diagnostics

Review
Diagnostic and Prognostic Roles of Procalcitonin and Other
Tools in Community-Acquired Pneumonia: A Narrative Review
Sedat Ozbay 1 , Mustafa Ayan 1 , Orhan Ozsoy 1 , Canan Akman 2 and Ozgur Karcioglu 3, *

1 Department of Emergency Medicine, Sivas Numune Education and Research Hospital, Sivas 58040, Turkey;
[email protected] (S.O.); [email protected] (M.A.); [email protected] (O.O.)
2 Department of Emergency Medicine, Canakkale Onsekiz Mart University, Canakkale 17100, Turkey;
[email protected]
3 Department of Emergency Medicine, University of Health Sciences, Taksim Education and Research Hospital,
Beyoglu, Istanbul 34098, Turkey
* Correspondence: [email protected]; Tel.: +90-505-5252399

Abstract: Community-acquired pneumonia (CAP) is among the most common causes of death and
one of the leading healthcare concerns worldwide. It can evolve into sepsis and septic shock, which
have a high mortality rate, especially in critical patients and comorbidities. The definitions of sepsis
were revised in the last decade as “life-threatening organ dysfunction caused by a dysregulated host
response to infection”. Procalcitonin (PCT), C-reactive protein (CRP), and complete blood count,
including white blood cells, are among the most commonly analyzed sepsis-specific biomarkers also
used in pneumonia in a broad range of studies. It appears to be a reliable diagnostic tool to expedite
care of these patients with severe infections in the acute setting. PCT was found to be superior to most
other acute phase reactants and indicators, including CRP as a predictor of pneumonia, bacteremia,
sepsis, and poor outcome, although conflicting results exist. In addition, PCT use is beneficial to judge
timing for the cessation of antibiotic treatment in most severe infectious states. The clinicians should
be aware of strengths and weaknesses of known and potential biomarkers in expedient recognition
and management of severe infections. This manuscript is intended to present an overview of the
definitions, complications, and outcomes of CAP and sepsis in adults, with special regard to PCT and
Citation: Ozbay, S.; Ayan, M.; Ozsoy,
O.; Akman, C.; Karcioglu, O.
other important markers.
Diagnostic and Prognostic Roles of
Procalcitonin and Other Tools in Keywords: pneumonia; bacteremia; sepsis; procalcitonin; diagnosis; biomarker; outcome; antibiotic
Community-Acquired Pneumonia: A stewardship
Narrative Review. Diagnostics 2023,
13, 1869. https://doi.org/
10.3390/diagnostics13111869
1. Introduction
Academic Editor: Georgina
Tzanakaki
1.1. Community-Acquired Pneumonia (CAP): Definitions and Diagnostic Approaches
Pneumonia is the acute infectious process of the pulmonary parenchymal tissue.
Received: 24 April 2023
Community-acquired pneumonia (CAP) is the leading healthcare concern worldwide. CAP
Revised: 24 May 2023
inflicts patients in the community, as opposed to nosocomial pneumonia [1,2]. Pneumonia
Accepted: 24 May 2023
is defined as symptoms and clinical manifestations such as high body temperature, cough,
Published: 26 May 2023
dyspnea, recent onset of weakness, and pleuritic chest pain [3].

The Situation in Turkey and the World

Copyright: © 2023 by the authors. Different studies revealed various prevalence figures in pneumonia. The annual
Licensee MDPI, Basel, Switzerland. incidence of pneumonia is reported to vary between 0.28 and 1.16%, and both incidence
This article is an open access article and mortality increase, especially in advanced ages [4,5]. A population-based study in
distributed under the terms and Germany showed that the yearly incidence of CAP admitted to the hospital was 0.3% [6].
conditions of the Creative Commons Male patients are reported to be more likely to be admitted to the hospital than females [7].
Attribution (CC BY) license (https:// Similar to the universal data, the incidence of pneumonia increases with age in Turkey.
creativecommons.org/licenses/by/ Pneumonia mortality varies between 1–60% in relation to the severity of the disease,
4.0/).

Diagnostics 2023, 13, 1869. https://doi.org/10.3390/diagnostics13111869 https://www.mdpi.com/journal/diagnostics

Diagnostics 2023, 13, 1869 2 of 17

and this rate rises significantly in hospitalized patients (10.3–60%) [8,9]. Patients with
pneumonia accounted for 1.9% of all hospitalizations in Turkey [10].
In a population-based multicentric study in Turkey, pneumococcal pneumonia was diag-
nosed with at least one supportive laboratory finding for Streptococcus pneumoniae (blood or
sputum culture or urinary antigens) in those with chest X-ray signs of pneumonia. Four hun-
dred sixty-five patients were recorded to have CAP, and among them, 13% had pneumococcal
pneumonia [11]. In another study focusing on elderly patients in Turkey, Pseudomonas spp.
(26.6%) was the most common agent, followed by Streptococcus pneumoniae (23.3%) [12].
Other typical bacterial agents were Staphylococcus aureus (13.3%), Haemophilus influenzae
(10%), and Acinetobacter spp. (10.0%). Around one-fourth of the S. aureus strains had
methicillin resistance.
CAP is accompanied by significant morbidity, mortality, and healthcare expenses.
The death rate in hospitalized patients with CAP is reported to range between 10 and
12% [13]. McLaughlin et al. criticized most studies in this area and postulated that most
exclusion criteria (i.e., those hospitalized with CAP or immunocompromising conditions)
or restrictions for defining cases (e.g., only including pneumonias coded in the primary
diagnosis position) paved the way to systematic bias to underestimate CAP incidence [14].
In the other research without these restrictive criteria, only around 2% of the patients were
hospitalized annually. In elderly patients, the percentage of hospitalization was found to
lie between 847 and 3500 per 100,000 patients CAP annually.
Although CAP has a predilection for the elderly, newborns, or young infants, it is
reported at all ages, especially those with compromised immunity and/or other comor-
bidities. Immune- and age-related changes make these subgroups more vulnerable to
pneumonia. For example, the incidence of CAP in the elderly (>65 years of age) comprise
around 3% inhabitants/year [15,16].

2. Clinical Findings
No clear group of symptoms and signs has been found to reliably predict whether
or not the patient has the disease [17]. Certain clinical findings support the diagnosis of
pneumonia. Signs and symptoms of CAP include cough, fever, sputum production, chest
pain (mostly pleuritic in nature), dyspnea, crackles, and diminished or bronchial breath
sounds, which may be encountered upon physical examination. Mucopurulent sputum
production is most frequently detected in conjunction with pneumonia of bacterial origin,
whereas watery sputum is suggestive of atypical pathogens. Nausea, vomiting, diarrhea,
and mental status changes are also noted frequently. Chest pain is a major complaint in
a third of cases, chills have been reported in up to half of cases, while rigors have been
reported in 15% of cases [18]. An acutely ill patient with somatic chest pain and leukocytosis
(>15 × 109 /L) is suggestive of S.pneumoniae aetiology [19].

3. The Diagnosis of CAP

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.
Diagnostics 2023, 13, 1869 3 of 17

Table 1. Frequency of etiologic agents of community-acquired pneumonia (CAP) in elderly patients.

Streptococcus pneumoniae Up to 50%

Atypical (Legionella pneumophila and others) Up to 25%
Haemophilus influenzae 0–13%
Staphylococcus aureus 0–7%
Methicillin-resistant Staphylococcus aureus (MRSA) 0–6%
Gram-negative bacilli including Pseudomonas aeruginosa Up to 27%
Virus 0–8%
Aspiration pneumonia 10%

Table 2. Differential diagnosis of patients with cough. These entities commonly masquerade as CAP.

Pulmonary embolism
Cryptogenic organizing pneumonia
Tuberculosis, Actinomycosis
Pulmonary vasculitis, lupus pneumonitis and hypersensitivity pneumonitis, acute or chronic
eosinophilic pneumonia
Sickle cell syndrome, sickling crisis
Acute hemorrhage in the alveoli
Radiation pneumonitis
Leukemia and neoplasms such as bronchogenic carcinoma
Drug-induced pulmonary infiltration

3.1. Radiological Findings

3.1.1. Chest X-rays
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 pneumo-
nia), 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].

3.1.2. Ultrasonography (USG)

Lung USG has been employed more commonly in the last decade to diagnose pneu-
monia with inappreciable diagnostic value in the patients in extremis who are hard to be
Diagnostics 2023, 13, 1869 4 of 17

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].

3.2. Microbiological Work-Up

3.2.1. Sputum Gram Stain
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.

3.2.2. Blood Count

An increased WBC count (up to 30,000/mm3 ) and a leftward shift are common find-
ings, 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 refer-
ence 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.

3.2.3. Blood Cultures

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].

3.2.4. Molecular Methods

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].

3.3. Biomarkers
3.3.1. Lactate
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.
Diagnostics 2023, 13, 1869 5 of 17

3.3.2. Monocyte Human Leukocyte Antigen—DR Isotype (mHLA–DR)

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].

