Long Covid Part 7 – Long Covid
Dr Graham Exelby Updated February 2023
What is Long COVID?
While the acute impacts of COVID-19 were the initial focus of concern, it is becoming clear that in the wake of COVID- 19, many patients (up to 20% in some studies) are developing chronic symptoms that have been called Long-COVID. Some of the symptoms and signs include those of postural tachycardia syndrome (POTS).(14)
Nearly 20% of COVID-19 patients develop serious complications with an overall mortality worldwide is around 6.4%, linked to the presence of the so-called “cytokine storm” induced by the virus, where an excessive production of pro-inflammatory cytokines, especially Interleukin-6 (IL-6) and Tissue Necrosis Factor a (TNFa ) leads to widespread tissue damage resulting in multi-organ failure and death.
The severe form of COVID-19 is marked by an abnormal and exacerbated immunological host response favouring to a poor outcome in a significant number of patients, especially those with obesity, diabetes, hypertension, and atherosclerosis. The chronic inflammatory process found in these cardio-metabolic co-morbidities is marked by the over-expression of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumoral necrosis factor-alpha (TNF-α), which are products of the Toll-Like receptors 4 (TLR4) pathway.
The SARS-CoV-2 initially infects cells in the upper respiratory tract and, in some patients, spread very quickly, needing respiratory support and systemically, causing collateral damage in tissues. We hypothesise that this happens because the SARS-CoV-2 spike protein interacts strongly with TLR4, causing an intensely exacerbated immune response in the host's lungs, culminating with the cytokine storm, accumulating secretions and hindering blood oxygenation, along with the immune system attacks the body, leading to multiple organ failure.
There is increasing DNA evidence from our studies that multiple mutations in the Toll-Like Receptors (especially “first responders” TLR2 and TLR4) play a large role in the individual immune response, and associated with “downstream” mutations can create a domino effect responsible for the individual problems being caused by Covid. These are common and look to provide directions for management in patients not responding to the first line mast cell blockade. The TLR2 and TLR4 mutations are currently being investigated. The TLR4 mutations may explain the effectiveness of Low Dose Naltrexone in chronic fatigue and cognitive impairment.
The TLR4 mutations appear to be potentially one of the critical “molecular connections” associated with the abnormally low “biomarkers” used to measure the inflammatory responses seen in many Covid patients. These patients have often “fallen below the radar” while in fact have an impaired immune response. Nigella Sativa (black cumin or black seed oil) is currently being looked at in the management of this with its role in modulating the TLR4 response.
Lungs show marked alveolar inflammatory infiltrate, diffuse alveolar damage, formation of hyaline membranes, diffuse thickening of the alveolar wall with consequent fibrosis.
Encephalopathy, with increased Alzheimers and Parkinsons disease can occur as the inflammatory response combines with amyloid and is deposited in the brain, neurodegenerative damage in infants when COVID is contracted by the mother in pregnancy, pulmonary emboli and the characteristic continuing microemboli formation, arterial thrombosis, disseminated intravascular coagulation (DIC), increased stroke, myocardial infarction, vasculitis, myocarditis, pericarditis septic shock and multi-organ failure and others can occur.(5)(6)
The combination of hyper- inflammation, coagulopathy, and low platelet counts places patients with cytokine storm at high risk for spontaneous haemorrhage, a significant issue when considering medication to treat the embolic cascade that is pathognomonic for COVID.(18)
Nearly all patients with cytokine storm are febrile, and the fever may be high grade in severe cases. In addition, patients may have fatigue, anorexia, headache, rash, diarrhoea, arthralgia, myalgia, and neuropsychiatric findings. These symptoms may be due directly to cytokine- induced tissue damage or acute-phase physiological changes or may result from immune- cell–mediated responses.(18)
Immune-mediated damage due to COVID-19 occurs in various organs. Lungs of patients of COVID-19 show marked alveolar inflammatory cell infiltrate, diffuse alveolar damage, formation of hyaline membranes, and diffuse thickening of the alveolar wall. The spleen shows atrophy, and lymph nodes show necrosis with reduction of lymphocytes in lymphoid organs. Older age, male gender, underlying co-morbidities, and secondary infections are reportedly associated with high fatality.(6)
Patient advocacy groups surveyed many post-COVID patients and reported the development of new symptoms: neurological (67%), pulmonary (53%), gastro-intestinal (51%), cardiac (49%), sensory (27%) and 34% reported new autonomic dysfunction and 18% autoimmune disease.(29) These mirror the results from Blitshteyn.(26) Nearly a third of the patients in this case series had confirmed mild abnormalities on cardiac or pulmonary testing, and 20% had abnormal markers of autoimmunity or inflammation. Many respondents in the study reported no pre-existing conditions and 90% had not fully recovered 40 days after the onset of their illness.
Long COVID affects survivors of COVID-19 at all disease severity, including mild to moderate cases and younger adults who did not require respiratory support or hospitalisation. Of major concern, it also targets children, including those who had asymptomatic COVID-19, resulting in symptoms such as dyspnoea, fatigue, myalgia, cognitive impairments, gastrointestinal symptoms, headache, palpitations, and chest pain that last for at least 6 months.(4)
Reinfection with COVID-19 produced increasing health risks and researchers saw worse health effects during active infection, but some symptoms lasted as long as 6 months, suggesting a direct link between reinfection and long COVID. The risks remained whether or not people were fully vaccinated.
The risk of cardiovascular disease, for example, increased after one infection, but doubled in people who had two infections, and tripled in those who had been infected thrice. The numbers translate into 50 extra cases of heart disease per 1,000 people who've had COVID-19 twice. They also found similar cumulative risks with each reinfection for pulmonary disease, clotting and blood disorders, neurological disease, mental health problems, kidney disease, musculoskeletal disease, fatigue, and so on. These problems occur most frequently in the first month after infection, but can emerge up to six months later.(107)
What is Long-COVID (PACS)
Transition Phase: Symptoms potentially associated with acute COVID-19: symptoms up to 4–5 week
Phase 1: Acute post-COVID symptoms: symptoms from week 5 to week 12
Phase 2: Long post-COVID symptoms: symptoms from week 12 to week 24
Phase 3:Persistent post-COVID symptoms: symptoms lasting more than 24 weeks(17)
Two year studies by Huang et al(3) found that 2 years after hospitalization for COVID-19, 55% of survivors have at least 1 sequelae symptom, down from 68% at 6 months, although most patients improved in physical and mental health. They confirmed fatigue was the most frequently reported symptom throughout the 2 years, regardless of initial disease severity.
