Variation in lung function and clinical aspects in adults with cystic fibrosis

TO THE EDITOR:

An important marker for monitoring disease progression is FEV₁, which is considered the single most important predictor of life expectancy in individuals with cystic fibrosis (CF).^1,2 The coefficient of variation (CoV) for FEV₁ has been studied in individuals with CF to investigate its relationship with treatment adherence, clinical outcomes, exacerbations, and hospitalizations, as well as a predictor of future decline in FEV₁ and of future reduction of functional capacity.^3-5 One study⁵ reported that patients who had a variation in FEV₁ ≥ 10% in one year had a worse rate of decline in FEV₁ in the next two years.

The present study aimed to assess the relationship between CoV for FEV₁ and the number of days of hospitalization for adult individuals with CF. Secondarily, the relationship of CoV for FEV₁ with the number of pulmonary exacerbations and performance in the six-minute walk test (6MWT) was also assessed.

This was a retrospective cohort study, conducted under the auspices of the Adult CF Program at the Hospital de Clínicas de Porto Alegre (HCPA), in the city of Porto Alegre, Brazil, over a period of one year (from January to December of 2019). Inclusion criteria were individuals ≥ 18 years of age with a confirmed diagnosis of CF, being regularly monitored at the adult CF outpatient clinic at least three times a year and having undergone at least three spirometry tests at three-month intervals.

Clinical and demographic data were extracted from electronic medical records from HCPA. Data on the following variables were recorded at the entry date in the study: BMI, sputum bacteriology, number of exacerbations in the last year, number of hospitalizations in the last year, length of hospital stay (days), 6MWT results, and spirometric parameters. The number of respiratory exacerbations was recorded by determining the number of hospital admissions due to exacerbations and the frequency of oral antibiotic use.

Spirometry was performed in accordance with Brazilian guidelines.⁶ The variables compiled were FEV₁, FVC and FEV₁/FVC expressed in liters and percentages of predicted values.⁶ The highest and lowest FEV₁ values obtained within the study period were extracted, and CoV was calculated as the ratio of standard deviation to the mean for each subject individually and expressed as a proportion.

The 6MWT was performed at the HCPA Pulmonary Physiology Unit in accordance with international guidelines.⁷ The distance walked on the 6MWT (6MWD) was expressed in meters and in percentage of predicted values.⁸ The presence of chronic infection with Staphylococcus aureus, Pseudomonas aeruginosa, or Burkholderia cepacia was recorded. Chronic bacterial infection was defined as three or more positive bacterial isolates during the previous 12 months.

For analysis purposes, subjects were classified into two groups according to CoV for FEV₁: CoV for FEV₁ < 10% and CoV for FEV₁ ≥ 10%. The correlations between CoV for FEV₁ and other variables were analyzed using Spearman’s correlation coefficient. Categorical variables were compared between the groups using the chi-square test, and data were expressed as number of cases.

The electronic medical records of 58 patients who attended the HCPA Adult CF Program during the study period were evaluated, and 47 were considered eligible and included in the study. The remaining 11 patients were excluded because of incomplete records. In the final sample, 20 and 27 patients were male and female, respectively, with a median age of 27 years and a mean BMI of 21.3 kg/m². Mean FEV₁ was 47% of the predicted value, and mean 6MWD was 81% of the predicted value. The median numbers for exacerbations and hospitalizations within a year were 2 and 1, respectively. Regarding the CoV groups, 28 (59.5%) and 19 (40.5%) of the subjects were allocated to the FEV₁ ≥ 10% and FEV₁ < 10% groups, respectively. The comparisons between the two groups are shown in Table 1.

