Martin Iversen

Respiratory symptoms in European animal farmers

Farmers are known to be at high risk for the development of occupational airway disease. The aim of this European study was to determine which airway symptoms predominate in different types of animal farmers (cattle, pigs, poultry, sheep) and to compare the prevalence of symptoms to the general population. A total of 6,156 randomly selected animal farmers in Denmark, Germany (Schleswig-Holstein, Niedersachsen), Switzerland, and Spain completed a questionnaire on respiratory symptoms and farming characteristics in 1995-1997. The prevalence of general respiratory symptoms was compared to the results of the European Community Respiratory Health Survey (ECRHS) obtained in the same regions. Pig farmers were at highest risk for the development of work-related symptoms. A significant dose-response relationship between daily hours worked inside animal houses and symptoms was established for pig and poultry farmers. Additionally, self-reported nasal allergies (odds ratio (95% confidence interval): 3.92 (3.26-4.71)) and nasal irritation during work (3.98 (3.35-4.73)) were shown to be associated with the development of chronic phlegm. The prevalence of wheezing, shortness of breath, asthma and nasal allergies was signficantly lower among all farmers in the age group 20-44 yrs than among the general population. However, the prevalence of usually bringing up phlegm in winter among farmers was significantly higher than in the general population (9.4 (8.3-10.5%) versus 7.5 (6.5-8.5%)). Individual factors have been shown to be related to the prevalence of chronic phlegm among farmers. Additionally, this study could support the hypothesis that farming could be negatively related to allergic diseases.

Interstitial inflammatory lesions of the pulmonary allograft: a retrospective analysis of 2697 transbronchial biopsies.

Background. Parenchymal and bronchial inflammatory and fibrotic lesions other than acute cellular rejection (ACR) and lymphocytic bronchiolitis are prevalent; however, the context in which they appear is unknown, and often no specific treatment is instigated. Objectives. To describe the prevalence, incidence and possible associations between commonly identified inflammatory and fibrotic lesions in the pulmonary allograft. Methods. Retrospective chart review of all transbronchial biopsies performed within the first 2 years of 299 lung-transplanted patients in the period 1996 to 2006. Results. A total of 2697 biopsies were evaluated corresponding to a mean of 6±2 (median 8) completed schedules per patient. Diffuse alveolar damage (DAD) was the second most common histological finding within the first 2 weeks after transplantation. The peak prevalence of bronchiolitis obliterans organizing pneumonia (BOOP) and interstitial pneumonitis occurred at 4 to 6 weeks, and 6 to 12 weeks, respectively. There was a steady increase in the cumulative proportion of patients with fibrosis and bronchiolitis obliterans, at each successive scheduled surveillance time point beyond 3 months posttransplantation. The strongest histological correlations were between ACR and lymphocytic bronchiolitis (OR 5.1, P<0.0001) or interstitial fibrosis (OR 3.2, P<0.0001). Patients with interstitial pneumonitis and pulmonary hemosiderosis were also more likely to demonstrate the finding of interstitial fibrosis (OR 3.0 and 3.7, P<0.0001, respectively). Acute cellular rejection was not associated with DAD, and patients with lymphocytic bronchiolitis were not more likely to demonstrate features of organizing pneumonia (DAD or BOOP). Conclusions. Histologic findings of ACR, lymphocytic bronchiolitis, BOOP, and interstitial pneumonitis were directly associated with the development of interstitial fibrosis and bronchiolitis obliterans.

Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients

Background: This was a retrospective study analyzing the mortality and incidence of Aspergillus infection and invasive disease, comparing patients given voriconazole for 3 months following transplantation to patients not given prophylaxis. Methods: All consecutive patients (n = 147) transplanted at Copenhagen University Hospital, Rigshospitalet from 2002 to 2006 were included in the study; the study period included the 2 years before the initiation of fungal prophylaxis (88 patients) and the 2 years after (59 patients). Eight patients transplanted in this period were excluded leaving 139 patients in the study. Results: No effect of voriconazole on the incidence of Aspergillus infection (colonization, or superficial or invasive infection) or on the time from transplantation to the first sign of infection was seen when the 2 groups of patients were compared. The cumulated incidence of infection was 45% without and 49% with prophylaxis, and in both groups approximately half of the infections occurred in the first 3 months, the time during which prophylaxis was given. There were significantly more cystic fibrosis (CF) patients among the Aspergillus-infected patients compared to other diagnoses, and the effect of prophylaxis was the same as in non-CF patients. There was a significantly lower mortality in the voriconazole-treated group compared to the non-prophylaxis group, but in an isolated analysis of Aspergillus-infected patients this difference no longer existed; hence, the difference in mortality must be attributable to a time effect and not to voriconazole prophylaxis. Conclusions: Routine use of voriconazole treatment for prophylaxis against Aspergillus infection in lung transplant recipients does not appear to be warranted.

