Respiratory Manifestations in COVID-19 and ‘Long Covid’: The Morbidity, Complications and Sequelae

It is being increasingly realized that the Covid-19 may have become the new reality associated with human existence...


The SARS-CoV-2 Virus and COVID-19
Following infection, the SARS-CoV-2 virus becomes an intracellular entity. The intracellular replication, ensuing cellular damage, and involvement of various cells in respiratory system,

Clinical Spectrum of Acute Covid-19 Illness
COVID-19 is primarily a respiratory disease presenting with a broad spectrum of respiratory tract involvement ranging from mild upper airway affliction to progressive life-threatening viral pneumonia. Coming into contact with the mucous membranes lining nose, mouth, and occasionally eyes, the SARS-CoV-2 virus enters the host cells, multiplies intracellularly and the released virions infect other cells. As it attacks the cells, it travels down the airways, from upper to lower respiratory tracts, finally infecting the alveoli and manifesting as pneumonia. In general, a significant number of those infected with the SARS-CoV-2 virus are asymptomatic, and as documented in a recent systematic review, at least one-third of SARS-CoV-2 infections in people who are exposed remain asymptomatic [2]. The study included serologic surveys from more than 365,000 people in England and more than 61,000 in Spain. When analysed, a similar proportion of asymptomatic cases 32.4% in England and 33% in Spain was noted. On being  In general, older adults and people who have concurrent health conditions like heart disease, cancer, obesity, and diabetes are prone to develop serious manifestations. The clinical manifestations of asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, etc. can suffer with worsening of respiratory conditions. The symptoms may be mild, such as cough, shortness of breath and fever, to severe and critical disease, including respiratory failure, shock, and multi-organ failure (MOF). In general, most people who develop clinical COVID-19, manifest mild to moderate symptoms [4]. They may have a dry cough or sore throat, whereas a minority of them goes on to develop pneumonia, with ground-glass Further, about 20-30% of critically ill patients can develop clots in the lungs, heart, brain, and legs. There may occur disseminated intravascular coagulation (DIC).

The Phases of SARS-CoV-2 Lung Infection
When the SARS-CoV-2 infection starts spreading into the respiratory tract and lungs, it triggers various symptoms and complications, and may be associated with constant coughing often without phlegm, and pain in chest. The pathophysiological processes underlying COVID-19 illness may or may not show clinical features of earlier or later phases.
Phase 1: Cell Invasion and Viral Replication: The SARS-CoV-2 virus gains entry via ACE2 receptors, which are present on goblet (secretory) cells and on ciliated (hairy) cells in the nose, and through ACE2 receptors in the mouth and tongue. Phase 2: Viral Replication and Immune Response: As part of the defensive immune response, the lymphocytes begin to produce the IgM-type antibodies at first and later the longer-term specific neutralizing antibodies (the IgG type). In a German study, about 50% of the participants showed circulating IgM or IgG antibodies by day 7, and by day 14 all of them had developed antibodies [5].
Here, it is noteworthy that the antibodies titre may not predict the clinical course of the disease [6].

Phase 3: Lung Inflammation and Pneumonia: Approximately
13.8% of people with COVID-19 suffer with dyspnoea and severe disease and require hospitalization. Out of these, three-fourth patients may have evidence of bilateral pneumonia [7]. The pneumonia in COVID-19 manifests as consolidation and collapse of lung regions. There is reduced surfactant in the alveoli due to destruction of pneumocytes by the virus, infiltration by white blood cells, such as neutrophils and macrophages, as part of the immune response, and oedema due to injury to blood vessels and leakage in response to proinflammatory factors released by the inflammatory cells. The fluid accumulation compresses the alveoli from outside and in combination with lack of surfactant, leads to their collapse.
As a result, the surface area in the lung for gaseous exchange is reduced leading to hypoxia and dyspnea.
Phase 4: ARDS, The Cytokine Storm, and MOF: The critical illness in COVID-19, frequently develops in a period of about 10 days, though it can occur suddenly in a small proportion of those with mild or moderate disease. There occurs formation of fibrin clots in the alveoli and fibrin-platelet microthrombi in the small blood vessels in the lungs affecting gaseous exchange at the alveolar level. The cytokines, such as IL1, IL6, and TNFα damage and dilate the vessel walls, making them more permeable and may lead to cardiovascular shock. The angiotensin converting enzyme 1 (ACE1), in response to infection, leads to excess availability of angiotensin-2 from angiotensin-1, resulting in pulmonary vasoconstriction and leaky blood vessels.

