First and second COVID-19 waves in Japan: A comparison of disease severity and characteristics.

Dear Editor,

We read with interest the recent article published in your journal detailing the severity of coronavirus disease 2019 (COVID-19) in China during the first wave of the pandemic. COVID-19 has become a global pandemic, occurring in forming several peaks in waves , . This study compared the severity and characteristics of the first and second waves in Japan.

We obtained the study data from the COVID-19 Registry Japan (COVIREGI-JP). The COVIREGI-JP includes data from a observational cohort study using medical records in Japan. The criteria for enrolment were (1) tests such as polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) that turned positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and (2) inpatient treatment at a health care facility. We evaluated age, sex, comorbidities, disease severity at admission, supportive care, medications, and the outcome on discharge. A patient's condition was denoted as “severe” on fulfilment of one or more of the following criteria: the need for invasive or non-invasive mechanical ventilation, need for supplemental oxygen, an oxygen saturation (SpO2) of < 94% at room air, and tachypnoea (respiratory rate of >24 breaths per minute). Patients who did not meet these criteria were classified as “non-severe” at admission. Patients admitted between 26 January and 31 May 2020, were included in the first wave, and those admitted between 1 June and 31 July 2020, were included in the second wave (frozen data as of 2 September 2020). Continuous variables were expressed as medians and interquartile ranges, and categorical variables were expressed as numbers (%). All statistical analyses were conducted using R version 4.0.2 (R core Team).

Data of 5194 cases from 327 facilities were included in the analysis: 3833 and 1361 cases from the first and second waves, respectively. At admission, the second wave had a smaller proportion of severe cases (12.0% vs 33.1%, Fig. 1 a); the duration from onset to admission was also shorter (median, 4 vs 7 days) than that in patients in the first wave (Fig. 1b, 1c). Patients in the second wave tended to be younger (median age, 37 vs 56 years), were less frequently transferred from other hospitals (3.8% vs 15.0%) and were less likely to have comorbidities such as cardiovascular diseases (1.9% vs 5.9%), and cerebrovascular disease (1.8% vs 6.1%). Mortality (1.2% vs 7.3%) in hospitalized or discharged patients was also lower in the second wave; the same trend was observed on stratification according to age and severity at admission (Table 1 ).

Fig. 1

Epidemic curve, severity, and days from onset to admission in COVID-19 patients in Japan

(a) Epidemic curve and severity from 26 January to 31 July 2020, as recorded in the COVID-19 Registry Japan.

(b) Number of days from onset to admission from 26 January to 31 May (first wave)

(c) Number of days from onset to admission from 1 June to 31 July (second wave)

Abbreviations: COVIREGI-JP, COVID-19 Registry Japan; COVID-19, coronavirus disease.

Table 1

Demographics, characteristics, comorbidities, treatments, and outcomes of the patients.

