Current Knowledge of Asthma-COPD Overlap (ACO) Genetic Risk Factors, Characteristics, and Prognosis

Abstract

Asthma-COPD overlap (ACO) is a newly identified phenotype of chronic obstructive airway diseases with shared asthma and COPD features. Patients with ACO are poorly defined, and some evidence suggests that they have worse health outcomes and greater disease burden than patients with COPD or asthma. Generally, there is no evidence-based and universal definition for ACO; several consensus documents have provided various descriptions of the phenotype. In addition, the mechanisms underlying the development of ACO are not fully understood. Whether ACO is a distinct clinical entity with its particular discrete genetic determinant different from asthma and COPD alone or an intermediate phenotype with overlapping genetic markers within asthma and COPD spectrum of obstructive airway disease remains unproven. This review summarizes the current knowledge of the genetic risk factors, characteristics, and prognosis of ACO.

Keywords:

• Asthma-COPD overlap
• genetic risk factors
• single nucleotide polymorphisms
• prognosis

Introduction

Asthma and chronic obstructive pulmonary disease overlap (Asthma-COPD overlap (ACO)) is an obstructive airway disease with a clinical presentation of features usually associated with both asthma and COPD [1]. Studies have shown that patients with ACO present with more frequent airflow obstruction symptoms, more exacerbation, lower quality of life, recurrent hospitalization, and more medical utilization than patients with COPD or asthma alone [2–5]. Alshabanat et al. [6] reported in a meta-analysis of 13 included studies a pooled ACO prevalence of 27% and 28% amongst COPD patients from general population-based and hospital-based studies, respectively. ACO patients were significantly younger, had a higher body mass index, increased healthcare utilization, and lower health-related quality of life than patients with COPD alone [6]. In 2019, the global prevalence of ACO was reported to be 2% in the general population [7]. In the same report, 26.5% and 29.6% of ACO patients were found in patients with previous diagnoses of asthma and COPD alone, respectively [7]. However, the prevalence of ACO was contingent upon the diagnostic criteria, definition, and management modalities applied in the various studies included in the reviews. Definitive treatment of asthma-COPD overlap is challenging because of clinical data’s paucity from randomized controlled trials explicitly addressing treatment regimens for patients with overlap phenotype. Most COPD clinical trials generally exclude patients with asthmatic history, and most asthma clinical trials exclude patients with a past diagnosis of COPD or significant smoking history [1,8].

Genetics plays a crucial role in developing obstructive airway diseases. Many genetic variants associated with asthma and COPD alone have been identified from genetic association studies [9–11]. The identification and recognition of genetic variants are important in understanding the underlying pathogenesis of diseases. In a recent review, Hall et al. [9] described remarkable advances made through genome-wide association studies in identifying genetic risk factors associated with asthma and COPD. Genetic loci of more than 58 genes, including CHRNA3/CHRNA5/IREB2, RIN3, MMP12, TGFB2, HHIP FAM13A, CYP2A6, MTCL1, SFTPD, SNRPF, PPT2, and AGER, have been associated with COPD [12,13]. Likewise, loci of more than 108 genes (e.g., IL2RB, HLA-DQ, IL18R1, IL33, SMAD3, ORMDL3/GSDMB) have been associated with asthma [13–16]. However, few genetic association studies have been carried out to investigate genetic variants associated with asthma-COPD overlap [17–19]. Several other studies have recently investigated potential metabolomic profiles, specific immunological mediators, and inflammatory pathways for ACO compared to asthma and COPD alone [20–33]. This review’s primary focus is to: (1) present our current knowledge of ACO on definition, genetic risk factors, clinical characteristics, and prognosis; (2) highlight areas that require further research, specifically in areas that would enable the discovery of genetic variants and other underlying biological mechanisms contributing to ACO development and inform the establishment of novel treatment modalities.

Description and definition of asthma-COPD overlap

The definition of ACO varied between studies which restricts the comparison of results from different studies. Many population-based studies defined ACO as irreversible airflow obstruction (post-bronchodilator FEV₁/FVC < 70%) with a combination of physician-diagnosed asthma or self-reported physician diagnosis of asthma or self-reported history of asthma or asthmatic symptoms and bronchodilator reversibility [2,6,17,19,34–56]. Currently, there is no validated definition for asthma-COPD overlap. However, various consensus documents have been proposed to address the issue for better characterization of the “overlap phenotype” [1,8,57]. The common similarity amongst the existing consensus documents is that the phenotypic term “asthma-COPD overlap” does not represent a single disease entity. These descriptive consensus documents, for operational purposes, serve the onerous objective of distinguishing the overlap phenotype from the classical definition of asthma or COPD alone.