The Recovery or Convalescence Phase
The usual recovery time for mild COVID-19 is about two weeks and three to six weeks for severe disease. However, the recovery is variable and depends on Constitutional factors such as patient's age and pre-existing comorbidities in addition to the severity of the disease. The studies in the U.S. show that only 39% of those who had been hospitalized reported a return to baseline health by 14-21 days after diagnosis [8]. Similar findings have been reported from the European studies. In a study of 143 patients hospitalized for COVID-19, only 13% were symptom-free after a mean period of 60 days following disease onset [9]. The remaining 87% patients reported persistence of symptoms such as, fatigue, cough, dyspnoea, joint pains, and chest pain following discharge from the hospital, with over 55% patients continuing to experience three or more symptoms. As measured by the EuroQol visual analog scale, a decline in quality of life (QOL) as was noted in about 44% patients.
The pneumonia-like manifestations may persist for several weeks in immunosuppressed patients. Even the patients with milder infection can suffer with prolonged symptoms. A recent survey showed that about 65% of those infected returned to baseline health by 14-21 days after diagnosis [10]. The persisting symptoms with delayed recovery include cough (43%), fatigue (35%) and rarely fever and chills in those with prior mild infection. which are rich in ACE2 receptors [11]. Other contributory factors for loss of surfactant are environmental factors, like air pollutants and smoke, and a hyperactive immune response. The direct damage of the virus-infected cells as well as cytokine hyper-response reduces the availability of surfactant in the alveoli leading to their collapse at the expiratory phase, manifesting as considerable stress on respiratory muscles at subsequent inspiratory phase evidenced as dyspnoea and hypercapnia [12].

Inter-Relationship of Pathophysiology and Clinical Spectrum
The respiratory involvement in COVID-19 may be mild to moderate to severe ( Figure 2). Depending on the extent of underlying pathophysiology in the mild disease there are infected AT I and II cells and presence of inflammatory cells and secretion of cytokines leading to reduced surfactant, vasodilatation, and reduced gaseous exchange leading to hypercapnia and hypoxia. Whereas, in a more severe disease, there occur increased interstitial fluid, widespread alveolar collapse, accumulation of protein and cellular debris and fibrosis leading to severely compromised gaseous exchange and inability to maintain tissue oxygenation in various organs. To prevent redundant blood circulation through the collapsed alveoli, there occurs constriction of blood vessels supplying these alveoli.
Depending on the severity of damage, the respiratory muscles work to handle the respiratory stress, but eventually tire, leaving the gaseous exchange compromised. In COVID-19, not only the respiratory cells richly endowed by ACE2 receptors are affected, the lung vasculature having ACE2 receptors is also infected and damaged impairing the compensatory blood redistribution from collapsed alveoli, resulting in significant redundant deoxygenated blood flow [13]. Further, the associated hypercoagulability with COVID-19, further hampers gaseous exchange in lungs and oxygen supply to various tissues and vital organs [14].

Host Immune System and SARS-CoV2 Infection
The viral genome typically consists of 6 open reading frames (ORFs), of which the ORF1a and ORF1b produce polypeptides, pp1a and pp1b, respectively, which form non-structural proteins

