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Chapter 1

THE PROBLEM AND ITS BACKGROUND

Introduction

At the beginning, the extensive majority of people suffering from tuberculosis

(TB) extend from the poorer and most susceptible division of society, global TB control

targets cannot be met unless this group of people is reached with essential health

services. Early diagnosis and effective treatment are important aspects that help reduce

the adverse social and financial consequences of the disease for TB patients and their

families. Consequently, all influential policy documents on TB control always highlight

the importance of developing strategies that ensure global access to essential health

services for all TB patients.

Despite the successes achieved by the adoption of the Directly Observed

Therapy, short course (DOTS) strategy in countries such as Philippines, the recent

emergence of multidrug resistant (MDR) TB and extremely drug resistant (XDR) TB has

slowed down the progress toward the ultimate goal of TB control and elimination.

Originally named after one of the components of the strategy, DOTS comprises

four other critical components including: government commitment, case detection by

sputum smear microscopy, uninterrupted drug supply and standardized reporting and

recording. Given this new understanding, a fast, simple and cost-effective tool to assess

anti-TB treatment efficacy becomes a paramount aspect of this goal.

Furthermore, tuberculosis (TB) has traditionally been one of the principal causes

of pleural disease and, up until the past decades of the earlier century, held as a

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foremost paradigm of "pleuritis". Undeniably in the presence of a noticeably exudative

effusion and a compatible clinical presentation the widely used term "pleuritis exudativa"

insinuated a tuberculous aetiology and has therefore been understood to be

synonymous with "pleuritis exudativa tuberculosa". At the same time as in the era of TB-

decline the term "pleuritis exudativa" has largely survived but may be simply mistaken

for exudative effusion in general, the full and precise term is required when addressing

the possibility of TB. Otherwise the term "tuberculous pleurisy" is used to depict this

entity. Separately from pleuritis exudativa tuberculosa, TB of the pleura may

occasionally also present as caseous pleurisy or specific (tuberculous) empyema

respectively. The following chapter reviews on tuberculosis, the different features and

mechanisms of tuberculous pleural involvement as well as their diagnostic and

therapeutic implications.

Background of the Study

An Era of Tuberculosis

Tuberculosis is one of the oldest documented infectious diseases and remains a

major public health problem today. The evolutionary origin of the causative organism,

Mycobacterium tuberculosis, is uncertain. It was believed to have originated in

prehistoric humans as a zoonotic infection transmitted from tuberculous animals most

probably cattle, between 8000 and 4000 BC (Bloom, 1994). However, a recent analysis

of genetic data based on tubercle bacilli from East Africa has shown that M.

tuberculosis, as a progenitor species about 3 million years old (Gutierrez et al., 2005).

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Indeed, signs of tuberculosis have been identified in the spines of Egyptians and South

American mummies dated over 6000 years old (McKinney et al., 1998).

Various names have been used to depict tuberculosis. The Greek poet Homer

described it as “a grievous consumption that separates soul and body” (Gallagher, 1969

p.167). Hippocrates (470-376 BC) called it phthisis; English speaking people called it

consumption, and later the “Captain of all the Men of Death,” and “The Great White

Plague.” The enlarged cervical lymph nodes were called “Scrofula” or “The King’s Evil”

(Myers, 1970 p.10). The disease also had significant social impact in history and was

prominent in arts and politics. For instance, Botticelli’s Venus is a popular painting

depicting a pale beauty to signify the disease that would take her life at the age of 23

and the self-entrusted power of 18th century English royalty to heal the disease by the

touch of their hands (McCray et al., 1997).

The cause of the disease was shrouded in mystery and it was believed to be an

inherited disease for a very long time (McKinney et al., 1998). A few people, however,

suspected the contagious nature of tuberculosis. Italy and Spain, for example, had

regulations to prevent its spread as early as 1699. Patients so afflicted were strictly

isolated, and when they died, their bedding and the doors to their rooms were burned

and their rooms were re-plastered (Dowling, 1977).

In 1722 Benjamin Marten, an English physician, explicitly said that the disease

might arise from a micro-organism, which may be an airborne contagion. His idea of

germ theory was mocked at that time (McKinney et al., 1998). In 1865, Jean-Antoine

Villemin went on to demonstrate that the disease could be transmitted using sputum or

caseous tissue from a patient to animal. This was widely discredited at that time

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(McKinney et al., 1998). In 1882, Robert Koch, a German physician and microbiologist

was able to identify and isolate the causative organism M. tuberculosis (McKinney et al.,

1998).

Antonin Marfan suggested the existence of acquired immunity to tuberculosis as

early as 1886, but it was not until 1919 that Calmette and Guerin succeeded in making

a stable vaccine (BCG) against the disease. Benjamin Weill-Halle and Raymond Turpin

used this vaccine for the first time in 1921 (McKinney et al., 1998). Following the initial

success, its use spread throughout Europe and to other continents in the world. In the

1940s, the WHO started promoting mass vaccination with BCG in its campaign to

control the disease (Raviglione and Pio, 2002).

Drugs that were used in the treatment of other diseases were also tried on

tuberculosis. For example, cod liver oil, prescribed for rheumatism in the late eighteenth

century, was later given for tuberculosis (Dowling, 1977).

In the absence of effective drugs, other measures were tried, including urging

patients to move to warmer climates. A movement towards high altitude, where the air

was believed to be beneficial, began in 1859 with establishment of a sanatorium for

patients suffering from pulmonary tuberculosis by a German physician, Herman

Brehmer (Dowling, 1977). Later, surgical resection of the affected parts of the lung

became the predominant practice in most parts of the world (Dowling, 1977).

In 1939, Selman Waksman attended a congress of microbiologists in New York

City, where he was intrigued by Alexander Fleming`s description of his experiments.

Although he had made earlier observation that avian tubercles were inhibited or killed in

septic soils, he failed to follow this up (McKinney et al., 1998). In 1943, Albert Schatz, a

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student of Selman Waksman, extracted streptomycin from soil fungus and showed it to

be active against the tubercle bacilli in vitro, leading to its administration for the first time

to a human patient on November 20, 1944 (McKinney et al., 1998). Around the same

period, Jorgan Lehman, noticed that synthetic para-aminosalicylic acid (PAS) inhibited

the growth of the tubercle bacilli in vitro and used it to treat tuberculosis in guinea pigs.

It was first successfully used in the treatment of tuberculosis in a human patient in 1944

(McKinney et al., 1998).

