Time to Discontinuation of Supplemental Oxygen Therapy and Predictors Among Adult Severe COVID-19 Patients Admitted at Eka Kotebe General Hospital, Addis Ababa, Ethiopia, 2022: Retrospective Follow Up Study

DOI: https://doi.org/10.21203/rs.3.rs-2111702/v1

Abstract

Background: Understanding predictors of duration of oxygen requirement helps to identify risk groups for prolonged need of oxygen therapy and ensure timely treatment. However, not adequately studied including important predictors at admission such as baseline vital signs, laboratory biomarkers and treatments. Therefore, aim of this study was to assess time to discontinuation of supplemental oxygen therapy and its predictors among severe COVID-19 adult patients admitted at Eka Kotebe General Hospital, Addis Ababa, Ethiopia, 2022.

Methods: A facility based retrospective follow-up study was conducted among severe COVID-19 adult patients received supplemental oxygen therapy admitted at Eka Kotebe General Hospital, Addis Ababa, Ethiopia from 13th March 2020 to 6th April 2022. Data were collected using structured data extraction checklist. Then coded and entered into EPI-data 3.1 cleaned and exported to StataSE 14 and recoded for analysis. Frequencies and percentage, median and interquartile range, Kaplan Meier plots and Log-rank tests were used to describe data and compare survival distribution between groups. Cox proportional hazard model assumption and model fitness were checked. Finally Stratified Cox regression model was fitted. Hazard ratio with 95% confidence interval and P-value < 0.05 were used as a statistically significant association and interpretation of results.

Results: Median survival time to discontinuation of supplemental oxygen therapy was 10 days (IQR=6-15). Preexisting Comorbidities (AHR; 0.45, 95% CI:0.36-0.57), shortness of breath (AHR= 0.49, 95%CI:0.36-0.66), chest pain (AHR; 0.43, 95%CI: 0.26-0.71), nausea/vomiting (AHR= 0.51,95%CI:0.38-0.68),systolic blood pressure≥140mmHg (AHR= 0.45, 95%CI:0.33-0.61),high white blood cell count(AHR; 0.65,95%CI:0.49-0.85), neutrophil (AHR; 0.56, 95%CI:0.43-0.73), elevated alkaline phosphatase(AHR; 0.20, 95%CI:0.15-0.29), creatinine (AHR; 0.32, 95%CI:0.22-0.47) were significant predictors.

Conclusions and Recommendations: Median survival time to discontinuation of supplemental oxygen was reasonably longer. Severe COVID-19 adult patients with preexisting comorbidities, shortness of breath, chest pain, nausea/vomiting, high systolic blood pressure, white blood cell, neutrophil count, elevated alkaline phosphatase and creatinine should be expected to require longer duration of oxygen therapy and identified early and given more attention.

Background

In late 2019, the novel coronavirus was identified as the cause of a group of cases of pneumonia in Wuhan, a city in Hubei Province, China. The pandemic caused by the virus called Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has become one of the biggest health challenges worldwide. The largest increase in COVID-19 cases currently accounts for nearly 463 million cases and 6 million deaths worldwide, 8.5 million cases and 170,000 deaths in Africa and 469,000 cases and 7,500 deaths in Ethiopia reported since 17 March 2022 (1). The case, announced on March 13, 2020, is the first to be reported in Ethiopia since the outbreak began in China in December 2019 (2).

Most people with COVID-19 have a mild or moderate illness (> 80%), WHO currently estimates that about 14% of cases may be severe and require oxygen and an additional 5% will be critical and need treatment in intensive care unit (3). One of the major problems with COVID-19 is Acute Respiratory Distress Syndrome (ARDS). A study done in Ethiopia, prevalence of Acute Respiratory Distress Syndrome among severe COVID-19 patients was 32% (4). Hypoxia not only represents the effect of respiratory disease, but also contributes to the ongoing lung injury after onset of initial injury and end up with death (5). WHO and Ministry of Health Ethiopia recommended immediate provision of oxygen therapy for patients with severe COVID-19 pneumonia. Any stable patient with SpO2 < 90% or patients while in emergencies such as airway obstruction, apnea, central cyanosis, shock, coma and seizures with SpO2 < 94%, need immediate airway management and resuscitation (5, 6). Delays in detecting and correcting hypoxia in pneumonia lead to more severe disease, increased invasive mechanical ventilation and mortality (7). Intensive treatment using tracheal intubation and mechanical ventilation seems to be of no benefit to patients or even harmful. The highest mortality rate for those COVID-19 patients in ventilators was reported to reach72–86% (8, 9). Tissues vary considerably in their sensitivity or tolerance to low oxygen saturation (hypoxia). For instance, neurological cells, kidney and liver cells tolerate low oxygen saturation only a few minutes. This has an important implication in the oxygen therapy of severely ill patients with hypoxemia (10).

Old age and male sex increased risk of failure of high flow nasal oxygen or mechanical ventilation, mortality or unfavorable outcomes (including mortality or intensive care) (1116).

Sign and symptoms such as fever, high respiratory rate, elevated systolic blood pressure, low SpO2 in admission, difficulty of breathing, chest pain, time from onset of symptoms to hospital admission and presence of comorbidities were associated with delayed recovery, high flow nasal oxygen (HFNO) ineffectiveness, increased oxygen demand or support, in hospital mortality or unfavorable out comes(1723).

High baseline white blood cell, neutrophil count, lymphocytopenia, increased serum creatinine elevated aspartate aminotransferase were associated with increased need for oxygen support, high flow nasal oxygen ineffectiveness, hospital stay, mortality rate or clinical deterioration (intensive care unit transfer or death)(17, 20, 2427).

