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Childhood Risk Factors and Adult Cardiovascular Events | NEJM

Childhood Risk Factors and Adult Cardiovascular Events | NEJM

To the Editor: Jacobs et al. (May 19 issue)1 explored the association of several childhood risk factors (body-mass index [BMI], systolic blood pressure, total cholesterol level, triglyceride level, and smoking status) with vascular events in adulthood. They found that there was an association between childhood risk factors and cardiovascular events in midlife. However, neither albuminuria nor the estimated glomerular filtration rate (eGFR) was assessed. Albuminuria and a decreased eGFR are key risk factors for cardiovascular events and, together with BMI, systolic blood pressure, lipid levels, and smoking, are used in adults to assess cardiovascular risk. An elevated eGFR may indicate . . .

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Climate change role clear in many extreme events but social factors also key, study finds

Climate change is to blame for the majority of the heatwaves being recorded around the planet but the relation to other extreme events impacts on society is less clear, according to a study.

“I think on the one hand we overestimate climate change because it’s now quite common that every time an extreme event happens, there is a big assumption that climate change is playing a big role, which is not always the case,” said Friederike Otto, a climate change and environment professor at the Grantham Institute at Imperial College London, who was one of the lead authors of the research.

“But on the other hand, we really underestimate those events where climate change does play a role in what the costs are, especially the non-economic costs of extreme weather events to our societies.”

In the study published in the journal IOP Publishing, Otto’s team used “attribution science” to pore over available international data, literature and climate models – as well as the latest Intergovernmental Panel on Climate Change reports – and calculate how human-induced climate change is affecting the impact of five types of extreme weather events: heatwaves, heavy rainfall, drought, wildfires and tropical cyclones.

They say that in the case of heatwaves, the role of climate change is unequivocal, and that the average and extreme heat levels in every continent across the globe are increasing specifically because of human-caused climate change.

A heatwave with a one in 50 chance of happening in pre-industrial times is now almost five times more likely to happen and will be 1.2C hotter, according to an IPCC report. In the past 20 years there have been 157,000 deaths from 34 heatwaves, according to data from the EMDAT disaster database. Yet the impact of human-induced climate change on heatwaves and the repercussions are still largely underestimated.

“One big reason why we underestimate heatwaves so dramatically is because no one’s dropping dead on the street during a heatwave, or at least very few people do,” Otto said.

Most people died from pre-existing conditions suddenly becoming acute, Otto said, and this often did not show up in data. Wildfires were also one of the big climate impacts not talked about enough, Otto said.

For other events such as droughts, floods and tropical cyclones, there is a more nuanced link to climate change. For example, there are some regions of the world where droughts are becoming worse because of human-caused climate change, such as southern Africa, Otto notes, while in other droughts the climate change signal is either not there or very small.

“By focusing too much on climate change, it really takes the responsibility, but also the agency, away to address these local drivers of disasters such as high poverty rates, missing infrastructure, investment, missing healthcare system … all these aspects of exposure and vulnerability that make every drought a catastrophe,” Otto said.

“That will not go away even if we stop burning fossil fuels today. I think that that is why the overestimation of climate change – by basically blaming this all on climate change – is not very helpful for actually dealing [with] and for actually improving resilience to these threats.”

Much of the problem in figuring out exactly to what extent climate change was responsible for the impact of extreme weather events, Otto said, lay in the lack of reliable data around the globe.

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There is not enough information coming from lower- and middle-income countries, although these are the places more likely to be at risk of the repercussions of human-induced climate change.

Already there’s been substantial scientific progress in the last few years in attributing extreme events and their consequences to human-made climate change, said Frances Moore, a professor of environmental economics at the University of California, Davis, who was not involved in the study.

“But an important caveat is that the consequences of climate change do not only operate through extremes,” said Moore. Changes in “average conditions” can also have large consequences for mortality, agriculture, worker productivity and safety. “It may well be that the aggregate consequences of these changing, ‘non-extreme’ conditions constitute a large fraction of total climate change impacts.”

