4 AJTCCM VOL. 30 NO. 1 2024
ORIGINAL RESEARCH: ARTICLES
Background. High-ow nasal oxygen (HFNO) is an accepted treatment for severe COVID-19-related acute hypoxaemic respiratory
failure (AHRF).
Objectives. To determine whether treatment outcomes at Groote Schuur Hospital, Cape Town, South Africa, during the third COVID-19
wave would be aected by increased institutional experience and capacity for HNFO and more restrictive admission criteria for respiratory
high-care wards and intensive care units.
Methods. We included consecutive patients with COVID-19-related AHRF treated with HFNO during the rst and third COVID-19 waves.
e primary endpoint was comparison of HFNO failure (composite of the need for intubation or death while on HFNO) between waves.
Results. A total of 744 patients were included: 343 in the rst COVID-19 wave and 401 in the third. Patients treated with HFNO in the
rst wave were older (median (interquartile range) age 53 (46 - 61) years v. 47 (40 - 56) years; p<0.001), and had higher prevalences of
diabetes (46.9% v. 36.9%; p=0.006), hypertension (51.0% v. 35.2%; p<0.001), obesity (33.5% v. 26.2%; p=0.029) and HIV infection (12.5% v.
5.5%; p<0.001). e partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at HFNO initiation and the ratio of
oxygen saturation/FiO2 to respiratory rate within 6 hours (ROX-6 score) aer HFNO commencement were lower in the rst wave compared
with the third (median 57.9 (47.3 - 74.3) mmHg v. 64.3 (51.2 - 79.0) mmHg; p=0.005 and 3.19 (2.37 - 3.77) v. 3.43 (2.93 - 4.00); p<0.001,
respectively). e likelihood of HFNO failure (57.1% v. 59.6%; p=0.498) and mortality (46.9% v. 52.1%; p=0.159) did not dier signicantly
between the rst and third waves.
Conclusion. Despite dierences in patient characteristics, circulating viral variant and institutional experience with HFNO, treatment
outcomes were very similar in the rst and third COVID-19 waves. We conclude that once AHRF is established in COVID-19 pneumonia,
the comorbidity prole and HFNO provider experience do not appear to aect outcome.
Keywords. COVID-19, high-ow, oxygen.
Afr J Thoracic Crit Care Med 2024;30(1):e1151. https://doi.org/10.7196/AJTCCM.2024.v30i1.1151
High-ow nasal oxygen in resource-constrained, non-intensive,
high-care wards for COVID-19 acute hypoxaemic respiratory
failure: Comparing outcomes of the rst v. third waves at a tertiary
centre in South Africa
G Audley,1 MB ChB, Dip HIV Man (SA), FCP (SA), MMed (Med) ; P Raubenheimer,1 MB ChB, FCP (SA); G Symons,1,2 MB ChB, FCP
(SA), Cert Pulmonology (SA) Phys; M Mendelson,3 MBBS, PhD; G Meintjes,1,4 MB ChB, FRCP, FCP (SA), MPH, PhD; N A B Ntusi,1,5,6
DPhil, MD; S Wasserman,1,3 MB ChB, MMed (Med), FCP (SA), Cert ID (SA) Phys; S Dlamini,1,3 MB ChB, FCP (SA), Cert ID (SA) Phys;
K Dheda,2,6,7,8 MB ChB, FCP (SA), FCCP, PhD, FRCP; R van Zyl-Smit,2 MB ChB, FRCP, FCP (SA), MMed (Med), Dip HIV Man (SA), Cert
Pulmonology (SA) Phys, PhD; G Calligaro,2,8 BSc Hons, MB ChB, Dip PEC (SA), MMed (Med), FCP (SA), Cert Pulmonology (SA) Phys
1 Division of General Internal Medicine, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur
Hospital, Cape Town, South Africa
2 Division of Pulmonology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
3 Division of Infectious Diseases and HIV Medicine, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote
Schuur Hospital, Cape Town, South Africa
4 Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town,
South Africa
5 Division of Cardiology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town,
South Africa
6 South African Medical Research Council/University of Cape Town Extramural Research Unit on the Intersection of Noncommunicable Diseases
