Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?

In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells in vitro and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy.

Ballooned neurons in semi-recent severe traumatic brain injury.

Traumatic brain injury (TBI) is now recognized as an insult triggering a dynamic process of degeneration and regeneration potentially evolving for years with chronic traumatic encephalopathy (CTE) as one major complication. Neurons are at the center of the clinical manifestations, both in the acute and chronic phases. Yet, in the acute phase, conventional neuropathology detects abnormalities predominantly in the axons, if one excludes contusions and hypoxic ischemic changes. We report the finding of ballooned neurons, predominantly in the anterior cingulum, in three patients who sustained severe TBI and remained comatose until death, 2 ½ weeks to 2 ½ months after the traumatic impact. All three cases showed severe changes of traumatic diffuse axonal injury in line with acceleration/deceleration forces. The immunohistochemical profile of the ballooned neurons was like that described in neurodegenerative disorders like tauopathies which were used as controls. The presence of αB-crystallin positive ballooned neurons in the brain of patients who sustained severe craniocerebral trauma and remained comatose thereafter has never been reported. We postulate that the co-occurrence of diffuse axonal injury in the cerebral white matter and ballooned neurons in the cortex is mechanistically reminiscent of the phenomenon of chromatolysis. Experimental trauma models with neuronal chromatolytic features emphasized the presence of proximal axonal defects. In our three cases, proximal swellings were documented in the cortex and subcortical white matter. This limited retrospective report should trigger further studies in order to better establish, in recent/semi-recent TBI, the frequency of this neuronal finding and its relationship with the proximal axonal defects.

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. SIGNIFICANCE: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

Prevalence, patterns and outcomes of cardiac involvement in Erdheim-Chester disease.

AIMS: Cardiac involvement of Erdheim-Chester disease (ECD), a rare L group histiocytosis, has been reported to be associated with poor outcomes, but systematic studies are lacking. The present study aimed to investigate the prevalence, clinical features, imaging features, and prognosis of cardiac involvement in ECD in a large series. METHODS AND RESULTS: All patients with ECD who underwent cardiac magnetic resonance (CMR) imaging between 2003 and 2019 at a French tertiary center were retrospectively included. Primary outcome was all-cause mortality. Secondary outcomes were pericarditis, cardiac tamponade, conduction disorders, device implantation and coronary artery disease (CAD). A total of 200 patients were included [63 (54-71) years, 30% female, 58% BRAFV600E mutated]. Median follow-up was 5.5 years (3.3-9 years). On CMR, right atrioventricular sulcus infiltration was observed in 37% of patients, and pericardial effusion was seen in 24% of patients. In total, 8 patients (4%) had pericarditis (7 acute, 1 constrictive), 10 patients (5%) had cardiac tamponade, 5 patients (2.5%) had ECD-related high-degree conduction disorders, and 45 patients (23%) had CAD. Overall, cardiac involvement was present in 96 patients (48%) and was associated with BRAFV600E mutation [Odds ratio (OR) = 7.4, 95% confidence interval (CI) (3.5-16.8), P < 0.001] and ECD-related clinical events [OR = 5, 95%CI (1.5-21.2), P = 0.004] but not with lower survival in multivariate analysis [adjusted hazard ratio (HR) = 1.4, 95% CI (0.8-2.5), P = 0.2]. CONCLUSION: Cardiac involvement is present in nearly half of ECD patients and is associated with BRAFV600E mutation and complications (pericarditis, cardiac tamponade, and conduction disorders) but not with lower survival.

Lack of early etiologic investigations in young sudden cardiac death.

