**2. Pneumonia in the clinic: classification, comorbidities, and pathogenesis**

#### **2.1. Classification**

Pneumonia is classified according to the patient population affected as: (a) communityacquired pneumonia (CAP), (b) hospital-acquired pneumonia (HAP), (c) ventilator-associated pneumonia (VAP), and (d) nursing home-associated pneumonia (NHAP) [3]. Of these classifications, CAP is the most frequently found, predominantly affecting young children because of the immaturity of their immune system, and older adults due to their immunosenescence and comorbidities of aging [4].

Community-acquired pneumonia is a common infection that affects the lower respiratory tract and it is acquired outside of the hospital or within 48 h of admission, and it is primarily associated with the presence of a new infiltrate on the chest radiograph [2, 3]. Community-acquired pneumonia is often caused by pathogens of the not multidrug-resistant type (MDR), which is an important distinction from the other types of pneumonia. However, some patients with recent antibiotic therapy could also present infection with MDR organisms [3, 5]. Furthermore, most patients are presented with common clinical symptoms, such as fever, cough, pleuritic chest pain, and breathing difficulty, although these symptoms can be absent in elderly patients. Elderly patients, on the other hand, can also have delirium, abdominal pain, or acute cardiac disorders as part of their clinical presentation [4].

#### **2.2. Incidence and risk factors**

Despite newer antimicrobial therapy and treatment guidelines, CAP continues to be a significant problem associated with high mortality, morbidity, and cost. In the United States alone, CAP affects approximately 5.6 million patients annually, and it is the sixth cause of death in individuals older than 65 years of age [6, 7]. According to the National Vital Statistics Report of the Centers for Disease Control, pneumonia and influenza were listed as the eighth leading causes of death in the United States in 2011 [8]. As a result, the economic burden of CAP remains significantly high, at more than \$17 billion dollars annually in the United States [9].

Several risk factors have been associated with CAP, including age and comorbid diseases [10]. Furthermore, exposure to air pollution and circulating levels of sex hormones also seem to play an important role in the predisposition of some respiratory infections [11, 12]. Although some studies in animals have shown that females are more resistant than males to some bacterial infections [13, 14], others have shown that these patterns are reversed if animals are pre-exposed to environmental pollutants, such as ozone [15–20]. Incidentally, some clinical studies have reported that men are more susceptible to developing CAP and receive more intensive care than women, and show increased risk to die from pneumonia [21]. Moreover, exposure to air pollution has been associated with an increased risk for respiratory disorders due to its negative effects on lung function and immunity [22]. In this regard, long-term exposures to air pollutants, such as ozone, nitric oxide, and particulate matter in older adults have been linked with increased hospitalization rates for CAP [11, 21, 23, 24]. In addition, exposure to diverse environmental agents has been linked to negative lung health outcomes in children and adults (**Table 1**). The mechanisms associated with these clinical outcomes will be discussed in the following sections.

and female sex hormones have been shown to control the lung immune response [1, 2]. This chapter combines evidence of three areas: pneumonia infection, air pollution, and hormonal control of sex-specific immune responses. We will discuss common pathogens responsible for pneumonia and associations with environmental exposures, and lessons learned from animal models of infection and exposure to various air pollutants. Together, this information could help better explain the differences observed in susceptibility to pneumonia between men and women, and help in the development of better treatment options for male and female patients.

Pneumonia is classified according to the patient population affected as: (a) communityacquired pneumonia (CAP), (b) hospital-acquired pneumonia (HAP), (c) ventilator-associated pneumonia (VAP), and (d) nursing home-associated pneumonia (NHAP) [3]. Of these classifications, CAP is the most frequently found, predominantly affecting young children because of the immaturity of their immune system, and older adults due to their immunose-

Community-acquired pneumonia is a common infection that affects the lower respiratory tract and it is acquired outside of the hospital or within 48 h of admission, and it is primarily associated with the presence of a new infiltrate on the chest radiograph [2, 3]. Community-acquired pneumonia is often caused by pathogens of the not multidrug-resistant type (MDR), which is an important distinction from the other types of pneumonia. However, some patients with recent antibiotic therapy could also present infection with MDR organisms [3, 5]. Furthermore, most patients are presented with common clinical symptoms, such as fever, cough, pleuritic chest pain, and breathing difficulty, although these symptoms can be absent in elderly patients. Elderly patients, on the other hand, can also have delirium, abdominal pain, or acute cardiac

