Etiology

The microbial etiology of CAP is quite often unspecified in clinical practice. Population-based studies for the etiology and incidence are currently lacking. Frequently identified bacteria in CAP are the following: 1) Streptococcus pneumoniae, 2) Haemophilus influenzea, and 3) Moraxella catarrhalis⁵. Other pathogens frequently encountered are Staphylococcus aureus. Gram-negative bacteria (Pseudomonas spp, Enterobacteriaceae), Group A streptococci, anaerobes (especially in adults with bad oral cavity hygiene), and micro-aerophilic bacteria may also cause CAP. Pseudomonas spp represent characteristic pathogens of patients with bronchiectatic lesions of the lung and end-stage Chronic Obstructive Pulmonary Disease. ‘Atypical’ bacteria, including Mycoplasma pneumoniae and Legionella spp, represent relatively common causes of CAP. Influenza A and B viruses, Human Bocaviruses, Parainfluenza viruses, Coronaviruses, Adenoviruses, Rhinoviruses, and Human Metapneumovirus represent leading causes of CAP^5,6.

Risk stratification

Pneumonia risk stratification scores, including CURB and PSI, guide management based on the 30-day mortality risk. PSI discriminates individuals with CAP into 5 groups with different 30-day mortality risk. The score is based on 20 clinical, radiographic, and laboratory parameters⁷.

CURB score is a clinical prediction tool able to stratify patients with CAP based on mortality risk and is an important tool to discriminate between patients that require outpatient versus inpatient treatment. The criteria included in the CURB score are confusion, elevated BUN above 20 mg/dL, respiratory rate above 30/min, and diastolic blood pressure below 60 mmHg. These criteria did not include one of the most critical risk factors of mortality, such as age⁸. A multivariate analysis led to the modified CURB-65 score, in which age >65 years was added as a criterion. The modified CURB-65 further increased the prognostic accuracy of this widely used score. Patients presenting with ≥3 positive criteria are classified as severe CAP and need hospital admission⁹.

PSI has higher prognostic accuracy with regard to mortality compared to the CURB-65 score since it considers a formal assessment of hypoxemia; yet PSI is majorly weighted by age and thus overestimates the risk of mortality in elderly male subjects with a history of active cancer (<6 months following diagnosis), irrespective of etiology. To this end, it is less valuable at extremes of age and invalid in children⁹. A main advantage of CURB-65 is the fact that it is simple and thus can provide prognostic information and guide treatment decisions in a fast manner, even in the emergency department.

While prognostic tools can provide valuable information to aid physicians in decision-making, their role is supplementary and they cannot replace clinical evaluation. For instance, although oxygen saturation is not included into the CURB 65 score, it may still be a crucial factor with regard to management decisions. Furthermore, patients with low PSI scores but no comorbidities may still require ICU care, while those with a high PSI score due to chronic illness may not. Ultimately, decisions regarding hospital admission should be also based on physician’s medical expertise and clinical judgment considering the limitations of these tools in the context of individual patient care⁷.

Diagnosis-procalcitonin

CAP is usually diagnosed following evaluation of clinical and radiologic findings. In the context of symptoms, CAP is characterized by shortness of breath of varying severity, productive (and sometimes non-productive) cough and systemic features including fever, rigors, and/or drills coupled with general fatigue and malaise. A clinical examination might reveal crackles or bronchial breath sounds as well as tachypnea, use of accessory respiratory muscles, and cyanosis¹⁰. CAP can also be defined as new radiographic findings in chest imaging coupled with compatible clinical findings. These may include consolidative areas, bilateral perihilar opacities, loss of the typical cardiac, diaphragmatic, and/or mediastinal silhouette, as well as interstitial infiltrates, for which there is no other explanation¹¹. Regarding bacterial infections, lab tests including complete blood count and regular biochemical tests should be done. Influenza testing is strongly recommended during the winter season, as viral superinfections can be commonly encountered. In case of availability, a molecular test for respiratory viruses using nasopharyngeal swabs methods could also be performed⁴.

