Ravindran
C, MD*, Jyothi E, MD**
* Professor of Pulmonary
Medicine & Dean, Govt. Medical College ,
Kozhikode , Kerala
** Assistant Professor
Dept. of
Pulmonary Medicine, Govt. Medical College ,
Kozhikode , Kerala
Abstract
Pneumonia is always diagnosed on the basis
of signs and symptoms, supported by demonstrable
radiographic infiltrate. But certain situations warrant an etiological diagnosis which is mostly
by microbiological intervention. However these tests are not always helpful
especially when the patient was put on an initial antibiotic therapy or when
atypical organisms or rarer organisms cause the pneumonia. Common tests are not routinely used due to low yield as
well as infrequent positive impact on management decisions. Even though there
is disagreement among experts about the composition of the diagnostic
investigations for pneumonia; a well-chosen evaluation can support a diagnosis
of pneumonia and identify a pathogen. Microbiological diagnosis is also
important for epidemiological purposes. Without the accumulated information
available from these culture results, empirical antibiotic recommendations are
less likely to be accurate. Newer culture methods and molecular technique has been evolved which
offers specific diagnosis that too in a shorter time frame. A well-chosen,
individually tailored evaluation can offer a lot of information to support the
diagnosis of pneumonia.
Keywords: Pneumonia, Chest imaging, Molecular
techniques, High resolution CT, Ultrasonography
Introduction
Pneumonia is
always diagnosed on the basis of suggestive signs and symptoms, supported by demonstrable radiographic infiltrate. Routine diagnostic
tests to identify an etiologic diagnosis are optional for outpatients with
community acquired pneumonia (CAP). In many cases of mild-to-moderate CAP, the
physician is able to diagnose and treat pneumonia based solely on a medical
history and physical examination. The patient's history is an important part of
making a pneumonia diagnosis. Patient’s history should include the report on
smoking, alcohol or drug abuse, exposure to occupational risks, recent travel
and exposure to people with infections including tuberculosis. Physical signs
on examination such as impaired note, abnormal breath sound, crackle or pleural
rub and findings of pleural effusion are all indicative of pneumonia.
Microbiological data is not
always sought for the initial diagnosis of pneumonia. There is disagreement
among experts about the composition of the diagnostic investigations for
pneumonia, but a well-chosen evaluation can support a diagnosis of pneumonia
and identify a pathogen. The yield from routine use of common investigations
like blood and sputum culture is usually low and a positive impact on the
treatment of the patient is unlikely. But culture reports can have major impact
in the treatment of individual patient. Microbiological
diagnosis is also important for epidemiological purposes. Along with antibiotic
susceptibility pattern, etiologic diagnosis is useful for developing treatment
guidelines. The present pneumonia guidelines are based on culture results and
sensitivity patterns from various studies. Without the accumulated information
available from these culture results, empirical antibiotic recommendations are
less likely to be accurate.
The most clear-cut indication for extensive diagnostic
testing is in the critically ill CAP patient. In hospitalized patients, it is
difficult to diagnose pneumonia, as the patients may be having similar symptoms
including fever and abnormal X-rays. Moreover the sputum and blood culture from
these patients may grow organisms, which may not be the causative agent for
pneumonia. Diagnosis becomes all the more difficult in pneumonia due to
atypical organisms, rare organisms and new and emerging pathogens. These
situations warrant newer methods of diagnosis such as serology and molecular
techniques.
The general recommendation1
is to encourage diagnostic testing in situations where the result is likely to
change management decisions and when the diagnostic yield is thought to be greatest.
Because of much emphasis on clinical data, a variety of diagnostic tests that
may be accurate but the results of which are not available within a time frame
are not recommended.
This article reviews
various investigations in the diagnostic work up of pneumonia giving special
attention to include newer techniques like molecular methods.
Microbiological
diagnosis of Pneumonia.
The role of microbiologic studies in determining the
etiology of pneumonia is questionable because of the lack of rapid, accurate,
easy and cost-effective methods which can be obtained before starting
treatment. Even in randomized controlled trials, the cause of community
acquired pneumonia is determined in only 20- 40% of cases2. But in a
study by Johansson N et al, the microbial etiology of community acquired
pneumonia could be identified in up to
67% of the patients by combining PCR based and conventional methods3.
Careful correlation of culture and smear result with clinical and radiological
finding is important in arriving at an etiological diagnosis of pneumonia (Table-1).
Pneumonia
|
Common
Organisms
|
Community Acquired
Pneumonia
|
S.pneumoniae,
H.influenzae, M.catarrhalis, M.pneumoniae, Respiratory Viruses.
|
Hospital acquired
Pneumonia
|
Early
HAP: S.pneumoniae, H.influenzae, Methicillin susceptible S.aureus. (MSSA),
Antibiotic sensitive enteric gram negative bacilli.
Late
HAP: MRSA, P.aeruginosa, Klebsiella pneumoniae, Acinetobacter species, Legionella
pneumophila.
|
Ventilator
Associated Pneumonia
|
Early VAP:
S.pneumoniae, H.influenzae, S.aureus(MSSA)
Late VAP:
P.aeruginosa, Enterobacter species, Acinetobacter species, MRSA
|
Pneumonia in the
Immunocompromised.
|
M.tuberculosis,
P.jiroveci, Toxoplasma gondii, Nocardia sp.,Cytomegalovirus,Aspergillus
fumigatus .
|
Table-1: Etiological agents causing pneumonia
The expectorated sputum is the least invasive but the most
contaminated specimen. The quality of expectorated or induced sputum is
important for obtaining a positive gram stain or culture report. To get a good
sputum specimen for culture the patient should be instructed to breathe deeply
and cough from deep down in the lungs. Mouth should be rinsed with water before
obtaining the specimen to reduce oral contamination. Ideally the sputum sample
should be collected before the patient is started on empiric antibiotics.
