The diagnosis of CAP generally necessitates an infiltration on CXR in a patient with fever, dyspnea, cough, and sputum.

While S. pneumonia is the most commonly isolated agent, S. aureus, Haemophilus influenzae, Enterobacteriaceae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumonia are among the culprits in patients with CAP. A Swedish study disclosed that in hospitalized patients with CAP, Pneumococci are the dominant agent, followed by Haemophilus influenzae and Mycoplasma pneumonia [20,21]. On the other hand, elderly patients have a different order of frequency of culprit agents in CAP (Table 1) [16,22]. Table 2 summarizes the differential diagnosis in patients presenting with cough.

Chest X-rays (CXR, PA and lateral) can mostly be adequate for decision-making in suspected patients, which render CT scans not necessary in selected situations. The diagnosis of CAP is generally based on the presence of predefined clinical properties and is supported by simple imaging modalities, mostly by CXR [23]. In this regard, CAP presents as one of three patterns as follows:

1.

Focal nonsegmental or lobar pneumonia.

2.

Bronchopneumonia in multiple foci or lobular pneumonia.

3.

Patterns compatible with interstitial pneumonia (focal or diffuse).

False-negative CXR can be seen in the initial stage of pneumonia in some situations, including patients with neutropenia, dehydration, and immunocompromise. A special example is Pneumocystis carinii pneumonia (PCP, a.k.a. Pneumocystis jirovecii pneumonia), in which spiral CT scans can be needed to adequately visualize findings suggestive of infection.

High-resolution computed tomography (HRCT) usually demonstrates the pattern and distribution of pneumonia more accurately than the CXR [24,25]. It is not routinely ordered in the diagnosis of patients with suspected CAP because of cost-effectiveness principles. Instead, HRCT can be ordered as an adjunct to CXR in selected cases. For example, HRCT has been postulated to be a useful alternative to RT–PCR in the diagnosis of COVID pneumonia, in which a negative test can rule out the diagnosis of COVID pneumonia [26].

Lung USG has been employed more commonly in the last decade to diagnose pneumonia with inappreciable diagnostic value in the patients in extremis who are hard to be transferred to the radiology unit. The sensitivity of lung USG was reported to be between 80 and 90%, and the specificity between 70 and 90% [27,28].

A systematic review and Bayesian meta-analysis pointed out that a gram stain was adequately accurate to diagnose S. pneumoniae and H. influenzae in those with CAP [29]. With good-quality specimens, it can form a basis of clinical actions for specified antibiotic therapies for certain pathogens.

An increased WBC count (up to 30,000/mm³) and a leftward shift are common findings, whereas leukopenia is suggestive of a poor outcome. The co-existence of fever, cough, tachycardia, and crackles had a sensitivity below 50% when CXR was used as a reference standard [30]. Legionella spp., Influenza A and B, MERS–CoV and SARS–CoV, and community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are among these organisms.

Blood cultures (BCs) and sputum gram stains and cultures should be obtained and studied in severe, hospitalized patients. BCs are expected to be positive in around one-fifth of patients. Patients with severe CAP requiring ICU admission, especially, should have BCs, Legionella and pneumococcus urinary antigen tests, and sputum culture. BCs are recommended in severe and critical patients with CAP because positive results indicate the specific microbial diagnosis in most cases [31]. False-positive BCs can be encountered in one-tenth of the patients [32]. Studies pointed out that positive BCs rarely result in a change of antibiotic treatment regimens [33].

The potential advantages of molecular methods are speed and enhanced sensitivity and specificity [34,35]. These methods are available in most centers to elucidate viral agents and some bacteriae, including M. pneumoniae and Legionella pneumophila. Polymerase chain reaction (PCR) boosts the accuracy of the microbiological tests for patients with CAP with its rapid turnaround time [20,36]. Since PCR specimens can be contaminated by the airway flora, a quantitative or semiquantitative PCR assay is needed in most cases [20,37,38].

Lactate is another biomarker with diagnostic and prognostic value in most severe infections [39]. Research disclosed that lactate was able to predict poor outcomes in CAP patients in the acute setting and augmented the predictive power for death [40]. High lactate value is associated with mortality of up to one-third of the samples in patients with CAP. An elevated lactate level suggests hypoperfusion and a marker for grave clinical course [41,42]. In accordance with the updated criteria for sepsis, both hypotension, which prompted inotropic infusions, and high lactate (>2 mmol/L) are necessary for the recognition of septic shock [43].

A recent study analyzed the impact of adding lactate levels to the Rapid Emergency Medicine Score (REMS) system to predict death and prognosis in the middle-aged and elderly (>40 years of age), who were admitted to the ED with dyspnea [44]. The REMS + L score (p < 0.001) was found to be more accurate than REMS (p < 0.001) and lactate values (p < 0.001) in the prediction of death.

Zhuang et al. evaluated the expression of monocyte human leukocyte antigen–DR (mHLA–DR) measured within 24 h after admission in the prediction of short-term survival, and mHLA–DR levels were reported to be higher in patients with mortality when compared to survivors [45].

As an important marker of the inflammatory process, CRP has a value in the diagnosis of pneumonia to some extent. A CRP level above 40 mg/L has a sensitivity of 70% to 73%, and a specificity of 90% to 65% in diagnosing bacterial pneumonia [46]. Another study by Boussekey et al. cited that CRP had lower sensitivity when compared to PCT for the recognition of bacterial respiratory infection [47].

