HIV PATIENTS

HIV PATIENTS

••••••••••••••••••••••••••••••••

By

DR. SANTHI V ARA THARAJA PILLA!

Dissertation Submitted in Partial Fulfilment of the Requirements for the Degree of Master of Medicine

(Radiology)

UNIVERSITI SAINI MALAYSIA UNIVERSITI SAINS MALAYSIA

2008

To

my mum Mdm Sakunthala Pillai and

my brother Mr Umasangar Pillai

a very special Thank You.

ACKNOWLEDGEMENT

The author would like to express her sincere gratitude to the following individuals for their valuable comments, guidance, support and co-operation that they have given during the preparation of this dissertation. Without them, this study would not have been successful.

o Special thanks goes to my supervisors, Dr Nik Munirah Nik Mahdi, lecturer and radiologist at Department of Radiology, Hospital Universiti Sains Malaysia, Kubang Kerian, and Dr Md. Ariff Bin Abas, AMP., Consultant radiologist and Head, Department of Diagnostic Imaging, Hospital Raja Perempuan Zainab II, Kota Bharu, who have given their effort, patience and full support throughout the period to make this study a success.

o Co-supervisor of this dissertation, Dr. Mahiran Mustafa, Consultant Physician &

ID Specialist, Department of Medicine, Hospital Raja Perempuan Zainab II, Kota Bharu, whose support and help in giving ideas, guidance and solutions to all problems that occurred during the study.

o My gratitude goes to Dr Mohd Ezane Aziz, lecturer, radiologist and Head of Department of Radiology, Hospital Universiti Sains Malaysia, Kubang Kerian.

o My special gratitude goes to Dr Win Mar@ Salmah Jallaluddin and Dr Noreen Norfaraheen Lee Abdullah, (my lecturers and radiologists) for their presence, valuable ad vices and comforting words helped me along the way.

o My appreciation also goes to Dr Mohd Shafie Abdullah and Dr Juhara Harun, (lecturers and radiologists) who directly or indirectly contributed their ideas and comments.

o I have furthermore to thank Dr Muhammad Naeem Khan (Department of

(Department of Biostatistic and Epidemiology), Dr Kamarul Imran Musa (Department of Community Medicine) and AP Dr Syed Hatim Noor@ Nyi Nyi Naing (Department of Biostatistic and Epidemiology) for their assistance in statistical analyses.

o Especially I am obliged to Dr Noor Azizah Binti Abdul Halim, Radiologist, Department of Diagnostic Imaging, Hospital Raja Perempuan Zainab II, Kota Bharu, for her assistance and support to complete this dissertation.

o I would particularly like to express my warmest gratitude to Mr Udin Abdullah (radiographer, formerly in the Department of Diagnostic Imaging, HRPZ-11) and Mdm Enikartini Daud (Guru Bahasa, Centre for Languages and Translation, USM) for their enthusiasm and helping me in Bahasa Malaysia (BM) translation.

o I would like to thank the staffs in the record office of chest clinic, microbiology laboratory and physician clinic in Hospital Raja Perempuan Zainab II, Kota Bharu for their ever willingness to trace the patient records, results and radiographs whenever required.

o Not forgetting, I am deeply indebted to my former radiologist and coordinator Dr Vijayalakshmi Krishnapillai, who is now Consultant Radiologist and Head, Department of Diagnostic Imaging in Hospital Tengku Ampuan Rahimah, Klang, for her everlasting encouragement, advice and guidance.

o Most of all to my brother Mr Umasangar Pillai and my mum Mdm Sakunthala Pillai for their endless encouragement, support and comforting words along the way, a very special Thank You.

TABLE OF CONTENTS

TABLE OF CONTENTS

CONTENTS

Title Page

Acknowledgement Table of Contents List of Tables List of Figures

Abbreviations and Symbols Abstract

Bahasa Malaysia English

SECTION 1

1. INTRODUCTION

SECTION2

2. LITERATURE REVIEW

2.1 GENERAL 2.2 EPIDEMIOLOGY

2.3 OVER-VIEWS ON THE PATHOGENESIS AND CLINICAL FEATURES OF PULMONARY TUBERCULOSIS

PAGE

I

11

v

XI

Xlli

XVI

XIX

XX

XXlli

1

2

4

5 5 5

7

2.4 OVER-VIEWS ON THE PATHOGENESIS AND CLINICAL FEATURES OF

TUBERCULOSIS IN HIV I AIDS 9

2.5 DIAGNOSIS OF THE PULMONARY TUBERCULOSIS 11

2.6 RADIOLOGICAL INVESTIGATION IN PULMONARY TUBERCULOSIS 12

2.7 BACTERIOLOGICAL EXAMINATION OF SPUTUM IN PTB 22

2.7 .1 SPUTUM MICROSCOPY FOR ACID-FAST BACILLI (AFB) SMEAR 22 2.7 .2 SPUTUM CULTURE FOR MYCOBACTERIA TUBERCULOSIS 25 2.8 INDICATION FOR SCREENING OF HIGH RISK GROUPS BASED ON MOH,

MALAYSIA GUIDELINE

2.9 MOH GUIDELINES ON MANAGEMENT OF TUBERCULOSIS

SECTION 3

3. OBJECTIVES AND HYPOTHESIS

3.1 GENERALOBJECTIVE 3.2 SPECIFIC OBJECTIVES 3.3 RESEARCH QUESTION 3.4 NULL HYPOTHESIS

SECTION 4

4. METHODOLOGY

4.1 RESEARCH DESIGN

4.2POPULATION AND SAMPLE 4.3 OPERATIONAL DEFINITION 4.4 INCLUSION CRITERIA 4.5 EXCLUSION CRITERIA 4.6 SAMPLE SIZE

26 26

29

30 30 30 30 30

31

32 32 32 33 35 35 36

4.8 DATA COLLECTION PROCEDURE 40

4.9 RESEARCH TOOL 41

4.10 MATERIALS AND METHODS 41

4.10.1 DIAGNOSIS OF TUBERCULOSIS 41

4.10.2 IMAGING PROTOCOL FOR CHEST RADIOGRAPH IN HRPZ-11 41

4.10.3 CHEST RADIOGRAPH REPORTING CRITERIA 42

4.10.4 SPUTUM FOR AFB SMEAR MICROSCOPY AND CULTURE MTB 46

4.10.5 BLOOD TEST FOR HIV STATUS 46

4.11 ETHICAL CONSIDERATION 47

4.12 STATISTICAL ANALYSIS 48

~CTIONS ®

5. RESULTS 50

5.1 PATIENTS CHARACTERISTICS 50

5.1.1 GENDER DISTRIBUTION 50

5.1.2 ETHNIC DISTRIBUTION 50

5.1.3 AGE DISTRIBUTION 50

5.1.4 SMOKING 51

5.1.5 CLOSE CONTACT WITH TUBERCULOSIS 51

5.1.6 CLINICAL SYMPTOMS AND SIGNS OF PTB 53

5.1.7 LABORATORY SPUTUM EXAMINATION FINDING AMONG NON-HIV AND

HIV PATIENTS. 54

5.2 STATISTICAL ANALYSIS 55

5.2.1 CHEST RADIOGRAPH FINDINGS AMONG NON-HIV AND HIV PATIENTS. 55

5.2.2 VARIABLE CHEST RADIOGRAPH APPEARANCES 57

SECTION6

6. DISCUSSION

6.1 GENERAL

6.2 PATIENTS CHARACTERISTICS 6.2.1 GENDER DISTRIBUTION 6.2.2 ETHNIC DISTRIBUTION 6.2.3 AGE DISTRIBUTION 6.2.4 SMOKING

6.2.5 CLOSE CONTACT WITH TB

6.2.6 CLINICAL SYMPTOMS AND SIGNS OF PTB

76

77 77 77 77 78 78

79 80 80

6.2.7 LABORATORY SPUTUM EXAMINATION FINDING AMONG NON-HN AND

HN PATIENTS 82

6.3 STATISTICAL ANALYSIS 84

6.3.1 CHEST RADIOGRAPH FINDINGS AMONG NON-HN AND HN PATIENTS 84 6.3.2 VARIABLE CHEST RADIOGRAPHS APPEARANCE 86 6.3.3 IMPORTANCE OF CLINICAL ASSESSMENT IN PTB

