Challenges in Diagnosis, Management, and Treatment of Allopurinol-Induced DRESS Syndrome: Case Report and Literature Review.

We describe the presentation, diagnosis, management, and treatment of a 62-year-old woman with a medical history of gout who presented with a maculopapular rash, facial and tongue edema. Her initial presentation, coupled with a history of recent allopurinol use for systematic relief, led to the diagnosis of allopurinol-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, further confirmed by the RegiSCAR scoring criteria including a skin biopsy. The patient was initially treated conservatively but required systemic corticosteroid therapy as she developed severe multi-organ dysfunction. This article will highlight the challenges involved in diagnosing DRESS syndrome from other adverse cutaneous drug reactions, delayed systemic complications, and the need for evidence-based treatment modalities and regimens using the most recent published literature and analysis of case reports. Among treatment modalities, pulsed parenteral steroids show promise in a few case reports. We also discuss the newer alternative gout therapies since the mainstay of gout treatment, allopurinol, is potentially associated with morbidity and mortality risks as manifested in our patient with DRESS.

The glutathione peroxidase 1-protein tyrosine phosphatase 1B-protein phosphatase 2A axis. A key determinant of airway inflammation and alveolar destruction.

Protein phosphatase-2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and chronic obstructive pulmonary disease (COPD). Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase-1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B affected lung PP2A activity and airway inflammation. Experiments using gene silencing techniques in mouse lung or human small airway epithelial cells determined that knocking down PTP1B expression blocked GPx-1's activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a nonresponsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung disease. Indeed, PTP1B protein was oxidized in the lungs of subjects with advanced emphysema, and cigarette smoke did not increase GPx-1 or PTP1B activity within epithelial cells isolated from subjects with COPD, unlike samples of healthy lung epithelial cells. In conclusion, these findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung-tissue destruction in response to cigarette smoke exposure.

The divergent roles of secreted frizzled related protein-1 (SFRP1) in lung morphogenesis and emphysema.

Developmentally expressed genes are believed to play a central role in tissue repair after injury; however, in lung disease their role has not been established. This study demonstrates that SFRP1, an inhibitor of Wnt signaling normally expressed during lung embryogenesis, is induced in the lungs of emphysema patients and in two murine models of the disease. SFRP1 was found to be essential for alveolar formation as Sfrp1(-/-) mice exhibited aberrant Wnt signaling, mesenchymal proliferation, and impaired alveoli formation. In contrast, SFRP1 activated ERK and up-regulated MMP1 and MMP9 without altering TIMP1 production when expressed in human lung epithelial cells. These findings demonstrate that SFRP1 promotes normal alveolar formation in lung development, although its expression in the adult up-regulates proteins that can cause tissue destruction. Thus, SFRP1 induction during tissue injury is unlikely to contribute to the repair response but rather is a participatory factor in the pathogenesis of emphysema and tissue destruction.

Diuretic and renal effects of spironolactone and heart failure hospitalizations: a TOPCAT Americas analysis.

AIMS: It is unclear whether spironolactone reduced heart failure (HF) hospitalizations in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial through potential diuretic or other effects. We examined the effects of spironolactone on weight, diuretic use, and renal function, and their subsequent impact on outcomes. METHODS AND RESULTS: We analysed data from TOPCAT Americas (1767 patients with HF and preserved ejection fraction; 886 in spironolactone, 881 in placebo arm). We used mixed-effects models for serial data and shared frailty models to identify determinants of recurrent HF hospitalizations among baseline and serial parameters. There were 800 HF hospitalizations after a median of 3.0 years. Despite more weight loss with spironolactone initially, weight trajectories overlapped after 12 months. Daily furosemide dose (time-averaged Δ: -4.8% vs. +11.6%, P < 0.001) and thiazide use (-4.3% vs. +1.7%; P = 0.003) decreased with spironolactone; however, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use decreased also (-13.1% vs. -7.3%; P = 0.004). Serum creatinine increased more with spironolactone (+12.5% vs. +3.5%; P < 0.001). In time-updated models, loop diuretic dose [hazard ratio (HR) per doubling 1.21; 95% confidence interval (CI) 1.10-1.32; P < 0.001], creatinine (HR per doubling 1.28; 95% CI 1.04-1.40; P = 0.019), and ACEI/ARB use (HR 0.82; 95% CI 0.67-1.00; P = 0.048) were associated with HF hospitalizations. However, the effect of spironolactone on HF hospitalizations persisted (HR 0.77; 95% CI 0.62-0.96; P = 0.021) in these models. Results were similar for cardiovascular mortality and time to first HF hospitalization. CONCLUSIONS: In TOPCAT Americas, the benefit of spironolactone on outcomes could not be solely attributed to potential diuretic effects, suggesting the presence of non-diuretic mechanisms.

