ASSESSING DIAGNOSTIC APPROACHES WITH CLINICAL DATA ON HUMAN IMMUNODEFICIENCY VIRUS INFECTED
TUBERCULOSIS PATIENTS AT NATIONAL INSTITUTE OF TUBERCULOSIS AND RESPIRATORY DISEASES,
NEW DELHI, INDIA
UPASNA AGARWAL
KUSUMA SCHOOL OF BIOLOGICAL SCIENCES
©Indian Institute of Technology Delhi (IITD), New Delhi, 2017
ASSESSING DIAGNOSTIC APPROACHES WITH CLINICAL DATA ON HUMAN IMMUNODEFICIENCY VIRUS INFECTED
TUBERCULOSIS PATIENTS AT NATIONAL INSTITUTE OF TUBERCULOSIS AND RESPIRATORY DISEASES,
NEW DELHI, INDIA
by
UPASNA AGARWAL
Kusuma School of Biological Sciences
Submitted
In fulfilment of the requirements of the degree of Doctor of Philosophy to the
Dedicated to my father who was
and always will be
the ‘wind beneath my wings’....
Certificate
CERTIFICATE
This is to certify that the thesis entitled “Assessing diagnostic approaches with clinical data on human immunodeficiency virus infected tuberculosis patients at National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India ”, being submitted by Dr. (Ms.) Upasna Agarwal to the Indian Institute of Technology Delhi for the award of degree of Doctor of Philosophy, is a record of bonafide research work carried out by her, which has been prepared under my supervision and guidance in conformity with the rules and regulations of Indian Institute of Technology Delhi. The research reports and the results presented in this thesis have not been submitted in part or full to any other University or Institute for the award of any degree or diploma.
Dr. Aditya Mittal Professor Kusuma School of Biological Sciences Indian Institute of Technology Delhi New Delhi - 110016, India
Date:
New Delhi
ii
Acknowledgements
Acknowledgements
First and foremost I would like to thank my PhD advisor, Prof. Aditya Mittal for his enormous contribution to this work. This thesis is a result of his outstanding ideas and step- by-step guidance. He gave invaluable time, effort and energy to this work, for which I will always be grateful to him. I sincerely thank him for his guidance and his confidence in my research which inspired me and gave me confidence.
My heartfelt gratitude is due to Dr. Rohit Sarin, Director, National Institute of Tuberculosis and Respiratory Diseases, New Delhi. He has been a driving force behind this work and has constantly motivated me to persevere during the tough times. He has wholeheartedly supported this effort of mine and has always motivated me to do high quality work.
I would also like to thank my Student Research Committee members: Dr. James Gomes and Dr. Manidipa Banerjee for their enthusiastic appreciation of my thesis work. I am thankful to the other students of KSBS, Saumya, Amita, Aastha, Chanchal and Snigdha, who helped me in many different ways throughout this journey of PhD. And among all these, my special thanks are due to Manish Kandpal , who has been a true ‘friend in need’ to me over these past years. I would also like to thank Ms. Mini for her administrative help.
And then there are my friends who have been the buttress supports all this time. Dr. Anand Jaiswal, my dearest friend was my perpetual sounding board. For years, he has patiently heard out my ranting and ravings, about my many frustrations and not so many accomplishments, with equal equanimity and has magically made everything okay when things had appeared to be twisted. Lokender, Rajnish and Saini are my 2:00 AM friends who have been there for me through every personal crisis that I went through during this time.
Acknowledgements
I cannot thank enough my husband, Rohit, for he has been my pillar of support. He is the one who took care of everything ‘else’ allowing me to focus on my work. He not only took care of my children and household chores, it was also his job to regularly calm me down during my innumerable nervous spells. He was my shrink, proof reader and odd jobs man, all rolled into one. I am extremely thankful to my children, Ashita and Rishabh, who didn’t complain when I worked evenings, weekends and holidays and gave time that was theirs to this Ph.D.
My heartfelt thanks to my mother, sister and brother who are perpetually applauding even the least significant of my efforts out of their love for me. I lost my father five years ago and will dearly miss the gleam of pride that would have been in his eyes had he been able to see this thesis.
I thank the entire staff of ART Centre and Dr. Sonam Spalgais who time and again helped in sorting more than 1000 case files needed for this work. And I am grateful to my patients for their smiles and the life lessons that they teach me every day of my life, without which this work would never have been possible. And finally, I thank the Almighty for constantly holding my hand and giving me the strength to complete my Ph.D.