and Infectious Diseases, University of Cape Town, South Africa
7 Faculty of Infectious and Tropical Diseases, Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, UK
8 Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute, University of Cape Town,
South Africa; South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, South Africa
Corresponding author: G Audley (ggaudley@gmail.com)
AJTCCM VOL. 30 NO. 1 2024 5
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At the end of 2019, the novel coronavirus SARS-CoV-2 resulted in an
acute respiratory illness outbreak, later named COVID-19, in Wuhan,
China.[1] e infection rapidly spread globally, and on 11 March 2020
the World Health Organization declared the outbreak a public health
emergency of international concern.[2] Healthcare systems were
overwhelmed globally, with associated high mortality rates.[3,4] e
development and roll-out of COVID-19 vaccines resulted in a marked
reduction in hospitalisation, severe disease and death.[5] Despite this,
inequality in global vaccine distribution resulted in delays in country-
wide vaccination in low- and middle-income countries (LMICs)
such as South Africa (SA).[6] ese countries were le vulnerable to
recurrent infection waves, and as a result SA experienced a severe
third wave of COVID-19 infections in the middle of 2021.[7,8]
Before roll-out of the vaccines, 1 in 5 people with COVID-19 required
hospitalisation.[9] In most cases the indication for hospitalisation was
hypoxaemia requiring variable levels of supplemental oxygen therapy.
[10] e rst three waves of the pandemic in SA were characterised
by severe constraints in access to mechanical ventilation in intensive
care units (ICUs) to treat patients with acute hypoxaemic respiratory
failure (AHRF).[11] One strategy that has been employed to manage
severe COVID-19 respiratory failure and hypoxaemia is high-ow
nasal oxygen (HFNO).[12] HFNO is a device that delivers 30 - 60 L/min
of heated and humidied air and oxygen blend at the desired fraction
of inspired oxygen (FiO2) via a wide-bore nasal interface.[13] HFNO
reduces anatomical dead space, work of breathing and respiratory rate,
and increases positive end-expiratory pressure and compliance.[13]
Prior to the pandemic, HFNO was used as a non-invasive alternative
for the management of hypoxaemia in critically ill patients.[14] Its
major benets are its ease of use and superior tolerability compared
with non-invasive ventilation and invasive mechanical ventilation
(IMV).[14] Several observational studies suggested that if IMV became
scarce, using HFNO was a feasible alternative to provide adequate
oxygenation for these severely hypoxaemic patients, reducing the
number needing IMV, increasing ventilator-free days and reducing
the length of ICU stay.[15-20]
Groote Schuur Hospital (GSH), a tertiary referral hospital in
Cape Town, SA, adopted the use of HFNO in non-ICU, high-care
wards. is strategy increased the capacity to manage patients with
AHRF secondary to COVID-19 outside an ICU, in anticipation
that ICU ventilation capacity would quickly be overwhelmed.[21] An
observational cohort study from GSH and Tygerberg Hospital showed
that IMV could be avoided through the use of HFNO in up to 50%
of patients with AHRF during the first COVID-19 wave.[16] This
nding prompted GSH to expand this high-care HFNO service into
subsequent waves of the pandemic.
We hypothesised that dierences in viral variant, wave duration,
HFNO bed capacity, corticosteroid use, institutional familiarity with
HFNO, and immunisation roll-out might lead to dierences between
waves in respect of patient characteristics and the need for IMV.
