β-Thalassemia is the most prevalent single gene blood disorder, while the assessment of its susceptibility to coronavirus disease 2019 (COVID-19) warrants it a pressing biomedical priority.
1. Introduction
Identifying medical conditions with a high or potentially deadly impact on the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a critical initial step towards containment of associated morbidity and mortality risks. Given that viral stress from SARS-CoV-2 elicits anabolic responses supported by increasing blood pressure to meet enhanced oxygen needs of vital organs and organ systems, hypoxemia is rendered a high-risk medical condition
[1,2][1][2]. As the most common blood disorder affecting approximately one third of the global population, anemia presents a low tolerance to hypoxemia and may have either acquired polysystemic or inherited poly- or monogenic background
[3]. Monogenic anemia—which is caused by abnormal hemoglobin—is a rather prevalent medical disorder with 270 million carriers worldwide
[4,5,6][4][5][6]. β-Thalassemia is the most common inherited single gene disorder in the world. Approximately one-third of all hemoglobinopathies and/or nearly 1.5% of the global population carry the β-thalassemia trait
[7]. In this context, β-thalassemia heterozygosity is a strong candidate condition for assessing an individual’s susceptibility to COVID-19.
2. ReAssultociations
Association of β-thalassemia heterozygosity with severe and critical COVID-19 symptoms
.
Considering the clinical spectrum of COVID-19 as a primary outcome, patients were categorized into three groups (asymptomatic and mild/ moderate/ severe and critical). No difference in chest X ray or CT scan was observed among study participants. In univariate analysis, sex (
p = 0.047), age (
p < 0.001), atrial fibrillation (
p = 0.022), coronary disease (
p = 0.041), hyperlipidemia (
p = 0.014), hypertension (
p < 0.001), and being heterozygous for thalassemia (
p = 0.004) were associated with severe COVID-19 symptoms (
Table 1). In multivariate analysis, male sex (
p = 0.023), increased age (
p < 0.001), and being heterozygous for thalassemia (
p = 0.002) were identified as independent risk factors for severe and critical clinical COVID-19 symptoms. Specifically, males had a 1.81 times (95% CI, 1.09 to 3.01) increased possibility for severe or critical clinical symptoms; increased age was associated with increased odds of severe and clinical symptoms with OR = 1.06 (95% CI, 1.04 to 1.08). A finding of great interest is that patients who were heterozygous for thalassemia were 2.89 times (95% CI, 1.49 to 5.62) more likely to have severe and critical clinical symptoms of COVID-19 (
Figure 1).
Table 1. Characteristics and COVID-19 clinical spectrum.
Severity |
Univariate |
Multivariate Ordinal Logistic Regression (Severe and Critical vs. Others) |
Mild (%) |
Moderate (%) |
Severe and Critical (%) |
p-Value |
p-Value |
aOR with 95% CI |
).
Table 2. Characteristics and mortality due to COVID-19.
Mortality |
Univariate |
MultivariateBinary Logistic Regression |
Yes (%) |
No (%) |
p-Value |
OR with 95% CI |
RR with 95% CI |
p-Value |
aOR with 95% CI |
Sex (M/F) |
34/34 |
67/46 |
52/22 |
0.047 * |
0.023 |
1.81 (1.09–3.01) |
Figure 2. Proportion of β-thalassemia heterozygotes relative to non-carriers regarding mortality due to COVID-19.
2.2. Admission of COVID-19 Infected β-Thalassemia Heterozygotes to the ICU
Regarding the requirement for ICU care, it was found through univariate analysis that age (
p = 0.03), respiratory disease (
p = 0.043), coronary disease (
p = 0.029) and hypertension (
p < 0.001) were associated with ICU admission (
Table 3). Through logistic regression analysis, patients with hypertension had 5.12 times (95% CI, 2.04 to 12.87) greater risk of requiring ICU care than patients without hypertension. On the contrary, hyperlipidemia was identified as a protective factor against ICU admission, with OR = 0.44 (95% CI, 0.21 to 0.94). Furthermore, in relation to the requirement for ICU care, being heterozygous for thalassemia had no effect on the possibility of admission to the ICU (
p = 0.505).
