LitCovid-sentences  

PMC:7309518 / 2666-23994 JSONTXT 12 Projects

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Id Subject Object Predicate Lexical cue
T20 0-247 Sentence denotes Guillain-Barré syndromes (GBSs) comprise a spectrum of polyneuropathies characterized by acute (within 1–4 weeks) ascending motor weakness, mild or moderate sensory abnormalities, occasional cranial nerve involvement, and muscle or radicular pain.
T21 248-1378 Sentence denotes According to the degree of involvement of the motor or sensory nerves, myelin sheath, axon, or cranial nerve predominance, the most common subtypes are the acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and the Miller Fisher syndrome (MFS) characterized by acute ophthalmoplegia, gait ataxia, and areflexia.1 GBS is one of the prototypic viral-triggered autoimmune neurologic diseases as approximately 70% of the patients have a preceding by 1–3 weeks, flu-like, viral illness.1–3 Among the infectious agents associated with triggering sporadic GBS are viruses, including influenza, enteroviruses, cytomegalovirus, Epstein–Barr virus, herpes simplex virus, hepatitis, or HIV, and bacteria, such as Campylobacter jejuni, Mycoplasma pneumoniae, and Haemophilus influenzae.1 GBS outbreaks have been also associated with viral epidemics or pandemics, including H1N1, swine flu A/New Jersey influenza strain, arthropod-borne flaviviruses, such as the West Nile virus, chikungunya, or Zika, and with coronaviruses, including the Middle East respiratory syndrome (MERS)-CoV and SARS-CoV.1–3
T22 1379-2077 Sentence denotes We are now more than 4 months into the peak of the COVID-19 pandemic with >5,000,000 infections and >330,000 deaths steadily increasingly worldwide, and although various respiratory and cardiac complications have been reported, we have not yet seen COVID-19–related neuroinflammatory or neuroautoimmune diseases as with the other viral outbreaks, including with coronaviruses MERS-CoV and SARS-CoV, which have 75–80% identical viral genome sequence with COVID-19.4 Whether this is due to COVID-19–inducing severe respiratory compromise soon after the median 4-day incubation period5 and underrecognition of neurologic events owing to overwhelming urgency to focus on life-saving efforts is unclear.
T23 2078-2851 Sentence denotes In the most up-to-date large published series, apart from multifactorial acute cerebrovascular events in 5.7% of patients, the main COVID-19–related neurologic symptoms have been hypogeusia (in 5.6%), hyposmia (5.1%), and very high creatine kinase (CK) levels, with myalgia (in 19.3%) indicating potential CNS, peripheral nervous system, and myopathic manifestations.6 Things are however rapidly changing as just only the last 4 weeks the first COVID-19–triggered neurologic events are reported with at least 11 cases of GBS, the prototypic viral-triggered autoimmune neurologic disease, observed in the 4 main COVID-19 hotspots, Wuhan, Italy, Spain, and now France.7–11 The cases are of special neuroimmunologic and practical interest while highlight what is more to come.
T24 2852-3232 Sentence denotes The very first case—and the only one from Wuhan—refers to a woman who 4 days after returning to Shanghai from Wuhan presented with acute lower extremity weakness and areflexia that progressed over 3 days to the arms without any systemic symptoms.7 When first seen, GBS was suspected and confirmed by elevated CSF protein and electromyographic features of demyelinating neuropathy.
T25 3233-3321 Sentence denotes Her laboratory test results were normal, except of lymphocytopenia and thrombocytopenia.
T26 3322-3459 Sentence denotes She was started on intravenous immunoglobulin (IVIg) but 4 days later developed fever, cough, and pneumonia and tested COVID-19 positive.
T27 3460-3528 Sentence denotes After 3 weeks, her strength normalized and lymphocytopenia resolved.
T28 3529-3734 Sentence denotes While at the regular neurology ward, however, 2 of her relatives taking care of her tested COVID-19 positive with pneumonia, while 2 of her neurologists and 6 nurses treating her GBS were put on isolation.
T29 3735-3984 Sentence denotes Italy has just reported 6 patients with GBS,8 1 in this issue.9 All presented with subacute onset of upper and lower extremity weakness, distal paresthesias, and sensory deficits 3–10 days after experiencing cough, anosmia, ageusia, and sore throat.
T30 3985-4091 Sentence denotes On admission, all had lymphocytopenia and high C-reactive protein (CRP) that led to diagnosis of COVID-19.
