Michael Ieong

Systemic sclerosis–associated pulmonary hypertension: Short‐ and long‐term effects of epoprostenol (prostacyclin)

OBJECTIVE To evaluate the short- and long-term effects of intravenous epoprostenol in patients with pulmonary hypertension (PH) associated with systemic sclerosis (SSc). METHODS Sixteen patients with SSc-associated PH and New York Heart Association (NYHA) class III or IV symptomatology underwent right heart catheterization for determination of baseline hemodynamic values. Vasoreactivity was assessed with either inhaled nitric oxide or intravenous adenosine. After a medication washout period, all patients received intravenous epoprostenol in incrementally increasing doses; tolerance was assessed according to symptoms and hemodynamic findings at each dose increment and at the conclusion of the medication trial. Once a stable medication regimen was established, patients were discharged and followed up as outpatients for assessment of symptoms and exercise tolerance as measured by change in the NYHA class. Repeat hemodynamic testing was performed in 4 patients at 1 year and in 2 patients at 2 years of treatment. RESULTS Therapeutic response to epoprostenol, defined by a reduction in the pulmonary vascular resistance of > or =25%, was achieved in the short-term treatment period in 13 of 16 patients (81.3%). Improvement in symptoms and exercise tolerance occurred in all patients, and a significant short-term hemodynamic response was observed. Followup hemodynamic tests revealed persistent favorable responses in all 4 of the patients studied. CONCLUSION Most patients with PH secondary to SSc manifest favorable hemodynamic responses to epoprostenol in the short term. Long-term epoprostenol was generally well tolerated and provides a potential therapeutic option for patients with PH secondary to SSc.

Use and outcomes of noninvasive positive pressure ventilation in acute care hospitals in Massachusetts.

BACKGROUND This study determined actual utilization rates and outcomes of noninvasive positive pressure ventilation (NIV) at selected hospitals that had participated in a prior survey on NIV use. METHODS This observational cohort study, based at eight acute care hospitals in Massachusetts, focused on all adult patients requiring ventilatory support for acute respiratory failure during predetermined time intervals. RESULTS Of 548 ventilator starts, 337 (61.5%) were for invasive mechanical ventilation and 211 (38.5%) were for NIV, with an overall NIV success rate of 73.9% (ie, avoidance of intubation or death while on NIV or within 48 h of discontinuation). Causal diagnoses for respiratory failure were classified as (I) acute-on-chronic lung disease (23.5%), (II) acute de novo respiratory failure (17.9%), (III) neurologic disorders (19%), (IV) cardiogenic pulmonary edema (16.8%), (V) cardiopulmonary arrest (12.2%), and (VI) others (10.6%). NIV use and success rates for each of the causal diagnoses were, respectively, (I) 76.7% and 75.8%, (II) 37.8% and 62.2%, (III) 1.9% and 100%, (IV) 68.5% and 79.4%, (V) none, and (VI) 17.2% and 60%. Hospital mortality rate was higher in patients with invasive mechanical ventilation than in patients with NIV (30.3% vs 16.6%, P < .001). CONCLUSIONS NIV occupies an important role in the management of acute respiratory failure in acute care hospitals in selected US hospitals and is being used for a large majority of patients with acute-on-chronic respiratory failure and acute cardiogenic pulmonary edema. NIV use appears to have increased substantially in selected US hospitals over the past decade. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00458926; URL: www.clinicaltrials.gov.

Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells

ABSTRACT Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-α) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-α activity, as measured by the TNF-α/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-α is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-α production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam3Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-α in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-α production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

Changes in forced vital capacity over time in systemic sclerosis: application of group-based trajectory modelling

OBJECTIVE An accelerated rate of decline in forced vital capacity (FVC) affects >50% of patients with SSc but data on the variability and determinants of this change are scarce. We sought to identify trajectories of FVC and their associated variables in SSc patients over a 12-year period. METHODS Clinical and pulmonary function data were retrospectively collected. SSc patients with three or more FVC values were included. Group-based modelling was used to cluster similar FVC patterns into trajectories. Baseline variables were associated with the trajectories using multinomial logistic regression. The effect of CYC on FVC was examined with each trajectory as a time-varying covariate. RESULTS In 254 SSc patients we identified seven distinct FVC trajectories: very low slow decline (5.5%), very low improve (13.8%), low fast decline (9.5%), low stable (19.7%), low-normal improve (31.1%), normal improve (16.1%) and normal stable (4.3%). Younger age and the presence of pulmonary hypertension, Interstitial lung disease and shortness of breath at baseline significantly increased the odds of declining trajectories vs the reference trajectory (low-normal improve). CYC was associated with FVC improvement in the low fast decline trajectory. CONCLUSION The course of FVC in SSc was highly variable, with improvement and stability experienced even by those with low baseline FVC. Trajectory modelling was able to identify SSc patients who were most likely to experience FVC decline and thus could be a useful tool for patient management as well as clinical trial design.