BACKGROUND: Since majority of sudden cardiac arrest (SCA) victims die in the intensive care unit (ICU), early etiologic investigations may improve understanding of SCA and targeted prevention. METHODS: In this prospective, population-based registry all SCA admitted alive across the 48 hospitals of the Paris area were enrolled. We investigated the extent of early etiologic work-up among young SCD cases (<45 years) eventually dying within the ICU. RESULTS: From May 2011 to May 2018, 4,314 SCA patients were admitted alive. Among them, 3,044 died in ICU, including 484 (15.9%) young patients. SCA etiology was established in 233 (48.1%) and remained unexplained in 251 (51.9%). Among unexplained (compared to explained) cases, coronary angiography (17.9 vs. 49.4%, P < 0.001), computed tomography scan (24.7 vs. 46.8%, P < 0.001) and trans-thoracic echocardiography (31.1 vs. 56.7%, P < 0.001) were less frequently performed. Only 22 (8.8%) patients with unexplained SCD underwent all three investigations. SCDs with unexplained status decreased significantly over the 7 years of the study period (from 62.9 to 35.2%, P = 0.005). While specialized TTE and CT scan performances have increased significantly, performance of early coronary angiography did not change. Autopsy, genetic analysis and family screening were performed in only 48 (9.9%), 5 (1.0%) and 14 cases (2.9%) respectively. CONCLUSIONS: More than half of young SCD dying in ICU remained etiologically unexplained; this was associated with a lack of early investigations. Improving early diagnosis may enhance both SCA understanding and prevention, including for relatives. Failure to identify familial conditions may result in other preventable deaths within these families.

Pearls & Oy-sters: Spinal Cord Candidiasis Linked to CARD9 Deficiency Masquerading as a Longitudinally Extensive Transverse Myelitis.

Candida spp. myelopathies are very rare. We report a case of subacute longitudinally extensive transverse myelitis in an apparently immunocompetent 55-year-old man. After a negative infectious workup, corticosteroids and plasma exchange were initiated. Although there was a transient initial improvement, symptoms then worsened, and the lumbar puncture was repeated. Candida albicans was isolated in the CSF, and a diagnosis of spinal cord candidiasis was made. Gene panel sequencing for inborn immune deficiencies identified a homozygous disease-causing CARD9 variant. Despite antifungal treatment, necrotic myelitis, meningoencephalitis, and cerebral vasculitis developed. Fungal spinal cord infections can mimic inflammatory myelitis, and beta-D-glucan testing of both serum and CSF may help narrow down the diagnosis. In cases of severe or unexpected invasive Candida spp. infection, even adults and apparently immunocompetent patients should be screened for inborn immune deficiencies and CARD9 deficiency in particular.

Memory CD4+ T-Cell Lymphocytic Angiopathy in Fatal Forms of COVID-19 Pulmonary Infection.

The immunopathological pulmonary mechanisms leading to Coronavirus Disease (COVID-19)-related death in adults remain poorly understood. Bronchoalveolar lavage (BAL) and peripheral blood sampling were performed in 74 steroid and non-steroid-treated intensive care unit (ICU) patients (23-75 years; 44 survivors). Peripheral effector SARS-CoV-2-specific T cells were detected in 34/58 cases, mainly directed against the S1 portion of the spike protein. The BAL lymphocytosis consisted of T cells, while the mean CD4/CD8 ratio was 1.80 in non-steroid- treated patients and 1.14 in steroid-treated patients. Moreover, strong BAL SARS-CoV-2 specific T-cell responses were detected in 4/4 surviving and 3/3 non-surviving patients. Serum IFN-γ and IL-6 levels were decreased in steroid-treated patients when compared to non-steroid treated patients. In the lung samples from 3 (1 non-ICU and 2 ICU) additional deceased cases, a lymphocytic memory CD4 T-cell angiopathy colocalizing with SARS-CoV-2 was also observed. Taken together, these data show that disease severity occurs despite strong antiviral CD4 T cell-specific responses migrating to the lung, which could suggest a pathogenic role for perivascular memory CD4 T cells upon fatal COVID-19 pneumonia.

Cerebral vasculitis due to Aspergillus spp. in immunocompromised patients: literature review.

OBJECTIVES: Invasive aspergillosis is a threat for immunocompromised patients. We present a case series of aggressive cerebral vasculitis caused by Aspergillus spp. infection in immunocompromised patients. METHODS: We present a retrospective case series of three autopsy-proven invasive cerebral aspergillosis with diffuse vasculitis affecting large caliber cerebral vessels. RESULTS: Three patients were immunosuppressed: one on rituximab, one on corticosteroids, and one with a renal transplant. Two of these patients were diagnosed with cerebral aspergillosis on postmortem. CONCLUSION: Aspergillus cerebral vasculitis is a rare form of invasive aspergillosis that should be considered in an immunocompromised individual with suggestive lesions on imaging. It should be suspected as a possible cause of aseptic neutrophil meningitis.