Despite newer antimicrobial therapy and treatment guidelines, CAP continues to be a significant problem associated with high mortality, morbidity, and cost. In the United States alone, CAP affects approximately 5.6 million patients annually, and it is the sixth cause of death in individuals older than 65 years of age [6, 7]. According to the National Vital Statistics Report of the Centers for Disease Control, pneumonia and influenza were listed as the eighth leading causes of death in the United States in 2011 [8]. As a result, the economic burden of CAP remains significantly high, at more than \$17 billion dollars annually in the

Several risk factors have been associated with CAP, including age and comorbid diseases [10]. Furthermore, exposure to air pollution and circulating levels of sex hormones also seem to play

**2. Pneumonia in the clinic: classification, comorbidities, and** 

**pathogenesis**

4 Contemporary Topics of Pneumonia

**2.1. Classification**

nescence and comorbidities of aging [4].

disorders as part of their clinical presentation [4].

**2.2. Incidence and risk factors**

United States [9].


**Table 1.** Effects of the environment on respiratory tract health in children and adults and observed sex differences.

#### **2.3. Pathogenesis of pneumonia**

Pneumonia is characterized by a severe inflammation of the peripheral alveolar compartment and abnormal filling with fluid consolidation and exudation caused by infection with viruses, bacteria, and/or pathogen-related molecules. The most common cause of CAP is bacterial infection, but the disease can also be triggered by viral agents (**Table 2**) [6, 25, 26]. Pneumonia-causing microorganisms are classified as typical, atypical (zoonotic and non-zoonotic), Gram-negative, and viruses. *Streptococcus pneumoniae* is the most common cause of pneumonia in adults in the United States. Nevertheless, other typical organisms are also included with some important associations. For example, *Haemophilus influenzae* is found particularly in patients who smoke or have chronic obstructive pulmonary disease (COPD), *Moraxella catarrhalis* and *Staphylococcus aureus* are often found in pneumonia following influenza infection, and in the form of methicillin-resistant *Staphylococcus aureus* (MRSA) [6]. In addition, atypical pneumonia could be produced by zoonotic pathogens, such as *Chlamydia psittaci*, *Francisella tularensis*, *Coxiella burnetii* (also known as Q fever) and by non-zoonotic pathogens like *Chlamydia pneumoniae*, *Mycoplasma pneumoniae*, and *Legionella pneumophila*. Furthermore, patients with these atypical infections have a more frequent presentation of a mild or ambulatory CAP, and also present extrapulmonary manifestations not found in CAP caused by typical pathogens [26]. *S*. *pneumoniae* colonize the human nasopharynx and can be transmitted from animals in captivity to humans [27]. Differences in strains of *S*. *pneumoniae* are responsible for differences in virulence and the presence of antigens [27].

The main mechanism of infection in CAP is micro-aspiration from a previously colonized oropharynx, but inhalation of suspended aerosolized microorganism is the route of infection for viruses and bacterial agents, such as *L. pneumophila* and *Mycobacterium tuberculosis*. However, other factors related to the host immune response, the virulence of the infecting organism, and the size of the inoculum also define the development of the disease [29]. Furthermore, the presence of medical comorbidities, such as chronic respiratory and cardiovascular diseases, cerebrovascular diseases, Parkinson's disease, epilepsy, dementia, dysphagia, HIV infection, and chronic renal, or liver disease can also lead to a defective cough, abnormal mucociliary clearance, and impaired humoral and local immunity that can influence the pathogenesis of pneumonia [30–32]. In addition, lifestyle and social factors including smoking and alcohol consumption, contact with pets, households with more than 10 people, interventions of upper airways, and poor dental health have also been associated with an increased predisposition for the development of CAP [10] (**Table 3**). Smoking affects the respiratory epithelium and the clearance of bacteria from the respiratory tract, increasing the susceptibility to respiratory infections, even in passive smokers [33–35]. Alcoholism has also been linked to alterations in innate and adaptive immunity [36]. Moreover, nutritional deficiencies appear to affect mechanisms of innate immunity, and are associated with the increased risk of CAP

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Increasing evidence suggests that sex hormones play a role in the expression of genes involved in the regulation of the immune system, which in turn can impact the individual susceptibility to infectious agents, and incidence of autoimmune diseases [13, 14]. In this regard, patients suffering from systemic autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, and others) are at increased risk of developing pulmonary infection, aspiration pneumonia, and bronchiolitis obliterans organizing pneumonia [40]. Furthermore, studies have shown that androgens in males can affect the immune system leading to an increased susceptibility to infection and disease caused by parasites, fungi, bacteria, and viruses. On the contrary, estrogen leads to an increase of cell-mediated and humoral immune responses in females, making them more resistant to some infectious diseases [41]. However, the role of estrogen in modulating the immune response remains