The Long-Term Lung Damage in COVID-19
As COVID-19 is a relatively new disease, the long-term effects of COVID-19 in those who recover, are still not known, but various recent observational case and cohort studies continue to provide data. Based on initial case studies from those with moderate-severe disease and those suffered with pneumonia, the initial damage to the lungs can persist leading to decreased lung function and impact the activities of daily living (ADL). Pulmonary fibrosis is one of the major complications of severe COVID-19 and even those fully recovered symptomatic patients, may have some long-term lingering effects persisting for several months. Depending on the severity of respiratory inflammation and damage, presence of comorbidities, duration of injury and ill-defined genetic factors, the progressive fibrosis may lead to compression of lung tissue and damage of pulmonary microvasculature. The chronic inflammation leads to epithelial damage and fibroblast activation, being the major causative factor for pulmonary fibrosis. In addition, the lope-sided regeneration and the presence of fibroblasts and the excessive deposition of hyaline, collagen, and other extracellular matrix proteins lead to alveolar damage and scarring in lungs. In case of about 23% of the recovered SARS patients, there was seen reduced lung exercise capacity and pulmonary function a year after infection [17]. The COVID-19 patients with moderate/severe symptoms are likely to have a similar level of long-term reduction in lung function.
Thus, depending on the severity of the disease, extensive and longlasting damage to the lungs can occur, which may persist well after the infection.  [19]. Autopsy findings reveal extensive lung damage, with firm, heavy and rubbery lungs with bilateral haemorrhagic edema, pleural effusion as well as signs of extensive shock characterized by variegated appearance of the liver and kidneys [20]. There is extensive endothelial injury associated with immune cell infiltration including T-lymphocytes and megakaryocytes.

Autopsy Findings in Lungs of COVID-19 Patients
In the pulmonary vessels there is widespread thrombosis with microangiopathy and alveolar capillary microthrombi in addition to neovascularization and angiogenesis. The SARS-CoV-2 genome has been found in respiratory cells, cells lining the blood vessels, and the syncytia, in these patients. These histopathologic changes are pathognomonic of COVID-19 pneumonia and the persistence of the abnormal cells and the virus-infected cells may be linked with continuance of ongoing viral replication and organ damage, and persistence of long Covid symptoms in those recovered from the disease.

Clinical Presentation of COVID-19
Depending on the severity of damage, the respiratory involvement may appear as asymptomatic, mild to moderate respiratory illness, severe bronchopneumonia, or acute respiratory distress syndrome (ARDS).

Asymptomatic COVID-19 Patients
A large proportion of healthy individuals, over 40%, found positive for SARS-CoV-2, do not exhibit obviously significant symptoms. They are, however, able to transmit the disease. The majority of these asymptomatic patients are from younger age group. But the asymptomatic patients not showing any signs of lung damage, may suffer subtle changes, potentially predisposing them for complications in future. In these asymptomatic COVID-19 patients, there have been shown lung abnormalities on chest CT scans. This is exemplified by the outbreak on Diamond Princess cruise ship, at beginning of the COVID-19 pandemic in February 2020, where 73% of those positive were asymptomatic, of which 54% showed lung opacities (ground-glass opacities; GGO) indicating alveolar edema, inflammation, and fibrosis in the lungs.
This may be an age-dependent effect and may occur to lesser extent in younger patients.

Symptomatic COVID-19 Patients
In most people, COVID-19 leads to very mild, mild, or moderate clinical manifestations. The variance in clinical presentation may be attributed to amount of viral load, age, pre-existing health conditions, genetic constitution, ethnicity/demographics, lifestyle, and environmental factors. The majority of pathological and imaging data come from hospitalized COVID-19 patients rather than non-severe symptomatic patients who may not visit a medical facility for diagnostic workup or treatment [21].

Severe COVID-19 Illness and Pneumonias
The patients with severe disease manifesting as pneumonia and ARDS, exhibit extensive alveolar damage, capillary congestion, necrosis of AT I and II pneumocytes, and interstitial and alveolar edema. Simultaneously, there is AT II pneumocyte hyperplasia, squamous metaplasia with atypia and platelet-fibrin thrombi in small arterial vessels, and increased D-dimer levels. As these changes hinder the pulmonary function, and the higher the impairment, the higher is disease severity and mortality. In severe disease, micro-thrombosis and associated ischemic events are common and the ARDS occurs due to the compromised gaseous exchange and the vascular insult to the alveolar architecture. The COVID-19 pneumonia presents with severe hypoxemia and altered respiratory mechanics [22]. The alveolar infiltration and the vascular insult are common factors responsible for the respiratory distress [23]. Accompanied with by hyper-activated coagulation cascade, with widespread micro-and macro-thromboses in the lung and in other organs and elevated serum D-dimer levels, this is associated with adverse outcomes. Simultaneously, the endothelial damage disrupts pulmonary vaso-regulation, promotes ventilationperfusion mismatch, and promotes thrombogenesis. In the lungs, the ARDS directly impacts the alveoli and other tissues leading to extensive damage with scarring and fibrosis.