3.3.3. C–Reactive Protein (CRP)

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 ex-
clude pneumonia. In this group, the evaluation of signs and symptoms identified diag-
nostic 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.

3.3.4. P–Calprotectin
P–calprotectin has been recently reported to be a useful aid in sepsis-suspected pa-
tients. 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.

3.3.5. Procalcitonin (PCT)

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 cal-
citonin [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 endo-
toxins [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
Diagnostics 2023, 13, 1869 6 of 17

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.

3.3.6. Comparisons of PCT with CRP and Other Markers

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.

4. Role of PCT in Comorbidities, Special Subgroups and Associated Conditions

4.1. COPD and PCT
An elevated PCT level (HR: 1.02, 95% CI: 1.00–1.03) is among the variables predicting
death, namely the age (hazard ratio: 1.12, 95% CI: 1.05–1.19) and a history of cancer
(HR: 7.04, 95% CI: 2.22–22.36) [67]. The use of PCT-based protocols in COPD exacerbations
reduced the use of antibiotics (RR: 0.56, 95% CI: 0.43–0.73) and decreased the number of
days of antibiotic administration (difference in days: −3.83, 95% CI: −4.32–0.35) but had
no effect on the total length of hospital stay and mortality [68].
In a study by Corti et al., patients with COPD exacerbations followed up for 28 days
were randomized to PCT and control groups, and the rate of antibiotic use was more
than 41% in the PCT group, whereas it was 67% in the controls [69]. Similarly, Stolz et al.,
reported that PCT-mediated care reduced prescriptions of antibiotics (40 versus 72%) [70].
PCT worked up in conjunction with CRP was advocated as a more useful test in the
recognition and management of acute exacerbations of COPD [71]. The levels of PCT and
CRP were (1.97 ± 0.13) µg/L and (7.34 ± 2.66) mg/L, respectively, in the infection group
after treatment, which was significantly lower than the levels before treatment. Levels of
CRP in combination with PCT is a reliable index for the detection of bacterial infection
in these patients. According to the results of a retrospective cohort study conducted by
Ulrich et al. in 2019, in which records of 238 COPD exacerbation cases were evaluated, the
duration of antibiotic administration was not shortened in patients directed by PCT within
a 6-month period, and no difference was noted in regard to mortality [72]. Meanwhile, it
was reported that the rate of 30-day readmissions was reduced in the group in which PCT
was measured compared to the group in which it was not worked up (21 versus 36%).
Diagnostics 2023, 13, 1869 7 of 17

In brief, the use of biomarkers will not be sufficient alone for prognostic purposes in
the management of COPD exacerbations. The use of PCT and CRP levels together with
other signs and symptoms may be considered to identify the etiology of exacerbation and to
predict the probability of readmission to the hospital [73]. The use of PCT-guided antibiotics
in patients admitted to the hospital with COPD exacerbation does not alleviate mortality
compared to standard care. Thus, routine PCT level measurement is not necessary.

4.2. Sepsis and PCT

Fever associated with signs of shock is commonly caused by sepsis, which encom-
passes a wide spectrum of illnesses caused by infection and its complications. The incidence
of sepsis is increasing worldwide with a high death toll. The mortality rate of severe sepsis
is between 30 and 50%, while septic shock has a death rate greater than 50% [74]. Expedient
recognition and management definitely reduce mortality. On the other hand, the symp-
tomatology and findings of a patient with sepsis are similar to other inflammatory reactions,
especially when the source of infection cannot be identified. Appropriate management
comprises empirical antibiotics and resuscitation. A PCT level > 2 SD above normal is
a typical finding of sepsis laboratory workup [75].
CAP and severe CAP comprise a continuum in which some patients worsen and
die from sepsis and septic shock. Severe sepsis can ensue at the beginning of the clinical
course of the infection in more than a third of cases with CAP. Patients with severe CAP
have been found to have significantly more positive BC results than those with non-severe
pneumonia. ATS guidelines describe severe CAP with minor and major criteria [1]. The
validated definition includes either one major criterion (septic shock and respiratory failure
requiring mechanical ventilation) or three or more minor criteria (tachypnea, PaO2 /FIO2
ratio < 250, multilobar infiltrates, altered mental status, uremia, leukopenia, thrombocy-
topenia, hypothermia, and hypotension).

4.3. Use of PCT Alone vs. PCT-Based Scores

Tsui et al. proposed a PCT-based score that has been revealed to perform better in
detecting sepsis and compared this with PCT concentrations alone, CRP, and infection
probability score [76]. The PCT-based score performed well in detecting sepsis (AU-
ROC 0.80; 95% CI 0.74–0.85; sensitivity 0.70; specificity 0.76), which outperformed the
other competitors.

4.4. PCT in Elderly Patients

PCT was found to be beneficial in the elderly who were investigated for bacteremia.
Lee et al. pointed out that PCT was not inferior to other tests in recognition of bacterial
etiology [77]. On the other hand, the deficient reliability of the test withheld recommenda-
tions on the use of the test in isolation. In a recent study on elderly patients with sepsis,
PCT, IL-10, IL-6, and IL-5 were noted to be accurate in estimating ICU follow-up but were
not effective in the prediction of mortality [78]. Another special population consists of those
residing in nursing homes. Pneumonia and CAP are also important acquired morbidities
in those dwelling in nursing homes. PCT levels were recorded to be 4.7 ± 5 ng/mL in
non-survivors and 0.86 ± 1 ng/mL in survivors in this group of patients (p < 0.001) [79].
The AUC for PCT in estimating death was 0.84 (95% CI 0.70–0.98, p = 0.001). A PCT level
measured as >1.1 ng/mL on presentation predicted mortality independently.

4.5. PCT in Congestive Heart Failure (CHF)

Elderly patients with CHF are commonly present at the ED with respiratory symp-
toms [13]. Some of the cases can have pneumonia-complicating CHF, and/or signs and
symptoms of CAP can be confused with those of CHF. The use of biomarkers, such as
PCT measurement, will help identify patients with bacterial infection and guide antibiotic
therapy. Elderly patients with CHF and elevated PCT levels indicate a high probability of
bacterial infection [80,81].
Diagnostics 2023, 13, 1869 8 of 17

4.6. Use of PCT in Chronic Renal Insufficiency (CRI)

PCT levels were found to be greater in patients with reduced renal function as com-
pared to the others, and levels can be lowered after dialysis by around 20–80% [82–85].
In general, PCT and CRP show poor sensitivity but adequate specificity in the recog-
nition of bacterial infection in patients with CRI. Their negative likelihood ratio is low,
which renders their value as a rule-out test questionable. In a meta-analysis published
by Lu et al., the positive LR for PCT (LR)+ 6.0, 95% CI 3.1–11.4) was sufficiently high as
a rule-in diagnostic tool, while the LR− was not low enough for an exclusion test (LR− 0.3,
95% CI 0.1–0.5) [86]. Therefore, clinicians are not recommended to rule out bacterial
pneumonia or sepsis in a patient with normal levels of PCT.
Mean levels of serum PCT in ESRD patients on dialysis were 0.7 ng/mL, and more
than a half (57%) of dialysis patients had pre-dialytic levels above 0.5 ng/mL [87].
Lee et al. measured serum PCT levels in ESRD patients on antibiotic therapy for bac-
terial infection (ESRD infection [iESRD] group) and compared them with those of ESRD
patients on dialysis without any infection signs (ESRD control [cESRD] group [88]). Serum
PCT is found to be a strong indicator of infection in ESRD patients, using 0.75 ng/mL as
a cutoff value. Seventy percent of uninfected children were demonstrated to have pre-
dialytic PCT levels > 0.5 ng/mL and were reduced substantially by 40% via dialysis [89].

4.7. PCT in Obesity

Being overweight frequently accompanies insulin resistance. PCT is reported to be
an important marker of fat accumulation and metabolic parameters associated with obesity.
Boursier et al. have demonstrated that PCT can be a valuable marker of fat accumulation
and metabolic parameters in obese individuals [90]. PCT has also been postulated to be
useful to schedule exercise and weight loss [59].

4.8. Use of PCT in Children

Damman et al. sought for the diagnostic accuracy of PCT in predicting bacteremia
in febrile children with indwelling central lines [91]. They reported that a PCT level
of ≥0.6 ng/mL was the best cutoff point, with a sensitivity of 85.6% and a specificity of 66%
(AUC 0.85), which approved PCT as a sensitive biomarker predicting bacteremia in febrile
children with a central line. A higher PCT was found to predict more severe pneumonia
and longer hospital stays in a study that enrolled around 490 children with pneumonia [92].
The marker can be used to aid clinicians in the accurate evaluation of pneumonia severity.
Although PCT is more accurate in predicting severe infectious states when compared
to CRP and other markers, it does not appear to be sensitive or specific enough to act as
a reliable test for the recognition of sepsis [93]. An elevated PCT level on admission indicates
a poorer outcome for patients with sepsis or septic shock, albeit serial measurements
provide more reliable estimation of the clinical course.