Methods
Study design
We conducted a prospective observational study at GSH, which
was approved by the Human Research Ethics Committee of the
University of Cape Town Faculty of Health Sciences (ref. no. UCT
HREC 295/2020). Informed consent was waived in acknowledgement
of the fact that the intervention was being assessed within the routine
clinical service. e study is reported in accordance with the STROBE
guidelines for reporting cohort studies.[22]
Setting
GSH serves a population of ~4.5 million with a high prevalence of
tuberculosis and HIV.[23] Waves of the pandemic were dened by
the National Institute for Communicable Diseases as the period
from when the COVID-19 weekly incidence was ≥30 cases per 100
000 persons until the weekly incidence fell to <30 cases per 100 000
persons.[24] e rst case of COVID-19 in SA was identied on 5
March 2020 and, according to the above denition, the rst wave
spanned from 8 June 2020 to 23 August 2020, while the third wave
spanned between 10 May and 19 September 2021.[24,25] In the present
study, patients were included during the rst wave between 7 May and
25 August 2020 (16 weeks) and during the third wave between 4 July
and 4 September 2021 (9 weeks) (Fig. 1). ere were 39 respiratory
high-care beds available during the rst wave and 10 - 30 HFNO
machines available to treat patients (the number of HFNO machines
increased during the wave as the utility of this method of non-invasive
respiratory support was increasingly recognised), v. 59 beds and 50
machines available at the peak of the third wave.
Participants
Inclusion criteria were consecutive adult patients aged ≥18 years
with AHRF and laboratory-confirmed COVID-19 pneumonia,
i.e. detection of SARS-CoV-2 by real-time reverse transcription
polymerase chain reaction on any respiratory sample who were
treated with HFNO during hospitalisation. AHRF was dened as
a respiratory rate ≥30 breaths per minute with oxygen saturation
≤92% despite inspired oxygen at 15 L/min via a reservoir bag, and/or
partial pressure of arterial oxygen to FiO2 (PaO2/FiO2) ratio <150. e
decision to initiate HFNO was at the discretion of the treating clinical
team, but HFNO was indicated in co-operative patients who were
Study synopsis
What the study adds. is study adds to the body of evidence demonstrating the utility of high-ow nasal oxygen (HFNO) in avoiding
invasive mechanical ventilation (IMV) in patients with severe COVID-19 hypoxaemic respiratory failure, and shows that this utility
remained consistent across dierent waves of the COVID-19 pandemic.
Implications of the study. In resource-constrained settings, HFNO is a feasible non-invasive alternative to IMV and can be employed with
favourable and consistent outcomes outside traditional critical care wards. It also conrms that the degree of gas exchange abnormality, and
not pre-existing patient-related factors, circulating wave variant or provider experience, is the main predictor of HFNO failure.
6 AJTCCM VOL. 30 NO. 1 2024
ORIGINAL RESEARCH: ARTICLES
able to comply with awake prone positioning.
Likewise, the decision on the timing of
intubation and IMV was not protocolised
but determined by the ICU team based
on a composite assessment of respiratory
effort, level of patient exhaustion, rising
arterial partial pressure of carbon dioxide
and altered mental state, rather than a single
measure of oxygenation such as saturation
or PaO2. Awake proning was encouraged
at every clinical encounter and reinforced
by nursing staff according to a shared
clinical protocol. Following the preliminary
report of the ecacy of dexamethasone by
the RECOVERY trial released on 16 June
2020, all patients on HFNO received either
dexamethasone 6 mg intravenously daily or
prednisone 40 mg daily for 10 days.[26]
Viral variant
e ancestral variant of the COVID-19 virus
in the rst wave and the delta variant in the
third wave were the predominant circulating
viral variants during our sampling period.[27]
Sample size
In a cohort study by Calligaro et al.[16] during
the first wave, the HFNO failure rate in
patients with severe COVID-19 hypoxaemic
respiratory failure was 53%. We calculated
that a sample size of 319 patients in each wave
would be required to detect a 10% dierence
between cohorts (OpenEpi, version 3,
open-source calculator developed by Dean,
Sullivan and Soe).
Heated and humidied HFNO
Heated and humidified HFNO was
exclusively provided in designated high-care
medical wards outside the ICUs at GSH where
patients were cohorted. HFNO was delivered
either by an Airvo 2 system (Fisher & Paykel
Healthcare, USA) or an Inspire O2FLO unit
(Vincent Medical, Hong Kong, China). Flow
was initiated at 50 - 60 L/min with FiO2 0.8 -
1.0, titrated to aim for an oxygen saturation
≥92%.
