CHINESE MEDICAL STUDY ON COVID-19 THAT WAS REMOVED BY CHINESE GOVERNMENT ON MARCH 25, 2020

Study Title:

Clinical Characteristics of Coronavirus Disease 2019 in China (references included)

Fudan University Link:  https://web.archive.org/web/20200409053204/http://www.it.fudan.edu.cn/Data/View/3657

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.)

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.)

In early December 2019, the first pneumonia cases of unknown origin were identified in Wuhan, the capital city of Hubei province.¹ The pathogen has been identified as a novel enveloped RNA betacoronavirus² that has currently been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has a phylogenetic similarity to SARS-CoV.³ Patients with the infection have been documented both in hospitals and in family settings.^4-8

The World Health Organization (WHO) has recently declared coronavirus disease 2019 (Covid-19) a public health emergency of international concern.⁹ As of February 25, 2020, a total of 81,109 laboratory-confirmed cases had been documented globally.^5,6,9-11 In recent studies, the severity of some cases of Covid-19 mimicked that of SARS-CoV.^1,12,13 Given the rapid spread of Covid-19, we determined that an updated analysis of cases throughout mainland China might help identify the defining clinical characteristics and severity of the disease. Here, we describe the results of our analysis of the clinical characteristics of Covid-19 in a selected cohort of patients throughout China.

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 recorded. The 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.⁸Our 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.

Supported by the National Health Commission of China, the National Natural Science Foundation, and the Department of Science and Technology of Guangdong Province.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Guan, Ni, Yu Hu, W. Liang, Ou, He, L. Liu, Shan, Lei, Hui, Du, L. Li, Zeng, and Yuen contributed equally to this article.

This article was published on February 28, 2020, and last updated on March 6, 2020, at NEJM.org.

We thank all the hospital staff members (see Supplementary Appendix for a full list of the staff) for their efforts in collecting the information that was used in this study; Zong-jiu Zhang, Ya-hui Jiao, Xin-qiang Gao, and Tao Wei (National Health Commission), Yu-fei Duan and Zhi-ling Zhao (Health Commission of Guangdong Province), and Yi-min Li, Nuo-fu Zhang, Qing-hui Huang, Wen-xi Huang, and Ming Li (Guangzhou Institute of Respiratory Health) for facilitating the collection of patients’ data; the statistical team members Zheng Chen, Dong Han, Li Li, Zhi-ying Zhan, Jin-jian Chen, Li-jun Xu, and Xiao-han Xu (State Key Laboratory of Organ Failure Research, Department of Biostatistics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, and Southern Medical University, respectively); Li-qiang Wang, Wei-peng Cai, Zi-sheng Chen (the Sixth Affiliated Hospital of Guangzhou Medical University) and Chang-xing Ou, Xiao-min Peng, Si-ni Cui, Yuan Wang, Mou Zeng, Xin Hao, Qi-hua He, Jing-pei Li, Xu-kai Li, Wei Wang, Li-min Ou, Ya-lei Zhang, Jing-wei Liu, Xin-guo Xiong, Wei-juna Shi, San-mei Yu, Run-dong Qin, Si-yang Yao, Bo-meng Zhang, Xiao-hong Xie, Zhan-hong Xie, Wan-di Wang, Xiao-xian Zhang, Hui-yin Xu, Zi-qing Zhou, Ying Jiang, Ni Liu, Jing-jing Yuan, Zheng Zhu, Jie-xia Zhang, Hong-hao Li, Wei-hua Huang, Lu-lin Wang, Jie-ying Li, Li-fen Gao, Cai-chen Li, Xue-wei Chen, Jia-bo Gao, Ming-shan Xue, Shou-xie Huang, Jia-man Tang, and Wei-li Gu (Guangzhou Institute of Respiratory Health) for their dedication to data entry and verification; Tencent (Internet-services company) for providing the number of hospitals certified to admit patients with Covid-19 throughout China; and all the patients who consented to donate their data for analysis and the medical staff members who are on the front line of caring for patients.