4.9. H1N1 Infection (Influenza) and PCT

Most patients are diagnosed on clinical grounds alone amidst influenza epidemics.
ICU patients complicated by bacterial pneumonia had higher PCT levels than those having
only H1N1 infection (6 mcg/L vs. 0.6 mcg/L) [94]. The test had 80% sensitivity and 73%
NPV in estimating pneumonia with the cut-off level accepted as 0.5 mcg/L. Moreover, tests
had a sensitivity around 50%, but specificity was above 95% [95,96].
Wu et al. published a systematic review and meta-analysis and pointed out that
the LR+ for PCT was 2.3 (95% CI: 1.9–2.8), which is not adequate for its reliability as
a diagnostic tool. Meanwhile, its LR− was low enough to employ as an exclusion tool
(LR− = 0.26; 95% CI: 0.1–0.4) [97]. PCT has a high sensitivity, particularly for ICU patients,
but a low specificity to diagnose secondary bacterial infections for those with influenza. It
can be a valuable rule-out test because of its high LR− but cannot be used as a standalone
rule-in test because of suboptimal LR+.
Diagnostics 2023, 13, 1869 9 of 17

Rodríguez et al. demonstrated that PCT has a high negative predictive value (94%),
and that lower PCT readings appear to be a useful instrument to rule out coinfection,
particularly for those without signs of hypoperfusion, in a prospective multicentric investi-
gation [98]. Of note, PCT (2.4 ng/mL vs. 0.5 ng/mL, p < 0.001), but not CRP (25 mg/dL vs.
38 mg/dL; p = 0.6), was higher in patients with coinfections.

Secondary Bacterial Infections in Primary Influenza Virus Infection

ATS reported that bacterial pneumonia can occur concurrently with influenza virus
infection or present later as a worsening of symptoms following primary influenza virus
infection (1). Ten to 30% of those hospitalized for influenza and bacterial pneumonia
die from these infections [99]. S. aureus is one of the most common bacterial infections
associated with influenza pneumonia, followed by S. pneumoniae, H. influenzae, and Group
A Streptococcus [100,101].

4.10. Use of PCT to Diagnose Bacterial Infection in Patients with Autoimmune Diseases
Pooled specificity was calculated to be 0.90 (95% CI 0.85–0.93) for PCT and 0.56
(95% CI 0.25–0.83) for CRP to identify bacterial infections in a meta-analysis [102]. The LR+
for PCT (7.3 [95% CI 5.1–10.4]) was adequate to make PCT a reliable diagnostic instrument,
while the LR− (0.3 [95% CI 0.2–0.4]) was not adequately low to accept PCT as a reliable
exclusion tool. In brief, PCT has a higher diagnostic reliability when compared to CRP in
the diagnosis of bacterial sepsis in patients with autoimmune disease, and PCT is more
specific than sensitive. A PCT test is not suggested to be used in isolation as a rule-out test.

5. Principles of Treatment
Empiric antibiotic therapy with a β-lactam, combined with a macrolide, respiratory
fluoroquinolones, or tetracyclines, comprise a management approach commonly recom-
mended for patients hospitalized with CAP. The prevalence of resistant microorganisms
increased in recent decades, including S. pneumoniae, which is resistant to frequently used
antibiotics (e.g., β-lactams, macrolides, and tetracyclines) [103].
The American Thoracic Society (ATS) formulated and provided the rationale for rec-
ommendations on selected diagnostic and treatment strategies for adult patients with CAP.
For healthy outpatient adults without significant comorbidities or risk factors for antibiotic
resistant pathogens, ATS recommended amoxicillin or doxycycline, or a macrolide for
empiric treatment of CAP in adults in the outpatient setting (1). An oral administration of
antibiotics is associated with a reduced risk of all-cause mortality compared with parenteral
therapy based on RCTs with low-to-moderate quality [104].
For outpatient adults with serious comorbidities (e.g., chronic heart, lung, liver, or
renal disease; diabetes mellitus; alcoholism; malignancy; or asplenia), ATS recommended
combination therapies such as amoxicillin/clavulanate and macrolide. On the other hand,
Montes–Andujar et al. have performed a network meta-analytic study recently to identify
the empiric antibiotic with the highest probability of being the best (HPBB) in terms of cure
rate and mortality rate in hospitalized patients with CAP [105]. They cited that for the cure
rate, ceftaroline and piperaciline are the options with the HPBB. However, for the mortality
rate, the treatment agents of choice are ceftriaxone plus levofloxacin, ertapenem, and
amikacin plus clarithromycin. In another meta-analytic study, the efficacy of doxycycline
was found to be comparable to macrolides or fluoroquinolones in mild-to-moderate CAP.
Thus, it represents a viable treatment option [106]. Ashy et al. compared the clinical success
attributed to specific macrolide agents and revealed that erythromycin use was associated
with significantly lower rates of clinical success (RR 0.79), clinical cure (RR 0.67), and
radiological success (RR 0.84) than clarithromycin [107].
The treatment success rate for azithromycin-beta-lactam after 10-to-14 days was
87.55%; for clarithromycin-beta-lactam after 5 to 7 days of therapy, it was 75.42% [108]. A
shorter hospital stay was achieved with a clarithromycin-beta-lactam regimen (7.25 days
versus 8.45 days). The authors recommended a macrolide and beta-lactam combination
Diagnostics 2023, 13, 1869 10 of 17

using susceptibility data from the treating facility. Five-day treatment and longer antibiotic
courses for CAP resulted in similar clinical and microbiological responses and exhibited
comparable safety profiles [109]. However, recent analyses pointed out that a shorter
treatment duration (3–5 days) probably offers the optimal balance between efficacy and
treatment burden for treating CAP in adults if they achieved clinical stability [29].

5.1. Use of PCT in Antibiotic Stewardship

PCT is commonly recommended to be used to exclude CAP and, thus, identify patients
who do not need antibacterial therapy. In a randomized controlled trial, the use of a “PCT
algorithm” helped shorten the duration of antimicrobial therapy and lowered antibiotic-
related adverse effect rates [110].
The Stop Antibiotics on Procalcitonin guidance Study (SAPS) trial enrolled more
than 1500 patients in the ICU with suspected or known infection (65% had a respiratory
infection) [111]. Clinicians stopped antibiotics when PCT levels were below 0.5 ng/mL or
decreased by ≥80% from the peak. The PCT-guided group had substantially less antibiotic
use (7.5 versus 9.3 defined daily doses) and lower 28-day mortality (19% vs. 25%) than
controls. Identical thresholds of ≤0.5 ng/mL, or an ≥80% reduction from the peak on
Day, 5 were used in the Procalcitonin-Guided Antimicrobial Therapy to Reduce Long-Term
Sequelae of Infections (PROGRESS) trial. Compared with usual care, PCT-guided antibiotic
discontinuation had lower antibiotic use (5 versus 10 days) and 28-day mortality [112].
These suggestions are in line with the 2021 Surviving Sepsis Campaign and the 2016 IDSA
antimicrobial stewardship guidelines for using PCT levels to guide antibiotic cessation in
patients with suspected infections in the ICU [113,114].
Consensus algorithms differ with regard to the timing of treatment (i.e., initiation in
low-risk patients or discontinuation in high-risk patients) and PCT cut-off points for the
recommendation/strong recommendation to discontinue antibiotics (≤0.25/≤0.1 µg/L
in ED and inpatients, ≤0.5/≤0.25 µg/L in ICU patients, and a reduction by ≥80% from
peak levels in sepsis patients) [115]. PCT levels > 0.25 µg/L necessitate the initiation of
antibiotics in those with CAP. In patients receiving antibiotics, PCT levels should be checked
in around two-to-three days. Antibiotic discontinuation is considered in patients with
a visible improvement, and if PCT levels are either below 0.25 µg/L or have reduced >80%
from peak levels. Causes of treatment failure include empyema, multi-resistant strains,
or incomplete antibiotic therapy, which should be searched in those without sufficient
decrease in PCT levels.
Tonkin–Crine et al. performed a systematic review of seven studies on the results
of interventions intended to influence physicians’ antibiotic prescribing behaviour for
pneumonia in ambulatory care [116]. They found that PCT-guided management appears to
reduce antibiotic prescribing in EDs (adjusted OR 0.3, 95% CI 0.3 to 0.4). The overall effect
of these interventions was small but likely to be clinically important.
In brief, PCT-guided treatment of pneumonia and other respiratory infections helps re-
duce antibiotic consumption and improve clinical outcomes, although launched algorithms
had differences in PCT cut-off points. If initial PCT levels are above 0.25 µg/L, a bacterial
infection is unlikely, and other illnesses (e.g., pulmonary embolism or heart failure) should
be ruled out.
Ventilator-associated pneumonia, acute bronchitis, and acute exacerbations of COPD,
as well as other chronic lung diseases, do not routinely require PCT levels for management.
PCT work-up can be reserved for selected cases in these situations.

