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Candel, F.J.; Salavert, M.; Basaras, M.; Borges, M.; Cantón, R.; Cercenado, E.; Cilloniz, C.; Estella, �.; García-Lechuz, J.M.; Garnacho Montero, J.; et al. Ten Issues for Updating in Community-Acquired Pneumonia. Encyclopedia. Available online: https://encyclopedia.pub/entry/54130 (accessed on 06 July 2024).
Candel FJ, Salavert M, Basaras M, Borges M, Cantón R, Cercenado E, et al. Ten Issues for Updating in Community-Acquired Pneumonia. Encyclopedia. Available at: https://encyclopedia.pub/entry/54130. Accessed July 06, 2024.
Candel, Francisco Javier, Miguel Salavert, Miren Basaras, Marcio Borges, Rafael Cantón, Emilia Cercenado, Catian Cilloniz, Ángel Estella, Juan M. García-Lechuz, José Garnacho Montero, et al. "Ten Issues for Updating in Community-Acquired Pneumonia" Encyclopedia, https://encyclopedia.pub/entry/54130 (accessed July 06, 2024).
Candel, F.J., Salavert, M., Basaras, M., Borges, M., Cantón, R., Cercenado, E., Cilloniz, C., Estella, �., García-Lechuz, J.M., Garnacho Montero, J., Gordo, F., Julián-Jiménez, A., Martín-Sánchez, F.J., Maseda, E., Matesanz, M., Menéndez, R., Mirón-Rubio, M., Ortiz De Lejarazu, R., Polverino, E., ...Serrano, L. (2024, January 19). Ten Issues for Updating in Community-Acquired Pneumonia. In Encyclopedia. https://encyclopedia.pub/entry/54130
Candel, Francisco Javier, et al. "Ten Issues for Updating in Community-Acquired Pneumonia." Encyclopedia. Web. 19 January, 2024.
Ten Issues for Updating in Community-Acquired Pneumonia
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This entry is adapted from the peer-reviewed paper 10.3390/jcm12216864

Community-acquired pneumonia represents the third-highest cause of mortality in industrialized countries and the first due to infection. Although guidelines for the approach to this infection model are widely implemented in international health schemes, information continually emerges that generates controversy or requires updating its management.

community acquired pneumonia aetiology

1. Introduction

Community-acquired pneumonia (CAP) represents the most important cause of mortality due to infection in industrialized countries. Excluding the impact of COVID-19, it has an incidence of 1.2 to 2.4 cases per 1000 adults in Europe–USA. These differences have been attributed to the higher rate of pneumococcal vaccination in Europe. At extreme ages (under 5 and over 65–70), the incidence increases [1].
Although the guidelines for the approach to this model of infection are widely implemented in international health schemes, there is variability in the diagnostic-therapeutic management, with differences in admission rates, the achievement of microbiological diagnosis, request for complementary studies, the choice of antimicrobial regimen, or the diversity of care applied. In addition, information that generates controversy or requires an update in its management is constantly emerging.