6.3.4 IMPLICATION OF RESULT

SECTION7

7. CONCLUSION

SECTIONS

8. LIMITATION AND RECOMMENDATION

8.1 LIMITATION OF THE STUDY 8.2 RECOMMENDATION

90

92

95

96

97

98 98

99

SECTION9

9. REFERENCES

SECTION 10

10. APPENDIX

10.1 CONSENT 10.2 DATA SHEET

10.2.1 DATA ENTRY SHEET (Filled by Clinician)

1 0.2.2 DATA COLLECTION SHEET (Filled by Reporting Radiologist) 1 0.2.3 DATA COLLECTION SHEET (Filled by Researcher)

10.3 ILLUSTRATIONS

101

102

108

109 109 120 120 121 123 124

LIST OF TABLES

LIST OF TABLES

TABLES PAGE

TABLE 1: Manifestations of Tuberculosis Activity in the Chest Radiograph 20 TABLE 2: Quantitation Scale for Sputum Acid-Fast Bacillus Smears

(IUAT SCALE) 24

TABLE 3: Standard Antituberculosis Drugs and the Recommended Dosages 27

TABLE 4: Chest Radiograph Classification ofPTB 43

TABLE 5: Descriptive Analysis between Non-HIV and HIV groups 52 TABLE 6: Clinical Signs and Symptoms of Tuberculosis among Non-HIV

and HIV Patients 53

TABLE 7: Pre-treatment Laboratory Sputum Examination Findings

in Non-HIV and HIV Patient 54

TABLE 8: Pre-treatment Chest Radiograph Findings between Non-HIV and

HIV Patients 55

TABLE 9: Pre-treatment Chest Radiograph Appearances between Non-HIV

and HIV Patients 55

TABLE I 0: Six Months Post-treatment Chest Radiograph Findings between

Non-HIV and HIV Patients 56

TABLE II: Six Months Post-treatment Chest Radiograph Appearances between

Non-HIV and HIV Patients 56

TABLE 12: Variable Chest Radiograph Appearance of Pulmonary Tuberculosis

among Non-HIV and HIV Patients 57

LIST OF FIGURES

LIST OF FIGURES

FIGURES PAGE

FIGURE 1: Flow Chart - Recommended by MOH, 24weeks/6months

Treatment Regimen (Adult) 28

FIGURE 2: Methodology Flow Chart 40

FIGURE 3: Histogram- Age Distribution among Non-HIV and HIV Patients 51

FIGURE 4: Tuberculoma 58

FIGURE 5: Cavitation 59

FIGURE 6: Pleural effusion 60

FIGURE 7: Hilar adenopathy 61

FIGURE 8: Pneumothorax 62

FIGURE 9: Miliary TB 63

FIGURE 10: Fibrosis and Bronchiectasis and Pleural thickening 64 FIGURE 11: Lung fibrosis and apical Pleural thickening 65

FIGURE 12: Cicatrization atelectasis 66

FIGURE 13: Nodules 67

FIGURE 14: Consolidation 68

FIGURE 15: Normal 69

FIGURE 16: Mildly Abnormal Pre-treatment Chest Radiograph 70 FIGURE 17: Moderately Abnonnal Pre-treatment Chest Radiograph 71 FIGURE 18: Severely Abnormal Pre-treatment Chest Radiograph 72 FIGURE 19: Mildly Abnormal Post-treatment Chest Radiograph 73 FIGURE 20: Moderately Abnonnal Post-treatment Chest Radiograph 74

FIGURE 22: Mildly Abnormal (minimal)

FIGURE 23: Moderately Abnormal (moderately advanced) FIGURE 24: Severely Abnormal (far advanced)

124 125 126

ABBREVIATIONS AND

SYMBOLS

ABBREVIATIONS AND SYMBOL

ABBREVIATIONS

AFB AIDS CDC CXR C/S D/S FNAC IU HIV HRPZ-11 HUSM MKAK MTB

M. Tuberculosis Non-HIV NTBC PCR PA PPD PTB TB TU WHO

Acid Fast Bacilli

Acquired Immunodeficiency Syndrome Centre for Disease Control

Chest Radiograph Culture and Sensitivity Direct Smear

Fine Needle Aspiration Cytology International Tuberculin Units Human Immunodeficiency Virus Hospital Raja Perempuan Zainab-11 Hospital Universiti Sains Malaysia Makmal Kesihatan Awam Kebangsaan Mycobacterium tuberculosis

Mycobacterium tuberculosis

Non Human Immunodeficiency Virus National Tuberculosis Centre

Polymerase Chain Reaction Posteroanterior

Purified Protein Derivative of Tuberculosis Pulmonary Tuberculosis

Tuberculosis Tuberculin Unit

World Health Organisation

SYMBOLS

n number of samples

=

vs. versus

I.e. that is

e.g. example

X times (multiply by)

kVp kilovoltage peak (x-ray tube voltage)

mAs milliamperes seconds (tube current)

6/12 six months

'05 2005

'08 2008

> more than

< less than

& and

ABSTRACT

ABSTRAK

PENGENALAN

Tuberkulosis paru-paru (PTB) merupakan satu penyakit berjangkit yang paling lazim berlaku di negara-negara membangun dan komplikasi penyakit ini merupakan satu cabaran dan amat sukar didiagnos. Kadar tuberkulosis di kalangan pesakit yang mempunyai daya pertahanan badan lemah adalah sangat tinggi dan ia juga merupakan antara penyumbang utama kepada mobiditi dan mortaliti.

OBJEKTIF

Tujuan utama kajian ini adalah untuk menentukan perhubungkan di antara tahap keparahan radiograf dada pada pesakit PTB dengan status HIV (bukan HIV dan HIV).

Kajian ini juga bertujuan untuk menilai perbezaan dalam pelbagai manifestasi radiograf dada yang berbeza di kalangan pengidap PTB bagi dua kumpulan kajian seperti yang dinyatakan di atas.

BAHAN DAN KAEDAH

Kajian ini berbentuk retrospektif, yang mana ia memfokus kepada pesakit PTB di kalangan dewasa yang dijangkiti dan tidak dijangkiti HIV di Hospital Raja Perempuan Zainab-11, Kota Bharu. Pesakit-pesakit yang dipilih untuk kajian ini adalah pesakit yang mempunyai simptom dan tanda-tanda PTB, yang telah disahkan melalui "sputum smear AFB" atau dengan kultur MTB.

KEPUTUSAN

Kadar umur untuk pesakit bukan HIV adalah 46.5 tahun dan untuk pesakit dengan HIV ialah 32.6 tahun. Analisa menunjukkan 93% pesakit bukan HIV dan 94% pesakit HIV pula menunjukkan keputusan radiograf dada yang tidak normal semasa fasa pra- perawatan. Keputusan radiograf dada yang dijalankan selepas enam bulan perawatan dijalankan didapati menunjukkan 18% pesakit bukan HIV dan 31% pesakit HIV mempunyai radiograf dada yang kembali normal. Kajian statistik bagi kedua-dua kumpulan ini didapati tidak mempunyai perbezaan signifikan dari segi tahap keparahan ("severity") radiograf dada pada pesakit PTB semasa fasa pra-perawatan (p- value=0.668) dan selepas perawatan (p-value=0.135). Perbandingan yang dibuat antara dua kumpulan kajian semasa pra-perawatan menunjukkan pesakit HIV dengan PTB lebih kerap menghidapi "pleural effusion" (23% vs. 14%, p-value=0.081) dan "miliari tuberculosis" (7% vs. 3%, p-value=O.l96) walaupun tidak signifikan. Pembesaran kelanjar "hilar/mediastinal lymphadenopathy" (32% vs. 4%, p-value<0.001) pula menunjukkan perubahan yang signifikan di kalangan kumpulan pesakit yang disahkan HIV. Manakala pesakit bukan HIV pula lebih ramai mempunyai "pleural thickening"

(36% vs. 11%, p-value<O.OO 1 ), "bronchiectasis" (16% vs. 5%, p-value=0.007) dan

"fibrosis" paru paru (41% vs. 17%, p-value<0.001). Perubahan radiograf dada yang menunjukkan "cavitation" (33% vs 24%, p-value=O.l77) pula lebih rendah di kalangan kumpulan pesakit HIV tetapi ianya tidak menunjukan perbezaan yang signifikan antara dua kumpulan kajian ini.

