To the Editor:
De Luna et al
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).
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
(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.
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.
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.
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.
This correspondence received no specific grant from any funding agency in the public,
commercial, or not‐for‐profit sectors.
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
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