2. Ten Issues for Updating in Community-Acquired Pneumonia

2.1. Aetiologic Update on CAP

The microbiological diagnosis of community-acquired pneumonia (CAP), as any other infectious process, involves the identification or detection of the causative agent and information regarding the most appropriate treatment based on in vitro susceptibility testing studies, particularly for bacterial pathogens. Traditionally, the aetiology of CAP has been established with studies limited by time and with laboratory techniques restricted to bacterial culture, immunological assays based on the detection of antibodies or antigens, and, occasionally, with molecular methods targeted to specific pathogens or just considering a limited number of them [1][2]. However, guidelines from different societies do not always recommend the use of the same techniques and respiratory samples [3]. Thus, the picture that has been obtained has sometimes been partial, limited to specific groups of population (paediatric, adult, elderly, immunocompromised patients, etc.), during periods characterized by seasonal pathogens, and almost always limited to patients requiring hospital admission, either on clinical wards or at critical care units [4]. From a microbiological point of view, causative organisms were not found in a high proportion of patients with CAP (up to 70%) [1]. Possible reasons that may explain this insufficient information of the aetiology of CAP might include the diversity of respiratory samples used from the lower respiratory tract (sputum, bronchial aspirates, brochoalveolar lavages, protected telescope catheter samples, etc.), difficulties in obtaining these samples, the effect of antibiotic use prior to sample collection, low sensitivity of some of the diagnostic tests, and the involvement of viruses that have not been frequently investigated in CAP [5].
This traditional picture could have been changed due to the progressive introduction of the so-called syndromic platforms or syndromic panels in laboratory CAP diagnosis [6]. They are generally based on real-time PCR techniques that include a relevant number of pathogens as targets (bacteria, viruses and/or fungi) and whose use improves the identification of the microorganism causing CAP, including the detection of co-infections and genes associated with resistance to antimicrobial agents. However, they also complicate the interpretation of the results by finding microorganisms with doubtful pathogenicity, coinfections, and resistance genes that are occasionally not expressed with discrepancies found with phenotypic susceptibility studies [7]. Moreover, these panels have different designs covering different pathogens from different manufacturers, causing complicated comparison of data from the studies and between laboratories [6][8]. 
In a pre-COVID-19 pandemic study, Gilbert et al. demonstrated the increase in pathogen detection in CAP, both bacterial and virus-related, using syndromic panels when compared with a bundle of conventional methods (66.4% vs. 75.5% and 40.5% vs. 60.9%, respectively) [9]. Interestingly, some classical pathogens decreased (e.g., Streptococcus pneumoniae), while others increased with the use of these panels (e.g., Haemophilus influenzae, Rhinovirus, and Influenza virus). This was corroborated in a recent published review that depicts how the introduction of different techniques over time has had an impact on the understanding of the involvement of classical pathogens on CAP [2]. 
Currently, the cost-effectiveness of the syndromic panels remains to be fully validated in terms of price and usefulness in the management of the patients and impact of the information [6]. Different studies demonstrated reduction in time to results and impact in antimicrobial stewardship actions, including early adaptation of antimicrobial therapy [10][11][12].
Regarding phenotypic in vitro susceptibility studies, the most important novelties correspond to the change in the criteria introduced by the European Committee of Antimicrobial Susceptibility testing (EUCAST) [13] in 2019, which affects the clinical susceptibility categories resulting from the interpretation of the antibiogram with the established breakpoints [14]. The most relevant change is in the “intermediate category”, which now becomes category “I”, with a meaning of “susceptible, increased exposure”. There is also a minor change in the “susceptible” (S) category, which is now defined as “susceptible, standard dose”, with no change in the consideration of the resistant (R) category. In S. pneumoniae, this change has not been drastic for beta-lactam antibiotics. EUCAST already established different categories for penicillin according to the dose used; microorganisms with certain increase in MIC values are considered susceptible as long as the dose used is higher (EUCAST Breakpoint table-202

2.2. Aetiologic Approach to CAP Using Imaging Techniques

CAP is defined as the presence of new pulmonary infiltrate on chest X-ray or other chest image techniques together with acute signs and symptoms suggestive of lower respiratory tract infection. The primary role of imaging examinations in CAP is to confirm the diagnosis of pneumonia. However, sometimes the radiological pattern may allow us to make an aetiologic approach of CAP at the time of diagnosis.
The chest X-ray is the most used image method to make the CAP diagnosis; it is low-cost and fast [15]. However, there are a small number of immunocompetent patients with CAP who had radiological evidence of pneumonia on computed tomography but not on a concurrent chest radiograph. Despite having less inflammatory charge, these patients have pathogens and clinical outcomes similar to those who had signs of pneumonia on a chest radiography [16][17]. Depending on the location and the type of the infiltrate, it is possible to distinguish between viral, typical bacterial, or atypical bacterial CAP. Typical CAP patterns on imaging examinations are consolidation (alveolar/lobar pneumonia), peribronchial nodules (bronchopneumonia), and ground-glass opacity (GGO). In fact, many pathogens can cause pneumonia with more than one pattern [18].
Consolidation predominant pneumonia is referred to as alveolar pneumonia and it usually appears in typical bacterial pneumonia such as that caused by S. pneumoniae. It is characterized in histology by the alveolar spaces being filled with an inflammatory exudate, with little or no tissue damage [19]. Radiographically, it shows a nonsegmental, homogenous consolidation involving predominantly or exclusively one lobe with or without visible air bronchogram. Peribronchial nodules predominant pattern occurs when infectious organisms deposited on the epithelium of the bronchi produce acute bronchial inflammation with epithelial ulcerations and fibrinopurulent exudate formation; CAP with this pattern is called bronchopneumonia [19]. The bacteria most often involved are S. aureus, Haemophilus influenzae, P. aeruginosa, anaerobes, and some species of fungus, especially Aspergillus. In ground-glass opacity predominant pattern, the initial damage is directed toward the mucosa of the bronchioles, and, later, the peribronchial tissue and interlobular septa become edematous and infiltrated with inflammatory cells [19]. It is usually bilateral and associated with viruses, Mycoplasma pneumoniae, and Pneumocystis jirovecii CAP.
Computed tomography (CT) scan might be helpful for diagnosing CAP, especially when the result of the chest X-ray is inconclusive, as it has higher sensitivity, and it may help to perform a differential diagnosis with other illnesses as lung cancer, pulmonary edema, or exacerbation of chronic obstructive pulmonary disease; it can also help to fidentify CAP complications [20]. On the other hand, it is more expensive, involves higher exposure to radiation, and is not as usually available as X-ray.