This fatigue severity fluctuated or relapsed over time. Muscle weakness and sleep difficulties were the other most commonly reported symptomatic sequelae throughout the 2-year follow-up, regardless of disease severity. Long COVID symptoms at the 2-year follow-up were related to decreased health-related quality of life and exercise capacity, psychological abnormality, and increased use of health care after discharge.
Dyspnoea (shortness of breath) gradually decreased from 26% at 6 months to 14% at 2 years.(3)
Chest pain has been reported in up to 22% of COVID-19 patients two months after discharge from hospital. It was however found that the proportion of COVID-19 survivors with restrictive ventilatory impairment increased during the late recovery period. Previous studies of SARS and Middle East respiratory syndrome described the fibrotic abnormalities during convalescence, and this sign could also be observed months or even years after COVID-19 infection, indicating that pulmonary fibrosis after COVID-19 might be a long-term outcome.(3)
Quality of Life continued to improve in almost all areas over the 2 year study, especially in terms of anxiety or depression, with the proportion of participants reporting symptoms of anxiety or depression dropping significantly from 40% post-Covid, 23% at 6 months to 12% at 2 years. The proportion of individuals with reduced walking distance ability declined continuously to 8% at 2 years.(3)
A UK study showed organ impairment in 201 low-risk patients, (mean age 44 years, 71% female,) with persisting symptoms (mainly fatigue, muscle pain and headache) as least 4 weeks after recovery from acute Covid.
70% showed MRI changes in at least 1 organ:
heart (26% -myocarditis 19% and systolic dysfunction 9%),
lungs 11% (reduced vital capacity),
kidney 4% (inflammation),
liver 28% (12% inflammation, 10% hepatomegaly),
pancreas 40% (15% inflammation),
spleen 4% (splenomegaly.)(17)
Other symptoms found included the typical fatigue, “brain fog,” gastrointestinal issues (e.g., abdominal pain, bloating, gastroparesis, and nausea) which persist in 30% of patients(17), chronic pain (e.g., headache, temporomandibular joint disorder, ﬁbromyalgia), and sleep abnormalities.
Co-morbidities included Ehlers-Danlos syndrome, mast-cell activation syndrome, sensory neuropathy, or autoimmune disorders (e.g., lupus and Sjögren syndrome).(6)
Even after mild Covid, there is around 35% increased risk of autoimmune disease and diabetes, even in the young adults.
Table 1: The Primary Symptoms- (Huang et al)(23)
Fatigue, muscle weakness, and sleep difficulties were the most common symptomatic sequelae.
Other symptoms include memory loss, gastrointestinal symptoms and shortness of breath.
Autonomic dysfunction is very common and the development of Postural Autonomic Tachycardia Syndrome (POTS) is not uncommon.
Symptoms of anxiety or depression decreased from 23% at 6 months to 12% at 2 years
Compared with controls, COVID-19 survivors at 2 years had more prevalent symptoms, more problems with pain or discomfort, and anxiety and depression.(23)
Source: Huang L, Li X, Gu X, Zhang H, Ren L, Guo L, Liu M, Wang Y, Cui D, Wang Y, Zhang X, Shang L, Zhong J, Wang X, Wang J, Cao B. Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study. Lancet Respir Med. 2022 doi: 10.1016/S2213-2600(22)00126-6. PMID: 3556805
Moderate to severe sleep disturbances and severe fatigue affect up to 40% of patients with long COVID, More than two thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue. In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia.
Hira et al (271)in a Canadian study in December 2022, described over 70% of Long-COVID have cardiovascular autonomic disorder, 30% of these with POTS (Postural Orthostatic Tachycardia Syndrome)
Larsen et al (29) examined multiple reports and case studies of post- COVID syndrome (Table 3) and have proposed possible mechanisms for the changes. Their studies confirm the widespread nature of the post-COVID autonomic dysfunction. Among the most common symptoms were those often reported by patients with autonomic disorders including fatigue, tachycardia, lightheadedness, difficulty concentrating (“brain fog”), insomnia, headache, gastrointestinal upset, and nausea. This area is examined more extensively in Part 7 “Long Covid POTS and Autonomic Dysfunction.”
Table 3: Symptoms commonly reported in post-acute COVID syndrome, association with autonomic complications (a)
Cognitive impairment (brain fog)
Dyspnoea (shortness of breath)
Labile blood pressure(a)
GI symptoms eg abdominal pain, bloating(a)
Symptoms of Mast Cell Activation Syndrome (eg pruritis, urticaria, flushing, angioedema, wheezing, GI symptoms, tachycardia, labile BP)
(a) Symptoms of Autonomic Dysfunction
Source: Larsen,N.et al, Preparing for the long-haul: Autonomic complications of COVID-19 (29)
Figure 1 : Summary of post-acute COVID-19 by time and organ
Source: Euro Heart J Suppl, Vol 23, Issue Supplement E, October 2021. https://doi.ord/10.1093/eurheartj/suab080
The overwhelming pathology in COVID-19 is inflammation and thromboembolism. The incidence of pulmonary embolism in ICU patients is high at 26%, and non-ICU hospitalized is 17%.(163) In ICU patients, 30-70% develop blood clots in the deep veins of the legs, or in the lungs. The increased incidence of pulmonary emboli (PE) and microemboli carries over into all COVID patients.(164) The report by Liao et al(164) indicates COVID-19 patients with PE may have up to 45% higher mortality rate compared to general cases (in-hospital mortality rate 4%).(164)
There are no accurate incidence figures available for non-hospitalized patients, as only case studies have been published up to this point.(166)
The hypercoagulable state in COVID-19
COVID-19 infection has been associated with venous and arterial thromboembolism. Studies have shown abnormalities of the coagulation cascade, with elevated D-dimer, thrombocytopenia, slightly elevated prothrombin time, and higher levels of fibrinogen and von Willebrand factor. The hypercoagulable state in COVID-19 infection is thought to be related to severe inflammatory response, cytokine storm, and endothelial damage, along with underlying patient comorbidities, especially malignancy, and obesity.(145)
New studies from Denmark by Kaltoft et al(159) have implicated elevated Lipoprotein (a) in increased thrombotic, inflammatory and vascular risk, adding to the increasing knowledge of genetic mutations that underpin COVID and Long COVID risk.