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	PDF	257KB
Supplementary Appendix	PDF	513KB
Disclosure Forms	PDF	534KB

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Citing Articles (327)

Letters

CORRESPONDENCE

Clinical Characteristics of Covid-19 in China

TO THE EDITOR

To the Editor: According to the World Health Organization (WHO), the case definition for surveillance of returning travelers requires that they need to present with fever and at least one respiratory symptom to be considered as having suspected cases of coronavirus disease 2019 (Covid-19).¹ In their article regarding 1099 patients with laboratory-confirmed Covid-19 at hospitals across China during the first 2 months of the pandemic, Guan et al. (Feb. 28 online publication, available at NEJM.org)² present compelling data supporting the need for a reassessment of these criteria. The authors found that only 43.8% of the patients presented with fever on admission, although fever developed in 88.7% during hospitalization. That means that if those travelers were returning from affected areas, more than half would not be suspected of having Covid-19, which would result in undetected patients who can spread the virus. This issue may be particularly relevant in low-income countries with less structured health care systems, which could not provide adequate follow-up of these travelers.

The study by Guan et al. suggests that fever is not the hallmark of the onset of Covid-19. Other studies have shown rates of fever from 83 to 98% on admission.^3,4 We believe that a case definition requiring fever and at least one respiratory symptom may lead to an underdiagnosis of a substantial proportion of patients with early Covid-19 and lead to increased transmission of the virus.

Alexandre P. Zavascki, M.D., Ph.D.
Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 
azavascki@hcpa.edu.br

Diego R. Falci, M.D., Ph.D.
Hospital Moinhos de Vento, Porto Alegre, Brazil

No potential conflict of interest relevant to this letter was reported.

This letter was published on March 27, 2020, at NEJM.org.

4 References

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TO THE EDITOR

To the Editor: In their article on the first cases of Covid-19 across China, Guan et al. use descriptive statistics to account for the events: 15.7% of patients with severe cases of the infection, 5% who were treated in the intensive care unit (ICU), and 1.4% who died. The mortality reported here is not to be confused with the true case fatality ratio, since 93.6% of the patients had not yet reached an outcome at the time of data censoring (January 31). As stated in the WHO consensus with respect to the 2002–2003 epidemic of severe acute respiratory syndrome (SARS),¹ “simple methods for calculating case fatality ratios from aggregate data will not give reliable estimates during the course of an epidemic.”

It is also important to qualify current mortality estimates, which are based on a health system with incredible response capabilities, including entire regions in quarantine² and expedited building of hospitals. Low- and middle-income countries (85% of the world)³ with already strained health systems should interpret developing data cautiously. The case fatality ratio in each system will depend on the active efforts made to prevent and slow the spread of the virus.

Andre T.C. Chen, M.D., Ph.D.
George B. Coura-Filho, M.D., Ph.D.
Marília H.H. Rehder, M.D., Ph.D.
Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil 
andre.chen@hc.fm.usp.br

Dr. Rehder reports being employed as a global patient safety physician at Eli Lilly do Brasil. No other potential conflict of interest relevant to this letter was reported.

This letter was published on March 27, 2020, at NEJM.org.

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TO THE EDITOR

To the Editor: Guan et al. cite hypertension and diabetes as the coexisting conditions that pose the highest risk of complications in patients with Covid-19. Do the authors have any data regarding the percentage of patients in their study who were receiving angiotensin-receptor blockers (ARBs) or angiotensin-converting–enzyme (ACE) inhibitors and whether such treatment had any effect on the incidence of infection, severity of disease, or their defined primary composite end point of admission to an ICU, the use of mechanical ventilation, or death?

Since SARS-CoV-2 (the virus causing Covid-19) infects cells through the ACE2 receptor,^1-3 the addition of an ARB may decrease the infectivity and potential injury caused by the virus. In addition, the use of an ACE inhibitor may worsen the situation. ARBs do not block the ACE2 receptor well, but there is some crossover, with each individual ARB having a different degree of affinity to the angiotensin II type 1 (AT1) receptor and to the angiotensin II type 2 receptor (AT2)⁴; ARBs also have an effect on the production of chymase and angiotensin II.⁵ At this point, do the authors have information on these questions?

