Jean M. Elwing

Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

BACKGROUND Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling. METHODS We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed. RESULTS Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections. CONCLUSIONS Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation

Receptor-mediated airway smooth muscle (ASM) contraction via G(alphaq), and relaxation via G(alphas), underlie the bronchospastic features of asthma and its treatment. Asthma models show increased ASM G(alphai) expression, considered the basis for the proasthmatic phenotypes of enhanced bronchial hyperreactivity to contraction mediated by M(3)-muscarinic receptors and diminished relaxation mediated by beta(2)-adrenergic receptors (beta(2)ARs). A causal effect between G(i) expression and phenotype has not been established, nor have mechanisms whereby G(i) modulates G(q)/G(s) signaling. To delineate isolated effects of altered G(i), transgenic mice were generated overexpressing G(alphai2) or a G(alphai2) peptide inhibitor in ASM. Unexpectedly, G(alphai2) overexpression decreased contractility to methacholine, while G(alphai2) inhibition enhanced contraction. These opposite phenotypes resulted from different crosstalk loci within the G(q) signaling network: decreased phospholipase C and increased PKCalpha, respectively. G(alphai2) overexpression decreased beta(2)AR-mediated airway relaxation, while G(alphai2) inhibition increased this response, consistent with physiologically relevant coupling of this receptor to both G(s) and G(i). IL-13 transgenic mice (a model of asthma), which developed increased ASM G(alphai), displayed marked increases in airway hyperresponsiveness when G(alphai) function was inhibited. Increased G(alphai) in asthma is therefore a double-edged sword: a compensatory event mitigating against bronchial hyperreactivity, but a mechanism that evokes beta-agonist resistance. By selective intervention within these multipronged signaling modules, advantageous G(s)/G(q) activities could provide new asthma therapies.

Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program

Background— Pulmonary hypertension (PH) is associated with increased morbidity across the cardiopulmonary disease spectrum. Based primarily on expert consensus opinion, PH is defined by a mean pulmonary artery pressure (mPAP) ≥25 mm Hg. Although mPAP levels below this threshold are common among populations at risk for PH, the relevance of mPAP <25 mm Hg to clinical outcome is unknown. Methods and Results— We analyzed retrospectively all US veterans undergoing right heart catheterization (2007–2012) in the Veterans Affairs healthcare system (n=21 727; 908-day median follow-up). Cox proportional hazards models were used to evaluate the association between mPAP and outcomes of all-cause mortality and hospitalization, adjusted for clinical covariates. When treating mPAP as a continuous variable, the mortality hazard increased beginning at 19 mm Hg (hazard ratio [HR]=1.183; 95% confidence interval [CI], 1.004–1.393) relative to 10 mm Hg. Therefore, patients were stratified into 3 groups: (1) referent (⩽18 mm Hg; n=4 207); (2) borderline PH (19–24 mm Hg; n=5 030); and (3) PH (≥25 mm Hg; n=12 490). The adjusted mortality hazard was increased for borderline PH (HR=1.23; 95% CI, 1.12–1.36; P<0.0001) and PH (HR=2.16; 95% CI, 1.96–2.38; P<0.0001) compared with the referent group. The adjusted hazard for hospitalization was also increased in borderline PH (HR=1.07; 95% CI, 1.01–1.12; P=0.0149) and PH (HR=1.15; 95% CI, 1.09–1.22; P<0.0001). The borderline PH cohort remained at increased risk for mortality after excluding the following high-risk subgroups: (1) patients with pulmonary artery wedge pressure >15 mm Hg; (2) pulmonary vascular resistance ≥3.0 Wood units; or (3) inpatient status at the time of right heart catheterization. Conclusions— These data illustrate a continuum of risk according to mPAP level and that borderline PH is associated with increased mortality and hospitalization. Future investigations are needed to test the generalizability of our findings to other populations and study the effect of treatment on outcome in borderline PH.