2.3. Diagnostic Stewardship in Different Clinical Settings

Rapid microbiological diagnosis is essential for a proper and targeted treatment. In the case of community-acquired pneumonia (CAP), early identification of the causative pathogen is crucial to guide antibiotic therapy, prevent the emergence of antimicrobial resistance, and reduce avoidable drug adverse effects [21]. However, approximately 30–50% of all CAP cases lack an etiologic diagnosis and, in most cases, the treatment is empirical [22][23]. New diagnosis tools such as point-of-care (POC) tests or rapid respiratory syndromic panels may have a positive effect on microbiological diagnosis of patients with CAP, although its impact on outcomes is controversial [22]. Therefore, diagnostic recommendations in patients presenting with CAP may differ according to patient setting, severity of presentation, and previous immunosuppression.
In community-care settings, including primary care, outpatient clinic, emergency department, and long-term care facilities, the prescription of antibiotics is often taken without availability of diagnostic tests. In these circumstances, POC tests could be helpful in differentiating bacterial and viral acute community-acquired lower respiratory tract infections, facilitating antimicrobial stewardship in the community [21][24]. However, although rapid antigen-based diagnostic tests for influenza, respiratory syncytial virus, human metapneumovirus, and Streptococcus pneumoniae show a high specificity (>80%), all have a sensitivity ranging from 49% to 84%, which is suboptimal. Therefore, when positive, they can be used to confirm the diagnosis, but negative results are not reliable due to its high false-negative rates [24]. 
In patients attending the emergency department with suspected CAP, the usefulness of routine microbiological testing to rationalize antibiotic use and improve clinical outcomes is under debate. Among patients hospitalized with CAP, the rate of positive blood cultures is low, ranging from 4.7 to 16%, and the diagnostic yield of sputum cultures is <50% [25][26]. Regarding the diagnosis of bacterial infections, in adults with severe CAP managed in the hospital setting and in immunocompromised patients with CAP, it is recommended to obtain blood cultures at the time of diagnosis and perform a pre-treatment Gram-stain and culture of respiratory secretions. Gram-stain and cultures are also recommended in patients who are being empirically treated for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa, those who were previously infected with these organisms, and in patients previously hospitalized that received parenteral antibiotics in the last 90 days [21][25][26]. 
Urinary antigen tests (UAT) for S. pneumoniae and L. pneumophila are simple, non-invasive, rapid, non-culture-based diagnostic tests that detect antigens from pathogens excreted in the urine and are unaffected by prior antibiotic administration. They show a high specificity (>90%) and moderate sensitivity (<80%) [27]. Data from a meta-analysis [24] showed an overall sensitivity of 70% (95%CI 60–79%) and specificity of 83% (95% CI 63–93%). Importantly, most of the commercially available Legionella spp. Tests are only able to detect the most common subtype, L. pneumophila serogroup 1, which may lead to missed diagnoses. Therefore, they should be used in combination with other diagnostic tests. In adults with severe CAP, Legionella spp. Culture on selective media or the use of nucleic acid amplification testing from respiratory samples is recommended [21][27][28]. Despite their potential usefulness, current American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) guidelines do not recommend the routine use of urinary antigen tests, except in patients with severe CAP and in those with epidemiological risk factors (as a potential outbreak) [21] or if the patient has hyponatremia, fever, headache, diarrhea, or a recent travel. The indications for UAT for S. pneumoniae include ICU admission, failure of outpatient antibiotic therapy, active alcohol abuse, pleural effusion, leukopenia, chronic liver disease, and asplenia [27][28].

2.4. Intensive Care Unit Admission Criteria and Clinical Stability (ICU-Ward-Discharge)

More than 30% of patients with community-acquired pneumonia (CAP) admitted to the hospital require admission to the ICU, with mortality in these cases being greater than 50%. Delayed ICU admission in patients with CAP has been shown to increase mortality, especially in elderly patients, patients with multiple comorbidities, and immunocompromised patients [1][29][30]. Timely appropriate antibiotic therapy and delay in ICU admission are two important factors that contribute to the better or worse outcome in CAP patients [31][32][33].
Since there is no universal definition of severe pneumonia, multiple severity scales have been developed to identify those patients who would benefit from ICU admission. The two most widely used scores were the pneumonia severity index-PSI and the CURB-65, which were validated to predict 30-day mortality in CAP patients but had limitations to predict the necessity of ICU admission. Prediction mortality is different from predict severity, and the main reasons are the strong influence of age and the lack of markers or criteria for organ dysfunction, which represent a severity criterion in pneumonia. This is the main reason that other prognostic scores such as the SMART-COP [34] and the American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) criteria [35] were developed to identify severe CAP cases that required ICU admission.
According to the ATS/IDSA criteria, the need for mechanical ventilation with endotracheal intubation or the presence of septic shock requiring receipt of vasopressors are major criteria for ICU admission. There are nine minor criteria that include respiratory rate (≥30 breaths/min), PaO2/FiO2 ratio (≤250), multilobar infiltrates, confusion/disorientation, uremia (BUN level, ≥20 mg/dL), leukopenia (<4000 white blood cells/mm3), thrombocytopenia (platelet count, <100,000 cells/mm3), hypothermia (core temperature, <36 °C), and hypotension requiring aggressive fluid resuscitation.
An interventional trial by Lim et al. [36] demonstrated the accuracy of the minor ATS/IDSA criteria in improving CAP outcomes. They identified severe cases of pneumonia early in the ED and initiated early intervention, such as initiation of antibiotic treatment within 3 h, rapid initiation of invasive mechanical ventilation in case of respiratory failure, and early interventions in case of patients presenting with hypotension (fluid resuscitation) or shock (vasopressors). The study reported a decrease in the mortality rate to 6% (intervention group) vs. 24% (control group), p < 0.001. They also reported a decrease in the rate of ICU admission from 53% to 39%, p < 0.008, respectively, and a decrease in the inappropriate delay ICU admission from 32% to 15%, p < 0.001, respectively.