Otto called for a broader definition of what was considered as “risk” in climate change modelling, rather than simply sticking to hazards and impact. Other factors such as the effects that extreme weather has on individuals, labour productivity, infrastructure, agricultural systems and property should be taken into account, he said.

“We started at ‘no one was ever talking about climate change’ and now we’ve sort of moved over to ‘blaming a lot of things on climate change’,” Otto said. “[This is] a plea towards realising that reality is somewhat messy, in the middle, and that we need to disentangle these drivers better in order to actually prioritise our adaptation and resilience building to really address climate change properly.”

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Prognostic factors for cardiovascular events in elderly pati | CIA

Angiotensinogen and Risk of Stroke Events in Patients with Type 2 Diab | DMSO


The burden of community-acquired pneumonia (CAP) ranks the first among all infectious diseases, especially in the elderly people, with higher morbidity and mortality, more comorbidities and complications, higher need for admission to intensive care unit (ICU) and rate of clinical failure (CF), and more medical expenses.1–5 Cardiovascular diseases (ischemic heart disease, stroke) are the world’s biggest killers, responsible for 27% of the world’s total deaths in 2019, according to the World Health Organization (WHO).6 The incidence of CAP and cardiovascular diseases significantly increases with advanced age.5,7 Previous study indicated that older patients hospitalized with pneumonia had fourfold increased risk of subsequent occurrence of acute cardiovascular events (CVEs) in the first 30 days after pneumonia.8 A clinical rule that stratifies the risk of cardiac complications in patients hospitalized for CAP revealed that older patients are at major risk of CVEs after pneumonia.9 A global systematic review and meta‐analysis of observational studies demonstrated that the overall rates of cardiac complications after CAP were 13.9%, and the rate of heart failure was 9.2%, arrhythmias 7.2%, acute coronary syndromes 4.5%, and stroke 1.7%.10 Meanwhile, the occurrence of CVEs complicated the course of hospitalization with CAP. Compared to CAP patients without CVEs, CAP patients with CVEs had higher rate of mechanical ventilation, more need to ICU admission, prolonged length of stay (LOS), higher rate of short-term and long-term mortality, and higher 30-day re-hospitalization.10–12 Therefore, the mutual interaction between these two diseases should arouse more attention of respiratory physicians and cardiologists.

Current studies mainly focus on the overall population of patients with CAP, yet rare data are for the certain elderly population.13 Accordingly, we performed a multicenter, retrospective study to evaluate the burden of CVEs during hospitalization and to explore the independent prognostic factors for the occurrence of CVEs and 30-day mortality in elderly patients with CAP.


Study Setting, Design and Participants

This study is a multicenter, retrospective research on hospitalized elderly patients with CAP from the CAP-China network. Data of patients aged 65 years or older were abstracted from 13 centers in seven cities in three provinces between January 1, 2014 and December 31, 2014 (details are made available in the study by Han et al4). The study was approved by the Human Subject Protection Program Institutional Review Board at China-Japan Friendship Hospital. Additional approval was obtained from the local institutional review board of each participating hospital. Patient consent was waived owing to the retrospective and observational study design.

Inclusion/Exclusion Criteria and CAP Definition

Inclusion criteria included (1) age ≥ 65 years; (2) one of the top five discharge diagnoses defined as CAP. Exclusion criteria included (1) hospital-acquired pneumonia; (2) active tuberculosis; (3) non-infectious diseases, such as pulmonary infarction, tumor or pulmonary edema; (4) acquired immune deficiency syndrome; (5) re-admission within 72 hours after discharge.

CAP was defined as follows: (1) community onset; (2) presence of new infiltrate on chest X-ray or computed tomography scan together with at least one of the following: (i) new or increased cough (productive, non-productive or with a change in sputum characteristics) with or without dyspnea, chest pain or hemoptysis, (ii) fever, (iii) rales and/or signs of consolidation, (iv) peripheral WBC counts >10,000 cells·mm−3 or <4000 cells·mm−3, with or without a left shift toward immature forms.

