A study of clinical profile, etiopathogenesis and outcome...

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A dissertation submitted in partial fulfilment of the rules and

regulations for MD General Medicine examination of the

Tamil Nadu Dr.M.G.R Medical University, Chennai, to be

held in May, 2018

A study of clinical profile,

etiopathogenesis and outcome of

patients with sodium and calcium

abnormality in tuberculosis

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DECLARATION

This is to declare that this dissertation titled ― “A study of

the clinical profile, etiopathogenesis and outcome of patients

with Sodium and Calcium abnormality in tuberculosis” is my

original work done in partial fulfilment of rules and

regulations for the MD General Medicine examination of the

Tamil Nadu Dr.M.G.R Medical University, Chennai to be

held in May, 2018.

CANDIDATE

Dr.Rohith Salim

Post graduate registrar in General Medicine

Department of Medicine

Christian Medical College, Vellore

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CERTIFICATE







held in May, 2018.

GUIDE

Dr. Ramya I

Professor



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CERTIFICATE







held in May, 2018.

PRINCIPAL HEAD OF THE DEPARTMENT

Christian Medical College Dr. O. C. Abraham

Vellore Professor and Head,



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ACKNOWLEDGEMENTS

It would be quite incongruous of me to not spend a few minutes to acknowledge the

guidance and well wishes bestowed upon me by a few people whose collective efforts

ensured the successful culmination of this dissertation. The first mention must be to

express my sincere gratitude to God the almighty, for giving me this wonderful

opportunity to study, research and benefit from an eminent institution such as Christian

Medical College, Vellore. Needless to say, this dissertation would have been proven to

be impossible if not for all the kind-hearted patients who more than willingly acceded

to my humble request to participate in this study.

Dr. Ramya I, my guide has been nothing short of constant support and inspiration. Her

clarity of thought right from the conceptualisation of this dissertation to the final

structuring has gone a long way in helping me understand and appreciate the end goal

and purpose of such a study. She was not only approachable but always ready to help

and served as an unwavering source of encouragement.

I would like to specifically mention my gratefulness to Dr. O.C. Abraham, the head of

the general medicine department, for his abundance of patience and belief in the

capability of his students.

Dr. Ravikar Ralph deserves a distinctive mention as he has been instrumental in

expanding the contours of this dissertation. I appreciate how he had truly gone out of

his way by investing a great deal of time to guide me with respect to the practical

execution of this study and its analysis. The credit of accurate reporting of the results

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of this study can be attributed to Mrs. Tunny Sebastian. I am thankful for her valuable

help in data entry and statistical analysis.

This dissertation would not have been a reality if not for the constant reminders, support

and realistic threats issued more than often by my friends Dr. Manisha Arthur, Dr.

Ebenezer Daniel. They have questioningly but willingly dealt with all my complaints

through the past couple of months and have surprisingly provided valuable insights

based on rational and reason which helped me a great deal in solving the issues. Thank

you both for sticking with me throughout.

This humble attempt of mine to express my gratitude towards people who have mattered

and been an inspiration would be unjustly incomplete if I don’t pay my over-due respect

and appreciation to my parents and sister. They have always been pillars of support and

an unwavering source of encouragement. For that, you will forever have my gratitude.

Last but not the least, there is someone who has earned a special mention. I am fully

indebted to Sandra Susan Mathew, for her understanding, wisdom, patience,

enthusiasm, encouragement and for pushing me farther than I thought I could go.

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ANTI- PLAGIARISM CERTIFICATE

This is to certify that this dissertation titled - “A study of the clinical

profile, etiopathogenesis and outcome of patients with Sodium and

Calcium abnormalities in tuberculosis” of the candidate Dr. Rohith Salim

with registration Number 201511464 has been submitted for verification

and I have personally verified the urkund.com website for the purpose of

plagiarism check. I found that the uploaded thesis file contains pages from

introduction to conclusion and the result shows 1 percentage of plagiarism

in the dissertation.

GUIDE

Dr. Ramya I

Professor, Department of Medicine


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Contents

AIM ................................................................................................................................................ 10

OBJECTIVES ................................................................................................................................. 10

INTRODUCTION ........................................................................................................................... 11

LITERATURE REVIEW ................................................................................................................ 12

METHODOLOGY .......................................................................................................................... 41

PATIENT POPULATION ........................................................................................................... 42

INCLUSION CRITERIA ......................................................................................................... 42

CASE DEFINITIONS ............................................................................................................. 43

EXCLUSION CRITERIA ........................................................................................................ 44

SETTING .................................................................................................................................... 44

STUDY METHODS.................................................................................................................... 44

.................................................................................................................................................... 45

FLOW CHART ........................................................................................................................... 46

