Incidence of cough and sputum in acute and post-acute COVID-19 infection during the 12-month follow-up
The prevalence of cough and sputum decreased significantly from the acute phase to the 3-month follow-up, with only slight decreases at the 6- and 12-month follow-ups (cough: 52.3% at onset, 8.8% at 3 months, 5.8% at 6 months, and 4.4% at 12 months; sputum: 32.8% at onset, 7.2% at 3 months, 5.9% at 6 months, and 5.0% at 12 months) (Fig. 2A). Most patients with cough or sputum at the 12-month follow-up presented with these symptoms during hospitalization. At the 3-month follow-up, coughing was more frequent than sputum production. However, at the 6- and 12-month follow-ups, sputum was more frequent than cough. The incidence rates of dry cough and productive cough were similar at hospitalization and within the 12-month follow-up (55.7% at onset, 48.8% at 3 months, 56.0% at 6 months, and 46.9% at 12 months) (Fig. 2B). In contrast, sputum was accompanied by cough during hospitalization in almost all patients (89.0% at onset). At all follow-up periods, patients with sputum without cough were more frequent than those with cough, and the rate increased from the 3- to 12-month follow-up (62.7%, 54.9%, and 41.7%, at 3, 6 and 12 months respectively) (Fig. 2C).
Patient characteristics with prolonged cough in long COVID
Next, we compared patient characteristics between patients with and without cough at the 3-, 6-, and 12-month follow-ups (3-month: Supplementary Tables 1–3; 6-month: Supplementary Tables 5–7; 12-month: Tables 1–3).
Table 1
Comorbidities, complications, and management of patients with and without cough or sputum in PRO after 12 months.
|
Cough
|
Sputum
|
|
Symptom (+) (N = 32)
|
Symptom (-) (N = 692)
|
p value
|
Symptom (+) (N = 36)
|
Symptom (-) (N = 688)
|
p value
|
Clinical characteristics
|
|
|
|
|
|
|
Age, mean (95%CI)
|
64 (55.75–73.75)
|
59 (47–71)
|
0.038a
|
65 (53–75)
|
59 (47–70)
|
0.036a
|
Male, n (%)
|
24 (75)
|
422 (61)
|
0.111b
|
30 (83.3)
|
416 (60.5)
|
0.006b
|
BMI, mean (95%CI)
|
24.33 (22.14–27.71)
|
23.77 (21.45–26.26)
|
0.290a
|
23.77 (21.51–26.3)
|
24.14 (21.84–25.35)
|
0.917a
|
Current smoking, n (%)
|
4 (12.5)
|
70 (10.1)
|
0.693b
|
6 (16.7)
|
68 (10)
|
0.161b
|
Smoking history, n (%)
|
17 (53.1)
|
239 (34.5)
|
0.021b
|
18 (50)
|
238 (34.6)
|
0.042b
|
Comorbidities, n (%)
|
|
|
|
|
|
|
Hypertension
|
19 (59.4)
|
238 (34.4)
|
0.004b
|
19 (52.8)
|
238 (34.6)
|
0.028b
|
Diabetes
|
14 (43.8)
|
108 (15.6)
|
< 0.001b
|
6 (16.7)
|
114 (16.6)
|
0.988b
|
Cardiovascular disease
|
3 (9.4)
|
40 (5.8)
|
0.409b
|
2 (5.6)
|
41 (59.6)
|
0.911b
|
Malignancy
|
2 (6.3)
|
40 (5.8)
|
0.920b
|
2 (5.6)
|
40 (58.1)
|
0.940b
|
COPD
|
2 (6.3)
|
22 (3.2)
|
0.350b
|
3 (8.3)
|
21 (3.1)
|
0.088b
|
Asthma
|
4(12.5)
|
36 (5.2)
|
0.082b
|
4 (11.1)
|
36 (5.2)
|
0.139b
|
Hyperuricemia
|
3 (9.4)
|
77 (11.1)
|
0.743b
|
7 (19.4)
|
73 (10.6)
|
0.105b
|
Chronic liver disorder
|
1 (3.1)
|
26 (3.8)
|
0.841b
|
1 (2.8)
|
26 (3.8)
|
0.745b
|
Chronic kidney disease
|
5 (15.6)
|
29 (4.2)
|
0.002b
|
2 (5.6)
|
32 (4.7)
|
0.789b
|
Management, n (%)
|
|
|
|
|
|
|
ICU
|
7 (21.9)
|
65 (9.4)
|
0.024b
|
6 (16.7)
|
66 (9.6)
|
0.183
|
Mechanical ventilator
|
5 (15.6)
|
32 (4.6)
|
0.007b
|
6 (16.7)
|
31 (4.5)
|
0.002b
|
Use of IMV/NPPV/NHF
|
5 (15.6)
|
42 (6.1)
|
0.036b
|
6 (16.7)
|
41 (6.0)
|
0.013b
|
Abbreviation: PRO, patient reported outcome; BMI, body mass index; COPD, chronic obstructive pulmonary disease. ICU, intensive care unit.