Immunocompromised patients referred to these with solid-organ or stem cell transplant or bone marrow transplantation within one year of admission, chemotherapy for hematological disease or solid-tumor malignancy within six months of admission or neutropenia <500 cells·m−3, chest radiation therapy within one month of admission, prescription with immunosuppressive therapy within three months of admission or splenectomy.

Data Collection

Details on admission such as demographic data, a series of clinical information, hematological data, evaluation of initial antimicrobial treatment, are also available in the study by Han et al.4

Clinical failure (CF) is divided into early (≤72 hours) CF and late (>72 hours) CF. The detailed definitions are available in the study by Han et al.3

Definition of CVEs

The CVEs considered during the hospitalization were defined as follows:

  1. Events related with cardiac diseases: ① congestive heart failure (CHF) (new onset heart failure, or worsening preexisting heart failure with typical signs and/or symptoms associated with elevation of brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP);②new onset arrhythmia, or worsening preexisting arrhythmia (multifocal atrial tachycardia, atrial fibrillation or flutter; ventricular tachycardia, flutter or fibrillation; new onset of high degree atrio-ventricular block (2nd and 3rd));③ acute myocardial infarction (AMI) with typical signs or symptoms associated with troponin level above the normal value (according to the reference range values of local laboratory) and/or ischemic electrocardiographic changes (new ST-T changes or new left bundle branch block).
  2. Events related with cerebrovascular diseases (CVDs): new onset of hemorrhagic or ischemic stroke or transient ischemic attack defined as clinical manifestations and was confirmed by computed tomography or magnetic resonance imaging.
  3. Events related with thromboembolic diseases: pulmonary embolism (PE) or deep venous thrombosis (DVT) was confirmed by clinical manifestations and by pulmonary artery angiography computed tomography or eco-Doppler ultrasound, respectively.

All the patients diagnosed with CVEs (International Classification of Diseases, tenth revision [ICD-10] codes (in the Additional file 1: Table S1)) were based on clinical manifestations, laboratory tests and consultation with specialists.

Statistical Analysis

According to the occurrence of CVEs during hospitalization, the patients were divided into CVEs group and non-CVEs group. Categorical variables are presented as frequencies or percentages, and continuous variables are presented as median (interquartile range, IQR). The χ2 test is used for categorical variables and the Mann–Whitney U-test for continuous variables.

Variables showing significant difference in univariate analysis (p<0.10) are included in multivariate logistic regression analysis model for the occurrence of any CVEs and 30-day mortality in elderly patients with CAP, and a stepwise forward model is used to select independent risk factor. The 95% confidence intervals (CIs) and level of significance are reported.

All data are analyzed with SPSS (version 20, IBM Corp., New York, USA); p<0.05 is considered statistically significant.


Study Population and Clinical Characteristics

Excluding immunosuppressed patients, 2941 patients aged ≥ 65 years were finally analyzed. 13.7% (n=402) of elderly patients with CAP occurred CVEs during hospitalization. Among them, 80.3% (n=323) were with acute CHF, 25.9% (n=104) with arrhythmia, 8.2% (n=33) with AMI, 6.2% (n=25) with CVDs, 4.0% (n=16) with thromboembolic diseases (six with PE and 10 with DVT). 73.1% (n=294) of patients had any one of CVEs, 22.6% (n=91) had two types of CVEs, 4.2% (n=17) had three types of CVEs.

Clinical characteristics of patients with or without CVEs are provided in Table 1. Patients with CVEs during hospitalization were older, higher risk of aspiration, long-term bedridden confinement and more comorbidities, especially cardiovascular disease and CVDs. Compared with non-CVEs patients, the pneumonia severity in patients with CVEs was more severe, history of CAP in past one year and use of glucocorticoids during hospitalization were more common.