Pulmonary hypertension associated with COPD

Although the prevalence of pulmonary hypertension (PH) in individuals with chronic obstructive pulmonary disease (COPD) is not known precisely, approximately 10%–30% of patients with moderate to severe COPD have elevated pulmonary pressures. The vast majority of PH associated with COPD is mild to moderate and severe PH occurs in <5% of patients. When COPD is associated with PH, both mortality and morbidity are increased. There are no clinical or physical examination findings that accurately identify patients with underlying PH. Radiographic imaging findings are specific but not sensitive indicators of PH. Echocardiography is the principle noninvasive diagnostic test but may be technically limited in a significant proportion of patients with COPD. Right heart catheterization is required for accurate measurement of pulmonary pressures. The combined effects of inflammation, endothelial cell dysfunction, and angiogenesis appear to contribute to the development of PH associated with COPD. Systemic vasodilators have not been found to be effective therapy. Selective pulmonary vasodilators including inhaled nitric oxide and phosphodiesterase inhibitors are promising treatments for patients with COPD associated PH but further evaluation of these medications is needed prior to their routine use.

Bronchovascular Fistula Formation: A Rare Airway Complication After Lung Transplantation

Although most late complications after lung transplantation are related to chronic rejection, airway anastomotic disease cannot be overlooked as a substantial contributor to morbidity and mortality. A rare, but nearly universally fatal example of anastomotic disease is fistula formation with the vascular system. Reports of fistula formation between the respiratory tree and the vascular system are not uncommon, but in the lung transplant population, specifically, only scattered case reports exist. Here we describe 3 cases of bronchovascular fistula formation after lung transplantation, with a review of the literature and exploration of possible risk factors, diagnostic techniques, and treatment modalities.

Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the VA-CART Program

Background— Pulmonary hypertension (PH) is associated with increased morbidity across the cardiopulmonary disease spectrum. Based primarily on expert consensus opinion, PH is defined by a mean pulmonary artery pressure (mPAP) ≥25 mm Hg. Although mPAP levels below this threshold are common among populations at risk for PH, the relevance of mPAP <25 mm Hg to clinical outcome is unknown. Methods and Results— We analyzed retrospectively all US veterans undergoing right heart catheterization (2007–2012) in the Veterans Affairs healthcare system (n=21 727; 908-day median follow-up). Cox proportional hazards models were used to evaluate the association between mPAP and outcomes of all-cause mortality and hospitalization, adjusted for clinical covariates. When treating mPAP as a continuous variable, the mortality hazard increased beginning at 19 mm Hg (hazard ratio [HR]=1.183; 95% confidence interval [CI], 1.004–1.393) relative to 10 mm Hg. Therefore, patients were stratified into 3 groups: (1) referent (⩽18 mm Hg; n=4 207); (2) borderline PH (19–24 mm Hg; n=5 030); and (3) PH (≥25 mm Hg; n=12 490). The adjusted mortality hazard was increased for borderline PH (HR=1.23; 95% CI, 1.12–1.36; P<0.0001) and PH (HR=2.16; 95% CI, 1.96–2.38; P<0.0001) compared with the referent group. The adjusted hazard for hospitalization was also increased in borderline PH (HR=1.07; 95% CI, 1.01–1.12; P=0.0149) and PH (HR=1.15; 95% CI, 1.09–1.22; P<0.0001). The borderline PH cohort remained at increased risk for mortality after excluding the following high-risk subgroups: (1) patients with pulmonary artery wedge pressure >15 mm Hg; (2) pulmonary vascular resistance ≥3.0 Wood units; or (3) inpatient status at the time of right heart catheterization. Conclusions— These data illustrate a continuum of risk according to mPAP level and that borderline PH is associated with increased mortality and hospitalization. Future investigations are needed to test the generalizability of our findings to other populations and study the effect of treatment on outcome in borderline PH.

Recommendations for the use of oral treprostinil in clinical practice: A delphi consensus project pulmonary circulation

Oral treprostinil was recently labeled for treatment of pulmonary arterial hypertension. Similar to the period immediately after parenteral treprostinil was approved, there is a significant knowledge gap for practicing physicians who might prescribe oral treprostinil. Despite its oral route of delivery, use of the drug is challenging because of the requirement for careful titration and management of drug-related adverse effects. We aimed to create a consensus document combining available evidence with expert opinion to provide guidance for use of oral treprostinil. Following a methodology commonly used in business and social sciences (the ‘Delphi Process’), two investigators from the oral treprostinil (Freedom) studies created a series of statements based on available evidence and the package insert. The set of ‘best practice’ statements was circulated to nine other Freedom trial investigators. Their comments were incorporated into the document as new line items for further vote and comment. The subsequent document was put to vote line by line (scale of −5 to +5) and a final statement was drafted. Consensus recommendations include initial therapy with 0.125 mg for treatment na patients, three times daily dosing, aggressive use of antidiarrheal medication, and a strong preference for use of the drug in combination with other approved PAH therapies. This process was particularly valuable in providing guidance for the management of adverse events (where essentially no data is available). The Delphi process was useful to codify investigator experience and subsequently develop investigator consensus about practical issues for physicians who may wish to prescribe oral treprostinil.

