Fibrosis is a highly dynamic process, and it can affect any organ including the skin, lungs, liver, and kidney. IPF is defined as an excessive deposition of extracellular matrix (ECM) proteins in the lung tissue, which makes the lungs unable to transport oxygen into the bloodstream efficiently and often leads to lung failure. Although the etiology of IPF is unknown, several risk factors such as cigarette smoking, occupational factors, genetic polymorphisms, and environmental exposure can contribute to the development of IPF. IPF is a clinically heterogeneous disease with an overall prognosis being very poor; typically, it has a median survival of 3–4 years (35, 53). Repetitive injury to the alveolar epithelium, failure to reepithelization, increased AEC apoptosis, and induction of growth factors and profibrotic cytokines such as transforming growth factor-β1 (TGF-β1), TNF-α, platelet-derived growth factor, and connective tissue growth factor (CTGF) are implicated in the progression of IPF (54). In addition to AEC apoptosis, fibroblast differentiation, accumulation of myofibroblasts, and excessive collagen deposition in the alveolar space promote the progression of fibrosis (55, 56).

CD4+ T cells in IPF: One of the main challenges in lung fibrosis is that the exact molecular and cellular mechanisms underlying the disease remain largely unknown. However, damage to the airway epithelium (apoptosis) is considered as an early pathogenic event, with an irregular repair process by epithelial-mesenchymal interactions, rather than an inflammatory response (57). Although over the several decades the role of inflammation has been questioned in fibrosis (58), data from IPF patients and experimental animal models have shown a prominent role of T helper cell type-2 (Th2) cells in IPF (59). It has been shown that each of the major Th2 cytokines such as IL-4, IL-5, and IL-13 contribute to the regulation of tissue remodeling and subsequent fibrosis. In-vitro studies have shown that stimulation with IL-4 increased collagen production in murine fibroblasts (60). Moreover, IL-4 concentrations were increased in the bronchoalveolar lavage fluids from patients with idiopathic pulmonary fibrosis (61). Along similar lines, IL-4 has been shown to induce periostin which may play a role in fibrosis (62).

IL-13 is another Th-2 cytokine that has been shown to play a key role in lung fibrosis and increased expression of IL-13 was repeatedly reported in IPF. Overexpression of IL-13 augmented subepithelial airway fibrosis in the mouse lung (63). Studies done in animal models have demonstrated that treating with anti-IL-13 antibodies significantly decreased aspergillus fumigatus-induced collagen levels in the lung (64). In a different study, it was demonstrated that IL-13 deficient mice were unaffected by radiation-induced fibrosis compared to wild-type mice (65).

In addition to IL-4 and IL-13, it has been observed that IL-5 can also play a role in tissue remodeling in several diseases including pulmonary fibrosis (66). It was demonstrated that IL-5 levels were increased in the lungs of bleomycin-treated mice (67). Further, it was shown that anti-IL-5 antibody caused a significant reduction in lung eosinophils and fibrosis in a bleomycin-induced pulmonary fibrosis mouse model (68). Given the role of IL-4, IL-5, and IL-13, it is crucial to identify other cytokines and receptors that may contribute to the aberrant cellular mechanisms in the IPF lung.

AEC apoptosis in IPF: The respiratory epithelium is a physical and functional barrier, shielding the underlying lung microenvironment. It plays a crucial role in the clearance of pathogens and harmful bacteria (69). Apoptosis, or programmed cell death, is a vital biological process in the maintenance of tissue homeostasis (70). However, in recent years, seminal works have supported the notion that excessive apoptosis is linked to diseases such as IPF, emphysema, and acute lung injury (71). It has been shown in a variety of animal models that blockade of AEC apoptosis reduces subsequent fibrosis (72). A broad-spectrum caspase inhibitor has been shown to decrease caspase-1 and caspase-3 activity, reducing the number of apoptotic cells. This led to a reduction in lung collagen in a bleomycin-induced mouse model (73). At a cellular and molecular level, there are many signaling pathways and factors that contribute to AEC apoptosis, such as the angiotensin (ANG) system. Several studies have demonstrated that manipulation of the ANG system can control apoptosis in the alveolar epithelium (74). Therefore, protecting AECs from apoptosis and sustaining their function might be an effective therapeutic strategy to decrease lung injury.

