TITLE

CLINICAL PROFILES , RISK FACTORS AND PULMONARY FUNCTION

TESTS OF ADULTS WITH OBSTRUCTIVE AIRWAY DISEASE WITH
SPECIAL REFERENCE TO DIAGNOSIS OF ASTHMA COPD(CHRONIC
OBSTRUCTIVE PULMONARY DISEASE) OVERLAPPED SYNDROME –
A CROSS SECTIONAL STUDY.

Dissertation for

M.D. (RESPIRATORY MEDICINE )

MAHARASHTRA UNIVERSITY OF

HEALTH SCIENCES, NASHIK

2021-2024
NAME OF COURSE M.D.

NAME OF SUBJECT RESPIRATORY MEDICINE

ADMISSION YEAR / 2021/

ACADEMIC YEAR
2021 - 2022

TOPIC
CLINICAL PROFILES , RISK FACTORS AND PULMONARY
FUNCTION TESTS OF ADULTS WITH OBSTRUCTIVE
AIRWAY DISEASE WITH SPECIAL REFERENCE TO
DIAGNOSIS OF ASTHMA COPD(CHRONIC OBSTRUCTIVE
PULMONARY DISEASE) OVERLAPPED SYNDROME –A
CROSS SECTIONAL STUDY.
 CONTENTS

CHAPTER PAGE NO.

1.INTRODUCTION

2.AIMS AND OBJECTIVES

3.REVIEW OF LITERATURE

4.MATERIALS AND METHODS

5.DISCUSSION

6.SUMMERY

7.CONCLUSION

8.BIBLIOGRAPHY

9.ANNEXURE

a)CASE RECORD FORM

b)PATIENT INFORMATION SHEET

c)INFORMED CONSENT FORM

d)TIME LINE/GANTT CHART

e)ABBREVATIONS
 f)MASTER CHART

INTRODUCTION
Asthma and chronic obstructive pulmonary disease (COPD) are two of the most
common forms of obstructive lung disease world-wide. Increasingly, patients with
clinical characteristics of both asthma and COPD have been identified as a unique
subset of obstructive lung disease. This was defined as “asthma-COPD overlap”
(ACO), and it represents a spectrum of airway pathology rather than a singular
disease process.1

A number of authors and different consensus guidelines have proposed various

definitions of ACO during the last decades, usually using several major and minor
criteria. Most of them emphasize the heterogeneity of clinical features and
functional and laboratory findings that should be considered as diagnostic criteria
that could apply for the identification of individuals with a possible diagnosis of
ACO. The main criteria in most of these reports include non-fully reversible
airflow limitation, a history of asthma diagnosed before the age of 40 years,
persistent symptoms that vary and progress over time, smoking history >10 years
or significant exposure in other noxious particles or gases, high levels of
eosinophils in sputum and/or in blood, exhaled breath nitric oxide (FeNO) levels >
45 to 50 ppm, history of atopy or high IgE for total serum or inhaled allergens,
metacholine challenge test positivity, and significant bronchodilation response. 2

The most widely accepted ACO definition is the one of the 2015 GINA/GOLD
documents. In this report, the patient should have a chronic airway disease
(medical history of cough, sputum production, wheezing, or repeated lower
respiratory tract infections) in combination with features of both asthma and
COPD. However, in the 2021 GOLD report the term ACO no longer exists and the
authors state that COPD and asthma are two distinct entities which can coexist in a
single individual. Despite the removal of ACO from the most important reports on
the management of asthma and COPD, i.e., the Global Initiative for Asthma
(GINA) and the GOLD, this entity still continues to be important and receive
attention in both clinical research and clinical practice. 2

In the general population, the prevalence of ACO ranges from 0.9% to 11.1%.
Among asthmatics, ACO can be recognized in 11.1–61.0% and among COPD
patients from 4.2–66%.2

There are multiple phenotypes of ACO, from patients with COPD and long-
smoking histories with peripheral eosinophilia to others with asthma with fixed
obstruction on pulmonary function testing (PFT) and a significant smoking history.
This heterogeneity is a result of variable host and environmental factors, making a
singular designation of ACO a difficult and controversial, diagnosis. Currently,
there is no universal consensus on the diagnostic criteria. Despite this, there are
important considerations for patients with clinical characteristics of both COPD
and asthma, as they have significantly worse quality of life and more frequent
healthcare contact than patients with either asthma or COPD individually. 3

Many of the studies that sought to evaluate the characteristics of patients with
ACO found that these individuals have more severe symptoms, a greater number of
exacerbations and hospitalizations, poorer quality of life, and poorer prognosis
than do those without ACO. These characteristics translate to high health costs for
these subjects.3
The aforementioned findings may be due to a lack of concrete data to inform the
appropriate therapeutic choice for each patient profile. Once the clinical features of
patients have been identified, treatment can be personalized and optimizing
outcomes in terms of functional performance.3

AIMS AND OBJECTIVES

OBJECTIVES

Primary objective:-

To Study of clinical profiles, risk factors and pulmonary function tests of adults with
obstructive airway disease.

Secondary objective:-

To diagnosed patients of asthma COPD overlapped syndrome in patients of obstructive

airway disease with respect to clinical profiles, risk factors and pulmonary function tests.
REVIEW OF LITERATURE

Industrialization and the Epidemiologic Transition

The process of industrialization during the 19th and early 20th centuries led to
what is known as the epidemiologic transition6. This transition involves lifestyle
changes associated with industrialization and better standards of living, including
improved nutrition and hygiene, which are accompanied by a shift in morbidity
and mortality patterns6,7. According to this model, there is a transition from
mortality among the young due to acute, often infectious, conditions to morbidity
and mortality primarily among the elderly from chronic, largely “man-made”
conditions6,7 . Prior research has linked these chronic conditions to lifestyle factors
such as smoking, exposure to environmental pollution, and sedentary habits6,8,9 .

It is important to note that this transition is neither complete nor static. The recent
COVID-19 pandemic highlights that infectious diseases continue to have a
significant mortality impact, even in developed regions10.Another example is the
resurgence of measles in Western countries due to rising anti-vaccine sentiment,
despite previous eradication efforts . Nevertheless, with a growing and aging
global population, particularly in areas experiencing increased industrialization, the
burden of chronic diseases is expected to increase substantially in the coming
decades11 .

Asthma

Asthma is another chronic respiratory disease characterized by airway

inflammation and obstruction, though its pathophysiology is better understood than
COPD’s13. Most asthma cases display an allergic pattern of inflammation, leading
to airway narrowing and hyperresponsiveness. However, different subtypes of
asthma are increasingly recognized . Like COPD, asthma has no cure, but effective
treatments exist, particularly inhaled corticosteroids16,17,18.

