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      Dramatic improvement after tocilizumab of severe COVID‐19 in a child with sickle cell disease and acute chest syndrome

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          Abstract

          To the Editor: De Luna et al 1 recently reported a favorable outcome of an acute chest syndrome (ACS) related to a SARS‐Cov‐2 infection treated with tocilizumab (TCZ), in a 45‐year‐old male patient with homozygous sickle cell disease (SCD). Following this successful observation, TCZ was administered to a teenage girl with SCD who developed a severe COVID‐19 associating ACS and pulmonary embolism. This 16‐year‐old girl has a severe form of homozygous SCD with bilateral ischemic retinopathy. Given the recurrence of vaso‐occlusive crises and abnormal transcranial doppler evaluations, she was treated with exchange transfusions from 5 to 11 years old, switched thereafter for hydroxyurea (22 mg/kg/day), with a favorable clinical outcome on vaso‐occlusive events. She had no history of ACS or pulmonary hypertension, and her respiratory function and chest radiography were previously normal. As recommended by the French authorities, because of the COVID‐19 outbreak, she was confined to her home with her parents. One week after her parents developed COVID‐19 symptoms (cough, fever and anosmia), she presented with an isolated fever treated by acetaminophen (without non‐steroidal anti‐inflammatory drugs). Seven days later, she developed an ACS characterized by an acute chest pain associated with a respiratory distress syndrome (SpO2 85%, superficial tachypnea 80/min, tachycardia 140/min). Real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) of nasopharyngeal swabs confirmed the SARS‐Cov‐2 infection. Levels of C‐reactive protein (355 mg/L), LDH (446 U/L) and D‐dimer (23 611 ng/mL) were increased. Given the tachycardia and elevation of D‐dimer in a SCD patient with COVID‐19, a pulmonary embolism was suspected, which is assumed to be more frequent in this context. Indeed, the computed tomography pulmonary angiography (CTPA) showed a bilateral pulmonary embolism complicating the ACS, and was compatible with COVID‐19 (bilateral consolidations with a halo sign on the right side, Figure S1). The patient was admitted to an intensive care unit (ICU) and required non‐invasive ventilation, red blood cell exchange transfusion followed by simple transfusion (hemoglobin nadir 6.4 g/dL), and anticoagulation. Because of the severity of the disease, and based on the experience of COVID‐19 in SCD adult patients,1, 2, 3 she also received one pulse of intravenous tocilizumab (TCZ, 8 mg/kg). 1 Plasma level of Interleukin (IL)‐6 was extremely high (629 pg/mL; normal <8.5 pg/mL) and was even higher after TCZ (724 pg/mL), in line with IL‐6 receptor blockade. To a much less extent, Tumor Necrosis Factor (TNF)‐α level was also elevated (32.5 pg/mL; normal <20 pg/mL); and, on the contrary, IL‐1β level was normal. The patient improved rapidly after TCZ treatment. Non‐invasive ventilation was stopped 4 days after TCZ, with no oxygen requirement thereafter, allowing the discharge from ICU. She was then referred to a medical unit where CTPA was repeated 5 days after TCZ. A dramatic improvement occurred with a disappearance on the right, and a decrease on the left of both the pulmonary embolism and the consolidation opacities, as