Background
Methods
Case selection
Mechanical ventilation, autopsy pulmonary pathology, and microbiology laboratory findings
Statistics
Results
COVID-19 case cohort clinicopathological findings
Case no. | Age (yr)/Sex | Major comorbidities | BMIa | D-dimerb | Ventilator (da) | COVID-19–related treatment | Survival (da)/time of death (hr) |
---|---|---|---|---|---|---|---|
1c, d | 67/M | DM2 | 20.1 | N/R | Acutely | N/R | 0.021/0530 |
2c | 61/F | N/R | N/R | N/R | Acutely | N/R | 0.035/1316 |
3 | 44/M | HIV, HCV, TB, head injury several months previously | 25.1 | N/R | Acutely | N/R | 0.063/0543 |
4 | 84/F | HTN, IHD, arthritis, dementia, chronic venous stasis | 23.4 | N/R | Acutely | N/R | 0.09/1408 |
5 | 47/F | HTN, DM | N/R | N/R | Acutely | N/R | 0.167/1728 |
6 | 72/F | Obesity, influenza A | 43 | N/R | Acutely | N/R | 0.25/1245 |
7 | 49/M | HTN, obesity, SAD, BD | 34.9 | 6.9 FEU | 1 | N/R | 1/1404 |
8 | 61/M | HTN, IHD, COPD, ethanol abuse | 22 | 620 DDU | 2 | DEX, REM | 4/0511 |
9 | 76/F | HTN, DM, IHD, HIV | 25.9 | 326 DDU | None | DEX | 5/0444 |
10c | 37/M | HTN, HCV, HPV, hepatocellular carcinoma, SAD | 26 | N/R | None | N/R | 5/0744 |
11c | 49/F | HTN, obesity | 67.2 | N/R | 3 | DEX, TOC | 8/2340 |
12 | 61/F | IHD, COPD, emphysema, asthma, rectal carcinoma | 22.7 | 167 DDU | 8 | DEX | 8/0243 |
13 | 64/F | HTN, DM2, old stroke, obesity | 34.6 | N/R | 2 | N/R | 10/1350 |
14 | 65/M | HTN, DM, IHD, COPD, pulmonary fibrosis, obesity | 32.6 | 2551 DDU | < 1 | DEX, REM | 10/1330 |
15 | 63/M | HTN, atrial fibrillation, obesity | 46.1 | 45144 DDU | 12 | DEX, VAN | 12/2025 |
16c | 53/F | HTN, DM2, COPD, pulmonary hypertension, emphysema, obesity | 47 | N/R | None | TOC | 13/1818 |
17c | 58/F | HTN, DM, IHD, obesity, atrial fibrillation, CRD | 52 | N/R | 5 | None | 16/1749 |
18 | 61/F | HTN, DM2, obesity | 51.4 | 2528 DDU | 17 | DEX | 17/1957 |
19 | 68/M | HTN, DM2, CRD, anemia of chronic disease | 21.8 | 2574 DDU | None | DEX | 19/1100 |
20 | 62/F | HTN, DM2, IHD, bilateral carotid artery stenosis, obesity, HCV, hypothyroidism | 36.8 | 523 DDU | 5 | DEX, REM | 19/0437 |
21 | 69/F | HTN, DM2, IHD, obesity, CRD | 44.5 | 2462 DDU | 11 | DEX, REM | 22/0708 |
22e | 56/F | HTN, DM, IHD, COPD, asthma, obesity, blood clotting disorder, DVT, liver disease, CRD | 45.4 | N/R | None | DEX, REM | 23/0914 |
23 | 73/F | DM2 | 29 | 2805 DDU | 7 | DEX, REM, TOC | 24/1033 |
24 | 59/F | IHD, remote head trauma, small recent and intermediate cerebral infarcts, small intermediate/remote cerebellar infarcts | 21.1 | 51317 DDU | None | DEX | 26/0248 |
25 | 70/M | HTN, DM2, IHD, obesity, COPD, asbestosis, obesity, CRD | 77.0 | 527 DDU | 23 | DEX, REM | 27/0322 |
26 | 61/M | N/R | 20.7 | 8.07 FEU | 28 | DEX, REM | 29/0423 |
27 | 63/M | HTN, DM2, IHD, SAD, HBV, HCV, schizophrenia, BD, hepatic cirrhosis | 21.4 | N/R | 2, later 5, later 9 | N/R | 29/1654 |
28c | 66/M | HTN, HBV, hepatic cirrhosis | 28.3 | 2884 DDU | 13 | DEX, REM | 33/2108 |
29e | 63/M | HTN, DM, IHD, COPD, asbestosis, TTRA, HIV, HCV, recent left-sided weakness, CRD, hepatic cirrhosis | 21.8 | 1450 DDU | None | N/R | 35/2345 |
30 | 34/F | DM, obesity | 58.5 | N/R | 10, then 20 | N/R | 36/2159 |
31e | 62/M | HTN, DM2, DVT, BD, seizure history | 24.8 | 21604 DDU | 13, later 15 | DEX, REM | 39/1514 |
32 | 66/F | HTN, obesity, schizophrenia, gout | 40.2 | 252 DDU | 18 | DEX, REM, TOC | 39/0724 |
33 | 64/F | COPD, obesity, colon cancer | 36 | 0.62 FEU | 24 | DEX, REM | 41/1800 |
