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Review Article

Indian J Med Res 151, April 2020, pp 287-302

DOI: 10.4103/ijmr.IJMR_1678_19
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Community-acquired bacterial pneumonia in adults: An update

Vandana Kalwaje Eshwara1, Chiranjay Mukhopadhyay1 & Jordi Rello2,3

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1
Department of Microbiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education,
Manipal, Karnataka, India, 2Department of Critical Care, Vall d’Hebron Research Institute &
3
Clinical Research & Innovation in Pneumonia and Sepsis, Barcelona, Spain

Received September 30, 2019

Community-acquired pneumonia (CAP) is the prominent cause of mortality and morbidity with
important clinical impact across the globe. India accounts for 23 per cent of global pneumonia burden
with case fatality rates between 14 and 30 per cent, and Streptococcus pneumoniae is considered a major
bacterial aetiology. Emerging pathogens like Burkholderia pseudomallei is increasingly recognized
as an important cause of CAP in Southeast Asian countries. Initial management in the primary care
depends on clinical assessment while the hospitalized patients require combinations of clinical scores,
chest radiography and various microbiological and biomarker assays. This comprehensive diagnostic
approach together with additional sampling and molecular tests in selected high-risk patients should be
practiced. Inappropriate therapy in CAP in hospitalized patients lengthens hospital stay and increases
cost and mortality. In addition, emergence of multidrug-resistant organisms poses tough challenges in
deciding empirical as well as definitive therapy. Developing local evidence on the cause and management
should be a priority to improve health outcomes in CAP.

Key words Antimicrobial resistance - bacteria - CABP - community acquired pneumonia - diagnosis - management -
Streptococcus pneumoniae

Introduction respiratory tract infections (LRTIs)1. Among these, sub-

Community-acquired pneumonia (CAP) is Saharan Africa, Southeast Asia and South Asia have
the leading cause of mortality and morbidity with documented higher fatality. In 2016, 197.05 million
substantial clinical and economic impact. Although episodes (112.83-287.64) of pneumococcal pneumonia
several organisms are implicated with the disease, were reported worldwide and thus represented the
data on the pathogen distribution are not uniformly leading cause of LRTI morbidity and mortality.
represented across the countries. Several factors such Globally, mortality due to LRTI remained unchanged
as geographical region, age and study period influence from 2005 to 2015 although age standardized death
the incidence of CAP in adults. However, reliable and rates fell by 19.5 per cent1. In recent years, there has
consistent data over a prolonged period are available been a steady increase in the hospitalization rates
from only a few countries. Reports suggest nearly including intensive care units (ICU) due to CAP,
2.4 million deaths occur among all ages due to lower especially in the older population2. The case fatality

© 2020 Indian Journal of Medical Research, published by Wolters Kluwer - Medknow for Director-General, Indian Council of Medical Research
287
 288 INDIAN J MED RES, APRIL 2020

rate ranges from 2 to 20 per cent reaching up to 50 per characteristics. The laboratory test utilization practices,
cent in patients admitted to ICUs and varies between access to healthcare, guideline recommendations
healthcare settings, geographical region, patient for testing and extent of laboratory facilities might
categories and age3. This narrative review focuses on further influence the reported pathogen frequency.
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the bacterial CAP in immunocompetent adults with Despite the geographical disparities, S. pneumoniae
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special emphasis on existing modalities and gaps in remains a predominant pathogen globally in all ages.
diagnostics, optimum utilization of testing strategies, Staphylococcus aureus, Haemophilus influenzae,
and individualized therapy decisions with a focus on K. pneumoniae, P. aeruginosa, and atypical pathogens,
Indian scenarios. Legionella pneumophila, Mycoplasma pneumoniae
and Chlamydia pneumophila are other pathogens
Disease burden of community-acquired pneumonia
contributing to the majority of CABP aetiology. A
in India and Southeast Asia
subset of bacterial pathogens that are resistant to
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India contributes about 23 per cent of global multiple antimicrobial agents, sometimes referred as
pneumonia burden and 36 per cent WHO regional PES pathogens (Pseudomonas, Enterobacteriaceae,
burden in patients under five years4. Reliable estimates methicillin-resistant S. aureus), are of major concern
of disease burden are not available particularly for the due to challenging antimicrobial therapy20-22.
adult population. The sparse data for adults come from
In a systematic review from India, S. pneumoniae
tertiary care teaching hospitals using cross-sectional
was the predominant pathogen in CAP with the
studies5. A study from Mumbai reported that severe
pooled proportion of 19 per cent [95% confidence
CAP (SCAP) reached 19 per cent of all patients and
interval (CI): 12-26%; I2=94.5%; P<0.01]. Other
Streptococcus pneumoniae and Gram-negative bacteria
pathogens were M. pneumoniae [15.5% (1.1-
(Pseudomonas aeruginosa and Klebsiella pneumoniae)
35.5%)], K. pneumoniae [10.5% (1.6-24.0%)] and
had increased occurrence in severe pneumonia6.
L. pneumophila [7.3% (2.5-23.8%)]23. Putting
A recent review underscores the importance of
together data from all Asian studies, Peto et al24 reported
pneumococci in the invasive pneumococcal diseases
Gram-negative bacilli (GNB) in 13 per cent of
in India7. The reported case fatalities are between
hospitalized CAP, more in Southeast Asia and India,
14 and 30 per cent in all CAP patients and 47 per cent
increasing to 21.5 per cent in SCAP.
in SCAP. An overview of studies representing CAP in
India is presented in Table I. CABP pathogens with special relevance to India
and other tropical countries
The WHO global health estimates for 2016 shows
783,000 deaths due to LRTIs in Southeast Asia17. Aetiology of CABP shows variations in several
Comprehensive data on aetiology, clinical outcome tropical Asian countries posing challenges in diagnosis
and risk factors were reported by the Asian Network and management. Although S. pneumoniae was
for Surveillance of Resistant Pathogens between 2002 recognized as the most common aetiology of CAP in
and 2004 from eight Asian countries18. Pneumonia two systematic reviews, national and regional variations
Severity Index (PSI) categories 4 and 5 comprised exist23,24. In a systematic review, >10 per cent of cases
28.4 per cent of patients. Among hospitalized (62.1%) of CAP in Asia were attributed to Mycobacterium
patients, 9.4 per cent were admitted to ICUs. The overall tuberculosis25. Due to overlapping features of acute
mortality was 7.3 and 50.6 per cent among patients in respiratory distress syndrome (ARDS) and pneumonia,
PSI class 4 and 518. S. pneumoniae was the commonest several fever syndromes in tropics are initially assessed
pathogen implicated (29.2%), followed by atypical as CAP. Scrub typhus, leptospirosis, malaria and
pathogens in 25 per cent and Gram-negative bacteria dengue among others are important distractors in early
(K. pneumoniae, P. aeruginosa) in 22 per cent. Acute recognition of CAP25. B. pseudomallei, a soil bacterium
respiratory infections were the major contributors to and causative agent of melioidosis is an important
sepsis in a Southeast Asian multicentre study19. cause of CAP and sepsis in Thailand, India, Vietnam,
Malaysia and other Southeast Asian countries26-28.
Bacterial pathogens in community-acquired
B. pseudomallei was the second commonest pathogen
pneumonia
in hospitalized CAP as reported from Thailand27. In
Bacterial pathogens implicated in CAP India, several reports of melioidosis presenting as CAP
[community-acquired bacterial pneumonia (CABP)] exist, however, denote only a tip of the iceberg28. The
vary with geographic distribution and host lack of widely available standard tests and awareness
 ESHWARA et al: CAP IN ADULTS 289

