Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19
Abstract
:1. Background
2. Methods
2.1. Study Design and Patients
2.2. Sample Size
2.3. Randomization
2.4. Blinding
2.5. Procedures
2.6. Clinical, Radiological, and Laboratory Monitoring
2.7. Data Management
2.8. Outcomes
2.9. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ACE2 | Angiotensin-converting enzyme 2 |
ALT | Alanine aminotransferase |
ANOVA | Analysis of variance |
AST | Aspartate aminotransferase |
CK | Creatine kinase |
COVID-19 | Coronavirus disease 19 |
CT | Computed tomography |
CTCAE | National Cancer Institute Common Terminology Criteria for Adverse Events |
ELISA | Enzyme-linked immunosorbent assay |
HCG | Human chorionic gonadotrophin |
HIV | Human immunodeficiency virus |
iC1e/K | Inhibitor of C1 esterase/kallikrein |
ICU | Intensive care unit |
LDH | Lactate dehydrogenase |
qSOFA | Quick sepsis-related organ failure score |
RT-PCR | Real-time polymerase chain reaction |
RTC | Randomized controlled trial |
TTCI | Time to clinical improvement |
References
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Parameter | SC | Icatibant | iC1e/K | p | All Patients |
---|---|---|---|---|---|
Female/male | 5/5 | 3/7 | 6/4 | 0.39 | 14/16 |
Age (y) | 48.9 ± 10.5 | 51.6 ± 9.1 | 54.4 ± 14.8 | 0.58 | 51.6 ± 11.5 |
BMI (kg/m2) | 29.6 ± 7.8 | 30.2 ± 5.1 | 32.3 ± 7.0 | 0.70 | 30.6 ± 6.7 |
BMI >30 | 4 | 4 | 6 | 0.59 | 14 (46%) |
BMI >25 <30 | 2 | 4 | 1 | 7 (23%) | |
Symptoms onset (d) | 8.8 ± 2.7 | 7.8 ± 2.2 | 8.1 ± 2.5 | 0.57 | 8.1 ± 2.5 |
Body temperature (°C) | 36.3 ± 0.5 | 36.0 ± 1.2 | 36.6 ± 0.6 | 0.41 | 36.4 ± 1.1 |
>37°C (n) | 2 | 2 | 2 | 6 | |
SatO2 (%) | 92.9 ± 3.3 | 90.7 ± 2.7 | 89.8 ± 7.2 | 0.35 | 91.4 ± 4.7 |
Lung CT score | 17.9 ± 7.8 | 16.0 ± 6.9 | 19.4 ± 6.4 | 0.60 | 17.8 ± 7.3 |
Systolic blood pressure (mmHg) | 117.4 ± 10.7 | 121.0 ±10.2 | 127.1 ± 26.0 | 0.51 | 124 ± 18 |
<90 mmHg (n) | 0 | 0 | 1 | 1 | |
Diastolic blood pressure (mmHg) | 75.5 ± 12.3 | 79.2 ± 10.4 | 75.4 ± 15.9 | 0.91 | 76.7 ± 12.7 |
<60 mmHg (n) | 0 | 0 | 0 | 0 | |
White cell count (×109/L) ¥ | 7.78 ± 4.39 | 7.76 ± 4.98 | 7.76 ± 2.78 | 0.99 | 7.76 ± 4.0 |
<4 × 109/L (n) | 2 | 2 | 1 | 5 (16.7%) | |
4–10 × 109/L (n) | 7 | 6 | 7 | 20 (66.7%) | |
>10 × 109/L (n) | 1 | 2 | 2 | 5 (16.7%) | |
Lymphocyte count (×109/L) ¥ | 1.08 ± 0.29 | 1.08 ± 0.39 | 1.37 ± 0.48 | 0.45 | 1.18 ± 0.48 |
<1 × 109/L (n) | 3 | 3 | 3 | 9 | |
>1 × 109/L (n) | 6 | 6 | 6 | 18 | |
Platelet count (×109/L) ¥ | 217.6 ± 55.8 | 217.5 ± 123.5 | 229.9 ± 98.2 | 0.97 | 221.7 ± 93.4 |
<100 × 109/L (n) | 0 | 1 | 0 | 1 | |
≥100 × 109/L (n) | 10 | 9 | 10 | 29 | |
Plasma glucose (mg/dL) ¥ | 176.8 ± 94.9 | 158.9 ± 91.8 | 182.4 ± 111.4 | 0.81 | 172.7 ± 96.2 |
<125 (mg/dL) (n) | 4 | 6 | 3 | 13 | |
>125 (mg/dL) (n) | 6 | 4 | 7 | 17 | |
Serum creatinine (mg/dL) ¥ | 0.9 ± 0.3 | 1.2 ± 0.9 | 0.9 ± 0.3 | 0.34 | 1.00 ± 0.61 |
<1.2 (mg/dL) (n) | 9 | 8 | 9 | 26 | |
>1.2 (mg/dL) (n) | 1 | 2 | 1 | 4 | |
AST (U/L) ¥ | 63.0 ± 54.0 | 82.7 ± 88.9 | 37.3 ± 12.7 | 0.13 | 61.8 ± 62.2 |
<40 (U/L) (n) | 4 | 3 | 4 | 11 | |
