Original Article

GHM Open. 2024; 4(1):23-31.
DOI: 10.35772/ghmo.2023.01025

Difference in clinical courses and causes of COVID-19-related deaths
in hospitalized patients infected with omicron and delta variants: A
retrospective study in Japan
Ayana Sakurai1, Shinichiro Morioka1,2,3,*, Shinya Tsuzuki1,2, Nobuaki Matsunaga2, Sho Saito1, Noritoshi Arai4,
Natsuyo Yamamoto5, Tetsuo Hara6, Masayuki Hojo7, Yukio Hiroi8, Kazuhiko Yamada9, Norio Ohmagari1,21

Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan;
AMR Clinical Reference Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan;
3
Emerging and Reemerging Infectious Diseases, Graduate School of Medicine, Tohoku University, Sendai, Japan;
4
Department of Neurology, National Center for Global Health and Medicine, Tokyo, Japan;
5
Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan;
6
Department of Neurosurgery, National Center for Global Health and Medicine, Tokyo, Japan;
7
Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan;
8Department of Cardiology, National Center for Global Health and Medicine, Tokyo, Japan;
9Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.
2

Abstract: Despite the lower rate of severe illness associated with the omicron variant than the delta variant, moredeaths have occurred among patients with mild-to-moderate COVID-19 in Japan since the omicron variant surge
during the sixth wave. This study aimed to elucidate the background, clinical course, and causes of death in patientswith COVID-19. We conducted a retrospective observational study on patients with COVID-19 admitted to the
National Center for Global Health and Medicine who subsequently died during the delta (July–September 2021) andomicron variant outbreaks (December 2021–August 2022). Among the 20 patients who died during the delta variant
epidemic, the main causes of death were pneumonia (n = 16, 80%), preadmission complications (n = 3, 15%),and complications occurring during hospitalization (n = 1, 5%). However, during the omicron variant epidemic,
7/24 patients (29%) died of pneumonia, 11 (46%) died of complications before admission, and 6 (25%) died ofcomplications during admission. During the omicron variant outbreak, two-thirds of the COVID-19 deaths duringhospitalization were not primarily caused by pneumonia, unlike the delta variant outbreak, during which pneumonia
had a greater impact on mortality. As patient demographics and clinical pictures change, the establishment of
medical infrastructure for patients with life-threatening comorbidities and careful monitoring of acute COVIDrelated complications are essential.
Keywords: pneumonia, respiratory failure, comorbidities, disease progression, medical infrastructure, COVIDrelated complications

Introduction

COVID-19 fatalities during the fifth wave (delta variant
outbreak period). This rate increased to 95% during thesixth wave (omicron variant outbreak period), indicatingthat a higher proportion of older adults are affected (4).
Nevertheless, a significant lack of understanding remains
regarding the direct causes, background, and progressionof COVID-19-related deaths, especially during theomicron variant outbreak.
Therefore, we conducted this retrospective
observational study on patients with COVID-19 admitted
to the National Center for Global Health and Medicine(NCGM) who subsequently died during both the delta
and omicron variant outbreaks to elucidate the clinicalThe delta variant of severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) has a higher severity
rate than the previous variants (1). During the fifth
wave, numerous severe COVID-19-related deaths werereported in Japan. The omicron variant has a lower
severity rate than the delta variant (2). However, during
the sixth wave and beyond, the number of deaths due tomild-to-moderate COVID-19 increased in Japan.
COVID-19 worsens complications likecardiovascular diseases, even in mild cases (3). In
Japan, patients aged ≥ 60 years accounted for 74% of(23)

GHM Open. 2024; 4(1):23-31.

www.ghmopen.com

course and causes of death.

for the death of 7 patients (29%), ii) exacerbation ofpreexisting complications for 11 patients (46%), and iii)
complications during hospitalization for 6 patients (25%).
Out of the 16 patients who died due to respiratory failure
due to pneumonia during the delta variant outbreak and7 patients during the omicron variant outbreak, chest
computed tomography (CT) scans performed at the endof hospitalization revealed lesions primarily centeredaround the bronchi and its surroundings in 1 (6%) and4 patients (57%) in the delta variant outbreak group.
Meanwhile, lesions primarily centered around the lunginterstitium were observed in 15 (94%) and 3 (43%)
patients, respectively.
In addition to this classification of causes of death,
we summarized the age, sex, underlying comorbidities,
pre-hospitalization ADL, COVID-19 vaccination history,complications that occurred during hospitalization, andstatistical classification of diseases, disabilities, andcauses of death (ICD-10) for each patient in Table 1 andTable 2. In total, 5 representative cases were selectedfrom the 3 causes of death groups, and their clinicalcourses are described below.

