TITLE: Community-Acquired Pneumonia AUTHORS: Luis Felipe Reyes,1,2,3 Andrew Conway Morris,4,5 Cristian Serrano-Mayorga,2,6 Lennie PG Derde,7 Robert P Dickson8,9,10 and Ignacio Martin-Loeches11 AFFILIATIONS: 1, Unisabana Center for Translational Science, School of Medicine, Universidad de La Sabana, Chia, Colombia; 2, Clinica Universidad de La Sabana, Chia, Colombia; 3, Pandemic Sciences Institute, University of Oxford, Oxford, United Kingdom; 4, Perioperative, Acute, Critical Care and Emergency Medicine Section, Department of Medicine, University of Cambridge, Level 4, Addenbrooke's Hospital, Hills Road, Cambridge, UK; 5, JVF Intensive Care Unit, Addenbrooke's Hospital, Hills Road, Cambridge, UK. 6, PhD Biosciences, Engineering School, Universidad de la Sabana, Chia, Colombia; 7, University Medical Center Utrecht, Utrecht, the Netherlands; 8, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA; 9, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; 10, Weil Institute for Critical Care Research & Innovation, Ann Arbor, MI, USA; 11, Multidisciplinary Intensive Care Research Organization (MICRO), St James's Hospital, Dublin, Ireland. CORRESPONDING AUTHOR: Luis F. Reyes, MD, PhD, MSc; Unisabana Center for Translational Science, School of Medicine, Universidad de La Sabana, Campus Puente del Común, KM 7.5 Autopista Norte de Bogotá, Chía, Colombia. Phone: (571)-861-5555 ext. 23342; Email: luis.reyes5@unisabana.edu.co. FUNDING: This study was sponsored by Universidad de La Sabana, Chia, Colombia (MED- 260-2019). ACM is supported by an MRC Clinician Scientist Fellowship (MR/V006118/1). RUNNING TITLE: Community-Acquired Pneumonia. MANUSCRIPT WORD COUNT: 6388 ABSTRACT WORD COUNT: 150 SUMMARY Community-acquired pneumonia (CAP) is a major global health challenge, disproportionately affecting vulnerable populations, including the elderly, immunocompromised, those with chronic conditions and young children. Once considered solely an acute illness, CAP is now recognised as a disease with long-term complications, including cardiovascular events, respiratory impairment, and cognitive decline. Recent advances, such as nucleic acid amplification tests (NAATs) and the broader availability of point-of-care lung ultrasound (LUS), allow rapid pathogen detection and personalised treatment. However, significant uncertainties remain regarding the role of NAATs, LUS, and serum biomarkers in clinical practice. Antibiotic treatment is the cornerstone in CAP treatment, whilst the role of adjunctive therapies, including corticosteroids and immunomodulators, remains incompletely defined. Comprehensive CAP management emphasises personalised treatment, rehabilitation after the acute episode, routine cardiovascular screening, and strengthening preventive measures such as vaccination. As precision medicine advances, integrating diagnostics and tailored therapies will improve outcomes and reduce the global burden of CAP. CAP: FAST FACTS Key Epidemiology • Global burden: Leading cause of infectious morbidity and mortality; ~2.5 million deaths/year. • High-risk groups: Elderly, immunocompromised, those with chronic comorbid conditions (e.g., COPD, heart failure), and young children. • Long-term impact: Not just an acute illness. It is linked to long-term cardiovascular events, respiratory impairment, and cognitive decline. Diagnostics • Traditional tools: Chest X-ray, sputum cultures (low sensitivity/specificity). • Current advancements in diagnosis: • Radiology: Point of Care Ultrasound (POCUS) is instrumental in diagnosing and following up. • NAATs: Rapid, accurate pathogen identification, including viral-bacterial co- infections. • Biomarkers: Procalcitonin and CRP aid severity assessment and treatment decisions. Treatment • Antibiotic therapy: • Empiric coverage tailored to severity, risk factors (e.g., Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa), and local resistance. • Shorter courses (5–7 days) are sufficient for clinical stability. • Adjunctive therapies: • Corticosteroids are only beneficial in patients with severe CAP. • Immunomodulators (e.g., IL-6 inhibitors) under investigation. Complications • Cardiovascular: High risk of myocardial infarction and arrhythmias post-CAP. • Respiratory: Prolonged lung dysfunction; risk of bronchiectasis, COPD exacerbations. • Neurology: headache, dizziness, hazy feeling, encephalopathy, and delirium. • Systemic: Cognitive decline, post-intensive care syndrome (PICS) in severe cases. Long-term Follow-Up • Rehabilitation: Early respiratory physiotherapy to improve lung function. • Screening: Regular cardiovascular checks post-discharge. • Prevention: Vaccination (influenza, pneumococcal), smoking cessation, and risk factor management. Emerging Challenges • Gaps in understanding systemic complications and severe disease mechanisms. • Antibiotic Resistance and Treatment Optimisation. • Emerging Pathogens, Global Travel, and Climate Change. • Socioeconomic Disparities and Public Health Determinants. • Advancements in Diagnostics and Precision Medicine. • Need for trials on adjunctive therapies and real-world use of rapid diagnostics. INTRODUCTION Community-acquired pneumonia (CAP) is the leading infectious cause of morbidity and mortality worldwide, with an estimated global incidence of 4350 cases per 100 000 population.1 It disproportionately affects vulnerable patients, including the elderly, very young, immunocompromised individuals, and those with chronic comorbidities.2 CAP is responsible for approximately 2·2 million deaths annually, or 27·7 deaths per 100 000. The highest mortality is observed in lower-middle-income countries (LMICs), where disparities in healthcare access, air quality, and vaccination coverage exacerbate the disease burden.2-5 Although CAP represents a significant public health problem, there are many challenges in its diagnosis, treatment, and long-term management. Clinically, no gold standard exists that allows clinicians to quickly and accurately diagnose bacterial pneumonia, often leading to the overuse of empirical antimicrobial therapies.6 This antimicrobial overuse is related to rising antibiotic resistance, increased risk of adverse clinical outcomes, and inaccurate diagnosis and follow-up challenges.7 Current recommendations emphasise using local epidemiology data and validated risk factors to guide empirical therapy, aiming to balance adequate coverage while minimising resistance development.8,9 Strengthening the implementation of rapid diagnostic tools and improving adherence to clinical guidelines are essential to address this persistent challenge and mitigate these issues. Advances in diagnostics and therapeutics are transforming the clinical management of CAP, moving away from traditional “one-size-fits-all” approaches towards personalised strategies adapted to the level of care, clinical severity, demographics, comorbidities, and pathogen detection. Nucleic acid amplification tests (NAATs) (Table 1) have the potential to revolutionise pathogen identification, enabling rapid and accurate detection of bacterial and viral pathogens (including co-infection). These diagnostic breakthroughs, accelerated by the widespread adoption of molecular testing during the COVID-19 pandemic, are increasingly incorporated into