Show Summary Details
Page of

Pneumonia: Comorbid and Coexisting 

Pneumonia: Comorbid and Coexisting
Chapter:
Pneumonia: Comorbid and Coexisting
Author(s):

Chrysanthi L. Skevaki

, Athanassios Tsakris

, and Nikolaos G. Papadopoulos

DOI:
10.1093/med/9780199918065.003.0012
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 20 January 2020

Key Points

  • Community-acquired pneumonia (CAP) is a common worldwide health care concern with associated high morbidity and mortality rates.

  • Common etiologic agents include Streptococcus pneumoniae, Haemophilus influenzae, Legionella species, atypical pathogens (Mycoplasma pneumoniae and Chlamydophila pneumoniae), and respiratory viruses (respiratory syncytial virus, human rhinovirus, influenza virus).

  • Typical symptoms include cough, tachypnea, dyspnea, and fever, and there may be reduced or bronchial breath sounds, inspiratory crackles, and other auscultatory abnormalities on physical examination. Diagnosis can be confirmed by demonstration of an infiltrate on a chest radiograph or other imaging technique.

  • Microbiologic diagnosis by means of culture, serology, antigen detection, or polymerase chain reaction should be considered for hospitalized patients and community patients not responding to initial empirical treatment.

  • Amoxicillin in Europe and macrolide or doxycycline in the United States are the recommended first-choice antibiotics for community-treated patients based on empirical practice.

  • Vaccination against pneumococcal disease and influenza and adherence to a healthy lifestyle, including proper nutritional support, can contribute to the prevention of CAP.

  • Respiratory pathogens associated with pneumonia have been shown to have a role in the inception, exacerbation, and chronicity of asthma.

  • Asthma can mimic other respiratory diseases and should be considered in the differential diagnosis of pneumonia, especially in younger and older groups of patients, in whom presentation of pneumonia is often atypical.

Introduction

Pneumonia is defined as an acute infection of the lung caused by bacteria, viruses, fungi, or other microorganisms and is characterized by inflammation both within and around the alveolar tissues (consolidation). Three broader types of pneumonia are recognized based on the causative pathogens, the setting of infection, and the outcome. These are community-acquired pneumonia (CAP), which is the most common presentation, hospital-acquired (nosocomial) pneumonia, and pneumonia in the immunocompromised patient. CAP represents a challenge for physicians because of the large number and diversity of causative agents, the difficulty in reaching the appropriate clinical diagnosis, and the fact that a single antimicrobial regimen able to combat all possible etiologies is currently missing.

CAP stands as the seventh leading cause of death in the United States1 and the fourth in Japan,2 and despite considerable advances in antimicrobial therapy, pneumonia-associated mortality has not significantly decreased since the advent and broad use of penicillin in the 1950s.1 The annual incidence of CAP diagnosed in the community is reported to be 5 to 11 per 1, 000 adults based on studies from Europe and North America.2 The incidence varies markedly with age and presents highest rates among elderly and very young people. Specifically, for European and North American children younger than 5 years, the annual incidence of pneumonia is 36 per 1, 000, and the respective value is 10 times higher in the developing world, where childhood pneumonia accounts for more than 2 million deaths annually.3

The most common pathogens associated with CAP are presented in Table 12.1. Streptococcus pneumoniae (often referred to as pneumococcus) is one of the predominant causative organisms (Figure 12.1), yet an etiologic agent cannot be identified in 25% to 60% of patients, and the yield can be even lower in routine hospital practice.2 Viruses also play an important role, particularly among infants and elderly people, but in school-aged children as well.4 Bacteria, like Haemophilus influenzae and Legionella species, and atypical pathogens, such as Mycoplasma pneumoniae and Chlamydophila pneumoniae, play a distinct role in the etiology of CAP, causing about one in every five cases.2 It is often assumed that a single pathogen is responsible for each CAP case, but the issue of mixed infections has received particular attention in recent years, largely because of improvements in virus diagnostic techniques.4

Table 12.1. Most Common Etiologic Agents of Community-Acquired Pneumonia According to Treatment Setting

Nonhospitalized Patients

Hospitalized, Non-ICU Patients

Hospitalized, ICU Patients

Streptococcus pneumoniae

Streptococcus pneumoniae

Streptococcus pneumoniae

Mycoplasma pneumoniae

Mycoplasma pneumoniae

Mycoplasma pneumoniae

Haemophilus influenzae

Haemophilus influenzae

Haemophilus influenzae

Moraxella catarrhalis

Chlamydophila pneumoniae

Chlamydophila pneumoniae

Chlamydophila psittaci

Chlamydophila psittaci

Chlamydophila psittaci

Staphylococcus aureus

Staphylococcus aureus

Respiratory viruses*

Respiratory viruses*

Respiratory viruses*

Legionella spp.

Legionella spp.

Legionella spp.

Gram-negative enteric bacteria

Gram-negative enteric bacteria

* Respiratory viruses: influenza A, influenza B, parainfluenza virus, adenovirus, respiratory syncytial virus.

Modified from Mandell LA, Wunderink RG, Anzueto AMandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–S72.

Figure 12.1 Culture of Streptococcus pneumoniae on blood agar with an inhibition zone around the optochin disk.

Figure 12.1 Culture of Streptococcus pneumoniae on blood agar with an inhibition zone around the optochin disk.

