Development and validation of a prognostic scoring model for Mycobacterium avium complex lung disease: an observational cohort study

Non-tuberculous mycobacteria (NTM) are environmental organisms that cause chronic and progressive lung infection [1]. On the basis of voluntary reporting, the annual incidence of non-tuberculous mycobacterial disease varies from 0.7 − 1.8 cases per 100,000 people worldwide [1]. The Mycobacterium avium complex (MAC), including M. avium and M. intracellulare, is the most common cause of chronic respiratory infections among the NTM species [1‐4].

In clinical practice, patients with MAC lung disease (LD) have an extremely heterogeneous prognosis, with some experiencing disease progression to respiratory failure, and others showing stable, indolent disease [2, 5‐7]. Although the 2007 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines recommend a three- or four-drug regimen for the treatment of MAC-LD [1], a previous study reported that more than half of patients could be observed without antibiotic treatment [5]. In order to select effective treatment strategies for patients with MAC-LD, it is critical that physicians are able to determine the patient prognosis. Although several factors are reported to be associated with the prognosis of MAC-LD [5], information regarding the prognosis of MAC-LD remains scarce. In addition, there have been no reports of an overall evaluation involving combinations of the prognostic factors of MAC-LD. A prognostic scoring model involving prognostic factors of MAC-LD identified at diagnosis could aid physicians in the prediction of the overall survival (OS) or MAC-specific survival. The purpose of this study was to identify prognostic factors at diagnosis associated with the OS of patients with MAC-LD, and to develop and validate a new prognostic scoring model stratifying the long-term outcomes of MAC-LD.

The MAC has emerged as an increasingly prevalent pathogen in respiratory infections [3]. The long-term outcomes of patients with infections caused by MAC vary from chronic indolence to rapid progression [2, 5‐7, 10]. Therefore, a prognostic scoring model is required to predict the heterogeneous prognosis of MAC-LD at diagnosis in clinical practice. In order for the prognostic scoring model to be clinically useful and easy to calculate, we investigated prognostic factors of OS which are easily available in the clinical setting for inclusion in the prognostic scoring model. Seven independent prognostic factors were identified in the multivariate analysis, including the male sex, advanced age, malignancy, low BMI, low lymphocyte counts, hypoalbuminemia, and FC disease. These factors were used to develop the prognostic scoring model that significantly stratified the OS of patients with MAC-LD into three groups according to risk (high/intermediate/low), the results of which were validated using an independent cohort. Further prospective studies are required to assess the long-term effectiveness of the treatment of MAC-LD. To our knowledge, this is the first study to devise a prognostic scoring model stratifying not only OS but also MAC-specific surival of patients with MAC-LD. This is very important in helping patients and physicians to select an optimal management strategy.

Of the systemic comorbidities, a malignancy was the most prevalent in this study; patients with lung cancer constituted 7.6% of the study population. Lande et al. conducted a retrospective analysis of patients with MAC-positive respiratory cultures and newly diagnosed lung cancer [11]. They concluded that the presence of MAC in the respiratory cultures of patients with lung cancer was particularly associated with squamous cell carcinomas located in the periphery of the lung. Chronic lung infections caused by mycobacterial organisms can stimulate proinflammatory reactions that cause extensive damage to the surrounding lung and bronchiolar tissues [12‐15]. It has been reported that chronic inflammatory processes nurture the development of malignancies in tissues before evident tumors are established [16], and may make tumor progression possible by promoting immune tolerance [17]. Therefore, when considering the treatment strategies for MAC-LD, physicians should be aware of the association between MAC and malignancy.

The 5-year survival rate of patients with MAC-LD in the present study was 77.5% in cohort 1 and 85.3% in cohort 2. These results were consistent with previous reports, which reported 5-year mortality rates ranging from 23.9 to 39.7% [2, 5, 18, 19]. There are few reports assessing the prognostic factors of MAC-LD. Hayashi et al. reported that the male sex, age ≥ 70 years, the presence of systemic and/or respiratory comorbidities, the radiographic features of FC, FC + NB, or other diseases, BMI <18.5 kg/m², Hb <10 g/dL, Alb <3.5 g/dL, and an erythrocyte sedimentation rate (ESR) ≥50 mm/h were negative prognostic factors for all-cause mortality in a multivariate analysis [5]. Ito et al. evaluated the data of 78 patients with definite MAC disease, and identified two independent factors for 5-year all-cause mortality: a high Charlson comorbidity index and cavity lesions [19]. In the present study, only FC disease, and not FC/NB disease, was included in the multivariate analysis, because FC disease showed the worst prognosis in the radiographic patterns (data not shown). Furthermore, ESRs were excluded from the analysis of prognosis because of the small number of patients who were evaluated for ESR at diagnosis. The multivariate analysis identified that a lymphocyte count <1000 cells/μL and the presence of a malignancy were independent prognostic factors for the OS, in addition to the male sex, age ≥ 70 years, radiographic features of FC diseases, a BMI <18.5 kg/m², and an Alb <3.5 g/dL. Lymphocyte count would be assumed to reflect host immunity. Malignancy is in itself a progressive and life-threatening disease. Besides, malignancy and its treatment often cause immunosuppression [20, 21], which might worsen various infections.

The most prescribed regimen in this study was the 2007 ATS/IDSA guidelines recommended regimen (CAM + RFP + EB). The 2007 ATS/IDSA guidelines suggests that the choice of therapeutic regimen for a specific patient depends to some degree on the goals of therapy for that patient, and that especially in treating older frail patients with comorbid conditions who have difficulty tolerating multidrug MAC treatment regimens, less aggressive or even suppressive treatment strategies should be considered [1]. The effect of multidrug treatment on long-term outcome may be difficult to evaluate, because treatment was introduced according to the decision of each physician, and because treatment regimens and durations were not uniform across patients. In this study, however, the patients with treatment experienced favorable OS as compared to those without treatment. In particular, subgroup analyses showed that of the three risk groups, patients in the intermediate-risk group received the best benefits of treatment. In the low-risk group, HR of patients who received treatment is the highest of all the subgroups (P = 0.877). Perhaps, the low-risk group patients could be observed with very good prognosis. The high-risk group patients might be so frail and likely to die of other causes including malignancy rather than MAC-LD. This result suggests that physicians should not miss the chance to treat patients especially in the intermediate-risk group and that the low-risk group patients could be observed without treatment. However, it should be kept in mind that continuous assessment is required even in low-risk group because individual patients may have more rapid clinical deterioration than others (and perhaps fall into a higher risk group). This prognostic scoring model should be used, auxiliary to the ATS/IDSA guidelines. An individual risk-benefit assessment of treatment of MAC-LD is necessary for all the patients regardless of risk groups.

One limitation of this study was that this was a retrospective study. Further prospective studies are required to assess the long-term effectiveness of the treatment of MAC-LD. Differences in the background patient characteristics or treatment strategies of MAC-LD among institutions would exist. Therefore, the results of this study should be validated in other multi-center studies. In addition, as patients with suspected MAC-LD who were unable to expectorate sputum were examined by bronchoscopy, the date of diagnosis might have been earlier for these patients and, thus, the 5-year survival rate might have been better.

This study was the first to develop and validate a prognostic scoring model for MAC-LD, which consisted of seven independent prognostic factors identified in a multivariate analysis. These factors included the male sex, age ≥ 70 years, the presence of a malignancy, BMI <18.5 kg/m², lymphocyte counts <1000 cells/μL, Alb <3.5 g/dL, and FC disease. This is an easy-to-calculate, clinically-relevant prognostic scoring model, which may help physicians to determine the prognosis of patients with MAC-LD and thereby might guide the selection of optimal treatment strategies.