SpO2/FIO2 ratio 3 days after treatment with tocilizumab is a prognostic factor in patients with COVID-19: A retrospective cohort study

doi:10.21203/rs.3.rs-2441043/v1

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SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab is a prognostic factor in patients with COVID-19: A retrospective cohort study

https://doi.org/10.21203/rs.3.rs-2441043/v1

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Background:

Tocilizumab is considered a critical treatment for severe COVID-19. Thus far, there are no established means of predicting outcomes of administering tocilizumab. Our goal was to determine the factors that predict the prognosis of patients with COVID-19 receiving tocilizumab.

Methods:

All patients admitted to our hospital from March 2020 to July 2021 who had received tocilizumab for COVID-19 were retrospectively identified from hospital charts. We identified 92 patients who were eligible for this observational cohort study. We assessed age, dyspnoea, number of comorbidities, history of cancer, neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio, lactate dehydrogenase, and total bilirubin. We also analysed the relationship between mortality and oxygen saturation/fraction of inspired oxygen (SpO₂/F_IO₂) and ratio of oxygen concentration to respiratory rate (ROX index). We assessed these data using the Cox proportional hazard and ROC curve models.

Results:

Survivors (n = 56; mean age 65 years) were younger than those who died (n = 36; mean age 78 years). According to multivariable analysis, multiple comorbidities, history of cancer, CURB-65 score, neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio, and lactate dehydrogenase were all greater in those who died than in those who survived. There were no significant differences in dyspnoea and total bilirubin. The SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab was strongly associated with subsequent mortality. According to multivariate analysis, of the variables analysed, only the SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab was significantly associated with mortality rate (p = 0.029; hazard ratio = 0.987, 95% confidence interval 0.977–0.997).

Conclusions:

The SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab is a useful prognostic indicator in patients with COVID-19. Our findings indicate that aggressive respiratory therapy and/or additional treatment should be instigated when the SpO₂/F_IO₂ ratio has not improved 3 days after treatment with tocilizumab.

COVID-19

coronavirus disease

fraction of inspired oxygen

high flow therapy

oxygen saturation

ratio of oxygen concentration index

tocilizumab

It has been well-established that respiratory status (oxygen saturation/fraction of inspired oxygen [SpO₂/F_IO₂]) and ratio of oxygen concentration to respiratory rate (ROX index) on admission are linked to the prognosis of patients with COVID-19 [1]. However, to the best of our knowledge, the usefulness of the SpO₂/F_IO₂ ratio as a prognostic indicator after treatment has not yet been established. In this paper, we focussed on examining the efficacy of tocilizumab against COVID-19.

Tocilizumab, a treatment option for severe COVID-19, may reduce the overall mortality rate [2]. In Japan, tocilizumab was therefore approved for this purpose on 21 January 2022. It was also approved for progression of respiratory failure and pulmonary radiological findings in patients with moderate (II) or severe disease [3, 4]. Several scores for predicting the prognosis of COVID-19 inpatients have been developed [5, 6], including one in Japan [7]. However, there are no indexes for predicting the effect of tocilizumab. Adding SpO₂/F_IO₂ to these indicators reportedly improves the prognostic accuracy [8]; however, to the best of our knowledge, the impact on prognosis of treatment beyond standard initial treatment has not yet been determined.

We therefore considered it necessary to determine to what extent improvement in oxygenation impacts prognosis. Indicators of respiratory status include SpO₂/F_IO₂ and ROX. SpO₂/F_IO₂ and the partial pressure of oxygen (PaO₂)/F_IO₂ ratio are reportedly essential predictors of prognosis in patients with acute respiratory distress syndrome (ARDS) [9]. The ROX index is also useful for assessing the severity of ARDS [10, 11]. Compared with these indexes, the SpO₂/F_IO₂ is highly versatile and simple. However, to the best of our knowledge, this index has never been used alone to predict post-treatment status. It is unclear whether, after instituting tocilizumab in patients with COVID-19, the SpO₂/F_IO₂ or ROX index better facilitates optimal treatment.

Prospective and retrospective observational studies investigating the efficacy of tocilizumab in severe cases [12, 13] have evaluated status at 24 and/or 72 hours. However, we consider 24 hours to be too early to determine the effect of tocilizumab. Others have assessed status after 14 and 28 days [2, 14, 15]. We did not investigate long-term outcomes because our aim was to identify predictors of therapeutic effects. Rather, we elected to assess outcomes on the 3rd and 7th days after initiation of tocilizumab.

Our hypothesis was that the SpO₂/F_IO₂ and ROX index 3 days post-initiation of tocilizumab predict mortality. We performed multivariate analysis to identify predictors of mortality and constructed ROC curves to analyse probabilities.