Early identification of predictors for prolonged time of oxygen therapy need help to timely differentiate the risk and safe increase in respiratory support and management prior to more clinical deterioration (intensive care unit transfer or death) of severe COVID-19 patients. But not adequately studied including important predictors at admission such as baseline vital signs, laboratory biomarkers and treatments and previous study in Ethiopia recommended further study by involving this listed predictors to predict the time to discontinuation of oxygen therapy (28, 29).

Therefore, this research was tried to fill those information gaps of time to discontinuation of supplemental oxygen therapy and its predictors among adult severe COVID-19 patients hospitalized at Eka Kotebe General Hospital, Addis Ababa, Ethiopia, 2022.

Methods

Design and settings

This was a retrospective follow-up study including all a real-time reverse transcriptase- polymerase chain-reaction (RT-PCR) assay of nasopharyngeal swab specimens confirmed severe COVID-19 adult patients admitted to Eka Kotebe General Hospital COVID-19 isolation and treatment Center located in the sub-city of Yeka, Addis Ababa, the capital of Ethiopia where the country's largest airport is located and the seat of Africa Union. It has a five-floor building that provides 150-bed mental health services and a 200-bed general medical service. The hospital was opened in September 2019 and with the outbreak of COVID-19 the hospital was thoroughly rebuilt and changed into a COVID-19 treatment center where became the first hospital to isolate and treat patients with COVID-19 in Ethiopia. It had the capacity to admit 600 cases with 16 dedicated ICU beds. Isolation and treatment center is a place where all Ethiopian and non-Ethiopian citizens with COVID-19 are accepted for isolation, care and support (3031) . The study was conducted from 13th March 2020 to 6th April 2022.

Variables

The outcome variable was time to discontinuation of supplemental oxygen therapy, constructed as the time between the initiations of supplemental oxygen therapy at admission to discontinuation of supplemental oxygen therapy for each patient (in days). 

Event: Discontinuation of supplemental oxygen therapy was decided by:-

1. If the indication for initiation of supplemental oxygen therapy resolved AND/OR (5).

2. Oxygen saturation level maintained:

SpO2 ≥ 94% any patient with emergency signs during resuscitation (obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma and/or convulsions) AND/OR 

SpO2 ≥ 90% on room airs any patient without emergency signs and hypoxemia (i.e. stable hypoxemic patient) both at rest and while ambulating (3233).

Censored: Includes patients lost to follow-up, transferred out to intensive care unit (ICU) or to other facilities, died or completed the follow-up period before supplemental oxygen therapy discontinued.

Demographic factors, underlying medical comorbidities, clinical symptoms and signs, laboratory tests, treatments were considered as independent variables and extracted from recorded medical charts of patients by trained nurses.  Laboratory tests consisted of Blood Routine (Neutrophil, lymphocyte, platelet counts, total WBC, Random blood glucose and Hemoglobin) and organs functions tests (BUN, creatinine, AST, ALT, and ALP).  Underlying medical comorbidities mainly included hypertension, diabetes and coronary heart disease. Treatment included pre-admission and chronic systemic corticosteroid intake, treatments during hospitalization (redmesivir, ACEI/ARBs, anti-pain and type of anti-pain therapy).

 

Statistical analysis

Frequency and percentage for categorical variables, median with interquartile range (IQR) to summarize continuous variables was used to describe the study population in relation to relevant variables and presented using tables and graphs. Survival experience of different groups was compared using Kaplan Meier survival curves. Log-rank test was used to assess significant difference among survival distributions of groups for equality.

Bivariable Cox-proportional hazards regression model was fitted for each predictor. Those variables having a p-value below 0.2 were selected as a possible predictor to be included into multivariable COX regression. Then, the further variable selection in multivariable Cox – proportional regression model was undertaken using a forward stepwise variable selection approach a p-value < 0.05 as a cut point. The fundamental assumption of Cox Proportional Hazard model, which is proportional hazards assumption, was tested using Log minus Log function before multivariable cox regression model fitted and also was checked using Schoenfeld residual test (global test) and the time varying Covariates (TVC) at P-value 0.05. If P – value > 0.05 were considered as fulfilling the assumption. Parallel lines of Log minus Log survival plot between groups indicate proportionality (34).The proportional hazard assumption was violated and the Cox-Snell residual plot suggested that the Cox proportional hazard regression model does not fit the data adequately. Therefore, the multivariable stratified Cox regression model was fitted and adequate to be used. The hazard ratio with its 95% confidence interval was used to measure the strength of association and the p-value < 0.05 was used to identify the statistically significant association.

Results

Socio-Demographic Characteristics

 The median age of the patients was 58((IQR = 41 – 66) years. The minimum and maximum ages of patients were 19 and 86 years respectively. Four hundred seventy two (69.01%) of the patients were males and six hundred twenty six (91.52 %) of the patients were from Addis Ababa (Table 1).

 

 

 

Table 1: Socio–demographic characteristics of adult severe COVID-19 patients who received supplemental oxygen therapy admitted at EKGH, Addis Ababa Ethiopia, March April 2020 to 2022 (n=684).

Variables 

Status at last follow up of  SO     therapy 

Total (%)

No. of

Event (%)

No. of

Censored (%)

Age     Median(IQR)

56.5(40 – 66)

60(49 – 70)       

58( 41 – 66)

Age

≤60

341(82.17)

74 (17.83)

415 (60.67)

> 60 

215(79.93)

54 (20.07)

269 (39.33)

Sex

Male 

404(85.59)

68(14.41)

472(69.01)

Female

152(71.70)

60(28.30)

212(30.99)

 

Clinical Characteristics 

All adult severe COVID-19 patients were symptomatic at admission. At admission, the median Spo2 those who were on supplemental oxygen therapy was 94 %( IQR=92 – 95%) and at the last date of follow up median SpO2 those who were censored and on oxygen therapy was 93% (IQR = 88 – 96%) and those who were experienced an event and on room air was 92 %( IQR = 91 – 94%).