Procalcitonin represents one of the most important prognostic and theragnostic biomarkers in the context of pneumonia. Its use was widely spread, based on mechanistic evidence showing that pathogens induce the upregulation of the CALC-1 gene of innate immune cells such as macrophages, which subsequently results in the increased production of procalcitonin. More specifically, procalcitonin’s production occurs in the pulmonary parenchyma, in the liver, as well as in the intestine. It is secreted within 120–180 min, while the maximum concentration is identified approximately at 6 hours¹². A main advantage of procalcitonin is the fact that it exhibits higher sensitivity and specificity in bacterial infections as well as favorable kinetics compared to C-reactive protein (CRP) due to its earlier increase, thus allowing timely interventions. In addition, its high negative predictive value was established in several cohorts mainly of adults with sepsis and septic shock. To this end, procalcitonin can limit irrational antibiotic usage, as it can reduce the duration of an antibiotic course and allow clinicians to de-escalate antibiotic regimens. Negative procalcitonin values in the appropriate clinical setting can reduce the implementation of broad-spectrum antibiotics. Based on that, procalcitonin might be a tool to avoid the danger of a substantial increase in health-related budgets following advent of novel, expensive antibiotics¹³.

While PCT seems to be a reliable biomarker for the reduction of antibiotic therapy duration, it cannot be utilized to determine the initiation of therapy. Serial monitoring of PCT levels can safely guide the reduction of antibiotic therapy duration for patients with severe ICU infections, including those with CAP, as observed in several large multicenter studies¹¹.

Empiric treatment of CAP in adults

IDSA/ATS guidelines for CAP, with regard to outpatient adults without comorbidities, recommend the use of empiric antibiotic treatment that includes amoxicillin (1 g administered/ eight hours) or doxycycline (100 mg administered/twelve hours) or a macrolide, if the resistance of Streptococcus pneumoniae to macrolides is less than 25% (azithromycin 500 mg as initial dose followed by half dose per day after day 1 or clarithromycin 500 mg every 12 hours)¹⁴. It is important to mention that monotherapy using macrolides is not an option for treating CAP in Greece due to the high incidence of S. pneumoniae resistance¹⁵.

Isolation of S. pneumoniae resistant to second-generation cephalosporins precludes the use of cefuroxime as treatment and thus, third generation cephalosporins should be preferred, including cefditoren, a cephalosporin with the lowest MIC for S. pneumoniae ¹⁴. Additionally, based on the ATS and IDSA guidelines for CAP outpatient treatment of adults with a history of alcoholism or comorbidities such as chronic heart disease, chronic lung diseases, renal dysfunction, liver abnormalities, diabetes mellitus, cancer or asplenia, the recommended treatment regimen includes a combination of amoxicillin/clavulanate (500125 mg every eight hours or 875/125 mg every twelve hours or 2000/125 mg every twelve hours), or a cephalosporin (i.e. cefuroxime 500 mg/twelve hours) with a macrolide (in the dosage previously described), or doxycycline (100 mg every twelve hours). Alternatively, monotherapy with a respiratory fluoroquinolone (mainly moxifloxacin 400 mg or levofloxacin 750 mg every twenty-four hours) is highly recommended, particularly in outpatients presenting with several comorbidities and a history of previous hospitalization within the past 6 months⁴ (Table 1). Evaluation of epidemiological data of resistance against specific agents, search for prescription of specific antibiotics during the last 6 months and consideration of allergic reactions to drugs, history of cardiac arrhythmia (i.e. for avoidance of macrolides) and vascular disease (for avoidance of fluoroquinolones) are strongly recommended prior the choice of the antibiotic^4,15.

Furthermore, for inpatient adults with non-severe CAP, without risk factors for MRSA or Pseudomonas Aeruginosa, the empiric treatment includes a combination therapy with a b-lactam (ampicillin-sulbactam 1.5–3 g four times per day, ceftaroline 600 mg twice daily, cefotaxime 1–2 g thrice per day or ceftriaxone 1–2 g daily) and a macrolide (azithromycin 500 mg every twenty-four hours or clarithromycin 500 mg every twelve hours), or even monotherapy with a fluoroquinolone (same dosage as described above)¹⁴. Awareness that the elimination half-life of azithromycin following multiple dosing is almost 68 hours is crucial; thus, meticulous evaluation of patients receiving azithromycin is needed. If there are contraindications to quinolones and macrolides use, the indicated treatment is a combination of b-lactam and doxycycline. It is suggested that hospitalized individuals with severe CAP without risk factors for P. aeruginosa or MRSA should receive a regimen comprising a b-lactam antibiotic and a macrolide or a b-lactam antibiotic plus a fluoroquinolone⁴.