The initial cytologic examination provides the quality of
the sputum and its suitability for culture. The presence of numerous
polymorphonuclear leucocytes (>25) and the number of squamous cells less
than 10 per low power magnification field is indicative of a good specimen for
bacteriologic evaluation.4 The presence of numerous squamous cells
indicates that the specimen is derived from upper respiratory tract.
The other specimens from the lower respiratory tract include
tracheal aspirate, bronchial washings, bronchioalveolar lavage, protected
specimen brush samples, bronchial biopsy, trans-tracheal aspirate, lung
aspirates and lung biopsy specimens.
Another important
non-invasive method to retrieve specimen for obtaining microbiological
diagnosis is induced sputum. Sputum induction is done by giving nebulization
with hypertonic saline, after proper hydration of the patient. The earliest
studies on induced sputum were in the cytologic diagnosis of lung cancer and the
diagnosis of pulmonary tuberculosis5. The role of induced sputum at
present is mainly for microbiological diagnosis in patients unable to
spontaneously produce sputum, especially children and immunosupressed patients
with pneumocystis jiroveci pneumonia6. In a study by Lahti E,
involving 101 children, aged 6 months to 15 years, good quality sputum specimen was obtained in
76 children and a positive result was obtained in 90% of specimens7.
Gram Staining
Gram staining originally devised by Hans Christian Gram
more than a century ago, is the standard method used for identifying
micro-organisms even today.8 The commonly seen organisms in gram
stained smears include Streptococcus pneumoniae (gram positive oval or lancet
shaped diplococci), Haemophilus influenzae (small pleomorphic gram negative
bacilli) and Moraxella catarrhalis (gram negative diplococci).9 In
nosocomial pneumonia, the infection is usually polymicrobial, and Staphylococcus aureus, Pseudomonas
aeroginosa, Enterobacter species and Klebsiella pneumonia are the commonly
identified organisms.
.
Acid Fast Staining
Examination of stained smear for acid fast bacilli (AFB) is
the most rapid and inexpensive method for detecting Mycobacterium tuberculosis.
The bacteriological examination of expectorated sputum for AFB should be done
in all patients with pneumonia especially in developing countries.
M.tuberculosis is typically a slightly curved or straight rod shaped microbe. (Fig-1)
It is 1-4mm in length and 0.3-0.6mm in diameter9. M. tuberculosis can
be stained with carbol fuchsin (Ziehl Neelsen or Kinyoun) and fluorochrome
(Auramine Rhodamine) stains. Recently most of the modern laboratories use the
fluorochrome staining method. In this staining method mycobacteria appear as
bright yellow rods against an inky black background. This is much easier to
perceive than the red- blue contrast of Ziehl- Neelsen staining. Auramine
Rhodamine staining is more sensitive than ZN staining, especially in
paucibacillary cases 10 and the specificity is similar11.
Special staining
Even though gram staining and traditional culture methods
are used routinely for the microbiological diagnosis of pneumonia, special
staining methods are essential for the isolation of organisms in varying
clinical situations.KOH preparation of sputum for elastin fibres is a sensitive
test for the diagnosis of necrotising pneumonia12. In intubated
patients also, the presence of elastin fibres in KOH added bronchial washings is
diagnostic of necrotizing pulmonary infection13. KOH preparation is
also useful for identifying fungi in respiratory specimens. The KOH will clear
the cellular debris and will make the fungal hyphae and spores more apparent.
Calcofluor white is a nonspecific fluorochrome stain that
binds to fungi and Pneumocystis
jiroveci.14 Fungal and parasitic organisms appear fluorescent bright
green or blue. Initially it was used for staining fungal hyphae, but now it
used as a rapid and inexpensive stain to detect P. jiroveci. The sensitivity
for diagnosing P.jiroveci in expectorated sputum is less compared to bronchial
washings and other invasive specimens.15
Modified Grocott Gomori methenamine silver stain is used
for staining Pneumocystis jiroveci cysts and Giemsa staining is used to stain
the trophozoites. Pneumocystis is rarely detected in expectorated sputum. Either
induced sputum or bronchial lavage specimens are required to diagnose
Pneumocystis jiroveci infection.
Sputum Direct
fluorescent antibody is a rapid method for the diagnosis of respiratory
pathogens. Prior to the advent of PCR, DFA test was considered as a rapid
diagnostic method for Bordetella and Legionella infections. The sensitivity of
DFA for Legionnairs disease is less compared to PCR and culture. So DFA testing for Legionella is not
routinely done for diagnosis as highly sensitive tests like PCR and Legionella
urinary antigens are available. Direct fluorescent antibody test requires
substantial expertise for interpretation of results. DFA tests for P. Jiroveci
are also available. In a study by Metersky ML et al it was found that there was
no much difference between expectorated and induced sputum when DFA was used
for the diagnosis of PJP.16
Culture Methods
Traditional culture methods for microbiological diagnosis
are slow, the sensitivity is low and the result may be influenced by prior
antibiotic therapy. So it is not possible to treat pneumonia based on culture
results. Over the past several decades, empiric
broad spectrum antibiotics are the accepted clinical practice in treating
pneumonia. But it is recommended that before starting the patient on empiric
therapy a sputum sample should be sent for culture and sensitivity. In a study
by Rello et al, positive microbiological test resulted in treatment
modification in 41.6% of patients including 5% of patients in whom the initial
antimicrobials were ineffective against the isolated organism.17
Another advantage of obtaining a positive microbiology diagnosis is to convert
the broad spectrum to narrow spectrum therapy. De-escalation of therapy will
help in controlling antibiotic prescription, minimizes the emergence of drug
resistance and reduces the treatment cost18
Traditionally sputum culture is done on the following
media- blood agar, chocolate agar and MacConkey agar. After assessing the
quality of sputum after initial cytologic examination a purulent portion of the
sputum sample should be inoculated into culture plates. When there is a
significant growth of organism, sensitivity tests should also be done. Specialized
culture media are required for atypical organisms like Legionella and
Mycoplasma. Legionella grows on buffered charcoal yeast extract (BCYE).