previously described by Cellina et al. 4 (Figure S1). She was finally discharged from the hospital 11 days after admission, with an oral anticoagulant treatment to be continued for a total of 6 weeks. To our knowledge, this is the first reported use of TCZ in a COVID‐19 pediatric SCD patient. A single injection of the treatment was followed by a rapid improvement of the patient's respiratory status, together with a dramatic improvement of CTPA images. The etiology of ACS in children with SCD is often multifactorial, combining increased adhesion of sickle red cells to pulmonary microvasculature, pulmonary fat embolism, infarction, and infection, with an excessive inflammatory lung injury response in the presence of a damaged lung microvasculature. Infections are particularly common in children and frequent cause of ACS. The infectious microorganisms principally involved are Streptococcus pneumoniae, Chlamydia pneumoniae, Mycoplasma pneumoniae, Respiratory Syncytial Virus, Influenza virus (notably the H1N1 strain), and Erythrovirus. Besides, monocyte activation has been reported in SCD and is responsible for an enhanced production of pro‐inflammatory cytokines such as IL‐6,IL‐1β and TNF‐α, which contributes to vaso‐occlusion by promoting endothelial activation. 5 Many cytokines are elevated during steady‐state in SCD, and some of them, especially IL‐6, are further increased during vaso‐occlusive crises. To date, SARS‐Cov‐2 infection has been reported to cause ACS in four adult patients with SCD.1, 2, 3 We recently managed two teenage SCD patients with ACS and COVID‐19, including the presented case. Note, COVID‐19 is characterized by an inflammatory storm enhanced by T cells and monocytes. Large amounts of IL‐6 and TNF‐α are found in the plasma of infected patients. Tocilizumab, that targets IL‐6 receptors, was suggested to be effective on clinical evolution as well as on immune dysregulation. 6 After a single TCZ injection, serum IL‐6 level first increases rapidly before decreasing. In the absence of significant clinical improvement with persistence of an elevated IL‐6 level, a second and a third dose of TCZ can be administered after 12 and 24‐36 hours respectively. A favorable CT evolution has been previously described in an adult patient 7 days after two TCZ injections at 12 hour intervals. 4 Cytopenia and increased transaminases have been reported and need to be monitored. No adverse effect of TCZ was observed in our patient. In the context of the COVID‐19 outbreak, this diagnosis has to be evoked in case of ACS in patients with SCD, as both ACS and COVID‐19 pneumonia may present with similar features. The hyper‐inflammatory state caused by the SARS‐Cov‐2 infection may be enhanced by the pro‐inflammatory state of SCD. In such patients, TCZ seems to be safe and effective in adults as well as in children, in association with the usual treatment of severe ACS, including non‐invasive ventilation and blood exchange transfusion. CONFLICT OF INTEREST The authors declare no potential conflict of interest. FUNDING INFORMATION This correspondence received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors. Supporting information Figure S1. Computed tomography pulmonary angiography performed before (A, B) and 5 days after (C, D) Tocilizumab in a child with sickle cell disease, acute chest syndrome and COVID‐19. Click here for additional data file.

