Lung function in relation to six-minute walk test in pulmonary hypertension.

Background: Pulmonary hypertension (PH) is a progressive disorder of the pulmonary circulation, associated with diverse medical conditions. Exercise limitation is the most prominent symptom in PH. Exercise capacity, commonly assessed through a six-minute walk test (6MWT), correlates with both functional status and survival in PH. Few studies have analysed the relation between respiratory function and exercise limitation. Therefore, we investigated the relationship between resting pulmonary function, exercise capacity, and exertional desaturation, assessed through the 6MWT, in unselected PH patients. Methods: Fifty consecutive patients with PH diagnosis, referred for pulmonary function testing (lung volume, spirometry, and diffusing capacity for carbon monoxide (DLCO)) and 6MWT, were recruited at Molinette University Hospital, Turin. Results: The majority of the patients (54%) had PH due to left heart disease. Airway obstruction (FEV1/VC-ratio < 0.7) was found in 46% of the patients and they performed significantly worse in the 6MWT than unobstructed patients (307 m vs. 377 m). Patients with PH due to left heart disease also performed significantly poorer 6MWT when airway obstruction was present (305 m vs. 389 m). Twenty-two patients (44%) presented exertional desaturation upon 6MWT. Lower DLCO divided by the alveolar volume (DLCO/VA), FEV1/VC-ratios and resting PaO2-values were significantly correlated with exertional desaturation after adjustments for age, sex, BMI, and smoking habits. DLCO/VA was the main determinant of exertional desaturation in a stepwise regression model. Conclusions: Spirometric parameters of airway obstruction were related to walk distance and exercise-induced desaturation in PH patients. This suggests a place for spirometry in clinical monitoring of PH patients.

Tailored combined cytomegalovirus management in lung transplantation: a retrospective analysis.

BACKGROUND: There is no univocal prophylactic regimen to prevent cytomegalovirus (CMV) infection/disease in lung transplantation (LT) recipients. The aim of this study is to evaluate short-term clinical outcomes of a tailored combined CMV management approach. METHODS: After 1-year follow up, 43 LT patients receiving combined CMV prophylaxis with antiviral agents and CMV-specific IgG were evaluated in a retrospective observational study. Systemic and lung viral infections were investigated by molecular methods on a total of 1134 whole blood and 167 bronchoalveolar lavage (BAL) and biopsy specimens. CMV immunity was assessed by ELISPOT assay. Clinical and therapeutic data were also evaluated. RESULTS: We found 2/167 cases of CMV pneumonia (1.2%), both in the donor-positive/recipient-positive (D+/R+) population, and 51/167 cases of CMV pulmonary infection (BAL positivity 30.5%). However, only 32/167 patients (19.1%) were treated due to their weak immunological response at CMV ELISPOT assay. Viremia ⩾100,000 copies/mL occurred in 33/1134 specimens (2.9%). Regarding CMV-serological matching (D/R), the D+/R- population had more CMV viremia episodes (p < 0.05) and fewer viremia-free days (p < 0.001). CONCLUSIONS: Compared to previous findings, our study shows a lower incidence of CMV pneumonia and viremia despite the presence of a substantial CMV load. In addition, our findings further confirm the D+/R- group to be a high-risk population for CMV viremia. Overall, a good immunological response seems to protect patients from CMV viremia and pneumonia but not from CMV alveolar replication. The reviews of this paper are available via the supplemental material section.

Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: A randomized controlled multicenter clinical trial.