Table 1
General characteristics of adult subjects with cystic fibrosis according to the coefficient of variation for FEV₁.^a,b

Variable	Overall sample	Group		p
		CoV for FEV1 ≥ 10%	CoV for FEV1 < 10%
	(n = 47)	(n = 28)	(n = 19)
Sex, n (%)				0.514
Male	20 (42,5)	13 (46.4)	7 (36.8)
Female	27 (57.5)	15 (53.5)	12 (63.1)
Age, years	27 (10)	25 (10)	27.5 (12)	0.185
Age at diagnosis, years	3 (10.8)	3 (8.5)	2 (10.8)	0.752
BMI, kg/m2	21.3 ± 3	20.4 ± 2.7	22.0 ± 3.1	0.068
Exacerbations/year	2 (3)	4 (3)	2 (3)	0.007
Oral antibiotics, cycles/year	2 (3)	4 (4)	2 (3)	0.003
Oral antibiotics, days/year	35 (37)	42 (51)	21 (28)	0.026
Hospitalizations/year	1 (2)	2 (2)	0 (2)	0.003
Hospitalizations, days/year	15 (38)	27 (30)	0 (24)	0.002
6MWD, m	525 (111)	475 (83)	536 (87)	0.009
6MWD, % predicted	81.2 (15.1)	76.4 (15.3)	84.1 (14.2)	0.018
SpO2 at the end of the 6MWT, %	94 (4)	93 (10)	95 (5)	0.031
Best spirometric results within a year
FEV1, L	1.78 (1.0)	1.47 (0.9)	1.91 (1.5)	0.135
FEV1, % predicted	46.90 (2.9)	45 (30.2)	48 (33.6)	0.274
FVC, L	2.69 (1.84)	2.05 (1.6)	2.97 (1.7)	0.031
FVC, % predicted	68.6 ± 24.7	63.7 ± 29.6	72.8 ± 20.4	0.220
FEV1 /FVC	68.3 + 12.2	68.7+ 10.6	65.1 + 13.1	0.220
FEV1 /FVC, % predicted	78 ± 14.6	80.3 ± 11.8	75.5 ± 16.2	0.256
Bacteriology, n (%)
MSSA	32 (68)	13 (46.4)	19 (100)	0.968
MRSA	7 (14.9)	3 (10.7)	4 (21)	0.887
Pseudomonas aeruginosa	32 (68)	15 (53.7)	17 (89.5)	0.188
Burkholderia cepacia	12 (25.5)	5 (17.8)	7 (36.8)	0.919

• CoV: coefficient of variation; 6MWD: six-minute walk distance; 6MWT: six-minute walk test; MSSA: methicillin-sensitive Staphylococcus aureus; and MRSA: methicillin-resistant Staphylococcus aureus. ^aValues expressed as mean ± SD (normal distribution) or median (IQR) for non-normal distribution, except where otherwise indicated. ^bOnly the best spirometric results were used in the calculations.

There were no statistically significant correlations of CoV for FEV₁ with age at diagnosis and sputum bacteriology. There were statistically significant correlations of CoV for FEV₁ with age (ρ = −0.358; p = 0.013); BMI (ρ = −0.423; p = 0.003); total number of exacerbations within a year (ρ = 0.345; p = 0.018); number of days of oral antibiotic use within a year (ρ = 0.356; p = 0.014); length of hospital stay in days within a year (ρ = 0.386; p = 0.007); 6MWD in % of the predicted value (ρ = −0.359; p = 0.013); and SpO₂ at the end of the 6MWT (ρ = −0.330; p = 0.024).

In this study, CoV for FEV₁ ≥ 10%, in comparison with CoV for FEV₁ < 10%, was related to a greater number of hospitalizations; that is, a greater number of pulmonary exacerbations and a greater number of days of oral or intravenous antibiotic use throughout the year. The findings are in agreement with those of Heinzmman-Filho et al.,⁵ who identified a significant relationship between variations in pulmonary function and the number of hospitalizations. Also, there was a relationship between that variation in one year and a higher number of hospitalizations in the two subsequent years.

In general, regular monitoring of pulmonary function in individuals with CF during outpatient visits is essential for establishing early and aggressive treatment of pulmonary exacerbations, seeking to avoid huge variations over time and ensuring greater disease stability.⁹ In this context, CoV for FEV₁ presents itself as a valid tool for monitoring the abrupt decline of lung function and progression of the disease in individuals with CF.

