We are reporting autopsy findings of three cases with prior history of SARS-CoV-2 infection several months prior to their death. All patients were tested negative for SARS-Cov-2 at the re-admission, but expired shortly. Especially the second patient was a young man with no significant past medical history. Autopsy findings mainly revealed pathological changes in the heart, lungs and brain. One month post SARS-CoV-2 infection, patient of case one showed extensive diffuse acute myocardial ischemic injury with the abundant microthrombi present in the epicardial small vessels, whereas the pulmonary pathologic changes were largely secondary to the heart failure. The cause of death to patient three was mainly due to catastrophic acute and subacute cerebral infarctions. Most interestingly, patient of case two had symptoms one month after the whole family had COVID-19, and he was positive for anti-SARS-Cov-2 IgG antibody five month later at the admission, confirming a past infection. He had pulmonary thrombosis with both acute and subacute hemorrhagic pulmonary infarctions complicated by rupture with hemothorax leading to respiratory failure and death. The current publications of autopsy findings are mostly from patients died with acute COVID-19. To our knowledge, this is the first autopsy case series describing long-term complications from prior SARS-CoV-2 infection.
COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe ARDS.10, 11 The pathologic changes of virus-injured lung can be DAD, diffuse thrombotic alveolar microvascular occlusion, and inflammatory mediator-associated airway inflammation.12 The patients may have more severely impaired pulmonary diffusion capacities,13 and the diffuse alveolar injury may cause pleura damage, producing air leakage and interstitial emphysema, even pneumothorax leading to sudden respiratory decompensation.14 On the other hand, SARS-CoV-2 can induce pulmonary fibrosis by promoting the upregulation of profibrotic signaling molecules, including transforming growth factor-beta (TGF- β).12 As a consequence, organizing pneumonia and pulmonary fibrosis may happen months after the severe virus infection. We had two additional autopsy cases showing such pathologic changes but are not reporting here. The acute and subacute pulmonary infarction in the patient of case two is a severe long-term complication that has not been reported.
About 20–40% of hospitalized COVID-19 patients showed evidence of myocardial injury, manifested clinically as cardiac chest pain, fulminant heart failure, and cardiac arrhythmias, and is associated with higher morbidity and mortality.10, 15 The pathology of cardiovascular complications from SARS-CoV-2 infection may include myocarditis, acute myocardial infarction, venous thromboembolisms, acute pericarditis, and cardiac tamponade.16–18 One cohort study demonstrated that among confirmed COVID-19 hospitalizations 19.7% patients showed cardiac injury, which was an independent risk factor for in-hospital mortality.19 It is well accepted that the transmembrane protein angiotensin-converting enzyme 2 (ACE2) is the target that S protein of SARS-CoV-2 binds to. It was found that ACE2 is expressed not only on pneumocytes and macrophages in the lung, but also pericytes and cardiomyocytes in the heart.20 Interestingly, ACE2 is a cardioprotective transmembrane protein whose expression is downregulated by SARS-CoV-2 infection.15 Direct viral myocardial infection with the virus could be one of the mechanisms of cardiac injury and myocarditis.15, 21 Surprisingly, the myocardial ischemic injury in our first patient was severe and extensive, and it indicates that the cardiovascular damage and subsequent coagulopathy persist even after SARS-CoV-2 has been cleared and the patient has recovered from COVID-19 pneumonia.
Interestingly, smell and taste disturbances in the absence of nasal obstruction are characteristic of COVID-19.22 In fact, besides cardiopulmonary damages, up to two-thirds of hospitalized patients show evidence of central nervous system (CNS) damage,23 with the presentations including anosmia, hypogeusia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, seizures, and demyelinating disorders such as acute disseminated encephalomyelitis.24–26 It has been suggested that SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory nerve fibers, or by hematogenous spread, and is capable of infecting endothelial cells, pericytes and probably neurons.23 Clinical data shows that cerebrovascular stroke has been the most common neurological abnormality seen among COVID-19 patients.26, 27 The blood clots in COVID-19 patients can not only lead to myocardial infarctions, pulmonary embolism and renal failure, but also can be present in both cerebral arteries and cerebral veins. The precise mechanism for cerebrovascular complications in such patients is not known, but there are some suggested mechanisms, such as exaggerated cytokine response triggered by the virus, and / or the resulting hypercoagulopathy and formation of blood clots in blood vessels throughout the body and the brain.25, 28 However, brain autopsy studies of such cases mainly show mild and non-specific picture, such as acute hypoxic injury, hemorrhage, and mild to moderate non-specific inflammation, with no evidence for CNS damage directly caused by SARS-CoV-2, such as neurotropism or meningitis/encephalitis.29, 30 Detecting of SARS-CoV-2 in human brain tissue by immunohistochemistry or PCR has been inconsistent.22, 31 In our reported patient three, the catastrophic brain pathology was acute and subacute infarcts, with no significant evidence for meningitis or encephalitis identified.