Current treatment strategies for IPF: Recent research contains a wealth of information on cellular and molecular signaling mechanisms in IPF, and we now have a better understanding of its pathophysiology. Specifically, IPF is no longer considered a pro-inflammatory disorder, but rather it is the result of a fibroproliferative environment and aberrant wound healing mechanisms (75) Currently, two antifibrotic therapies are available for IPF patients: pirfenidone and nintedanib. Pirfenidone has been recognized for its antioxidant and antifibrotic effects (76) is a tyrosine kinase inhibitor that inhibits fibroblast proliferation and differentiation and improves lung function (77). Given the heterogeneity of IPF, targeting multiple signaling pathways and multiple cell types may offer novel therapeutics to patients.

COPD is a disease with high morbidity and mortality rates. It is characterized by chronic inflammation that leads to poorly reversible airway obstruction (78). The most common risk factor for the development of COPD is cigarette smoke. However, other harmful environmental factors such as exposure to air pollutants might contribute to COPD. Patients with COPD have significant levels of circulating inflammatory markers, demonstrating the presence of systemic inflammation (79). Persistent airway inflammation in COPD contributes to airway remodeling, loss of small airways, and emphysema (80). Emphysema is a major pathological change of COPD, which is characterized by the enlargement of alveolar airspaces due to the destruction of the alveolar epithelium (81).

Inflammation in COPD: The pathogenesis of COPD is multifaceted and the underlying cellular and molecular mechanisms remain poorly understood. In COPD, the inflammatory response involves both innate and adaptive immunity. The predominant form of COPD is neutrophilic inflammation, which correlates with the rate of decline in lung function (82, 83). In addition to the well-known augmented influx of neutrophils in COPD, aberrant clearance of neutrophils possibly contributes to the dysregulated inflammation in COPD (84). Aberrant clearance of neutrophils might be a result of defective phagocytic responses in alveolar macrophages. It was demonstrated that cigarette smoke could hinder the clearance of neutrophils, inducing pro-inflammatory cytokines such as TNF-α (85). According to a recent study by Borges et al., the administration of TNF-α weakened the removal of apoptotic cells from the lungs in a mouse model of LPS-induced neutrophilic inflammation (86). Even though neutrophil-associated inflammation is the most common inflammatory phenotype in COPD, 10%–40% of COPD patients demonstrate increased eosinophilic inflammation (87). Additionally, it was shown that airway β-defensin-1 levels were significantly elevated in the sputum of COPD patients (88) whereas secretory IgA (sIgA) levels were markedly reduced due to altered epithelial cell differentiation in the airways of COPD patients (89) Following exposure to cigarette smoke, pollutants, and microbes, alarmins such as TSLP, IL-33, and IL-25 are released from the epithelium. Following T-cell differentiation, Th-2 cells produce IL-4, IL-5, and IL-13, all of which contribute to an inflammatory environment ( Figure 2 ) (90). Induction of IL-4 can lead to an increase in total IgE levels in eosinophilic COPD, which might contribute to a decline in lung function (91).

Current treatment strategies for COPD: Although current therapies for COPD have significantly improved the management of the disease, novel therapeutic approaches are still urgently needed, especially for suppressing inflammation in small airways (92). Cigarette smoke is one of the major factors for COPD and smoking cessation has so far been shown to diminish disease progression. Currently, several methods of nicotine replacement therapies are in use. However, the efficacy of these therapies remain to be further investigated (93). A variety of other interventions can lower the exacerbations in COPD, including influenza vaccination (94), anti-cholinergic bronchodilators (95), long-acting β₂-agonists (LABAs) (96), and inhaled corticosteroids (ICSs). Further research is needed to understand the cell signaling mechanisms of COPD so that biomarkers can be identified and new therapies can be developed (92).

Asthma is a chronic inflammatory disease characterized by airway obstruction, excessive mucus production, and airway hyperresponsiveness (AHR). Asthma affects over 300 million people worldwide (97). The prevalence of asthma is increasing in many parts of the world, contributing to a substantial global economic burden. Clinically, asthma patients show episodes of cough, chest tightness, wheeze, and shortness of breath (55). There is currently no cure for asthma, but treatment can help ameliorate symptoms and improve the quality of life. Currently, the therapeutic challenge is to generate better inhalation technologies to improve the delivery of anti-inflammatory agents to the lung parenchyma (98). It was interesting to note that polymorphisms in antimicrobial proteins such as β-defensins can contribute to the severity of asthma. In fact, Baines et al., demonstrated that airway β-defensin-1 was elevated in severe asthma patients regardless of the inflammatory phenotype and may act as an effective biomarker and potential therapeutic target (88). Recent seminal work indicates that asthma is generally associated with Th2 immune responses, which is like other conditions such as atopic dermatitis. In this section of the review, we discuss the Th2 immune responses in asthma. Further, we discuss the available treatments and their limitations for asthma.