Patients and Methods
Age, sex, preexisting comorbidities, activities of dailyliving (ADL) status before hospitalization, COVID-19
vaccination history, complications during hospitalization,
cause of death categorized according to the International
Statistical Classification of Disease and Related Health
Problems (ICD-10), and clinical course were comparedand described for patients admitted to the NCGM during
the delta (July 2021–September 2021) and omicron
variant outbreak (December 2021–August 2022) periods,
who were diagnosed with SARS-CoV-2 infection basedon positive microbiological testing and subsequently
died during hospitalization.
Additionally, we classified the causes of death into
three groups: i) respiratory failure due to pneumonia,ii) exacerbation of preexisting comorbidities before
hospitalization, and iii) complications that occurred
during hospitalization. Clinical course descriptions of 5
representative cases are provided.
This study was reviewed and approved by the Ethics
Committee of the Center Hospital of the National Center
for Global Health and Medicine (NCGM-S-004634-00)
on the condition that a document that declares an opt-out
policy by which any patient and/or relatives could refuse
to be included in this study was uploaded on the web
page of the Center Hospital of the NCGM. The study
was conducted in accordance with the principles of the
Declaration of Helsinki.

Case 1: Respiratory failure due to pneumonia (COVID-19
pneumonia)
A male in his 80s with a medical history of myocardial
infarction treated with percutaneous coronary
intervention, type 2 diabetes, and hypertension had
trouble moving while in his home bathtub and wasurgently transported to the hospital. The patient did
not receive the COVID-19 vaccine. Upon initialassessment, he exhibited poor oxygenation. Treatment
was initiated with high-flow nasal cannula therapy, 2 mg/
kg methylprednisolone (no remdesivir was administered
due to hepatic and renal dysfunction), heparin, andantibiotics. On the third day in hospital, his respiratory
condition worsened, necessitating noninvasive positive
pressure ventilation (NPPV) and the initiation of
tocilizumab therapy. Despite receiving pulse therapy
with methylprednisolone at a dose of 250 mg starting on
the 11th day, the patient's symptoms did not improve,leading to the worsening of respiratory failure on the
33rd day after death.

Results
Among the patients with COVID-19 admitted during
the delta and omicron variant outbreaks, 20 and 24 diedduring hospitalization, respectively. The median age(interquartile range) was 63.0 years (55.3–78.0) and 74.5
years (68.3–85.3), with 9 (45%) and 18 (75%) being
males, respectively. Regarding COVID-19 vaccination
history during the delta variant outbreak, 1 patient (5%)
had received 2 doses, 2 patients (10%) had received 1
dose, 13 patients (65%) had no vaccination history, and4 patients (20%) had unknown vaccination histories(Table 1). During the omicron variant outbreak, 4patients (17%) had received 3 doses, 6 patients (25%)
had received two doses, 8 patients (33%) had no
vaccination history, and 6 patients (25%) had unknown
vaccination histories.
During the delta variant outbreak, cause i) respiratory
failure due to pneumoniae accounted for the death of
16 patients (80%), cause ii) exacerbation of preexistingcomorbidities before hospitalization for the death of
3 patients (15%), and cause iii) complications that
occurred during hospitalization for the death of 1 patient(5%). However, during the omicron variant outbreak,cause i) respiratory failure due to pneumoniae accountedCase 2: Respiratory failure due to pneumonia (aspiration
pneumonia)
A male in his 90s had a history of pulmonary
emphysema, right leg block, and disuse syndrome. Whileattending the day-care facility, the patient contracted
COVID-19 and was admitted on the fourth day of illness
with a diagnosis of severe COVID-19. Treatment was
initiated with remdesivir, dexamethasone, and heparin.
Due to difficulty with oral intake, the patient experienced
recurrent episodes of aspiration pneumonia after
admission. Intravenous fluid therapy was maintained, but

(24)

(25)

F

F

F

F

M

70s

70s

70s

90s

F

60s

70s

M

60s

F

F

50s

70s

M

50s

M

M

50s

70s

M

50s

M

M

30s

70s

F

Sex

20s

Age
(years)

