Clinical and CT features of mild-to-moderate COVID-19 cases after two sequential negative nucleic acid testing results: a retrospective analysis

This retrospective single-center study was conducted by using the data of all consecutive patients with confirmed COVID-19 who had been diagnosed at government-assigned hospitals in Shenzhen according to the Chinese Program for the Diagnosis and Treatment of COVID-19 [17] and were transferred to the Hezheng ward of Shenzhen Hospital, Southern Medical University, Shenzhen, China, between January 31 and February 28, 2020. All patients with confirmed COVID-19 were required to undergo daily SARS-CoV-2 nucleic acid testing until two consecutive negative results were obtained. Based on their overall condition, the patients were then discharged or transferred to other government-assigned hospitals for further treatment. The Hezheng ward was responsible for providing further treatment to patients who had obtained two consecutive negative results. The patients’ clinical characteristics and outcomes were monitored up to March 7, 2020, the last date of follow-up.

This study was approved by the Ethics Committee of Shenzhen Hospital, Southern Medical University.

Using structured data collection forms, the clinical characteristics and outcomes of the enrolled patients at the first admission due to COVID-19 and after transfer to the Hezheng ward after two consecutive negative nucleic acid test results were obtained from the electronic medical records. All data were reviewed by a trained team of physicians. The recorded information included demographic data, the epidemiological history, underlying comorbidities (e.g., bronchial or lung diseases and other comorbidities), symptoms, signs, laboratory parameters (e.g., white blood cell and lymphocyte counts, neutrophil and lymphocyte percentages, erythrocyte sedimentation rate, and C-reactive protein, D-dimer, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase concentrations), and chest CT scan data, if available. The patients’ treatment and outcome data were also extracted.

COVID-19 cases were diagnosed according to the guideline for the prevention and control of COVID-19 (7th edition) published by General Office of National Health Committee of China [17]. An epidemiological history was defined as: 1) travelling to or residence in Wuhan or other cities with continuous and local SARS-CoV-2 transmission in the 14 days before symptom onset; 2) contacting with SARS-CoV-2-infected patients in the 14 days before symptom onset; 3) contacting with patients with a fever or respiratory symptom from Wuhan or other cities with continuous local transmission in the 14 days before symptom onset; or 4) clustered onsets. A suspected case was defined as a patient with an epidemiological history and any two clinical features of COVID-19 or without an epidemiological history but with all of the following clinical features: 1) fever and/or respiratory symptoms; 2) imaging features consistent with COVID-19; and 3) a normal or reduced total white blood cell count and/or normal or reduced lymphocyte count during the early stage of the disease. A confirmed case was further defined using the criteria for a suspected case (the criteria shown in the supplementary materials) and one of the following pathogenic criteria: 1) a positive real-time PCR-based SARS-CoV-2 nucleic acid test result; 2) high homogeneity between viral gene sequencing results and the known SARS-CoV-2 sequence; and 3) positive serum SARS-CoV-2-specific IgM and IgG antibody test results, or a switch from a negative to a positive SARS-CoV-2-specific IgG antibody test result, or a 4-fold increase in serum SARS-CoV-2-specific IgG antibody levels in the recovery phase relative to the acute phase. In this study, COVID-19 patients who received two sequential negative nucleic acid testing results with sampling interval at least 24 h were classified as having mild or moderate disease according to the baseline severity. Mild cases were those with mild clinical features and no imaging features of pneumonia. Moderate cases were those with fever or respiratory symptoms and imaging features of pneumonia [17].

Because mild cases had no imaging features of pneumonia, only patients with moderate COVID-19 underwent chest CT re-examinations. To determine changes in the imaging manifestations during the recovery phase, the chest CT scans were performed at 5 to 7 day intervals over a 2-week period. Typical CT imaging manifestations of COVID-19 include ground-glass density shadows alone, interlobular septal thickening combined with ground-glass changes, intralobular interstitial thickening combined with ground-glass changes, consolidation combined with ground-glass changes, fibrous stripes, solid nodules, and other features such as pleural effusion. All CT images were reviewed by the same doctor (Wang J).