The most common symptom at admission was cough (93.86%) and only few had diarrhea (8.92%) (Fig1). Among overall COVID-19 patients, four hundred forty (64.33%) had a history of at least one preexisting medical condition. The majority of patients had diabetes mellitus, followed by hypertension, HIV/AIDS, cardiac illness, tuberculosis, asthma and COPD (Fig2) (Table 2).

HTN: Hypertension; DM: Diabetes Mellitus; CI: Cardiac illness; COPD: Chronic Obstructive Pulmonary Disease; TB: Tuberculosis; CKD: Chronic Kidney Disease; CLD: Chronic Liver Disease; HIV: Human Immunodeficiency Virus

Table 2: Clinical features and preexisting comorbidities of adult severe COVID-19 patients who received supplemental oxygen therapy admitted at EKGH, Addis Ababa Ethiopia, March 2020 to April 2022 (n=684).

Clinical characteristics  and co- morbidities

Status at last follow up of  

SO  therapy 

Total (%)

No. of 

Event (%)

No. of 

Censored (%)

Duration of symptoms onset prior to admission    (Median(IQR) )

7(5 – 10)

10(7 – 14)

7(5 – 11)

Easily fatigue 

yes      

487(80.36)

119(19.64)

606(88.60)

no

69(88.46)

9(11.15)             

78(11.40)

Febrile sensation(fever)

yes      

369(86.01)

60(13.99)

429(26.72)

no

187(73.33)

68(26.67)

255(37.28)

Headache 

yes      

278(91.45)

26(8.55)            

304(44.44)

no

278(73.16)

102(26.84)            

380(55.56)

Arthralgia

yes      

224(89.60)

26(10.40)

250(36.55)

no

332(76.50)

102(23.50)

434(63.45)

Myalgia

yes      

196(91.59)

18(8.41)       

214(31.29)

no

360(76.60)

110(23.40)

470(68.71)      

Sore throat

yes      

57(78.08)

16(21.92)

73(10.67)

no

499(81.67)

112(18.33)

611(89.33)

Diarrhea

yes      

53(86.89)

8(13.11)

61(8.92)  

no

503(80.74)

120(19.26)            

623(91.08)           

Temperature (℃)  (Median(IQR))

36.4(36.1 – 37.1)

36(35 – 37 )        

36.4 (36 – 37)

Temperature (℃)

<37.5 

454(80.35)

111(19.65)

565(82.60)

≥37.5 

102(85.71)

17(14.29)

119(17.40)

RR(breath/min)  (Median(IQR)) 

28 (26 – 36)       

32 (28 – 40)

30 (26 – 36)

HR( beats/min)  (Median(IQR))

  89(82 – 102)       

96 (96 – 109)         

94 (83 – 103)

HR( beats/min)

< 100

376(83.00)

77(17.00)

453(66.23)

≥ 100

180(77.92)

51(22.08)

231(33.77)

SBP(mmHg)   (Median(IQR) )

125(110 – 135)      

 121(110 – 141)      

125 (110 – 135)

HTN

Yes

169(83.23)

34(16.75)

203(29.68)

no

387(80.46)

94(19.54)

481(70.32)

DM

Yes

210(83.33)

42(16.67)

252(36.84)

no

346(80.09)

86(19.91)

432(63.16)

CI

Yes

50(100)

0(0.00)

50(7.31)

no

506(79.81)

128(20.19)

634(92.69)

COPD

Yes

19(67.86)

9(32.14)  

28(4.09)            

no

537(81.86)

119(18.14)

656(95.91)

Asthma

Yes

33(78.57)

9(21.43)

42(6.14)            

no

523(81.46)

119(18.54)

642(93.86)

TB

Yes

32(65.31)

17(34.69)

49(7.16)            

no

524(82.52)

111(17.48)

635(92.84)

CKD

Yes

1(10.00)

9(90.00)

10(1.46)

no

555(82.34)

119(17.66)

674(98.54)

CLD

Yes

8(100)

0(0.00)

8(1.17)

no

548(81.07)

128(18.93)      

676 (98.83) 

HIV

Yes

56(76.71)

17(23.29)

73(10.67)

no

500(81.83)

111(18.17)

611(89.33)

Chronic neurological disease

Yes

2(20.00)

8(80.00)

10(1.46)

no

554(82.20)

120(17.80)

674(98.54)

 

Treatments and Medications Histories 

Most of the patients (79.68%) were received anti-pains. But small numbers of patients were treated with redmesivir (6.58%), ACEI/ARBS (12.57%). Only 3.80% of adult severe COVID-19 patients had a history of chronic corticosteroid use prior to admission (Table 3).  

Table 3: Treatment and medication histories of adult severe COVID-19 patients who received supplemental oxygen therapy admitted at EKGH, Addis Ababa Ethiopia, March 2020 to April 2022 (n=684).