T31 4092-4221 Sentence denotes One patient had facial diplegia and sensory ataxia.8 The CSF showed elevated protein concentration but was negative for COVID-19.
T32 4222-4288 Sentence denotes Electrophysiology was consistent with demyelinating or axonal GBS.
T33 4289-4354 Sentence denotes MRI showed enhancement of the caudal nerve roots or facial nerve.
T34 4355-4431 Sentence denotes Symptoms rapidly progressed to tetraplegia requiring mechanical ventilation.
T35 4432-4496 Sentence denotes Antiganglioside antibodies in 3/6 tested patients were negative.
T36 4497-4546 Sentence denotes All received IVIg with variable recovery; 1 died.
T37 4547-4941 Sentence denotes The third series refers to 2 men from Spain who, 3–5 days after experiencing low-grade fever, malaise, anosmia, and ageusia, developed MFS or polyneuritis cranialis.10 The patient with MFS presented with oculomotor nerve palsies, diplopia, perioral paresthesias, areflexia, ataxia, and elevated CSF protein concentration and the other with diplopia, bilateral abducens nerve palsy, and anosmia.
T38 4942-5029 Sentence denotes Both had lymphopenia and tested positive for COVID-19; their SCF was COVID-19 negative.
T39 5030-5119 Sentence denotes The patient with MFS was positive for GD1b ganglioside antibodies and improved with IVIg.
T40 5120-5214 Sentence denotes In both, the neurologic features completely resolved, except for residual anosmia and ageusia.
T41 5215-5686 Sentence denotes Last, 2 cases from France, a 43-year-old man and a 70-year-old woman, also presented with acute anosmia, followed by rapidly progressive weakness, paresthesias, ataxia, areflexia, and multiple cranial palsies (including III, V, VI, VII, and VIII), MRI enhancement of cranial nerves, roots, and plexus, high CSF protein concentration but negative for COVID-19, typical features of acute demyelinating neuropathy by electrophysiology, and clinical improvement after IVIg.11
T42 5688-5716 Sentence denotes GBS in the COVID-19 pandemic
T43 5717-6155 Sentence denotes These early GBS cases, despite incomplete immunologic workup considering the enormous difficulties in highly stressed in-hospital settings, provide early clues on what to expect in the months ahead regarding the common acute autoimmune neurologic conditions, such as GBS, polyneuritis cranialis, encephalitis, encephalomyelitis, or myositis, which for years we have been casually referring to as postviral if seen after febrile illnesses.
T44 6156-6447 Sentence denotes First and foremost, the practicing neurologists in this pandemic should now be aware that a patient who presents with an acute paralytic disease—like GBS, encephalomyelitis, or myositis—even without fever, dyspnea, or any systemic symptoms, may represent the first manifestation of COVID-19.
T45 6448-6645 Sentence denotes This is compelling, considering that only 43% of COVID-19–positive patients on admission have fever,4–6 and many of the present patients with GBS did not have any COVID-19 symptoms at presentation.
T46 6646-6876 Sentence denotes These early GBS cases also highlight that 2 clinical and laboratory signs, anosmia/ageusia and lymphocytopenia/thrombocytopenia, are red flags in suspecting COVID-19 in otherwise asymptomatic patients with acute neurologic events.
T47 6877-7502 Sentence denotes They further confirm what we had feared from other viral pandemics that COVID-19 can trigger neurologic autoimmunity; in contrast to the other postviral neurologic diseases, however, COVID-19 requires high degree of suspicion as a potential hidden trigger to prevent inadvertent viral transmission to health care personnel and patient relatives, as in the Wuhan case.7 The series also highlights that GBS peaks 5–10 days after the first COVID-19 symptoms, which in intensive care unit (ICU) settings helps to distinguish GBS from critical illness neuropathy that usually appears later in the course of very sick ICU patients.
T48 7504-7567 Sentence denotes Significance of anosmia/ageusia and other cranial nerve palsies
T49 7568-7953 Sentence denotes The early manifestation of anosmia and ageusia not only in the present GBS series that often occurred in conjunction with other cranial neuropathies but also in large worldwide cohorts reporting sudden loss of smell and taste early in the infection in up to 60% of COVID-19 carriers5,6,12 is highly informative about COVID-19 neurovirulence or even possible viral entry into the brain.