|
IMV/NPPV/NHF, intermittent mandatory ventilation/ noninvasive positive pressure ventilation/ nasal high flow. a t-test, b Chi-Square test.
|
Table 2
Clinical symptoms of patients with and without cough or sputum in PRO after 12 months.
|
Cough
|
Sputum
|
|
Symptom (+)
(N = 32)
|
Symptom (-)
(N = 692)
|
p value
|
Symptom (+)
(N = 36)
|
Symptom (-)
(N = 688)
|
p value
|
Clinical symptoms on admission, n (%)
|
Fever
|
23 (71.9)
|
587 (84.8)
|
0.049a
|
29 (80.6)
|
581 (84.4)
|
0.532a
|
Cough
|
26 (81.3)
|
406 (58.7)
|
< 0.001a
|
27 (75.0)
|
405 (58.9)
|
0.054a
|
Sputum
|
22 (68.8)
|
248 (35.8)
|
< 0.001a
|
28 (77.8)
|
242 (35.2)
|
< 0.001a
|
Sore throat
|
12 (37.5)
|
194 (28.0)
|
0.189a
|
16 (44.4)
|
191 (27.7)
|
0.006a
|
Taste impairment
|
9 (28.1)
|
250 (36.1)
|
0.356a
|
16 (44.4)
|
215 (31.3)
|
0.098a
|
Smell impairment
|
6 (18.8)
|
235 (34.0)
|
0.074a
|
11 (30.6)
|
200 (29.1)
|
0.848a
|
Dyspnea
|
22 (68.8)
|
319 (46.1)
|
0.012a
|
22 (61.1)
|
315 (45.8)
|
0.072a
|
Abdominal pain
|
5 (15.6)
|
65 (9.4)
|
0.002a
|
5 (13.9)
|
65 (9.4)
|
0.379a
|
Diarrhea
|
4 (12.5)
|
151 (21.8)
|
0.209a
|
7 (19.4)
|
148 (21.5)
|
0.768a
|
aChi-Square test.
|
Table 3
Laboratory and imaging findings of patients with and without cough or sputum in PRO after 12 months.
|
Cough
|
|
Sputum
|
|
|
Symptom (+)
(N = 32)
|
Symptom (-)
(N = 692)
|
p value
|
Symptom (+)
(N = 36)
|
Symptom (-)
(N = 688)
|
p value
|
Laboratory findings, median (IQR)
|
WBC (cells/µl)
|
5070 (4125–7250)
|
4846 (3900–6200)
|
0.151a
|
5065 (4007-7457.5)
|
4840 (3900–6200)
|
0.121a
|
%NEU
|
73.5 (64.7–84.1)
|
68.95 (60–77)
|
0.004a
|
72 (63.2–82.8)
|
69 (60–77)
|
0.012a
|
%EOS
|
0 (0–1)
|
0 (0–1)
|
0.494a
|
0 (0–1)
|
0 (0–1)
|
0.099a
|
%LYM
|
17 (9.75-25)
|
22.5 (15.8–30)
|
0.006a
|
19 (10.3–26)
|
22.75 (15.3–30)
|
0.056a
|
Cre (mg/dl)
|
0.87 (0.65–1.08)
|
0.8 (0.65–0.97)
|
0.665a
|
0.86 (0.65-1.00)
|
0.81 (0.65–0.97)
|
0.947a
|
LDH (IU/L)
|
293 (239–402)
|
229 (190–297)
|
< 0.001a
|
278 (204–329)
|
230 (191-294.5)
|
0.087a
|
UA (mg/dl)
|
5 (4.05–5.85)
|
4.45 (3.575-5.5)
|
0.107a
|
5 (3.75–5.65)
|
4.5 (3.5–5.5)
|
0.245a
|
ferritin (ng/ml)
|
423 (171.75–639.9)
|
314 (150-596.9)
|
0.172a
|
409 (232-616.85)
|
314.5 (148.75-3597.18)
|
0.786a
|
KL-6 (U/ml)
|
304 (217–531)
|
220 (171–312)
|
0.022a
|
232 (177.75–336.5)
|
221.5 (172-318.75)
|
0.745a
|
HbA1c (%)
|
6.4 (5.9–7.2)
|
5.9 (5.6–6.4)
|
0.031a
|
6.05 (5.7–6.85)
|
5.9 (5.6–6.4)
|
0.539a
|
D-dimer (µg/ml)
|
0.9 (0.6–1.5)
|
0.8 (0.5–1.3)
|
0.576a
|
1.04 (0.7–1.55)
|
0.8 (0.5–1.3)
|
0.254a
|
Imaging examination n (%)
|
Chest X-ray (GGO)
|
16 (50.0)
|
318 (46.0)
|
0.153b
|
22 (61.1)
|
312 (45.3)
|
0.179b
|
Chest X-ray (infiltration)
|
6 (18.8)
|
124 (17.9)
|
0.314b
|
8 (22.2)
|
122 (17.7)
|
0.198b
|
Chest X-ray ( ≧ 50% within 48hrs)
|
2 (6.3)
|
49 (7.1)
|
0.848b
|
2 (6.3)
|
49 (71.2)
|
0.806b
|
Chest CT (GGO)
|
28 (87.5)
|
429 (62.0)
|
0.004b
|
31 (86.1)
|
426 (61.9)
|
0.128b
|
Chest CT (infiltration)
|
12 (37.5)
|
193 (27.9)
|
0.112b
|
13 (36.1)
|
192 (27.9)
|
0.169b
|