HYPONATREMIA ALGORITHM ............................................................................................. 47

STATISTICS .............................................................................................................................. 48

SAMPLE SIZE CALCULATION ............................................................................................ 48

STATISTICAL ANALYSIS .................................................................................................... 49

FUNDING AND APPROVAL .................................................................................................... 49

RESULTS ....................................................................................................................................... 50

STROBE figure ........................................................................................................................... 50

BASELINE CHARACTERISTICS ............................................................................................. 51

AGE DISTRIBUTION ............................................................................................................ 52

GENDER ................................................................................................................................ 54

TREATMENT STATUS AT RECRUITMENT ....................................................................... 54

COMORBID ILLNESSES ....................................................................................................... 56

TYPE OF TUBERCULOSIS ................................................................................................... 57

SODIUM ABNORMALITY ....................................................................................................... 58

ETIOLOGY OF HYPONATREMIA ........................................................................................... 59

STATISTICAL ANALYSIS OF SODIUM LEVELS ................................................................... 61

DISTRIBUTION OF HYPONATREMIA ACROSS TYPES OF TUBERCULOSIS ................ 66

DISTRIBUTION OF SIADH ACROSS TYPES OF TUBERCULOSIS ................................... 67

CALCIUM ABNORMALITY ..................................................................................................... 69

STATISTICAL ANALYSIS OF CALCIUM LEVELS ................................................................ 70

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OUTCOME OF ILLNESS ........................................................................................................... 74

OUTCOME IN RELATION TO THE SODIUM STATUS ...................................................... 75

OUTCOME IN RELATION TO THE CALCIUM STATUS.................................................... 76

DISCUSSION ................................................................................................................................. 77

LIMITATIONS ............................................................................................................................... 81

CONCLUSIONS ............................................................................................................................. 81

REFERENCES................................................................................................................................ 83

ANNEXURE 1: IRB APPROVAL .................................................................................................. 89

ANNEXURE 2: FLUID GRANT FUND LETTER .......................................................................... 93

ANNEXURE 3: CLINICAL RESEARCH FORM ........................................................................... 94

ANNEXURE 4: CONSENT FORM ................................................................................................ 96

ANNEXURE 5: PATIENT INFORMATION SHEET ..................................................................... 98

ANNEXURE 6: EXTRA TABLES/FIGURES............................................................................... 100

ANNEXURE 7: THESIS DATA ................................................................................................... 102

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AIM

The aim of this study is to estimate the prevalence of electrolyte abnormality (sodium and

calcium) in adults admitted with active tuberculosis in a tertiary hospital.

OBJECTIVES

PRIMARY OBJECTIVE

1. To calculate the prevalence of hypo/hypernatremia and hypo/hypercalcemia.

SECONDARY OBJECTIVES

1. To assess the mechanism of hyponatremia

2. To assess the relation between type of tuberculosis and electrolyte abnormality

3. To assess outcome at discharge in relation to electrolyte abnormality

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INTRODUCTION

Tuberculosis is a communicable infectious disease, transmitted almost exclusively by

cough aerosol, caused by the Mycobacterium tuberculosis complex, and characterised

pathologically by necrotising granulomatous inflammation usually in the lung (~85%

of cases), although almost any extrapulmonary site can be involved.

Tuberculosis is one of the most common infection in India and is associated with high

mortality. In India, an estimated 2.8 million people developed TB in 2015. Prevalence

of tuberculosis in India is estimated to be about 250 (per 100000 population).

Tuberculosis ranks above HIV/AIDS as one of the leading causes of death from an

infectious disease, despite the fact that with timely diagnosis and correct treatment,

most people who develop tuberculosis can be cured. Electrolyte abnormalities are

associated with increased duration of hospitalization, mortality and morbidity in

hospitalized patients. Previous studies have shown electrolyte abnormalities are quite

common in tuberculosis. There are no studies done in India estimating the prevalence

of electrolyte abnormalities in hospitalized adult patients with active tuberculosis. The

mechanism of these abnormalities has also not been studied. Knowledge of electrolyte

abnormality seen in tuberculosis patients can result in early detection and treatment of

these abnormalities, possibly shorten the hospital stay, morbidity and mortality

associated with the disease. Hence, we intend to study and estimate the prevalence of

dyselectrolytemia among tuberculosis patients.

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LITERATURE REVIEW

10.4 million new cases of tuberculosis were reported worldwide in 2015, out of which

an estimated 5.9 million (56%) cases were among men, 3.5 million (34%) cases were

among women and 1.0 million (10%) cases were among children. 1.2 million (11%)

new tuberculosis cases were among people living with human immunodeficiency

virus infection. In 2015, an estimated 1.4 million people succumbed to tuberculosis

and an additional 0.4 million died from tuberculosis among people with human

immunodeficiency virus infection. More than 60% of these patients were in China,

India, the Russian Federation, Pakistan, and South Africa. The absolute number of

cases is highest in Asia, with India and China having the greatest burden of disease

globally.

