Sendaway capillary NT-proBNP in pulmonary hypertension.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. Sendaway sampling may enable patients to perform NT-proBNP tests remotely. This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing. METHODS: Reference venous NT-proBNP was collected from PH patients. Samples for capillary and venous sendaway tests were collected contemporaneously, mailed to a reference laboratory and processed at 3 and 7 days using a Roche Cobas e411 device. Differences in paired measurements were analysed with Passing-Bablok regression, percentage difference plots and the % difference in risk strata. RESULTS: 113 patients were included in the study. 13% of day 3 capillary samples were insufficient. Day 3 capillary samples were not equivalent to reference samples (Passing Bablok analysis slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9)). The relative median difference was -7% and there were acceptable limits of agreement. Day 3 capillary NT-proBNP accurately risk stratified patients in 93.5% of cases. By comparison, day 3 venous results accurately risk stratified patients in 90.1% of cases and were equivalent by Passing-Bablok regression. Delayed sampling of sendaway tests led to an unacceptable level of agreement and systematically underestimated NT-proBNP. CONCLUSIONS: Sendaway NT-proBNP sampling may provide an objective measure of right ventricular strain for virtual PH clinics. Results must be interpreted with caution in cases of delayed sampling.

Cardiac geometry, as assessed by cardiac magnetic resonance, can differentiate subtypes of chronic thromboembolic pulmonary vascular disease.

Background: Ventricular septal flattening reflects RV pressure overload in pulmonary arterial hypertension. Eccentricity index (EI) and pulmonary artery distensibility (PAD) correlate with pulmonary artery pressure. We assessed the utility of these using cardiac magnetic resonance (CMR) to assess for pulmonary hypertension (PH) in patients with chronic thromboembolic disease. This may allow non-invasive differentiation between patients who have chronic thromboembolic pulmonary hypertension (CTEPH) and those with pulmonary vascular obstructions without PH at rest, known as chronic thromboembolic pulmonary disease (CTEPD). Methods: Twenty patients without resting pulmonary hypertension, including ten with chronic thromboembolic disease, and thirty patients with CTEPH were identified from a database at the Scottish Pulmonary Vascular Unit. CMR and right heart catheter had been performed within 96 h of each other. Short-axis views at the level of papillary muscles were used to assess the EI at end-systole and diastole. Pulmonary artery distensibility was calculated using velocity-encoded images attained perpendicular to the main trunk. Results: Eccentricity index at end-systole and end-diastole were higher in CTEPH compared to controls (1.3 ± 0.5 vs. 1.0 ± 0.01; p ≤ 0.01 and (1.22 ± 0.2 vs. 0.98 ± 0.01; p ≤ 0.01, respectively) and compared to those with CTED. PAD was significantly lower in CTEPH compared to controls (0.13 ± 0.1 vs. 0.46 ± 0.23; p ≤ 0.01) and compared to CTED. End-systolic EI and end-diastolic EI correlated with pulmonary vascular hemodynamic indices and exercise variables, including mean pulmonary arterial pressure (R0.74 and 0.75, respectively), cardiac output (R-value -0.4 and -0.4, respectively) NTproBNP (R-value 0.3 and 0.3, respectively) and 6-min walk distance (R-value -0.7 and -0.8 respectively). Pulmonary artery distensibility also correlated with 6-min walk distance (R-value 0.8). Conclusion: Eccentricity index and pulmonary artery distensibility can detect the presence of pulmonary hypertension in chronic thromboembolic disease and differentiate between CTEPH and CTED subgroups. These measures support the use of non-invasive tests including CMR for the detection pulmonary hypertension and may reduce the requirement for right heart catheterization.

Autoimmunity Is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension.

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multicentre study.