1

None

None

None

None

None

2

None

None

None

None

None

None

None

None

None

Number of
vaccinations

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

ICD-10Independent

Daily support byhelpers

No record

Independent

Independent

No record

Independent

Independent

Independent

Independent

Independent

Independent

Independent

Independent

Independent

Independent

Preexisting ADL

After cholecystectomy

SLE, Sjögren's syndrome,
atrioventricular block

None

Hypertension, HCV hepatitis

Hypertension, hyperlipidemia,
osteoporosis

None

Lymphoma, prostate cancer,
hypertension

Hypertension, atrial fibrillation,
bronchial asthma

Diabetes, obesity

Nephritis in childhood

Diabetes, schizophrenia

None

Rheumatoid arthritis, hypertension,
diabetes, obesity

Myocardial infarction, diabetes,
obesity

Obesity

Hypertension, diabetes, obesity

Preexisting comorbidities

Reservoir mask (No intubation
request)

Mask

NPPV

NPPV (No intubation request)

HFNC (No intubation request)

NPPV (There was no key
person, and due to the lackof expected improvement,
intubation was not performed.)

Mechanical ventilation

NPPV (No intubation request)

Mechanical ventilation

Mechanical ventilation

Mechanical ventilation

Mechanical ventilation

Mechanical ventilation

Mechanical ventilation

Mechanical ventilation

ECMO

Oxygen therapy

Progression of respiratory failure due to pneumonia

Aspiration pneumonia, pyelonephritis

Respiratory failure progression due to pneumonia,
malignant genital bleeding (under heparin use)

Progression of respiratory failure due to pneumonia

Progression of respiratory failure due to pneumonia

Progression of respiratory failure due to pneumonia

Respiratory failure progression due to pneumonia,
suspected aspiration, pneumothorax

Respiratory failure progression due to pneumonia,
atrial fibrillation, cerebral infarction, splenic
infarction, gastrointestinal bleeding (under heparinuse

Respiratory failure progression due to pneumonia,
mediastinum emphysema

Respiratory failure progression due to pneumonia,
pneumothorax, pyothorax, multiple organ failure

Progression of respiratory failure due to pneumonia,
Pseudomonas aeruginosa bacteremia

Progression of respiratory failure due to pneumonia

Progression of respiratory failure due to pneumonia

Progression of respiratory failure due to pneumonia

Progression of respiratory failure due to pneumonia,
emphysema, and pneumothorax

Progression of respiratory failure due to pneumonia

Complications during hospitalization

Abbreviations: ADL, Activities of daily living. SLE, Systemic lupus erythematosus. ECMO, Extracorporeal membrane oxygenation. NPPV, Non-invasive positive pressure ventilation. HFNC, High-flow nasal cannula.

i) Pneumonia (n = 16)

Cause of death

Table 1. Primary causes of death in patients with COVID-19 admitted during the delta variant outbreak, characteristics, preexisting comorbidities, and complications during hospitalization (n= 20)

GHM Open. 2024; 4(1):23-31.
www.ghmopen.com

the patient died on the 26th day due to respiratory failurecaused by aspiration pneumonia.

Abbreviations: ADL, Activities of daily living. SLE, Systemic lupus erythematosus. ECMO, Extracorporeal membrane oxygenation. NPPV, Non-invasive positive pressure ventilation. HFNC, High-flow nasal cannula.

Respiratory failure progression due to pneumonia,
cerebral hemorrhage (under ECMO)
ECMO
None
Independent
Others
None
F

F
80s

50s
iii) Complications
during hospitalization(n = 1)−
Rheumatoid arthritis, hypertension, None
acute myocardial infarction (at thetime of admission)F
50s

Unknown

Cardiovasculardiseases

Walk with acane, eat without
assistanceHypovolemic shock due to low albumin
Alcoholic cirrhosis (Child-Pugh C), NPPV
esophageal varicose vein rupture,obesity
No record
Respiratory failure

Othersii) Preexistingcomorbidities (n = 3)

M

Unknown

www.ghmopen.com

30s

1

Independent

Acute traumatic subdural
hematoma, cervical spine fracture(at the time of admission)

None (incubation only)−

Complications during hospitalization
Oxygen therapy
Preexisting comorbidities
Preexisting ADL
ICD-10
Number of
vaccinations
Sex
Age(years)
Cause of death

Table 1. Primary causes of death in patients with COVID-19 admitted during the delta variant outbreak, characteristics, preexisting comorbidities, and complications during hospitalization (n= 20) (continued)

GHM Open. 2024; 4(1):23-31.