2.5. Antibiotic Treatment Update

Community acquired pneumonia is defined as an acute infection of the pulmonary parenchyma acquired outside of health care settings. It deserves special attention because of immunological worn-out after the SARS-CoV-2 pandemic [37].
Primary care management of patients with a lower respiratory tract infection or community pneumonia is based on the following steps: (1) Identify the patients who need to be treated in a hospital Emergency Department, that is, establish the severity of the disease; (2) Establish which patients can benefit from specific antibiotic treatment; (3) Decide when rapid diagnostic microbiological tests are indicated, including influenza, VRS, and COVID tests; and (4) prescribe the most effective antibiotic treatment. The current guidelines published by scientific societies for the antibiotic treatment of patients with CAP recommend to choose initial treatment depending on the pneumonia setting: outpatient, hospitalization in conventional ward, or in ICU.
In outpatients, the current recommendations consider that quinolones in monotherapy or the combination of a beta-lactam and a macrolide are the regimens with adequate spectrum for typical and atypical intracellular bacteria. In some countries, especially those in the north of Europe, monotherapy with a betalactam alone (amoxicillin or amoxiclav are preferred, may still be effective in non-severe cases [38]. However, this is not the case in the south of Europe, where the combination betalactam plus macrolide leads protocols and national guidelines [39]. There is a controversy about the necessity of adding a macrolide to cover atypical microorganisms instead of using beta-lactam in monotherapy [40] because its superiority has not yet been definitively established. However, Asadi et al. [41] have reported lower mortality and admission requirements in those treated with macrolide combinations (0.2% vs. 3%). The effect of macrolide is also found in patients with drug-resistant S. pneumoniae [42]. 
In patients with CAP who require hospital admission, treatment with the combination of a beta-lactam and a macrolide or a quinolone is recommended to cover the most frequent causal microorganisms. A meta-analysis of 28 observational studies [43] with 9850 patients diagnosed with severe CAP demonstrated a 3% reduction in mortality (relative risk, RR 0.82, p = 0.02) when a macrolide was included in the antibiotic regimen compared to other antibiotics. Its proven benefit may be due to its anti-inflammatory effect in severe patients. 
The optimal duration of antibiotic treatment in CAP is not well established, and there are discrepancies between the different guidelines published to date. Nevertheless, there is agreement that it should be individualized and based on clinical stability criteria, with a minimum of 5 days, and it can be suspended after 48 h of absence of fever (temperature < 37.8 °C) and without more than one sign of clinical instability (pressure systolic blood pressure < 90 mmHg, heart rate > 100 beats/min, respiratory rate > 24/min, <90% room air) [39]. The optimal duration of therapy in necrotizing pneumonia, lung abscess, complicated pleural effusion, or suspicion of unusual microorganisms (P. aeruginosa, S. aureus, anaerobes) is not well known, and it could be prolonged in those circumstances.
There are three keys for selecting the appropriate oral antibiotic for respiratory infections. First is effectiveness, with the aim of achieving maximum microbiological eradication using the antibiotic with the narrowest spectrum for the most isolated microorganisms in this type of infection. Second is safety, minimizing the probability of adverse effects related to the antibiotic, especially the most serious ones, and finally, the microbiota, trying to have the least possible impact on it, since the loss of its diversity leads to greater vulnerability to infection and resistance selection [44]. The current policy is reducing the burden of antibiotics and their adverse effects while ensuring no negative impact on outcomes. The negative effects of prolonging the duration of antibiotic administration are numerous: Clostridioides difficile infection, MDR, adverse effects, and others. In a recent meta-analysis [45] that included 15 randomized and controlled clinical trials with 2796 patients with mild-moderate CAP, no differences were observed in the efficacy of short antibiotic regimens of <7 days vs. ≥7 days.
Biomarkers may be useful to safely reduce and/or personalize treatment duration. The use of procalcitonin (PCT) has shown good potential to reduce antibiotic treatment without adverse effects for patients. In the PRORATA study [46] carried out in critically ill patients, an algorithm was implemented to discontinue the administration of antibiotics after a reduction in PCT of at least 80% or with values < 0.5 µg. Patients in the PCT group had more antibiotic-free days, with an absolute difference of 2.7 days (95% CI 1.4–4.1, p < 0.0001) compared to the control group. 