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure.1745 patients with idiopathic PAH (IPAH), drug-induced PAH (DPAH), heritable PAH (HPAH) (collectively "(I/D/H)PAH"), or connective tissue disease-associated PAH (CTD-PAH), who had completed emPHasis-10 questionnaires at one of six UK referral centres between 2014 and 2017, were identified. Correlations with exercise capacity and World Health Organization (WHO) functional class were assessed, and exploratory risk stratification thresholds were tested.Moderate correlations were seen between emPHasis-10 scores and 6-min walk distance (r=-0.546), incremental shuttle walk distance (r=-0.504) and WHO functional class (r=0.497) (all p<0.0001). Distribution of emPHasis-10 score differed significantly between each WHO functional class (all p<0.0001). On multivariate analysis, emPHasis-10 score, but not WHO functional class, was an independent predictor of mortality. In a risk stratification approach, scores of 0-16, 17-33 and 34-50 identified incident patients with 1-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO functional class III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 scores had improved exercise capacity (p<0.0001) and patients who transitioned between risk groups demonstrated similar survival to patients originally in those risk groups.The emPHasis-10 score is an independent prognostic marker in patients with (I/D/H)PAH or CTD-PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity.

Social deprivation in Scottish populations with pulmonary hypertension secondary to connective tissue disease and chronic thromboembolic disease.

Socioeconomic factors have been shown to have an adverse impact on survival in some respiratory diseases. Studies from the USA and China have suggested worse survival in idiopathic pulmonary arterial hypertension in low socioeconomic groups. We looked at the effect of deprivation on the outcomes in patients with connective tissue disease-associated pulmonary hypertension (CTDPH) and chronic thromboembolic pulmonary hypertension (CTEPH) in a retrospective observational study. Data were obtained from 232 patients with CTDPH and 263 with CTEPH who were under the care of the Scottish Pulmonary Vascular Unit, Glasgow, UK. We used Cox proportional hazards regression to assess for a relationship between deprivation and survival. We found no difference in survival across deprivation quintiles in the CTDPH (p=0.26) or CTEPH cohorts (p=0.18). We constructed multivariate models using enrolment time, age, sex and body mass index, with no significant change in findings. There was no difference between expected and observed population distribution of CTDPH (p=0.98) and CTEPH (p=0.36). Whilst there was no difference in presenting functional class in the CTDPH group, the CTEPH patients in more deprived quintiles presented in a worse functional class (p=0.032). There was no difference between quintiles of CTEPH patients who had distal or proximal disease (p=0.75), or who underwent surgery (p=0.5). Increased social deprivation is not associated with worse survival in patients with CTDPH and CTEPH managed in the Scottish National Health Service. Whilst there is no evidence of referral barriers in CTDPH, this may not be the case in CTEPH, as lower deprivation was associated with worse functional class at presentation.

Idiopathic pulmonary arterial hypertension and co-existing lung disease: is this a new phenotype?

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients (IPAH lung disease ) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease (IPAH no lung disease ). Patients with 'IPAH lung disease ' have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with 'IPAH no lung disease '. We described the outcome of the cohort of patients with 'IPAH no lung disease ' in a previous paper. Here, we have compared incident 'IPAH lung disease ' patients with 'IPAH no lung disease ' patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001-2009. Compared with 'IPAH no lung disease ' (n = 355), 'IPAH lung disease ' patients (n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in 'IPAH lung disease ' and 'IPAH no lung disease '. However, survival of 'IPAH lung disease ' was lower than 'IPAH no lung disease ' (one year survival: 72% compared with 93%). This survival was significantly worse in 'IPAH lung disease ' even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. 'IPAH lung disease ' patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with 'IPAH no lung disease ' patients. This suggests that 'IPAH lung disease ' are a separate phenotype and should not be lumped with 'IPAH no lung disease ' in clinical trials of Group 1 pulmonary arterial hypertension.

Understanding longitudinal biventricular structural and functional changes in a pulmonary hypertension Sugen-hypoxia rat model by cardiac magnetic resonance imaging.

