Portal de Periódicos da CAPES

Effect of polymerised type I collagen on hyperinflammation of adult outpatients with symptomatic COVID‐19

2022; Springer Science+Business Media; Volume: 12; Issue: 3 Linguagem: Inglês

10.1002/ctm2.763

2001-1326

Silvia Méndez‐Flores, Ángel A. Priego‐Ranero, Daniel Azamar‐Llamas, Héctor Olvera‐Prado, Kenia Ilian Rivas‐Redonda, Eric Ochoa‐Hein, Andric C. Perez‐Ortiz, Mario Enrique Rendón-Macı́as, Estefano Rojas‐Castañeda, Said Urbina‐Terán, Luis Septién‐Stute, Thierry Hernández‐Gilsoul, Adrián Andrés Aguilar‐Morgan, Dheni A. Fernández‐Camargo, Elizabeth Olivares‐Martínez, Diego F. Hernández‐Ramírez, Gonzalo Torres‐Villalobos, Janette Furuzawa‐Carballeda,

Long-Term Effects of COVID-19

Although dexamethasone is approved for the hyperinflammation treatment of hospitalised COVID-19 patients, non-hospitalised patients do not benefit from this therapy.1 A potential drug for treating COVID-19 patients is polymerised type I collagen (PTIC). A downregulator of pro-inflammatory cytokines, adhesion molecules (ELAM-1, VCAM-1, and ICAM-1), cyclooxygenase (Cox)-1 enzyme and the collagenases expression through the modulation of transcription of factor NF-kB.2-6 The intramuscular or subcutaneous administration of PTIC to patients with active RA (Phase II studies) improved the count of swollen joints and morning stiffness; 57% of patients achieved an ACR score of 50, and 30% had disease remission with this therapeutic combination. PTIC was safe and well-tolerated in long-term treatment, without adverse effects.7-9 A double-blind, randomised, placebo-controlled clinical trial evaluated the PTIC intramuscular administration's safety and efficacy on hyperinflammation, oxygen saturation and symptom improvement in adult symptomatic COVID-19 outpatients (https://www.medrxiv.org/content/10.1101/2021.05.12.21257133v1). Eighty-nine participants with a confirmed COVID-19 diagnosis (mild to moderate disease) were included from August 31 to November 7, 2020, and followed for 12 weeks. Patients were randomly assigned to receive either 1.5 ml of PTIC intramuscularly every 12 h for 3 days and then every 24 h for 4 days (n = 45) or a matching placebo (n = 44) (sample size is describe in Methodology S1). Demographics, clinical characteristics, coexisting conditions and symptoms are described in Table 1. Ninety-eight per cent of patients in the PTIC group and 95.5% in the placebo group were analysed by the intention-to-treat principle (Figure S1). Of 89 patients at baseline, 64 (72%) were being treated with acetaminophen, 28 (31.5%) with acetylsalicylic acid, 5 (5.6%) with antivirals and 36 (40.4%) with antibiotics. The use of acetaminophen (71% vs. 73%), acetylsalicylic acid (27% vs. 39%), antivirals (7% vs. 5%) and antibiotics (40% vs. 41%) were similar in the PTIC and placebo groups, respectively. No patients were treated with anticoagulants or steroids. Age (years), mean ± SD Median Range 48.5 ± 14.1 48.0 19.0–78.0 48.4 ± 14.4 47.0 19.0–77.0 48.6 ± 13.9 48.0 22.0–78.0 BMI (kg/m2), mean ±SD Median Range 28.0 ± 4.5 27.9 18.6–40.8 27.8 ± 4.5 27.9 18.6–40.3 28.2 ± 4.5 27.7 20.1–40.8 Baseline Guangzhou Severity Index, mean ± SD Median Range 87.6 ± 25.9 90.1 29.4–137.5 87.9 ± 30.2 92.0 29.4–135.1 87.3 ± 20.8 88.7 