Case 3: Exacerbation of preadmission complications
A woman in her 80s presented with severe valvular heartdisease, chronic heart failure, and a history of stroke. The
patient had received 3 doses of the COVID-19 vaccine.
The patient was transported to our facility because of
respiratory distress and was diagnosed with worsening
chronic heart failure caused by severe valvular heartdisease. Upon admission, the patient tested positive for
SARS-CoV-2 by polymerase chain reaction. Respiratory
failure, believed to be associated with heart failure,
progressed, and the patient died on the fourth day ofillness.
Case 4: Exacerbation of preadmission complications
A man in his 60s with stage 4 advanced small celllung cancer received supportive care. He called for
emergency assistance because of respiratory distressand was hospitalized. Although the patient had planned
to be transferred to a hospice, on the 6th day of illness
the patient came in close contact with a patient with
COVID-19, and on the 7th day, the patient was diagnosed
as an asymptomatic carrier of SARS-CoV-2. The patient
was treated with a 3-day course of remdesivir to prevent
severe disease progression. The patient experienced
severe cancer-related pain, nausea, and fatigue, andsedation was initiated on the 8th day. The patient died on
the 11th day.
Case 5: Complications during hospitalization
The patient was a male in his 80s with a history of
hypertension, atrial fibrillation, and chronic obstructive
pulmonary disease. The patient had received 2 dosesof the COVID-19 vaccine. The patient developed afever and cough, which led to hospital admission on
the fourth day of illness with a diagnosis of moderate
COVID-19 and chronic interstitial pneumonia.
Remdesivir and antibiotics were administered. The
following day, the patient required supplemental
oxygen, and methylprednisolone treatment (250 mg)
was initiated. However, pneumonia worsened, andpulse therapy with 1 g methylprednisolone and various
immunosuppressive agents (cyclophosphamide,bortezomib, and tacrolimus) were administeredsequentially. On the 11th day of illness, the patientdeveloped heart failure, which improved with theinitiation of diuretics and NPPV. On the 24th day, thepatient was diagnosed with acute exacerbation of heart
failure and hypotension with ST-elevation myocardial
infarction. Due to respiratory distress, coronary artery
catheterization was not performed, and the patient diedon the 26th day due to worsening heart failure.

(26)ii) Preexistingcomorbidities (n = 11)i) Pneumonia (n = 7)

Cause of death

(P27)

M

F

M

M

60s

60s

60s

70s

M

90s

M

M

90s

50s

M

80s

M

M

80s

50s

F

80s

M

M

70s

40s

M

Sex

60s

Age
(years)Unknown

None

Unknown

Unknown

None

3

Unknown

2

None

Unknown

None

Unknown2

2

Number of
vaccinations

Malignant neoplasms

Malignant neoplasms

Malignant neoplasms

Malignant neoplasms

OthersCardiovasculardiseases

OthersRespiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

Respiratory infections

ICD-10Unknown

Unknown

Unknown

HFNC

NPPV

Oxygen therapy

Reservoir mask

HFNC

NPPV

HFNC

None

Multiple metastases of liver cancer, heart
failureMultiple metastases of small cell lungcancer, hypertension

Multiple metastasis of rectal cancer,
hypertension

Nasal cannula

None

None

Nasal cannula

Polycystic Kidney, chronic kidney disease None

Sarcoidosis, chronic kidney disease

Alcoholic cirrhosis

Hypertension, cerebral infarction, chronic Nasal cannula
kidney disease

Emphysema, right bundle branch block

Normal pressure hydrocephalus,
postoperative bladder cancer, angina
pectoris, dementia

Hypertension, diabetes, myocardial
infarction, dyslipidemia

Rheumatoid arthritis, Parkinson's disease, NPPV
after heart valve replacement

Diabetes, lung squamous cell carcinoma,
MPA, chronic kidney disease

Hypertension, chronic kidney disease

Preexisting comorbidities

Requiring long-term care level 3 HIV infection, multiple metastases ofgastric cancer, diabetes, hypertension

Independent

Independent

Unknown

Walking with assistance,
requiring long-term care level 2

Cognitive impairment, requiringlong-term care level 2

Needs long-term care level 4,
requiring partial assistance withbathing and dressing

Independent

Requiring long-term care level
3*, walk with supervision

Independent

Independent

Preexisting ADL

Exacerbation of heart failure

Hemorrhage from tumor

Hemorrhage from tumor, anemia

MSSA bacteremia, uremia

Exacerbation of heart failure

Rupture of varicose vein in colon

Aspiration pneumonia

Aspiration pneumonia

Aspiration pneumonia

Disseminated intravascular coagulation
syndrome, multiple organ failure

Aspiration pneumonia, pulmonary pyogenic
diseaseAspiration pneumonia, Pseudomonas
aeruginosa pneumonia, acute myocardial
infarction