Meta-Analysis of Relation of Vital Exhaustion to Cardiovascular Disease Events.

To assess the net impact of vital exhaustion on cardiovascular events and all-cause mortality, we conducted a systematic search of PubMed, EMBASE, and PsychINFO (through April 2016) to identify all studies which investigated the relation between vital exhaustion (VE) and health outcomes. Inclusion criteria were as follows: (1) a cohort study (prospective cohort or historical cohort) consisting of adults (>18 years); (2) at least 1 self-reported or interview-based assessment of VE or exhaustion; (3) evaluated the association between vital exhaustion or exhaustion and relevant outcomes; and (4) reported adjusted risk estimates of vital exhaustion/exhaustion for outcomes. Maximally adjusted effect estimates with 95% CIs along with variables used for adjustment in multivariate analysis were also abstracted. Primary study outcome was cardiovascular events. Secondary outcomes were stroke and all-cause mortality. Seventeen studies (19 comparisons) with a total of 107,175 participants were included in the analysis. Mean follow-up was 6 years. VE was significantly associated with an increased risk for cardiovascular events (relative risk 1.53, 95% CI 1.28 to 1.83, p <0.001) and all-cause mortality (relative risk 1.48, 95% CI 1.28 to 1.72, p <0.001). VE also showed a trend for increased incident stroke (relative risk 1.46, 95% CI 0.97 to 2.21, p = 0.07). Subgroup analyses yielded similar results. VE is a significant risk factor for cardiovascular events, comparable in potency to common psychosocial risk factors. Our results imply a need to more closely study VE, and potentially related states of exhaustion, such as occupational burnout.

Increased matrix metalloproteinase (MMPs) levels do not predict disease severity or progression in emphysema.

RATIONALE: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. METHODS: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. MAIN RESULTS: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. CONCLUSIONS: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease.

Protein phosphatase 2A regulates innate immune and proteolytic responses to cigarette smoke exposure in the lung.

Protein phosphatase 2A (PP2A) is the primary serine-threonine phosphatase of eukaryotic cells, and changes in its activity have been linked to neoplastic and neurodegenerative diseases. However, the role of PP2A in noncancerous lung diseases such as chronic obstructive pulmonary disease (COPD) has not been previously examined. This study determined that PP2A activity was significantly increased in the lungs of advanced emphysema subjects compared with age-matched controls. Furthermore, we found that cigarette smoke exposure increases PP2A activity in mouse lung in vivo and in primary human small airway epithelial (SAE) cells in vitro. In mice, intratracheal transfection of PP2A protein prior to cigarette smoke exposure prevented acute smoke-induced lung inflammation. Conversely, inhibiting PP2A activity during smoke exposure exacerbated inflammatory responses in the lung. To further determine how PP2A modulates the responses to cigarette smoke in the lung, enzyme levels were manipulated in SAE cells using protein transfection and short hairpin RNA (shRNA) techniques. Increasing PP2A activity in SAE cells via PP2A protein transfection downregulated cytokine expression and prevented the induction of proteases following cigarette smoke extract (CSE) treatment. Conversely, decreasing enzymatic activity by stably transfecting SAE cells with shRNA for the A subunit of PP2A exacerbated these smoke-mediated responses. This study establishes that PP2A induction by cigarette smoke modulates immune and proteolytic responses to cigarette smoke exposure. Together, these findings suggest that manipulation of PP2A activity may be a plausible means to treat COPD and other inflammatory diseases.

Transgenic expression of matrix metalloproteinase-9 causes adult-onset emphysema in mice associated with the loss of alveolar elastin.

Matrix metalloproteinase (MMP)-9 has been consistently identified in the lungs of patients with chronic obstructive pulmonary disease (COPD). However, its role in the development of the disease remains undefined. Mice that specifically express human MMP-9 in their macrophages were generated, and morphometric, biochemical, and histological analyses were conducted on the transgenic and littermate control mice over 1 yr to determine the effect of macrophage MMP-9 expression on emphysema formation and lung matrix content. Lung morphometry was normal in transgenic mice at 2 mo of age (mean linear intercept = 50+/-3 littermate mice vs. 51+/-2 transgenic mice). However, after 12 mo of age, the MMP-9 transgenic mice developed significant air space enlargement (mean linear intercept = 53+/-3 littermate mice vs. 61+/-2 MMP-9 transgenic mice; P<0.04). Lung hydroxyproline content was not significantly different between wild-type and transgenic mice, but MMP-9 did significantly decrease alveolar wall elastin at 1 yr of age (4.9+/-0.3% area of alveolar wall in the littermate mice vs. 3.3+/-0.3% area of alveolar wall in the MMP-9 mice; P<0.004). Thus these results establish a central role for MMP-9 in the pathogenesis of this disease by demonstrating that expression of this protease in macrophages can alter the extracellular matrix and induce progressive air space enlargement in mice.