Variables 

Status at last follow up of  SO     therapy 

Total (%)

No. of

Event (%)

No. of

Censored (%)

Redmesivir

yes  

28(62.22)

17(37.78)            

45(6.58)

no

528(82.63)

111(17.67)

639(93.42)

ACEI/ARBS

yes     

77(89.53)

9(10.47)

86(12.57)

no

479(80.10)

119(19.90)

598(87.43)

Anti – pains 

yes     

442(81.10)

103(18.90)

545(79.68)

no

114(82.01)

25(17.99)

139(20.32)

Type of Ant – pains

NSAIDS

40(59.70)

27(40.30)

67(12.29)

Other types

376(84.68)

68(15.32)

444(81.47)

Mixed 

26(76.47)

8(23.53)

34(6.24)

Chronic corticosteroids  use prior to admission 

yes     

17(65.38)

9(34.62)

26(3.80)

no

539(81.91)

119(18.09)

658(96.20)       

Baseline Laboratory Biomarkers of the Patients 

Nearly one third of adult severe COVID-19 patients had lymphocytopenia (72.66%). More than half of the patients had RBS above 140mg/dl (53.36%) and high neutrophil count (66.37%). Leukocytosis was found in 21.19%, thrombocytopenia in 31.58% and anemia in 4.18% of the patients.  Elevated level of AST (45.18%) and BUN (42.25%) were more common than elevated levels of ALP (19.74%), ALT (21.93%) and creatinine (17.69%) (Table 4)

Table 4: Baseline laboratory biomarkers results at admission  of  adult severe COVID-19 patients who received supplemental oxygen therapy admitted at EKGH, Addis Ababa Ethiopia, March 2020 to April 2022 (n=684). 

Variables 

Status at last follow up of  

SO  therapy 

Total (%)

No. of

Event (%)

No. of

Censored (%)

Total WBC cells×10^3/µl)  (Median(IQR)) 

6.72(5.31 – 9.04)             

12.35( 6.42 – 15.71) 

7.52(5.32 –10.90)

Lymphocytes count (%)    (Median(IQR))

11.8(7.1 – 24.7)            

8.2(3.5 – 10.4 )            

10.30(6.1 0–24.05)

Lymphocytes count (%)

≥21

187(100.00)

0(0.00)

187(27.34)

<21

369(74.25)

128(25.75)

497(72.66)

Neutrophils (%) (Median(IQR))

80.9(66.9 – 88)           

86.3(80 – 93.9)        

81.85(68.30 – 90.60)

     Platelets (cells×10^3/µl)      (Median(IQR)

188(146 – 262 )

197(126 – 221 )      

188(145 – 228)

Platelets

(cells×10^3/µl) 

≥150

384(82.05)

84(17.95)

468(68.42)

<150

172(79.63)

44(20.37)

216(31.58)

Hemoglobin (g/dl) (Median(IQR))

14.6(13.9 – 16)             

14.2(12.7 – 15.8 )           

14.5(13.80 – 15.80)

Anemia

 

yes     

73(75.26)

24(24.74)

97(14.18)

no

483(82.28)

104(17.72)

587(85.82)

RBS (mg/dl)  (Median(IQR))

143(122 – 199)

222(126 – 272)     

144(122 – 206)

RBS (mg/dl)

≤140

267(83.70)

52(16.30)

319(46.64)

>140

289(79.18)

76(20.82)

65(53.36)

AST(IU/L)   (Median(IQR))

36(26 – 63)

42(31 – 85)          

36(27.50 – 63)

AST (IU/L)

≤ 37

323(86.13)

52(13.87)  

375(54.82)

> 37

233(75.40)

76(24.60)

309(45.18)

ALT(IU/L)  (Median(IQR))

39(30 – 61)

39(24 – 80)          

39(29 – 61)

ALT(IU/L)

≤ 63

441(82.58)

93(17.42)

534(78.07)

> 63

115(76.67)

35(23.33)

150(21.93)

ALP (IU/L)  (Median(IQR))

68(56.5 – 101)              

73(50 – 127)            

68(56 – 104)

ALP (IU/L)

≤116 

464(84.52) 

85(15.48) 

549(80.26) 

> 116 

92(68.15) 

43(31.85) 

135(19.74) 

Creatinine(mg/dl)(Median(IQR)

0.94(0.78 – 1.1)       

1.26(1.06 – 1.75)           

1.01(1 – 13)

Creatinine(mg/dl)

≤1.3 

495(87.92) 

68(12.08) 

563(82.31) 

> 1.3 

61(50.41) 

60(49.59) 

121(17.69) 

BUN(mg/dl) (Median(IQR))

 15(11 – 22)

23(19 – 41)      

7(0.82 – 1.16)

BUN(mg/dl)

 

≤18

369(93.42)

26(6.58)

395(57.75)

> 18

187(64.71)

102(35.29)

289(42.25)

RBS: Random Blood Sugar; AST: Aspartate Transaminase; ALT: Alanine Transaminase; ALP: Alkaline Phosphatase; BUN: Blood Urea Nitrogen

Censoring Status at the Last Follow-up 

Among the 684 patients, 556 (81%) of the patients achieved the event (supplemental oxygen therapy discontinued) while 128 (19%) were censored. Among the 128 censored observation, 9 (7.03%) died and 119(92.97 %) were transferred to ICU for further care (Figure 3)

Overall Survival Estimates for Time to Discontinuation of Supplemental Oxygen Therapy and Comparison of Survival Status among Groups

The median follow up time was 9 days (IQR= 5-13) and the lowest and the highest length of follow-up time were 2 and 61 days respectively, and the total person-time risk was 6829. The overall supplemental oxygen therapy discontinuation rate was 8.14 (95% CI: 7.49 – 8.85) per 100 person day observation.  

The estimated median survival time to discontinuation of supplemental oxygen therapy was 10 days (IQR= 6-15).