Procedures
Demographic and clinical variables,
and contemporaneous peripheral blood
differential white blood cell counts and
inflammatory biomarkers (D-dimers and
C-reactive protein) if available, were recorded
on commencement of HFNO. HFNO settings
(FiO2 and ow rate) along with heart rate,
respiratory rate and peripheral oxygen
saturation were recorded 6 hours after
initiation of HFNO. Using these variables, we
calculated the validated ROX score (ratio of
oxygen saturation/FiO2 to respiratory rate) at
6 hours (ROX-6).[28,29] For patients who were
intubated before 6 hours, the variables at
the time the decision was made that HFNO
was failing were recorded. COVID-19
vaccination status was recorded, with ‘full
vaccination’ dened as 2 weeks aer a single
dose of Johnson & Johnson’s Janssen vaccine
or 2 weeks aer the second dose of the Pzer-
BioNTech.[30]
Outcomes
The primary endpoint was comparison of
HFNO failure rates during the rst and third
waves of the pandemic at GSH. HFNO failure
was dened as a composite of the need for
intubation or death while on HFNO. Death
on HFNO was a combination of unexpected
deaths and patients who died on HFNO
because they were not deemed candidates
for IMV in the ICU. Secondary outcomes
were overall predictors of HFNO failure and
overall in-hospital mortality, and dierences
in outcomes associated with early v. late
intubation. Early intubation was dened as
occurring within 48 hours of initiation of
HFNO; late intubation occurred thereaer.
Statistical analysis
Categorical variables were expressed as
frequencies and percentages and were
compared using Pearson’s χ2 tests or Fisher’s
exact tests. Continuous variables were
expressed as means with standard deviations,
or medians with interquartile ranges (IQRs).
Non-parametric data were compared using
Wilcoxon rank-sum tests. A CONSORT
diagram reported the flow of patients in
the study (Fig. 2). The crude cumulative
proportion of HFNO failure for each wave
was calculated. We analysed univariate and
multivariate associations between need
for intubation initiation using clinically
important variables selected a priori for the
model. Data were analysed using Stata version
12.1 (StataCorp, USA). A p-value <0.05 was
considered statistically signicant.[31]
Results
Patient population
A total of 744 patients were included, 343
(46.1%) in the rst wave and 401 (53.9%) in
the third. e median (IQR) age was 50 (42
- 58) years, and 385/744 (51.7%) were male.
Every patient was on at least a reservoir face
mask at 15 L/min prior to initiation of HFNO
(often, as became the practice, with the
addition of nasal prong oxygen – so-called
‘double oxygen’). Although similar numbers
of patients were included in each wave, the
institutional capacity to treat patients with
HFNO was considerably higher in the third
wave compared with the rst, as reected by
the average number of patients included per
week: 21/week in the rst wave v. 45/week
in the third. Patients treated with HFNO in
the rst wave were older (median 53 (46 -
61) years v. 47 (40 - 56) years; p<0.001), and
had higher prevalences of diabetes (46.9%
v. 36.9%; p=0.006), hypertension (51.0% v.
35.2%; p<0.001), obesity (33.5% v. 26.2%;
p=0.029) and HIV infection (12.5% v. 5.5%;
p<0.001). Patients in the rst wave had worse
oxygenation indicators prior to HFNO
Jun
e
202
Novemb
er 2020
March
2021
August
2021
Seven-day average number of
cases
5,000
10,000
0
15,000
20,000
25,000
Wave 1
Sample
Wave 3
Sample
Wave 1 sample Wave 2 sample
25 000
20 000
15 000
10 000
5 000
0
1 June 2020 1 November 2020 1 March 2021 1 August 2021
7-day average number of cases
Fig. 1. Temporal relationship of the study sample (rst wave v. third) to the national caseload.[25]
AJTCCM VOL. 30 NO. 1 2024 7
ORIGINAL RESEARCH: ARTICLES
initiation (PaO2/FiO2 57.9 v. 64.3 mmHg; p=0.005) and lower ROX-6
scores aer initiation of HFNO (3.19 v. 3.43; p<0.001) (Table 1). As
expected from the change in practice following the results from the
RECOVERY trial,[26] patients in the third wave were more likely to
have been treated with corticosteroids (100% v. 81.9%; p<0.001).