Remarkably, physiological changes in male and female sex hormone levels (estradiol, testosterone) play important roles in human lung development, and differences in susceptibility to pulmonary infection are also present at an early age [44–47]. Gender disparities are also displayed in expression of surfactant production that appears earlier in female than male during lung development, and in the incidence of neonatal conditions of prematurity, such as respiratory distress syndrome and bronchopulmonary dysplasia [48, 49]. The earlier presence of surfactant in female neonatal lungs helps open the small airways and may contribute to their higher airflow rate observed [50]. Evidence from human studies suggests that male infants are more susceptible to lung infection, with greater associated morbidity and mortality than female infants, but the reverse is applied in children and adolescents [47, 51, 52]. Regarding respiratory tract infections (RTIs), women are more

development and mortality [37–39].

controversial [42, 43].

**2.4. Gender differences in community-acquired pneumonia**

Community-acquired pneumonia can also be caused by a variety of viral infections. The most frequent viruses associated with CAP are influenza A and B, and parainfluenza. Less frequently, respiratory syncytial virus (RSV), severe acute respiratory syndrome virus, varicella, hantavirus, and adenovirus, are also responsible for CAP. Furthermore, most of these viral infections present in combination with multiple bacterial pathogens including *S*. *pneumoniae* and *C. pneumoniae*. However, patients with congestive heart failure (CHF) are at increased risk of acquiring CAP caused by pure viral infections [6, 25]. Gram-negative bacteria (*Pseudomonas aeruginosa*, *Klebsiella pneumoniae*, *Escherichia coli*, *Enterobacter* spp., and *Serratia* spp.) are common in patients with CAP who have had recent contact with health care environments, such as previous hospitalization, probable aspiration, antimicrobial treatment, and pulmonary comorbidities [28]. **Table 2** summarizes common associations of pathogens with clinical factors, history, and environmental factors in patients with CAP [4–6, 25, 26].

#### **Typical**

*Streptococcus pneumoniae*, *Haemophilus influenza*, *Moraxella catarrhalis*, *Staphylococcus aureus*

#### **Atypical**

**Zoonotic**: *Chlamydia psittaci*, *Francisella tularensis*, *Coxiella burnetii* **Non-zoonotic**: *Mycoplasma pneumoniae*, *Chlamydophila pneumoniae*, and *Legionella pneumophila*

#### **Gram-negative**

*Pseudomonas aeruginosa*, *Klebsiella pneumoniae*, *Escherichia coli*, *Enterobacter* spp*.*, *Serratia* spp., *Proteus* spp.

#### **Viruses**

*Parainfluenza virus*, *Influenza virus A* and *B* **Less frequently**: Respiratory syncytial virus (RSV), severe acute respiratory syndrome virus, varicella, hantavirus, and adenovirus

**Table 2.** Common pathogens in community-acquired pneumonia.

The main mechanism of infection in CAP is micro-aspiration from a previously colonized oropharynx, but inhalation of suspended aerosolized microorganism is the route of infection for viruses and bacterial agents, such as *L. pneumophila* and *Mycobacterium tuberculosis*. However, other factors related to the host immune response, the virulence of the infecting organism, and the size of the inoculum also define the development of the disease [29]. Furthermore, the presence of medical comorbidities, such as chronic respiratory and cardiovascular diseases, cerebrovascular diseases, Parkinson's disease, epilepsy, dementia, dysphagia, HIV infection, and chronic renal, or liver disease can also lead to a defective cough, abnormal mucociliary clearance, and impaired humoral and local immunity that can influence the pathogenesis of pneumonia [30–32]. In addition, lifestyle and social factors including smoking and alcohol consumption, contact with pets, households with more than 10 people, interventions of upper airways, and poor dental health have also been associated with an increased predisposition for the development of CAP [10] (**Table 3**). Smoking affects the respiratory epithelium and the clearance of bacteria from the respiratory tract, increasing the susceptibility to respiratory infections, even in passive smokers [33–35]. Alcoholism has also been linked to alterations in innate and adaptive immunity [36]. Moreover, nutritional deficiencies appear to affect mechanisms of innate immunity, and are associated with the increased risk of CAP development and mortality [37–39].