clinical practice.10-12 This shift offers the potential to guide individualised treatment plans tailored to pathogen-specific therapies and patient risk profiles, potentially reducing the burden of antimicrobial resistance and improving outcomes. However, interpretation of results continues to be challenging, depending on the sample used for the test, since there is controversy about whether the identification results correspond to colonising versus infecting microorganisms. Additionally, concerns exist about the availability of these technologies in resource-constrained countries. Personalised treatment approaches for CAP are urgently needed to address its complexity and heterogeneity. Stratifying patients based on clinical severity, serum biomarkers such as procalcitonin or C-reactive protein, and risk factors for specific pathogens like Pseudomonas aeruginosa or Methicillin-resistant Staphylococcus aureus (MRSA) has become critical.13,14 Notably, the potential of biomarkers to inform the empirical use of antimicrobials remains open and continues to be a subject of ongoing study. Furthermore, accounting for local epidemiology, including variations in pathogen prevalence and antimicrobial resistance patterns, is essential to optimise empirical therapy. For example, the prevalence of some microorganisms has declined with the broader adoption of vaccination strategies, which have changed the epidemiology in North America and parts of Europe.15 Still, Streptococcus pneumoniae remains a dominant pathogen in many low-income settings and is the most frequently identified bacterial pathogen in CAP patients worldwide.16,17 Similarly, respiratory viruses account for an increasing proportion of microbiologically proven CAP globally, now detectable in up to 30% of cases due to advances in molecular diagnostics.18,19 The evolving understanding of CAP's pathophysiology challenges its traditional characterisation as merely an acute infection. Increasing evidence links CAP to long-term complications, including cardiovascular events, persistent respiratory dysfunction, and cognitive decline, particularly among older adults and those with severe CAP.20-26 These findings highlight the need to reframe CAP as a disease with potential chronic sequelae, requiring comprehensive management strategies, extending beyond the acute phase to include long-term follow-up and prevention.27-29 As CAP continues to impose a significant global health burden, integrating advanced diagnostics, personalised treatment strategies, and focusing on long-term outcomes represents a transformative shift in its management. This seminar explores these developments, emphasising global epidemiology, pathophysiological insights, diagnostics, and therapeutic innovations that redefine our approach to CAP in acute and chronic contexts. By leveraging these advances, clinicians can move closer to achieving the goal of precise, patient-centred care for this pervasive and complex disease. SEARCH STRATEGY AND SELECTION CRITERIA We conducted a comprehensive literature search in PubMed covering publications from January 1, 1990, to April 1, 2025. The search included combinations of the terms “pneumonia,” “community-acquired pneumonia,” or “CAP,” along with “diagnosis,” “therapy,” “antibiotics,” “prevention,” and “vaccines.” No filters were applied for language or publication date. To ensure a thorough review, we manually screened the reference lists of relevant narrative and systematic reviews focused on CAP to identify additional key articles and international clinical guidelines. Furthermore, we consulted the websites of the World Health Organization (WHO) and other international health agencies to gather essential documents that might not have been indexed in PubMed. EPIDEMIOLOGY AND RISK FACTORS CAP's incidence varies widely by demographic and geographic factors, contributing to a considerable healthcare burden, especially in cases requiring hospitalisation or admission to an Intensive Care Unit (ICU). Biological and Environmental Risk Factors and Social Determinants of CAP Key biological risk factors for developing CAP have been identified, including advanced age, previous history of pneumonia (including COVID-19), smoking, chronic lung conditions (e.g., COPD and asthma), chronic cardiovascular disease, and diabetes.30-32 Immunosuppression due to illness or treatment also elevates the risk for CAP. Lifestyle factors such as alcohol/neurologic depressants abuse (which increases the risk of broncho aspiration and swallowing disorders) and poor nutrition weaken immune defences, further increasing susceptibility to CAP, with air pollution particularly affecting urban and industrial areas.33 Likewise, socioeconomic status, healthcare access, housing quality, and education significantly impact CAP incidence, severity, and outcomes.34-36 Individuals from lower- income backgrounds often face higher rates of CAP related to inadequate housing, limited healthcare access, and increased exposure to pollutants that compromise respiratory health.36 Crowded living conditions and limited access to healthcare can promote pathogen transmission and delay CAP diagnosis and treatment, thereby worsening outcomes. Additionally, low health literacy has been associated with reduced acceptance of preventive behaviours/strategies, including vaccination.37,38 Incidence of CAP and Severe CAP Requiring ICU Admission CAP incidence is high in older populations and individuals with chronic diseases.32 In High- income countries, CAP incidence is approximately 1188·6 cases per 100 000 population, increasing significantly among those aged 70 and older to around 4846·6 cases per 100 000 population.1,2,39 The European CAP incidence rate is 1664·0 cases per 100 000 in the general population, with rates rising steeply in those over 70 and reaching up to 5062·9 cases per 100 000 population.30,40,41 Severe CAP cases represent approximately 13–22% of hospitalised CAP patients and often require ICU care, with respiratory failure, septic shock, and multi- organ dysfunction driving high mortality rates.40-42 CAP patients treated in ambulatory settings reach an average cost of US$ 2 394 per episode.43 While in-hospital CAP patients reach a mean cost of US$ 17 736 with a mean length of stay (LOS) of 5·7 days in uncomplicated cases,44 these costs can increase to US$ 51 219 in complicated cases.45 The all-cause readmission rate at 30- and 180-days reaches 8·8% and 20·1%, respectively.44 30- day mortality rates of CAP vary significantly depending on several factors; nevertheless, in recent years, the mortality has decreased, reaching rates between 4·1 % and 9·6 % among hospitalised patients.46,47 Conversely, ICU-requiring CAP patients have 30-day mortality rates between 27% and 49·4%.40,48-50 Pathogen Detection Rate Despite extensive diagnostic testing, a specific pathogen can only be identified in less than half of CAP cases,18 underscoring the gaps in CAP etiological diagnosis. As molecular diagnostics improve and real-time reverse transcription qPCR (RT-qPCR) and multiplex real- time PCR assays are more broadly used,12 identification of CAP microbiological aetiology is expected to increase. This may improve diagnostic yields even in patients who have already received