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1. Severe community-acquired pneumonia in the post COVID-19 era Curr Opin Crit Care 2023, 29:400–406 DOI:10.1097/MCC.0000000000001083 Capt.Pyae Zone Kyaw PG2

2. Introduction Community-acquired pneumonia (CAP) remains as a public health issue worldwide with high clinical burden. Its related mortality is exceeds 30% in patients who develop acute respiratory distress syndrome (ARDS) or septic shock. T he severity of the disease at onset, the presence of co-morbidities , patients’ immune status , i ncreasing biological age and male gender are also important risk factors for death from CAP.

3. Recent findings Regardless of a large number of published CAP guidelines, most of their recommendations are based on low-level evidence. Viruses have an increasing role as sCAP etiology with an impact on mortality. Accordingly, it is imperative to strengthen the demand for vaccines and newer antivirals. Considering an early monitoring of the immune response in patients with severe Influenza, may help to evaluate a personalized immunomodulatory strategy. Despite growing evidence, the use of corticosteroids as an adjunctive therapy in bacterial sCAP continues to be controversial.

4. BACTERIAL PNEUMONIA: RELEVANT CONSIDERATIONS TO TAKE INTO ACCOUNT Bacterial infections account for nearly half of severe CAP ( sCAP ) events, but mixed infections by virus and bacteria, can also occur. Streptococcus pneumonia remains as the most isolated bacterial pathogen globally; in the outpatient setting, general wards and in intensive care units (ICU), with different resistance patterns across countries . Haemophilus influenzae , methicillin-susceptible Staphylococcus aureus , Legionella spp and nonresistant enteric Gram-negative bacteria follow S. pneumoniae in frequency. Hence, empirical antibiotic therapy should be directed at these pathogens.

5. Severe atypical pneumonia related to Chlamydia pneumoniae or Mycoplasma pneumoniae accounts for 1–30%. Although considered as less severe pneumonia, when it requires ICU admission, mortality can reach up to 11% Only prior Pseudomonas aeruginosa infection/colonization together with severe chronic obstructive pulmonary disease were found to be the most consistent risk factors for its coverage. D espite isolating Pseudomonas aeruginosa in only 1.6% of CAP episodes, around 37% of hospitalized patients were prescribed antipseudomonal antibiotics.

6. Only prior Pseudomonas aeruginosa infection/colonization together with severe chronic obstructive pulmonary disease were found to be the most consistent risk factors for its coverage. These findings support that only this well defined subgroup of individuals may benefit from empiric antipseudomonal antibiotics initiation.

7. Use of antipseudomonal antibiotics in patients without Pseudomonas is also associated with increased mort rates , possibly in part due to increased renal toxicity particularly if used in combination with vancomycin . M ethicillin-sensitive Staphylococcus aureus (MSSA) has been an emergent etiology of CAP. It should raise greater concern that in the setting of influenza, S. aureus can affect young and healthy individuals. Clinicians will only effectively achieve this if they understand their own local sCAP etiology, a key recommendation in the most recent ATS/IDSA CAP guidelines.

8. VIRAL PNEUMONIA AND ITS INCREASING RELEVANCE OVER TIME Respiratory viruses are isolated in about one-third of CAP cases. The emergence of new molecular techniques improved pathogens recognition, both viral and bacterial , and over time it is likely that the estimated proportion of sCAP due to viruses is going to increase. Common community-acquired respiratory viruses include influenza virus A and B, parainfluenza virus, respiratory syncytial virus (RSV), rhinovirus/ enterovirus , adenovirus, human metapneumovirus ( hMPV ) and coronavirus such as SARS- CoV and SARS-CoV2.

9. Although previously well described in children, currently there is major concern about RSV as an emergent cause of severe viral pneumonia in adult patients; mostly in subjects older than 65 years and in the immunocompromised , with mortality rates exceeding 70% Treatment with ribavirin should be considered only for patients with immunocompromise due to hematological malignancy and lower respiratory tract infections, as there is a lack of evidence to support its use in other populations.