Table I. Indian studies on community‑acquired pneumonia highlighting the geographical distribution, aetiology and diagnostic tests
Author Site Period Number Age Methods Pathogens Overall Mortality
(%) diagnostic (%)
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yield (%)
Para et al8 Kashmir 2013‑2015 225 All Blood culture Streptococcus 72 8
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adults Sputum culture pneumoniae (30.5)

Antigen detection Legionella (17.5)
Viral PCR Mycoplasma (7.2)
Chlamydia pneumophila (5.5)
Staphylococcus aureus (5.2)
Klebsiella pneumoniae (4.8)
Mycobacterium
tuberculosis (4.8)
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Pseudomonas aeruginosa (3.1)

Influenza viruses (15.4)
Nagesh Bengaluru 2012‑2014 122 All Sputum culture S. pneumoniae (15.6) 60.7 8.2
Kumar adults Blood culture K. pneumoniae (8.2)
et al9 Immunofluorescence Mycoplasma pneumoniae (7.4)
for IgM antibody Legionella (5.7)
against atypical Haemophilus influenzae (6.6)
bacterial and viruses S. aureus (3.3)
(Pneumoslide‑M P. aeruginosa (3.3)
assay)
Bin et al10 Bijapur 2008‑2010 50 Adults Sputum culture S. pneumoniae (16) 32 16
≥65 yr K. pneumoniae (6)
H. influenzae (4)
P. aeruginosa (4)
S. aureus (2)
Shah et al11 Kashmir 1998‑2000 100 All Sputum culture P. aeruginosa (9) 29 14
adults Blood culture S. aureus (6)
Transthoracic needle Escherichia coli (5)
aspiration K. pneumoniae (3)
S. pneumoniae (1)
Dagaonkar Mumbai NR 100 All Sputum culture S. pneumoniae (23) 58 9
et al6 adults Blood culture Chlamydia (11)
Urinary antigen H. influenzae (9)
Serology for atypical Moraxella (6)
bacteria Mycoplasma (5)
Legionella (3)
Klebsiella (3)
P. aeruginosa (2)
Chaudhry Delhi 2011‑2014 453 Adults Any respiratory M. pneumoniae (25.6) NR NR
et al12* and specimen Legionella (27.2)
children Legionella and
Mycoplasma culture
Urinary antigen
Serology
PCR
Prasad and Mangalore NR 165 All Sputum, BAL, other K. pneumoniae (29) 48 2.4
Bhat13 adults respiratory culture P. aeruginosa (18.1)
S. pneumoniae (13.1)
H. influenzae (4.8)
Sharma Pune 2010‑2012 85 All Sputum cultures K. pneumoniae (21.7) NR
et al14 adults S. aureus (15.2)
S. pneumoniae (12.9)
Contd...
 290 INDIAN J MED RES, APRIL 2020

