Según
este reciente estudio, el 55% de los contagiados son personas entre 15 y
49 años, y dentro de ellas, el 12% presenta un caso de neumonía
"grave".
https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
Clinical Characteristics of Coronavirus Disease 2019 in China
Abstract
Background
Since
December 2019, when coronavirus disease 2019 (Covid-19) emerged in
Wuhan city and rapidly spread throughout China, data have been needed on
the clinical characteristics of the affected patients.
Methods
We
extracted data regarding 1099 patients with laboratory-confirmed
Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and
municipalities in mainland China through January 29, 2020. The primary
composite end point was admission to an intensive care unit (ICU), the
use of mechanical ventilation, or death.
Results
The
median age of the patients was 47 years; 41.9% of the patients were
female. The primary composite end point occurred in 67 patients (6.1%),
including 5.0% who were admitted to the ICU, 2.3% who underwent invasive
mechanical ventilation, and 1.4% who died. Only 1.9% of the patients
had a history of direct contact with wildlife. Among nonresidents of
Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who
had visited the city. The most common symptoms were fever (43.8% on
admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea
was uncommon (3.8%). The median incubation period was 4 days
(interquartile range, 2 to 7). On admission, ground-glass opacity was
the most common radiologic finding on chest computed tomography (CT)
(56.4%). No radiographic or CT abnormality was found in 157 of 877
patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%)
with severe disease. Lymphocytopenia was present in 83.2% of the
patients on admission.
Conclusions
During
the first 2 months of the current outbreak, Covid-19 spread rapidly
throughout China and caused varying degrees of illness. Patients often
presented without fever, and many did not have abnormal radiologic
findings. (Funded by the National Health Commission of China and
others.)
Methods
We
extracted data regarding 1099 patients with laboratory-confirmed
Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and
municipalities in mainland China through January 29, 2020. The primary
composite end point was admission to an intensive care unit (ICU), the
use of mechanical ventilation, or death.
Results
The
median age of the patients was 47 years; 41.9% of the patients were
female. The primary composite end point occurred in 67 patients (6.1%),
including 5.0% who were admitted to the ICU, 2.3% who underwent invasive
mechanical ventilation, and 1.4% who died. Only 1.9% of the patients
had a history of direct contact with wildlife. Among nonresidents of
Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who
had visited the city. The most common symptoms were fever (43.8% on
admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea
was uncommon (3.8%). The median incubation period was 4 days
(interquartile range, 2 to 7). On admission, ground-glass opacity was
the most common radiologic finding on chest computed tomography (CT)
(56.4%). No radiographic or CT abnormality was found in 157 of 877
patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%)
with severe disease. Lymphocytopenia was present in 83.2% of the
patients on admission.
Conclusions
During
the first 2 months of the current outbreak, Covid-19 spread rapidly
throughout China and caused varying degrees of illness. Patients often
presented without fever, and many did not have abnormal radiologic
findings. (Funded by the National Health Commission of China and
others.)
Methods
Study Oversight
The
study was supported by National Health Commission of China and designed
by the investigators. The study was approved by the institutional
review board of the National Health Commission. Written informed consent
was waived in light of the urgent need to collect data. Data were
analyzed and interpreted by the authors. All the authors reviewed the
manuscript and vouch for the accuracy and completeness of the data and
for the adherence of the study to the protocol, available with the full text of this article at NEJM.org.
Data Sources
We
obtained the medical records and compiled data for hospitalized
patients and outpatients with laboratory-confirmed Covid-19, as reported
to the National Health Commission between December 11, 2019, and
January 29, 2020; the data cutoff for the study was January 31, 2020.
Covid-19 was diagnosed on the basis of the WHO interim guidance.14
A confirmed case of Covid-19 was defined as a positive result on
high-throughput sequencing or real-time
reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of nasal
and pharyngeal swab specimens.1 Only laboratory-confirmed cases were included in the analysis.
We obtained data regarding cases outside Hubei
province from the National Health Commission. Because of the high
workload of clinicians, three outside experts from Guangzhou performed
raw data extraction at Wuhan Jinyintan Hospital, where many of the
patients with Covid-19 in Wuhan were being treated.
We
extracted the recent exposure history, clinical symptoms or signs, and
laboratory findings on admission from electronic medical records.
