In this study, we retrospectively assessed the efficacy of ulinastatin on patients with Covid-19. Our preliminary observational study revealed that high dose of ulinastatin treatment was safe and had a potential beneficial effect for patients with Covid-19, with rapidly improvement of clinical symptoms, blood parameters and absorption of the pulmonary lesions.
Covid-19 is spreading rapidly around the world and this unprecedented challenge demands clinicians to identify an effective and safe treatment to protect people at high risk. Remdesivir, which shows potent in vitro activity against SARS-CoV-2, is considered as the most promising antiviral drug and has been successfully used in several case series of patients with Covid-19[16, 17]. Recently, compassionate use of remdesivir without placebo for 53 patients with severe Covid-19 was reported to have a 68% efficacy . Notably, 23% patients had serious adverse events and 8% patients discontinued remdesivir treatment prematurely. Lopinavir–ritonavir, another antiviral drug, has been showed to have no benefit for hospitalized adult patients with severe Covid-19 according to a recent open-label, individually randomized, controlled trial which conducted in China. Similarly, lopinavir–ritonavir is also related with serious gastrointestinal side effects and 13.8% of patients should be terminated earlier because of the adverse events. Unfortunately, older patients, especially those with comorbidities, were the most vulnerable populations with significantly increased risk of deterioration and fatality [20–22]. Therefore, it is of utmost importance to identify effective therapeutics with high-safety, probably from clinically approved drugs. Ulinastatin, an intrinsic glycoprotein which has been widely used in clinical practice, was an ideal candidate. A safety and tolerability study of ulinastatin in adult healthy volunteers revealed that intravenously infused of 8 000 000 IU ulinastatin over 2 h period associated with no severe adverse effects. From our study, patients received 1 000 000 IU ulinastatin every 8 h through intravenous injection, and no adverse effects were noticed.
It is reported that about 14% of the patients will develop into severe cases. Inhibition the deterioration of the illness is of utmost importance during the treatment. Potential risk factors predicting poor prognosis included older age, high Sequential Organ Failure Assessment (SOFA) score and d-dimer greater than 1 µg/mL. Therefore, application of timely, effective and safe supportive therapies seems critical for those patients with high risk factors. Within our study, no patients progressed to more severe cases when received ulinastatin treatment, and no mortality was observed among those patients.
Cytokine storm are believed to play an essential role in the pathogenesis of Covid-19 and might be correlated with disease severity and fatality [4, 5]. Ulinastatin, an intrinsic broad-spectrum protease inhibitor, could effectively inhibit a variety of cell proteolytic enzymes and have multifunctional therapeutic mechanisms . Firstly, ulinastatin has an inhibitory effect on the production of inflammatory cytokines and adhesion molecules . Meanwhile, ulinastatin improves the stability of lysosomal membrane and reduces the synthesis and delivery of lysosomal enzymes, thus scavenging oxygen or hydroxyl radicals . In the present study, we observed the beneficial effect of ulinastatin for patients with Covid-19. Unfortunately, we did not investigate the changes of cytokines during treatment due to limitation of the hospital facility.
There were several limitations in our study. Firstly, the number of patients enrolled was limited. Secondly, it was an observational, retrospective study. And other factors might interfere with the outcomes. However, our preliminary results revealed the promising efficacy of ulinastatin for patients with Covid-19. Thus, further randomized, controlled trials are warranted.
In conclusion, our observational data revealed that administration of high dose ulinastatin showed a potential beneficial effect for patients with Covid-19. Considering the safety of this agent, the sharply rising fatality of Covid-19 and no other approved agent available, timely initiation of ulinastatin treatment is strongly recommended.