Sakr et al(165) reported the hypercoagulable state in COVID-19 in which higher levels of D-dimer, fibrinogen, and fibrinogen degradation products, prolonged prothrombin time (PT), international normalized ratio (INR), and thrombin time (TT) associated with poor prognosis in patients infected with SARS-CoV-2.
Rauchet al(249) found phosphatidylserine was associated with increased thrombo-inflammation and vascular complications. It is yet to be seen if this finding provides an answer to the non-resolving problem of persistent D-Dimer elevation seen frequently. There are no tests to confirm this, and the likelihood seen only in DNA testing. Ramya Dwivedi(253) describes thrombo-inflammation as playing a critical role through complement activation and cytokine release, platelet overactivity, apoptosis (thrombocytopathy), as well as coagulation abnormalities (coagulopathy).”(253) “It is known that vascular complications may occur in COVID-19 patients where autoantibodies may target phosphatidylserine (PS)/prothrombin complexes. PS is a plasma membrane component that is actively retained by an ATP-requiring process at the inner membrane surface in living cells; it participates in the immune response. PS-enveloped foreign particles (such as microparticles or viruses) are released from cells to interact with extracellular proteins, including coagulation and complement systems.”(253)
“Once activated, the platelet-derived microparticles (PMPs) are released, which cause thrombin formation, coagulation, activation of the complement system, and inflammation in a PS-dependent manner. COVID-19 severity is associated with immune abnormalities such as increased inflammatory cytokines, immune cell exhaustion, and general lymphopenia. Hyperactivated platelets, elevated levels of circulating PMPs, and an increased risk of thromboembolic complications - related to PS-associated immune mechanisms - contribute to COVID-19 disease severity and death.”(253)
Oudkerk et al.(167) believe that the very high D-dimer levels observed in COVID-19 patients are not only secondary to systemic inflammation, but also reflect true thrombotic disease, possibly induced by cellular activation that is triggered by the virus. Cui et al.(168) demonstrated that a cut-off value of 3.0 μg/mL for D-dimer had sensitivity, specificity and negative predictive values of 76.9%, 94.9% and 92.5% to predict VTE, respectively. The level of D-dimer decreased gradually after anti-coagulants, showing that D-dimer levels may not only predict thrombosis but also monitor the effectiveness of anticoagulant therapy.(165)
Predisposition to thrombotic complications is another feature of COVID-19 which causes diffuse intravascular coagulation and thromboembolic events involving different organs. Endothelitis can also potentially contribute to persistent damage to other organs, including the lungs, brain, liver and kidneys.(45)
There is a 28% increased risk of type 2 diabetes following COVID-19. Diabetes diagnoses were increased by 81% in acute COVID-19 and remained elevated by 27% from 4 to 12 weeks after the infection.(98) Diabetes incidence remained elevated for at least 12 weeks following COVID-19 before declining.(100)
Acute COVID-19 was associated with a 6-fold increase in cardiovascular diagnoses overall, including an 11-fold increase in pulmonary embolism, a 6-fold increase in atrial arrhythmias, and a 5-fold increase in venous thromboses.(100) These declined from 4 to 12 weeks after COVID-19 and returned to baseline levels or below from 12 weeks to 1 year after the infection. People without pre-existing CVD who suffer from COVID-19 do not appear to have a long-term increase in incidence of these conditions.(100)
The mechanisms of coronavirus disease-2019 (COVID-19)–related myocardial injury comprise both direct viral invasion and indirect (hypercoagulability and immune-mediated) cellular injuries. Some patients with COVID-19 cardiac involvement have poor clinical outcomes, with preliminary data suggesting long-term structural and functional changes. These include persistent myocardial ﬁbrosis, oedema, and intra-ventricular thrombi with embolic events, while functionally, the left ventricle is enlarged, with a reduced ejection fraction and new-onset arrhythmias reported in a number of patients.(143)
Xie et al(42)reported cardiac complications, in particular, arrhythmias and myocardial injury even in those experiencing mild symptoms, increasing the risk of heart failure and other future complications.
In a prospective observational cohort study, they showed 78% of the COVID-19 patients who had recently recovered from the illness demonstrated abnormal cardiovascular magnetic resonance and 60% had ongoing myocardial inflammation.
The prevalence of these abnormalities 71 days after the original COVID-19 diagnosis was independent of pre-existing conditions, severity of the disease, presence of cardiac symptoms and time from original diagnosis.(42)
In a cohort of competitive athletes who had recovered from COVID- 19, the majority without any reported symptoms and none requiring hospitalization, Cardiac MRI imaging provided evidence of myocarditis and prior myocardial injury in 15% and 31% of the cohort, respectively.
These observations of cardiovascular involvement even in patients with mild acute symptoms, mostly home-based recovery and relatively lower prevalence of pre-existing cardiovascular conditions, indicate increased risk of significant cardiac complications in the early convalescent stage and the long-term period post-acute COVID-19 disease. (42)
In a large study of US Veterans, Xie et al(42) reported increased risk for multiple cardiovascular and cerebrovascular conditions was seen even among previously healthy young adults with mild acute COVID-19 and also among the relatively few women which followed risks for 12 months.