A Single Exposure to Organic Dust of Non-Naïve Non-Exposed Volunteers Induces Long-Lasting Symptoms of Endotoxin Tolerance

Background: Work with occupational levels of organic dust is associated with a chronic inflammatory response that must somehow be controlled. Endotoxin tolerance has previously been described in vitro and animal studies as a mechanism that modifies the threshold at which response occurs. Objective: We investigated the response of non-naïve, currently non-exposed persons to a single exposure of organic dust in a swine confinement building. Methods: We exposed 16 non-naïve persons in a swine confinement building with low-to-moderate representative levels of organic dust and characterized their acute immune response. Results: Under work-like 3-hour exposure conditions, non-naïve volunteers developed an inflammatory response documented by an increase in interleukin-6 (IL-6) in bronchoalveolar lavage (BAL) from 3.1 to 6.1 pg/ml and visual indices of bronchial inflammation. Similarly, serum IL-6 increased with a peak 3 h after exposure. Tumor necrosis factor (TNF)-α was not detected in BAL, and serum TNF-α was reduced from 3.7 pg/ml at baseline to less than 2 pg/ml within 3 h after exposure, and remained decreased until 2 weeks after exposure. This is a cardinal marker for immune suppression which was confirmed by other markers: reduction in HLA-DR expression on alveolar macrophages and CD14 expression on blood monocytes. Conclusion: We report findings that suggest that long-lasting endotoxin tolerance and immune suppression may be induced by a brief exposure to organic dust concentrations in the medium-low range of occupational levels.

Cytomegalovirus infection in lung transplant patients: the role of prophylaxis and recipient-donor serotype matching.

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality in lung transplant recipients. We investigated the incidence of CMV infection in relation to CMV prophylaxis, and recipient-donor CMV serotype, in a cohort of 250 consecutive lung transplant recipients. All patients received 3 months CMV prophylaxis with acyclovir (n = 67) or gancyclovir (n = 183). Recipient-donor CMV serotype matching was performed in patients receiving acyclovir: R + /D+(n = 38), R + /D−(n = 10), R − /D+(n = 1), R − /D−(n = 16), unknown (n = 2). Recipient-donor CMV serotype matching was not performed in patients receiving gancyclovir: R + /D+(n = 71), R + /D−(n = 42), R − /D+(n = 38), R − /D−(n = 31), unknown (n = 1). The overall incidence of CMV infection was 51% (n = 34) in the acyclovir group, and 42% (n = 77) in the gancyclovir group (p = 0.14). During the first 9 months after transplantation, the rate of CMV infection was higher in the acyclovir group (42%) compared with the gancyclovir group (30%) (p = 0.005). Multivariate analysis demonstrated the incidence of CMV infection during the first 9 months was higher for acyclovir prophylaxis (p<0.001) and R − /D+ serostatus (p<0.001) and lower with R − /D− serostatus (p = 0.02). In conclusion, gancyclovir significantly delays the onset of first CMV infection among lung transplant patients. CMV surveillance and choice of prophylaxis may be modified according to donor-recipient CMV serotype.