Th2 immune responses in asthma: The pathophysiology of asthma is complex and involves various host-environment interactions and inflammatory responses occurring at various levels. There are two subtypes of asthma: allergic and non-allergic. Allergic asthma is the most common form of disease that affects many individuals. Allergic asthma may get triggered in response to house dust mites, animal dander, mold, and pollens, whereas non-allergic asthma might be the result of respiratory viral infections, cold air, and tobacco smoke leading to chronic airway inflammation (99). Inflammation of the airways is a key component that leads to airway remodeling and damage. Th2 cytokines, including interleukin (IL)-5, IL-4, and IL-13 play a significant role in initiating the inflammatory cascade in asthma (100). A recent study showed that blockade of Th2-cell-mediated responses reduced symptoms for many patients, thereby demonstrating the central role of Th2 cells in the pathophysiology of asthma (101).

Eosinophils are bilobed leukocytes that are present in low numbers in healthy individuals. However, during asthma, Th2 cytokines such as IL-5 can induce prolonged eosinophil survival, activation, and trafficking to the site of injury (102). Recruitment of eosinophils to the site of injury results in an induction of cytokines and growth factors such as tumor growth factor b (TGF-β), leading to airway remodeling (103). An increased number of eosinophils have been observed in bronchoalveolar lavage (BAL) fluid and bronchial tissue in asthma patients (104). Further, elevated eosinophil counts correlate with disease severity, suggesting that these cells may play a significant role in asthma pathogenesis (104). IL-4 is a major cytokine in the development of inflammation in asthma. It is associated with the induction of isotype switching and secretion of IgE by B cells (105). IgE production, in turn, triggers the release of inflammatory cytokines, such as histamine, from mast cells that causes contraction of the smooth muscle in the airways, edema, and increased mucus secretion (106). Additionally, another crucial activity of IL-4 in stimulating inflammation is the induction of vascular cell adhesion molecule (VCAM)-1 on vascular endothelium in the asthmatic lung (107). Through the interaction of VCAM-1 and integrins on leukocytes, T lymphocytes, monocytes, and eosinophils can migrate to the injury site (108). Aberrant production of IL-4 due to genetic mutations or hyperresponsiveness to this cytokine might further contribute to the severity of asthma (109). Another cytokine that contributes to the pathophysiology of asthma is IL-13, a pleiotropic Th2 cytokine that contributes to goblet cell differentiation, activation of fibroblasts, and increased airway hyperresponsiveness (110). Further, IL-13 is believed to be a central regulator of mucus hypersecretion and fibrosis, leading to airway remodeling (111).

Most recently, a Th9 subtype of CD4⁺ T cells has emerged. These cells produce IL-9 a pleiotropic cytokine that may play role in inflammatory responses in asthma (83). IL-9 is secreted not only by CD4⁺ T cells but also by a variety of other T cells such as mast cells, and innate lymphoid cells (ILC-2) cells (112). It has been shown that in the presence of IL-4 and TGF-β, naïve CD4⁺ T cells develop into Th9 cells. In allergic diseases IL-9 has been shown to induce IgE production by B cells, activate mast cells, and play a pivotal role in mucus secretion (113, 114).

Role of thymic stromal lymphopoietin in asthma: Our understanding of the airway epithelium in driving asthma pathogenesis has progressed extensively in recent years. In response to allergic and non-allergic triggers, airway epithelial cells release cytokines, known as “alarmins,” such as TSLP, IL-33, and IL-25 ( Figure 2 ), which stimulate downstream inflammatory responses (115). More recently, TSLP has emerged as an important factor in the pathogenesis of asthma, and increased levels of TSLP have been detected in asthma patients (116). TSLP can be induced by proinflammatory cytokines such as IL-1, TNF-α, bacterial and viral infections, Toll-like receptors, and allergens. The nuclear factor-kappa-B (NF-kB) pathway plays an important role in the mechanism of TSLP activation (117). Once TSLP is upregulated, it binds to its receptor TSLPR (118). A recent study showed that IL-7Rα binds to the TSLP/TSLPR complex with high affinity (119), and this ternary complex initiates a signaling cascade that activates STAT5 transcriptional factors (120). TSLP can interact with dendritic cells (DCs) to enhance antigen presentation to induce CD4⁺ cells (121). TSLP-activated mature DCs can then migrate to lymph nodes to initiate adaptive responses. Further, during non-allergic asthma, TSLP activates innate lymphoid cells (ILC-2) to produce Th2-like cytokines (121). According to a recent study, the blockade of TSLP reduces allergen-induced inflammation in animal models (122).