KESIMPULAN

Kajian statistik bagi kedua-dua kumpulan yang dikaji mendapati tidak mempunyai perbezaan signikan dari segi tahap keparahan (severity) radigraf dada pada pesakit

mengidap PTB semasa fasa pra-perawatan (p-value=0.668) dan selepas perawatan (p- value=0.135). Kajian ini juga terdapat perbezaan yang signifikan secara statistik di antara pesakit PTB yang dijangiti HIV semasa fasa selepas enam bulan perawatan dengan menunjukan lebih banyak bilangan radiografi dada yand normal. Pesakit PTB yang mengidap HIV juga mempunyai perbezaan yang ketara pada radiograf dada terutamanya dalam manifestasi nodul limfa (lymphadenopathy) "hilar and mediastinum". Sementara itu "pleural thickening", "bronchiectasis", "fibrosis" dan

"consolidation" pula lebih kerap pada pesakit bukan HIV.

ABSTRACT

INTRODUCTION

Pulmonary tuberculosis (PTB) is the most common infectious disease in developing countries and the development of complications remains a difficult diagnostic challenge.

The proportion of tuberculosis developing in the immunocompromised hosts is especially high and is one of the leading causes of morbidity and mortality.

OBJECTIVE

The main purpose of this study was to determine the association between the chest radiograph severity of pulmonary tuberculosis with HIV status (non-HIV and HIV).

This study also evaluated the differences in the various chest radiograph appearances of pulmonary tuberculosis among the above mentioned two study groups.

MATERIALS AND METHODS

This was a retrospective study, focused on adult pulmonary tuberculosis patients with non-HIV and HIV coinfection form Hospital Raja Perempuan Zainab-11, Kota Bharu.

Those patients who had clinical symptoms and signs of PTB with either sputum smear AFB or culture MTB proven pulmonary tuberculosis were recruited for this study.

RESULT

Mean age of the patients in both non-HIV and HIV groups were 46.5 and 32.6 respectively. Ninety three percent (93%) of non-HIV and 94% of HIV patients demonstrated abnormal chest radiograph during pre-treatment phase. Whereas the chest radiograph done six months after the commencement of treatment demonstrated 18%

and 31% of normal finding in non-HIV and HIV patients, respectively. There was no significant statistical difference found among these two study groups in the chest radiograph severity/extent of PTB during pre-treatment (p-value=0.668) and post- treatment (p-value=O.l35) phases. Comparison of the two groups showed HIV patients with PTB had higher incidence of pleural effusion (23% vs. 14%, p-value=0.081) and miliary tuberculosis (7% vs. 3%, p-value=0.196), even-though non-significant.

Nevertheless, hilar/mediastinal lymphadenopathy (32% vs. 4%, p-value<0.001) demonstrated significant difference in the HIV group. Whereas in non-HIV patients more of pleural thickening (36% vs. 11%, p-value<0.001), bronchiectasis (16% vs. 5%, p-value=0.007) and lung fibrosis (41% vs. 17%, p-value<0.001) were demonstrated.

Lesser incidence of chest radiograph presentation with cavitation (33% vs. 24%, p- value=0.177) found in the HIV group, however no significant statistical difference among the two study groups.

CONCLUSION

There was no significant statistical difference found among the two study groups in the chest radiograph severity of PTB during pre-treatment (p-value=0.668) and (p- value=O.l35) post-treatment phases. This study also demonstrated significant statistical difference among the PTB with HIV co-infected patients by showing more number of normal chest radiograph in the post-treatment phase. HIV with PTB coinfected patient had considerable differences in the various chest radiograph presentations specifically with hilar/mediastinal lymphadenopathy. While pleural thickening, bronchiectasis, fibrosis and consolidation found more commonly in non-HIV patients.

SECTION 1

INTRODUCTION

1. INTRODUCTION

Tuberculosis (TB) is contagious and spreads through the air; if not treated, each person with active TB infects on average 10 to 15 people every year (World Health Organization, 2007). Worldwide, there are 1 0 million people infected with PTB, whereas 5-10% of those exposed having active TB and 30-40% of them with HIV coinfection. Tuberculosis, a frequent opportunistic infection in HIV coinfected patients, leads to further immune suppression and a faster progression of disease.

Chest radiograph (CXR) remains the first procedure in the imaging work-up of patients.

Sputum smear microscopy for acid-fast bacilli (AFB), although relatively insensitive, is still the cornerstone of tuberculosis diagnosis in the developing world (Bruchfeld J, 2000). Barnes et al found that chest radiograph was more effective screening tool than sputum AFB smear microscopy for detecting pulmonary tuberculosis (PTB), particularly when the disease (in HIV patient) was clinically inapparent (Barnes PF, 1991).

Increased awareness of HIV -related PTB and other pulmonary infections are required, together with improved diagnostic tools for patients with suspected PTB (Bruchfeld J, 2002). This is because so many organisms can affect these patients and chest radiograph findings are often non-specific, radiologists often have difficulty in interpreting imaging studies. Some specific pathogens are likely to manifest in specific clinical settings, thus correlating the chest radiograph findings with the clinical setting is very helpful in narrowing the list of potential pathogens and in increasing diagnostic confidence (Yu Whan Oh, 2000). Majority of the patients developed pulmonary complications due to

the delay in establishing a specific diagnosis. The clinician has high responsibility to avoid the serious consequences of delayed diagnosis to a patient with PTB.

Tuberculosis is also commonly occurring infection and a major cause of mortality in Malaysia (Ministry of Health Malaysia, 2002). In year 2004, there were 15,429 recorded PTB cases and 1,318 deaths, in Malaysia (reference from Unit TB, JKA, Ministry of Health Malaysia). Total of 15,875 PTB cases with 1435 deaths were recorded in the year of 2005. In the past, very limited studies have been conducted on assessing the severity of pulmonary tuberculosis among the non-HIV and HIV patients based on the chest radiograph. This study is therefore designed to recognize the chest radiograph variables of PTB and thereby assess the severity of pulmonary tuberculosis among non- HIV and HIV patients in local population. This will facilitate the clinicians for early diagnosis and institution of appropriate treatment for this potentially hazardous disease to the general population.

SECTION 2

LITERATURE REVIEW

2. LITERATURE REVIEW

2.1 GENERAL

Tuberculosis (TB) is an infectious disease that has been known for centuries and is extremely common in developing countries. TB may occur at any site in the body such as the lung, liver, spleen, kidney, brain, and bone. However the most important organ and the prime target of the disease is the lungs (Thomas, 1954, O'Connor, 2002, Richard Long, 1999).

TB should be considered in high-risk group of patients who have an underlying factor known to compromise cell-mediated immunity, such as HN infection, diabetes, alcoholism, end-stage renal disease or use of immunosuppressive drugs. In accordance with the virulence of the particular micro-organism, the defences of the host and the severity of the existing immunosuppression, tuberculosis can occur in the pulmonary and in extrapulmonary organs (Hyae Young Kim, 2001).

