Catherine A. Bonham

Identifying patients with severe sepsis using administrative claims: Patient-level validation of the angus implementation of the international consensus conference definition of severe sepsis

Background:Severe sepsis is a common and costly problem. Although consistently defined clinically by consensus conference since 1991, there have been several different implementations of the severe sepsis definition using ICD-9-CM codes for research. We conducted a single center, patient-level validation of 1 common implementation of the severe sepsis definition, the so-called “Angus” implementation. Methods:Administrative claims for all hospitalizations for patients initially admitted to general medical services from an academic medical center in 2009–2010 were reviewed. On the basis of ICD-9-CM codes, hospitalizations were sampled for review by 3 internal medicine-trained hospitalists. Chart reviews were conducted with a structured instrument, and the gold standard was the hospitalists’ summary clinical judgment on whether the patient had severe sepsis. Results:Three thousand one hundred forty-six (13.5%) hospitalizations met ICD-9-CM criteria for severe sepsis by the Angus implementation (Angus-positive) and 20,142 (86.5%) were Angus-negative. Chart reviews were performed for 92 randomly selected Angus-positive and 19 randomly-selected Angus-negative hospitalizations. Reviewers had a &kgr; of 0.70. The Angus implementation’s positive predictive value was 70.7% [95% confidence interval (CI): 51.2%, 90.5%]. The negative predictive value was 91.5% (95% CI: 79.0%, 100%). The sensitivity was 50.4% (95% CI: 14.8%, 85.7%). Specificity was 96.3% (95% CI: 92.4%, 100%). Two alternative ICD-9-CM implementations had high positive predictive values but sensitivities of <20%. Conclusions:The Angus implementation of the international consensus conference definition of severe sepsis offers a reasonable but imperfect approach to identifying patients with severe sepsis when compared with a gold standard of structured review of the medical chart by trained hospitalists.

Prognosis of Myocardial Damage in Sarcoidosis Patients With Preserved Left Ventricular Ejection Fraction: Risk Stratification Using Cardiovascular Magnetic Resonance.

Background—Cardiac sarcoidosis is associated with an increased risk of heart failure and sudden death, but its risk in patients with preserved left ventricular ejection fraction is unknown. Using cardiovascular magnetic resonance in patients with extracardiac sarcoidosis and preserved left ventricular ejection fraction, we sought to (1) determine the prevalence of cardiac sarcoidosis or associated myocardial damage, defined by the presence of late gadolinium enhancement (LGE), (2) quantify their risk of death/ventricular tachycardia (VT), and (3) identify imaging-based covariates that predict who is at greatest risk of death/VT. Methods and Results—Parameters of left and right ventricular function and LGE burden were measured in 205 patients with left ventricular ejection fraction >50% and extracardiac sarcoidosis who underwent cardiovascular magnetic resonance for LGE evaluation. The association between covariates and death/VT in the entire group and within the LGE+ group was determined using Cox proportional hazard models and time-dependent receiver–operator curves analysis. Forty-one of 205 patients (20%) had LGE; 12 of 205 (6%) died or had VT during follow-up; of these, 10 (83%) were in the LGE+ group. In the LGE+ group (1) the rate of death/VT per year was >20× higher than LGE− (4.9 versus 0.2%, P<0.01); (2) death/VT were associated with a greater burden of LGE (14±11 versus 5±5%, P<0.01) and right ventricular dysfunction (right ventricular EF 45±12 versus 53±28%, P=0.04). LGE burden was the best predictor of death/VT (area under the receiver-operating characteristics curve, 0.80); for every 1% increase of LGE burden, the hazard of death/VT increased by 8%. Conclusions—Sarcoidosis patients with LGE are at significant risk for death/VT, even with preserved left ventricular ejection fraction. Increased LGE burden and right ventricular dysfunction can identify LGE+ patients at highest risk of death/VT.

The epidemiology of acute organ system dysfunction from severe sepsis outside of the intensive care unit.