Author Site Period Number Age Methods Pathogens Overall Mortality

(%) diagnostic (%)
yield (%)
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Acharya Mangalore NR 100 All Sputum cultures S. pneumoniae (31) 39 NR

et al15 adults P. aeruginosa (15)
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K. pneumoniae (13)
S. aureus (8)
Moraxella (8)
E. coli (8)
H. influenzae (5)
Menon Cochin 2009 145 All Sputum cultures S. pneumoniae (32.4) 76 NR
et al16 adults K. pneumoniae (20)
P. aeruginosa (8.9)
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E. coli (6.2)
*
Tests done only for atypical bacterial pathogens. NR, not reported; BAL, bronchoalveolar lavage

has led to clinical and laboratory oversight in correctly differ in their viewpoints on chest radiography (CR) in
diagnosing this condition. all cases of suspected pneumonia29,31, although studies
have found CR as a useful tool in primary care33.
Clinical diagnosis and assessment of the severity of
CAP In the settings where CR is not routinely available,
several clinical decision support system based on
CAP is suspected by acute symptoms such as
combinational symptoms and C-reactive protein
dyspnoea, cough and fever and presence of new focal
(CRP) may be considered. The diagnosis of CAP was
chest signs without other obvious cause, whereas new
strongly associated with elevated CRP and positive
pulmonary infiltrate on a chest radiograph is required
CR (P<0.001)33. Negative CR may not, however, rule
for a definite diagnosis29-31. Subgroups of patients as
out pneumonia as it may not be present if the patient
in elderly people, the clinical presentation can have
presents early. Risk for severity may be assessed by
less evident classical symptoms (may present with
CRB 65 in locations where urea testing is not available.
an altered state of consciousness, gastrointestinal
The measurement of oxygen saturation on room air
discomfort and fever may be absent) delaying the
using pulse oximetry is a simple non-invasive tool
diagnosis frequently.
endorsed in numerous guidelines to aid the assessment
RTIs are the most common reasons for unnecessary of CAP30. A study involving 2,923 patients of CAP
and inappropriate antimicrobial prescriptions in both managed in outpatient departments in Canada analyzed
primary and hospital settings, contributing significantly the oxygen saturation and its association with patient
to the development of antimicrobial resistance outcome and reported oxygen saturation <90 per cent
(AMR)32. Since a vast majority of CAP are managed was significantly associated with 30 days mortality34.
in primary care, it is essential for the primary care However, the physicians should adhere to the right
physicians to correctly identify and manage patients application of this test and use only the approved
with CAP. Management of CAP focuses particularly instruments for measurements.
on early identification of risk for severe disease and
In adult outpatient settings, the American College
early administration of the appropriate antimicrobial
of Chest Physicians has provided recommendations to
agent, not ignoring the risk of development of AMR.
rationalize the antibiotic use, reduce hospitalizations
Individual components of the history or physical
and improve outcome in patients presenting with acute
examination are not reliable in accurately diagnosing
cough for less than three weeks (Fig. 1)35 along with
pneumonia while the presence of several findings
diagnostic indicators (Table II)36.
assists in the clinical decision. Only a few clinical
scores have been developed to increase the likelihood SCAP is a progressive disease evolving from
of CAP diagnosis in primary care. These scores help a local to systemic infection with the spectrum of
ruling out bronchitis or upper respiratory infections. sepsis-related complications requiring ICU admission.
The Infectious Diseases Society of America/American In the management of CAP patients, assessment of
Thoracic Society (IDSA/ATS) and European guidelines severity is fundamental not only to assign the appropriate
 ESHWARA et al: CAP IN ADULTS 291
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Fig. 1. Summary of guidelines on the management of acute cough at primary care. CRP, C-reactive protein; CR, chest radiograph; PCT, procalcitonin.
Source: Refs 35, 36.

Table II. Diagnostic performance measures of indicator tests at primary care in the diagnosis of community acquired pneumonia
Specificity >80%* Positive LR >2.0* High diagnostic odds ratio*
Temperature >38°C Temperature >38°C Cough
Pulse rate >100/min Pulse rate >100/min Crackles
Crackles Respiratory rate ≥20/min Respiratory rate ≥20/min
Reduced breath sound Crackles Temperature >38°C
PCT >0.25 ng/ml and CRP >20 mg/l Pulse rate >100/min
Reduced breath sound
PCT >0.25 ng/ml and CRP >20 mg/l
*
Diagnostic performances for individual factors. PCT, procalcitonin; CRP, C‑reactive protein; LR, likelihood ratio
Source: Ref. 36

site of care but also to select empirical antibiotic and The mortality in SCAP may go up to 50 per cent39,
adjuvant therapy. During the assessment of pneumonia, however, a few studies have shown a decline in
it is crucial to identify organ dysfunctions and disease mortality presumably due to advancement in intensive
severity as even a mild dysfunction is associated with care management, adherence to treatment guidelines
10 per cent excess mortality37. and early administration of appropriate therapy40. In a
Predisposing factors contributing to SCAP have review article, Pereira et al41 narrated the comparative
been identified as increasing age, alcoholism, chronic benefits of several pneumonia specific severity scores
obstructive pulmonary disease (COPD), renal disease, in the management of CAP. The PSI and CURB 65
chronic heart disease and immunosuppression38. scores are good at predicting 30 days mortality but do
 292 INDIAN J MED RES, APRIL 2020

not assess for CAP complications which is an important 28.2 per cent of these samples47. Antibiotic exposure
step in the early stabilization of SCAP patients. The before LR sampling occurred in 84.8 per cent patients
latter has been better addressed by IDSA/ATS 2007 in another study, significantly reducing the culture
and SMART-COP scores29,42. Studies have identified yield (P<0.0001; odds ratio: 9.1; 95% CI: 4.1-22.4)48.
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delayed ICU admission as a short-term risk factor Further, culture return is influenced by the time to
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for mortality in CAP patients29,42. Besides, differing transport and processing of specimen and relative
epidemiology and aetiology of CAP in different abundance of oral flora. Interpreting positive cultures
geographical regions highlight the need for research would be problematic in situations where pathogens
with alternate clinical endpoints other than mortality are also known to be the colonizers of airway or in
alone37,43. mixed infections.
Microbiological diagnostics in CABP-bridging In Asian countries, detection of B. pseudomallei,
ideal and real with a quest to future diagnostics a common cause of severe pneumonia and sepsis,
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from expectorated sputum is a challenge due to