Tuberculosis is one of the most common infection in India and is associated with high

mortality. Although mortality rate in tuberculosis decreased by 22% between 2000

and 2015, tuberculosis remained as one of the top ten causes of death worldwide in

2015. It ranked above HIV/AIDS as one of the leading causes of death from an

infectious disease, despite the fact that with a timely diagnosis and correct treatment,

most people who develop tuberculosis can be cured. In India, an estimated 2.8 million

people developed TB in 2015. Incidence of tuberculosis in India is estimated to be

about 217 (per 100000 population)(1). Mortality rate in India is 36 (per 100000

population, excluding HIV + tuberculosis) and 2.8 (per 100000, only HIV +

tuberculosis).

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In a retrospective review published in 2014, mortality records of 249 culture-proven

cases of tuberculosis diagnosed during 2003-2007, who died before completion of

treatment in a tertiary hospital in Taiwan were analysed. The mortality rate (all-cause)

among tuberculosis patients was 12.4%, and this was mainly attributed to non-

tuberculosis-related causes (82.7%). Majority of non-tuberculosis related deaths were

due to malignancy and secondary bacterial infection. A sizeable proportion of deaths

among tuberculosis patients was due to underlying comorbid conditions. Malignancy,

cirrhosis of liver, renal failure, miliary and pneumonic radiographic patterns were

main predictors of mortality in tuberculosis deaths(2).

TUBERCULOSIS

In 1882, Robert Koch discovered the causative agent of tuberculosis (TB), an airborne

infectious disease caused by organisms of the Mycobacterium tuberculosis complex.

tuberculosis continues to be a major cause of morbidity and mortality, primarily in

low-income and middle-income countries(1).

M. tuberculosis can cause disease throughout the body, despite being a primary

pulmonary pathogen. Besides, tuberculosis can present as a dynamic spectrum, from

asymptomatic infection to a life-threatening disease(3). From a clinical and public

health point of view, patients with tuberculosis are pragmatically classified as having

latent tuberculosis infection (LTBI), which is an asymptomatic and non-transmissible

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state, or active tuberculosis disease, which is transmissible (in active pulmonary

tuberculosis) and for which culture-based or molecular diagnostics can be used.

Patients with active tuberculosis experience symptoms such as fever, fatigue, lack of

appetite and weight loss, and those with pulmonary disease can have persistent cough

and haemoptysis in advanced disease. However, some patients with active, culture-

positive disease may be asymptomatic and are best described as having subclinical

tuberculosis(3).

Standard tuberculosis treatment comprises four first-line antimicrobials: isoniazid,

rifampicin, pyrazinamide and ethambutol. Resistance to all drugs can occur.

Multidrug-resistant tuberculosis (MDR-TB) — defined as M. tuberculosis resistant to

at least isoniazid and rifampicin — is a well-recognized entity that has been

reported(1). Extensively drug resistant tuberculosis disease, which causes even more

severe disease manifestations, is not only resistant to isoniazid and rifampicin but also

to any fluoroquinolone and any of the three injectable second-line aminoglycosides.

Diagnostic and therapeutic options vary for latent tuberculosis infection and

active tuberculosis disease, and for drug-sensitive and drug-resistant tuberculosis.

Among major known risk factors for tuberculosis, HIV infection is the strongest(4);

HIV-positive cases account for 12% of all new active tuberculosis cases and 25% of

all tuberculosis-related deaths. The majority (75%) of HIV associated active

tuberculosis cases and deaths occur in Africa(5). A systematic review showed that

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active tuberculosis was the leading cause of hospitalization among HIV-infected

adults (18%) and children (10%)(6). As HIV-positive individuals make up only 0.5%

of the world’s population, other risk factors are responsible for the remaining fraction

of tuberculosis cases in the general population. An estimated 27% of tuberculosis

cases worldwide are attributable to undernutrition and 22% to indoor air pollution(7).

Other risk factors for tuberculosis include type 2 diabetes mellitus(8), excessive

alcohol use(9) (both of which roughly triple the risk of TB) and smoking (which

doubles the risk)(10).

The natural history of tuberculosis is defined by its airborne route of transmission and

the diversity of its clinical manifestations. M. tuberculosis is not highly infectious as

compared with infectious agents such as measles virus and varicella zoster virus, an

average infectious individual might infect 3–10 people per year, of whom only a

minority will progress to active TB disease(11). However, among those with active

tuberculosis, the average duration of infection — as inferred from the incidence to

prevalence ratio — is >1 year in many high-burden settings(12). In the absence of

treatment, approximately 50% of individuals who develop active tuberculosis will

succumb to it(13).