34 | 52/F | HTN, IHD, obesity | 54.6 | 5507 DDU | 18 | DEX | 44/1138 |
35 | 32/M | DM | 23.1 | N/R | 44 | DEX, REM | 56/0717 |
36 | 64/F | HTN, obesity, schizophrenia, ulcerative colitis | 33.3 | 962 DDU | 2, then 32 | DEX, CP | 84/2152 |
The most numerous brain findings in this cohort, aside from frequent neuronal hypoxic change, were in the microcirculation. The most common microcirculatory alteration was simple dilation (ectasia). In all but one case, variable numbers of microcirculatory channels had adventitial collagenosis or more compact hyaline sclerosis (Fig. 1). The third type of reactive microvasculopathy was intussusceptive arborization (IA), often seen as ‘mini-glomeruloid’ formations that were found in 15/36 (41.7%) cases.
Case no. | CNS microcirculatory intravascular PMN karyorrhexis/acute endotheliitis | Acute perivasculitis |
---|---|---|
1 | L thalamus, L int capsule | None |
2 | L frontal lobe, parietal lobes, R lat temp lobe, R insula, L calcarine cortex, L med hypothalamus, R int capsule, R lent nuc, cblr inf vermis, rostral and mid-level pons | Mid-level pons |
3 | Cblr inf vermis, R midbrain teg, L pontine teg, bulbar nuc of spinal tract of nerve V, nuc cuneatus | None |
4 | R occipital lobe, L basal ganglia, rostral R midbrain, caudal L midbrain, rostral pons, mid pons, caudal pons | Rostral L midbrain teg |
5 | R parietal lobe, med and lat temp lobes, R insula, L calcarine cortex, R and L corpus striatum, R thalamus, cblr R lat lobe and vermis, rostral L pons | None |
6 | Occipital lobe, putamen, thalami, anterior perforated substance, cblr lat lobes, midbrain and pontine teg levels, basis pontis and bulbar levels | R temp fusiform gyrus |
7 | R lat temp lobe, R int capsule, cblr white matter, R pontine teg, L pontine locus coeruleus, multiple basis pontis levels | Cblr L lat lobe |
8 | L frontal lobe, white matter adjacent to tail of caudate nucleus, R hippocampus, cblr R lat lobe | None |
9 | R frontal lobe, L temp entorhinal cortex, R lat temp lobe, R parietal lobe, calcarine cortex, R thalamus, R putamen, int capsule, midbrain tectum, caudal midbrain, rostral basis pontis, substantia reticularis by inf olivary nucleus | R substantia nigra, caudal midbrain teg, R basis pontis |
10 | L frontal lobe; parietal lobes; L med temp lobe; R and L insula; L corpus striatum; thalami; lent nuclei; cblr lat lobes and vermis; rostral, mid-level, and caudal midbrain and pons; mid-level medulla | R lat temp lobe, R insula, L lent nuc, mid-level midbrain, pons, medulla |
11 | Parietal lobes, R and L insula, R and L corpus striatum, lenticular nuclei, thalami, int capsules, R rostral midbrain, L mid-level and caudal midbrain | L frontal lobe, L insula, L int capsule, L mid-level midbrain |
12 | R frontal lobe; lat and med temp lobes; R and L insula; L calcarine cortex; R and L corpus striatum; lent nuclei; thalami; cblr lat lobes and vermis; rostral, mid-level, and caudal midbrain and pons; rostral and mid-level medulla | Rostral pons |
13 | L frontal lobe, R calcarine cortex, L int capsule, cblr R lat lobe, mid-level midbrain, mid-level pons | None |
14 | Frontal, parietal, temp, insular, and calcarine cortex; R hippocampus; lent nuclei; thalami; caudate nuclei; int capsules; L external and extreme capsules; cblr lat lobes and vermis; middle cblr peduncle; midbrain; pontine teg and basis pontis; nuc of tractus solitarius area; nuclei of cranial nerves V and XII; inf vestibular nuclei; inf olivary nuclei; olivocerebellar tracts; pyramid | L globus pallidus interna |