Antibiotics for anaerobic coverage should not be routinely included for suspected aspiration pneumonia unless lung abscess or empyema is suspected. An aspiration represents a common event in adults, especially during sleep when gastric contents cause aspiration pneumonitis. Many of these cases resolve within 1 to 2 days simply following supportive treatment¹⁶.

Antibiotic coverage for P. aeruginosa or MRSA in individuals with CAP must be considered in case risk factors for these bacteria are identified¹⁷. Empiric treatment options for MRSA include linezolid (600 mg every twelve hours) and vancomycin (15–20 mg/kg every twelve hours following modification according to trough levels), and for P. aeruginosa regimens include piperacillin-tazobactam (4.5 g every six hours), cefepime (2 g every eight hours), ceftazidime (2 g every eight hours), aztreonam (2 g every eight hours), meropenem (1 or 2 g every eight hours), or imipenem (500 mg every six hours). With regard to vancomycin, adjusting dosage following measurement of trough levels at least before the fourth dose is strongly recommended⁴.

The most important risk factors for infection with P. aeruginosa or MRSA are the following: 1) previous isolation of these microorganisms (especially from the respiratory tract), 2) recent hospitalization, and 3) exposure to parenteral antibiotics. De-escalation of antibiotic therapy is safer 48 hours after negative cultures for MRSA or P. aeruginosa^4,18.

Individuals with CAP tested positive for Influenza should receive oseltamivir (75 mg bid), independent of the time of onset of symptoms. The treatment is preferred to be initiated within 48 hours following symptom initiation or hospitalization, although there could be some benefits when the treatment starts 4 or 5 days after symptoms begin¹⁹. In the outpatient setting, the anti-influenza agents have higher efficacy if received within 2 days following the onset of symptoms. Patients (outpatient or inpatient) with clinical and radiological features of CAP and positive Influenza testing should receive antibacterial and anti-influenza treatment, considering the high rates of concomitant infections (almost 30%)²⁰. The mortality of patients hospitalized for Influenza and bacterial pneumonia is nearly 10%, mainly attributed to their complications. The most frequent bacteria related to influenza pneumonia are S. aureus, S. pneumoniae, group A Streptococcus and H. influenzae group A Streptococcus^21-23 (Table 2). Treatment with corticosteroids for adults with CAP is not recommended. A seminal double-blind, randomized controlled trial by Blum et al.²⁴ showed that administration of prednisolone for 7 days shortened clinical recovery in CAP without increasing complications; yet more data are needed to support this concept and to this end, corticosteroids do not currently belong to the standard of care in CAP.

The appropriate duration of antibiotic treatment

The duration of antibiotic therapy is related to the patient’s clinical stability. It should be continued for at least 5 days until a substantial improvement in the patient is achieved. In case of other complications such as endocarditis or colonization with less-frequent pathogens (e.g. fungi or Burkholderia pseudomallei) longer courses of treatment are recommended. The duration of antibiotics can be shortened based on procalcitonin levels^13,14.

Diagnosis of VAP

IDSA/ATS guidelines suggest that the diagnosis of VAP requires new pulmonary infiltrations on chest imaging, increasing oxygen requirements, leukocytosis, fever, and increasing sputum production. In patients with suspected VAP, blood or sputum cultures should be obtained. Also, PCR testing can be used, especially during the influenza period, and measuring serum procalcitonin for separate bacterial and viral infections²⁶.

Empirical treatment of clinically suspected VAP

Initially, all hospitals should have a local antibiogram, according to the pathogen population of their ICU and their susceptibility profile.

If VAP is suspected, it is strongly recommended to use empirical antibiotic treatment covering bacteria such as S. aureus and P. aeruginosa. The following conditions are suggestive of empirical treatment for MRSA: 1) individuals having risk factors for antimicrobial resistance, 2) units where methicillin-resistant S. aureus is isolated >10–20% of the cases, and 3) units with an unknown prevalence of MRSA resistance. Typically, MRSA is <10–20% of S. aureus, which is isolated in ICUs²⁷.