2.2 EPIDEMIOLOGY

The World Health Organization (WHO) estimated about one-third of the world's population is infected with Mycobacterium tuberculosis, resulting in 8 million new cases of tuberculosis and nearly 2 million deaths per year. Approximately 10 million people are estimated to be coinfected with M tuberculosis and HIV, and over 90% of these dually infected individuals reside in developing nations. Every year, approximately 10% of HIV -infected patients develop TB, whereas the annual risk of developing TB in non-HIV-infected patients is only 0.2% (VanDyck, 2003).

In 1993 the World Health Organization (WHO) declared TB a "global emergency".

Worldwide, 1. 7 billion of people were infected with M. tuberculosis, every year 3 million of people died from TB, and approximately 8 million new cases occurred.

Globally, tuberculosis is the most common cause of death among patients with AIDS, killing 1 of every 3 patients (Lisa Gooze, 2003).

At the end of 2007, worldwide approximately 33.2 million persons were living with HIV infection. In 2007, approximately 2 billion persons (one third of the world's population) were infected with Mycobacterium tuberculosis. An estimated one third of the persons living with HIV infection are coinfected with PTB. Tuberculosis is the cause of death for as many as half of all persons with AIDS. Since 1990, TB infection rates have increased 4-fold in countries that are heavily affected by HIV (Centers for Disease Control and Prevention USA, 2008, World Health Organization, 2007).

Tuberculosis is also an important cause of mortality amongst the infectious diseases in Malaysia. An average of 40 new cases of PTB is detected everyday, and 2 patients die of the disease daily. In 1995, the number of reported deaths due to PTB was 571 out of a total of 11,778 cases, giving a case-fatality rate of 4.8 percent. This has increased over the years and in 1999, there were 778 deaths due to TB out of a total of 14,908 cases, giving a case-fatality rate of 5.2 percent. 23.6% of all TB deaths in 1999 occurred among HIV infected individuals co infected with TB. 60% of patients were diagnosed at an advanced stage of the disease (Chua Jui Meng, 2000).

In year 2002 the HIV with PTB co-infections, representing 6.5% of the total number of reported TB cases in our country (Surin, 2003). In year 2004, there were 15,429

recorded PTB cases, out of these, 1276 cases were HIV co-infected and 1,318 deaths in our country; while a total of 15,875 PTB cases with 1,468 dually infected (HIV and PTB) cases and 1435 deaths were recorded in the year of2005 (reference from Unit TB, JKA, Ministry of Health, Malaysia). There were 16,825 recorded PTB cases and deaths of 1,4 72 cases in 2007, that was an increase from the 16,665 recorded cases and 1,431 deaths from the previous year in Malaysia (Global Health Reporting org., 2008).

In the year of2004, there were 359 PTB cases enrolled in the Adult Chest and Physician clinic at Hospital Raja Perempuan Zainab-ll, Kota Bharu. Out of 359 cases, 144 cases were PTB and HIV co-infected with death toll of 69 cases; whereas in 2005, out of 296 PTB cases there were 121 PTB-HIV co-infected with 43 deaths (reference from TB census 2003-2005, Adult Respiratory Clinic, HRPZ-ll).

2.3 OVER-VIEWS ON THE PATHOGENESIS AND CLINICAL FEATURES OF PULMONARY TUBERCULOSIS

Pulmonary tuberculosis is a contagious bacterial infection caused by Mycobacterium tuberculosis. It can be acquired as a consequence of the inhalation of bacillus-laden droplets sprayed into the air while coughing, sneezing, laughing or even talking by someone infected with TB. The active PTB infection has been classified as primary or post-primary (secondary). The commonest form of TB in adults is post-primary PTB,

the only form which is infectious and has great epidemiological significance (Anjali Agrawal, 2004, Ministry of Health Malaysia, 1992b, Ministry of Health Malaysia, 2002). Many researchers consider primary and secondary TB to reflect the time between the initial infections with M. tuberculosis and the onset of clinical disease. In the

literature, the exact interval that distinguishes the primary from secondary TB ranges from 1 to 5 years (Elvin Geng, 2005).

Tuberculosis is the infectious disease associated with defective cell-mediated immunity which is affected primarily by means of macrophages plus T -lymphocytes and becomes a serious problem in patients with progressive HIV -induced immunosuppression.

During the initial infection of immunocompetent people, alveolar macrophages ingest the M. tuberculosis organisms, and process and present mycobacterial antigens to lymphocytes bearing CD4 receptors {T-helper cells). CD4 cells secrete lymphokines, in particular interferon-gamma, which enhances the capacity of the macrophages to ingest and kill the mycobacteria. In most people, the infection is contained, and active TB does not develop, although small numbers of dormant bacilli often remain viable within the macrophages in the body. Clinically apparent (active) TB develops in approximately 10% of infected people, either soon after primary infection or years later (Richard Long, 1999).

In most immunocompetent individuals the infection is self-limited and often subclinical.

The contained infection in immunocompetent hosts is called primary TB. Primary TB is seen most often in children. However adults may present with chest radiograph findings similar to those of primary TB in patients with AIDS. Postprimary (reactivation) TB is seen in patients in whom the initial infection was contained successfully by the pulmonary macrophages, with bacilli remaining viable within the macrophages.

Infection results when the host's immune status (T cells) is compromised. This fonn may appear in the elderly population (Tara M Catanzano, 2008).

At the microscopic level, the initial tissue reaction to a primary encounter with M.

tuberculosis is local mobilisation of neutrophil polymorphs at the site of implantation.

Caseation necrosis rapidly ensues, provoking a variable lymphocytic, histiocytic, and giant cell reaction, which is usually followed by mural fibrosis. In the primary tuberculosis, fibrosis and healing occur. In the postprimary form, the disease tends to progress, with foci of inflammation and necrosis enlarging to occupy greater portions of the lung parenchyma. During this process, communication with airways is common. In

addition to erosion into an airway, the expanding infection may extend toward the periphery of the lung and rupture into the pleural space, resulting in development of tuberculous empyema (Hyae Young Kim, 2001).

2.4 OVER-VIEWS ON THE PATHOGENESIS AND CLINICAL FEATURES OF TUBERCULOSIS IN HIV/AIDS

HIV infection has contributed to a significant increase in the worldwide incidence of TB. Reactivation of TB and the rapid progression of newly acquired infection has become the most important manifestation of AIDS. Tuberculosis is the most important cause of pulmonary complication in patients with HIV infection. Most of these involve the lungs, pleura, and hilar or mediastinal lymph nodes (Karen A. Wendel, 2002, Woodhouse, 2003, Murray, 1998, Tara M Catanzano, 2008, Ronald G. Grainger, 2001).

In the immunocompromised patients, notably the population with HIV/AIDS, pulmonary macrophages are unable to contain the bacilli and leading to a clinically apparent infection. This form of TB is called progressive primary tuberculosis. Patients

with progressive primary TB may present with pulmonary manifestations or with manifestations of systemic or disseminated disease (Tara M Catanzano, 2008).

There are two distinct clinical patterns of tuberculosis in HIV -infected patients (Ronald G. Grainger, 2001):

1. When tuberculosis develops in the late stages of HIV disease, just before or even after the onset of AIDS:

(A) patients often have a negative tuberculin skin test reaction;

(B) more than half will have extrapulmonary (especially lymph node) involvement;

(C) upper-lobe cavitary disease is infrequent and the chest radiographs are usually atypical.

2. Tuberculosis is indistinguishable from 'ordinary' disease (i.e. PTB in non-HIV) when it develops in the earlier stage of HIV infection and whose cellular immunity is better preserved (Angelfire, 2000). Cutaneous reactivity to tuberculin is present; the usual upper-lobe predominance of infiltrations those tend to cavitate is seen radiographically.

In HIV-infected persons, the risk for progressing to active disease is approximately 10%

per year, and the immediate risk for progressive primary disease after recent infection with M. tuberculosis approaches 40%. TB has been associated with a 5 to 160 fold increase in HIV viral replication (World Health Organization, 2003a). Increasing numbers ofPTB cases with HIV/AIDS pose an increased risk ofTB transmission to the general community (World Health Organization, 2003a). In some hospitals in the world, as well as in Malaysia, all HIV -infected patients with PTB are isolated to lessen the risks of nosocomial transmission (Kooi Eng San, 2001).