Respiratory infections are the most common
overgrowth by other commensals and the delayed
precipitating conditions leading to sepsis. The
growth of B. pseudomallei which may take three or
aetiological diagnosis of bacterial pneumonia
more days to grow in cultures. The prior exposure
supports early appropriate antimicrobial therapy and
to amoxicillin-clavulanic acid and fluoroquinolones
reduce mortality and morbidity. In the absence of a
to which this bacterium is susceptible, further
gold standard diagnostic test for CAP, establishing
reduces the culture yield in respiratory samples.
aetiological diagnosis fails in >50 per cent of patients
Inexperienced laboratory personnel might disregard
due to the challenges in identifying the implicating
the culture growth as non-fermenting GNB leading
pathogen in the laboratory44. According to REACH
to underreporting. In a study from south India,
multinational study, 35-67 per cent patients with CAP
the routine culture of expectorated sputum could
did not have microbiological diagnosis resulting in high
detect only one in six cases of polymerase chain
empirical antibacterial therapy45. Diagnostic testing in
reaction (PCR) confirmed melioidosis49. In the
patients with suspected pneumonia is driven mostly by
endemic regions, high index of suspicion, special
the type of care facility (inpatient, outpatient, ICU),
culture methods (enrichment culture) and prolonged
disease severity, access to healthcare and availability of
incubation of culture plates are essential in patients
clinically useful tests46. Several guidelines recommend
with risk factors for melioidosis.
microbiological testing based on clinical severity29-31.
Comprehensive microbiological assessment in CAP Analyzing cellular response in the expectorated
has shown to be a useful approach in antimicrobial specimen by Gram’s stain is a good tool to screen
stewardship. sample quality in CAP, however, the interpreter must be
aware of the other conditions displaying similar results
Diagnostic utility of sputum Gram’s stain and culture
as in acute exacerbation of COPD or acute/chronic
in CABP
bronchitis. Culture from these conditions shows
The yield of sputum cultures for bacteria in similar pathogens as CAP such as S. pneumoniae,
patients with suspected pneumonia has a variable H. influenzae or Moraxella50. Gram’s stain is variable
outcome and influenced by the quality of the in its sensitivity for early identification of aetiology.
specimen, subsequent analytical process and prior From a good-quality specimen, the sensitivity for
antibiotic therapy29. In elderly patients, the inability to the detection of S. pneumoniae and H. influenzae
expectorate good-quality sputum limits its usefulness. was 35.4 and 42.8 per cent, and specificity 96.7 and
Studies show varying reports on the culture requests, 99.4 per cent, respectively, when there was a single
quality and yield of sputum specimen. A study from or predominant morphotype (90%)51,52. Another
Brazil reported 78.8 per cent of patients of CAP study on good-quality sputum samples which was
presented with expectoration while only 33.6 per cent possible in 63 per cent of patients showed a diagnostic
of them were subjected to bacteriological tests. Despite sensitivity of 76 per cent for S. aureus, 79 per cent
productive cough, 45 per cent were unable to provide H. influenzae, 82 per cent S. pneumoniae and 78
a sample for testing or physician failed to order the per cent Gram-negative bacteria53. A recent meta-
tests. Only 13.5 per cent samples were satisfactory for analysis considering the diagnostic threshold of >50
analysis and aetiological agents were detected only in per cent for predominant morphotype reported a
 ESHWARA et al: CAP IN ADULTS 293

pooled sensitivity of 64 per cent for GNB, 72 per cent Antigen tests
for S. aureus and 78 per cent for H. influenzae. The
Urinary antigen testing (UAT) is a useful rapid
positive likelihood ratio was highest for GNB (37.49),
point-of-care (POC) test in diagnosing respiratory
followed by H. influenzae (21.08), S. aureus (16.27)
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infection caused by S. pneumoniae and L. pneumophila.

and least for S. pneumoniae (4.60)54. Besides poor to
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Guidelines from developed nations recommend UAT