The 2017 updated collaboration between GINA and GOLD project described “asthma-COPD overlap” as persistent airflow limitation with several diagnostic features associated with asthma and several features associated with COPD. According to the joint consensus document, ACO is identified by having an equal number of features from a checklist with both asthma and COPD syndromic characteristics. In addition to syndromic attributes, spirometric peculiarities of asthma, COPD and ACO are also included. Some of the diagnostic indicators proffered by the GINA/GOLD statement were: (1) a persistent yet reversible airflow limitation described as post-bronchodilator forced expiratory volume in one second to forced vital capacity ratio (FEV₁/FVC) less than 0.7; (2) a marked reversibility post-bronchodilator FEV₁ increase greater than 12% and 400 mL from baseline; (3) a history of asthma diagnosed by a doctor, atopy, allergies, or exposure to noxious agents; (4) presence of either sputum neutrophilia or eosinophilia; (5) an age of onset of 40 years or older. However, the GINA and GOLD joint document’s objectives were not to serve as a definition but rather to help clinicians identify, differentiate ACO from asthma and COPD, and make an interim clinical judgment on the best initial treatment [1].

In 2017 Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), through a joint effort of the Spanish COPD Guidelines (GesEPOC) and the Spanish Guidelines on the Management of Asthma (GEMA), developed a consensus document regarded as the unified criteria for defining and diagnosing ACO [57]. The definition of ACO was established based on the simultaneous existence of three factors: (1) chronic persistent airflow limitation; (2) significant current and past smoking history; (3) previous diagnosis of asthma (according to GEMA criteria) [58]. However, to confirm the diagnosis of ACO, these three essential factors apply to patients who are 35 years or older, with a current and past smoking history of at least ten pack-years, and confirmed post-bronchodilator forced expiratory volume in one second to a forced vital capacity ratio that is < 0.7 even after treatment with bronchodilators and inhaled corticosteroids. The unified consensus document further proposed that if an asthma diagnosis cannot be confirmed, ACO diagnosis will be established if positive bronchodilator response is substantial (FEV₁≥15% and ≥400 mL from baseline) and an elevated blood eosinophil count is ≥300 eosinophils/L [57].

While the SEPAR unified consensus document for defining and diagnosing ACO has marked similarities with the 2017 GINA AND GOLD updated joint statement, there are apparent dissimilarities. A discrepancy exists in the age of onset in both consensus documents. While the age of onset for asthma-COPD overlap in the SEPAR document was reported as ≥ 35 years, the GINA and GOLD joint statement described this reference age as ≥ 40 years. Furthermore, there was a contrasting criterion for marked reversibility. In the GINA and GOLD statement, marked reversibility was regarded as a Post bronchodilator increase in FEV₁ > 12% and 400 mL from baseline, a value divergent from the SEPAR guideline’s reversibility test reference value (FEV₁≥15% and ≥400 mL from baseline). An additional distinguishing diagnostic factor in the proposed systems is the inclusion of current and previous smoking history in the SEPAR guidelines as an essential element in ACO definition. Nonetheless, the input of environmental exposures (smoking) was not categorically expressed in the GINA/GOLD statement.

In a round table agreement held between 2015 and 2016, a committee of experts recommended using major and minor criteria to define and identify asthma-COPD overlap [8]. The committee suggested that patients who satisfy all three major criteria and at least one minor criterion be considered for an ACO diagnosis (Table 1).

Table 1. Criteria for ACO definition of ACO [8].

Major criteria	Persistent airflow limitation (post-BD FEV1 /FVC < 0.70 or LLN) in individuals 40 years of age or older. At least ten pack-years of tobacco smoking or indoor or outdoor air exposure to pollutants Asthma history prior to 40 years of age or BDR of > 400 mL in FEV1
Minor criteria	Documented history of atopy or allergic rhinitis BDR ≥ 200 mL and 12% in FEV1 from baseline values on two or more visits Peripheral blood eosinophil count ≥300 cells·uL^−1

LLN: Lower limit of normal; post-BD: post-bronchodilator; BDR: Bronchodilator response; FEV₁: Forced expiratory volume in 1 s; FVC: Forced vital capacity.

Despite the heterogeneity and subtle limitations in proposed descriptive and diagnostic consensus statements, the documents currently serve as a provisional clinical recommendation for efficacious and safety-centered treatment of patients with asthma-COPD overlap. Nevertheless, it does not invalidate the need for evidence-based recommendations that will inform specific diagnostic criteria, clinical practice, and homogeneity of inclusion definition of overlap patients in future epidemiological studies.

Genetic risk factors of asthma COPD overlap

Asthma and chronic obstructive pulmonary disease are heterogeneous complex entities that generally involve many genetic and environmental risk factors. Heterogenous genetic risk factors play intrinsic roles in the development of obstructive airway diseases. Many genomic loci that influence asthma and COPD susceptibility have been discovered through family-based, candidate, and genome-wide association studies [9–12,14,16,59–61]. However, no family base-genetic studies have been carried out on ACO. Furthermore, those genetic variants identified through genome-wide association studies cannot account for the heritability of asthma and COPD. In a genome-wide association study of 15,256 cases and 47,936 controls, Hobbs et al. [59] identified a genetic correlation of 0.38 (p value 6.25 × 10⁻⁵) between asthma and COPD in European ancestry subjects. None of the genome-wide significant loci for COPD overlapped with known loci for asthma and asthma-associated traits in this study.

