Characteristics and risk factors for post-COVID-19 breathlessness after hospitalisation for COVID-19

Luke Daines; Bang Zheng; Omer Elneima; Ewen Harrison; Nazir I. Lone; John R. Hurst; Jeremy S. Brown; Elizabeth Sapey; James D. Chalmers; Jennifer K. Quint; Paul Pfeffer; Salman Siddiqui; Samantha Walker; Krisnah Poinasamy; Hamish McAuley; Marco Sereno; Aarti Shikotra; Amisha Singapuri; Annemarie B. Docherty; Michael Marks; Mark Toshner; Luke S. Howard; Alex Horsley; Gisli Jenkins; Joanna C. Porter; Ling-Pei Ho; Betty Raman; Louise V. Wain; Christopher E. Brightling; Rachael A. Evans; Liam G. Heaney; Anthony De Soyza; Aziz Sheikh

doi:10.1183/23120541.00274-2022

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Supplementary Materials

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FIGURE 1
Flow diagram of participants. PSQ: patient symptom questionnaire; BNP: B-type natriuretic peptide; NT-pro-BNP: N-terminal pro-BNP.
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FIGURE 2
Dates of discharge and research visit for the 1226 study participants.
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FIGURE 3
Multivariable logistic regression for post-COVID-19 breathlessness. BMI: body mass index; WHO: World Health Organization.

TABLE 1

Patient characteristics

	Total, N (%)	Post-COVID-19 breathlessness		Total
	Total, N (%)	No	Yes	Total
Total, N (%)		611 (49.8)	615 (50.2)	1226
Age at admission, years	1213 (98.9)
<30		10 (1.6)	15 (2.4)	25 (2.0)
30–39		38 (6.2)	41 (6.7)	79 (6.4)
40–49		87 (14.2)	103 (16.7)	190 (15.5)
50–59		151 (24.7)	203 (33.0)	354 (28.9)
60–69		183 (30.0)	174 (28.3)	357 (29.1)
70–79		107 (17.5)	61 (9.9)	168 (13.7)
≥80		29 (4.7)	11 (1.8)	40 (3.3)
Data missing		6 (1.0)	7 (1.1)	13 (1.1)
Sex at birth	1226 (100.0)
Male		416 (68.1)	352 (57.2)	768 (62.6)
Female		195 (31.9)	263 (42.8)	458 (37.4)
Ethnicity	1203 (98.1)
White		422 (69.1)	451 (73.3)	873 (71.2)
South Asian		82 (13.4)	71 (11.5)	153 (12.5)
Black		52 (8.5)	40 (6.5)	92 (7.5)
Mixed		17 (2.8)	16 (2.6)	33 (2.7)
Other		27 (4.4)	25 (4.1)	52 (4.2)
Data missing		11 (1.8)	12 (2.0)	23 (1.9)
Index of Multiple Deprivation	1204 (98.2)
1, most deprived		112 (18.3)	154 (25.0)	266 (21.7)
2		135 (22.1)	131 (21.3)	266 (21.7)
3		116 (19.0)	112 (18.2)	228 (18.6)
4		111 (18.2)	103 (16.7)	214 (17.5)
5, least deprived		127 (20.8)	103 (16.7)	230 (18.8)
Data missing		10 (1.6)	12 (2.0)	22 (1.8)
BMI, kg·m⁻², mean±sd	1090 (88.9)	31.4±7.1	32.7±7.1	32.0±7.1
Smoking	1213 (98.9)
Never-smokers		350 (57.3)	339 (55.1)	689 (56.2)
Ex-smokers		246 (40.3)	260 (42.3)	506 (41.3)
Current smokers		7 (1.1)	11 (1.8)	18 (1.5)
Data missing		8 (1.3)	5 (0.8)	13 (1.1)
Number of comorbidities, median (IQR)	1226 (100.0)	2.0 (0.0–3.0)	2.0 (1.0–4.0)	2.0 (0.0–3.0)
Pre-existing cardiovascular condition	1226 (100.0)
No		329 (53.8)	350 (56.9)	679 (55.4)
Yes		282 (46.2)	265 (43.1)	547 (44.6)
Pre-existing respiratory condition	1226 (100.0)
No		449 (73.5)	444 (72.2)	893 (72.8)
Yes		162 (26.5)	171 (27.8)	333 (27.2)
Pre-existing depression or anxiety	1207 (98.5)
No		538 (88.1)	471 (76.6)	1009 (82.3)
Yes		66 (10.8)	132 (21.5)	198 (16.2)
Data missing		7 (1.1)	12 (2.0)	19 (1.5)
Breathlessness before COVID-19, PSQ	1226 (100.0)
0		374 (61.2)	407 (66.2)	781 (63.7)
1–2		103 (16.9)	128 (20.8)	231 (18.8)
≥3		134 (21.9)	80 (13.0)	214 (17.5)

