Acute neutrophilic vasculitis (leukocytoclasia) in 36 COVID-19 autopsy brains

Abstract

Background: Hypercytokinemia, the renin-angiotensin system, hypoxia, immune dysregulation, and vasculopathy with evidence of immune-related damage are implicated in brain morbidity in COVID-19 along with a wide variety of genomic and environmental influences. There is relatively little evidence of direct SARS-CoV-2 brain infection in COVID-19 patients.

Methods: Brain histopathology of 36 consecutive autopsies of patients who were RT-PCR positive for SARS-CoV-2 was studied along with findings from contemporary and pre-pandemic historical control groups. Immunostaining for serum and blood cell proteins and for complement components was employed. Microcirculatory wall complement deposition in the COVID-19 cohort was compared to historical control cases. Comparisons also included other relevant clinicopathological and microcirculatory findings in the COVID-19 cohort and control groups.

Results: The COVID-19 cohort and both the contemporary and historical control groups had the same rate of hypertension, diabetes mellitus, and obesity. The COVID-19 cohort had varying amounts of acute neutrophilic vasculitis with leukocytoclasia in the microcirculation of the brain in all cases. Prominent vascular neutrophilic transmural migration was found in several cases and 25 cases had acute perivasculitis. Paravascular microhemorrhages and petechial hemorrhages (small brain parenchymal hemorrhages) had a slight tendency to be more numerous in cohort cases that displayed less acute neutrophilic vasculitis. Tissue burden of acute neutrophilic vasculitis with leukocytoclasia was the same in control cases as a group, while it was significantly higher in COVID-19 cases. Both the tissue burden of acute neutrophilic vasculitis and the activation of complement components, including membrane attack complex, were significantly higher in microcirculatory channels in COVID-19 cohort brains than in historical controls.

Conclusions: Acute neutrophilic vasculitis with leukocytoclasia, acute perivasculitis, and associated paravascular blood extravasation into brain parenchyma constitute the first phase of an immune-related, acute small-vessel inflammatory condition often termed type 3 hypersensitivity vasculitis or leukocytoclastic vasculitis. There is a higher tissue burden of acute neutrophilic vasculitis and an increased level of activated complement components in microcirculatory walls in COVID-19 cases than in pre-pandemic control cases. These findings are consistent with a more extensive small-vessel immune-related vasculitis in COVID-19 cases than in control cases. The pathway(s) and mechanism for these findings are speculative.

Keywords: Acute neutrophilic vasculitis; Antigen-antibody complex; COVID-19; Central nervous system; Complement component; Karyorrhexis; Microcirculation; Microvessel; SARS-CoV-2.

Fig. 1

Cerebral microvasculopathy with mural collagenosis. (A) Severe mural distortion with irregular adventitial collagenosis of a microvessel in midbrain tegmentum near substantia nigra (Case 13). (B) Dilated microvessel with somewhat compact adventitial collagenosis in periventricular calcarine white matter (Case 12). Scale bars: 20 μm in (A); 50 μm in (B)

Fig. 2

Acute endotheliitis. (A) In midbrain tegmentum, a thin-walled microcirculatory channel has many karyorrhectic PMNs including some fragmenting into dot-like nuclear dust (Case 10). (B) Similar finding as in (A) is seen here in subarachnoidal microvessels between folia of the cerebellar superior vermis (Case 10). (C) Small microcirculatory channel with mural collagenosis in medial temporal subependymal white matter has intraluminal karyorrhectic PMNs and mononuclear cells (Case 14). (D) In lateral temporal white matter, a dilated thin-walled microvessel is filled with PMNs, many with karyorrhexis, and mononuclear cells. There is scattered ‘nuclear dust’ (black arrow) and a few karyorrhectic PMNs appear to be transmigrating into fibrous adventitia (white arrow) (Case 14). (E) Mixture of karyorrhectic PMNs, some ‘nuclear dust’, and many mononuclear cells in very dilated microvessel in internal capsule near hypothalamus (Case 23). (F) Pyknotic and karyorrhectic PMNs arrayed along luminal border of microvessel in lateral hypothalamus (Case 34). Scale bars: 10 μm in (A–C, E and F); 20 μm in (D)

Fig. 3

Nucleus of the tractus solitarius region. (A) Small, dilated microcirculatory channel adjacent to the nucleus in the rostral medulla contains PMNs with karyorrhectic nuclei (Case 14). (B) There is a thromboembolized microcirculatory channel at edge of nucleus of tractus solitarius (arrow) and similar blood vessel near the nucleus, with prominent reactive gliosis in the field (Case 36). Scale bars: 10 μm in (A); 20 μm in (B)

Fig. 4

Acute perivasculitis and mural PMN transmigration. (A) Dilated, thin-walled microvessel with serpiginous profile (arrows) is surrounded by perivascular hemorrhage containing PMNs in rostral pontine tegmentum (Case 25). (B) Higher magnification of perivascular hemorrhage in A includes many PMNs indicating acute perivasculitis (Case 25). (C) Cerebellar folial white matter microvessel with collagenosis and perivascular hemorrhage with PMNs (Case 31). (D) Temporal fusiform gyrus white matter microvessel has perivascular hemorrhage with PMNs, some appearing to be karyorrhectic (Case 31). (E) Many PMNs ringing microvessel in mid-level basis pontis are karyorrhectic (Case 10). (F) Subarachnoidal arteriolar wall with transmigrating PMNs (Case 31). Scale bars: 50 μm in (A); 20 μm in (B) and (C); 10 μm in (D–F)

Fig. 5

Complement component activation. (A) Dilated microcirculatory wall in rostral basis pontis is focally positive with immunostaining for C3d (Case 25). (B) Microcirculatory wall shown in (A) is seen here heavily positive for C4d. C5b-9 immunostaining was negative (Case 25). (C) Rostral basis pontis microcirculatory channel with immunostaining positive for C4d, with separation of mural layers (Case 25). (D) C4b positive immunostain associated with PMNs, in perivascular hemorrhage in periaqueductal central gray matter of midbrain, indicates acute perivasculitis with complement component activation (Case 4). (E) C5b-9 positive stain associated with PMNs in perivascular hemorrhage shown in (D) indicates membrane attack complex formation in acute perivasculitis (Case 4). (F) C5b-9 immunostaining in acute perivasculitis in rostral pontine tegmentum (Case 25). Scale bars: 10 μm in (A–F)