Primary outcome (rst v. third wave)
HFNO failure did not dier between the rst and third waves (57.1%
v. 59.6%; p=0.498) (Table 1). Fig. 3 shows the proportions of patients
with HFNO failure over time. ere was no signicant dierence
between the waves.
Secondary outcomes
Univariate predictors for HFNO failure were older age, obesity, not
being treated with corticosteroids, lower PaO2/FiO2 ratio at the time
of HFNO initiation, lower ROX-6 score aer HFNO commencement,
and higher D-dimer level (Table 2). e wave itself was not a predictor
of poor outcome. On multivariate analysis of predictors of HFNO
failure, not being on corticosteroids, lower PaO2/FiO2 at the time of
initiating HFNO, and lower ROX-6 score on HFNO were predictive.
An increase in ROX-6 by one point was associated with a 59% relative
reduction in the risk of HFNO failure.
Of all patients treated with HFNO, 309 (41.5%) were successfully
weaned o HFNO (Fig. 2), and of these patients 306 (99.0%) were
discharged (home or to a step-down facility). The proportion of
patients who died on HFNO was 15.4% in the rst wave v. 22.6% in
the third wave (p=0.008). A total of 291 patients were intubated and
received IMV, 143 patients in the rst wave and 148 patients in the
third wave (p=0.183). ICU mortality in patients requiring intubation
was high: 223/291 (76.6%) died, with the rest all surviving to discharge
(Fig. 2). Overall, in-hospital mortality did not dier signicantly
between the rst and third waves (46.9% v. 52.1%; p=0.159).
Of the 291 patients requiring IMV, 155 (53.3%) were intubated
within 48 hours of initiating HFNO (early failures): in-hospital
mortality was 112/155 (72.3%) in this group. In-hospital mortality was
111/136 (81.6%) for patients intubated aer 48 hours (late failures)
(p=0.060).
Vaccination
No patients in the rst-wave cohort were vaccinated. No patients in the
third-wave cohort were fully vaccinated, with only 11 patients having
received ≥1 dose of a COVID-19 vaccine. Of those who had started
the vaccination process, 7/11 had received one of the two scheduled
doses of the Pzer-BioNTech vaccine, 1/11 presented within 1 week of
the second dose of the Pzer-BioNTech vaccine, and 3/11 presented
within 1 week of having received the Johnson & Johnson vaccine.
Discussion
is study, which to our knowledge is the only comparison of outcomes
between waves of patients with severe COVID-19 treated with HFNO
Not candidates for mechanical ventilation,
n=127/144 (88.2%)
Unexpected deaths on HFNO,
n=17/144 (11.8%)
Patients treated with HFNO,
N=744
(rst wave n=343, third wave n=401)
HFNO success,
n=309 (41.5%)
HFNO failure,
n=435 (58.5%)
Intubated,
n=291/435 (66.9%)
Died,
n=144/435 (33.1%)
Discharged from ICU,
n=68/291 (23.4%)
Died,
n=223/291 (76.6%)
Discharged home,
n=306/309 (99.0%)
Died after weaned from HFNO but before discharge
n=3/309 (1.0%)
Discharged home,
68/68 (100%)
Fig. 2. CONSORT diagram. (HFNO = high-ow nasal oxygen; ICU = intensive care unit.)
8 AJTCCM VOL. 30 NO. 1 2024
ORIGINAL RESEARCH: ARTICLES
in SA, found no dierence in HFNO success or mortality in patients
treated in the rst wave v. the third, despite several dierences between
the waves including viral variant, wave duration, corticosteroid use,
HFNO bed capacity, clinician experience, patient risk factor prole,
and baseline measures of oxygenation.