T50 7954-8168 Sentence denotes In contrast to commonly reversible anosmia when the non-neural olfactory epithelial cells are virally infected, the often persistent anosmia/ageusia after COVID-19 suggests neurotropism targeting olfactory neurons.
T51 8169-8957 Sentence denotes SARS-CoV and MERS-CoV, the 2 coronaviruses similar to COVID-19, are neurovirulent and can enter the brain via olfactory nerves.13 In mice, after oronasal infection with SARS-CoV, the virus not only infects epithelial cells of the respiratory tract but also the olfactory receptor neurons in the neuroepithelium gaining access to the olfactory bulb and brainstem.13 These viruses can also enter the CNS via retrograde axonal transport through other cranial nerves, such as trigeminal, which possesses nociceptive neuronal receptors in the nasal cavity, the sensory fibers of the glossopharyngeal, and via peripheral nerves.13 The present GBS series, where oculomotor, trigeminal, and MRI-enhanced facial and nerves roots were concurrently affected, strengthens (but not prove) this notion.
T52 8958-9202 Sentence denotes Accordingly, it will not be unexpected in the weeks and months ahead to see other COVID-19–infected patients with neurologic signs related to multiple cranial nerves, brainstem, and peripheral nerves with MRI enhancement in nerves and meninges.
T53 9204-9319 Sentence denotes Autoimmunity of COVID-19–GBS: significance of sialic acids present in the coronaviruses and peripheral nerve myelin
T54 9320-9469 Sentence denotes In 7/11 tested patients with COVID-19–GBS, the virus was not detected in the CSF, implying no direct root infection or intrathecal viral replication.
T55 9470-9863 Sentence denotes The improvement of several patients with IVIg and the presence of GD1b antibodies in 1 tested patient suggest a postviral-triggered immune response similar to other postviral-induced GBS cases1–3 or other postviral autoimmune neurologic disorders.14 The reported GD1b ganglioside antibodies, however, although in contrast to GQ1b antibodies typically seen in MFS, are of very special interest.
T56 9864-11656 Sentence denotes The SARS-CoV 3a protein contains oligosaccharides with direct evidence that sialic acids play a critical role in human coronavirus infection.15 It has been just shown that the attachment of coronaviruses to the surface of respiratory cells is mediated by the spike (S) viral protein, which binds not only to the angiotensin-converting enzyme 2 (ACE-2) receptor for entry16 but also to sialic acid–containing glycoproteins and gangliosides on cell surfaces.15 Such a dual receptor/attachment is proposed to be a reason for the increased transmissibility of COVID-19 compared with SARS-CoV that binds only to ACE-2 receptor.15,16 Of relevance to GBS is that various gangliosides, most commonly those containing either a disialosyl moiety, such as GD1b, GQ1b, and GT1b, or 2 gangliosides that share epitopes with GM2, or a combination of GM2 and GM1, GM1 and GD1b, can serve as antigens in patients with neuropathies.17 When IgM recognizes the Gal (pl-3) GalNAc moiety of GM1, which is found on the surface of motor neurons, there is clinically a motor neuropathy, but if recognizes epitopes containing disialosyl groups of GDlb, which is present on the dorsal root ganglionic neurons, there is sensory ataxic neuropathy.17 Immunization of rabbits with GDlb also causes sensory ataxic neuropathy mimicking the human disease.18 Of interest, the first described patient with sensory ataxic neuropathy and GDlb antibodies had also ophthalmoplegia,19 as seen in MFS and the present series.10 As COVID-19 spike interacts with the GalNAc residue of GM1 and ganglioside dimers for anchoring to cell surface gangliosides,15 cross-reactivity between epitopes within the COVID-19 spike-bearing gangliosides and signature sugar residues of surface peripheral nerve glycolipids is a very likely possibility.
T57 11657-11962 Sentence denotes Such typical molecular mimicry has been shown between peripheral nerve glycolipids and Campylobacter jejuni or Zika virus that also trigger GBS.1–3 Accordingly, all GBS subtypes (AIDP, AMAN, and MFS) can be expected with COVID-19, necessitating screening for ganglioside antibodies to assess autoimmunity.