Radiologic assessments included chest radiography or computed tomography
(CT), and all laboratory testing was performed according to the
clinical care needs of the patient. We determined the presence of a
radiologic abnormality on the basis of the documentation or description
in medical charts; if imaging scans were available, they were reviewed
by attending physicians in respiratory medicine who extracted the data.
Major disagreement between two reviewers was resolved by consultation
with a third reviewer. Laboratory assessments consisted of a complete
blood count, blood chemical analysis, coagulation testing, assessment of
liver and renal function, and measures of electrolytes, C-reactive
protein, procalcitonin, lactate dehydrogenase, and creatine kinase. We
defined the degree of severity of Covid-19 (severe vs. nonsevere) at the
time of admission using the American Thoracic Society guidelines for
community-acquired pneumonia.15
All
medical records were copied and sent to the data-processing center in
Guangzhou, under the coordination of the National Health Commission. A
team of experienced respiratory clinicians reviewed and abstracted the
data. Data were entered into a computerized database and cross-checked.
If the core data were missing, requests for clarification were sent to
the coordinators, who subsequently contacted the attending clinicians.
Study Outcomes
The
primary composite end point was admission to an intensive care unit
(ICU), the use of mechanical ventilation, or death. These outcomes were
used in a previous study to assess the severity of other serious
infectious diseases, such as H7N9 infection.16
Secondary end points were the rate of death and the time from symptom
onset until the composite end point and until each component of the
composite end point.
Study Definitions
The
incubation period was defined as the interval between the potential
earliest date of contact of the transmission source (wildlife or person
with suspected or confirmed case) and the potential earliest date of
symptom onset (i.e., cough, fever, fatigue, or myalgia). We excluded
incubation periods of less than 1 day because some patients had
continuous exposure to contamination sources; in these cases, the latest
date of exposure was recordedThe summary statistics of incubation periods were
calculated on the basis of 291 patients who had clear information
regarding the specific date of exposure.
Fever was
defined as an axillary temperature of 37.5°C or higher. Lymphocytopenia
was defined as a lymphocyte count of less than 1500 cells per cubic
millimeter. Thrombocytopenia was defined as a platelet count of less
than 150,000 per cubic millimeter. Additional definitions — including
exposure to wildlife, acute respiratory distress syndrome (ARDS),
pneumonia, acute kidney failure, acute heart failure, and rhabdomyolysis
— are provided in the Supplementary Appendix, available at NEJM.org.
Laboratory Confirmation
Laboratory
confirmation of SARS-CoV-2 was performed at the Chinese Center for
Disease Prevention and Control before January 23, 2020, and subsequently
in certified tertiary care hospitals. RT-PCR assays were performed in
accordance with the protocol established by the WHO.17 Details regarding laboratory confirmation processes are provided in the Supplementary Appendix.
Statistical Analysis
Continuous
variables were expressed as medians and interquartile ranges or simple
ranges, as appropriate. Categorical variables were summarized as counts
and percentages. No imputation was made for missing data. Because the
cohort of patients in our study was not derived from random selection,
all statistics are deemed to be descriptive only. We used ArcGIS,
version 10.2.2, to plot the numbers of patients with reportedly
confirmed cases on a map. All the analyses were performed with the use
of R software, version 3.6.2 (R Foundation for Statistical Computing).
Results
Demographic and Clinical Characteristics
Figure 1. 
Distribution of Patients with Covid-19 across Mainland China.
Of
the 7736 patients with Covid-19 who had been hospitalized at 552 sites
as of January 29, 2020, we obtained data regarding clinical symptoms and
outcomes for 1099 patients (14.2%). The largest number of patients
(132) had been admitted to Wuhan Jinyintan Hospital. The hospitals that
were included in this study accounted for 29.7% of the 1856 designated
hospitals where patients with Covid-19 could be admitted in 30
provinces, autonomous regions, or municipalities across China (Figure 1).
Table 1. 
Clinical
Characteristics of the Study Patients, According to Disease Severity
and the Presence or Absence of the Primary Composite End Point.
The demographic and clinical characteristics of the patients are shown in Table 1.