Interestingly, a previous diagnosis of asthma is common among people later

diagnosed with COPD. For instance, a study by Soriano et al. Reported that 43.2%
of incident COPD cases in the UK also had a previous asthma diagnosis17 . When
asthma and COPD coexist and interact, the resulting condition is called Asthma-
COPD Overlap Syndrome (ACOS)18,19,20 . ACOS is increasingly recognized as
a distinct clinical phenotype with features of both asthma and COPD13,19,20 .
Research suggests that patients with ACOS tend to have more severe respiratory
dysfunction than those with either COPD or asthma alone13,21-23 .
Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is one such chronic disease with a
significant and growing global burden11,12 . COPD is a debilitating, progressive
disease characterized by airway obstruction and alveolar destruction 12,13. Localized
and systemic inflammation in COPD leads to fibrosis and loss of elasticity in the
lung tissue, causing irreversible airway collapse and gas trapping13 . Additionally,
reversible, cholinergic airway narrowing is commonly observed in COPD patients .
Recognized by the World Health Organization as part of the global epidemic of
noncommunicable diseases14, COPD has no cure, and current treatment options are
limited, even in regions with advanced healthcare infrastructure15. In resource-poor
areas, COPD often goes unrecognized and untreated16 .

Prevention of COPD focuses mainly on smoking cessation or avoidance, reducing

the need for burning biomass fuels, and reducing other airborne pollutants through
improved community infrastructure15 .

Comparative Studies on ACOS

Park et al. conducted cross-sectional and longitudinal analyses comparing ACOS

patients to those with asthma alone in a Korean cohort. They found that ACOS
patients were older, more likely to be male, less likely to have atopy, and had
lower baseline lung function with greater airway obstruction. Additionally, ACOS
patients had more significant variation in FEV1 over time, higher rates of
exacerbations, and a larger decline in pulmonary function compared to asthma-
only patients23. These results suggest that ACOS is phenotypically distinct from
asthma and leads to more substantial respiratory decline .

Hardin et al. compared American patients with ACOS to those with COPD alone 22.
They found that ACOS patients were younger, smoked less, had a higher
prevalence of hay fever, were more likely to be African American, and
experienced more frequent and severe COPD exacerbations than those with COPD
alone. ACOS patients also had worse health-related quality of life scores,
suggesting that airway inflammation rather than parenchymal destruction may
explain the differences in disease severity and quality of life23.

Public Health Significance

Globally, COPD affects approximately 328 million people, with 168 million men
and 160 million women affected. This estimate is likely an underestimate due to
under diagnosis, particularly in low- and middle-income countries11,15. By 2030,
COPD is expected to account for 7.8% of all deaths and 27% of smoking-related
deaths, making it the third leading cause of death globally, after cancer and
cardiovascular disease11,14 .Given the tremendous burden and economic impact of
COPD, understanding and mitigating disease development and progression
represent important public health concerns12,14,22 .

The economic and social burden of COPD is directly associated with disease
severity, frequency of exacerbations, and presence of comorbidities, including
asthma16 . As mentioned, asthma is a frequent comorbid condition in COPD
patients, and those with ACOS may have worse outcomes16,21,22 . Historically,
patients with both asthma and COPD have been excluded from COPD-targeted
studies due to concerns that disease etiology or presentation may differ,
particularly due to previous use of inhaled corticosteroids11,21,22,24 . In studies where
dual diagnoses are allowed, comorbid asthma is associated with poorer outcomes
and increased healthcare utilization18,21,23. However, understanding disease
progression using longitudinal approaches is still needed to determine how asthma
and COPD interact to produce a distinct clinical phenotype with unique treatment
needs23.

According to the latest guidelines from GOLD (Global Initiative for Chronic
Obstructive Lung Disease)4and GINA (Global Initiative for Asthma)5, obstructive
airway disease encompasses several conditions, primarily chronic obstructive
pulmonary disease (COPD) and asthma.

Definition:

Asthma: A heterogeneous disease, usually characterized by chronic airway

inflammation. It is defined by the history of respiratory symptoms such as wheeze,
shortness of breath, chest tightness, and cough that vary over time and in intensity,
together with variable expiratory airflow limitation4.
COPD: Defined as a common, preventable, and treatable disease characterized by
persistent respiratory symptoms and airflow limitation due to airway and/or
alveolar abnormalities usually caused by significant exposure to noxious particles
or gases5.

ACOS: defined by the presence of features of both asthma and COPD. The
diagnosis is considered in patients over 40 years old who have a history or current
diagnosis of both diseases. Key features that help identify ACOS include6:

● Persistent airflow limitation on spirometry.

● A history of childhood asthma or allergies.

● A history of smoking or exposure to noxious particles and gases.

Diagnosis:

Asthma: Diagnosis is based on clinical history and objective measures of lung

function. This includes spirometry to assess the presence of reversible airflow
obstruction (increased FEV1 after bronchodilator administration) and variability in
airflow limitation over time (diurnal variability or variability with treatment) 4.

COPD: Diagnosis involves spirometry to confirm the presence of persistent

airflow limitation (post-bronchodilator FEV1/FVC < 0.70). Symptoms such as
dyspnoea, chronic cough, and sputum production should also be considered5.
ACOS: Diagnosis requires careful assessment of the patient’s history, symptoms,
and lung function. The GINA/GOLD joint document on ACOS Suggest the
following approach6.

Detailed Medical History:

Assess symptoms such as chronic cough, wheeze, and dyspnoea, and gather
information on risk factors including smoking, occupational exposures, and a
family history of respiratory diseases.

Spirometry:

Perform post-bronchodilator spirometry to assess the degree of airflow limitation

and its reversibility.

Differential Diagnosis:

Distinguish ACOS from pure asthma and COPD by looking for overlapping
features such as significant variability in airflow limitation (more typical of
asthma) and persistent airflow limitation (more typical of COPD).
Patients with ACOS often display greater symptom burden, more frequent
exacerbations, and higher healthcare utilization compared to those with either
disease alone. Treatment typically involves a combination of inhaled
corticosteroids and bronchodilators, tailored to the individual’s dominant
symptoms and disease features.

Differentiation:

Clinical Features: COPD typically presents with a history of smoking,

progressive dyspnoea, and chronic cough with sputum production. Asthma often
begins in childhood or adolescence and includes symptoms that vary Over time,
often with triggers such as allergens or exercise.

Spirometry: While both conditions can show airflow limitation, COPD tends to be
less reversible after bronchodilator use compared to asthma.

Inflammatory Markers: Eosinophil levels are often elevated in asthma, reflecting

allergic or eosinophilic inflammation, whereas COPD may show neutrophilic or
mixed inflammation.

Asthma
Historical prospective:

Ancient to Medieval Times:

Asthma’s early history begins in Ancient Egypt, where it was treated with herbal
mixtures like kyphi 25 . Hippocrates provided one of the first formal descriptions of
asthma, using a term derived from the Greek word for “panting”26. In the 12th
century, Maimonides’ comprehensive treatise on asthma, written in Arabic,
marked a significant 27. His work compiled contemporary knowledge, proposed
treatments, and emphasized environmental factors such as climate and air quality
28
.

19th Century Advances:

The late 19th century saw significant progress in asthma research and treatment. In
1873, a pivotal medical paper attempted to elucidate the disease’s pathophysiology
. Concurrently, treatments evolved, including the use of chloroform liniment for
symptom 29,30 . By 1880, intravenous pilocarpine emerged as a treatment option31 .
The connection between asthma and hay fever was established in 1886 by F. H.
Bosworth 32. These advancements laid the groundwork for more effective
treatments in the following decades.
Early 20th Century Developments:

The early 20th century brought further medical innovations. Epinephrine was first
recommended as a treatment for asthma in 1905, marking a significant
milestone33 . The introduction of oral corticosteroids in the 1950s revolutionized
asthma management, offering a new approach to controlling symptoms. The 1960s
saw the advent of inhaled corticosteroids and selective short-acting beta agonists,
which became mainstays in asthma treatment due to their effectiveness 34,35 .