Incubation up to 10 days is required for the isolation of the organism and
hence culture for Legionella is not done routinely. If fungal infection is
suspected sputum should be cultured on Sabaraud’s agar.
For the detection of Mycobacterium tuberculosis both
conventional and rapid culture methods are available. Conventional culture
media like Lowenstein- Jensen medium will require up to 6 weeks for obtaining a
positive culture. (Fig-2) The available rapid culture methods for
M.tuberculosis are BACTEC culture medium, Mycobacterial Growth Indicator Tube
(MGIT), Septi check AFB and MB/Bact system. These methods will take 1-2 weeks
for a positive culture report.
Until now bacterial etiology was considered in most
patients with pneumonia, but in recent years respiratory virus has been recognized
as an important cause of pneumonia.3 Tissue culture was the gold
standard for the diagnosis of viral pneumonia, but not routinely done now for
diagnosis of viral pneumonia, because of the significant advancement of various
rapid diagnostic methods.
Blood culture
Blood cultures are
used to identify the organism that caused pneumonia and guide the treatment.
Guidelines from the Infectious Disease Society of America and the American
Thoracic Society recommend two blood culture samples for all patients admitted
to the hospital with pneumonia. The overall yield of blood culture is below
20%. In a study by Campbell SG et al the rate of modification of treatment
based on blood culture reports was only 1.97%19. In another recent
study by Abe T et al, a positive blood culture was obtained in 3.7% and
resulted in change of antibiotics in only 2.4%20. In a study by
Waterer GW et al, the yield of positive blood culture increased with pneumonia
severity index (PSI) grade, increasing to 26.7% in PSI grade V and resulted in
a change in antibiotic treatment in 20.0% of patients with grade V21.
So to reduce expenditure and to preserve resources it is recommended to
restrict blood culture to high risk patients.
Urinary Antigen
Immunochromatogrphic tests that detect pneumococcal and
legionella antigen in urine is a significant advancement in the diagnosis of
these 2 pathogens. The advantage of this test is that, the results are not
modified by prior antibiotic treatment. It is a rapid and non invasive test for
early diagnosis of etiologic agent. Studies in adults have shown a sensitivity
of 70% and specificity of 89.7% for the diagnosis of pneumococcal pneumonia22.
But in children, sensitivity and specificity is less in a study by Dominguez et al23. The disadvantage of
urinary antigen is the cost and the lack of an organism for drug susceptibility
testing. The test will be positive for several weeks to months after the
illness. In a study by Smith MD et al in
adults with community acquired pneumonia, comparing PCR with urinary antigen
for the diagnosis of Streptococcal pneumoniae, it was found that urinary
antigen test was positive in 51 of 58 bacteremic cases whereas PCR was positive
only in 31 cases24. In 77 patients with nonbacteremic pneumonia,
urinary antigen was detected in 21(27%) patients compared to a positive PCR in
6 (8%) patients.
Legionella urinary antigen is 76% sensitive and > 90%
specific for infections caused by Legionella pneumophila serogroup-125.(
Table- 2) The major advantage is the rapidity of the test compared to culture,
direct fluorescent antibody and serology. Legionella urinary antigen detection
is not recommended as a routine investigation for hospitalized patients with
community acquired pneumonia, as narrowing antibiotics spectrum based on the
results has a higher risk of clinical relapse.26
|
Organism
|
Sensitivity%
|
Specificity%
|
|
|
0-58
|
>90
|
|
Legionella pneumophilia-Serogroup-1
|
76
|
>90
|
Table- 2:
Urinary Antigen detection for CAP25
Nucleic Acid
Amplification Tests
The development of nucleic acid amplification tests is a
major development providing an etiologic diagnosis in respiratory infections.
These investigations help in rapid and efficient identification of etiologic
agents in pneumonia. It may eventually help in pathogen directed therapy at the
time of starting initial antibiotics.
Polymerase Chain Reaction (PCR) detects microbial nucleic
acid from cultured sample or direct respiratory specimens. DNA extraction is
done from the respiratory sample and the target gene is amplified. There will be exponential amplification of
target gene. These are then identified by gel electrophoresis and DNA
sequencing.
The major advancement in PCR has been the multiplex PCR. It
is a variant of PCR which enables simultaneous amplification of many targets in
one reaction by using more than one pair of primers, so that multiple
respiratory pathogens can be identified in a single test27. It was
first described by Chamberlain in 1988. In a study by Templeton et al , on 358
respiratory samples over one year period, respiratory virus were detected by
viral culture in 67 (19%) samples and by
multiplex PCR in 87 (24%) samples showing that PCR was sensitive in detecting respiratory
virus than culture.27
Real time PCR combines the standard PCR method with
fluorescent probe detection of the amplified product in the same reaction
vessel28. Since the amplified product detection is also done
simultaneously, results can be obtained very fast, so that specific treatment
decisions can be done based on the results. The sensitivity and specificity of
real time PCR is equivalent to that of conventional PCR. Real time PCR can also
be used to detect the DNA quantitatively and thus will be able to differentiate
between colonization and infection. In a study on 86 non-HIV immunocompromized
patients 17 were diagnosed as having Pneumocystis pneumonia. Induced sputum was obtained from the patients
and it was evaluated for the presence of P.jiroveci DNA using conventional PCR
and real time PCR. Conventional PCR had a high false positive rate of 46.4% as
it was positive in patients with colonization also29. Concentration
of DNA detected by real time PCR was significantly higher in Pneumocystis
patients than in colonizers.
PCR is not recommended for the diagnosis of pneumococcal
pneumonia as currently available PCR methods lack sensitivity and specificity
and there are no FDA approved PCR tests for S. pneumoniae (Table-3). For the
diagnosis of M.pneumoniae the sensitivity of PCR is less compared to serology30.