HIV -infected smear-positive PTB patients have an increased case fatality. In HIV infected smear-negative PTB patients, the case fatality is even higher, probably reflecting their greater degree of immunosuppression (World Health Organization, 2003b ). Particularly frustrating for physicians who care for these patients is the fact that many of the patients are young and have undergone aggressive interventions in hopes of a cure.

INTERACTION OF TB AND HIV/AIDS (Hausler, 2000, South African Department of Health, 2000)

• TB can occur at any time, but often occurs early in the course of HIV disease.

• TB probably accelerates the progression of HIV disease.

• In the absence of HIV infection, only about 10% of people infected with TB bacilli get sick with TB during their lifetime.

• In people who are infected with HIV, about 50% may get sick with TB.

• TB can be prevented in people living with HIV I AIDS using isoniazid prophylaxis.

• TB can be cured, whether a patient is infected with HIV or not.

2.5 DIAGNOSIS OF THE PULMONARY TUBERCULOSIS

Diagnosis ofTB involves clinical, radiological and/or bacteriological evidence. Clinical symptoms which suggest PTB include cough usually more than two weeks, cough with sputum which is occasionally blood stained, loss of appetite, fatigue, loss of weight and fever. Hemoptysis occurs in about 20% of patients, and its presence should alert the clinician to the possibility of TB (Richard Long, 1999). Symptoms such as dypsnoea,

night sweats, anorexia, chest pain and hoarseness of voice are not common. Dyspnea is less common in more acute pulmonary condition. When present, dyspnea suggests advanced fibrocavitary or miliary disease or PTB complicated by pneumothorax. In about 30% of patients, pulmonary symptoms are absent, and constitutional symptoms represent the only clue that the patient is ill (Richard Long, 1999).

Pulmonary signs are nonspecific or can be subtle. If parenchymal disease is present, there may be crackles on auscultation, dullness to percussion, decreased breath sounds or bronchial breathing. Stony dullness, decreased breath sounds and a friction rub may be found with pleural effusion. Enlarged or tender lymph nodes may be present in the neck or other areas. Clubbing of the fingers or toes may be present.

2.6 RADIOLOGICAL INVESTIGATION IN PULMONARY TUBERCULOSIS

CHEST RADIOGRAPH

The chest radiograph is a widely used diagnostic tool though the findings are not specific for TB. Sputum examination is mandatory to provide a definitive proof of disease. The role of chest radiograph includes as a screening tool for the detection of new infiltrates, for monitoring response to therapy, to assess the extent of disease, to detect complications (i.e. cavitation, abscess formation, pneumothorax, pleural effusion), to detect additional or alternative diagnoses and sometimes to guide invasive diagnostic procedures (Franquet, 2001). The chest radiograph is also the only way to select those who need further investigation, e.g. those with healed ("inactive") TB and

those with apical scars or other evidence of past TB which was never documented ("presumed PTB, inactive"). Treatment may be initiated on the chest radiograph finding alone, despite negative sputums (British Columbia Ministry of Health, 1999).

INDICATIONS FOR CHEST RADIOGRAPH

• case contact who has a skin test greater than 5 mm,

• skin test positive (1 0 mm) on general screening,

• suspect case with symptoms or in high risk group (e.g., HIV infection, recent landed immigrants, refugees, etc.), or

• others as determined by the Division of Tuberculosis Control.

NOTE: Pregnant women during the first two trimesters should avoid chest radiograph if possible. In these situations, tuberculin and sputum testing can be utilized for the diagnosis of TB. If chest radiographs are essential, abdominal shielding should be used (British Columbia Ministry of Health, 1999).

CHEST RADIOGRAPH PATTERNS OF PULMONARY TUBERCULOSIS

Primary and secondary tuberculosis are also having characteristic chest radiograph and clinical features. Primary TB is characterized by lower lobe disease (apical segment), adenopathy, and pleural effusions, and termed atypical; whereas secondary, or reactivation, TB is associated with upper lobe disease (apical and posterior segments) and cavitation, termed typical (Elvin Geng, 2005). Primary TB is usually asymptomatic and usually appears as air-space consolidation in the lower lobes, hilar and mediastinal lymphadenopathy, miliary disease and pleural effusion. Post-primary TB most commonly appears as nodular and linear opacity or increased attenuation at the lung

are often soft in active PTB and there is usually no or little fibrosis or calcification.

These latter findings would suggest healed TB. Cavities in the apex further enhance the diagnosis of active disease unless the patient has been previously treated (Ministry of Health Malaysia, 2002).

When the organism overpowers host defenses, the disease progresses, either locally or even disseminated to extrapulmonary organs. Therefore, various forms of intrathoracic sequelae and pulmonary complications may result from both primary and post-primary PTB and is extremely common in people infected with HIV, which are likely to supervene as the HIV-induced immunodeficiency steadily worsens. These can be categorized as follows (Hyae Young Kim, 2001):

(a) parenchymal lesions, which include tuberculoma, cavity, cicatrization, end-stage lung destruction, aspergilloma, and bronchogenic carcinoma;

(b) airway lesions, which include bronchiectasis, tracheobronchial stenosis, and broncholithiasis;

(c) vascular lesions, which include pulmonary or bronchial arteritis and thrombosis, bronchial artery dilatation, and Rasmussen aneurysm;

(d) mediastinal lesions, which include lymph node calcification and extranodal extension, esophagomediastinal or esophagobronchial fistula, constrictive pericarditis, and fibrosing mediastinitis;

(e) pleural lesions, which include chronic empyema, fibrothorax, bronchopleural fistula, and pneumothorax; and

(f) chest wall lesions, which include rib tuberculosis, tuberculous spondylitis, and malignancy associated with chronic empyema.

Tuberculoma is a round or oval granuloma with central portion of caseation necrosis. It appears as a coin lesion on the chest radiograph with evidence of calcification, adjacent smaller "satellite" lesions and typically with smooth or sharply defined margin.

Tuberculomas can be solitary or multiple and range in size from 0.4 to 5.0cm in diameter. Lesions greater than 3.0cm in diameter are more likely to be active (Richard Long, 1999). Satellite lesions (small round opacities) are seen in the immediate vicinity of the main lesion up to 80% of cases (Van Dyck, 2003). The majority of lesions remains stable in size and may calcify. Calcification is found in 20%-30% of tuberculomas and is usually nodular and diffuse. Although pulmonary tuberculomas are most often the result of healed primary TB, they are seen in 3-6% ofpostprimary TB as the main or only abnormality on chest radiograph (VanDyck, 2003, Hyae Young Kim, 2001).

Cavitation may be seen in both active and inactive disease (Hyae Young Kim, 2001). It most commonly occurs within areas of consolidation and indicates a high likelihood of activity (Mukesh G. Harisinghani, 2000). The cavity walls may range from thin and smooth to thick and nodular. After antituberculous chemotherapy, the tuberculous cavity may disappear; occasionally, the wall becomes paper-thin and an air-filled cystic space remains. The wall of a chronic cavity varies from 0.1 em to l.Ocm in thickness and may be smooth, sometimes simulating an emphysematous bulla. It can be difficult to distinguish true thin-walled cavities from bullae, cysts, or pneumatoceles. Cavitation in one or multiple sites is evident in 40% of postprimary disease chest radiograph (P. Van Dyck, 2003 ). Air-fluid levels in the cavity are rare occur in 10% of cases (P. Van Dyck, 2003), but when present they suggest the possibility of superadded infection (Mukesh G.

Harisinghani, 2000).

Pleural Effusion is usually unilateral and of moderate size. The fluid is almost always an exudate with a high percentage of lymphocytes. In addition to raising the possibility of malignancy, a lymphocytic exudative effusion should always suggest TB (Richard Long, 1999). Pleural effusion is the only chest radiograph finding indicative of primary TB in approximately 5% of adult cases (VanDyck, 2003). Tuberculous empyema is the persistent, grossly purulent pleural fluid containing tubercle bacilli.