In an era of 1940’s, the discovery of anti-TB drugs and combination of

chemotherapy made TB a curable disease. The treatment of tuberculosis began in

1946, when streptomycin was demonstrated to be efficacious against the disease

(McKinney et al., 1998). In 1952, isoniazid became available, and in 1965, rifampicin

was also found to be as effective as isoniazid, making tuberculosis curable in the

majority of patients (Mandell and Bennett, 2000). The discovery of these drugs ushered

in the concept of combination chemotherapy, dubbed, ‘short course’ with duration of not

less than 6 months (Harries and Dye, 2006). In the developed countries, it was hoped to

eradicate this disease because of its effective treatment.

The Threat

The Philippines ranks ninth on the list of 22 high-burden tuberculosis (TB)

countries in the world, according to the World Health Organization’s (WHO’s) Global TB

Report 2009. After China, it had the second highest number of cases in the WHO

Western Pacific Region in 2007, and TB is the sixth greatest cause of morbidity and

mortality in the country. In 2007, approximately 100 Filipinos died each day from the

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disease, but significant strides have been made in increasing case detection and

treatment. In 2004, the country achieved a TB case detection rate of 72 percent,

exceeding WHO’s target of 70 percent, and reached 75 percent in 2007. The DOTS (the

internationally recommended strategy for TB control) treatment success rate reached

WHO’s target of 85 percent in 1999 and has remained around 88 percent since then.

Nowadays, with its recent emerging of population growth in cities and quickening

development arising from globalization, today's urban settings are focusing on the field

of public health. Diseases at this time vary and much more become a threat. Such in a

case of tuberculosis, is now out of control and increasing at an alarming rate across

most of the poorest regions of the world.

Nearly one third of the global population i.e. two billion people are infected with

mycobacteria tuberculosis and are at risk of developing the disease. Pleural effusion is

one of the common complications of pulmonary tuberculosis.

The first step in the evaluation of patients with pleural effusion is to determine

whether the effusion is a transudate or an exudate. An exudative effusion is diagnosed

if the patient meets Light’s criteria. The serum to pleural fluid protein or albumin

gradients may help better categorize the occasional transudate misidentified as an

exudate by these criteria. If the patient has a transudative effusion, therapy should be

directed toward the underlying heart failure or cirrhosis. If the patient has an exudative

effusion, attempts should be made to define the etiology. Pneumonia, cancer,

tuberculosis, and pulmonary embolism account for most exudative effusions. Many

pleural fluid tests are useful in the differential diagnosis of exudative effusions. Other

tests helpful for diagnosis include helical computed tomography and thoracoscopy.

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Pleural effusion develops when morel fluid enters the pleural space than is

removed. Potential mechanisms of fluid increased interstitial fluid in the lungs secondary

to increased pulmonary capillary pressure (i.e., heart failure) or permeability (i.e.,

pneumonia); decreased intrapleural pressure (i.e., atelectasis); decreased plasma

oncotic pressure (i.e., hypoalbuminemia); increased pleural membrane permeability and

obstructed lymphatic flow (e.g., pleural malignancy or infection); diaphragmatic defects

(i.e., hepatic hydrothorax); and thoracic duct rupture (i.e., chylothorax). Although many

different diseases may cause pleural effusion, the most common causes in adults are

heart failure, malignancy, pneumonia, tuberculosis, and pulmonary embolism, whereas

pneumonia is the leading etiology in children (Light  RW, 2002).

Need for Study

Tuberculosis is still a great threat to our community and remains a major health

problem despite laudable efforts of the National TB Program after the implementation of

DOTS in 1996. While the initiation and preservation of DOTS in the public sector, and

the consequent development concerning the private sector, several accomplishments

have been reported.

In spite of the significant achievements, several issues and concerns related to

TB control have been recognized. Different problems linked to factors attributable to the

patient, the health care provider, and the program contributes to the persistence of

tuberculosis in the country.

This study entitled, “Retrospective Analysis of Pleural Fluid: Patient’s

Demographics, AFB Pleural Stain and MTB Culture in Relation to Medical

Treatment of Pulmonary Tuberculosis in Santo Tomas University Hospital from

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January 2011- October 2011” is an attempt to describe conditions of tuberculous

pleural effusion and its impact to present protocol specifically thoracentesis. The study

also aims to give us further awareness on medical treatment of tuberculosis and ways

to manage it.

Study Objectives

General Objective

The goal of this study is to review the efficiency of pleural fluid AFB staining and

to discuss thoracenthesis and its role in PTB to pleural effusion among patients. It would

also highlight the current medical treatment and management practices/protocols

towards in combating this infectious disease.

Specific Objectives

1. To determine the efficiency of AFB staining as a tool in the diagnosis of

tuberculous effusion.

2. To understand on how pleural effusion in TB can be properly managed with its

practices and protocols.

3. To impart better insights of ways to fight this disease with appropriate

recommendations.

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Significance of the Study

There is a need to supervise and evaluate treatment outcomes so as to make

comparisons with standard protocols in managing this disease. Identification and

tackling of managing TB protocols will enable optimal hospitalization to reconsider

appropriate and concise protocols to help patients in a comfortable manner. This

research report will describe the management practices. Such a study targeting

hospitalized TB protocols at Santo Tomas Hospital has not been done since the

introduction of standardized TB treatment regimens. The outcomes of the study will be

valuable in assessing past performance and informing situation-specific operational

planning at the hospital.

Furthermore, this study seeks to provide further understanding in determining

several ways of its medical treatment to have better options in seeking for its cure. This

information, however, is vital to the proper management of TB cases.

Understanding the current conditions of the medical treatments provided for the

patients, we hope, will help public health and government officials to fight the disease

more astutely and to take greater programs toward eliminating it without delay and

proficiently as possible.

Theoretical Framework

A health system has been defined by WHO (2007) to consist of “all

organizations, people and actions whose primary intent is to promote, restore or

maintain health”. Considerably, a health system consists of six components imparted to

as “health system building blocks” and they include: leadership and governance, health

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financing, information system, health workforce, medical technologies and service

delivery (WHO, 2009). Several relationships and interactions between these six

components result in four functions of the health system, namely: stewardship

(oversight), creating resources (investment and training), financing (collecting, pooling

and purchasing), and delivering services (provision) (WHO, 2007). Generally, health

system goals (Figure 1) are to improve health and health equity, in ways that are

responsive, financially fair, and make the best, or most efficient, use of available

resources (WHO, 2007-2009). There are also important intermediate goals which are to

achieve greater access to and coverage for effective health interventions, without

compromising efforts to ensure provider quality and safety. Worthy of note is that the

people are at the centre of the health system because they play important roles

including serving as key factors driving the components of the building blocks in various

capacities, and as beneficiaries of the health system (WHO, 2009).