Cardiac magnetic resonance-derived ventricular variables are predictive of mortality in pulmonary arterial hypertension. Rodent models which emphasize ventricular function, allowing serial monitoring, are needed to identify pathophysiological features and novel therapies for pulmonary arterial hypertension. We investigated longitudinal changes in the Sugen-hypoxia model during disease progression. Sprague Dawley rats (n = 32) were divided into two groups. (1) Sugen-hypoxia: a dose of subcutaneous Sugen-5416 and placed in hypobaric hypoxia for two weeks followed by normoxia for three weeks. (2) Normoxia: maintained at normal pressure for five weeks. Rats were examined at five or eight weeks with right-heart catheter, cardiac magnetic resonance, and autopsy. Compared to normoxic controls (23.9 ± 4.1 mmHg), right ventricular systolic pressure was elevated in Sugen-hypoxia rats at five and eight weeks (40.9 ± 15.5 mmHg, p = 0.026; 48.9 ± 9.6 mmHg, p = 0.002). Right ventricular end-systolic volume index was increased in eight weeks Sugen-hypoxia (0.28 ± 0.04 µlcm-2, p = 0.003) compared to normoxic controls (0.18 ±0.03 mlcm-2). There was progressive dilatation of the right ventricular at eight weeks Sugen-hypoxia compared to normoxic controls (0.75 ± 0.13 µlcm-2 vs 0.56 ± 0.1 µlcm-2 p = 0.02). Ventricle mass index by cardiac magnetic resonance at five weeks (0.34 ± 0.06, p = 0.003) and eight weeks Sugen-hypoxia (0.34 ± 0.06, p = 0.002) were higher than normoxic controls (0.21 ± 0.04). Stroke volume, right ventricular ejection fraction, and left ventricular variables were preserved in Sugen-hypoxia. Ventricular changes during the course of illness in a pulmonary arterial hypertension rodent model can be examined by cardiac magnetic resonance. These changes including right ventricular hypertrophy and subsequent dilatation are similar to those seen in pulmonary arterial hypertension patients. Despite the persisting pulmonary hypertension, there are features of adaptive cardiac remodeling through the study duration.

Short-Term Hemodynamic Effects of Apelin in Patients With Pulmonary Arterial Hypertension.

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170).

Social deprivation and prognosis in Scottish patients with pulmonary arterial hypertension.

Several demographic and clinical factors have prognostic significance in idiopathic pulmonary arterial hypertension (IPAH). Studies in China and the USA have suggested an association between low socioeconomic status and reduced survival. The impact of social deprivation on IPAH survival in the UK is not known.280 patients with IPAH and hereditary PAH (HPAH) attending the Scottish Pulmonary Vascular Unit (Glasgow, UK) were assigned to social deprivation quintiles using the Scottish Index of Multiple Deprivation database. The association between survival and social deprivation quintile was assessed using Cox proportional hazards regression analysis.The distribution of IPAH/HPAH patients was more socially deprived than would be expected based on Scottish citizenry as a whole (Chi-squared 16.16, p=0.003), suggesting referral and access to care is not impeded by socioeconomic status. Univariate analysis demonstrated no significant association between social deprivation and survival (p=0.81), and this association failed to reach significance with inclusion of time, sex and age as covariates in the model (p=0.23). There were no statistically significant correlations between social deprivation and baseline clinical variables of prognostic importance except for age, sex and quality of life.Social deprivation is not a significant referral barrier or prognostic factor for IPAH and HPAH in Scotland.

Validation of impedance cardiography in pulmonary arterial hypertension.

BACKGROUND: Non-invasive methods of measuring cardiac output are highly desirable in pulmonary arterial hypertension (PAH). We therefore sought to validate impedance cardiography (ICG) against thermodilution (TD) and cardiac magnetic resonance (CMR) in the measurement of cardiac output in patients under investigation for PAH. METHODS: A prospective, cross-sectional study was performed to compare single-point measurements of cardiac output obtained by impedance cardiography (COICG ) technology (PhysioFlow® ) with (i) contemporaneous TD measurements (COTD ) at rest and steady-state exercise during right heart catheterization and (ii) CMR measurements (COCMR ) at rest obtained within 72 h. RESULTS: Paired COICG and COTD measurements were obtained in 25 subjects at rest and 16 subjects at exercise. COCMR measurements were obtained in 16 subjects at rest. There was unsatisfactory correlation and agreement between COICG and COTD at rest (r = 0·42, P = 0·035; bias: 1·21 l min-1 , 95% CI: -2·33 to 4·75 l min-1 ) and exercise (r = .65, P = .007; bias: 1·41 l min-1 ; 95% CI: -3·99 to 6·81 l min-1 ) and in the change in COICG and COTD from rest to exercise (r = 0·53, P = 0·033; bias: 0·76 l min-1 , 95% CI: -3·74 to 5·26 l min-1 ). There was also a lack of correlation and unsatisfactory agreement between resting COICG and COCMR (r = 0·38, P = 0·1; bias: 1·40 l min-1 , 95% CI: -2·48 to 5·28 l min-1 ). In contrast, there was close correlation and agreement between resting COTD and COCMR (r = 0·87, P<0·001; bias: -0·16 l min-1 , 95% CI: -1·97 to 1·65). CONCLUSIONS: In a representative population of patients under investigation for PAH, ICG showed insufficient qualitative and quantitative value in the measurement of resting and exercise cardiac output when compared with TD and CMR.

