A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia.
A prospective series of 100 consecutive patients ...admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response.
The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24–72 h and 10 days after tocilizumab administration.
Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 IQR 0–2), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died.
All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10.
In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.
COVID-19 associated pulmonary aspergillosis (CAPA) is common and linked with high fatality rates. To assess the impact on the incidence and outcome of CAPA of an antifungal prophylaxis (AFP) we ...compared two cohorts of COVID-19 patients admitted to intensive care units (ICU) in Brescia, Italy, from January to August 2021.
The study cohort included all mechanically ventilated patients observed between April 2021 and August 2021 with SARS-CoV-2-pneumonia, who received AFP with oral posaconazole (200 mg every 6 h) and nebulized liposomal amphotericin B (50 mg every 2 weeks) from ICU admission to 7 days after discharge or, if applicable, until tracheostomy removal. The control cohort included COVID-19 patients admitted to the same ICU between January and March 2021 who did not receive any AFP. Subjects with CAPA at ICU admission were excluded.
We included 270 patients, of whom 64 (23.7%) received AFP. In patients in the study group, CAPA-related mortality was significantly reduced (29% vs. 48% p = 0.04), as well as the incidence of CAPA (3.1% vs 12.1%, p = 0.03). Patients who developed CAPA were older (mean of 70-y-old vs 63-y-old, p < 0.001). One subject discontinued posaconazole due to an adverse reaction. Among the 46 patients who received it, only one patient reached an effective plasma concentration of posaconazole.
AFP was associated with reduced incidence and mortality from CAPA and was well tolerated in patients with severe COVID-19. Posaconazole concentrations below the efficacy threshold in almost all patients may be attributable to drug interactions and prompt further studies to define its clinical significance.
The SARS-nCoV-2019 epidemic has spread since December 2019, quickly gaining worldwide attention. Symptoms consist of fever, cough and breathing difficulties. An increasing number of studies are ...focusing on neurological manifestations. In addition to the typical ageusia and anosmia, up to 30% of cases can present headache, nausea and vomiting. More serious neurological manifestations, such as encephalitis, thrombosis and cerebral haemorrhage have been reported.
We described the case of a 47-year-old man who tested positive for COVID-19 virus in early March 2020. After two negative nasopharyngeal swabs, 41 days after the diagnosis of COVID-19 infection, he developed intense headache with fever, and he was hospitalized. He had subsequent generalized epileptic seizures and intubation was necessary. Contrast Head MRI was negative for brain abscesses or tumours but detected severe vasogenic oedema of the white matter with 10 mm shift of the midline and compression of the right lateral ventricle. Massive cortisone support therapy was ineffective. We diagnosed brain death on day 43 from the infection diagnosis.
COVID-19 virus can reach the brain, penetrating into the neuronal cells through the interaction between the spike protein S1 and the host ACE-2 receptor, expressed in the capillary endothelium. We believe that in this infection, the pro-inflammatory state induced by the cytokine storm can cause a cerebral cell-mediated response, with subsequent vasodilatation and brain oedema.
To our knowledge, this is the first description of a delayed onset cell-mediated encephalitis caused by COVID-19 virus after more than 40 days from the diagnosis.
Introduction
Decompressive craniectomy (DC) is the most common surgical procedure to manage increased intracranial pressure (ICP). Hinge craniotomy (HC), which consists of fixing the bone operculum ...with a pivot, is an alternative method conceived to avoid some DC-related complications; nonetheless, it is debated whether it can provide enough volume expansion. In this study, we aimed to analyze the volume and ICP obtained with HC using an experimental cadaver-based preclinical model and compare the results to baseline and DC.
Methods
Baseline conditions, HC, and DC were compared on both sides of five anatomical specimens. Volume and ICP values were measured with a custom-made system. Local polynomial regression was used to investigate volume differences.