Psychosomatic Perspectives (1930s-1950s):

During this period, asthma was considered one of the “holy seven” psychosomatic
illnesses, with a focus on psychological 37. Treatments often involved
psychoanalysis and other talking cures. The asthmatic wheeze was interpreted as a
suppressed emotional response, and addressing psychological factors, particularly
depression, was deemed crucial for effective 37.

Case Study – Theodore Roosevelt:

Theodore Roosevelt’s battle with asthma provides a poignant example of the

disease’s impact in the absence of effective treatments. Roosevelt’s severe night
time asthma attacks and the consequent sense of suffocation profoundly affected
his life36. His case underscores the historical challenges faced by asthma sufferers
and the need for medical advancements .
Modern Era:

The latter half of the 20th century and beyond has seen continuous improvements
in asthma management. The development of more effective medications, such as
long-acting beta agonists and biologics, has significantly improved patient
outcomes. Ongoing research continues to explore the genetic, environmental, and
immunological factors underlying asthma, aiming to develop more personalized
and effective treatments.

Epidemiology of Asthma

Global Prevalence:

Asthma affects between 1% to18% of the population in various countries, with its
prevalence increasing over time.4

The prevalence of 'current asthma symptoms' among adults varies significantly

worldwide, from less than 1% in Tunisia to over 25% in Australia and Wales.38
According to estimates by the Global Initiative for Asthma (GINA), the prevalence
of asthma in Southern Asia (Bangladesh, Bhutan, India, Nepal, Seychelles, and Sri
Lanka) is about 3.5%.38

India-Specific Prevalence:

India accounts for approximately one-tenth of the global asthma population.39

In India, the prevalence ranges from 3-38% in children and 2-12% in adults,
making it the most common chronic disorder among children.40

The Indian Study on Epidemiology of Asthma, Respiratory Symptoms, and

Chronic Bronchitis (INSEARCH) estimates asthma prevalence in India at 2.05%
among those aged over 15 years, with a national burden of 18 million asthmatics.

Mortality and Morbidity of Asthma

Asthma significantly impacts daily activities, leading to missed school and work
days, reduced lung function, lower quality of life, and socioeconomic challenges.

Globally, around 15 million disability-adjusted life years (DALYs) are lost

annually due to asthma, representing 1% of the total global disease burden.
Approximately 489,000 deaths per year are attributed to asthma, with the majority
occurring in low- and middle-income countries, especially in regions like Oceania,
South and Southeast Asia, the Middle East, and Africa.41

Patients from these regions often experience more severe symptoms due to factors
like incorrect diagnosis, limited healthcare access, poor adherence to treatment,
exposure to environmental irritants, and genetic susceptibility.42

Pathophysiology of Asthma

Asthma involves several changes in the airways that lead to recurrent airflow
limitation.

1.Bronchoconstriction

Acute Bronchoconstriction: During an asthma attack, the bronchial smooth

muscle rapidly contracts, narrowing the airways and causing symptoms like
wheezing and shortness of breath.

Allergen-Induced Bronchoconstriction: Exposure to allergens can trigger an

IgE-dependent release of mediators from mast cells, such as histamine, tryptase,
leukotrienes, and prostaglandins, which contract the airway smooth muscle.

Drug-Induced Bronchoconstriction: Aspirin and other NSAIDs can block the

COX pathway, leading to airflow obstruction in some individuals. This response,
not dependent on IgE, also involves the release of mediators from airway cells.
2.Airway Edema

Over time, chronic inflammation in asthma leads to factors that further restrict
airflow:

Edema: Swelling of airway walls.

Inflammation: Persistent inflammation narrows the airways and increases

sensitivity.

Mucus Hypersecretion: Excess mucus production can block the airways.

Inspissated Mucus Plugs: Thickened mucus can obstruct airways.

Structural Changes: Hypertrophy and hyperplasia of airway smooth muscle can

lead to permanent narrowing, often resistant to standard treatments.

3.Triggers of Acute Airflow Obstruction

Exercise

Cold Air

Irritants (e.g., smoke, strong odors)

Stress

Aeroallergens (e.g., pollen, dust mites)

Aspirin and Other NSAIDs

Characteristics of Clinical Asthma

Clinical symptoms

Airway obstruction

Inflammation

Hyperresponsiveness

Airway Hyperresponsiveness
Airway hyperresponsiveness is an exaggerated response of the airways to various
stimuli, resulting in significant bronchoconstriction. This condition's severity can
be assessed by measuring the airways' reaction to methacholine, a substance that
induces bronchoconstriction. The extent of hyperresponsiveness is directly related
to the clinical severity of asthma, making it a critical factor in understanding and
managing the disease.

Mechanisms Influencing Airway Hyperresponsiveness:

1. Inflammation: Inflammation is a key determinant of airway

hyperresponsiveness. It contributes significantly to the sensitivity and
reactivity of the airways. Anti-inflammatory treatments can help reduce this
hyperresponsiveness, thereby improving asthma control.
2. Dysfunctional Neuroregulation: Abnormal nerve regulation can also
contribute to airway hyperresponsiveness. This dysfunction can lead to
increased bronchoconstriction and airway sensitivity.
3. Structural Changes: Changes in the airway structure, such as thickening of
the airway walls, can exacerbate hyperresponsiveness. These structural
modifications can make the airways more reactive to stimuli.

Airway Remodeling
In some asthma patients, there is a partial and sometimes irreversible limitation to
airflow. This condition, known as airway remodeling, involves permanent
structural changes in the airways, leading to a gradual decline in lung function.
These changes are often resistant to current therapeutic interventions, making
management more challenging.

Features of Airway Remodeling:

● Inflammation: Persistent inflammation can lead to structural changes in the

airways.
● Mucus Hypersecretion: Excess mucus production can obstruct airflow and
contribute to remodeling.
● Subepithelial Fibrosis: Thickening of the tissue beneath the airway
epithelium can lead to reduced elasticity and increased stiffness of the
airways.
● Airway Smooth Muscle Hypertrophy: Enlargement of the airway smooth
muscle can narrow the airways and increase reactivity.
● Angiogenesis: The formation of new blood vessels within the airways can
contribute to inflammation and remodeling.
Mechanisms in the Development of Airway Inflammation

Inflammation is central to asthma's pathophysiology, involving interactions

between various inflammatory cells and mediators with the airways. This
interaction leads to the characteristic symptoms of asthma, such as recurrent
episodes of cough, wheezing, and shortness of breath. Despite the different
phenotypes of asthma (intermittent, persistent, exercise-associated, aspirin-
sensitive, or severe), airway inflammation is a common underlying feature. The
pattern of inflammation does not significantly vary with the severity, persistence,
or duration of the disease. The cellular response and profile remain relatively
consistent across different asthma phenotypes.

