Given the limited knowledge of the novel pathogen, SARS-CoV-2, and the current worldwide outbreak of COVID-19, effective treatment options are urgently needed. In the present study, we summarized the clinical characteristics of COVID-19 patients in Hangzhou, China, an important imported metropolis outside Wuhan. Our data indicated the effectiveness of the 3-drug combination of LPV/r, recombinant interferon α-2b, and arbidol on COVID-19, especially in adult common cases.
As seen in Fig. 1, the total number of non-pneumonia cases was 14 (14/110, 12.7%). And especially, 4 cases were asymptomatic, including 2 patients with radiologic evidence and 2 patients without radiologic evidence. Under the same definition of non-pneumonia cases, the ratio of non-pneumonia cases in all symptomatic cases (except severe patients) was about 14.7% (14/95, see Fig. 1) in our study, higher than another research in Beijing, China, conducted by Tian and colleagues (5.4%, 11/203) [13]. And a study from Shenzhen, China, including 55 asymptomatic cases at the time of hospital admission, indicated that the majority of them developed to be mild or ordinary COVID-19 during hospital [14]. Altogether, these data might reflect the characteristics of patients at different stages of SARS-CoV-2 infection, or very few patients might have a subclinical infection. From the perspective of controlling the epidemic, these findings suggested that the absence of clinical symptoms could not rule out the diagnosis of SARS-CoV-2 infection. Persons with a clear history of exposure to SARS-CoV-2, regardless of clinical symptoms, should be considered for medical observation, home isolation, and further examination [15].
There were 3 cases (3/110, 2.7%) whose SARS-CoV-2 RNA was found to be positive again after discharge in our study. Some case reports also suggested this phenomenon [16, 17]. Zhou and colleagues suggested some possible reasons to explain this status in their recent review [18]: 1) Virological properties of SARS-CoV-2 were not sufficiently understood given that it was just discovered recently; 2) Some host factors, such as the immune function status or coexisting disorders, might influence the control of the virus in the body; 3) Use of systemic corticosteroids might be related to the recurrence of SARS-CoV-2 RNA; 4) The tests results had been false negative when the patients were discharged; 5) Secondary infection of SARS-CoV-2 might occur in some patients. In addition, another noteworthy phenomenon was that some patients had a long duration of viral shedding. In our study, the longest time with pharyngeal swab specimen positive was 28 days. And the longest duration of viral shedding was 37 days in a recent study by Zhou and colleagues [19]. People with positive SARS-CoV-2 RNA of respiratory tract specimens are the infectious source of COVID-19. During treatment or follow-up after discharge, the level and duration of infectious virus replication are important factors in assessing the risk of transmission and guiding decisions regarding the isolation of patients and the length of antiviral treatment. Data above indicated that SARS-CoV-2 RNA of respiratory tract specimens might be persistent or recurrent positive during the course, calling for further researches on dynamic profile and infectivity assessment of SARS-CoV-2 infection.
Severe patients seemed older and to have more coexisting disorders, lower levels of lymphocyte counts, sodium and chloride, and higher levels of C reactive protein and procalcitonin (see Table 1 and Table 2). These findings were consistent with the results of other studies with larger sample sizes [19–21]. Researches from Wuhan, China, indicated that older age (odds ratio 1.10, 95% CI 1.03–1.17, per year increase; P = 0·0043) was an independent risk factor for in-hospital death [19] and showed more comorbidities and higher plasma levels of C reactive protein in severe cases [22]. These data indicate that older persons, particularly those with multimorbidity, are at high risk of being severer or death if infected by SARS-CoV-2. The elderly should be one of the key groups for infection prevention.
Judging from the CT imaging data, lesions being simultaneously present in more than one lobe or with more than one radiologic feature could be seen in a considerable number of patients (see Table 3). And within lobes, peripheral and peripheral involving central lesions were more common. These radiologic characteristics were similar to other reports [15, 23]. However, we must note that the CT findings of COVID-19 are variable. Some patients have no initial abnormal lung findings and can be misdiagnosed with other common diseases. Sixteen patients in our study had no CT evidence of pneumonia, including 14 non-pneumonia cases and 2 cases, asymptomatic and no radiologic evidence (see Fig. 1). Therefore, epidemiological history, clinical manifestations, and the RT-PCR detection of the viral RNA from a respiratory tract sample can be considered to represent the comprehensive analysis necessary to diagnose SARS-CoV-2 infection [24]. Especially, for cases of high clinical suspicion of SARS-CoV-2 infection with a negative RT-PCR result, the combination of repeated swab tests and CT examinations can be helpful for diagnosis. CT images and the detection of nucleic acid can mutually complement each other in the diagnosis of COVID-19.