Epidemiology trends of tuberculosis reveal marked disparities. From 1900 to 1980,

tuberculosis related deaths in western Europe and the United States fell by more than

100-fold(14). Majority of this decline occurred before the discovery of effective anti-

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tuberculosis drugs. This decline was attributed to general improvements in hygiene

and socioeconomic conditions. However, progress in most high-burden settings has

been much slower. The current worldwide rate of decline in incidence is only about

1.5% per year(1). More-rapid progress has been seen in certain areas; for example,

China halved its prevalence of active tuberculosis disease and reduced tuberculosis-

related mortality by an estimated 80% over a period of 20 years (1990–2010)(15). By

contrast, because of the effect of the HIV epidemic, the incidence of active

tuberculosis increased during the same time period in Africa, primarily(1).

Treatment for tuberculosis saved an estimated 43 million lives between 2000 and

2014. The WHO estimates that over one-third of all individuals who develop active

tuberculosis are never diagnosed or notified to public health authorities, based on the

difference between estimated and notified cases — these ‘missing 3.6 million’

constitute a major challenge in ongoing efforts to control TB(1).

Another major concern is the emergence of drug resistance, and its distribution is

particularly heterogeneous. The prevalence of MDR-tuberculosis (globally) is

estimated at 5% (3.5% in new cases of active TB disease and 20.5% in previously

treated cases). The prevalence varies widely from approximately 1% in many

countries in sub-Saharan Africa, western Europe and north America to more than

20% in areas of the former Soviet Union, such as Azerbaijan, Belarus, Kyrgyzstan and

Moldova(16). Of concern in recent years has been the problem of drug resistant

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tuberculosis in China (where one-quarter of all active tuberculosis cases are resistant

to either isoniazid or rifampicin)(17) and India (which has witnessed the emergence of

so-called totally drug-resistant strains)(18). Most cases of MDR-tuberculosis are

estimated to reflect transmission rather than initial acquisition(19). Thus, a high

priority for the response to drug-resistant tuberculosis is to identify and target

‘hotspots’ of MDR-tuberculosis transmission(20).

A complete understanding of how M. tuberculosis develops resistance has the

potential to revolutionize tuberculosis care, so efforts to catalogue resistance-

associated mutations are ongoing, using epidemiologically representative strain

collections coupled with patient outcome data(21). Genome sequencing and molecular

platforms that detect mutations that confer drug resistance also need to be developed

to support the introduction of new drug regimens for active tuberculosis(22).

Current regimens are long, cumbersome and toxic. New medicines and universal

regimens (that can be used in both drug sensitive tuberculosis and MDR-tuberculosis)

are being studied to shorten duration, facilitate administration and enable safe use in

people with comorbidities. However, the development pipeline remains very limited.

Regimens that simplify and shorten latent tuberculosis treatment are also a priority, as

any attempt to eradicate tuberculosis needs to address the huge pool of individuals

with latent tuberculosis.

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CASE DEFINITIONS

A bacteriologically confirmed tuberculosis case has a biological specimen positive by

smear microscopy, culture or world health organisation approved rapid diagnostic

methods (such as Xpert MTB/RIF).

A clinically diagnosed tuberculosis case is defined as one who does not fulfil

bacteriological confirmation criteria, but has been diagnosed by a clinician or other

medical practitioner as active tuberculosis and has been initiated on full course

empirical tuberculosis treatment. This definition includes cases diagnosed based on

radiographical abnormalities or suggestive histology and extrapulmonary cases without

laboratory/microbiological confirmation.

Pulmonary tuberculosis (PTB) refers to tuberculosis involving the lung parenchyma or

the tracheobronchial tree which is confirmed bacteriologically or clinically diagnosed.

When tuberculosis involves organs other than the lungs, which is confirmed

bacteriologically or diagnosed clinically, it is classified as Extrapulmonary tuberculosis

(EPTB). Organs involved can be pleura, lymph nodes, abdomen, genitourinary tract,

skin, joints and bones or meninges (23).

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Disseminated tuberculosis refers to tuberculosis involving the blood stream, bone

marrow, liver, or two or more non-contiguous sites, or miliary tuberculosis(24).

PATHOGENESIS

Transmission

Tuberculosis transmission occurs when the organism is exhaled as an aerosol by the

cough of an infected patient and inhaled into the alveoli of a new host.

Outcomes after infection

The human host serves as a natural reservoir for M. tuberculosis. Exposure to M

tuberculosis infrequently leads to symptomatic disease. The ability of the organism to

efficiently establish latent infection has enabled it to spread to nearly 30% of

individuals worldwide.