moderate sensitivity, Grams stain is affected by lack of in moderate and severe grade CAP29,30. In a large
quality control tool and high interobserver variations European multicentre study, S. pneumoniae emerged
when observed by different technologists55. Gram’s as a predominant pathogen in CAP and 71 per cent of
stain is still a useful tool in the early recognition 916 patients with pneumococcal CAP was exclusively
of S. pneumoniae and H. influenzae pneumonia diagnosed by UAT with a sensitivity and specificity
in antibiotic-naïve patients in both outpatient and of 60 and 99.7 per cent, respectively61. Incremental
inpatient settings. In primary care, non-availability diagnosis of pneumococcal pneumonia in 43.8
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of the skilled microbiologist is another limitation for per cent was demonstrated in another study using
Gram’s stain utility. UAT. Authors demonstrated targeted antimicrobial
Invasive techniques to collect respiratory samples therapy in 8.6 per cent of all CAP with favourable
outcome62. The sensitivity of pneumococcal urinary
Several invasive techniques such as antigen (UA) did not decline despite prior antibiotic
thoracocentesis, transthoracic needle aspiration therapy63. Disease severity positively correlated with
(TNA) of infected lung site, bronchoscopic protected UA detection. A meta-analysis reported a pooled
specimen brush and bronchoalveolar lavage (BAL) sensitivity and specificity of 74 and 97.2 per cent in
are practiced in different clinical situations and diagnosing pneumococcal CAP64. Apart from urine,
severity states. Diagnostic thoracocentesis should empyema fluid was also found to be a useful sample
be attempted in patients with pneumonia and an for pneumococcal antigen test with a sensitivity and
associated pleural effusion although effusion occurs specificity of 71 and 93 per cent65.
in 40 per cent of patients. Despite poor sensitivity,
the bacterial organism when detected reflects an Legionella UAT has gained prominence due
accurate aetiology. However, published reports to the lack of alternate diagnostic strategies. UA
represent poor clinical relevance of the pleural is detected in 2-3 days after clinical symptoms
fluid culture with regard to therapy modifications appear66. Concentrating urine specimen increases the
and patient outcome56. To improve the disease sensitivity of Legionella UAT. Despite early initiation
ascertainment, pleural fluid should be additionally of specific treatment and direct impact on clinical
cultured into the commercial automated blood management, routine testing of Legionella may not
culture bottles wherein 21 per cent incremental influence outcome and cost benefit is debatable in low
increase in the yield is demonstrated57. TNA allows prevalence settings or in patients without some clinical
specimen collection directly from the infected focus features suggestive of legionellosis67. An introduction
in the lung without contamination by the upper of rapid POC test for the detection of B. pseudomallei
airway flora. Culture of TAN has shown varied antigen in any clinical specimen (whole blood has
sensitivities between 33 and 80 per cent58 and overall poor yield) has shown to be a useful tool in early
yield increased by combinational testing procedures. recognition of melioidosis. This test has a comparable
Culture of BAL demonstrated good sensitivity (80%) performance with PCR and special enrichment culture.
in the detection of bacterial pathogens in patients The high negative predictive value of this test [98.57%
who did not show improvement in the initial three (CI: 94.65 to 99.63%) 0.846; P<0.001] is an added
days of therapy59. In contrast, the low sensitivity is advantage to rule out this disease during the early
reported in studies involving subgroup of patients evaluation of SCAP as the antimicrobial therapy of this
who received antibiotics60. Early stratification of disease differs from the conventional CAP therapy68.
patients with a risk for severe pneumonia is valuable The universal UAT recommendations by CAP
in determining who would benefit from the invasive guidelines have prompted the evaluation of the
procedures for microbiological sampling. Although usefulness of these tests and the results are presented
invasive sampling increases the yield slightly as the recently69. The results indicate that the CAP guidelines
disease progresses in severity, the laboratory result show poor sensitivity in identifying patients with
might not be clinically relevant at the stage of sepsis. positive results. No clinical characteristics were
 294 INDIAN J MED RES, APRIL 2020

strongly associated with positive pneumococcal UATs, positivity rose from 9.5 (0-1 organ failure) to 15.6 per
while features associated with positive Legionella cent (≥2 organ failure) with increasing numbers of
UATs were hyponatremia, fever, diarrhoea and recent organ failure in a study72.
travel.
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Development of bacteraemia has been studied by

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Blood cultures in CABP several investigators in pneumococcal CAP. Varying

blood culture positivity has been shown reaching up to
Fever is a common symptom in pneumonia, and
45 per cent in CAP patients. Most studies demonstrated
reflex blood culture orders have been a common
an increase in the in-hospital mortality in bacteraemic
practice. IDSA/ATS guidelines29 recommend blood
pneumococcal pneumonia73. Analysis of Etiology
cultures in SCAP and those with risk for SCAP while
of Pneumonia in the Community (EPIC) study data
European Respiratory Society and European Society from the USA showed the presence of bacteraemia in
of Clinical Microbiology and Infectious Diseases 56.7 per cent of cases of CAP by S. aureus74. Another
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(ESCMID) recommend in all patients hospitalized with study demonstrated bacteraemia in 20 per cent of
CAP31. In uncomplicated CAP, blood cultures have a S. aureus pneumonia, and presence of bacteraemia
relatively low yield of 6-9 per cent. A recent study on independently contributed to a six-fold risk of
517 consecutive hospitalizations with CAP, 95 per cent mortality75. An Indian study on S. aureus bacteraemia
had blood cultures drawn resulting in overall positivity revealed respiratory source in 24 per cent of patients76.
of 8.5 per cent. SCAP showed 13.8 per cent positivity
while non-SCAP had only 7.9 per cent yield of blood In Asian and African countries, K. pneumoniae
cultures. Only 65 per cent of bacteraemic CAP had has been found to be increasingly associated with
organisms that were likely pneumonia related while bacteraemia CAP77,78. Increased mortality due to
35 per cent had bacteria implicated from non-pulmonary SCAP by this bacteria and detection of hypervirulence
source70. strains have been demonstrated. Pneumonia by
B. pseudomallei in the Asian region is associated with
The limitations of sputum cultures such as low a high rate of bacteraemia and mortality. Reports from
yield, difficulty in differentiating colonizers and India showed lungs as a common source of bacteraemic
pathogens and loss of viability of pathogens particularly melioidosis while 54 per cent of pulmonary melioidosis
S. pneumoniae and H. influenzae if specimen transport had bacteraemia79,80. In a Thai study, 56 per cent of
is delayed, might be partially overcome by blood bacteraemic melioidosis had pneumonia81.
cultures in SCAP. The blood cultures techniques
need special attention in developing nations such as Molecular tests
to collect appropriate volume and number of sets, The recent outbreaks such as pandemic influenza
entering the blood culture system with minimum delay and Middle East respiratory syndrome coronavirus
(<2 h) and immediate processing of positive signalled (MERS CoV) have largely contributed to the wider
bottles, all contributing to better yield in pneumococcal availability and renewed interests on the molecular
bacteremia71. With the high background resistance assays in CAP diagnosis. The nucleic acid tests (NAT)
and increasing occurrence of CAP by Gram-negative have several advantages as these detect low levels of
bacteria, it is appropriate to perform blood cultures in pneumonia pathogens, not affected by prior antibiotic
severe disease. Despite low yield, it is still beneficial to therapy and provide results within a clinically relevant
collect blood cultures in all hospitalized patients with time frame. Further, atypical bacterial pathogens
CAP. not routinely detected by conventional culture are
The microbial aetiology and bacteraemia are increasingly diagnosed by NATs82. In recent years,
independently associated with severity of illness and molecular techniques based on multiplex PCR are
sepsis in CAP38. Blood culture yield increases in severe developed to simultaneously detect and quantify
pneumonia needing ICU admissions and in those with multiple respiratory pathogens along with resistance
risk factors such as asplenia, chronic liver diseases, genes83. The NATs are generally customized to
individual healthcare settings providing an enhanced
leukopenia and alcoholism. In these situations,
aetiological diagnosis over routine culture and antigen
blood culture positivity goes up to 33 per cent72.
tests48,84.
Bacteria associated with SCAP such as S. aureus,
S. pneumoniae, Enterobacteriaceae and Pseudomonas Several commercial multiplex platforms are
are likewise responsible for bacteraemia. Blood culture available for comprehensive molecular testing of
 ESHWARA et al: CAP IN ADULTS 295