35.5–137.5 .4362 Baseline Chest CT Score 50% 53 (59.6) 20 (22.5) 27 (60.0) 8 (17.8) 5 (11.1) 3 (6.7) 26 (59.1) 12 (27.3) 12 (27.3) 0 (0.0) .3353 Days from symptom onset to onset of treatment (Median, IQR) 7.0 (4.0) 7.0 (4.0) 7.0 (4.0) .7257 pSO2; mean ± SD Median IQR 92 ± 2.5 92.0 –91 to 94 93 ± 2.0 93 –91 to 95 92 ± 2.9 92 –91 to 93 Leukocyte count (×103/μl), mean ± SD Median Range 5.87 ± 2.08 5.30 2.80–12.50 6.03 ± 2.04 5.60 2.80–12.40 5.70 ± 2.13 5.00 3.00–12.50 Haemoglobin (g/dl), mean ± SD Median Range 15.48 ± 1.72 15.30 10.50–20.10 15.50 ± 1.80 15.40 11.90–20.10 15.45 ± 1.66 15.15 10.50–18.70 Platelets (K/μl), mean ± SD Median Range 273.80 ± 116.16 249 73–910 283.18 ± 130.35 249 148–910 264.20 ± 100.21 250 73–568 Lymphocyte count (%), mean ± SD Median Range 30.13 ± 10.79 30.80 8–57 30.15 ± 10.99 31.40 8.1–57 30.13 ± 10.72 30.45 8–54 Neutrophil count (%), mean ± SD Median Range 60.05 ± 11.23 58.70 31–82 59.89 ± 11.82 58.70 31–81 60.22 ± 10.73 58.85 39–82 Neutrophil-lymphocyte ratio (NLR), mean ± SD Median Range 2.58 ± 1.91 1.88 0.54–10.25 2.62 ± 2.05 1.81 0.54–9.93 2.53 ± 1.78 1.91 0.72–10.25 Total bilirubin (mg/dl), mean ± SD Median Range 0.62 ± 0.28 0.56 0.18–1.87 0.62 ± 0.24 0.54 0.26–1.34 0.62 ± 0.33 0.57 0.18–1.87 Direct bilirubin (mg/dl), mean ± SD Median Range 0.13 ± 0.07 0.11 0.03–0.44 0.13 ± 0.06 0.11 0.04–0.33 0.14 ± 0.08 0.12 0.03–0.44 Indirect bilirubin (mg/dl), mean ± SD Median Range 0.49 ± 0.22 0.45 0.15–1.56 0.49 ± 0.19 0.45 0.22–1.11 0.49 ± 0.26 0.46 0.15–1.56 Aminotransferase, serum aspartate (AST) (U/L), mean ± SD Median Range 31.09 ± 20.82 26 9–158 28.39 ± 15.60 22 11–83 33.87 ± 24.97 27.50 9 –1 58 Aminotransferase, serum alanine (ALT) (U/L), mean ± SD Median Range 37.42 ± 28.14 29.80 7–129.80 35.64 ±29.90 23 9–129.80 39.24 ± 26.43 31.50 7–120 Albumin (g/dl), mean ± SD Median Range 4.35 ± 0.44 4.34 2.55–5.71 4.40 ± 0.50 4.43 2.55–5.71 4.32 ± 0.38 4.30 3.52–5.45 Fasting glucose (mg/dl) Mean ± SD Median Range 116.75 ± 61.85 98 66–386 119.31 ± 64.32 102 66–386 114.14 ± 59.86 96.50 72–354 .380b Lactate dehydrogenase (LDH) (U/L) Mean ± SD Median Range 166.70 ± 50.59 155 97–325 165.09 ± 60.76 150 97–325 168.34 ± 38.15 160 99–311 .500b C-reactive protein (high sensitivity) (mg/dl) Mean ± SD Median Range 1.63 ± 2.58 0.73 0.02–16.47 1.32 ± 2.67 0.50 0.05–16.47 1.95 ± 2.49 0.97 0.02–11.49 .650b Ferritin (ng/ml) Mean ± SD Median Range 243.46 ± 285.20 161.70 4–1614.40 235.14 ± 293.70 161.70 4–1614.40 251.96 ± 279.39 161.45 5.60–1277 .599b D-dimer (ng/dl) Mean ± SD Median Range 1106.74 ± 3537.99 456 185–29948 1732.33 ± 4916.88 491 185–29948 466.93 ± 225.22 417 210–1264 .226b On day 1 after the last PTIC or placebo administration, the IP-10 levels decreased 75% in the PTIC group (p < .001) and 40% in the placebo group (p = .015) vs. baseline; this reduction was greater in the former group than in the latter (p = .0047; Figure 1A and F). The IL-8 (44%, p = .045), M-CSF (25%, p = .041) and IL-1Ra (36%, p = .05) levels were also decreased in PTIC group vs. baseline (Figure 1B–F). TRAIL levels were decreased in the placebo group (14%, p = .002) vs. baseline (Figures 1E and S2). On days 1, 8 and 90 after the last PTIC or placebo administration, the patient percentage with oxygen saturation readings ≥92% in the