Latent tuberculosis

Stimulation by Mycobacterium tuberculosis antigens results in a state of persistent

immune response without evidence of clinically manifested active tuberculosis called

Latent tuberculosis infection (LTBI). It is estimated that the lifetime risk of

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reactivation for a person with documented latent tuberculosis infection is between 5 to

10%.

Development of disease is a function of the immunocompetency of the host. Although

human immunodeficiency virus coinfection is the most notable cause for progression

to active disease, there are other variables, such as uncontrolled diabetes mellitus,

sepsis, renal failure, malnutrition, smoking, chemotherapy, organ transplantation, and

long-term corticosteroid usage, that can potentially trigger reactivation of latent

tuberculosis.

Primary disease

Out of the approximately 5 to 10 percent of infected individuals who eventually

progress to develop active tuberculosis, approximately 50% will do so within the first

two to three years following the infection.

Primary pulmonary tuberculosis

Primary pulmonary tuberculosis occurs immediately after infection with tuberculosis.

It maybe asymptomatic or may present as fever with occasional pleuritic chest pain. In

areas of high tuberculosis transmission, this form of disease is usually known to affect

children. After the initial infection, the lesion (Ghon focus) is usually peripheral and

is accompanied by transient paratracheal or hilar lymphadenopathy. The expansion of

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the tubercle into the lung parenchyma with associated lymphadenopathy results in

Ghon complex.

Progressive primary tuberculosis

Primary pulmonary tuberculosis may progress rapidly to clinical illness in young

children with immature cell mediated immunity and in persons with impaired cell

mediated immunity (e.g., due to malnutrition or human immunodeficiency virus

infection). The primary site can rapidly increase in size in severe cases, with central

necrosis and development of cavity resulting in progressive primary tuberculosis.

Post-primary (adult type) disease

Also referred to as secondary or reactivation tuberculosis, it may result from

reactivation of distant latent tuberculosis infection or recent infection (primary or re-

infection). It is usually localized to the apical and posterior segments of the upper

lobe. The extent of lung parenchymal involvement varies greatly, from small

infiltrates to extensive cavitary disease.

SODIUM ABNORMALITIES

The serum sodium concentration and thus serum osmolality are controlled closely by

water homeostasis, which is mediated by thirst, arginine vasopressin, and the kidneys.

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Water homeostasis disruption is manifested as an abnormality in the serum sodium

concentration — hyponatremia or hypernatremia.

HYPONATREMIA

Hyponatremia is the most common electrolyte disorder encountered in clinical

practice, with an incidence rate reported between 15-30%. True hyponatraemia is

always associated with hypoosmolality. Hyponatremia is almost always the result of a

combination of intake of free water combined with increased circulating AVP and/or

increased renal sensitivity to AVP.

Hyponatraemia is defined as a serum sodium concentration of < 135 mmol/l after the

exclusion of ‘‘pseudo-hyponatraemia’’. In the latter, the non-aqueous components of

plasma such as in hypertriglyceridaemia or hyperproteinaemia increases, resulting in a

spuriously low sodium.

It is important to recognize hyponatremia because of the potential morbidity

associated with it and because it can be a marker of underlying disease. Although

morbidity varies widely in severity, the disorder itself and errors in management can

lead to serious complications.

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ACUTE HYPONATREMIA

Acute onset hyponatremia (< 48 hours) has severe symptoms as compared to chronic

hyponatremia, where patients maybe asymptomatic or may have subtle symptoms like

increased frequency of falls(25).

The clinical manifestations of acute hyponatremia vary with severity with serious

effects manifesting at lower sodium levels. The earliest findings, nausea and malaise,

may be seen when the serum sodium concentration falls between 125 and 130

mmol/L. Progressive central nervous system effects ranging from headache, lethargy,

obtundation and eventually seizures, coma, and respiratory arrest can occur if the

serum sodium concentration drops to between 115 and 120 mmol/L. Non-cardiogenic

pulmonary edema leading to normocapneic respiratory failure has also been described.

CHRONIC HYPONATREMIA

The cerebral adaptation permits patients with chronic hyponatremia to appear to be

asymptomatic despite a serum sodium concentration below 120 mmol/L. When

symptoms do occur in patients with serum sodium concentrations at this level, they

are relatively nonspecific.

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Symptoms associated with chronic hyponatremia are - fatigue, nausea, dizziness, gait

disturbance, forgetfulness, confusion, lethargy and muscle cramps. Seizures and coma

are uncommon and often reflect an acute exacerbation of the hyponatremia.

Symptomatic chronic hyponatremia is rarely associated with cerebral edema severe

enough to cause herniation of the brain.

ETIOLOGY AND PATHOPHYSIOLOGY

Hyponatremia is classified into 3 types on the basis of volume status:

1. Hypovolemic hyponatremia - where there is a decrease in total body water with

greater decrease in sodium level.