Abbreviation: WBC, white blood cell; NEU, neutrophil; EOS, eosinophil; LYM, lymphocyte; LDH, lactate dehydrogenase; CT, computed tomography; GGO, ground-glass opacity, a t-test, b Chi-Square test.
|
At the 3-month follow-up, the proportion of female sex was higher in the group of patients with a cough than in the group of patients without a cough (Supplementary Table 1). Multiple symptoms during the acute phase of COVID-19 during hospitalization were correlated with prolonged cough. Laboratory tests revealed higher levels of HbA1c in patients with cough. There were no significant differences in imaging findings between the two groups.
At the 6-month follow-up, a higher percentage of current smokers was found in patients with a cough than in patients without a cough (Supplementary Table 4). There was a positive correlation between cough and several other symptoms during hospitalization (Supplementary Table 5). Laboratory tests showed a higher ratio of neutrophils to blood leukocytes in patients with cough at the 6-month follow-up. Imaging findings demonstrated a higher proportion of patients in the cough group with chest radiographs showing consolidation and/or ground-glass opacity of more than 50% within 48 hours after onset of acute COVID-19 infection patients with cough at this timepoint (Supplementary Table 6).
At the 12-month follow-up, a larger proportion of older patients presented cough group (Table 1). Patients with prolonged cough at this point presented several risk factors for severe COVID-19, including hypertension, diabetes, and chronic kidney disease (Table 1). The incidence of ICU admission, ventilator management, and renal dysfunction during hospitalization was significantly higher in the patients with cough (Table 1). Respiratory symptoms (cough, sputum, and dyspnea) and abdominal pain were correlated with prolonged cough at this point (Table 2). Laboratory tests revealed a higher ratio of neutrophils to peripheral blood leukocytes, a lower proportion of lymphocytes, and higher levels of LDH, KL-6, and HbA1C in patients with cough (Table 3). The imaging findings showed that a higher proportion of patients in the cough group at the 12-month follow-up had GGO on chest computed tomography (CT) images during hospitalization (Table 3).
Patient characteristics with prolonged sputum in long COVID
Next, we compared patient characteristics between patients with sputum and those without sputum at the 3-, 6-, and 12-month follow-ups (3-month: Supplementary Table 1–3; 6-month: Supplementary Table 4–6; 12-month: Tables 1–3).
At 3-month follow-up, different symptoms during hospitalization were correlated with prolonged sputum production (Supplementary Table 2). The incidence of ventilator management during hospitalization was significantly higher in patients with sputum production (Supplemental Table 1). Laboratory tests revealed a higher ratio of neutrophils to peripheral blood leukocytes and a lower proportion of lymphocytes in patients with prolonged sputum (Supplementary Table 3). There were no significant differences in the imaging findings between the two groups.