Data are presented as n (%) unless otherwise stated. BMI: body mass index; IQR: interquartile range; PSQ: Patient Symptom Questionnaire.

TABLE 2

Patient characteristics available during hospital admission

	Total, N (%)	Post-COVID-19 breathlessness		Total
	Total, N (%)	No	Yes	Total
Total, N (%)		611 (49.8)	615 (50.2)	1226
Admission duration, days, median (IQR)	1225 (99.9)	7.0 (4.0–14.0)	9.0 (4.0–22.0)	8.0 (4.0–17.0)
SARS-CoV-2 PCR result	1137 (92.7)
Negative		47 (7.7)	51 (8.3)	98 (8.0)
Positive		522 (85.4)	517 (84.1)	1039 (84.7)
Data missing		42 (6.9)	47 (7.3)	89 (7.3)
WHO clinical progression scale	1226 (100.0)
WHO class 3–4		110 (18.0)	113 (18.4)	223 (18.2)
WHO class 5		252 (41.2)	225 (36.6)	477 (38.9)
WHO class 6		136 (22.3)	120 (19.5)	256 (20.9)
WHO class 7–9		113 (18.5)	157 (25.5)	270 (22.0)
Proning during mechanical ventilation	1102 (89.9)
No		466 (76.3)	426 (69.3)	892 (72.8)
Yes		87 (14.2)	123 (20.0)	210 (17.1)
Data missing		58 (9.5)	66 (10.7)	124 (10.1)
Pulmonary embolism	1146 (93.5)
No		518 (84.8)	507 (82.4)	1025 (83.6)
Yes		56 (9.2)	65 (10.6)	121 (9.9)
Data missing		37 (6.1)	43 (7.0)	80 (6.5)
Coronary thrombosis	1140 (93.0)
No		570 (93.3)	565 (91.9)	1135 (92.6)
Yes		<5	<5	5 (0.4)
Data missing				86 (7.0)
Antibiotic therapy	1187 (96.8)
No		115 (18.8)	121 (19.7)	236 (19.2)
Yes		477 (78.1)	474 (77.1)	951 (77.6)
Data missing		19 (3.1)	20 (3.3)	39 (3.2)
Systemic steroids, oral or i.v.	1144 (93.3)
No		319 (52.2)	294 (47.8)	613 (50.0)
Yes		250 (40.9)	281 (45.7)	531 (43.3)
Data missing		42 (6.9)	40 (6.5)	82 (6.7)
Therapeutic dose anticoagulation	1150 (93.8)
No		352 (57.6)	333 (54.1)	685 (55.9)
Yes		220 (36.0)	245 (39.8)	465 (37.9)
Data missing		39 (6.4)	37 (6.0)	76 (6.2)

Data are presented as n (%) unless otherwise stated. World Health Organization (WHO) clinical progression scale: not requiring continuous supplemental oxygen (levels 3–4); continuous supplemental oxygen only (level 5); continuous positive airway pressure ventilation, bilevel positive airway pressure or high-flow nasal oxygen (level 6); invasive mechanical ventilation, extra-corporeal membrane oxygenation and acute renal replacement therapy (levels 7–9). n<5 and related subtotals have been suppressed. IQR: interquartile range.

