS and dramatically high IL-6 levels (out of range and the highest observed in our cohort) in endotracheal and pleural fluids, in contrast to much lower plasma levels, are consistent with our prior observations and suggest that IL-6 is not only produced in the airways during ACS but also in the lung parenchyma. During the COVID-19 pandemic, a very rapid favorable outcome was reported after administration of tocilizumab in a child and an adult with SCD hospitalized for ACS in the context of SARS-CoV-2 infection.1, 4 Although tocilizumab was used in both patients because of COVID-19, it may also have been effective because of the role of IL-6 in ACS pathophysiology. Notably, ACS shares many similarities with COVID-19 pneumopathy, in which tocilizumab has recently been shown to effectively prevent unfavorable outcomes with a very good safety profile and a decreased incidence of serious bacterial infections compared to placebo.5 Herein, we report for the first time the use of tocilizumab in an SCD patient with ACS unrelated to COVID-19. Although we cannot deduce that this treatment was solely responsible for the patient's favorable outcome, as other therapies, including erythropheresis, inhaled nitric oxide, and chest drainage may clearly have contributed, it should be noted that the respiratory evolution was particularly and rapidly favorable, with extubation 36 h after tocilizumab administration, and weaning from noninvasive ventilation the next day and from oxygen therapy 48 h later.

Current therapeutic strategies for ACS are mainly supportive and do not target pulmonary and systemic inflammation, although this is a major hallmark of the disease. Steroids have been shown in the past to reduce ACS severity (especially duration of oxygen therapy and length of hospitalization) but are not considered a good option as they increase the risk of severe secondary VOC and readmission.6 Our observation is the first to suggest a potential benefit of anti-human IL-6 receptor monoclonal antibody therapy in SCD patients during ACS, independently of SARS-CoV-2 infection. A double-blind, randomized, placebo-controlled, clinical trial of tocilizumab will be necessary to assess the efficacy and safety of this novel treatment for ACS.

The author declares that there is no conflict of interest.

All data are available on request from the corresponding author.