Setting

The Clinical Research Ethics Committee of the Nihon University Itabashi Hospital (Approval number RK-200714-13) waived the need for informed consent due to a retrospective study of patients. All protocols and practices were conducted in accordance with the World Medical Association’s Declaration of Helsinki. A search of medical records yielded 92 patients with COVID-19 who had been treated with tocilizumab between March 2020 and July 2021 in the intensive care units and general wards of our university hospital; these patients were enrolled in this study. Tocilizumab had been administered to patients at moderate (I) and high risk of deteriorating, and all patients with moderate (II) or severe COVID-19. The dose of tocilizumab was 8 mg/kg and it was administered as a single dose or by intravenous infusion.

Participants

The study cohort comprised 92 patients who had received tocilizumab in our hospital. Daily recordings of clinical data including vital signs and oxygen delivery equipment were obtained on the 1st, 3rd, and 7th days after treatment with tocilizumab. Patients who received tocilizumab had developed COVID-19-associated acute respiratory failure caused by pneumonia and/or were at high risk of deterioration and had a wide range of chest radiological findings.

Oxygen Delivery Equipment

We used nasal cannulas, Venturi masks, non-rebreather masks, nasal high flow, and intermittent positive pressure ventilation. The criterion for changing the means of administering oxygen was failure to maintain SpO₂ at 90% or higher with some means of oxygen administration, at which point an alternative means was substituted (Table 1).

Table 1

Oxygen delivery equipment
Device	Flow rate (L/min)	Percent F_IO₂ delivered
Nasal cannula	1 2 3 4	25 29 33 37
Venturi mask	Red Green	40 60
Non-rebreather mask	10–15	80

Variables

Studied variables comprised age, dyspnoea, lactate dehydrogenase, total bilirubin, CURB-65 score (confusion, urea > 7 mmol/L, respiratory rate ≥ 30/min, systolic blood pressure < 90 mmHg, diastolic blood pressure < 60 mmHg, age > 65 years), SpO₂/F_IO₂, and ROX index. These were measured on admission, immediately before administration of tocilizumab, and on the 3rd and 7th days after initiating tocilizumab. However, we did not examine the potentially confounding or effect-modifying factors of smoking, body mass index, radiological evidence of pneumonia, other treatments (antiviral drugs administered or not, dosage and route of administration of steroids), route of administration of oxygen, prone position therapy or not, implementation of artificial respiration or not. We prioritised investigation of factors that are more critical clinically, considering it unlikely that the above-listed factors had significant impacts on our findings.

Statistical methods

In this study, we calculated the sample size required to determine whether the SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab is a predictor of outcomes. Specifically, we assumed that the hazard ratio is 0.4 when the SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab is 100-fold greater in survivors than in those who died [10, 16] and set the significance level at 5% and the detection power at 90%. Under the condition that the ratio of death to survival was 0.6, the sample size required to detect a significant difference was calculated to be 90; thus, 92 cases was sufficient. SPSS Statistics 26 (IBM, Armonk, NY, USA) was used for all statistical analyses.

Because the data to be compared included scores, categories, and test values that were not normally distributed, Fisher's direct probability and Mann–Whitney's U test were used to compare data of survivors and those who died. Additionally, a Cox proportional hazard model was used to determine the relationship between survival time and assessed clinical variables. ROC analysis with the outcome as the objective variable was used to determine cut-off values for survival and death of variables with significant hazard ratios.

Patient characteristics

All participants were inpatients of our hospital. Their ages ranged from 20 to 82 years and they comprised 66 men and 26 women. Thirty-six patients were treated in the intensive care unit, 14 of whom died; 56 in general wards, 21 of whom died; and 25 were intubated, 17 of whom died.

First, the Shapiro–Wilk test was performed to determine the normality of the factors investigated for possible associations with survival/death. This revealed that none of the factors were normally distributed. We therefore used a non-parametric method to analyse the associations of these factors and identify those that might affect future treatment policies. We planned to analyse the associations of assessed clinical data 3 and 7 days after treatment with tocilizumab. However, having documented a significant difference in mortality 3 days after this treatment, we considered that later evaluation was unnecessary and did not analyse the findings 7 days after treatment. Additionally, by the 7th day more deaths had occurred and more data were missing (Table 1). Missing data were not documented or their possible impact studied; we simply analysed the available data.

Univariate analysis

All assessed factors (except for total bilirubin) showed significant associations with outcomes according to univariate analysis (Table 2).

