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1/ THREAD: New Autopsy Series (NYC/ @uiowa) in @NEJM
Microvascular Injury in the Brains of Patients with #COVID19
https://www.nejm.org/doi/full/10.1056/NEJMc2033369#.X-z9hxRCh2s.twitter
N = 19
Interesting observations from the paper, but I found the most intriguing data was actually in the supplement
HT @NeuroIDdoc https://twitter.com/NeuroIDdoc/status/1344409875128999938
Microvascular Injury in the Brains of Patients with #COVID19
https://www.nejm.org/doi/full/10.1056/NEJMc2033369#.X-z9hxRCh2s.twitter
N = 19
Interesting observations from the paper, but I found the most intriguing data was actually in the supplement
HT @NeuroIDdoc https://twitter.com/NeuroIDdoc/status/1344409875128999938
2/ N=19
* Convenience sample of patients who had died from #COVID19 March-July 2020*
(All patients confirmed #SARSCoV2 positive by PCR Nasopharyngeal swab ante- or post- mortem)
16 = #NYC
3 = @uiowa
50 y = Median Age (range 5-73y)
15 (78.9%) = Male
4 (21.0%) = Female
* Convenience sample of patients who had died from #COVID19 March-July 2020*
(All patients confirmed #SARSCoV2 positive by PCR Nasopharyngeal swab ante- or post- mortem)
16 = #NYC
3 = @uiowa
50 y = Median Age (range 5-73y)
15 (78.9%) = Male
4 (21.0%) = Female
3/ 14 (73.6%) = Chronic Illness
Many patients had more than one risk factor:
6 = CVD/HTN
6 = DM
5 = Obesity
3 = Nursing Care Residence
3 (15.7%) = SUD
1 = SLE
1 = MPS III
Many patients had more than one risk factor:
6 = CVD/HTN
6 = DM
5 = Obesity
3 = Nursing Care Residence
3 (15.7%) = SUD
1 = SLE
1 = MPS III
4/ OF CONCERN:
8 (42.1%) = FOUND DEAD at home or in public settings with limited known recent medical history but with sufficient concern on the part of family members to prompt testing for #SARSCoV2
@JAMA_current article excess mortality: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2774273 @jeremyfaust
8 (42.1%) = FOUND DEAD at home or in public settings with limited known recent medical history but with sufficient concern on the part of family members to prompt testing for #SARSCoV2
@JAMA_current article excess mortality: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2774273 @jeremyfaust
5/ 16 = Had available medical histories for #COVID19 Sx including:
→ 1 = Delirium
→ 5 = Mild respiratory symptoms
→ 4 = ARDS
→ 2 = PE
→ 3 = Unknown
→ 1 = Delirium
→ 5 = Mild respiratory symptoms
→ 4 = ARDS
→ 2 = PE
→ 3 = Unknown
6/ 13 = Brains examined by MR microscopy (MRM) brain
→ 10 = Abnormalities seen in brain
→ 5 = Examined with Mulitplex fluorescence imaging
→ 10 = chromogenic immunostaining
18 = Conventional Histopathological Exam
→ 10 = Abnormalities seen in brain
→ 5 = Examined with Mulitplex fluorescence imaging
→ 10 = chromogenic immunostaining
18 = Conventional Histopathological Exam
7/ MR Microscopy (N=13)
→ 9 = Punctate hyperintensities (areas of microvascular injury and fibrinogen leakage w/ corresponding features on histopathological exam w/ fluorescence imaging)
→ 5 = Thinning of basal lamina of endothelial cells by collagen IV immunostaining
#Covid
→ 9 = Punctate hyperintensities (areas of microvascular injury and fibrinogen leakage w/ corresponding features on histopathological exam w/ fluorescence imaging)
→ 5 = Thinning of basal lamina of endothelial cells by collagen IV immunostaining
#Covid
8/ → 10 = Punctate hypointensities on imaging corresponded to congested blood vessels with surrounding areas of fibrinogen leakage and relatively intact vasculature.