Absolute rates of these disorders, which included stroke, transient ischaemic attack, atrial fibrillation, heart failure, ventricular arrhythmias, pericarditis, cardiac arrest, pulmonary embolism, and myocarditis, ranged from 1 to 12 per 1000 people. Risk for these conditions increased in a graded fashion depending on severity of the initial COVID-19 illness.(42)
At the 12-month mark, compared with the contemporary control group, for every 1000 people, Xie et al found COVID-19 was associated with an extra:
45.29 incidents of any pre-specified cardiovascular outcome
23.48 incidents of major adverse cardiovascular events (MACEs), including myocardial infarction, stroke, and all-cause mortality
19.86 incidents of dysrhythmias, including 10.74 incidents of atrial fibrillation
12.72 incidents of other cardiovascular disorders including 11.61 incidents of heart failure and 3.56 incidents of non-ischemic cardiomyopathy
9.88 incidents of thromboembolic disorders, including 5.47 incidents of pulmonary embolism and 4.18 incidents of deep vein thrombosis
7.28 incidents of ischaemic heart disease including 5.35 incidents of acute coronary disease, 2.91 incidents of myocardial infarction, and 2.5 incidents of angina
5.48 incidents of cerebrovascular disorders, including 4.03 incidents of stroke
1.23 incidents of inflammatory disease of the heart or pericardium, including 0.98 incidents of pericarditis and 0.31 incidents of myocarditis
The risk was also magnified in the over 65 year old group and in patients with more severe disease—determined by whether they recuperated at home, were hospitalised, or were admitted to the intensive care unit. But the risks were evident even among those who were not hospitalised with COVID-19.
Other subgroup analysis found increased risks regardless of age, race, sex, obesity, smoking, hypertension, diabetes, chronic kidney disease, hyperlipidaemia, and pre-existing cardiovascular disease. Those who had had covid-19 had a 72% increased risk of heart failure, 63% increased risk of heart attack, and 52% increased risk of stroke compared with controls.(42)
Recommendations for managing arrhythmias are similar to those for non-COVID patients, including electrolyte optimization, avoidance of triggers, and medication modification.
Concomitant ECG monitoring for patients who have long QTc or taking medications known to prolong the QTc interval is required.(145) Cardiac arrest was reported in 11% of COVID-19 patients with ECG evidence of ST elevation in a case series from New York.(145)
Our clinic has been actively involved with QT prolongation for some years as it is a common finding in POTS. Generally speaking, we have found this can be controlled with “Kiiko” acupuncture which reduces sympathetic overactivity in an as-yet unpublished study of 50 POTS patients. Watching the QT and PR intervals we believe is an important component on managing Long-COVID cardiac complications, especially when medications are added that may affect the QT interval. It appears most effective when taken in both lying and standing positions.
Lungs are the main organs affected by SARS-CoV-2 infection. A wide variety of long-term respiratory complications secondary to COVID-19 have been described ranging from persistent symptoms and radiologically observable changes to impaired respiratory physiology, vascular complications, and pulmonary fibrosis. (97)
The atypical pneumonia and acute respiratory distress syndrome (ARDS) associated with COVID-19 can cause lasting damage to the lung alveoli through irreversible scarring or fibrosis. This may lead to long-term breathing problems as well as the development of pulmonary fibrosis.(45)
The long-term sequela of viral pneumonia, in general, vary depending upon two factors:
1. direct injury caused by the viral organisms,
2. the host's immune reaction to those organisms.
The histologic manifestations of acute pulmonary viral infections can be divided broadly into two primary patterns:
1. bronchiolitis and inflammation adjacent to airways, and
2. diffuse alveolar damage.
On imaging, bronchiolitis and airway inflammation manifest as bronchial wall thickening, centrilobular nodules, and tree-in-bud opacities; whereas diffuse alveolar damage manifests as bilateral ground-glass opacity and/or consolidation. (97)
The long-term effects of these two patterns are also characteristic. Inflammation within and around the airways may induce concentric fibrosis around the bronchioles resulting in airway narrowing or obliteration. This is termed constrictive (or obliterative) bronchiolitis. Development of constrictive bronchiolitis may result in persistent dyspnoea after resolution of the acute infection with an associated obstructive defect on pulmonary function tests. (97)
The most common finding on chest CT in post-COVID studies is pulmonary interstitial changes. Typical CT findings of constrictive bronchiolitis include mosaic attenuation and air trapping, sometimes associated with bronchiectasis. The long-term manifestations of diffuse alveolar damage (DAD), on the other hand, are quite different.
Histologically, fibrosis develops 1-2 weeks after the development of acute symptoms. On imaging, this is associated with the development of reticulation and traction bronchiectasis. Over time, usually months, this fibrosis may improve, although residual fibrosis is common. This residual fibrosis is often located in the anterior subpleural lung and may be associated with restrictive physiology on pulmonary function testing. (97)
Organizing pneumonia (OP) is particularly common with COVID-19. The clinical and imaging features of OP have been studied mainly in the setting of cryptogenic (idiopathic) disease. Organizing pneumonia is usually a highly steroid-responsive disease with opacities that quickly improve or resolve with treatment, although residual fibrosis may occur. This residual fibrosis often has a pattern that resembles nonspecific interstitial pneumonia with basilar predominant reticulation, traction bronchiectasis, and subpleural sparing. It is also important to note that OP and diffuse alveolar damage (DAD) may co-exist with overlapping imaging findings. (97)
Understanding the different patterns of injury associated with viral infections and their long-term sequela is important in putting the long-term effects of COVID-19 infection in context. Han et al(146). were among the first to describe the persistent CT findings of COVID-19 six months after the onset of acute symptoms. In their study, over one-third of patients showed evidence of fibrotic changes. (97)
Several studies have shown varying degrees of structural and functional pulmonary abnormalities long after recovery from the acute illness among COVID-19 patients. In addition to direct viral invasion via ACE2 expression in the upper airway (goblet and ciliated epithelial cells), lower respiratory tract epithelium (type II alveolar), pulmonary vasculature (arterial smooth muscle), and endothelial cells, immunological damage has been implicated in the development of ARDS and subsequent long-term respiratory impairments.