CAP pathogens including atypical bacteria and and geographical locations. The absence of antiviral
viruses. Curetis Unyvero, a cartridge-based PCR treatment for most of the identified viruses further
to detect 18 bacterial and one fungal pathogen, has impedes the test utilization.
shown enhanced yield over conventional culture
Sj32S5aMfaURMPpSpx6kqHsrJYCAzwc87vjF9AWfsygSxegOxz5e3FbD7ohHzTFC7/g1/iY6b1fgM1dwHV5bdUkgkLXb6GtqgJ2+

Biomarkers in CABP
(55 vs. 8.2%) in the diagnosis of severe nosocomial
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pneumonia. Short turnaround time (TAT) of 6.5 h Fundamental problems in establishing pneumonia
favours its usefulness in ICU settings85. This system aetiology using conventional methods have prompted
has been tested on BAL samples in ICU patients and the search for a biomarker in the bloodstream as a result
shown to increase pathogen detection and positive of the infection process in the lung. Two approaches,
predictive value in diagnosing Gram-negative to differentiate bacterial or viral aetiology of CAP and
bacteria with a sensitivity and specificity of 68.4 and predict the severity of the disease are of special interest
86 per cent86. Another multiplex PCR, Fast Track to researchers and care providers. In differentiating
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Diagnostics FTD-29.19, tests nine bacterial pathogens viral or bacterial aetiologies, proteins of acute phase
and has demonstrated more pathogen detection in 37 inflammation and signalling molecules are potential
per cent over 11 per cent by conventional methods indicators90,91. Cytokine regulatory network as a
in elderly patients87. Multiplexing several gene result of alveolar macrophage recruitment as first line
targets for detection of atypical pathogens has shown defence marks the basis of the immune response in lung
comparable performance with in-house individual pathologies. Only procalcitonin and C-reactive protein
PCRs in a study demonstrating overall 52 per cent are the most used biomarkers in clinical practice while
PCR positivity in patients suspected with atypical several others are fully investigated for their clinical
pneumonia88. utility.
The BioFire FilmArray Pneumonia panel plus A systematic review assessed the diagnostic value
is a recent Food and Drug Administration (FDA) of CRP in primary care and emergency department to
cleared rapid POC NAT to detect 18 bacteria rule in or rule out CAP92. At the cut-off value of CRP
(11 Gram-negative, 4 Gram-positive, 3 atypical,
≤20 mg/l, the pooled positive likelihood ratio (LR)
14 reported semiquantitatively), seven antibiotic
was 2.1 (95% CI: 1.8-2.4) and pooled negative LR
resistance markers and nine viruses causing
0.33 (95% CI: 0.25-0.43). The results did not produce
pneumonia and other LRTIs with a total TAT of 60
homogenous LR at the cut-off values of ≤50 and
min. A study comparing the investigational use only
>100 mg/l. Based on several randomized controlled
version of this test with standard of care (SOC)
trials and other studies, the National Institute for
methods such as culture and PCR on BAL samples
showed a positive and negative correlation of 96.2 Health and Care Excellence guidelines suggest not to
and 97.6 per cent. Depicted false-positive and false- use antibiotics routinely if CRP is <20 mg/l in patients
negative results by FilmArray was found in patients with symptoms of LRTI in primary care93. In patients
receiving antibiotics within 72 h and in those specimen admitted to ICUs, the diagnostic ability of CRP to
containing significant normal flora obscuring the identify bacterial pneumonia is only 0.64 by area under
pathogen in SOC cultures. Among the evaluable the curve (AUC)94.
patients, antibiotic modifications were achievable in PCT levels showed good sensitivity (84%) to
68 per cent patients89. differentiate mixed bacterial and viral pneumonia in a
Even after demonstrating satisfactory performance meta-analysis95. The specificity was 64 per cent when
and good analytical sensitivity, interpretations of viral pneumonia had a secondary bacterial infection.
molecular tests face the challenges of discriminating The discriminatory power of PCT to differentiate
pathogen from colonization for those organisms viral and bacterial pneumonia was better than CRP
forming a part of normal flora. Certain platforms (AUC 0.76)94. There was no association of PCT levels
providing semiquantitative results might be a useful with individual bacterial pathogens; however, the
solution in this regard. The wide pathogen spectra in value was higher in pneumonia by typical bacteria and
the commercial molecular tests are alluring for POC not atypical bacteria96,97. The science and practicality
tests but at the same time suffer setbacks due to high of other less important biomarkers are reviewed by
cost involved and the inability to customize the test a few others but none have shown a wide clinical
panel to individual patient settings, risk categories application98.
 296 INDIAN J MED RES, APRIL 2020