Table 1 Comparison of Clinical Characteristics in Hospitalized Elderly CAP Patients with or without CVEs (n=2941)

Clinical Manifestations, Laboratory and Radiologic Findings

Compared with non-CVEs patients, the rates of wheezing, cyanosis and lower extremity edema were more common in patients with CVEs, as well as unstable vital signs. Leukocytosis, hyperglycemia, azotemia, hyponatremia, hypoxemia, acidosis, hypoproteinemia, multilobe infiltration and pleural effusion were more prone to occur in patients with CVEs. During hospitalization, the incidence of related acute organ failure, diffuse intravascular coagulation (DIC) and gastrointestinal bleeding was notably different between the two groups (Table 2).

Table 2 Comparison of Clinical Manifestations, Laboratory and Radiologic Findings in Hospitalized Elderly CAP Patients with or without CVEs (n=2941)


Compared with non-CVEs patients, patients with CVEs during hospitalization were more prone to be admitted to ICU, administrated more guideline-discordant antibiotic therapy, higher rate of CF, and lower rate of clinical stability before discharge. The median LOS in patients with CVEs was 12 days, significantly longer than that (11 days) in non-CVEs patients (p=0.019). The in-hospital mortality and 30-day mortality were also significantly higher in CVEs patients than those in non-CVEs patients (p<0.001), 27.1% versus 2.0%, 30.3% versus 3.4% respectively. Median total cost for one elderly CAP patient with CVEs was RMB 20,315.5, significantly higher than that (RMB 12,207.1) for non-CVEs patient (p<0.001). All the data are provided in Table 1.

The occurrence of CVEs significantly increased with age (p<0.001), and the incidence in patients aged ≥ 86 years was as high as 25.9%, nearly fourfold than that in patients aged 65–70 years (Figure 1). The rate of CF, in-hospital mortality and 30-day mortality significantly increased with the numbers of CVEs (p<0.001). The rate of in-hospital mortality and 30-day mortality in patients with three types of CVEs was 64.7% and 70.6%, respectively, threefold than that in patients with one type of CVEs and 20–30 folds than that in patients without CVEs (p<0.001) (Figure 2).

Figure 1 The occurrence of CVEs, CF, in-hospital mortality, and 30-day mortality in elderly patients of different age groups. 1) As for the occurrence of CVEs, there are statistical differences between the two groups (p<0.05), except for the group aged 65–70 years and 71–75 years, group aged 76–80 years and 81–85 years. 2) As for the rate of CF, there are statistical differences between the group aged ≥86 years and all other groups (p<0.05). 3) As for the rate of in-hospital, there are statistical differences between the group aged 65–70 years versus group aged 81–85 years and group aged ≥86 years (p<0.05); There are statistical differences between the group aged ≥86 years and all other groups (p<0.05). 4) As for the rate of 30-day mortality, there are statistical differences between the group aged ≥86 years and all other groups (p<0.05).

Abbreviations: CVE, cardiovascular event; CF, clinical failure.

Figure 2 The occurrence of CF, in-hospital mortality, and 30-day mortality in elderly patients with different numbers of cardiovascular events. As for the rate of CF, in-hospital and 30-day mortality, there are statistical differences between the two groups (p<0.05), except for group with two and three types of CVEs.

Abbreviation: CF, clinical failure.

Predictive Factors for the Occurrence of CVEs During Hospitalization

Table 3 shows that previous history of CHF (OR 6.16; 95% CI, 4.14–9.18, p<0.001), CF (OR 4.69; 95% CI, 3.392–6.48, p<0.001), previous history of ischemic heart disease (OR 2.22; 95% CI, 1.61–3.07, p<0.001), use of glucocorticoids during hospitalization (OR 2.0; 95% CI, 1.39–2.89, p<0.001), aspiration (OR 1.88; 95% CI, 1.26–2.81, p=0.002), pleural effusion (OR 1.66; 95% CI, 1.25–2.20, p<0.001), multilobe infiltration (OR 1.50; 95% CI, 1.15–1.96, p=0.003), age (OR 1.05; 95% CI, 1.04–1.07, p<0.001), and blood urea nitrogen (BUN) (OR 1.03; 95% CI, 1.01–1.06, p=0.007) were independent predictors for the occurrence of any CVE during hospitalization in the multivariable logistic regression model. While level of blood sodium (OR 0.98; 95% CI, 0.97–0.99, p=0.007) was a protective factor.