Pneumothorax, mediastinal emphysema

Complications during hospitalization

Table 2. Primary causes of death in patients with COVID-19 admitted during the omicron variant outbreak, characteristics, preexisting comorbidities, and complications duringhospitalization (n = 24)

GHM Open. 2024; 4(1):23-31.
www.ghmopen.com

(28)

M

M

M

F

70s

80s

90s

M

60s

70s

M

F

80s

60s

F

70s

F

M

70s

90s

Sex

Age
(years)

None

2

None

None

2

2

3

3

3

None

Number of
vaccinations

OthersCardiovasculardiseases

Respiratory infections

OthersCardiovasculardiseases

OthersCardiovasculardiseases

Cardiovasculardiseases

OthersMalignant neoplasms

ICD-10Hypertension, diabetes

Interstitial pneumonia, thymoma

Esophageal cancer, hypertension,transient ischemic attack

Obesity, hypertension

Valvular disease, heart failure, chronic
kidney disease, hypertension

Valvular disease, heart failure, cerebral
infarction

Diabetes, extensive cerebral infarction

Transverse colon cancer multiple
metastases, Bowel obstruction, Obesity

Preexisting comorbidities

NPPV

Mechanicalventilation

Mechanicalventilation

None

NPPV

None

NPPV

Nasal cannula

Nasal cannula

Oxygen therapy

Requiring long-term care level 5, Polymyalgia rheumatoid arthritis, bullous Reservoir mask
use a wheelchair
pemphigoid, cerebral infarction

Requiring long-term care level 2, Interstitial pneumonia, chronic
requires partial assistance with
obstructive pulmonary disease, atrial
excretion
fibrillation, hypertension

Independent

Independent

Independent

Independent

Requiring long-term care level4, Walking only indoors withassistanceIndependent

Independent

Independent

Preexisting ADL

Bacteremia, pyelonephritis, bacterial
pneumonia, pneumothorax, bleeding fromgastric and duodenal ulcers

Acute myocardial infarction

Bacteremia, septic shock, acute respiratory
distress syndrome, acute renal dysfunction,
ventilator-associated pneumonia

Intracranial hemorrhage

Aortic rupture

Iliopsoas hematoma, hemorrhagic shock,acute renal failure

Acute pyelonephritis, exacerbation of heart
failure, renal failure

Exacerbation of heart failure

Brain herniation

Transverse colon ileus, multiorgan failure

Complications during hospitalization

Abbreviations: ADL, Activities of daily living. MPA, microscopic polyangiitis. NPPV, Non-invasive positive pressure ventilation. HFNC, High-flow nasal cannula. MSSA, Methicillin-Susceptible Staphylococcus Aureus.
*Types of long-term care: Care Level 1: A person faces difficulty in performing essential daily life activities by himself/herself. One person's ability to handle task-based activities in daily life is lower than that of patients in the
Support Required 2 category. Care Level 2: The person is in a state similar to that detailed under Care Level 1 but requires more care to be able to perform essential daily life activities. Care Level 3: Compared with the state ofCare Level 2, a person's abilities to perform essential daily life activities and task-based activities were significantly lower. Consequently, they require almost constant care. Care Level 4: The person is in a state similar to thatdetailed in Care Level 3, but his/her ability to act is lower. As a result, they face difficulties in living without constant care. Care Level 5: The person's ability to act is even lower than that of patients in the Care Level 4 category.
Consequently, they require constant care.

iii) Complications
during hospitalization(n = 6)

Cause of death

Table 2. Primary causes of death in patients with COVID-19 admitted during the omicron variant outbreak, characteristics, preexisting comorbidities, and complications duringhospitalization (n = 24) (continued)

GHM Open. 2024; 4(1):23-31.
www.ghmopen.com

GHM Open. 2024; 4(1):23-31.

www.ghmopen.com

Discussion

comorbidities, representing the highest proportion. These
cases involved patients infected with SARS-CoV-2 withsevere underlying conditions. The breakdown of thesecomorbidities included 4 cases of heart failure, 4 casesof malignancy, 1 case of hepatic dysfunction, 1 caseof renal dysfunction, and 1 case of extensive cerebral
infarction. Worsening underlying conditions, such as
cancer and cardiovascular diseases, were considered theprimary cause of death. Three deaths were attributed
to preexisting comorbidities during the delta variant
outbreak: traumatic subdural hematoma, decompensatedliver cirrhosis, and acute myocardial infarction.
From the early stages of COVID-19 to the deltavariant outbreak, pneumonia accounted for most deaths,
necessitating the establishment of facilities capableof managing patients with severe respiratory failure.
However, during the omicron variant outbreak, infection
control measures must be prioritized for patients withpreexisting comorbidities who are at high risk ofapproaching the end of life before hospital admission.