In summary, understanding airway hyperresponsiveness and remodeling is crucial

for managing asthma. While inflammation, dysfunctional neuroregulation, and
structural changes are key factors influencing hyperresponsiveness, persistent
airway inflammation and structural changes characterize airway remodeling. These
insights highlight the importance of targeted treatments to manage asthma
effectively.
Inflammatory Cells and Mediators in Asthma

Lymphocytes

Lymphocytes, especially T-helper (Th) cells, are key in asthma's development. Th2
cells produce cytokines such as IL-4, IL-5, and IL-13, which promote eosinophilic
inflammation and airway hyperresponsiveness. The balance between different
lymphocyte subgroups, like regulatory T cells that suppress Th2 cells, and natural
killer (NK) cells that release Th1 and Th2 cytokines, is vital for controlling the
inflammatory response. T cells in the airways intensify inflammation, and while it's
an oversimplification to label asthma solely as a Th2-dominated condition,
recognizing the roles of various cytokines and chemokines is crucial for
understanding airway inflammation.

Mast Cells

Mast cells initiate the inflammatory response in asthma. When activated, they
release mediators such as histamine, cysteinyl-leukotrienes, and prostaglandin D2,
leading to bronchoconstriction. Allergen activation occurs through high-affinity
IgE receptors. Sensitized mast cells can also be triggered by osmotic changes,
contributing to exercise-induced bronchospasm (EIB). Mast cells in airway smooth
muscle may be linked to airway hyperresponsiveness and release cytokines that
sustain inflammation even with limited allergen exposure.
Eosinophils

Eosinophils are drawn to the airway epithelium by chemotactic signals from

cytokines, chemokines, and adhesion molecules. Although they are common in the
airways of many asthmatic individuals, their exact role is complex. Eosinophils
contain inflammatory enzymes, produce leukotrienes, and express pro-
inflammatory cytokines. Asthma severity often correlates with eosinophil numbers,
and corticosteroids can reduce these cells. However, anti-IL-5 treatments that
lower eosinophil counts haven't consistently improved asthma control, suggesting
that eosinophils, while important, are not the only players in asthma.

Neutrophils

Neutrophils' role in asthma is still being studied. They are regulated by leukotriene
B4 and found in the airways and sputum of patients with severe asthma, acute
exacerbations, and smokers. Activated neutrophils produce reactive oxygen species
and release enzymes like neutrophil elastase, contributing to inflammation.
Neutrophil-driven airway inflammation often resists corticosteroid treatment.

Dendritic Cells

Dendritic cells present antigens and interact with allergens in the airways, then
migrate to lymph nodes to stimulate naive T cells to produce Th2 cells. They
express HLA-DR molecules in the airway epithelium, initiating immune responses.
Their precise role in asthma is still under investigation.
Macrophages

Macrophages release inflammatory mediators and cytokines after allergen

activation via low-affinity IgE receptors. They derive from blood monocytes and
contribute to airway constriction by producing pro-inflammatory mediators. In
asthma, macrophages secrete high levels of metalloproteases, recruiting and
activating other leukocytes.

Resident Cells of the Airway

Inflammation and inflammatory factors cause airway smooth muscle cells to

proliferate, activate, contract, and hypertrophy, contributing to airway dysfunction
in asthma. Thus, airways play an active role in asthma pathogenesis.

Epithelial Cells

Airway epithelial cells generate inflammatory mediators and recruit and activate
inflammatory cells. Respiratory viral infections increase inflammatory mediator
production, injuring the epithelium. Abnormal repair processes following epithelial
injury can lead to airway obstructions in asthma.
Inflammatory Mediators

Chemokines

Chemokines recruit inflammatory cells into the airways and are expressed by
airway epithelial cells. Thymus and activation-regulated chemokines (TARCs) and
macrophage-derived chemokines (MDCs) attract Th2 cells.

Cytokines

Cytokines direct and modify inflammation in asthma. Th2-derived cytokines

include IL-5 (for eosinophil differentiation and survival), IL-4 (for Th2 cell
differentiation), and IL-13 (for IgE production). Other key cytokines, such as IL-1β
and TNF-α, drive the inflammatory response, while GM-CSF prolongs eosinophil
survival. Recent studies targeting single cytokines have not significantly improved
asthma outcomes.

Cysteinyl-Leukotrienes

These potent bronchoconstrictors mainly come from mast cells. Inhibiting these
mediators has improved lung function and asthma symptoms.

Nitric Oxide (NO)

Produced by inducible NO synthase in airway epithelial cells, NO is a potent

vasodilator. Measuring fractional exhaled NO (FeNO) helps monitor asthma
treatment response, as FeNO levels correlate with airway inflammation.

Immunoglobulin E (IgE)

IgE is crucial for activating allergic reactions and the pathogenesis of allergic
diseases. It regulates inflammation by binding to high-affinity receptors on mast
cells, basophils, dendritic cells, and lymphocytes. Activated mast cells release
mediators causing bronchospasm and airway inflammation. Monoclonal antibodies
against IgE reduce IgE levels and have proven effective in asthma treatment,
highlighting IgE's importance in asthma.
Pathogenesis of Asthma

Host Factors and Environmental Exposures

Host Factors

1.Innate Immunity

Asthma often originates early in life, influenced by genetics and environmental

exposures.

Immune system development and its regulation of inflammation are critical.

Imbalances in Th1 and Th2 cytokine profiles are significant, with asthma typically
skewed towards a Th2-dominant response.

The “hygiene hypothesis” suggests that newborns are inclined towards Th2
responses, and environmental stimuli post-birth shift this balance towards Th1. If
genetically predisposed to a Th2 bias, individuals are more prone to asthma and
allergies due to elevated IgE production.

2.Genetics

Asthma has a genetic component, with many genes implicated in its development
and expression. Genes such as ADAM33, DPP10, PHF11, HLA-G, and NPSR1
have been linked to asthma.
Genetics also influence IgE production, airway hyperresponsiveness, and response
to therapy, although the complete picture remains unclear.

3.Sex

Asthma prevalence is higher in boys early in life but shifts to being more common
in women post-puberty. Sex hormones may influence the onset and persistence of
asthma.

Environmental Factors
1.Perinatal Factors

Factors such as premature birth, low birth weight, maternal age, and diet can
influence asthma development.

2.Allergens

Both indoor and outdoor allergens are significant triggers. Indoor allergens include
house-dust mites, molds, cockroaches, and pet dander. Outdoor allergens involve
tree, grass, pollen, and weed.

Sensitization and exposure to these allergens, especially early in life, are crucial in
asthma development.

3.Respiratory Infections

Early-life respiratory viral infections, such as those caused by RSV and

parainfluenza virus, are linked to increased asthma risk.

Infections can trigger wheezing and, in some cases, protect against asthma
development, as proposed by the hygiene hypothesis.

4.Other Environmental Exposures

Tobacco smoke, air pollution, occupational exposures, and diet can increase
asthma risk.
In utero exposure to tobacco smoke can lead to wheezing, while adult smokers
with asthma may experience increased severity and reduced response to inhaled
corticosteroids.

Air pollution’s role is debated but linked to allergic sensitization and asthma
exacerbations. Low intake of antioxidants and omega-3 fatty acids, along with
obesity, may also correlate with asthma prevalence.

Asthma phenotypes

According to GINA Guideline 2024

Asthma is a heterogeneous disease, with different underlying disease processes.