But the advantage over serology is that the results can be obtained in a few
hours.
|
Study
|
PCR
|
Culture
|
|
Massimo Resti et al
|
45(15.4%) of 292
|
11(3.8%) of 292
|
|
Deng J et al
|
32 of 176 (S.pneumoniae)
29 0f 176 (H. Influenza)
|
7 of 176
23 of 176
|
|
Rosario Menedez et al
|
41 of 184(S.pneumoniae-blood)
|
7 of 184
|
|
Allin Uskudar Guclu
|
67 0f 107(62.6%)
|
33 0f 107(31%)
|
|
Mervat Gamal Eldin Mansour
( Nosocomial pneumonia)
|
19 of 25 (76%) endotracheal aspirate
17 of 25 (68%) blood
|
6 of 25(24%)endotracheal aspirate
2 of 25(8%) blood
|
|
Templeton KE et al(virus)
|
87 0f 358(24%)
|
67 of 358 (19%)
|
Table-3: Comparative outcome of PCR and culture in
community acquired pneumonia 31, 32, 33, 34
For the diagnosis of tuberculosis by PCR, FDA approval has
been obtained, and is commercially available. It is most useful in patients
with positive acid fast smears. A negative PCR in a smear negative patient will
not rule out tuberculosis. Majority of PCR for M.tuberculosis detect
Mycobacterium tuberculosis complex and do not differentiate the species within
the complex. Halse TA et al was able to differentiate the species based on a
real time PCR method35. Many novel multiplex real times PCR have
been developed for the differentiation of Mycobacterium tuberculosis complex
strains36. Compared to the conventional and rapid culture methods
PCR can provide the results in a few hours.
The area where PCR has greatest impact on pathogen
identification in pneumonia is in the identification of respiratory viruses.
Viruses are usually neglected cause of community acquired pneumonia as they are
difficult to isolate and treatment with anti-viral agents are not routinely recommended.
However recently there had been few viral epidemics like Hantavirus in New Mexico , Severe Acute Respiratory Syndrome (SARS) in Asia , and the world wide H1N1 epidemic of 2009, where an
etiological diagnosis was important clinically and epidemiologically.37
At present PCR is the most sensitive diagnostic method for
respiratory viruses. Reverse transcriptase (RT-PCR) is used to detect RNA
viruses. Reverse transcriptase enzyme is used to synthesize a complimentary
strand of DNA from RNA, and this DNA is used as the template in PCR assay.
In a study of community acquired pneumonia in which PCR for
viruses, Legionella, Mycoplasma and Mycobacterium tuberculosis, and urinary
antigen for S pneumoniae and Legionella pneumophila serogroup 1, a microbial etiology
was obtained in 67%.3 An etiologic diagnosis was obtained in 89% of
patients in whom all diagnostic methods were applied. In this study viruses were the second most
common etiologic agent after S pneumonia. So by combining PCR with traditional
diagnostic method, viruses are more frequently being recognized as etiologic
agent of community acquired pneumonia.
The major problem with PCR assay is the risk of false
positive results. This can result from contamination by exogenous material or
by detection of colonizing organisms as a result of the extreme sensitivity of
PCR assay.
Serology
Serologic tests may be useful to establish the cause of
pneumonia when the causative agents are difficult to isolate. But a single
antibody titre is not enough for the microbiologic diagnosis. A four fold or greater rise in titre between
acute and convalescent sera is required for the diagnosis. So it is not useful
in the initial antibiotic selection for treatment. The antibodies may persist
for months or years after an initial infection in Legionella infection. So a
single titre of 1:256 or higher may reflect a prior Legionella infection.
Serology tests may be useful for the epidemiologic diagnosis. The commonly
diagnosed infections by serology are L.pneumophila, C.psittaci, M.pneumoniae,
C.burnetti and F.tularensis. Serologic tests may also be useful in the
retrospective diagnosis of infections due to Influenza A and B, Respiratory
syncytial virus, adenovirus and parainfluenza virus.
Levels of IL-1β and IL-8 in bronchoalveolar lavage fluid
(BALF) are one of the strongest markers investigated for accurately identifying
VAP. Based on this, it is possible to reduce unnecessary antibiotics in
suspected VAP patients, but this requires further validation in larger
populations38. Mid-regional pro-atrial natriuretic
peptide (MR-proANP) and C-terminal pro-atrial vasopressin (CT-proAVP)
estimation are the new and emerging tools for the prediction of short-term and
long-term risk stratification of patients with CAP.39
Invasive Diagnostic
Procedures
Routine diagnostic procedures
are used to establish the diagnosis of pneumonia in a patient with suggestive
signs and symptoms, and also to identify the causative agent as far as possible.
But the positive yield of these routine tests such as sputum and blood culture
is often low so that clinician seldom depends on these tests. Better positive
outcome is achieved with lower respiratory tract sample for which invasive
procedures are required. Invasive diagnostic
procedures are advised in pneumonia in the following situations
·
Slowly resolving or
non resolving pneumonia
·
Patients having
life-threatening complications
·
Pneumonia in immuno-compromised
host
·
Hospital acquired or
ventilator associated pneumonia
Invasive
procedures include:
(i) Thoracentesis
(ii) Transthoracic Needle
aspiration
(iii) Bronchoscopic
Procedure
a)
Bronchoscopic BAL
b)
Bronchoscopic PSB
(iv) Non Bronchoscopic
Procedures
a) Blind Bronchial
aspirate
b) Blind BAL
c) Blind PSB
(v)
Lung Biopsy
(i) Thoracentesis:
It is reported that parapneumonic effusions are seen in
more than 40% of patients with bacterial pneumonia. It is more common in
pneumococcal pneumonia; seen in up to 60% of patients. Small pleural effusions
are seen in viral and mycoplasma pneumonia, in up to 20% of patients. S. aureus
is the commonly isolated organism in empyema thoracis in post-surgical patients40
If there is associated pleural effusion or
empyema, every effort should be taken to retrieve adequate quantity of fluid
for establishing an etiological diagnosis. Diagnostic
thoracentesis can aid in the diagnosis and treatment plan for almost all
pleural effusions. The exceptions to this rule are patients with a very small
effusion41. All parapneumonic effusions having a thickness of >10
mm on the lateral decubitus x-ray, ultrasound or CT scan should be subjected
for sampling.