COVID-19 Related ARDS and Respiratory Failure
With the progression of COVID-19 pneumonia, increasing number of alveoli become affected and filled with exudative fluid clinically manifesting as shortness of breath. Further progression leads to ARDS, a form of lung failure requiring respiratory support to improve gaseous exchange. The ARDS is a serious and potentially fatal complication, and in the survivors may have lasting symptoms due to pulmonary fibrosis and scarring. It is helpful to assess and categorize the COVID-19 patients as per symptoms and signs of the respiratory failure, as different ventilatory approaches are needed, depending on the underlying pathology [24]. In general, the severe COVID-19 illness presents with two types of respiratory syndromes, the type 1 without ARDS, and type 2 with ARDS [25].

CT Imaging During Acute COVID-19 Illness
The computed tomography (CT) is an important tool for early diagnosis and monitoring of the affliction of lungs in COVID-19.
Studies have shown a higher frequency of multifocal, bilateral, peripheral, and nonspecific distribution of GGO with sub-segmental patchy consolidations in SARS-CoV2-infected individuals compared to controls [26]. Another study highlighted that more than 50% of the SARS-CoV2-infected patients have significant ground-glass and consolidative opacities on chest CT scans [27]. The chest CT scans can be helpful for the diagnosis as well as for monitoring the prognosis. There are peripheral lung ground-glass opacities seen in CT imaging of the chest. Peripheral pulmonary vascular changes are less well characterized. The effects of SARS-CoV-2 infection on the alveolar architecture manifesting as GGOs depend on the severity of the infection and its effects on the immune system, and imply partial collapse of alveoli, partial filling of air space, and interstitial thickening. The severity of the disease is related to the extent of lesions on initial chest CT scans and the abnormalities on CT scans have been related to the disease course [28]. In the course of the disease, the GGO occurs from the beginning of COVID-19 and tends to decrease after 14 days, whereas consolidations appear around day 9, followed by fibrosis after 14 days.  Whereas the atypical findings are isolated segmental consolidation, discrete small centrilobular nodules, lung cavitations and bilateral smooth interlobular septal thickening with pleural effusion [29].
In general, at time of initial presentation 88% patients show GGOs with bilateral involvement, 80 % show posterior distribution, 79 % multi-lobar involvement, and 76% have peripheral distribution, whereas only 32% have consolidation on initial presentation [30].

CT Imaging for The Long-Term Follow Up
A long-term study highlights that in the SARS infection, the fibrosis-like findings on CT in recovering patients diminish over time [31]. It is expected that similar prognosis may be possible in convalescent COVID-19 patients [32]. In the Post-COVID-19 patients, the follow up CT scans may reveal probable lifetime lung damage in about one-third of the patients. About 20-30% of patients who have suffered mild disease may have persisting diminished lung function and exercise capacity, whereas in 55% of patients with critical disease may continue to have the lung function impairment three months following hospital discharge. Further, there has been shown a definite correlation between initial chest CT scan involvement and impaired PFT [33]. The lung function, exercise capacity, persistent radiologic abnormalities, and quality of life data have been related to radiologic lung involvement at admission. In fact, the later radiological and functional sequelae have been related to initial lung involvement on CT scans. On chest CT, the main abnormalities are ground glass opacities at hospital admission and fibrosis 3 months later, and the patients remained largely disabled 3 months after discharge in terms of lung function, exercise capacity, and QoL. Radiologic impairment may improve following recovery, but normalization is seen only in a small number of patients. In general, about 12%-23% COVID-19 hospitalized patients show restrictive pattern on PFT one month after discharge [33]. In the study, the exercise capacity was still poor 3 months after ICU discharge and decreased QoL was associated with severity parameters during ICU admission and chest CT abnormalities on admission.

