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SARS-CoV-2 infection might be a predictor of mortality in intracerebral hemorrhage

Published:November 22, 2022DOI:https://doi.org/10.1016/j.jns.2022.120497

      Highlights

      • SARS-COV2 infection might be associated with Intracerebral Hemorrhage (ICH).
      • ICH patients with COVID-19 were younger, had higher ICH scores, a more frequent history of diabetes, and lower platelet counts.
      • Infection with SARS-CoV-2 was associated with increased odds of in-hospital mortality in ICH patients.

      Abstract

      Background

      SARS-CoV-2 infection may be associated with uncommon complications such as intracerebral hemorrhage (ICH), with a high mortality rate. We compared a series of hospitalized ICH cases infected with SARS-CoV-2 with a non-SARS-CoV-2 infected control group and evaluated if the SARS-CoV-2 infection is a predictor of mortality in ICH patients.

      Methods

      In a multinational retrospective study, 63 cases of ICH in SARS-CoV-2 infected patients admitted to 13 tertiary centers from the beginning of the pandemic were collected. We compared the clinical and radiological characteristics and in-hospital mortality of these patients with a control group of non-SARS-CoV-2 infected ICH patients of a previous cohort from the country where the majority of cases were recruited.

      Results

      Among 63 ICH patients with SARS-CoV-2 infection, 23 (36.5%) were women. Compared to the non-SARS-CoV-2 infected control group, in SARS-CoV-2 infected patients, ICH occurred at a younger age (61.4 ± 18.1 years versus 66.8 ± 16.2 years, P = 0.044). These patients had higher median ICH scores ([3 (IQR 2–4)] versus [2 (IQR 1–3)], P = 0.025), a more frequent history of diabetes (34% versus 16%, P = 0.007), and lower platelet counts (177.8 ± 77.8 × 109/L versus 240.5 ± 79.3 × 109/L, P < 0.001). The in-hospital mortality was not significantly different between cases and controls (65% versus 62%, P = 0.658) in univariate analysis; however, SARS-CoV-2 infection was significantly associated with in-hospital mortality (aOR = 4.3, 95% CI: 1.28–14.52) in multivariable analysis adjusting for potential confounders.

      Conclusion

      Infection with SARS-CoV-2 may be associated with increased odds of in-hospital mortality in ICH patients.