TABLE 3

Patient characteristics available at the research visit

	Total, N (%)	Post-COVID-19 breathlessness		Total	OR (95% CI)
	Total, N (%)	No	Yes	Total	OR (95% CI)
Total, N (%)		611 (49.8)	615 (50.2)	1226
Discharge to review period, months	1226 (100.0)	4.7 (3.4–6.0)	4.7 (3.3–6.0)	4.7 (3.4–6.0)	1.00 (1.00–1.00)
Breathlessness at research visit, PSQ	1226 (100.0)
0		462 (75.6)	0 (0.0)	462 (37.7)
1–2		70 (11.5)	143 (23.3)	213 (17.4)
≥3		79 (12.9)	472 (76.7)	551 (44.9)
PHQ-9 total score	1188 (96.9)	3.0 (1.0–8.0)	8.0 (3.0–13.0)	5.0 (2.0–11.0)	1.09 (1.07–1.12)
GAD-7 total score	1187 (96.8)	2.0 (0.0–6.0)	5.0 (1.0–11.0)	3.0 (0.0–8.0)	1.07 (1.05–1.09)
PCL-5 total severity score	1184 (96.6)	6.0 (2.0–15.0)	15.0 (5.0–31.2)	9.0 (3.0–23.0)	1.03 (1.02–1.04)
CRP, mg·L⁻¹	800 (65.3)	4.0 (1.4–5.0)	4.0 (2.0–5.0)	4.0 (1.8–5.0)	1.01 (0.99–1.04)
BNP/NT-pro-BNP above threshold	642 (52.4)				0.65 (0.32–1.33)
No		293 (48.0)	304 (49.4)	597 (48.7)
Yes		29 (4.7)	16 (2.6)	45 (3.7)
Haemoglobin, g·dL⁻¹	861 (70.2)	14.4 (13.3–15.2)	14.0 (13.1–15.0)	14.2 (13.2–15.2)	0.88 (0.79–0.98)
Males	537 (43.8)	14.7 (13.9–15.6)	14.6 (13.6–15.5)	14.7 (13.8–15.5)	0.90 (0.79–1.03)
Females	324 (26.4)	13.5 (12.8–14.3)	13.4 (12.6–14.0)	13.4 (12.7–14.1)	0.80 (0.65–0.99)
ISWT distance, m	737 (60.1)	440.0 (270.0–615.0)	350.0 (230.0–540.0)	380.0 (257.5–570.0)	0.91 (0.85–0.97)^#
ISWT, % predicted	658 (53.7)	60.5 (42.0–81.9)	52.5 (35.1–71.2)	56.3 (37.9–75.9)	0.99 (0.98–1.00)
Oxygen saturations post-ISWT, %	727 (59.3)	96.0 (94.0–98.0)	96.0 (94.0–98.0)	96.0 (94.0–98.0)	0.98 (0.94–1.02)
Borg leg fatigue score post-ISWT	722 (58.9)	2.0 (0.5–3.0)	3.0 (2.0–4.0)	3.0 (1.0–4.0)	1.14 (1.06–1.23)
FEV₁, L	748 (61.0)	2.8 (2.3–3.4)	2.7 (2.2–3.3)	2.8 (2.2–3.3)	0.96 (0.81–1.15)
FEV₁, % predicted	683 (55.7)	93.9 (83.4–105.7)	89.9 (77.9–101.3)	91.7 (79.7–103.7)	1.00 (0.99–1.00)
FEV₁ <LLN	683 (55.7)				1.61 (1.05–2.45)
No		274 (85.4)	284 (78.5)	558 (81.7)
Yes		47 (14.6)	78 (21.5)	125 (18.3)
FVC, L	746 (60.8)	3.6 (2.9–4.3)	3.3 (2.6–4.0)	3.5 (2.8–4.2)	0.70 (0.57–0.86)
FVC, % predicted	681 (55.5)	93.7 (83.0–105.4)	86.8 (74.5–98.5)	90.0 (78.2–102.4)	0.98 (0.97–0.99)
FVC <LLN	681 (55.5)				2.43 (1.60–3.70)
No		276 (86.2)	260 (72.0)	536 (78.7)
Yes		44 (13.8)	101 (28.0)	145 (21.3)
FEV₁/FVC ratio, %	736 (60.0)	79.4 (73.9–84.0)	81.6 (77.3–86.0)	80.6 (76.0–85.5)	1.04 (1.02–1.06)
FEV₁/FVC <LLN	673 (54.9)				0.58 (0.28–1.19)
No		295 (93.1)	342 (96.1)	637 (94.7)
Yes		22 (6.9)	14 (3.9)	36 (5.3)
T_LCO, mmol·min⁻¹·kPa⁻¹	272 (22.2)	7.6 (6.4–8.7)	6.8 (5.8–8.3)	7.3 (6.1–8.4)	0.94 (0.83–1.07)
T_LCO, % predicted	252 (20.6)	90.1 (78.6–102.7)	90.7 (74.2–104.2)	90.7 (76.8–103.2)	0.99 (0.99–1.00)
T_LCO <80% predicted	252 (20.6)				1.48 (0.79–2.77)
No		86 (72.3)	90 (67.7)	176 (69.8)
Yes		33 (27.7)	43 (32.3)	76 (30.2)
K_CO, mmol·min⁻¹·kPa⁻¹·L⁻¹	276 (22.5)	1.5 (1.3–1.6)	1.5 (1.2–1.7)	1.5 (1.3–1.6)	0.49 (0.18–1.29)
K_CO, % predicted	259 (21.1)	103.5 (92.6–108.7)	99.6 (87.4–112.3)	101.8 (89.2–110.1)	0.99 (0.97–1.00)
K_CO <80% predicted	259 (21.1)				1.43 (0.53–3.88)
No		112 (92.6)	127 (92.0)	239 (92.3)
Yes		9 (7.4)	11 (8.0)	20 (7.7)