5.2. Value of PCT in Outpatient Follow-Up

PCT can be ordered in combination with a positivity for influenza or COVID-19 to
withhold antibiotics or stop them early, provided that there are no other signs of bacterial
infection (e.g., dense consolidation on chest imaging, increased WBC count, or positive BC)
and that the patient has a close follow-up. Other experts prefer to treat empirically with
Diagnostics 2023, 13, 1869 11 of 17

antibiotics because bacterial CAP is hard to exclude definitively, the morbidity association
with CAP is high, and outpatient treatment courses for CAP are short (e.g., five days).
While data directly supporting PCT-guided antibiotic decision-making in outpatients
with CAP are limited, one randomized trial comparing >150 outpatients with CAP found
that clinical outcomes were similar, and that antibiotic exposure was decreased when PCT
was used [117]. A recent study evaluated 469 general practice patients with any kind of
respiratory infections [118]. Antibiotic use was reduced at a rate of 26% when PCT was used
to guide antibiotic decision-making, while clinical outcomes were similar. Interestingly,
point-of-care lung USG did not further reduce antibiotic prescription, although a potential
added value cannot be excluded.

5.3. General Trends in Procalcitonin (PCT) Levels with Agents and Clinical Conditions
Table 3 summarizes and lists the conditions triggering increases in PCT levels with
and without pneumonia. False positive and negative PCT elevations should be accounted
for in clinical grounds before affecting decision-making processes [119].

Table 3. Procalcitonin (PCT) levels with regard to various microbiologic agents and clinical variables.

PCT > 0.25 ng/mL PCT < 0.25 ng/mL

Bacterial infections (PCT levels may not increase in case of abscesses or empyema)
Typical pneumonia agents Most reported thus far
Chlamydia pneumonia,
Atypical pneumonia agents Legionella spp., mycobacteria spp. Mycoplasma pneumonia,
mycobacteria spp.
Viral agents None All
Mucormycosis,
Fungal agents Candida spp. aspergillosis,
coccidioidomycosis
Parasitic agent Plasmodium spp. (malaria)
Trauma, surgery, burn, pancreatitis
Bowel ischemia
Physiologic stress Cerebrovascular accident, intracerebral
hemorrhage
Shock (all causes)
Clostridioides difficile-associated disease,
Toxin-mediated entities C. difficile colonization
mushroom poisoning
Rheumatoid arthritis,
gout and pseudogout,
Behçet disease
Comorbid diseases, immune and Kawasaki disease, renal and hepatic Crohn’s disease
rheumatologic entities failure Systemic lupus erythematosus,
polyarteritis nodosa,
temporal arteritis,
granulomatosis with polyangiitis
Lymphoma and sarcoma
Malignant tumors Thyroid and lung cancers Splanchnic cancers (e.g., pancreatic and
renal cell carcinoma)

6. Blank Areas for PCT Use

PCT had shortcomings that restricted its use in most decision-making processes.
Severe inflammatory states included major surgery, trauma, burns, inhalational injury,
necrotic lesions of pancreas, and hypothermic treatment methods [120–122].
Diagnostics 2023, 13, 1869 12 of 17

7. Conclusions
Pneumonia and sepsis are diseases of utmost importance to diagnose and treat ur-
gently, since they are responsible for a high worldwide death toll. Although an elaborate
history and clinical examination are mainstays for an accurate diagnostic process, certain
laboratory adjuncts can comprise invaluable aids in appropriate management. PCT is one
of the extensively investigated sepsis biomarkers also employed in pneumonia in a wide
range of studies, together with CRP and a complete blood count. It appears to be a reliable
diagnostic tool to expedite care of these patients with severe infections in the acute setting.
PCT is an inflammatory biologic marker that can be useful in distinguishing between
bacterial and nonbacterial etiologies of pulmonary infection. It was reported to be more
accurate than most other acute phase reactants and indicators as a predictor of pneumo-
nia, bacteremia, sepsis, and poor outcomes. In addition, PCT use is beneficial to judge
timing to stop antibiotic therapy in serious infections. The physicians need to gauge
pluses and minuses of the useful biomarkers in expedient recognition and management of
severe infections.
PCT can help direct antibiotic decisions for the treatment of acute respiratory infections
to minimize antibiotic prescription and orders to improve prognoses in this regard. PCT
algorithms may be adapted to the type of infection and the unique case scenario. PCT has
shown potential benefits in antibiotic stewardship protocols.

Author Contributions: Conceptualization, O.K. and S.O.; methodology, S.O. and C.A.; software,
M.A.; validation, M.A., C.A. and O.O.; formal analysis, C.A.; investigation, O.O. and M.A.; resources,
C.A.; data curation, C.A. and M.A.; writing—original draft preparation, S.O.; writing—review and
editing, O.K.; visualization, O.O.; supervision, S.O. and O.K.; project administration, S.O. and O.K.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data sharing not applicable. No new data were created or analyzed in
this study. Data sharing is not applicable to this article.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Metlay, J.P.; Waterer, G.W.; Long, A.C.; Anzueto, A.; Brozek, J.; Crothers, K.; Cooley, L.A.; Dean, N.C.; Fine, M.J.; Flanders, S.A.; et al.
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. Am. J. Respir. Crit. Care Med. 2019, 200, e45–e67. [CrossRef] [PubMed]
2. Musher, D.M.; Thorner, A.R. Community-acquired pneumonia. N. Engl. J. Med. 2014, 371, 1619. [CrossRef]
3. Athlin, S.; Lidman, C.; Lundqvist, A.; Naucler, P.; Nilsson, A.C.; Spindler, C.; Strålin, K.; Hedlund, J. Management of community-
acquired pneumonia in immunocompetent adults: Updated Swedish guidelines 2017. Infect. Dis. 2018, 50, 247–272. [CrossRef]
4. Marrie, T.J.; Huang, Q.J. Epidemiology of community-acquired pneumonia in Edmonton, Alberta: An emergency department-
based study. Can. Respir. J. 2005, 12, 139–142. [CrossRef]
5. Almirall, J.; Bolibar, I.; Vidal, J.; Sauca, G.; Coll, P.; Niklasson, B.; Bartolome, M.; Balanzo, X. Epidemiology of community-acquired
pneumonia in adults: A population-based study. Eur. Respir. J. 2000, 15, 757–763. [CrossRef] [PubMed]
6. Ewig, S.; Birkner, N.; Strauss, R.; Schaefer, E.; Pauletzki, J.; Bischoff, H.; Schraeder, P.; Welte, T.; Hoeffken, G. New perspectives
on community-acquired pneumonia in 388 406 patients. Results from a nationwide mandatory performance measurement
programme in healthcare quality. Thorax 2009, 64, 1062–1069. [CrossRef] [PubMed]
7. Pletz, M.W.; Von Baum, H.; Van der Linden, M.; Rohde, G.; Schütte, H.; Suttorp, N.; Welte, T. The burden of pneumococcal
pneumonia—Experience of the German competence network CAPNETZ. Pneumologie 2012, 66, 470–475. [CrossRef]
8. Köksal, I.; Ozlü, T.; Bayraktar, O.; Yılmaz, G.; Bülbül, Y.; Oztuna, F.; Caylan, R.; Aydın, K.; Sucu, N. Etiological agents of
community-acquired pneumonia in adult patients in Turkey; a multicentric, cross-sectional study. Tuberk. Toraks. 2010, 58,
119–127.
9. Kurutepe, S.; Ecemiş, T.; Ozgen, A.; Bicmen, C.; Celik, P.; Aktoğu, Ö.S.; Sürücüoğlu, S. Investigation of bacterial etiology with
conventional and multiplex PCR methods in adult patients with community-acquired pneumonia. Mikrobiyol. Bul. 2012, 46,
523–531.
Diagnostics 2023, 13, 1869 13 of 17

