Mortality among patients with pulmonary non-tuberculous mycobacteria disease.

SETTING: Tertiary referral center, National Institutes of Health (NIH), USA. OBJECTIVE: To estimate the mortality rate and its correlates among persons with pulmonary non-tuberculous mycobacteria (PNTM) disease. DESIGN: A retrospective review of 106 patients who were treated at the NIH Clinical Center and met American Thoracic Society/Infectious Diseases Society of America criteria for PNTM. Eligible patients were aged ⩾18 years and did not have cystic fibrosis or human immunodeficiency virus (HIV) infection. RESULTS: Of 106 patients followed for a median of 4.9 years, 27 (25%) died during follow-up, for a mortality rate of 4.2 per 100 person-years. The population was predominantly female (88%) and White (88%), with infrequent comorbidities. Fibrocavitary disease (adjusted hazard ratio [aHR] 3.3, 95% confidence interval [CI] 1.3-8.3) and pulmonary hypertension (aHR 2.1, 95%CI 0.9-5.1) were associated with a significantly elevated risk of mortality in survival analysis. CONCLUSIONS: PNTM remains a serious public health concern, with a consistently elevated mortality rate across multiple populations. Significant risk factors for death include fibrocavitary disease and pulmonary hypertension. Further research is needed to more specifically identify clinical and microbiologic factors that jointly influence disease outcome.

Micro-CT scouting for transmission electron microscopy of human tissue specimens.

Transmission electron microscopy (TEM) provides sub-nanometre-scale details in volumetric samples. Samples such as pathology tissue specimens are often stained with a metal element to enhance contrast, which makes them opaque to optical microscopes. As a result, it can be a lengthy procedure to find the region of interest inside a sample through sectioning. We describe micro-CT scouting for TEM that allows noninvasive identification of regions of interest within a block sample to guide the sectioning step. In a tissue pathology study, a bench-top micro-CT scanner with 10 µm resolution was used to determine the location of patches of the mucous membrane in osmium-stained human nasal scraping samples. Once the regions of interest were located, the sample block was sectioned to expose that location, followed by ultra-thin sectioning and TEM to inspect the internal structure of the cilia of the membrane epithelial cells with nanometre resolution. This method substantially reduced the time and labour of the search process from typically 20 sections for light microscopy to three sections with no added sample preparation.

Interferon alpha treatment of patients with impaired interferon gamma signaling.

Patients with deficiency in the interferon gamma receptor (IFN-γR) are unable to respond properly to IFN-γ and develop severe infections with nontuberculous mycobacteria (NTM). IFN-γ and IFN-α are known to signal through STAT1 and activate many downstream effector genes in common. Therefore, we added IFN-α for treatment of patients with disseminated mycobacterial disease in an effort to complement their IFN-γ signaling defect. We treated four patients with IFN-γR deficiency with adjunctive IFN-α therapy in addition to best available antimicrobial therapy, with or without IFN-γ, depending on the defect. During IFN-α treatment, ex vivo induction of IFN target genes was detected. In addition, IFN-α driven gene expression in patients' cells and mycobacteria induced cytokine response were observed in vitro. Clinical responses varied in these patients. IFN-α therapy was associated with either improvement or stabilization of disease. In no case was disease exacerbated. In patients with profoundly impaired IFN-γ signaling who have refractory infections, IFN-α may have adjunctive anti-mycobacterial effects.

Pulmonary non-tuberculous mycobacterial infection in congenital contractural arachnodactyly.

Congenital contractural arachnodactyly (CCA) is caused by mutations within the fibrillin-2 gene (FBN2), which is crucial for microfibril structure. Affected individuals may have contractures, chest wall deformities, scoliosis, abnormal ear folding and elongated limbs. We describe a novel FBN2 mutation in a woman with CCA who also had pulmonary non-tuberculous mycobacteria (NTM) infection. The population with pulmonary NTM infections shares phenotypic features with CCA, such as elongated body habitus, scoliosis and pectus deformities. While it is unlikely that FBN2 defects account for susceptibility to NTM infection in the majority of cases, the overlap between these two diseases suggests some shared pathophysiology.

Skin test reactions to Mycobacterium tuberculosis purified protein derivative and Mycobacterium avium sensitin among health care workers and medical students in the United States.

SETTING: Health care workers and medical students in the United States subject to annual tuberculin skin testing. OBJECTIVE: To use skin testing with Mycobacterium avium sensitin (MAS) to determine contemporary rates of infection with non-tuberculous mycobacteria (NTM) and their effect on reactions to M. tuberculosis purified protein derivative (PPD). DESIGN: Dual skin testing was performed with PPD and MAS on 784 health care workers and medical students in the northern and southern US. MAS reactions that were > or = 5 mm and also > or = 3 mm larger than the PPD reaction were defined as MAS dominant and due to NTM. RESULTS: MAS reactions were > or = 5 mm in 40% and > or = 15 mm in 18% of subjects; 95% were MAS dominant. MAS dominant reactions were more common in the south than the north (P < 0.001). PPD reactions were > or = 15 mm in 3% of subjects. PPD reactions > or = 15 mm were more common among males, foreign born subjects and subjects with BCG immunization (all P < 0.001). MAS dominant reactions were found in 82% of subjects with 5-9 mm PPD reactions and 50% with 10-14 mm PPD reactions; these reactions were more common among whites (P = 0.046), US-born (P = 0.038) and subjects without BCG immunization (P = 0.004). CONCLUSIONS: Infections with NTM are responsible for the majority of 5-14 mm PPD reactions among US-born health care workers and medical students subject to annual tuberculin testing.