In addition to describing the clinical course of thedisease in patients, the cases were classified into
three groups based on the primary cause of death: i)pneumonia (including COVID-19 pneumonia andaspiration pneumonia), ii) exacerbation of preadmission
complications, and iii) complications that occurred
during hospitalization.
Deaths due to pneumonia
In total, 16/20 patients (80%) who died during the deltavariant epidemic and 7/24 patients (29%) who diedduring the omicron outbreak died of pneumonia. The
pneumonia group was broadly divided into patientswith lesions mainly in the bronchi and surrounding
areas and those with lesions mainly in the pulmonary
interstitium. In typical viral pneumonia caused by SARSCoV-2 infection, lesions in the pulmonary interstitium
are observed on chest CT scans (5). In contrast, incases where lesions were found in the bronchi andperibronchial centers, the patient likely developed
pneumonia secondary to the SARS-CoV-2 infection. The
impact of aspiration should also be considered based on
the patient's age, ADL, and underlying diseases.
Moreover, 15/20 patients who died during the deltavariant epidemic had lesions mainly in the pulmonary
interstitium, suggesting that most patients during thedelta variant epidemic died due to the progression of viralpneumonia caused by SARS-CoV-2 infection. In animalmodels, the omicron variant (B.1.1.529) was reported tohave similar nasal growth potential as the delta variant(B.1.617.2) but lower growth potential and pathogenicity
in the lungs (6). In addition, omicron variants replicate
rapidly in human airway models and ex vivo cultures ofhuman bronchioles. However, their replication efficiency
is reduced in human alveolar models and ex vivo culturesof human lungs (7). These findings indicate that omicron
variants tend to infect the upper respiratory tract rather
than the lungs, which is consistent with the results ofprevious studies.

Deaths due to complications during hospitalization
Factors other than preexisting comorbidities, such as
infections, bleeding, and cardiovascular diseases, are themain causes of death among the complications that occur
during hospitalization. During the delta variant outbreak,1 patient died from complications that emerged duringhospitalization, and during the omicron variant outbreak,
6 patients died.
Out of the 6 patients who died from complications
during the omicron variant outbreak, 4 succumbedto cardiovascular events. The causes of death were
hemorrhagic shock due to iliopsoas hematoma, cerebral
hemorrhage, aortic dissection, and acute myocardial
infarction. The remaining 2 patients died from acuterespiratory distress syndrome and septicemia caused bypyelonephritis. Out of these 6 patients, 4 were completely
independent in ADL before admission, and 1 required
only mild support. No in-hospital deaths were anticipatedduring admission.
During the omicron variant outbreak, patients with
COVID-19 admitted to the hospital who subsequently
died showed a notable prevalence of cardiovasculardiseases. From a wider standpoint, excess mortality fromcardiovascular diseases has been reported domesticallyand internationally. Nishiura et al. (8) predicted asignificant increase in selective deaths attributed to
cardiovascular diseases and senility in Japan during
the 2022 fiscal year. Nomura et al. (9) reported excess
mortality due to cardiovascular diseases, respiratory
diseases, malignancies, and senility in 2021. Globally,
previous reports have indicated a higher incidence of
cardiovascular complications in patients with COVID-19(10).
COVID-19 is associated with an increased riskof cardiovascular diseases, potentially leading to

Death due to factors other than pneumonia
During the delta epidemic, 4/ 20 patients died fromcauses other than pneumonia, and during the omicron
epidemic, 17/24 patients died from complications
before or during hospitalization. In both groups, thedeterioration of the general condition due to the SARSCoV-2 infection may have affected the disease course.
Deaths due to preexisting comorbidities
Among the patients who died from causes other thanpneumonia during the omicron variant outbreak, 11
patients (46%) died due to the exacerbation of preexisting(29)

GHM Open. 2024; 4(1):23-31.