Cardiopulmonary Exercise Testing with Right-heart Catheterization in Patients with Systemic Sclerosis

Objective. To examine the role of cardiopulmonary exercise testing with right-heart catheterization (CPET/RHC) in patients with systemic sclerosis (SSc) with potentially multifactorial exertional limitation. Methods. This was a single-center retrospective cohort study of patients with SSc referred for CPET/RHC. Results. A total of 19 patients with SSc [subtypes: 10 limited, 5 diffuse, 1 systemic lupus erythematosus (SLE)/SSc overlap, and 3 with no subtype specified in the medical record] underwent CPET/RHC testing from February 2003 to February 2008. Of these patients, the primary limitations to exercise were found to be ventilatory (n = 6), deconditioning/cardiovascular (n = 6), pulmonary vascular (PVL; n = 3), and exercise-induced left ventricular diastolic dysfunction (exercise-LVDD; n = 4). No prior physical examination, pulmonary function test, imaging, or echocardiographic data reliably predicted the etiology of exercise limitation determined by CPET/RHC. Vital capacity and ventilatory equivalent for CO2 did not differ during CPET testing between PVL and exercise–LVDD, limiting the utility of CPET alone for discriminating these etiologies of dyspnea. Exercise alveolar-arterial oxygen gradient was elevated in subjects shown to have PVL [median 48 mm Hg (interquartile range 45.3, 62.0)] compared to those with exercise-LVDD [26.0 (IQR 10.6, 36.0)] and deconditioning [13.9 (IQR 4.0, 16.4); p = 0.02]. Major therapeutic changes occurred in 11/19 (58%) subjects after CPET/RHC testing. Conclusion. CPET/RHC testing in subjects with SSc and potentially multifactorial dyspnea adds potentially useful diagnostic information unavailable from noninvasive testing.

Use and Outcomes of Noninvasive Ventilation for Acute Respiratory Failure in Different Age Groups.

BACKGROUND: The prevalence of chronic disease and do-not-intubate status increases with age. Thus, we aimed to determine characteristics and outcomes associated with noninvasive ventilation (NIV) use for acute respiratory failure (ARF) in different age groups. METHODS: A database comprising prospective data collected on site on all adult patients with ARF requiring ventilatory support from 8 acute care hospitals in Massachusetts was used. RESULTS: From a total of 1,225 ventilator starts, overall NIV utilization, success, and in-hospital mortality rates were 22, 54, and 18% in younger (18–44 y); 34, 65, and 13% in middle-aged (45–64 y); 49, 68, and 17% in elderly (65–79 y); and 47, 76, and 24% in aged (≥80 y) groups, respectively (P < .001, P = .08, and P = .11, respectively). NIV use for cardiogenic pulmonary edema and subjects with a do-not-intubate order increased significantly with advancing age (25, 57, 57, and 74% and 7, 12, 18, and 31%, respectively, in the 4 age groups [P < .001 and P = .046, respectively]). For subjects receiving NIV with a do-not-intubate order, success and in-hospital mortality rates were similar in different age groups (P = .27 and P = .98, respectively). CONCLUSIONS: NIV use and a do-not-intubate status are more frequent in subjects with ARF ≥65 y than in those <65 y, especially for subjects with cardiogenic pulmonary edema. However, NIV success and mortality rates were similar between age groups. (ClinicalTrials.gov registration NCT00458926.)

Myeloid ZFP36L1 Does Not Regulate Inflammation or Host Defense in Mouse Models of Acute Bacterial Infection

Zinc finger protein 36, C3H type-like 1 (ZFP36L1) is one of several Zinc Finger Protein 36 (Zfp36) family members, which bind AU rich elements within 3′ untranslated regions (UTRs) to negatively regulate the post-transcriptional expression of targeted mRNAs. The prototypical member of the family, Tristetraprolin (TTP or ZFP36), has been well-studied in the context of inflammation and plays an important role in repressing pro-inflammatory transcripts such as TNF-α. Much less is known about the other family members, and none have been studied in the context of infection. Using macrophage cell lines and primary alveolar macrophages we demonstrated that, like ZFP36, ZFP36L1 is prominently induced by infection. To test our hypothesis that macrophage production of ZFP36L1 is necessary for regulation of the inflammatory response of the lung during pneumonia, we generated mice with a myeloid-specific deficiency of ZFP36L1. Surprisingly, we found that myeloid deficiency of ZFP36L1 did not result in alteration of lung cytokine production after infection, altered clearance of bacteria, or increased inflammatory lung injury. Although alveolar macrophages are critical components of the innate defense against respiratory pathogens, we concluded that myeloid ZFP36L1 is not essential for appropriate responses to bacteria in the lungs. Based on studies conducted with myeloid-deficient ZFP36 mice, our data indicate that, of the Zfp36 family, ZFP36 is the predominant negative regulator of cytokine expression in macrophages. In conclusion, these results imply that myeloid ZFP36 may fully compensate for loss of ZFP36L1 or that Zfp36l1-dependent mRNA expression does not play an integral role in the host defense against bacterial pneumonia.

