Investigations of deceased COVID-19 patients have shed light on possible lung damage caused by the virus

Investigations of deceased COVID-19 patients have shed light on possible lung damage caused by the virus.

The study, published today in The Lancet’s eBioMedicine, by King’s College London in collaboration with University of Trieste and the International Centre for Genetic Engineering and Biology in Italy, shows the unique characteristics to the SARS-CoV-2 virus and may explain why patients suffer from ‘long COVID’.

Patients with COVID-19 can experience symptoms such as blood clotting and loss of smell and taste.

Some who survive the infection can experience the effects of the disease for months – known as ‘long COVID’ – with a feeling of fatigue and lack of breath.

There have been a limited number of studies that have analyzed the organs of COVID-19 patients which means the characteristics of the disease are still largely unknown.

Researchers analyzed the organs of 41 patients who died of COVID-19 at the University Hospital of Trieste, Italy, from February to April 2020, at the start of the pandemic. The team took lung, heart, liver, and kidney samples to examine the behavior of the virus.

Findings show extensive lung damage in most cases, with patients experiencing profound disruption of the normal lung structure and the transformation of respiratory tissue into fibrotic material.

Almost 90% of patients showed two additional characteristics that were quite unique to COVID-19 compared to other forms of pneumonia.

First, patients showed extensive blood clotting of the lung arteries and veins (thrombosis). Second, several lung cells were abnormally large and had many nuclei, resulting from the fusion of different cells into single large cells.

This formation of fused cells (syncytia) is due to the viral spike protein, which the virus uses to enter the cell. When the protein is present on the surface of cells infected by the COVID-19 virus, it stimulates their fusion with other normal lung cells, which can be a cause for inflammation and thrombosis.

Additionally, research showed the long-term persistence of the viral genome in respiratory cells and in cells lining the blood vessels, along with the infected cell syncytia.

The presence of these infected cells can cause the major structural changes observed in lungs, which can persist for several weeks or months and could eventually explain ‘long COVID’.

The study found no overt signs of viral infection or prolonged inflammation detected in other organs.

Professor Mauro Giacca, at the British Heart Foundation Centre at King’s College London, said: “These findings are very exciting. The findings indicate that COVID-19 is not simply a disease caused by the death of virus-infected cells but is likely the consequence of these abnormal cells persisting for long periods inside the lungs.”

The team is now actively testing the effect of these abnormal cells on blood clotting and inflammation and are searching for new drugs that can block the viral spike protein which causes cells to fuse.

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The first reports of a novel respiratory virus which was subsequently shown to be a coronavirus, severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), emerged from Wuhan, China in December 2019.1

The highly transmittable virus spread rapidly and on 11 March 2020, coronavirus disease 2019 (COVID-19) was declared a global pandemic by the World Health Organisation.

By 10 May 2020, there were over 4 million confirmed cases worldwide with over 280 000 deaths. In the UK alone by this date, there were over 215 000 confirmed cases and over 30 000 deaths.

The clinical manifestations of SARS-Cov-2 infection vary, ranging from asymptomatic carriage to atypical pneumonia, a hyperinflammatory phenotype, respiratory failure and acute respiratory distress syndrome (ARDS).2–5 An unexpectedly high prevalence of venous thromboembolic (VTE) disease and pulmonary embolism (PE) has become apparent6 and this is an important consideration for acute management and subsequent follow-up.

Those most severely affected by COVID-19 are older men, individuals of black, Asian and minority ethnicity and those with comorbidities such as obesity, hypertension and diabetes.2–4 7–9 By far, the the most common indication for admission to hospital is viral pneumonia and over 80% of hospitalised patients are cared for in general medical wards.10

A smaller proportion of patients with more severe disease require additional ventilatory support and are admitted to high dependency and intensive care units (ICUs). In a Chinese study of 1099 hospitalised COVID-19 patients, 173 patients (16%) had severe disease based on American Thoracic Society (ATS) community-acquired pneumonia guidelines11 and 55 (5%) required ICU admission.2

The mortality associated with COVID-19 is considerable – in a large UK study, in-hospital mortality was 26% for patients on general wards rising to 32% in those requiring ICU care.10 Depending on the series, COVID-19-related ICU mortality has been reported to be between 16% and 78%.3 4 8 10 12–15

As effective vaccines and treatments for SARS-Cov-2 emerge, a key objective will be to identify and proactively manage complications from the infection and support patients through the recovery phase with the goal of preserving their health status.

In this guidance document, we provide a suggested structure to achieve these aims with a focus on the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia.

This guidance has been adopted by the British Thoracic Society (BTS) and the British Society of Thoracic Imaging (BSTI) after wide consultation and peer review. It is available online (https://brit-thoracic.org.uk/about-us/covid-19-information-for-the-respiratory-community/).