www.ghmopen.com

myocarditis, acute coronary syndrome, atherosclerosis,
heart failure, thromboembolic events, and arrhythmias.
The acute phase of COVID-19 and its long-term
effects after acute infection may contribute to increased
hospitalization and mortality rates in patients withcardiovascular diseases (11). A meta-analysis of 17
cohort studies involving 5815 patients showed thatthe most common cardiovascular complications areheart failure, myocardial injury, arrhythmias, andacute coronary syndromes (12). Even in mild cases, anincreased risk of cardiovascular diseases for up to 1 year
has been reported, with higher rates of heart failure andstroke (3).
The findings of this study corroborate those ofprevious studies from a broader perspective, indicating
the prevalence of cardiovascular complications in
COVID-19 cases. However, many aspects of COVID-19
pathogenesis remain unclear. Therefore, data that cancontribute to our understanding of the disease and excess
mortality can be obtained by collecting epidemiological
data on the causes of death, including events with unclear
associations with COVID-19. Consequently, startingfrom April 2023, Japan has revised the case reporting
form for COVID-19 Registry Japan (COVIREGIJP) to collect detailed information on patients who
have succumbed to COVID-19, aiming to gather
comprehensive data.
In addition to the direct impact on organs caused
by COVID-19 infection, observations have pointed tosecondary changes, including disruptions in healthcare
access due to medical system breakdown and lifestylealterations, as contributing factors. Brant et al. (13)reported changes in cardiovascular disease mortality rates
in 6 major cities in Brazil. Mortality rates varied, ranging
from +46.1% (Manaus) to -7.1% (Rio de Janeiro), withmore pronounced effects observed in areas where thehealthcare system serving the most socioeconomicallydisadvantaged populations collapsed. In Brazil's mostaffected northern region, Jardim et al. (14) estimated
a 2.5-fold excess mortality increase in cardiovasculardisease-related mortality in 2020. Several other studies
have suggested that barriers to healthcare access
contribute to increased cardiovascular diseases (15, 16).
Reports on the strain on Japanese medical
infrastructure up until the delta variant surge and thefourth wave indicated no overwhelming numbers of
COVID-19 cases beyond the capacity of acceptance andno depletion of medical equipment such as ventilators.
Thus, it was inferred that the Infection control team
capacity was not exceeded. However, during the fourthwave, there were indications of excess mortality forthe first time, suggesting a potential reflection of strain
on medical institutions. Whether appropriate accessto medical facilities is sufficient during the peak ofinfection spread remains unclear. During the fifth andsixth waves, an increase in difficult cases of emergency
transport was noted alongside a rise in the number of

infected patients, pointing to the possibility of strain on
medical infrastructure (17).
The limitations of this study were as follows. The
analysis was limited to hospitalized patients from asingle facility in Japan, making it difficult to directly
extrapolate the results to the causes and backgrounds of
COVID-19-related deaths in all patients. As we did notobserve the causes and backgrounds of the patients who
received at-home treatment, their characteristics may
differ from those of hospitalized patients. Therefore, weplan to conduct future observational studies involving
multiple facilities. Additionally, we did not conduct
a comparison with surviving patients, and the causal
relationship between patient background and causeof death remains unclear. Furthermore, as the period
following the omicron variant outbreak is expected toshow continued circulation of different variants, thetrends observed in this study may change under the
influence of different variants.
In conclusion, from the early stages of COVID-19
to the delta variant outbreak, numerous cases of severe
respiratory failure caused by the typical SARS-CoV-2
infection leading to viral pneumonia were reported.
Establishing medical systems capable of treating patientswith severe respiratory failure was crucial during thisperiod. However, during the omicron variant outbreak,approximately two-thirds of the deceased patients at our
hospital had non-pneumonia-related conditions as theprimary cause of death, exhibiting a different clinicalprofile compared with the delta variant cases.
Moving forward, we aim to adapt our medical
systems by considering these changing patient profiles
and continue to collect data at the macro level. We
hope that this study, which observed changes in thenumber of deceased patients between delta and omicron
variant outbreaks, will be the starting point for further
understanding of the pathogenesis of the disease.
Funding: None.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
References
1.

2.

3.
4.