Figure 1. The health system building blocks and its overall goals/outcomes

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This thesis uses the health system framework depicted in Figure 1 to address

research objectives. The system building blocks which composed of six categories

address the objectives of the study. As leadership/governance, it pertains to an

accurate strategic plan to combat the prevalence of this infectious disease. In service

delivery, pertains to ways on how to properly execute the plan for combating TB. Health

workforce, as to broaden their knowledge on ways to manage and have a better grasp

of protocols. Financing, coming from the partnership of DOH and Global funds to

provide treatments and awareness on the current status of tuberculosis locally and

worldwide. Medical products, vaccines, information and technology, for enhanced

knowledge to reduce or as well to eliminate this infectious disease.

Scope and Limitation

The study presents a model of “Retrospective Analysis of Pleural Fluid: Patient’s

Demographics, AFB Pleural Stain and MTB Culture in Relation to Medical Treatment of

Pulmonary Tuberculosis in Santo Tomas University Hospital from January 2011-

October 2011” is based on descriptive retrospective approach. This approach would be

discussed extensively in Chapter 3, on the study’s research methodology.

The study performed at Santo Tomas University Hospital, Manila, of study period

from January 2011 through October 2011. A total of 47 patients were included.

Exempted from the study are other diseases not mentioned in this research.

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Definition of Terms

Pleura – a delicate membrane that encloses the lungs. The pleurae are divided

into two areas separated by fluid: the visceral pleura, which cover the lungs, and the

parietal pleura, which line the chest wall and cover the diaphragm.

Pleural effusion – is excess fluid that accumulates between the two pleural

layers, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid

can impair breathing by limiting the expansion of the lungs during ventilation.

Thoracentesis – also known as thoracocentesis or pleural tap, is an invasive

procedure to remove fluid or air from the pleural space for diagnostic or therapeutic

purposes.

Tuberculosis (TB) – is a potentially fatal contagious disease that can affect

almost any part of the body but is mainly an infection of the lungs. It is caused by a

bacterial microorganism, the tubercle bacillus or Mycobacterium tuberculosis

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Chapter 2

REVIEW OF RELATED LITERATURE AND STUDIES

This chapter provides background information on TB and control activities. A

brief history of TB, the natural course of infection, clinical presentation, and diagnosis,

with a focus on developing countries, pleural effusion and the role of thoracenthesis in

PTB are outlined.

Natural history of TB infection

Patients with open pulmonary tuberculosis (PTB) are the most important source

of infection, the risk of infection being determined by how infectious the source is, the

closeness of the contact, and the immune state of the host (Harries and Dye, 2006).

The initial infection occurs by the inhalation of droplets containing the bacilli when a

PTB patient coughs, sneezes, spits or speaks. These infectious particles are generated

in large numbers and can remain suspended in the air for long periods. The small sizes

of the droplets allow them to bypass the protective barriers in the throat and reach the

alveoli where they get deposited. The infectivity of a patient depends on the number of

viable bacilli produced during coughing or sneezing. When the patient produces

sufficient bacilli to be visible on microscopic examination of sputum, it is referred to as a

smear positive case (Enarson et al., 2000). Such patients are most important in the

spread of the infection.

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As with many infectious diseases, the events following such infection vary from

person to person. Local multiplication of the bacilli at the site of implantation leads to the

formation of a small lesion termed the Ghon focus. From this focus bacilli are carried

through the lymphatic systems to adjacent lymph nodes where multiplication of the

bacilli continues. The resulting lesion consisting of the Ghon focus and the enlarged

regional lymph nodes is termed the primary focus (Collins, 1997).

The presence of bacilli in the lungs usually stimulates a cell-mediated protective

immune response, which is due to activation of macrophages by chemical mediators

called lymphokines released by T-lymphocytes attracted to the site of infection.

Activated macrophages and lymphocytes form a compact aggregate around the bacilli

thereby creating the histological structure termed the granuloma (Collins, 1997).

Of those who become infected, 80-90% will never become ill with tuberculosis

unless their immunity is seriously compromised later in life. The bacilli remain dormant

within the body and their presence is indicated by a significant size of reaction to a

tuberculin skin test (Collins, 1997). In this group of infected individuals, there may

eventually be reactivation of such dormant lesions in about 5% of them, leading to post-

primary tuberculosis several years or even decades after the initial infection.

Alternatively, post-primary tuberculosis may be due to exogenous re-infection

(McKinney et al., 1998).

However, in the remainder of those infected, the disease process may progress

in one or more ways to give rise to overt primary tuberculosis. In these individuals,

bacilli may spread from the primary complex to other sites by the lymphatic or blood

streams. This may lead to tuberculous meningitis, which may occur about three months

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after infection, or to progressive lesions in bones, joints or the kidney, which are usually

detected a year or more after infection (Collins, 1997).

About two-thirds of all untreated smear-positive cases of PTB will die within 5-8

years of developing the disease (Harries and Dye, 2006). Most of those who survive

beyond 8 years develop dormant TB, whilst a few continue to excrete the tubercle bacilli

in their sputum (Harries and Dye, 2006, Enarson et al., 2000).

Aetiology of tuberculosis

The causative organism of tuberculosis, M. tuberculosis, belongs to the family

Mycobacteriaceae, and the order Actinomycetales. The bacillus is aerobic, non-spore

forming and non-motile, with a high cell wall content of high molecular weight lipids. It

measures between 1μm to 4μm in length and 0.3μm to 0.6μm in diameter (Brooks and

Jawetz, 1995).

Mycobacteria are classified as Acid and Alcohol Fast (AAFBs), because they

cannot be decolourised by acid or alcohol after using basic dyes to stain them. This

property depends on the integrity of the waxy envelope. They grow very slowly, with

generation time of about 18 hours. They tend to be more resistant to chemical agents

than other bacteria because of the hydrophobic nature of the cell surface. The cell walls

can induce delayed hypersensitivity (Brooks and Jawetz, 1995). The Ziehl-Neilsen

technique of staining is employed for the identification of acid-fast bacteria.

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Clinical presentation of TB

Tuberculosis can affect any organ in the body and hence can present in different

ways. The diagnosis of the disease is based on clinical presentation and the use of

certain investigative tools. The clinical presentation can be broadly grouped into

constitutional, pulmonary and other symptoms (Grange, 1996).

