Risk factors identified for death from COVID-19
Being of an older age, showing signs of sepsis and having blood clotting issues when admitted to hospital are key risk factors associated with higher risk of death from the new coronavirus (COVID-19), according to an observational study published in The Lancet.
The study is said to be the first time researchers have examined risk factors associated with severe disease and death in hospitalised adults who have either died or been discharged from hospital, and could help clinicians to identify patients with poor prognosis at an early stage.
The new analysis included 191 adults (aged 18 or older) with laboratory-confirmed COVID-19 admitted to Jinyintan Hospital and Wuhan Pulmonary Hospital after 29 December 2019, who had been discharged or died by 31 January 2020. These were the two designated hospitals for transferring patients with severe COVID-19 from across Wuhan up until 1 February 2020.
During the study, the researchers compared clinical records, treatment data, laboratory results and demographic data between survivors who had been discharged from hospital (137) and non-survivors (54). They looked at the clinical course of symptoms, viral shedding and changes in laboratory findings during hospitalisation (eg, blood examinations, chest X-rays and CT scans), and used mathematical modelling to examine risk factors associated with dying in hospital.
On average, patients were middle-aged (median age 56 years), most were men (62%, 119 patients) and around half had underlying chronic conditions (48%, 91 patients) — the most common being high blood pressure (30%, 58 patients) and diabetes (19%, 36 patients). The researchers found the median duration of fever was about 12 days in survivors, which was similar in non-survivors. But the cough may last for a long time — 45% of survivors still had cough on discharge. In survivors, dyspnoea (shortness of breath) would cease after about 13 days, but would last until death in non-survivors. From illness onset, the median time to discharge was 22 days and the average time to death was 18.5 days.
Compared with survivors, patients who died were more likely to be older (average age 69 years vs 52 years), to have a higher sequential organ failure assessment (SOFA) score indicating sepsis and to have elevated blood levels of the d-dimer protein (a marker for coagulation) on admission to hospital. Additionally, lower lymphocyte (a type of white blood cell) count, elevated levels of Interleukin 6 (IL-6, a biomarker for inflammation and chronic disease) and increased high-sensitivity troponin I concentrations (a marker of heart attack) were more common in severe COVID-19 illness. The frequency of complications such as respiratory failure, sepsis and secondary infections was also higher in those who died than survivors.
“Older age, showing signs of sepsis on admission, underlying diseases like high blood pressure and diabetes, and the prolonged use of non-invasive ventilation were important factors in the deaths of these patients,” said study co-author Dr Zhibo Liu from Jinyintan Hospital, China. “Poorer outcomes in older people may be due, in part, to the age-related weakening of the immune system and increased inflammation that could promote viral replication and more prolonged responses to inflammation, causing lasting damage to the heart, brain and other organs.”
In addition, the authors revealed that the median duration of viral shedding was 20 days in survivors (ranging from 8–37 days) and that the virus was detectable until death in the 54 non-survivors. While prolonged viral shedding suggests that patients may still be capable of spreading COVID-19, the authors caution that the duration of viral shedding is influenced by disease severity, and note that all patients in the study were hospitalised, two-thirds of whom had severe or critical illness. Moreover, the estimated duration of viral shedding was limited by the low frequency of respiratory specimen collection and the lack of measurable genetic material detection in samples.
“The extended viral shedding noted in our study has important implications for guiding decisions around isolation precautions and antiviral treatment in patients with confirmed COVID-19 infection,” said co-lead author Professor Bin Cao from the China-Japan Friendship Hospital and Capital Medical University, China. “However, we need to be clear that viral shedding time should not be confused with other self-isolation guidance for people who may have been exposed to COVID-19 but do not have symptoms, as this guidance is based on the incubation time of the virus.
“We recommend that negative tests for COVID-19 should be required before patients are discharged from hospital. In severe influenza, delayed viral treatment extends how long the virus is shed, and together these factors put infected patients at risk of dying. Similarly, effective antiviral treatment may improve outcomes in COVID-19, although we did not observe shortening of viral shedding duration after antiviral treatment in our study.”
The authors note several limitations of the study, including the small sample size and the fact that, due to excluding patients still in hospital as of 31 January, the number of deaths does not reflect the true mortality of COVID-19. They also point out that not all laboratory tests were done in all patients, so their exact role in predicting in-hospital death might be underestimated. Finally, a lack of effective antivirals, inadequate adherence to standard supportive therapy and high doses of corticosteroids, as well as the transfer of some patients to hospital late in their illness, might have also contributed to the poor outcomes in some patients.
The release of the study coincides with the news that Sydney-headquartered biotech contract research organisation (CRO) Novotech has been selected to carry out Komipharm International’s clinical trial of Panaphix as a potential treatment for COVID-19. Panaphix is a cytokine storm inhibitor that restrains the overproduction of immune cells and their activating compounds, cytokines, which would otherwise lead to severe inflammatory disease such as pneumonia in some individuals.
Novotech CEO Dr Moller said Novotech is well positioned to partner with Komipharm on this important trial of a drug that is having a particularly strong impact in Asia Pacific. He said Novotech’s model of having experienced local leadership, the ability to engage with regulators and strong relationships with key opinion leaders and sites in the Asia Pacific region will allow it to accelerate this trial.
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