Covid Follow Up: Links with Neoplastic Lesions
The SARS-CoV-2 Infection causes molecular changes and recruitment of inflammatory cytokines/chemokines in lung tissue microenvironment [16]. As well known, several pro-inflammatory

The Covid-19 Delayed and Long-Term Effects
There is a growing evidence of persisting multisystem effects of COVID-19, indicating substantial continuing morbidity after resolution of the infection [9]. While most people recover quickly and completely from the virus, persistent manifestations, especially respiratory symptoms are frequently seen and reports from cohort studies suggest that one in three people may not fully recover several weeks after initial illness and a smaller but still substantial proportion continue to have symptoms and disabilities that persist for months [38]. Further, the long-term effects of COVID-19 are seen in the younger population also, though the risk of 'long Covid' increases with age. People who suffer with severe form of the disease, experience long-term inflammation and damage in lungs, heart, immune system, brain, the vasculature, and other organs.
These long-term effects may last for months and years. The 'long Covid' is not contagious and results due to the body's response to the virus infection continuing beyond the initial illness. Most Covid-19 patients recover within few weeks without significant complications. In others, often the persisting symptoms may go unnoticed, as they are vague and nonspecific. But some patients, even those who had mild versions of the disease, including the younger people afflicted with mild or asymptomatic disease and those who did not suffer with serious disease or require hospitalization, may continue to experience symptoms after their initial recovery [39].
These patients have been described as long haulers and the clinical condition due to persisting or continuing symptoms has been called post-COVID-19 syndrome or 'long COVID-19'. The clinical condition encompasses a delayed convalescence or recovery, persistence of symptoms, and emergence of symptoms related to the organs involved and damaged, and incapacitating complications and sequelae ( Figure 5).
The long-haul COVID patients carry their symptoms well beyond the normal course of recovery lasting for weeks and months or longer. Further, of various facets of the disease, the long-Covid syndrome may in due course prove to be the most difficult to deal with. These symptoms are often varied and relatively common and may defy a COVID-related diagnosis. Several patients who are expected to recover, continue to suffer for a variable period of weeks and months with various general symptoms such as breathlessness on exertion, fatigue, dizziness, memory lapses and other cognitive issues, digestive disorders, erratic heart rates, headaches, fluctuating blood pressure, and muscular and joint pains, which are often considered by the patient himself and family members as related to the weakness developed following the disease. These patients report weeks and months-long symptoms affecting lungs, heart and other organs and given the multitude of COVID-19 cases worldwide, the prevalence of 'long Covid' is expected to be substantial and likely to increase with the recurrent outbreaks of the disease. Furthermore, the 'long Covid' with debilitating and prolonged illness may have profound impact on health of people, their social life and livelihoods, and the economy. replication during acute illness. The syndrome has vastly emerged from self-reporting but is a real clinical entity with the chronic health manifestations, and characterised by symptoms of fatigue, headache, dyspnoea, and anosmia and likely to increase with age, higher BMI, and female sex. Further, as deciphered from various studies, experiencing more than five symptoms during the first week of illness is associated with 'long-Covid' [40].
In a study with online survey data involving over 4,000 Covid-19 patients, about 13.3% of all ages suffered with the symptoms lasting >28 days, whereas 10% of those aged 18-49 years had the related symptoms 4 weeks after acquiring the infection. Further, 4.5% patients of all age-groups suffered with the symptoms for more than 8 weeks, and 2.3% of all ages for more than 12 weeks.
The study was conducted by health-science firm Zoe Global Limited in conjunction with Biomedical Research Centre based at GSTT NHS Foundation Trust and supported by the UK Research and Innovation [41]. The analysis and inference derived from similar studies could be used to identifying individuals with 'Long-Covid' may help to reduce long-term complications and sequelae and planning health education, guidance, and rehabilitation services [42].

