Complement C4 deficiency--a plausible risk factor for non-tuberculous mycobacteria (NTM) infection in apparently immunocompetent patients.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment and they infect mainly persons with underlying pulmonary diseases but also previously healthy elderly women. Defects in host resistance that lead to pulmonary infections by NTM are relatively unknown. A few genetic defects have been associated with both pulmonary and disseminated mycobacterial infections. Rare disseminated NTM infections have been associated with genetic defects in T-cell mediated immunity and in cytokine signaling in families. We investigated whether there was an association between NTM infections and deficiencies of complement components C4A or C4B that are encoded by major histocompatibility complex (MHC). METHODS: 50 adult patients with a positive NTM culture with symptoms and findings of a NTM disease were recruited. Patients' clinical history was collected and symptoms and clinical findings were categorized according to 2007 diagnostic criteria of The American Thoracic Society (ATS). To investigate the deficiencies of complement, C4A and C4B gene copy numbers and phenotype frequencies of the C4 allotypes were analyzed. Unselected, healthy, 149 Finnish adults were used as controls. RESULTS: NTM patients had more often C4 deficiencies (C4A or C4B) than controls (36/50 [72%] vs 83/149 [56%], OR = 2.05, 95%CI = 1.019-4.105, p = 0.042). C4 deficiencies for female NTM patients were more common than for controls (29/36 [81%] vs 55/100 [55%], OR = 3.39, 95% CI = 1.358-8.460, p = 0.007). C4 deficiences seemed not to be related to any specific underlying disease or C4 phenotype. CONCLUSIONS: C4 deficiency may be a risk factor for NTM infection in especially elderly female patients.

Prognostic value of American Thoracic Society criteria for non-tuberculous mycobacterial disease: a retrospective analysis of 120 cases with four years of follow-up.

BACKGROUND: Non-tuberculous mycobacteria (NTM) cause disease in healthy and immunocompromised patients. The American Thoracic Society (ATS) 2007 diagnostic criteria were devised to distinguish NTM disease from airway colonization. The aim of this study was to evaluate the prognostic value of the ATS criteria. METHODS: In a 4-y follow-up study that ended on 8 June 2006, we retrospectively analyzed the symptoms, underlying diseases, and mortality of 120 adult non-HIV patients with NTM culture findings obtained between 1990 and 1998. We categorized the patients according to the 2007 ATS NTM case definition into positive and negative groups. RESULTS: Only 61/120 patients (51%) fulfilled the ATS criteria for NTM disease. As compared to ATS-negative subjects, the ATS-positive group showed lower age, a higher proportion of females, and fewer fatal underlying diseases. Among ATS-negative subjects, 46/59 (78%) did not fulfil the microbiological criteria and 43/59 (73%) did not fulfil the radiological criteria. Mycobacterium avium complex (MAC) comprised 61% of isolations in the ATS-positive and 47% in the ATS-negative group (p = 0.15). No significant difference in median survival time was found between the groups: ATS-positive 7.4 y (95% confidence interval (CI) 0.2-14.6) and ATS-negative 5.3 y (95% CI 3.0-7.6). No significant difference was found in symptoms except fatigue, which was more common in the ATS-positive (56% vs 37%, p = 0.04). Symptoms lasted for less than a year in 48%, which suggests a more rapid disease progression than has previously been reported. CONCLUSIONS: The fulfillment of ATS criteria was poorly associated with any difference in prognosis, and based on our findings would be a poor prognostic marker.

Clinical symptoms and survival in non-smoking and smoking HIV-negative patients with non-tuberculous mycobacterial isolation.