Current treatment options for severe asthma: Multiple phenotypes of severe asthma have been identified, showing the significance of tailored treatment options to meet individual needs. Most patients with asthma attain decent control of the disease with the use of inhaled corticosteroids and bronchodilators (123) However, many patients with asthma, especially in developing countries, remain unattended and suffer from poor quality of life (124). Recently, monoclonal antibodies have emerged as a new treatment option for uncontrolled asthma, targeting different signaling molecules in the pathways causing airway inflammation. Omalizumab is the first FDA-approved drug to treat severe asthma (125). It binds to IgE and prevents binding to its receptor on mast cells (125). Mepolizumab is a fully-humanized anti–IL-5 antibody that binds to IL-5 with high affinity to prevent IL-5 from binding to IL-5 receptors on eosinophils (126). Although many treatment options are available for patients with asthma, not all people with severe disease can benefit from the same biological drug, and therefore, an appropriate biological drug must be carefully selected for each patient. Although management of asthma varies among individuals, it’s crucial to protect patients with asthma from infectious lung diseases caused by bacteria and viruses. People with asthma are more susceptible to developing pneumonia due to previous lung damage. The section below explains several lung infectious diseases such as bronchitis, pneumonia, and disease pathogenesis.

Etiology: Bronchitis and bronchiolitis involve inflammation of the bronchial tree. Bronchitis is usually preceded by an upper respiratory tract infection and can be caused by a combination of environmental factors and bacterial infections by pathogens such as Haemophilus influenzae and Streptococcus pneumoniae. Chronic bronchitis is classically defined as persistent cough and sputum production with periodic exacerbation (171). Bronchiolitis is a viral respiratory disease of infants and is caused primarily by respiratory syncytial virus (RSV), influenza viruses, or rhinovirus. Bronchiolitis is a mild, self-limited infection in most children but may sometimes progress to respiratory failure in infants (172).

Pathogenesis and clinical manifestations: When the bronchial tree is infected, inflammation ensues, and the mucosa becomes hyperemic and edematous. Bronchial secretion increases in the mucosa and mucociliary function of the epithelium reduces. This reduces lower respiratory volume and leads to increased dyspnea, tachypnea, large amounts of sputum, tightness in the chest, fatigue, and confusion (173). The extent of damage to the mucosa can depend on the organisms(s) involved, bacterial toxins secreted, and other metabolic products produced (174). Infants with bronchiolitis suffer from inflammation in the airways and necrosis of the respiratory epithelium. Bronchial and bronchiolar walls thicken in bronchiolitis, and an exudate made up of necrotic material and respiratory secretions narrow the bronchial lumen, leading to airway obstruction. Clinical manifestations include fever, deepening of cough, dyspnea, tachypnea, wheezing, or actual lack of breath. Areas of air-pockets can develop, which may eventually result in respiratory failure and death (172, 174).

Microbiological diagnosis: Cough in the absence of fever, tachycardia, and tachypnea suggests bronchitis; however, bacteriological examination and culture of purulent respiratory secretions must be done for confirmation (175). Rapid diagnostic tests can be used to detect several pathogens linked to acute bronchitis; however, not all rapid tests are widely available and cost-effective. Aspirations of nasopharyngeal secretions or swabs from infants with bronchiolitis are collected as samples and serologic tests are done to identify the virus (176).

Prevention and treatment: With only a few exceptions, viral infections are treated with symptomatic care. Children with mild-to-moderate symptoms can be treated with nasal saline, antipyretics, and a cool-mist humidifier. On the contrary, children with severe respiratory distress should be admitted to the hospital and carefully monitored. The use of corticosteroids, bronchodilators, or prophylactic measures may benefit children with chronic bronchitis. RSV infections in infants may be treated with ribavirin, and influenza type A viruses may be treated with amantadine and rimantadine (175).