2. Euvolemic hyponatremia - where there is an increase in total body water with

normal sodium level.

3. Hypervolemic hyponatremia - where there is an increase in total body water

compared with sodium(26).

HYPOVOLEMIC HYPONATREMIA

Hypovolemic hyponatremia is usually associated with cerebral salt wasting, diuretic

use, gastro-intestinal loss, mineralocorticoid deficiency and third spacing. Patients

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typically have signs and symptoms associated with volume depletion (e.g.,

tachycardia, vomiting, diarrhoea, elevated blood urea nitrogen–to-creatinine ratio).

Urinary sodium level is usually less than 20 mEq/l (due to reabsorption by kidneys),

unless the kidney is the site of sodium loss. If the patient is receiving diuretics,

fractional excretion of sodium is often inaccurately elevated because of diuretic-

induced natriuresis. In these patients fractional excretion of urea can be utilized

instead(27).

Treatment of hypovolemic hyponatremia generally consists of volume repletion with

isotonic (0.9%) saline, occasional use of salt tablets, and treatment of the underlying

condition.

EUVOLEMIC HYPONATREMIA

Most common cause of euvolemic hyponatremia is SIADH, but it can also be caused

by hypothyroidism and glucocorticoid deficiency. Euvolemia is diagnosed clinically

by findings from the history and physical examination, low serum uric acid levels, a

normal blood urea nitrogen–to-creatinine ratio, and spot urinary sodium greater than

20 mEq/L. Treatment generally consists of increased salt intake, fluid restriction and

correcting the underlying cause. Fluid restriction should be limited to 500 mL less

than the daily urinary volume(28).

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HYPERVOLEMIC HYPONATREMIA

Hypervolemic hyponatremia occurs when the kidneys cannot excrete water efficiently.

In volume overload states, the effective arterial blood volume is decreased compared

with venous volume, resulting in excess ADH secretion. The most common etiology

of hypervolemic hyponatremia are congestive heart failure, liver cirrhosis, and chronic

kidney failure. Treatment consists of correcting the underlying cause, sodium and

fluid restriction, and diuretic therapy to increase excretion of solute-free water(28).

SIADH

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the most

frequent cause of hyponatremia (29). SIADH was first described in 1956 in two

patients with bronchogenic carcinoma in whom a physiologic stimulus for the release

of the antidiuretic hormone was lacking(30). The level of secretion of antidiuretic

hormone was deemed inappropriate. Later, antidiuretic hormone in humans was found

to be arginine vasopressin (AVP).

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AVP is produced predominantly in magnocellular neurons in the supraoptic nuclei in

the hypothalamus, subsequently transported down axon terminals through the

supraoptic hypophyseal tract, and eventually stored in the posterior pituitary as

inactive complexes with neurophysins(31). AVP is released quantally by exocytosis

from secretory granules in response to osmotic and non-osmotic stimuli.

AVP levels may not be elevated in all patients with the syndrome, hence the term

syndrome of inappropriate anti-diuresis (SIAD) was proposed as an accurate

description of this condition(25). Although inappropriate anti-diuresis is an essential

feature of this syndrome, excessive water intake, driven by non-osmotic stimuli, is

also required for hyponatremia to develop.

DIAGNOSIS OF SIADH

Decreased effective osmolality (< 275 mOsm per kilogram of water) with associated

urine osmolality which exceeds 100 mOsm per kilogram of water suggests SIAD.

The presence of clinical euvolemia is essential, because arginine vasopressin secretion

is appropriate when effective arterial volume is depleted.

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In the absence of a single laboratory test to confirm the diagnosis, the syndrome of

inappropriate antidiuretic hormone secretion (SIADH) is best defined by the classic

criteria introduced by Bartter and Schwartz in 1967(32).

Hypouricemia, low blood urea nitrogen, and a urinary sodium level greater than 40

mmol/l with normal dietary sodium intake in patients with hyponatremia suggest

SIAD, but are not diagnostic. Measurement of the serum level of arginine vasopressin

is not routinely recommended, urinary osmolality above 100 mOsm per kilogram of

water is usually sufficient to indicate excess of circulating arginine vasopressin.

Normal thyroid and adrenal function and absence of diuretic use adds to the

diagnosis(25).

SIADH has been reported in various conditions such as malignancies (lung,

gastrointestinal, genitourinary), pulmonary diseases (infections like pneumonia,

tuberculosis, aspergillosis; asthma, cystic fibrosis), disorders of the central nervous

system (infections, stroke, tumours). Drugs are also implicated in causing SIADH, by

stimulating the release of arginine vasopressin or potentiating its action (SSRI, TCA,

carbamazepine, oxytocin)(33).