T58 11963-12470 Sentence denotes An interesting therapeutic component in this association is the emerging data that chloroquine, an antimalarial drug under investigation for treating COVID-19, binds with high-affinity sialic acids and GM1 gangliosides and, in the presence of chloroquine, the SARS-CoV viral spike cannot bind gangliosides to infect the targeted cells.15 If benefit is confirmed and safety is established, chloroquine may be of added therapeutic value in future patients with COVID-19–triggered GBS in conjunction with IVIg.
T59 12472-12520 Sentence denotes What is more to come with myositis in the offing
T60 12521-13018 Sentence denotes Among the other potential COVID-19–associated autoimmune diseases, the first alarming concern is inflammatory myopathy, especially necrotizing autoimmune myositis (NAM) because very high CK levels >10,000 with myalgia and weakness are now reported in more than 10% of COVID-19–infected patients.6 Although COVID-19–associated myopathy has not yet been studied but only characterized as skeletal muscle injury or rhabdomyolysis,6 2 just published cases suggest an autoimmune COVID-19–triggered NAM.
T61 13019-13352 Sentence denotes One, an 88-year-old man from New York presented with acute bilateral thigh weakness and inability to get up from the toilet, without fever or other systemic symptoms, and very high CK level (13,581 U/L).20 He was found COVID-19 positive and given hydroxychloroquine, and a week later, his painful weakness improved with CK reduction.
T62 13353-13704 Sentence denotes The other, a 60-year-old man from Wuhan had a 6-day history of fever, cough, and COVID-19–positive pneumonia with normal strength and CK; 7 days later, although systemically had improved, his CRP doubled and developed painful muscle weakness with very high CK (11,842 U/L).21 He was given IVIg and his strength improved while became COVID-19 negative.
T63 13705-14382 Sentence denotes Myopathic symptoms in a severe systemic viral disease are multifactorial, but an acute onset of severe muscle weakness with increased inflammatory markers and very high CK levels in the thousands, as described above, is consistent with autoimmune inflammatory myopathy within the spectrum of NAM, similar to what was first reported with HIV early in that epidemic.22,23 The most common causes of NAM are not chronic statin use as overstated, but autoimmune, paraneoplastic, or postviral.22–25 Considering that very high CK level and painful muscle weakness were seen in 10% of COVID-19–positive patients,6 a potentially treatable autoimmune myopathy has been likely overlooked.
T64 14383-14845 Sentence denotes Studies with muscle biopsy and antibody screening are urgently needed in such patients because therapy with IVIg can improve strength, reduce morbidity, and facilitate recovery, as reported in the first 2 cases.20,21 COVID-19–associated myositis is also highly interesting because ACE-2, the SARS-CoV receptor, is reportedly expressed in skeletal muscle.26 If this is confirmed, COVID-19 may represent the first virus directly capable of infecting muscle fibers.
T65 14846-15137 Sentence denotes None of the viruses implicated in viral-triggered myositis has so far been shown to infect muscle27,28; instead, viruses induce an immune T cell with clonal expansion of viral-specific T cells or macrophage-mediated, muscle fiber autoinvasion with abundant proinflammatory cytokines.22,29,30
T66 15139-15200 Sentence denotes Other emerging postinfectious autoimmune neurologic disorders
T67 15201-15381 Sentence denotes Acute disseminated encephalomyelitis, as described for the other coronaviruses, or postinfectious brainstem encephalitis, myelitis, and radiculoneuropathies will not be unexpected.
T68 15382-16462 Sentence denotes An atypical case of acute necrotizing encephalopathy, attributed to immune-mediated process and proinflammatory cytokines, and another with meningoencephalitis and leptomeningeal enhancement have been already noted.31 This picture is now becoming more clear with 2 reports in this issue of the Journal, documented by impressive MRIs; one, a case of acute necrotizing brainstem encephalopathy, presented with epilepsy and changes in the right mesial temporal lobe and hippocampus32 and another with altered mental status and multiple white matter tumefactive lesions with postgadolinium enhancement in periventricular areas and corpus callosum suggestive of demyelination.33 Not underestimating the overwhelming burden of acute COVID-19 to medical staff, vigilance for these disorders is needed along with screening for autoimmune encephalitis autoantibodies14 because these cases can potentially respond to early initiation of immunotherapy, especially with IVIg, whenever indicated, which may additionally offer various potentially protective antibodies and anticytokine effects.
T69 16464-16552 Sentence denotes Residual neurologic deficits in COVID-19–recovered patients: need for a systematic study
T70 16553-16671 Sentence denotes No neurologic data are yet available about the discharged patients who survived the catastrophic effects of the virus.