BACKGROUND Severe sepsis is a common, costly, and complex problem, the epidemiology of which has only been well studied in the intensive care unit (ICU). However, nearly half of all patients with severe sepsis are cared for outside the ICU. OBJECTIVE To determine rates of infection and organ system dysfunction in patients with severe sepsis admitted to non-ICU services. DESIGN Retrospective cohort study. SETTING A large, tertiary, academic medical center in the United States. PATIENTS Adult patients initially admitted to non-ICU medical services from 2009 through 2010. MEASUREMENTS All International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes were screened for severe sepsis. Three hospitalists reviewed a sample of medical records evaluating the characteristics of severe sepsis. RESULTS Of 23,288 hospitalizations, 14% screened positive for severe sepsis. A sample of 111 cases was manually reviewed, identifying 64 cases of severe sepsis. The mean age of patients with severe sepsis was 63 years, and 39% were immunosuppressed prior to presentation. The most common site of infection was the urinary tract (41%). The most common organ system dysfunctions were cardiovascular (hypotension) and renal dysfunction occurring in 66% and 64% of patients, respectively. An increase in the number of organ systems affected was associated with an increase in mortality and eventual ICU utilization. Severe sepsis was documented by the treating clinicians in 47% of cases. CONCLUSIONS Severe sepsis was commonly found and poorly documented on the wards at our medical center. The epidemiology and organ dysfunctions among patients with severe sepsis appear to be different from previously described ICU severe sepsis populations.

The Epidemiology of Acute Organ System Dysfunction from Severe Sepsis Outside of the ICU

BACKGROUND Severe sepsis is a common, costly, and complex problem, the epidemiology of which has only been well studied in the intensive care unit (ICU). However, nearly half of all patients with severe sepsis are cared for outside the ICU. OBJECTIVE To determine rates of infection and organ system dysfunction in patients with severe sepsis admitted to non-ICU services. DESIGN Retrospective cohort study. SETTING A large, tertiary, academic medical center in the United States. PATIENTS Adult patients initially admitted to non-ICU medical services from 2009 through 2010. MEASUREMENTS All International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes were screened for severe sepsis. Three hospitalists reviewed a sample of medical records evaluating the characteristics of severe sepsis. RESULTS Of 23,288 hospitalizations, 14% screened positive for severe sepsis. A sample of 111 cases was manually reviewed, identifying 64 cases of severe sepsis. The mean age of patients with severe sepsis was 63 years, and 39% were immunosuppressed prior to presentation. The most common site of infection was the urinary tract (41%). The most common organ system dysfunctions were cardiovascular (hypotension) and renal dysfunction occurring in 66% and 64% of patients, respectively. An increase in the number of organ systems affected was associated with an increase in mortality and eventual ICU utilization. Severe sepsis was documented by the treating clinicians in 47% of cases. CONCLUSIONS Severe sepsis was commonly found and poorly documented on the wards at our medical center. The epidemiology and organ dysfunctions among patients with severe sepsis appear to be different from previously described ICU severe sepsis populations.

Prostacyclin and oral vasodilator therapy in sarcoidosis-associated pulmonary hypertension: a retrospective case series.

BACKGROUND It is unclear whether recent advances in pulmonary arterial hypertension therapy can be safely applied to sarcoidosis-associated pulmonary hypertension (SAPH). Evidence for prostacyclin (PG) therapy in SAPH is limited. METHODS We conducted a single-center, retrospective review of 46 patients with sarcoidosis, 26 of whom had SAPH. Thirteen received PG as monotherapy or in combination with oral vasodilators. RESULTS Follow-up right-sided heart catheterization at a mean of 12.7 months revealed improved cardiac output, cardiac index, and pulmonary vascular resistance. Functional class and N-terminal pro-brain natriuretic peptide levels also improved in patients treated with PG. No significant change in oxygen requirement was seen with vasodilator therapy initiation. At 2 years, 15 patients with SAPH survived, including eight on PG, and at 5 years, seven survived, including five on PG. Survival was significantly reduced in patients with SAPH compared with patients who had sarcoidosis without pulmonary hypertension. Multivariate analysis demonstrated that the use of PG therapy in SAPH is not associated with increased mortality. CONCLUSIONS Many patients with severe SAPH showed significant hemodynamic and clinical improvement on long-term IV or subcutaneous PG therapy and had survival outcomes similar to patients with moderate SAPH on oral vasodilator therapy.

Transforming Growth Factor (TGF)-β Promotes de Novo Serine Synthesis for Collagen Production

TGF-β promotes excessive collagen deposition in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). The amino acid composition of collagen is unique due to its high (33%) glycine content. Here, we report that TGF-β induces expression of glycolytic genes and increases glycolytic flux. TGF-β also induces the expression of the enzymes of the de novo serine synthesis pathway (phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH)) and de novo glycine synthesis (serine hydroxymethyltransferase 2 (SHMT2)). Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for TGF-β-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of fibrotic diseases including IPF.