The purpose of this chapter is to provide a concise reference on pneumonia as a possible comorbid or coexisting condition with asthma. It provides basic information on pneumonia and its clinical features, mentions the main causative agents, and describes the diagnosis and treatment of the disorder. It also discusses lifestyle changes that could potentially reduce associated morbidity and argues on unmet needs in the area.

Clinical Features

Symptoms of pneumonia include fever (>38°C), dyspnea, pleuritic chest pain, cough, production of sputum, and tachypnea. Physical examination of the chest may reveal dullness on percussion, crackles, bronchial breathing, or decreased chest expansion.2

Clinical features of the disease are also dependent on specific etiologic agents. S. pneumoniae is linked to increasing age, cardiovascular comorbidity, acute onset of symptoms, high fever, and pleuritic chest pain.

Bacteremia-associated pneumococcal pneumonia may be more likely in females or linked to the presence of a positive history for excessive alcohol consumption, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and dry cough. Legionella pneumophila appears to be more common in men and young patients without comorbidities, in smokers, and in individuals who received antibiotic therapy. This microbe may cause neurologic and gastrointestinal symptoms, and the patient may be presenting a more severe infection in the absence of prominent upper respiratory tract symptoms, pleuritic pain, or purulent sputum. Pneumonia from infection with M. pneumoniae may occur in younger patients and in those with less multisystem involvement (compared with Legionella-caused pneumonia) and more frequent intake of antibiotics before hospital admission. C. pneumoniae is more commonly associated with headaches, usually infects older patients, and has a rather atypical clinical presentation that may lead to a longer duration of symptoms before hospital admission. CAP due to Coxiella burnetii is also associated with nonspecific clinical symptoms, but infection may be more common in younger men who present with high fever and dry cough. Klebsiella pneumoniae lower respiratory tract infection appears to be more common in men and in individuals with a history of alcohol abuse, and a complete blood count may demonstrate thrombocytopenia and leukopenia. Pneumonia caused by some less common respiratory pathogens, like Acinetobacter species, is observed more often in older patients with a history of alcoholism and is associated with a high mortality rate. CAP from other strains of Streptococcus such as Streptococcus milleri may originate from a dental or abdominal source of infection, whereas Streptococcus viridans is associated with aspiration.2

CAP in children commonly presents with fever, tachypnea, cough, chest pain, breathlessness or difficulty in breathing, and wheeze. Abdominal pain or vomiting, as well as headache, may also be present. Similar to adulthood pneumonia, clinical manifestations can be quite diverse, but classic presentation includes fever, cough, and tachypnea, preceded by upper respiratory symptoms and low-grade fever.3 Tachypnea is a nonspecific clinical sign but is the most sensitive and most specific finding associated with pneumonia and indicates respiratory distress or hypoxemia.5 Increased respiratory rate is present twice as often in children with radiographically proven pneumonia as in children without positive radiographs but with other symptoms of pneumonia.

The age of the child should always be considered during assessment for pneumonia because values for key criteria (e.g., respiratory rate or tachycardia) determining severity range are largely age dependent.5,6 Clinical presentation of children with pneumonia can range from those who are acutely ill to those who look reasonably well, and this is partly dependent on the etiologic organism. In addition to the presence of persistent or repetitive fever (body temperature >38.5°C), together with chest recession and tachypnea, bacterial pneumonia can also be characterized by abdominal pain and mucus production. Atypical pneumonias, such as those caused by M. pneumoniae or C. pneumoniae, are often accompanied by less severe symptoms of a more gradual onset. Such symptoms may include headache, malaise, and low-grade fever.7 Asthmatic children with deficient interleukin-18 (IL-18) response are reported to present with more severe forms of pneumonia caused by M. pneumoniae.8

Among elderly people, the clinical presentation of CAP is frequently described as more subtle. Nonspecific pneumonia symptoms, including fever, are often missing, whereas mental confusion of new onset may appear.9

Severity of CAP ranges from the mild, self-limited disease to severe and occasionally fatal disease, rendering the decision on site of care as the first and most vital in the management of CAP. A number of tools have been developed to assist the clinician in deciding whether a patient with pneumonia should be treated at home or requires either non–intensive care unit (ICU) or ICU hospitalization.2 The Pneumonia Severity Index is a rather complex model involving 20 variables that performs well and is based on a 30-day mortality prognosis. Limitations include the requirement for sufficient support resources10 and that it may underestimate pneumonia severity in younger patients.10 A simpler, usually preferred index, CURB-65, evaluates the risk for mortality by means of a six-point score (one point for each of confusion, blood urea nitrogen level >7 mmol/L (20 mg/dL), Respiratory rate ≥30 breaths/minute, blood pressure [systolic <90 mmHg or diastolic ≤60 mmHg], and age ≥65 years). The even simpler severity assessment tool CRB-65 does not require blood urea nitrogen determination and is reported to be of similar value to CURB-65.2

Diagnosis

The presence of pneumonia is supported by focal chest signs and a radiograph or other imaging techniques (e.g., computed tomography [CT]) indicating lung shadowing that is likely to be new. Commonly, CAP is diagnosed at the primary care level, where access to chest radiography is limited. In this setting, diagnosis is based on the history of the patient, clinical features, and physical examination.