15 | Frontal lobes, parietal lobes, R temp entorhinal cortex, L lat temp lobe, occipital lobes, R putamen, thalami, L basal forebrain, cblr R lat lobe, rostral and caudal midbrain, basis pontis | Rostral L basis pontis |
16 | Int capsules, R putamen, R thalamus | L putamen |
17 | L parietal lobe, R calcarine cortex, R corpus striatum, R int capsule | None |
18 | R frontal lobe, L parietal lobe | R lat temp lobe |
19 | R frontal lobe, L lat temp lobe, R thalamus, midbrain, mid-level and caudal basis pontis | None |
20 | R frontal orbital cortex; R lat temp lobe; L parietal lobe; L int capsule; cblr R lat lobe, dentate nuc, and middle cblr peduncle; caudal pons; rostral medulla; caudal bulbar pyramidal tract | R frontal orbital cortex, R thalamus, L lent nuc, L hypothalamus, rostral and caudal midbrain, pons |
21 | Frontal lobes, R parietal lobe, lat temp lobes, R med temp lobe, L int capsule, cblr L lat lobe, mid-level pons, mid-level medulla | Parietal lobes, R med temp lobe, L corpus striatum, R putamen, mid-level medulla |
22 | R frontal lobe; R lat temp lobe; L lat and med temp lobe; R and L insula; L thalamus; R int capsule; cblr lat lobes and vermis; caudal L midbrain; middle cblr peduncle; rostral, mid-level, and caudal pons and medulla | L lent nuc |
23 | Parietal lobes; R entorhinal cortex; R lat temp lobe; L insula; L calcarine cortex; R and L corpus striatum; thalami; cblr L lat lobe and vermis; caudal midbrain; rostral, mid-level, and caudal pons; mid-level and caudal medulla | R int capsule, cblr R lat lobe and vermis, mid- level pons |
24 | R med temp lobe, R putamen, mid-level pons | None |
25 | L parietal lobe, R lat and med temporal lobe, R caudate nuc, putamina, R thalamus, R midbrain teg and bilateral crus cerebri, L pontine teg, basis pontis | Rostral R midbrain, multiple L pontine levels |
26 | Cblr vermis, caudal pontine teg | None |
27 | L frontal lobe, L insula, R parietal lobe, cblr lat lobes and vermis, rostral R midbrain, mid-level pons, rostral medulla | None |
28 | L frontal lobe, L lat temp lobe, R and L insula, parietal lobes, R and L corpus striatum, lent nuclei, R claustrum, L thalamus, int capsules, cblr lat lobes, L middle cblr peduncle, R and L mid-level midbrain, rostral pontine teg and basis pontis, mid-level R and L basis pontis, caudal basis pontis, caudal medulla | R hypothalamus |
29 | L lat temp lobe, L insula, R calcarine cortex, head of L caudate nuc, rostral R pontine teg, caudal L pontine teg near superior vestibular nuc, mid-level medulla near lat reticular nuc | R supraoptic nuc |
30 | R parietal lobe, R calcarine cortex, L thalamus, rostral bulbar inf olivary nuc | R parietal lobe |
31 | Frontal lobes; L parietal lobe; L insula; L claustrum; extreme capsules; L corpus striatum; L globus pallidus; cblr L lat lobe and vermis; rostral, mid-level, and caudal pons; mid-level medulla | R frontal lobe, cblr lat lobes, rostral midbrain, mid-level and caudal pons, mid-level medulla |
32 | R frontal lobe, L parietal lobe, R corpus striatum, posterior thalami, cblr L lat lobe | R frontal lobe, R lent nuc, caudal L midbrain, rostral and mid-level pons |
33 | R frontal lobe, L temp and parietal lobes, L thalamus, L putamen, globus pallidus externa, cblr lat lobes, rostral and caudal R midbrain teg and substantia nigra, rostral L substantia nigra, caudal R crus cerebri, rostral R basis pontis, pyramidal tract | None |