Pleural fluid studies
- Blood cell
count (WBC count) and differential count generally help in differentiating
between transudate and exudate. WBC counts in empyema are generally more than
50,000 cells/µL.
- Pleural
fluid total protein, LDH, and glucose estimation are also useful for
differentiating between exudates and transudates.
- Pleural
fluid pH: Values of less than 7.20 are suggestive of a complicated pleural
effusion.
- Microbiology:
Gram stain, Acid-fast bacilli stain and bacterial culture are essential
investigations to prove the causative pathogen.
(ii)
Bronchoscopic techniques:
Bronchoscopic procedure is
used for collecting secretions from lower airways by either protected specimen
brush (PSB) or Bronchoalveolar lavage (BAL). This will give a sample of
uncontaminated specimen for culture and sensitivity. This specimen is used for
either quantitative or qualitative culture. In
a study on 76 patients with VAP by Montravers et al, specimens for culture were
collected using PSB. The diagnosis of pneumonia was confirmed by a bacteria
count of ≥ 103 cfu/ml42. The clinicians’ initial
antibiotic choice was modified on the basis of bronchoscopy results. However,
it is not proved beyond doubt whether this information leads to improved
outcome. In another study by Luna et al43 quantitative
BAL was done and an etiologic organism was identified in 65 of 132 patients
(49%).
More than half of the patients among this group were already on
antibiotic treatment for either community-acquired pneumonia or nosocomial
pneumonia.
Quantitative cultures have
been demonstrated to have good diagnostic utility for the presence of
pneumonia, especially in patients with a low or equivocal clinical suspicion of
infection44. In a study on VAP patients by Rello et al 45,
out of a total of 113 patients, an organism was identified by bronchoscopy in
88% of patients. Out of this, 27 patients had an initial inadequate antibiotic
therapy, and the mortality rate was
significantly higher in this group. Consistent recovery of potential pathogens
with invasive techniques can identify patients at high risk of mortality.
The major problem on relying
culture reports for treating patients is that a negative culture can result in
denying treatment to a specific patient or a specific pathogen. In a
prospective study by Gibot and coworkers on 148 patients on mechanical
ventilation, with suspected infectious pneumonia, a rapid immunoblot technique
was done on BAL fluid, and it was found that levels of soluble triggering
receptor expressed on myeloid cells (sTREM-1) was the strongest independent
predictor of pneumonia.46. To differentiate between infection and
colonization the diagnostic threshold varies with the technique used.
Bronchoscopic BAL uses a diagnostic threshold of 104 or 105 cfu/ml.
PSB samples require a diagnostic threshold of 103 cfu/ml or more.
PSB is more specific than sensitive for diagnosing pneumonia48.
(iii) Non bronchoscopic technique
The
non-bronchoscopic technique involves passage of a catheter through the
endotracheal tube and then it is advanced and wedged into the bronchus. Samples
are taken with a catheter containing a brush (blind PSB), 49or by
aspiration of secretions through a distally wedged catheter., BAL may be
performed by using a balloon-tipped catheter with the balloon inflated after
the catheter has been advanced to the wedged position (protected BAL).The yield
of bronchoscopic and non-bronchoscopic technique for obtaining quantitative
cultures of lower respiratory specimens is comparable50. The choice
depends on local resources and expertise.
(iv) Lung
Biopsy.
In very severe cases of
pneumonia or when the diagnosis is not clear, particularly in patients with a
damaged immune system, a lung biopsy may be required. This can be done by
bronchoscopic biopsy, needle aspiration, open lung biopsy or video assisted
thoracoscopic biopsy. Open lung biopsy through a very limited anterior
thoracotomy is employed in the diagnosis of P jeroveci pneumonia (PJP).
Gaensler and co-workers51 have already shown the high yield of positive
diagnoses by this procedure in diffuse pneumonic processes. Early open lung
biopsy with frozen section staining should be undertaken at the first
opportunity. Routine permanent section stains and cultures of lung tissue for
bacteria, fungi, and acid-fast bacilli should also be performed.
(v) Transthoracic needle aspiration (TNA)
Moser et al52
demonstrated in an experimental model of dog with pneumococcal pneumonia that
TNA has the best sensitivity and specificity rate. Furthermore, TNA is an easy
procedure to carry out with very few complications and well tolerated by most
of the patients. Ultrasound guided percutaneous cutting biopsy is a valuable
method for diagnosing pulmonary consolidation of unknown aetiology. The
diagnostic yield is high and the procedure appears to be relatively safe.
Diagnostic
Imaging in Pneumonia
(i) Chest Radiograph
Chest radiography is the most important investigation among the routine
procedures employed for evaluating pneumonia. Patients who presented with
fever, chills, and rusty sputum, and whose chest radiograph showed parenchymal
infiltrates were considered to have typical pneumonia. Chest radiographs are sometimes useful for suggesting the
etiologic agent, prognosis, alternative diagnoses, and associated conditions. Even
though Chest X-ray can be considered as a gold standard for diagnosing
pneumonia, it is taken in only 11% of cases in clinical practice. Studies also
have shown that clinical judgment in ordering a chest x-ray is 100% sensitive
and thus that all patients with pneumonia have been correctly identified. 53
Radiologic phases
It is indeed interesting to note that the radiological findings
to a large extent correspond to the pathologic stages of pneumonia. In the
initial phase lasting approximately 24 hours there is active hyperemia. In the
next phase known as red hepatization, neutrophils and fibrin material fill the
alveoli along with red blood cells resulting in a homogenous opacity. This is
followed by gray hepatization when fibrin and exudative cells accumulate, seen
in radiographs as a clear zone adjoining alveolar and acinar shadows. If the
process extends to the pleural space, associated parapneumonic effusion (PPE)
may be present. Finally the radiological shadow is cleared as the pneumonia
resolves, but always there is a time lag between clinical resolution and
radiological resolution.
