Page 218 - 2021_10-Haematologica-web

Letters to the Editor
Low incidence of COVID-19 severe complications in a large cohort of children with sickle cell disease: a protective role for basal interferon-1 activation?
Despite an initial expectation of severe COVID-19 in patients with sickle cell disease (SCD) due to their well- known susceptibility to infection-related acute respirato- ry distress syndrome, a low incidence of intensive care unit hospitalization and deaths were observed in SCD patients during the first outbreak of the pandemic.1 Regarding SCD children, it was unclear however, whether they were not prone to severe infection like their healthy peers or if they had been less exposed. A prospective outpatient survey of SARS-CoV-2 seropreva- lence and related symptoms in SCD children was under- taken to address this issue and confirmed indeed very low morbidity despite substantial exposure (18.5 % immunoglobulin G [IgG] seropositivity). Subsequent monitoring of IgG titers showed a rapid and dramatic decrease after 3 months. In order to further address the absence of vulnerability of SCD children regarding SARS- CoV-2 complications, we analyzed the type I interferon (IFN-I) signature and found that 80% had an abnormally high IFN-I signature. Altogether, the basal activation of this pathway may explain partial protection against SARS-CoV-2 severe complications in SCD children.
The outbreak of the SARS-CoV-2 infection hit France at the beginning of 2020 resulting in a national shut down mid-March 2020. By mid-May 2020, the viral cir- culation was considered under control and the first wave of COVID-19 was over. COVID-19 was found to be par- ticularly harmful in senior people and those presenting comorbidities and chronic illnesses. Regarding the gener- al pediatric population, it was soon established that COVID-19 infection resulted in a very mild course.
The IFN-I response constitutes the major first line of defense against viruses. IFN-1 (including IFN-α and IFN-b) activate a powerful antiviral defense program of hundreds of interferon-stimulated genes (ISG), which have the capacity to interfere with every step of viral replication.2 Conversely, an exacerbated inflammatory response has been associated with a highly impaired IFN- I response, characterized by low IFN-α production and activity in patients with severe COVID-19. A reduced type IFN-I signature in bronchoalveolar lavage macrophages was also demonstrated, altogether suggest- ing that IFN-I deficiency could be a hallmark of severe COVID-19.3
SCD was initially regarded as a disease potentially favoring poor outcome in case of SARS-CoV-2 infection because vaso-occlusive events are often triggered by infectious agents,4 particularly the acute chest syndrome (ACS), a severe acute respiratory distress syndrome. Previous viral epidemics like influenza H1N1 have been associated with increased morbidity and mortality in this population.5 Early reports of COVID-19 infection in SCD adult and pediatric patients were in line with expected severity.6 However, these reports focused on hospitalized patients with positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) and were hence potentially skewed towards severity. Moreover, comor- bidities such as obesity or diabetes were generally not collected, nor were the local socio-economic conditions such as access to care, that may further influence out- comes. Last, but not least, these reports did not address the overall exposure of SCD patients to SARS-CoV-2.
In order to decipher the actual vulnerability of SCD children to SARS-CoV-2, we set up a prospective outpa- tient survey of SARS-CoV-2 seroprevalence and clinical symptoms during the first wave of COVID-19 outbreak. This survey took place in the largest pediatric SCD center of the Parisian area (Robert Debré Hospital) during the period ranging from 11/05/2020 to 31/08/2020. Symptoms compatible with COVID-19 were collected (fever, cough, loss of taste or smell, myalgia, fatigue) for all members living in the same household. COVID-19 serology was based on the detection of the IgG anti- nucleocapsid of SARS-CoV-2 in serum by chemilumines- cent microparticle immuno assay (CMIA) (Architect- Abbott). A rate <0.49 was considered negative, a rate between 0.49 and 1.68 was considered intermediate, and a rate ≥1.68 was considered positive by the manufacturer, with a specificity of 100%.7
A total of 211 consecutive SCD children, all black Africans born in France, aged 1 to 19 years old (median age 11.25 years, interquartile range [IQR], 6.8-14.2) were analyzed, with 18.5 % (n=39) of them showing a positive SARS-CoV-2 serology. Clinical characteristics of patients are summarized in Table 1. Among seropositive patients, none had displayed symptoms except one who was hos- pitalized for mild vaso-occlusive symptoms with a favor- able outcome. This cohort displayed a higher seropreva- lence than that reported to date in children in Europe (0.8% among children aged 5-9 years-old, 9.6% among children aged 10-19 in Switzerland and 3.4% among chil- dren aged 5- 19 in Spain8,9) albeit possibly comparable to the general pediatric population living in the same area
Table 1. Patients’ characteristics. Patients
n (%)
Median age, years (range) Genotype
SS, n (%) SC, n (%) Sb+, n (%)
HU treatment
Yes, n (%)
No, n (%)
All 211 (100)
11.25 (1-19)
190 (90) 12 (5,7) 9 (4.3)
146 (69.2) 65 (30.8)
Positive SARS-CoV-2 serology 39 (18.5)
11.84 (2-19)
35 (89.7) 3 (7.7) 1 (2.6)
25 (64.1) 14 (35.9)
Intermediate SARS-CoV-2 serology 4 (1.9)
11.55 (6-17)
3 (75) 0 (0) 1 (25)
3 (75) 1 (25)
Negative P SARS-CoV-2 serology
168 (79.6)
10.99 ns (1-19)
152 (90.5) ns 9 (5.3)
7 (4.2)
118 (70.2) ns 50 (29.8)
ns: not significant; HU: hydroxyurea.
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haematologica | 2021; 106(10)