In a similar GWAS of 35,735 cases and 222,076 controls, Sakornsakolpat and colleagues [62] investigated genetic overlap using identified GWAS-associated loci for COPD and previous GWAS results in asthmatic subjects of European ancestry. The authors identified genetic segments near ADAM19, ARMC2, ELAVL2, and STAT6 shared by asthma and COPD. The discrepancy observed between the Hobbs et al. [59] and Sakornsakolpat et al. [62] studies could result from the differences in sample size and lack of considering many environmental factors. Notwithstanding, genome-wide association studies have not explicitly identified overlapping genetic loci for asthma and COPD. These could, to a reasonable extent, suggest the distinctness in the pathogenesis of both diseases. It is unclear whether specific genetic determinants associated with asthma-COPD overlap alone will be demonstrated in GWAS studies or if asthma-COPD overlap will share genetic variants with previously identified asthma and COPD GWAS-associated loci.

In a GWAS investigating genetic features of ACO in Non-Hispanic white and African Americans by comparing 450 patients with ACO and 3120 COPD patients, Hardin et al. identified rs11779254 in the CSMD1 gene and rs59569785 in the SOX5 gene on chromosomes 8 and 12, which are located in an intronic region as top hits nearing genome-wide significance of 5 × 10⁻⁸ for ACO compared to COPD patients in the Non-Hispanic white population [17]. CSMD1 gene is a tumor suppressor that is important in lung squamous cell carcinomas [63]. Furthermore, variants near the CSMD1 gene were amongst the top hits associated with qualitative emphysema in a previous genome-wide association study[64]. SOX5 gene has been previously reported to be associated with COPD. Further investigation in a mouse model (SOX5 gene knocked out) demonstrated impaired embryonic lung development [65].

Also, a SNP (rs2686829) in PKD1L1 gene on chromosome 7 approached the genome-wide significance threshold in the African American cohort [17]. The top hit SNPs from the Non-Hispanic white cohort associated with asthma-COPD overlap were not replicated in the African American population and vice versa. Further analysis in a meta-analysis combining the Non-Hispanic white and African American cohorts identified the most significant variant, rs6574978, in the GPR65 (G Protein-Coupled Receptor 65) gene on chromosome 14 (p = 1.18 × 10⁻⁷) for ACO compared to COPD subjects [17]. However, none of the top hits reached the pre-specified genome-wide significant threshold of 5 × 10⁻⁸. Kottyan and colleagues [66] demonstrated that GPR65 has increased expression on eosinophils and asthmatic inflammation and showed that GPR65 knock-out mice had decreased airway eosinophilia.

Smolonska et al. [18] reported three loci associated with both asthma and COPD alone from a meta-analysis and replication in nine independent cohorts. SNPs (rs1477253) in DEAD-box polypeptide 1 (DDX1), (rs254149) in COMM domain containing 10 (COMMD10) and (rs9534578) in guanine nucleotide-binding protein, gamma 5 pseudogene 5 (GNG5P5) in chromosomes 2p24.3, 5q23.1, and 13q14.2, respectively, were identified. Only SNP (rs9534578) in GNG5P5 reached the genome-wide significance threshold after first phase replication and meta-analysis in 2 cohorts (p value 9.96 × 10⁻⁹). However, None of the SNPs attained the genome-wide significance threshold in subsequent replication studies using seven other independent cohorts [18].

As shown in Table 2, in a GWAS where asthma patients were compared with asthma-COPD overlap; No overlap was observed at the genome-wide significant threshold of 5 × 10⁻⁸ among the top ten SNPs associated with ACO compared to asthma alone [19]. In comparing ACO and normal subjects, three of the top ten SNPs (rs35614679, rs1677005, and rs1786253) associated with ACO were located in the intronic and downstream region of the TAF4B gene on chromosome 18. At the same time, five of the top ten SNPs (rs117733692, rs3772010, rs4601609, rs2149063, and rs34186721) were also located in the intronic region near MSRA, RNF144A, LINC01135, GPC5, and RAD51B) genes, respectively. Two SNPs (rs11665213 and rs12336157) located on chromosomes 18 and 9 from Kwon et al. study [19] had no gene-based annotation information.

Table 2. SNPs identified through Genome-wide association study for asthma-COPD overlap.