Table 3 Predictive Factors for the Occurrence of CVEs During Hospitalization in Univariate and Multivariable Logistic Regression Analysis

Predictive Factors for 30-Day Mortality in Elderly Patients with CAP

Table 4 shows that renal failure (OR 9.46; 95% CI, 4.17–21.48, p<0.001), respiratory failure (OR 9.32; 95% CI, 5.91–14.71, p<0.001), sepsis/sepsis shock (OR 7.87; 95% CI, 3.58–17.31, p<0.001), new CVDs (OR 5.94; 95% CI, 1.78–19.87, p=0.004), new heart failure (OR 4.04; 95% CI, 1.15–14.14, p=0.029), new arrhythmia (OR 2.38; 95% CI, 1.11–5.14, p=0.027), aspiration (OR 1.95; 95% CI, 1.09–3.50, p=0.025), CURB-65 (OR 1.57; 95% CI, 1.21–2.02, p=0.001), and white blood cell (WBC) count (OR 1.05; 95% CI, 1.02–1.09, p=0.006) were independent predictors for 30-day mortality in elderly patients with CAP in multivariable logistic regression model. While lymphocyte count (OR 0.63; 95% CI, 0.46–0.87, p=0.006) was a protective factor.

Table 4 Predictive Factors for 30-Day Mortality in Elderly CAP Patients in Univariate and Multivariable Logistic Regression Analysis


This is the first retrospective multicenter study to evaluate the disease burden of CVEs and risk factors for incidence of CVEs in hospitalized elderly patients with CAP in China. Our study discovers that: 1) 13.7% of elderly patients with CAP experience CVEs during hospitalization with higher rate of CF and poorer prognosis. 2) Independent risk factors associated with CVEs are age, aspiration, previous history of CHF and ischemic heart disease, level of BUN, CF, use of systematic glucocorticoids during hospitalization, pleural effusion, and multilobe infiltration; while level of blood sodium is a protective factor. 3) Independent risk factors associated with 30-day mortality are renal failure, respiratory failure, sepsis/sepsis shock, new CVDs, new heart failure, new arrhythmia, aspiration, CURB-65, and WBC count; while lymphocyte count is a protective factor.

Nowadays, there were some researches on CVEs during the course of or after CAP. However, the incidence of CVEs differs as the different inclusion criteria of CVEs. In a multicenter prospective study enrolled 1266 patients with CAP, data indicated that 23.8% of patients experienced at least a CV event (excluded the thromboembolic diseases),12 higher than that in our study. We considered the gap is mainly related to the low proportion of patients in PSI class IV or V or CURB-65 class 3–5. The most common CVE during hospitalization is newly diagnosed acute heart failure (11.0%), followed by arrhythmia (3.5%) and AMI (1.1%), similar with the data from systematic review and meta-analysis of observational studies.10 As to the mechanisms about the occurrence of CVEs in patients with CAP, previous studies demonstrated acute or persistent inflammation after CAP became the fuse of potential triggers for cardiac events, leading to the increased pro-inflammatory cytokines or activation of pro-coagulant factors. Plaque-related CVEs (AMI) and plaque-unrelated CVEs (arrhythmias and heart failure) occurred after plaque rupture, in-situ thrombus formation, and alteration of the balance of arterial perfusion or diffuse organ abnormalities with cellular dysfunction.14–18 Additionally, the occurrence of type 2 myocardial infarction (T2MI) after acute infection is considered to be related to“demand ischemia” (a mismatch in myocardial oxygen supply and demand).19 In older adults, coronary stenosis from chronic plaques and possibly toxin-mediated vasoconstriction after acute infection may lead to increased cardiac metabolic mismatch.20 Data discovered T2MI gradually increased with advanced age, especially among patients aged over 75 years old.21 Thence, appropriate antimicrobial regimens, effective treatment against other underlying diseases, anticoagulation therapy, dynamic monitoring of laboratory indicators, and timely adjustment of therapeutic plans can play an important role in the control of inflammation.