*Areas of linear hypointensities were interpreted as microhemorrhages (a finding seen in other #COVID autopsies)
*Areas of linear hypointensities were interpreted as microhemorrhages (a finding seen in other #COVID autopsies)
9/ This is particularly intriguing considering work done by @AkassoglouLab @GladstoneInst @UCSF
Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model https://www.cell.com/neuron/fulltext/S0896-6273(19)30015-7
Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model https://www.cell.com/neuron/fulltext/S0896-6273(19)30015-7
10/ 13 = Perivascular activated microglia, macrophage infiltrates and hypertropic astrocytes were seen
8 = CD3+ and CD8+ T cells in perivascular spaces and in lumens adjacent to enthothelial cells
#COVID19 #coronavirus #MedTwitter #NurseTwitter
8 = CD3+ and CD8+ T cells in perivascular spaces and in lumens adjacent to enthothelial cells
#COVID19 #coronavirus #MedTwitter #NurseTwitter
11/ 5 = Activated microglia were found adjacent to neurons, suggestive of neuronophagia in the olfactory bulb, substantia nigra, dorsal motor nucleus of the vagal nerve and the Pre-Botzinger complex in the medulla
#COVID19 #coronavirus #MedTwitter #NurseTwitter
#COVID19 #coronavirus #MedTwitter #NurseTwitter
12/ Which leads me to another interesting paper from @AkassoglouLab and team at @GladstoneInst @UCSF
Microglial Gi-dependent dynamics regulate brain network hyperexcitability
https://www.nature.com/articles/s41593-020-00756-7
Microglial Gi-dependent dynamics regulate brain network hyperexcitability
https://www.nature.com/articles/s41593-020-00756-7
13/ The Main Point:
"Multifocal microvascular injury was observed in the brain and olfactory bulbs by means of MR microscopy, histopathological evaluation and immunohistochemistry analysis of corresponding sections without evidence of viral infection."
#Covid #coronavirus
"Multifocal microvascular injury was observed in the brain and olfactory bulbs by means of MR microscopy, histopathological evaluation and immunohistochemistry analysis of corresponding sections without evidence of viral infection."
#Covid #coronavirus
14/ - #SARSCoV2 was not detected in the brain by RT-PCR, RNA sequencing, RNA ISH, immunostaining
HOWEVER:
- Limited clinical information was available so no conclusions can be drawn in relation to neurologic features of #COVID19
HOWEVER:
- Limited clinical information was available so no conclusions can be drawn in relation to neurologic features of #COVID19
15/ IMPORTANT NOTES:
- Sample of *convenience* not a #COVID neurological symptom specific population
- 2 patients had pre-existing TBI
- 1 child had pre-existing neurodegenerative disorder
--> Interestingly though the earlier German study was similar: https://twitter.com/ErinSandersNP/status/1333468497284911107?s=20
- Sample of *convenience* not a #COVID neurological symptom specific population
- 2 patients had pre-existing TBI
- 1 child had pre-existing neurodegenerative disorder
--> Interestingly though the earlier German study was similar: https://twitter.com/ErinSandersNP/status/1333468497284911107?s=20
16/ ADD'L OBSERVATIONS:
All 3 patients ages 37-39yo were MALE
→ 3 = SUD [IA#2, NY#3, NY#11]
→ 3 = Cardiac hypertrophy/LVH [IA#2, NY#3, NY#11]
→ 2 = HTN [IA#2, NY11]
→ 1 = Sudden death (6 wks AFTER acute infection) [NY#11]
→ 1 = Pulmonary/renal infarcts
→ 1 = SLE
@EricTopol
All 3 patients ages 37-39yo were MALE
→ 3 = SUD [IA#2, NY#3, NY#11]
→ 3 = Cardiac hypertrophy/LVH [IA#2, NY#3, NY#11]
→ 2 = HTN [IA#2, NY11]
→ 1 = Sudden death (6 wks AFTER acute infection) [NY#11]
→ 1 = Pulmonary/renal infarcts
→ 1 = SLE
@EricTopol
17/ BOTH patients age 19 and 24yo were:
- MALE
- Previously HEALTHY with no known illnesses
- Died of sudden death (NY#6 = Collapsed while standing, NY#15 = Found in vfib)
- Died weeks after either initial exposure to case or initial symptoms (NY#6 = Flu sx x 3 weeks
@EricTopol
- MALE
- Previously HEALTHY with no known illnesses
- Died of sudden death (NY#6 = Collapsed while standing, NY#15 = Found in vfib)
- Died weeks after either initial exposure to case or initial symptoms (NY#6 = Flu sx x 3 weeks
@EricTopol