The survival status of adults with severe COVID-19 who were received supplemental oxygen therapy was estimated by the Kaplan-Meier survival curve. The curve tends to decrease rapidly within the first ten days indicating that most the cases discontinued from supplemental oxygen therapy within this time (Fig 4). The survival estimates of adult severe COVID-19 patients who were received supplemental oxygen therapy were varied in relation to presence of comorbidity, SOB, chest pain, SBP ≥140 mmHg, high total WBC, neutrophil count and elevated level of ALP and serum creatinine. The KM survival function graph showed that those severe COVID-19 patients presented with conditions (variables) mentioned above at admission had a longer survival experience (time to discontinuation of supplemental oxygen therapy) as compared to those without such conditions. For instance as shown in figure 5 patients come with SOB at admission had a longer survival experience than those without SOB. This means patients with SOB required longer duration of supplemental oxygen therapy than those without the complaint of SOB at admission. 

Log-Rank test was also used test survival function differences between categories of predictors. According to the log rank test result, found that there is a significant difference in survival experience among the following categories of predictors at p-value < 0.05. The   median  duration of oxygen therapy was longer among patients with age above 60 years(11days) compared to those ≤ 60 years(9days) ,female sex(12 days) than male patients(10days)  and  a complaint of shortness of breath (11 days) compared to those with no such complaint (7 days), Chest pain (19days) compared to those with no chest pain (10 days), sore throat (11days) compared to those with sore throat (10 days), diarrhea (16 days) to those with no such complaint (10days). Patients with SBP≥140mmHg, RR > 30 breath/min also needed a longer duration of oxygen therapy.  On the other hand patients with a complaint of febrile sensation, headache or myalgia were needed shorter duration of oxygen therapy. But the log rank test didn’t show any significant difference in the survival function among the other sign and symptom groups (all p-values >0.05). The survival time were significantly longer among patients with a history of one or more pre-existing co-morbid illness, hypertension, COPD, tuberculosis and chronic liver disease

It was also found that there was a statistically   significant longer median survival time to discontinuation of oxygen therapy among those who were treated with anti-pains and had leukocytosis ,high neutrophil count, lymphocytopenia , anemia ,elevated AST,ALT,ALP, serum creatinine and BUN  whereas on contrary treatment with ACEI/ARBS reduced the survival time

Predictors of the Survival Time (Time to Discontinuation of Supplemental Oxygen Therapy) 

Figure 6 showed that the log minus log survival curve seems to be parallel among the groups classified by presence of SOB and high WBC count but clearly crossed each other (i.e. non- proportional) among the groups of anemia and HIV/AIDS. Global fitness test of multivariable Cox PH model were found to be p-value < 0.001 and the time- varying covariates (TVC) were also found that anemia, myalgia, respiratory rate and HIV/AIDS had time varying effect. Therefore, there were significant evidences that suggested the assumptions of proportional-hazard were violated.  Even if the proportional hazard assumptions were found to be violated, the model adequacy and fitness of final multivariable Cox PH model was checked by Cox-Snell residual plot showed it was not a well fitted model.

Predictors that had association at a p-value of < 0.2 in bivariable Cox PH regression were included in multivariable Cox regression. On the bivariable Cox PH model  Age, sex ,cough ,SOB  ,febrile sensation , chest pain ,headache ,myalgia  ,sore throat , nausea/vomiting ,diarrhea ,duration of symptoms,  body temperature ,RR, SBP ,presence of   comorbidities , HTN ,DM ,COPD ,TB ,CLD   ,HIV ,remdesivir ,ACEI   ,Anti-pains , total WBC ,   Lymphocyte, Neutrophil count , Anemia , AST, ALT,ALP, Creatinine and BUN were found to be possible  predictors of time to discontinuation of supplemental oxygen therapy  among adult severe COVID-19patients. The forward stepwise approach was used for variable selection to fit the final multivariable Cox PH model at a p-value of <0.05. Finally multivariable stratified Cox regression model stratified by HIV/AIDS, Myalgia, RR and anemia, and including ten predictors in the model that were not violated PH assumption (Preexisting comorbidities, cough, SOB, chest pain, nausea/vomiting, SBP, and total WBC, Neutrophil count, ALP and serum creatinine level) . All were statistically significant predictors of time to discontinuation of supplemental oxygen therapy (Table 5)

 Before interpretation of the result of the fitted multivariable stratified Cox proportional hazard regression model, overall model adequacy and model fitness were checked by Cox-Snell residual plot and global fit test and found that it was appropriate. After stratified Cox proportional hazard model fitted there was no a significant evidence suggested the violation of assumptions of proportional hazard (global test p-value= 0.1308). This supported the Cox-Snell residual plot finding of model adequacy (Fig 7).

The result of multivariable analysis after adjusting for other covariates revealed that the rate of  discontinuation of supplemental oxygen therapy  of adult severe COVID-19 patients with preexisting comorbidities decreased by 55% as compared to those without comorbidities (AHR; 0.45, 95% CI (0.36 – 0.57), p-value<0.001). Having a complaint of shortness of breath at admission was associated with a 51% lower rate of discontinuation of supplemental oxygen therapy compared to those patients with no such complaint (AHR= 0.49, 95%CI (0.36 – 0.66), p-value<0.001).Supplemental oxygen therapy discontinuation rate among adult severe COVID-19 patients admitted with chest pain reduced by 57% as compared to those who had no (AHR; 0.43, 95%CI (0.26 – 0.71), p-value=0.001). The rate of discontinuation of supplemental oxygen therapy among patients with nausea/vomiting was 49% lower than patients without such complaint at admission (AHR= 0.51, 95%CI (0.38 – 0.68), p-value<0.001). Discontinuation of supplemental oxygen therapy among patients admitted with systolic blood pressure ≥140mmHg the rate was decreased by 55% as compared to patients  with   systolic blood pressure <140mmHg at admission (AHR= 0.45, 95%CI (0.33 – 0.61), p-value<0.001). On contrary patients presented with cough at admission the rate of discontinuation of supplemental oxygen therapy was 91% higher than patients had no cough (AHR; 1.91, 95%CI (1.19 –3.04), p-value=0.007) (Table 5).