While the reasons for the dierences in patient characteristics
between waves is likely to be multifactorial, one explanation was
the implementation of the Western Cape Critical Care Triage Tool
in the third wave, which favoured selection of younger patients
with fewer comorbidities associated with in-hospital mortality from
COVID-19.[32,33] Another possible explanation relates to the vaccine
roll-out in SA, which only began (starting with the elderly) on 17
May 2021, 7 days aer what later proved to be the start of the third
wave.[24,34] is prioritisation of vaccinating the elderly may explain
why the third-wave cohort was younger – reecting the protective
eect of the vaccine against severe disease. However, it is more likely
Table 1. Patient characteristics and outcomes across waves
Vari able
Total (N=744),
n (%)*
First wave
(n=343), n (%)*
ird wave
(n=401), n (%)* p-value
Age (years), median (IQR) 50 (42 - 58) 53 (46 - 61) 47 (40 - 56) <0.001
Sex male 385 (51.7) 174 (50.7) 211 (52.6) 0.607
Diabetes 309 (41.5) 161 (46.9) 148 (36.9) 0.006
HbA1c (%), median (IQR) 9.45 (7.2 - 11.5) 9.8 (7.45 - 11.7) 8.5 (7 - 11.2) 0.165
Hypertension 316 (42.5) 175 (51.0) 141 (35.2) <0.001
BMI (kg/m2)
≤25 79 (10.6) 48 (14.0) 31 (7.6) 0.006
25 - 30 365 (49.1) 146 (42.6) 219 (54.6) 0.001
30 - 35 220 (29.6) 115 (33.5) 105 (26.2) 0.029
≥35 80 (10.8) 34 (9.9) 46 (11.5) 0.494
HIV status
Negative 519 (69.8) 238 (69.4) 281 (70.1) 0.839
Positive 65 (8.7) 43 (12.5) 22 (5.5) <0.001
Unknown 160 (21.5) 62 (18.1) 98 (24.4) 0.035
CD4 count (if HIV positive) (cells/µL), median (IQR) 280 (138 - 416) 277 (130 - 423) 283 (201 - 370) 1.00
ART use (if HIV positive) 51/65 (78.5) 33/43 (76.7) 18/22 (81.8) 0.322
Duration of symptoms (days), median (IQR) 7 (6 - 11) 7 (5 - 10) 8 (6 - 14) 0.347
Corticosteroids as treatment 682 (91.7) 281 (81.9) 401 (100) <0.001
PaO2/FiO2 ratio at HFNO initiation (mmHg), median (IQR) 62.2 (48.6 - 77.7) 57.9 (47.3 - 74.3) 64.3 (51.2 - 79) 0.005
ROX-6 score, median (IQR) 3.34 (2.65 - 3.92) 3.19 (2.37 - 3.77) 3.43 (2.93 - 4) <0.001
Creatinine (μmol/L), median (IQR) 68 (56 - 87) 70 (58 - 89) 66 (55 - 85) 0.031
Lymphocyte count (× 109/L), median (IQR) 1.19 (0.88 - 1.63) 1.23 (0.92 - 1.63) 1.16 (0.8 - 1.58) 0.141
C-reactive protein (mg/L), median (IQR) 148 (85 - 236) 171 (106 - 267) 120 (75 - 180) 0.001
D-dimers (mg/L), median (IQR) 0.59 (0.36 - 1.41) 0.69 (0.38 - 1.66) 0.53 (0.34 - 1.17) 0.003
Outcome on HFNO
Success 309 (41.5) 147 (42.9) 162 (40.4) 0.498
Failure 435 (58.5) 196 (57.1) 239 (59.6) 0.498
Intubated 291 (39.1) 143 (41.7) 148 (36.9) 0.183
Died on HFNO 17 (2.3) 8 (2.3) 9 (2.2) 0.936
Palliated 127 (17.1) 45 (13.1) 82 (20.4) 0.008
In-hospital mortality 370 (49.7) 161 (46.9) 209 (52.1) 0.159
IQR = interquartile range; BMI = body mass index; ART = antiretroviral therapy; HFNO = high-ow nasal oxygen; PaO2/FiO2 = partial arterial oxygen pressure/fractional inspired oxygen; ROX-6 = ratio
of oxygen saturation/FiO2 to respiratory rate within 6 hours.
*Except where otherwise indicated.
Fig. 3. Proportions of patients with unsuccessful outcome from initiation
of HFNO. (HFNO = high-ow nasal oxygen.)