The disease burden of elderly patients with CAP experienced CVEs is heavier. In a prospective multicenter cohort of 1182 CAP inpatients enrolled between 2011 and 2016, Francesco Violi et al reported patients who experienced a CVE were older, had a higher prevalence of underlying diseases and complications, higher disease severity, unstable vital signs and 30-day mortality,22 in line with our results. In our study, a significant increasing trend in the proportion of patients with CVEs, CF, and short-term mortality was found across the advanced age; meanwhile, the increased numbers of CVEs lead to poorer prognosis. Patients with CVEs had significantly lower proportion of guideline-concordant antibiotic therapy than that in patients without CVEs, thus, the proportion of CF significantly increased accordingly as well as prolonged LOS and higher short-term mortality.3 This result suggests that appropriated evaluation of pathogens plays an important role in the choice of optimal antimicrobial regimen.

We confirmed previous reports showing that history of heart failure, previously diagnosed coronary artery disease, pleural effusion, multilobe infiltration, age and BUN were independently associated with CVEs.12,16,23–26 In the first analysis of prospectively collected data from the Pneumonia Patient Outcomes Team cohort study in patients with CAP, sodium<130 mmol/L was considered as independent risk factor for incident cardiac complications.25 In our data, level of blood sodium (OR 0.98; 95% CI, 0.97–0.99, p=0.007) was protective factor for the occurrence of CVEs, suggesting the similar conclusion. Adjunctive use of corticosteroids for patients with CAP has been controversial, even for severe CAP.27–29 In a propensity-score adjusted Cox model by Cangemi et al, use of corticosteroid for patients with CAP was associated with a lower incidence of intra-hospital myocardial infarction (OR 0.46; 95% CI 0.24–0.88, p=0.02), albeit not reducing either overall mortality or cardiovascular death.30 Conversely, we found adjunctive use of corticosteroids during hospitalization was associated with a higher incidence of CVEs (OR 2.0; 95% CI, 1.39–2.89, p<0.001). In an observational study of 500 consecutive patients hospitalized with CAP who were enrolled in the Community-Acquired Pneumonia Organization (CAPO) cohort study, data addressed CF was significantly related to the occurrence of AMI (OR, 4.22; 95% CI, 1.10–16.29),31 generally consistent with our conclusion. 21.4% of elderly patients with CVEs in our population had higher risk of aspiration. Aspiration can bring about chemical pneumonia, bacterial pneumonia, or lipoid pneumonia, and thus lead to acute or chronic infection and inflammation. Acute infections not only destabilize vascular endothelium and result in an imbalance between myocardial oxygen supply and demand, but also have both systemic and local effects on coronary vessels, thence creating an increased risk of cardiovascular events.32,33 In our multivariable logistic regression analysis, aspiration was confirmed as an independent predictor for CVEs.

The results of the current study are concordant with previous evidence that aspiration, CURB-65, WBC count, sepsis/sepsis shock and respiratory failure were independent predictors for short-term mortality for elderly patients with CAP.4,34–37 We found the complication after CAP, renal failure was significantly associated with increased 30-day mortality (OR 9.46; 95% CI, 4.17–21.48, p<0.001). Yet, in the past literatures, BUN is more used to an evaluation indicator. A retrospective cohort study from China by Kang and coworkers assessing 4880 CAP patients aged ≥ 65 years showed that BUN was a prognostic factor for in-hospital mortality.35 Data from a multicenter prospective study on the Implications of acute Cardiovascular Events in patients hospitalized for Community-Acquired Pneumonia (ICECAP), enrolling patients consecutively hospitalized from 2016 to 2018, indicated the occurrence of any CVE during hospitalization independently and significantly increased the risk of 30-day mortality (HR 1.69; 95% CI, 1.14–2.51, p = 0.009); while newly diagnosed heart failure, new onset atrial fibrillation or flutter, acute coronary syndrome, separately, were not associated with increased risk of 30-day mortality.12 The current study is the first to our knowledge to illustrate new CVDs, new heart failure, and new arrhythmia were independently and significantly increased the risk of 30-day mortality for elderly patients with CAP.