2.6. Oxygen and Steroidal Therapy in CAP

Oxygen therapy. Pneumonia is a frequent cause of hypoxemia and is one of the most frequent causes of acute respiratory distress syndrome (ARDS) [47]. The SARS-CoV2 pandemic has also highlighted the potential severity of respiratory failure in viral pneumonia and has generated the proliferation of many oxygen therapy devices [48][49]. Hypoxemia is the consequence of an imbalance in the ventilation/perfusion ratio related to flooding or collapse of the alveoli and local inflammatory phenomena caused by the etiologic agent. This situation results in a shunt effect and secondary hypoxic pulmonary vasoconstriction that diminishes or makes gas exchange impossible. The clinical impact of hypoxemia will increase with age, frailty, or comorbidities and will depend on the lung surface area affected [50].
Hypoxemia is an indication for respiratory support. There are different forms of supplemental oxygen administration depending on clinical oxygen requirements, ranging from low-flow oxygen therapy to extracorporeal oxygenation systems (ECMO). The treatment of hypoxemia must be balanced with the risk of excessive oxygen intake and matched to the clinical response and the rest of the therapeutic strategy [51][52]. In view of this variability in the presentation and therapeutic possibilities, there are several aspects, included in the clinical practice guidelines, aimed at personalizing this support [53][54][55][56]: (i) Monitoring of the oxygen level achieved by SpO2 should be maintained. The target to achieve is an SpO2 between 94% and 98%, which can be decreased to a range between 88% and 92% in patients with known chronic respiratory failure or patients with ARDS requiring very high levels of O2 supply (over 70%); (ii) The use of high or low flow systems should be decided according to the level of oxygenation achieved and the patient’s work of breathing. There is controversy about which system to use [57][58].
Corticosteroid therapy. Corticosteroid therapy has been the subject of debate for several years. The results of randomized clinical trials are variable when mortality is measured [59][60][61][62][63]. In patients admitted to the hospital ward, benefits have been described in other objectives, such as avoiding admission to the ICU or reducing therapeutic failure, but without benefits in reducing mortality [63]. The variability in the benefits of corticosteroid treatment depends on the severity of the pneumonia, the patient’s comorbidity, and the intensity of the inflammatory response related to its etiology. In patients admitted with severe pneumonia, no mortality benefits have been found, even adjusting for severity by the Pneumonia Severity Score Index (PSI) [64]. Although a recent meta-analysis focused only on clinical trials on severe community pneumonia points to the benefits of corticosteroids, it still raises doubts since the criteria for severity of pneumonia were not uniform and the pooled evidence remains inconclusive [65]. 

2.7. Out-of-Hospital Management of CAP Requiring Hospitalization

The Pneumonia Severity Index (PSI) and CURB-65 [66][67] severity and mortality risk scales have been used as decision-making tools for the management of community-acquired pneumonia (CAP) patients. However, there are clinical situations where these scales do not adequately identify whether treatment should be on an outpatient or inpatient basis. Up to one third of hospitalized patients with a low-risk PSI (categories I to III) may present a contraindication to outpatient treatment [68], while some patients with a high-risk category (PSI IV and V) could avoid hospital admission with adequate resources [69]. Outpatient management in hospital at home (HaH) units may be an alternative for patients with CAP where severity scales do not adequately discriminate the most appropriate treatment site.
HaH is model of care that allows patients to be cared for at their place of residence, who would otherwise have to remain hospitalized. HaH has proven to be an effective and safe alternative for a variety of acute illnesses [70]. In CAP patients, HaH teams provide parenteral antimicrobial therapy, oxygen therapy, as well as iv corticotherapy and nebulised bronchodilator therapy when associated bronchospasm is present. In addition, it is possible to monitor and treat co-morbidities, obtain samples for laboratory analysis and microbiological studies, and manage imaging tests, as with hospitalized patient.
Currently, there are no universally accepted criteria for admission to HaH of patients with CAP in their admission avoidance scheme. Sometimes, the final decision is based on the clinical judgement of HaH professionals, which poses a risk of variability in clinical practice. Traditionally, pleural effusion, multilobar pneumonia, and respiratory failure have been considered exclusion criteria for admission to HaH from hospital EDs. However, even these situations require individualized assessment.
One of the procedures that greatly facilitates the treatment of CAP in HaH is the possibility of intravenous antibiotics [71]. To avoid overuse, parenteral antimicrobial therapy should be reserved only for cases with (1) need to rapidly achieve high concentrations of the drug at the site of infection; (2) need for an antimicrobial available only parenterally; (3) inability for oral intake or reasonable doubts about adherence to treatment; (4) absence of a functional gastrointestinal tract or inability to ensure drug absorption; and (5) infection at a site that is unlikely to be treatable with the concentrations of a chosen antibiotic available after oral administration.
As in any healthcare setting, it is necessary to follow clinical practice guidelines and recommendations on antibiotic stewardship programs (ASPs) in CAP patients treated through HaH [72]. Simplification of treatment with easy-to-use antibiotics (usually those administered once daily) should be avoided if they are not part of the treatment alternatives, as well as unnecessary prolongation of intravenous treatment, with both being risks associated with OPAT [73]. In this sense, sequential therapy is indicated when clinical stability has been achieved, temperature, blood pressure, heart rate, respiratory rate, and oxygen saturation has been normalized and peak C-reactive protein has been reduced by more than 50%. Faced with the challenges of appropriate antimicrobial use in HaH, this modality of care also represents an opportunity to improve ASPs in the hospital setting, especially when prolonged treatment is required in patients with complicated CAP (pleural effusion, empyema, multilobar pneumonia), in infections with multidrug-resistant microorganisms, or when sequential therapy is not possible [74].