BACKGROUND: Pulmonary hypertension (PH) is a well-known independent prognostic factor in chronic obstructive pulmonary disease (COPD) and a sufficient criterion for lung transplant candidacy. Limited data are currently available on the hemodynamic and clinical effect of phosphodiesterase 5 inhibitors in patients with severe PH associated with COPD. This study assessed the effect of sildenafil on pulmonary hemodynamics and gas exchange in severe PH associated with COPD. METHODS: After screening, this multicenter, randomized, placebo-controlled double-blind trial randomized patients to receive 20 mg sildenafil or placebo 3 times a day (ratio 2:1) for 16 weeks. The primary end point was the reduction in pulmonary vascular resistance. Secondary end points included BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, 6-minute walk test, and quality of life questionnaire. Changes in the partial pressure of arterial oxygen were evaluated as a safety parameter. RESULTS: The final population included 28 patients, 18 in the sildenafil group and 10 in the placebo group. At 16 week, patients treated with sildenafil had a decrease in pulmonary vascular resistance (mean difference with placebo -1.4 WU; 95% confidence interval, ≤ -0.05; p = 0.04). Sildenafil also improved the BODE index, diffusion capacity of the lung for carbon monoxide percentage, and quality of life. Change from baseline in the partial pressure of arterial oxygen was not significantly different between the sildenafil and placebo groups. CONCLUSIONS: This pilot study found that treatment with sildenafil reduced pulmonary vascular resistance and improved the BODE index and quality of life, without a significant effect on gas exchange.

[Preliminary results and future perspectives of the Piedmont Adult Congenital Heart Disease Registry]. / Risultati iniziali e prospettive future del Registro Piemontese delle Cardiopatie Congenite dell'Adulto.

BACKGROUND: Adults with congenital heart disease are a relatively new population that progressively increases in size and complexity. In Italy, there are no accurate data concerning the distribution of congenital defects and the long-term outcome relating to both congenital heart disease per se and comorbidities, due to the aging process. METHODS: The Piedmont Adult Congenital Heart Disease Registry has been designed to investigate these aspects and to support a high quality healthcare development for grown-up congenital heart patients. Within 2 years, 459 consecutive patients routinely followed in 10 divisions of cardiology in Piedmont were included in the project. Electronic dedicated software has supported data collection. RESULTS: Mean age of patients is 35 ± 16 years. Septal defects are the most common type of congenital heart disease (35.3%). At baseline evaluation, 71.7% of patients reported a previous surgical and/or percutaneous treatment and 6.3% an electrophysiological procedure. Freedom from intervention is 44%, 81% and 56% at the age of 18, 30 and 45 years, respectively. Patients who had a treatment during infancy show a better intervention-free survival (p=0.038) compared with patients treated during adulthood. Despite the majority of the population had an almost preserved functional status, 27.5% had ≥1 long-term sequelae (arrhythmias 27.5%; pulmonary hypertension 5.2%; neurological problems 4.1%; cyanosis 4.8%; liver dysfunction 2.4%; enteropathy 2.4%; lung disease 2.2%). During 2 years of follow-up, the estimated mortality rate is 0.88%. CONCLUSIONS: Adults with congenital heart disease are a heterogeneous population of relatively young patients with relevant clinical and social problems. The late sequelae related to both the underlying heart disease and the advancing age require continuous monitoring and lifelong specialized care.

Supraventricular Arrhythmias in Patients With Pulmonary Arterial Hypertension.

The onset of supraventricular arrhythmias (SVA) may be associated with clinical worsening in patients with pulmonary arterial hypertension (PAH). However, limited data have been reported, especially at long-term follow-up. Aim of this study was to investigate the incidence of SVA in our patients with PAH, the risk factors correlated to their onset and the prognostic impact. All consecutive patients with PAH without history of SVA were enrolled. Incidence of new SVA was investigated and also the risk factors for SVA. Primary end point of the study was the impact of SVA on a composite of all-cause mortality and re-hospitalization, whereas mortality was the secondary end point. Seventy-seven patients were enrolled. No significant differences in the clinical or instrumental baseline characteristics between the 2 study groups were reported. During a median follow-up of 35 months (interquartile range 21.5 to 53.5), 17 (22%) patients experienced SVA. Development of SVA was associated with worsening of prognostic parameters at the follow-up: increasing of World Health Organization (WHO) functional class (p = 0.005) and N-terminal-pro-brain natriuretic peptide (NT-proBNP) (p = 0.018) and reduction of 6-minute walking distance (p = 0.048), tricuspid annular plane systolic excursion (TAPSE) (p = 0.041), and diffusing capacity of the lung for carbon monoxide (p = 0.025). The primary end point occurred in 13 patients (76%) in the SVA group and in 22 patients (37%) in the group without SVA (p = 0.004), whereas 9 patients (53%) among those with SVA died during the follow-up compared with 8 (13%) among those without (p = 0.001). At multivariate analysis, development of SVA was independently associated with an increased risk to meet the both primary (hazard ratio 2.13; 95% confidence interval 1.07 to 4.34; p = 0.031) and secondary (hazard ratio 4.1; 95% confidence interval 1.6 to 10.6; p = 0.004) end points. In conclusion, during the 3-year follow-up period, 1/3 of patients with PAH developed SVA, which was related to worsening of hemodynamic and functional parameter and independently predicted adverse prognosis.