Constitutional symptoms

Common symptoms of tuberculosis include fatigue, loss of appetite, irritability

and weight loss. There is usually a low-grade fever, which persists for weeks and

becomes marked as the disease progresses. Night sweats may accompany the fever. It

should be noted that the absence of fever or other symptoms does not however mean

the absence of the disease.

Pulmonary manifestation

In pulmonary tuberculosis, there is usually a progressive cough with production

of sputum, which may be blood stained in 8% of adults with active disease (Lutwick,

1995). There may be localised or generalised chest pain and breathlessness when a

massive amount of lung tissue is involved.

Other symptoms

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The disease may present in many other forms because it can affect virtually any

organ in the body. Under such circumstances, the manifestation will depend on the

organ involved.

Investigation of TB

Table 1 summarises some of the investigative methods used in the diagnosis of

tuberculosis and identifies the advantages and disadvantages of each, emphasizing

methods that are relevant to developing countries.

TABLE 1. Investigative methods used in the diagnosis of tuberculosis

Type(s) of Test Advantages Disadvantages

Sputum smear

microscopy

Smear microscopy is the

only means by which the

diagnosis of PTB can be

confirmed in most

developing countries. It

efficiently identifies the

most infectious cases. It is

cheap and affordable and

can be performed with

minimal skill.

May be problematic

depending on the

competence of the

laboratory staff. No bacilli

may be found in the sputum

of advanced HIV positive

patients. Cannot be used in

children since they cannot

produce sputum. It is not

sensitive and may pick

other mycobacteria species

Sputum culture This is the definitive way of It needs skilled laboratory

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making a diagnosis of TB.

When sputum smear is

negative, culture may be

positive. It is commonly

used in monitoring drug

sensitivity patterns in

recurrent TB, and

community prevalence of

drug-resistant TB.

facilities, which may not be

available in most

developing countries. It is

very slow and takes 4-8

weeks to get results. It is

very expensive and may

not be affordable to most

developing countries. Only

in 50% (higher in good

laboratories) of cases is it

possible to isolate the bacilli

from the sputum.

Radiological test Very efficient in the

diagnosis of TB when used

by trained medical officer. It

identifies sputum negative

cases missed by sputum

microscopy. Very useful in

the diagnosis of

tuberculosis in children

since they cannot produce

sputum.

It is unreliable;

abnormalities identified on

a chest radiograph may be

due to TB or a variety of

other conditions. Individuals

previously treated for TB

may show signs of the

disease on radiographic

examination. Advanced

HIV-positive individuals

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may not show the classical

pattern of TB on chest

radiograph.

Tuberculin test Very useful in measuring

the prevalence of TB in the

community, especially if not

vaccinated with BCG. Very

valuable in making

diagnosis in a young child

at an age when fewer

children in the community

will normally have a positive

test. A strong positive test

is a point in favour of

tuberculosis.

A positive test may not be

caused by TB and a

negative test does not

always rule it out, especially

in HIV positive. It may be

negative in malnutrition or

other diseases even though

the person may have TB.

Its use is very limited in

high-prevalence countries

where about 50% of the

adult population are

infected with TB. It is not

routinely available in many

peripheral health

institutions; it is expensive,

has a very short expiry

date, must be kept

protected from light and

heat and requires some

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technical skills in its

administration and reading.

Others-Biopsies of

lymph nodes, laryngeal

swabs, and

immunological tests etc.

These tests are very useful

in skilled hands since they

are very fast and specific.

Immunological tests, for

example, are very useful in

patients who cannot

produce sputum. They are

very useful in research

work on TB

Most of the tests are

expensive and cannot be

afforded by most

developing countries.

Technical skills are needed

in their performance and

this may not readily be

available in low-income

countries. Expensive

equipments are needed for

most of these tests and this

limits their use developing

countries.

Since the vast majority of people suffering from tuberculosis (TB) come from the

poorer and most vulnerable segments of society, global TB control targets cannot be

met unless this group of people is reached with essential health services. Early

diagnosis and effective treatment are important aspects that help reduce the adverse

social and financial consequences of the disease for TB patients and their families.

Consequently, all influential policy documents on TB control always highlight the

importance of developing strategies that ensure global access to Despite the successes

21

achieved by the adoption of the Directly Observed Therapy, short course (DOTS)

strategy in countries such as Philippines, the recent emergence of Latent and Multiple

Drug Resistant Tuberculosis has slowed down the progress toward the ultimate goal of

TB control and elimination. Originally named after one of the components of the

strategy, DOTS comprises four other critical components including: government

commitment, case detection by sputum smear microscopy, uninterrupted drug supply

and standardized reporting and recording. Given this new understanding, a fast,

simple and cost-effective tool to assess anti-TB treatment efficacy becomes a

paramount aspect of this goal.

Initial Evaluation of Pleural Effusion

The history and physical examination are critical in guiding the evaluation of

pleural effusion (Table 2). Signs and symptoms of an effusion vary depending on the

underlying disease, but dyspnea, cough, and pleuritic chest pain are common. Chest

examination of a patient with pleural effusion is notable for dullness to percussion,

decreased or absent tactile fremitus, decreased breath sounds, and no voice

transmission (Light RW, (2001), Porcel JM, Light RW, (2004), and Sahn SA, Heffner JE

(2003).

TABLE 2. Causes of Pleural Effusions: History, Signs, and Symptoms

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Condition Potential causes of the pleural effusion

History

Abdominal surgical procedures Postoperative pleural effusion, subphrenic

abscess, pulmonary embolism

Alcohol abuse or pancreatic disease Pancreatic effusion

Artificial pneumothorax therapy Tuberculous empyema, pyothorax-

associated lymphoma, trapped lung

Asbestos exposure Mesothelioma, benign asbestos pleural

effusion

Cancer Malignancy

Cardiac surgery or myocardial injury Pleural effusion secondary to coronary artery

bypass graft surgery or Dressler’s syndrome

Chronic hemodialysis Heart failure, uremic pleuritis

Cirrhosis Hepatic hydrothorax, spontaneous bacterial

empyema

Childbirth Postpartum pleural effusion

Esophageal dilatation or endoscopy Pleural effusion secondary to esophageal

perforation

Human immunodeficiency virus infection Pneumonia, tuberculosis, primary effusion

lymphoma, Kaposi sarcoma

Medication use Medication-induced pleural disease

Remote inflammatory pleural process Trapped lung

Rheumatoid arthritis Rheumatoid pleuritis, pseudochylothorax

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Condition Potential causes of the pleural effusion