Laboratory biomarkers that found to be an independent predictor of time to discontinuation of supplemental oxygen therapy were high total WBC count  (AHR; 0.65, 95%CI (0.49 – 0.85), p-value=0.002),high Neutrophil count (AHR; 0.56, 95%CI(0.43 – 0.73),  p-value<0.001), elevated Alkaline phosphatase (ALP) (AHR; 0.20, 95%CI (0.15 – 0.29), p-value<0.001), elevated serum creatinine (AHR; 0.32, 95%CI (0.22 – 0.47), p-value<0.001) (Table 5).

The Cox- Snell plot of Figure 14 indicates that at beginning the plot makes Nelson-Aalen cumulative hazard function straight lines through the origin and follows the Cox-Snell estimate of residuals 45 degree line very closely except for some large values of time suggesting that the fitted model is appropriate. It is very common for models with censored data to have some wiggling at large values of time and it is not something which should cause much concern. 

Discussion

The overall median survival  time to discontinuation of supplemental oxygen therapy was 10 days (IQR, of 6-15) which is almost consistent with a study conducted at MCCC Ethiopia (6 days) , at Amhara regional state to assess factors affecting time to recovery from COVID-19 (11 days)  and a study done  Germany(8 days),Colombia(6days) and New Zealand(5.6 days) (222835-37). But the overall rate of discontinuation of supplemental oxygen therapy  was higher than a study done at MCCC Ethiopia (78.3%) (28). This variation might be due to the sample size in this study was larger and relatively better cares and treatments were given to the patients recently than before. This finding   also higher than the study done in Colombia(58%) and New Zealand(55%)  to assess  HFNO effectiveness and associated predictors  (3637). This variation might be due HFNO commonly administered for patients with ARF and those near to the need of intubation. These variations also could be due to the type of health facilities setups across the world. For instance, there could be differences of admission and discharging criteria, and resources exist to manage the patients. Moreover, other socio demographic characteristics differences, such as age among study subjects (COVID-19) patients, could cause the variation. Age of patients in the two previous study New Zealand (mean SD =68±12) and Colombia, median age was 59 were older as compared to the current study (median age 58). Additionally a study in New Zealand, PaO2/FIO2 was used to determine the need of mechanical respiration inclusive of HFNO. However in our study admission criteria was  based on Spo2 at room air and work of breathing (3637).

This study indicated that the rate of discontinuation of supplemental oxygen therapy among adult severe COVID-19 patients with preexisting comorbidities was 55% lower than those without comorbidities. This study finding supported by the study done in Amhara region claims that patient without comorbidity recovers faster than the counter parts(22). This was also supported by the study conducted to assess factors of HFNO ineffectiveness and mortality among hospitalized COVID-19 patients, comorbidity was found to be an independent factor (141517). However, comorbidity was not  found to be an independent  predictor in the previous studies done at MCCC in Ethiopia(28). The possible reason for the observed discrepancy between the studies might be due to variation in sample size and the study population, in the current study only considers adult COVID-19 patients.  

SARS-CoV-2 affects different parts of the body by infecting cells in the respiratory and GI tract, as well as cells in other areas. The virus enters cells after its characteristic spike proteins bind to ACE-2. Once inside the cell, the virus uses the cells’ own machinery to produce copies of viral proteins and RNA. Like many viruses, SARS-CoV-2 carries its genetic information on a strand of RNA, much like human DNA. The ACE-2 receptor is embedded in cellular membranes. It helps regulate blood pressure by controlling levels of the protein angiotensin, which encourages blood vessels to constrict and raise blood pressure. When SARS-CoV-2 particles leave an infected cell, it triggers the release of cytokines, small proteins that play a role in inflammation. This process causes different symptoms accordingly the affected body part(3839).

 

 

 

Table 5: Multivariable Stratified Cox proportional hazard regression model for predictors of time to discontinuation of supplemental oxygen therapy among adult severe COVID-19 patients admitted at EKGH, Addis Ababa Ethiopia, 2020 to 2022 (n=684). 

                            _t

Status at last follow up 

Cox-PH regression model

Stratified Cox-PH model

P>|z|

No. of

Event (%)

No. of

Censored (%)

Crude HR(95%CI)

   Adjusted HR(95%CI)

Preexisting comorbidities    

no   

364(82.73)

76(17.27)

1

1

0.000*

yes

192(78.69)

52(21.31)

0.65(0.55 – 0.78)

0.45 (0.36 – 0.57)

Creatinine

  (mg/dl)      

 

≤ 1.3

 

495(87.92)

68(12.08)

1

1

0.000*

 

>1.3

 

61(50.41)

60(49.59)

0.62(0.47 – 0.81)

0.32(0.22 – 0.47)

Total WBC 

count    (cells×10^3/µl) 

≤ 10

437(87.75)

61(12.25)

1

1

0.002*

>10

119(63.98)

67(36.02)

0.51(0.41 – 0.63)

0.65(0.49 – 0.85) 

Chest pain                           

no

43(55.13)

35(44.87)

1

1

0.001*

yes

513(84.65)

93(15.35)

0.47(0.34 – 0.64)

0.43(0.26 – 0.71)

Neutrophils 

Count (%)

≤75

230(100.00)

0(0.00)

1

1

0.000*

>75

326(71.81)

128(28.19)

0.46(0.39 – 0.55)

0.56(0.43  – 0.73)

 

SBP

(mmHg)       

<140

457(82.94)