Accelerated lung fibrosis in some COVID-19 patients after the resolution of infection may be triggered by elevated levels of pro-inflammatory cytokines, which are implicated in the pathogenesis of lung fibrosis. The increased pulmonary microthrombi and macrothrombi formation in COVID-19 patients may also contribute to the long-term respiratory sequelae.(45)
Dr Sahan Bandara,(169)in a discussion group advising Long Covid Management on the Gold Coast described “chronic respiratory sequelae, aside from thromboembolism and long COVID, are typically due to one of three possibilities:
residual fibrotic lung disease post ARDS and related diffuse alveolar damage (DAD)
secondary organising pneumonia like changes - where longer duration of steroids is of benefit
immunosuppressed patients, particularly haematology patients on antiCD20 agents, (monoclonal antibodies used in autoimmune disease,) tend to be unable to clear the virus - these patients are less likely to benefit from dexamethasone/baricitinib(170) and more likely to benefit from antivirals, IVIgs, COVID specific antibodies(169)”
Research from Denmark by Schousboe et al(162) demonstrated low levels of surfactant in COVID patients which can severely impose alveolar collapse, impair gas exchange, and increase work of breathing and could also predispose to barotrauma (e.g.pneumothorax.) Surfactant is a complex mixture of lipids, proteins and carbohydrates produced in the lungs by type 11 alveolar cells that reduces surface tension at the air-liquid interface of the alveoli and contributes to the elastic properties of pulmonary tissue preventing the alveoli from collapsing. A number of centres have now shown improved oxygenation and outcomes in patients with use of surfactant. (161)(162)
Patients with mild to moderate COVID-19 pneumonia may not be at risk for post-COVID-19 pulmonary fibrosis. Pulmonary fibrosis results from abnormal repair of lung injury caused by various mechanisms including viral infections, inflammation, or idiopathic. In severe forms of lung injury due to COVID-19, the basement membrane becomes damaged and the repair process ends up with the formation of fibroblastic tissue and scarring, leading to architectural distortion and fibrosis.(97)
Understanding the different patterns of injury associated with viral infections and their long-term sequela is important in putting the long-term effects of COVID-19 infection in context.(97) Histologically, fibrosis develops 1-2 weeks after the development of acute symptoms. On imaging, this is associated with the development of reticulation and traction bronchiectasis. Over time, usually months, this fibrosis may improve, although residual fibrosis is common. This residual fibrosis is often located in the anterior subpleural lung and may be associated with restrictive physiology on pulmonary function testing.(97)
COVID-19 infection has been associated with cerebrovascular accidents. The incidence of acute ischaemic stroke in patients with COVID-19 is approximately 1%–3%. A review of 37 studies with 370 patients with COVID-19 who had developed acute ischaemic stroke or transient ischaemic attack found that most patients had underlying co-morbidities predisposing them to ischaemic stroke.(145)
Efstathiou, V. et al(151) reported that the formation of thrombi due to endothelial dysfunction, hypercoagulability and the lingering cytokine storm in patients with ‘long COVID’ may be associated with a high incidence of thrombotic cerebral complications.
Additionally, direct damage to the blood-brain barrier by the virus and hypertension due to elevation in ACE2 may cause haemorrhagic complications with persistent sequelae following the resolution of acute SARS-CoV-2 infection.
The high susceptibility of white matter to ischaemia renders it particularly vulnerable to ischaemic changes. Furthermore, long-term alterations have recently been confirmed by the neuroradiological evidence of structural damage and impaired functional integrity of the brain, at a 3-month follow-up of COVID-19 survivors.(151)
Sashindranath and Nandurkar (185) confirm these findings, and write” The COVID-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications.
There is an increasing incidence of large vessel ischaemic strokes as well as intracranial haemorrhages, frequently in younger individuals. COVID-19 is characterized by hypercoagulability with alterations in haemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this reveals that COVID-19 is a thrombo-inflammatory disease.”
“Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19.
There is an established link between COVID-19 and neurological symptoms in up to 50% of patients, including loss of smell and taste, necrotizing encephalitis, seizures, and rarely, Guillain-Barre syndrome. Acute cerebrovascular disease with a relatively low mean age (ranging from 45 to 67 years) is a significant complication of COVID-19. The incidence of acute cerebrovascular complications was 5.7% in patients with severe COVID-19; in fact, cerebrovascular disease is thought to be an independent predictor of mortality after SARS-CoV2 infection.”(185)
“That the overall incidence of large vessel occlusions is 2-fold higher than in normal acute ischaemic stroke cases and they occur among patients from all age groups, even those without risk factors or comorbidities, strongly implicates COVID-19-related hypercoagulability as the underlying cause.”(185)
“The endothelium has a pivotal role in cerebrovascular disease. Endothelial dysfunction occurs after stroke and leads to oxidative stress, inflammation, increased vascular tone, blood-brain barrier (BBB) damage, and further thrombo-vascular complications in the brain. Endothelial damage as a result of denudation, fluctuations in shear stresses, or inflammation can also trigger onset of stroke.”(185)
A review of 37 studies with 370 patients with COVID-19 who had developed acute ischaemic stroke or transient ischaemic attack (TIA) found that most patients had underlying co-morbidities predisposing them to ischaemic stroke.(145)
The persistence of cognitive impairment and motor deficits in a third of the discharged patients reinforces the risk of developing long-term neurological consequences COVID 19 has thus, been linked with the risk of developing Parkinson’s disease and Alzheimer’s disease. (45)
However, case reports also describe large-vessel strokes in young adults with COVID-19 who did not have any cardiovascular risk factors. In addition to arterial strokes, cerebral venous sinus thrombosis has been reported in 13 patients in 9 studies.(145) The results show that most patients (54%) had mild symptoms without the need for hospitalisation. The duration between a negative test for COVID-19 and the onset of neurological symptoms ranged from three to 186 days, with a mean duration of 73 days.