TGF-β Promotes de novo Serine Synthesis for Collagen Production

TGF-β promotes excessive collagen deposition in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). The amino acid composition of collagen is unique due to its high (33%) glycine content. Here, we report that TGF-β induces expression of glycolytic genes and increases glycolytic flux. TGF-β also induces the expression of the enzymes of the de novo serine synthesis pathway (phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH)) and de novo glycine synthesis (serine hydroxymethyltransferase 2 (SHMT2)). Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for TGF-β-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of fibrotic diseases including IPF.

Skewed Lung CCR4 to CCR6 CD4+ T Cell Ratio in Idiopathic Pulmonary Fibrosis Is Associated with Pulmonary Function

Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease. While it has been suggested that T cells may contribute to IPF pathogenesis, these studies have focused primarily on T cells outside of the pulmonary interstitium. Thus, the role of T cells in the diseased lung tissue remains unclear. Objective To identify whether specific CD4+ T cell subsets are differentially represented in lung tissue from patients with IPF. Methods CD4+ T cell subsets were measured in lung tissue obtained from patients with IPF at the time of lung transplantation, and from age- and gender-matched organ donors with no known lung disease. Subsets were identified by their surface expression of CCR4, CCR6, and CXCR3 chemokine receptors. CD4+ T cell subsets were correlated with measurements of lung function obtained prior to transplantation. Results Compared to controls, IPF patients had a higher proportion of lung CD4+ T cells, a higher proportion of CCR4+ CD4+ T cells, and a lower proportion of CCR6+ CD4+ T cells. The increase in CCR4+ CD4+ T cells in IPF lung tissue was not due to increased Tregs. Intriguingly, the increase in the ratio of CCR4+ cells to CCR6+ cells correlated significantly with better lung function. Conclusion Our findings suggest a new paradigm that not all T cell infiltrates in IPF lungs are detrimental, but instead, specialized subsets may actually be protective. Thus, augmentation of the chemokines that recruit protective T cells, while blocking chemokines that recruit detrimental T cells, may constitute a novel approach to IPF therapy.

From granuloma to fibrosis: sarcoidosis associated pulmonary fibrosis.

Purpose of review Up to twenty percent of patients with sarcoidosis develop pulmonary fibrosis, transforming an often benign disease into a highly morbid and potentially fatal one. We highlight the fibrotic pulmonary sarcoidosis phenotype as an area of intense clinical and translational investigation, review recent developments in treatment, and provide a roadmap for future research in sarcoidosis associated pulmonary fibrosis. Recent findings Granulomatous inflammation in a lymphatic distribution is the hallmark finding of pulmonary sarcoidosis and the nidus for fibrosis. Recent research demonstrates that fibrotic sarcoidosis begins in the setting of persistent, uncontrolled inflammation, and is aided by pro-fibrotic genetic features and immune responses. Comparison to other fibrotic lung diseases also reveals key features that inform our understanding of common pathways in fibrosis. Summary Understanding the mechanisms of fibrotic transformation in sarcoidosis enhances clinical care and facilitates development of novel therapeutic options. The impact of these findings in fibrotic sarcoidosis may be amplified through application to other interstitial lung diseases marked by inflammatory to fibrotic transformation. Important aspects of clinical management of fibrotic sarcoidosis include surveillance for co-morbidities, such as pulmonary hypertension, airway disease, and infection, and assessment for pulmonary disease activity that may benefit from immunosuppression.

Asthma Outcomes and Management During Pregnancy

&NA; Asthma during pregnancy poses a common, increasingly prevalent threat to the health of women and their children. The present article reviews recent insights gained from the epidemiology of asthma during pregnancy, demonstrating the many short‐ and long‐term risks to mother and fetus incurred by poorly controlled maternal asthma. We further discuss emerging evidence that active management of asthma during pregnancy can positively influence and perhaps completely mitigate these poor outcomes. Recent high‐quality trials examining best methods for asthma treatment are reviewed and synthesized to offer an evidence‐based pathway for comprehensive treatment of asthma in the outpatient setting. Safe and effective medications, as well as nonpharmacologic interventions, for asthma during pregnancy are discussed, and treatment options for related conditions of pregnancy, including depression, rhinitis, and gastroesophageal reflux, are presented. Throughout, we emphasize that an effective treatment strategy relies on a detailed patient evaluation, patient education, objective measurement of asthma control, and frequent and supportive follow‐up. The cardiovascular and respiratory physiology of pregnancy is reviewed, as well as its implications for the management of patients with asthma, including patients requiring intubation and mechanical ventilation. For the situation when outpatient asthma management has failed, an approach to the critically ill pregnant patient with status asthmaticus is detailed. Multidisciplinary teams that include pulmonary specialists, obstetricians, primary care providers, nurses, pharmacists, and asthma educators improve the care of pregnant women with asthma.