Pregnancy and Pulmonary Arterial Hypertension

Pregnancy in women with pulmonary arterial hypertension (PAH) due to defined or unknown causes is associated with greatly increased maternal morbidity. Significant respiratory, cardiac, and hematologic adaptations occur during pregnancy that may exacerbate the hemodynamic consequences of PAH and may precipitate malignant dysrhythmias and acute right ventricular overload and failure. Because of these potentially fatal consequences, the European Society of Cardiology and the American College of Cardiology/American Heart Association dissuade conception in women with PAH and recommend termination should pregnancy occur (Oakley 2003). Recent reviews suggest that significant progress has been achieved in the treatment and management of PAH during pregnancy (Bedard 2009). From 1978 to 1996 the overall maternal mortality rate was 38% and declined to 25% from 1997 to 2007 (Bedard 2009). Despite this improvement, mortality rates remain significantly elevated and the consideration of pregnancy in women with PAH should be thoroughly reviewed and discussed prior to conception (Roberts 1990) and, for those women with PAH who become pregnant or are diagnosed with PAH during pregnancy, a multidisciplinary management team with expertise in high risk pregnancy, maternal-fetal medicine, and pulmonary hypertension is warranted (Kiely 2010).

Psychosis: call a surgeon? A rare etiology of psychosis requiring resection.

Objective: Anti–N-methyl-d-aspartate receptor encephalitis is a rare but emerging cause of autoimmune encephalitis. Our objective is to present a case of this rare disease while highlighting the importance of an aggressive search for underlying malignancy as well as the common mischaracterization of primary psychiatric illness that occurs in these patients. Methods: A young Caucasian female with no known psychiatric history presented with acute onset of seizures and psychosis. Results: Magnetic resonance imaging abdomen and pelvis showed a 6-mm ovarian teratoma which was not visualized on initial computed tomographic scans. Pathology was consistent with a mature teratoma. Both serum and cerebrospinal fluid N-methyl- d -aspartate receptor antibodies were positive. Conclusion: An exhaustive search for underlying malignancy and specifically ovarian teratoma in young women should be completed in these patients. Diagnosis often is delayed given the prominent psychiatric manifestations and providers should be aware and strongly consider this in younger women with acute onset of neuropsychiatric symptoms.

Pulse dose steroids in severe pulmonary arterial hypertension secondary to systemic lupus erythematosus

Objective: The pulmonary vascular targeted treatment for systemic lupus erythematosus–associated pulmonary arterial hypertension is similar to other connective tissue disease–associated pulmonary arterial hypertension. In addition, there also appears to be a role for immunosuppression in the overall management. However, the optimal immunosuppressive regimen and what patients will respond to treatments are currently not clearly elucidated given the lack of randomized controlled trials on the subject. Our objective is to highlight the importance of early immunosuppression in systemic lupus erythematosus–associated pulmonary arterial hypertension and the role of pulse dose steroids in management. Methods: This case describes a 23-year-old woman who presented with pulmonary arterial hypertension diagnosed by right heart catheterization with mean pulmonary artery pressure of 74 mmHg, pulmonary capillary wedge pressure of 12 mmHg, and a pulmonary vascular resistance of 1908 dyne s cm−5. Due to the aggressive nature of her disease, she declined despite management with epoprostenol and sildenafil. Because of coexisting systemic lupus erythematosus with hemolytic anemia and worsening pulmonary arterial hypertension, intensive immunosuppressive therapy with pulse dose steroids was initiated. Results: Shortly after initiation of pulse dose steroids and maintenance immunosuppression, she had a dramatic symptomatic and hemodynamic response with a decrease in her pulmonary vascular resistance from 1908 to 136 dyne sec cm−5 and improvement in her mean pulmonary artery pressure from 74 to 27 mmHg on repeat right heart catheterization. Conclusion: Early immunosuppression is important to consider in those with systemic lupus erythematosus–associated pulmonary arterial hypertension. Limited studies are available, but most have focused on the use of cyclophosphamide. Pulse dose steroids may be a potentially less toxic but equally effective manner to aid in the treatment of systemic lupus erythematosus–pulmonary arterial hypertension when intensive immunosuppression is being considered.