Radiologic examination is perceived as the gold standard for the diagnosis of pneumonia. A chest radiograph will not necessarily provide a specific infiltrate pattern useful in identifying underlying etiology, although certain features may guide the physician. Pneumococcal pneumonias will present with lobar consolidation, cavitation, and large pleural effusions. The presence of a bilateral diffuse infiltrate is indicative of Pneumocystis, Legionella, or a primary viral pneumonia, whereas multiple nodular infiltrates throughout the lung point toward staphylococcal pneumonia. Pseudomonas and other gram-negative bacilli often yield lower lobe pneumonia. For Mycoplasma-caused pneumonia, an interstitial pattern in a peribronchial and perivascular distribution is present, cavitation is rare, and pleural effusions may exist occasionally. CT is particularly useful in cases of recurrent pneumonia and in pneumonia linked to tumors or other forms of immunosuppression, in which lung infection may be present in the absence of abnormal chest radiographs.

Although identification of the etiologic agent and its drug susceptibility would permit the confirmation and modification (if necessary) of the initial empirical choice of antimicrobials, microbiologic testing is not routinely recommended for patients managed in the community.2 Pathogen-specific antimicrobial therapy is not any more effective than the empirical practice.11 Specific microbial identification is, however, recommended in cases of severe pneumonia and ICU admission, failure of empirical antibiotic therapy, leukopenia, chronic liver disease, asplenia, pleural effusion, possibility of tuberculosis, and specific epidemiologic (e.g., alcohol abuse, intravenous illicit drug use, exposure to bird droppings or birds, travel to Southeast Asia or East Asia) and clinical (e.g., COPD, cystic fibrosis, HIV infection, chronic glucocorticosteroid treatment, lung abscess) conditions.12 A positive result can be expected in about 60% of cases,13 but this may require aggressive efforts and the use of most advanced techniques. Diagnostic yield is higher in severely ill patients, for whom the information obtained is most helpful.13 A palette of diagnostic tests is available to identify microbial causes of pneumonia ranging from culture (e.g., of blood or sputum) to serology, antigen tests, and molecular techniques. In any case, microbiologic analyses should not delay the initiation of empirical treatment for acute pneumonia.

Blood Specimen

The presence of positive blood cultures is highly specific in pneumonia and can facilitate narrowing of antibiotic use, or it may identify the presence of unusual organisms that would not be adequately covered by routine empirical antibiotic coverage, thus helping patients who are not responsive to treatment. Blood culture yield (commonly S. pneumoniae) is reported to be 5% to 15% in an unselected hospitalized CAP population and higher in patients with severe CAP, chronic liver disease, asplenia, and leukopenia. Caution must be taken with contamination-related isolates of coagulase-negative staphylococci because misinterpretation can lead to longer hospital stay and overuse of vancomycin.12 Strains of nonhemolytic Streptococcus pyogenes can also be difficult to recognize and isolate from blood culture. Given that β‎-hemolysis guides the preliminary identification of this species, the absence of hemolysis may be misleading to unimportant commensals. In this context, omission of further identification steps may be detrimental because such isolates appear to retain at least most of their pathogenicity.14

Serologic assays for influenza A and B virus antibody detection are often performed2 and are simple, fast, and reliable tests with sensitivity ranging from 50% to 70% (depending on the type of test and sample and the time interval since the onset of symptoms).15 However, an increased rate of false-negative results, especially 3 days after onset of symptoms, as well as false-positive results in association with adenovirus infections may occur.1 Serum antibody assays are the gold standard for the conventional diagnosis of M. pneumoniae and are also used for the detection of Chlamydophila species because culture-based techniques for the aforementioned pathogens are usually not available in diagnostic laboratories. In this context, the serologic test most commonly applied is the complement fixation test (CFT). For M. pneumoniae, CFT titers normally take up to 10 to 14 days after infection to elevation, yet many patients already have elevated titers at the time of admission, because of the slow progression of symptoms.2 Serology also has been used to diagnose infections caused by Legionella species and C. burnetii,16 but their sensitivity and specificity are currently limiting their usefulness in rapid diagnosis.

Antigen detection tests, like enzyme immunoassays and microimmunofluorescence, are also available for blood samples and are routinely used for M. pneumoniae and Chlamydophila species identification. For the latter, enzyme immunoassays are considered more sensitive and specific than microimmunofluorescence.17

A variety of cytokines that are released into the circulation as a result of infection could serve as useful adjuncts in the diagnosis of pneumonia and prediction of disease severity. Procalcitonin, C-reactive protein, and soluble triggering receptor expressed on myeloid cells are the markers most often investigated in pneumonia, with procalcitonin being the earliest to appear during the course of the infection.18

Molecular approaches, mainly polymerase chain reaction, have been applied for the detection of S. pneumoniae19 and of Pneumocystis species in patients with AIDS.20

Urine Specimen

Detection of the S. pneumoniae urinary antigen by an immunochromatographic technique provides satisfactory sensitivity (50% to 80%) and specificity (>90%),21 is easy and rapid to perform (about 15 minutes), and is not affected by prior use of antibiotics. Nevertheless, it does not allow the isolation of the organism and thus does not provide information on drug susceptibility. False-positive results are possible in children colonized with S. pneumoniae and in subjects with a pneumococcal CAP episode within the previous 3 months.