Radiologic
pattern
1) Airspace
Pneumonia
Airspace
Pneumonia is seen as homogenous consolidation, relatively sharply demarcated
from adjacent uninvolved parenchyma which characteristically crosses segmental
boundaries54.It usually abuts interlobar fissure but seldom involves
entire lobe. When there is enormous exudation, expansion of the affected lobe
occurs which is seen as bulging fissure 55.Since the conducting airways
are patent air lucency can be seen through the opacities (Air bronchogram). Characteristic
"silhouette" sign (Fig-3 & 4) obliterating cardiac or
diaphragmatic border help in localizing the pneumonia.56
Rarely, it appears as spherical pneumonia, which is a
solitary round nodule with or without hilar lymphadenopathy. This lesion is mostly
seen in the posterior parts of the lung.57
2) Bronchopneumonia
Bronchopneumonia is a focal peribronchial or
peribronchiolar area of consolidation involving one or more segments of a
single lobe to multilobar bilateral consolidation 57,58.This is seen
as poorly defined centrilobular nodular opacities measuring 4-10 mm with air
alveologram or may involve the entire secondary lobule (Lobular consolidation)59.
Bronchopneumonia frequently results in loss of volume of affected segment or
lobe. Confluence of pneumonia in adjacent lobule may be extensive and may
result in a pattern simulating non segmental airspace pneumonia.
3) Interstitial Pneumonia
Here diffuse,
patchy ground-glass
opacities are seen associated with linear or reticular opacities. (Fig-5) Characteristic
findings are seen as 1-5 mm, poorly defined nodules and patchy peribronchial
opacity and airspace consolidation. Patchy unilateral or bilateral consolidations
and ground glass opacity or poorly defined centrilobular nodules are often seen
in viral pneumonia.
Typical versus
atypical pneumonia
Bacterial pneumonias are usually lobar, and there can be
cavitation and pleural effusion. Multilobar involvement with nodular or
reticular infiltrates, lobar or segmental collapse or perihilar adenopathy are
seen in infection with atypical pathogens. But it is not possible to definitely
differentiate between typical and atypical pneumonia based on radiologic
findings. Therefore, the radiographic findings described above should be used
along with clinical and laboratory data to narrow the possibilities.
The typical
description of dense parenchymal shadow with air bronchogram is seldom seen in
children. Mostly it is unilateral or bilateral alveolar shadows or interstitial
infiltrates60. In their study Drummond et al 61 could not
find any significant difference in aetiology
among the five radiographic groups into which their cases were divided (lobar
consolidation, patchy consolidation, increased perihilar and peribronchial
markings, pneumonitis and effusion). In another study by Korppi et al62 on
101 Italian children, no association was found between radiographic findings
and etiology.
Structural lung disease with abnormal lung parenchyma affects the pattern
of infiltrates. In cases of hyperinflation as in severe emphysema, there is a
chance to underestimate the radiographic infiltrates. Shadows are usually
patchy due to partial filling of enlarged airspaces. There will be large areas
of involvement, unilateral or bilateral where air space opacities are
interrupted by radiolucency (resembles Cheddar cheese)
The time required for the opacity to
appear on chest radiographs in pneumonia is controversial. Usually the
opacities appear within 12 hours. But in community acquired pneumonia, by the
time the patient is referred to the radiologist for X-ray, adequate time will
be usually lapsed for its detection. But in suspected nosocomial pneumonia,
chest radiograph may be taken within a few hours, when opacity may not yet be
visible63. Similarly in a
dehydrated patient shadows may not be apparent even with extensive involvement.
In immunosuppressed patients also, especially those with coexistent
neutropenia, diabetes, alcoholism, or uremia, the appearance of infiltrates may
be delayed.
Non resolving Pneumonia
The terms nonresolving and slowly resolving pneumonia have been
used interchangeably to refer to persistence of radiographic abnormalities
beyond the expected time course64. The expected time course for
resolution is controversial, and variable definitions have been set arbitrarily
by investigators. In a 1987 review, Fein et al 65 defined non-resolving
pneumonia as a clinical syndrome in which focal infiltrates clearly begin with
some clinical association of acute pulmonary infection and do not resolve in
the expected time. Non-resolving pneumonia should be considered when the patient fails to
improve clinically, or when the radiological resolution is slow despite
adequate and appropriate antibiotic therapy. Arbitrarily 4 weeks is considered
as the cut off period for expressing radiological non resolution. About 10% of
diagnostic bronchoscopy procedures and 15% of pulmonary consultations are
performed to evaluate a nonresolving infiltrate. Rather than the infecting pathogen,
it is usually the host defense that is responsible for delayed resolution. Host
factors that may contribute to delayed resolution include age more than 50
years, smoking, chronic diseases like diabetes mellitus, renal failure, chronic
obstructive pulmonary disease (COPD) and alcoholism. Consolidation persisted at 30 days in 27% of patients older
than 50 years, compared with 18% among younger patients.65
Despite initial antibiotic therapy, during the early
phase of the illness there can be radiological worsening, which is more common
in bacteremic patients compared to non-bacteremic patients. According to the
recommendation by Jay and colleagues66, the appropriate interval for
repeating chest radiograph is 6 weeks, unless otherwise indicated by patient’s
clinical worsening. In patients above 50 years, with COPD and alcoholism, 60%
of patients have an abnormal chest radiograph at 14 weeks. But in patients
below 50 years with bacteremia, 40% have an abnormal chest radiograph at 2
weeks. Taking both groups together, 37%
have residual radiological lesion at 4 weeks, and complete resolution was found
in almost all patients by 18 weeks.