Recognizable clusters of demographic, clinical and/or pathophysiological
characteristics are often called ‘asthma phenotypes’.43-46In patients with more
severe asthma, some phenotype-guided treatments are available. However, except
in patients with severe asthma, no strong relationship has been found between
specific pathological features and particular clinical patterns or treatment
responses. More research is needed to understand the clinical utility of phenotypic
classification in asthma.

Many clinical phenotypes of asthma have been identified.43-45Some of the most

common are:

• Allergic asthma:
This is the most easily recognized asthma phenotype, which often commences in
childhood and is associated with a past and/or family history of allergic disease
such as eczema, allergic rhinitis, or food or drug allergy. Examination of the
induced sputum of these patients before treatment often reveals eosinophilic
airway inflammation. Patients with this asthma phenotype usually respond well to
ICS treatment.

• Non-allergic asthma:

Some patients have asthma that is not associated with allergy. The cellular profile
of the sputum of these patients may be neutrophilic, eosinophilic or contain only a
few inflammatory cells (paucigranulocytic). Patients with non-allergic asthma
often demonstrate a lesser short-term response to ICS.

• Cough variant asthma and cough predominant asthma:47

In some children and adults, cough may be the only symptom of asthma, and
evidence of variable airflow limitation may be absent apart from during bronchial
provocation testing. Some patients subsequently also develop wheezing and
bronchodilator responsiveness. ICS-containing treatment is effective.
• Adult-onset (late-onset) asthma:

Some adults, particularly women, present with asthma for the first time in adult
life. These patients tend to be non-allergic, and often require higher doses of ICS
or are relatively refractory to corticosteroid treatment. Occupational asthma (i.e.,
asthma due to exposures at work) should be ruled out in patients presenting with
adult-onset asthma.

• Asthma with persistent airflow limitation:

Some patients with long-standing asthma develop airflow limitation that is

persistent or incompletely reversible. This is thought to be due to airway wall
remodeling.

• Asthma with obesity:

Some obese patients with asthma have prominent respiratory symptoms and a
different pattern of airway inflammation, with little eosinophilic inflammation. 48

There is little evidence about the natural history of asthma after diagnosis, but one
longitudinal study showed that approximately 16% of adults with recently
diagnosed asthma may experience clinical remission (no symptoms or asthma
medication for at least 1 year) within 5 years.49
Risk Factors and Triggers Involved in Asthma

Endogenous Factors

Atopy

Airway hyperresponsiveness

Ethnicity

Gender

Genetic predisposition

Environmental Factors

Allergens: indoor Allergens,outdoor (fungi, pollens)

Obesity

Occupational sensitizers

Parasitic infections

Respiratory infections (early childhood, viral)

Socioeconomic status

Tobacco smoking (active and passive)

Triggers
Allergens (especially house dust mite, animal dander, cockroach, indoor fungi,
perennial allergens, and seasonal pollens)

Changes in the weather (cold air, thunderstorms)

Drugs (angiotensin-converting enzyme inhibitors, aspirin, β-blockers, NSAIDs)

Exercise and hyperventilation Extreme emotional expression (laughing, stress)

Irritants (household sprays, paint fumes) Respiratory infections Sulfur dioxide and
pollutant gases Tobacco smoking

Patterns of respiratory symptoms that are characteristic of asthma

The following features are typical of asthma and, if present, increase the
probability that the patient has asthma.(GINA Guidelines)

Respiratory symptoms of wheeze, shortness of breath, cough and/or chest

tightness:

• Symptoms are often worse at night or in the early morning.

• Symptoms vary over time and in intensity.

• Symptoms are triggered by viral infections (colds), exercise, allergen exposure,

changes in weather, laughter, or irritants such as car exhaust fumes, smoke or
strong smells.
The following features decrease the probability that respiratory symptoms are due
to asthma:

• Chronic production of sputum

• Shortness of breath associated with dizziness, light-headedness or peripheral

tingling (paresthesia)

• Chest pain

• Exercise-induced dyspnea with noisy inspiration

Physical examination

Physical examination in people with asthma is often normal. The most frequent
abnormality is expiratory wheezing (rhonchi) on auscultation, but this may be
absent or only heard on forced expiration. Wheezing may also be absent during
severe asthma exacerbations, due to severely reduced airflow (so called ‘silent
chest’), but at such times, other physical signs of respiratory failure are usually
present. Wheezing may also be heard with inducible laryngeal obstruction, COPD,
respiratory infections, tracheomalacia, or inhaled foreign body (when wheezing
may be unilateral). Crackles (crepitations) and inspiratory wheezing are not
features of asthma. Examination of the nose may reveal signs of allergic rhinitis or
nasal polyps.

INITIAL DIAGNOSIS
Making the diagnosis of asthma before treatment is started is based on identifying
both a characteristic pattern of respiratory symptoms such as wheezing, shortness
of breath (dyspnea), chest tightness or cough, and variable expiratory airflow
limitation.50 The pattern of symptoms is important, as respiratory symptoms may
be due to acute or chronic conditions other than asthma. If possible, the evidence
supporting a diagnosis of asthma should be documented when the patient first
presents, as the features that are characteristic of asthma may improve
spontaneously or with treatment. As a result, it is often more difficult to confirm a
diagnosis of asthma once the patient has been started on ICS-containing treatment,
because this reduces variability of both symptoms and lung function. GINA
recognizes that, globally, many health professionals lack access (or ready access)
to spirometry51 so advice has also been provided for using PEF in asthma
diagnosis.

Category Feature Details

1.HISTORY OF TYPICAL Symptoms or features that -Wheeze, shortness of breath, chest

tightness, and/or cough
VARIABLE support the diagnosis of
RESPIRATORY asthma -Symptoms occur variably over

SYMPTOMS time and vary in intensity

- Symptoms are often worse at

night or on waking

- Symptoms are often triggered by

exercise, laughter, allergens, cold
air
 - Symptoms often appear or worsen
with viral infections

2. CONFIRMED Excessive variability in The greater the variations, or the

more occasions excess variation is
VARIABLE expiratory lung function
seen, the more confident the
EXPIRATORY AIRFLOW (one or more of the
diagnosis of asthma. If initially
LIMITATION following): negative, tests can be repeated
during symptoms or in the early
morning. If spirometry is not
possible, PEF may be used, but it is
less reliable.

Positive bronchodilator Adults: Increase from baseline in

FEV1 or FVC of ≥12% and 200
(BD) responsiveness
mL, with greater confidence if the
(reversibility) test with
increase is ≥15% and 400 mL; or
spirometry (or PEF+): increase in PEF+ ≥20% if
spirometry is not available.

Children: Increase from baseline

in FEV1 of ≥12% predicted (or in
PEF+ of ≥15%). Measure change
10-15 minutes after 200-400 mcg
salbutamol (albuterol) or
equivalent, compared with pre-BD
readings. Positive test more likely if
BD withheld before test: SABA ≥4
hours, long-acting bronchodilators
24-48 hours .