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Tuberculosis can induce hyponatremia by various mechanisms including,

infection of adrenal gland (adrenal insufficiency)(34,35), infection of hypothalamus or

pituitary gland(36,37), inappropriate ADH secretion via pulmonary infection(38,39)

and secondary hyperaldosteronism(40). Antidiuretic agents identical to arginine

vasopressin have been demonstrated in tuberculous lung tissues(38).

Hyponatremia is reported frequently in tuberculosis patients(41–43). Hypernatremia is

not reported in any studies.

In 1954, Doxiadis and Goldfinch, reviewed serum sodium levels of 19 patients

diagnosed with tuberculosis. Approximately 19% of patients with active tuberculosis

had hyponatremia(44).

In 1965, Weiss and Katz, reviewed 4 patients with TB and hyponatremia and

proposed SIADH to be the responsible for hyponatremia(45).

In 1969, Chung and Hubbard, reviewed serum sodium levels of 522 newly diagnosed

patients with tuberculosis. Approximately 11 % of patients with active TB

were affected with hyponatremia, and the main cause of hyponatremia in

these patients was thought to be dilutional(46).

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In 1970, Vorherr et al. reported a case with pulmonary tuberculosis and hyponatremia

and found antidiuretic agents in tuberculous lung tissues(47).

In 1974, Schorn et al. reported two cases of PTB and an abnormal inappropriate

antidiuretic hormone level as a justifier mechanism(48).

In 1976, Cockcroft et al., reported a 74-year-old woman with miliary tuberculosis who

presented with severe hyponatremia due to SIADH(49).

In 1990, Hill et al. studied 22 patients with tuberculosis. Volume status was evaluated

by urine sodium concentration, blood and urine urea nitrogen, and plasma renin

activity. Endocrine, renal, and other recognized causes of SIADH were excluded.

Plasma vasopressin, was detectable despite hypo-osmolality in 16 patients (72%)(50).

In 2003, Nzerue et al. published a retrospective study of 168 patients with severe

hyponatremia (< 115mmol/L) seen at a tertiary teaching hospital, in Atlanta. Mortality

rate was high. 34 (20.2%) patients died. Sepsis, respiratory failure and the presence of

symptoms predicted poor outcome in hospitalized patients with severe

hyponatremia(51).

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In 2006, Jafari et al. prospectively evaluated patients with a diagnosis of PTB who

were admitted to the infectious wards. Hyponatremia was detected in 51% patients.

Mechanism of hyponatremia was not evaluated(52).

HYPERNATREMIA

As sodium contributes to effective osmolality (tonicity) being a functionally

impermeable solute, it induces the movement of water across cell membranes.

Therefore, hypernatremia invariably denotes hypertonic hyper osmolality and always

causes cellular dehydration. The morbidity resulting from hypernatremia may be

inconsequential, serious, or even life-threatening. Hypernatremia frequently develops

as an iatrogenic condition in hospitalized patients, and inappropriate treatment results

in some of its most serious complications(53).

ETIOLOGY AND PATHOPHYSIOLOGY

Hypernatremia can represent loss of water or gain of hypertonic sodium. Majority of

the cases of hypernatremia are due to net water loss. It can occur in the absence of a

sodium deficit (pure water loss) or in its presence (hypotonic fluid loss). Hypertonic

sodium gain is usually iatrogenic. Groups at highest risk are patients with altered

mental status, intubated patients, infants, and elderly persons because sustained

hypernatremia can occur only when thirst or access to water is impaired.

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Hypernatremia in elderly persons is usually associated with infirmity or febrile

illness(54).

Signs and symptoms of hypernatremia are prominent when the increase in the serum

sodium concentration is large or occurs rapidly (i.e., over a period of hours). The

symptoms usually manifest as central nervous dysfunction.

MANAGEMENT

Proper treatment of hypernatremia requires management of the underlying cause and

correcting the existing hypertonicity. Methods to address the underlying cause include

controlling pyrexia, reducing gastrointestinal fluid losses, treating hyperglycemia and

glucosuria, treating hypercalcemia and hypokalemia, withholding lactulose and

diuretics and correcting the feeding preparation.

Hypotonic fluids are preferred for correction and oral or feeding tube is preferred

route for administering fluids. Intravenous route is used if not feasible. Fluids used

include pure water, 5 percent dextrose, 0.2 percent sodium chloride, 0.45 percent

sodium chloride. The speed of correction depends on the rapidity with which

hypernatremia developed. In patients with hypernatremia that has developed over

hours, rapid correction is appropriate without increasing risk of cerebral edema,

33

because accumulated electrolytes are rapidly extruded from brain cells. A slower rate

of correction is appropriate in patients with hypernatremia of longer or unknown

duration(55).