Results
The area of the bone opercula resulting from measurements was 115.55 cm
2
; the mean supratentorial volume was 955 mL. HC led to intermediate results compared to baseline and DC. At an ICP of 50 mmHg, HC offers 130 mL extra space but 172 mL less than a DC. Based on local polynomial regression, the mean volume difference between HC and the standard craniotomy was 10%; 14% between DC and HC; both are higher than the volume of brain herniation reported in the literature in the clinical setting. The volume leading to an ICP of 50 mmHg at baseline was less than the volume needed to reach an ICP of 20 mmHg after HC (10.05% and 14.95% from baseline, respectively).
Conclusions
These data confirm the efficacy of HC in providing sufficient volume expansion. HC is a valid intermediate alternative in case of potentially evolutionary lesions and non-massive edema, especially in developing countries.
The SARS-nCoV-2019 epidemic has spread since December 2019, quickly gaining worldwide attention. Symptoms consist of fever, cough and breathing difficulties. An increasing number of studies are ...focusing on neurological manifestations. In addition to the typical ageusia and anosmia, up to 30% of cases can present headache, nausea and vomiting. More serious neurological manifestations, such as encephalitis, thrombosis and cerebral haemorrhage have been reported.
We described the case of a 47-year-old man who tested positive for COVID-19 virus in early March 2020. After two negative nasopharyngeal swabs, 41 days after the diagnosis of COVID-19 infection, he developed intense headache with fever, and he was hospitalized. He had subsequent generalized epileptic seizures and intubation was necessary. Contrast Head MRI was negative for brain abscesses or tumours but detected severe vasogenic oedema of the white matter with 10 mm shift of the midline and compression of the right lateral ventricle. Massive cortisone support therapy was ineffective. We diagnosed brain death on day 43 from the infection diagnosis.
COVID-19 virus can reach the brain, penetrating into the neuronal cells through the interaction between the spike protein S1 and the host ACE-2 receptor, expressed in the capillary endothelium. We believe that in this infection, the pro-inflammatory state induced by the cytokine storm can cause a cerebral cell-mediated response, with subsequent vasodilatation and brain oedema.
To our knowledge, this is the first description of a delayed onset cell-mediated encephalitis caused by COVID-19 virus after more than 40 days from the diagnosis.
Background
There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better ...characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg.
Results
In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7–1366.3 h mg/L), paralleled by high-peak plasma concentration (
C
max
) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17–6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-
C
max
(range: 6.04–9.54 h). The terminal half-life between plasma and CSF was similar.
t
max
values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%.
Conclusions
Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC,
t
max
and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.
Scarce data are available regarding rebleeding predictors in poor-grade aneurysmal subarachnoid hemorrhage (aSAH).
To investigate predictors and clinical impact of rebleeding in a national ...multicentric poor-grade aSAH.
Retrospective analysis of prospectively collected data from the multicentric Poor Grade Aneurysmal Subarachnoid Hemorrhage Study Group (POGASH) registry of consecutive patients treated from January 1, 2015, to June 30th, 2021. Grading was defined as pretreatment World Federation of Neurological Surgeons grading scale IV-V. Ultra-early vasospasm (UEV) was defined as luminal narrowing of intracranial arteries not due to intrinsic disease. Rebleeding was defined as clinical deterioration with evidence of increased hemorrhage on subsequent computed tomography scans, fresh blood from the external ventricular drain, or deterioration before neuroradiological evaluation. Outcome was assessed by the modified Rankin Scale.
Among 443 consecutive World Federation of Neurological Surgeons grades IV-V patients with aSAH treated within a median of 5 (IQR 4-9) hours since onset, rebleeding occurred in 78 (17.6%). UEV (adjusted odds ratio OR 6.8, 95% CI 3.2-14.4; P < .001) and presence of dissecting aneurysm (adjusted OR 3.5, 95% CI 1.3-9.3; P = .011) independently predicted rebleeding while history of hypertension (adjusted OR 0.4, 95% CI 0.2-0.8; P = .011) independently reduced its chances. 143 (32.3) patients died during hospitalization. Rebleeding emerged, among others, as an independent predictor of intrahospital mortality (adjusted OR 2.2, 95% CI 1.2-4.1; P = .009).