#### **2.4. Gender differences in community-acquired pneumonia**

**2.3. Pathogenesis of pneumonia**

6 Contemporary Topics of Pneumonia

factors in patients with CAP [4–6, 25, 26].

*Parainfluenza virus*, *Influenza virus A* and *B*

**Zoonotic**: *Chlamydia psittaci*, *Francisella tularensis*, *Coxiella burnetii*

**Table 2.** Common pathogens in community-acquired pneumonia.

**Typical**

**Atypical**

**Viruses**

**Gram-negative**

and adenovirus

Pneumonia is characterized by a severe inflammation of the peripheral alveolar compartment and abnormal filling with fluid consolidation and exudation caused by infection with viruses, bacteria, and/or pathogen-related molecules. The most common cause of CAP is bacterial infection, but the disease can also be triggered by viral agents (**Table 2**) [6, 25, 26]. Pneumonia-causing microorganisms are classified as typical, atypical (zoonotic and non-zoonotic), Gram-negative, and viruses. *Streptococcus pneumoniae* is the most common cause of pneumonia in adults in the United States. Nevertheless, other typical organisms are also included with some important associations. For example, *Haemophilus influenzae* is found particularly in patients who smoke or have chronic obstructive pulmonary disease (COPD), *Moraxella catarrhalis* and *Staphylococcus aureus* are often found in pneumonia following influenza infection, and in the form of methicillin-resistant *Staphylococcus aureus* (MRSA) [6]. In addition, atypical pneumonia could be produced by zoonotic pathogens, such as *Chlamydia psittaci*, *Francisella tularensis*, *Coxiella burnetii* (also known as Q fever) and by non-zoonotic pathogens like *Chlamydia pneumoniae*, *Mycoplasma pneumoniae*, and *Legionella pneumophila*. Furthermore, patients with these atypical infections have a more frequent presentation of a mild or ambulatory CAP, and also present extrapulmonary manifestations not found in CAP caused by typical pathogens [26]. *S*. *pneumoniae* colonize the human nasopharynx and can be transmitted from animals in captivity to humans [27]. Differences in strains of *S*. *pneu-*

*moniae* are responsible for differences in virulence and the presence of antigens [27].

*Streptococcus pneumoniae*, *Haemophilus influenza*, *Moraxella catarrhalis*, *Staphylococcus aureus*

**Non-zoonotic**: *Mycoplasma pneumoniae*, *Chlamydophila pneumoniae*, and *Legionella pneumophila*

*Pseudomonas aeruginosa*, *Klebsiella pneumoniae*, *Escherichia coli*, *Enterobacter* spp*.*, *Serratia* spp., *Proteus* spp.

**Less frequently**: Respiratory syncytial virus (RSV), severe acute respiratory syndrome virus, varicella, hantavirus,

Community-acquired pneumonia can also be caused by a variety of viral infections. The most frequent viruses associated with CAP are influenza A and B, and parainfluenza. Less frequently, respiratory syncytial virus (RSV), severe acute respiratory syndrome virus, varicella, hantavirus, and adenovirus, are also responsible for CAP. Furthermore, most of these viral infections present in combination with multiple bacterial pathogens including *S*. *pneumoniae* and *C. pneumoniae*. However, patients with congestive heart failure (CHF) are at increased risk of acquiring CAP caused by pure viral infections [6, 25]. Gram-negative bacteria (*Pseudomonas aeruginosa*, *Klebsiella pneumoniae*, *Escherichia coli*, *Enterobacter* spp., and *Serratia* spp.) are common in patients with CAP who have had recent contact with health care environments, such as previous hospitalization, probable aspiration, antimicrobial treatment, and pulmonary comorbidities [28]. **Table 2** summarizes common associations of pathogens with clinical factors, history, and environmental

Increasing evidence suggests that sex hormones play a role in the expression of genes involved in the regulation of the immune system, which in turn can impact the individual susceptibility to infectious agents, and incidence of autoimmune diseases [13, 14]. In this regard, patients suffering from systemic autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, and others) are at increased risk of developing pulmonary infection, aspiration pneumonia, and bronchiolitis obliterans organizing pneumonia [40]. Furthermore, studies have shown that androgens in males can affect the immune system leading to an increased susceptibility to infection and disease caused by parasites, fungi, bacteria, and viruses. On the contrary, estrogen leads to an increase of cell-mediated and humoral immune responses in females, making them more resistant to some infectious diseases [41]. However, the role of estrogen in modulating the immune response remains controversial [42, 43].