Superovulation with gonadotrophins Pleural effusion secondary to ovarian

hyperstimulation syndrome

Systemic lupus erythematosus Lupus pleuritis, pneumonia, pulmonary

embolism

Trauma Hemothorax, chylothorax, duropleural fistula

Signs

Ascites Hepatic hydrothorax, ovarian cancer, Meigs’

syndrome

Dyspnea on exertion, orthopnea,

peripheral edema, elevated jugular venous

pressure

Heart failure, constrictive pericarditis

Pericardial friction rub Pericarditis

Unilateral lower extremity swelling Pulmonary embolism

Yellowish nails, lymphedema Pleural effusion secondary to yellow nail

syndrome*

Symptoms

Fever Pneumonia, empyema, tuberculosis

Hemoptysis Lung cancer, pulmonary embolism,

tuberculosis

Weight loss Malignancy, tuberculosis, anaerobic bacterial

pneumonia

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*—Yellow nail syndrome results from an abnormality of lymphatics and consists of the

triad of yellow nails, lymphedema, and pleural effusion.

Thoracentesis

Except for patients with obvious heart failure, thoracentesis should be performed

in all patients with more than a minimal pleural effusion (i.e., larger than 1 cm height on

lateral decubitus radiograph, ultrasound, or CT) of unknown origin (Porcel JM and Light

RW, 2004). In the context of heart failure, diagnostic thoracentesis is only indicated if

any of the following atypical circumstances is present: According to their study, (1) the

patient is febrile or has pleuritic chest pain; (2) the patient has a unilateral effusion or

effusions of markedly disparate size; (3) the effusion is not associated with

cardiomegaly, or (4) the effusion fails to respond to management of the heart failure.

Thoracentesis is urgent when it is suspected that blood (i.e., hemothorax) or pus

(i.e., empyema) is in the pleural space, because immediate tube thoracostomy is

indicated in these situations. If difficulty in obtaining pleural fluid is encountered because

the effusion is small or loculated, ultrasound-guided thoracentesis minimizes the risk for

iatrogenic pneumothorax (Jones PW et al., 2003). In most instances, analysis of the

pleural fluid yields valuable diagnostic information or definitively establishes the cause

of the pleural effusion. This is the case when malignant cells, microorganisms, or chyle

are found, or when a transudative effusion is found in the setting of heart failure or

cirrhosis. Although common, chest radiography is not necessary after thoracentesis

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unless air is obtained during the procedure; the patient develops symptoms such as

dyspnea, cough, or chest pain; or tactile fremitus is lost over the upper part of the

aspirated hemithorax.

Should a thoracentesis be performed?

Most patients who have a pleural effusion should undergo a diagnostic

thoracentesis. There are, however, two situations in which a diagnostic thoracentesis is

not recommended. Firstly, if the effusion is very small, the risk/benefit ratio of a

thoracentesis increases. The amount of pleural fluid can be semiquantitated by

obtaining a decubitus chest radiograph with the side of the effusion down, and

measuring the distance between the outer border of the lung and the inner border of the

chest wall. If this distance is less than 10 mm, a diagnostic thoracentesis is not

recommended (Light RW, 1995). The use of ultrasound to facilitate the performance of

the thoracentesis is recommended in patients with relatively small effusions (10–15 mm

thickness on the decubitus radiograph). Secondly, if the patient has congestive heart

failure, a thoracentesis is recommended only if the patient meets one of the following

three conditions: 1) the effusions are not bilateral and comparably sized; 2) the patient

has pleuritic chest pain; or 3) the patient is febrile. If none of these three conditions is

met, then treatment of the congestive heart failure is initiated. If the pleural effusions do

not rapidly disappear, a diagnostic thoracentesis is performed several days later. It

should be noted that, with diuresis, the characteristics of the pleural fluid may

occasionally change from those of a transudate to those of an exudates (Shinto RA,

Light RW, 1993). However, in such patients, the serum to pleural fluid albumin gradient

usually remains above 1.2 g·dL-1; in this situation, this gradient can be used to assess

26

when the patient has a transudative or an exudative pleural effusion (Mlika-Cabanne N,

Brauner M, Magusi F, et al, 1995.)

Analysis of Pleural Fluid

Furthermore, pleural effusions are either transudates or exudates based on the

biochemical characteristics of the fluid, which usually reflect the physiologic mechanism

of its formation. 1) A transudative pleural effusion is one producing a clear fluid. This is

not a disease in the pleura itself, but rather an imbalance in the removal and intake of

pleural fluid. Forty percent of the time, congestive heart failure is the known main cause

of pleural effusion. As a result, a bilateral type of effusion is usually observed. For a

one-sided effusion, the right part of the lungs is frequently the one affected because

people tend to lie on the right side. 2) Exudative pleural effusion comes about when the

pleura itself is diseased. The causes are several and varying, most common of which

are infections due to bacterial pneumonia and tuberculosis (Jones PW et al., 2003). 

Consequently, pleural effusions are commonly seen in a variety of diseases. In

order to identify which disease is involved, the pleural fluid is usually subjected to

several examinations. These are the tests for chemical characteristics like specific

gravity, ph, protein and glucose; tests for changes of its components like the total

leukocyte and differential cell counts and determinations of other elements like gram

and AFB staining and culture (Table 3). Light et al have shown that two groups of

patients can be separated as initial part of the diagnostic work-up by measuring the

protein and lactate dehydrogenase (LDH) in the serum and in the pleural fluid 5 in to

the exudative and transudative effusions (Table 4).

27

TABLE 3. Routine tests on pleural fluid

Chemistries Bacteriologic Studies Ph Culture of centrifuged cell sediment Glucose Aerobes Lactate dehydrogenase Protein Anaerobes Amylase Acid fast bacilliBacteriologic Studies Fungi Stains of centrifuged cell sediment Cytologic studies of centrifuged sediment Gram stain Papanicolaou's stain Acid-fast stain Romanovsky-type stains Silver or PAS stain Complete cell and differential count

TABLE 4. Values distinguishing transudative from exudative pleural effusion

Value Transudate Exudate

Total protein (pleural fluid) < 3 gm% >3 gm%Lactate dehydrogenase (LDH) < 200 IU > 200 IUPleura1fluid total protein/Serum total < 0.5 > 0.5proteinPleural fluid LDH/Serum LDH < 0.6 > 0.6Specific gravity by hydrometer < 1.016 > 1.016

Another study, conducted by Tantongco (1987), in his thesis entitled, “Pleural

Fluid AFB Staining: Useful or Not? A 5-Year CVGH Experience”, found the following:

The 5 year review of patients admitted at Cebu Velez General Hospital and

diagnosed to have tuberculous pleural effusion, revealed that AFB staining of the

pleural fluid is not an efficacious tool in the initial work-up. The result is in

accordance with the proposed pathophysiologic mechanism for pleural effusion

based on hypersensitivity reaction to tuberculous protein. Although foreign

reports have shown the possibility of a positive AFB smear, it was generally

28

considered insignificant, attributed to other pathophysiologic mechanisms of less

practical value. Omission of AFB smear may lessen the cost of diagnosis which

ultimately rests on other tests used to demonstrate the organism and other

supportive evidences of the disease.