First Case of Lethal Encephalitis in Western Europe Due to European Bat Lyssavirus Type 1.

BACKGROUND: Inaccurate diagnosis of encephalitis is a major issue as immunosuppressive treatments can be deleterious in case of viral infection. The European bat lyssavirus type 1 (EBLV-1), a virus related to rabies virus, is endemic in European bats. No human case has yet been reported in Western Europe. A 59-year-old patient without specific past medical history died from encephalitis. A colony of bats lived in an outbuilding of his house. No diagnosis was made using standard procedures. METHODS: We used a next generation sequencing (NGS) based transcriptomic protocol to search for pathogens in autopsy samples (meninges and brain frontal lobe). Results were confirmed by polymerase chain reaction (PCR) and by antibody testing in serum. Immunochemistry was used to characterize inflammatory cells and viral antigens in brain lesions. Cells and mice were inoculated with brain extracts for virus isolation. RESULTS: The patient's brain lesions were severe and diffuse in white and gray matter. Perivascular inflammatory infiltrates were abundant and rich in plasma cells. NGS identified European bat lyssavirus type 1a in brain, which was confirmed by PCR. A high titer of neutralizing antibodies was found in serum. No viral antigen was detected, and the virus could not be isolated by cell culture or by mouse inoculation. CONCLUSIONS: The patient died from European bat lyssavirus type 1a infection. NGS was key to identifying this unexpected viral etiology in an epidemiological context that did not suggest rabies. People exposed to bats should be strongly advised to be vaccinated with rabies vaccines, which are effective against EBLV-1.

Disturbances of brain cholesterol metabolism: A new excitotoxic process associated with status epilepticus.

The understanding of the excitotoxic processes associated with a severe status epilepticus (SE) is of major importance. Changes of brain cholesterol homeostasis is an emerging candidate for excitotoxicity. We conducted an overall analysis of the cholesterol homeostasis both (i) in fluids and tissues from patients with SE: blood (n = 63, n = 87 controls), CSF (n = 32, n = 60 controls), and post-mortem brain tissues (n = 8, n = 8 controls) and (ii) in a mouse model of SE induced by an intrahippocampal injection of kainic acid. 24-hydroxycholesterol levels were decreased in kainic acid mouse hippocampus and in human plasma and post-mortem brain tissues of patients with SE when compared with controls. The decrease of 24-hydroxycholesterol levels was followed by increased cholesterol levels and by an increase of the cholesterol synthesis. Desmosterol levels were higher in human CSF and in mice and human hippocampus after SE. Lanosterol and dihydrolanosterol levels were higher in plasma from SE patients. Our results suggest that a CYP46A1 inhibition could occur after SE and is followed by a brain cholesterol accumulation. The excess of cholesterol is known to be excitotoxic for neuronal cells and may participate to neurological sequelae observed after SE. This study highlights a new pathophysiological pathway involved in SE excitotoxicity.

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

CC17 group B Streptococcus exploits integrins for neonatal meningitis development.

Group B Streptococcus (GBS) is the major cause of human neonatal infections. A single clone, designated CC17-GBS, accounts for more than 80% of meningitis cases, the most severe form of the infection. However, the events allowing blood-borne GBS to penetrate the brain remain largely elusive. In this study, we identified the host transmembrane receptors α5ß1 and αvß3 integrins as the ligands of Srr2, a major CC17-GBS-specific adhesin. Two motifs located in the binding region of Srr2 were responsible for the interaction between CC17-GBS and these integrins. We demonstrated in a blood-brain-barrier cellular model that both integrins contributed to the adhesion and internalization of CC17-GBS. Strikingly, both integrins were overexpressed during the postnatal period in the brain vessels of the blood-brain barrier and blood-cerebrospinal fluid barrier and contributed to juvenile susceptibility to CC17 meningitis. Finally, blocking these integrins decreased the ability of CC17-GBS to cross into the CNS of juvenile mice in an in vivo model of meningitis. Our study demonstrated that CC17-GBS exploits integrins in order to cross the brain vessels, leading to meningitis. Importantly, it provides host molecular insights into neonate's susceptibility to CC17-GBS meningitis, thereby opening new perspectives for therapeutic and prevention strategies of GBS-elicited meningitis.