      Keywords

      1. Introduction

      Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be associated with potentially life-threatening thrombotic complications such as cerebrovascular and venous thromboembolic events. [
      • Dorche M.S.
      • et al.
      Neurological complications of coronavirus infection; a comparative review and lessons learned during the COVID-19 pandemic.
      ,
      • Shakibajahromi B.
      • et al.
      Cerebral venous sinus thrombosis might be under-diagnosed in the COVID-19 era.
      ,
      • Mowla A.
      • et al.
      Cerebral venous sinus thrombosis associated with SARS-CoV-2; a multinational case series.
      ,
      • Khaljiri H.J.
      • et al.
      Comprehensive Review on Neuro-COVID-19 Pathophysiology and Clinical Consequences.
      ] The association of ischemic stroke with SARS-CoV-2 infection is implicated in multiple studies. [
      • Mowla A.
      • et al.
      Unusual pattern of arterial macrothrombosis causing stroke in a young adult recovered from COVID-19.
      ,
      • Shahjouei S.
      • et al.
      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      ,
      • Dmytriw A.A.
      • et al.
      Ischaemic stroke associated with COVID-19 and racial outcome disparity in North America.
      ,
      • Jabbour P.
      • et al.
      Characteristics of a COVID-19 Cohort With Large Vessel Occlusion: A Multicenter International Study.
      ,
      • Shahjouei S.
      • et al.
      SARS-CoV-2 is a culprit for some, but not all acute ischemic strokes: a report from the multinational COVID-19 stroke study group.
      ,
      • Dmytriw A.A.
      • et al.
      Acute ischaemic stroke associated with SARS-CoV-2 infection in North America.
      ,
      • Shahjouei S.
      • et al.
      SARS-CoV-2 and stroke characteristics: a report from the multinational COVID-19 stroke study group.
      ] However, there are limited data in the literature describing hemorrhagic stroke in COVID-19 patients, mainly including case reports and case series. [
      • Cheruiyot I.
      • et al.
      Intracranial hemorrhage in coronavirus disease 2019 (COVID-19) patients.
      ,
      • Beyrouti R.
      • et al.
      Characteristics of intracerebral haemorrhage associated with COVID-19: a systematic review and pooled analysis of individual patient and aggregate data.
      ,
      • Mishra S.
      • et al.
      Intracranial hemorrhage in COVID-19 patients.
      ]
      Intracerebral hemorrhage (ICH) is a devastating cerebrovascular event with a high mortality rate [
      • An S.J.
      • Kim T.J.
      • Yoon B.W.
      Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: an update.
      ,
      • Zahuranec D.B.
      • et al.
      Intracerebral hemorrhage mortality is not changing despite declining incidence.
      ]. Glasgow Coma Scale (GCS) on admission, hemorrhage volume, presence of intraventricular hemorrhage (IVH), infratentorial site of hemorrhage, and higher age are associated with increased mortality [
      • Hemphill 3rd, J.C.
      • et al.
      The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.
      ]. The association of ICH development and its mortality with SARS-CoV-2 infection is not clear yet.
      Herein, we presented a series of hospitalized ICH cases infected with SARS-CoV-2 and compared them with a cohort of non-SARS-CoV-2 infected ICH patients in terms of clinical outcome and in-hospital mortality. We also evaluated whether infection with SARS-CoV-2 could be a predictor of mortality in ICH patients.

      2. Materials and methods

      2.1 Study design and patients

      This is a multicenter multinational observational study, conducted according to the guidelines of Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [
      • von Elm E.
      • et al.
      The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.
      ] and Enhancing the QUAlity and Transparency Of health Research (EQUATOR) [
      • Network E.
      The Equator Network: Enhancing the QUAlity and Transparency of Health Research.
      ].
      Adult hospitalized patients with the diagnosis of ICH and SARS-CoV-2 infection confirmed by reverse transcription-polymerase chain reaction (RT-PCR), were included. ICH was considered as any primary intraparenchymal hemorrhage (IPH) on the head computed tomography (CT) or brain magnetic resonance imaging (MRI) with or without intraventricular extension or subarachnoid hemorrhage. Other types of intracranial hemorrhage such as ischemic infarct with hemorrhagic transformation, subdural hemorrhage, epidural hemorrhage, subarachnoid hemorrhage alone, cerebral amyloid angiopathy and hemorrhagic leukoencephalopathy were excluded. We also excluded those patients with the diagnosis of SARS-CoV-2 infection onset earlier than three weeks prior to the ICH occurrence or beyond two days after ICH diagnosis.
      The study was conducted by the investigators at the Neuroscience Institute of Geisinger Health System, Pennsylvania, USA, and was approved by the Institutional Review Board (IRB) of Geisinger Health System. The IRBs of other participating institutions approved the study protocol whenever required.
      The data that support the findings of this study are available from the corresponding author upon reasonable request.

      2.2 Data collection

      The principal investigators of this study invited collaborators from several countries via phone calls or emails. We received the cases of ICH and SARS-CoV-2 infection from the beginning of the pandemic from 13 centers in the United States, Iran, Turkey, Spain, Greece, and Italy.
      Data for each patient were gathered on a standardized electronic datasheet. Collaborators collected the data from patients' medical records, images on picture archiving and communication systems (PACS), and hospital information systems. The following variables were assessed: demographic data including age and sex, admission GCS and ICH Hemphill score and its components [
      • Hemphill 3rd, J.C.
      • et al.
      The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.
      ], timelines of SARS-CoV-2 infection and ICH, past medical history, medication history, admission lab data, radiological characteristics of ICH including location and volume of hemorrhage, discharge outcome based on modified Rankin Scale (mRS), length of hospital stay and in-hospital mortality.
      For the control group, we used a dataset from a previous cohort of 107 ICH patients admitted between October 2015 and March 2016 [
      • Rahmani F.
      • et al.
      Predicting 30-day mortality in patients with primary intracerebral hemorrhage: evaluation of the value of intracerebral hemorrhage and modified new intracerebral hemorrhage scores.
      ], from Iran, the country where the majority of cases were recruited. Data harmonization was conducted to combine data from different sources and provide a comparable data view for analysis.