10. Bulbul, Y. Community-Acquired Pneumonia Data in Turkey. Güncel Göğüs Hast. Serisi 2014, 2, 1–10. (In Turkish)
11. Şenol, E.; Cilli, A.; Günen, H.; Şener, A.; Dumlu, R.; Ödemiş, A.; Topçu, A.F.; Yıldız, Y.; Güner, R.; Özhasenekler, A. The Role of
Pneumococcal Pneumonia among Community-Acquired Pneumonia in Adult Turkish Population: TurkCAP Study. Turk. Thorac.
J. 2021, 22, 339–345. [CrossRef] [PubMed]
12. Surme, S.; Balkan, I.I.; Bayramlar, O.F.; Ali, R.K.; Mete, B.; Tabak, F.; Saltoğlu, N. Predictors of Long-term Outcomes in the Older
Adults with Community-Acquired Pneumonia. J. Infect. Dev. Ctries 2021, 15, 1910–1916. [CrossRef] [PubMed]
13. Cillóniz, C.; Polverino, E.; Ewig, S.; Aliberti, S.; Gabarrús, A.; Menéndez, R.; Mensa, J.; Blasi, F.; Torres, A. Impact of age and
comorbidity on cause and outcome in community-acquired pneumonia. Chest 2013, 144, 999–1007. [CrossRef]
14. McLaughlin, J.M.; Khan, F.L.; Thoburn, E.A.; Isturiz, R.E.; Swerdlow, D.L. Rates of hospitalization for community-acquired
pneumonia among US adults: A systematic review. Vaccine 2020, 38, 741–751. [CrossRef]
15. Ochoa-Gondar, O.; Vila-Córcoles, A.; de Diego, C.; Arija, V.; Maxenchs, M.; Grive, M.; Martin, E.; Pinyol, J.L.; EVAN-65 Study
Group. The burden of community-acquired pneumonia in the elderly: The Spanish EVAN-65 study. BMC Public Health 2008,
8, 222. [CrossRef] [PubMed]
16. Vila-Corcoles, A.; Ochoa-Gondar, O.; Rodriguez-Blanco, T.; Raga-Luria, X.; Gomez-Bertomeu, F.; EPIVAC Study Group. Epi-
demiology of community-acquired pneumonia in older adults: A population-based study. Respir. Med. 2009, 103, 309–316.
[CrossRef]
17. Moore, M.; Stuart, B.; Little, P.; Smith, S.; Thompson, M.J.; Knox, K.; van den Bruel, A.; Lown, M.; Mant, D. Predictors of
pneumonia in lower respiratory tract infections: 3C prospective cough complication cohort study. Eur. Respir. J. 2017, 50, 1700434.
[CrossRef]
18. Marrie, T.J. Community-acquired pneumonia. Clin. Infect. Dis. 1994, 18, 501. [CrossRef]
19. Bohte, R.; Hermans, J.; van den Broek, P.J. Early recognition of Streptococcus pneumoniae in patients with community-acquired
pneumonia. Eur. J. Clin. Microbiol. Infect. Dis. 1996, 15, 201–205. [CrossRef]
20. Johansson, N.; Kalin, M.; Tiveljung-Lindell, A.; Giske, C.G.; Hedlund, J. Etiology of community-acquired pneumonia: Increased
microbiological yield with new diagnostic methods. Clin. Infect. Dis. 2010, 50, 202–209. [CrossRef]
21. Strålin, K.; Olcén, P.; Törnqvist, E.; Holmberg, H. Definite, probable, and possible bacterial aetiologies of community-acquired
pneumonia at different CRB-65 scores. Scand. J. Infect. Dis. 2010, 42, 426–434. [CrossRef] [PubMed]
22. Viasus, D.; Núñez-Ramos, J.A.; Viloria, S.A.; Carratalà, J. Pharmacotherapy for community-acquired pneumonia in the elderly.
Expert Opin. Pharmacother. 2017, 18, 957–964. [CrossRef] [PubMed]
23. Franquet, T. Imaging of Community-acquired Pneumonia. J. Thorac. Imaging 2018, 33, 282–294. [CrossRef] [PubMed]
24. Nyamande, K.; Lalloo, U.G.; Vawda, F. Comparison of plain chest radiography and high-resolution CT in human immunode-
ficiency virus infected patients with community-acquired pneumonia: A sub-Saharan Africa study. Br. J. Radiol. 2007, 80, 302.
[CrossRef] [PubMed]
25. Claessens, Y.E.; Debray, M.P.; Tubach, F.; Brun, A.L.; Rammaert, B.; Hausfater, P.; Naccache, J.M.; Ray, P.; Choquet, C.; Carette, M.F.; et al.
Early Chest Computed Tomography Scan to Assist Diagnosis and Guide Treatment Decision for Suspected Community-acquired
Pneumonia. Am. J. Respir. Crit. Care Med. 2015, 192, 974. [CrossRef] [PubMed]
26. Murtaza, H.G.; Javed, N.; Iqbal, A.; Ramzan, M.; ul haq Lodhi, O.; Majid, S.; Abbas, K.; Rehman, A.; Murtaza, H.G. Comparison
of High-Resolution Computed Tomography and Real-Time Reverse Transcriptase Polymerase Chain Reaction in Diagnosis of
COVID-19 Pneumonia in Intensive Care Unit Population. Cureus 2021, 13, e13602. [CrossRef]
27. Long, L.; Zhao, H.T.; Zhang, Z.Y.; Wang, G.Y.; Zhao, H.L. Lung ultrasound for the diagnosis of pneumonia in adults: A
meta-analysis. Medicine 2017, 96, e5713. [CrossRef]
28. Llamas-Álvarez, A.M.; Tenza-Lozano, E.M.; Latour-Pérez, J. Accuracy of Lung Ultrasonography in the Diagnosis of Pneumonia
in Adults: Systematic Review and Meta-Analysis. Chest 2017, 151, 374. [CrossRef]
29. Furukawa, Y.; Luo, Y.; Funada, S.; Onishi, A.; Ostinelli, E.; Hamza, T.; Furukawa, T.A.; Kataoka, Y. Optimal duration of antibiotic
treatment for community-acquired pneumonia in adults: A systematic review and duration-effect meta-analysis. BMJ Open 2023,
13, e061023. [CrossRef]
30. Metlay, J.P.; Kapoor, W.N.; Fine, M.J. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history
and physical examination. JAMA 1997, 278, 1440. [CrossRef]
31. Musher, D.M.; Montoya, R.; Wanahita, A. Diagnostic value of microscopic examination of Gram-stained sputum and sputum
cultures in patients with bacteremic pneumococcal pneumonia. Clin. Infect. Dis. 2004, 39, 165. [CrossRef] [PubMed]
32. Corbo, J.; Friedman, B.; Bijur, P.; Gallagher, E.J. Limited usefulness of initial blood cultures in community acquired pneumonia.
Emerg. Med. J. 2004, 21, 446. [PubMed]
33. Chalasani, N.P.; Valdecanas, M.A.L.; Gopal, A.K.; McGowan, J.E., Jr.; Jurado, R.L. Clinical utility of blood cultures in adult patients
with community-acquired pneumonia without defined underlying risks. Chest 1995, 108, 932. [CrossRef]
34. File, T.M., Jr. New diagnostic tests for pneumonia: What is their role in clinical practice? Clin. Chest Med. 2011, 32, 417–430.
[CrossRef] [PubMed]
35. Cho, M.C.; Kim, H.; An, D.; Lee, M.; Noh, S.A.; Kim, M.N.; Chong, Y.P.; Woo, J.H. Comparison of sputum and nasopharyngeal
swab specimens for molecular diagnosis of Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.
Ann. Lab. Med. 2012, 32, 133. [CrossRef]
Diagnostics 2023, 13, 1869 14 of 17