antimicrobials, which often render cultures negative, leading to better-targeted treatments.51,52 Bacterial aetiology of CAP Although S. pneumoniae is CAP's most frequently detected bacterial aetiology worldwide, other causative bacterial pathogens include Staphylococcus aureus, Haemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Enterobacteriaceae, the latter being amongst the less common causes.2,3,18,53 However, depending on various factors, including comorbidities, habits, immunosuppression, and previous colonisation, other causal agents, such as Pseudomonas aeruginosa and Legionella pneumophila, may be prevalent.2,3,18,53,54 Notably, the incidence of S. pneumoniae has declined due to the widespread use of pneumococcal vaccination, reducing pneumococcal pneumonia rates and contributing to population-level herd immunity.11 Regional vaccination recommendations and uptake differences affect S. pneumoniae prevalence in CAP patients, as it causes roughly 30% of CAP cases in Europe but only 10–15% in the US, where higher pneumococcal vaccination rates are reported.18 However, in LMICs, vaccination strategies are less efficient, contributing to higher prevalence of S. pneumoniae.5,55-57 H. influenzae also remains an important pathogen in CAP; however, vaccination strategies, demographic factors, and external events such as the COVID-19 pandemic influence the dynamics of its detection and reporting.58,59 The introduction of the H. influenzae type b (Hib) vaccine has led to decreased Hib infections; however, an increase in non-Hib serotypes has been observed.60,61 The changes in trends of H. influenza identification suggest that the pandemic could have influenced the infection landscape, possibly due to changes in healthcare-seeking behaviours, public health measures, or viral-bacterial interactions.62 Viral aetiology of CAP Advances in molecular diagnostics have increased the detection of respiratory viruses in CAP, with studies indicating that viruses are present in approximately one-third of adult CAP cases, with rhinovirus and influenza A and B making up 9% of cases.18 Other viruses frequently identified in CAP patients are Respiratory syncytial virus (mainly in the elderly and children), Human Metapneumovirus, Parainfluenza viruses, Coronaviruses (229E, OC43, NL63, HKU1 and SARS), Hantavirus, Cytomegalovirus, Herpes simplex virus, and Varicella Zoster virus.63,64 Acknowledging the complex interplay between viral and bacterial infections in CAP is essential. Viral infections potentially predispose individuals to secondary bacterial infections, and the cooperative existence between viruses and bacteria involves mechanisms such as impairment of the host immune response and disruption of epithelial barrier integrity, leading to more severe clinical manifestations and increasing risk of respiratory failure.65,66 This highlights the need for further research to better understand viral contributions to CAP pathogenesis.18,19,63 PATHOPHYSIOLOGY CAP occurs when pathogens (i.e., bacterial, viral, or fungal) proliferate rapidly in the lower respiratory tract, provoking robust local and systemic inflammation with subsequent tissue destruction. Pathogens access the lower respiratory tract by inhalation of airborne particles (in the case of viral pathogens) or via aspiration of pharyngeal secretions.67 Subclinical aspiration of pharyngeal contents is common even amongst healthy, asymptomatic individuals,68 explaining the presence of viable, oropharynx-associated bacteria in the lungs of healthy volunteers.67,69 Microbiologically, recent studies using culture-dependent or- independent techniques do not support the traditional distinction between "aspiration pneumonia" and other CAPs.70 Essentially, all bacterial CAP arises via aspiration, and the mere presence of microbes in the lungs cannot explain the disease's pathogenesis. Bacterial pneumonia occurs when a sufficient burden of specific microbes with pathogenic potential accesses the lower respiratory tract, exceeding the host's complementary mechanisms of microbial clearance (i.e., cough, mucociliary clearance, immune defences). While the healthy lung environment is nutrient-poor for reproducing microbes, the onset of pneumonia alters this landscape: the influx of oedema and mucus to the airspaces provides a nutrient-rich medium that fosters microbial proliferation.67 Under physiological conditions, resident macrophages in the alveolar space clear pathogenic microorganisms.71 If the phagocytes' capacity is exceeded, closely coordinated inflammatory pathways will be triggered.72 This leads to the expression of early inflammatory cytokines, including interleukin 1-beta and chemokines, including CXCL8,71,73 driving the recruitment of neutrophils and inflammatory monocytes from the circulation. The lytic enzymes, oxidants and extruded nuclear material from these cells damage the delicate alveolar epithelium, leading to plasma protein fluid leakage and disruption of gas exchange.74 These pathological features drive the clinical picture of pneumonia, with breathlessness, pyrexia and, as severity increases, hypoxia and hypercarbia. Although neutrophils are considered central to the development of acute lung injury,74 it is also recognised that injury may develop in patients with neutropenia.75 Recent data has identified a wider group of patients with lung injury without alveolar neutrophilia.76 Evidence of macrophage-lymphocyte-driven pathology in COVID-1977 and enrichment for respiratory viruses in the non-neutrophil-driven phenotype identified by Jeffery et al.55 indicates multiple pathways by which similar clinical presentations may arise. There is growing enthusiasm for identifying divergent immunological mechanisms underpinning common clinical syndromes,78 aiming to personalise immunomodulatory therapies, but these approaches almost exclusively focus on blood immune profiling.78 Given the compartmentalised nature of lung inflammation, tailoring therapies based on blood indices may result in misapplication.79 Patients who develop severe manifestations of pneumonia seldom die of refractory hypoxaemia. The mechanisms of extrapulmonary organ failure are diverse but include direct bacterial invasion and bacteraemia,80 systemic inflammatory activation with complement activation and cytokine release, immunoparesis,81 and inability to clear the primary or secondary pathogens. The development of extrapulmonary organ failures, such as acute kidney and liver injury or cardiovascular failure and shock, portends poorly and helps explain the significant global mortality burden of CAP. CLINICAL FEATURES AND DIAGNOSTIC APPROACH The inflammatory infiltration of the alveolar space drives the clinical symptomatology of CAP. However, this disease presents marked variability in its respiratory and systemic manifestations across patients. Symptom severity largely depends on the intensity of the host's immune response, with younger, immunocompetent patients presenting more pronounced clinical features. Both respiratory and systemic symptoms may be mild or absent among patients with impaired immune responses due to comorbidities (e.g., HIV/AIDS), iatrogenesis (e.g., corticosteroids), or other factors (e.g., the elderly).82 Notably, the absence of "classic" pneumonia symptoms does not exclude the diagnosis in these populations. Respiratory manifestations dominate CAP's clinical presentation. Cough (often productive of sputum), dyspnoea, and pleuritic chest pain are hallmark features (Figure 1). Physical examination findings commonly include tachypnoea, adventitious breath sounds (rales or rhonchi), and evidence of consolidation, including dullness to percussion or egophony. The diagnostic approach for CAP is variable in the literature, and this can be attributed to a lack of “gold standard” definition; nevertheless, some features are globally accepted an the most common diagnosis criteria involves identifying pulmonary clinical signs (i.e. “classic” pneumonia symptoms and radiological signs of pulmonary consolidation) alongside systemic features such as abnormal body temperature (>38° C or < 36°C),83-86 tachypnoea, and tachycardia.85-87 Detection of systemic inflammation may extend to laboratory parameters, including total leucocyte and neutrophil counts (leukocyte count <4 000 /uL or > 10 00 uL; or >15% band-type neutrophils), elevated C-reactive protein (CRP) or procalcitonin (PCT). No single clinical sign has good predictive power for identifying patients with radiographic infiltrates, although the absence of abnormal pulmonary examination and physiology has good negative predictive power.83 Hence, clinical examination alone cannot confirm pneumonia diagnosis, but can support ruling it out. Likewise, older or immunocompromised patients may lack fever and present with nonspecific findings (such as confusion or functional decline) or present with atypical pneumonia, where patients may exhibit mild respiratory symptoms such as a dry cough, sore throat, mild fever, and more severe extrapulmonary symptoms, including confusion, diarrhoea, headache and myalgia.88,89 CAP is a leading cause of sepsis, and severe cases may present with hypotension, altered mental status, and other organ dysfunctions alongside respiratory failure.84 A recent meta-diagnostic analysis of CRP and PCT in CAP found the modest diagnostic performance of both tests.85 CRP at a cut-off of 50mg/L had sensitivity and specificity of 75%, whilst PCT at a cut-off of 0·5mcg/L had sensitivity of 44% but specificity of 93%. This diagnostic performance is insufficient to guide the initiation of antimicrobial therapy, and both US and European/South American guidelines and other studies recommend against using biomarkers to guide antimicrobial initiation.9,90-92 However, PCT has a proven role in antimicrobial de-escalation in sepsis arising from sCAP and other severe infections,93- 96 whilst the role of CRP is less clear.94,97,98 CRP-guided and PCT-guided treatment algorithms significantly reduced the duration of antibiotic therapy in hospitalised patients with CAP compared to standard care. Median days on antibiotics were reduced to 4 days in the CRP group and 5.5 days in the PCT group, compared to 7 days in the control group. A recent meta-analysis suggested that CRP and PCT levels can serve as reliable tools to support the de-escalation of antimicrobial therapy in CAP, contributing to shorter antibiotic courses and potentially mitigating the development of antimicrobial resistance and adverse drug effects. Nonetheless, the interpretation of these biomarkers should be complemented by thorough clinical evaluation to ensure optimal therapeutic decision-making.99,100 Given the imperfect diagnostic performance of clinical and laboratory measures, demonstrating alveolar infiltration is a key step in securing a diagnosis. This can be achieved through chest radiography, computed tomography, or lung ultrasound (LUS) (Figure 1). Radiographic assessment is recommended in all cases in the US guidelines,101 although only in hospitalised cases in the UK guidelines.102 Although plain chest radiology is frequently used as the 'standard' for radiologic assessment of CAP, it is insensitive relative to computed tomography,85 and infiltrates are not specific for pulmonary infection. Computed tomography is advised in the ATS/IDSA guidelines for uncertain or non-conclusive cases.9 LUS has better sensitivity and specificity than plain radiology, with pooled values of 92% (95% CI 88-95%) and 89% (95% CI 81-95%), respectively.85 The finding of dynamic air bronchograms is considered a pathognomonic sonographic feature of pneumonia. Nevertheless, the most common signs are lung consolidation or interstitial patterns.103-105 However, whilst LUS is often helpful in the resuscitation room and the ICU, it lacks sufficient sensitivity to rule out pneumonia and depends on the experience and expertise of the operator.103-107 Notably, in a recent survey of international practice of severe pneumonia diagnosis, a third of ICU clinicians did not consider radiographic infiltrates mandatory to diagnose pneumonia.12 The definitive diagnosis of CAP is secured by identifying a respiratory pathogen, combined with the clinical, radiological, and laboratory features outlined above; even though a “gold standard” definition of pneumonia remains absent. Microbiological sampling is generally not required for low-severity diseases managed in the community, as the results do not affect management.63,72 Blood and sputum samples are commonly obtained for culture in patients hospitalised with CAP,108 although the yield from culture is low (7% and 18%, respectively). Antigen detection is available for identifying specific pathogens, notably urinary antigen testing for S. pneumoniae and Legionella pneumophila, as well as a growing number of respiratory viruses on upper-respiratory swabs.109 Antigen testing has good positive predictive value; however, false negatives are common, and these tests do not rule out other co-infecting organisms. As a result, antigen testing has a limited impact on antimicrobial prescribing, and indeed, there is concern that it may drive inappropriate narrowing of the antimicrobial spectrum and increased risk of relapse.110 The growing availability of NAATs has improved viral detection. Tests for SARS- CoV-2 and Influenza are recommended in mild and severe CAP, but only when viruses are actively circulating or exposure is suspected. When these tests are used at admission, they decrease time to antimicrobial use, antiviral initiation, and length of stay.9,87,111,112 Expanded viral tests (i.e., beyond SARS-CoV-2 and Influenza) may be performed in patients with severe CAP to guide treatment by aetiology.112-114 NAATs are also increasingly available in multi-organism, syndromic formats, with panels increasingly extended to cover conventional bacteria, respiratory viruses, and atypical microorganisms.51 The evidence that syndromic NAATs impact antimicrobial prescribing in hospitalised CAP is uncertain, with divergent trial results.115-119 Patient context (i.e., management in the community, emergency department, ward, or ICU settings and severity of illness) alongside biomarker assessment as part of embedded antimicrobial stewardship approaches are likely required to achieve changes in antimicrobial prescribing.93,94 In severe CAP managed in the ICU, there are few trials of NAATs, and none have yet been published in full. However, abstract reports from Voiriot G120 and observational data121 suggest