Identification of Umbre Orthobunyavirus as a Novel Zoonotic Virus Responsible for Lethal Encephalitis in 2 French Patients with Hypogammaglobulinemia.

BACKGROUND: Human encephalitis represents a medical challenge from a diagnostic and therapeutic point of view. We investigated the cause of 2 fatal cases of encephalitis of unknown origin in immunocompromised patients. METHODS: Untargeted metatranscriptomics was applied on the brain tissue of 2 patients to search for pathogens (viruses, bacteria, fungi, or protozoans) without a prior hypothesis. RESULTS: Umbre arbovirus, an orthobunyavirus never previously identified in humans, was found in 2 patients. In situ hybridization and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) showed that Umbre virus infected neurons and replicated at high titers. The virus was not detected in cerebrospinal fluid by RT-qPCR. Viral sequences related to Koongol virus, another orthobunyavirus close to Umbre virus, were found in Culex pipiens mosquitoes captured in the south of France where the patients had spent some time before the onset of symptoms, demonstrating the presence of the same clade of arboviruses in Europe and their potential public health impact. A serological survey conducted in the same area did not identify individuals positive for Umbre virus. The absence of seropositivity in the population may not reflect the actual risk of disease transmission in immunocompromised individuals. CONCLUSIONS: Umbre arbovirus can cause encephalitis in immunocompromised humans and is present in Europe.

An overview of forensic operations performed following the terrorist attacks on November 13, 2015, in Paris.

On the evening of November 13, 2015, the city of Paris and its surroundings was hit by a series of attacks committed by terrorist groups, using firearms and explosives. The final toll was 140 people deceased (130 victims and 10 terrorists or their relatives) and more than 413 injured, making these attacks the worst mass killings ever recorded in Paris in peacetime. This article presents the forensic operations carried out at the Medicolegal Institute of Paris (MLIP) following these attacks. A total of 68 autopsies of bodies or body fragments and 83 external examinations were performed within 7 days, and the overall forensic operations (including formal identification of the latest victims) were completed 10 days after the attacks. Over this period, 156 body presentations (some bodies were presented several times) were provided to families or relatives. Regarding the 130 civilian casualties, 129 died from firearm wounds and one died from blast injuries after an explosion. Of the 10 terrorists or their relatives who were killed, eight died from suicide bombing, one was shot by police and one died from crush injuries due to partial collapse of a building following the police raid against a terrorist's hideout after the attacks. All mass shootings were perpetrated with AK-47 or Zastava M70 assault rifles using 7.62 mm × 39 mm cartridges. In the case of ballistic injuries, death was most often obviously caused by craniocerebral injuries, extensive organ lacerations and/or massive haemorrhage. Among the terrorists killed by bombing, the lesion patterns were body transection, multiple amputations, extreme organ lacerations and the presence of foreign bodies owing to the shrapnel load (steel nuts, glass fragments) or the explosive charge fastening system of the devices. This discussion highlights the particular difficulties of interpretation encountered within the framework of ballistic injuries, a conclusion that should lead to a modest and realistic approach in these exceptional situations where forensic operations involve a very large number of victims in a constrained time.

Terrorist attacks: cutaneous patterns of gunshot and secondary blast injuries.