Data are presented as median (interquartile range) or n (%), unless otherwise stated. PSQ: Patient Symptom Questionnaire; PHQ-9: Patient Health Questionnaire-9; GAD-7: General Anxiety Disorder-7; PCL-5: Post Traumatic Stress Disorder Checklist; CRP: C-reactive protein; BNP: B-type natriuretic peptide; NT-pro-BNP: N-terminal pro-BNP; ISWT: incremental shuttle walk test; FEV₁: forced expiratory volume in 1 s; LLN: lower limit of normal; FVC: forced vital capacity; T_LCO: transfer capacity of the lung for carbon monoxide; K_CO: carbon monoxide transfer coefficient. ^#: refers to the risk of worsening breathlessness for each 100 m achieved.

TABLE 4

Multivariable logistic regression for post-COVID-19 breathlessness

	Post-COVID-19 breathlessness		OR (95% CI)
	No	Yes	Univariable	Multivariable	Multiple imputation
Sex at birth
Male	416 (54.2)	352 (45.8)	1 (ref)	1 (ref)	1 (ref)
Female	195 (42.6)	263 (57.4)	1.59 (1.26–2.01) (p<0.001)	1.44 (1.10–1.90) (p=0.009)	1.56 (1.21–2.00) (p=0.001)
Age at admission, years
<30	10 (40.0)	15 (60.0)	1.12 (0.49–2.63) (p=0.795)	1.20 (0.47–3.12) (p=0.706)	1.35 (0.57–3.23) (p=0.498)
30–39	38 (48.1)	41 (51.9)	0.80 (0.49–1.31) (p=0.378)	0.83 (0.48–1.44) (p=0.511)	0.86 (0.51–1.44) (p=0.568)
40–49	87 (45.8)	103 (54.2)	0.88 (0.62–1.26) (p=0.482)	0.96 (0.64–1.44) (p=0.832)	0.96 (0.66–1.40) (p=0.832)
50–59	151 (42.7)	203 (57.3)	1 (ref)	1 (ref)	1 (ref)
60–69	183 (51.3)	174 (48.7)	0.71 (0.53–0.95) (p=0.022)	0.62 (0.44–0.88) (p=0.007)	0.70 (0.51–0.96) (p=0.025)
70–79	107 (63.7)	61 (36.3)	0.42 (0.29–0.62) (p<0.001)	0.41 (0.26–0.64) (p<0.001)	0.43 (0.28–0.64) (p<0.001)
≥80	29 (72.5)	11 (27.5)	0.28 (0.13–0.57) (p=0.001)	0.27 (0.11–0.60) (p=0.002)	0.31 (0.14–0.66) (p=0.003)
Index of Multiple Deprivation
5, least deprived	127 (55.2)	103 (44.8)	1 (ref)	1 (ref)	1 (ref)
4	111 (51.9)	103 (48.1)	1.14 (0.79–1.66) (p=0.480)	1.30 (0.85–1.99) (p=0.220)	1.22 (0.82–1.81) (p=0.328)