2.8. Factors for Readmission in CAP

In Spain, between 22–60% of patients with community-acquired pneumonia (CAP) are admitted from the hospital emergency department (ED) and, after an average stay of 7–10 days, are discharged [75]. Of these, approximately 10–35% require further reassessment by primary care, ED, or even readmission [76][77][78][79] during the following 30 days. Currently, readmission is considered “an adverse outcome” and a relevant “quality care indicator” in patients admitted with CAP. In this regard, factors related to readmission have been differentiated into those derived from the evolution of CAP and those related to other causes, such as comorbidities, social factors, etc. [75].
The factors related to readmission in CAP in the different studies reviewed [77][78][79][80] could be classified into those related to the evolution of CAP itself and those unrelated. The former would include treatment failure, which would include inadequate antimicrobial therapy [75][76][81][82]. Treatment failure is known as clinical deterioration during hospitalization or convalescence with any of the following: radiological progression or complication (involvement of more lobes, cavitation, effusion, empyema, atelectasis, pneumothorax), respiratory failure, need for mechanical ventilation, hemodynamic instability, or development of a new focus of infection. Inappropriate initial antibiotic therapy is defined by the lack of antibiogram-proven sensitivity to the prescribed empirical antibiotic or that which does not conform to the recommendations of clinical practice guidelines.
The most important cause of readmission unrelated to the CAP itself is comorbidity destabilization [76][83][84], generally with Charlson indices ≥2. Among the most important reasons for this destabilization are cardiovascular disorders (congestive heart failure, arrhythmias such as atrial fibrillation and supraventricular tachycardia, acute myocardial infarction, cardiomyopathy, thromboembolic disease, acute arterial ischemia), pulmonary functional or structural alteration (exacerbation of COPD, asthma, pulmonary thromboembolism), deterioration of renal function (acute or chronic acute renal failure), and gastrointestinal disorders (gastrointestinal bleeding, enterocolitis/acute diarrhea associated or not with Clostridium difficile, pancreatitis, hepatitis) or endocrine-metabolic disorders (complicated diabetes, ionic disorders, hyperglycemia). Any clinical disorder is susceptible to destabilization in the context of a CAP. Lastly, social problems are included (loneliness, caregiver’s claudication, etc.)

2.9. Therapeutic Failure and Rescue in CAP

It is estimated that TF in patients with CAP occurs between 10–15%, and, of those patients who die with CAP, more than 40% have TF. An interesting review that included more than 80 studies identified TF in 16% of patients, and the main reason identified for the cases (30%) was due to detected side effects; only 6% were due to inappropriate empirical antimicrobial therapy (EAT) due to resistant pathogens [85][86].

