A Systematic Review of the Prognostic Significance of the Body Mass Index in Idiopathic Pulmonary Fibrosis

The identification of novel prognostic biomarkers might enhance individualized management strategies in patients with idiopathic pulmonary fibrosis (IPF). Although several patient characteristics are currently used to predict outcomes, the prognostic significance of the body mass index (BMI), a surrogate measure of excess fat mass, has not been specifically investigated until recently. We systematically searched PubMed, Web of Science, and Scopus, from inception to July 2022, for studies investigating associations between the BMI and clinical endpoints in IPF. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the risk of bias. The PRISMA 2020 statement on the reporting of systematic reviews was followed. Thirty-six studies were identified (9958 IPF patients, low risk of bias in 20), of which 26 were published over the last five years. Significant associations between lower BMI values and adverse outcomes were reported in 10 out of 21 studies on mortality, four out of six studies on disease progression or hospitalization, and two out of three studies on nintedanib tolerability. In contrast, 10 out of 11 studies did not report any significant association between the BMI and disease exacerbation. Our systematic review suggests that the BMI might be useful to predict mortality, disease progression, hospitalization, and treatment-related toxicity in IPF (PROSPERO registration number: CRD42022353363).


Mortality
A significant association between the BMI and mortality was reported in 10 studies, including nine retrospective studies and nine with low risk of bias [21,24,29,38,49 [24]. Kishaba et al. investigated the impact of changes in BMI during the first year on 12-year mortality. In their analysis, the magnitude of BMI reduction was significantly associated with mortality after adjusting for several confounders, including hospitalization during the first year. Similar associations with 12-year mortality were observed with absolute values of baseline and one-year BMI [29]. Kulkarni et al. also investigated the association between BMI temporal trajectories and one-year transplant or mortality and post-transplant mortality in a discovery cohort (n = 131). The quartile with the greatest temporal BMI reduction (>0.68%/month) was independently associated with a higher risk of transplant or death. The association with mortality was maintained after excluding patients undergoing transplant (HR = 2.9, 95% CI 1.6 to 5.2, p = 0.0002). In further analysis, patients with temporal BMI reduction >0.68%/month in the year preceding the transplant also had a greater risk of mortality following surgery (HR = 4.6, 95% CI 1.7 to 12.6, p = 0.003). The same authors confirmed the presence of an independent association between temporal BMI reduction >0.68%/month and risk of transplant or death in a validation cohort (n = 148) [38]. Sangani et al. retrospectively investigated 138 IPF patients categorized as non-obese (BMI < 30 kg/m 2 ) and obese (BMI ≥30 kg/m 2 ). The usual interstitial pneumonia pattern was less prevalent in the obese group (69% vs. 85%, p = 0.007). Significantly lower mortality was observed in this group. A similar trend was also observed when BMI values were analyzed as tertiles (mortality of 20%, 47%, and 75% for BMI values of 25-29.9, 20-24.9, and <20 kg/m 2 , respectively, p < 0.001) [49]. Two cohorts receiving antifibrotic treatment with pirfenidone or nintedanib, for a total of 208 IPF patients, were investigated by Suzuki et al. A significant, negative, and independent association was observed with five-year mortality both when considering BMI values as a continuous variable and using a cut-off value of 24.1 kg/m 2 [50]. Zinellu et al. reported a negative and independent association between the baseline BMI and four-year mortality in a cohort of 82 IPF patients, after adjusting for several confounders including the recently developed aggregate index of systemic inflammation [52,[57][58][59][60]. In another prospective cohort study in 153 newly diagnosed IPF patients, Jouneau et al. reported that a lower baseline BMI was independently associated with one-year mortality in multivariate analysis, after adjusting for age, sex, GAP score, and self-evaluation of food intake [53]. Yoo et al. similarly reported that a lower baseline BMI was independently associated with higher three-year mortality in 445 patients with IPF, after adjusting for several confounders including the Charlson comorbidity index, disease progression, and acute exacerbation [55]. Finally, Zinellu et al. investigated 90 IPF patients and reported an independent association between the baseline BMI and four-year mortality, with an area under the curve (AUC) of 0.702 [56]. Incorporating the BMI into a four-domain predictive model (IC4) including the six-minute walking distance, FVC, and D LCO significantly increased the AUC to 0.859 (95% CI 0.770-0.924, p < 0.0001) [56].
In contrast, 11 studies, including eight retrospective studies and six with low risk of bias, failed to report a significant association between the BMI and mortality [22,23,26,30,32,33,37,39,40,45,54]. A non-significant association between the BMI and mortality was reported in multivariate analyses in six studies [26,32,33,39,40,45]. Four studies failed to demonstrate a significant association in univariate analysis [22,23,30,37], whereas the remaining study, a post-hoc analysis of five randomized placebo-controlled trials investigating the effects of pirfenidone, interferon-γ-1b, and the monoclonal antibody lebrikizumab, did not report a formal statistical analysis of the association between the BMI and one-year mortality [54].

Disease Exacerbation
Only one study reported significant associations between the baseline BMI and risk of disease exacerbation. Kondoh et al. observed an independent and positive association between the baseline BMI and risk of three-year exacerbations in 64 IPF patients [22]. In contrast, no significant associations were reported in the remaining 10 studies, including six retrospective studies and nine with a high risk of bias, all of which reported data from univariate analyses [23,25,27,28,31,34,37,41,46,55].

Disease Progression
Two studies reported a significant impact of the BMI on IPF progression. Fang et al. reported that patients exhibiting disease progression at one year had significantly lower baseline BMI values than those with stable disease. A significant association was also observed with the Kaplan-Meyer log-rank test using a cut-off of ≥25 kg/m 2 [42]. Similarly, in a post-hoc analysis of a randomized placebo-controlled trial investigating pirfenidone, Ikeda et al. observed that a lower baseline BMI was independently associated with one-year progression. Notably, this association was observed both in the placebo and pirfenidone groups [43]. In contrast, two studies failed to report a significant association with disease progression in univariate analyses [44,47]. In one study, while a significantly greater decline in FVC was observed in patients with BMI < 27 kg/m 2 , no significant BMI-related differences were reported with temporal changes in FVC (% predicted) and St. George's Respiratory Questionnaire [44]. In a further study, no formal statistical analysis was presented on the association between the baseline BMI and one-year disease progression [54].

Nintedanib Tolerance
Two Japanese studies investigated the potential influence of the BMI on the risk of early discontinuation of treatment with the antifibrotic drug nintedanib, with contrasting results. Ikeda et al. observed that lower baseline BMI values were significantly and independently associated with increased risk of discontinuation in 72 IPF patients [35]. In contrast, no significant association was observed between the baseline BMI and risk of early discontinuation after adjusting for FVC (% predicted) in the study by Uchida et al. involving 78 patients with IPF [51]. In another Japanese study, a BMI of <21.6 kg/m 2 was independently associated with a tenfold increase in the risk of developing nausea and a threefold increase in the risk of developing diarrhea during nintedanib treatment [36].

Other Clinical Outcomes
Two studies reported a negative association between the BMI at baseline and the risk of hospitalization. Kim et al. observed that a lower BMI was significantly and independently associated with a higher rate of respiratory-related hospitalizations within two years in 1002 IPF patients [48]. Similarly, Jouneau et al. reported that a lower BMI was independently associated with one-year hospitalization in 153 patients with IPF [53]. In another study by Jouneau et al., the associations between BMI tertiles and all-cause hospitalization at one year were not statistically assessed [54]. Finally, Nishimoto et al. reported that lower BMI values at baseline were independently associated with a statistically higher risk of pneumothorax in a retrospective study of 71 IPF patients. In this study, incident pneumothorax was independently associated with increased mortality after adjusting for age, sex, and FVC (% predicted) [32].

Discussion
In our systematic review, we identified 36 studies assessing the prognostic role of baseline and temporal changes in BMI values in IPF patients receiving a range of immunosuppressive and antifibrotic therapies. Whilst there is currently no evidence of a link between the BMI and a diagnosis of IPF, the available evidence suggests that this routinely assessed surrogate marker of body fatness is a promising predictor of mortality, disease progression, hospitalization, tolerability to specific antifibrotic treatments, and specific complications, i.e., pneumothorax, in this group. In particular, relatively low BMI values at baseline and/or greater temporal declines in BMI are associated with adverse clinical outcomes, barring the risk of disease exacerbation.
The BMI was first described by Quetelet, a Belgian scientist, as an anthropometric index in the nineteenth century under the denomination "social physics" [61]. Following the first publication under its current name in 1972 [62], the BMI has been extensively used in clinical practice and public health screening and intervention programs to categorize people as underweight (<18.5 kg/m 2 ), normal weight (≥18.5 and <25.0 kg/m 2 ), overweight (≥25.0 and <30.0 kg/m 2 ), and obese (≥30.0 kg/m 2 ). Although several experts have questioned the physiological significance of the BMI as a reliable indicator of adiposity and excess fat, its use has significantly contributed to the stratification of short-and long-term risks associated with key disease states, e.g., cardiovascular disease, diabetes, and several types of cancer, and to promote lifestyle interventions aimed at reducing this risk both individually and at the population level [15][16][17][18]63]. However, while the health risks associated with relatively higher BMI values are well established, an increasing number of studies over the last decade have reported that individuals with relatively higher BMI and specific overt disease states, e.g., heart failure and cancer, have a more favorable prognosis than those with lower BMI values [64,65]. This phenomenon, known as the "obesity paradox," has also been described in respiratory conditions such as chronic obstructive pulmonary disease [66,67]. One possible explanation for the putative protective effects of higher BMI values in these conditions and IPF is related to the inherent limitations of this index as a reliable measure of excess fat mass and adiposity. The formula used for its calculation (body weight in kg divided by height in m 2 ) does not take into consideration whether changes in body weight are secondary to changes of specific body composition compartments, e.g., fat mass vs. fat-free mass, and/or their distribution, e.g., visceral vs. subcutaneous adiposity [68,69]. Furthermore, a concomitant increase in fat mass (obesity) and a reduction in fat-free mass (sarcopenia) can occur in the same individual. This condition, also known as sarcopenic obesity, is associated with a worse prognosis in disease states such as heart failure and cancer [70][71][72]. Therefore, it is possible that a higher BMI in patients with IPF experiencing a more favorable prognosis is not primarily associated with an increase in fat mass, but rather with an increase in fat-free mass, e.g., muscle mass. This might lead to increased exercise tolerance and cardiorespiratory fitness through increased oxygen consumption via increased muscle diffusion, mitochondrial respiration capacity, and skeletal muscle strength, as already proposed in patients with heart failure [73,74]. This hypothesis is further supported by the results of studies reporting that lower skeletal muscle mass and strength are significantly associated with advanced disease and mortality in patients with IPF [75][76][77]. Furthermore, one study in our systematic review reported a significant and positive association between BMI and the cross-sectional area of elector spine muscles, an imaging parameter used to investigate sarcopenia and cachexia. However, no significant associations were reported with another parameter, muscle attenuation of elector spine muscles [33]. In another study, a significant and positive association was reported between the relative temporal decline in BMI and temporal reduction in the cross-sectional area of elector spine muscles in IPF patients [45]. Another possibility is that interplay between the BMI and clinical outcomes in patients with IPF is modulated by the coexistence of disease states, e.g., heart failure, where an inverse association between BMI values and adverse outcomes has been described [64]. However, this hypothesis requires further investigation as the presence of comorbidities was described in only nine of the studies identified in our systematic review [23,25,29,[40][41][42]49,52,53].
It is important to emphasize that several studies failed to report significant associations between the BMI and mortality [22,23,26,30,32,33,37,39,40,45,54] or disease progression [44,47]. Possible reasons for such discrepancies include between study differences in baseline patient characteristics, including severity of IPF, comorbidity burden, ethnicity, and specific treatment received. However, as previously mentioned, information regarding comorbidities was provided in a limited number of studies [23,25,29,[40][41][42]49,52,53]. More research is required to investigate possible differences in studies reporting negative findings and to determine whether the prognostic significance of the BMI varies across IPF subgroups.
Another intriguing observation is the possible reduced tolerance to the antifibrotic agent nintedanib in IPF patients with lower BMI reported in two of three studies [35,36,51]. This issue is clinically relevant as the early discontinuation of antifibrotic therapy is associated with worse outcomes in this group [78]. Nintedanib is a relatively fat-soluble drug with a large volume of distribution in humans [79,80]. Assuming that a lower BMI value is secondary, at least partly, to a reduced fat mass, the consequent reduction in the volume of distribution might theoretically lead to higher circulating concentrations of this agent. However, whether this phenomenon accounts for increased risk of toxicity and early treatment discontinuation deserves further study.
In order to establish the prognostic significance of the BMI in IPF, larger and appropriately designed prospective studies are warranted to confirm the findings of our review. Such trials should investigate the predictive capacity of the BMI, singly or in combination with other clinical characteristics and lung function parameters, in IPF patients with a wide range of clinical severity, comorbid status, sarcopenia, and immunosuppressive and antifibrotic treatments. The potential utility of combining the BMI with other parameters in prediction models was recently reported by Zinellu et al. in a study where the incorporation of BMI with 6MWD, FVC, and D LCO significantly increased the AUC for predicting four-year mortality [56].
The strengths of our systematic review include the assessment of a wide range of clinical endpoints as well as the association between the BMI and other relevant patient characteristics, including parameters of lung function and functional capacity. Furthermore, the selected studies investigated Asian, European, and North American patient populations, ensuring some degree of generalization of the findings, and the risk of bias was considered low in the majority of studies (20 out of 36). The limitations of our review include the lack of meta-analytical evaluation given the between study differences in the assessment of the BMI as a continuous variable or cut-off value, baseline variable vs. temporal changes, type of endpoint assessed, and the paucity of details regarding specific comorbidities, markers of muscle mass, and sarcopenia in most studies.

Conclusions
Our systematic review has shown that the BMI has the potential to be used as an easily measured and inexpensive predictive marker in IPF, particularly for mortality, disease progression, risk of hospitalization, and tolerability to specific therapies. However, prospective, accurately designed studies are warranted to convincingly demonstrate the prognostic utility of this anthropometric parameter and justify its widespread use in the routine management of patients with IPF.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm12020498/s1, Table S1: PRISMA 2020 abstract checklist; Table S2: PRISMA 2020 manuscript checklist.  Data Availability Statement: The datasets used and/or analyzed in this study are available from the corresponding author on reasonable request.

Conflicts of Interest:
The authors declare no conflict of interest.