(30)

Twohig KA, Nyberg T, Zaidi A, et al. Hospital admission
and emergency care attendance risk for SARS-CoV-2
delta (B.1.617.2) compared with alpha (B.1.1.7) variantsof concern: A cohort study. Lancet Infect Dis. 2022;
22:35-42.
Arabi M, Al-Najjar Y, Mhaimeed N, et al. Severity of
the Omicron SARS-CoV-2 variant compared with theprevious lineages: A systematic review. J Cell Mol Med.
2023; 27:1443-1464.
Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascularoutcomes of COVID-19. Nat Med. 2022; 28:583-590.
Ministry of Health, Labour and Welfare. 105th Meeting of
the COVID-19 Advisory Board of the Ministry of Health,Labour and Welfare (November 9, 2022) https://www.

GHM Open. 2024; 4(1):23-31.

www.ghmopen.com

mhlw.go.jp/stf/seisakunitsuite/bunya/0000121431_00395.
html (accessed August 2, 2023). (in Japanese)
5. Kanne JP, Bai H, Bernheim A, Chung M, Haramati
LB, Kallmes DF, Little BP, Rubin GD, Sverzellati N.
COVID-19 imaging: What we know now and what
remains unknown. Radiology. 2021; 299:E262-E279.
6. Halfmann PJ, Iida S, Iwatsuki-Horimoto K, et al. SARSCoV-2 Omicron virus causes attenuated disease in miceand hamsters. Nature. 2022; 603:687-692.
7. Hui KPY, Ho JCW, Cheung MC, Ng KC, Ching RHH, Lai
KL, Kam TT, Gu H, Sit KY, Hsin MKY, Au TWK, Poon
LLM, Peiris M, Nicholls JM, Chan MCW. SARS-CoV-2
Omicron variant replication in human bronchus and lungex vivo. Nature. 2022; 603:715-720.
8. Ministry of Health, Labour and Welfare. 110th Meeting of
the COVID-19 Advisory Board of the Ministry of Health,Labour and Welfare (December 14, 2022), https://www.
mhlw.go.jp/stf/seisakunitsuite/bunya/0000121431_00395.
html (accessed August 2, 2023). (in Japanese)
9. Nomura S, Eguchi A, Ghaznavi C, Tanoue Y, Kawashima T,
Yoneoka D, Yamasaki L, Suzuki M, Hashizume M. Excess
deaths from non-COVID-19-related causes in Japan and
47 prefectures from January 2020 through May 2021 byplace of death. SSM Popul Health. 2022; 19:101196.
10. Wan EYF, Mathur S, Zhang R, Yan VKC, Lai FTT, Chui
CSL, Li X, Wong CKH, Chan EWY, Yiu KH, Wong ICK.
Association of COVID-19 with short- and long-term riskof cardiovascular disease and mortality: A prospective
cohort in UK Biobank. Cardiovasc Res. 2023; 119:17181727.
11. Vosko I, Zirlik A, Bugger H. Impact of COVID-19 on
cardiovascular disease. Viruses. 2023; 15:508.
12. Ahmad Malik J, Ahmed S, Shinde M, Almermesh
MHS, Alghamdi S, Hussain A, Anwar S. The impact of

13.

14.

15.
16.
17.

COVID-19 on comorbidities: A review of recent updates
for combating it. Saudi J Biol Sci. 2022; 29:3586-3599.
Brant LCC, Nascimento BR, Teixeira RA, Lopes M,
Malta DC, Oliveira GMM, Ribeiro ALP. Excess of
cardiovascular deaths during the COVID-19 pandemic in
Brazilian capital cities. Heart. 2020; 106:1898-1905.
Jardim BC, Migowski A, Correa FM, Silva GAE.
Covid-19 in Brazil in 2020: Impact on deaths from cancer
and cardiovascular diseases. Rev Saude Publica. 2022;
56:22.
Roifman I, Arora RC, Bewick D, et al. Cardiovascularcare delivery during the second wave of COVID-19 in
Canada. Can J Cardiol. 2021; 37:790-793.
Raisi-Estabragh Z, Mamas MA. Cardiovascular healthcare implications of the COVID-19 pandemic. Heart FailClin. 2023; 19:265-272.
Ministry of Health, Labour and Welfare. 71st meetingof the COVID-19 advisory board of the Ministry of
Health, Labour and Welfare, https://www.mhlw.go.jp/stf/
seisakunitsuite/bunya/0000121431_00333.html (accessed
August 2, 2023). (in Japanese)---Received November 30, 2023; Revised February 8, 2024;
Accepted March 22, 2024.
Released online in J-STAGE as advance publication March 30,
2024.
*Address correspondence to:
Shinichiro Morioka, Disease Control and Prevention Center,
National Center for Global Health and Medicine Hospital,
1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
E-mail: shmorioka@hosp.ncgm.go.jp(31)