Pneumonia is an inflammation of the lung parenchyma, caused by several factors such as environmental contaminants, autoimmune diseases, and infection. Anatomically, pneumonia can be classified as lobar pneumonia (affecting the entire lobe) or bronchopneumonia (affecting patches of the lobe). Further, it can be etiologically classified as community-acquired pneumonia (CAP, infection in a previously healthy individual) or hospital-acquired pneumonia (infection in a hospitalized individual within 48 hours of admission).

Etiology: Bacterial pneumonias- S. pneumoniae is the most common cause of CAP and a leading cause of illness in children below 2 years of age, the elderly, and immunocompromised individuals (177). Pneumonias caused by other Streptococci are uncommon. Streptococcus pyogenes pneumonia is often associated with hemorrhagic pneumonitis and empyema. Pneumonia due to H. influenzae (usually nontypable) and Klebsiella pneumoniae are more common among patients over 50 years old with chronic obstructive lung disease or alcoholism, whereas pneumonia due to Mycoplasma pneumoniae and Chlamydophila pneumoniae are more common in school-aged children. Other less common agents causing pneumonias include Francisella tularensis, Legionella pneumophila, Yersinia pestis, and Neisseria meningitidis (178). Mycobacterium tuberculosis (Mtb) causes pulmonary pneumonia; however, the incidence of tuberculosis is low in industrialized countries. Nonetheless, it remains to be a significant public health problem in the United States.

Viral pneumonias- Pneumonias by RSV and Adenoviruses are rare in the healthy population. Pneumonia caused by influenza viruses is still a cause of high mortality in the elderly and in patients with underlying diseases. A serious complication of influenza is a secondary bacterial pneumonia which can be fatal in infants.

Other pneumonias- Actinomyces and Nocardia spp can cause pneumonitis. Aspergillus and Candida spp cause pneumonias in severely ill or immunosuppressed patients and neonates, whereas Pneumocystis carinii causes life-threatening pneumonia in patients with HIV.

Pathogenesis and clinical manifestations: The onset of pneumonia is quite abrupt; it develops with a shaking chill, fever, malaise, cough, and dyspnoea. Left untreated, this toxic illness can progress to acute respiratory failure, septic shock, multiorgan failure, and death within several days from onset (179). Respiratory failure due to pneumonia occurs when inflammatory exudate fills the alveoli and reduces its normal functional capacity. The persistence of pulmonary artery blood flow to the consolidated lung airspace during pneumonia leads to an intrapulmonary shunt that can also result in respiratory failure (180).

Microbiological diagnosis: A clinical examination of sputum is done to identify the infectious agent. Cultures of sputum, blood, and pleural fluid help in identifying the causative agent. The sputum quellung test can be used to identify S. pneumoniae, H. influenzae, and K. pneumoniae by serotype. In addition, rapid diagnostic tests based on PCR, ELISA, or other DNA probes can be used to identify other causative agents of pneumonia. Viral infections are usually diagnosed by serological testing for related antigens or antibodies in pulmonary secretions.

Prevention and treatment: Clinical diagnosis of the pathogen causing pneumonia is of utmost importance to deploy effective treatment options. Amoxicillin or amoxicillin clavulanate is the most common first-line antimicrobial agent used for CAP (181). In children suspected of having influenza and moderate-to-severe CAP, early antiviral therapy has been proven to be very helpful (182). Pneumococcal vaccines are available for high-risk populations; and along with yearly influenza vaccinations have been proven to reduce pneumonia burden and hospitalizations in children and adults (176). However, due to the presence of allelic variations amongst the bacterial serotypes, the current vaccines do not provide protection against all serotypes (183, 184). Since transmission occurs by droplets or contact, good hand washing, and good personal hygiene are the most important measures to prevent the spread of pneumonia.