There are some limitations in our study that should be acknowledged. The present study was a retrospective design; thus, missing data were inevitable There were no records about the timing of onset of CVEs, the detailed type of new arrhythmia and CVDs during hospitalization. Furthermore, medications like statins and anticoagulants during hospitalization were also not evaluated. Meanwhile, we did not evaluate the association between pathogens or antimicrobial treatment and the occurrence of CVEs. Finally, biomarkers such as D-dimer, BNP, NT-proBNP presented lots of missing values, thereby, the relationship between biomarkers and the occurrence of CVEs could not be explored.


CVEs during hospitalization are common in elderly patients with CAP in China. Patients with CVEs have heavier disease burden and poorer outcomes, especially those with new CVDs, new heart failure, and new arrhythmia, which are independently and significantly prognostic factors for short-term mortality. It is critical for clinicians to early identify risk factors and strengthen the hierarchical management of elderly patients with CAP.


CVEs, cardiovascular events; CAP, community-acquired pneumonia; CHF, congestive heart failure; CVDs, cerebrovascular diseases; CF, clinical failure; OR, odds ratio; ICU, intensive care unit; WHO, World Health Organization; LOS, length of stay; BNP, brain natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; AMI, acute myocardial infarction; PE, pulmonary embolism; DVT, deep venous thrombosis; IQR, interquartile range; CIs, confidence intervals; DIC, diffuse intravascular coagulation; BUN, blood urea nitrogen; WBC, white blood cell; PSI, pneumonia severity index; T2MI, type 2 myocardial infarction; CAPO, Community-Acquired Pneumonia Organization; ICECAP, Implications of acute Cardiovascular Events in patients hospitalized for Community-Acquired Pneumonia; DIC, disseminated intravascular coagulation; COPD, chronic obstructive pulmonary disease; HCAP, healthcare-associated pneumonia; RR, respiratory rate; HR, heart rate; HCT, hematocrit; Cr, creatinine; Na, sodium; PaO2/FiO2, partial arterial oxygen pressure/fraction of inspired oxygen; PaO2, partial arterial oxygen pressure; SaO2, arterial oxygen saturation; CT, computed tomography.

Data Sharing Statement

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Ethics Approval and Informed Consent

This study was approved by the China-Japan Friendship Hospital Ethics Committee (No. 2015–85) on October 12, 2015. We also confirmed that all patient data was treated with confidentiality, in accordance with the Declaration of Helsinki.

Consent for Publication

All authors have confirmed that the details of the paper.


The authors are grateful for the contributions of all the staff of the CAP-China network for their help with data collection and input. Thanks to Yimin Wang, Guangqiang Wang, Xuexin Yao, Hongxia Yu, Guohua Yu, Meng Liu, Chunxue Xue, Bo Liu, Xiaoli Zhu, Yanli Li, Ying Xiao, Xiaojing Cui, Lijuan Li, and Lei Wang for collecting the information. Thanks to Yi Wang for revising the figures.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.


This work was supported by the National Science Grant for Distinguished Young Scholars (grant number 81425001/H0104), the National Key Technology Support Program from Ministry of Science and Technology (grant number 2015BAI12B11) and the Beijing Science and Technology Project (grant number D151100002115004).


The authors declare that they have no competing interests.


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Hemophilia A Gene Therapy Reduced Bleeding Events, Need for Clotting Factors

Hemophilia A Gene Therapy Reduced Bleeding Events, Need for Clotting Factors

The phase 3 trial of valoctocogene roxaparvovec for severe hemophilia A showed it reduced bleeding events as well as the use of factor VIII concentrates.

A phase 3 trial of valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, showed it reduced bleeding events as well as the use of factor VIII concentrates and increased endogenous production of clotting factors.