Table 2

Patient characteristics
Outcome	Survived (n = 57)	Died (n = 35)
Age (years)	65.3	78.3
Female	15	11
SpO₂/F_IO₂ ratio (Day 3)	244	166
ROX index (Day 3)	12.9	8.48
Asthma	5 (8.8)	0 (0.0)
Chronic obstructive pulmonary disease	5 (8.8)	1 (2.9)
Interstitial pneumonia	1 (1.8)	1 (2.9)
Hypertension	30 (52.6)	24 (68.6)
Hyperlipidaemia	18 (31.6)	15 (42.9)
Diabetes	17 (29.8)	15 (42.9)
Coronary artery disease	6 (10.5)	7 (20.0)
Heart failure	2 (3.5)	7 (20.0)
Cancer	10 (17.5)	13 (37.1)
Chronic kidney disease	5 (8.8)	7 (20.0)
Diabetes drug	15 (26.3)	11 (31.4)
Antihypertensive drug	30 (52.6)	23 (65.7)
Lipid metabolizer	17 (29.8)	14 (40.0)
Immunosuppression	5 (8.8)	3 (8.6)
CT pneumonia image on admission	42 (73.7)	27 (77.1)
Avigan	48 (84.2)	29 (82.9)
Dexamethasone	51 (89.5)	33 (94.3)
Remdesivir	25 (43.9)	19 (54.3)
Polymyxin B	9 (15.8)	9 (25.7)
Steroid pulse	11 (19.3)	17 (48.6)
Anticoagulant	39 (68.4)	28 (80.0)
Intravenous immunoglobulin	12 (21.1)	8 (22.9)
Dialysis	2 (3.5)	6 (17.1)
Zithromax	26 (45.6)	6 (17.1)
Antibacterial drugs (other than azithromycin)	31 (54.4)	29 (82.9)

Cox proportional hazard model with significant factors in univariate analysis

Only SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab was significantly associated with survival time (p = 0.008; hazard ratio 0.987; 95% Confidence Interval (CI): 0.977–0.997). Of note, in a multivariate model that considers the effects of multiple factors, interference between factors may obscure their associations. The SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab showed a significant association despite the multiple factors assessed, suggesting that it was indeed associated with survival time (Table 3).

Table 3

Factors associated with death
Relevance to outcome	p
1. Age	0.000
2. Dyspnoea	0.299
3. Number of complications	0.015
4. History of cancer	0.041
5. CURB-65 score (on admission)	0.001
6. Neutrophil cells (Day 0, Day 3)	0.002
7. Lymphocyte cells (Day 0, Day 3)	0.033
8. Neutrophil/lymphocyte ratio (Day 0, Day 03)	0.007
9. LDH (Day 0, Day 3)	0.010
10.T-Bil (Day 0, Day 3)	0.340
11. SpO₂/F_IO₂ (Day 3)	0.000
12. ROX index (Day 3)	0.000

The ROX index was also significantly associated with survival time (p = 0.029; hazard ratio 0.887; 95% CI: 0.797–0.988) when replaced by SpO₂/F_IO₂ (Table 4).

Table 4

Findings on logistic regression analysis
Predictor	β	SEβ	Wald’s	df	p	Odds ratio
Age	0.118	0.063	3.468	1	0.063	1.125
Complications	1.204	0.722	2.780	1	0.095	3.334
Cancer	0.100	1.151	0.007	1	0.931	1.105
CURB-65	−0.991	0.919	1.164	1	0.281	0.371
Neutrophils (%)	0.244	0.208	1.378	1	0.240	1.277
Lymphocytes (%)	0.037	0.308	0.014	1	0.905	1.037
LDH (U/L)	0.003	0.004	0.534	1	0.465	1.003
S/F ratio	−0.016	0.006	6.146	1	0.013*	0.984

Predictor	β	SEβ	Wald’s	df	p	Odds ratio
Age	0.032	0.030	1.169	1	0.280	1.032
Complications	-0.046	0.2622	0.031	1	0.860	0.955
Cancer	0.453	0.553	0.671	1	0.413	1.573
CURB-65	0.616	0.413	2.217	1	0.137	1.851
Neutrophils (%)	0.048	0.119	0.617	1	0.683	1.050
Lymphocytes (%)	0.023	0.150	0.022	1	0.881	1.023
LDH (U/L)	0.002	0.001	1.527	1	0.217	1.002
ROX index	-0.119	0.055	4.775	1	0.029*	0.887
*Significant finding

Logistic regression analysis

Like the Cox proportional hazard model, logistic regression analysis was performed using eight factors as covariates. Only SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab was significantly associated with outcomes (p = 0.013; odds ratio 0.984; 95% CI: 0.972–0.997). The association with the ROX index was not statistically significant (p = 0.057; odds ratio 0.851; 95% CI: 0.722–1.004).