A total of 3.5% were health care workers, and a history of contact with
wildlife was documented in 1.9%; 483 patients (43.9%) were residents of
Wuhan. Among the patients who lived outside Wuhan, 72.3% had contact
with residents of Wuhan, including 31.3% who had visited the city; 25.9%
of nonresidents had neither visited the city nor had contact with Wuhan
residents.
The median incubation period was 4
days (interquartile range, 2 to 7). The median age of the patients was
47 years (interquartile range, 35 to 58); 0.9% of the patients were
younger than 15 years of age. A total of 41.9% were female. Fever was
present in 43.8% of the patients on admission but developed in 88.7%
during hospitalization. The second most common symptom was cough
(67.8%); nausea or vomiting (5.0%) and diarrhea (3.8%) were uncommon.
Among the overall population, 23.7% had at least one coexisting illness
(e.g., hypertension and chronic obstructive pulmonary disease).
On
admission, the degree of severity of Covid-19 was categorized as
nonsevere in 926 patients and severe in 173 patients. Patients with
severe disease were older than those with nonsevere disease by a median
of 7 years. Moreover, the presence of any coexisting illness was more
common among patients with severe disease than among those with
nonsevere disease (38.7% vs. 21.0%). However, the exposure history
between the two groups of disease severity was similar.
Radiologic and Laboratory Findings
Table 2. 
Radiographic and Laboratory Findings.
Table 2
shows the radiologic and laboratory findings on admission. Of 975 CT
scans that were performed at the time of admission, 86.2% revealed
abnormal results. The most common patterns on chest CT were ground-glass
opacity (56.4%) and bilateral patchy shadowing (51.8%). Representative
radiologic findings in two patients with nonsevere Covid-19 and in
another two patients with severe Covid-19 are provided in Figure S1 in
the Supplementary Appendix.
No radiographic or CT abnormality was found in 157 of 877 patients
(17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with
severe disease.
On admission, lymphocytopenia was
present in 83.2% of the patients, thrombocytopenia in 36.2%, and
leukopenia in 33.7%. Most of the patients had elevated levels of
C-reactive protein; less common were elevated levels of alanine
aminotransferase, aspartate aminotransferase, creatine kinase, and d-dimer.
Patients with severe disease had more prominent laboratory
abnormalities (including lymphocytopenia and leukopenia) than those with
nonsevere disease.
Clinical Outcomes
Table 3. 
Complications, Treatments, and Clinical Outcomes.
None
of the 1099 patients were lost to follow-up during the study. A primary
composite end-point event occurred in 67 patients (6.1%), including
5.0% who were admitted to the ICU, 2.3% who underwent invasive
mechanical ventilation, and 1.4% who died (Table 3).
Among the 173 patients with severe disease, a primary composite
end-point event occurred in 43 patients (24.9%). Among all the patients,
the cumulative risk of the composite end point was 3.6%; among those
with severe disease, the cumulative risk was 20.6%.
Treatment and Complications
A
majority of the patients (58.0%) received intravenous antibiotic
therapy, and 35.8% received oseltamivir therapy; oxygen therapy was
administered in 41.3% and mechanical ventilation in 6.1%; higher
percentages of patients with severe disease received these therapies (Table 3).
Mechanical ventilation was initiated in more patients with severe
disease than in those with nonsevere disease (noninvasive ventilation,
32.4% vs. 0%; invasive ventilation, 14.5% vs. 0%). Systemic
glucocorticoids were given to 204 patients (18.6%), with a higher
percentage among those with severe disease than nonsevere disease (44.5%
vs. 13.7%). Of these 204 patients, 33 (16.2%) were admitted to the ICU,
17 (8.3%) underwent invasive ventilation, and 5 (2.5%) died.
Extracorporeal membrane oxygenation was performed in 5 patients (0.5%)
with severe disease.
The median duration of
hospitalization was 12.0 days (mean, 12.8). During hospital admission,
most of the patients received a diagnosis of pneumonia from a physician
(91.1%), followed by ARDS (3.4%) and shock (1.1%). Patients with severe
disease had a higher incidence of physician-diagnosed pneumonia than
those with nonsevere disease (99.4% vs. 89.5%).
Discussion
During
the initial phase of the Covid-19 outbreak, the diagnosis of the
disease was complicated by the diversity in symptoms and imaging
findings and in the severity of disease at the time of presentation.