Hilar and Mediastinal Adenopathy is usually unilateral but may be bilateral in 10% of

cases (Richard Long, 1999). Right paratracheal and hilar localizations are the most common sites (VanDyck, 2003) and often there is an adjacent parenchymal infiltrate. In the active stage, the nodes often measuring more than 2.0cm and have central low attenuation, which correspond to caseation or liquefaction necrosis (Van Dyck, 2003).

Tuberculous mediastinal lymphadenitis is a frequent manifestation of primary PTB.

Hilar and mediastinal lymphadenopathy are uncommon manifestations of postprimary TB and occur in only approximately 5% of cases (Ann N. Leung, 1999). Although enlarged nodes occur in 83o/o-96% of pediatric cases, the prevalence of lymphadenopathydecreases with increasing age (Hyae Young Kim, 2001). Pubertal and young adult women, the elderly and patients with acquired immunodeficiency syndrome are the most commonly affected among adult patients (Hyae Young Kim, 2001).

Pleural Thickening results from organization of a variety of chronic inflammatory processes involving the pleura causing marked thickening of the extrapleural fat, giving the appearance of pleural thickening on chest radiographs. It is particularly associated with TB in association with fibrosis of adjacent lung parenchyma and peripheral atelectasis (VanDyck, 2003).

Pneumothorax secondary to tuberculosis occurs in approximately 5% of patients with postprimary TB, usually in severe cavitary disease but rarely in miliary tuberculosis (Hyae Young Kim, 2001). The pathogenesis involves pleural caseous infiltrates that undergo liquefaction, resulting in pleural necrosis and rupture. Pneumothorax is manifests as visualization of the visceral pleura separated from the chest wall with loss of lung markings laterally, demonstration of a deep sulcus sign, crisp definition of the hemidiaphragm, and demonstration of a continuous diaphragm sign. Pneumothorax often heralds severe and extensive pulmonary involvement by the infectious process and the onset ofbronchopleural fistula and empyema. Therefore, if any apical abnormality is seen after reexpansion of a spontaneous pneumothorax, active TB should be considered (VanDyck, 2003).

Miliary Tuberculosis represents hematogenous dissemination of the tubercle bacillus in lungs and other organs, where innumerable small tuberculous granulomas develop.

When the bacilli spread to the lungs, the classic miliary pattern on conventional chest radiograph shows multiple discrete noncalcified micronodular infiltrates of 1.0-2.0mm in size, which are all very similar, diffusely scattered throughout both lungs, especially the lung apices. It can be seen in primary or postprimary disease (VanDyck, 2003).

Bronchiectasis more commonly occurs by excessive airway as well as surrounding parenchymal destruction and fibrosis of the lung parenchyma with secondary bronchial dilatation (traction bronchiectasis). Bronchiectasis located in the apical and posterior segments of the upper lobe is highly suggestive of a tuberculous origin. When multiple apical cavities are encountered, the possibility that cystic bronchiectasis is present in addition to necrotic cavities must be considered (Hyae Young Kim, 2001).

Fungal Ball/ Aspergilloma is usually located within a cavity or ectatic bronchus and

appears on chest radiograph as a mobile, rounded mass surrounded by a crescentic air shadow is noted inside a lung cavity (air-crescent sign). Thickening of the walls of tuberculous cavities or of the adjacent pleura is reported to be an early chest radiograph sign (Hyae Young Kim, 2001 ). Approximately 2So/o-SS% of patients with aspergilloma have a history of chronic cavitary TB. The prevalence of aspergilloma associated with chronic TB has been reported to be 11% (Hyae Young Kim, 2001). Although aspergilloma may exist for years without symptoms, hemoptysis is the most common clinical complication, with a prevalence ofS0%-90% (Hyae Young Kim, 2001).

Lung Fibrosis/ Scarring has a nonspecific chest radiographic pattern of parenchymal

bands (reticular, discrete and linear opacities), discrete fibrotic nodules with volume reduction and cavities, or traction bronchiectasis is occasionally encountered. After antituberculous therapy, chest radiographs show disappearance of infiltrates and fibrosis develops. Fibrosis can be stable or regress (Van Dyck, 2003 ).

Cicatrization Atelectasis is a common finding after postprimary TB. Up to 40% of

patients with postprimary TB have a marked fibrotic response, which manifests as atelectasis of the upper lobe, retraction of the hilum, compensatory lower lobe hyperinflation, and mediastinal shift toward the fibrotic lung. Tuberculosis is almost always present in the opposite upper lobe (Hyae Young Kim, 2001).

Lymph Node Calcification: Areas of caseation in a diseased lymph node frequently calcify. With treatment, the nodes become homogeneous and finally disappearing or resulting in a residual mass composed of fibrotic tissue and calcifications. This may be

the only sign of previous primary infection. Calcification may occur from 6 months to 4 years after infection (Hyae Young Kim, 2001, Ann N. Leung, 1999, VanDyck, 2003).

Nodules defined on chest radiograph as multiple, small, well-marginated distinct borders without surrounding pneumonitis, discrete opacities ranging in diameter 5.0 to 1 O.Omm nodules distributed in a segmental or lobar distribution, distant from the site of cavity formation and typically involving the lower (dependent) lung zones. It occurs due to bronchogenic spread of disease when an area of caseous necrosis liquefies and communicates with the bronchial tree. Bronchogenic spread is identified in approximately 20% of cases ofpostprimary TB chest radiograph (Ann N. Leung, 1999).

Consolidation/ Tuberculous Pneumonia is the earliest chest radiograph finding in postprimary TB, which manifests as patchy, ill-defined parenchymal infiltrations with predilection for the apical or posterior segment of the upper lobes or the superior segment of the lower lobes (VanDyck, 2003). Two or more segments are involved in most cases and bilateral upper lobe disease may be present (Mukesh G. Harisinghani, 2000). Endobronchial spread of infection manifests in the chest radiograph as widespread small acinar nodules with ill defined margins (Ann N. Leung, 1999).

TABLE 1: MANIFESTATIONS OF TUBERCULOSIS ACTIVITY IN THE CHEST RADIOGRAPH

Chest Radiograph Manifestations of Tuberculosis Activity

Activity Primary Post-primary

Normal chest radiograph Normal chest radiograph Inactive Scarring (any site) + Scarring (restricted site.!) +

sequelae sequelae

Calcification (nodes, lung) Calcification (lung, nodes, pleura)

Consolidation (any site) Consolidation (restricted site.!) Cavitation (restricted site.!) Adenopathy + sequelae Endobronchial lesion + sequelae Active

Effusion (pleural, Effusion (pleural, pericardia!) pericardia!)

Miliary tuberculosis Miliary tuberculosis Other (e.g. bone) Other (e.g. bone) Indeterminate Tuberculoma Tuberculoma

activity

*

(Ronald G. Grainger, 2001)

CHEST RADIOGRAPH FEATURES OF TUBERCULOSIS IN HIV PATIENTS

The chest radiograph features of TB in patients with advanced HIV-induced immunosuppression differ from the conventional patterns of immunocompetent individuals. Diffuse bilateral coarse reticulonodular opacities are typically demonstrated as a mid- or lower-lobe predominance of lesions (Ronald G. Grainger, 2001). Hilar and/or mediastinal adenopathy is well documented (Long, 1991). Pleural effusion was observed in HIV-infected patients with TB (Ronald G. Grainger, 2001).

With effective antituberculosis therapy, the great majority of patients will demonstrate both clinical and chest radiograph improvement within 1-2 weeks. Recently, reports of new chest radiograph abnormalities (mediastinal adenopathy, worsening and new lung opacities) and increasing symptoms following initiation of antiretroviral therapy in patients being treated for TB suggest a systemic inflammatory response related to immune reconstitution rather than worsening disease (World Health Organization, 2003a, Blumberg, 2003, American Thoracic Society, 2003).