In the outpatient conditions, CRP levels can supply meaningful information to exclude pneumonia. In this group, the evaluation of signs and symptoms identified diagnostic risks accurately in around one-fourth of patients [48]. On the other hand, with the majority of patients in whom diagnostic doubt remained, CRP levels were useful to exclude pneumonia.

The predictive power of CAP was improved by adding biomarkers, such as CRP, to the other well-known scores. Menendez et al. reported that the added value of CRP to PSI, CURB–65, or CRB–65 augmented the prediction of death for hospitalized patients [49]. These combinations retained a sensitivity of 0.77 and a specificity of 0.78. Therefore, it can be valued as a prognostic instrument, hampered by a lack of sensitivity and/or specificity in individual decision-making. A recent meta-analytic study disclosed that CRP has been found to be the most reliable marker (AUC = 0.8), together with leukocytosis (0.77) and PCT (0.77) [50]. For CRP, LR+ and LR− were 2.08 and 0.32 (cutoff: 20 mg/L), 3.64 and 0.36 (cutoff = 50 mg/L), and 5.89 and 0.47 (cutoff: 100 mg/L), respectively. For PCT, LR+ and LR− were 2.50 and 0.39 (cutoff: 0.10 µg/L), 5.43 and 0.62 (cutoff: 0.25 µg/L), and 8.25 and 0.76 (cutoff: 0.50 µg/L), respectively. On the other hand, the combination of CRP > 49.5 mg/L with PCT > 0.1 µg/L had an LR+ of 2.24 and LR− of 0.44.

P–calprotectin has been recently reported to be a useful aid in sepsis-suspected patients. This biomarker has been found to be significantly elevated in critical patients after an assessment by a multidisciplinary team [51]. P–calprotectin was superior to traditional biomarkers in predicting the need for intensive care.

PCT, on the other hand, is a 116-amino acid precursor polypeptide for calcitonin produced in C cells of the thyroid, which is expressed in reaction to microbial toxins and pro-inflammatory mediators such as IL-1B (interleukin-1beta, TNF-α, and IL-6), bacterial products (e.g., lipopolysaccharides) and necrotic tissue cells, and immune-reactive calcitonin [52]. They act as factors to reduce serum calcium levels, and their levels can be detected in healthy adults that rapidly rise 1000-fold with severe disease states [53]. PCT also responds to modulate immunity-related functions, vasomotility, and microcirculation, as well as changes in cytokine expression during hypoperfusion states mediated by endotoxins [54]. PCT is expressed and converted to calcitonin in the C-cells in the thyroid glands of healthy people without inflammation, presenting very low PCT levels (<0.1 ng/mL) [55].

PCT is a widely used serum biomarker, which is closely related to bacterial structure and severity of the infection. It is most specific to infections incited by bacteria, as it is attenuated by INF9 expressed in response to viral infections [56]. The metabolic response to elevated PCT in critical diseases has not been explained so far. The inflammatory response is critical to understand metabolic changes during extreme stress [57].

PCT is accepted as a valuable inflammatory biomarker to discern bacterial from viral, and other causes of pneumonia [34,58]. Besides acute bacterial infections, PCT helps to identify various medical conditions, including post-surgical anastomotic leaks, acute kidney injury, and consequences of intracerebral hemorrhage [59]. Research revealed that PCT levels rise in correlation with bacteremia and severe infection and predict death in patients with CAP and sepsis [60,61]. Studies from Northern Europe pointed out a link between elevated PCT readings and pneumonia severity [62]. PCT is not routinely worked up in the diagnostic process of CAP as its predictive accuracy is only moderate. Most clinicians order a PCT level at the time of diagnosis and serially to help decide the most beneficial duration of antibiotics.

Some investigations highlighted its diagnostic value in different clinical scenarios. PCT was more accurate than CRP to predict bacteremia, for discriminating bacterial from nonbacterial infections, and for determining bacterial species (i.e., AUC of PCT and CRP were 0.79 and 0.66, respectively) [63]. The optimal cutoff value for PCT was 0.5 mcg/L (sensitivity 70% and specificity 70%), whereas it was 50.0 mg/L for CRP (sensitivity 63% and specificity 65%). Using these cutoff values as a reference, the OR was 71.11 and the hazard ratio was 6.27 for PCT > 2.0 mcg/L, and the rate of BC positivity was markedly elevated.

Some studies advocated CRP against PCT in specific subgroups. For example, CRP was better than PCT at predicting pneumonia, as demonstrated in a retrospective study of elderly patients with comorbid diseases [64]. Zhang et al. compared patients with sepsis and those with local inflammatory diseases admitted to the ICU in China [65]. The combined AUC was significantly larger than the sum of IL–10, IL–17, and PCT. A clinical decision curve analysis disclosed that the three combined tests performed better than the individual tests with regard to the total clinical benefit rate. It was concluded that there was a considerable net therapeutic benefit ranging from 3 to 87%.

The analyses of soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-a (TNF-a), and PCT were found to carry a considerable benefit in the recognition of septic course in closed abdominal trauma complicated with severe multiple injuries [66]. The high concentrations of PCT and TNF-a can be used as valuable predictors of sepsis.