BACKGROUND: Non-tuberculous mycobacteria (NTM) cause infections in patients with smoking-related chronic lung diseases and also in non-smoking healthy elderly women. We analyzed the clinical symptoms, underlying diseases and mortality in patients with NTM culture findings, with special emphasis on smoking status. METHODS: A total of 120 consecutive adult HIV-negative patients with NTM isolation were followed between 1990 and 1998 by retrieving data from their medical records for a period of at least 4 y, until 8 June 2006. Their clinical pictures and outcomes were analysed according to smoking status. RESULTS: In this study, 42% of the patients had never smoked. Females accounted for 72% of non-smokers, but only 30% of smokers (p < 0.001). Mycobacterium avium complex (MAC) accounted for 72% of all isolates in non-smokers and 41% in smokers (p = 0.001). Furthermore, 28% of non-smokers and 19% of smokers had no previous pulmonary diseases (p = 0.223). In nearly half of all patients (48%), symptoms of NTM infection started within a year prior to NTM isolation. Smokers had a higher risk of mortality compared to non-smokers (hazard ratio 1.64, p = 0.049), though this was not found after adjusting for underlying diseases. No fatal underlying diseases were found for 82% of non-smokers and 59% of smokers (p < 0.01). CONCLUSIONS: Non-smokers with NTM isolates had fewer previous lung diseases but had a higher incidence of MAC and bronchiectasis. Time from symptoms to NTM isolation was shorter than previously reported.

Human herpesvirus-6 and -7 after lung and heart-lung transplantation.

BACKGROUND: The impact of herpesvirus-6 and -7 (HHV-6, HHV-7) activation in lung transplant recipients is still poorly understood. We report the appearance of HHV-6 and HHV-7 antigenemia after lung transplantation and evaluate the efficacy of anti-viral drugs against these viruses. METHODS: Twenty-two lung or heart-lung recipients were monitored for HHV-6, HHV-7 and cytomegalovirus (CMV) during 12 post-operative months. HHV-6- and HHV-7-specific antigens and CMV pp65 antigens were analyzed in blood leukocytes and bronchoalveolar lavage fluid cells by monoclonal antibodies. Ganciclovir or valganciclovir prophylaxis for a minimum of 3 months was given to 19 recipients at risk for CMV infection. RESULTS: HHV-6, HHV-7 and CMV antigenemia was detected in 20 (91%), 11 (50%) and 12 (55%) recipients (median 16, 31 and 165 days) after transplantation, respectively. HHV-6 antigenemia occurred in 15 (79%), HHV-7 antigenemia in 7 (37%) and CMV antigenemia in 1 (7%) of these patients during anti-viral prophylaxis. HHV-6 or HHV-7 antigenemia was frequently associated with CMV antigenemia, which was detected 3 to 12 months after transplantation. Ganciclovir or valganciclovir treatment of CMV infection was effective against the concomitant HHV-6 and HHV-7 antigenemia in 9 of 12 (75%) and 5 of 6 (83%) cases, respectively. One case of pneumonitis and 1 of encephalitis were temporally associated with HHV-6. No other clinical manifestations could be linked solely to HHV-6 or -7. CONCLUSIONS: HHV-6 and -7 antigenemia was common and appeared early after lung transplantation. CMV prophylaxis was not able to prevent the appearance of HHV-6 and -7 antigenemia.

ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis.

We performed a genomewide scan in six multiplex families with familial idiopathic pulmonary fibrosis (IPF) who originated from southeastern Finland. The majority of the Finnish multiplex families were clustered in the region, and the population history suggested that the clustering might be explained by an ancestor shared among the patients. The genomewide scan identified five loci of interest. The hierarchical fine mapping in an extended data set with 24 families originating from the same geographic region revealed a shared 110 kb to 13 Mb haplotype on chromosome 4q31, which was significantly more frequent among the patients than in population-based controls (odds ratio 6.3; 95% CI 2.5-15.9; P = .0001). The shared haplotype harbored two functionally uncharacterized genes, ELMOD2 and LOC152586, of which only ELMOD2 was expressed in lung and showed significantly decreased messenger-RNA expression in IPF lung (n = 6) when compared with that of healthy lung (n = 7; P = .05). Our results suggest ELMOD2 as a novel candidate gene for susceptibility in familial IPF.

A prospective study comparing cytomegalovirus antigenemia, DNAemia and RNAemia tests in guiding pre-emptive therapy in thoracic organ transplant recipients.