Excessive variability in Adults: Average daily diurnal PEF

variability >10%
twice-daily PEF over 2
weeks Children: Average daily diurnal
PEF variability >13%

Increase in lung function Adults: Increase from baseline in

FEV1 by ≥12% and ≥200 mL (or
after 4 weeks of treatment
PEF+ by ≥20%) after 4 weeks of

Positive bronchial challenge
test:
Excessive variation in lung
function between visits
(good specificity but poor
sensitivity):
daily ICS-containing treatment
Children: Increase from baseline in
FEV1 of ≥12% predicted (or in
PEF+ of ≥15%).
Adults: Fall from baseline in FEV1
of ≥20% with standard doses of
methacholine, or ≥15% with
standardized hyperventilation,
hypertonic saline or mannitol
challenge, or >10% and >200 mL
with standardized exercise
challenge.
Children: Fall from baseline in
FEV1 of >12% predicted (or fall in
PEF+ >15%) with standardized
exercise challenge. If FEV1
decreases during a challenge test,
check that FEV1/FVC ratio has also
decreased, since incomplete
inhalation, e.g., due to inducible
laryngeal obstruction or poor effort,
can result in a false reduction in
FEV1.
Adults: Variation in FEV1 of
≥12% and 200 mL (or in PEF+ of
≥20%) between visits
Children: Variation in FEV1 of
≥12% (or ≥15% in PEF+) between
visits
PEF+: Peak Expiratory Flow FEV1: Forced Expiratory Volume in 1 second

FVC: Forced Vital Capacity ICS: Inhaled Corticosteroids SABA: Short-Acting Beta-2 Agonists

Diagnostic flowchart for patients with chronic or recurrent respiratory symptoms

Credit: GINA Guideline 2024

Chronic Obstructive Pulmonary Disease

History of COPD

The term “emphysema” originates from the Greek word meaning “to blow into,”
implying “air-containing” or “inflated.” Historical descriptions of emphysema can
be traced back to Bonet in 167952, who referred to “voluminous lungs,” and
Morgagni in 176953, who described lungs as being “turgid particularly from air.”
The first detailed description of enlarged airspaces in emphysema in humans,
accompanied by illustrations, was provided by Ruysh in 172154. This was followed
by Matthew Baillie in 1807, who not only identified and illustrated emphysema but
also highlighted its destructive nature55,56.

In the early 1800s, Laennec57 made several significant contributions to the

understanding of COPD. He was the first to distinctly differentiate between
interstitial emphysema and true emphysema, linking the enlarged airspaces to the
clinical syndrome of emphysema. He also identified air trapping and increased
collateral ventilation as features of emphysematous lungs and recognized that
peripheral airways were the primary site of obstruction in emphysema.
Furthermore, Laennec noted that airspaces enlarged with age and differentiated
these changes from emphysema. He also described the association of emphysema
with chronic bronchitis and provided a clear description of the pathology of
bronchiectasis.
For nearly 150 years, little was added to the gross descriptive morphology of
emphysema. However, a significant advancement was made by J. Gough in 195258,
who described centrilobular emphysema and distinguished it from panlobular
emphysema. This advancement was largely due to the paper section technique
developed by Gough and Wentworth59, which facilitated the examination of entire
inflated lung sections. McLean60,61 later provided a comprehensive microscopic
description of emphysema, demonstrating the relationship between destruction and
inflammatory changes in the bronchioles and discussing alterations in the
vasculature.

Epidemiology of COPD

Chronic Obstructive Pulmonary Disease (COPD) is a major global health issue,

affecting over 400 million people worldwide. According to the Global Burden of
Disease Study, COPD was the sixth leading cause of disease in 1990 but has now
risen to the third leading cause of death, following cardiovascular disease and
stroke62.The World Economic Forum projects that by 2030, the global costs
associated with COPD will amount to $50 trillion annually63.

While traditionally seen as a disease primarily caused by tobacco smoking,

understanding of COPD's epidemiology has evolved. Research by Fletcher and
colleagues in the 1960s demonstrated that lung function decline was more
pronounced in susceptible smokers, but smoking cessation could slow this
decline64. Despite a decrease in smoking rates in developed countries, the global
burden of COPD continues to increase due to various factors, including rising
tobacco use in low- and middle-income countries, preterm births, poor nutrition,
childhood infections, and exposure to environmental pollutants65-70. Both indoor
and outdoor pollution from burning fuels like gas, coal, charcoal, wood, or dung
significantly contribute to COPD cases among non-smokers71-73, with women and
children in areas using biomass for cooking and heating being disproportionately
affected74,75.

Globally, prevalence rates range from 7% to 19%. Despite its widespread impact,
COPD is often underrecognized and underdiagnosed76-80. In the U.S., the age-
adjusted prevalence of COPD is 6.2%, with higher rates observed among less
educated individuals, those with lower socioeconomic status, rural populations,
women, older adults, and American Indians/Alaska Natives78. Studies support these
statistics; for instance, a survey of 1,575 cigarette smokers aged 30 or older with at
least a 10 pack-year smoking history found that approximately 20% met the
spirometric criteria for COPD81.

The Third National Health and Nutrition Examination Survey (NHANES III)
highlighted that men aged 65 with GOLD stage 4 COPD have a reduced life
expectancy by 5.8 years, with an additional 3.5 years lost if they continue
smoking82. The increasing burden of COPD underscores the urgent need for
primary prevention strategies and enhanced recognition and management of this
debilitating disease.
Etiology and Risk factors for COPD

1.Cigarette Smoking

Primary Cause: Cigarette smoking is the most significant risk factor for
developing COPD. The harmful chemicals in tobacco smoke cause chronic
inflammation in the airways and lung tissue, leading to structural changes and
airflow limitation.

Dose-Response Relationship: There is a strong dose-response relationship

between the amount of smoking and the risk of developing COPD. The risk
increases with the number of cigarettes smoked per day and the number of years
smoked83.

2.Environmental and Occupational Exposures

Air Pollution: Long-term exposure to outdoor air pollution, including particulate

matter, ozone, and nitrogen dioxide, is associated with an increased risk of COPD.

Occupational Exposures: Exposure to dust, fumes, and chemicals in the

workplace, such as in mining, construction, and manufacturing industries, can lead
to the development of COPD. Workers exposed to organic and inorganic dusts,
chemical agents, and fumes are at higher risk84.
3.Biomass Fuel Exposure

Indoor Air Pollution: In many developing countries, the use of biomass fuels
(wood, animal dung, crop residues) for cooking and heating in poorly ventilated
spaces leads to high levels of indoor air pollution. Women and children are
particularly at risk due to prolonged exposure85.

Smoke from Biomass Fuels: The smoke contains high concentrations of

pollutants that can cause chronic respiratory problems and contribute to the
development of COPD.

4.Genetic Factors

Alpha-1 Antitrypsin Deficiency: This genetic disorder is a well-documented risk

factor for COPD. Alpha-1 antitrypsin is a protein that protects the lungs from
neutrophil elastase. Deficiency leads to uncontrolled enzyme activity, resulting in
lung tissue damage and emphysema86.

Family History: Having a family history of COPD increases the risk, suggesting a
genetic predisposition to the disease.

5.Respiratory Infections

Childhood Infections: Severe respiratory infections in childhood, such as

whooping cough and tuberculosis, can impair lung development and function,
increasing the risk of COPD in 87.
Frequent Respiratory Infections: Adults who frequently suffer from respiratory
infections are at a higher risk of developing COPD, as these infections can cause
chronic inflammation and damage to the airways.

6.Socioeconomic Factors

Low Socioeconomic Status: Individuals with lower socioeconomic status are at

higher risk of developing COPD. Factors such as poor nutrition, overcrowded
living conditions, and limited access to healthcare contribute to this increased
risk88.