A study of clinical and physiological relations of daily physical activity in precapillary pulmonary hypertension.

Daily physical activity is reduced in precapillary pulmonary hypertension (PH), but the underlying mechanisms are inadequately explored. We sought to investigate clinical and physiological relations of daily physical activity and profile differences between less and more active patients with precapillary PH. A prospective, cross-sectional study of 20 patients with precapillary PH who undertook 1) a comprehensive clinical assessment, 2) a preliminary treadmill test, 3) 7-day monitoring of daily walking intensity with triaxial accelerometry, and 4) a personalized treadmill test corresponding to the individual patient mean daily walking intensity with real-time physiological measurements. Significant clinical correlations with individual patient mean walking intensity [1.71 ± 0.27 (SD) m/s2] were observed for log-transformed N-terminal probrain natriuretic peptide (log NT-proBNP; r = -0.75, P = <.001), age (r = -0.70, P = 0.001), transfer factor for carbon monoxide %predicted (r = 0.51, P = 0.022), and 6-min walk distance (r = 0.50, P = 0.026). Significant physiological correlations were obtained for heart rate reserve (r = 0.68, P = 0.001), quadriceps tissue oxygenation index (Q-[Formula: see text]; r = 0.58, P = 0.008), change in Q-[Formula: see text] from rest (r = 0.60, P = 0.006), and ventilatory equivalent for oxygen uptake (r = -0.56, P = 0.013). Stepwise multiple regression analyses retained log NT-proBNP (R2 = 0.55), heart rate reserve (R2 = 0.44), and Q-[Formula: see text] (R2 = 0.13) accounting for a significant variance in individual walking intensity. Less active patients had greater physical activity-induced cardiopulmonary impairment, worse quadriceps oxygenation profile, and compromised health-related quality of life compared with more active patients. These preliminary findings suggest a significant relation between right ventricular and peripheral muscle oxygenation status and reduced daily physical activity in precapillary PH. Further research is warranted to unravel the physiological determinants, establish clinical predictors, and identify beneficial interventions.NEW & NOTEWORTHY Daily physical activity holds promise to be a meaningful, patient-related outcome measure in pulmonary hypertension. In this study, novel findings in a representative sample of patients with precapillary pulmonary hypertension link reduced daily walking activity, as measured by triaxial accelerometry, with compromised right ventricular and pulmonary vascular status, peripheral muscle oxygenation, and health-related quality of life, providing a preliminary insight into the physiological mechanisms and clinical predictors of daily physical activity in precapillary pulmonary hypertension.

Pulmonary vascular and cardiac impairment in interstitial lung disease.

Pulmonary vascular and cardiac impairment is increasingly appreciated as a major adverse factor in the natural history of interstitial lung disease. This clinically orientated review focuses on the current concepts in the pathogenesis, pathophysiology and implications of the detrimental sequence of increased pulmonary vascular resistance, pre-capillary pulmonary hypertension and right heart failure in interstitial lung disease, and provides guidance on its management.

Imaging right ventricular function to predict outcome in pulmonary arterial hypertension.