Up to now, no specific treatment has been recommended for coronavirus infection [8]. Given the urgency of the COVID-19 outbreak and the absence of definitive antiviral drugs or vaccines, diverse treatment regimes have been explored for the treatment of COVID-19, such as oseltamivir, ganciclovir, LPV/r, remdesivir, chloroquine phosphate, herbal treatments, and passive immunization [8, 25–29]. Some of these treatments may have been tried out of desperation, and among these, some show initial promise.
Approved protease inhibitors including lopinavir and ritonavir have been reported to be active against SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). They were also potential virally targeted agents for SARS-CoV-2 [7]. A study in the early stage of the SARS-CoV-2 epidemic in Wuhan, China, showed the initial therapeutic effect of arbidol, with a higher discharge rate in the arbidol-treated group compared to the arbidol-untreated group [22]. In addition, a recent retrospective cohort study showed that arbidol and LPV/r combination therapy was associated with a significant elevated negative conversion rate of coronavirus test in 7-day and 14-day and significantly improved the chest CT scans in 7-day, compared with LPV/r monotherapy [30]. Pegylated interferon α-2a and − 2b, approved for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, had the potential activity to stimulate innate antiviral responses in patients infected with SARS-CoV-2 [7]. In our hospital, since the beginning of the SARS-CoV-2 epidemic in Hangzhou, all COVID-19 patients of 18 years or older were treated with the combination of LPV/r, recombinant interferon α-2b, and arbidol, if no contraindications. The course was at least 10 days. Our results showed that completing the 3-drug combination antiviral therapy was an independent related factor to a shorter hospital staying time, both in the whole group including common and severe patients and in the group excluding important confounding factors (see Table 4). Especially, given that 82 cases in Model 1 (82/93, 88.2%) were common cases and the 51 cases in Model 2 were all common cases, we draw the conclusion cautiously that the adult common COVID-19 patients might benefit from the 3-drug combination antiviral therapy. Meanwhile, another issue that needed attention was the side effects of antiviral drugs. In our study, 50.9% of the patients reported side effects of any of the 3 antiviral drugs, while 16.4% of the patients discontinued at least one of the 3 antiviral drugs because of side effects. Overall, prospective or even randomized researches with larger sample sizes are called for to evaluate the efficacy and tolerance of the 3-drug combination antiviral therapy in COVID-19 patients. And phase 3 or 4 clinical trials for LPV/r, arbidol or recombinant interferons in the treatment of COVID-19 are currently in progress [7, 19]. These might help to stratify patients to improve efficacy and reduce side effects.
Notably, a recent randomized clinical trial comparing LPV/r monotherapy plus standard care with standard care alone indicated that no benefit was observed with LPV/r treatment beyond standard care in hospitalized adult patients with severe COVID-19 [29]. This trial included only the severe cases with “an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) (Pao2:Fio2) at or below 300 mg Hg”. In our study, there were more common cases. As seen in the “Treatment and clinical outcome, Results” section and Supplementary Table 1, Model 1 included 93 patients, including only 11 severe cases and 51 cases in Model 2 were all common cases. In addition, in our study, patients were treated with 3-drug combination therapy, not with one drug monotherapy. There was a hypothesis that reducing the viral load as soon as possible might benefit the delay of the progression of lung lesions. A combination of two or three antiviral drugs might facilitate the rapid decline of viral load. These two differences between the resent clinical trial and our study might cause differences in treatment effects. And in the clinical trial conducted by Doctor Cao and colleagues, in the modified intention-to-treat analysis, which excluded three patients with early death, the between-group difference in the median time to clinical improvement (median, 15 days vs. 16 days) was significant, although modest [29]. As the authors discussed in their article [29], further studies should be done to answer these questions: “whether earlier LPV/r treatment in COVID-19 could have clinical benefit?”, “whether LPV/r treatment given at a certain stage of illness can reduce some complications in COVID-19?”, and “whether combining LPV/r with other antiviral agents, as has been done in SARS and is being studied in MERS-CoV might enhance antiviral effects and improve clinical outcomes?”. Corresponding to these questions, in our study, most patients were common cases and combination therapy including LPV/r was evaluated. So the results of our research might be a well complement to the research conducted by Doctor Cao and colleagues.
There were several notable limitations in our study. Firstly, respiratory tract specimens were detected by RT-PCR, while results reporting is qualitative rather than quantitative in the clinical practice. This would cause the loss of some information. For example, the dynamic profile of SARS-CoV-2 RNA load could not be carefully observed. Secondly, the viral load in the serum was not detected in the clinical practice. That was a potentially useful marker related to the severity of COVID-19. Thirdly, this was a retrospective study, so recall bias might exist. That would influence the accuracy of the evaluation of some parameters, such as the incubation period. Meanwhile, this retrospective character also had advantages. For example, most patients had been discharged, which allowed us to obtain relatively complete data including the hospital staying time.