36. Templeton, K.E.; Scheltinga, S.A.; Van Den Eeden, W.C.; Graffelman, W.A.; Van Den Broek, P.J.; Claas, E.C. Improved diagnosis
of the etiology of community-acquired pneumonia with real-time polymerase chain reaction. Clin. Infect. Dis. 2005, 41, 345.
[CrossRef]
37. Park, H.K.; Lee, H.J.; Kim, W. Real-time PCR assays for the detection and quantification of Streptococcus pneumoniae. FEMS
Microbiol. Lett. 2010, 310, 48. [CrossRef]
38. Resti, M.; Micheli, A.; Moriondo, M.; Becciolini, L.; Cortimiglia, M.; Canessa, C.; Indolfi, G.; Bartolini, E.; de Martino, M.; Azzari, C.
Comparison of the effect of antibiotic treatment on the possibility of diagnosing invasive pneumococcal disease by culture or
molecular methods: A prospective, observational study of children and adolescents with proven pneumococcal infection. Clin.
Ther. 2009, 31, 1266. [CrossRef]
39. Besen, B.A.M.P.; Romano, T.G.; Nassar, A.P.; Taniguchi, L.U.; Azevedo, L.C.P.; Mendes, P.V.; Zampieri, F.G.; Park, M. Sepsis-3
definitions predict ICU mortality in a low–middle-income country. Ann. Intensive Care 2016, 6, 107. [CrossRef]
40. Frenzen, F.S.; Kutschan, U.; Meiswinkel, N.; Schulte-Hubber, B.; Ewig, S.; Kolditz, M. Admission lactate predicts poor prognosis
independently of the CRB/CURB-65 scores in community-acquired pneumonia. Clin. Microbiol. Infect. 2017, 24, 306-e1. [CrossRef]
41. Dellinger, R.P.; Levy, M.M.; Rhodes, A.; Annane, D.; Gerlach, H.; Opal, S.M.; Sevransky, J.E.; Sprung, C.L.; Douglas, I.S.;
Jaeschke, R.; et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012.
Crit. Care Med. 2013, 41, 580–637. [CrossRef] [PubMed]
42. Howell, M.D.; Donnino, M.; Clardy, P.; Talmor, D.; Shapiro, N.I. Occult hypoperfusion and mortality in patients with suspected
infection. Intensive Care Med. 2007, 33, 1892–1899. [CrossRef] [PubMed]
43. Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.D.;
Coopersmith, C.M.; et al. The third international consensus definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315,
801–810. [CrossRef] [PubMed]
44. Vargun, P.; Yilmaz, S.; Tatliparmak, A.C.; Karcioglu, O. Should lactate levels be combined with rapid emergency medicine scores
(REMS) to predict outcomes of patients with dyspnea. Signa Vitae 2023, 19. [CrossRef]
45. Zhuang, Y.; Li, W.; Wang, H.; Peng, H.; Chen, Y.; Zhang, X.; Chen, Y.; Gao, C. Predicting the Outcomes of Subjects with Severe
Community-Acquired Pneumonia Using Monocyte Human Leukocyte Antigen-DR. Respir. Care 2015, 60, 1635–1642. [CrossRef]
46. Holm, A.; Nexoe, J.; Bistrup, L.A.; Pedersen, S.S.; Obel, N.; Nielsen, L.P. Aetiology and prediction of pneumonia in lower
respiratory tract infection in primary care. Br. J. Gen. Pract. 2007, 57, 547.
47. Boussekey, N.; Leroy, O.; Alfandari, S.; Devos, P.; Georges, H.; Guery, B. Procalcitonin kinetics in the prognosis of severe
community-acquired pneumonia. Intensive Care Med. 2006, 32, 469. [CrossRef]
48. van Vugt, S.F.; Broekhuizen, B.D.; Lammens, C.; Zuithoff, N.P.; de Jong, P.A.; Coenen, S.; Ieven, M.; Butler, C.C.; Goossens, H.;
Little, P. Grace Consortium. Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs
to predict pneumonia in patients presenting to primary care with acute cough: Diagnostic study. BMJ 2013, 346, f2450. [CrossRef]
49. Menéndez, R.; Martínez, R.; Reyes, S.; Mensa, J.; Filella, X.; Marcos, M.A. Biomarkers improve mortality prediction by prognostic
scales in community-acquired pneumonia. Thorax 2009, 64, 587–591. [CrossRef]
50. Ebell, M.H.; Bentivegna, M.; Cai, X.; Hulme, C.; Kearney, M. Accuracy of Biomarkers for the Diagnosis of Adult Community-
acquired Pneumonia: A Meta-analysis. Acad. Emerg. Med. 2020, 27, 195–206. [CrossRef]
51. Parke, Å.; Unge, C.; Yu, D.; Sundén-Cullberg, J.; Strålin, K. Plasma calprotectin as an indicator of need of transfer to intensive care
in patients with suspected sepsis at the emergency department. BMC Emerg. Med. 2023, 23, 16. [CrossRef] [PubMed]
52. Lee, H. Procalcitonin as a biomarker of infectious diseases. Korean J. Intern. Med. 2013, 28, 285–291. [CrossRef] [PubMed]
53. Maruna, P.; Nedelnikova, K.; Gurlich, R. Physiology and genetics of procalcitonin. Physiol. Res. 2000, 49 (Suppl. 1), S57–S61.
[PubMed]
54. Hoffmann, G.; Czechowski, M.; Schloesser, M.; Schobersberger, W. Procalcitonin amplifies inducible nitric oxide synthase gene
expression and nitric oxide production in vascular smooth muscle cells. Crit. Care Med. 2002, 30, 2091–2095. [CrossRef]
55. Vijayan, A.L.; Vanimaya; Ravindran, S.; Saikant, R.; Lakshmi, S.; Kartik, R.; Kartik, R. Procalcitonin: A promising diagnostic
marker for sepsis and antibiotic therapy. J. Intensive Care 2017, 5, 51. [CrossRef]
56. Philipp, S.; Werner, A.; Beat, M. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: Past, present and future.
BMC Med. 2011, 9, 107.
57. Kobayashi, H.; Amrein, K.; Lasky-Su, J.A.; Christopher, K.B. Procalcitonin metabolomics in the critically ill reveal relationships
between inflammation intensity and energy utilization pathways. Sci Rep. 2021, 11, 23194. [CrossRef]
58. Upadhyay, S.; Niederman, M.S. Biomarkers: What is their benefit in the identification of infection, severity assessment, and
management of community-acquired pneumonia? Infect. Dis. Clin. N. Am. 2013, 27, 19–31. [CrossRef]
59. Choi, J.J.; McCarthy, M.W. Novel applications for serum procalcitonin testing in clinical practice. Expert Rev. Mol. Diagn. 2018, 18,
27–34. [CrossRef]
60. Christ-Crain, M.; Stolz, D.; Bingisser, R.; Muller, C.; Miedinger, D.; Huber, P.R.; Zimmerli, W.; Harbarth, S.; Tamm, M.; Muller, B.
Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: A randomized trial. Am. J. Respir. Crit. Care
Med. 2006, 174, 84–93. [CrossRef]
61. Jensen, J.U.; Heslet, L.; Jensen, T.H.; Espersen, K.; Steffensen, P.; Tvede, M. Procalcitonin increase in early identification of critically
ill patients at high risk of mortality. Crit. Care Med. 2006, 34, 2596–2602. [CrossRef] [PubMed]
Diagnostics 2023, 13, 1869 15 of 17

