کلنیزاسیون نوکاردیا: عامل خطری برای زوال ریه در بیماران کیستیک فیبروز؟ Nocardia Colonization: A Risk Factor for Lung Deterioration in Cystic Fibrosis Patients?

Patients with cystic fibrosis have a predisposition to become colonized and infected by a large array of microbes. Some bacteria, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Stenotrophomonas maltophilia, accelerate the deterioration of pulmonary disease, while others have little or no data to define their role as a pathogen or colonizer in the cystic fibrosis patient, and the benefits of treatment after their isolation is unknown [11,12]. The literature describing Nocardia in CF are mostly case reports, including 1 report describing 3 patients in Australia [5] and a report of 9 patients in Spain [6], which concluded that isolation represents colonization rather than infection. Three more case reports of children with CF and Nocardia isolation were published and found other risk factors for infection, such as corticosteroid treatment for ABPA [7–۹]. Most patients described were treated with cotrimoxazole, but the outcomes for the treated versus the untreated patients were similar or unknown [5–۹]. To the best of our knowledge, the present study is the first to evaluate such a large cohort of patients, 25% of them carriers of a unique mutation prevalent in Israel (W1282X), for such a long period of time (10 years). We found no statistically significant difference in PFTs before or after the Nocardia isolation. No difference in PFTs were found between patients with a single episode versus those with recurrent Nocardia growth, nor in those treated with antibiotics, some for prolonged periods of time, versus those who were not treated. There was no difference in mean FEV1 or FVC between symptomatic versus asymptomatic patients during the episode, but a significantly lower mean FEF 25–۷۵% was found among the symptomatic patients (35.7 vs. 73.3, p=0.01). Regarding this finding, we hypothesized that a graver disease of the smaller airways and perhaps a more parenchymal involvement could result in subjective pulmonary symptomatology. In this study we expanded the follow­up period and evaluated the changes in pulmonary functions throughout the entire period of 10 years and not only during the year of the episode of Nocardia isolation, realizing that in some cases a bacteria could colonize the lungs without growing in our sputum cultures. Furthermore, we compared our study group patients to paired CF patients with similar status as their peers by mutation class, age, and sex, but no Nocardia isolation, a comparison not carried out until this time. In these patients we found a mean decline of FEV1 per year of −۱٫۸۷%, similar to the average rate of decline known for CF patients. No difference in the rate of decline was found comparing the period prior to the positive Nocardia culture to the years following the isolation until the end of the study period. Surprisingly, the mean decline of FEV1 per year for our control group CF patients was ­۰٫۵%. Comparing the rates for both groups showed a trend to significance in FEV1 (p=0.08) and FVC (p=0.09), with no difference in FEF25– ۷۵% (p=0.2), meaning that the cystic fibrosis patients who had positive sputum cultures with Nocardia declined faster than matched controls without isolation of this microbe. It is possible that this difference was not statistically significant because of the small study group. Since it does not seem that Nocardia causes a deterioration of lung functions, we hypothesized that this microbe might grow more often in patients with more significant lung disease and worse prognosis. Perhaps other genetic or environmental factors affect the lungs of this group of patients or protect the lungs of the “healthier” patients and differentiate them from each other. These factors will need to be studied in larger groups of patients. In a previous retrospective study from Arizona [10], 17 patients with CF had a sputum culture positive for Nocardia spp. during the years 1997–۲۰۰۷ (of 123 CF patients – ۱۴%), a similar percentage as in our clinic. Several patients had persistent positive Nocardia sputum cultures despite repeated antibiotic courses and did not appear to have different outcomes from the ones with a single isolated culture. As opposed to our center, in Arizona 78% of episodes were treated with antibiotics. Despite this, mean FEV1 and FVC values showed no significant linear trend before, during, and after an episode of positive Nocardia isolation in sputum, which led to the conclusion that treatment likely has no value in improving pulmonary function. Our study strengthens these conclusions of our colleagues. Optimal treatment recommendations for pulmonary Nocardiosis have not been firmly established due to variable in vitro antimicrobial susceptibility patterns. Sulfonamides have been the antimicrobials of choice since they were introduced 50 years ago [13], but resistance has been described lately in up to 15% of the isolates [14]. Alternative antibiotics used orally are minocycline or doxycycline, while some strains of Nocardia are moderately sensitive to amoxicillin­clavulanate or to fluoroquinolones. Several intravenous antibiotics are also effective against Nocardia such as carbapenems, ceftriaxone, cefotaxime, amikacin, and linezolid. When treating pulmonary Nocardiosis, combination therapy should be considered and a duration of 6–۱۲ months of therapy is recommended. However, as shown in the literature and highlighted in our study, in CF patients the need to treat as well as the duration of treatment is less well defined. Despite all this, it is believed that Nocardia eradication or a very long period of treatment might be needed in some patients with CF, especially if they are to undergo lung transplantation or are in need of prolonged and high doses of corticosteroids, such as for treatment of ABPA. The reason for this is that the corticosteroids as well as the immunosuppressive regimen during the post­operative period are well­established risk factors for invasive Nocardiosis and disseminated disease that lead to high rate of mortality [15,16]. Indeed, mediastinal mass and pericardial effusion with cardiac tamponade was diagnosed as an invasive Nocardial infection in a renal transplant immunosuppressed patient [17]. There are some limitations to our study. The major limitation is the small study sample, making firm conclusions difficult. However, it is the largest study group assessed so far, to the best of our knowledge. It seems that a multicenter study with more cases could provide more information and better statistics. The retrospective method of our study is another limitation. Accordingly, we significantly expanded the period of follow­up of the patients to the entire study period, enabling us to estimate yearly changes in pulmonary functions. Another limit of our study was the lack of differentiation of Nocardia into different species and establishment of drug sensitivity in our microbiologic laboratory, which could possibly separate the patients into different sub­groups according to the virulence and resistance of the specific microbe.