100
80
60
40
20
0
*
** **
*
Wave 1 Wave 3
* p=0.498
**p=0.159
HFNO failure
Mortality
Patients, %
AJTCCM VOL. 30 NO. 1 2024 9
ORIGINAL RESEARCH: ARTICLES
that more rigorous triaging, necessitated by the increased caseload
due to the more rapid epidemiological surge related to the increased
transmissibility of the delta variant, skewed this demographic in the
third wave.[35]
There are two possible explanations for the lack of observed
dierences between wave outcomes. Firstly, we speculate that the
signicantly younger third-wave cohort with fewer comorbidities
balanced the expected increase in mortality associated with the higher
caseload seen in the third wave.[7] Additionally, although HFNO
provider experience and competence are likely to have improved as
the waves progressed, HFNO bed capacity in the third wave increased
disproportionally to the number of doctors and nurses looking aer
these patients (in particular, the number of doctors available aer
hours). The negative effect of reduced staffing ratios and senior
oversight aer hours on outcomes in critically ill patients is well
described, and this too may have had a deleterious eect that further
balanced the inter-wave outcomes.[36]
e signicant independent predictors of HFNO failure in our study
were corticosteroid use, pre-HFNO PaO2/FiO2, and the ROX-6 score.
is nding is in keeping with our previously published study[16] as
well as the conclusions and recommendation of a systematic review by
Attaway et al.[37] of the application of the ROX index in the COVID-19
setting. Patients with a ROX index ≥4.88 aer 2, 6 and 12 hours of
treatment were found to have a low risk of intubation, whereas a
ROX index <3.85 at the same time points was associated with a high
risk of failure. It is interesting that none of the other demographic
variables or laboratory parameters were predictive of HFNO failure.
is nding suggests that, while these other factors may be important
in the development of severe acute respiratory distress syndrome
from COVID-19 pneumonia, once this pathological process is
rmly established it is only whether or not HFNO is actually able to
improve gas exchange and respiratory rate within a few hours of its
initiation (via the many putative mechanisms already described) that
determines whether intubation or death will ultimately be avoided.
e protective eects of corticosteroids on progression to AHRF and
mortality in COVID-19 are well established, and the present study
further reinforces that corticosteroid use reduces the incidence of
HFNO failure.[26]
Our study found no significant difference in survival between
patients intubated early or late. Timing of intubation in those failing
HFNO remains an area of great interest. Guidelines from China, the UK
and the USA recommend early intubation in critically ill COVID-19
patients.[38-40] e rationale for early intubation is the avoidance of
‘crash’ intubations and the potential prevention of patient self-inicted
lung injury associated with distressed spontaneous respiration.[41] In a
prospective observational cohort study by Vera et al.,[42] late intubation
(>48 hours aer HFNO initiation) was associated with increased ICU
mortality. is nding is in keeping with a systematic review and
meta-analysis of non-randomised cohort studies by Papoutsi et al.[43]
that evaluated the impact of timing of intubation (within 24 hours
of ICU admission or later) and found that timing had no signicant
effect on mortality and morbidity of critically ill patients with
COVID-19. To our knowledge, no randomised controlled trials have
been done to evaluate outcomes of early v. late intubation in patients
Table 2. Predictors of HFNO failure
Vari able nEstimated OR (95% CI) p-value Adjusted OR* (95% CI) p-value
Age (per year increase) 744 1.02 (1.00 - 1.03) 0.008 1.02 (1.00 - 1.04) 0.074
Male (v. female) 744 1.07 (0.80 - 1.43) 0.644 - -
ird wave (v. rst wave) 744 1.11 (0.83 - 1.48) 0.498 - -
HIV status (v. negative)
Positive 65 1.61 (0.96 - 2.71) 0.068 - -
Unknown 160 1.19 (0.67 - 2.13) 0.539 - -
Hypertension 316 1.23 (0.92 - 1.66) 0.164 - -
Diabetes 309 1.21 (0.90 - 1.63) 0.208 - -
Obesity (BMI ≥30 kg/m2 v. normal) 665 1.79 (1.12 - 2.86) 0.015 1.93 (0.87 - 4.29) 0.107