The effective treatment of respiratory disorders using inhalation devices is closely associated with the formulations available for different types of diseases and the efficiency of the inhaler to aerosolize and deliver the drug to the appropriate location in the respiratory tract. For example, albuterol and ipratropium are bronchodilators used to treat COPD. These are available as liquid formulations (solutions) that can be conveniently aerosolized and delivered to the patient using nebulizers and pressurized metered-dose inhalers (pMDI) (190–193). Three processes govern the deposition of aerosol particles in the respiratory tract: inertial impaction, sedimentation, and diffusion. For most of the inhaled medications, the principal mechanisms of aerosol deposition are impaction and sedimentation (194, 195). Particles of size 3-7 µm get deposited by impaction predominantly in the oropharynx and the larger conduits of the respiratory tract. This impaction takes place particularly at the bifurcation of airways and sites, posing an obstruction to free flow of air, whereas the smallest aerosol particles (2-3 µm) can reach the terminal bronchioles and alveoli (194–196). Aerosol particle sedimentation is influenced by several factors including gravity, dimensions of air conduits, and breath hold time. The fine-particle fraction (FPF) of the inhaled drug that contains <5 µm aerosol particles is most crucial in bringing about desired clinical effects. Inhalers differ widely in respect to the fine-particle fraction, ranging from 10%–50% for pMDI, 12%–35% for dry powder inhalers (DPI), to 30%–50% for the soft mist inhalers (SMI).

The physicochemical and pharmacokinetic properties of drugs, such as half-life, molecular weight, solubility, lipophilicity, charge, and protein binding are important in determining their clearance from the lungs (8). Lipid-soluble molecules can traverse the respiratory tract epithelium by passive transport, whereas hydrophilic molecules travel through extracellular conduits. Medications administered by inhalation are deliberately rendered lipophilic to allow slow dissipation from the lungs and thus exert their effect over a longer duration.

The choice and suitability of an aerosol delivery device for a particular patient depends on the recommendations of the physician, available types of formulations, and compliance with the personal ease and comfort of the patient ( Table 4 and Figure 3 ).

pMDIs were the foremost among the extensively used inhaler devices (190, 191, 197) and continue to be popular to date due to ready availability, reasonably low cost, multidose drug administration, small size, easy portability, and the availability of many compatible formulations. The majority of the patients with asthma or COPD are administered with bronchodilators (albuterol/ipratropium) using pMDIs. Inhaled drugs for the treatment of obstructive lung disorders are widely available for use with pMDI, either singly or in combination. The formulation used in PMDIs may be a solution, suspension, or co-suspension. In addition, it contains other ingredients like propellants, co-solvents, and surfactants (for example, lecithin or oleic acid) (198). Sometimes, pMDIs show a problem of flocculation of drug crystals, leading to sedimentation. Particle crystal agglomeration can be minimized using surfactants. A novel strategy, known as co-suspension technology, helps to ameliorate this problem. It involves attaching phospholipid particles to the drug molecules to render a more uniform drug suspension, enabling the formulation of drug combinations and relying less on the need for shaking before use (199). pMDIs are not suitable for inhaled drug administration to young children without the use of a valved holding chamber. Moreover, administration using pMDIs results in high deposition of the drug in the oropharynx with relatively less amount reaching the finer airways in the lungs. The requirement of a propellant and the need to shake vigorously before use are some other concerns pertaining to the use of pMDIs.

Nebulizers are the earliest among the modern methods of delivering aerosols to the lungs for respiratory drug delivery. Nebulizers are routinely used in hospitals and home settings. Several newer nebulization technologies have enabled more efficient use of nebulizers as drug delivery devices. A jet nebulizer harnesses a stream of compressed gas to generate droplets from the drug solution or suspension (200). Some conventional jet nebulizer designs (like non-vented jet nebulizers) result in substantial loss of the aerosolized drug into the room air. This problem has been circumvented by the development of mesh nebulizers and ultrasonic nebulizers. Mesh nebulizers can produce droplets of uniform size without imposing high mechanical stress on the drug solution, they are associated with relatively less temperature rise during the nebulization process (201), and they can administer higher drug doses leading to faster patient recovery (202), they do not require baffles, thus minimizing residual losses, and they can nebulize a myriad of solutions and suspensions. These devices operate using batteries or a direct power supply, eliminating the requirement of an external gas flow. However, mesh nebulizers have some issues associated with them. They are costlier than jet nebulizers. The apertures in the mesh are prone to clog, and the high surface area of the mesh (owing to the presence of numerous apertures) requires careful cleaning (202). Examples of FDA-approved drugs for delivery using mesh nebulizers include glycopyrrolate (a long-acting muscarinic antagonist for COPD) and aztreonam (an antibiotic for cystic fibrosis).