10. Immune dysfunction related to severe influenza infection Influenza A was the leading cause of respiratory viral disease and ARDS, alone or associated with bacterial coinfection , until the COVID-19 pandemic. Therefore, in contrast to previous years, the influenza season during 2020–2021 exhibited a different course, consisting of a shorter period and lower positivity rates.

11. The virus can directly affect the respiratory tract through local damage and indirectly through the developed systemic immune-mediated inflammatory response. P atients with severe influenza H1N1pdm09disease, presented an immune dysfunction related to decreased lymphocytes and monocytes population counts. Regarding surviving patients, their monocyte count doubled that of non-survivors with a concomitant higher expression of HLA-DR.

12. All lymphocyte subpopulations (TCD3, TCD4, TCD8) including NKCD56 were statistically higher in the survivors group. The consequent immune-paralysis (low HLA-DR) observed in the non-survivors, was associated with increased mortality, and if hyperinflammation (high ferritin levels) was added, a significant increase in mortality was observed .

13. What's new regarding influenza treatment? Extensively used neuraminidase inhibitors (NAIs) remain as the standard care for hospitalized patients with influenza. Notwithstanding, influenza severe disease is associated with 25% mortality, despite adequate Oseltamivir prescription . Polymerase inhibitors, such as Baloxavir , have a role in viral replication and are positioning themselves as an alternative treatment.

14. Invasive aspergillosis co-infection Invasive pulmonary aspergillosis (IPA) is one of the most frequent invasive fungal diseases among nonimmunocompromised critically ill patients . It has been increasingly reported in patients with influenza and COVID-19 admitted to the ICU, in patients who are mainly immuno -competent with comorbidities.

15. IMMUNOCOMPROMISED PATIENTS: WHERE A SIGNIFICANT GAP OF KNOWLEDGE STILL EXISTS C hronic use of corticosteroids was the most frequent risk factor for immunocompromise , followed by hematological malignancies and chemotherapy. Even though S. pneumoniae remained as the leading cause of CAP, these patients were also more frequently infected by Nocardia spp., nontuberculous mycobacteria, Pneumocystis jirovecii , Aspergillus fumigatus , and viruses excepting for influenza.

16. ADJUNCTIVE THERAPIES FOR SEVERE COMMUNITY-ACQUIRED PNEUMONIA: THE ONGOING CONTROVERSY WITH CORTICOSTEROIDS R ole of corticosteroids as immune modulators favoring the downregulation of this systemic response has been widely discussed, yet with conflicting results. A phase 3 multicenter trial by Dequin et al., found a trend towards lower mortality by day 28 in patients receiving hydrocortisone therapy compared to placebo. Regarding safety outcomes, corticosteroids were associated with increased incidence of hyperglycemia, but not with infections or gastrointestinal bleeding .

17. The ESCAPe RCT by Meduri et al., evaluated the administration of a low dose of methylprednisolone in patients with sCAP compared to placebo during 20 days. They did not demonstrate a significant difference in 60-day mortality. Neither an association between corticosteroids with septic shock or ARDS development was evidenced, nor with ICU length of stay or ventilator free days.

18. Treatment Guidelines

19. Summary Mortality due to sCAP still remains undesirably high. This fact strengthens the need for more high-quality research to increase evidence. It also highlights the need for clinicians to be aware of the level of evidence of the stated recommendations, taking this into consideration before decision making

20. KEY POINTS Due to the growing number of immunocompromised patients with different underlying conditions, generating a widely accepted definition for immunocompromised host pneumonia becomes imperative. Currently, we are facing an increase in the diagnosis of severe pneumonia due to respiratory syncytial virus (RSV) in the adult population, mostly in the elderly and the immunocompromised . The data supporting ribavirin is weak and only in patients with hematological immune compromise.

21. KEY POINTS continued Both excessive and deficient inflammatory responses are related to poor outcomes. In bacterial community acquired pneumonia, there are some benefits regarding corticosteroids administration; but when referring to severe influenza pneumonia, high-dose steroids does not improve patients’ outcomes and are related with worse prognosis. The development of techniques to monitor the individual host immune response at the bedside, would allow to stratify patients based on their immune response and to guide personalized immunomodulatory therapy.

22. Thank you