CHEST RADIOGRAPH CLASSIFICATION OF PTB

The Ministry Of Health Malaysia and Academy of Medicine of Malaysia has developed

"Practice Guidelines for the Control and Management of Tuberculosis" and classified the abnormal chest radiograph appearance of PTB into minimal, moderately advanced and far advanced in order to assess the severity of the disease (Ministry of Health Malaysia, 2002). Classification of radiological extent of disease in the initial chest radiograph for cases of pulmonary tuberculosis may be standardized using the criteria which have been discussed in detail under methodology (refer Table 5).

Extra pulmonary TB involvement is classified as severe disease if there is either a significant acute threat to life (e.g. pericardia! TB) or risk of subsequent severe handicap (e.g. spinal TB) or both (e.g. meningeal TB). The following forms of extra pulmonary TB are classified as severe: meningitis, military, pericarditis, peritonitis, bilateral or extensive pleural effusion, spinal, intestinal, genitor-urinary. The following forms of extra pulmonary TB are classified as less severe: lymph node, pleural effusion (unilateral), bone (excluding spine), peripheral joint, skin (Ministry of Health Malaysia, 2002).

2.7 BACTERIOLOGICAL EXAMINATION OF SPUTUM IN PTB

Bacteriological examination often used as an initial diagnostic tool and the diagnosis of tuberculosis rests on the isolation and identification of M. tuberculosis. Sputum should be examined in any patient with chronic productive cough (greater than two weeks) and in those with other symptoms suggestive of TB. The bacteriologic diagnosis of TB involves the use of Ziehl-Neelsen staining and culture of the organism.

2.7.1 SPUTUM MICROSCOPY FOR ACID-FAST BACILLI (AFB) SMEAR

The detection of AFB in sputum smears is the first bacteriologic evidence of the presence of mycobacteria in a clinical specimen, which are usually positive in cavitary disease. The smear is of vital clinical and epidemiologic importance in assessing the patient's infectiousness because it gives a quantitative estimation of the number of bacilli being excreted (American Thoracic Society, 2000).

Positive direct smear for AFB may serve as presumptive proof for tuberculous infection but may be also represent non-tuberculous mycobacteria known as mycobacteria other than tuberculosis (MOTT). These two groups of mycobacterium are indistinguishable on direct smear. Many organisms in the MOTT group cause disease which is clinically, radiologically and histo-pathologically indistinguishable from TB. The main variation between these two groups are that the MOTT are ubiquitous organism and not contagious. Other differences are the sensitivity patterns to the antituberculous drugs.

There are also definitive biochemical differences between these two groups (Kooi Eng San, 2001).

Finding AFB recognized microscopically by an intense staining with aniline dye in secretions or tissue from any source provides an indication for antituberculous treatment but is not diagnostic. The identification of organisms is critical in diagnosing TB, careful attention should be given to the collection and handling of specimens. Three single specimens should be collected initially (preferably on different days) from sputum-producing patients. Acid-fast stains should be performed within 24h of receipt in the laboratory (American Thoracic Society, 2000). The detection of AFB on stained smears varies with sensitivities ranging from 22% to 78% (Gerd Laifer, 2004).

STAINING AND DIRECT MICROSCOPIC EXAMINATION

Detection of AFB in stained smears examined microscopically, which gives a quantitative estimation of the bacilli being excreted. Smears may be prepared directly from clinical specimens or from concentrated preparations. Two procedures are commonly used for acid-fast staining; the carbolfuchsin methods, which include the Ziehl-Neelsen and Kinyoun methods, and a fluorochrome procedure using auramine-0 or auramine-rhodamine dyes. The acid-fast staining procedure depends on the ability of mycobacteria to retain dye when treated with an acid-alcohol solution.

Several studies have shown that there must be 5,000 to 10,000 bacilli per milliliter for the demonstration of the bacteria in stained smears (Beth Potter, 2005). In contrast, 1 0 to 100 organisms are needed for a positive culture (American Thoracic Society, 2000).

Negative smears, however, do not preclude tuberculosis disease. Various studies have indicated that 50 to 80% of patients with PTB will have positive sputum smears (American Thoracic Society, 2000, Toman K, 2004).

In reading smears, the microscopist should provide the clinician with a rough estimate of the number of AFB detected as it is significant to determine the severity of the disease. The following table shows a frequently used scheme in most of the hospitals in Malaysia to quantify organisms seen on AFB smear using International Union Against Tuberculosis (IU AT) Scale.

TABLE 2: Quantitation Scale for Acid-Fast Bacillus Smears According To Stain Used (IUAT SCALE)

QUANTITATION SCALE FOR ACID-FAST BACILLUS SMEARS USING CARBOLFUCHSIN STAIN (IUAT SCALE)

0/3L (No AFB) Negative ^-

1-49/3L Weakly Positive 1+

> 50/3L Moderately Positive 2+

11-49/L Strongly Positive 3+

> 50/L (Numerous) Heavily Positive 4+

*L= line (Ministry of Health Malaysia, 2000.)

The smeared slides are examined under direct fluorescent microscopy and the number of acid fast bacilli (AFB) should be counted in three different lines/directions (L).

Sputum smears are graded as negative contain no (0) AFB/3L, 1 + is weakly positive which counts 1 to 49 AFB/3L, 2+ is moderately positive which counts more than 50 AFB/3L or less than 10 AFB/L, 3+ is strongly positive which counts 11-49 AFB/L and 4+ is heavily positive which counts more than 50 AFB/L.

2.7.2 SPUTUM CULTURE FOR MYCOBACTERIA TUBERCULOSIS

The sputum culture is regarded as the most reliable diagnostic method. All clinical specimens suspected of containing mycobacterium should be inoculated after appropriate digestion and decontamination, if required, onto culture media for four reasons as follow (American Thoracic Society, 2000);

1. culture is much more sensitive than microscopy as being able to detect as few as 10 bacteria per milliliter of material

2. growth of the organisms is necessary for precise species identification 3. drug susceptibility testing requires culture of the organisms

4. Genotyping of cultured organisms may be useful to identify epidemiological links between patients or to detect laboratory cross-contamination.

The specimen should be inoculated into both liquid and solid media. Three different types of traditional culture media are available such as egg based (Lowenstein-Jensen), agar based (Middlebrook 7H10 or 7Hll medium), and broth culture media which is liquid based (Middlebrook 7H12), and each can be made into selective media by adding antibiotics. Improved commercial broth systems for mycobacterial growth detection are also obtainable, for example automated culture systems namely BACTEC 460, mycobacterial growth indicator tube (MOlT) systems and BacT/ALERT MB Susceptibility Kit. Automated liquid systems must be checked at least every 2 to 3 days for growth while solid media should be checked once or twice a week. Mycobacteria on culture appear similar as acid-fast staining (American Thoracic Society, 2000).

The percentage of specimens shown positive by smear but negative in culture should be less than 1% (American Thoracic Society, 2000). In general, the sensitivity of culture is

80-85% with a specificity of approximately 98% (American Thoracic Society, 2000).

Failure to isolate M. tuberculosis from appropriately collected specimens in persons who are suspected of having PTB, because of clinical or radiographic findings, does not totally exclude a diagnosis of active TB (American Thoracic Society, 2003). Drug susceptibility tests should be performed on initial isolates from all patients in order to identify what should be an effective antituberculous regimen (American Thoracic Society, 2000).

2.8 INDICATION FOR SCREENING OF HIGH RISK GROUPS BASED ON MOH, MALAYSIA GUIDELINE

The following constitute high risk groups which should be screened for active tuberculosis; (Ministry of Health Malaysia, 2002)

• Contacts of sputum positive tuberculosis cases.

• Persons with HIV infection.

• Immigrants from countries with high tuberculosis prevalence.

• Persons in institutions such as prisons and drug rehabilitation centers.

• Persons with other medical risk factors such as diabetes mellitus, silicosis, renal failure, those on prolonged corticosteroid or other immunosuppressive therapy and hematological malignancy.