Hence in our locality, whenever a patient is found to have exudative effusion, a

diagnosis of tuberculous pleuritis is considered. The obvious explanation to this

is the continued high incidence of tuberculosis in the Philippines. In the desire to

establish the diagnosis, AFB staining of the pleural fluid is one of the most

commonly ordered laboratory examination. A review of foreign literature has

consistently shown that this procedure is not an efficacious tool in the diagnosis

of tuberculous effusion.

Treatment Protocols of PTB

The World Health Organization (2009) procured a standard regimen for the

treatment of tuberculosis with regards to new and previously treated patients,

recommended doses for the first-line anti-TB drugs and considerations in selecting a

regimen for defined patient groups. It aims to cure the disease and to restore the quality

of life of the patient, prevent death and avoid possible complications of the disease,

prevent relapse, reduce transmission to others and avoid the development of drug

resistance.

29

Directly Observed Treatment Short Course was started by the World Health

Organization in order to effectively diagnose, give standard treatment under direct

observation, and systematic monitoring and evaluation of patients undergoing

treatment. The five principles of the DOTS program as recommended by the World

Health Organization include effective political and administrative commitment, case

finding primarily by microscopic examination of sputum of patients presenting to health

facilities, short-course therapy given under direct observation, adequate drug supply,

and systematic monitoring accountability for every patient diagnosed (ICMR Bulletin,

2001). In the Philippines, TB-DOTS Program in still being currently implemented. As of

2004, the case detection rate (CDR) improved from 53% in 2003 to 68% and the cure

rate increased from 75% in 2003 to80.6%. Both are however still below global targets of

70% and 85% respectively.

As of the present study of WHO (200), case detection and treatment success

rates have exceeded the global targets since 2004. PPM initiatives have been further

expanded, and their contribution to the national case detection rate reached 9% in

2007, with only 40% population coverage. The country is now scaling up programmatic

management of drug-resistant TB to include areas beyond Metro Manila, expanding

services for TB in children and addressing TB in high-risk groups including among the

HIV-infected, the urban poor and the prison population. The third prevalence survey in

2007 showed a 34% decrease in bacteriologically-confirmed TB compared with the

1997 survey. The survey results will help re-estimate the burden of TB in the Philippines

and improve understanding of risk factors. Government commitment is strong, and the

30

increases in funding from domestic sources and the Global Fund grant have helped to

reduce funding gaps.

Synthesis

The present study - Retrospective Analysis of Pleural Fluid: Patient’s

Demographics, AFB Pleural Stain and MTB Culture in Relation to Medical Treatment of

Pulmonary Tuberculosis in Santo Tomas University Hospital from January 2011-

October 2011 – basically differs from the aforementioned related studies published in

books and journals for the following reasons. First, this study attempts to describe the

over-all aspects of pleural effusion in tuberculosis. Second, it raises awareness and

consciousness of the diagnostic approach, specifically using thoracentesis. Third, the

study provides more in-depth knowledge on the treatments of PTB in our country.

Currently, no study has taken into consideration of pleural fluid AFB staining as

one of the procedures of evaluating pleural effusion in PTB among Santo Tomas

Hospital. This study will bridge this gap in the literature.

Chapter 3

RESEARCH METHODLOGY

This chapter describes the methodology used in the study. It is divided into the

following sections: research design, data collection methods, inclusion criteria,

31

exclusion criteria, and data analysis. The methodology is based on the research

objectives of the study.

Research Design

A retrospective analysis with descriptive study was done. The study entailed a

detailed retrospective review of medical census from Junior Interns Batch 2012 of UST

– Faculty of Medicine and Surgery. Medical censuses of 47 patients, who were admitted

and underwent thoracentesis at Santo Tomas University Hospital from January 2011 –

December 2011.

Data Collection Methods

The method used to address the objectives of the study was done by collecting

all the medical censuses made by the Junior Interns Batch 2012 of admitted patients.

The records include name, age, gender, and admitting diagnosis. Results of

thoracenteses done are also included.

Inclusion Criteria

All patients admitted at the Medicine Ward of the Clinical Division of Santo

Tomas University Hospital, presenting with pleural effusion and subsequently

underwent thoracentesis from January 2011 – December 2011.

32

Exclusion criteria

Patients who have proven malignancies, on pub treatment, have other primary

considerations for cause of pleural effusion other than PTB.

Research Setting

The study was conducted at Santo Tomas University Hospital, Clinical Division.

Chapter 4

RESULTS AND CONCLUSIONS

This chapter presents the results and discussion of data gathered based on the

main research goal of the study.

33

Patients’ Demographics

In these patients, the diagnosis of tuberculous effusion was made through either

of the following criteria:

1. The demographic of patients diagnosed with tuberculous effusion along with

age and sex shown in Table 5. The clinical history, physical examination findings,

pleural fluid analysis, pleural biopsy results and response to treatment were suggestive

of tuberculous effusion and sufficient to rule out other diseases like congestive heart

failure, liver cirrhosis, nephrosis, malignancy, parapneumonic effusion or effusion

associated with connective tissue diseases.

Table 5. Demographics based on criteria No. 1

DemographicsAge

<2525-5050-75>75

622172

Sex Male Female

2522

Demonstration of AFB Staining

2. The demonstration of acid fast bacilli in the sputum examination on PTB and

the diagnosis of the patients, Table 6.