PTIC and placebo groups were 90% vs. 67% (p = .007; mean oxygen saturation: 94 ± 2.4 vs. 93 ± 3.3, p = .085), 98% vs. 80% (p = .009; mean oxygen saturation; 95 ± 1.7 vs. 93 ± 2.2, p = .003) and 100% vs. 89% (p = .033; mean oxygen saturation: 95 ± 2.1 vs. 95 ± 2.3, p = .429), respectively (Table 2). pSO2; mean ± SD Median IQR 94 ± 2.4 94 92–95 93 ± 3.3 93 91–95 95 ± 1.7 95 93–96 93 ± 2.2 93 92–95 95 ± 2.1 95 93–97 95 ± 2.3 95 93–97 Dyspnoea, n (%) Δ (%) 6 (13.6) –66.6 10 (25.6) –33.3 3 (7.1) –83.3 9 (23.1) –40 6 (15) –66.6 6 (16.2) –60 Cough, n (%) Δ (%) 17 (38.6) –50 22 (56.4) –33.3 11 (26.2) –67.6 21 (53.8) –36.3 4 (10) –88.2 6 (16.2) –81.8 Chest pain, n (%) Δ (%) 8 (18.2) –57.8 9 (23.1) –43.7 5 (11.9) –73.6 6 (15.4) –62.5 7 (17.5) –63.1 1 (2.7) –93.7 Rhinorrhoea, n (%) Δ (%) 9 (20.5) –52.6 9 (41) –55.0 6 (14.3) –68.4 6 (15.4) 0.0 5 (12.5) –73.6 3 (8.1) –85.0 Headache, n (%) Δ (%) 12 (27.3) –45.4 16 (41) –33.3 9 (21.4) –59.0 15 (38.5) –37.5 10 (25) –54.5 14 (37.8) –41.6 Sore throat, n (%) Δ (%) 9 (30.5) –55.0 10 (25.6) –52.3 5 (11.9) –75.0 6 (15.4) –71.4 6 (15) –70.0 7 (18.9) –66.6 Malaise, n (%) Δ (%) 16 (36.4) –40.7 18 (46.2) –33.3 12 (28.6) –55.5 11 (28.2) –59.2 11 (27.5) –59.2 8 (21.6) –70.3 Arthralgia, n (%) Δ (%) 8 (18.2) –55.5 8 (20.5) –69.2 6 (14.3) –66.6 6 (15.4) –76.9 7 (17.5) –61.1 8 (21.6) –69.2 Myalgia, n (%) Δ (%) 12 (27.3) –47.8 11 (28.2) –56.0 5 (11.9) –78.2 6 (15.4) –76.0 7 (17.5) –69.5 3 (8.1) –88.0 Brain fog, n (%) Δ (%) 7 (15.9) –72.0 12 (30.8) –33.3 6 (14.3) –76.0 7 (17.9) –61.1 9 (22.5) –64.0 10 (27) –44.4 Ageusia, n (%) Δ (%) 18 (40.9) –37.9 13 (33.3) –31.5 11 (26.2) –62.0 8 (20.5) –57.8 5 (12.5) –82.7 4 (10.8) –78.9 Anosmia, n (%) Δ (%) 23 (52.3) 23.33 13 (33.3) 35.0 16 (38.1) 46.6 9 (23.1) 55 6 (15) 80.0 2 (5.4) 90.0 Diarrhoea, n (%) Δ (%) 4 (9.1) –63.63 6 (15.4) –25 3 (7.1) –72.7 2 (5.1) –75 1 (2.5) –90.9 0 (0.0) –100.0 Abdominal pain, n (%) Δ (%) 5 (11.4) –37.5 6 (15.4) –57.1 0 (0.0) –100.0 3 (7.7) –78.5 1 (2.5) –87.5 3 (8.1) –78.5 Jaundice, n (%) Δ (%) 0 (0.0) –100.0 2 (5.1) 100.0 0 (0.0) –100.0 0 (0.0) –100.0 0 (0.0) –100 1 (2.7) 0.0 Vomiting and nausea, n (%) Δ (%) 0 (0.0) –100.0 0 (0.0) –100.0 1 (2.4) –50 0 (0.0) –100.0 0 (0.0) –100.0 0 (0.0) –100.0 Conjunctivitis, n (%) Δ (%) 1 (2.3) –88.88 1 (2.6) –90.9 1 (2.4) –88.8 1 (2.6) –90.9 2 (5.0) –77.7 1 (2.7) –90.9 Cyanosis, n (%) Δ (%) 0 (0.0) 0.0 1 (2.6) 100.0 0 (0.0) 0.0 0 (0.0) 0.0 0 (0.0) 0.0 0 (0.0) 0.0 The Kaplan–Meier survival curve for oxygen saturations ≥92% while breathing ambient air was statistically different between groups (log-rank p = .0109; Figure 2A). Since there were no significant differences between groups at baseline, we did not make any adjustments. The Cox regression model indicated that the hazard for meeting an oxygen saturation lower than 92% was significantly lower in the PTIC than in the placebo group (HR 0.25, Wald p value = .0384). When stratifying by age, no changes occurred. Based on the accelerated time failure model, subjects of the PTIC group reached oxygen saturations 92% or greater 2.7-fold faster than the placebo group at 3 and 8 days (p < .001 in both cases). In terms of risk, this implied that the PTIC group had a 63% lower risk for mean oxygen saturations readings below 92% (p < .001; Figure 