      2.3 Outcome measure

      The primary outcome measure in this study was in-hospital mortality, defined as the all-cause death during hospitalization.

      2.4 Statistical analysis

      We compared the baseline characteristics, laboratory and radiological findings, and outcomes between the ICH patients with SARS-CoV-2 infection and the control group, as well as within the group with ICH and SARS-CoV-2 infection, between dead and survived patients. We applied an independent sample t-test, Mann–Whitney U test, Chi-Square, and Fisher's exact tests for univariate analyses. Mean ± standard deviation (SD) or median (interquartile, IQR) was reported for quantitative variables, and frequencies and relative frequencies were reported for qualitative variables.
      In addition, we assessed the association of SARS-CoV-2 infection and mortality in patients with ICH through logistic regression analysis. Assumptions for binary logistic regression analysis were met. We adjusted the model for age, admission GCS, presence of IVH, the volume of hemorrhage, and location of hemorrhage (infratentorial versus supratentorial). Crude and adjusted odds ratios (cOR and aOR) with 95% confidence interval (CI) were reported. A P-value of <0.05 was considered significant. SPSS software, version 23, was used for statistical analysis. [
      • Corp I.
      Ibm SPSS Statistics: Version 23.
      ]

      3. Results

      We received 70 cases presenting with ICH and positive for SARS-CoV-2 infection. Seven patients were excluded because they did not meet our timeline criteria. Among 63 included patients, the mean age was 61.4 ± 18.1, ranging from 18 to 94 years. Twenty-three patients (36.5%) were women.
      Eleven cases (17.5%) in the COVID-19 group had no known ICH risk factors. In two patients, ICH presented before the COVID-19 diagnosis or symptom onset, and in the other 61 patients, ICH occurred on the same day or after COVID-19 onset or diagnosis. Table 1 compares baseline, and radiologic characteristics and in-hospital mortality between SARS-CoV-2 infected and SARS-CoV-2 non-infected ICH patients. Patients with SARS-CoV-2 infection were significantly younger (P = 0.044), had a higher ICH score (P = 0.025), a more frequent history of diabetes (P = 0.007), and significantly lower platelet count (P < 0.001). IVH occurred less frequently in SARS-CoV-2 infected cases (P < 0.001).
      Table 1Comparison of baseline and radiological characteristics and the outcome of ICH patients with SARS-CoV-2 infection with those without SARS-CoV-2 infection. ICH = Intracerebral Hemorrhage; INR = International Normalized Ratio; IQR = Interquartile Range; IVH = Intraventricular Hemorrhage; PTT = Partial Thromboplastin Time.
      VariablesCurrent series (ICH patients with SARS-CoV2 infection) N = 63Control group (ICH patients without SARS-CoV2 infection) N = 107P-value
      Demographic and baseline characteristics
      Age (years)61.4 ± 18.166.8 ± 16.20.044
      Female23 (36.5%)54 (50.5%)0.077
      Admission GCS (median (IQR))11 (7–13)9 (5–13)0.215
      ICH score (median (IQR))3 (2–4)2 (1–3)0.025
      Diabetes21 (33.9%)17 (15.9%)0.007
      Hypertension47 (75.8%)74 (69.2%)0.356
      History of trauma0 (0.00%)3 (2.8%)0.299
      Anti-coagulant use4 (6.5%)10 (9.3%)0.511
      Anti-Platelet use26 (41.3%)
      Lab data
      INR1.15 ± 0.641.24 ± 0.620.486
      PTT30.5 ± 8.232.8 ± 10.30.219