Nontuberculous mycobacterial pulmonary disease.

The prevalence of the nontuberculous mycobacteria (NTM) among clinical mycobacterial isolates is increasing. Reports of human pulmonary disease ascribed to these isolates, particularly the Mycobacterium avium complex, have involved hosts who did not possess the traditional risk factors of structural airways disease or apparent conditions that alter local or systemic immune function. More definitive evidence supporting a causal relationship between recovery of M. avium complex and the presence of small peripheral nodules with or without focal bronchiectasis now exists from biopsy studies as well as longitudinal evaluations. The concept of airway colonization, the nonpathogenic presence of NTM in the lower airways, is less viable. However, given the very slowly progressive nature of noncavitary disease, the remaining question is whether to aggressively treat patients with a multidrug regimen or to diligently follow them with frequent microbiologic and radiologic evaluations. The advent of the newer macrolide-azide antibiotics with demonstrated effectiveness against M. avium complex has significantly improved the management outcome of multidrug chemotherapeutic regimens. The potential for prevention of significant bronchiectatic lung disease merits an aggressive diagnostic approach to identify NTM in the appropriate clinical presentation. Recognizing the changing presentations of NTM pulmonary disease is requisite for suspecting NTM as potential etiologic agents.

Seizures in lung transplant recipients.

PURPOSE: We wished to assess organ transplant recipients, who incur a significant risk for seizures. METHOD: We reviewed 85 lung transplants performed in 81 patients at the University of North Carolina hospitals between 1991 and 1994. All patients were reviewed for age, reason for transplant, detailed description of seizures, neurological examination, medications, and laboratory results, including cyclosporine level, EEG, and brain imaging. RESULTS: Eighteen of 81 (22%) patients experienced seizures. Patients aged < 25 years had the greatest risk of seizures and 15 of the 18 patients had cystic fibrosis. Sixteen of the 18 (89%) patients, by history, had partial-onset seizures. Eleven of the 18 (61%) patients had seizures < or = 10 days after initiation of intravenous methylprednisolone for allograft rejection. Two patients had seizures associated with sustained hypertension: 1 of these patients was simultaneously being treated for rejection. Four patients had strokes (1 before transplant) and seizures. Two patients were receiving imipenem. Magnetic resonance imaging (MRI) of the brain demonstrated areas of increased T2 signal in 8 of 9 patients. CONCLUSIONS: Our findings demonstrate multiple etiologies for seizures in our transplant recipients. However, we believe that patients, especially those aged < 25 years, being treated with intravenous methylprednisolone for rejection may be at increased risk of seizures. We hypothesize that the focal loss of blood-brain barrier (BBB) may play a significant role in the development of partial seizures in lung transplant recipients.

Nontuberculous mycobacterial pulmonary disease in cystic fibrosis.

Since 1990, there have been an increasing number of reports of nontuberculous mycobacteria (NTM) recovered from lower respiratory tract specimens of patients with cystic fibrosis (CF) lung disease. The eight reports from series of prospectively screened patients collectively note a prevalence of approximately 13%. Reasons for the increased reports in CF patients may be related to: (1) active searching for NTM; (2) complications of advancing survival length in which more pathogens are emerging; (3) improvements in culture technique that decrease bacterial overgrowth: (4) factors that favor transmission such as contaminated hospital water supplies; and (5) a more susceptible host reflecting increasing NTM infection in the general population. Distinguishing airway colonization by NTM from pathogenic NTM infection that contributes to the progression of the underlying CF lung disease can be particularly difficult. Treatment of NTM in CF can also be more difficult because: (1) altered drug absorption and metabolism, (2) pre-treatment polypharmacy including multiple antimicrobials, and (3) the susceptibility of other pathogens to some antimycobacterial agents confounding assessment of NTM treatment response.

Acute safety and effects on mucociliary clearance of aerosolized uridine 5'-triphosphate +/- amiloride in normal human adults.

Impaired mucociliary clearance contributes to the pathophysiology of several airways diseases including cystic fibrosis, asthma, and chronic bronchitis. Extracellular triphosphate nucleotides (adenosine 5'-triphosphate [ATP], uridine 5'-triphosphate [UTP]) activate several components of the mucociliary escalator, suggesting they may have potential as therapeutic agents for airways diseases. We conducted initial (Phase I) studies of acute safety and efficacy of aerosolized UTP alone and in combination with aerosolized amiloride, the sodium channel blocker, in normal human volunteers. Safety was assessed by measurement of pulmonary function. Neither UTP alone nor in combination with amiloride caused any clinically significant adverse effects on airway mechanics, (subdivisions of) lung volumes, or gas exchange. Acute efficacy of UTP and amiloride alone and in combination, was assessed by measuring changes in the clearance of inhaled radiolabeled particles. A 2.5-fold increase in mucociliary clearance was seen in response to UTP alone and in combination with amiloride. We conclude that aerosolized UTP +/- amiloride clearly enhances mucociliary clearance without acute adverse effects in normal adults, and may have therapeutic potential to enhance airways clearance in diseases characterized by retained airways secretions.