>40 (U/L) (n) | 6 | 7 | 5 | 18 | |
ALT (U/L) ¥ | 38.6 ± 35 | 76.7 ± 76.4 | 27.6 ± 13 | <0.01 | 48.3 ± 52.7 |
<40 (U/L) (n) | 7 | 2 | 8 | 17 | |
≥40 (U/L) (n) | 3 | 8 | 1 | 12 | |
LDH (U/L) ¥ | 308.7 ± 55.4 | 396.5 ± 135.2 | 376.5 ± 254.7 | 0.91 | 362.2 ± 176.0 |
<245 (U/L) (n) | 1 | 2 | 2 | 5 | |
≥245 (U/L) (n) | 7 | 8 | 8 | 23 | |
CK (U/L) ¥ | 282.7 ± 245.8 | 299.0 ± 359.2 | 123.0 ± 99.9 | 0.24 | 221.0 ± 213.5 |
<185 (U/L) (n) | 4 | 1 | 5 | 10 | |
≥185 (U/L) (n) | 3 | 1 | 1 | 4 | |
C-Reactive Protein (mg/L) ¥ | 123.2 ± 61.8 | 109.0 ± 81.4 | 110.9 ± 86.3 | 0.76 | 117.6 ± 74.3 |
<10 (mg/L) (n) | 10 | 10 | 9 | 29 | |
≥10 (mg/L) (n) | 0 | 0 | 0 | 0 |
Comorbidities at baseline | All patients (n:30) | SC (n:10) | Icatibant (n:10) | iC1e/K (n:10) | p-Value |
---|---|---|---|---|---|
Hypertension, n (%) | 15 (50) | 4 (40) | 4 (40) | 7 (70) | 0.30 |
Diabetes Mellitus, n (%) | 14 (46.7) | 5 (50) | 4 (40) | 5 (50) | 0.88 |
Obesity, n (%) | 13 (43.3) | 3 (30) | 4 (40) | 6 (60) | 0.39 |
Overweight, n (%) | 7 (23.3) | 2 (20) | 4 (40) | 1 (10) | -- |
Dyslipidemia, n (%) | 5 (16.67) | 1 (10) | 1 (10) | 3 (30) | -- |
Former smoker, n (%) | 4 (13.3) | 1 (10) | 1 (10) | 2 (20) | -- |
Hypothyroidism, n (%) | 2 (6.67) | 0 (0) | 0 (0) | 2 (20) | -- |
Asthma, n (%) | 1 (3.33) | 0 (0) | 0 (0) | 1 (10) | -- |
Current smoker, n (%) | 1 (3.33) | 1 (10) | 0 (0) | 0 (0) | -- |
Fibromyalgia, n (%) | 1 (3.33) | 0 (0) | 1 (10) | 0 (0) | -- |
SC | Icatibant | iC1e/K | p | All Patients | |
---|---|---|---|---|---|
TATD (days) | 10.5 ± 7.1 | 11.0 ± 8.9 | 14.2 ± 10.1 | 0.62 | 11.9 ± 8.6 |
TIICU (days) | 4.6 ± 8.9 | 6.2 ± 10.5 | 8.7 ± 11.8 | 0.71 | 6.5 ± 10.2 |
Deaths | 1 | 0 | 1 | 2 |
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Mansour, E.; Palma, A.C.; Ulaf, R.G.; Ribeiro, L.C.; Bernardes, A.F.; Nunes, T.A.; Agrela, M.V.; Bombassaro, B.; Monfort-Pires, M.; Camargo, R.L.; et al. Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19. Viruses 2021, 13, 309. https://doi.org/10.3390/v13020309
Mansour E, Palma AC, Ulaf RG, Ribeiro LC, Bernardes AF, Nunes TA, Agrela MV, Bombassaro B, Monfort-Pires M, Camargo RL, et al. Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19. Viruses. 2021; 13(2):309. https://doi.org/10.3390/v13020309
Chicago/Turabian StyleMansour, Eli, Andre C. Palma, Raisa G. Ulaf, Luciana C. Ribeiro, Ana Flavia Bernardes, Thyago A. Nunes, Marcus V. Agrela, Bruna Bombassaro, Milena Monfort-Pires, Rafael L. Camargo, and et al. 2021. "Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19" Viruses 13, no. 2: 309. https://doi.org/10.3390/v13020309
APA StyleMansour, E., Palma, A. C., Ulaf, R. G., Ribeiro, L. C., Bernardes, A. F., Nunes, T. A., Agrela, M. V., Bombassaro, B., Monfort-Pires, M., Camargo, R. L., Araujo, E. P., Brunetti, N. S., Farias, A. S., Falcão, A. L. E., Santos, T. M., Trabasso, P., Dertkigil, R. P., Dertkigil, S. S., Moretti, M. L., & Velloso, L. A. (2021). Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19. Viruses, 13(2), 309. https://doi.org/10.3390/v13020309