Diagnosis and Manifestations of 'Long Covid'
As a matter of fact, medical advice should be routinely sought for all the patients having delayed recovery and persistence or emergence of symptoms. There is a multitude of adverse physical and mental health effects due to 'long Covid' and these afflictions may last for an indefinite period. According to a study published in the Lancet, which included 1,733 people tested positive for Covid-19 and followed for 4 months, documented that more than 75% of the people who were hospitalized for COVID -19, continued to suffer with at least one symptom for 6 months after recovery.
Further, it was noted that about 76% of them experienced lingering symptoms of COVID-19 long after being cured of the illness (17). In another recent study, Carvalho-Schneider et al. followed-up of 150 adults with only mild to moderate COVID cases for two-month and found that two thirds of them were still experiencing symptoms, most commonly shortness of breath, loss of smell and taste, and/ or asthenia and fatigue [43]. Another study by Italian researchers, covering 143 COVID patients who had been discharged from the hospital, found that only about one in eight was completely free of symptoms 60 days from the beginnings of the illness [44]. The King's College London study, one of the largest surveys so far, reported that around 10 percent of patients had persistent symptoms for one month, with 1.5 to 2 percent having sustained symptoms at three months. Further, the study documented that long COVID was twice as common in women as men, and the older people, and those with more than five symptoms during their first week of illness were more likely to develop 'long Covid' [41].

Management Of 'Long Covid' Syndrome
The

Activity Guidance and Occupational Rehabilitation
In general, all COVID-19 patients should be risk stratified following recovery before recommending a return to physical activity, which should be gradual, individualised, and based on subjective tolerance of the activity (Figure 7). It is noteworthy that apart from the severe cases and elderly, even those with mild disease and a proportion of people from all age groups may experience a prolonged recovery [47]. In general, a return to physical activity should be after at least seven days period free of symptoms, followed by two weeks of minimal exertion. As a rule, those with ongoing symptoms or history of severe covid-19 need cardio-pulmonary assessment before advising return to physical activity [48]. In practice, thus, for those with mild symptoms during the Covid illness and asymptomatic during convalescence period, there should be a phased return to physical activity with at least a week in between every phase. The phases have been outlined as - Usually, a light intensity activity is advised for initial two weeks. The

Post-Covid Pulmonary Damage and Fallouts
The post-Covid pulmonary damage and fibrosis is characterized These patients are known as the 'long-haulers' and the persisting affliction as 'long Covid' or 'Post-Acute Sequelae of SARS-CoV-2 infection (PASC)'. In general, thus, the diagnosis of the 'Long Covid' or 'Long haulers" should be entertained for various symptoms and signs that linger well beyond the period of convalescence in COVID-19 [50]. The most common of persisting signs and symptoms of post-Covid-19 illness related to respiratory system include extreme tiredness (fatigue) and giddiness, chest pain and tightness, palpitations, shortness of breath and Cough.
The underlying disease state may vary from mild restrictive lung function to decompensated persistent chronic lung disease ( Figure   8).

Pulmonary Sequelae and Therapeutic Options
Presently, there is no proven and fully documented effective therapeutic modalities for the treatment of post-inflammatory pulmonary fibrosis following COVID-19. But, as the disorder bears similarities in its pathogenesis with idiopathic pulmonary fibrosis including cytokine profiles, it has been suggested that the drugs useful in the treatment of IPF could be also beneficial for symptomatic and supportive therapy for COVID-19 patients. The most important factor in limiting pulmonary fibrosis is timely antiviral treatment and elimination of the causative agent.
Though, currently, there is no fully substantiated therapeutic modality for the treatment of post-inflammatory pulmonary fibrosis after COVID-19, some therapies may be considered [51]. Tocilizumab, the monoclonal antibody against IL-6, has been claimed to have a beneficial effect on coronavirus patients with severe lung damage and elevated interleukin six levels. As the final option, lung transplantation has been considered and tried [52,53].

The 'Long Covid' Challenges and Solutions
The SARS-CoV-2 virus uses ACE2 receptors to cause can be tackled by harnessing of existing healthcare infrastructure, development of scalable healthcare models and integration across disciplines with a combination of pharmacological and nonpharmacological modalities for improved physical and mental health outcomes for COVID-19 survivors in the long-run [54].