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          Vaso‐occlusive crisis and acute chest syndrome in sickle cell disease due to 2019 novel coronavirus disease ( COVID ‐19)

          In March 2020, during the 2019 novel coronavirus disease (COVID‐19) pandemic, caused by the newly emerged virus SARS‐CoV‐2, two patients with homozygous sickle cell disease (SCD) were admitted to our hospital with a painful vaso‐occlusive crisis (VOC) triggered by COVID‐19. Both patients had no flu‐like complaints characteristic of COVID‐19 during or preceding the VOC episode. Patient 1, a 24‐year‐old man with a previous medical history of minor pain episodes without indication for hospitalization, presented with severe right thoracic pain for 3 days. At presentation he had a temperature of 37.6°C; pulse of 76/minute, blood pressure of 106/65 mmHg; respiration rate of 18/min and a peripheral oxygen saturation (SpO2) of 97%. A non‐contrast chest CT showed double‐sided infiltrates without ground‐glass opacities or crazy paving and was not characteristic of COVID‐19 (Image 1A). Throat and nose swabs were negative for SARS‐CoV‐2. IMAGE 1 A, Chest CT imaging of patient 1 at first presentation to the emergency room (ER) showing infiltrates at basal fields. B, CT imaging at second ER presentation of patient 1, showing an increase in double‐sided infiltrates A diagnosis of VOC complicated by acute chest syndrome (ACS) was made. Treatment with oxygen, intravenous morphine with patient‐controlled analgesia (PCA), fluid replacement therapy and amoxicillin/clavulanic acid was initiated. After 1 day, the level of pain had decreased significantly (numeric rating scale decreasing from nine to two) and the patient remained respiratory stable throughout his hospital stay. He was discharged with amoxicillin/clavulanic acid continued at home. However, the next day he returned to the emergency room with increased pain, dyspnea, respiration rate of 20/minutes, SpO2 of 93% and a temperature of 38.9°C. Chest CT imaging showed progression of the double‐sided infiltrates in the lower lobes of the lungs (Image 1B). A second PCR, this time of a sputum sample, was positive for SARS‐CoV‐2. He was treated with oxygen (up to 5 L/min) and morphine (PCA) while amoxicillin/clavulanic was continued. The patient had a smooth recovery, without a need for exchange transfusion. He was discharged again after 3 days and was instructed to stay at home (in isolation) until 24 hours after becoming completely symptom‐free. Patient 2, a 20‐year‐old woman with a history of frequent VOCs presented with severe pain of the back and extremities for 1 day. She had no respiratory or gastro‐intestinal complaints. Because of a dip in SpO2 to 88% after a 100 μg parenteral fentanyl bolus in the ambulance, the suspicion of COVID‐19 rose which led to performing a chest CT and a throat and nose swab for a SARS‐CoV‐2 PCR. While the CT imaging did not show any pulmonary abnormalities, the PCR was positive for SARS‐CoV‐2. She remained hospitalized to treat her VOC without developing any respiratory symptoms. The World Health Organization (WHO) recently declared SARS‐CoV‐2 infection a pandemic. Severe respiratory illness occurs in approximately 15%‐20% of infected patients. 1 As of March 31, 2020, 800.049 laboratory‐confirmed cases and 38.714 deaths have been documented globally. 2 In SCD, COVID‐19 can potentially cause severe (pulmonary) complications, either by directly causing severe pneumonia or by triggering a VOC and/or ACS. While further experience regarding the clinical presentation of COVID‐19 in SCD needs to be awaited, the following important points need to be taken into consideration based on the above described patients. Similar to what we know from other viral infections,3, 4 SARS‐CoV‐2 can also cause ACS in SCD. Furthermore, as can be seen in patient 1, an ACS can develop without the typical pulmonary complications that can be seen with COVID‐19. Both patient 1 and especially patient 2 illustrate that COVID‐19 might trigger a VOC without the presence of flu‐like symptoms of COVID‐19. With respect to diagnosis, the history of patient 1 illustrates the low sensitivity of the PCR of the throat and nose swabs in the primary diagnosis of COVID‐19, which is estimated to be around 70%. We therefore suggest to perform a second PCR, preferably on a sputum sample, and non‐contrast chest CT imaging when there is no alternative explanation for VOC or when the clinical suspicion for COVID‐19 remains high. Based on these two patients, at our center we decided to include SARS‐CoV‐2 PCR in the evaluation of SCD patients presenting with VOC.
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            COVID-19 Pneumonia as a Cause of Acute Chest Syndrome in an Adult Sickle Cell Patient

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              Author and article information

              Contributors
              harriet.corvol@aphp.fr
              Journal
              Am J Hematol
              Am. J. Hematol
              10.1002/(ISSN)1096-8652
              AJH
              American Journal of Hematology
              John Wiley & Sons, Inc. (Hoboken, USA )
              0361-8609
              1096-8652
              16 May 2020
              Affiliations
              [ 1 ] Department of General Pediatrics Center for Sickle Cell Disease, Trousseau Hospital, Assistance Publique ‐ Hôpitaux de Paris (AP‐HP), Sorbonne Université Paris France
              [ 2 ] Pediatric Intensive Care Unit Necker‐Enfants‐Malades Hospital, AP‐HP, Université de Paris Paris France
              [ 3 ] Imaging Department Trousseau Hospital, AP‐HP, Sorbonne Université Paris France
              [ 4 ] Department of General Pediatrics and Pediatric Infectious Diseases Reference Center for Sickle Cell Disease, Necker‐Enfants‐Malades Hospital, AP‐HP, Université de Paris Paris France
              [ 5 ] Pediatric Pulmonology Department Trousseau Hospital, AP‐HP, Sorbonne Université Paris France
              Author notes
              [* ] Correspondence

              Harriet Corvol, Pediatric Pulmonology Department, Trousseau Hospital, 26 Avenue du Dr Netter, 75012 Paris, France.

              Email: harriet.corvol@ 123456aphp.fr

              Article
              AJH25855
              10.1002/ajh.25855
              7267654
              32358817
              © 2020 Wiley Periodicals, Inc.

              This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

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              Figures: 0, Tables: 0, Pages: 2, Words: 1374
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              Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:03.06.2020

              Hematology

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