Noninfectious Pulmonary Complications of Hiv

Pulmonary complications of HIV infection increase as the disease progresses. Although the most common cause of pulmonary disease continues to be infection, a number of noninfectious entities should be considered when evaluating the HIV-infected individual with pulmonary symptoms. With the advent of highly active antiretroviral therapy, there have been significant changes in the epidemiology of these diseases. Improved understanding of pathogenesis has led to new therapies, especially for HIV-associated pulmonary hypertension. In those patients in whom a thorough microbiologic survey reveals no infection, one should consider noninfectious entities; these can be broadly categorized into 3 groups: malignant, inflammatory, or pulmonary vascular disease. Clinical history is critical in providing clues, but bronchoscopic visualization and tissue sampling are often required to confirm many of these diagnoses. As successful antiretroviral therapy continues to extend the lives of HIV-infected patients, the medical community should be able to recognize and diagnose these noninfectious pulmonary diseases.

The RNA uridyltransferase Zcchc6 is expressed in macrophages and impacts innate immune responses

Alveolar macrophages orchestrate pulmonary innate immunity and are essential for early immune surveillance and clearance of microorganisms in the airways. Inflammatory signaling must be sufficiently robust to promote host defense but limited enough to prevent excessive tissue injury. Macrophages in the lungs utilize multiple transcriptional and post-transcriptional mechanisms of inflammatory gene expression to delicately balance the elaboration of immune mediators. RNA terminal uridyltransferases (TUTs), including the closely homologous family members Zcchc6 (TUT7) and Zcchc11 (TUT4), have been implicated in the post-transcriptional regulation of inflammation from studies conducted in vitro. In vivo, we observed that Zcchc6 is expressed in mouse and human primary macrophages. Zcchc6-deficient mice are viable and born in Mendelian ratios and do not exhibit an observable spontaneous phenotype under basal conditions. Following an intratracheal challenge with S. pneumoniae, Zcchc6 deficiency led to a modest but significant increase in the expression of select cytokines including IL-6, CXCL1, and CXCL5. These findings were recapitulated in vitro whereby Zcchc6-deficient macrophages exhibited similar increases in cytokine expression due to bacterial stimulation. Although loss of Zcchc6 also led to increased neutrophil emigration to the airways during pneumonia, these responses were not sufficient to impact host defense against infection.

Pathobiology and Treatment of Pulmonary Hypertension in HIV Disease

Among HIV-infected people, the primary pulmonary complications among adults remain infectious. However, for those HIV-infected persons who receive highly active antiviral therapy, the spectrum of pulmonary disease is changing as a decrease in the incidence of opportunistic infections of the lung yields an increase of noninfectious complications. HIV-associated pulmonary arterial hypertension (HIV-PAH) is among these noninfectious complications. The prevalence of HIV-PAH (determined in different cohorts) is approximately 0.5%. The prevalence in HIV-PAH has dramatically changed during the last ten years, which is in stark contrast to another pulmonary complication of HIV infection, Pneumocystis pneumonia, in which the total number of cases declined fivefold between 1995 and 2003. The stable prevalence of HIV-PAH leads to three key observations. First, the prevalence of PAH among HIV infected patients is much greater than that of IPAH in the general population (6–12-fold greater). Second, because 40 million people in the world are estimated to be infected with HIV and these individuals are surviving much longer, the number of PAH cases identified is certain to increase. Finally, the observation that the prevalence of PAH in HIV-infected people is essentially unchanged in spite of reduced viral load suggests that the pathogenesis of HIV-PAH is only partly dependent on the degree of HIV viremia. The clinical implication of these observations is that current and investigative therapies used in PAH should significantly reduce the symptoms and improve the quality of life in HIV-PAH. The major limiting factor for use of any PAH-modulating medication is the complicated pharmacokinetics related to concurrent antiretroviral use and the higher prevalence of hepatic impairment among HIV-infected patients. Despite these limitations, it seems reasonable that, as is the case with other types of PAH, early intervention has the potential of significantly delaying disease progression.