COVID-19 pneumonia imaging and specific respiratory complications for consideration

In typical cases of COVID-19 pneumonia, the chest X-ray (CXR) shows multiple bilateral peripheral opacities (figure 1A). In some patients, the morphological pattern of lung disease on CT scan with regions of ground-glass opacification and consolidation, which variably comprise foci of oedema, organising pneumonia and diffuse alveolar damage, are not too far removed from those in patients with an acute inflammatory pneumonitis (figure 1B–F).

The radiological changes in COVID-19 pneumonia do not appear to resolve fully in all patients and in some, inflammation matures to form residual pulmonary fibrosis (figure 2).

Predicting the likely respiratory consequences of COVID-19 is challenging but reviewing data from this and other coronavirus infections provides insights.

There may be important parallels from the severe acute respiratory syndrome (SARS) outbreak of 2002–2003 caused by SARS-CoV and Middle East respiratory syndrome (MERS) first identified in 2012.16–20

In a longitudinal CT study of 90 patients with COVID-19, 94% of individuals had residual changes on CT at discharge (median duration of 24 days after symptom onset) with ground-glass opacity the most common pattern.21 At discharge, in a study of 110 patients with COVID-19, 91 (83%) of whom had a mild–moderate disease and 19 (17%) of whom had severe disease, almost half had impairment of the transfer factor of the lung for carbon monoxide (TLco).22

The duration between onset of illness and pulmonary function testing ranged from an average of 20 days in mild cases to an average of 34 days in severe pneumonia. The TLco was lower in patients with severe disease and was more sensitive to disease severity than other lung function measures such as forced vital capacity (FVC) and total lung capacity (TLC).

Interestingly in this study, and although still largely within normal ranges at an average of 83% predicted, the TLco/alveolar volume (Kco) was significantly lower in those with severe disease than those with mild to moderate COVID-19 possibly implying a degree of pulmonary vasculopathy.

In a study of SARS survivors, 12 weeks after discharge, 36% of patients had residual CXR abnormalities and at 6 months, these were still present in 30% of the entire cohort, with airspace opacification and reticulation the predominant abnormalities.23 CXR abnormalities were correlated with lung function test parameters including FVC, TLco and TLC but not with measures of respiratory muscle strength.

Six months from hospital discharge, 16% of patients had persistent impairment of TLco with the preservation of the Kco.23 The implication, therefore, is that these CXR imaging abnormalities were physiologically relevant and related to parenchymal lung disease.

Similarly, in MERS survivors, at a median follow-up point of 6 weeks (range 32–230 days), 36% of patients had residual CXR changes, the vast majority of which were due to pulmonary fibrosis.16

These data suggest that the majority of patients infected with coronaviruses are discharged from hospital with persisting radiological change but that (at least in SARS23 and MERS16) by 12 weeks, approximately two-thirds of patients have full CXR resolution. The optimal time for follow-up imaging to assess for radiological clearance in COVID-19 is unknown.

Current BTS guidelines recommend a repeat CXR 6 weeks after a (bacterial or viral) community-acquired pneumonia24; the rationale being to exclude primary bronchial neoplasms that can contribute to lobar or segmental pneumonia.

The ATS does not recommend routine follow-up imaging for patients recovering satisfactorily from community-acquired pneumonia.11

The patchy ground-glass opacification classically observed in COVID-19 pneumonia (figure 1A–F) is, however, much less suspicious of harbouring a malignancy, particularly in the context of a pandemic.

A 6-week follow-up CXR is, therefore, not advised and the 12-week time point is considered to be optimal in providing sufficient time for imaging resolution while also ensuring that non-resolving changes are addressed sufficiently early. Given that persisting imaging abnormalities correlate with physiological impairment, it is likely that these patients are at a greater risk of long-term parenchymal lung disease and are the group in whom closer follow-up and further investigation are indicated.

Unlike the MERS and SARS outbreaks, acute COVID-19 infection is associated with a high prevalence of VTE disease25–27 and in situ thrombosis. Indeed, patients remain hypercoagulable for a variable period of time and prolonged immobility in the most severely affected patients represents an additional VTE risk factor.

It is increasingly appreciated that a number of patients are diagnosed with acute PE and deep vein thromboses de novo during the pneumonia recovery phase. Although the follow-up of COVID-19 pneumonia may hinge on the radiological resolution, it is crucial to be mindful of the high risk of PE in this group; this follow-up guidance should highlight to clinicians the need for prompt identification and treatment of acute PE and post-PE complications such as chronic thromboembolic disease and pulmonary hypertension (PH).

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Journal information: EBioMedicine