Study	SNPs	Chr	Gene/nearest gene	Allele MA or R.A.*	p value
Hardin et al. [17]	rs6574978	14	GPR65	T*	1.18 × 10^−7
	rs8004567	14	GPR65	A*	1.18 × 10^−7
	rs1441809	14	GPR65	A*	1.58 × 10^−7
	rs3759712	14	GALC	C*	1.80 × 10^−7
	rs2686829	7	PKD1L1	T	4.03 × 10^−7
	rs11779254	8	CSMDI	G	1.57 × 10^−6
	rs59569785	12	SOX5	C	1.61 × 10^−6
Smolonska et al. [18]	rs1477253	2	DDX1	T	7.28 × 10^−6
	rs254149	5	COMMD10	G	9.76 × 10^−6
	rs9534578	13	GNG5P5	A	9.96 × 10^−9
Kwon et al. [19]	rs117733692‡	8	MSRA	A	1.45 × 10^−5
	rs3772010‡	2	RNF144A	C	3.14 × 10^−6
	rs11665213‡	18	NR	T	7.12 × 10^−6
	rs1677005‡	18	TAF4B	C	8.40 × 10^−6
	rs35614679‡	18	TAF4B	A	8.46 × 10^−6
	rs4601609‡	1	LINC01135	C	9.69 × 10^−6
	rs2149063‡	13	GPC5	C	1.17 × 10^−5
	rs1786253‡	18	TAF4B	G	1.46 × 10^−5
	rs12336157‡	9	NR	G	1.96 × 10^−5
	rs34186721‡	14	RAD51B	A	2.06 × 10^−5
	rs11665213**	18	NR	T	1.15 × 10^−5
	rs7967352**	12	NR	G	1.23 × 10^−5
	rs1046706**	3	SLC9A9	T	1.31 × 10^−5
	rs78276030*	6	NR	G	1.93 × 10^−5
	rs8115801**	20	PAK7	T	2.02 × 10^−5
	rs7732758**	5	LHFPL2	C	2.15 × 10^−5
	rs4773144**	13	COL4A2	G	2.53 × 10^−5
	rs35614679**	18	TAF4B	A	3.17 × 10^−5
	rs6837266**	4	ATP10D	C	3.22 × 10^−5
	rs1786253**	18	TAF4B	G	3.52 × 10^−5

SNPs: Single nucleotide polymorphisms; Chr: Chromosome; MA: Minor allele; *RA: Reference allele; **SNPs associated with ACO compared to asthma; ‡SNPs associated ACO compared to normal subjects; NR: Not reported.

Most recently, In a published conference abstract, Joo et al. carried out a GWAS using data from the UK biobank to identify genetic variants associated with asthma-COPD overlap (ACO) and investigate whether genetic loci associated with ACO overlap with known asthma or COPD loci [67]. The study identified 24 loci associated with ACO at a genome-wide significant level of 5 × 10⁻⁸, including well-known asthma and COPD loci such as ORMDL3, GSDMB, and HHIP [9], respectively. Interestingly, Joo et al. indicated that some loci (near HRNR and ID2 genes) associated with asthma-COPD overlap at the genome-wide significant threshold were not genome-wide significant for COPD and asthma [67]. These suggest that asthma-COPD overlap might have its specific associated genetic variants, despite the recognition of many overlapping clinical features amongst ACO, COPD, and asthma. Furthermore, through candidate gene association studies, some genes have been associated with both asthma and COPD [10,68]. These genes (ADAM33, TNFα, MMP9, TGFβ1, GSTM1, GSTP1), especially ADAM33 and genes from the GST family, have been linked to lung function growth as well as lung function reduction in childhood and adulthood, respectively [10]. SNPs from the ADAM33 gene have been associated with childhood asthma [69], COPD, and lung function in tobacco smokers with greater than 20 pack-years smoking history [70]. It has been shown in a recent case-control study involving COPD (n = 194) and asthma (n = 150) cases compared to healthy control (n = 220) that SNPs from ADAM33 gene (V4 [rs2787094], T1[rs2280091], S2[rs528557]) and AQP5 gene (rs3736309) were commonly associated with both COPD and asthma alone [71]. Furthermore, the association of these genes with airway remodeling and lung function decline in asthma and COPD has also been documented [72–74]. Therefore, polymorphisms in these genes could potentially play crucial roles in ACO pathogenesis.

The majority of previous genome-wide association studies investigating the genetic background of asthma-COPD overlap were underpowered to detect any significant association (Table 2). However, top hit SNPs identified in these studies should be regarded as variants of interest in future studies. In general, genetic association research on asthma-COPD overlap is still at an early stage; more genome-wide association studies, including environmental risk factors; with larger sample sizes that have undergone replication in at least one independent population are needed to demonstrate and understand the genetic determinants of asthma-COPD overlap while seeking a plausible explanation to the pathobiology and pathogenesis of the disease

Characteristics of ACO

Asthma-COPD overlap presents similar clinical features as other obstructive airways diseases. Many epidemiological studies have compared demographic features, symptoms burden, frequency of exacerbation, pulmonary functions, quality of life, and burden of comorbidities among patients with asthma-COPD overlap, asthma, and COPD alone [2,17,19,35–44,46,75–77]. The Gina and Gold report highlighted features that could be used to differentiate the overlap phenotype from classical asthma and COPD (Table 3).

Table 3. The characteristic feature of asthma, COPD, and ACO [1].