2B). Symptom improvement was reported daily by every patient and compared with baseline. Symptom duration in the PTIC group was reduced by 6.1 ± 3.2 days vs. placebo (Figure S3 and Table 2). At day 1 post-treatment, 6/87 patients (7%) received supplemental oxygen via nasal cannula: 2/44 (4.5%) of the PTIC group (one patient received 2 L/min and another one received 3 L/min) and 4/43 (9.3%) of the placebo group (4–10 L/min). At day 8 post-treatment, 2 of 81 patients (2.5%) received supplemental oxygen via nasal cannula: 1/42 (2.3%) of the PTIC group (one patient received 2 L/min) and 1/39 (2.6) of the placebo group (4 L/min). At day 90 post-treatment, none of the patients required supplemental oxygen (Table 2). At 1 day post-treatment, 3/43 subjects (7%) of the placebo group were hospitalised for 5–21 days (Table 2). All patients were discharged alive, and no deaths occurred. On days 1 and 8 post-treatment with PTIC, serum levels of LDH and high sensitivity CRP (hs-CRP) decreased (52% and 73%, respectively) vs. baseline levels (p = .002 and p < .001). In the placebo group, hsCRP levels were 3% and 67% lower at 1 and 8 days compared with baseline levels (Figure S4 and Table S3). At days 1 and 8 post-treatment, D-dimer levels in PTIC subjects decreased (55% and 61%, respectively); in the placebo group, D-dimer increased 42% and 32%, respectively Figure S4 and Table S3). No differences were detected in the other laboratory variables compared to the baseline. No serious adverse events were detected (Table S1 and S2). PTIC was safe and well-tolerated. In summary, it has been demonstrated that intramuscular PTIC treatment of symptomatic COVID-19 outpatients was useful for decreasing IP-10, IL-8 and M-CSF, all of them biomarkers of severe disease,10 during the first week of treatment. It was associated with better oxygen saturation values when compared to placebo. Also, PTIC shortened symptom duration. On days 1 and 8 post-treatment with PTIC, a higher mean oxygen saturation value and a higher proportion of patients retaining oxygen saturation values ≥92% were observed. This could be related to decreased dyspnoea, chest pain and cough. Regarding systemic inflammation, treatment with PTIC, statistically significant lower levels of hsCRP, D-dimer and LDH, all of them identified as important biomarkers for the activity and severity of the disease, were observed. The benefit was evident in the early stage of the infection (7 days after symptom onset). PTIC was safe and well-tolerated. It did not induce liver damage, impairment of haematopoiesis or alterations in blood count. We think that treating outpatients with PTIC could potentially avoid visits to the Emergency Department and hospitalisations. As judged by symptom improvement, it could aid in preventing sequelae, such as persistent dyspnoea. Polymerised type I collagen was donated by Aspid SA de CV. We thank Dr. Alicia Frenk-Mora, Dr. Judith González-Sánchez and Ivonne Aidé Lomelí Almanza for their valuable assistance with the organisation of patient appointments. We thank all patients involved in the study. We also thank the Triage and Emergency Departments. The authors declare that they have no competing interests. The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.