Duration of symptoms (per 1 day increase) 744 1.00 (0.96 - 1.03) 0.799 - -
Treatment with corticosteroids 744 0.22 (0.10 - 0.45) <0.001 0.24 (0.08 - 0.75) 0.014
PaO2/FiO2 ratio before HFNO initiation 479 0.98 (0.98 - 0.99) <0.001 0.99 (0.98 - 1.00) 0.050
ROX-6 score (per 1 point increase) 744 0.41 (0.34 - 0.50) <0.001 0.52 (0.40 - 0.69) <0.001
Lymphocyte count (per 1 × 109 increase) 505 0.82 (0.62 - 1.08) 0.158 - -
C-reactive protein (v. <100 mg/L) 100 - -
100 - 199 116 0.62 (0.36 - 1.08) 0.091 - -
200 - 399 82 0.88 (0.48 - 1.61) 0.675 - -
≥400 17 4.22 (0.91 - 19.50) 0.065 - -
D-dimers (v. <1.5 mg/L) 461 - -
1.5 - 5.0 85 1.67 (1.03 - 2.71) 0.037 1.88 (0.78 - 4.54) 0.159
>5 61 2.07 (1.16 - 3.70) 0.014 1.88 (0.78 - 4.54) 0.159
OR = odds ratio; CI = condence interval; BMI = body mass index; PaO2/FiO2 = partial arterial oxygen pressure/fractional inspired oxygen; HFNO = high-ow nasal oxygen; ROX-6 = ratio of oxygen
saturation/FiO2 to respiratory rate within 6 hours.
*Best model t obtained with inclusion of corticosteroid use, PaO2/FiO2 ratio before HFNO initiation and ROX-6.
10 AJTCCM VOL. 30 NO. 1 2024
ORIGINAL RESEARCH: ARTICLES
failing HFNO. Furthermore, no studies of the impact of timing of
intubation on patients on HFNO in a non-intensive care ward-based
environment are available to guide practice in resource-constrained
settings employing this strategy of respiratory support.[44]
Study limitations
Our study had several limitations. First, it was a single-centre
study in a tertiary academic hospital and therefore may not reect
the reality of the experience in other hospitals in SA or in LMICs
with fewer resources. Second, patient management, particularly
the decision to intubate, was at the discretion of the treating team
and not fully protocolised. This approach may differ from other
local and international institutions, inuencing the generalisability
of the results. Additionally, with ever-changing pressure on ICU
resources as the waves of the pandemic surged, triage criteria were
adjusted, inuencing patient selection for admission and resulting in
signicantly diering cohort demographics with the rise and fall of
each wave. Furthermore, the sampling period was not of equal duration
across each wave, which may have introduced selection bias; however,
patients were included at the peak of both waves. Another limitation
is the lack of data on the number and characteristics of patients who
were not able to access HFNO because of resource limitations due
to caseload and implementation of the Western Cape Critical Care
Triage Tool, which means that inferences about dierences in patient
characteristics between waves being a result of triaging are strongly
suggested but, in the absence of denominator data, unconrmed.
Conclusion
Despite dierences in overall caseload, baseline patient characteristics,
viral variant and institutional experience with HFNO, we found no
signicant dierence in treatment outcomes between the rst and
third COVID-19 waves. We conclude that once severe respiratory
failure is established in COVID-19 pneumonia, comorbidities and
HFNO provider experience make little difference to outcome.
Declaration. KD, RvZS and GC are members of the editorial board.
The research for this study was done in partial fulfilment of the
requirements for GA’s MMed (Med) degree at the University of Cape
Town.
Acknowledgements. We acknowledge with immense gratitude all
those who, throughout the COVID-19 pandemic, gave so much towards
the care of our patients with severe COVID-19. We dedicate this article
to all the patients, those who have passed on and those who have left
our hospital to return to friends and family.
Author contributions. GA, KD and GC were involved in the
conception and design of the study. GA and GC were involved in study
implementation and data collection. GA and GC did the data analysis.
GA, KD and GC interpreted the data and provided important
intellectual input. All authors contributed to writing and editing the
manuscript.
Funding. None.
Conflicts of interest.None.
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Submitted 5 June 2023. Accepted 8 January 2024. Published 4 April 2024.