			1st wave: From 26 January to 31 May			2nd wave: From 1 June to 31 July
		All	All	Non-severe	Severe	All	Non-severe	Severe
No. (%)a		5194	3833 (73.8)	2563 (66.9)	1270 (33.1)	1361 (26.2)	1198 (88.0)	163 (12.0)
Demographics
Sex (Male)		3068 (59.2)	2272 (59.5)	1398 (54.8)	874 (68.9)	796 (58.6)	687 (57.5)	109 (66.9)
Age, y	Median [IQR]	52 [34, 68]	56 [40, 71]	51 [35, 66]	67 [53, 79]	37 [25, 53]	35 [25, 50]	57.5 [39.25, 72.75]
	0–64	3609 (69.8)	2447 (64.0)	1871 (73.2)	576 (45.4)	1162 (86.1)	1066 (89.7)	96 (59.3)
	≥65	1565 (30.2)	1377 (36.0)	685 (26.8)	692 (54.6)	188 (13.9)	122 (10.3)	66 (40.7)
Ethnicity (Japanese)	4928 (95.2)	3634 (95.1)	2412 (94.4)	1222 (96.4)	1294 (95.3)	1140 (95.4)	154 (94.5)
Transfer from other hospitals	624 (12.1)	573 (15.0)	218 (8.6)	355 (28.0)	51 (3.8)	29 (2.5)	22 (13.5)
Days from onset to admission	Median [IQR]	6 [3, 9]	7 [4, 10]	6 [4, 10]	7 [4, 10]	4 [2, 7]	4 [2, 6.25]	5 [3, 7]
Comorbidity
Cardiovascular diseasesb	251 (4.8)	225 (5.9)	87 (3.4)	138 (10.9)	26 (1.9)	16 (1.3)	10 (6.1)
Cerebrovascular disease	257 (4.9)	232 (6.1)	105 (4.1)	127 (10.0)	25 (1.8)	15 (1.3)	10 (6.1)
Chronic respiratory diseasesc	184 (3.5)	155 (4.0)	45 (1.8)	110 (8.7)	29 (2.1)	13 (1.1)	16 (9.8)
Severe renal diseases or dialysis	65 (1.3)	56 (1.5)	29 (1.1)	27 (2.1)	9 (0.7)	7 (0.6)	2 (1.2)
Diabetes		738 (14.2)	630 (16.4)	312 (12.2)	318 (25.0)	108 (7.9)	71 (5.9)	37 (22.7)
Obesityd		249 (4.8)	192 (5.0)	107 (4.2)	85 (6.7)	57 (4.2)	41 (3.4)	16 (9.8)
Solid tumour		193 (3.7)	173 (4.5)	88 (3.4)	85 (6.7)	20 (1.5)	16 (1.3)	4 (2.5)
Immunosuppressione	131 (2.6)	122 (3.2)	74 (2.9)	48 (3.9)	9 (0.7)	8 (0.7)	1 (0.6)
Supportive caref
Oxygen therapy		1664 (32.1)	1487 (38.8)	452 (17.7)	1035 (81.6)	177 (13.0)	89 (7.4)	88 (54.0)
Invasive mechanical ventilation / ECMO	389 (7.5)	371 (9.7)	47 (1.8)	324 (25.6)	18 (1.3)	5 (0.4)	13 (8.0)
Medicationf
Favipiravir		1806 (68.3)	1542 (70.0)	781 (64.0)	761 (77.5)	264 (59.7)	192 (55.8)	72 (73.5)
Steroid (excluding Ciclesonide)	468 (9.1)	374 (9.9)	99 (3.9)	275 (21.8)	94 (6.9)	51 (4.3)	43 (26.4)
Anticoagulant		420 (8.1)	363 (9.5)	92 (3.6)	271 (21.3)	57 (4.2)	28 (2.3)	29 (17.8)
Remdesivir		40 (1.5)	11 (0.5)	2 (0.2)	9 (0.9)	29 (6.6)	14 (4.1)	15 (15.5)
Ciclesonide		1373 (52.1)	1142 (52.1)	663 (54.8)	479 (48.8)	231 (52.1)	192 (55.7)	39 (39.8)
Nafamostat		224 (9.8)	189 (10.3)	78 (8.0)	111 (13.0)	35 (7.9)	23 (6.7)	12 (12.2)
Outcome
Death		295 (5.7)	279 (7.3)	63 (2.5)	216 (17.0)	16 (1.2)	4 (0.3)	12 (7.4)
	Age: 0–9	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
	Age: 10–19	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
	Age: 20–29	1 (0.1)	1 (0.3)	0 (0)	1 (2.9)	0 (0)	0 (0)	0 (0)
	Age: 30–39	1 (0.1)	1 (0.2)	1 (0.3)	0 (0)	0 (0)	0 (0)	0 (0)
	Age: 40–49	4 (0.5)	4 (0.7)	1 (0.2)	3 (2.5)	0 (0)	0 (0)	0 (0)
	Age: 50–59	10 (1.1)	10 (1.4)	1 (0.2)	9 (4.1)	0 (0)	0 (0)	0 (0)
	Age: 60–69	47 (6.8)	46 (7.7)	10 (2.9)	36 (14.1)	1 (1.1)	0 (0)	1 (4.5)
	Age: 70–79	78 (12.1)	75 (13.3)	18 (6.2)	57 (20.6)	3 (3.7)	1 (2.0)	2 (6.2)
	Age: ≥80	154 (27.1)	142 (28.0)	32 (14.1)	110 (39.1)	12 (20.0)	3 (8.3)	9 (37.5)
Selfcare ability (Worsened)g	398 (8.2)	361 (10.2)	123 (4.9)	238 (22.8)	37 (2.8)	14 (1.2)	23 (15.3)
Walking ability (Worsened)g	384 (9.0)	344 (11.8)	110 (5.4)	234 (26.0)	40 (3.0)	17 (1.4)	23 (15.3)
Transfer to long-term care facilityg	84 (1.6)	73 (1.9)	39 (1.5)	34 (2.7)	11 (0.8)	6 (0.5)	5 (3.1)

Since the number of missing values varies for each parameter, the number of cases in the severity category for each parameter was used as the denominator to calculate the percentages.

Cardiovascular diseases include myocardial infarction, congestive heart failure, and peripheral vascular disease.

Chronic respiratory diseases include chronic obstructive pulmonary disease and chronic lung diseases, which were defined as pulmonary diseases resulting in dyspnoea upon slight activity.

Obesity was based on physician diagnosis.

Immunosuppression includes neutropenia (< 500 neutrophils/μL), use of glucocorticoids/steroids within 1 month (doses greater or equal to an equivalent of 20 mg of prednisone per day for at least 1 month), chemotherapy or radiation therapy or the use of immunosuppressants (such as antitumor necrosis factor-α therapy, anti-IL-6 receptor/anti-CD20 monoclonal antibodies, selective T-cell co-stimulation blockers, methotrexate, tacrolimus) within the past 3 months, post hematopoietic stem cell transplantation, post organ transplantation, asplenia, and primary immunodeficiency syndrome or HIV infection.

Patients who received these treatments at least once during their hospitalization were included.

Data were counted only for patients who were alive at discharge.

Abbreviations: COVID-19, coronavirus disease; ECMO, extracorporeal membrane oxygenation; IQR, interquartile range.

Our study showed that the proportion of cases involving severe disease at admission was smaller in the second wave. Considering the lower percentage of patients transferred from other hospitals in the second wave, it is likely that the first wave had a more critical effect on the ability of healthcare institutions to receive patients. Moreover, the number of PCR tests performed was greater in the second wave than in the first wave . Earlier admission of patients in the second wave may reflect the increase in the number of PCR tests performed and the number of beds available to COVID-19 patients. Data from the second wave indicated a demographic shift toward a younger population with fewer comorbidities, a lower proportion of severe patients at admission, and decreased mortality. However, the mortality was lower in second wave even if stratifying age and severity at admission. This may be because of the shorter time between disease onset and admission, differences in patient background, comorbidities, and advances in treatment methods.

Although this registry gathers information on a large number of patients, it does not cover all patients in Japan, and data from the second half of the second wave was not included in this study; this may be a source of bias in this study. In addition, since data are updated daily, there is a possibility that future findings will differ from the current results.

The findings of our study indicated that in the first wave, the medical system was under greater strain with more severe cases on admission. In the second wave, patients were younger with fewer underlying diseases and lower mortality rates.

Declaration of Competing Interest

H.O. reports personal fees as a statistician and as an external consultant for clinical trials from EPS International, outside the submitted work. All other authors report no potential conflicts.