3	116 (50.9)	112 (49.1)	1.19 (0.82–1.72) (p=0.352)	1.21 (0.80–1.84) (p=0.365)	1.22 (0.82–1.79) (p=0.327)
2	135 (50.8)	131 (49.2)	1.20 (0.84–1.71) (p=0.321)	1.31 (0.87–1.96) (p=0.195)	1.20 (0.82–1.76) (p=0.338)
1, most deprived	112 (42.1)	154 (57.9)	1.70 (1.19–2.42) (p=0.004)	1.87 (1.24–2.84) (p=0.003)	1.67 (1.14–2.44) (p=0.009)
Ethnicity
White	422 (48.3)	451 (51.7)	1 (ref)	1 (ref)	1 (ref)
South Asian	82 (53.6)	71 (46.4)	0.81 (0.57–1.14) (p=0.231)	0.83 (0.55–1.26) (p=0.378)	0.80 (0.55–1.17) (p=0.244)
Black	52 (56.5)	40 (43.5)	0.72 (0.46–1.11) (p=0.137)	0.57 (0.34–0.95) (p=0.031)	0.56 (0.35–0.89) (p=0.015)
Mixed	17 (51.5)	16 (48.5)	0.88 (0.44–1.77) (p=0.720)	0.98 (0.44–2.20) (p=0.956)	0.85 (0.41–1.75) (p=0.656)
Other	27 (51.9)	25 (48.1)	0.87 (0.49–1.52) (p=0.616)	0.84 (0.44–1.62) (p=0.606)	0.80 (0.44–1.44) (p=0.448)
BMI, kg·m⁻²	31.4±7.1	32.7±7.1	1.03 (1.01–1.04) (p=0.002)	1.08 (0.97–1.21) (p=0.164)	1.08 (0.98–1.19) (p=0.107)
Number of comorbidities	2.0±2.0	2.4±2.3	1.09 (1.03–1.15) (p=0.002)	1.09 (1.00–1.18) (p=0.049)	1.08 (1.00–1.17) (p=0.049)
Pre-existing respiratory condition
No	449 (50.3)	444 (49.7)	1 (ref)	1 (ref)	1 (ref)
Yes	162 (48.6)	171 (51.4)	1.07 (0.83–1.37) (p=0.611)	0.85 (0.62–1.17) (p=0.312)	0.82 (0.61–1.11) (p=0.195)
Pre-existing depression or anxiety
No	538 (53.3)	471 (46.7)	1 (ref)	1 (ref)	1 (ref)
Yes	66 (33.3)	132 (66.7)	2.28 (1.66–3.16) (p<0.001)	1.54 (1.00–2.38) (p=0.050)	1.58 (1.06–2.35) (p=0.026)
Admission duration, days	13.2±17.2	17.2±22.2	1.01 (1.00–1.02) (p=0.001)	1.01 (1.00–1.02) (p=0.064)	1.01 (1.00–1.02) (p=0.002)
WHO clinical progression scale
WHO class 3–4	110 (49.3)	113 (50.7)	1 (ref)	1 (ref)	1 (ref)
WHO class 5	252 (52.8)	225 (47.2)	0.87 (0.63–1.19) (p=0.388)	0.88 (0.61–1.29) (p=0.522)	0.84 (0.60–1.18) (p=0.314)
WHO class 6	136 (53.1)	120 (46.9)	0.86 (0.60–1.23) (p=0.407)	0.90 (0.58–1.38) (p=0.619)	0.80 (0.54–1.18) (p=0.260)
WHO class 7–9	113 (41.9)	157 (58.1)	1.35 (0.95–1.93) (p=0.097)	1.17 (0.70–1.98) (p=0.548)	0.92 (0.57–1.47) (p=0.715)