Effect of uridine 5'-triphosphate plus amiloride on mucociliary clearance in adult cystic fibrosis.

Cystic fibrosis (CF) is characterized by abnormal airway epithelial electrolyte transport leading to viscous airway secretions that are difficult to clear. By enhancing Cl- secretion onto and blocking Na+ absorption from the airway surface, treatment with aerosolized uridine 5'-triphosphate (UTP) plus amiloride may improve the rheology of airway secretions and enhance mucociliary clearance in patients with CF. After performing safety studies of aerosolized UTP/amiloride in adult patients with CF, we investigated the effects of inhaled vehicle and UTP/amiloride on mucociliary clearance of [99mTc] iron oxide particles from the airways of adult patients with CF (n = 14). We found no clinically significant adverse effects from inhalation of therapeutic doses of UTP/amiloride. Mean baseline peripheral clearance rates during the first 40 min of clearance measurements were significantly less in patients with CF than in normal subjects (mean +/- SE: 0.30 +/- 0.05 versus 0.54 +/- 0.07%/min, respectively; p = 0.01). Aerosolized UTP and amiloride in combination improved mucociliary clearance from the peripheral airways of the CF lungs to near normal values (0.51 +/- 0.09%/min; p = 0.04) during this period. These data support the concept for the use of UTP in combination with amiloride as therapy to improve clearance of secretions from the lungs of patients with CF.

Skin testing with Mycobacterium avium sensitin to identify infection with M. avium complex in patients with cystic fibrosis.

We sought to determine if patients with cystic fibrosis and sputum cultures positive for Mycobacterium avium complex (MAC) have delayed-type hypersensitivity to an M. avium sensitin. Seventeen (33%) of 51 selected patients had MAC isolated from at least one sputum culture. Skin tests with purified protein derivative and M. avium sensitin demonstrated that five (10%) of 51 patients were anergic, and anergy was correlated with use of systemic steroids. Sixteen (35%) of 46 nonanergic patients had M. avium-dominant skin test reactions. Twelve (75%) of these 16 patients with cultures positive for MAC had M. avium-dominant skin tests; the specificity of skin testing was 87%. These data suggest that most patients with cystic fibrosis and sputum cultures positive for MAC have infection rather than colonization with MAC. Skin testing with M. avium sensitin is a sensitive and specific method for screening these infections.

Pharmacologic treatment of abnormal ion transport in the airway epithelium in cystic fibrosis.

Cystic fibrosis (CF) is a recessive genetic disease reflecting mutations in the gene coding for the CF transmembrane regulator (CFTR) protein, which normally functions as a cyclic adenosine monophosphate (cAMP)-regulated chloride (Cl-) channel. Functional abnormalities include thick airway secretions resulting from defective cAMP-mediated Cl- (liquid) secretion and a related defect, excessive sodium (Na+) (liquid) absorption. Novel pharmacologic agents are being tested as therapy for these ion transport defects. Aerosolized amiloride inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show slowing of the disease-associated decline in lung function. Clinical trials of amiloride are currently underway in adults and adolescents, and short-term safety studies have been initiated in children. Aerosolized uridine triphosphate (UTP) induces Cl- (and liquid) secretion in CF airway epithelia via non-CFTR Cl- channels. Short-term aerosolized UTP is well tolerated by normal subjects and patients with CF, and pilot studies in normal subjects show that aerosolized UTP is an effective stimulator of mucociliary clearance. Pharmacotherapy that modifies airway epithelial ion transport may provide new opportunities for treatment of CF lung disease.

Modulation of the ionic milieu of the airway in health and disease.

Airway surface liquid (ASL) is an integral part of lung defense mechanisms. Ion transport by airway epithelia regulates the volume and composition of this fluid. A better understanding of the mechanisms of ion transport will enable the development of new therapies for airway diseases associated with defects in these mechanisms. A useful model of a disease with abnormal airway epithelial ion transport is cystic fibrosis (CF), a distinct genetic syndrome of altered lung defense mechanisms characterized by chronic bacterial infection and a steady decline in lung function. Traditional therapies for CF include antibacterial drugs and augmentation of clearance of secretions, but investigators are now studying pharmacological approaches to target the more basic defect of the disease, i.e. abnormal sodium and chloride ion transport. Early treatment in childhood, prior to lung damage, might prevent or at least retard the decline in pulmonary function that remains the hallmark of CF. Ion transport dysfunction may also contribute to other airway diseases such as asthma and chronic bronchitis. Pharmacological intervention at this level may prove beneficial in these common lung diseases as well.