34 | L frontal lobe; parietal lobes; R lat and med temp lobe; L lat temp lobe; R and L insula; R and L calcarine cortex; R and L corpus striatum; R hypothalamus; int capsules; cblr lat lobes and vermis; rostral L midbrain; mid-level midbrain crus cerebri and substantia nigra; caudal midbrain; rostral, mid-level, and caudal pons and medulla | Rostral L midbrain, mid- level R and L midbrain, inf cblr peduncle, caudal medulla |
35 | Frontal lobes, R parietal lobe, lat temp lobes, R and L insula, R and L corpus striatum, R lent nucleus, L thalamus, cblr vermis, caudal midbrain, mid-level and caudal pons | R basis pontis |
36 | L frontal lobe, R and L lateral temp lobes, R hippocampus, R parietal lobe, R ant comm, R thalamus, R lent nuc, L globus pallidus, internal capsules, R hypothalamus, cblr lat lobes, right substantia nigra, caudal crus cerebri, R rostral basis pontis, R and L mid-level and caudal basis pontis, R and L caudal pontine teg, bulbar reticular formation | L lat temp lobe, R midbrain teg |
Contemporary and historical control cases compared to COVID-19 cohort cases
Case no. | Age (yr)/Sex | Major clinical and autopsy diagnoses; positive blood cultures | Ventilator use (da) | Anti-coagulation treatment | Karyorrhectic CNS small blood vessels | Hospital survival (da) |
---|---|---|---|---|---|---|
Non-COVID-19 cases | ||||||
1 | 67/F | HTN, DM, COPD, obesity, cancer | N/R | Aspirin, heparin, enoxaparin | No | 5 |
2 | 34/F | SAD, acute pancreatitis, hepatic cirrhosis | Acutely | N/R | Yes | 0.03 |
3 | 54/M | HTN, DM, CRD, clinical sepsis, necrotizing pneumonia | 4 | N/R | Yes | 4 |
4 | 67/F | DM2, obesity, cancer, acute Candida albicans pneumonia | Acutely | Heparin | No | 0.25 |
5 | 61/M | HTN, DM2, IHD, SAD | Acutely | Aspirin | No | 0.06 |
6 | 60/F | HTN, IHD, obesity, DVT, PE, retroperitoneal abscess (Streptococcus anginosus), transverse colectomy, small bowel resection | E/P | Heparin, apixaban | Yes | 3 |
7 | 47/M | HTN, IHD, obesity, atrial fibrillation; Klebsiella pneumoniae | Acutely | Heparin | Yes | 0.04 |
8a | 64/M | HTN, DM, IHD, cancer, CRD | Acutely | Heparin | Yes | 0.04 |
9 | 59/M | HTN, DM, obesity, CRD, PE | 3.5 | Aspirin, heparin | No | 3.5 |
10b | 55/F | HTN, DM, IHD, SAD, hepatic cirrhosis | Acutely | N/R | Yes | 9 |
11 | 71/M | HTN, COPD, GI ulcer hemorrhages; Clostridium innocuum, Bacteriodes uniformis, Lactobacillus spp. | Acutely | N/R | Yes | 0.4 |
12a, c | 64/M | HTN, IHD, SSD, MDS | Acutely | Aspirin, apixaban | Yes | 9 |
13a | 67/F | HTN, IHD, COPD, obesity, CRD, diffuse cerebral atrophy; Citrobacter braakii, Serracia marcesens, Klebsiella pneumoniae | N/R | N/R | No | 13 |
14a | 61/M | HTN, DM2, IHD, HCV, CRD, hepatic cirrhosis, small remote cerebellar infarct | 1 | Aspirin, clopidogrel | Yes | 1.5 |
15 | 62/F | HTN, obesity, SAD, hepatic cirrhosis, toxic epidermal necrosis, diffuse cerebral atrophy; Staphylococcus aureus | N/R | N/R | No | 5 |
16a | 49/M | IHD, obesity, gastric necrosis, intestinal gangrene, recent globus pallidus infarcts; Enterococcus faecalis, Escherichia coli, Enterobacter cloacae complex, Bacteroides thetaiotaomicron, Clostridium sporogenes | E/P | Heparin | Yes | 2 |
17 | 78/F | IHD, non-COVID ARDS, obesity, DVT, PE | 4 | Heparin, apixaban, enoxaparin | Yes | 9.5 |
18 | 43/M | HTN, asthma, obesity, bronchial mucous plugs; Escherichia coli | Acutely | N/R | No | 0.04 |