ROC analysis

ROC analysis of the SpO₂/F_IO₂ identified a cut-off point of 155.83 for SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab. The area under the curve was 0.819 (p = 0.000, 95% CI: 0.728–0.909), indicating that SpO₂/F_IO₂ ratio 3 days after this treatment is a moderately accurate predictor of outcomes. Additionally, Fisher’s test confirmed a significant difference (Fig. 1; left panel). ROC analysis of the ROX index identified a cut-off point of 14.52 3 days after treatment with tocilizumab. The area under the curve was 0.770 (p = 0.000; 95% CI: 0.673–0.868), indicating that the ROX index 3 days after this treatment is a moderately accurate predictor of outcomes. Additionally, Fisher’s test confirmed a significant difference (Fig. 1; right panel).

Course of respiratory status after administration of tocilizumab

Only three patients showed improvement in respiratory status on the 3rd day of tocilizumab administration, the respiratory status of the remaining patients having deteriorated in the first 3 days after administration (Fig. 2). The number of days between onset and administration of tocilizumab was the same for both survivors and those who died, about 10 days; this difference was not significant (Fig. 3). The relationship between SpO₂/F_IO₂ and the ROX index is shown in a scatter diagram. The solid line indicates the cut-off values. The scatter plot shows that SpO₂/F_IO₂ is a slightly better prognostic indicator (Fig. 4).

Prognosis and means of oxygen delivery

When we assessed our findings by means of administering oxygen, both S/F ratio and ROX index tended to be higher for nasal cannulas, whereas S/F ratio and ROX index tended to be lower for intermittent positive pressure ventilation, non-rebreather masks, and nasal high flow (Fig. 5). In terms of survival and death, nasal cannulas tended to be associated with a greater proportion of survivors, whereas intermittent positive pressure ventilation, non-rebreather masks, and nasal high flow tended to be associated with a greater proportion of deaths (Fig. 6). The means of administering oxygen was changed in 38 patients, 35 of whom because their condition had deteriorated (Table 5). These changes in means of administering oxygen did not affect survival and death (χ² = 0.1149 (p ≥ 0.05)).

Table 5

Effects of change in oxygen delivery equipment
Deterioration
NHF⇨IPPV	1	VM⇨NHF	4	NC⇨IPPV	2
NM⇨IPPV	4	VM⇨NM	6	NC⇨NHF	5
NM⇨NHF	7			NC⇨VM	6
Improvement
NM⇨VM	1	VM⇨NC	1	NC⇨Room air	1

Numbers after each change denote number of patients managed in this way.

IPPV: intermittent positive pressure ventilation; NC: nasal cannula; NHF: nasal high flow;

NM: non-rebreather mask; VM: Venturi mask

This is the first published report to show the usefulness of the SpO₂/F_IO₂ and ROX index in predicting outcomes of treatment with tocilizumab. We performed this study because we thought that determining the relationships between SpO₂/F_IO₂ and ROX index 3 days after treatment with tocilizumab and mortality would provide data that would impact future treatment policies for COVID-19. We found that the ROX index was not significantly associated with outcomes according to odds ratios; however, it did show a significant hazard ratio for survival time. Larger studies may therefore reveal a significant relationship between the ROX index and outcomes.

We did not examine the effects of intubation in this study. Three of the 25 patients who underwent intubation and artificial respiration had been intubated before administration of tocilizumab; two of them died. Nine patients, six of whom died, had been intubated within 3 days after treatment with tocilizumab. Thirteen patients, nine of whom died, had been intubated 4 days after initiating tocilizumab. We did not evaluate the impact of timing of intubation in this study; however, we can state that it was not associated with mortality rate.

In addition, we used the respiratory therapy algorithm of the Japanese COVID-19 guidelines for changing the means of administration of oxygen. Depending on how this study is viewed, everything is determined by whether tocilizumab has a beneficial effect by the third day, regardless of whether the patient has severe respiratory failure initially. Changing the means of administering oxygen during the course of treatment could impact the effectiveness of tocilizumab. Our opinion is that, even if the oxygen concentration during oxygen administration differs depending on the inspiratory volume and the way the patient wears the means of delivery of oxygen, this is irrelevant because this study is not a before-and-after comparison. Also, provided oxygen-related variables do not differ significantly, the conclusion of this study is highly significant, that is, that tocilizumab is ineffective. We performed the χ² test to determine whether survival, death, and the presence or absence of changes in the means of administering oxygen were independent variables; this showed that they were not independent. Means of administering oxygen, such as nasal high flow, can reportedly both aggravate the disease and improve the prognosis [19]. It is possible that we did not identify a significant difference because we had too few participants. However, we do not believe that a larger study would reach a different conclusion.