18/ NY#15 = dad+ 4 weeks prior]
- Had acute lung injury on gross pathologic inspection (NY#15 also had splenomegaly)
This is particularly gripping in light of the findings we are seeing in young male athletes: https://twitter.com/ErinSandersNP/status/1341946671471747074?s=20
@EricTopol @uche_blackstock @EbonyJHilton_MD
- Had acute lung injury on gross pathologic inspection (NY#15 also had splenomegaly)
This is particularly gripping in light of the findings we are seeing in young male athletes: https://twitter.com/ErinSandersNP/status/1341946671471747074?s=20
@EricTopol @uche_blackstock @EbonyJHilton_MD
19/ On microscopy NY#6 (24M)
- Panel G shows CD68+ perivascular macrophages in the pons
- Panel J shows intraluminal and perivascular CD8+ cells in the pons
- Panel K shows perineuronal IBA1 cells in the pons
@VirusesImmunity @ShelFarFar @ericsongg @AkassoglouLab @NeuroIDdoc
- Panel G shows CD68+ perivascular macrophages in the pons
- Panel J shows intraluminal and perivascular CD8+ cells in the pons
- Panel K shows perineuronal IBA1 cells in the pons
@VirusesImmunity @ShelFarFar @ericsongg @AkassoglouLab @NeuroIDdoc
20/ Of 3 children age <18yo:
- 3 = MIS-C [NY#9, NY#13, NY#16]
- 3 = Acute lung injury on gross pathologic inspection
- 2 = ECMO [NY#9, NY#16]
- 2 = Male [NY#9, NY#13]
- 2 = Hyper sensitivity myocarditis on gross pathologic inspection & hypertrophic cardiomyopathy [NY#9, NY#13]
- 3 = MIS-C [NY#9, NY#13, NY#16]
- 3 = Acute lung injury on gross pathologic inspection
- 2 = ECMO [NY#9, NY#16]
- 2 = Male [NY#9, NY#13]
- 2 = Hyper sensitivity myocarditis on gross pathologic inspection & hypertrophic cardiomyopathy [NY#9, NY#13]
21/ Of the 4 females, excluding the 1 child with neurogenerative disorder, the 3 were age 64, 58, 58 and had multiple comorbidities.
- IA#3 = Obesity, DM, asthma & schizophrenia
- NY#4 = HTN/CAD, DM, & bladder cancer
- NY#5 = Obesity
Not unexpected for #COVID...HOWEVER...
- IA#3 = Obesity, DM, asthma & schizophrenia
- NY#4 = HTN/CAD, DM, & bladder cancer
- NY#5 = Obesity
Not unexpected for #COVID...HOWEVER...
22/ Microscopy of 2/3 adult females that died of #COVID:
- Microglial nodules containing neurons undergoing neuronophagia were also seen in the thalamus of NY#5 (Q), and in the pons (R, S) and dmX (T) of NY#4.
- Panel H shows perivascular astrocytosis in the basal ganglia in NY#5
- Microglial nodules containing neurons undergoing neuronophagia were also seen in the thalamus of NY#5 (Q), and in the pons (R, S) and dmX (T) of NY#4.
- Panel H shows perivascular astrocytosis in the basal ganglia in NY#5
23/ In summary, of the 19 cases:
- 11 = Vascular pathology as demonstrated by MR multiplex fluorescent imaging and/or H&E
- 13 = Perivascular infiltrates
- 6 = Acute ischemic hypoxic neurons on H&E staining
- 5 = Changes suggestive of neuronophagia with microglial activation
- 11 = Vascular pathology as demonstrated by MR multiplex fluorescent imaging and/or H&E
- 13 = Perivascular infiltrates
- 6 = Acute ischemic hypoxic neurons on H&E staining
- 5 = Changes suggestive of neuronophagia with microglial activation
24/ Again, this study creates about a million more questions for me than it answers...
It is intriguing that the findings in this study are so different from the Germany series and the @YaleIBIO study despite all 3 not screening for neuro sx. https://twitter.com/VirusesImmunity/status/1333493473526288389?s=20
It is intriguing that the findings in this study are so different from the Germany series and the @YaleIBIO study despite all 3 not screening for neuro sx. https://twitter.com/VirusesImmunity/status/1333493473526288389?s=20
25/ However, the study is consistent with my belief that the neurological symptoms and damage seen in #Covid are not primarily due to direct viral invasion (although possible) but an aberrant immune response. There was also an interesting hypothesis in the @YaleIBIO study:
@threadreaderapp please unroll
For a list of my threads: https://docs.google.com/spreadsheets/d/1-jqwvJ_KDQ14s-yn9hj2ysX0HAoQqOZtO9UyLhXWyeo/edit#gid=0
For a list of my threads: https://docs.google.com/spreadsheets/d/1-jqwvJ_KDQ14s-yn9hj2ysX0HAoQqOZtO9UyLhXWyeo/edit#gid=0