Table 6. Distribution of AFB staining based on criteria No. 2

MTB Culture

34

AFB Pleural fluid Stain

(+) (-) NIL(culture)

(+)

(-)11 15

Tally patients scoring system

Diagnosis No. of PatientsPneumoniaMalignancy 11Hypoalbuminemia 1Parapneumonic effusion 7Unknown 2

Not sent: 10

Total Respondents population (47)

Results

Population (N) 47 Forty-seven patients were included in the study. All underwent

thoracentesis from January 2011- December 2011 at the UST Hospital Clinical Division. Of the

forty-seven (47) patients, twenty-six (26) patients were diagnosed to have Pulmonary

Tuberculosis, eleven (11) with Malignancy, one (1) with Hypoalbuminemia, seven (7) with

Parapneumonic effusion and two (2) with unknown diagnosis. Twenty-two (22) patients were

female while twenty-five (25) were male. Patients who were included in the study belong to

different age group. Six (6) were aged twenty-five and below (<25), twenty-two (22) were aged

twenty-five to fifty (25-50), seventeen (17) were fifty to seventy-five (50-75) and two (2) were

seventy-five and above (>75).

35

In the twenty-six patients who were diagnosed to have PTB, all were able to send their

pleural fluid for AFB staining and culture. All the patients had negative results for AFB staining.

Eleven (11) patients had positive culture while fifteen (15) had negative results.

There were a total of ten (10) patients who were not able to send their pleural fluids for

AFB or culture studies.

Discussion

1. Pleural fluid analysis is used to aid in analyzing the cause of inflammation of

the pleura (pleuritis) and/or accumulation of fluid in the pleural space

(pleural effusion). make short paragraph about pleural fluid analysis. discuss each

parameter then narrow it down to the importance of culture as a gold standard and AFB

staining. Light (2001) has theorized that rupture of the pleuralcaseous foci often

detected by pleural biopsy into the pleural space allow tuberculous protein to enter and

generate the hypersensitivity reaction. This is further supported by Sallach, et al (2002)

in their study, which demonstrated the presence of T-lymphocytes in the pleural fluid

specifically sensitized to tuberculous protein. The ensuing reaction caused increased

permeability of the pleural capillaries to protein and the increased protein levels in the

pleural fluid then lead to the accumulation of pleural fluid. Such is probably the

pathophysiologic explanation for the low or zero recovery rate of the AFB smear. As

shown by this study, there were 26 cases with negative AFB staining of the pleural fluid

where TB effusion was the subsequent diagnosis. The technique of AFB staining

36

adopted by the SantoTomas University Hospital, was universally accepted or

recognized. This was used not only during the period covered by this study but also in

preceding years.

2. In a study by Tantongco (1987), he pointed out that the probability of a positive AFB

stain in exudates of unknown cause to be low, e.g. 7%, in subsequently proven cases of

tuberculosis as to render the test virtually useless. This further supports the idea that

mechanisms other than hypersensitivity reaction play a negligible role in the

development of tuberculous pleural effusion. It was even mentioned the role of multiple

pleural fluid cultures as a means of increasing diagnostic yield. Though this may sound

ideal, we question its practical usefulness in the local setting. As far as our experience

with AFB smear is concerned, the test was useless. Physicians should therefore not rely

strongly on the diagnostic reliability of AFB staining and should make use of other tests

for the diagnosis of tuberculous effusion. One still has to maximize the benefits of a

good history, physical examination, supportive evidences obtained from pleural fluid

analysis, chest x-ray, response to treatment, and more definitely, the isolation of the

organism from specimens.

3. Currently, several authors have endorsed the use of histopathologic examinations and

culture for AFB of pleural tissue obtained by closed pleural biopsy. Added to the fact

that the AFB stain costs 410 pesos and one culture for 1480 pesos. In a practical sense,

the patients could use this money for medicines.

4. The other 10 patients whom did not go through AFB staining are most likely having

insufficient funds to continue this test.

37

Conclusion

The review of patients by medical censuses who were admitted and underwent

thoracentesis at Santo Tomas University, revealed that AFB staining of the pleural flu id is not

an effective tool in the preliminary set up. The result is in arrangement with the proposed

pathophysiologic mechanism for pleural effusion based on hypersensitivity reaction to

tuberculous protein. As much as overseas information have shown the chance of a positive

AFB smear, it was generally considered irrelevant, attributed to other pathophysiologic

mechanisms of less practical value. Exclusion of AFB smear may lessen the cost of diagnosis

which ultimately rests on other tests used to demonstrate the organism and other supportive

evidences of the disease.

Recommendation

More subjects, more parameters, more tertiary hospitals

38

REFERENCES

1. Light  RW.  Clinical practice. Pleural effusion.  N Engl J Med.  2002;346:1971–7.

2. Efrati  O, Barak  A.  Pleural effusions in the pediatric population.  Pediatr Rev. 2002;23:417–26.

3. Light RW. Pleural diseases. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2001.

4. Porcel  JM, Vives  M.  Etiology and pleural fluid characteristics of large and massive effusions.  Chest.  2003;124:978–83.

5. Porcel JM, Light RW. Thoracentesis. PIER, American College of Physicians, 2004. Accessed online October 28, 2004, at:http://pier.acponline.org. Subscription required.

6. Jones  PW, Moyers  JP, Rogers  JT, Rodriguez  RM, Lee  YC, Light  RW. Ultrasound-guided thoracentesis: is it a safer method?.  Chest.  2003;123:418–23.

7. Villena  V, López-Encuentra  A, García-Luján  R, Echave-Sustaeta  J, Martínez  CJ. Clinical implications of appearance of pleural fluid at thoracentesis.  Chest. 2004;125:156–9.

8. Porcel  JM, Vives  M, Vicente de Vera  MC, Cao  G, Rubio  M, Rivas  MC.  Useful tests on pleural fluid that distinguish transudates from exudates.  Ann Clin Biochem. 2001;38:671–5.

9. Romero-Candeira  S, Fernández  C, Martín  C, Sánchez-Paya  J, Hernández  L. Influence of diuretics on the concentration of proteins and other components of pleural transudates in patients with heart failure.  Am J Med.  2001;110:681–6.

10. Romero-Candeira  S, Hernández  L.  The separation of transudates and exudates with particular reference to the protein gradient.  Curr Opin Pulm Med.  2004;10:294–8.

11. Heffner  JE, Highland  K, Brown  LK.  A meta-analysis derivation of continuous likelihood ratios for diagnosing pleural fluid exudates.  Am J Respir Crit Care Med. 2003;167:1591–9.

12. Barnes  TW, Olson  EJ, Morgenthaler  TI, Edson  RS, Decker  PA, Ryu  JH.  Low yield of microbiologic studies on pleural fluid specimens.  Chest.  2005;127:916–21.

13. Sahn SA, Heffner JE. Pleural fluid analysis. In: Light RW, Gary Lee YC. Textbook of pleural diseases. London: Arnold, 2003:191–209.