Contrary to the common long-term pulmonary complications, the patient one showed diffuse myocardial ischemic injury with microthrombi present in the epicardial microvasculature. This was unusual because the patient had COVID-19 one month earlier and the microthrombi were only present in epicardial vasculature, whilst absent in lung and kidney vasculatures, making the status of DIC unlikely. The patient was negative for SARS-CoV-2 at the second admission. It is unclear the cause of microthrombi, but likely due to endothelial lesion and microvascular damage post SARS-CoV-2 infection. The patient two was also unusual for catastrophic lung hemorrhagic infarction complicated by rupture and hemathorax, in the setting of thrombi identified in the pulmonary arteries. Additional cerebellar infarct was also identified in this patient, indicating high risk of coagulopathy. This young man did not have comorbidities but did have COVID-19 vaccination four days before admission. However, his symptoms were present long before the vaccination, making the vaccine as a cause of thrombosis less likely. The last case showed catastrophic acute and subacute brain infarctions.
Microthrombosis and/or microvascular coronary dysfunction has been posited to be one of the mechanisms of acute organ damages during COVID-19.15 The excessive inflammation, hypoxia, and DIC could cause both venous and arterial thromboembolism.32 On the other hand, SARS-CoV-2 may cause vascular thrombosis directly through aggravating the vessels and indirectly by causing cytokine cascade leading to hypercoagulable state, which has been manifested as pulmonary embolisms, deep vein thrombosis, arterial thrombosis of the abdominal small vessels, as well as ischemic and hemorrhagic strokes.33 In fact, it has been postulated that the continuous and uncontrolled activation of the immune system caused by the viral infection, with subsequent excessive cytokine release or “cytokine storm” could play a pivotal role in brain stroke and damage.27 However, it is unexpected and remains unclear that the hypercoagulable state and risk for infarction may persist much longer than previous expected period after patients recovered from COVID-19.
The pandemic of COVID-19 has been only less than two years, and it remains largely unclear the long-term health consequences post SARS-CoV-2 infection. It has been reported that 3 to 6 months after acute infection, 87.4% COVID-19 survivors commonly show clinical sequalae, such as general symptoms (i.e. fatigue or muscle weakness, sleep difficulties, and anxiety or depression), respiratory symptoms (i.e. dyspnea, chest pain, cough, excessive sputum and throat pain), and cardiovascular-related symptoms (i.e. tachycardia, palpitation, and hypertension).13, 21, 34, 35 Based on the data from previous coronavirus outbreaks such as SARS and MERS, it can be speculated that some patients may experience long-term respiratory complications of the infection, including chronic cough, fibrotic lung disease, bronchiectasis, and pulmonary vascular disease.11, 36, 37 With millions of COVID-19 confirmed cases world wide, there is growing concerns regarding long-term infection related chronic respiratory symptoms or fibrotic diseases among recovered individuals, as well as calling for formulation of relevant prevention and intervention strategies.12, 37 Our autopsy findings indicate the necessity of early evaluation and continued monitoring of respiratory and cardiac damages, as well as coagulative status after hospitalization, so as to identify patients with vital organ injury in a timely fashion and take the steps to prevent severe COVID-19 complications.10
In conclusion, the vital organs may be damaged directly from SARS-CoV-2 infection and also from the massive immune storm that the host exerts to fight against the virus. Furthermore, in some patients the damage and subsequent repairing may persist beyond the clearing of the virus, which may cause long-term complications and functional impairment of vital organs, such and lung, heart and brain. Our autopsy findings have shown that some patients may experience severe post infection complications leading to death. It is important to follow these patients regularly, screen for signs of potential complications, and initiate prophylactic therapeutic strategies to prevent severe long-term complications from happening.