      Platelet Count (Count x 10^9/L)177.8 ± 77.8240.5 ± 79.3<0.001
      Radiologic findings
      Supratentorial52 (85.2%)91 (85.0%)0.972
      Infratentorial9 (14.8%)16 (15.0%)
      Location of Hemorrhage:
      Basal Ganglia/Thalamus33 (55.9%)52 (48.6%)0.846
      Lobar9 (15.3%)24 (22.4%)
      Cerebellar3 (5.1%)6 (5.6%)
      Brain stem4 (6.8%)8 (7.5%)
      Multiple10 (16.9%)17 (15.9%)
      Presence of IVH14 (22.2%)56 (52.3%)<0.001
      Volume of Hemorrhage (cm3)27.3 ± 32.026.1 ± 17.10.830
      Outcome
      In-hospital mortality41 (65.1%)66 (61.7%)0.658
      Duration of hospital stay was 12.4 ± 13.2 days in patients with SARS-CoV-2 infection, and ICH and 41 (65%) of these patients died during hospitalization. In the univariate analysis, in-hospital mortality did not differ cases and controls (65% vs. 62%; P = 0.658); however, in a multivariable model, after adjustment for age, admission GCS, presence of IVH, the volume of hemorrhage, and location of hemorrhage (infratentorial versus supratentorial), the presence of SARS-CoV-2 infection was significantly associated with higher rates of in-hospital mortality (aOR: 4.31, 95% CI: 1.28–14.52). (Table 2).
      Table 2Logistic regression analysis of predictors of mortality in patients with ICH. GCS = Glasgow Coma Scale; ICH = Intracerebral Hemorrhage; IVH = Intraventricular Hemorrhage; OR = Odds Ratio.
      VariableCrude ORAdjusted OR95% CIP-value
      SARS-CoV-2 infection1.164.311.28–14.520.018
      Age1.021.071.03–1.11<0.001
      Admission GCS0.6910.7160.611–0.838<0.001
      Presence of IVH2.363.091.10–8.670.032
      Bleeding Volume1.061.061.02–1.090.003
      Infratentorial location of ICH1.082.350.467–11.870.300
      Table 3 shows the univariate comparison of the baseline and radiologic findings within the SARS-CoV-2 infected ICH cases between dead and survived patients. Lower admission GCS (P = 0.001), higher ICH score (P = 0.001), and higher volume of hemorrhage (P < 0.001) were independently associated with mortality.
      Table 3Comparison of baseline and radiological characteristics of ICH patients with SARS-CoV-2 infection between dead and survived patients. GCS = Glasgow Coma Scale; ICH = Intracerebral Hemorrhage; INR = International Normalized Ratio; IQR = Interquartile Range; IVH = Intraventricular Hemorrhage; PTT = Partial Thromboplastin Time.
      VariablesDeceased N = 41Survived N = 22P-value
      Demographic and baseline characteristics
      Age (years)62.7 ± 19.258.9 ± 15.90.423
      Female17 (41.5%)6 (27.3%)0.265
      Admission GCS (median (IQR))8.5 (6.25–12)13 (11.5–15)0.001
      ICH score (median (IQR))3 (2–4)2 (1–3)0.001
      History of diabetes15 (37.5%)6 (27.3%)0.416
      History of hypertension33 (82.5)14 (63.6%)0.097
      History of trauma0 (0.0%)0 (0.0%)
      Anti-coagulant use3 (7.5%)1 (4.5%)1.000
      Anti-Platelet use17 (42.5%)9 (40.9%)0.903
      Lab data
      INR1.16 ± 0.791.14 ± 0.150.952
      PTT (s)30.1 ± 9.531.3 ± 5.20.687
      Platelet Count (Count x 10^9/L)184.9 ± 76.4164.7 ± 80.80.355
      Radiologic findings
      Supra-tentorial34 (87.2%)18 (81.8%)0.710
      Infra-tentorial5 (12.8%)4 (18.2%)
      Location of Hemorrhage:
      Basal Ganglia/Thalamus23 (59.0%)10 (50.0%)0.232
      Lobar4 (10.3%)5 (25.0%)
      Cerebellum1 (2.6%)2 (10.0%)
      Brain stem4 (10.3%)0 (0.0%)
      Multiple7 (17.9%)3 (15.0%)
      Presence of IVH9 (22.0%)5 (22.7%)1.000
      Volume of Hemorrhage (cm3)37.9 ± 34.77.2 ± 8.4<0.001