39

14. Colice  GL, Curtis  A, Deslauriers  J, Heffner  J, Light  R, Littenberg  B, et al. Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline.  Chest.  2000;118:1158–71.

15. Davies  CW, Gleeson  FV, Davies  RJ, Pleural Diseases Group.  Standards of Care Committee, British Thoracic Society. BTS guidelines for the management of pleural infection.  Thorax.  2003;58(suppl 2):ii18–28.

16. Villena  V, Pérez  V, Pozo  F, López-Encuentra  A, Echave-Sustaeta  J, Arenas  J, et al.  Amylase levels in pleural effusions: a consecutive unselected series of 841 patients.  Chest.  2002;121:470–4.

17. Villena  V, López-Encuentra  A, Pozo  F, Echave-Sustaeta  J, Ortu˜o-de-Solo  B, Estenoz-Alfaro  J, et al.  Interferon gamma levels in pleural fluid for the diagnosis of tuberculosis.  Am J Med.  2003;115:365–70.

18. Porcel  JM, Vives  M, Cao  G, Esquerda  A, Rubio  M, Ribas  MC.  Measurement of probrain natriuretic peptide in pleural fluid for the diagnosis of pleural effusions due to heart failure.  Am J Med.  2004;116:417–20.

19. Porcel  JM.  The use of probrain natriuretic peptide in pleural fluid for the diagnosis of pleural effusions resulting from heart failure.  Curr Opin Pulm Med.  2005;11:329–33.

20. Falguera  M, López  A, Nogués  A, Porcel  JM, Rubio-Caballero  M.  Evaluation of the polymerase chain reaction method for detection ofStreptococcus pneumoniae DNA in pleural fluid samples.  Chest.  2002;122:2212–6.

21. Pai  M, Flores  LL, Hubbard  A, Riley  LW, Colford  JM  Jr.  Nucleic acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis.  BMC Infect Dis.  2004;4:6

22. Dikmen  G, Dikmen  E, Kara  M, Sahin  E, Dogan  P, Özdemir  N.  Diagnostic implications of telomerase activity in pleural effusions.  Eur Respir J.  2003;22:422–6.

23. Porcel  JM, Vives  M, Esquerda  A, Salud  A, Pérez  B, Rodríguez-Panadero  F. Use of a panel of tumor markers (carcinoembryonic antigen, cancer antigen 125, carbohydrate antigen 15–3, and cytokeratin 19 fragments) in pleural fluid for the differential diagnosis of benign and malignant effusions.  Chest.  2004;126:1757–63.

24. Porcel  JM, Salud  A, Vives  M, Esquerda  A, Rodriguez-Panadero  F.  Soluble oncoprotein 185(HER-2) in pleural fluid has limited usefulness for the diagnostic evaluation of malignant effusions.  Clin Biochem.  2005;38:1031–3.

25. Conner  BD, Lee  YC, Branca  P, Rogers  JT, Rodriguez  RM, Light  RW.  Variations in pleural fluid WBC count and differential counts with different sample containers and different methods.  Chest.  2003;123:1181–7.

40

26. Porcel  JM, Vives  M.  Differentiating tuberculous from malignant pleural effusions: a scoring model.  Med Sci Monit.  2003;9:CR175–80.

27. Goto  M, Noguchi  Y, Koyama  H, Hira  K, Shimbo  T, Fukui  T.  Diagnostic value of adenosine deaminase in tuberculous pleural effusion: a meta-analysis.  Ann Clin Biochem.  2003;40:374–81.

28. Greco  S, Girardi  E, Masciangelo  R, Capoccetta  GB, Saltini  C.  Adenosine deaminase and interferon gamma measurements for the diagnosis of tuberculous pleurisy: a meta-analysis.  Int J Tuberc Lung Dis.  2003;7:777–86.

29. Porcel  JM, Vives  M.  Adenosine deaminase levels in nontuberculous lymphocytic pleural effusions.  Chest.  2002;121:1379–80.

30. Jiménez Castro  D, Díaz Nuevo  G, Pérez-Rodríguez  E, Light  RW.  Diagnostic value of adenosine deaminase in nontuberculous lymphocytic pleural effusions.  Eur Respir J.  2003;21:220–4.

31. Davies PD. Tuberculous pleuritis. In: Bouros D, ed. Pleural disease. New York: Marcel Dekker, 2004:677–97.

32. Hasaneen  NA, Zaki  ME, Shalaby  HM, El-Morsi  AS.  Polymerase chain reaction of pleural biopsy is a rapid and sensitive method for the diagnosis of tuberculous pleural effusion.  Chest.  2003;124:2105–11.

33. Maskell  NA, Butland  RJ, Pleural Diseases Group, Standards of Care Committee, British Thoracic Society.  BTS guidelines for the investigation of a unilateral pleural effusion in adults.  Thorax.  2003;58(suppl 2):ii8–17.

34. Sallach  SM, Sallach  JA, Vasquez  E, Schultz  L, Kvale  P.  Volume of pleural fluid required for diagnosis of pleural malignancy.  Chest.  2002;122:1913–7.

35. Arenas-Jiménez  J, Alonso-Charterina  S, Sánchez-Paya  J, Fernández-Latorre  F, Gil-Sanchez  S, Lloret-Llorens  M.  Evaluation of CT findings for diagnosis of pleural effusions.  Eur Radiol.  2000;10:681–90.

36. Duysinx  B, Nguyen  D, Louis  R, Cataldo  D, Belhocine  T, Bartsch  P, et al. Evaluation of pleural disease with 18-fluorodeoxyglucose positron emission tomography imaging.  Chest.  2004;125:489–93.

37. Prakash  UB, Reiman  HM.  Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusion: analysis of 414 cases.  Mayo Clin Proc. 1985;60:158–64.

41

38. Maskell  NA, Gleeson  FV, Davies  RJ.  Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial.  Lancet.  2003;361:1326–30.

39. Antony  VB, Loddenkemper  R, Astoul  P, Boutin  C, Gold-straw  P, Hott  J, et al. Management of malignant pleural effusions.  Eur Respir J.  2001;18:402–19.

40. Light  RW.  Update: management of the difficult to diagnose pleural effusion.  Clin Pulm Med.  2003;10:39–46.

41. Venekamp  LN, Velkeniers  B, Noppen  M.  Does “idiopatic pleuritis” exist? Natural history of non-specific pleuritis diagnosed after thoracoscopy.  Respiration. 2005;72:74–8.