Simultaneous diagnosis of severe SARS-CoV-2 infection and sickle cell disease in two infants

During the ongoing pandemic of coronavirus disease 2019 (COVID-19), sickle cell disease (SCD) has been seen to be both a possible protective and an adverse prognostic factor^1–3. So far, there have been few case reports of COVID-19 leading to the diagnosis of sickle cell trait or SCD⁴ and, to our knowledge, none in the pediatric population.

Here we describe the first two infants in whom a severe SARS-CoV-2 infection revealed a hidden condition of SCD.

CASE 1

A previously healthy 9-month-old boy of Nigerian origin presented to the emergency department in critical condition with fever and severe respiratory distress.

Blood test showed neutrophilia (white blood cell count [WBC] 18.1×10⁹/L, with neutrophil count 14.1×10⁹/L), normocytic anaemia, haemoglobin (Hb) 6.5 g/dL, mean corpuscular volume (MCV) 78 fL, and a normal platelet (PLT) count. C-reactive protein (CRP) level was 5.1 mg/L, procalcitonin (PCT) 10.71 ng/mL, and lactate dehydrogenase (LDH) 1,346 UI/L. Chest X-ray (Figure 1) showed bilateral interstitial infiltrates with right medium-basal and left retro-cardiac consolidation.

Figure 1.

Chest X-ray of patient 1 at admission

Extensive bilateral interstitial infiltrates with right medium-basal and left retro-cardiac consolidation.

The child had tested positive for SARS-CoV-2 by nasopharyngeal swab, confirmed by broncho alveolar lavage (BAL) analysis.

The respiratory distress quickly worsened, requiring mechanical ventilation in the Intensive Care Unit (ICU). For progressive severe hypoxaemic respiratory failure, venovenous extracorporeal membrane oxygenation (VV-ECMO) was started. As supportive therapy, the patient received dexamethasone and intravenous immunoglobulins. On day 3, he started remdesivir.

The patient’s origins and clinical picture resembling an acute chest syndrome immediately raised the suspicion of a hidden haemoglobinopathy. Hb high performance liquid chromatography (HPLC) revealed sickle haemoglobin (HbS) 56% and fetal haemoglobin (HbF) 32.9%; after transfusion these dropped to 30% and 19.5%, respectively. Molecular analysis confirmed the homozygous state for HbS.

Red blood cell exchange transfusion was also started from day 5, to maintain HbS <30%. After 18 days, the patient’s pulmonary improvement allowed him to be weaned off VV-ECMO.

CASE 2

A previously healthy 20-month-old girl of Nigerian origin, presented to the emergency department in critical condition with fever, hypotonia and lethargy.

Blood test showed hypoglycaemia and normocytic anaemia (Hb 6 g/dL; MCV 79 fL) with normal WBCs and PLTs. CRP was 12.8 mg/L and PCT was 50 ng/mL.

Hb HPLC showed HbS 84% and HbF 7.6%. Molecular analysis confirmed the diagnosis of HbS homozygosis. Nasopharyngeal swab tested positive for SARS-CoV-2.

After 5 hours her clinical condition rapidly worsened with significant respiratory distress requiring mechanical ventilation and admission to the ICU. Chest X-ray showed interstitial infiltrates with no consolidation. SARS-CoV-2 was confirmed on BAL.

Laboratory tests were suggestive for sepsis and disseminated intravascular coagulation with thrombotic microangiopathy: PCT >400 ng/mL, CRP 37 mg/L, WBCs 18.1×10⁹/L, Hb 3.9 g/dL, PLTs 68×10⁹/L, LDH 2,112 UI/L, undetectable haptoglobin and schistocytes on blood smear, negative direct and indirect Coombs test. Blood culture resulted positive for Streptococcus pneumoniae. Meropenem, vancomycin and immunoglobulins were started. She subsequently received red blood cell transfusions to target Hb 10 g/dL and HbS <20%.

The child’s condition continued to worsen with severe renal failure requiring renal replacement therapy (CRRT). Her condition improved, and after 48 hours it was possible to interrupt CRRT. Mechanical ventilation was discontinued on day 11.

DISCUSSION

During the COVID-19 pandemic, the paediatric population in Italy has shown milder symptoms with little need for hospital care and few deaths⁵. Since March 2020, only five patients out of 65 admissions for SARS-CoV-2-related symptoms (7.7%) entered the ICU in our tertiary care paediatric hospital⁶.

Prognosis of SARS-CoV-2 infection in SCD is a subject of debate and there are few published data.

In a large international registry, the mortality rate is high (3.81%; 16 deaths out of 420 cases as of November 2^nd, mean age 24.2 years±14.98), but differs widely between paediatric and adult cases (0.6 vs 6.3%).⁷

Several hypotheses have been raised as to the potential protective factors: a pro-inflammatory status, asplenia, disease-modifying therapies such as hydroxyurea and blood transfusion^2–3. Our two cases developed a severe COVID-19 at diagnosis of SCD with negative history for any previous SCD-like event. If so, we could argue that full SCD phenotype, including a proinflammatory status, was not fully expressed at the moment of SARS-CoV-2 infection, preventing a potential protective effect.

The severe clinical course of our patients led us to consider endothelial dysfunction as the common result of different pathogenetic mechanisms. Endothelialitis in patients with COVID-19 has been demonstrated, probably as a consequence of direct infection of endothelial cells by virus through angiotensin converting enzyme 2 (ACE2). Viral replication causes inflammatory cell infiltration, endothelial cell apoptosis and microvascular prothrombotic effects⁸. In SCD, sickling determines intravascular haemolysis and the release of free haemoglobin which reduces nitric oxide bioavailability and induces the expression of adhesion molecules leading to activation of endothelial cells⁹. Endothelial involvement could also be identified as the main connection between the different clinical course observed in our two patients (Figure 2).

Figure 2.

Clinical timeline of the two sickle cell disease (SCD) infants

Endothelial involvement as the main connection between pulmonary impairment in case 1 and thrombotic microangiopathy in case 2. HbS: sickle haemoglobin; Hbf: fetal haemoglobin ; NC: nasal canula; HFNC: high flow nasal cannula; PCV: pressure control ventilation; HFOV: high frequency oscillatory ventilation; VV-ECMO: veno-venous extra corporeal membrane oxygenation; CRRT CVVHDF: continuous renal replacement

The co-infection of SARS-CoV-2 and Streptococcus pneumoniae is, to the best of our knowledge, a novel finding also for SCD. A bacterial infection is frequent among patients admitted to the ICU for acute respiratory failure related to SARS-CoV-2, with Pneumococcus responsible for around 20% of cases¹⁰. In our cases, it was difficult to determine the relative effect of the infections on lung findings as it was not possible to perform a computed tomography scan¹¹. However, the possibility of an exponential impact of both the infections and SCD on the development of respiratory failure is biologically plausible. Whether a preclinical diagnosis of SCD could have prevented the severity of the clinical course of our patients is unknown. However, we should consider that better control of the underlying haematological condition could have facilitated the early management and mitigated the severity of the manifestations.

Early diagnosis and screening for SCD is fundamental in order to educate and protect this population¹². Such a warning takes on even more importance if considered in the context of the current COVID-19 pandemic.