Features	Asthma	COPD	Asthma-COPD overlap
Age of onset	Usually in childhood	Usually, >40 years	Usually, ≥40 years but may have had earlier symptoms in early adulthood or childhood
Pattern of respiratory symptoms	May vary over time, often triggered by exposure to an allergen, exercise and emotions	Chronic, usually continuous symptoms, particularly during exercise	Symptoms persistent but may exhibit variability
Lung function	Current and/or historical reversible airflow obstruction	Post-BD FEV1 /FVC ratio < 0.70 persist	Airflow obstruction not fully reversible, but often with variability
Lung function between symptoms	May be normal between symptoms	Persistent airflow obstruction	Persistent airflow obstruction
History or family history	History of allergies, personal or family history of asthma	History of exposure to noxious particles/ gases (mainly tobacco smoke and biomass fuel)	Frequently personal and family history of asthma and allergies, and history of noxious exposures (tobacco smoke)
Time course	Often improves spontaneously or with treatment	Slowly progressive over years despite treatment	Symptoms partly but significantly reduced by treatment. Progression is typical and treatment needs are high
Chest X-ray	Usually, normal	Severe hyperinflation and other changes	Similar to COPD
Exacerbations	Exacerbation risk reduced by treatment	Risk may be reduced by treatment; comorbidities may contribute to worse outcome	May be more common than in COPD but responsive to treatment. comorbidities may contribute to worse outcome
Airway inflammation	Characterized as Eosinophils ± neutrophils	Neutrophils ± eosinophils in sputum, may have systemic inflammation	Eosinophils ± neutrophils in sputum

Post-BD FEV₁/FVC: Post-bronchodilator Forced expiratory volume in 1 s to Forced vital capacity ratio.

Demographic features (age, sex, smoking history, and BMI)

Various studies have reported that patients with ACO were younger than patients with COPD [2,17,36,37,40,41,43,77,78] and older than asthmatic patients [19,36–38,41,78]. Some studies have shown that the mean age of COPD and ACO patients was similar and indistinguishable [35,44,46,52,79,80]. In a population-based cross-sectional study using data from the Canadian Health Measures Survey (CHMS), the mean age of patients with ACO was between that of COPD patients and asthmatic patients alone. The authors reported that the observed difference in mean age amongst the groups was significant [37]. Hardin et al. [2,17] also reported in two studies a significant difference in mean age between patients with ACO and COPD.

In two other studies of asthmatic and ACO patients, the mean age of patients in the ACO group was significantly higher than patients in the asthmatic group [19,38]. Furthermore, epidemiological studies have reported conflicting sex distributions in ACO patients, with certain studies showing predominantly males [2,36,39,43,44,77,78] while others indicate that ACO is preponderant in females [17,19,35,41]. In a CanCOLD study, comparing individuals with asthma-COPD overlap stratified by seven different definitions and COPD alone; Barrecheguren et al. showed that the overall patients with ACO were younger (66.6 ± 10.1 vs. 68.1 ± 9.3 years) and had more female sufferers (n = 111 vs. 90) than COPD patients [40]. However, Chung et al. demonstrated a different sex distribution trend; In that study, 67% of ACO patients were males [36].

Similar to COPD and asthma alone, smoking in ACO patients is well documented. Epidemiological studies have shown that compared to patients with COPD and asthma alone, patients with ACO were more likely to have lesser pack-years of smoking than COPD patients and greater pack-years than asthmatics [2,17,19,23,27,28,35,40,43,77,81]. However, some studies have reported no significant difference in smoking history between COPD and ACO subjects [39,41,78] and higher pack-years of smoking history in subjects with ACO than COPD [24].

Chung et al. analyzed data of 9104 subjects from the Fourth Korea National Health and Nutrition Examination Survey of 2007–2009; 73% of ACO patients (n = 210) were current and former smokers, while 65% and 54% were current and former smokers in COPD (n = 700) and asthma patients (n = 560), respectively [36]. Similarly, Senthilselvan and Beach [37] showed that the percentage of current smokers was higher in ACO (n = 144) subjects than in COPD (n = 200) and asthma (n = 602) subjects (44.83% vs. 40.96% vs. 23.05%).

ACO patients have also been reported in some studies to have lower body mass index (BMI) than patients with asthma and, at the same time, higher BMI compared with patients with COPD [17,35,36,41,43]. One study found that greater percentage of ACO subjects (44.74%) were obese compared to asthma (32.06%) and COPD subjects (38.26%) alone [37]. However, contrasting findings have been observed in some other studies, where mean BMI values were comparable and not significantly different amongst patients with asthma, ACO, and COPD [2,19,38,46,78].

Symptom burden, lung function, imaging features, and quality of life

In a CanCOLD multicenter study, 264 individuals with ACO (ACO defined using 7 different definition criteria) had significantly worse lung functions in forced expiratory volume in 1 s (FEV₁[L], and FEV₁% predicted) than 258 COPD patients ([2.2 ± 0.8 vs. 2.4 ± 0.8] and [76.6 ± 18.3 vs. 83.9 ± 19.9] p-value < 0.001). In this study, the authors showed that a greater percentage of ACO patients (13.8%) had higher levels of dyspnea, with a score of 3 and above in the Medical Research Council Dyspnea Scale (MRC) in contrast to COPD patients (5.3%). Furthermore, ACO patients were reported to have significantly higher St George’s Respiratory Questionnaire (SGRQ) scores, signifying a lower respiratory-specific quality of life than COPD patients [40].