The SpO₂/F_IO₂ (235–315) is reportedly a helpful index for evaluating acute lung injury and ARDS, as is the PaO₂/F_IO₂ (200–300) [16]. It has also been reported that a pre-admission SpO₂/F_IO₂ of 50–100 predicts post-admission death [10]. These data indicate that an SpO₂/F_IO₂ cut-off value of ≤ 155 is an important prognostic indicator.

One possible explanation for our high cut-off value for ROX is that measurement of the respiratory rate (15 seconds) was inaccurate. Furthermore, hypoxia may not drive dyspnoea, even when the former is severe [20].

In our study, we investigated the SpO₂/F_IO₂ and ROX index, the latter being regarded as indicating when additional treatments, including aggressive artificial respiration, should be initiated. In the future, it may also be used to predict the effectiveness of tocilizumab.

On 11 Feb 2022, tocilizumab was the first monoclonal antibody used to treat COVID-19. An important finding in severe COVID-19 is that protective immunity can switch to immune dysregulation [21]. In the JOVITA study in Japan, the usefulness of tocilizumab for severe COVID-19 was evaluated at 28 days [22]. This was also the timing of evaluation in the REMDACTA and EMPACTA studies [23, 24]. There are some reports of achieving reduction of fever and CRP concentrations in patients with CRP ≥ 40 [25]. Additionally, some studies have found relationships with medium- to long-term prognosis [24, 25]; however, these findings vary between studies.

Limitations of our study include that it was a single-armed, retrospective study of patients with varying severity of disease and we did not compare our findings with those in patients who did not receive tocilizumab. Tocilizumab was administered to all participants in many other studies. Another limitation may be the small number of variables analysed. Additionally, we did not investigate potential bias. Our patient cohort comprised patients aged 18 years or older who had received tocilizumab. We cannot be sure of the generalisability of our findings because all participants were Japanese and the study cohort was relatively small. However, we consider it likely that our findings are generalisable. We also did not study respiratory therapy in those who died. Our findings indicate that artificial respiration should be initiated when the SpO₂/F_IO₂ ratio is ≤ 155. Of note, during this research period, the only available antiviral drug was remdesivir. Other drugs have since become available; thus, how to modify current treatment requires further study.

We found that the SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab predicts efficacy and prognosis. Further investigation is essential to confirm our findings.

ARDS

acute respiratory distress syndrome

CRP

C-reactive protein

HFT

high flow therapy

PaO₂

partial pressure of oxygen

ROX index

ratio of oxygen concentration to respiratory rate

SpO₂/F_IO₂

oxygen saturation/fraction of inspired oxygen

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Our study was approved by the Clinical Research Ethics Committee of the Nihon University Hospital (Approval number RK-200714-13). The need for written informed consent was waived by the ethics committee. All protocols and practices were in accordance with the World Medical Association’s Declaration of Helsinki.

CONSENT FOR PUBLICATION

Not applicable.

Availability of data and materials

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

COMPETING INTERESTS

The authors declare that they have no competing interests.

FUNDING

No funding was received specifically for this study.

AUTHORS’ CONTRIBUTIONS

I.Y., F.N., O.R., N.T., J.Y., and Y.S. carried out the experiment. N.M., H.A., H.M., Y.S., F.A., N.T., S.K., and S.S. contributed with acquisition. H.K. and H.H. contributed with analysis. Y.K. took the lead in writing the manuscript. S.T., T.T., K.C. and Y.G. helped supervise the final version of the manuscript. All authors discussed the results and contributed to the final manuscript.

ACKNOWLEDGEMENTS: We thank S. Ohtsuki for valuable discussions and statistics, K. Soda for assistance with creating the figures, and Y. Gon for carefully proofreading the manuscript. Additionally, we thank Dr Trish Reynolds, MBBS, FRACP, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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No competing interests reported.

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SpO₂/F_IO₂ ratio 3 days after treatment with tocilizumab is a prognostic factor in patients with COVID-19: A retrospective cohort study

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Abstract

Background:

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Conclusions:

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Background

Methods

Setting

Participants

Oxygen Delivery Equipment

Variables

Statistical methods

Results

Patient characteristics

Univariate analysis

Cox proportional hazard model with significant factors in univariate analysis

Logistic regression analysis

ROC analysis

Course of respiratory status after administration of tocilizumab

Prognosis and means of oxygen delivery

Discussion

Conclusions

List Of Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1