Mortality in COVID-19 patients with radiological changes on admission

April 27, 2020

Ashleigh Kernohan¹, Anna Boath¹, Maria Calderon², Ewan Hunter², Sara Graziadio^3,4 

On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford

¹Population Health Sciences Institute
Newcastle University, Newcastle upon Tyne, NE2 4AX

²Department of Infection and Tropical Medicine, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, NE1 4LP

³NIHR Newcastle In Vitro Diagnostics Co-operative,
Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, NE1 4LP

⁴Translational and Clinical Research Institute,
Newcastle University, Newcastle upon Tyne, NE1 4LP

Correspondence to sara.graziadio@newcastle.ac.uk

VERDICT
There is a current paucity of evidence that relates specifically to mortality in patients with COVID-19 who have radiological changes of COVID-19 on admission to hospital and who require supplemental oxygen therapy.

In the evidence that we have identified there is a significantly higher mortality rate for those who have received oxygen therapy, particularly those who have received mechanical ventilation. One study also reported that the presence of ground glass opacities is associated with mortality.

Potential predictors of mortality in patients who require oxygen support were age and development of Acute Respiratory Distress Syndrome (ARDS).  Less consistently identified risk factors were co-morbidities (with an emphasis on cardiac problems and malignancies), body mass index (BMI), previous respiratory illness, need for mechanical ventilation, elevated D-dimer levels and a lower oxygenation index.

BACKGROUND
As the novel COVID-19 virus is a respiratory disorder, many of those who require hospitalisation require supplemental oxygen therapy as part of their care.  Huang et al found oxygen support was necessary in 32% of patients [1] whereas Chen found that support was necessary in 76% of cases [2].  In those patients who do require oxygen support there are a number of factors which may influence the likelihood of survival for these individuals, including age, gender, comorbidities or other patient characteristics of the patients.  It is also important to assess the clinical features of the chest X-rays (CXRs) of patient who require oxygen therapy.  These may include the presence of pneumonia (unilateral or bilateral) or ground glass opacities [3].  Understanding the impact of both the clinical and radiological characteristics on a patient’s potential survival will aid clinical decision making for specific groups of patients, particularly those who have more severe manifestations of the disease.  To contribute to this knowledge base, we conducted a rapid literature review using a systematic search method to identify relevant studies to inform evidence-based patient management and care pathway development.

CURRENT EVIDENCE

Included studies

The search returned 544 results (after duplicates were removed), of which 33 studies were included.  The majority of the included studies were in Chinese populations in Wuhan, with five studies being from elsewhere: the United States, Taiwan, Spain, and Italy; one study included patients from multiple countries (United States, Japan, Italy, Austria, France, Germany, Netherlands, Spain and Canada).  Two of the included studies were systematic reviews. Mathematical estimations of mortality and data from national registries where it was not clear if the individuals were admitted to hospital were not included in this summary.

Studies including information about oxygen therapy

Of the 33 included studies, four reported information specifically relating to patients who required oxygen therapy [4-7].  All of these studies were case series. Shen et al [4] reported on five critically ill patients but no deaths, with a mean patient age of 54.  He et al [5] reported on 54 critically ill patients with a mean age of 68.  This study reported 26 deaths, however the specific details of the patients cannot be extracted due to the original study being published in Chinese which the review team were unable to translate.  Bhatraju et al [7] reported on 24 cases of critically ill patients in the United States, with an average age of 64 (±18 years).  Yang et al [6] reported on a case series of 52 patients and reported on 32 deaths. The average age of patients in this study was 59.7 (±13.3) years.  Grein et al [8] compared the mortality between patients receiving invasive and non-invasive oxygen therapy.  The study reported on 53 patients of which 7 died; mortality was 18% (6 of 34). Wu et al [9] reported on 201 hospitalised patients, of whom 44 (21.9%) died.

Yang et al [6] described the characteristics of patients who required oxygen support.  This study found that non-survivors were older (64.6 years [11.2] vs 51.9 years [12.9]), (the authors carried out significance testing but did not report the p values).  They also identified that non-survivors were more likely to develop Acute Respiratory Distress Syndrome (ARDS) (26 [81%] patients vs 9 [45%] patients).  Non-survivors were also and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively.  Two further studies, Chen et al and Liu et al [10, 11], reinforce the risk of age, concluding that older patients’ use of oxygen therapy, mechanical ventilation, and expectorant were significantly higher than those of the younger patients.  In Wu et al [9], of those who died 38/44 (86.4%) received non-invasive mechanical ventilation, 5/44 (11.4%) received invasive mandatory ventilation and 1/44 (2.3%) received intermittent mandatory ventilation with extracorporeal membrane oxygenation.  In Grein et al [8], among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation; the hazard ratio (HR) for patients receiving invasive ventilation as compared with those receiving non-invasive oxygen support was 2.78 (95% CI, 0.33 to 23.19).

Studies reporting information about oxygen therapy or radiological changes in their populations

Other studies included patients that were admitted to hospital, but did not specifically compare those that needed oxygen therapy against those who did not.  These studies did describe, however, oxygen therapy or CXR/computed tomography (CT) abnormalities in their populations.  A number of other studies identified age as a risk factor for mortality in hospitalised populations, although specific details are often limited [2, 11-18].  For example, Chen et al [10] provide details about only two of the nine patients who died, and there is no further information about the other patients.  Ruan et al found no difference between hospitalised males and females in a population of 66 patients [14].