Also, in a multivariate analysis, Kauppi et al. [76] observed that ACO is associated with the poorest HRQoL compared to COPD and asthma alone (OR:1.93, CI: 1.16–3.22, p value 0.011). Furthermore, the mean score from the airway questionnaire 20 (AQ20) amongst subjects with ACO (8.8 ± 5.1) was significantly higher than COPD (7.4 ± 5.2) and asthma (6.8 ± 4.8).

In a similar study conducted in Australia, lung function, dyspnea, and St. George’s Respiratory Questionnaire scores were compared between 60 ACO patients and 204 patients with COPD alone [39]. The mean pre-bronchodilator values of FEV₁% predicted and FVC % predicted were significantly lower in the ACO group than in the COPD group ([58.4 ± 14.3 vs. 67.5 ± 20.1] and [82.1 ± 16.9 vs. 91.9 ± 17.2] p value < 0.001, respectively). In contrast, there was no difference in Post-bronchodilator spirometry values, quality of life scores assessed with SGRQ, and dyspnea evaluation using modified Medical council research council scale (mMRC) between ACO and COPD groups [39].

Senthilselvan and Beach [37], in a population-based cross-sectional study, using data from the Canadian Health Measures Survey (CHMS), ACO subjects reported more cough, cough accompanied by phlegm and wheeze than in patients with asthma, COPD, and normal subjects. Compared with the healthy controls, the proportion of patients with poor general health in ACO subjects (21.30%) was higher than it in COPD (11.41%) or asthma alone(5.37%) [37].

In “Gene-Environment Interaction in Respiratory Diseases study” (GEIRD), de Marco et al. [42] observed a significantly higher prevalence of medical research council dyspnea score≥ 3 in the ACO group (38.8%) than the COPD (20.8%) and asthma groups (9.3%). The authors also reported that the ACO group was more likely to have cough or phlegm, more wheezing, higher frequency of asthmatic attacks, greater use of anti-asthmatic medications, and increased hospitalization (3.1% vs. 2.5% vs. 1.1%) than COPD and asthma groups alone [42].

In the PLATINO study, Menezes et al. analyzed data from 767 individuals; Subjects with ACO (n = 89) had more respiratory symptoms (cough and phlegm), worse lung function (pre and post-bronchodilator FEV₁, FVC, and FEV₁/FVC in [L] and % predicted) used more respiratory medication and recorded worse general health status than asthma (n = 84) and COPD (n = 594) subjects [41]. Worse lung function parameters observed in ACO patients than in COPD and asthma patients were consistent with other studies [19,34–36,38,48].

In contrast, in the studies by Hardin et al. [2,17], lung function parameters of (FEV₁, FVC% predicted, and FEV₁ [L]) of patients with ACO and COPD were comparable. Nevertheless, in Hardin et al. [17], post-bronchodilator FEV₁/FVC value in COPD patients was significantly lower than in patients with ACO despite comparable post-bronchodilator FEV₁values (% predicted and [L]). Furthermore, In this study, subjects with ACO had worse BODE index (Body Mass Index, airflow obstruction, dyspnea, and 6 min exercise capacity) and SGRQ scores than COPD patients, suggesting worse disease severity and poorer quality of life, respectively [17]. Hardin and colleagues [17] also analyzed data from chest CT-Scan for COPD and ACO patients. The authors showed that patients with ACO had more airway wall thickness and less emphysema than COPD patients. This finding was consistent with three other studies [40,75,81].

In a prospective longitudinal study using data obtained from stable COPD patients enrolled in Ishinomaki COPD Network Registry, Kobayashi et al. [43] reported that patients with ACO did not exhibit worse pulmonary functions. Neither did ACO patients display increased dyspnea symptoms than COPD patients. Park et al. [75], in a separate longitudinal study of 47 patients diagnosed with ACO from a cohort of 239 COPD patients, showed the post-bronchodilator FEV₁ (mL and predicted) were significantly higher in ACO patients than in COPD subjects (n = 192). In contrast, baseline pre-bronchodilator FEV₁(mL and predicted values) were not significantly different between the two groups. They also observed that ACO subjects had a slower annual decline in pre-bronchodilator FEV₁ than patients with COPD alone over a median follow-up period of 5 years. Conversely, no significant difference was observed in the prevalence of dyspnea and respiratory-specific quality of life between patients with ACO and COPD [75].

Exacerbation

The mechanism underlying the aggravation of respiratory symptoms in ACO is unclear. However, exacerbations in asthma and COPD might result from external stimuli such as allergens, environmental pollutants, and microbial infections of the respiratory tract [82,83]. Available data on the frequency of exacerbation in ACO patients compared to COPD have been Inconsistent, whereas in ACO patients compared to asthma, the exacerbation frequency has been consistently higher in patients with ACO. Patients with ACO have been shown to have more exacerbation in various studies than subjects with COPD [2,17,35,40,41,45,84] and asthma alone [19,34]. Nonetheless, some other studies showed no significant difference in the exacerbation frequency between COPD and ACO patients [27,50,51,77,80]. As frequent and severe exacerbation of respiratory symptoms may increase lung function decline, mortality, and morbidity, more studies are needed to examine and understand how it changes the natural course of the disease.