improved antimicrobial targeting is possible.121 Nonetheless, there is not enough evidence to support antimicrobial withdrawal, and some guidelines do not recommend NAAT use.9,115 ASSESSMENT OF DISEASE SEVERITY Severe CAP is the most life-threatening form of CAP, characterised by high morbidity and mortality.122 Severe CAP often presents with clinical features such as respiratory distress, multilobar infiltrates on imaging, septic shock, and acute respiratory failure. With its heightened mortality, guidelines advise risk stratification and early ICU admission.123-125 The most widely accepted criteria for defining severe CAP are those from the IDSA/ATS (Major criteria: (1) Need for invasive mechanical ventilation, (2) Septic shock requiring vasopressors. Minor criteria: (1) Respiratory rate ≥30 breaths/min, (2) PaO₂/FiO₂ ratio ≤250, (3) Multilobar infiltrates, (4) Confusion/disorientation, (5) Uraemia (BUN ≥20 mg/dL), (6) Leukopenia (WBC <4,000/μL), (7) Thrombocytopenia (platelets <100,000/μL), (8) Hypothermia (core temp <36°C), (9) Hypotension requiring aggressive fluid resuscitation. Severe CAP is diagnosed with one major or three or more minor criteria.9,126 However, other severity scores such as the CURB-65, PSI, SMART COP, SAPS II, and Pneumonia SHOCK are available (Table 2).23 Notably, the current clinical practice guidelines emphasise the clinician's judgment in tailoring management based on specific risk profiles.124 A significant challenge with risk scoring is that whilst the scores have good performance for predicting mortality and thus help guide hospitalisation, they are typically less effective at predicting the need for ICU admission and organ support.127 Attempts to improve the prediction of the need for ICU have found the SOFA score to be most effective,128 although in many cases, this is simply identifying organ failure manifesting at the time of hospital presentation. Assessing illness severity helps determine how quickly antimicrobials and supportive treatments should be initiated. At the same time, clinicians should evaluate the likely causative organisms and consider the risk of multidrug-resistant or opportunistic pathogens, which may require targeted antimicrobial strategies. Risk factors for MDRO infection include known carriage of MDRO and recent (<90 days) receipt of intravenous antibiotics during hospitalisation.63 Opportunistic pathogens should be considered amongst patients with profound immunocompromise (e.g., HIV with low CD4 count, neutropaenia following chemotherapy or solid organ and haematopoietic stem cell recipients). However, it is essential to recognise that sporadic and epidemic causes of CAP are also common amongst these patient groups. TREATMENT: ANTIMICROBIAL THERAPY The treatment of CAP is dependent on (1) the severity of illness and (2) the (likely) causative pathogen(s). Initial therapy is empiric as the causative pathogen is usually unknown at presentation. Typical pathogens are generally covered with a beta-lactam antibiotic, assuming no history of allergy, with local resistance patterns determining the specific agents.124 Coverage for intracellular organisms, including those with severe CAP and those suspected of atypical infections, is recommended with fluoroquinolones or macrolides. Some quinolones, such as levofloxacin, cover both Gram-positive and Gram-negative typical and atypical pathogens. Most guidelines advise macrolides over fluoroquinolones, primarily based on data from observational studies (Figure 2).129 The potential immunomodulatory effects of macrolides may explain their apparent superior performance. This was recently investigated in the ACCESS trial,130 where 7 days of twice-daily clarithromycin reduced a composite endpoint (a decrease in respiratory symptom severity score and SOFA score, PCT, or both) from 68% to 38% at day 4. However, it remains uncertain whether these improvements in surrogate outcomes translate into tangible benefits for patients, such as enhanced quality of life, faster functional recovery, or reduced mortality. In a randomised trial comparing beta- lactam monotherapy to beta-lactam plus macrolide in moderate severity CAP, time to stability did not include the pre-defined non-inferiority limit and favoured combination therapy; however, this effect appeared to be restricted to patients with atypical infections or more severe (PSI category IV) pneumonia.131 A systematic review of observational data concerning mortality, dual therapy (i.e., beta-lactam plus macrolide) was associated with a reduced mortality risk in patients with CAP.132 These findings suggest that macrolides can be effective as immunomodulatory agents in treating CAP, particularly in severe cases, and should be used in CAP patients requiring hospital admission. Standard empiric treatment should be modified for patients at risk of carrying MDRO. However, the severity of illness alone is no justification for using anti-pseudomonal/anti- MRSA agents, such as piperacillin/tazobactam or cefepime and vancomycin, in patients without risk factors for MDRO infection or carriage. Clinicians should shift the perspective to individualised patient assessment, evaluating specific risk factors for MDRO, prior colonisation, disease severity, and comorbidities to select the best antimicrobial regimen whilst avoiding universal use of broad-spectrum regimens.47,133,134 Where empiric MDRO coverage is started, it should be de-escalated rapidly if screening tests are negative. Additionally, there is no reason to specifically cover anaerobes empirically, even in the presence of aspiration.124 It has even been suggested that anaerobic coverage may disrupt the healthy microbiome in these patients, increasing the risk of adverse outcomes.135,136 In terms of anti-viral therapy, those targeting SARS-CoV-2 have the strongest evidence. Remdesivir may help prevent progression to severe disease, but has no significant benefit in patients requiring invasive mechanical ventilation or Extra Corporeal Membrane Oxygenation.137 Of note, during the recent COVID-19 pandemic, some critically ill patients presented with a hyper-inflammatory profile, clinically representing ARDS, following the cessation of viral replication.138 However, patients with severe CAP from SARS-CoV-2 are now frequently immunocompromised, and their illness may be related to viral replication, hyperinflammation, or both. In addition, the current circulation of the Omicron strain variants is notably different from earlier variants. Whether the trial findings obtained during the pandemic apply to the current case mix is unclear. Although high-quality evidence for treating severe CAP arising from influenza is lacking,139 recommendations for treatment are provided by the WHO. These cluster patients into non-severe and severe symptomatic influenza. Non-severe influenza patients should not receive antiviral treatment. Baloxavir is only suggested in non-severe influenza patients with a risk of progression to severe influenza.. The recommendation for severe symptomatic influenza patients is to use Oseltamivir; other antivirals are not recommended,140 although the low quality of the evidence for these recommendations is recognised. The lack of high-quality evidence in non-SARS-CoV-2 viral pneumonia