UPASNA AGARWAL
iv
Abstract
Abstract
Analysis of data generated in course of patient care can provide evidence based solutions for unanswered questions encountered in day-to-day clinical practice. However, this data is often neither adequately documented nor scientifically analysed. At the Antiretroviral Therapy (ART) Centre, a human immunodeficiency virus (HIV) Clinic, at National Institute of TB and Respiratory Diseases, detailed patient data is recorded in structured patient charts. We analyzed data collected at this clinic over an eight year period for HIV cases with and without active tuberculosis (TB). To begin with, we undertook analysis of data from HIV infected TB (HIV-TB) patients who had paradoxical worsening of TB disease after initiation of HIV therapy due to the manifestation of a clinical entity known as TB associated immune reconstitution inflammatory syndrome (TB-IRIS). From our analysis, we identified TB-IRIS to be a frequent problem at our clinic and that meningeal TB-IRIS cases had high mortality, based on which information we made effective modification in treatment of such cases at our Centre. Following analysis of another dataset from the NITRD-ART Centre, we also demonstrated that abdominal TB is a frequent form of TB in HIV which can be easily diagnosed if a simple USG of the abdomen is ordered in HIV-TB suspects, thereby resulting in timely diagnosis and treatment of TB. We now understood the need for a universal TB test. For this we analyzed the data on tuberculin skin test (TST) from the NITRD-ART Centre as well as from global studies to assess its performance as such a test, which could be applicable for all forms of TB and all types of patient populations. Our rigorous statistical analysis of collated data led to development of a comprehensive statistical criterion for assessing the clinical reliability of a diagnostic test i.e. ‘Diagnostics of diagnostic test’ wherein the predictive values of a diagnostic test should 1) have absolute values of more than 80 %,
Abstract
2) be independent of the country’s overall prevalence of disease where the test is performed, and 3) be correlated to and be higher than the test’s sensitivity/specificity. All three conditions need to be met for a test to be reliable across different clinical settings.
Application of the above criterion to TST data, affirmed its clinical unreliability for active TB diagnosis. In addition, we could also develop analytical benchmarks for quantitative diagnosis of reliability of any diagnostic test used in clinical practice. By means of analysis of our clinical data, we were able to assess different diagnostic approaches and provide scientific evidence for better patient care decisions both at our Centre, as well as in general medical practice on a whole. This work has therefore, contributed towards reduction in disease related morbidity and mortality. We propose that more such analyses of data must be carried out in clinics and hospitals and that all clinicians must enhance their documentation and analytical skills.
vi
Lkkjka”k
Lkkjka”k
fnu&izfrfnu uSnkfud vH;kl esa mRrj ugha fn, x, iz”uksa ds fy, jksxh dh ns[kHkky ls mRiUu vkadM+ksa dk fo”ys’k.k lk{; vk/kkfjr lek/kku iznku dj ldrs gSaA gkykafd] ;s vkadMsa+ vDlj u rks i;kZIr :i ls izysf[kr gSa vkSj u gh oSKkfud :i ls fo”ysf’kr gSaA jk’Vªh; {k; ,oa “olu jksx laLFkku] ,aVhfjVªksok,jy FkSjsih ¼, vkj Vh½ dsUnz ds ,p vkbZ oh Dyhfud esa lajfpr jksxh pkVZ ds :i esa jksxh ds vkadM+ksa dk fjdkWMZ gksrk gSA geus bl Dyhfud ls {k;jksx vkSj xSj {k;jksx ds lkFk ,pvkbZoh ekeyksa ds fy, vkB o’kZ ls vf/kd lax`ghr vkadM+ksa dk fo”ys’k.k fd;k gSaA izkjEHk esa] ge Vhch ¼,pvkbZoh&Vhch½ ds mu laØfer jksfax;ksa ds vkadM+ksa dk fo”ys’k.k djrs gSa] ftudks Vhch ds lkFk izfrj{kk iquZxBu flaMªkse ¼Vhch&vkbvkjvkb,l½ ds :i esa uSnkfud bdkbZ dh vfHkO;fDr ds dkj.k ,pvkbZoh FkSjsih ds ckn fojks/kkHkk’kh chxM+h gqbZ Vhch gks xbZ FkhA geus vius fo”ys’k.k esa ;g ik;k gS fd gekjs Dyhfud esa Vhch&vkbvkjvkb,l ls vDlj leL;k gksrh gS vkSj tks efLr’d