Comorbidities

The burden of concomitant diseases in ACO complicates the natural course of the disease and leads to increased mortality and morbidity. Comorbidity profile in ACO has been reported in several studies [37,47,76,85–90]. For instance, in a large case-control study in Germany using national data of statutory insured individuals, Atmatov et al. [89] identified the most prevalent top 20 comorbid diseases in ACO patients in the German population. The first 10 of the comorbid diseases were essential primary hypertension, disorders of lipoprotein metabolism, dorsalgia, type 2 diabetes mellitus, obesity, depression, chronic ischemic heart disease, spondylosis, gastroesophageal reflux disease, and gonarthrosis [89]. Similarly, Leung and Sin [91], in a review, highlighted the burden of comorbidity in ACO in diseases such as gastroesophageal reflux disease, osteoarthritis, osteoporosis, depression, and anxiety [91].

The extent of heterogeneity observed in the various reports of several studies describing the characteristics and clinical features of asthma-COPD overlap compared to asthma “alone” and COPD “alone” apparently stems from different diagnostic descriptions, eligibility criteria, and case definition criteria applied in the studies.

Prognosis

There are conflicting reports on the prognosis of patients with ACO compared to COPD and asthma patients. It has been reported that patients with ACO experience more frequent exacerbations, higher risk of hospital admission, poorer quality of life, more rapid decline in lung function, and higher mortality than patients with asthma or COPD alone [2,3,35,76,92–94]. Nevertheless, data from studies investigating the mortality rates in ACO and COPD subjects have been inconsistent.

Two studies found that mortality rates in ACO and COPD were indistinguishable [79,95]. However, COPD subjects in one of the studies had a higher risk of all-cause mortality (HR:2.12, 95% CI: 1.71–2.63, p < 0.001) than ACO patients (HR:1.82, 95% CI:1.38–2.38, p < 0.001) when both diseases were compared to control subjects during a 15-year follow-up [79].

Some studies reported higher mortality rates in ACO subjects [94,96–99], while other studies revealed lower rates in patients with concomitant asthma and COPD with respect to COPD alone [80,84,100,101]. For instance, an observational study using data from NHANES III dataset where patients with a self-reported diagnosis of asthma (n = 120), COPD (340), and ACO (n = 126) were drawn from 4434 participants, Kumbhare and Strange [99] noted that death as a result of chronic lower respiratory disease was the highest in subjects with ACO (21.4%) than in patients with COPD (12.6%) and asthma (9.5%). In the same study, ACO subjects had a higher mortality rate of 3.2% due to influenza and pneumonia than COPD (2.1%) and asthma (1.6%) [99]. Tkacova et al. [97] observed a two-fold increased risk of death (HR:2.38, 95% CI:1.38–4.11, p = 0.002) due to respiratory cause in patients with ACO (defined as COPD with airway hyperactivity) than in COPD patients [97].

Lange et al. [94], in a population-based study of participants from Copenhagen City Heart Study, demonstrated that ACO with late asthma onset had the worse prognosis in terms of respiratory mortality, all-cause mortality, and life expectancy than ACO with early asthma onset, COPD, Asthma, ever-smokers without disease, and never-smokers without the disease. Lange and colleagues quantified the reduction of life expectancy in ACO with late-onset asthma patients as 12.8 years, 10.1 years in COPD, and 9.3 years in asthma. These comparisons were made using subjects who are never smokers and without disease as the reference group [94]. Similarly, a study with an 18-year follow-up found that subjects with ACO had a higher risk of mortality than their COPD and asthma counterpart. The authors reported a hazard ratio of 1.45, 1.28, and 1.04 for ACO, COPD, and asthma patients, respectively, after adjusting for covariates such as age, sex, ethnicity, smoking status, education level, body mass index, respiratory disease, and lung function status [96].

Contrastingly decreased mortality and improved survival in ACO have been reported in few studies compared to COPD. ACO patients (n = 6279) were found to have in-hospital all-cause mortality of 2.3% opposed to 9.7% for COPD patients (n = 4261) [100]. Another study pointed out in comparison to patients with COPD, ACO patients had better median survival years (9.1 vs. 7.9 years) and survival probability (0.35 vs. 0.25) during 15 years follow-up [79].

While analyzing data from 65 ACO patients and 65 COPD patients, Bai and colleagues observed that despite more frequent exacerbations in the past 12 months (2.3 ± 2.2 vs. 1.4 ± 1.3, respectively), patients with ACO had a lesser number of deaths (3 deaths) and shorter days of hospitalization than COPD patients (13 deaths) during a median follow-up period of 45 months [84]. These might be due to better response to steroid treatments in patients with ACO than COPD.

Studies assessing lung function decline in ACO patients have reported conflicting results in comparison to COPD patients. However, one consistent trend observed in most studies except one [45] is the faster decline in FEV₁ seen in ACO patients than in patients with asthma. Marco et al. [45] reported similar changes in FEV₁ decline amongst young adults (age: 20–40 years) with asthma and ACO over nine years follow-up; However, ACO patients had a more favorable decline in FEV₁ than COPD patients within the same timeframe. Likewise, a longitudinal study of older patients with chronic obstructive airway disease (age: > 55 years) showed no significant difference amongst asthma, COPD, and ACO subjects in FEV₁ decline during four years of follow-up [46].