Everolimus-based immunosuppressive regimens in lung transplant recipients: impact on CMV infection.

UNLABELLED: Cytomegalovirus (CMV) is one of the most important viral pathogen in solid organ transplant (SOT) recipients, with heart and lung transplant patients being at considerably high risk for CMV direct and indirect effects. Prevention strategies have resulted in significant reduction in disease and CMV related morbidity and mortality. Few studies reported a lower incidence of CMV infections in solid organ transplant recipients treated with immunosuppressive protocols including the mTOR inhibitor everolimus (EVR). PURPOSE: The aim of the current study was to evaluate the impact of EVR-based immunosuppressive regimens on the occurrence and kinetics of CMV infection in a population of lung transplant recipients, at both systemic and pulmonary level. Thirty-two lung transplants (LT) were investigated; eighteen were on EVR-based immunosuppressive regimens. CMV events occurring in the first two years post-transplantation at both systemic and pulmonary levels were reported. PRINCIPAL RESULTS: No differences were reported in CMV viraemia occurrence at both one- and two-year follow up between patients undergoing EVR-based and EVR-free immunosuppressive regimens. Considering CMV episodes at pulmonary levels, as determined by routinely performed broncho-alveolar lavages (BALs), during EVR-administration the patients experienced significantly fewer episodes of high-load CMV (as defined by viral loads⩾10(5) copies/mL) than during EVR-free immunosuppressive regimens. MAJOR CONCLUSION: EVR-based immunosuppressive regimens in lung transplantation settings appear to be associated to lower incidence of clinically relevant CMV episodes at pulmonary levels, striking the possibility of extending the use of EVR to such a group of transplant recipients.

Detection of human cytomegalovirus in transbronchial biopsies from lung transplant recipients.

The role of human cytomegalovirus (HCMV) in lung transplantation (LT) and drawbacks related to viral quantification in bronchoalveolar lavage (BAL) underline the potential usefulness of investigating other specimens. Thirty-three LT recipients were prospectively studied by HCMV quantitative real time PCR on matched transbronchial biopsy (TBB), BAL, and whole blood specimens. Overall, 27/33 patients turned out HCMV-positive in at least one specimen: 7.1 %, 37.1 %, and 13.5 % of TBB, BAL, and blood samples, respectively. No significant association between HCMV on all types of specimens and acute rejection, lymphocytic bronchiolitis, bronchiolitis obliterans and bronchiolitis obliterans syndrome was found. HCMV pneumonia was associated to HCMV detection on TBB (p = 0.003) and whole blood (p = 0.008), not on BAL (p = 0.47). The highest mean viral load was detected in TBB from cases with HCMV pneumonia in comparison to all other cases, suggesting the potential use of HCMV investigation in TBB for evaluating posttransplant complications.

Echo Doppler predictors of pulmonary artery hypertension in patients with systemic sclerosis.