Community acquired Pneumonia
S.pneumoniae is the etiologic agent responsible for 10-50% of community
acquired pneumonia. Alveolar consolidation begins in the peripheral airspaces. It
usually causes lobar or segmental consolidation, but patchy bronchopneumonic
pattern is seen in the elderly. Pneumococcal pneumonia has a tendency to
involve pleura in the early course of disease leading to parapneumonic
effusion.66
The characteristic finding in
staphylococcal pneumonia in children is the presence of pneumatoceles. Pneumatoceles
may develop rapidly and there can be rapid progression with multilobar
involvement. Empyema is also frequently seen in staphylococcal pneumonia. 67
Radiographically it is difficult to differentiate H.influenza from
pneumococcal pneumonia. Multilobar infiltrate is common and pleural effusion is
seen in 50% of cases.
Resolution is usually slow. Klebsiella pneumonia present as patchy
bronchopneumonia or dense lobar consolidation. The alveoli are frequently
filled with large amounts of exudates and may cause an increase in the volume
of the affected lobe with resultant bulging of the interlobar fissures,
radiologically producing the bulging fissure sign or sagging fissure sign (Fig-6).
Though these findings were thought to be characteristic of klebsiella pneumonia,
they may be seen in other pneumonia also68. Abscess formation and
cavities develop rapidly in klebsiella pneumonia and pleural effusion is also
common.
Tuberculous pneumonia present as lobar or segmental consolidation
and development of cavity is quite common. Even though upper lobes are the
common site, any part of the lung may be involved. The most common sites of
cavity development are both upper lobe and apical segment of lower lobe
(Fig-7). Diffuse miliary shadowing suggests disseminated disease. In
immunosuppressed patients radiographic findings are more of a disseminated
disease with acinar nodules or miliary shadows distributed predominantly in the
lower zones. Findings such as tuberculous
rnediastinitis, mass like densities mimicking carcinoma, tuberculornas, chronic
lower lobe infiltrates, miliary tuberculosis, bronchopleural fistula, pleural
effusion, and negative chest radiographs have been reported to occur in up to
one-third of new adult cases of pulmonary tuberculosis 69. Another
report in the radiologic literature suggested that up to 22% of patients with
cavitary disease may have air-fluid levels 70.
Legionella pneumonia typically causes a patchy localized infiltrate in
the lower lobes with associated hilar adenopathy. Rarely cavitation and mass
like appearance are seen. In up to 30% of cases pleural effusion is reported. It may take longer duration
for the complete resolution of legionella pneumonia. As long as 6-12 months may
be needed for resolution, and residual fibrosis is seen in as many as 25% of
patients71. Mycoplasma pneumoniae is another common cause of community acquired
pneumonia Unilateral or bilateral infiltrates with hilar adenopathy may be seen
and pleural effusion is reported in about 20% of cases. Extensive radiographic
infiltrates may be seen in elderly patients. In up to 40% of patients
radiological infiltrates resolve by 4 weeks and in 80% of the patients by 8
weeks72. Residual radiological lesions are uncommon.
Characteristic radiographic findings in fungal pneumonia
include patchy infiltrates, nodules, consolidation, cavitation, or pleural
effusion. Radiological
presentation of Aspergillosis and mucormycosis can be as round pneumonia with
irregular margins which can slowly increase in size and number. It may progress
to hemorrhagic pulmonary infarction73. Miliary nodular pattern is
seen in disseminated infection. Non-resolving pneumonia leading to
lung abscess is always a challenge to the treating physician especially in a
diabetic patient. Atypical radiological features of lung abscess should raise
the suspicion of unusual organisms. Rare fungus like basidiobolus can cause
pneumonia and lung abscess in immuno-compromised individuals.74
Radiographic
manifestations of viral pneumonia are protean75 and
usually present as bilateral bronchopneumonia and overinflation. Radiological
resolution usually occurs in 2 weeks76. Radiographic manifestation of
influenza pneumonia may range from mild interstitial prominence to patchy areas
of consolidation and extensive airspace consolidation. Pleural effusion and
cavity formation is rare and if present indicates bacterial superinfection. Hanta virus pneumonia show interstitial edema
with or without progression to airspace disease, with a central or bibasilar
distribution and pleural effusions.
In anaerobic bacterial pneumonia infiltrate with or
without cavitation will be seen in one of the dependant segments of the lung
ie, posterior segment of upper lobe or superior segment of lower lobe.
Cavitation suggests necrotizing pneumonia. Air fluid level in a circumscibed
infiltrate suggests a lung abscess or bronchopleural fistula.
Hospital acquired Pneumonia:
Hospital acquired pneumonia (HAP) is
diagnosed by the appearance of a new parenchymal infiltrate after 48 hours of
hospitalization. X ray may show airspace
consolidation, interstitial pattern or mixed shadows. It is difficult to
differentiate atelectasis from HAP and the two may co exist. As many as 60%
ventilated patients with the clinical diagnosis of pneumonia has some other
process causing abnormalities in the chest radiograph 77. For the
diagnosis of pneumonia in ventilated patients portable chest radiograph is
mandatory, but its sensitivity and specificity is low. Usually the quality of
the film is poor and it is difficult to diagnose pneumonia. Cavitation of
pulmonary infiltrate, air space opacification, and localized air bronchogram
are highly suggestive of VAP78.
Aspiration Pneumonia
Depending on the
position of the patient during the time of aspiration79, the site of
aspiration pneumonia varies. Due to the vertical orientation and larger diameter,
the common site of aspiration pneumonia is middle and lower lobe of right lung.
In the standing position bilateral lower lobe infiltrates is common. Left sided
pneumonia is common if the patient was in the left lateral position. In prone
position the right upper lobe is the common site for aspiration. Chest
radiographic findings in patients with anaerobic bacterial pneumonia typically
demonstrate an infiltrate with or without cavitation.
