Small Solitary Ground-Glass Nodule on CT as an Initial Manifestation of Coronavirus Disease 2019 (COVID-19) Pneumonia

A new dangerous coronavirus (2019 novel coronavirus, 2019-nCoV), leading to an outbreak of atypical pneumonia (coronavirus disease 2019, COVID-19), emerged in Wuhan, Hubei province, China at the end of December 2019 (1). As of March 3, 2020, more than 90000 people have been confirmed to have COVID-19 and more than 3000 people have died from the disease worldwide. Without any suitable therapeutic drugs, early detection and timely isolation are the best methods of preventing the disease from progressing and spreading. The role of high-resolution computed tomography (CT) has been crucial in the diagnosis of COVID-19 pneumonia and typical radiologic findings of COVID-19 pneumonia were included in the diagnostic criteria in China (2). Moreover, initial chest CT had a higher sensitivity than reverse transcription-polymerase chain reaction (RT-PCR) for 2019-nCoV (3). The typical CT findings of COVID-19 pneumonia include bilateral multiple ground-glass opacities and consolidative lesions in peripheral lung fields (4, 5). However, we treated three patients with COVID-19 pneumonia initially manifesting as a solitary sub-centimeter nodule on baseline CT imaging in hospital. The purpose of the study is to share our experience of atypical manifestations of COVID-19 on CT with the aim of achieving a comprehensive radiological understanding of COVID-19.

In December 2019, 2019-nCoV broke out in Wuhan, China and the outbreak quickly spread across the country and abroad. According to Wu et al. (6), the basic reproduction number of COVID-19 was estimated to be 2.68 (95% confidence interval, 2.47–2.86), which means the 2019-nCoV has great transmission capacity. The aim of this study was to alert radiologists that some patients with COVID-19 infection could have only a sub-centimeter ground-glass nodule on baseline chest CT images. These patients will be prone to misdiagnosis in the clinic if the radiologists disregard the possibility of COVID-19 in the radiology report. In addition, we recorded the evolution of chest CT findings in COVID-19 pneumonia. RT-PCR analysis is the gold standard for diagnosing 2019-nCoV infection, but in the context of limited medical resources with an overwhelming outbreak, the role of chest CT is particularly important.

These three patients with COVID-19 had a similar feature on CT, a history of exposure to a suspected or confirmed patient with 2019-nCoV. All patients developed a fever in a short period after the exposure, but two patients presented with symptoms after the CT abnormalities were first seen. According to recent studies, abnormal CT findings can be found even in asymptomatic patients (7, 8). All patients had abnormal laboratory investigation findings; one had a decreased lymphocyte count and the others had an increase in C-reactive protein, which both indicate viral infection. Some laboratory tests could provide clues suggestive of COVID-19, such as leukocytopenia, lymphopenia, and elevated C-reactive protein in the recent report (9).

We reviewed the serial CT images of patients with COVID-19. All patients recovered and we obtained all imaging data from onset to recovery. Based on the observations of previous studies (5, 10, 11), COVID-19 pneumonia is mainly characterized by multiple lesions that are preferentially distributed in the posterior or peripheral areas of both lungs. Furthermore, radiologic findings were associated with disease severity (8). In our study, the initial lesion was a solitary sub-centimeter ground-glass nodule distributed in the boundary between the outer one-third and inner two-thirds of pulmonary lobes, along with adjacent bronchovascular bundles (Figs. 1A, 2A, 3A). The small ground-glass nodule can easily be misdiagnosed as a benign nodule or early lung adenocarcinoma, or even not detected due to a lack of experience.

Furthermore, the reported imaging features in COVID-19 are variable and nonspecific (12). The radiological features of the patients as the disease progressed are shown below. The disease progressed over a period of 2–3 days, presenting as an enlarged nodule with a blurred margin on CT. Interestingly, the small ground-glass nodules were initially separate from the pleura; however, as the nodule evolved, the shape of the lesions became patchy to confluent and were predominantly found in subpleural areas. Multiple solid and ground-glass opacities always began to appear in the local lobe. Soon after, crazy-paving pattern, diffuse bilateral pulmonary ground-glass opacities with segmental consolidation appeared in the peripheral areas of the lung during the peak stage of the disease (approximately 10 days after onset of initial symptoms). The above imaging findings were associated with the death of a large number of epithelium and foam cells in the alveoli, inflammatory exudate filling the alveolar cavity, and pulmonary tissue necrosis (13). After the peak of COVID-19, the lesion was gradually absorbed and there was residual fibrosis in the original location.

In summary, we suspect that a solitary sub-centimeter nodule reflects an incipient stage of COVID-19 when it just begins to involve the lower respiratory tract. More remarkably, chest CT images can depict minute incipient lesions before the onset of symptoms. The Fleischner guideline is a commonly used guideline when a small ground-glass nodule is incidentally encountered on CT. The guideline recommends no routine follow-up or 6–12 months follow-up based on whether the nodule was 6 mm in size (14). In the endemic areas of COVID-19, such follow-up strategies may miss incipient COVID-19 pneumonia. Accordingly, short-interval follow-up CT scan is required, particularly for suspected cases with a history of exposure to 2019-nCoV, considering its rapid progression. A few patients lack symptoms in the early stages of infection but also exhibit positive CT findings according to Ai et al. (3). Moreover, we revealed the evolution of disease as seen on chest CT and these findings are nearly consistent with a recent report (10, 11, 15). Thus, chest CT is of great significance in the diagnosis of COVID-19 infection in areas where COVID-19 infection prevails. Accurate diagnosis requires an in-depth understanding of COVID-19 with a combination of the patient's symptoms, epidemic history, and other medical examination findings at the same time.