Data are presented as n (%) or mean±sd, unless otherwise stated. The dependent variable was post-COVID-19 breathlessness. World Health Organization (WHO) clinical progression scale: not requiring continuous supplemental oxygen (levels 3–4); continuous supplemental oxygen only (level 5); continuous positive airway pressure ventilation, bilevel positive airway pressure or high-flow nasal oxygen (level 6); invasive mechanical ventilation, extra-corporeal membrane oxygenation and acute renal replacement therapy (levels 7–9). The logistic regression model also included body mass index (BMI)².

TABLE 5

Multinomial modelling for post-COVID-19 breathlessness

	Post-COVID-19 breathlessness OR (95% CI)
	Mild	Severe
Sex at birth
Male	1 (ref)	1 (ref)
Female	1.34 (0.95–1.88)	1.67 (1.26–2.22)
Age at admission, years
<30	2.22 (0.78–6.33)	0.95 (0.35–2.62)
30–39	1.23 (0.62–2.43)	0.68 (0.38–1.22)
40–49	1.38 (0.84–2.26)	0.78 (0.51–1.18)
50–59	1 (ref)	1 (ref)
60–69	0.79 (0.51–1.23)	0.64 (0.46–0.91)
70–79	0.44 (0.25–0.80)	0.39 (0.25–0.62)
≥80	0.58 (0.23–1.41)	0.13 (0.04–0.44)
Index of Multiple Deprivation
5, least deprived	1 (ref)	1 (ref)
4	1.14 (0.68–1.90)	1.26 (0.79–2.00)
3	1.05 (0.63–1.74)	1.38 (0.88–2.18)
2	0.82 (0.49–1.36)	1.52 (0.99–2.35)
1, most deprived	1.02 (0.61–1.71)	2.22 (1.44–3.44)
Ethnicity
White	1 (ref)	1 (ref)
South Asian	0.80 (0.49–1.33)	0.74 (0.48–1.14)
Black	1.02 (0.61–1.71)	0.46 (0.27–0.80)
Mixed	0.76 (0.27–2.15)	0.88 (0.39–1.98)
Other	0.88 (0.39–1.96)	0.77 (0.39–1.49)
BMI, kg·m⁻²	0.99 (0.96–1.02)	1.01 (0.99–1.04)
Number of comorbidities	1.12 (1.02–1.24)	1.06 (0.98–1.16)
Pre-existing respiratory condition
No	1 (ref)	1 (ref)
Yes	0.94 (0.64–1.39)	0.76 (0.55–1.07)
Pre-existing depression or anxiety
No	1 (ref)	1 (ref)
Yes	1.41 (0.83–2.38)	1.64 (1.06–2.54)
Admission duration, days	1.01 (1.00–1.02)	1.02 (1.01–1.02)
WHO clinical progression scale
WHO class 3–4	1 (ref)	1 (ref)
WHO class 5	0.92 (0.59–1.45)	0.81 (0.55–1.20)
WHO class 6	0.76 (0.45–1.31)	0.83 (0.53–1.30)
WHO class 7–9	0.90 (0.48–1.69)	0.98 (0.58–1.65)

The dependent variable was post-COVID-19 breathlessness categorised into three levels, No/Mild/Severe. The reference group (not shown) were those with no post-COVID-19 breathlessness (n=611). Mild post-COVID-19 breathlessness: n=213; severe post-COVID-19 breathlessness: n=402. World Health Organization (WHO) clinical progression scale: not requiring continuous supplemental oxygen (levels 3–4); continuous supplemental oxygen only (level 5); continuous positive airway pressure ventilation, bilevel positive airway pressure or high-flow nasal oxygen (level 6); invasive mechanical ventilation, extra-corporeal membrane oxygenation and acute renal replacement therapy (levels 7–9). BMI: body mass index.

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Supplementary material 00274-2022.SUPPLEMENT