requires large-scale clinical trials on treating severe viral pneumonia. Bacterial co-infection with S aureus is a common complication of severe influenza. Some guidelines recommend empiric antibacterial therapy to cover common bacterial pathogens, but others do not encourage antimicrobials without biomarkers supporting that decision.9,140,141 Co-infection with Aspergillus species may occur, especially in those patients with severe viral pneumonia (i.e., COVID-19 and influenza) with risk factors such as prolonged mechanical ventilation, corticosteroid use, or underlying chronic respiratory disease. Initiation of empiric antifungal therapy should be guided by clinical suspicion and diagnostic findings.18,142,143 Bacterial co- infection at the time of presentation with COVID-19 is rare, but secondary infection in the form of nosocomial pneumonia is common.144,145 In patients with confirmed severe viral CAP, guidelines recommend joint antimicrobial and antiviral treatment to cover for bacterial co-infection with early de-escalation when bacterial co-infection is subsequently ruled out.9,87,124 Depending on the patient's treatment setting (i.e., outpatient, inpatient, and ICU), the availability of the microbiological tests, samples (i.e., nasopharyngeal swab, sputum, blood cultures, urine, bronchoalveolar lavage) for culture and/or molecular diagnostics should be collected before initiating empiric antimicrobial therapy. However, this should not delay the administration of antimicrobials.146 Microbiological testing allows for subsequent narrowing of the therapeutic spectrum as the causative pathogen(s) are identified and resistance profiles are established. The optimal duration of therapy remains uncertain. The duration of the antimicrobial treatment depends on where the patient will be treated, how soon the patient achive clinical stability, changes in serum biomarkers, as well as local epidemiology and individualised assessment of risk factors. If the patient is treated as an outpatient, the recommended duration ranges from 3-5 days, in-hospital without ICU requirement, 5-7 days, and for ICU-admitted patients, 7-10 days. These times should be adjusted according to the patient's response to treatment. Although studies support short antimicrobial courses (e.g., 3 days) in out-of- hospital environments,147 the median duration remains 5 days. In patients who require in- hospital treatment, if there is a good clinical response, five days of antimicrobial therapy is the most evidence-based recommendation,148 when the antibiotic chosen is confirmed to be appropriate (i.e., the right drug for the correct bug) and adequate (i.e., accomplishing therapeutic drug levels in the lung). Prolonged antimicrobial courses (>7 days) should be avoided except in specific indications such as severe CAP, S aureus bacteraemia, or pleural collections that cannot be drained.9 Current clinical guidelines recommend using clinical stability, supplemented by biomarkers, to guide the duration and limit prolonged antimicrobial therapy. TREATMENT: IMMUNOMODULATION AND ADJUNCTIVE THERAPIES The immune system aims to rapidly restore immune homeostasis by balancing disease resistance (eradicating pathogens with collateral tissue damage) and disease tolerance (limiting the severity of infection without directly affecting pathogen burden).149 Thus, adjuvant treatment with corticosteroids, a broad immunosuppressant, targeted immunomodulatory drugs, and antimicrobial therapy could be beneficial.150 Use of corticosteroids is based on their potential to reduce mortality, decrease the need for mechanical ventilation, reduce the length of stay, and improve clinical stability. However, hyperglycaemia, secondary effects such as secondary infections and gastrointestinal bleeding, and the potential increased risks of hospital readmission have been discussed as negative aspects of using corticosteroids.151-154 Studies on corticosteroids in CAP vary widely in selection criteria, drug type, timing, dosage, duration of treatment, and choice of primary endpoint. Most trials have been either underpowered or stopped early due to signals for benefit or low recruitment rates. Notably, the CAPE COD study found that treatment with hydrocortisone reduced the 28-day mortality in patients with severe CAP.155 In another study, Smit JM et al., in a data-driven analysis of randomised trials, found that steroids were associated with lower 30-day mortality in patients with CAP, especially in those with higher CRP at admission.156 The recently published multinational Randomized Embedded Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) non-pandemic steroid arm study found that a 7-day course of hydrocortisone did not reduce mortality in patients with severe CAP.157 However, adding this recent study to a meta-analysis did not alter the conclusion that corticosteroids reduced short-term mortality, and probably reduced longer-term mortality.152 The overlap between severe CAP, septic shock, and ARDS further complicates the interpretation of the evidence, and patients may be treated with corticosteroids for these indications. Future studies should focus on diseases rather than syndromes, address the heterogeneity of treatment effects, use prognostic and predictive enrichment,59,158 and aim to find treatable traits,159 to determine which corticosteroid treatment strategy benefits each patient. This uncertainty is reflected in current guidelines from both the US and European/South American, which advise the use of corticosteroids as adjunctive therapy in cases of concurrent septic shock but are ambivalent on their use in non-shock inflammatory severe CAP states,156,160 although these were published before the most recent trials and meta-analyses were available. Targeted immune modulation is commonly used in oncology and chronic autoimmune diseases, but has been infrequently employed in the ICU until recently. The reduced mortality from interleukin-6 receptor, JAK-STAT, and complement-5a pathway blockade in COVID-19 suggests that such adjuvant therapies may also benefit other causes of severe CAP. There are currently no established immune modulation therapies for severe bacterial CAP. Notably, the REMAP-CAP platform is currently investigating the use of tocilizumab and baricitinib in severe influenza pneumonia.161 Adjunctive therapy with simvastatin was safe but did not improve clinical outcomes in patients with ARDS, much of which was driven by pneumonia, compared to placebo in the HARP-2 trial in a frequentist analysis.162 In a secondary post-hoc analysis, using latent class analysis, a hyperinflammatory sub-phenotype was identified, associated with improved survival in the simvastatin group.163 In 2684 critically ill patients with COVID-19 in REMAP-CAP, there was a high likelihood (95.9% posterior probability of superiority) of a reduction in organ support-free days for simvastatin compared to control. At 90 days, the hazard ratio for survival with simvastatin was 1.12 (95% CrI, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority to control.164 However, these patients were almost uniquely of a hypo-inflammatory sub-phenotype. The effects of simvastatin observed in the HARP-2 and REMAP-CAP trials appear to differ, suggesting a