COVID-19 sets up outbreaks in multiple small areas of the lung instead of rapidly infecting large regions

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Bacteria or viruses like influenza that cause pneumonia can spread across large regions of the lung over the course of hours. In the modern intensive care unit, these bacteria or viruses are usually controlled either by antibiotics or by the body’s immune system within the first few days of the illness.

But in a study published in Nature on January 11, investigators at Northwestern Medicine show COVID-19 pneumonia is different.

Instead of rapidly infecting large regions of the lung, the virus causing COVID-19 sets up shop in multiple small areas of the lung.

It then hijacks the lungs’ own immune cells and uses them to spread across the lung over a period of many days or even weeks, like multiple wildfires spreading across a forest. As the infection slowly moves across the lung, it leaves damage in its wake and continuously fuels the fever, low blood pressure and damage to the kidneys, brain, heart and other organs in patients with COVID-19.

The severe complications of COVID-19 compared with other pneumonias might be related to the long course of disease rather than more severe disease, the study authors said.

This is the first study in which scientists analyzed immune cells from the lungs of COVID-19 pneumonia patients in a systematic manner and compared them to cells from patients with pneumonia from other viruses or bacteria.

Drug trial to treat newly discovered targets in COVID-19 pneumonia

As a result of the detailed analysis, researchers identified critical targets to treat severe SARS-CoV-2 pneumonia and lessen its damage.

The targets are the immune cells: macrophages and T cells. The study suggests macrophages – cells typically charged with protecting the lung – can be infected by SARS-CoV-2 and can contribute to spreading the infection through the lung.

Northwestern Medicine will test an experimental drug to treat these targets in COVID-19 pneumonia patients in a clinical trial early in 2021. The drug to be tested quiets the inflammatory response of these immune cells, thus enabling initiation of the repair process in the injured lung.

Aim to make COVID-19 like a bad cold

“Our goal is to make COVID-19 mild instead of severe, making it comparable to a bad cold,” said study co-senior author Dr. Scott Budinger, chief of pulmonary and critical care medicine at Northwestern University Feinberg School of Medicine and Northwestern Medicine.

“This effort truly represents a ‘moonshot’ in COVID-19 research,” said study co-senior author Dr. Richard Wunderink, professor of pulmonary and critical care medicine at Feinberg and medical director of Northwestern Medicine’s ICU.

COVID-19 unlikely to completely disappear

COVID-19, like influenza, is unlikely to ever go away, even if much of the population is vaccinated, said senior co-author Dr. Ben Singer, assistant professor of pulmonary and critical care medicine at Feinberg and a Northwestern Medicine physician.

“Already, researchers at Northwestern and elsewhere are anticipating mechanisms by which this RNA virus, which mutates quickly, will evade current vaccines,” Singer said. “This study will help us develop treatments to reduce the severity of COVID-19 in those who develop it.”

Mortality in COVID-19 patients on ventilators lower than regular pneumonia patients

The study also revealed why the mortality among patients on a ventilator for COVID-19 was lower than patients on a ventilator due to regular pneumonia, the study reports. An intense conflagration in the lungs (regular pneumonia) has a higher risk of death. Those with COVID-19 pneumonia are sick for a long time, but the inflammation in their lungs is not as severe as regular pneumonia.

“If patients with COVID-19 are carefully managed and the health care system isn’t overwhelmed, you can get them through it,” Budinger said. “These patients are very sick. It takes a really long time for them to get better. But If you have enough beds and health care providers, you can keep the mortality to 20%. When health systems are overwhelmed mortality rates double up to 40%.”

For the study, scientists performed a high-resolution analysis of the lung fluid of 86 COVID-19 patients on a ventilator and compared it with lung fluid from 256 patients on a ventilator who had other types of pneumonia. Because of the safety concerns, only a handful of groups around the world performed analysis of the immune response in the lungs of patients with COVID-19. As a result, important information about what was killing patients with severe COVID-19 was missing.

Northwestern scientists, studying pneumonia for years, poised for COVID lung research

The study performed at Northwestern Medicine is unique because Wunderink and colleagues have been studying pneumonia for years before the pandemic. As a result, when the COVID-19 pandemic hit, they were prepared to collect fluid from the lungs of these patients in a safe and systematic manner and compare it with fluid collected from other ICU patients with pneumonia collected before the pandemic. This research infrastructure allowed them to show that pneumonia in patients with COVID-19 is different from other pneumonia, and more importantly, how it is different.

Scientists took cells from patients’ lung fluid and looked at the RNA and the proteins those cells express, enabling them to identify how these immune cells drive inflammation.

“This level of resolution could never be achieved without directly sampling lung fluid,” said study co-senior author Dr. Alexander Misharin, an assistant professor of pulmonary and critical care medicine at Feinberg and a Northwestern Medicine physician.

The complex nature of the study, in which samples from patients were analyzed with the most sophisticated technologies available in Northwestern’s state-of-the art research labs, required the concerted effort of more than 100 researchers.


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).

Figure 1
Figure 1(A) Plain chest radiograph in a male patient with COVID-19 pneumonia referred for extracorporeal membrane oxygenation support. (B) CT images showing broadly symmetrical air space opacification with dependent dense parenchymal opacification and extensive ground-glass opacification with thickened interlobular and intralobular septa (the ‘crazy-paving’ pattern) in the non-dependent lung. Note that the airways are conspicuous against the ground-glass opacification but, importantly, taper normally (arrows) and have smooth walls. (C) CT performed 10 days later again showing widespread air space opacification but now with ‘varicose’ dilatation (non-tapering) of airways in the left upper lobe indicative of developing pulmonary fibrosis. (D) Classical ‘crazy-paving’ appearance in COVID-19. There is patchy but very extensive ground-glass opacification with superimposed fine thickening of interlobular and intralobular septa throughout both lungs. Relatively limited dense parenchymal opacification is present in the dependent lung bilaterally, likely to reflect variable combinations of the consolidated and atelectatic lung. (E) A patient with COVID-19-related acute respiratory distress syndrome (ARDS) with image section though the lower zones showing characteristic findings of ARDS with symmetrical air space opacification but with a gradient of increasing density from the ventral to the dorsal lung. (F) Image just below the carina demonstrating foci of non-dependent consolidation (arrows), conceivably denoting areas of organising pneumonia.
Figure 2
Figure 2CT in COVID-19 extubated survivor: a study performed during recovery (26 days after onset of COVID-19 pneumonia). Image section at the level of the carina demonstrating widespread ground-glass opacification and considerable architectural distortion. There is definite CT evidence of fibrosis—note the varicose dilatation (‘traction bronchiectasis’) of the anterior segmental bronchus in the right upper lobe (arrows).

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).

reference link :https://thorax.bmj.com/content/75/11/1009


More information: undefined undefined et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia, Nature (2021). DOI: 10.1038/s41586-020-03148-w

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