Ruan et al found that a total of 63% (43/68) of patients in the mortality group and 41% (34/82) in the surviving group had underlying diseases (p=0.0069).  The study does not specify which underlying diseases were specifically associated with mortality [14].  In terms of co-morbidities, Peng et al found an association between increased BMI and survival.  Among non-survivors, there were 88.24% (15/17) patients with BMI > 25 kg/m(2), which was significantly higher than that of survivors (18.95% (18/95), P<0.001) [19].  He et al [5] identified myocardial injury as a risk factor for mortality (14 (60.9%) vs. 8 (25.8%, p=0.013).  Shi et al [20] also identified cardiac injury as a risk factor, HRs were calculated in relation to time from symptom onset (HR 4.26 [95% CI, 1.92- 9.49]) or time from admission to study end point (HR, 3.41 [95% CI, 1.62-7.16]).  Another potential risk factor identified was respiratory illness.  Du et al [15] found an association with respiratory illness and mortality more generally (p=0.036), and Grein et al found that those with asthma were more likely to require invasive ventilation (5 invasive compared to 1 non-invasive).  Feng et al [16] also noted a significant association (p=0.002) between COPD and severity (as defined by respiratory distress, respiratory rate ≥ 30 per min, oxygen saturation on room air at rest ≤ 93% or partial pressure of oxygen in arterial blood / fraction of inspired oxygen ≤ 300 mmHg).

In terms of laboratory and radiological factors, elevated D-dimer levels were also associated with mortality in four studies [9, 12, 13, 21].  For example Zhou et al reported that of the 44/54 (81.5%) of the patients who died had a D-dimer of >1 μg/mL.  Wu et al reported that of that 44 patients who died had a significantly higher D-dimer level (p=0.001) which was significantly greater than the survivors.  Peng et al also identified that the oxygenation index was significantly lower in those who survived compared to those who did not survive (130 (102, 415) vs. 434 (410, 444), p<0.001) [19].

Several studies noted CXR and CT abnormalities in their study populations.  These included unilateral pneumonia [22], bilateral pneumonia [1, 7, 13, 22, 23], bilateral infiltrates [6] and ground glass opacities [13, 20-24].  One study (Cao et al [18] found a mortality rate of 17/102 patients.  They concluded that ground-glass opacity was associated with mortality, present in 41.2% cases where the patient died vs. 12.9% of those who lived.

Systematic Reviews

Two systematic reviews were identified, both reporting case fatality rates but not specifically in populations requiring oxygen therapy.  Rodriguez-Morales et al carried out a review of 7 studies describing 632 hospitalized patients [25].  The study reported a Case Fatality Rate (CFR) of 13% and that 32.8% presented with ARDS.  Fu et al [26] carried out a systematic review and meta-analysis of 43 studies that included data derived from 3,600 hospitalised patients.  This study reported on the prevalence of ground-glass opacities (80.0%), bilateral pneumonia (73.2%) and oxygen therapy (71.5%); the overall mortality rate in this review was 3.6% but no mortality information was reported in the populations with ground glass opacities and bilateral pneumonia.

CONCLUSIONS
There is a current paucity of good or strong evidence relating to associations with and predictors of mortality in patients with COVID-19 who require oxygen therapy and who have radiological changes of COVID-19 at admission to hospital.  Most studies are retrospective case series with relatively small populations.  In the evidence identified there is a significantly higher mortality rate for those who have received oxygen therapy, particularly those who have received mechanical ventilation.  One study also reported that the presence of ground glass opacities is associated with mortality.

Potential risk factors for mortality identified in a population who require oxygen support are age and development of ARDs.  Other studies did also identify older age as a risk factor for mortality although these were in general hospitalised populations rather than those who specifically required oxygen therapy.  Other factors which were purported to potentially impact mortality were co-morbidity (two studies with specifically cardiac disease and one with co-morbidities more generally).  Another study suggested higher BMI could have an impact on mortality.  Other potential risk factors were malignancies and previous respiratory illness.

Clinical factors associated with increased mortality in a population requiring oxygen support were the receipt of mechanical ventilation.  Elevated D-dimer levels and a lower oxygenation index was also associated with greater mortality in general hospitalised populations.

Disclaimer: This article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked.  The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care.  The views are not a substitute for professional medical advice.

SEARCH TERMS
The search strategy which was applied to MEDLINE and EMBASE is below.  The search was carried out on 20/04/2020.

(COVID-19 OR “2019 novel coronavirus infection” OR COVID19 OR COVID-19 OR “coronavirus disease 2019” OR “coronavirus disease-19” OR “2019-nCoV disease” OR “2019-nCoV infection” OR “severe acute respiratory syndrome coronavirus 2” OR “Wuhan coronavirus” OR “COVID-19 virus” OR “SARS-CoV-2” OR “SARS2” OR “2019-nCoV” OR “2019 novel coronavirus”) AND (Mortality OR Mortalit* OR “Case Fatality Rate” OR “Excess Mortality” OR “Mortality Decline” OR “Mortality Determinant” OR “Differential Mortalities” OR “Age-Specific Death Rate” OR “Death Rate” OR “Mortality Rate”).

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