Fever was identified in 43.8% of the patients on presentation but
developed in 88.7% after hospitalization. Severe illness occurred in
15.7% of the patients after admission to a hospital. No radiologic
abnormalities were noted on initial presentation in 2.9% of the patients
with severe disease and in 17.9% of those with nonsevere disease.
Despite the number of deaths associated with Covid-19, SARS-CoV-2
appears to have a lower case fatality rate than either SARS-CoV or
Middle East respiratory syndrome–related coronavirus (MERS-CoV).
Compromised respiratory status on admission (the primary driver of
disease severity) was associated with worse outcomes.
Approximately
2% of the patients had a history of direct contact with wildlife,
whereas more than three quarters were either residents of Wuhan, had
visited the city, or had contact with city residents. These findings
echo the latest reports, including the outbreak of a family cluster,4 transmission from an asymptomatic patient,6 and the three-phase outbreak patterns.8 Our study cannot preclude the presence of patients who have been termed “super-spreaders.”
Conventional
routes of transmission of SARS-CoV, MERS-CoV, and highly pathogenic
influenza consist of respiratory droplets and direct contact,18-20
mechanisms that probably occur with SARS-CoV-2 as well. Because
SARS-CoV-2 can be detected in the gastrointestinal tract, saliva, and
urine, these routes of potential transmission need to be investigated21 (Tables S1 and S2).
The
term Covid-19 has been applied to patients who have
laboratory-confirmed symptomatic cases without apparent radiologic
manifestations. A better understanding of the spectrum of the disease is
needed, since in 8.9% of the patients, SARS-CoV-2 infection was
detected before the development of viral pneumonia or viral pneumonia
did not develop.
In concert with recent studies,1,8,12
we found that the clinical characteristics of Covid-19 mimic those of
SARS-CoV. Fever and cough were the dominant symptoms and
gastrointestinal symptoms were uncommon, which suggests a difference in
viral tropism as compared with SARS-CoV, MERS-CoV, and seasonal
influenza.22,23 The absence of fever in Covid-19 is more frequent than in SARS-CoV (1%) and MERS-CoV infection (2%),20 so afebrile patients may be missed if the surveillance case definition focuses on fever detection.14 Lymphocytopenia was common and, in some cases, severe, a finding that was consistent with the results of two recent reports.1,12 We found a lower case fatality rate (1.4%) than the rate that was recently reportedly,1,12
probably because of the difference in sample sizes and case inclusion
criteria. Our findings were more similar to the national official
statistics, which showed a rate of death of 3.2% among 51,857 cases of
Covid-19 as of February 16, 2020.11,24
Since patients who were mildly ill and who did not seek medical
attention were not included in our study, the case fatality rate in a
real-world scenario might be even lower. Early isolation, early
diagnosis, and early management might have collectively contributed to
the reduction in mortality in Guangdong.
Despite
the phylogenetic homogeneity between SARS-CoV-2 and SARS-CoV, there are
some clinical characteristics that differentiate Covid-19 from SARS-CoV,
MERS-CoV, and seasonal influenza infections. (For example, seasonal
influenza has been more common in respiratory outpatient clinics and
wards.) Some additional characteristics that are unique to Covid-19 are
detailed in Table S3.
Our study has some notable
limitations. First, some cases had incomplete documentation of the
exposure history and laboratory testing, given the variation in the
structure of electronic databases among different participating sites
and the urgent timeline for data extraction. Some cases were diagnosed
in outpatient settings where medical information was briefly documented
and incomplete laboratory testing was performed, along with a shortage
of infrastructure and training of medical staff in nonspecialty
hospitals. Second, we could estimate the incubation period in only 291
of the study patients who had documented information. The uncertainty of
the exact dates (recall bias) might have inevitably affected our
assessment. Third, because many patients remained in the hospital and
the outcomes were unknown at the time of data cutoff, we censored the
data regarding their clinical outcomes as of the time of our analysis.
Fourth, we no doubt missed patients who were asymptomatic or had mild
cases and who were treated at home, so our study cohort may represent
the more severe end of Covid-19. Fifth, many patients did not undergo
sputum bacteriologic or fungal assessment on admission because, in some
hospitals, medical resources were overwhelmed. Sixth, data generation
was clinically driven and not systematic.