¼esfuaxsy½ Vhch&vkbvkjvkb,l ds jksxh gksrs gS] muesa e`R;qnj vf/kd gSA bl tkudkjh ls geus vius
dsUnz ij bl rjg ds jksfx;ksa ds mipkj esa izHkkoh lq/kkj fd;k gSA ,uvkbZVhvkjMh&,vkjVh dsUnz ls
vU; vkadM+ksa ds fo”ys’k.k ds ckn] geus ;g Hkh iznf”kZr fd;k gS fd isV dh Vhch vDlj ,pvkbZoh
esa Vhch dk :i /kkj.k dj ysrh gS] ftldk ge isV ds vYVªklkmaM ds ek/;e ls vklkuh ls irk
yxk ldrs gSa vkSj le; ij funku dj Vhch dk mipkj fd;k tk ldrk gSA vc geus ;g tku
fy;k gS fd funku ds fy, lkoZHkkSfed Vhch ijh{k.k ¼;wuholZy Vhch VsLV½ t:jh gSA geus
,uvkbZVhvkjMh&,vkjVh dsUnz ls V~;wcjdwyhu Ldhu VsLV ¼Vh,lVh½ ds vkadM+ksa dk ,oa oSf”od
vkadkMksa dk v/;;u fd;kA gekjk fo”ys’k.k fdlh Hkh Mk;XuksfLVd VsLV dh Dyhfudy
fo”oluh;rk ds ewY;kadu ds fy, ,d lkaf[;dh; ekinaM izLrqr djrk gSa
( ßuSnkfud tkap dkfunkuß)] tksfd fuEufyf[kr gS%& fdlh Hkh VsLV dh fizfMDfVo oSY;wt+ ¼1½ 80% ls vf/kd gksus
pkfg,] ¼2½ ns”k dh laiw.kZ chekjh dh ek+=k ij fuHkZj ugh gksuh pkfg, vkSj ¼3½ tkap dh
lsaflfVfoVh@LisflfQdflVh ls c<+dj vkSj mlls lacaf/kr gksuh pkfg,A fofHkUu Dyhfudy
Lkkjka”k
ifjfLFkfr;ksa eas fo”oluh;rk gsrq rhuksa “krksZa dks iw.kZ gksus dh vko”;drk gSA Vh,lVh vkadM+ksa ds fy, mi;qZDr ekinaM lfØ; Vhch ds funku ds fy, mldh Dyhfudy vfo”oluh;rk dh iqf’V djrk gSA blds vyok bl lkaf[;dh; ekinaM ds }kjk dksbZ Hkh uSnkfud tkap dh fo”oluh;rk ds ckjs esa tkuk tk ldrk gSaA ge vius Dyhfudy vkadM+ksa ds fo”ys’k.k ls fofHkUu uSnkfud n`f’Vdks.kksa dk ewY;kadu djus esa vkSj jksfx;ksa dh csgrj ns[kHkky ds fy, oSKkfud izek.k miyC/k djus esa l{ke gw,] blfy, bl dk;Z us fcekjh vkSj mlls gksus okyh e`R;q dks de djus esa ;ksxnku fn;k gSA ge
;g izLrko nsrs gSa fd bl rjg ds fo”ysf’kr vkadMs+a Dyhfudksa vkSj vLirkyksa ls vo”; fy, tk,a
rFkk lHkh Dyhfud vius izys[kuksa vkSj fo”ys’k.kkRed dkS”kyksa esa Hkh vo”; lq/kkj djsaaA
viii
Table of contents
Table of contents
Title Page number
Certificate i
Acknowledgements ii
Abstract iv
Table of Contents viii
List of Figures xii
List of Tables xiii
List of Abbreviations xv
Chapter 1. Introduction and objectives 1-7
1.1 Introduction 1
1.2 Objectives 6
Chapter 2. Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: meningitis a potentially life threatening manifestation
8-21
2.1 Summary 8
2.2 Introduction 9
2.3 Methods 10
2.4 Data analysis 13
Table of contents
2.5 Results 13
2.6 Discussion 19
2.7 Conclusions 20
2.8 Clinical impact of the study 21
Chapter 3. Role of routine abdominal ultrasonography in intensified tuberculosis case finding algorithms at HIV clinics in high TB burden settings
22-40
3.1 Summary 22
3.2 Introduction 23
3.3 Methods 24
3.4 Data analysis 27
3.5 Results 27
3.6 Discussion 35
3.7 Conclusions 39
3.8 Clinical impact of the study 39
Chapter 4. Assessing the clinical reliability of a diagnostic test beyond sensitivity and specificity
41-72
4.1 Summary 41
x
Table of contents
4.3 Methods 44-48
4.3.1 Data collection at NITRD HIV Clinic 44
4.3.2 Data collection from global studies on TST 45
4.4 Data analysis 46-48
4.4.1 Data from NITRD HIV Clinic 46
4.4.2 Data from global studies 47
4.4.3 Application of Baye’s Theorem 47
4.5 Results 48-68
4.5.1 NITRD HIV Clinic data 48
4.5.2 Data from published studies 51
4.5.3 Understanding PPV and NPV from the data 61
4.5.4 Diagnostics of a diagnostic test 62
4.6 Discussion 69
4.7 Conclusions 72
5. Discussion 73-81
6. Summary and conclusions 82-84
6.1 Summary 82
6.2 Conclusions 83
Table of contents
6.3 Future direction 83
References 85-93
Appendix 94-99
List of publications and conferences 100-102
Author’s Resume 103-105
xii
List of Figures
List of Figures
Figure no. Title Page no.
