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Unraveling the complexity of ‘Long-COVID’ and its impact on respiratory

In a recent article published in The Lancet, researchers described the heterogeneous nature of long coronavirus disease (Long-COVID), specializing in its pulmonary and extrapulmonary sequelae. They reviewed pre-existing respiratory issues [e.g., lung fibrosis, asthma, and chronic obstructive pulmonary disease (COPD)] that possibly aggravate pulmonary sequelae of COVID-19 or affect its outcomes. Moreover, the discussed clinical care, rehabilitation, and non-pharmacological strategies for people affected by post-COVID-19 dyspnea, a form of persistent disabling breathlessness.

Study: Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation. Image Credit: Lightspring / Shutterstock


The post-acute sequelae of COVID 2019 (COVID-19), or PASC, systematically affects multiple organs, especially individuals with chronic lung diseases like thromboembolic disease.

Multiple previous studies have described worsening of respiratory systems during PASC resulting from destabilizing of pre-existing symptoms or COVID-19-related effects, independent of the severity of acute illness; nonetheless, the precise mechanisms governing these changes remain unclear. 

Several published studies have also described, using a big dataset, the cluster of respiratory symptoms constituting PASC, as an example, erratic respiratory, hyperventilation, and chronic cough. Perhaps, mechanisms like viral persistence, autoimmunity, and systemic inflammation, including activation of interferon (IFN) I and III and interleukin 6, contribute to the worsening of respiratory systems during PASC.

By March 2023, worldwide COVID-19 mortality had reduced from 101,600 deaths to six,500 deaths per week. Also, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related hospital admissions have reduced drastically. Researchers have attributed these improvements, partially, to the increased availability of vaccines and coverings, resembling IL-6 therapies. Nevertheless, it stays critical to grasp the long-term effects of COVID-19 on the respiratory system for studies focused on the post-COVID-19 landscape.

In regards to the study

To this end, in the current study, researchers extensively searched databases, resembling PubMed and CINAHL, using keywords like dysfunctional respiratory, post-COVID fibrosis, fibrosis, and rehabilitation, to call a couple of.

Regarding post-COVID-19 conditions, they uncovered that probably the most prevalent symptoms were independent of the severity of acute illness. As an illustration, understanding the precise mechanisms that underlie symptoms of acute lung injury, the dominant insult in severe acute COVID-19 patients requiring mechanical ventilation, in contrast to any post-COVID-19 sequelae, requires proper assessments and targeted interventions.

The team identified a meta-analysis that covered 54 studies and two medical records that discussed respiratory symptoms as a very important cluster alongside fatigue and cognitive problems post-long COVID. In contrast, one other study defined a positive correlation between the burden of symptoms and their severity with all of the symptoms combined.

Extrapulmonary and pulmonary sequelae of COVID-19

On this study, researchers discussed the incidence and mechanisms of pulmonary fibrosis, pulmonary emboli, and microvascular thrombi, COPD, reduced exercise tolerance, and frailty after COVID-19. As well as, they highlighted studies discussing all these features of long COVID to bring attention to the incontrovertible fact that these contribute to breathlessness and respiratory pattern disorders, hence, need attention when devising therapeutic and rehabilitative strategies.

Here it’s noteworthy that conventional measures of lung function cannot consistently predict breathlessness. It’s a fancy condition, which, if pathologically triggered, doesn’t necessarily improve after treatment with bronchodilators. Thus, treatment approaches for breathlessness needs to be guided by an intensive assessment that covers routine spirometry.

The most important cohort study conducted amongst 1,733 people discharged from the hospital after COVID-19 recovery performed lung function tests in 349 participants six months post-discharge. It was biased toward adults with clinical symptoms of pulmonary issues. As well as, it should cover Dyspnoea Profile questionnaires that explore the multidimensional components of breathlessness. Clinicians must also consider cardiopulmonary exercise testing and more complex investigations, resembling magnetic resonance imaging (MRI) in cases of diagnostic uncertainties related to breathlessness

In post-COVID-19 conditions, cardiopulmonary exercise testing identified dysfunctional respiratory or an erratic respiratory pattern within the absence of a respiratory limitation or impaired oxygen delivery and reported a lower peak oxygen uptake in individuals with persistent breathlessness compared with those that had a full recovery after COVID-19.

Small cohort studies documented altered respiratory patterns in ~20% of individuals admitted to hospitals with acute COVID-19, and people not admitted to hospital were referred to specialist follow-up clinics. They attributed aberrant respiratory patterns to changes in lung function and effects of sedation and mechanical ventilation on respiratory centers, etc.

The Nijmegen Questionnaire specifically accessed hyperventilation syndrome, and the Respiration Pattern Assessment Tool (BPAT) accessed all respiratory pattern disorders with high sensitivity and specificity.

Likewise, mechanistic similarities between COVID-19-related pneumonia and idiopathic pulmonary fibrosis (IPF), raise the potential for a possible global burden of long-term fibrosis arising post-COVID-19.

At present, rehabilitation programs for individuals with post-COVID-19 conditions are highly heterogeneous, but they need to cover aerobic and resistance exercises and spread awareness on symptom management. A recent systematic review showed they improved dyspnoea, physical function, and QoL. Nevertheless, patients needs to be chosen per symptom profiles, and further research should concentrate on high-quality evidence, particularly for people not admitted to hospital for COVID-19.

Research evaluating the effectiveness of non-pharmacological interventions is ongoing. Nevertheless, respiratory and rehabilitation specialists needs to be on the core of integrated multidisciplinary teams offering support to patients with post-COVID-19 conditions. Most significantly, these teams should use therapeutic and rehabilitative strategies tailored to every patient’s symptom profiles and specific needs to make sure they offer culturally appropriate, equitable access to the various set of affected populations.


Like other critical illnesses, severe COVID-19 leaves patients with long-term morbidity that affects their quality of life (QoL) and physical and mental well-being. As well-recognized, symptoms-like brain fog and cognitive deficits are common in patients with long COVID. These manifestations may be related to the disease, its treatment, or each; notably, doctors administer such treatments within the intensive care unit (ICU) to enrich life-support therapies.

In the longer term, studies should goal characterizing the long-term complications of pulmonary and extrapulmonary sequelae of COVID-19 in-depth, e.g., its mechanisms of causing insult. Further, these studies should determine optimal diagnostic and management approaches for this debilitating condition to enhance outcomes on this population.

Other future research priorities needs to be as follows:

i) identifying mechanisms governing reduced asthma and COPD control after COVID-19

ii) extrapulmonary complications that give rise to or worsen breathlessness after COVID-19

iii) diagnostic modality for detection of post-COVID-19 pulmonary vascular disease

iv) strategies to forestall, mitigate, and treat pulmonary fibrosis

v) mechanisms driving symptoms of breathlessness post-COVID-19 and rehabilitation or respiratory exercises that effectively reduce it.

Journal reference:

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