Ultrasonic nebulizers are electrically powered devices in which a drug solution is subjected to ultrasonic waves of high frequency, resulting in an aerosol generation. Portable, small-sized ultrasonic nebulizers are available in the market for the administration of bronchodilators. They are more expensive than jet nebulizers but are comparable to mesh nebulizers in this regard. Treprostinil (available for inhalation under the brand name Tyvaso) has been successfully used to treat patients with pulmonary arterial hypertension using an ultrasonic nebulizer (203). A major drawback of ultrasonic nebulizers is the possible drug inactivation due to ultrasonic waves. Moreover, they are not efficient in nebulizing a suspension (204).

Soft mist inhalers (SMIs) (Respimat, Boehringer Ingelheim, Ingelheim am Rhein, Germany) were originally available for the administration of ipratropium/albuterol, which later became available for other bronchodilators (205, 206). A compressed spring within the device pushes the drug through a membrane, emitting an aerosol (205). It is not necessary to shake before using the device. It is a portable, multi-dose device that generates aerosols with a high fine-particle fraction, resulting in substantial deposition of drugs in the lungs. In comparison to pMDIs, Respimat discharges aerosols slower (205, 206) and over a longer duration (-1.2 s as compared to < 0.5 s from pMDIs) which may reduce the coordination required for actuation and inspiration, thus improving the likelihood for greater lung deposition. Further, it does not require a propellant and is suitable for use in children.

Dry powder inhalers (DPIs) are excellent alternatives to pMDIs as they help to circumvent many limitations associated with pMDIs such as low lung deposition of drugs and the need for propellants. In 1967, Fisons (Ipswich, UK) launched the Spinhaler^® device. Thereafter, striking advances have been made in DPI design. and a wide variety of medications are available as dry powder formulations, making them extremely useful to patients with respiratory tract diseases. Some of the commercially available DPI designs are Genuair, Breezhaler, Podhaler, Dreamboat, Conix, Twincer, Twincaps, and Staccato. They are compact and easily portable and can help impart short treatment times. The TOBI^® Podhaler^® (Novartis, Basel, Switzerland) holds merit over jet nebulizers for the treatment of cystic fibrosis. Administration of Tobramycin Inhalation Solution (TIS™) (Novartis, Basel, Switzerland) using a jet-nebulizer posed several problems. For example, the device requires long inhalation times cleaning of the nebulizer is required after every use, which increases the chances of lung infection from devices that are not cleaned properly (207). Moreover, nebulizers are rather voluminous and require a jet of compressed air to generate aerosols. Further, TIS should be refrigerated during storage (208), and the product may undergo degradation before use. Considering these factors, the TOBI Podhaler is safer and more convenient for cystic fibrosis patients.

However, there are some demerits of DPIs. Due to inter-particulate forces like electrostatic interactions and van der Waals forces (209), micronized powders are adhesive/cohesive and spontaneously form agglomerates. These agglomerates must be deagglomerated prior to or during the processes of aerosolization and inhalation to produce a substantial fraction of particles within the range of 1–5 µm in size. These particles can reach small tubules and alveolar spaces in the lungs. In passive DPIs, the energy required to overcome the above-mentioned inter-particulate forces is derived from the patient’s inspiratory flow (210, 211), whereas, in active DPIs, energy is harnessed via other sources. The merit of a passive DPI is that it averts the need to synchronize the actuation and inspiration maneuver by the patient. However, this requires a pronounced inspiratory effort on the part of the patient, which might be difficult for the elderly and children, and those suffering from COPD or asthma (212). Because the rheological properties of micronized powders are often poor, in most formulations, drug particles are blended with larger carrier particles (30–90 μm in size) such as lactose to facilitate deagglomeration and powder flow (213). The performance of DPIs is susceptible to environmental humidity as dry powder formulations might absorb moisture from the environment. Further, these devices are not amicable to use with valved holding chambers.

A wide variety of inhaler devices are commercially available today; however, knowledge of correct device use, device maintenance, and stringent compliance to the instructions provided by the medical practitioner are pivotal in achieving maximum and timely therapeutic benefits. Newer models of inhalers are constantly on the horizon to make them more user-friendly and convenient. Effective communication and coordination among doctors, nurses, and patients and being updated with the latest developments in the field of inhaler device designs and applications can help in the effective and timely implementation of treatment regimens.