Comprehensive diagnostic approach and future such as length of stay, time to clinical resolution and
diagnostics antibiotic days/de-escalation time. A comprehensive
and schematic guide to diagnostics based on large
A variety of diagnostic tools targeting pathogens
studies on hospitalized patients is provided in Figure 2.
Sj32S5aMfaURMPpSpx6kqHsrJYCAzwc87vjF9AWfsygSxegOxz5e3FbD7ohHzTFC7/g1/iY6b1fgM1dwHV5bdUkgkLXb6GtqgJ2+

and biomarkers have gained prominence in the

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aetiological diagnosis of CABP while very few Recent advancement in sepsis research has added a
tests have been considered in well-designed clinical new dimension to the management of severe infections
outcome studies. Not any one test is likely to replace including CAP by precision medicine. Besides
another in the time to come but only to complement pathogen-specific diagnostics including rapid tests, a
each other to offer an overall betterment in the new approach is to understand the molecular endotypes,
clinically relevant yield. Pulmonary infections, being gene expressions and transcriptomic analysis. Blood
one of the greatest challenges to diagnostics, suffer microarray analysis has identified a few molecular
an inherent drawback of best sampling time and biomarkers that are expected to improve knowledge on
imK/icbKUHM2OIeJcBKnJRfjC8MfTw== on 06/17/2024

methods. Globally, CAP diagnostics face contrasting host response to infection and customize the therapy99.
situations in developed and developing nations. On one
Outcome of CABP and associated factors
hand, there is an advancement in syndromic and high
sensitivity detection methods while on the other hand, CAP is identified as the commonest cause of sepsis
there is a lack of healthcare access, non-availability and septic shock in adults. GenOSept study from Europe
of diagnostic tests including RDTs in the developing showed ICU mortality of 19 per cent and independent
nations where highest disease burden and AMR are factors associated with outcome were APACHE II
prevalent. Most of the management guidelines are score, haematocrit, mechanical ventilation and blood
based on data from developed nations and are mostly pH. S. aureus was related with SCAP fatality100. Another
country/region specific while there is a paucity of study on non-streptococcal SCAP demonstrated shock
high-quality data from developing nations. As no at admission and acute kidney injury as significant risk
single test detects all pathogens in a given setting, the factors for mortality while combined antibiotic therapy
approach of customized sampling and testing should and early antibiotic therapy within three hours were
be the priority. Moreover, any approach should be associated with a favourable outcome. Legionella and
based on the reliable baseline data, local epidemiology, P. aeruginosa were less likely to be covered empirically
and type of healthcare settings and appropriate risk and hence showed worse outcome101. The association of
stratification of the patients with CAP. Management microbial aetiology with mortality is less understood.
protocols should target alternate outcome priorities Gram-negative bacterial pneumonia and bacteraemia

Fig. 2. Microbiological tests that may be adapted for comprehensive sampling strategy in community acquired pneumonia-based on disease
severity and underlying risk in hospitalized patients. ICU, intensive care unit; PCR, polymerase chain reaction.
Source: Refs 29, 38, 54, 58, 59, 82, 85, 86, 88.
 ESHWARA et al: CAP IN ADULTS 297

were found to be independent risk factors for mortality, constrained settings. Combined clinical scores and
and S. aureus pneumonia was shown to be associated risk for MDROs should be used before the selection
with more organ failure72. of empirical therapy in selected situation105. For that, a
careful assessment of risk before initiation of empirical
Sj32S5aMfaURMPpSpx6kqHsrJYCAzwc87vjF9AWfsygSxegOxz5e3FbD7ohHzTFC7/g1/iY6b1fgM1dwHV5bdUkgkLXb6GtqgJ2+

Optimum therapy and individualization

therapy could improve outcome.
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Inappropriate initial antimicrobial therapy (IIAT)