Similarly, soluble L. pneumophila antigen can be detected in urine using a commercially available enzyme immunoassay (EIA). This test only detects L. pneumophila serogroup 1 (which is responsible for the majority of community-associated legionellosis), has an 80% to 95% sensitivity with an estimated 99% specificity, and is easy and rapid to perform.22 It can provide a positive result from the first day of illness throughout weeks thereafter; however, it shares the same advantages and disadvantages with the pneumococcal urinary antigen test with respect to inability of organism isolation and persistence of antigenuria even after therapy completion.22

Sputum Specimen

The microscopic examination and culture of expectorated sputum are basic diagnostic techniques for pneumonia. Sputum samples should be taken from patients able to expectorate purulent samples who have not yet received antibiotic therapy. The specimen needs to be rapidly transported to the laboratory and promptly processed in order to reduce influence of the nasopharyngeal flora. Sputum should initially be observed for color, odor, and consistency. Given that pneumococci often constitute part of the nasopharyngeal flora among healthy adults and additionally colonize the lower airways of patients with chronic bronchitis, identification of the organism is not necessarily diagnostic. Anaerobic infection commonly presents organisms of mixed morphology, whereas Legionnaires’ disease, mycoplasma, or viral pneumonias may be indicated by the presence of few bacteria. The sputum Gram stain is helpful to identify pneumococci, H. influenzae, and staphylococci, but special staining techniques must be employed for organisms like mycobacteria.

Antigen detection with direct fluorescent antibody assays is commonly used for L. pneumophila and Pneumocystis jirovecii. Although direct fluorescent tests have been used for Chlamydophila trachomatis, the assay has insufficient sensitivity for C. pneumoniae.23

Pleural Fluid

Early thoracocentesis is indicated for all patients with a parapneumonic effusion.2 Microscopy and cultures are influenced by antibiotic therapy, and therefore, these investigations should ideally be initiated before treatment; nevertheless, several pathogens often involved in severe CAP (other than S. pneumoniae) may be unaffected by a single antibiotic dose.1

Other Respiratory Tract Specimens

Invasively collected specimens, like endotracheal aspirates, bronchoscopic or nonbronchoscopic bronchoalveolar lavage (BAL) fluid, protected specimen brushing, and transthoracic needle aspirates (TNAs), are more clinically significant than sputum. BAL can be considered for diagnosing pneumonia caused by M. tuberculosis because culture of this specimen has enhanced sensitivity even in the presence of negative sputum cultures. Additionally, BAL could be used for diagnosing atypical pneumonias caused by Legionella species and M. pneumoniae. TNA has been linked to high diagnostic yields,23 but it should be applied only in specific cases of severe CAP because of potential complications. Endotracheal aspirates, which are safe to perform, are recommended for intubated patients, preferably soon after intubation to avoid tracheal colonization by nosocomial flora.1

Molecular techniques for the detection of pulmonary pathogens in respiratory tract samples are increasingly becoming available, but lack of standardization and high rates of false-negative results have withheld their wider application.

Differential Diagnosis

The clinician is challenged to differentiate pneumonia from other acute lower respiratory tract infections and alternative diagnoses. The key decisions are whether to administer an antibiotic, which antibiotic to use, and whether the patient should be hospitalized.2

A common disease interfering with the differential diagnosis of pneumonia is COPD, especially among adults with a history of tobacco use. Shadowing consistent with infection on a chest radiograph is suggestive of CAP.2

Chest signs on examination are not specific, and therefore consideration of other potential diagnoses, such as pulmonary edema, fibrosing alveolitis, pulmonary emboli, and bronchiectasis is needed. Chest radiographs are useful tools in reaching a definitive diagnosis of pneumonia,24 although they cannot usually discriminate pulmonary tuberculosis. Clinicians should also be alert for the detection of an underlying malignancy, especially in heavy smokers presenting with CAP, even in the absence of obvious pointers to a neoplasm.24

Asthma and Pneumonia

The association between infectious agents and asthma is complex, and evidence implicates respiratory tract infection, including pneumonia, both at the inception and in exacerbations of preexisting asthma. The most common viruses identified during early-life wheezing illnesses are respiratory syncytial virus (RSV, the principal cause of pneumonia and bronchiolitis in infants), human rhinovirus (HRV, the most frequent cause of the common cold but also a potential cause of pneumonia and bronchiolitis), and multiple other respiratory viruses, such as parainfluenza, metapneumovirus, coronavirus, influenza virus, bocavirus, and adenovirus. RSV lower respiratory tract illnesses, particularly those severe enough to lead to hospitalization, are believed to be associated with an increased risk for asthma at school age25; however, several studies argue against a causal role of RSV in asthma inception. However, wheezing illnesses caused by HRV are a more robust predictor of asthma development than RSV episodes.26

Regarding atypical pathogens, there is convincing evidence linking infection caused by M. pneumoniae and C. pneumoniae with exacerbations and chronicity of asthma. M. pneumoniae has been detected significantly more often in adult patients with chronic stable asthma and children with acute episodes of wheezing compared with healthy subjects.27,28 An association between M. pneumoniae infection and the pathogenesis of atopic asthma in children has been suggested, but more studies are required to demonstrate causality.29 Additionally, subjects with refractory asthma appeared to be chronically infected with M. pneumoniae, without, however, an accompanying increase in immunoglobulin G or the ability to eradicate the infectious agent with macrolides.30

Typical bacteria, like S. pneumoniae, H. influenzae, Moraxella catarrhalis, and Staphylococcus aureus, seem to have no role in asthma pathogenesis in children, unlike their atypical counterparts.31 However, asthma is an important risk factor for severe pneumococcal infections, even more so when the underlying disease is not well controlled and necessitates frequent oral use of corticosteroids.32 Individuals with severe asthma have been found to present a history of pneumonia at 63%, compared with 35% to 36% in individuals with nonsevere asthma.33