Pneumonia in immuno compromised Host
The
chest film in Pneumocystis jerovci pneumonia typically shows diffuse, fine,
reticular interstitial or perihilar opacification which may appear somewhat
granular. This will progress to airspace consolidation over 3-4 days. This
appearance may be followed by coarse reticulation as the pneumonia resolves.80 Chest radiograph findings may be
normal in 10-39% of patients, or radiographic changes may lag behind the
clinical symptoms.
Pneumatoceles increase the risk of pneumothorax81.
Less commonly, lobar infiltrates, effusions or cavitary lesions mimic other
pulmonary processes.82 Atypical radiographic manifestations include cystic lung
disease, spontaneous pneumothorax and lobar or segmental consolidation with
upper lobe predominance. Pleural effusions and hilar lymphadenopathy are
uncommon. Cyst formation is seen more frequently in HRCT (33%) rather than in
chest radiographs (10%).
Chest radiographs in an immuno
compromised patient with CMV pneumonia reveal an interstitial pattern of
disease, which is usually diffuse and which involves the bases. The
interstitial pattern consists of accentuation of Kerley A and Kerley B lines or
of diffuse, hazy, ground-glass opacities.83
(ii) Computed Tomography
CT scanning provides a better definition of the diseased
areas and is used to differentiate parenchymal abnormalities from pleural
abnormalities. Computed tomography (CT) scan is not routinely employed in the
diagnosis of pneumonia and is indicated in specific situations involving the
following. 84
·
Non resolution/ Delayed resolution of pneumonia
·
An indistinct, abnormal opacity on chest radiographs
·
Patchy, ground-glass, linear, or reticular opacities on chest radiographs
·
Possible pleural effusion
·
Neutropenia and fever of unknown origin
High resolution CT findings in
CAP
Tanaka et al compared high resolution
CT (HRCT) scan findings in CAP with pathologic findings and evaluated its role
in differentiating between bacterial and atypical pneumonias in 32 patients
with CAP.85 Consolidation or
cavitating nodules were seen on CT and the nodules varied in size from 1 mm to 3 cm.86
The nodules had irregular or smooth margin without any zonal predominance. Tree
in bud pattern was also seen87. Majority of patients (88%) had
ground glass opacification and all lobes were equally involved.
Bacterial pneumonia often showed a
pattern of airspace consolidation with segmental distribution (72%) that
typically distributed towards the middle and outer zones of the lungs (Fig-8). In
tuberculous pneumonia area of consolidation is
seen in 52.8 %. Bronchogenic dissemination outside the consolidation appeared
in 52.4%. Lymph node enlargement and pleural reaction were seen in 55.6 and
35.6%, respectively 88. Tree-in-bud pattern (Fig-9) is the most characteristic, but
not pathognomonic feature of endobronchial spread of tuberculosis and can be
found in 72% of patients with active disease 89.
Atypical pneumonia caused by Mycoplasma, Chlamydia and
influenza virus causes centrilobular lesions, acinar shadows, consolidation or
ground glass opacity. In majority of cases the lesions are distributed in the
inner, middle, and outer layers of the lung.
CT manifestations of Legionella pneumonia include
bilateral lung parenchymal involvement. Peripheral lung consolidation, ground
glass opacity, lung cavitations and bulging fissures are also seen. There can be residual lung parenchymal
scarring63.
In a study on 28
patients by Reittner et al, ground-glass opacification as well as airspace
consolidation were reported in majority of patients. Nodules were better
delineated in HRCT compared to X-ray, and the nodules had a predominant
centrilobular distribution. Thickening of bronchovascular markings were also
better appreciated in CT thorax compared to chest x-ray72.
The usual CT findings in fungal pneumonia include patchy
infiltrates, consolidation, cavity formation, nodules and pleural effusion. In
disseminated disease miliary nodules may be seen. Unilateral or bilateral
mediastinal adenopathy is commonly seen in endemic fungal pneumonia. HRCT
scanning allows observation of the halo sign in patients with aspergillosis.
This is a nodular lesion usually surrounded by a ground-glass opacity or halo. Greene
and co workers reported halo sign in 61% of 235 patients with invasive
aspergillosis88. Diagnosis may be
difficult through imaging as many lesions are non-specific and also due the
presence of parenchymal abnormalities from the underlying lung disease.
Ground-glass attenuation is the
characteristic HRCT finding of Pneumocystis jerovci pneumonia (PJP). In more
than 90% of patients, lesion are bilateral, symmetrical and perihilar in
distribution. There may be geographic pattern with areas of normal lung
adjacent to diseased lung (Dark bronchus sign).89
(iii) Ultrasonography
The role of ultrasonography in pneumonia is
mainly to differentiate between consolidation and pleural effusion. Consolidation
appears as hypoechoic area with blurred margins. It becomes more heterogenous
with aeration and in dense consoldation it will be homogenous. In a study by
Bency et al consolidation was seen as large hypoechoic lesions or small round
subpleural hypoechoic lesions. The sensitivity
of ultrasound is similar to that of conventional radiography, but it is less
useful in interstitial pneumonia90. The literature also reports that
ultrasonography may aid in the diagnosis of empyema and abscesses. However, most authors
believe that in clinical practice, ultrasonography's usefulness is limited to
the identification and quantification of parapneumonic effusions. This can
correctly identify the site for subsequent diagnostic or therapeutic
thoracentesis.
Summary
Community acquired pneumonia is
diagnosed based on symptoms and signs and a radiographic abnormality. But
certain situations warrant an etiological diagnosis which is mostly by
microbiological intervention. However these tests are not always helpful especially
when the patient was put on an initial antibiotic therapy or when atypical
organisms or rarer organisms cause the pneumonia. Common tests are not routinely used due to low yield as
well as infrequent positive impact on management decisions. It becomes more difficult to
establish an etiology in hospital acquired pneumonia. Newer culture methods and
molecular technique has been evolved which offers specific diagnosis that too
in a shorter time frame. The composition of
the diagnostic workup for pneumonia has been the subject of some disagreement
for years, but a well-chosen, individually tailored evaluation can offer a lot
of information to support the diagnosis of pneumonia.
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