Covid-19
has spread rapidly since it was first identified in Wuhan and has been
shown to have a wide spectrum of severity. Some patients with Covid-19
do not have fever or radiologic abnormalities on initial presentation,
which has complicated the diagnosis.
Author Affiliations
From
the State Key Laboratory of Respiratory Disease, National Clinical
Research Center for Respiratory Disease, Guangzhou Institute of
Respiratory Health, First Affiliated Hospital of Guangzhou Medical
University (W.G., W.L., J.H., R.C., C.T., T.W., S.L., Jin-lin Wang,
N.Z., J.H., W.L.), the Departments of Thoracic Oncology (W.L.), Thoracic
Surgery and Oncology (J.H.), and Emergency Medicine (Z.L.), First
Affiliated Hospital of Guangzhou Medical University, and Guangzhou
Eighth People’s Hospital, Guangzhou Medical University (C.L.), and the
State Key Laboratory of Organ Failure Research, Department of
Biostatistics, Guangdong Provincial Key Laboratory of Tropical Disease
Research, School of Public Health, Southern Medical University (C.O.,
P.C.), Guangzhou, Wuhan Jinyintan Hospital (Z.N., J.X.), Union Hospital,
Tongji Medical College, Huazhong University of Science and Technology
(Yu Hu), the Central Hospital of Wuhan (Y.P.), Wuhan No. 1 Hospital,
Wuhan Hospital of Traditional Chinese and Western Medicine (L.W.), Wuhan
Pulmonary Hospital (P.P.), Tianyou Hospital Affiliated to Wuhan
University of Science and Technology (Jian-ming Wang), and the People’s
Hospital of Huangpi District (S.Z.), Wuhan, Shenzhen Third People’s
Hospital and the Second Affiliated Hospital of Southern University of
Science and Technology, National Clinical Research Center for Infectious
Diseases (L. Liu), and the Department of Clinical Microbiology and
Infection Control, University of Hong Kong–Shenzhen Hospital (K.-Y.Y.),
Shenzhen, the Fifth Affiliated Hospital of Sun Yat-sen University,
Zhuhai (H.S.), the Department of Medicine and Therapeutics, Chinese
University of Hong Kong, Shatin (D.S.C.H.), and the Department of
Microbiology and the Carol Yu Center for Infection, Li Ka Shing Faculty
of Medicine, University of Hong Kong, Pok Fu Lam (K.-Y.Y.), Hong Kong,
Medical ICU, Peking Union Medical College Hospital, Peking Union Medical
College and Chinese Academy of Medical Sciences (B.D.), and the Chinese
Center for Disease Control and Prevention (G.Z.), Beijing, the State
Key Laboratory for Diagnosis and Treatment of Infectious Diseases,
National Clinical Research Center for Infectious Diseases, First
Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou
(L. Li), Chengdu Public Health Clinical Medical Center, Chengdu (Y.L.),
Huangshi Central Hospital of Edong Healthcare Group, Affiliated Hospital
of Hubei Polytechnic University, Huangshi (Ya-hua Hu), the First
Hospital of Changsha, Changsha (J. Liu), the Third People’s Hospital of
Hainan Province, Sanya (Z.C.), Huanggang Central Hospital, Huanggang
(G.L.), Wenling First People’s Hospital, Wenling (Z.Z.), the Third
People’s Hospital of Yichang, Yichang (S.Q.), Affiliated Taihe Hospital
of Hubei University of Medicine, Shiyan (J. Luo), and Xiantao First
People’s Hospital, Xiantao (C.Y.) — all in China.
Address
reprint requests to Dr. Zhong at the State Key Laboratory of
Respiratory Disease, National Clinical Research Center for Respiratory
Disease, Guangzhou Institute of Respiratory Health, First Affiliated
Hospital of Guangzhou Medical University, 151 Yanjiang Rd., Guangzhou,
Guangdong, China, or at nanshan@vip.163.com.
A list of investigators in the China Medical Treatment Expert Group for Covid-19 study is provided in the Supplementary Appendix, available at NEJM.org.
-
Supplementary Material
| Protocol | 257KB | |
| Supplementary Appendix | 513KB | |
| Disclosure Forms | 534KB |
https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
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