OBJECTIVES: Evaluate echocardiographic predictors of pulmonary artery hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc). METHODS: 38 patients with SSc who did not have PAH and significant left heart disease, with peak tricuspid regurgitant velocity (TRV) ≤ 2.8 m/sec and systolic pulmonary artery pressure (sPAP) < 40 mmHg on echo Doppler were enrolled. Patients underwent: clinical assessment, NT-proBNP, and DLco measurements. Echo Doppler evaluation included right ventricular (RV) dimensions, tricuspid annular plan systolic excursion, fractional area change, tricuspid DTI systolic velocity, Tei index, pulmonary flow acceleration time (AcT), ratio of TRV to RV outflow tract time-velocity integral (TVI) and a parameter of disturbed RV ejection (TRV/AcT). After a planned 12-month follow-up we evaluated the predictive value of these parameters for the development of PAH, as demonstrated by right heart catheterization (RHC). Criteria for RHC were TRV ≥ 3 m/sec or sPAP ≥ 40 mmHg. RESULTS: Four patients developed PAH. Only TRV/TVI and TRV/AcT ratios significantly predicted PAH development (TRV/TVI ratio ≥ 0.16 [predefined and ROC confirmed]: OR 99, CI 95%: 4.865-2015, P = 0.004; TRV/AcT ratio ≥ 0.022 [predefined and ROC confirmed]: OR 12.68, CI 95% 1.163-379.3, P = 0.036). Both parameters showed a good diagnostic power (TRV/TVI ratio: ROC area 79%, sensitivity 75%, specificity 97% and diagnostic accuracy 94.74% for cutoff value of 0.16; TRV/AcT ratio: ROC area 75%, sensitivity 75%, specificity 71% and diagnostic accuracy 72% for cutoff value of 0.022). CONCLUSIONS: This prospective study identified increased values of the two ratios TRV/TVI and TRV/AcT as predictors of PAH in SSc.

Effect of CMV-immunoglobulins (cytotect biotest) prophylaxis on CMV pneumonia after lung transplantation.

Lung transplant (LT) recipients among solid organ transplant recipients are at high risk for cytomegalovirus (CMV) infections. We evaluated the effect of CMV-Immunoglobulins (CMV-IG) (Cytotect Biotest) on CMV pneumonia diagnosed in 303 follow-up transbronchial biopsies (TBB) of lung transplant recipients. 24 patients (control group, 155 TBB from 1999 to 2002) received acyclovir for 24 months and 33 recipients (study group, 148 TBB from 2003 to 2008) received a combined CMV prophylaxis consisting of CMV-IG (Cytotect Biotest) for 12 months and a short Ganciclovir or Valganciclovir therapy from 21th to 42th postoperative day followed by acyclovir up to 24 months. In our study the percentage of pneumonia at first month TBB was similar in the study group vs the control group, 9.1% (3/33) vs 8.3% (2/24), p=0.9 ns, but after the first month the percentage was significantly lower in the study group in the first year at follow-up TBB, 1% (1/99) vs 6.4% (5/78), p=0.048, and in first two years follow-up TBB, 0.8% (1/122) vs 6.5% 8/124), p=0.018 (STATISTICAL ANALYSIS: Chi-square test for proportion differences). Our data suggest a strong efficacy of CMV-IG prophylaxis in reducing CMV pneumonia after first month in lung transplant recipients.

Detection of parvovirus B19 in the lower respiratory tract.

BACKGROUND: Human parvovirus B19 infection generally displays a self-limiting course followed by viral clearance; although, in some cases, persistent infection may occur. Few cases of severe pulmonary disease following primary infection in both immunocompetent and immunocompromised patients were reported. OBJECTIVES: To investigate the prevalence and clinical impact of parvovirus B19 in the lower respiratory tract. STUDY DESIGN: The prevalence of parvovirus B19-DNA was evaluated by Real-Time PCR in 264 bronchoalveolar lavages (BAL) from 189 adult patients over a full-year period and related to demographic characteristics, underlying pathologies, immune status, admission to intensive care unit, mortality within 28 days, and discharge diagnosis. RESULTS: Parvovirus B19-DNA was detected in 7/189 (3.7%) patients, without significant association to demographic characteristics, immune status, transplant versus non-transplant status, admission to intensive care unit, presence of haematological conditions. In two lung transplant recipients surveillance specimens were positive to B19. Four of the remaining five patients presented respiratory insufficiency. A significant association to mortality was found, as 3/7 (42.9%) positive patients died within 28 days. No patient presented serological evidence of recent or acute infection and viremia. CONCLUSIONS: Parvovirus B19 may be detected at low frequency in BAL specimens from patients with different pathological backgrounds. This finding could be due to chronic infection with virus persistence in the lower respiratory tract, also in the absence of symptoms unequivocally attributable to B19. The high rate of mortality warrants the need for further studies to evaluate the opportunity to consider parvovirus B19 in the diagnostic work-up of lower respiratory tract infections.