In general, there are no clinical trials demonstrating better outcomes in CAP using different antibiotics. Although a study with more than 3900 patients identified a higher rate of TF with azithromycin than with levofloxacin [87], a more recent clinical trial observed no difference in the rate of TF between macrolides and quinolones [65]. However, the two most recent guidelines recommend starting empiric antimicrobial therapy (EAT) in hospitalized patients with severe CAP, combining a beta-lactam plus a macrolide and not with quinolones due to the greater efficacy of the former combination than the latter [21][88]. It is true that these guidelines are based on observational studies since they do not include clinical trials indicating differences and that these are necessary to confirm these findings. However, important studies describe significantly lower mortality and less need for IMV with the beta-lactam plus macrolide combination [88].
Inappropriate coverage of EAT can be due to drug-resistant pathogens (DRP) or viral etiology. Although the percentage of CAP due to DRP such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing Enterobacteriaceae, Acinetobacter spp., and S. maltophilia is usually low in most patients (between 1–5%), it is true that, in different subgroups of patients, these figures may be higher, for example, in immunosuppressed patients, those who have received antibiotics, or in certain geographical areas [65][89].
Martin-Loeches et al. suggest using validated prediction clinical scores based on local epidemiology and previous colonization such as “PES” score to avoid DRP and TF [88][89][90]. This score is a predictive model of whether pneumonia is produced Pseudomonas aeruginosa, extended-spectrum-betalactamase-producing Enterobacteriaceae, or methicillin-resistant Staphylococcus aureus. The score assesses factors such as age (<40 = 0 pts, 40–65 = 1 pts and > 65 = 2 pts), sex (Male = 1 pts), previous antibiotic use (2 pts), Chronic respiratory disorder (COPD plus bronchiectasis) = 2 pts, Chronic renal disease = 3 pts, Impaired consciousness in emergency = 2 pts, Fever = −1 pts. For a PES score over 5, the sensitivity, specificity, negative and positive predictive values, and negative and positive likelihood ratios were 36%, 83%, 96%, 11%, 0.77, and 2.09, respectively. These scores are characterized by high negative predictive values (mostly more than 90%), suggesting that their use may allow us to rule out patients who need broad-spectrum empiric antibiotic treatment. Therefore, the use of validated scoring systems together with the data about mucosal colonization and prior antibiotic use can help us to guide appropriate empirical antibiotic treatment in patients with CAP caused by DRP and avoid TF.

2.10. Prevention and Vaccination against Community Acquired Pneumonia (CAP): Immunocompetent and Immunocompromised Host

CAP is fundamentally caused by viruses against many of which there are no vaccines, followed by other microorganisms against which there are vaccines mainly addressed to capsulated bacteria. The importance and recommendations for use differ according to age and pre-existing medical conditions, and those recommendations are more extensive for immunocompromised patients.

2.10.1. Active Immunoprophylaxis with Approved Viral Vaccines

Influenza. Currently, for all viruses causing CAP, active immunoprophylaxis is available against influenza virus, SARS-CoV-2, and varicella-zoster virus. Several types of influenza vaccines are available for the adult and children populations.
WHO and ECDC recommend one dose of influenza vaccine annually for older adults and all persons (over six months of age) with chronic medical conditions [91][92]. In Spain, Interterritorial Council of the National Health System (CISNS) recommends an annual dose for those 65 years and over, for all healthy children six month to <5 yrs, and for Health Care Workers and people who care for institutionalized individuals. People with added risk who should be vaccinated are pregnant women in any trimester of gestation, institutionalized people of any age, adults with chronic cardiovascular, neurological or respiratory diseases, liver diseases, cancer, diabetes mellitus, morbid obesity, etc. Students practicing in health care centers are also encouraged to be vaccinated [93].
Vaccination among the immunocompromised of the above target population should be done with inactivated influenza vaccines (IIV). For adults for whose age group the vaccine is licensed, a quadrivalent vaccine containing two strains of type A influenza virus (H1N1pdm09 and H3N2) and two of influenza B type (Victoria and Yamagata lineages), either adjuvanted, high-dose antigen, or recombinant, are recommended [93][94].
For children between six months and eight years of age who have never received doses of influenza vaccine before, it is recommended that they receive two doses four weeks apart. A single full dose is recommended for children younger than 9 years old who have been vaccinated in previous influenza seasons and for everyone, regardless of age. Influenza vaccine should be administered in October–November for those living in the Northern Hemisphere. Vaccination is indicated until the end of the annual influenza season for those who did not receive the vaccine in October–November [93][94].
SARS-CoV-2 (COVID19 causing virus). At present, among all the vaccines marketed against SARS-CoV-2, priority is given to the monovalent mRNA vaccine adapted to the omicron lineage (XBB.1.5) [95][96]. The administration of a booster dose against COVID-19 is recommended for the population aged 60 years and older, for institutionalized people in nursing homes and other disability centers, and for those at risk of contracting SARS-CoV-2 and transmitting it to others, including health care workers and health providers. Certain people younger than 60 years should also receive a booster dose, including pregnant women in any trimester of gestation, institutionalized people of any age, and adults with chronic cardiovascular, neurological, or respiratory diseases, as well as those with liver diseases, cancer, diabetes mellitus, and morbid obesity [97]. 