Figure 3 Details of HIV infected cases registered at NITRD ART Centre included in the analysis
28
Figure 4.1 Flow Chart of Search Results 52
Figure 4.2 Positive and Negative Predictive values (PPV, NPV) of Tuberculin Skin Test
62
Figure 4.3 Parameters of Tuberculin Skin Test (TST) for assessing reliability of the test in a clinical setting (data from Non- HIV TB studies)
64
Figure 4.4 Parameters of Tuberculin Skin Test (TST) for assessing reliability of the test in a clinical setting (data from HIV- TB studies)
65
Figure 4.5 Positive and Negative Predictive values (PPV, NPV) of Tuberculin Skin Test (TST) for pulmonary TB (PTB) and extra pulmonary TB (EPTB) from different Non-HIV TB studies vs. number of studies from which reported
67
Figure 4.6 Parameters of Tuberculin Skin Test (TST) for assessing reliability of the test in a clinical setting (data for Pulmonary TB (PTB) and Extra pulmonary TB (EPTB) from Non-HIV TB studies
68
Figure 5 Flow diagram of analysis of clinical data from NITRD- ART Centre
79
List of Tables
List of Tables
Table no. Title Page no.
Table 2.1 Details of patients developing paradoxical TB-IRIS 15
Table 2.2 Comparison of patient characteristics and outcome of TB treatment in cases with and without paradoxical TB –IRIS (univariate analysis)
18
Table 3.1 Diagnostic criterion for probable and possible abdominal TB
26
Table 3.2 Microbiologically confirmed and clinically diagnosed HIV-TB cases
30
Table 3.3 Patient screening characteristics 31
Table 3.4 Abdominal ultrasound examination findings in HIV cases with abdominal TB
31
Table 3.5 Diagnostic criterion for probable and possible abdominal TB among cases already diagnosed and those newly diagnosed as TB at entry to HIV care
33
Table 3.6 Presenting symptoms in cases with HIV-abdominal TB (N=200)
34
Table 4.1 Comparison of patient characteristics and outcome of TB treatment in TST positive and negative HIV infected cases with and without active TB at NITRD
49
xiv
List of Tables
without active TB and the reported / calculated sensitivity and specificity of TST in each study
Table 4.3 Studies with data on TST results in HIV uninfected/unknown individuals with and without active TB (Non-HIV TB studies)
57
Table 4.4 Studies with data on TST results in HIV infected individuals with and without active TB (HIV-TB studies)
59
List of abbreviations
List of Abbreviations and short forms
AIDS Acquired Immunodeficiency Syndrome
ART Antiretroviral Therapy
ART Centre Antiretroviral Therapy Centre (HIV clinic)
GOI Government of India
HIV Human Immunodeficiency Virus
HIV-TB HIV infected cases with active tuberculosis HIV-TB studies Studies reporting data on HIV infected TB cases NACO National AIDS Control Organization
NITRD National Institute of Tuberculosis and Respiratory Diseases NITRD-ART Centre Antiretroviral Therapy Centre at
National Institute of Tuberculosis and Respiratory Diseases Non-HIV
TB studies
Studies reporting data on HIV uninfected/unknown TB cases
PLHIV People Living with HIV
RNTCP Revised National Tuberculosis Control Program
TB Tuberculosis
TB-IRIS Tuberculosis associated Immune Reconstitution Inflammatory Syndrome
TST Tuberculin Skin Test
USG Ultrasound Sonography