2.9 MOH GUIDELINES ON MANAGEMENT OF TUBERCULOSIS

The Medical Consensus Development Panel in Ministry Of Health Malaysia and the Academy of Medicine of Malaysia has developed guideline on management of

pulmonary tuberculosis and standardized with following criteria. Treatment regimens are divided into the intensive phase and the continuation phase. Five drugs are considered essential to the treatment of TB. They are Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Streptomycin (S) and Ethambutol (E). The following are the recommended regimen by the MOH, Malaysia (Ministry of Health Malaysia, 1992a, Ministry of Health Malaysia, 2002).

TABLE 3: STANDARD ANTITUBERCULOSIS DRUGS AND THE RECOMMENDED DOSAGES

Drug Daily dose BW. dose Max. dose Adverse reaction Rifampicin 10mg/kglday 10-15 Dly600mg -Orange

mg/kglday BW600mg discolouration of body fluid

-Hepatitis

-Flu like reaction -Vomiting

-Thrombocyto- pema

Isoniazid 5-8 15-20 Dly300mg -Hepatitis

mg/kglday mg/kglday BW 1200mg -Peripheral neuritis

-Hypersensitivity

Pyrazinamide 20-40 - ^{Dly l.Sgm} -Hepatotoxicity

mg/kglday -Hyperuricaemia

Ethambutol 15-25 Dly 1.2gm -Optic neuritis

mg/kglday

-

disturbance -Hypersensitivity

Streptomycin 15-20 15-20 1.0gm. -Ototoxicity

mg/kglday mg/kglday -Nephrotoxicity

-Skin rash

Dly: daily, BW: biweekly (Ministry of Health Malaysia, 2002)

INITIATION OF TREATMENT

1) SHRZ (PREFERRED REGIMEN)

* 2) EHRZ (ALTERNATIVE REGIMEN) (56 DAILY DOSES - 8 WEEKS)

sputum DIS & CIS MTB

SHR I HR (BIWEEKLY)

(16 doses)

sputum DIS, CXR -8th. Week

SHR I HR (BIWEEKLY)

(16 doses)

sputum DIS, CXR - 16th. Week

TREATMENT COMPLETION

sputum DIS, CXR

**Sputum CIS MTB - 24th week

1st FOLLOW UP (3 MONTHS)

2nd FOLLOW UP (6MONTHS)

3rd FOLLOW UP (9MONTHS)

Foot Notes: Total Follow Up Period of 18 Months after Completing Treatment.

* EHRZ usually given for HIV patient as to avoid needle stick injury. **Recommended to be done where facilities are available, sputum DIS x 3 and sputum culture MTB if DIS negative.

S=STREPTOMYCIN, H=ISONIAZID, R=RIF AMPICIN, Z=PYRAZINAMIDE, E=ETHAMBUTOL

FIGURE 1: FLOW CHART FOR RECOMMENDED 24WEEKS/ 6MONTHS TREATMENT REGIMEN (ADULT)

(Ministry of Health Malaysia, 1992a, Ministry of Health Malaysia, 2002)

SECTION 3

OBJECTIVES AND

HYPOTHESIS

3. OBJECTIVES AND HYPOTHESIS

3.1 GENERAL OBJECTIVE

The aim of this study is to assess the chest radiographic severity of pulmonary tuberculosis among the non-HIV and HIV patients.

3.2 SPECIFIC OBJECTIVES

o To determine the associations between the chest radiographic severity of pulmonary tuberculosis with HIV status (non-HIV and HIV patients).

o To evaluate the differences in the various chest radiographic appearances of pulmonary tuberculosis among non-HIV and HIV patients.

3.3 RESEARCH QUESTION

o Are there any associations between the chest radiographic severity of pulmonary tuberculosis with HIV status (non-HIV and HIV patients)?

o Are there any differences in the various chest radiographic appearances of pulmonary tuberculosis among non-HIV and HIV patients?

3.4 NULL HYPOTHESIS

o There is no association between the chest radiographic severity of pulmonary tuberculosis with HIV status (non-HIV and HIV patients).

o There is no difference in the various chest radiographic appearances of pulmonary tuberculosis among non-HIV and HIV patients.

SECTION 4

METHODOLOGY

4. METHODOLOGY

4.1 RESEARCH DESIGN

This is a comparative cross sectional study held in Hospital Raja Perempuan Zainab-ll [HRPZ-11], conducted retrospectively from January 2004 until December 2005.

4.2 POPULATION AND SAMPLE

REFERENCE POPULATION

o All adult pulmonary tuberculosis patients in Kelantan.

SOURCE POPULATION

o All adult pulmonary tuberculosis patients with non-HIV and HIV coinfection in Kelantan from January 2004 until December 2005.

STUDY SAMPLE

o All adult pulmonary tuberculosis attended to chest clinic at HRPZ-ll, Kota Bharu, during the study period (from January 2004 until December 2005) whom had fulfilled inclusion criteria and consented to participate in the study.

4.3 OPERATIONAL DEFINITION

o Definition for pulmonary tuberculosis in this study was those patients had clinical sign and symptoms of PTB with laboratory confirmation of either sputum smear AFB or culture MTB positive.

o Definition for non-HIV group in this study was those patients who had non-reactive Elisa (HIV) screening blood test before or during treatment of PTB.

o Definition for HIV group was those patients with reactive Elisa (HIV) screening test before or during treatment of PTB.

o Co-morbid disease indicates the presence of one or more medical problems or systemic diseases such as hypertension, diabetes mellitus, liver cirrhosis, hepatitis, blood dyscrasias, malignancy and congestive heart failure, existing simultaneously but independently in addition to a primary disease or disorder in a patient. The effect of such additional disorders or diseases which might have been alluded to as significant contributory factors in the radiological appearance of pulmonary tuberculosis.

o In this project, pre-treatment stands for the period before the initiation of any anti- tuberculous drugs.

o Six months post-treatment means six months period after the initiation of anti- tuberculous treatment.

o In this study, the chest radiograph appearance of the PTB disease was broadly classified as follow:

1. Normal

No chest radiograph findings ofPTB or other pathological changes.

2. Abnormal

The presence of chest radiograph findings that was suggestive ofPTB changes.

The abnormal chest radiograph manifestations of PTB were further sub-classified as minimal, moderately advanced and far advanced in order to assess the chest radiographic severity/extent of the disease based on the classification from the "Practice Guidelines for the Control and Management of Tuberculosis", by MOH (Ministry of Health Malaysia, 2002) and used as reporting criterion in this project. The description of the chest radiograph classifications were discussed under methodology (refer Table 4).

However for simplicity, the chest radiograph severity/extend of pulmonary tuberculosis were categorized as follows;

1. normal

2. mildly abnormal (minimal)

3. moderately abnormal (moderately advanced) 4. severely abnormal (far advanced)

No illustrations were given for the chest radiograph classification of PTB in the above mentioned guidelines. Hence according to the classification, the illustrations were taken from our study groups (refer Appendix 10.3).

4.4 INCLUSION CRITERIA

o Patients had clinical symptoms and signs of PTB with laboratory confirmation of either sputum smear AFB or culture MTB positive.

o Adult population aged 18 years and above.

o All recruited patients should have pre-treatment and six month post-treatment chest radiographs (ofPA view) available.

o The recruited PTB patients were further subdivided into two groups i.e. non-HIV and HIV infected;

A) patient defined not to have HIV co-infection by proven non-reactive to HIV ELIZA screening blood test.

B) patient defined to have HIV co-infection by proven reactive to HIV ELIZA screening blood test.

4.5 EXCLUSION CRITERIA

o Patients with other co-morbid disease (those patients in whom the clinical, laboratory and radiological evidence suggested the co-existence of another associated pathological diseases).

o Any patient suspected to have other opportunity infection such as PCP, fungal and mycobacterium avium suspected by the clinician were excluded.

o Those patients who defaulted treatment and follow-up.

4.6 SAMPLE SIZE

Sample size was ca