Factors associated with the development of cytomegalovirus infection following solid organ transplantation

Abstract Background: Infection with cytomegalovirus (CMV) remains a potentially serious complication in transplant patients. In this study we explored the risk factors for CMV infection in the 12 months following a solid organ transplantation (n = 242) in patients monitored for CMV infection from 2004 to 2007. Methods: CMV infection was defined as 2 consecutive quantifiable CMV-polymerase chain reaction (PCR) values or 1 measurement of >3000 copies/ml. Data describing pre- and post-transplantation variables were extracted from electronic health records. Time to CMV infection was investigated using Cox proportional hazards analysis. Results: Overall, 31% (75/242) of solid organ transplant patients developed CMV infection: 4/8 (50.0%) heart, 15/43 (34.9%) liver, 30/89 (33.7%) lung and 26/102 (25.5%) kidney transplant patients. The risk of CMV infection according to donor (D)/recipient (R) CMV serostatus (positive + or negative−) was highest for D+/R−(adjusted hazard ratio 2.6, 95% confidence interval 1.6–4.2) vs D+/R+, and was reduced for D−/R+(adjusted hazard ratio 0.2, 95% confidence interval 0.2–0.8) vs D+/R+. Conclusion: Positive donor CMV-serostatus is a major risk factor for CMV-infection in CMV-na ve recipients, but also in recipients with positive CMV-serostatus. Conversely, if donor is CMV serostatus is negative, the risk of CMV infection is low, irrespective of recipients CMV-serostatus. These findings suggest poorer immune function towards donor-induced strains of CMV versus recipient own latent strains.

Cytomegalovirus Viral Load in Bronchoalveolar Lavage to Diagnose Lung Transplant Associated CMV Pneumonia.

Background The diagnostic yield for cytomegalovirus (CMV) polymerase chain reaction (PCR) viral load in bronchoalveolar lavage (BAL) or in plasma to diagnose CMV pneumonia in lung transplant recipients remains uncertain and was investigated in a large cohort of consecutive lung transplant recipients. Methods Bronchoscopies within the first year of lung transplantation with CMV detectable in BAL by PCR (ie, viral load, ≥273 IU/mL) were included (66 recipients; 145 bronchoscopies); at each bronchoscopy episode, 2 independent experts reviewed clinical and laboratory information to determine whether the patient at that time fulfilled the criteria for CMV pneumonia per current international recommendations. Corresponding plasma CMV PCR viral load determined at time of the bronchoscopy (n = 126) was also studied. Optimal CMV PCR viral load cutoff for CMV pneumonia diagnosis was determined using receiver operating characteristics. Results CMV was detected in BAL with CMV PCR in 145 episodes, and 34 (23%) of these episodes fulfilled the criteria for CMV pneumonia. The area under the curve-receiver operating characteristics for CMV in BAL was 90% at the optimum cutoff (4545 IU/mL) with a corresponding sensitivity of 91% and specificity of 77% (in plasma the corresponding values were 274 IU/mL, 63% and 76%, respectively). Conclusions CMV PCR viral load in BAL had a high performance to diagnose CMV pneumonia in lung transplant recipients; plasma CMV viral load did not reliably aid as a diagnostic tool.

The effect of baseline lung function on the determination of time to bronchiolitis obliterans syndrome

Long term survival after lung transplantation depends on the development and severity of bronchiolitis obliterans syndrome (BOS). The objective of this study was to identify the relationship between baseline FEV1 and transplant procedure type, on the development and progression of BOS grade 0p to 3. All patients receiving a cadaveric lung transplant 1992-2004 were included in the study (n = 389). Exclusion criteria were patients surviving <3 months (n = 39) and missing spirometry measurements (n = 4). There were significant differences between the transplant procedures, heart-lung (HLTx), double-lung (DLTx), and single-lung (SLTx), with respect to recipient age, BMI, and indication for transplantation. Baseline FEV1 for HLTx (median 2.9L, quartiles 2.3–4.3L) and DLTx recipients (median 2.9L, quartiles 2.4–3.7L) were significantly larger than for patients undergoing SLTx procedures (median 1.6L, quartiles 1.3–1.9L), p<0.0001, respectively. Survival analyses demonstrated a significant association between baseline FEV1 per litre and the development of BOS: grade 0p (HR: 0.59, CI: 0.51–0.68, p<0.0001); grade 1 (HR: 0.60, CI: 0.51–0.70. p<0.0001); grade 2 (HR: 0.62, CI 0.52–0.74, p<0.0001); and grade 3 (HR: 0.73, CI 0.60–0.89, p = 0.002). There was a significant log-log linear relationship between baseline FEV1 and time to the development of BOS grades 0p to 3 in all patients developing the respective BOS grade (p<0.0001, respectively). Baseline lung function is an important confounder and should be considered in future risk factor evaluations for the development and progression to BOS.