This systematic review and pooled analysis provides new insights into incidence, mortality and key clinical features of ICH in COVID19 patients.
The calculated incidence for ICH in COVID-19 patients in our study was low (0.85%, 95% CI 0.36%-1.99%; I2 = 97.5%), but moderately increased in comparison to a large cohort on hemorrhagic stroke in COVID-19 patients (0.3%; data from French national administrative database).(17) More importantly, it was higher than the incidence reported from the 2018–2019 seasonal influenza cohort (0.2%).(17) However, a substantial amount of patients in our report suffered microbleeds, which are not mentioned and might have been missed in the French administrative database. Apart from microbleeds, frequent subtypes of ICH were IPH and SAH. Mortality in our study was 52.18% (95% CI 40.40%-67.39%; I2 = 51.7%), whereas case-fatality rate for ICH in non-COVID-19 patients is reported at approximately 40%.(18) Case fatality rates for COVID-19 patients requiring invasive mechanical ventilation was found to be 45% in a large meta-analysis. (19) As only our cohort combines both potentially fatal diagnosis (ICH and COVID-19), a higher mortality is reasonable.
On individual patient level, critical disease stage (20.0% vs 66.4%, p < 0.001), time from COVID-19 diagnosis to ICH diagnosis (9.5 days vs 16.0 days, p = 0.012), headache (40.0% vs 11.2%, p = 0.012) and palliative care (0% vs 38.6%, p = 0.015) were significant predictors of outcome (mRS 0–2 vs mRS 3–6). Critical stage of COVID-19 and headaches in the context of IPH have been previously described as predictors for worse outcome.(20, 21) In our study, however, headache predicted a better functional outcome (mRS 0–2) at discharge. The discrepancy to already published data may be explained by a bias that could have developed because headache had been coded for both, COVID-19 and ICH. Although bleeding diathesis has been a fundamental factor in ICH in both COVID-19 and non-COVID-19 patients,(22, 23) and a significant proportion of patients had anticoagulation and showed changes in the respective biological biomarkers (aPTT, INR) in this cohort, we did not find anticoagulation to be a significant variable in our study. However, as we were not able to specify whether patients received prophylactic or therapeutic dose anticoagulation from the data provided, the effect on the outcome might be underestimated.
By pooled analysis of aggregate level data, we provided detailed descriptive statistics but refrained from meta-regression due to incomplete data sets and thus insufficient statistical power. Patients with ICH during active COVID-19 were predominantly male with a median age of 58.8 years [95% CI 54.8; 62.9]. Basic epidemiological data are thus comparable to already published cohorts of COVID-19.(21, 24) The majority of patients experienced a critical phase of disease, with respiratory symptoms and altered level of consciousness being the dominant clinical features. The high proportion of patients with critical stage of COVID-19 is consistent with studies reporting a relative increase of neurological symptoms with more severe disease.(2, 25) Median time from COVID-19 diagnosis to diagnosis of ICH was 21.5 days [95% CI 14.9; 28.0], which might be due to diagnostic difficulties in critically ill patients, or due to COVID-19-specific vasculopathy in the subacute stage of disease, or both. The high proportion of patients of receiving ECMO further illustrates severity of disease in this cohort. Yet, with a recent analysis reporting similar rates of IPH in COVID-19 and propensity score matched controls without COVID-19,(26) it appears unlikely that the viral infection is an independent risk factor further aggravating the already existing substantial risk of ICH during ECMO therapy. As ICH has been known to be a fatal complication of ECMO in COVID-19, as well as in other etiologies of acute respiratory distress syndrome (ARDS), cranial imaging should be encouraged in cases with neurological deterioration.(27, 28)
The pathomechanism behind COVID-19’s association with ICH is still highly controversial, and many hypothetical constructs describing both direct and indirect effects of virus infection have been described.(8) With neurotropism having been demonstrated, potential direct mechanisms include infection of vascular endothelium and consecutive endothelitis(7, 29) as well as downregulation of ACE2 leading to elevated levels of angiotensin II with inflammation, increase of blood pressure and other deleterious downstream effects.(30) Hyperinflammatory syndrome with loss of vascular integrity and disseminated coagulation are further described to play a role as indirect mechanisms.(31, 32)
Given that the different subtypes of ICH have a distinct pathophysiology, it appears plausible that the magnitude of the role of SARS-CoV2 described above varies.