At the 6-month follow-up, multiple symptoms during hospitalization were correlated with sputum (Supplementary Table 5). The incidence of ventilator management during hospitalization was significantly higher in patients with sputum (Supplementary table 4). Laboratory tests revealed a higher proportion of neutrophils in peripheral blood leukocytes, a lower proportion of lymphocytes, and higher LDH levels in patients with sputum (Supplementary Table 6). There were no significant differences in imaging findings between the two groups.
At the 12-month follow-up, a larger proportion of older patients presented sputum (Table 1). Male sex, smoking history, hypertension, and ventilator management during hospitalization were associated with prolonged sputum production (Table 1). Sputum production and sore throat during hospitalization correlated with prolonged sputum production (Table 2). Laboratory tests revealed a higher proportion of neutrophils in the peripheral blood leukocytes of patients with sputum (Table 3). There were no significant differences in imaging findings between the two groups.
Risk factors for persistent cough and sputum in long COVID
At the 12-month follow-up, we identified multiple risk factors for persistent cough and sputum production that were closely associated with severe COVID-19.
First, we performed a univariate logistic regression analysis (Supplementary Table 7). Smoking history, hypertension, diabetes mellitus, and the need for intermittent mandatory ventilation (IMV) were common risk factors for prolonged coughing at the 12-month follow-up. Age, male sex, smoking history, and IMV use were common risk factors for prolonged sputum at the 12-month follow up. We performed a multivariable logistic regression analysis to evaluate age, sex, male sex, smoking history, hypertension, diabetes mellitus, and IMV use as potential risk factors for prolonged cough. We also performed a multivariable logistic regression analysis using age, sex, male sex, smoking history, hypertension, and IMV use as risk factors for prolonged sputum Table 4). The use of IMV was an independent risk factor for prolonged coughing (odds ratio [OR] 95% confidence interval [95%CI]: 3.721 [1.252–11.053], p = 0.018). Similarly, multivariable logistic regression analysis showed that the use of IMV was also an independent risk factor for prolonged sputum (OR [95%CI] 3.078 [1.060–8.935, p = 0.039].
Table 4
Multivariable analysis for persistent cough and sputum at 12 months.
|
|
Cough
|
|
|
Sputum
|
|
|
OR
|
95%CI
|
p value
|
OR
|
95%CI
|
p value
|
Sex (male)
|
1.155
|
0.427–3.124
|
0.855
|
2.667
|
0.925–7.689
|
0.069
|
Age
|
1.003
|
0.972–1.035
|
0.855
|
1.022
|
0.991–1.054
|
0.161
|
Smoking history
|
1.539
|
0.632–3.747
|
0.342
|
1.265
|
0.547–2.913
|
0.581
|
Hypertention
|
1.37
|
0.557–3.370
|
0.493
|
1.147
|
0.518–2.542
|
0.735
|
Diabetes Mellitas
|
3.136
|
1.334–7.374
|
0.009
|
N/A
|
N/A
|
N/A
|
Use of IMV
|
3.721
|
1.252–11.053
|
0.018
|
3.133
|
1.083–9.060
|
0.035
|
Abbreviation: IMV, intermittent mandatory ventilation; N/A, not assessed
|
These findings indicate a positive correlation between ventilator management during hospitalization and persistent cough and sputum production in patients with prolonged COVID-19. In accordance with these findings, of the 690 patients who answered a longitudinal questionnaire on symptoms at all periods, 33 patients who received ventilator management during hospitalization had higher rates of cough symptoms and sputum at the 6-month (cough: 2.20 times; sputum: 2.60 times) and 12-month (cough: 2.57 times; sputum: 2.50 times) follow-up time points.
Patients who received ventilator management during hospitalization were defined as having severe acute COVID-19. Thus, we analyzed the relationship between prolonged cough and follow-up periods using classification of severity in acute COVID-19 infection: moderate II and severe COVID-19 patients who required oxygen therapy more frequently presented cough at the 12-month follow-up than non-severe patients who did not require oxygen therapy (Fig. 3A: Log-rank (Mantel-Cox) test: p = 0.0033, HR [95%CI] 1.843 [1.225–2.771]). In addition, patients who required oxygen therapy more frequently presented sputum at the 12-month follow-up than non-severe patients (Fig. 3B: Log-rank (Mantel Cox) test: p = 0.0053, HR [95%CI] 1.875 [1.205–2.916]).