94(17.06)

1

1

0.000*

≥140  

99(74.44)

34(25.56)

0.44(0.35 – 0.56)

0.45(.33  – 0.61) 

 

ALP

(IU/L)

≤116 

464(84.52)

85(15.48)

1

1

0.000* 

>116 

92(68.15)

43(31.85)

0.39(0.30 – 0.50)

0.20(0.15  – 0.29)

SOB

No

443(79.96)

111(20.04)           

1

1

0.000*

yes

113(86.92)

17 (13.08)

0.36(.29 – 0 .45)

0.49(0.36 – 0.66)

Nausea/

Vomiting            

No

108(76.06)

34(23.94)

1

1

0.000*

yes

448(82.66)

94(17.34)

0.86(.69 – 1.06)

0.51(0.38  – 0.68)

Cough  

no

531(82.71)

111(17.29)

1

1

0.007*

yes

25(59.52)

17(40.48)

1.33(.89 – 1.98)

1.91(1.19 –3.04) 

Stratified by Anemia, Myalgia, Respiratory rate and HIV/AIDS

* indicates the variables significantly associated with outcome variable at P-value < 0.05.

According to the current study, having a complaint of shortness of breath at admission was associated with a 51% lower rate of discontinuation of supplemental oxygen therapy as compared to those patients with no such complaint. The current finding was consistent with the finding of a study conducted at MCCC in Ethiopia (29.5%) and also supported by a study conducted in china on the prediction of factors related to requirement of oxygen therapy claim shortness of breath at admission attributed to early oxygen requirement and more intensive care such as mechanical ventilation care, extracorporeal membrane oxygenation and death SARS COV-2 cases (202128). When SARS-CoV-2 infects lung tissue, it spreads rapidly and may affect the epithelial cells lining the airways. The immune system responds by releasing cells that cause inflammation in the affected tissues. When this inflammatory immune response continues to happen, it inhibits the regular transfer of gases, including oxygen, in the lungs, and fluid can build up. These make it difficult to breathe(40).

This study had also identified nausea/vomiting an independent significant predictor for the rate of discontinuation of supplemental oxygen therapy. Severe COVID-19 patients with nausea/vomiting had 49% lower rate of discontinuation of supplemental oxygen therapy than patients without such complaint at admission. This finding supported by the finding of  a pooled analysis,  nausea and vomiting was significantly associated with severe COVID-19(41). Once inside the GI tract, the virus can also travel through the portal vein, the vein that drains blood from the digestive tract. This process could allow viruses to affect the vagus nerve either through vascular or lymphatic routes. In addition, the cytopathic effect caused by SARS-CoV-2 combined with cytokine storm can stimulate central and peripheral (autonomic nervous) pathways, culminates into a sensation of nausea (with or without vomiting). Once neural pathways are stimulated, gastric dysrhythmia can occur, resulting in vomiting(42).  

This   study confirmed that the rate of discontinuation of supplemental oxygen therapy among patients admitted with systolic blood pressure ≥140mmHg was 55% lower than patients  with  systolic blood pressure <140mmHg at admission . This finding supported by   previous study found that elevated SBP was associated with mortality  and used as a prediction of survival of COVID-19 patients (23).

A finding of this study revealed that supplemental oxygen therapy discontinuation rate among adult severe COVID-19 patients admitted with chest pain was 57% lower than those who had no. The previous studies done in China and Iran    also reported that chest pain was an independent predictor for  early oxygen requirement and more intensive care need in COVID-19 patients (2143). The mechanism of chest pain caused by the invasion of the SARS-CoV-2 remains unclear. The enhanced release and activation of inflammatory cytokines can damage myocardial cells(44). Furthermore, some inflammatory mediators released into the pleural space can trigger pain receptors on the pleura, thus may  causing chest pain(45). 

This implies that the duration of supplemental oxygen requirement (time to discontinuation of supplemental oxygen therapy ) was significantly longer among patients who had one of above mentioned predictors as compared to those had no such factors at admission. 

The current study had also identified that cough as a good prognostic factor of COVID-19 cases. The rate of discontinuation of supplemental oxygen therapy patient presented with cough at admission was 91% higher than patient had no cough. Existing evidences were also supported the current study finding, for instance, the study done USA revealed that presence of cough among COVIID-19 patients was associated with greater survival (46). But a systematic review and meta-analysis in India that assessed predictors of severe COVID-19 reported cough had a strong association. This  differences might be  due to large sample size and  type of cough was coughing up blood in the previous study which is the manifestation of advanced diseases but not in the current study (19). Coughing is a natural reflex that occurs in response to irritation in the throat or lungs. It is the body’s way of removing irritants such as fluid and phlegm. When it is a productive cough it helps to prevent buildup of mucus and clear the airways. Thereby reduce further complications, such as breathing difficulties and infection(47).

Furthermore, our study had also identified some of laboratory biomarkers abnormality at admission as independent predictor of delayed time to discontinuation of supplemental oxygen therapy. At admission adult severe COVID-19 patients with high WBC count (leukocytosis) the rate of discontinuation of supplemental oxygen therapy was 45% lower as compared to those patients with equal or lower than the upper limit of WBC count. This finding was supported by the finding from study conducted in Ethiopia found that patients who had an increase in leukocyte counts at admission had a significant association with longer hospital stay(27). Also supported by the results of systematic review and meta-analysis suggested that baseline high WBC count was associated with increased risk of mortality and intensive care requirement among all COVID-19 patients(48). This finding also supported by a study in china found that leukocytosis was markedly higher in deceased patients than in recovered patients(49).