UEV and presence of dissecting aneurysms are the strongest predictors of aneurysmal rebleeding. Their presence should be carefully evaluated in the acute management of poor-grade aSAH.
Background
Lombardy was the most affected Italian region by the first phase of the COVID-19 pandemic and underwent urgent reorganization for the management of emergencies, including subarachnoid ...hemorrhage from a ruptured cerebral aneurysm (aSAH). The aim of the study was to define demographics, clinical, and therapeutic features of aSAH during the COVID-19 outbreak and compare these with a historical cohort.
Methods
In this observational multicenter cohort study, patients aged 18 years or older, who were diagnosed with aSAH at the participating centers in Lombardy from March 9 to May 10, 2020, were included (COVID-19 group). In order to minimize bias related to possible SAH seasonality, the control group was composed of patients diagnosed with aSAH from March 9 to May 10 of the three previous years, 2017–2018-2019 (pre-pandemic group). Twenty-three demographic, clinical, and therapeutic features were collected. Statistical analysis was performed.
Results
Seventy-two patients during the COVID-19 period and 179 in the control group were enrolled at 14 centers. Only 4 patients were positive for SARS-CoV-2. The “diagnostic delay” was significantly increased (+ 68%) in the COVID-19 group vs. pre-pandemic (1.06 vs. 0.63 days, respectively,
p
-value = 0.030), while “therapeutic delay” did not differ significantly between the two periods (0.89 vs. 0.74 days,
p
-value = 0.183). Patients with poor outcome (GOS at discharge from 1 to 3) were higher during the COVID-19 period (54.2%) compared to pre-pandemic (40.2%,
p
= 0.044). In logistic regression analysis, in which outcome was the dichotomized Glasgow Outcome Scale (GOS), five variables showed
p
-values < 0.05: age at admission, WFNS grade, treatment (none), days in ICU, and ischemia.
Conclusions
We documented a significantly increased “diagnostic delay” for subarachnoid hemorrhages during the first COVID-19 outbreak in Lombardy. However, despite the dramatic situation that the healthcare system was experiencing, the Lombardy regional reorganization model, which allowed centralization of neurosurgical emergencies such as SAHs, avoided a “therapeutic delay” and led to results overall comparable to the control period.
The fetal and infant life are periods of rapid development, characterized by high susceptibility to exposures. Birth cohorts provide unique opportunities to study early-life exposures in association ...with child development and health, as well as, with longer follow-up, the early life origin of adult diseases. Piccolipiù is an Italian birth cohort recently set up to investigate the effects of environmental exposures, parental conditions and social factors acting during pre-natal and early post-natal life on infant and child health and development. We describe here its main characteristics.
Piccolipiù is a prospective cohort of expected 3000 newborns, who will be recruiting in six maternity units of five Italian cities (Florence, Rome, Trieste, Turin and Viareggio) since October 2011. Mothers are contacted during pregnancy or at delivery and are offered to participate in the study. Upon acceptance, their newborns are recruited at birth and followed up until at least 18 years of age. At recruitment, the mothers donate a blood sample and complete a baseline questionnaire. Umbilical cord blood, pieces of umbilical cord and heel blood spots are also collected. Postnatal follow-up currently occurs at 6, 12, and 24 months of age using on-line or postal self administered questionnaire; further questionnaires and medical examinations are envisaged. Questionnaires collect information on several factors, including mother's and/or child's environmental exposures, anthropometric measures, reproductive factors, diet, supplements, medical history, cognitive development, mental health and socioeconomic factors. Health promotion materials are also offered to parents.
Piccolipiù will broaden our understanding of the contribution of early-life factors to infant and child health and development. Several hypotheses on the developmental origins of health can be tested or piloted using the data collected from the Piccolipiù cohort. By pooling these data with those collected by other existing birth cohorts it will be possible to validate previous findings and to study rare exposures and outcomes.
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