The retrospective nature of the present study, the small number of participants, the lack of assessment of adherence to treatment, and the unavailability of other, more sophisticated, tests, such as imaging tests and the lung clearance index, are some of the limitations of the study. Another important limitation is that only FEV₁ was used for the prognostic evaluation of hospitalizations and pulmonary exacerbations.

In conclusion, our findings suggest that a CoV for FEV₁ ≥ 10% over a year is associated with a greater number of exacerbations and hospitalizations in adult individuals with CF. The use of CoV for FEV₁ can benefit the screening and monitoring of disease progression in this population.

REFERENCES

• ¹
  Breuer O, Caudri D, Stick S, Turkovic L. Predicting disease progression in cystic fibrosis. Expert Rev Respir Med. 2018;12(11):905-917. https://doi.org/10.1080/17476348.2018.1519400
  » https://doi.org/10.1080/17476348.2018.1519400
• ²
  Taylor-Robinson D, Whitehead M, Diderichsen F, Olesen HV, Pressler T, Smyth RL, et al. Understanding the natural progression in %FEV1 decline in patients with cystic fibrosis: a longitudinal study. Thorax. 2012;67(10):860-866. https://doi.org/10.1136/thoraxjnl-2011-200953
  » https://doi.org/10.1136/thoraxjnl-2011-200953
• ³
  White H, Shaw N, Denman S, Pollard K, Wynne S, Peckham DG. Variation in lung function as a marker of adherence to oral and inhaled medication in cystic fibrosis. Eur Respir J. 2017;49(3):1600987. https://doi.org/10.1183/13993003.00987-2016
  » https://doi.org/10.1183/13993003.00987-2016
• ⁴
  Morgan WJ, VanDevanter DR, Pasta DJ, Foreman AJ, Wagener JS, Konstan MW; et al. Forced Expiratory Volume in 1 Second Variability Helps Identify Patients with Cystic Fibrosis at Risk of Greater Loss of Lung Function [published correction appears in J Pediatr. 2018 Jun;197:322]. J Pediatr. 2016;169:116-21.e2. https://doi.org/10.1016/j.jpeds.2015.08.042
  » https://doi.org/10.1016/j.jpeds.2015.08.042
• ⁵
  Heinzmann-Filho JP, Pinto LA, Marostica PJ, Donadio MV. Variation in lung function is associated with worse clinical outcomes in cystic fibrosis. J Bras Pneumol. 2015;41(6):509-515. https://doi.org/10.1590/s1806-37562015000000006
  » https://doi.org/10.1590/s1806-37562015000000006
• ⁶
  Sociedade Brasileira de Pneumologia e Tisiologia (SBPT). Diretrizes para testes de função pulmonar. J Bras Pneumol. 2002;28(Suppl 3):S1 S238.
• ⁷
  Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, et al. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014;44(6):1428-1446. https://doi.org/10.1183/09031936.00150314
  » https://doi.org/10.1183/09031936.00150314
• ⁸
  Soares MR, Pereira CA. Six-minute walk test: reference values for healthy adults in Brazil. J Bras Pneumol. 2011;37(5):576-583. https://doi.org/10.1590/S1806-37132011000500003
  » https://doi.org/10.1590/S1806-37132011000500003
• ⁹
  Eakin MN, Riekert KA. The impact of medication adherence on lung health outcomes in cystic fibrosis. Curr Opin Pulm Med. 2013;19(6):687-691. https://doi.org/10.1097/MCP.0b013e3283659f45
  » https://doi.org/10.1097/MCP.0b013e3283659f45

• FINANCIAL SUPPORT

  This study received financial support from the Fundo de Incentivo à Pesquisa (FIPE, Research Incentive Fund) of the HCPA (Protocol no. 2018-0459).

Publication Dates

• Publication in this collection
  25 July 2022
• Date of issue
  2022