Covid-19 can alter the functioning of different organs and, therefore, it has been considered a systemic disease. And, even when evaluating only the small portion of those infected who develop respiratory failure, it is possible to see that Sars-CoV-2 affects the lung in different ways.
In a study published on the platform medRxiv, still without peer review, researchers from the University of São Paulo (USP) and collaborators analyzed lung samples from 47 people who died from severe acute respiratory syndrome (SRAG) caused by the new coronavirus and identified two very distinct patterns of damage.
Five patients (10.6%) had what the authors called the “fibrotic phenotype”, characterized by thickening of the alveolar septum – the structure where gas exchange takes place. In other words, in these individuals, the normal lung tissue damaged by the virus was replaced by scar tissue (fibrosis), which made breathing difficult. In another ten patients (21.2%), classified as “thrombotic phenotype”, the lung tissue was practically normal. However, it was possible to notice signs of clots (thrombi) in small vessels. There is also a third group in which 32 patients (68.1%) who presented both phenotypes simultaneously were included.
The mean age of patients included in the study was 67.8 years, with a similar proportion between men and women. All had preexisting diseases, the most common being hypertension (55%) and obesity (36%). At the time of hospital admission, 66% had shortness of breath. Clinical complications during hospitalization include septic shock (62%), acute kidney failure (51%), and acute respiratory distress syndrome (45%).
Lung samples were obtained by minimally invasive autopsy and then fixed in formalin and paraffin. The blocks were then cut into slides with a thickness of 3 micrometers (µm, the equivalent of one millionth of a meter), which were stained and analyzed by microscopy and immunohistochemistry (a technique that involves the use of antibodies against target proteins, for example , collagen). Sars-CoV-2 RNA was identified in all samples by RT-PCR.
“We started from an assessment of the morphology of the lung to, subsequently, study the clinical history and radiological exams of these patients. And it was possible to notice, after the statistical analysis, that the data were correlated,” he tells FAPESP Agency pathologist Alexandre Fabro, professor at the Faculty of Medicine of Ribeirão Preto (FMRP-USP) and research coordinator. The work was supported by FAPESP through three projects (19/01517-3, 19/19591-5 and 20/13370-4).
In the article, the authors report that, in the days before death, patients with the fibrotic phenotype experienced a progressive decline in the oxygenation index – measured by the relationship between arterial oxygen partial pressure and the fraction of inspired oxygen (PaO2/FiO2) – in addition to loss of lung compliance (the organ’s ability to expand and retract during breathing) and increased production of collagen (one of the main components of fibrotic tissue) in the organ.
In the patients in the thrombotic group, an improvement in breathing patterns was reported in the days prior to death, as well as a high level of pulmonary compliance throughout the hospitalization period. “In some cases, the doctor reported that they came close to being discharged and then died,” says Fabro.
On the other hand, patients in this second group had an increase in the level of platelets (blood cells involved in clot formation) and in thrombus formation. Furthermore, it was observed that, at the time of hospital admission, they had higher levels of D-dimer – a protein considered a marker of thrombosis – than the mean of the patients analyzed.
“These findings reinforce that, despite the infection being the same, the response to the virus varies a lot, even among severe cases. And this may have clinical implications. These findings suggest that patients in each group need different treatments. , we show that the evolution of respiratory parameters [PaO2/FiO2] and the level of D-dimer on admission, for example, can help doctors differentiate these phenotypes,” says Fabro.
According to the researcher, the study portrays how the process of pulmonary fibrosis begins, which has left sequelae in many covid-19 survivors. “The current scientific question is how to treat and how to prevent this process from evolving and becoming permanent. There are some antifibrotic medications, but they have not yet been tested in the post-covid context”, he says.
The article COVID-19 Bimodal Clinical and Pathological Phenotypes can be read at www.medrxiv.org/content/10.1101/2021.09.03.21262841v1.