Remarkably, physiological changes in male and female sex hormone levels (estradiol, testosterone) play important roles in human lung development, and differences in susceptibility to pulmonary infection are also present at an early age [44–47]. Gender disparities are also displayed in expression of surfactant production that appears earlier in female than male during lung development, and in the incidence of neonatal conditions of prematurity, such as respiratory distress syndrome and bronchopulmonary dysplasia [48, 49]. The earlier presence of surfactant in female neonatal lungs helps open the small airways and may contribute to their higher airflow rate observed [50]. Evidence from human studies suggests that male infants are more susceptible to lung infection, with greater associated morbidity and mortality than female infants, but the reverse is applied in children and adolescents [47, 51, 52]. Regarding respiratory tract infections (RTIs), women are more


**3. Pneumonia in the laboratory: animal models and mechanisms of** 

insight into the physiological processes associated with the disease.

Wide-ranging research is required to understand the mechanisms underlying pulmonary diseases, such as pneumonia. Studies of human populations, *in vitro* experiments, and exploratory infections of species are needed to advance in the development of new treatments for this condition. Animal models have been widely used in the field and have often provided

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A variety of species have been used as animal models of pneumonia. Even though some species, such as *Danio rerio* (zebrafish) and *Caenorhabditis elegans* (roundworm) do not use lungs to acquire oxygen, and do not have similar sexual characteristics when compared to humans, they can be useful models to provide valuable information about host-pathogen interactions in lung disease [73]. Researchers utilize zebrafish as an alternative vertebrate model to study the pathogen's ability to infect the host [74]. Because zebrafish embryos and 3-week old larvae look transparent, it is feasible to follow the evolution of lung infection in real time [74–76]. In addition, zebrafish have a developed adaptive immune system and a high rate of conserved gene orthologs in humans [77, 78]. On the other hand, *C. elegans* is used as a non-vertebrate model for studying lung bacterial agents. Interestingly, the immune system of *C. elegans* and humans has similar signaling cascades in response to infection [79]. Despite anatomical differences, it is possible to recognize pathogen-specific virulence factors in epithelial surfaces of *C. elegans*, making this model ideal for the study of host defense mechanisms. Likewise, insects, such as *Drosophila melanogaster* (fruit fly) are valuable models of infection for the analysis of bacterial pathogenesis and genetic contributions. Insects have an advanced antimicrobial defense mechanism and a complex and conserved immune system [80]. In addition, a large number of genes that encode for proteins in the immune system are found on the X chromosome, which promote a higher activation of toll and immune deficiency signaling in *D. melanogaster* females than males [81]. Together, all these species possess advantages, such as low cost of maintenance, short life span, small size, fast development, and rapid reproduction making them feasible models for the study of infectious diseases. However, most pneumonia studies performed in animals are conducted in mammals because of their anatomical, genetic,

Larger mammalian species, such as rabbits, piglets, and primates are ideal for specialized experiments when physiological monitoring and therapies are evaluated [82]. Currently, primates are the only species able to assess primate-specific infectious agents, but due to ethical concerns, piglets are the most frequently used model to study ventilator-associated pneumonia (VAP). Even though large mammalian animals are phylogenetically close to the human species, the disadvantages associated with their use as models is that they are only useful for a limited number of studies, and they are expensive to house and feed, slow to breed, and genetically diverse. For this reason, infections in the lung have primarily been studied in small mammalian species, predominantly rodents. Rodents are small, inexpensive, and highly reproductive.

**infection**

**3.1. Animal models of pneumonia**

and morphological similarities with humans.

**Table 3.** Common pathogens in community-acquired pneumonia and environmental associations.

commonly affected by upper RTIs, such as sinusitis, tonsillitis, and otitis externa. On the other hand, men are at higher risk of developing otitis media, croup, and lower RTIs, including CAP [11]. Furthermore, these infections are more severe and show poorer outcomes and more complications in male than female individuals, leading to increased mortality, especially in CAP [21]. To date, the specific contributions of sex hormones or other factors, such as exposure to air pollution, socioeconomic, racial, and/or behavioral factors, obesity, and other comorbidities have only been explored in small studies [24, 53–56]. Several other factors including anatomic differences of the respiratory tract, behavioral, socioeconomic, and lifestyle factors have also been related with differences in incidence and severity of respiratory infections between genders [11, 41]. **Table 1** summarizes epidemiological data on associations of sex and environmental exposures on various lung health outcomes including pneumonia in children and adults [10, 27, 57–72].