Pneumonia and asthma in children can represent a differential diagnostic challenge because they have a number of similarities (Table 12.2). Indeed, a large proportion of infants and children with asthma are mistakenly referred for recurrent pneumonia (or other respiratory tract infections).34

Table 12.2. Comparison of Asthma and Pneumonia in Children

Clinical Features

Pneumonia

Asthma

History

Commonly acute onset of a single episode

Chronic or recurrent with acute exacerbations

Symptoms and signs

Cough, tachypnea, dyspnea, fever, chest retraction, nasal flaring, chest pain, reduced or bronchial breath sounds, inspiratory crackles, lethargy, cyanosis, inability to feed in severe cases

Cough, dyspnea, wheezing, tachypnea, fever (if viral infection acts as a trigger for asthma exacerbation), chest retraction, nasal flaring, chest pain, prolonged expiration, lethargy, cyanosis, inability to feed in severe cases

Causative agents

Bacteria, viruses, and other

Viruses (commonly respiratory syncytial virus, human rhinovirus), allergens

Laboratory tests

Nonspecific

Nonspecific

Chest radiograph

Lobar consolidation ± cavitation and pleural effusion, bilateral diffuse, multiple nodular infiltrates, interstitial perihilar changes, atelectasis

Hyperinflation, airway wall thickening, perihilar changes, atelectasis

Modified from Ostergaard MS, Nantanda R, Tumwine JK, Aabenhus R. Childhood asthma in low income countries: an invisible killer? Prim Care Respir J. 2012;21(2):214–219; and Brand PL, Hoving MF, de Groot EP. Evaluating the child with recurrent lower respiratory tract infections. Paediatr Respir Rev. 2012;13(3):135–138.

Asthma is commonly reported as an underlying cause for recurrent pneumonia, but this notion was challenged based on results failing to indicate a causality between these two conditions.35 In the differential workup of an asthma exacerbation, wheezing is a supporting feature,24 and chest radiography can help further: a pneumonia-indicative radiograph would present with the typical appearance of lobar consolidation, which is strongly associated with bacterial pneumonia, whereas the presence of mild perihilar changes would point toward viral infections or asthma.36

Certain disorders can cause both pneumonia and asthma, like extrinsic allergic alveolitis, allergic bronchopulmonary aspergillosis, or both allergic angiitis and granulomatosis (Churg-Strauss syndrome). The clinician will be prompted to consider such conditions when generalized wheezing or other signs of bronchospasm are present during physical examination in the absence of underlying lung disease.

Lifestyle and Behavior Modification Strategies

Prevention of pneumonia heavily relies on vaccination; based on existing recommendations, all elderly adults (>65 years of age) are advised to receive vaccination against pneumococcal disease and influenza. Immunization is also recommended for patients affected by chronic diseases such as heart and kidney disorders, asthma, COPD, diabetes mellitus, hepatic cirrhosis, functional or anatomic asplenia, and alcoholism, and in the case of immunocompromised hosts, including HIV infection, cancer chemotherapy, and hematologic malignancies.32

A number of risk factors significantly predispose to the occurrence of pneumococcal pneumonia, including lifestyle factors. Smoking is linked to increased susceptibility to CAP in several epidemiologic studies, so smoking cessation is advisable. Daily hygiene may offer protection from pneumonia because hand washing (even with a nonmedicated soap) is known to be an effective means of preventing bacterial transmission.37 Hand washing with an antimicrobial agent may prove even more effective, and proper hygiene of the nasal and oropharyngeal cavities is also important because the primary step in the pathogenesis of pneumococcal invasive infections is nasopharyngeal colonization.38

Sufficient hours of sleep and an enhanced social role of elderly women are associated with a reduced mortality from pneumonia and other age-related diseases.39 Excessive weight gain is a risk factor for CAP among men and women in the United States, whereas physical activity is inversely associated with the risk for development of CAP among women.40

Malnutrition is a key contributor to the development of pneumonia among ICU patients, probably by impairing host defense. Along these lines, the use of immune-enhancing feeds enriched with a variety of nutrients including the amino acids arginine and glutamine, as well as nucleotides, is associated with fewer nosocomial infections, such as pneumonia.41 Still, further studies are needed to precisely establish the blend of nutrients able to provide the most beneficial effects. Nutritional studies suggest that higher intakes of α‎-linolenic and linoleic acids and possibly of fish may significantly reduce the risk for pneumonia.37

In children, a wide range of environmental factors is thought to potentially have a positive impact on health, including proper nutrition (proteins, vitamins, antioxidants), lifestyle and behavior choices (abstinence from tobacco and alcohol use), good parental health, socioeconomic status, choice of living environment (urban versus rural), and parent-sibling behavior.42

Pharmacologic Treatment

The principal treatment of pneumonia relies on addressing the underlying etiology. At presentation, clinical and laboratory features do not allow prediction of microbial cause; thus, knowledge of likely causative pathogens based on local epidemiology and consideration of possible antibiotic resistance spread are important to direct appropriate treatment. Prompt initiation of empirical antibiotic therapy is paramount for a favorable outcome, although this is not always achieved. Common reasons for delaying antibiotic therapy are administrative issues; incorrect diagnosis; and insufficient knowledge, experience, or confidence on the part of the physician, often leading to a delay in obtaining results of microbial testing. Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension has been associated with a survival rate of 79.9%, whereas each hour of delay over the next 6 hours was related to an average decrease in survival of 7.6%.43