Severe hemophilia A, defined as a factor VIII level of 1 IU/dL or lower, carries the highest risk of spontaneous and traumatic bleeding, resulting in loss of limbs, chronic pain, decreased quality of life, and higher risk of mortality. About 1 in 5000 males is born with the rare disease, and about 60% have the most severe form, according to the National Organization for Rare Disorders.

Outcomes for individuals with hemophilia A, caused by a deficient F8 gene, have improved with factor VIII concentrates that are used prophylactically, but bleeding events are not eliminated.

If approved by the FDA, the adeno-associated virus (AAV) vector gene therapy would be sold as Roctavian by BioMarin, which funded the study. The FDA has granted valoctocogene roxaparvovec Regenerative Medicine Advanced Therapy and Breakthrough Therapy designations; according to press reports, it could be priced as high as $3 million, making it the most expensive therapy to date.

Writing in The New England Journal of Medicine, the authors said the gene therapy enables steady production of factor VIII without additional prophylactic measures. However, the authors also said, “The expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”1

Participants in the trial (GENEr8-1) were 134 adult men 18 years or older who had previously been treated with clotting-factor prophylaxis for at least 1 year, 2 of whom were living with HIV. At baseline, 61.9% of the participants were receiving factor VIII prophylaxis with standard half-life products, 27.6% with extended half-life products, and 17.9% with plasma-derived products. None of the participants were receiving emicizumab (Helimbra), a humanized bispecific monoclonal antibody that joins both factor IXa and X, which are proteins necessary to activate the natural coagulation cascade and restore the blood clotting process.

Exclusion criteria for the open-label, single-group, multicenter, phase 3 study included those who had preexisting anti-AAV5 antibodies, factor VIII inhibitors, or significant liver disease.

Patients received a single infusion of valoctocogene roxaparvovec at a dose of 6×1013 vector genomes per kilogram of body weight, and investigators examined the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion.

Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates.

Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. The analysis included data from 132 HIV-negative participants, including 112 participants enrolled from a prospective noninterventional study.

Results showed:

  • A decline in annualized rates of factor VIII use of 98.6% and treated bleeding of 83.8% (P <.001 for both comparisons)
  • A median factor VIII activity level of 5 IU/dL or higher in 88.1% of participants

As for safety, all participants had at least 1 adverse event (AE); 22 of 134 (16.4%) reported serious AEs.

Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with glucocorticoids. The other most common AEs were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%).

There were no deaths in the trial or withdrawals due to AEs, and there was no thrombosis or development of factor VIII inhibitors.

The investigators wrote that “intra- and interindividual variability in factor VIII activity after gene transfer were notable.” Seven participants had a median factor VIII activity level of greater than 150 IU/dL; 12 participants had a median factor VIII activity level of less than 3 IU/dL, measured by chromogenic assay; and 2 participants, measured by a 1-stage assay, had a factor VIII activity level of less than 1 IU/dL.

The causes of the variability are not fully known; the authors said biologic variables and molecular events related to gene transfer and expression may impact endogenous factor VIII production.

There were a few limitations to the study. The 2 participants with HIV were excluded from the primary analysis, and so generalizing the results to that population may be constrained. In addition, direct comparisons to emicizumab cannot be made because the participants had previously been using factor VIII concentrates, but the authors said “the annualized rates of treated bleeding here were similar to those reported with long-term emicizumab prophylaxis.”

In an accompanying editorial, the author called valoctocogene roxaparvovec “a new choice for care that could be truly transformative and liberating for eligible men with hemophilia” and called on payers, policymakers, and others to get ready for its entrance.2


1. Ozelo MC, Mahlangu J, Pasi KJ, et al; GENEr8-1 Trial Group. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022;386:1013-1025. doi:10.1056/NEJMoa2113708

2. Thornberg CD. Prepare the way for hemophilia A gene therapy. N Engl J Med. 2022;386:1081-1082. doi:10.1056/NEJMe2200878