BACKGROUND: Right ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation. METHODS: We measured RV end-systolic and end-diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV-arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or as Pmax/mean pulmonary artery pressure (mPAP) minus 1 (pressure method) (n=84). RV function was also assessed by ejection fraction (EF), right atrial pressure (RAP) and SV. RESULTS: Higher Ea and RAP, and lower compliance, SV and EF predicted outcome at univariate analysis. Ees/Ea estimated by the pressure method did not predict outcome but Ees/Ea estimated by the volume method (SV/ESV) did. At multivariate analysis, only SV/ESV and EF were independent predictors of outcome. Survival was poorer in patients with a fall in EF or SV/ESV during follow-up (n=44, p=0.008). CONCLUSION: RV function to predict outcome in PAH is best evaluated by imaging derived SV/ESV or EF. In this study, there was no added value of invasive measurements or simplified pressure-derived estimates of RV-arterial coupling.

Respiratory and limb muscle dysfunction in pulmonary arterial hypertension: a role for exercise training?

Respiratory and limb muscle dysfunction is emerging as an important pathophysiological abnormality in pulmonary arterial hypertension (PAH). Muscle abnormalities appear to occur frequently and promote dyspnea, fatigue, and exercise limitation in patients with PAH. Preliminary data suggest that targeted muscle training may be of benefit, although further evidence is required to consolidate these findings into specific recommendations for exercise training in patients with PAH. This article reviews the current evidence on prevalence, risk factors, and implications of respiratory and limb muscle dysfunction in patients with PAH. It also reviews the impact of exercise rehabilitation on morphologic, metabolic, and functional muscle profile and outcomes in PAH. Future research priorities are highlighted.

Severe pulmonary hypertension in lung disease: phenotypes and response to treatment.

Pulmonary hypertension (PH) due to lung disease (World Health Organization (WHO) group 3) is common, but severe PH, arbitrarily defined as mean pulmonary artery pressure ≥35 mmHg is reported in only a small proportion. Whether these should be treated as patients in WHO group 1 (i.e. pulmonary arterial hypertension) with PH-targeted therapies is unknown. We compared the phenotypic characteristics and outcomes of 118 incident patients with severe PH and lung disease with 74 idiopathic pulmonary arterial hypertension (IPAH) patients, all treated with pulmonary vasodilators. Lung disease patients were older, more hypoxaemic, and had lower gas transfer, worse New York Heart Association functional class and lower 6-min walking distance (6MWD) than IPAH patients. Poorer survival in those with lung disease was driven by the interstitial lung disease (ILD) cohort. In contrast to IPAH, where significant improvements in 6MWD and N-terminal pro-brain natruiretic peptide (NT-proBNP) occurred, PH therapy in severe PH lung disease did not lead to improvement in 6MWD or functional class, but neither was deterioration seen. NT-proBNP decreased from 2200 to 1596 pg·mL(-1) (p=0.015). Response varied by lung disease phenotype, with poorer outcomes in patients with ILD and emphysema with preserved forced expiratory volume in 1 s. Further study is required to investigate whether vasodilator therapy may delay disease progression in severe PH with lung disease.

Novel serum biomarkers in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) remains a difficult-to-treat condition with high mortality. Biomarkers are utilized to aid with diagnosis, prognostication and response to treatment. A clinically useful and PAH-specific single biomarker that is easy to measure remains elusive. This is in part due to the heterogeneity of PAH and its complex etiology. Brain natriuretic peptide and its N-terminal fragment are currently the most widely used serum markers; however, several novel serum biomarkers have been investigated recently. Taken individually, the evidence for each of these seems provisionally promising though currently weak overall. It is likely that a multibiomarker panel will be recommended in the future, with the optimal combination yet to be determined.

Pulmonary hypertension in POEMS syndrome: resolution following radiotherapy.

Pulmonary hypertension (PH) is defined by the presence of a mean pulmonary artery pressure (mPAP) ≥25 mmHg. It may be idiopathic or arise as a consequence of a number of diverse conditions. PH has been reported in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes), with reversal following systemic treatment with corticosteroids. We report a case of pulmonary hypertension associated with POEMS syndrome treated with radical radiotherapy locally to bone lesions with resolution of systemic disease.