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Abstract To evaluate the safety and the potential antiviral treatment of inhaled enriched heparin in patients with COVID-19. The specific objectives were to investigate the anticoagulation profile, antiviral and anti-inflammatory effects, and respiratory evolution of inhaled enriched heparin. We conducted a randomized, triple-blind, placebo-controlled Phase I/II clinical trial in hospitalized adults with COVID-19 receiving inhalation of enriched heparin or saline (placebo) every 4 h for 7 days. Among the 27 patients who completed the study, no changes in blood coagulation parameters were observed, indicating the safety of inhaled enriched heparin. The group receiving enriched heparin showed a significant reduction in the need for supplemental oxygen and improvement in respiratory parameters, such as the PaO2/FiO2 ratio. Inhalation of enriched heparin is shown to be safe and has also demonstrated potential therapeutic benefits for patients with COVID-19. These promising results justify the continuation of the study to the next phase, Phase II/III, to further evaluate the therapeutic efficacy of inhaled enriched heparin in the treatment of COVID-19-associated viral pneumonia. Trial registration: ClinicalTrials.gov. 08/02/2021. Identifier: NCT04743011.

COVID-19 causes more severe and frequently fatal disease in patients with pre-existing comorbidities such as hypertension and heart disease. SARS-CoV-2 virus enters host cells through the angiotensin-converting enzyme 2 (ACE2), which is fundamental in maintaining arterial pressure through the renin-angiotensin system (RAS). Hypertensive patients commonly use medications such as angiotensin-converting enzyme inhibitors (ACEi), which can modulate the expression of ACE2 and, therefore, potentially impact the susceptibility and severity of SARS-CoV-2 infection. Here we assessed whether treatment of ACE2-humanized (K18-hACE2) mice with the ACEi Lisinopril affects lung ACE2 levels and the outcome of experimental COVID-19. K18-hACE2 mice were treated for 21 days with Lisinopril 10 mg/kg and were then infected with 105 PFU of SARS-CoV-2 (Wuhan strain). Body weight, clinical score, respiratory function, survival, lung ACE2 levels, viral load, lung histology, and cytokine (IL-6, IL-33, and TNF-α) levels were assessed. Mice treated with Lisinopril for 21 days showed increased levels of ACE2 in the lungs. Infection with SARS-CoV-2 led to massive decrease in lung ACE2 levels at 3 days post-infection (dpi) in treated and untreated animals, but Lisinopril-treated mice showed a fast recovery (5dpi) of ACE2 levels. Higher ACE2 levels in Lisinopril-treated mice led to remarkably higher lung viral loads at 3 and 6/7dpi. Lisinopril-treated mice showed decreased levels of the pro-inflammatory cytokines IL-6 and TNF-α in the serum and lungs at 6/7dpi. Marginal improvements in body weight, clinical score and survival were observed in Lisinopril-treated mice. No differences between treated and untreated infected mice were observed in respiratory function and lung histology. Lisinopril treatment showed both deleterious (higher viral loads) and beneficial (anti-inflammatory and probably anti-constrictory and anti-coagulant) effects in experimental COVID-19. These effects seem to compensate each other, resulting in marginal beneficial effects in terms of outcome for Lisinopril-treated animals.

Bovine respiratory disease (BRD) is responsible for great economic losses in bovine production with major impact on family farming. Among all possible causes of bovine respiratory disease, viruses are commonly categorized as primary etiological agents. The present study aimed to identify the presence of bovine parainfluenza type 3 virus and Influenza virus D (IVD) in tracheobronchial fluid samples of healthy calves and calves showing clinical signs of bovine respiratory disease. Samples were collected from 42 family farming farms in São Paulo State, Brazil. A total of 141 tracheobronchial fluid samples from healthy calves (n=100) and calves showing clinical signs of bovine respiratory disease (n=41) were enrolled in this study. No sample was positive for both viruses after Real-Time PCR. Serum neutralization for bovine Parainfluenza type 3 virus (bPI-3v) was performed using 88 randomly selected serum samples and antibodies were detected in 45.45% (40/88) samples. Serum reactive samples were detected in both healthy (46.8%; 22/47) and BRD calves (43.9%; 18/41). Regarding antibody titer, numerical differences were detected between healthy (3%) and BRD calves (9%) for titers 128-512 (P > 0.05). The present research was the first that aimed to study the presence of bPI-3V and IVD in family farming herds from São Paulo State, Brazil. This research revealed that bPI-3v is circulating in the region studied and is possibly involved in some BRD cases. On the other hand, IVD was not detected.