62. Johansson, N.; Kalin, M.; Backman-Johansson, C.; Larsson, A.; Nilsson, K.; Hedlund, J. Procalcitonin levels in community-acquired
pneumonia-correlation with aetiology and severity. Scand. J. Infect. Dis. 2014, 46, 787–791. [CrossRef] [PubMed]
63. Nishikawa, H.; Shirano, M.; Kasamatsu, Y.; Morimura, A.; Iida, K.; Kishi, T.; Goto, T.; Okamoto, S.; Ehara, E. Comparison between
procalcitonin and C-reactive protein in predicting bacteremias and confounding factors: A case-control study. Clin. Chem. Lab.
Med. 2017, 55, 1043–1052. [CrossRef] [PubMed]
64. Nouvenne, A.; Ticinesi, A.; Folesani, G.; Cerundolo, N.; Prati, B.; Morelli, I.; Guida, L.; Lauretani, F.; Maggio, M.; Aloe, R.; et al.
The association of serum procalcitonin and high-sensitivity C-reactive protein with pneumonia in elderly multimorbid patients
with respiratory symptoms: Retrospective cohort study. BMC Geriatr. 2016, 16, 16. [CrossRef] [PubMed]
65. Zhang, W.; Wang, W.; Hou, W.; Jiang, C.; Hu, J.; Sun, L.; Hu, L.; Wu, J.; Shang, A. The diagnostic utility of IL-10, IL-17, and PCT in
patients with sepsis infection. Front. Public Health 2022, 10, 923457. [CrossRef]
66. Zhai, G.H.; Zhang, W.; Xiang, Z.; He, L.Z.; Wang, W.W.; Wu, J.; Shang, A.Q. Diagnostic Value of sIL-2R, TNF-α and PCT for Sepsis
Infection in Patients with Closed Abdominal Injury Complicated with Severe Multiple Abdominal Injuries. Front Immunol. 2021,
12, 741268. [CrossRef]
67. Flattet, Y.; Garin, N.; Serratrice, J.; Perrier, A.; Stirnemann, J.; Carballo, S. Determining prognosis in acute exacerbation of COPD.
Int. J. Chron. Obstruct. Pulmon. Dis. 2017, 12, 467–475. [CrossRef]
68. Mathioudakis, A.G.; Chatzimavridou-Grigoriadou, V.; Corlateanu, A.; Vestbo, J. Procalcitonin to guide antibiotic administration
in COPD exacerbations: A meta-analysis. Eur. Respir. Rev. 2017, 26, 160073. [CrossRef]
69. Corti, C.; Fally, M.; Fabricius-Bjerre, A.; Mortensen, K.; Jensen, B.N.; Andreassen, H.F.; Porsbjerg, C.; Knudsen, J.D.; Jensen, J.U.
Point-of-care procalcitonin test to reduce antibiotic exposure in patients hospitalized with acute exacerbation of COPD. Int. J.
Chron. Obstruct. Pulmon. Dis. 2016, 11, 1381–1389. [CrossRef]
70. Stolz, D.; Christ-Crain, M.; Bingisser, R.; Leuppi, J.; Miedinger, D.; Müller, C.; Huber, P.; Müller, B.; Tamm, M. Antibiotic treatment
of exacerbations of COPD: A randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007,
131, 9–19. [CrossRef]
71. Li, Y.; Xie, L.; Xin, S.; Li, K. Values of procalcitonin and C-reactive proteins in the diagnosis and treatment of chronic obstructive
pulmonary disease having concomitant bacterial infection. Pak. J. Med. Sci. 2017, 33, 566–569. [CrossRef] [PubMed]
72. Ulrich, R.J.; McClung, D.; Wang, B.R.; Winters, S.; Flanders, S.A.; Rao, K. Introduction of Procalcitonin Testing and Antibiotic
Utilization for acute exacerbations of chronic obstructive pulmonary disease. Infect. Dis. 2019, 12, 1178633719852626. [CrossRef]
[PubMed]
73. Doğan, N.Ö.; Varol, Y.; Köktürk, N.; Aksay, E.; Alpaydin, A.; Çorbacıoğlu, Ş.K.; Aksel, G.; Baha, A.; Akoğlu, H.; Karahan, S.; et al. 2021
Guideline for the Management of COPD Exacerbations: Emergency Medicine Association of Turkey (EMAT)/Turkish Thoracic
Society (TTS) Clinical Practice Guideline Task Force. Turk. J. Emerg. Med. 2021, 21, 137–176. [CrossRef] [PubMed]
74. Molinero-Fernández, Á.; Moreno-Guzmán, M.; López, M.Á.; Escarpa, A. Magnetic bead-based electrochemical immunoassays
on-drop and on-chip for procalcitonin determination: Disposable tools for clinical sepsis diagnosis. Biosensors 2020, 10, 66.
[CrossRef]
75. Reifel Saltzberg, J.M. Fever and signs of shock: The essential dangerous fever. Emerg. Med. Clin. N. Am. 2013, 31, 907–926.
[CrossRef] [PubMed]
76. Tsui, T.L.; Huang, Y.T.; Kan, W.C.; Huang, M.S.; Lai, M.Y.; Ueng, K.C.; Shiao, C.C. A novel procalcitonin-based score for detecting
sepsis among critically ill patients. PLoS ONE 2021, 16, e0245748. [CrossRef]
77. Lee, S.H.; Chan, R.C.; Wu, J.Y.; Chen, H.W.; Chang, S.S.; Lee, C.C. Diagnostic value of procalcitonin for bacterial infection in
elderly patients—A systemic review and meta-analysis. Int. J. Clin. Pract. 2013, 67, 1350–1357. [CrossRef]
78. Lee, W.J.; Woo, S.H.; Kim, D.H.; Seol, S.H.; Park, S.K.; Choi, S.P.; Jekarl, D.W.; Lee, S.O. Are prognostic scores and biomarkers
such as procalcitonin the appropriate prognostic precursors for elderly patients with sepsis in the emergency department? Aging
Clin. Exp. Res. 2016, 28, 917–924. [CrossRef]
79. Porfyridis, I.; Georgiadis, G.; Vogazianos, P.; Mitis, G.; Georgiou, A. C-reactive protein, procalcitonin, clinical pulmonary infection
score, and pneumonia severity scores in nursing home acquired pneumonia. Respir. Care 2014, 59, 574–581. [CrossRef]
80. Demissei, B.G.; Valente, M.A.; Cleland, J.G.; O’Connor, C.M.; Metra, M.; Ponikowski, P.; Teerlink, J.R.; Cotter, G.; Davison, B.;
Givertz, M.M.; et al. Optimizing clinical use of biomarkers in high-risk acute heart failure patients. Eur. J. Heart Fail. 2016, 18,
269–280. [CrossRef]
81. Demissei, B.G.; Cleland, J.G.; O’Connor, C.M.; Metra, M.; Ponikowski, P.; Teerlink, J.R.; Davison, B.; Givertz, M.M.;
Bloomfield, D.M.; Dittrich, H.; et al. Procalcitonin-based indication of bacterial infection identifies high risk acute heart failure
patients. Int. J. Cardiol. 2016, 204, 164–171. [CrossRef]
82. Contou, D.; d’Ythurbide, G.; Messika, J.; Ridel, C.; Parrot, A.; Djibré, M.; Hertig, A.; Rondeau, E.; Fartoukh, M. Description and
predictive factors of infection in patients with chronic kidney disease admitted to the critical care unit. J. Infect. 2014, 68, 105–115.
[CrossRef]
83. Lavín-Gómez, B.A.; Palomar-Fontanet, R.; Gago-Fraile, M.; Quintanar-Lartundo, J.A.; Gómez-Palomo, E.; González-Lamuño, D.;
García-Unzueta, M.T.; Arias-Rodríguez, M.A.; Gómez-Gerique, J.A. Inflammation markers, chronic kidney disease, and renal
replacement therapy. Adv. Perit. Dial. 2011, 27, 33–37. [PubMed]
84. Dumea, R.; Siriopol, D.; Hogas, S.; Mititiuc, I.; Covic, A. Procalcitonin: Diagnostic value in systemic infections in chronic kidney
disease or renal transplant patients. Int. Urol. Nephrol. 2014, 46, 461–468. [CrossRef] [PubMed]
Diagnostics 2023, 13, 1869 16 of 17

85. Grace, E.; Turner, R.M. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement
therapy. Clin. Infect. Dis. 2014, 59, 1761–1767. [CrossRef] [PubMed]
86. Lu, X.L.; Xiao, Z.H.; Yang, M.Y.; Zhu, Y.M. Diagnostic value of serum procalcitonin in patients with chronic renal insufficiency: A
systematic review and meta-analysis. Nephrol. Dial. Transplant. 2013, 28, 122–129. [CrossRef]
87. Level, C.; Chauveau, P.; Delmas, Y.; Lasseur, C.; Pellé, G.; Peuchant, E.; Montaudon, D.; Combe, C. Procalcitonin: A new marker
of inflammation in haemodialysis patients? Nephrol. Dial. Transplant. 2001, 16, 980–986. [CrossRef]
88. Lee, W.S.; Kang, D.W.; Back, J.H.; Kim, H.L.; Chung, J.H.; Shin, B.C. Cutoff value of serum procalcitonin as a diagnostic biomarker
of infection in end-stage renal disease patients. Korean J. Intern. Med. 2015, 30, 198–204. [CrossRef]
89. Lorton, F.; Veinberg, F.; Ielsch, D.; Deschênes, G.; Bensman, A.; Ulinski, T. Procalcitonin serum levels in children undergoing
chronic haemodialysis. Pediatr. Nephrol. 2007, 22, 430–435. [CrossRef]
90. Boursier, G.; Avignon, A.; Kuster, N.; Boegner, C.; Leprieur, E.; Picandet, M.; Bargnoux, A.S.; Badiou, S.; Dupuy, A.M.; Cristol, J.P.; et al.
Procalcitonin, an independent marker of abdominal fat accumulation in obese patients. Clin. Lab. 2016, 62, 435–441. [CrossRef]
91. Damman, J.; Arias, P.; Kerner, J.; Zhang, K.Y.; Dehghan, M.; Krishnan, G.; Nespor, C.; Bensen, R.; Park, K. Procalcitonin as a
Predictive Marker for Bacteremia in Children with a Central Line and Fever. Hosp. Pediatr. 2019, 9, 434–439. [CrossRef]
92. Sartori, L.F.; Zhu, Y.; Grijalva, C.G.; Ampofo, K.; Gesteland, P.; Johnson, J.; McHenry, R.; Arnold, D.H.; Pavia, A.T.; Edwards, K.M.; et al.
Pneumonia Severity in Children: Utility of Procalcitonin in Risk Stratification. Hosp. Pediatr. 2021, 11, 215–222. [CrossRef]
[PubMed]
93. Downes, K.J.; Fitzgerald, J.C.; Weiss, S.L. Utility of Procalcitonin as a Biomarker for Sepsis in Children. J. Clin. Microbiol. 2020, 58,
e01851-19. [CrossRef] [PubMed]
94. Pfister, R.; Kochanek, M.; Leygeber, T.; Brun-Buisson, C.; Cuquemelle, E.; Machado, M.P.; Piacentini, E.; Hammond, N.E.;
Ingram, P.R.; Michels, G. Procalcitonin for diagnosis of bacterial pneumonia in critically ill patients during 2009 H1N1 influenza
pandemic: A prospective cohort study, systematic review and individual patient data meta-analysis. Crit. Care 2014, 18, R44.
[CrossRef] [PubMed]
95. Landry, M.L. Diagnostic tests for influenza infection. Curr. Opin. Pediatr. 2011, 23, 91. [CrossRef]
96. Centers for Disease Control and Prevention. Evaluation of 11 commercially available rapid influenza diagnostic tests—United
States, 2011–2012. MMWR Morb. Mortal. Wkly. Rep. 2012, 61, 873.
97. Wu, M.H.; Lin, C.C.; Huang, S.L.; Shih, H.M.; Wang, C.C.; Lee, C.C.; Wu, J.Y. Can procalcitonin tests aid in identifying bacterial
infections associated with influenza pneumonia? A systematic review and meta-analysis. Influenza. Other Respir. Viruses 2013, 7,
349–355. [CrossRef]
98. Rodríguez, A.H.; Avilés-Jurado, F.X.; Díaz, E.; Schuetz, P.; Trefler, S.I.; Solé-Violán, J.; Cordero, L.; Vidaur, L.; Estella, Á.;
Laderas, J.C.P.; et al. Procalcitonin (PCT) levels for ruling-out bacterial coinfection in ICU patients with influenza: A CHAID
decision-tree analysis. J. Infect. 2016, 72, 143–151. [CrossRef]
99. Metersky, M.L.; Masterton, R.G.; Lode, H.; File, T.M.; Babinchak, T., Jr. Epidemiology, microbiology, and treatment considerations
for bacterial pneumonia complicating influenza. Int. J. Infect. Dis. 2012, 16, e321–e331. [CrossRef]
100. Jean, C.; Louie, J.K.; Glaser, C.A.; Harriman, K.; Hacker, J.K.; Aranki, F.; Bancroft, E.; Farley, S.; Ginsberg, M.; Hernandez, L.B.; et al.
Invasive group A streptococcal infection concurrent with 2009 H1N1 influenza. Clin. Infect. Dis. 2010, 50, e59–e62. [CrossRef]
101. Paddock, C.D.; Liu, L.; Denison, A.M.; Bartlett, J.H.; Holman, R.C.; DeLeon-Carnes, M.; Emery, S.L.; Drew, C.P.; Shieh, W.J.;
Uyeki, T.M.; et al. Myocardial injury and bacterial pneumonia contribute to the pathogenesis of fatal influenza B virus infection.
J. Infect. Dis. 2012, 205, 895–905. [CrossRef] [PubMed]
102. Wu, J.Y.; Lee, S.H.; Shen, C.J.; Hsieh, Y.C.; Yo, P.H.; Cheng, H.Y.; Chan, R.C.; Lee, C.C.; Chang, S.S. Use of serum procalcitonin to
detect bacterial infection in patients with autoimmune diseases: A systematic review and meta-analysis. Arthritis Rheum. 2012, 64,
3034–3042. [CrossRef] [PubMed]
103. Amin, A.N.; Cerceo, E.A.; Deitelzweig, S.B.; Pile, J.C.; Rosenberg, D.J.; Sherman, B.M. The hospitalist perspective on treatment of
community-acquired bacterial pneumonia. Postgrad. Med. 2014, 126, 18–29. [CrossRef] [PubMed]
104. Teng, G.L.; Chi, J.Y.; Zhang, H.M.; Li, X.P.; Jin, F. Oral vs. parenteral antibiotic therapy in adult patients with community-acquired
pneumonia: A systematic review and meta-analysis of randomized controlled trials. J. Glob. Antimicrob. Resist. 2023, 32, 88–97.
[CrossRef]
105. Montes-Andujar, L.; Tinoco, E.; Baez-Pravia, O.; Martin-Saborido, C.; Blanco-Schweizer, P.; Segura, C.; Silva, E.P.; Reyes, V.;
Cobo, A.R.; Zurdo, C.; et al. Empiric antibiotics for community-acquired pneumonia in adult patients: A systematic review and a
network meta-analysis. Thorax 2021, 76, 1020–1031. [CrossRef]
106. Choi, S.H.; Cesar, A.; Snow, T.A.C.; Saleem, N.; Arulkumaran, N.; Singer, M. Efficacy of Doxycycline for Mild-to-Moderate
Community-Acquired Pneumonia in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Clin.
Infect. Dis. 2023, 76, 683–691. [CrossRef]
107. Ashy, N.; Alharbi, L.; Alkhamisi, R.; Alradadi, R.; Eljaaly, K. Efficacy of erythromycin compared to clarithromycin and
azithromycin in adults or adolescents with community-acquired pneumonia: A Systematic Review and meta-analysis of
randomized controlled trials. J. Infect. Chemother. 2022, 28, 1148–1152. [CrossRef]
108. Al-Salloum, J.; Gillani, S.W.; Mahmood, R.K.; Gulam, S.M. Comparative efficacy of azithromycin versus clarithromycin in
combination with beta-lactams to treat community-acquired pneumonia in hospitalized patients: A systematic review. J. Int. Med.
Res. 2021, 49, 3000605211049943. [CrossRef]
Diagnostics 2023, 13, 1869 17 of 17