We evaluated the usefulness of DNAemia and mRNAemia tests in guiding the pre-emptive therapy against cytomegalovirus (CMV) infections in thoracic organ transplant recipients using antigenemia test as the reference. Seven lung (LTR) and 14 heart (HTR) transplant recipients were prospectively monitored for CMV by antigenemia, DNAemia (Cobas Amplicor PCR Monitor) and pp67-mRNAemia (NASBA) tests. However, only the antigenemia test guided pre-emptive therapy with cut-off levels of >or=2 and >or=5-10 pp65-positive leukocytes/50 000 leukocytes in the LTRs and HTRs, respectively. CMV DNAemia was detected in 26/28 (93%) and RNAemia in 17/28 (61%) of the CMV antigenemias requiring antiviral therapy (P = 0.01). Optimal DNAemia levels (sensitivity/specificity) estimated from receiver-operating characteristic curve to achieve maximal sum of sensitivity and specificity were 400 (75.9/92.7%), 850 (91.3/91.3%) and 1250 (100/91.5%) copies/ml for the antigenemia of 2, 5 and 10 pp65-positive leukocytes, respectively. The sensitivities of nucleic acid sequence-based amplification (NASBA) were 25.9%, 43.5% and 56.3% in detecting the same cut-off levels of antigenemia. In thoracic organ transplant recipients, the Cobas PCR assay is comparable with the antigenemia test in guiding pre-emptive therapy against CMV infections when threshold levels of over 5 pp65-antigen-positive leukocytes are used as the reference. In contrast, the low sensitivity of NASBA limits its usefulness in the guidance of pre-emptive therapy.

Bronchoscopy in the diagnosis and surveillance of respiratory infections in lung and heart-lung transplant recipients.

Fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) is a widely used method to detect respiratory infections and to differentiate them from other postoperative complications in lung transplant (LTX) recipients, but the usefulness of surveillance FOBs is not yet established. The aim of this study was to evaluate the usefulness of FOB in the diagnosis and surveillance of infections in LTX recipients. We reviewed all the consecutive 609 FOBs performed on 40 lung or heart-LTX recipients between February 1994 and November 2002. The overall diagnostic yield was 115/190 (61%) and 43/282 (15%) for clinically indicated and surveillance FOBs respectively (P < 0.001). Infection was established by bronchoscopic samples in 96/190 (50.5.%) of the clinically indicated FOBs and 34/282 (12.1%) of the surveillance FOBs (P < 0.001). The diagnostic yield of the clinically indicated FOBs was highest (72%) from 1 to 6 months post-transplant (P = 0.04). Pneumocystis carinii was detected in 23 (4.9%) of the bronchoscopic specimens and 15 (65%) of the P. carinii infections were detected during adequate chemoprophylaxis. To conclude, in LTX recipients clinically indicated FOB has a good diagnostic yield in detecting infections and other postoperative complications, whereas the information received from surveillance FOB has remained less significant. With current prophylaxis and screening strategies FOB is still required to detect P. carinii infections.

The polymorphism C5507G of complement receptor 1 does not explain idiopathic pulmonary fibrosis among the Finns.

Idiopathic pulmonary fibrosis is the most common of the idiopathic interstitial lung diseases referring to the histo-pathological entity of usual interstitial pneumonia. It has been hypothesized that inflammation may trigger the multiformic fibrotic lesions found in the affected lung, and defects in the innate immune defense, including the complement, can predispose to pulmonary fibrosis. The polymorphism C5507G in the Complement Receptor 1 gene has been recently associated with idiopathic pulmonary fibrosis. C5507G causes an amino acid change from proline to arginine, and opens a potential cleavage site for trypsin-like enzymes and, therefore, a potential mechanism for increased shedding of the molecule from the cell surface. We studied the polymorphism in 96 Finnish patients with idiopathic pulmonary fibrosis and 164 population based controls. All the patients and controls were C5507 homozygous suggesting that either the Finns do not carry the G5507 polymorphism or it is extremely rare. We conclude that G5507 is not a susceptibility allele for idiopathic pulmonary fibrosis among Finnish patients.

A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax.