Terrorist attacks have been on the rise. During the recent terrorist attacks in France, terrorists perpetrated their acts using weapons of war, as well as explosive charges. These two modes of action, when combined, can create skin lesions with similar macroscopic appearances, which can sometimes go unnoticed because of body fragmentation. A total of 68 autopsies, 83 external examinations, 140 standard radiographic examinations, and 49 computed tomography (CT) scans were performed over 7 days during the 2015 terrorist attacks in France. Bodies were injured by firearms and shrapnel-like projectiles. We analysed the clinical findings for the secondary blast cutaneous lesions from the explosive devices and compared these lesions with ballistic-related lesions to highlight that patterns can be macroscopically similar on external examination. Secondary blast injuries are characterised by penetrating trauma associated with materials added to explosive systems that are propelled by explosive air movement. These injuries are caused most often by small, shrapnel-like metallic objects, such as nails and bolts. Propulsion causes ballistic-type injuries that must be recognised and distinguished from those caused by firearm projectiles. Differentiating between these lesions is very difficult when using conventional criteria (size, shape, number and distribution on the body) with only external examination of corpses. This is why the particularities of these lesions must be further illustrated and then confirmed by complete autopsies and radiological and anatomopathological examinations.Key pointsWhen occurring simultaneously in terrorist attacks, injuries caused by secondary blasts appear as cutaneous wound patterns that can be macroscopically very similar to those caused by firearm projectiles.The criteria usually found in the literature for distinguishing these two types of projectiles may be difficult to use.It is important in these difficult situations to benefit from systematic postmortem imaging.Systematic autopsy and then anatomopathological analyses of the orifices also help determine the cause of the wounds.

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

Ultradeep sequencing reveals HIV-1 diversity and resistance compartmentalization during HIV-encephalopathy.

OBJECTIVES: To examine viral diversity and resistance mutations in different brain areas in cases of HIV-encephalopathy. DESIGN: Twelve postmortem brain areas from three cases of possible or certain HIV-encephalopathy were analyzed. METHODS: After amplification of the reverse transcriptase and the V3 loop region of the gp120 protein, ultradeep sequencing was performed with Illumina technology. Phylogenetic analysis was performed with Fastree v2.1 using the generalized time-reversible (GTR) model. Identification of resistant viral variants was performed on Geneious software, according to HIV-1 genotypic drug resistance interpretation's algorithms, 2018 administered by the French Agency for Research on AIDS and Viral Hepatitis. RESULTS: Phylogenetic analysis revealed significant inter-regional and intra-regional diversity reflecting persistent HIV-1 viral replication in the different brain areas. Although some cerebral regions shared HIV-variants, most of them harbored a specific HIV-subpopulation reflecting HIV compartmentalization in the central nervous system. Furthermore, proportion and distribution of resistance mutations to nucleoside and non-nucleoside reverse transcriptase inhibitors differed among different brain areas of the same case suggesting that penetration of antiretroviral treatment may differ from one compartment to another. CONCLUSION: This study, performed with a powerful sequencing technique, confirmed HIV compartmentalization in the central nervous system already shown by classical sequencing, suggesting that there are several reservoirs within the brain.

Low rates of immediate coronary angiography among young adults resuscitated from sudden cardiac arrest.

AIM: Coronary artery disease (CAD) has recently been emphasized as a major cause of sudden cardiac arrest (SCA) in young adults. We aim to assess the rate of immediate coronary angiography performance in young patients resuscitated from SCA. METHODS: From May 2011 to May 2017, all cases of out-of-hospital SCA aged 18-40 years alive at hospital admission were prospectively included in 48 hospitals of the Great Paris area. Cardiovascular causes of SCA were centrally adjudicated, and management including immediate coronary angiography performance was assessed. RESULTS: Out of 3579 SCA admitted alive, 409 (11.4%) patients were under 40 years of age (32.3 ± 6.2 years, 69.7% males), with 244 patients having a definite cause identified. Among those, CAD accounted for 72 (29.5%) cases, of which 64 (88.9%) were acute coronary syndromes. The rate of immediate coronary angiography was only 41.7% compared to 65.1% among those ≥40-years (P < 0.001). During the study period, while the rate of immediate coronary angiography increased from 60.5% to 70.3% (P < 0.001) in patients aged ≥40 years, the rate in patients aged less than 40 years remained stable (43.5% to 45.3%, P = 0.795). Patients younger than 40 years were significantly less likely to undergo immediate coronary angiography (OR = 0.34, 95% CI: 0.25-0.47), although early angiography was associated with survival at hospital discharge (OR = 2.68, 95% CI: 1.21-6.00). CONCLUSION: CAD is the first cause of SCA in young adults aged less than 40 years. The observed low rates of immediate coronary angiography suggest a missed opportunity for early intervention.