potential divergence in outcomes depending on the causative pathogens. Notably, these differences may be influenced by the patient's inflammatory sub-phenotype, whilst the nature of these phenotypes and their extension, or otherwise, to the pulmonary compartment76,79 remain to be fully defined, thus highlighting the need for future research in this area. In summary, future clinical trials should prospectively stratify patients by inflammatory sub-phenotypes to better interpret these findings and assess whether simvastatin yields differential effects among biologically distinct groups. There is currently insufficient evidence for using other adjunctive therapies outside well-conducted clinical trials, including thrombomodulin, colony-stimulating factors, immunoglobulins, and mesenchymal stem cells. MANAGEMENT OF COMPLICATIONS AND LONG-TERM FOLLOW-UP Managing complications and long-term follow-up care is a critical component of CAP treatment, reflecting the growing recognition of its post-acute sequelae.24 While traditionally considered an acute infection, CAP often has lasting effects, necessitating a structured and multidisciplinary approach to ensure optimal recovery and prevent long-term morbidity. Respiratory complications are among the most common long-term consequences of CAP. Patients with severe disease frequently experience prolonged pulmonary dysfunction, including impaired gas exchange, reduced lung capacity, and an increased risk of chronic conditions such as bronchiectasis and exacerbations of COPD. Early rehabilitation, including respiratory physiotherapy, can accelerate recovery, improve lung function, and reduce these patients' risk of recurrent infections.165-167 Follow-up imaging is not recommended in CAP patients whose symptoms have resolved within 5 to 7 days. However, imaging follow-up in four to six weeks after treatment to identify residual abnormalities is suggested, especially in patients with persistent symptoms or risk factors for lung cancer, as early detection of malignancies may have been obscured by initial pneumonia.9 Cardiovascular complications represent a significant burden following CAP, with studies consistently showing an elevated risk of myocardial infarction, arrhythmias, heart failure, and stroke in the weeks to months after hospitalisation.22,168,169 This is thought to result from systemic inflammation, endothelial dysfunction, and prothrombotic states induced by the acute infection. Consequently, all patients recovering from CAP should undergo regular cardiovascular screening, particularly those with preexisting cardiac conditions or risk factors such as diabetes, hypertension, and smoking.170,171 Interventions to optimise cardiovascular health, including lifestyle modifications, pharmacological management of risk factors, and routine follow-up with cardiology, where indicated, are essential to reduce long- term morbidity and mortality. The systemic effects of CAP extend beyond the respiratory and cardiovascular systems. Many survivors, particularly older adults and those who require intensive care, experience post-intensive care syndrome (PICS), characterised by physical weakness, cognitive impairment, and psychological disorders such as depression and post-traumatic stress. Emerging syndromes such as Long-COVID-19 have also been studied. These may include neurological symptoms that persist even after lung inflammation appears to have resolved.27,172 Rehabilitation programs that address physical and cognitive deficits are vital for enhancing functional recovery and improving quality of life. Close monitoring for these complications also allows timely interventions to address unmet needs. A comprehensive approach to CAP follow-up should also include vaccination to reduce the risk of recurrence, addressing modifiable risk factors such as smoking and alcohol use, and improving access to primary care. By emphasising early rehabilitation, ongoing screening for cardiovascular and systemic complications, and holistic patient management, clinicians can mitigate the long-term impact of CAP, reduce hospital readmissions, and enhance overall survival and quality of life for these patients. CURRENT GUIDELINES The accumulation of knowledge around CAP diagnosis and management in recent years has been reflected in the updated recommendations of international guidelines, which are reflected in the sections above. Two guidelines from major groups released in the past five years are "Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America" in 2019 and "ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia" in 2023.9,124 The major shifts from previous versions and other older guidelines, such as those from the British Thoracic Society (BTS)91 and European Respiratory Society (ERS), include differentiated recommendations for CAP and SCAP 9, improving diagnostic stewardship to enhance resource allocation and reduce costs. The guidelines shift the clinical approach towards one in which patients' risk profiles, clinical presentation, and tailored testing usage play a prominent role. CONTROVERSIES AND UNCERTAINTIES Several controversies and uncertainties persist in managing CAP, particularly in severe cases where clinical decision-making is complex. As noted in the sections above, the evidence for adjunctive therapies, such as corticosteroids (except in severe CAP), macrolides, and immunomodulatory agents, remains limited and benefits uncertain. Ongoing and forthcoming clinical trials will hopefully resolve this uncertainty. It is possible, indeed likely, that therapies targeted at well-defined phenotypes with specific mechanisms of disease may prove most effective. Another area of uncertainty lies in the mechanisms driving systemic complications, such as cardiovascular events, cognitive decline, and long-term respiratory dysfunction. Although systemic inflammation and immune dysregulation are thought to play key roles, the precise pathways remain poorly understood. For instance, the relationship between the acute inflammatory response and the heightened risk of myocardial infarction and stroke observed after CAP has not been fully elucidated. This lack of mechanistic clarity hampers the development of targeted interventions to mitigate these complications. The management of severe CAP is further complicated by gaps in knowledge regarding factors contributing to adverse outcomes. While advanced age, comorbidities, and delayed ICU admission are recognised risk factors, the interplay of genetic predispositions, host immune responses, and local epidemiological factors requires further study. In addition, the lack of robust data on the effectiveness of personalised therapies, such as biomarker- guided treatment, limits their implementation in routine practice. Finally, the evolving landscape of molecular diagnostics raises questions about their impact on CAP management. While NAATs have improved pathogen identification, their integration into clinical workflows, influence on antibiotic stewardship, and impact on patient-centred outcomes require establishment through real-world studies. Resolving these uncertainties is essential to advancing CAP care and improving patient outcomes. OUTSTANDING RESEARCH QUESTIONS The field of CAP faces critical research