First, it is reasonable that in traumatic ICH, such as EDH, SDH or traumatic SAH, concomitant SARS-CoV2 infection is probably not a driving cause.
Second, critical illness-associated cerebral microbleeds are discussed to be a consequence of hypoxemia, uremia and microangiopathy, or a combination of such.(33–37) Cerebral microbleeds are frequently observed in patients with high-altitude cerebral edema(34) and those affected exhibit significant respiratory failure. When compared to patients without microbleeds, respiratory failure is more pronounced.(33, 35–37) Furthermore, such bleeding patterns have also been observed in COVID-19- and non-COVID- acute respiratory distress syndrome (ARDS) patients.(36, 38) The currently available data, however, do not allow to speculate on whether or not this is a specific complication of ECMO or due to hypoxemia during the course ARDS. Furthermore, the formation of microthrombi described in COVID-19 as well as in disseminated intravascular coagulation (DIC) in the context of critical disease might also play a relevant role in the pathogenesis of microbleeds(39, 40). Two studies investigating microbleeds in COVID-19 suggested a potential role for COVID-19-associated microangiopathy as patients with microbleeds showed thrombocytopenia and elevated D-Dimers.(33, 36) Overall, it is impossible to state whether the observed bleedings are COVID-19-associated rather than a phenomenon caused by critical illness.
Third, the above-mentioned hypercoagulable features may predispose patients for thromboembolic complications in the venous and arterial circulation. However, with regards to ischemic stroke, epidemiological data do not show a higher incidence among COVID-19 patients.(17, 41) Thus, secondary ICH due to hemorrhagic transformation/parenchymal hematoma is likely to be dependent on the use of antithrombotic agents in stroke management rather than direct effects of SARS-CoV2. Sinus venous thrombosis is infrequently reported in the context of COVID-19 but may be driven by its hypercoagulable features.(42) Overall reports included too small patient numbers to deduct a reasonable incidence.
Fourth, only very few cases of SAH during COVID-19 have been described. In aneurysmal SAH, the hypothesis of arterial weakening by viral infection has been eliminated decades ago. Today, there is no additional evidence that SARS-CoV2 could contribute to the pathogenesis of non-traumatic SAH.(43)
As for IPH, a systematic review and pooled analysis revealed 67.7% of patients exhibited atypical, lobar IPH, while in non-COVID-19 cohorts, proportions of 32–38% are reported. Furthermore, COVID-19 patients with ICH had multilocular manifestation of ICH in 20.6%, while others reported a prevalence of only about 6% for more heterogeneous cohorts. In line with those findings of atypical localization, only 53% of patients had arterial hypertension. Overall, this suggests that additional factors may play a role in ICH in COVID-19 patients. As a majority receives anticoagulation and some even receive ECMO, it is likely that, besides the complex mechanisms already described above, those therapeutic interventions play a pivotal role. Indeed, therapeutic anticoagulation was found to increase the risk of IPH in COVID-19 by approximately 5-fold and was found to be a predictor of mortality.
This review has several limitations. First, data sets are incomplete due to a great heterogeneity of variables being reported, with detailed information for the cohort of interest often being unavailable in aggregate level data. Second, and although inherent to any meta-analysis of special significance in this case, there are relevant sources of bias. As the pandemic is highly dynamic and often requires rapid review and publication of scientific results, it is likely that data irregularities due to methodological issues or publication bias are particularly relevant in this research field. On the other hand, the limited resources during the pandemic with potentially limited access to health care facilities could lead to a substantial amount of undetected and underreported cases. Finally, data on an adequate control group has not been available.