The most common neurological presenting symptoms in Long- COVID were headache (46%), and fatigue (13.5%). Magnetic resonance imaging (MRI) was performed on 27 patients, with unremarkable findings in 22 cases. Almost half of the patients (47.5%) recovered completely.(90)
The Primary Symptoms:
Fatigue, muscle weakness, and sleep difficulties were the most common symptomatic sequelae.
Other symptoms include memory loss, gastrointestinal symptoms and shortness of breath.
Autonomic dysfunction is very common and the development of Postural Autonomic Tachycardia Syndrome (POTS) is not uncommon. Hira et al (271)in a Canadian study in December 2022, described over 70% of Long-COVID have cardiovascular autonomic disorder, 30% of these with POTS (Postural Orthostatic Tachycardia Syndrome)
Symptoms of anxiety or depression decreased from 23% at 6 months to 12% at 2 years
Compared with controls, COVID-19 survivors at 2 years had more prevalent symptoms, more problems with pain or discomfort, and anxiety and depression.(23)
Surveys of COVID-19 survivors reveal the development of new symptoms: neurological (67%), pulmonary (53%), gastrointestinal (51%), cardiac (49%), sensory (27%) and 34% reported new autonomic dysfunction and 18% autoimmune disease.(27) These mirror the results from Blitshteyn.(26) Nearly a third of the patientsin this case series had confirmed mild abnormalities on cardiac or pulmonary testing,and 20% had abnormal markers of autoimmunity or inflammation.
Henderson(148) reported moderate to severe sleep disturbances and severe fatigue affecting up to 40% of patients with long COVID. More than two thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, and in addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances.(148) An analysis by Targuin et al(152) of 2-year retrospective cohort studies showed an increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout.
Efstathiou et al(151) noted that studies demonstrated that the “systemic immune-inflammation index” (SII) was elevated at the 3-month follow-up in patients reporting depressive and cognitive impairment symptomatology. The SII is an objective marker of host systemic inflammation and immune response, implicating neutrophils, platelets and lymphocytes, cells involved in various inflammatory pathways.
Table 5: Neurological Manifestations of “Long-COVID” Syndrome, according to the localization in the Nervous System
1. Central Nervous System
2.Peripheral Nervous System
Sensorimotor deficits eg tremor, hypoesthesia, dysesthesia.
Source: Stefanou M-I, Palaiodimou L, Bakola E, et al. Neurological manifestations of long-COVID syndrome: a narrative review. Therapeutic Advances in Chronic Disease. January 2022. doi:10.1177/20406223221076890
Patients with a marked decrease in the SII exhibited a decrease in the severity of depression, while by contrast, increased levels of SII had a negative effect on neurocognitive performance (memory, verbal fluency, speed of information processing, psychomotor coordination), since this elevation reflected prolonged systemic inflammation. (151)
Inflammatory microglial activation (IL-6 and TNFa) is the most common brain pathology found in patients who died of COVID-19: 42% are affected, and another 15% have microclots in brain tissue.(105) Post-mortem examinations highlighted an unsettled glial homeostasis, with significant changes in both astrocytes and microglia. These alterations are consistent with morphological and functional astrocyte remodelling in chronic stress and major psychiatric diseases.(151)
Another factor thought by Efstathiou et al(151) to account for the delayed sequelae of COVID-19 is the failure of reactive neuroglia to return to the physiological state. Neuroglia undergo complex remodelling in response to systemic pathology, a process known as gliosis, in order to remove pathogens, strengthen brain-organism barriers and contribute to the regenerative potential of the CNS. This reactive response results in the formation of a glial scar isolating the damaged area, protecting the adjacent healthy nervous tissue. The resolution of systemic pathology is what enables the restoration of homeostatic status of neuroglial cells.(151)
The dysregulation of the immune system by Covid promotes the development of autoimmune phenomena reported Gracia-Ramos(55)(172) and others, completed in the 18 to 65 age group where this increased risk was confirmed.(173) Changes to the immune system after Covid-19 are part of the Post-Covid Syndrome, with autoimmunity emerging as being characteristic.(172) Some (3% in the Rojas study)(172) continued to progress to overt autoimmune disease with testing showing over 80% in the patient study group and over 60% in the health control group having positive antibodies. Gracia-Ramos et al(55) reported the main diseases as vasculitis and arthritis, with limited numbers of idiopathic inflammatory myopathies, SLE and sarcoidosis, and isolated cases of systemic sclerosis and adult-onset Still’s Disease.
From the early months of the COVID-19 pandemic, vasculitis-like manifestations of autoimmune disease and full-blown vasculitic syndromes were reported, mainly in children and adolescents. Post-COVID-19 acral skin lesions or chilblains, the so-called COVID-19 toes were confirmed in some reports were a result of endothelial damage induced by the virus.(55) Further reports of different types of vasculitides emerged and it became evident that COVID-19 was capable of inducing vasculitis without directly damaging the vessel wall, as demonstrated by the absence of SARS-CoV-2 in the skin biopsies. Type 3 hypersensitivity is thought to be the mechanism by which COVID-19 may elicit a vasculitic syndrome. This is thought to be mediated through TLR 4.
This type of delayed inflammatory response appears days to weeks after the initial antigenic challenge and is due to the failure of the innate immune system to clear from the circulation immune complexes, which later precipitate inside tissues and elicit an inflammatory response mediated by complement activation.(55)
The most common diseases involving a type III hypersensitivity reaction are serum sickness, post-streptococcal glomerulonephritis, systemic lupus erythematosus, farmers’ lung (hypersensitivity pneumonitis), and rheumatoid arthritis. The principle feature that separates type III reactions from other hypersensitivity reactions is that in type III reactions, the antigen-antibody complexes are pre-formed in the circulation before their deposition in tissues.(174)
Gracia-Ramos et al (55) found cases of small, medium and large vessel vasculitides. The large vessel group was the least frequent. One of the most common vasculitides encountered was Kawasaki disease which was not unexpected, as Kawasaki disease was reported concurrent or following several viral infections such as rhinovirus, enterovirus, adenovirus, other coronaviruses, and dengue virus.(55)
Historically, viral infections have had a complex relationship with a variety of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), systemic vasculitis, coeliac disease, and multiple sclerosis. Examples of viruses that play a role in triggering autoimmune disease include hepatitis C virus, hepatitis B virus, Chikungunya virus, parvovirus B19, herpes viruses, and others.
Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, were the predominant mechanisms by which infection can lead to a T-cell-mediated autoimmune response.(55) However, other hypotheses including virus-induced decoy of the immune system also warrant discussion regarding their potential for triggering autoimmunity.(55) Several studies have reported the presence of autoantibodies in patients with COVID-19 in different frequencies: antinuclear antibodies (ANA) in 35.6%, anti-Ro/SSA in 25%, rheumatoid factor in 19%, lupus anticoagulant in 11% and antibodies against interferon (IFN)-I in 10%.(55)
Despite the high autoimmune activation, studies also found the percentage with active autoimmune diseasehad dropped to small numbers by 12 months.
Targuin et al(152) analysed 2-year retrospective cohort studies showing that the increased incidence of mood and anxiety disorders from COVID-19 was transient, with no overall excess of these diagnoses compared with other respiratory infections, while in contrast, the increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout. This suggested different pathogenesis for these outcomes. Children had a more benign overall profile of psychiatric risk than adults and older adults, but their sustained higher risk of some diagnoses is seen of concern. (152)
Efstathiou, V. et al described the activation of the hypothalamus-pituitary-adrenal glands axis that mediates glucocorticoid secretion (i.e., the main hormonal response to physical and mental stress stimuli) and this axis is one of the main neurobiological mechanisms in depression as it inhibits neurogenesis and decreases the proliferation and survival of nerve cells in the dentate gyrus of the hippocampus.(151)
From Wikipedia: “The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a pea-shaped structure located below the hypothalamus), and the adrenal (also called "suprarenal") glands (small, conical organs on top of the kidneys). These organs and their interactions constitute the HPA axis.”(158)
Image 1. The hypothalamic-pituitary-adrenal axis, or HPA axis- the interaction between the hypothalamus, pituitary gland, and adrenal glands; it plays an important role the body’s response to stress. The pathway of the axis results in the production of cortisol.
Source: Guy-Evans, O. (2021, Sept 27). Hypothalamic-Pituitary-Adrenal Axis. Simply Psychology. www.simplypsychology.org/hypothalamic–pituitary–adrenal-axis.html
“The HPA axis is a major neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, energy storage and energy expenditure.
There is bi-directional communication and feedback between the HPA axis and the immune system. A number of cytokines, such as IL-1, IL-6, IL-10 and TNF-alpha can activate the HPA axis, although IL-1 is the most potent.
The HPA axis in turn modulates the immune response, with high levels of cortisol resulting in a suppression of immune and inflammatory reactions. This helps to protect the organism from a lethal over-activation of the immune system, and minimizes tissue damage from inflammation. During an immune response, pro-inflammatory cytokines (e.g. IL-1) are released into the peripheral circulation system and can pass through the blood-brain barrier where they can interact with the brain and activate the HPA axis. Interactions between the pro-inflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause symptoms such as fatigue, depression, and mood changes.”(158)
The cytokine storm as part of the systemic hyper-inflammatory state observed in acute COVID-19 infection, was described by Efstathiou, V. et al(151) to play a “key role in persistent maladies, precipitated by changes in cerebral perfusion, an increased permeability of the blood-brain barrier, changes in astrocytes involved in synaptogenesis and the imbalance of neurotransmitters."
"These molecules dysregulate neurogenesis, causing neurons, oligodendrocytes and glial cells to lose their physiological function. This occurring disruption of neuronal plasticity, synaptic function, myelination and blood-brain barrier maintenance can subsequently impair cognitive function and may lead to a number of the long-term neuropsychiatric symptoms of COVID.”(151)
Long COVID can cause an increase in challenges to our mental health.(149) When symptoms of COVID-19 linger for months, the mental health impacts can be significant. “Beyond Blue”(149) provides some suggestions to help manage mental health whether Long COVID, or if there is anxiety about developing it. While fatigue is well-known to be a major Post-COVID problem, it is associated with many secondary factors that are discussed is “Long Covid Management.”
Symptoms that are usually attributed to psychological disturbance include:
inability to work and perform daily activities.
relationship and financial difficulties.
Impact of Stress
Chronic life event stress is a powerful predictor of symptom intensity in irritable bowel syndrome, as well as being a potent activator of IL-6, as here we can see the complex interplay between autonomic stability and inflammatory activation. The psychophysiological responses to such chronic stress should include alterations in cardio-sympathetic and abdominal parasympathetic function. Autonomic dysregulation, which is consistent with the effects of chronic stress, is a feature of IBS.
Studies by Leach et al (51) on patients with constipation-predominant constipation IBS demonstrated enhanced cardiosympathetic and attenuated abdominal parasympathetic tone. IBS patients with predominant diarrhoea also exhibit enhanced cardiosympathetic tone but no apparent attenuation in abdominal parasympathetic tone. These researchers felt that the predominant alteration of bowel habit may be associated with subtle differences in the overall pattern of central and abdominal autonomic reactivity. (51)
Meringer and Mehandru(104) describe that “owing to the robust constitutive expression of angiotensin-converting enzyme 2 on the brush border of the small intestinal mucosa, acute COVID-19 is associated with gastrointestinal symptoms such as nausea, vomiting, diarrhoea and abdominal pain. In patients with PACS, gastrointestinal-related symptomatology includes loss of appetite, nausea, weight loss, abdominal pain, heartburn, dysphagia, altered bowel motility and irritable bowel syndrome.”