Recommendations for initial empirically reasoned antibiotic therapy in CAP are based on prediction of the most likely pathogen, after consideration of both the regional patterns of resistance and the individual patient toxicity risk associated with selected antibiotics. Available guidelines also evaluate the need for and feasibility of more aggressive treatment and the setting of the individual patient because this pragmatically reflects disease severity and mortality risk. For home-treated patients, U.S. recommendations indicate the use of macrolides or doxycycline (if the former is not tolerated), whereas European guidelines advocate administration of amoxicillin, which, although ineffective for atypical pathogens, may successfully treat the often macrolide-resistant S. pneumoniae strains circulating in Europe.2,12 For non-ICU hospitalized patients, both European2 and U.S.1 guidelines advise the use of a respiratory fluoroquinolone alone or a β‎-lactam and macrolide combination. For patients hospitalized in the ICU because of severe CAP, institution of therapy targeting S. pneumoniae, Legionella species, and most of the clinically relevant Enterobacteriaceae family is warranted,1,2 thus directing the use of a potent antipneumococcal β‎-lactam in combination with either a macrolide or a fluoroquinolone.

Asthma and lower respiratory tract infections such as pneumonia can be significant causes of chest pain. Analgesic medications can improve chest pain associated with pulmonary pathologies, but the mainstay of therapy is to treat the underlying etiology. The chest pain generally resolves with the resolution of other respiratory symptoms.

Considerations for Patients with Asthma

Antibiotics prescribed for pneumonia do not currently play a major role in the treatment of chronic asthma in stable patients. Nevertheless, emerging evidence depicts improvement of the symptoms and markers of airway inflammation in patients who have atypical bacterial infection as a cofactor in their asthma and are treated with macrolide antibiotics.44

Inhaled corticosteroids (ICSs) are the mainstay of asthma treatment, but the effect of such inhaled agents on CAP is unclear. Studies in COPD reported increased rates of pneumonia associated with ICS intake,45 and there are concerns about an increased pneumonia risk in patients with asthma under ICS treatment. A study illustrated that there was no increased risk for pneumonia acquisition among patients with asthma receiving budesonide.46 In contrast, according to a Japanese report, there may be a greater risk for nontuberculous Mycobacterium infection in asthmatic patients who are older, have more severe airflow limitation, and receive higher doses of ICS therapy.47

Inhaled anticholinergics also are associated with an increased risk for development of CAP among asthmatic patients.48 Although it is difficult to differentiate between the effect of inhaled therapy and the impact of asthma severity on the risk for CAP, this relationship, even if not causal, could call attention to inhaled therapy in COPD and asthma patients.48

An earlier report describes the development of Pneumocystis carinii pneumonia as a consequence of asthma treatment with methotrexate. Investigation of new infiltrates in a patient with asthma receiving methotrexate treatment should be thoroughly performed to determine the cause and to differentiate from drug-induced pneumonitis.49

Unmet, Future Research Needs

  1. 1. There is a need to improve clinical outcomes in hospitalized patients with bacterial CAP because 6% to 15% of such patients and up to 40% of those initially admitted to the ICU fail to respond to original antibiotic therapy.1

  2. 2. There are limitations to identifying the etiologic agent of CAP in more than 50% of cases,11 a fact that dictates the necessity of faster and more specific diagnostic methods.

  3. 3. There is a documented emergence of drug-resistant strains of S. pneumoniae (DRSP) and community-acquired methicillin-resistant S. aureus (CA-MRSA), often associated with necrotizing pneumonia, shock, respiratory failure, and formation of abscesses and empyemas.2 Still, the clinical relevance of DRSP remains uncertain, with current levels of β‎-lactam resistance not resulting in treatment failures in patients with CAP, as long as appropriate dosages and compounds are used. However, macrolide-resistant S. pneumoniae strains may lead to clinical failure.50 Drug-resistance levels in DRSP and CA-MRSA are highly location specific, as are penicillin-, macrolide-, or dual-resistance rates of S. pneumoniae.50 The European Antimicrobial Resistance Surveillance Network project (http://www.ecdc.europa.eu/en/activities/surveillance/EARS-Net/Pages/index.aspx) regularly provides data on the resistance of S. pneumoniae across many European countries; nevertheless, related data must soon become available for the widest range of countries possible. Improvement in both the identification rate of the causative agent and the acquisition of data on resistance patterns will substantially aid advances toward prescribing narrow-spectrum and effective antibiotics for the management of bacterial CAP.

  4. 4. Future research efforts also should contribute to unraveling the complex relationship between causative agents of pneumonia and asthma. Viruses are the most common triggers of wheezing attacks; however, the mechanism by which they contribute to disease onset or progression remains elusive. Even less is known about the role of bacterial pathogens related to CAP (including the atypical pathogens) in the pathogenesis of asthma. Moreover, the microbial flora colonizing the airway may also influence asthma onset or progression. Serologic evidence of an immune response to S. pneumoniae, H. influenzae, and M. catarrhalis can be found in 20% of wheezing children,7 whereas M. pneumoniae and C. pneumoniae have been identified in 5% to 25% of children with asthma exacerbations.8

  5. 5. Finally, in regard to cost-related aspects of pneumonia, national health systems should consider increasing support to infection control programs in order to ultimately avert or reduce preventable community and nosocomial infections and their associated expenditures, which in the case of pneumonia are exceptionally high.