The duration of treatment of CAP has gained
in patients with CAP is associated with longer hospital attention in the era of AMR. International guidelines
stays, increased hospital costs and mortality102. recommend a minimum five days of therapy and early
Prediction of likely pathogen and knowledge of discontinuation based on clinical stability criteria29,31,
local susceptibility patterns is the key to initiate but the information regarding the real clinical practice
appropriate therapy (IAT). Adherence to guidelines is minimal in the literature. A RCT endorsed the
has shown better outcomes in American and European short duration therapy based on clinical stability
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studies. Guidelines tailored to national and regional criteria in non-ICU hospitalized patients without
contexts are essential considering the differences in any adverse outcome106. A longer duration therapy is
socio-economic factors, healthcare systems, local considered for extrapulmonary involvement, delay
healthcare access, variations in pathogen occurrence in establishing aetiological diagnosis and pulmonary
and susceptibility. Data on the common CAP complications29,31.
pathogens and susceptibilities are lacking from the
developing world. In India, due to the high overall Immunization in CABP
prevalence of Gram negative bacterial infections Given the increased mortality and morbidity of
including pneumonia, the CAP national guidelines CAP, particularly in older adults, Advisory Committee
suggest empirical therapy with β-lactam-β-lactamase on Immunization Practices (ACIP) recommends107
inhibitor combinations combinations along with routine use of pneumococcal vaccines for all adults
macrolide in hospitalized CAP. The empirical use of ≥65 yr and adults >18 yr with risk factors. Two vaccines,
fluoroquinolones is generally avoided due to the high PCV 13 and PPSV23, have been used with varied
tuberculosis incidence103. coverage between the countries. In line with ACIP,
Association of Physicians of India (API) recommends
In India, high prevalence of tuberculosis and
pneumococcal and influenza vaccines for all adults
noteworthy proportion presenting as CAP points
>18 yr in India108. However, data on vaccine coverage
towards the urgent need of locally relevant
and health benefits are lacking. The clinical benefit of
management guidelines. Decisions to cover atypical
adult pneumococcal vaccination is conflicting109,110.
pathogens empirically are controversial among The lack of clinical benefit might be due to the shift in
international guidelines. A systematic review from pathogen occurrence and thus showing a null effect on
China showed Mycoplasma as a predominant CAP all cause pneumonia outcomes. Despite controversies,
pathogen in adults104. Following the global reduction in it is prudent to administer the vaccine to high-risk group
drug-resistant S. pneumoniae (DRSP), it is prudent to use adults given the benefits and safety of the vaccine.
β-lactam antibiotics as empirical therapy in hospitalized
patients. Analysis of global data identified asthma, Conclusions
liver disease and non-cystic fibrosis bronchiectasis as CABP contributes to significant healthcare burden
independent risk factors for DRSP. Another determinant with higher impact on the developing countries. Lack
of IIAT is the local prevalence of multidrug-resistant of appropriate and rapid diagnostics delay the care
organisms (MDROs). However, the health benefit of adding to the adverse outcomes. Aetiological variations
IIAT using broad spectrum and last resort antibiotics is are driven by the geographical regions, climate,
a double edged sword. The risk of MDROs increases environmental factors, AMR, quality of healthcare and
with prior hospitalization, antibiotic exposure and test availability. The transition towards resistant GNB
the presence of MDRO in the local environment. The infections challenges the therapy choices. Clinical
mere isolation of easily cultivable MDROs such as and diagnostic decision support systems should be
methicillin-resistant S. aureus, K. pneumoniae and P. developed to assist the risk stratification of patients
aeruginosa may not always indicate disease but might and utilize the laboratory tests optimally. Knowledge
mask the isolation of S. pneumoniae or prevent further of endemic pathogens of CAP will further clarify the
workup on other atypical/viral pathogens in resource management pathways.
 298 INDIAN J MED RES, APRIL 2020

Acknowledgment: Authors thank Dr Joao Coimbra, Internal 11. Shah BA, Singh G, Naik MA, Dhobi GN. Bacteriological
Medicine Physician, Sao Joao Hospital, Porto, Portugal, for his and clinical profile of community acquired pneumonia in
helpful comments on the manuscript. hospitalized patients. Lung India 2010; 27 : 54-7.
12. Chaudhry R, Valavane A, Sreenath K, Choudhary M,
Sj32S5aMfaURMPpSpx6kqHsrJYCAzwc87vjF9AWfsygSxegOxz5e3FbD7ohHzTFC7/g1/iY6b1fgM1dwHV5bdUkgkLXb6GtqgJ2+

Financial support & sponsorship: The study was Sagar T, Shende T, et al. Detection of Mycoplasma
Downloaded from http://journals.lww.com/ijmr by HqANVXLJBTa/LZllVlNtExDcKk5+KxZ8e7ym37mFxA+WMXju5wmL

funded in part by Centro de Investigacion Biomedica en Red de pneumoniae and Legionella pneumophila in patients having
Enfermedades Respiratorias (CIBERES), Institute of Health Carlos community-acquired pneumonia: A multicentric study from
III, Madrid, Spain. New Delhi, India. Am J Trop Med Hyg 2017; 97 : 1710-6.
13. Prasad P, Bhat S. Clinicomicrobiological study of
Conflicts of Interest: Dr Rello served in the speaker’s bureau community-acquired pneumonia. Lung India 2017; 34 : 491-2.
or consultant for Pfizer, Anchoagen, and ROCHE. The remaining
14. Sharma R, Deoskar R, Bargaje M, Kumar P, Agarwal Y. A
authors have no conflicts of interest to declare.
study of etiological and clinical profile of community acquired
pneumonia in a tertiary care hospital in Western India.
imK/icbKUHM2OIeJcBKnJRfjC8MfTw== on 06/17/2024

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For correspondence: Dr Vandana Kalwaje Eshwara, Department of Microbiology, Kasturba Medical College, Manipal,
Manipal Academy of Higher Education, Manipal 576 104, Karnataka, India
e-mail: [email protected]