If there are indications for MRSA empirical coverage, either vancomycin or linezolid should be given, while for MSSA (and not MRSA) empirical treatment, it is suggested piperacillin-tazobactam, respiratory fluoroquinolones, cefepime or carbapenems. When MSSA is proven as the causal pathogen of VAP, the preferred agents are oxacillin, nafcillin, or cefazolin²⁷.

Furthermore, antipseudomonal empirical treatment from different classes should be given in patients suspected of VAP with any of the following criteria: a risk factor for antimicrobial resistance, units with isolation >10% of gram-negative pathogens that are resistant to a compound used as single-therapy, and patients with unknown antimicrobial susceptibility in ICU²⁸ (Table 3). Aminoglycosides or colistin should be avoided if there are alternative agents against gram-negative pathogens in individuals with suspected VAP²⁶ (Table 4). The duration of treatment is suggested to be a 7-day course, and the antibiotic therapy should be de-escalated according to the antibiogram. There are some exceptions in the duration of the treatment. These include patients with VAP owing to glucose-non-fermenting gram-negative bacteria that lead to an increased risk for recurrent infections if the treatment duration is only 7–8 days. Clinical criteria and serum procalcitonin levels should guide the discontinuation of antibiotic treatment^27,28. Taken together, despite the devastating impact of VAP, a considerable proportion of patients receiving the appropriate regimen can be extubated after the onset of VAP.

HOSPITAL-ACQUIRED PNEUMONIA (HAP)

HAP represents a lower respiratory tract infection which did not exist at the time of hospitalization and is shown at least 48 hours after that time point.

In case HAP is suspected (non-VAP), patients are treated according to the microbiological profile. Respiratory samples for culture can be obtained via multiple ways, including spontaneous expectoration or sputum induction. Hospitals in their entirety should regularly produce a local antibiogram, ideally based on their HAP population. Therefore, the empirical antibiotic regimens are tailored to the local pathogens’ distribution and susceptibility profile²⁹.

The empirical management of clinically suspected HAP (Non-VAP)

With regard to individuals who are treated empirically for HAP, it is suggested to use an antibiotic against S. aureus, P. aeruginosa and other gram-negative bacilli. On the contrary, in case that patients with HAP are receiving empirical treatment and present with risk factors for MRSA infection (such as: 1. previous intravenous antibiotic use within 90 days; 2. hospitalization in a unit where methicillin-resistant S. aureus accounts for over 20% of isolates; 3. in case the prevalence of MRSA is unknown; and 4. when there is a high risk of mortality), healthcare providers are advised to administer an antibiotic with MRSA activity (vancomycin or linezolid)³⁰.

For patients with HAP who are not at high risk of MRSA infection or high risk of mortality, the treatment should include an established anti-MSSA antibiotic such as piperacillin-tazobactam, levofloxacin, cefepime, meropenem or imipenem. In the context of MSSA specifically, the preferred treatment includes oxacillin, nafcillin, or cefazolin. However, one of the above medications does not need to be used. Patients with HAP under empirical treatment that have factors increasing the possibility of P. aeruginosa or other gram (-) bacilli infection (such as prior iv antibiotic treatment in the past 90 days) or high risk of mortality must be treated with 2 compounds of different categories with established activity against P. aeruginosa. An aminoglycoside should not be used as the only antipseudomonal agent^27,29 (Table 5). The duration of antibiotic therapy for HAP should be approximately 7 days. The exact regimen and duration are typically decided on a case-by-case basis²⁷.

Therapeutic algorithm for non-hospitalized patients

All outpatient individuals with mild to moderate COVID-19 require symptoms management. Palliative treatment including adequate hydration, use of antipyretics, antitussives, or analgesics on a case-by-case basis and depending on the symptoms is encouraged. Monitoring of temperature and oxygen saturation is highly recommended³¹.