In this study, patients who presented with high neutrophil count at admission the rate of discontinuation of supplemental oxygen therapy was 44% lower than the patients who presented with other than high neutrophil count. This implies that patients with high neutrophil count required longer duration of supplemental oxygen therapy. Thus, the study conducted in China supported this study finding,  that COVID-19 patients presented with high neutrophil count were  associated with a higher need for supplemental oxygen support and more serious outcomes(50).

This study revealed that patients with elevated ALP the rate of discontinuation of supplemental oxygen therapy was 80% lower than patients presented with normal or lower ALP level. This finding supported by a Japanese study describing an increase in disease severity as increased oxygen demand found that elevated liver enzyme were important  for predicting  for increased in supplemental oxygen needs(18). The current study finding also guided by a study in China showed that concentrations  of ALP were markedly higher in deceased patients than in recovered patients COVID-19 patients(49). A recent study suggested that SARS-CoV-2 may directly bind to ACE2-positive cholangiocytes, and therefore, liver abnormalities in COVID-19 patients may be due to cholangiocyte dysfunction and systemic inflammatory response-induced liver injuries(51).

The other predictor that had a significant effect identified in this study a high serum creatinine. Severe COVID-19 patients with raised serum creatinine at admission the rate of discontinuation of supplemental oxygen therapy was 68% lower as compared to patients had no raised serum creatinine level. This finding supported by a study conducted in Italy found that high serum creatinine was a significant predictor of clinical deterioration (ICU transfer OR death) of hospitalized COVID-19 patients(26). The current finding also supported by study in Poland claim that increased serum creatinine at admission was an independent  predictor of HFNO ineffectiveness(need intubation or death)(17).

This study had some strong points that was investigated the predictors of duration of supplemental oxygen requirement involving baseline laboratory biomarkers and vital signs as new aspects of the clinical features of among adult severe COVID-19 patients. On the other hand, a study was a retrospective single-center study that it failed to include all variables particularly important behavioral factors such as smoking, alcohol consumptions and some laboratory biomarkers such as coagulation biomarkers and biochemical test and imaging.  And also since this study included too many new predictors so the sample size that may not be adequate enough because it was calculated using only two significant predictors from previous study.  These were the main limitations of the current study.

Conclusions

In conclusion, this study demonstrated that median time to discontinuation of supplemental oxygen therapy among adult severe COVID-19 patients was longer. The overall supplemental oxygen therapy discontinuation rate was 8.14 (95% CI: 7.49–8.85) per 100 person day observation. Patients who presented with shortness of breathing, chest pain, nausea/vomiting, one or more comorbidities, raised SBP and had a leukocytosis, high neutrophil count, elevated ALP and serum creatinine should be expected to require a longer duration of supplemental oxygen therapy.

In service area clinician should early identify patients at greater risk of prolonged oxygen therapy requirement and give a special attention at the beginning of hospitalization based on symptoms (shortness of breath, chest pain, high systolic blood pressure) and laboratory results (high white blood cell, neutrophil count, elevated alkaline phosphatase and creatinine). Hence, patients with prolonged length of oxygen therapy requirement associating predictive factors should be expected to consume more pharmacological and non-pharmacological resources during hospital care receiving. This can be used as a guide in planning institutional oxygen requirement, bed demand at Intensive care unit and wards with inbuilt oxygen supply system, and in predicting patient turn over at these units. This in turn can be used to predict institutional capacity to admit and treat patients who require oxygen therapy. Early intervention and maximum care can be provided to prevent complication from the disease and the supplemental oxygen therapy itself.

This also helps MOH Ethiopia to allocate limited resources like supplemental oxygen and devices, laboratory facilities for maximum care provision for severe COVID-19 patients who required supplemental oxygen.

For researchers, we recommend further multi- center study including above mentioned prognostic factors among patients hospitalized with severe COVID-19 requiring supplemental oxygen therapy.

Abbreviations

ARDS: Acute Respiratory Distress Syndrome; COVID-19: Coronavirus Disease of 2019; ICU: Intensive Care Unit; MCCC: Millennium COVID-19 Care Center; SARS-CoV: Severe Acute Respiratory Syndrome Coronavirus; SOB: Shortness of Breath; SpO2: Peripheral Oxygen Saturation 

Declarations

Acknowledgments

The authors thank Dega Damot district and the staffs, administrators and those participated as data extractor and supervisor at Eka Kotebe General Hospital for their invaluable financial, material, and moral support as well as cooperativeness. 

Authors’ contributions 

MZ, LY and MT conceived and designed the study, revised data extraction sheet and drafted the initial manuscript. MZ designed data extraction sheet. All authors contributed to the conception and obtained patient data. MZ performed statistical analysis. All authors undertook review and interpretation of the data. All authors revised the manuscript and approved the final version.

Funding 

This work was supported by Dega Damot district and Debre Markos University College of Health Sciences Department of Public Health. And the funding source did not interfere with the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author and data was publicly available on reasonable request.

Ethics approval and consent to participate

This study was approved by the ethics review committee of Debre Markos University and Eka Kotebe General Hospital conforms to the code of ethics of the Helsinki declaration in 2013. 

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.

Author details

Epidemiology, Department of Public Health, College of Health Science, Debre Markos University, Debre Markos Ethiopia

2  Biostatistics Unit, Department of Public Health, College of Health Science, Debre Markos University, Debre Markos Ethiopia

3  Epidemiology Unit, Department of Public Health, College of Health Science, Debre Markos University, Debre Markos Ethiopia

Epidemiology Unit, Department of Public Health, College of Health Science, Debre Markos University, Debre Markos Ethiopia

*Corresponding Author: E-mail: [email protected] (MZ)                                                                               

Email addresses     MT: [email protected]

                                LY: [email protected]

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