Primary spontaneous pneumothorax (PSP), a condition in which air enters the pleural space and causes secondary lung collapse, is mostly sporadic but also occurs in families. The precise etiology of PSP remains unknown, although it is associated with emphysemalike changes (bullae) in the lungs of almost all patients. We describe the results of a genetic study of a large Finnish family with a dominantly inherited tendency to PSP. A genomewide scan suggested linkage to chromosome 17p11. Screening of the best candidate gene, FLCN, revealed a 4-bp deletion in the first coding exon, which causes a frameshift that predicts a protein truncation 50 missense amino acids downstream. All carriers of the deletion had bullous lung lesions. Mutations in FLCN are also responsible for Birt-Hogg-Dubé (BHD) syndrome (a dominantly inherited disease characterized by benign skin tumors, PSP, and diverse types of renal cancer) and, rarely, are detected in sporadic renal and colorectal tumors. Unlike other FLCN mutations, the exon 4 deletion seems to be associated with bullous lung changes only with 100% penetrance. These results suggest that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema, a chronic pulmonary disease that often leads to formation of bullous lesions and lowered pulmonary function. Additionally, given the strong association of PSP and BHD, the connection between these conditions needs to be investigated further, particularly in patients with familial PSP, who may be at a greater risk of developing renal cancer.

Clinical usefulness of bronchoalveolar lavage in heart transplant recipients with suspected lower respiratory tract infection.

BACKGROUND: Bronchoscopy with bronchoalveolar lavage (BAL) is the recommended initial invasive diagnostic procedure when lower respiratory tract infection is suspected in solid-organ transplant recipients. In this study, we evaluated the clinical impact and safety of bronchoscopy with BAL in heart transplant recipients. METHODS: We reviewed all 44 consecutive diagnostic bronchoscopies with BAL that were performed in 35 heart transplant recipients at Helsinki University Central Hospital between May 1988 and December 2001. RESULTS: Bronchoscopy findings established specific microbiologic diagnoses in 18 of 44 (41%) cases, and 14 of 44 (32%) bronchoscopic findings led to changes in therapy. The diagnostic yield of bronchoscopy from 1 to 6 months after transplantation was 73%, significantly better (p = 0.002) than diagnostic yield during the first month (18%) and after 6 months (28%). Pneumocystis carinii and cytomegalovirus were the most frequently detected pathogens in the BAL fluid. Cytomegalovirus pneumonia carried a high mortality rate (44%), whereas all patients with P carinii pneumonia recovered. Fourteen episodes were diagnosed as bacterial pneumonia, but because of empiric antibiotic therapy that was started widely before bronchoscopy, a microbiologic diagnosis was established in only 1 case. However, all patients with community-acquired pneumonia responded to empiric therapy. Four cases of major complications occurred after bronchoscopy, all cardiovascular but none fatal. CONCLUSIONS: Bronchoscopy with BAL is a useful diagnostic tool in heart transplant recipients, especially between 1 and 6 months after transplantation.

Early treatment of stage II sarcoidosis improves 5-year pulmonary function.

STUDY OBJECTIVE: To evaluate the 5-year prognosis of patients with stage I and stage II newly detected (< 3 months) pulmonary sarcoidosis treated immediately after diagnosis with prednisolone for 3 months followed by inhaled budesonide for 15 months. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study for 18 months. Thereafter, open follow-up without treatment. SETTING: Twenty pulmonary medicine departments in Finland. PATIENTS: One hundred eighty-nine adult patients, most of them with normal lung function, were randomized to treatment. One hundred forty-nine patients were followed up for 5 years: 79 patients with initial stage I disease and 70 patients with stage II disease. TREATMENT: Oral prednisolone for 3 months followed by inhaled budesonide for 15 months (800 microg bid), or placebo tablets followed by placebo inhaler therapy. Thereafter, treatment only on an individual basis in the case of clinical deterioration. MEASUREMENTS: Yearly follow-up visits with chest radiographs, lung function tests (FEV(1), FVC), diffusion capacity of the lung for carbon monoxide (DLCO), serum angiotensin-converting enzyme (SACE), and serum and urinary calcium measurements. RESULTS: No initial differences were observed in chest radiographic findings between the active-treatment and placebo-treatment groups, either in patients with initial stage I or stage II(-III) disease. However, after the 5-year follow-up, 18 steroid-treated patients (26%) and 30 placebo-treated patients (38%) still had remaining chest radiographic changes. Placebo-treated patients more frequently required treatment with corticosteroids during the 5-year follow-up (p < 0.05). Steroid-treated patients with initial stage II(-III) disease improved more in FVC and DLCO (p < 0.05). No differences in reported adverse events or in SACE, serum calcium, or urinary calcium values were seen. CONCLUSION: Immediate treatment of pulmonary stage II(-III) sarcoidosis-but not stage I disease-improved the 5-year prognosis with regard to lung function variables.