questions that span clinical, socioeconomic, and environmental factors. The rising threat of antibiotic resistance underscores the need for new antibiotics and protocols for safely initiating and discontinuing antibiotics in patients with confirmed viral CAP. Likewise, there is a need to standardise the use of biomarkers to guide antimicrobials. Additionally, the efficacy of shorter antibiotic courses, early and safe switch to oral antimicrobials, the potential benefits of steroids in severe CAP, and the avoidance of anti-anaerobic antibiotics in CAP warrant further exploration (Table 3). Broader determinants of CAP risk, such as income, education, and housing quality, are crucial to understanding CAP disparities. Targeted public health interventions could mitigate these risks, particularly in underserved communities. Meanwhile, the role of the host microbiome in CAP susceptibility and whether it can be modified to enhance immunity remains an important area of investigation. Emerging pathogens associated with CAP require study, particularly regarding regional variations and the impact of global travel and climate change. Enhanced diagnostics to differentiate between viral and bacterial CAP could guide appropriate antibiotic use and reduce disparities in care. 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Bacteria: Bordetella pertussis, Chlamydophila pneumoniae, Mycoplasma pneumoniae Nasopharyngeal swab ~1 hour 90% and 95% FilmArray Pneumonia Panel19-121 33 pathogens: Viruses: Influenza A (H1, H3, H1- 2009), Influenza B, Coronaviruses (229E, HKU1, NL63, OC43), Human Metapneumovirus, Human Rhinovirus/Enterovirus, RSV, Parainfluenza 1-4. Bacteria: Streptococcus pneumoniae, Staphylococcus aureus (including MRSA), Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Moraxella catarrhalis, Legionella pneumophila, among others. Mycoplasma pneumoniae, Chlamydophila pneumoniae. Resistance genes: mecA/C, MREJ, blaKPC, blaNDM, blaOXA-48-like, blaVIM, blaIMP Bronchoalveolar lavage (BAL), sputum, endotracheal aspirate ~1 hour >96.2 % and >98.3% Xpert Xpress Flu/RSV173 3 pathogens Viruses: Influenza A (subtypes H1, H3, H1- 2009) Influenza B RSV Nasopharyngeal swab ~30 minutes >95% and >95% ePlex Respiratory 20 pathogens Viruses: Adenovirus, Nasopharyngeal swab ~1.5 hours 90% and 95% Pathogen Panel174-176 Coronaviruses (229E, HKU1, NL63, OC43), Human Metapneumovirus, Human Rhinovirus/Enterovirus, Influenza A (H1, H3, H1-2009), Influenza B, Parainfluenza 1-4, RSV. Bacteria: Bordetella pertussis, Chlamydophila pneumoniae, Mycoplasma pneumoniae Simplexa Flu A/B & RSV Direct173 3 pathogens Viruses: Influenza A Influenza B RSV Nasopharyngeal swab ~1 hour >90% and 95% Verigene Respiratory Pathogens Flex Test177-179 12 pathogens Viruses: Influenza A (H1, H3, H1- 2009), Influenza B, RSV, Adenovirus, Human Metapneumovirus, Human Rhinovirus/Enterovirus, Parainfluenza 1-4. Bacteria: Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Legionella pneumophila Nasopharyngeal swab ~2 hours >90% and 95% Xpert MTB/RIF180-182 Mycobacterium tuberculosis and rifampicin resistance Sputum or other clinical samples ~2 hours 86.3% and 85.3% RT-LAMP for SARS-CoV-2183 SARS-CoV-2 Nasopharyngeal swab or saliva ~30-60 minutes 97% and 81% Table 2. Comparison among CURB-65, PSI, SMART-COP, SAPS II, and Pneumonia Shock Score Score Name Primary Use Setting Variables Included Score Range Risk Stratification Key Strengths / Limitations CURB- 65184,185 Assess mortality and the need for admission in CAP Outpatient & ED Confusion, Urea > 7 mmol/L, Respiratory rate ≥ 30, BP < 90 systolic or ≤ 60 diastolic, Age ≥ 65 0–5 0–1: Low risk (outpatient) 2: Consider admission ≥3: Severe (consider ICU) Simple and fast; lacks comorbidities and most labs. PSI (PORT)184,186 Predict 30-day mortality in CAP Inpatient & ED 20 variables: age, sex, comorbidities, physical exam, labs (ph, sodium, glucose, haematocrit), and radiographic findings I–V (0– >130 points) I–II: Low risk III: Moderate IV–V: High risk; consider hospital or ICU admission Highly validated but complex, time- consuming, and without a calculator. SMART- COP187 Predict the need for IRVS ED & ICU SBP < 90 mmHg, Multilobar infiltrates, Albumin < 35 g/L, RR ↑, HR > 125, Confusion, Low PaO₂, pH < 7.35 0–16 0–2: Low risk 3–4: Moderate risk ≥5: High risk for IRVS Strong predictor of ICU needs, even in younger adults. Not a mortality tool. SAPS II188 General severity of illness score (ICU mortality) ICU 17 variables: age, GCS, HR, SBP, Temp, FiO₂, PaO₂, urine output, labs, chronic diseases 0–163 Higher scores = higher predicted mortality It requires full lab and physiologic data; it is not pneumonia- specific. Pneumonia Shock Score PSS23,189 Predict ICU mortality in septic shock due to CAP ICU Hypoxemia (PaO₂/FiO₂), Lactate > 4, Acute renal failure, Vasopressors, Confusion, Thrombocytopenia 0–6 0–1: Low risk 2–3: Intermediate ≥4: High mortality risk Designed specifically for severe pneumonia with shock; incorporates organ failure. ED: Emergency Department, ICU: Intensive Care Unit, CAP: Community-Acquired Pneumonia, SBP: Systolic Blood Pressure, RR: Respiratory Rate, HR: Heart Rate, PaO₂: Arterial Oxygen Pressure, FiO₂: Fraction of Inspired Oxygen, IRVS: Intensive Respiratory or Vasopressor Support, GCS: Glasgow Coma Scale. Table 3. Future research needs. RESEARCH AREA OBJECTIVE NEW ANTIBIOTICS Address antibiotic resistance in CAP pathogens DISCONTINUING ANTIBIOTICS (VIRAL) Safely initiate and stop antibiotics when viral CAP is confirmed. Biomarkers to guide antimicrobials. STEROIDS IN SEVERE CAP Determine the benefit-risk balance of steroids in inflammatory sCAP AVOIDING ANTI ANAEROBES Minimise unnecessary antibiotic exposure in CAP without anaerobe risk IMMUNE PHENOTYPES Developing consensus immune phenotypes including those in the lung compartment. Using these to stratify trials and personalise therapies SHORTER ANTIBIOTIC TREATMENTS Assess the efficacy of shorter antibiotic courses and a safe switch to oral antimicrobials NEW ANTIVIRAL AGENTS Evaluate novel antiviral therapies for viral CAP IMMUNOSTIMULANTS Study the impact of immunostimulants, particularly in immunocompromised patients HIGH-FLOW NASAL OXYGEN (HFNO) Assess HFNO's role in managing respiratory distress in CAP patients SOCIOECONOMIC AND ENVIRONMENTAL INFLUENCES Investigate how factors like income, education, and housing affect CAP risk; develop targeted interventions EMERGING PATHOGENS AND GLOBAL TRENDS Understand how travel, climate, and social factors shape CAP pathogen prevalence EARLY DIAGNOSTICS FOR VIRAL VS. BACTERIAL CAP Improve diagnostic tools to guide antibiotic use and reduce disparities in resource-limited settings HOST MICROBIOME AND CAP SUSCEPTIBILITY Explore the microbiome's role in CAP risk and potential for enhancing immunity IMPACT OF IMMUNOSUPPRESSIVE THERAPIES ON CAP Develop prevention strategies for immunosuppressed patients across socioeconomic backgrounds NEUROLOGIC IMPACT To elucidate the mechanisms by which neurological complications occur after severe disease. FIGURES LEGENDS Figure 1. Considerations for diagnosis and treatment initiation of Community-acquired pneumonia (CAP) patients. Figure 2. Considerations for taking care of patients with Community-acquired pneumonia (CAP).