J. Douglass Rolf, M.D.
Kelowna Respiratory Clinic, Kelowna, BC, Canada 
roldresp@kelresp.com

No potential conflict of interest relevant to this letter was reported.

This letter was published on March 27, 2020, at NEJM.org.

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TO THE EDITOR

To the Editor: Guan et al. observed severe cases of Covid-19 at higher frequency in patients with diabetes, hypertension, cardiovascular disease, or a history of smoking. SARS-CoV-2 uses as its host receptor ACE2,¹ which is highly expressed in the lungs and converts angiotensin II (Ang II) to angiotensin 1–7 (Ang 1–7).² The axis consisting of ACE2, Ang 1–7, and Mas receptor opposes the vasoconstrictive, proinflammatory, and pro-oxidative properties of the ACE–Ang II–AT1 axis.² Decreased ACE2 levels are reported in patients who have a history of diabetes, hypertension, cardiovascular disease, or smoking.^2,3 We suspect that virus binding attenuates residual ACE2 activity, which leads to further imbalance between Ang II and Ang 1–7. High circulating levels of Ang II induce pulmonary vasoconstriction, which promotes ventilation–perfusion mismatch and increases vascular permeability, inflammation, and oxidative stress and can lead to acute lung injury or acute respiratory distress syndrome (ARDS).⁴ Thus, we encourage investigation of AT1 blockers, Ang 1–7, and recombinant ACE2 as potential therapeutic agents to mitigate acute lung injury or ARDS in patients with severe Covid-19.

Brandon M. Henry, M.D.
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 
brandon.henry@cchmc.org

Jens Vikse, M.D.
Stavanger University Hospital, Stavanger, Norway

No potential conflict of interest relevant to this letter was reported.

This letter was published on March 27, 2020, at NEJM.org.

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RESPONSE

The authors reply: We concur with Zavascki and Falci that approximately half the patients with Covid-19 would have been underdiagnosed if the diagnostic criteria had been solely based on the presence of fever. This finding was similar to the result of a study involving 81 patients with varying disease severity showing that approximately 30% of the patients in whom Covid-19 was diagnosed were afebrile on admission.¹ Our findings might have been attributable to the variation in the predominant symptoms or signs among the study population and the different timing of examination. As the correspondents point out, fever developed in nearly 90% of the patients in our study during their hospital stay. Therefore, afebrile patients with a recent contact history and radiologic manifestations consistent with atypical pneumonia on admission should be screened for Covid-19 by viral nucleic acid assay of respiratory samples.

Chen and colleagues express concern regarding the validity of the estimated case fatality rate during the epidemic. A more precise estimate could have been derived from a study that included a longer follow-up duration among all study patients. Given the urgency to inform clinicians worldwide, we defined the censoring time as the data cutoff (January 31), when a considerable proportion of the patients remained in the hospital. In spite of this shortcoming, our mortality estimate (1.4%) was close to the national official estimates (2.0 to 3.5%) between February and March.²

Rolf comments on a valuable approach to determine the effect of ARBs on the clinical outcomes of patients with Covid-19. However, given the urgency and the incompleteness of records in some participating sites, plus the variable length of follow-up, our database cannot convincingly address further the potential benefits of this class of medication.

We appreciate the suggestions of Henry and Vikse, who propose the use of angiotensin 1 blockers, Ang 1–7, and recombinant human ACE2 in patients with Covid-19. We are planning to initiate a clinical trial that compares the effects of an intravenous infusion of recombinant ACE2 (at a dose of 0.4 mg per kilogram of body weight twice daily for 7 days) plus the standard of care, as compared with the standard of care alone, on the time course of body temperature and the dynamics of viral loads (ClinicalTrials.gov number, NCT04287686. opens in new tab). The hope is that such treatment with a novel class of medications may show a benefit in patients with Covid-19.

Wei-jie Guan, Ph.D.
Nan-shan Zhong, M.D.
First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 
nanshan@vip.163.com