With regard to patients at high risk of progression to severe COVID-19, antiviral compounds such as ritonavir-nirmatrelvir (Paxlovid) and remdesivir can reduce the risk of death or hospitalization³². Particular attention should be paid to the use of nirmatrelvir/ritonavir, given that its combination is contraindicated with drugs that are potent CYP3A inducers. Alternative therapies include bebtelovimab and molnupiravir³³. Antiviral compounds have shown far higher efficacy if implemented as early as possible. Treatment should be initiated immediately or at least seven days after symptom onset³⁴. Especially for nirmatrelvir/ritonavir, treatment initiation within the first 3 days of symptoms is crucial, given that administration during this window reduces the risk for COVID-19 related hospitalization or death by 89%³². Evaluation of the risk of disease progression is important to decide whether to prescribe an antiviral drug to patients that have been vaccinated. The risk is linearly associated with the underlying comorbidome. Patients of older age, immunocompromised individuals, as well as patients with substantial latency time since the most recent COVID-19 vaccine dose (i.e. >4–6 months) are among the groups that are more likely to benefit from antiviral compounds³⁵.

Except the treatment of COVID-19 per se, meticulous evaluation for co-infection is needed even if the coexistence is not that common. Concomitant viral infections in the setting of COVID-19 are generally rare (1–2%)³⁶. Community-acquired bacterial pneumonia can also exist, but it is uncommon, as it can be identified in 4–6% of the subjects with SARS-CoV-2 infection². Antibiotics are not generally recommended unless additional evidence for bacterial pneumonia is observed³⁶.

Therapeutic algorithm for hospitalized patients

Hospitalized patients for a different reason than COVID-19 not requiring supplementary oxygen

Patients with mild to moderate illness from COVID-19 at high risk of progression may benefit from the administration of remdesivir. Τhose who are at greater risk of getting seriously ill from COVID-19, are patients with cancer, cerebrovascular disease, chronic lung diseases such as COPD, liver diseases, renal failure, cystic fibrosis, disabilities, diabetes mellitus, HIV (human immunodeficiency virus), chronic heart conditions, mental health disorders, neurological conditions limited to dementia, tuberculosis, solid organ or hematopoietic cell transplantation, primary immunοdeficiencies, obesity (BMI: >30 kg/m²), pregnancy, smokers, patients with limited physical inactivity, and patients using corticosteroids or other immunosuppressive medications. An age >65 years remains the strongest risk factor for severe disease³⁷.

Hospitalized patients for COVID-19 not in need of supplementary oxygen

Implementation of remdesivir is recommended for patients not in need of supplementary oxygen that have increased risk of progression to severe COVID-19³⁵. It is not recommended to use dexamethasone for the management of COVID-19 in patients not requiring supplementary oxygen. In case there is no indication for therapeutic anticoagulation, a prophylactic dose of heparin is typically recommended³⁸.

Hospitalized patients for COVID-19 who require conventional oxygen

The use of remdesivir without corticosteroids is recommended if the needs for oxygen supplementation are minimal. For individuals who require conventional oxygen, administration of dexamethasone plus remdesivir is suggested. If dexamethasone is unavailable in medical care, an equivalent dose of another corticosteroid category may be used. If remdesivir is not available, the use of dexamethasone alone is suggested^38-40. For non-pregnant patients requiring conventional oxygen with D-dimer levels exceeding the upper limit of normal and without an increased risk of bleeding, administration of a therapeutic dose of heparin is suggested. Patients not meeting the criteria for therapeutic heparin, including pregnant individuals, should be given a prophylactic dose of heparin, unless this is not recommended due to contraindications in pregnancy⁴¹. Patients have increased bleeding risk with any of the following: 1) bleeding within the past 30 days, 2) need of dual antiplatelet therapy, 3) Hgb <8 g/dL, 4) platelet count <50×10⁹ per L, 5) history of a bleeding disorder, or 6) acquired bleeding disorder⁴². In patients with rapidly progressive disease, a second immunomodulatory compound (e.g. the IL-6R antagonist denominated tocilizumab or the Janus Kinase 1/2 inhibitor denominated baricitinib) should be added to dexamethasone^43,44. Several studies have shown clinical improvement and improved survival in hospitalized patients treated for COVID-19 with tocilizumab and other monoclonal antibodies⁴³.