7.Age and Gender

Aging: The risk of COPD increases with age due to the natural decline in lung
function and the cumulative exposure to risk factors over time.

Gender Differences: Historically, COPD was more common in men due to higher
smoking rates. However, with the increase in smoking among women, the
prevalence of COPD in women is rising. Additionally, women may be more
susceptible to the harmful effects of smoking.

8.Asthma and Airway Hyperresponsiveness

Overlap with Asthma: Individuals with asthma who smoke or have severe asthma
are at increased risk of developing COPD. Chronic airway inflammation and
remodeling in asthma can lead to fixed airflow obstruction characteristic of COPD.
Airway Hyperresponsiveness: Increased airway responsiveness to various stimuli
is associated with a higher risk of COPD, especially in smokers.

9.Nutritional Factors

Poor Nutrition: Malnutrition can impair immune function and lung repair
mechanisms, increasing susceptibility to respiratory infections and COPD.

Pathophysiology of COPD

Chronic Obstructive Pulmonary Disease (COPD) is characterized by significant

changes in the structure and function of alveolar tissue and small airways. These
changes are driven by processes such as inflammation, cell proliferation, apoptosis,
and remodeling of the extracellular matrix. Key mediators in these processes
include proteinases, oxidants, and cytokines, which play crucial roles in the
pathophysiology of COPD.

Small Airway Resistance and Pathology

Research by Hogg and colleagues has shown that small airways with an internal
diameter of 2 mm or less, which normally contribute minimally to total airway
resistance, become the main sites of increased resistance in COPD. This increased
resistance is due to a combination of factors, including emphysema, which leads to
airway instability and collapse, and various anatomical abnormalities that narrow
the small airway lumens.
Both emphysema and small airway pathology are prevalent in COPD, complicating
the determination of their individual contributions to airflow obstruction. In
advanced COPD, pathological changes in small airways include goblet cell
metaplasia, replacement of Clara cells with mucus-secreting cells, infiltration of
airway walls by inflammatory cells, and increased connective tissue in the
subepithelial and adventitial compartments.

Role of Alveolar Tissue

Alveolar tissue surrounding small airways provides radial traction on bronchioles.

When these attachments are lost due to proteolytic destruction, it contributes to
airway distortion, narrowing, and instability. Advanced imaging techniques, such
as parametric response mapping (PRM), have enhanced our ability to identify early
signs of disease by analyzing the pattern and location of emphysema, airway
caliber, and distal airway dropout.
 Credit: Cleveland clinic 2021

Radiologic and Pathologic Findings

In advanced COPD, the significant loss of terminal airways leads to increased

small airway resistance. In the early stages, this loss may result from pathologic
destruction, severe wall thickening, or mucus plugging that obscures the lumen.
More severe airflow obstruction correlates with increased thickness of all airway
wall components, especially the connective tissue-rich adventitial layer. The
epithelial layer, lamina propria, and smooth muscle-containing layer also thicken
significantly, and mucus plugs in small airways are strongly linked to airflow
limitation.
Airflow Obstruction

COPD is typically diagnosed by a post-bronchodilator FEV1/FVC ratio of less

than 0.70, as recommended by the American Thoracic Society (ATS) and GOLD
guidelines. Patients with a reduced FEV1 but normal FEV1/FVC and normal TLC
are classified as having preserved ratio impaired spirometry (PRISm). The FEV1 is
a critical measure of airflow, indicating the balance between lung elastic recoil and
airway resistance during forced vital capacity (FVC) performance.

In mild COPD, abnormalities in airflow are noticeable only at lung volumes at or

below functional residual capacity, presenting as a “scooped out” lower part of the
descending limb of the flow-volume curve. In advanced COPD, the entire curve
shows decreased expiratory flow. The relationship between FEV1 and small
airway pathology is strong, contributing to FEV1 reduction independently of
emphysema.

Airway Hyperresponsiveness (AHR)

Airway hyperresponsiveness (AHR) in COPD is indicated by an acute decrease in

maximal expiratory airflow in response to bronchoconstricting agents such as
methacholine or histamine. The “Dutch hypothesis” historically suggested that
asthma and COPD are different manifestations of the same disease due to their
shared feature of AHR. However, the nature and consequences of airway
inflammation in COPD differ from those in asthma.
AHR is a significant predictor of accelerated FEV1 decline and a negative
prognostic marker. In the Lung Health Study, AHR was a major determinant of
FEV1 decline, second only to smoking, and was more significant in women
smokers than in men. Although AHR decreases after smoking cessation and
bronchodilator responsiveness improves, the latter does not correlate with the rate
of FEV1 decline. AHR in COPD is often underestimated due to infrequent
bronchoprovocation testing and may result from emphysema, airway wall stiffness,
and parenchymal tethering by the extracellular matrix

Pathogenesis of COPD

Chronic Obstructive Pulmonary Disease (COPD) is characterized by dysregulated

inflammatory reactions, oxidative stress, mucus hypersecretion, and proteinase-
antiproteinase imbalance, leading to lung tissue damage, elastic fiber degradation,
and increased collagen turnover.

Inflammation

Innate Immune Responses: Exposure to tobacco smoke and other irritants recruits
and activates inflammatory cells in the lungs and airways. Key cells involved
include neutrophils, macrophages, eosinophils, dendritic cells, and lymphocytes.
Macrophages release proteinases that degrade lung extracellular matrix and
chemotactic factors that recruit other inflammatory cells. Neutrophilic
inflammation, a hallmark of COPD, drives mucus hypersecretion but is
unresponsive to current therapies. Eosinophilic inflammation is present in 20-40%
of COPD patients and is associated with exacerbations.

Acquired Immune Responses: Cellular and humoral immunity contribute to COPD

progression, even after smoking cessation. Increased presence of cytotoxic CD8+
T cells, Th1, Th17 cells, and altered T regulatory cells (TREGs) are noted. B cells
and antibody production, as well as natural killer (NK) and NKT cells, also play
roles in COPD inflammation.

Oxidative Stress

Cigarette smoke contains numerous oxidants and free radicals that cause
inflammation, cell injury, and apoptosis. Genetic mutations in antioxidant genes,
such as GST and SOD3, are linked to COPD susceptibility and severity. Oxidants
modify and inactivate protease inhibitors and anti-inflammatory proteins,
contributing to lung damage.

Proteinase-Antiproteinase Imbalance

The imbalance between proteinases and their inhibitors is critical in emphysema

development. Key proteinases include neutrophil elastase and matrix
metalloproteinases (MMPs). This imbalance leads to lung tissue destruction,
affecting cytokine processing and surface receptors involved in inflammation.

Mucus Hypersecretion

Excess mucus production, driven by cytokines, chemokines, and inflammatory

mediators, is common in COPD. Changes in mucus composition, including altered
mucin proteins and decreased antimicrobial peptides, contribute to airway
obstruction and disease progression.

Lung Elastic Fiber and Collagen Turnover

Destruction of elastic fibers and increased collagen turnover contribute to

emphysema. Proteinases degrade alveolar elastic fibers, leading to tissue loss and
altered alveolar structure. Increased collagen deposition and breakdown, mediated
by MMPs and other enzymes, further exacerbate lung damage.
 (A)nonemphysematous lung (B)Holes are more numerous in alveolar walls in the
emphysematous lung than in the normal lung.