In a questionnaire to 1,783 COVID-19 survivors, patients (29%) self-reported gastrointestinal symptoms at 6 months that included diarrhoea (10%), constipation (11%), abdominal pain (9%), nausea and/or vomiting (7%) and heartburn (16%). In a different study of 73,435 users of the Veterans Health Administration, motility disorders (including constipation and diarrhoea), oesophageal disorders, dysphagia and abdominal pain were reported.(175) Laboratory abnormalities included an increased risk of high incident serum levels of alanine aminotransferase. (104)
Efstathiou, V. et al(151)described viral induced colon inflammation, but also how gut microbial imbalance and α-synuclein up-regulation play a role in the disruption of interplay between the gastrointestinal tract and the CNS. (151) Gastrointestinal symptoms are common, and may be the presenting symptom of a COVID-19 infection. Viral stool shedding continues throughout the disease course and often persists beyond it, so attention to preventing faecal-oral transmission is very important. 70% of patients had persistently positive stool RNA even after respiratory tests had become negative.(101)
Marshall-Gradisnik and Eaton-Fitch describe proposed mechanisms underlying the GI symptoms of Myalgia Encephalomyelitis and Long COVID: “the presence of GI dysregulation, through proposed disturbances in GI nerve and consequently smooth muscle activity, emphasises the involvement of impaired ANS regulation in the symptomatology of ME/CFS.” “Cross talk between the nervous, GI, and immune systems has been reported in other post-infectious disease states, such as Long Covid.”(181)
Symptom frequency varied between studies, but overall:
· Anorexia (27% of patients)
· Diarrhoea (12%)
· Nausea and vomiting (10%)
· Abdominal pain (9%)
· Abnormal liver function tests are seen in 19% of patients.
The severity of the underlying COVID-19 disease also seemed to correlate with the degree of abdominal pain and hepatic dysfunction.(45)
Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication. Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses.
Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.
Yeoh et al(102) described how gut microbiota composition reflects disease severity and dysfunctional immune responses. Their findings include:
“Composition of the gut microbiota in patients with COVID-19 is concordant with disease severity and magnitude of plasma concentrations of several inflammatory cytokines, chemokines and blood markers of tissue damage.”
“Patients with COVID-19 were depleted in gut bacteria with known immunomodulatory potential, such as Faecalibacterium prausnitzii, Eubacterium rectale and several bifidobacterial species.”
“The dysbiotic gut microbiota composition in patients with COVID-19 persists after clearance of the virus.(102)”
Paediatric GI Tract
Overall the burden of Long COVID in children is low. Acute illness severity, age younger than 5 and comorbid complex chronic disease increased the risk of PASC.(153)(154)
In children the GI manifestations include anorexia, nausea, vomiting, diarrhoea and abdominal pain. Rarely, significant gut inflammation eg terminal ileitis mimicking appendicitis has been reported.(103)
Ding et al(176) found that GI symptoms such as diarrhoea, vomiting and feeding difficulties are common at disease presentation. The prognosis is generally excellent compared to the older population or those with significant co-morbidities.(103)
Mitochondrial oxidative stress is thought to cause dysbiosis that contributes to the progression and severity ofCOVID-19. The microbiome of the gastrointestinal tract is essential for the establishment of immune homeostasis, and the composition of the gut microbiota was altered in patients with COVID-19, and together with inflammatory cytokines and blood markers reflected disease severity and dysfunctional immune response . The dysbiosis of gut microbiota further persisted for up to 30 days after disease resolution.(45)
Diet becomes very important in managing long COVID, POTS, and their co-morbidities. The consumption of food that the body sees as a threat triggers inflammatory and autonomic changes (release of ILs 2,6,8, 10 and TNFa).(48) The choice of diet becomes even more important as we try to reduce the mitochondrial dysfunction from the viral intrusion. Mast cells have been identified in the gut, especially around neurovascular bundles and are thought to play a major part in gut symptomatology.
Recent studies confirm that the most important mechanisms in IBS include visceral sensitivity, abnormal gut motility, and autonomous nervous system dysfunction. The interactions between these 3 mechanisms make bowel's function susceptible to many exogenous and endogenous factors, like gastrointestinal flora, feeding, and psychosocial factors. Recent data indicate that according to the above mechanisms, the influence of genetic factors and polymorphisms of human DNA in the development of IBS is equally important.(53)
Most IBS symptoms are directly related to specific abnormalities of the ANS, although increasingly it is felt that IBS is symptomatic of Mast Cell Activation. The pathophysiology of IBS is complex and poorly understood, so Liu et al (49) studied whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhoea-predominant IBS. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. They also had a significantly higher level of calprotectin. They also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction.(49)
Low-grade inflammation has also been implicated as one of the underlying mechanisms of IBS. Polymorphisms of the gene for the proinflammatory IL-6 and variations in the circulating levels of IL-6 have been demonstrated in patients with IBS. Basasharti et al (52) found elevated levels of proinflammatory interleukins 2, 6, and 8 in IBS patients—especially in those with post-infectious IBS (as opposed to non–post-infectious IBS)—and a reduction of anti-inflammatory IL-10 in both.(52)
The main mechanism inducing abdominal pain is the visceral hypersensitivity.(52) There is evidence that interactions within the brain and gut axis (BGA) that involves both, the afferent- ascending and the efferent-descending pathways as well as the somatosensory cortex, insula, amygdala, anterior cingulate cortex and hippocampus are deranged in IBS showing both the activation and inactivation.(52)
Alterations in the bi-directional signalling between the enteric nervous system and the central nervous system and consequently between the brain and the gut may play a significant role in the pathophysiology of IBS.(52) It is known that visceral sensitivity is regulated in many levels. Specifically this regulation is mediated at the level of enteric mucosa and submucosa, the level of spinal cord, the level of thalamus and the level of cerebral cortex.(52)
COVID-19 in pregnancy linked to increased risk of neurodevelopmental disorders in infants
Edlow et al(156) reported that COVID-19 infection during pregnancy may be associated with an increased risk of neurodevelopmental disorders in infants. They found that babies born to COVID-19-positive women were more likely to be diagnosed with a doubling of risk of neurodevelopmental disorder at 12 months. This appeared worse when the infection was contracted in the third trimester.
They said: “These preliminary findings suggest greater risk for adverse neurodevelopmental outcomes at one year among offspring exposed to SARS-CoV-2, and highlight the urgency of follow-up studies in large and representative cohorts.”(155)(156)
Dr Graham Exelby