Hospitalized patients for COVID-19 requiring support with non-invasive ventilation or high-flow nasal cannula oxygen

For this group of patients, the guidelines suggest the administration of dexamethasone plus either per os baricitinib or tocilizumab iv. Our group conducted an open-label, randomized-controlled trial in patients with severe COVID-19, which showed non-inferiority of baricitinib to tocilizumab for mechanical ventilation or death and the time to discharge⁴⁵. If baricitinib and tocilizumab are not available, tofacitinib and sarilumab can be implemented instead, respectively. If none is available, the use of dexamethasone alone is recommended. Remdesivir should also be included in the treatment regimen for this group of patients. The treatment should typically include a prophylactic dose of heparin as well. A therapeutic or intermediate dose of anticoagulation for VTE prophylaxis should not be administered⁴².

Patients who are hospitalized for COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

With regard to patients who need mechanical ventilation or ECMO, the administration of dexamethasone plus tocilizumab or baricitinib is suggested. If baricitinib, tocilizumab, sarilumab and tofacitinib are not available, it is recommended to use dexamethasone alone. For patients progressing to invasive mechanical ventilation or ECMO, despite having started remdesivir, it is suggested to continue remdesivir until the treatment course is completed. A prophylactic dose of heparin should be typically administered as well. Patients who were given a therapeutic dose of heparin in a hospital ward without evidence of thromboembolism and then transferred to the ICU, should continue a prophylactic dose^42,46,47.

Finally, the Greek guidelines for COVID-19 in hospitalized patients are worth mentioning. According to these guidelines, patients with mild disease who do not require supplementary oxygen should not receive any specific medication. In patients with risk factors for disease progression, oxygen therapy is administered within hospital early treatment to avoid progression to severe disease. Risk factors include an age >65 years, obesity BMI >35 kg/m², immunosuppression, hemodialysis, chronic heart disease, chronic obstructive pulmonary disease, chronic respiratory deficiency under oxygen therapy, idiopathic pulmonary fibrosis, diabetes mellitus, hemoglobinopathies, 3rd trimester pregnancy. Non-vaccination, or an interval >6 months since vaccination, increases additionally the risk posed by the individual risk factors. For hospitalized patients who require conventional oxygen and do not exhibit symptoms or signs of severe disease such as oxygen saturation <90% on room air (or <94% but rapidly worsening), signs of severe respiratory distress (>30 breaths/min, inability to complete sentences, use of accessory respiratory muscles), extensive infiltrates (>50%) on chest imaging, or laboratory combination (lymphocytes <1000/μL, ferritin >1000 mg/mL, CRP >75 mg/L with normal value <5 mg/L), remdesivir plus a prophylactic dose of heparin should be administered. With regard to patients with increasing oxygen needs, dexamethasone should be implemented^38,39. Anakinra can be administered to patients with pneumonia who have a high risk of respiratory failure, as determined by serum levels of soluble urokinase plasminogen activator receptor (suPAR) ≥6 ng/mL⁴⁸. Antibiotics are administered for documented or suspected bacterial pneumonia based on clinical, imaging, or laboratory findings, following the guidelines of the Hellenic Society of Infectious Diseases for community-acquired pneumonia. Remdesivir, dexamethasone plus a prophylactic dose of heparin should be administered to patients on high-flow oxygen supply on non-invasive ventilation, or those exhibiting symptoms and signs of severe disease. Baricitinib or tocilizumab should be added in non-improving patients with increased markers of inflammation^43-45. Anakinra may be used for patients with pneumonia receiving high levels of oxygen supply and who are at serious risk of respiratory failure, as determined by serum levels of soluble urokinase plasminogen activator receptor (suPAR) ≥6 ng/mL⁴⁸. Additionally, the patient should be positioned in a prone position. The administration of antibiotics for bacterial pneumonia, either documented or suspected, is based on clinical, imaging, or laboratory findings, and follows the guidelines established by the Hellenic Society of Infectious Diseases for community-acquired pneumonia³⁶. If patients are on mechanical ventilation or ECMO and have not received or completed a 10-day course of dexamethasone, or if tocilizumab has not already been administered and there are no contraindications, the patient should be given the appropriate medication. To ensure optimal treatment, remdesivir should be administered only as part of a treatment regimen and for the complete 5-day duration. Additionally, all patients should receive a prophylactic dose of low molecular weight heparin⁴¹.