      4. Discussion

      We presented a series of 63 ICH patients with concomitant SARS-CoV-2 infection. Compared to controls, ICH in SARS-CoV-2 infected patients occurred at a younger age and primarily in men (63.5%); this observation is consistent with the results of previous studies. [
      • Beyrouti R.
      • et al.
      Characteristics of intracerebral haemorrhage associated with COVID-19: a systematic review and pooled analysis of individual patient and aggregate data.
      ,
      • Cheruiyot I.
      • et al.
      Intracranial hemorrhage in coronavirus disease 2019 (COVID-19) patients.
      ,
      • Lawton M.T.
      • et al.
      Coronavirus disease 2019 (COVID-19) can predispose young to intracerebral hemorrhage: a retrospective observational study.
      ] These patients had higher ICH scores, a more frequent history of diabetes, and lower platelet counts. The in-hospital mortality was 65% within the SARS-CoV-2 infected group. In multivariable analysis, SARS-CoV-2 infection was significantly associated with a four-fold increase in in-hospital mortality.
      The majority of our cases had well-established risk factors which predisposed them to ICH, with hypertension being the most frequent one (75% of cases). This finding is in line with the result of the previous studies. [
      • Cheruiyot I.
      • et al.
      Intracranial hemorrhage in coronavirus disease 2019 (COVID-19) patients.
      ,
      • Benger M.
      • et al.
      Intracerebral haemorrhage (ICH) and COVID-19: clinical characteristics from a case series.
      ] Eleven SARS-CoV-2 infected patients (17.5%) had no known ICH risk factors. It is not fully clear whether the SARS-CoV-2 infection could contribute to ICH development or these two conditions occurred coincidentally. Hospitalized patients with COVID-19 receive prophylactic or therapeutic doses of anticoagulants according to the current guidelines. [

      COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed 01/05/2022.