In another longitudinal study evaluating long-term prognosis in asthma, COPD, and ACO subjects over an 18 − 22 years period, ACO subjects with late-onset asthma (defined as asthma onset after 40 years of age) had the worst prognostic outcome with FEV₁decline of 49.6 mL/year. Patients with COPD, ACO with early-onset asthma, and asthma alone had FEV₁ decline of 39.5 mL/year, 27.3 mL/year, and 25.6 mL/year, respectively [94]. Another study also reported a higher annual decline in FEV₁ in patients with ACO than in COPD patients (−49.6 mL/year vs. −38.1 mL/year) [40]. ACO patients (i.e., in definition 2 category; see Table S1) who were faster decliners in FEV1 (defined as a reduction >40 mL/year) had a significantly higher decline in FEV₁ than patients with COPD.(−81.1 mL/year, 95% CI: [−116.5, −45.6] vs −38.1 mL/year, 95% CI:[−49.3,−26.9]) [40].

Contrarily, a more and faster annual decline in pre-bronchodilator FEV₁ was reported in COPD patients from the Korean Obstructive Lung Disease cohort. A cohort of 239 COPD patients showed that patients diagnosed with ACO (n = 47) had a significantly lower annual pre-bronchodilator FEV₁ than patients with COPD alone (−13.9 mL/year vs. − 29.3 mL/year, p = 0.042) [75]. The result remained consistent after controlling for baseline age, body mass index, smoking status, exacerbation rate, and medication use (−13.61 mL/year vs. −29.16 mL/year, p = 0.042) [75]. The variations in the results could be attributed to the better response to ICS/LABA or ICS treatment in patients with ACO than patients in the non-ACO group.

Poorer prognosis in ACO patients appears to be influenced by the burden of comorbidities. ACO patients with three or more comorbid medical conditions have been shown to have poorer survival (n = 81; median survival years: 3.7) and worse prognosis than in ACO patients with less than three comorbidities (n = 48; median survival years: 6.0) [102]. Furthermore, similar comorbidity profiles and causes of death, notably cardiovascular, malignant, gastrointestinal diseases, and diabetes, are plausibly present in asthma, ACO, and COPD [99,101–103]. The possible explanation for the observed variations in the findings of various studies evaluating the prognosis of ACO could be due to varying diagnostic criteria, the sample size of the cohorts, and disparities in obstructive airway disease severities of the cohorts.

Future direction

The recent pro-con debate and the non-inclusion of the term ACO in the GOLD 2020 report raise uncertainty on the utility of the term ACO to describe a subset of patients with shared COPD and asthmatic features [104–106]. Despite the non-inclusion of ACO as a term in the GOLD 2020 report, it acknowledged the coexistence of asthma and COPD in certain patients. There is some truth in that ACO is a blend of conditions as opposed to its entity. The absence of a globally unified definition, the heterogeneity in several diagnostic criteria, and the yet to be identified replicable specific genetic and biomarkers associated with the “overlap” phenotype could be the attributable factors for the exclusion. However, it will make further study of “a subset of patients with shared COPD and asthmatic features” harder. For example, the real important question is about identifying who will respond to what treatments?

Furthermore, who is more likely to be harmed by a treatment. For instance, it is a known clinical fact that COPD patients are not supposed to get Inhaled corticosteroids (ICS) alone, but it is the mainstay of treatment for asthma patients. What about patients with emphysema on high resolution computed tomography (HRCT) who also have high eosinophils or exhibit significant reversibility? Are they more or less likely to benefit or be harmed when treated with ICS? Are they more or less likely to manifest better response in FEV₁ when treated with ICS? Therefore, in order to advance our understanding of the “overlap phenotype,” taking into consideration the heterogeneity that exists in its presentation, just as asthma and COPD are evidently heterogenous, identification and a better understanding of both genetic and novel biomarkers may allow recognition of patients who would respond to specific pharmacotherapies rather than the current extrapolations of evidence from asthma and COPD studies.

Conclusion

ACO might be a distinct chronic obstructive lung disease phenotype with unique genetic risk factors or an intermediate phenotype with overlapping genetic architecture between asthma and COPD alone. Although the genetic risk factors associated with ACO may still be at a conjecture stage, the possibility that ACO might possess ACO-specific and shared genetic mechanisms of asthma and COPD should be considered. Therefore, future extensive genetic association studies need to identify genetic determinants associated with ACO, its molecular patterns, and the influence of environmental factors in developing the phenotypic trait. Therefore, it is necessary to explore if there are distinguishing pathogenetic factors that could differentiate ACO from classic asthma and COPD. A deep understanding of the genetic and inflammatory mechanisms associated with ACO will improve its characterization and the development of therapeutic options tailored toward managing treatable traits.

Declaration of interest

The authors declare no conflicts of interest.

Funding

This project has been funded by the Canadian Institutes of Health Research (CIHR), the Catalyst Grant (ACD 162989)