Definitions

MILD COPD: used only to describe the severity of airflow obstruction measured .

YOUNG COPD: occurs around 20-25 years of age.

Pre-COPD: who have respiratory symptoms and/or other detectable structural
and/or functional abnormalities, in the absence of airflow obstruction on forced
spirometry

PRISm: The term PRISm (preserved ratio impaired spirometry) describes

individuals with preserved ratio (FEV1/FVC ≥ 0.7 after bronchodilation) but
impaired spirometry (FEV1 < 80% of reference, after bronchodilation)

Proposed Taxonomy (Etiotypes) for COPD

Adapted from Celli et al. (2022) and Stolz et al. (2022)

1.Genetically Determined COPD (COPD-G)

Alpha-1 Antitrypsin Deficiency (AATD): A genetic condition leading to low levels

of alpha-1 antitrypsin, increasing the risk of lung damage.

Other Genetic Variants: Variants with smaller effects that may act in combination
to contribute to COPD development.

2. COPD Due to Abnormal Lung Development (COPD-D)

Early Life Events: Factors such as premature birth, low birth weight, and other
early life conditions that affect lung development.
3.Environmental COPD

Cigarette Smoking COPD (COPD-C):

Exposure to Tobacco Smoke: This includes active smoking, in utero exposure, and
passive smoking (secondhand smoke).

Vaping or E-Cigarette Use: Use of electronic nicotine delivery systems.

Cannabis Use: Smoking cannabis as a contributing factor.

4.Biomass and Pollution COPD (COPD-P):

Household Pollution: Exposure to indoor air pollutants such as cooking smoke

from biomass fuels.

Ambient Air Pollution: Exposure to outdoor air pollutants including industrial

emissions and traffic-related air pollution.

Wildfire Smoke: Exposure to smoke from wildfires.

Occupational Hazards: Exposure to dust, fumes, and chemicals in the workplace.

5.COPD Due to Infections (COPD-I)

Childhood Infections: Respiratory infections during childhood that may contribute

to long-term lung damage.

Tuberculosis-Associated COPD: COPD resulting from pulmonary tuberculosis.

HIV-Associated COPD: COPD development in individuals with HIV due to
chronic inflammation and opportunistic infections.

6.COPD & Asthma (COPD-A)

Asthma-COPD Overlap (ACO): Presence of both COPD and asthma, particularly

childhood asthma that persists into adulthood.

7.COPD of Unknown Cause (COPD-U)

Unidentified Etiologies: Cases where the cause of COPD cannot be determined.

Clinical Presentation

Symptoms

Chronic dyspnea is the hallmark symptom of COPD. Cough with sputum

production affects up to 30% of patients and can fluctuate daily, sometimes
predating airflow obstruction by several years. People with COPD risk factors
presenting with these symptoms should be thoroughly evaluated to identify the
underlying causes. Notably, airflow obstruction can exist without chronic dyspnea,
cough, or sputum production, and vice versa. Despite COPD being defined by
airflow obstruction, the decision to seek medical help is usually driven by the
impact of symptoms on functional status. Patients may seek medical attention for
chronic respiratory symptoms or acute episodes of exacerbated respiratory
symptoms.
Dyspnea

Dyspnea is a primary symptom of COPD, significantly contributing to the

disability and anxiety associated with the disease. It includes both sensory and
affective components. COPD patients often describe dyspnea as an increased effort

to breathe, chest heaviness, air hunger, or gasping. The experience of dyspnea can
vary individually and culturally and is prevalent across all stages of airflow
obstruction, particularly during physical exertion. More than 40% of COPD
patients in primary care report moderate-to-severe dyspnea. Dyspnea's
pathogenesis involves multiple mechanisms, including impaired respiratory
mechanics due to airflow obstruction and lung hyperinflation, gas exchange
abnormalities, peripheral muscle dysfunction from deconditioning and systemic
inflammation, psychological distress, dysfunctional breathing, and comorbid
cardiovascular or other diseases. Dyspnea severity, measured by the 5-level
modified Medical Research Council scale, is part of the GOLD clinical
classification scheme due to its association with higher healthcare resource
utilization and costs. Various detailed questionnaires are available to measure
dyspnea in daily life, offering more discrimination and sensitivity to change.
Chronic Cough

Chronic cough often marks the onset of COPD but is frequently dismissed by
patients as a normal consequence of smoking or environmental exposures. Initially
intermittent, it can become a daily occurrence. Chronic cough in COPD may be
productive or nonproductive, and significant airflow obstruction can develop
without a cough. Chronic cough can also be caused by other conditions. In severe
COPD, syncope during coughing can occur due to rapid increases in intrathoracic
pressure. Persistent coughing spells can lead to rib fractures, sometimes without
symptoms.

Sputum Production

COPD patients typically raise small amounts of thick sputum with coughing.
Chronic bronchitis is classically defined by the production of sputum for three or
more months in two consecutive years, excluding other conditions. However, this
definition does not cover the full range of sputum production in COPD. Evaluating
sputum production can be challenging because patients may swallow sputum rather
than expectorate it, and this habit varies by culture and sex. Sputum production can
also be intermittent, with flare-ups and remissions. Large volumes of sputum may
indicate underlying bronchiectasis. Purulent sputum suggests increased
inflammatory mediators and may signal the onset of a bacterial exacerbation,
though this association is relatively weak.
Wheezing and Chest Tightness

Wheezing and chest tightness can vary daily and within a single day. Wheezes,
either inspiratory or expiratory, may be heard on auscultation. Chest tightness,
often following exertion, is poorly localized and muscular in character, possibly
arising from isometric contraction of the intercostal muscles. The absence of
wheezing or chest tightness does not rule out COPD, nor does their presence
confirm asthma.

Fatigue

Fatigue, a subjective feeling of tiredness or exhaustion, is a common and

distressing symptom in COPD. Patients describe it as "general tiredness" or feeling
"drained of energy." Fatigue affects daily activities and quality of life.

Additional Clinical Features in Severe Disease

Weight loss, muscle mass loss, and anorexia are common in severe and very severe
COPD, have prognostic significance, and could indicate other diseases like
tuberculosis or lung cancer, warranting investigation. Ankle swelling may signal
cor pulmonale. Depression and anxiety are common in COPD, associated with
poorer health status, increased risk of exacerbations, emergency hospital
admissions, and are treatable.
Physical Examination

While essential to patient care, physical examination alone is seldom diagnostic for
COPD. Physical signs of airflow obstruction typically do not appear until there is
significant lung function impairment. Consequently, detecting COPD based solely
on physical examination has low sensitivity and specificity. Various physical signs,
such as lung hyperinflation and cyanosis, may be observed in COPD patients, but
their absence does not rule out the diagnosis.

Credit: GOLD Guidelines

COPD Assessment

In the 2023 GOLD report, GOLD proposed a further evolution of the ABCD
combined assessment tool that recognized the clinical relevance of exacerbations,
independently of the level of symptoms of the patient. The A and B groups
remained unchanged, but the C and D groups were merged into a single group
termed “E” to highlight the clinical relevance of exacerbations. It was
acknowledged that this proposal would have to be validated by appropriate clinical
research.
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