      ] Anticoagulation is considered associated with ICH occurrence in several studies. [
      • Kvernland A.
      • et al.
      Anticoagulation use and hemorrhagic stroke in SARS-CoV-2 patients treated at a New York healthcare system.
      ,
      • Dogra S.
      • et al.
      Hemorrhagic stroke and anticoagulation in COVID-19.
      ] However, in this series, only three patients were on anticoagulant therapy prior to the ICH development since the majority of patients were recruited at the beginning of the pandemic when routine administration of anticoagulation in COVID-19 patients was uncommon. It has been suggested that besides the well-established risk factors and anticoagulant administration, additional mechanisms might lead to ICH occurrence in SARS-CoV-2 infected patients. SARS-CoV-2 neurotropism, direct endothelial cell invasion via SARS-CoV-2 entry protein, angiotensin-converting enzyme 2 (ACE2) and resulting endothelitis, pro-inflammatory cytokines-associated vascular wall remodeling and disintegrity, hypertension induced by downregulation of ACE2 and unopposed effects of renin-angiotensin II-aldosterone system (RASS) are among the potential mechanisms through which SARS-CoV2 predispose patients to the ICH. [
      • Yachou Y.
      • et al.
      Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: understanding the neurological manifestations in COVID-19 patients.
      ,
      • Varga Z.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ,
      • Mehta P.
      • et al.
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      ,
      • Sprague A.H.
      • Khalil R.A.
      Inflammatory cytokines in vascular dysfunction and vascular disease.
      ,
      • Divani A.A.
      • et al.
      Coronavirus disease 2019 and stroke: clinical manifestations and pathophysiological insights.
      ,
      • Zhang H.
      • et al.
      Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.
      ] Another notable mechanism that can predispose patients with COVID-19 to hemorrhage is dysfunction in the coagulation cascade and fibrinolytic homeostasis. Zuo et.al reported that tissue plasminogen activator (tPA) is markedly elevated in hospitalized COVID-19 patients and is associated with mortality. [
      • Zuo Y.
      • et al.
      Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients.
      ]
      A pooled analysis of previous studies showed that ICH could occur in COVID-19 patients with an incidence ranging from 0.13 to 2.03% and mortality of 54%. [
      • Beyrouti R.
      • et al.
      Characteristics of intracerebral haemorrhage associated with COVID-19: a systematic review and pooled analysis of individual patient and aggregate data.
      ] The rate of mortality in our study was higher, probably because the majority of our cases were recruited from Iran, a developing country with limited resources. The in-hospital mortality rate in cases was similar to a previous cohort of non-COVID-19 ICH patients from Iran [
      • Hemphill 3rd, J.C.
      • et al.
      The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.
      ], which we used as the control group (65% in SARS-CoV-2 infected patients versus 62% in non-SARS-CoV-2 infected control group). Our results showed that after adjustment for other known predictors of ICH mortality [
      • Hemphill 3rd, J.C.
      • et al.
      The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.
      ], SARS-CoV-2 infection was associated with an increased risk of in-hospital mortality in ICH patients. Pulmonary involvement and respiratory compromise, systemic inflammation, and multi-organ failure in severe COVID-19 might worsen the ICH outcome, as such could occur while COVID-19 accompanies other comorbidities other than ICH. [
      • Mokhtari T.
      • et al.
      COVID-19 and multiorgan failure: a narrative review on potential mechanisms.
      ] According to the univariate analysis, among SARS-CoV-2 infected patients, lower GCS and the higher ICH score on admission, and the larger hematoma volume were significantly associated with in-hospital mortality. Previous studies on the predictors of ICH mortality demonstrated similar findings. [
      • Hemphill 3rd, J.C.
      • et al.
      The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.
      ,
      • Togha M.
      • Bakhtavar K.
      Factors associated with in-hospital mortality following intracerebral hemorrhage: a three-year study in Tehran, Iran.
      ,
      • Bhatia R.
      • et al.
      A prospective study of in-hospital mortality and discharge outcome in spontaneous intracerebral hemorrhage.
      ]
      The current study has several methodological shortcomings. One limitation is that the data on COVID-19 severity was not available for most cases. Therefore, we were not able to assess the association of COVID-19 severity with in-hospital mortality. Also, the study's retrospective nature led to missing data in some variables, such as laboratory findings. In addition, the small sample size of SARS-CoV-2 patients with ICH decreased the power of the study. Nevertheless, this is the largest case series on SARS-CoV-2 patients developing ICH to the best of our knowledge. Furthermore, we selected and used the data of a historical cohort collected in 2015–2016 as the control group. The variation in demographics between the two cohorts might limit the strength of our comparison. Also, since the care of ICH patients has improved in recent years, the time variation between these two studies might be a source of bias.

      5. Conclusions

      ICH “in association” with SARS-CoV-2 infection, may increase the mortality risk compared to non-SARS-CoV-2 infected patients. Therefore, we suggest close monitoring of neurological manifestations and deterioration in COVID-19 patients, especially those with underlying ICH risk factors.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      None.

      Acknowledgments

      We would like to thank Dr. Elahe Mohammadi Vosough and Dr. Hamid Reza Mirkarimi for their invaluable contribution to our data collection.

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