Conclusion

Pneumonia is an acute lower respiratory tract infection with significant worldwide morbidity and mortality, especially in underdeveloped nations. The clinical presentation of pneumonia is quite diverse with a range of symptoms, of which fever, cough, and tachypnea are most common. Diagnosis of pneumonia is supported by a chest radiograph displaying new shadowing, but most often, diagnosis is performed at the primary care level, in the absence of an imaging technique, and based only on symptoms and physical examination. Pneumonia is caused by a broad spectrum of microorganisms, whose identification can be difficult and time consuming and may often require invasive techniques and procedures of uncertain diagnostic success. Therefore, antimicrobial treatment is provided empirically and before any diagnostic test because prompt initiation of treatment is imperative and decisive for patient outcome.

Viral and bacterial causative agents of CAP are implicated in asthma pathogenesis. Early-life RSV and HRV lower respiratory tract infections are linked to an increased asthma risk at school age, whereas pneumonia caused by Mycoplasma or Chlamydia is associated with the inception, exacerbation, and chronicity of asthma. Moreover, asthma presents an important risk factor for the acquisition of severe pneumococcal infections. Macrolide antibiotics are found to benefit asthma patients with an atypical bacterial pulmonary infection.

Vaccination against pneumococci and influenza virus may significantly contribute to pneumonia prevention. A proactive lifestyle including refraining from smoking, avoidance of increased weight, physical activity, and proper nutrition can also significantly reduce the risk for pneumonia.

Future research should include efforts toward a better understanding of the epidemiology of pneumonia and related microorganisms and development of improved and more rapid diagnostics. Another scientific area requiring particular attention is in relation to the clinical relevance of the continuously increasing appearance of drug-resistant strains. Finally, research efforts should also decipher the interactions between asthma pathogenesis and lower respiratory tract infections.

References

1. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44(Suppl 2):S27–S72.Find this resource:

    2. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 2009;64(Suppl 3):iii1–55.Find this resource:

      3. Hale KA, Isaacs D. Antibiotics in childhood pneumonia. Paediatr Respir Rev. 2006;7(2):145–151.Find this resource:

        4. Tsolia MN, Psarras S, Bossios A, et al. Etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections. Clin Infect Dis. 2004;39(5):681–686.Find this resource:

          5. Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25–e76.Find this resource:

            6. Harris M, Clark J, Coote N, et al. British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax. 2011;66(Suppl 2): ii1–23.Find this resource:

              7. Durbin WJ, Stille C. Pneumonia. Pediatr Rev. 2008;29(5):147–158; quiz 159–160.Find this resource:

                8. Chung HL, Shin JY, Ju M, Kim WT, Kim SG. Decreased interleukin-18 response in asthmatic children with severe Mycoplasma pneumoniae pneumonia. Cytokine. 2011;54(2):218–221.Find this resource:

                  9. Loeb M. Pneumonia in older persons. Clin Infect Dis. 2003;37(10):1335–1339.Find this resource:

                    10. Dean NC, Suchyta MR, Bateman KA, Aronsky D, Hadlock CJ. Implementation of admission decision support for community-acquired pneumonia. Chest. 2000;117(5):1368–1377.Find this resource:

                      11. van der Eerden MM, Vlaspolder F, de Graaff CS, et al. Comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study. Thorax. 2005;60(8):672–678.Find this resource:

                        12. Carbonara S, Stano F, Scotto G, Monno L, Angarano G. The correct approach to community-acquired pneumonia in immunocompetent adults: review of current guidelines. New Microbiol. 2008;31(1):1–18.Find this resource:

                          13. Hohenthal U, Vainionpaa R, Meurman O, et al. Aetiological diagnosis of community acquired pneumonia: utility of rapid microbiological methods with respect to disease severity. Scand J Infect Dis. 2008;40(2):131–138.Find this resource:

                            14. Taylor MB, Barkham T. Fatal case of pneumonia caused by a nonhemolytic strain of Streptococcus pyogenes. J Clin Microbiol. 2002;40(6):2311–2312.Find this resource:

                              15. Bellei N, Benfica D, Perosa AH, Carlucci R, Barros M, Granato C. Evaluation of a rapid test (QuickVue) compared with the shell vial assay for detection of influenza virus clearance after antiviral treatment. J Virol Methods. 2003; 109(1):85–88.Find this resource:

                                16. Campbell JF, Spika JS. The serodiagnosis of nonpneumococcal bacterial pneumonia. Semin Respir Infect. 1988;3(2):123–130.Find this resource:

                                  17. Miyashita N, Ouchi K, Kawasaki K, et al. Comparison of serological tests for detection of immunoglobulin M antibodies to Chlamydophila pneumoniae. Respirology. 2008;13(3):427–431.Find this resource:

                                    18. Jensen JU, Heslet L, Jensen TH, Espersen K, Steffensen P, Tvede M. Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med. 2006;34(10):2596–2602.Find this resource:

                                      19. Kee C, Palladino S, Kay I, et al. Feasibility of real-time polymerase chain reaction in whole blood to identify Streptococcus pneumoniae in patients with community-acquired pneumonia. Diagn Microbiol Infect Dis. 2008;61(1):72–75.Find this resource:

                                        20. Schluger N, Godwin T, Sepkowitz K, et al. Application of DNA amplification to pneumocystosis: presence of serum Pneumocystis carinii DNA during human and experimentally induced Pneumocystis carinii pneumonia. J Exp Med. 1992;176(5):1327–1333.Find this resource:

                                          21. Dominguez J, Gali N, Blanco S, et al. Detection of Streptococcus pneumoniae antigen by a rapid immunochromatographic assay in urine samples. Chest. 2001;119(1):243–249.Find this resource:

                                            22. Ruf B, Schurmann D, Horbach I, Fehrenbach FJ, Pohle HD. Prevalence and diagnosis of Legionella pneumonia: a 3-year prospective study with emphasis on application of urinary antigen detection. J Infect Dis. 1990;162(6):1341–1348.Find this resource:

                                              23. Skerrett SJ. Diagnostic testing for community-acquired pneumonia. Clin Chest Med. 1999;20(3):531–548.Find this resource:

                                                24. Hoare Z, Lim WS. Pneumonia: update on diagnosis and management. BMJ. 2006;332(7549):1077–1079.Find this resource:

                                                  25. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med. 2000;161(5):1501–1507.Find this resource:

                                                    26. Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178(7):667–672.Find this resource:

                                                      27. Esposito S, Blasi F, Arosio C, et al. Importance of acute Mycoplasma pneumoniae and Chlamydia pneumoniae infections in children with wheezing. Eur Respir J. 2000;16(6):1142–1146.Find this resource:

                                                        28. Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Am J Respir Crit Care Med. 1998; 158(3):998–1001.Find this resource:

                                                          29. Jeong YC, Yeo MS, Kim JH, Lee HB, Oh JW. Mycoplasma pneumoniae infection affects the serum levels of vascular endothelial growth factor and interleukin-5 in atopic children. Allergy Asthma Immunol Res. 2012;4(2):92–97.Find this resource:

                                                            30. Peters J, Singh H, Brooks EG, et al. Persistence of community-acquired respiratory distress syndrome toxin-producing Mycoplasma pneumoniae in refractory asthma. Chest. 2011;140(2): 401–407.Find this resource:

                                                              31. Korppi M. Bacterial infections and pediatric asthma. Immunol Allergy Clin N Am. 2010;30(4):565–574, vii.Find this resource:

                                                                32. Obert J, Burgel PR. Pneumococcal infections: association with asthma and COPD. Med Mal Infect. 2012;42(5):188–192.Find this resource:

                                                                  33. Moore WC, Bleecker ER, Curran-Everett D, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol. 2007;119(2):405–413.Find this resource:

                                                                    34. Ostergaard MS, Nantanda R, Tumwine JK, Aabenhus R. Childhood asthma in low income countries: an invisible killer? Prim Care Respir J. 2012;21(2):214–219.Find this resource:

                                                                      35. Brand PL, Hoving MF, de Groot EP. Evaluating the child with recurrent lower respiratory tract infections. Paediatr Respir Rev. 2012;13(3):135–138.Find this resource:

                                                                        36. Greenberg D, Leibovitz E. Community-acquired pneumonia in children: from diagnosis to treatment. Chang Gung Med J. 2005;28(11):746–752.Find this resource:

                                                                          37. Vincent JL. Prevention of nosocomial bacterial pneumonia. Thorax. 1999;54(6):544–549.Find this resource:

                                                                            38. Oliveira TF, Gomes Filho IS, Passos Jde S, et al. Factors associated with nosocomial pneumonia in hospitalized individuals. Rev Assoc Med Bras. 2011;57(6):630–636.Find this resource:

                                                                              39. Goto A, Yasumura S, Nishise Y, Sakihara S. Association of health behavior and social role with total mortality among Japanese elders in Okinawa, Japan. Aging Clin Exp Res. 2003;15(6): 443–450.Find this resource:

                                                                                40. Baik I, Curhan GC, Rimm EB, Bendich A, Willett WC, Fawzi WW. A prospective study of age and lifestyle factors in relation to community-acquired pneumonia in US men and women. Arch Intern Med. 2000;160(20):3082–3088.Find this resource:

                                                                                  41. Merchant AT, Curhan GC, Rimm EB, Willett WC, Fawzi WW. Intake of n-6 and n-3 fatty acids and fish and risk of community-acquired pneumonia in US men. Am J Clin Nutr. 2005;82(3):668–674.Find this resource:

                                                                                    42. Pallapies D. Trends in childhood disease. Mutat Res. 2006;608(2):100–111.Find this resource:

                                                                                      43. Rello J. Demographics, guidelines, and clinical experience in severe community-acquired pneumonia. Crit Care. 2008;12(Suppl 6):S2.Find this resource:

                                                                                        44. Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121(6):1782–1788.Find this resource:

                                                                                          45. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300(20):2407–2416.Find this resource:

                                                                                            46. O’Byrne PM, Pedersen S, Carlsson LG, et al. Risks of pneumonia in patients with asthma taking inhaled corticosteroids. Am J Respir Crit Care Med. 2011;183(5):589–595.Find this resource:

                                                                                              47. Hojo M, Iikura M, Hirano S, et al. Increased risk of nontuberculous mycobacterial infection in asthmatic patients using long-term inhaled corticosteroid therapy. Respirology. 2012;17(1):185–190.Find this resource:

                                                                                                48. Almirall J, Bolibar I, Serra-Prat M, et al. Inhaled drugs as risk factors for community- acquired pneumonia. Eur Respir J. 2010;36(5): 1080–1087.Find this resource:

                                                                                                  49. Kuitert LM, Harrison AC. Pneumocystis carinii pneumonia as a complication of methotrexate treatment of asthma. Thorax. 1991;46(12): 936–937.Find this resource:

                                                                                                    50. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections—full version. Clin Microbiol Infect. 2011;17(Suppl 6):E1–E59.Find this resource: