Predicted Values for Spirometry may Underestimate Long-Standing Asthma Severity

INTRODUCTION

According to guidelines, symptom severity, short-acting bronchodilator usage, disease exacerbations in the previous month and pulmonary function level set asthma treatment. Especially when spirometry values are below the predicted value normal limit, patients should be treated regularly and therapy level might be increased when necessary. This concerns also asymptomatic patients with an airway obstruction to be considered as poorly controlled. In addition, a significant peak expiratory flow (PEF) reduction >20% and/or a FEV₁ decrease ≥12%, when compared to measurements performed days/weeks/months earlier, indicate significant lung function/asthma worsening and therefore a treatment step-up [1, 2]. However, asthma guidelines [1] do not suggest using slower/not easily detectable FEV₁ long-term decline to establish if lung function (and therefore asthma) worsened after several years despite a good asthma control. In fact, if FEV₁, checked after inhaling bronchodilator, is compared to previous measurements (effected at least 5 years earlier) [3] and if a FEV₁ change >30 ml/year or ≥15% is found, such decrease should be regarded as pathological (airway obstruction) [2, 3]. Significant long term FEV₁ reduction/decline measurements can be considered an indirect method for assessing bronchial wall thickening and disease progression [3]. However, FEV₁ changes may be mistaken for those occurring among repeated measurements [2, 4]. Therefore, we should evaluate them by comparing such FEV₁ changes with an at least five-year-old measurement, in order not to confuse deterioration due to remodeling with the above said lung function fluctuations [3]. We know that “declining” asthmatics, whose significant irreversible airways obstruction develops over time, are approximately 20-35% of asthmatic patients. This may also regard asthmatics with pulmonary function within the predicted normal range if their latest “normal” lung function is compared with an at least five-year-old higher measurement. This apparent “normality” is due to a yearly predicted reference reduction that may hide a possible lung function decline due to asthma, leading to an underestimation of airflow limitation [3, 5]. In fact, pulmonary function might be within the predicted normal range despite a significant lung function decline. The absence of symptoms in such patients might lead to an undervaluation of asthma severity [3]. This is why it may be important to compare the latest spirometry with at least a five-year-old one when managing asthma. Nowadays, we do not know how many “well controlled” long acting asthmatics, with apparent lung function normality, can actually show an accelerated FEV₁ decline, leading to an evaluation bias.

Recently, the Global Lungs Initiative (GLI) 2012 has made available spirometric prediction equations for the 3–95 age range, including appropriate age-dependent lower limits of normal [6-8]. Adopting GLI 2012 prediction equations will have little effect on the detection of obstructive patterns when compared to previous NHANES and ECSC/ERS equations.

On the basis of these considerations, objective of this study was to establish the number of subjects that showed a significant FEV₁ decline in a group of asthmatics with normal lung function in the latest assessment, according to GLI2012 references. Furthermore, we wanted to know the number of subjects with significant FEV₁ changes in time, taking as reference points the highest predicted values measured at 21 years for females and 23 for males, (when these references are higher) in order to calculate such decline.

RESULTS

In Table 1 are summarized spirometric measurements obtained in the three groups with low (<5%), medium (5-15%) and high (>15%) FEV₁ decline. Obviously, in groups with a greater lung function dceline, the oldest and latest parameters were different (Table 1). When we considered the highest predicted or older values as reference to calculate their FEV₁% and z-score, the first and the last measurements were similar in the group with a 5% FEV₁ long-term change, but not in the groups with 5-10% and >15% decrease (Table 1).

The time that separated the previous measurements from the latest ones were similar (8.3±1.5, 7.8±1.2 and 8.3±1.6 years in subjects with low, medium and high FEV₁ decline respectively). Also the time between the highest predicted and latest measurements was similar (Table 2). Obviously, the FEV₁ decline from the oldest value, both expressed in ml/year and percentage was different in the 3 groups (Table 2). Mean values of the highest predicted FEV₁ were 3.88±0.65, 3.73±0.56 and 3.9±0.7 liters in subjects with low, medium and high FEV₁ decline respectively. When the highest predicted FEV₁ was used as reference point, FEV₁ changes were different among three groups (Table 2). Physiological FEV₁ decline (calculated by the difference between the highest predicted FEV₁ and the predicted value of the latest measurement), both expressed in ml/year and percentage, were similar in all groups (Table 2).

Thirteen patients (28.3%; mean age: 50.1±10.1) highlighted a significant FEV₁ decline higher than 15% in comparison to an older FEV₁ (Fig. (1A)), even though their latest FEV₁ and FEV₁/VC were higher than the GLI2012 low limit of normality and their z-score > -1.5 (see Table 1 for mean values). The prevalence of subjects with long term FEV₁ decrease <5% were 14 (30.4%; mean age: 46.85±17), whereas those with FEV₁ 5-15% change resulted to be 19 (41.3%; mean age: 48.6±8.9) (Fig. (1A)). The prevalence of subjects with a decrease <30, 30-60 and >60 ml/year, calculated by the formula [(FEV_{1 previous} – FEV_{1 latest})/years], was 39, 37 and 24% respectively (Fig. (1B)). When the highest predicted value was used as reference point, and the reduction was corrected by subtracting the physiological decline, 6 (13%) patients showed a FEV₁ decrease higher than 15% (Fig. (2A)). Subjects with a FEV₁ change >30 ml/year, compared to the highest predicted values ([(FEV_{1 highest predicted} – FEV_{1 latest})/years]), were 17 (36.9%) (Fig. (2B)).

DISCUSSION

As highlighted by this study, approximately 28% of well-controlled asthmatics showed a significant FEV₁ decline (>15%) when compared to an approximately 8-year earlier measurement, despite their latest FEV₁ and FEV₁/VC (and z-scores) were normal, greater than the LLN (according to GLI2012). The percentage of subjects with “normal” lung function, but with a significant FEV₁ decline rose to 60% when a cut-off >30ml/year was used to define a pathological limit of long-term FEV₁ change [2, 3]. Therefore, this accelerated lung function deterioration might regard a remarkable number of subjects with “normal” pulmonary function that would remain undiagnosed without a comparison with a previous spirometry. Identification of “declining” asthmatics may indicate that they are either steroid-resistant or inadequately treated because they are either under-perceivers or poorly adherent to therapy. They may also be unable to use devices properly or have an inadequate lifestyle. We should also consider greater noxious environmental exposure (allergens, smoking habits, working exposure, air pollution, etc.) and other associated diseases (rhinitis, gastro-esophageal reflux, etc.) that may influence lung function deterioration [3].

The three different FEV₁ decline levels identified in this population of treated long-standing asthmatics are perfectly in line with what was found in another study conducted on asthmatics assessed after 5, 10 and 15 years [9], that showed a FEV₁ decline of <60 ml and >60 ml in 35–60% and 20–35% of patients respectively, whereas no change were observed in 10–25% of them. These different severities of FEV₁ decline may identify distinct asthma phenotypes with dissimilar responses to anti-inflammatory therapies. In fact, different levels of lung function decline may be simply due to diverse inflammatory patterns characterizing asthmatics: Th2, Th2/17 and Th17. These phenotypes may have no/scarce, moderate and severe FEV₁ decline respectively, that may be associated with an inverse response to anti-inflammatory treatment [10, 11]. Therefore, it is also likely that a different severity of decline (mild–moderate or severe), in well treated asthmatics, may be a marker that would allow identifying ‘responsive’ and ‘non-responsive’ subjects to treatment and therefore those with more severe asthma.

As already stated, according to this study, a latest measured value within normal range of references (>LLN) may lead us to an incorrect evaluation of long-standing asthmatics. In fact, such “normal” values might lead to an underestimation of bronchial obstruction and therefore asthma severity, if we do not make a comparison with an at least 5-year-old spirometry. This apparent normality is due to the annual physiological reduction of normal range references (including the ones proposed by GLI2012) [6-8] that may hide a significant lung function decrease in time. In fact, normal predicted values and low limit of normal (LLN) increase until the age of 21-23 and then decrease in the following years, even though height (used to calculate predicted values) remains unchanged [6-8]. This progressive reference value reduction with age may conceal a significant functional deterioration due to asthma airway remodeling. Besides, low limit of normal (LLN) (also decreasing with age) may be lower than the predicted value of approximately 20% or more (700-800 ml). Such a large normality range may falsely lead to consider a low (but higher than LLN) FEV₁ measured value as normal, in case we have no past functional reference measurements. Consequently, percentage values calculated from the predicted and their z scores, obtained in two measurements effected at a distance of years, may be approximately similar and higher than LLN values, which consequently result normal. Changes in predicted values may be excessive for some asthmatics over the course of time: lung function was and remained normal despite its significant decline in time. Therefore, asthma-induced lung function decline may be unchecked if it is higher than the physiological reduction of predicted lower limit of normality. This may regard especially younger subjects showing high lung function values at asthma onset, much higher than normal references, and that during the following years are characterized by a moderate asthma FEV₁ decline (between 30-80 ml/year). Their predicted and LLN values may be unable to detect these significant variations occurring during a long period of time, as it has been observed in some patients in this study. An early decrease of normal predicted and LLN values, starting after 21-23 years of age, might explain such erroneous assessment. In our opinion, reference values should begin to decrease later. Likely, such values should reach their peak at the above said age (due to growth). Later, we suppose they should remain constant in time (at least in some subjects to be identified) or decrease more slowly until the age of 35 (or later) and then begin to decrease physiologically. In fact, observing the distribution of healthy subjects with normal/high values of pulmonary function, we can see that this remains unchanged in a remarkable number of 20-40 age-bracket individuals [7]. Therefore, not all subjects seem to show a physiological lung function decline during youth. Even asthmatics may not report any lung function deterioration. In fact, approximately 30% of our asthmatics showed that their lung function remains unchanged in time, when compared to older measurement. Furthermore, several factors may influence loss in pulmonary function which is not evaluated in healthy subjects taken into consideration for population lung function references. For example, air pollution, workplace exposure, fat diet and obesity can affect lung function decline [3]. In addition, the presence of most respiratory diseases was excluded only by a questionnaire during the recruitment of reference population samples. In fact, also other respiratory diseases (COPD, interstitial diseases, and occupational exposure damages) can show lung function deterioration in time.

Often, when we manage long-standing asthmatics, we might not have an old spirometry and therefore we might not have a reference point to calculate FEV₁ decline. The “highest predicted FEV₁ value” (measured at 21 years for females and 23 years for males) may be a valid alternative, as a fixed point of reference, instead of a previous FEV₁ value”. In fact, using this reference point, reduced by subtracting the physiological change in time, (i.e. [(FEV_{1 highest predicted} – FEV_{1 latest}) – (FEV_{1 highest predicted} – FEV_{1 latest predicted}) / FEV_{1 highest predicted}]*100) we found that 6 (13%) patients showed a significant FEV₁ decline (higher than 15%) showing that these patients were really affected by airway obstruction. Subjects with an accelerated lung function decline became 17 (36.9%) in case we used a FEV₁ change in time >30 ml/year (compared to the highest predicted) as a significant long-term decrease cut-off. If we had these long-term changes available on each spirometry (automatically calculated), we could have reference values that might allow considering asthma airway remodeling on lung function. A fixed reference point could therefore permit to calculate FEV₁ decline (to be shown in spirometry reports) which may improve asthma monitoring and give spirometry a different role. Fixed “highest” values, taken as reference values, may give a “dynamic” vision in time, whereas “FEV₁ predicted value”, reducing with age, gives only a “static” asthma evaluation only at a specific moment in time.

We retain that FEV₁ decline should always be considered because it allows evaluating the real impact of asthma on long-standing asthmatics more correctly, otherwise they would be erroneously considered as well controlled. This evaluation of pulmonary function decline is currently performed for workers with the purpose of screening possible pulmonary damages caused by occupational exposure (asbestos, coke oven emissions, cadmium, cotton dust, benzene, formaldehyde etc) [5]. Since asthma is due to allergen-exposure causing inflammation-induced airway remodeling [1, 3], and thus lung function decline, a long-term monitoring should be also considered in asthma, in order to establish treatment efficacy, despite a good symptom control [3]. Therefore, as already stated, despite a good symptom control, identifying declining asthmatics may allow us to make some treatment adjustments, i.e. improving adherence and /or increasing inhaled corticosteroid doses when they are particularly low. In fact, long-term clinical trials have shown that inhaled corticosteroids can slow down lung function decline in asthma [12-16]. In particular, an early treatment with inhaled corticosteroids can reduce FEV₁ loss more significantly [12, 16]. Furthermore, it may be advisable to reduce harmful environmental exposure and improve lifestyle in order to contrast lung function deterioration in time [3]. In fact, some studies have shown that weight reduction may be beneficial on asthma outcomes and above on all lung function decline [17, 18].

However, it must be underlined that, when evaluating changes between two measurements (at a distance of several years), variability of FEV₁ in repeated measurements should be considered [2-4]. Therefore, it is advisable to calculate FEV₁ decline considering the FEV₁ values obtained after using a bronchodilator. Furthermore, lung function decline evaluation should be supported by some intermediate, progressively decreasing measurements (between the first and the last spirometries) in order to confirm deterioration in time.

CONCLUSION

In approximately 28% of asymptomatic long-standing asthmatics, if their latest lung functional value within reference normal range is compared with one at least 5 years older, we can see a significant pulmonary function decline (>15%). The apparent “normality” of the latest measurement may lead us to an underestimation of asthma severity in these asthmatics. This bias is due to a physiological reduction of reference values for spirometry with age that can hide an asthma-induced lung function decline (remodeling). The highest predicted value obtained at the age of 21 years for females and 23 years for males may be used as fixed reference point, alternatively to a previous FEV₁ measured at least five years earlier, to calculate FEV₁ decline. In subjects with “normal” lung function, availability of the FEV₁ decline measurement on the report of spirometry, either from previous or from the highest predicted values, may allow us to see how severe their asthma is despite the absence of symptoms and, consequently, lead to a better disease management. Obviously, further studies should be necessary to validate this approach to asthma.

REFERENCES