Quantitative detection of Epstein-Barr virus in bronchoalveolar lavage from transplant and nontransplant patients.

BACKGROUND: The lower respiratory tract is a latency site of Epstein-Barr virus (EBV); however, its pathogenic role is poorly known, particularly in transplant patients. The aim of this study was to evaluate the prevalence and role of EBV in bronchoalveolar lavages (BAL) from transplant recipients (TR) in comparison with nontransplant (NT) patients. METHODS: Real-time quantitative polymerase chain reaction for EBV, human herpesvirus-6 (HHV-6), and HHV-7 and rapid shell-vial culture for human cytomegalovirus (HCMV) were performed on 272 consecutive BAL from 194 patients (107 from 59 TR and 165 from 143 NT). RESULTS: EBV-DNA was positive in 65 specimens (23.9%) from 57 patients (29.4%): 24 of 59 (40.7%) TR and 33 of 143 (23.1%) NT (P<0.05). There was no significant difference of EBV positivity considering the type of transplanted organ. Viral load did not significantly differ comparing specimens of TR versus NT, specimens of solid organ transplant versus bone marrow transplant recipients. EBV was frequently positive in patients with a diagnosis of pneumonia (28.6%), respiratory insufficiency (24.5%), and exacerbation of underlying bronchopneumopathies (30.8%); however, there was no difference comparing TR and NT. EBV was mostly detected in concomitance with other infectious pathogens. Mortality within 28 days of BAL sampling was not related to EBV-DNA positivity and load. CONCLUSIONS: EBV is frequently detected in BAL from TR and NT; however, its pathogenic role in lower respiratory tract remains poorly known, also because of the frequent detection of concomitant infectious pathogens. Further studies are needed to better elucidate this issue and the underlying local conditions favoring viral replication.

Posttransplantation chronic renal damage in nonrenal transplant recipients.

BACKGROUND: The growing problem of relentless deterioration of renal function in patients who undergo transplantation of nonrenal solid organs is bound to have an increasingly important impact as it may not only worsen patient morbidity and mortality but also increase transplantation costs. METHODS: We reviewed the literature in order to provide a sum of the most important data on the incidence, clinical picture, renal pathology pattern, damage mechanisms, and risk factors, along with strategies for prevention and treatment of chronic renal damage following nonrenal solid organ transplantation. RESULTS: Literature data report that 10% to 80% of transplanted patients have some degree of renal dysfunction and that they share a common clinical picture characterized by relentless asymptomatic progression, frequent hypertension, mild urinary abnormalities, and pathology features of vascular, glomerular, tubular, and interstitial involvement. These changes are very similar to those reported for chronic nephrotoxicity from calcineurin inhibitors. The occurrence of end-stage renal disease (ESRD) requiring chronic dialysis has been reported in up to 20% of nonrenal transplant recipients. Although there are some organ-specific differences, a group of common risk factors has been recognized, including the use of calcineurin inhibitors as immunosuppressive agents, age, pretransplantation renal function, intraoperative/perioperative factors, concomitant use of other nephrotoxic drugs, infections, and posttransplantation acute renal failure. CONCLUSION: Calcineurin inhibitor-induced nephrotoxicity is a growing problem and, as the age of recipients of nonrenal organs is increasing, this problem is destined to increase. It would therefore be advisable for nephrologists to share their experiences in immunomodulation with other specialties, so as to favor the cautious extension of calcineurin inhibitor-sparing protocols to the area of life-saving transplants.