T71 16672-16893 Sentence denotes We know that several people have permanently lost smell and taste, which is a form of disability affecting quality of life, depriving tasting pleasures, and the ability to detect danger signals, like smelling gas or fire.
T72 16894-17431 Sentence denotes Many discharged patients require assistance because of muscle weakness and gait unsteadiness, which is arguably multifactorial; some patients may have had critical illness neuropathy and deconditioning with significant muscle atrophy worsened by comorbidities; others may have neurotoxicity or myocytotoxicity from antiviral therapies, like first described with antiretrovirals or chloroquine34–36; still others may have the residual effects from an unrecognized primary myopathy, neuropathy, or myelopathy due to postviral autoimmunity.
T73 17432-17759 Sentence denotes A study exploring the patients' current causes of residual muscle weakness and sensory deficits is urgently needed using EMG, muscle or nerve biopsies, autoantibody screening, and CSF or imaging studies to determine immediate or long-term recovery prospects, identify potential reversibility, and accelerate return to normalcy.
T74 17761-17882 Sentence denotes Patients with autoimmune neurologic diseases: how is COVID-19 changing ongoing immunotherapies and the role of complement
T75 17883-18267 Sentence denotes Patients with autoimmune neuropathies, especially chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy, but also with other autoimmunities like myasthenia gravis, MS, and inflammatory myopathies, have been justifiably concerned as to whether their disease status adds an additional risk placing them into an immunosuppressed or immunocompromised category.
T76 18268-18539 Sentence denotes There is no current evidence that any of the aforementioned autoimmune disorder itself makes them more susceptible to COVID-19, but some immunosuppressive or even immunomodulating therapies they are receiving may have this potential, although there are no validated data.
T77 18540-18720 Sentence denotes Most autoimmune neuromuscular patients are maintained on steroids, mycophenolate, or azathioprine while most chronic inflammatory demyelinating polyneuropathy receive monthly IVIg.
T78 18721-18851 Sentence denotes The same applies to patients with MS where it seems safe to start or continue treatment with the standard disease-modifying drugs.
T79 18852-19009 Sentence denotes If clinically stable and not lymphopenic, there are no compelling or data-driven reasons to change anything in these patients and disturb clinical stability.
T80 19010-19588 Sentence denotes For patients on monthly IVIg, there may be even a theoretical advantage that IVIg offers additional protection due to natural autoantibodies; if IVIg is not infused as home infusion, switching to self-administered subcutaneous IgG might be an option to diminish exposure, as has been proven effective.37 For patients on rituximab, the infusion intervals can be prolonged to more than 6 months because both B-cell reduction and clinical benefit can persist longer.38 New emerging data provide credence and reassurance regarding these issues, especially on immunomodulating drugs.
T81 19589-19874 Sentence denotes In a large number of patients from Wuhan, published in this issue of the Journal,39 it was shown that altered immunity induced by disease-modifying drugs in patients with MS or neuromyelitis optica spectrum disorder appears insufficient to enhance susceptibility to COVID-19 infection.
T82 19875-20119 Sentence denotes The results are important but not unexpected considering that most of these therapies target the adaptive immune response with little, if any, effect on suppressing the innate immunity that facilitates infection of macrophages and viral spread.
T83 20120-21328 Sentence denotes Similar data from New York City area show that the incidence of hospitalization among patients with immune-mediated inflammatory diseases on therapy with steroids and biologic agents was consistent with that among patients with COVID-19 in the general population, concluding that ongoing use of biologics is not associated with worse COVID-19 outcomes.40 There is also new evidence suggesting possible beneficial effect of anticomplement therapies.41 Complement is an integral component of the innate immune response to viruses and an instigator of proinflammatory responses with evidence that activation of C3 exacerbates SARS-CoV–associated acute respiratory distress syndrome and C3-C5 complement deposits are abundant in the lung biopsies from patients with COVID-19.41 It was proposed that complement inhibition may alleviate the inflammatory complications of COVID-19 infection leading to ongoing trials with anti-C3 and anti-C5 agents.41,42 On this basis, eculizumab, an anti-C5 monoclonal antibody approved for neuromyelitis optica spectrum disorder and myasthenia gravis with some benefits in patients with GBS, may not be withheld, if indicated, as, like IVIg, may theoretically have added benefit.