19a | 48/M | HTN, DM2, IHD, obesity, SAD, acute bronchopneumonia | 3 | Heparin, enoxaparin | No | 3 |
20 | 35/F | HTN, obesity, post-partum presumptive viral meningoencephalitis, pulmonary artery saddle embolus | N/R | N/R | No | 0.5 |
21a | 44/M | HTN, DM1, cancer, small corpus striatum resolving infarct; E. faecalis, E. faecium, E. casseliflavus, K. pneumoniae | N/R | N/R | No | 7 |
Resolved COVID-19 cases/post-COVID survival time (mo.) | ||||||
22 | 74/M | HTN, DM, IHD, renal failure, LUE AVF severe hemorrhage/9 | N/R | N/R | No | 0.03 |
23 | 76/M | HTN, IHD, atrial fibrillation, SAD, CRD/10 | 3 | Apixaban | No | 3 |
24 | 43/M | SAD, HCV, hepatic cirrhosis, CML with brain metastases/2 | 0.5 | N/R | No | 5 |
25 | 60/F | HTN, IHD, SAD, ruptured aortic aneurysm/5 | N/R | Heparin | No | 9 |
26b | 64/F | HTN, IHD, COPD, obesity, cancer/15; Staphylococcus aureus, Achromobacter xylosoxidans | None | Heparin | No | 0.25 |
27 | 69/M | HTN, IHD, atrial fibrillation, obesity/10; Streptococcus agalactiae, Enterobacter cloacae complex | N/R | Enoxaparin | Yes | 11 |
Case no. | Age (yr)/Sex | Major clinical and autopsy diagnoses; positive blood cultures | Ventilator use (da) | Anti-coagulation treatment | Karyorrhectic CNS small blood vessels | Hospital survival (da) |
---|---|---|---|---|---|---|
1 | 61/M | HTN, DM2, obesity, DLE, lung abscess; diphtheroids | Acutely | Enoxaparin | Yes | 3 |
2 | 64/F | HTN, DM, COPD, IHD, obesity, cancer; Acinetobacter baumannnii, diphtheroids | 2 | Enoxaparin | No | 2 |
3 | 70/F | HTN, obesity, clinical remote stroke; Klebsiella pneumoniae | N/R | Warfarin, enoxaparin | Yes | 4 |
4 | 53/F | HTN, DM2, IHD, obesity; Clostridium perfringens, α-hemolytic Streptococcus | Acutely | N/R | Yes | 0.2 |
5 | 66/F | HTN, DM, IHD, obesity, remote stroke NCH; Enterococcus faecalis, Pseudomonas mirabilis | N/R | Aspirin, apixaban | Yes | 1 |
6 | 52/M | HTN, DM, IHD, CRD, pancreatitis; Klebsiella pneumoniae | Acutely | N/R | No | 9 |
7 | 61/F | HTN, obesity, cancer, PE; Enterococcus gallinarum | E/P | Heparin, enoxaparin | Yes | 11 |
8 | 69/F | HTN, BD, basal ganglia hemorrhage; K. pneumoniae | Acutely | N/R | No | 0.2 |
9 | 65/F | HTN, COPD, focal frontal lobe perivascular brain hemorrhage; diphtheroids | Acutely | Heparin | No | 0.04 |
10 | 57/M | DM2, PE | Acutely | Enoxaparin, tPA | No | 2 |
11 | 35/M | Obesity, epilepsy, frontotemporal FCD | Acutely | N/R | No | 0.04 |
12 | 38/M | Obesity, aortic dissection, PE | N/R | Heparin, tPA | Yes | 12 |
13 | 39/M | HCV, Lyme disease, SAD, CAH, cervical spinal epidural abscesses; Staphylococcus aureus | N/R | N/R | Yes | 6 |
14 | 47/F | HTN, DM2, IHD, COPD, obesity, congenital heart disease | N/R | tPA | No | 0.6 |
15 | 86/F | HTN, cancer, CRD, aortic dissection, small remote basal ganglia infarcts; Staphylococcus aureus, α-hemolytic Streptococcus | Acutely | N/R | No | 0.02 |
16 | 91/F | HTN, IHD, CRD, BD, schizophrenia, stroke NCH; K. pneumoniae, Escherichia coli, Clostridium perfringens | Acutely | N/R | Yes | 0.04 |
17 | 63/M | HTN, IHD, BD, DVT, PE, 0.5-cm left frontal remote infarct | E/P | Enoxaparin | Yes | 11 |
18 | 59/F | HTN, arthritis, gastric ulcers, sepsis, intestinal and gall bladder necrosis; Candida glabrata | E/P | N/R | No | 2 |
19 | 58/M | HTN, cancer | N/R | Heparin | No | 8 |
20 | 60/M | Obesity, SAD, hepatic cirrhosis, thrombocytopenia; Candida albicans | 2 | Aspirin | No | 4 |
21 | 71/M | HTN, DM2, IHD, obesity, cancer, CRD | Acutely | Aspirin | No | 6 |