The baseline characteristics were presented for all patients with COVID-19 and for subgroups categorized by the severity of disease (mild or moderate). Data were presented as numbers and frequencies for categorical data or as medians with interquartile ranges (IQRs) for continuous data. The frequencies of categorical variables were compared using the χ² test; Fisher’s exact test was used when the data were limited. The Mann–Whitney test was used to compare median values between two independent groups, while the Wilcoxon test was used to compare two paired groups. All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) version 21.0 software (SPSS Inc., Chicago, IL, USA). A two-sided α of < 0.05 was considered statistically significant.

Fifty-one patients with confirmed COVID-19 were transferred to our hospital for further treatments after two consecutive negative nucleic acid testing results and were included in this study. The median age was 34.0 years (range: 7 months to 67 years; IQR: 20–44 years). Twenty-four patients (47.1%) were male and 36 (70.6%) had ever traveled to Hubei province (Table 1). The median (IQR) incubation time and time to negative nucleic acid testing were 7.5 (1.0, 11.75) days and 3 (2, 7) days.

Information about the symptom time course, positive throat swab, hospital admission, and discharge for each SARS-CoV-2-infected patient is presented in Fig. 1. Upon hospital admission, 34 of the 51 (66.7%) patients were febrile, with a fever duration of 5.0 (IQR: 2.0, 7.0) days, and 31 of the 51 (60.8%) patients had a cough. Regarding other symptoms, 3.9–13.7% of the patients presented with expectoration, pharyngitis, headache, fatigue, nasal congestion and discharge, gastrointestinal reactions, and chest tightness and dyspnea. Generally, the proportions of symptoms were higher among moderate cases than among mild cases (fever: 74.2% vs. 55.0%; cough: 71.0% vs. 45.0%), but these differences were not statistically significant. None of the patients who were transferred to the Hezheng ward after two consecutive negative nucleic acid tests reported a fever, and the frequency of patients with a cough (17/51, 33.3%) also significantly decreased (both P < 0.05). The proportions of the other symptoms generally remained the same. Ten of the 51 (19.6%) patients in the moderate group and none in the mild group had complicating bronchial or lung diseases or other coexisting conditions, such as glioma, nephrectomy, and hyperlipidemia. Regarding treatment, 34.7% of the patients were treated with western medicine only, 30.6% with Chinese medicine only, and 34.8% with both treatments.

The laboratory results of the included patients with COVID-19 and two consecutive negative nucleic acid tests are presented in Table 2. Compared with the baseline characteristics, a repeated-measures analysis revealed no statistically significant differences 3–5 days after the two consecutive negative nucleic acid tests (Table 3). For longer repeated-measure intervals (> 1 week; Table 4), the laboratory values decreased steadily, but these differences were not statistically significant.

All patients with moderate COVID-19 had undergone a chest CT scan by the time of transfer to the Hezheng ward. Among these patients (Table 5 and Fig. 2), only one lobe was affected in 7 (22.6%) patients and two or more lobes were affected in 24 (77.4%). The left lower lobe was the most common location of lesions (71.0%, 22/31), followed by the right lower lobe (61.3%, 19/31), left upper lobe (48.4%, 15/29), and right middle lobe (38.7%, 12/29). Right upper and lower and left lower lobe involvement were generally distributed evenly between cases with single affected lobe and those with multiple affected lobes. However, 83.3% (10/12) of the cases with right middle lobe involvement only involved a single lobe and 66.7% (10/15) of the cases with left upper lobe involvement had multiple affected lobes.

The most common CT imaging manifestations were ground-glass opacities (51.6%, 16/31) and fibrous stripes (54.8%, 17/31) (Table 6 and Supplementary Table 1). Twelve of the 31 patients underwent repeated chest CT scans after negative nucleic acid test results; of them, seven patients (58.3%) exhibited a > 60% reduction in the ground-glass opacities. However, a reduction < 5% was observed in four patients. In case 17, the ground-glass opacity with a reduction of < 5% persisted for almost month. In addition, the 12 patients with negative throat swabs (case nos. 38–47, 49, and 50) occasionally had repeated positive fecal tests (Table 7 and Supplementary Table 2).