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

In a recent article published in The Lancet, researchers described the heterogeneous nature of long coronavirus disease (Long-COVID), focusing on 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. Additionally, the discussed clinical care, rehabilitation, and non-pharmacological strategies for people affected by post-COVID-19 dyspnea, a type 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

Background

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

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

Several published studies have also described, using a large dataset, the cluster of respiratory symptoms constituting PASC, for instance, erratic breathing, hyperventilation, and persistent 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 6,500 deaths per week. Also, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related hospital admissions have reduced drastically. Researchers have attributed these improvements, in part, to the increased availability of vaccines and treatments, such as IL-6 therapies. However, it remains critical to understand the long-term effects of COVID-19 on the respiratory system for studies focused on the post-COVID-19 landscape.

About the study

To this end, in the present study, researchers extensively searched databases, such as PubMed and CINAHL, using keywords like dysfunctional breathing, post-COVID fibrosis, fibrosis, and rehabilitation, to name a few.

Regarding post-COVID-19 conditions, they uncovered that the most prevalent symptoms were independent of the severity of acute illness. For instance, 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 an important cluster alongside fatigue and cognitive problems post-long COVID. In contrast, another study defined a positive correlation between the burden of symptoms and their severity with all the symptoms combined.

Extrapulmonary and pulmonary sequelae of COVID-19

In 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. In addition, they highlighted studies discussing all these features of long COVID to bring attention to the fact that these contribute to breathlessness and breathing pattern disorders, hence, need attention when devising therapeutic and rehabilitative strategies.

Here it is noteworthy that conventional measures of lung function cannot consistently predict breathlessness. It is a complex condition, which, if pathologically triggered, does not necessarily improve after treatment with bronchodilators. Thus, treatment approaches for breathlessness should be guided by an extensive assessment that covers routine spirometry.

The largest cohort study conducted among 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. In addition, it should cover Dyspnoea Profile questionnaires that explore the multidimensional components of breathlessness. Clinicians must also consider cardiopulmonary exercise testing and more complex investigations, such as magnetic resonance imaging (MRI) in cases of diagnostic uncertainties related to breathlessness

In post-COVID-19 conditions, cardiopulmonary exercise testing identified dysfunctional breathing or an erratic breathing pattern in 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 who had a full recovery after COVID-19.

Small cohort studies documented altered breathing patterns in ~20% of people admitted to hospitals with acute COVID-19, and those not admitted to hospital were referred to specialist follow-up clinics. They attributed aberrant breathing 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 Breathing Pattern Assessment Tool (BPAT) accessed all breathing pattern disorders with high sensitivity and specificity.

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

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

Research evaluating the effectiveness of non-pharmacological interventions is ongoing. However, respiratory and rehabilitation specialists should be at the core of integrated multidisciplinary teams offering support to patients with post-COVID-19 conditions. Most importantly, these teams should use therapeutic and rehabilitative strategies tailored to each patient’s symptom profiles and specific needs to ensure they give culturally appropriate, equitable access to the diverse set of affected populations.

Conclusions

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 might be related to the disease, its treatment, or both; notably, doctors administer such treatments in the intensive care unit (ICU) to complement life-support therapies.

In the future, studies should target 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 improve outcomes in this population.

Other future research priorities should 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 prevent, mitigate, and treat pulmonary fibrosis

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