2.10.2. Active Immunoprophylaxis with Approved Bacterial Vaccines

Prevention against encapsulated bacteria causing CAP is focused on vaccination against Haemophilus influenzae type b and pneumococcus. Haemophilus influenzae type b vaccine is recommended in the adult population only in certain situations such as anatomical or functional asplenia (one dose) and hematopoietic stem cell transplant (three doses starting six months after successful transplant) [98].
Several pneumococcal vaccines are available for adult vaccination, including the 23-serotype polysaccharide (PPSV23v) and the 13-serotype (PCV13v) and 20-serotype (PCV20v) conjugate vaccines. The objective is to improve protection against pneumococcus with a single dose, reducing the burden of care and, therefore, the possibility of better coverage. In Spain, systematic vaccination with PPSV23 with one dose is recommended for persons over 65 years of age and risk groups (with revaccination at five years of age). Chronic cardiovascular and respiratory disease, neurological diseases, chronic liver disease, diabetes mellitus, celiac disease, institutionalized persons. PCV13v vaccine followed by PPSV23v (at least eight weeks) are indicated in the adult population of risk groups, as well as immunodeficiencies, immunosuppressive treatment, asplenia, HIV infection, transplantation, cochlear implantation, liver cirrhosis, and Down syndrome [98][99].

2.10.3. New Trends: The Role of Artificial Intelligence in Managing Community Acquired Pneumonia (CAP)

The advances of artificial intelligence have naturally been applied in CAP to improve different aspects of management: hospitalization and mortality risk assessment, prediction of complications (ARDS) and antibiotic treatment, differential etiological diagnosis. A Chest X-ray-based artificial intelligence (AI) model was applied by Quah et al. [100] to generate a mortality risk score based on chest X-ray (CAPE score) that showed a similar prediction capacity (AUC) to traditional PSI and CURB-65 scores but that could improve their discrimination when combined. Similar data were obtained by a validate a causal probabilistic network (CPN) based on clinical data [101].
An artificial neural network model was used by Mo et al. [102] to predict the risk of ARDS in CAP patients based on clinical and laboratory variables; this model based on artificial neural network model has good prediction ability (AUC: 0.977; 95% CI:0.956–1.000), which can be used to calculate the accuracy of ARDS in CAP patients, and specific preventive measures can be given. A machine learning tool was applied by König et al. (CAPNETZ study) to support clinicians in the decision of adding macrolides for treatment of moderately severe CAP to expand the coverage to atypical pathogens and attenuate pulmonary inflammation [103]. This large study (4898 patients) was able to reduce 180-day mortality rate by 27% in comparison to standard of care.

3. Conclusions

CAP represents the most important cause of mortality due to infection in industrialized countries. Although diagnostic and treatment guidelines are in place internationally, information has recently emerged that would help in optimizing its management. The etiological vision is beginning to change thanks to the progressive introduction of syndromic platforms based on real-time PCR techniques that demonstrate the majority participation of viruses as the main etiological agent or at least in coinfection. This constitutes a new challenge, both for the pathogenic interpretation of the syndrome and for therapeutic management in the world of stewardship. The choice of therapy in CAP requires a risk-benefit assessment for each individual patient, taking into account local epidemiological data, individual risk factors, as well as documented antibiotic allergy. The combination of a beta-lactam with a macrolide seems to be the most recommended starting strategy, with a duration of 5 to 7 days. The treatment of hypoxemia should be balanced with the risk of excessive oxygen supply and should be adapted to the clinical response and the rest of the therapeutic strategy. Similarly, steroid treatment must also be individualized, since it has proven to be useful in distress and shock situations but has not benefited all clinical profiles in the case of COVID and may have a negative impact on the immunological control of the infection. Continuity of care in HaH units is the most important challenge, especially in patients in whom, due to comorbidity or intolerance, optimal defervescence cannot be guaranteed in sequential therapy. Administering intravenous drugs at the required doses and frequency and monitoring comorbidity destabilization are critical to avoid readmission. The most frequent causes of therapeutic failure in CAP are the presence of resistant pathogens, inadequate concentration of antimicrobials in the focus and the severity of the pneumonic process that often destabilizes comorbidity. Vaccination is the measure with the greatest impact in reducing the incidence and mortality of pneumonia, both in immunocompetent and immunocompromised patients.

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Subjects: Respiratory System
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Francisco Javier Candel
,
Miguel Salavert
,
Miren Basaras
,
Marcio Borges
,
Rafael Cantón
,
Emilia Cercenado
,
Catian Cilloniz
,
Ángel Estella
,
Juan M. García-Lechuz
,
José Garnacho Montero
,
Federico Gordo
,
Agustín Julián-Jiménez
,
Francisco Javier Martín-Sánchez
,
Emilio Maseda
,
Mayra Matesanz
,
Rosario Menéndez
,
Manuel Mirón-Rubio
,
Raúl Ortiz de Lejarazu
,
Eva Polverino
,
Pilar Retamar-Gentil
,
Luis Alberto Ruiz-Iturriaga
,
Susana Sancho
,
Leyre Serrano
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Update Date: 22 Jan 2024
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