Table 3. Characteristics and ICU admission due to COVID-19.
ICU |
Univariate |
MultivariateBinary Logistic Regression |
Yes (%) |
No (%) |
p-Value |
OR with 95% CI |
RR with 95% CI |
p-Value |
aOR with 95% CI |
Sex (M/F) |
50/20 |
103/82 |
0.022 * |
1.99 (1.10–3.61) |
Sex (M/F) |
36/17 |
117/851.67 (1.06–2.64) |
0.036 |
2.09 (1.05–4.18) |
0.186 * |
1.54 (0.81–2.92) |
1.41 (0.84–2.37) |
0.305 |
1.45 (0.72–2.93) |
Age (median, IQR) |
51.5 (34) |
64.0 (17) |
70.5 (15) |
<0.001 ± |
<0.001 |
1.06 (1.04–1.08) |
Age (median, IQR) |
72.5 (15) |
61.0 (24) |
<0.001 ± |
- |
- |
<0.001 |
1.06 (1.03–1.09) |
0.030 ± |
- |
- |
0.649 |
Atrial Fibrillation |
17 (25.0) |
Age (median, IQR) |
66.2 (17) |
32 (28.3) |
33 (44.6) |
0.022 * |
0.787 |
0.92 (0.49–1.71) |
60.4 (24) | 1.01 (0.98–1.04) |
Atrial Fibrillation |
33 (47.1) |
49 (26.5) |
0.002 * |
2.48 (1.40–4.39) |
1.88 (1.28–2.78) |
Atrial Fibrillation |
21 (36.9) |
61 (30.2) |
0.191* |
1.52 (0.81–2.84)0.201 |
1.64 (0.77–3.48) |
1.39 (0.85–2.25) |
0.966 |
0.98 (0.43–2.23) |
Respiratory Disease |
5 (7.4) |
13 (11.5) |
Respiratory Disease |
14 (20.0)14 (18.9) |
0.104 * |
0.325 |
1.47 (0.68–3.15) |
18 (9.7) |
0.027 |
Respiratory Disease |
11 (20.8) * |
2.32 (1.08–4.97) |
1.74 (1.11–2.74) |
21 (10.4) |
0.043 * |
2.26 (1.01–5.04)0.297 |
1.61 (0.66–3.95) |
1.83 (1.05–3.17) |
0.205 |
1.80 (0.73–4.46) |
Coronary Disease |
7 (10.3) |
23 (20.4) |
20 (27.0) |
Coronary Disease | 0.041 |
Coronary Disease | * |
20 (28.6) |
16 (30.2) |
34 (16.8) |
0.029 * |
2.14 (1.07–4.27)0.955 |
1.02 (0.50–2.09) |
30 (16.2) |
0.027 * |
2.07 (1.08–3.96) |
1.64 (1.08–2.49) |
0.808 |
0.90 (0.39–2.09) |
1.77 (1.08–2.92) |
0.393 |
1.48 (0.61–3.59) |
Diabetes |
10 (14.7) |
25 (22.1) |
18 (24.3) |
0.331 * |
0.619 |
Diabetes | 0.85 (0.45–1.60) |
18 (25.7) |
35 (18.9) |
0.233 * |
1.48 (0.77–2.84) |
Diabetes |
10 (18.9) | 1.32 (0.85-2.05) |
0.758 |
0.87 (0.41–1.91) |
43 (21.3) |
0.699 * |
0.86 (0.40–1.85) |
0.87 (0.48–1.64) |
0.098 |
0.49 (0.21–1.14) |
Neoplasia |
7 (10.3) |
11 (9.7) |
11 (14.9) |
0.529 * |
0.209 |
0.61 (0.28–1.32) |
Neoplasia |
10 (14.3) |
Neoplasia |
4 (7.5)19 (10.3) |
0.367 * |
1.46 (0.64-3.31) |
25 (12.4) |
0.466 † |
0.58 (0.19–1.74)1.30 (0.75–2.24) |
0.395 |
0.67 (0.26–1.70) |
0.64 (0.25–1.63) |
0.102 |
0.37 (0.11–1.22) |
Hyperlipidemia |
21(30.9) |
60 (53.1) |
32 (43.2) |
0.014 |
Hyperlipidemia | * |
0.138 |
0.65 (0.37–1.15) |
30 (42.9) |
83 (44.9) |
Hypertension |
24 (35.3) |
62 (54.9) |
56 (75.7) |
<0.001 * |
0.104 |
1.67 (0.90–3.08) |
0.773 * |
0.92 (0.53–1.61) |
0.94 (0.63–1.41) |
0.008 |
0.38 (0.19–0.78) |
Hypertension |
