Since late December, 2019, an outbreak of a novel coronavirus disease (COVID-19; previously
known as 2019-nCoV)1, 2 was reported in Wuhan, China,
2
which has subsequently affected 26 countries worldwide. In general, COVID-19 is an
acute resolved disease but it can also be deadly, with a 2% case fatality rate. Severe
disease onset might result in death due to massive alveolar damage and progressive
respiratory failure.2, 3 As of Feb 15, about 66 580 cases have been confirmed and
over 1524 deaths. However, no pathology has been reported due to barely accessible
autopsy or biopsy.2, 3 Here, we investigated the pathological characteristics of a
patient who died from severe infection with severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) by postmortem biopsies. This study is in accordance with regulations
issued by the National Health Commission of China and the Helsinki Declaration. Our
findings will facilitate understanding of the pathogenesis of COVID-19 and improve
clinical strategies against the disease.
A 50-year-old man was admitted to a fever clinic on Jan 21, 2020, with symptoms of
fever, chills, cough, fatigue and shortness of breath. He reported a travel history
to Wuhan Jan 8–12, and that he had initial symptoms of mild chills and dry cough on
Jan 14 (day 1 of illness) but did not see a doctor and kept working until Jan 21 (figure
1
). Chest x-ray showed multiple patchy shadows in both lungs (appendix p 2), and a
throat swab sample was taken. On Jan 22 (day 9 of illness), the Beijing Centers for
Disease Control (CDC) confirmed by reverse real-time PCR assay that the patient had
COVID-19.
Figure 1
Timeline of disease course according to days from initial presentation of illness
and days from hospital admission, from Jan 8–27, 2020
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
He was immediately admitted to the isolation ward and received supplemental oxygen
through a face mask. He was given interferon alfa-2b (5 million units twice daily,
atomisation inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally)
as antiviral therapy, and moxifloxacin (0·4 g once daily, intravenously) to prevent
secondary infection. Given the serious shortness of breath and hypoxaemia, methylprednisolone
(80 mg twice daily, intravenously) was administered to attenuate lung inflammation.
Laboratory tests results are listed in the appendix (p 4). After receiving medication,
his body temperature reduced from 39·0 to 36·4 °C. However, his cough, dyspnoea, and
fatigue did not improve. On day 12 of illness, after initial presentation, chest x-ray
showed progressive infiltrate and diffuse gridding shadow in both lungs. He refused
ventilator support in the intensive care unit repeatedly because he suffered from
claustrophobia; therefore, he received high-flow nasal cannula (HFNC) oxygen therapy
(60% concentration, flow rate 40 L/min). On day 13 of illness, the patient's symptoms
had still not improved, but oxygen saturation remained above 95%. In the afternoon
of day 14 of illness, his hypoxaemia and shortness of breath worsened. Despite receiving
HFNC oxygen therapy (100% concentration, flow rate 40 L/min), oxygen saturation values
decreased to 60%, and the patient had sudden cardiac arrest. He was immediately given
invasive ventilation, chest compression, and adrenaline injection. Unfortunately,
the rescue was not successful, and he died at 18:31 (Beijing time).
Biopsy samples were taken from lung, liver, and heart tissue of the patient. Histological
examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates
(figure 2A, B
). The right lung showed evident desquamation of pneumocytes and hyaline membrane
formation, indicating acute respiratory distress syndrome (ARDS; figure 2A). The left
lung tissue displayed pulmonary oedema with hyaline membrane formation, suggestive
of early-phase ARDS (figure 2B). Interstitial mononuclear inflammatory infiltrates,
dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells
with atypical enlarged pneumocytes characterised by large nuclei, amphophilic granular
cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing
viral cytopathic-like changes. No obvious intranuclear or intracytoplasmic viral inclusions
were identified.
Figure 2
Pathological manifestations of right (A) and left (B) lung tissue, liver tissue (C),
and heart tissue (D) in a patient with severe pneumonia caused by SARS-CoV-2
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
The pathological features of COVID-19 greatly resemble those seen in SARS and Middle
Eastern respiratory syndrome (MERS) coronavirus infection.4, 5 In addition, the liver
biopsy specimens of the patient with COVID-19 showed moderate microvesicular steatosis
and mild lobular and portal activity (figure 2C), indicating the injury could have
been caused by either SARS-CoV-2 infection or drug-induced liver injury. There were
a few interstitial mononuclear inflammatory infiltrates, but no other substantial
damage in the heart tissue (figure 2D).
Peripheral blood was prepared for flow cytometric analysis. We found that the counts
of peripheral CD4 and CD8 T cells were substantially reduced, while their status was
hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38
(CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased
concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells (appendix p 3).
Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules,
in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive,
and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results
imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity
of CD8 T cells, accounts for, in part, the severe immune injury in this patient.
X-ray images showed rapid progression of pneumonia and some differences between the
left and right lung. In addition, the liver tissue showed moderate microvesicular
steatosis and mild lobular activity, but there was no conclusive evidence to support
SARS-CoV-2 infection or drug-induced liver injury as the cause. There were no obvious
histological changes seen in heart tissue, suggesting that SARS-CoV-2 infection might
not directly impair the heart.
Although corticosteroid treatment is not routinely recommended to be used for SARS-CoV-2
pneumonia,
1
according to our pathological findings of pulmonary oedema and hyaline membrane formation,
timely and appropriate use of corticosteroids together with ventilator support should
be considered for the severe patients to prevent ARDS development.
Lymphopenia is a common feature in the patients with COVID-19 and might be a critical
factor associated with disease severity and mortality.
3
Our clinical and pathological findings in this severe case of COVID-19 can not only
help to identify a cause of death, but also provide new insights into the pathogenesis
of SARS-CoV-2-related pneumonia, which might help physicians to formulate a timely
therapeutic strategy for similar severe patients and reduce mortality.
This online publication has been corrected. The corrected version first appeared at
thelancet.com/respiratory on February 25, 2020