109. Lan, S.H.; Lai, C.C.; Chang, S.P.; Lu, L.C.; Hung, S.H.; Lin, W.T. Five-day antibiotic treatment for community-acquired bacterial
pneumonia: A systematic review and meta-analysis of randomized controlled trials. J. Glob. Antimicrob. Resist. 2020, 23, 94–99.
[CrossRef]
110. Schuetz, P.; Christ-Crain, M.; Thomann, R.; Falconnier, C.; Wolbers, M.; Widmer, I.; Neidert, S.; Fricker, T.; Blum, C.;
Schild, U.; et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract
infections: The ProHOSP randomized controlled trial. JAMA 2009, 302, 1059–1066. [CrossRef]
111. de Jong, E.; van Oers, J.A.; Beishuizen, A.; Vos, P.; Vermeijden, W.J.; Haas, L.E.; Loef, B.G.; Dormans, T.; van Melsen, G.C.;
Kluiters, Y.C. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients:
A randomised, controlled, open-label trial. Lancet Infect. Dis. 2016, 16, 819. [CrossRef] [PubMed]
112. Kyriazopoulou, E.; Liaskou-Antoniou, L.; Adamis, G.; Panagaki, A.; Melachroinopoulos, N.; Drakou, E.; Marousis, K.; Chrysos, G.;
Spyrou, A.; Alexiou, N.; et al. Procalcitonin to Reduce Long-Term Infection-associated Adverse Events in Sepsis. A Randomized
Trial. Am. J. Respir. Crit. Care Med. 2021, 203, 202. [CrossRef] [PubMed]
113. Evans, L.; Rhodes, A.; Alhazzani, W.; Antonelli, M.; Coopersmith, C.M.; French, C.; Machado, F.R.; Mcintyre, L.; Ostermann, M.;
Prescott, H.C.; et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit.
Care Med. 2021, 49, e1063. [CrossRef]
114. Barlam, T.F.; Cosgrove, S.E.; Abbo, L.M.; MacDougall, C.; Schuetz, A.N.; Septimus, E.J.; Srinivasan, A.; Dellit, T.H.; Falck-Ytter, Y.T.;
Fishman, N.O.; et al. Executive Summary: Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious
Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin. Infect. Dis. 2016, 62, 1197. [CrossRef]
115. Schuetz, P.; Bolliger, R.; Merker, M.; Christ-Crain, M.; Stolz, D.; Tamm, M.; Luyt, C.E.; Wolff, M.; Schroeder, S.; Nobre, V.; et al.
Procalcitonin-guided antibiotic therapy algorithms for different types of acute respiratory infections based on previous trials.
Expert Rev. Anti-Infect. Ther. 2018, 16, 555–564. [CrossRef] [PubMed]
116. Suijkerbuijk, Y.B.; Schaafsma, F.G.; van Mechelen, J.C.; Ojajärvi, A.; Corbiere, M.; Anema, J.R. Clinician-targeted interventions to
influence antibiotic prescribing behaviour for acute respiratory infections in primary care: An overview of systematic reviews.
Cochrane Database Syst. Rev. 2017, 9, CD012252. [CrossRef]
117. Long, W.; Deng, X.; Zhang, Y.; Lu, G.; Xie, J.; Tang, J. Procalcitonin guidance for reduction of antibiotic use in low-risk outpatients
with community-acquired pneumonia. Respirology 2011, 16, 819. [CrossRef]
118. Lhopitallier, L.; Kronenberg, A.; Meuwly, J.Y.; Locatelli, I.; Mueller, Y.; Senn, N.; D’Acremont, V.; Boillat-Blanco, N. Procalcitonin
and lung ultrasonography point-of-care testing to determine antibiotic prescription in patients with lower respiratory tract
infection in primary care: Pragmatic cluster randomised trial. BMJ 2021, 374, n2132. [CrossRef]
119. Rhee, C.; Mansour, M.K. Procalcitonin Use in Lower Respiratory Tract Infections. UpToDate® 2023 UpToDate, Inc. Available
online: https://www.uptodate.com/contents/procalcitonin-use-in-lower-respiratory-tract-infections/abstract/83 (accessed
on 28 March 2023).
120. Becker, K.L.; Snider, R.; Nylen, E.S. Procalcitonin assay in systemic inflammation, infection, and sepsis: Clinical utility and
limitations. Crit. Care Med. 2008, 36, 941–952. [CrossRef]
121. Schuetz, P.; Affolter, B.; Hunziker, S.; Winterhalder, C.; Fischer, M.; Balestra, G.M.; Hunziker, P.; Marsch, S. Serum procalcitonin,
C-reactive protein and white blood cell levels following hypothermia after cardiac arrest: A retrospective cohort study. Eur. J.
Clin. Investig. 2010, 40, 376–381. [CrossRef]
122. Moyer, M.W. New biomarkers sought for improving sepsis management and care. Nat. Med. 2012, 18, 999. [CrossRef] [PubMed]

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