52 (74.3) |
90 (48.6) |
<0.001 * |
3.05 (1.66–6.60) |
2.30 (1.43–3.70) |
0.198 |
1.67 (0.77–3.62) |
β-Thalassemia Heterozygotes |
5 (7.4) |
19 (16.8) |
21 (28.4) |
0.004 * |
0.002 |
2.89 (1.49–5.62) |
Figure 1. Proportion of β-thalassemia heterozygotes relative to non-carriers regarding clinical symptoms to COVID-19.
2.1. Association of β-Thalassemia Heterozygotes with Mortality Due to COVID-19
Regarding mortality associated with COVID-19 infection, in univariate analysis sex (
p = 0.022), age (
p < 0.001), atrial fibrillation (
p = 0.002), respiratory disease (
p = 0.027), coronary disease (
p = 0.027), hypertension (
p < 0.001), and being heterozygous for thalassemia (
p = 0.005) were associated with mortality (
Table 2). In logistic regression analysis, male patients had a 2.09 times (95% CI, 1.05 to 4.18) greater possibility of dying and patients with increased age were 1.06 times (95% CI, 1.03 to 1.09) more likely to die. It is worth noting that hyperlipidemia plays a beneficial role in COVID-19 mortality, as the odds ratio of mortality in patients with hyperlipidemia is 0.65 (95% CI 0.37–1.15). It should be highlighted that patient who are heterozygous for thalassemia have a 2.79 times (95% CI, 1.28 to 6.09) greater possibility of dying than other patients (
Figure 2
Hyperlipidemia |
22 (41.5) |
91 (45.0) |
0.644 * |
0.87 (0.47–1.60) |
0.89 (0.55–1.45) |
0.033 |
0.44 (0.21–0.94) |
Hypertension |
42 (79.2) |
100 (49.5) |
<0.001 * |
3.90 (1.90–7.99) |
3.04 (1.64–5.63) |
0.001 |
5.12 (2.04–12.87) |
β-Thalassemia Heterozygotes |
20 (28.6) |
25 (13.5) |
0.005 * |
2.56 (1.31–4.99) |
1.87 (1.24–2.80) |
β-Thalassemia Heterozygotes |
11 (20.8) | 0.010 |
2.79 (1.28–6.09) |
34 (16.8) |
0.505 * |
1.29 (0.61–2.77) |
1.22 (0.68–2.18) |
0.508 |
1.33 (0.57–3.06) |
2.3. Length of Hospitalization until Death
When comparing the median length of hospitalization (days) between patients being heterozygous for thalassemia and non-carriers, a statistically significant difference was observed (
p = 0.046) (
Figure 3). More specifically, the median duration of hospitalization among carriers and non-carriers was 12 and 17.5 days, respectively.
Figure 3. Days of hospitalization until death between carries and non-carriers.
2.4. Length of Hospitalization among Patients Who Survived
Regarding days of hospitalization among patients that survived COVID-19, the median duration was eight days for patients that were heterozygous for thalassemia and six days for non-carriers (
p = 0.014) (
Figure 4).
Figure 4.
Days of hospitalization between carries and non-carriers that survived.