CALCIUM ABNORMALITIES

Calcium abnormalities have been variedly reported in studies related to tuberculosis,

with majority of the studies reporting hypercalcemia and a few others reporting

hypocalcemia as a major biochemical finding. The usual range of serum calcium in

adults is between 2.15 and 2.60 mmol/L (8.6-10.4 mg/dL; 4.3-5.2 mEq/L).

Approximately 45% of calcium in blood is bound to plasma proteins, particularly

albumin, and about 10% is bound to anions such as citrate and phosphate. Ionised or

free calcium (normal values 1.17-1.33 mmol/L) represents about 45% of total calcium.

Although the ionised fraction of calcium is the one readily available for physiological

processes, total serum calcium is usually measured in clinical practice. However, the

total serum calcium may vary, when the serum protein concentration fluctuates, while

ionised calcium remains stable.

Total corrected serum calcium can be derived from the formula: total measured

calcium concentration (mg/dL) + 0.8 (4−serum albumin concentration(mg/dL))(56).

34

Equilibrium constant of the albumin-ionised calcium complexes can be altered by

variation in blood pH, with acidosis reducing the binding and alkalosis enhancing it.

Measurement of ionised calcium is recommended, when major variation in serum

protein levels or blood pH is suspected to determine the physiological serum calcium

level(57).

Parathyroid hormone (PTH), in association with vitamin D, is the main regulator of

calcium concentration in serum. PTH increases resorption and delivery of calcium

from the skeleton to the extracellular fluid. It also acts on the kidney to increase

tubular reabsorption of calcium and stimulates the renal 1- - hydroxylase enzyme

which is responsible for the 1- -hydroxylation of 25-hydroxycholecalciferol

[25(OH)D3] to 1,25-dihydroxycholecalciferol [1,25(OH)2D3]. The active form of

vitamin D [1,25 (OH)2D3] increases the fractional absorption of calcium from the

gut(58).

HYPERCALCEMIA

Hypercalcaemia is diagnosed when the concentration of serum calcium is 2 standard

deviations above the mean of values found in people with normal calcium levels, in at

least two samples at least one week apart over a period of three months.

35

The most common cause of hypercalcemia is primary hyperparathyroidism with an

estimated prevalence of 1-7 cases per 1000 adults. It predominantly affects the older

population (≥65 years) and women are affected two or three times more frequently

than men(59).

Other main etiologies of hypercalcemia include malignancy, drugs (thiazide, lithium),

thyrotoxicosis and granulomatous diseases. Granulomatous disease in which

hypercalcemia has been documented include sarcoidosis, berylliosis, histoplasmosis,

coccidioidomycosis and candidiasis in addition to tuberculosis(60). Sarcoidosis is the

most common granulomatous disease causing hypercalcemia.

Hypercalcemia in association with high serum calcitriol (1,25-

dihydroxycholecalciferol [1,25(OH)2D3]) levels has been reported in

tuberculosis(61,62). Dysregulated production of 1,25(OH)2D3 by activated

macrophages trapped in pulmonary alveoli and granulomas are likely the source of

high calcitriol levels(63). In patients with pulmonary TB, T-lymphocytes (possibly

CD8+ T-lymphocytes), and alveolar macrophages obtained by bronchoalveolar lavage

have been shown to produce 1,25-dihydroxycholecalciferol [1,25(OH)2D3](64).

The 1-alpha-hydroxylase activity in macrophages is activated by other mechanisms,

such as gamma interferon or endotoxin, instead of parathyroid hormone(65).

1,25(OH)2D3 produced by T-cells plays an important role in the immune response

36

against mycobacteria as it is an important component of cell-mediated immunity to

tuberculosis. The produced vitamin D does not normally affect calcium metabolism,

and has only a local effect in enhancing macrophages to kill mycobacteria. However,

if large quantities of 1,25(OH)2D3 are produced, the subsequent spill over into the

circulation results in hypercalcaemia(66). Increased intestinal absorption of calcium

and possibly increased bone resorption due to elevated circulating concentrations of

[1,25(OH)2D3] is thought to be responsible for this(67).

Patients with hypercalcaemia often presents with polyuria, polydipsia, abdominal

pain, vomiting, constipation and obtundation.

The prevalence of hypercalcemia in patients with tuberculosis varies widely between

countries in patients with active tuberculosis. This difference has been attributed to

difference in vitamin D and calcium intake, difference in degree of exposure to

sunlight and varying laboratory criteria for diagnosis of hypercalcemia(68).

During exposure to sunlight, Ultraviolet B radiation converts 7-dehydrocholesterol to

vitamin D3. Further hydroxylation occurs in liver and kidney respectively to the

physiologically active form 1,25-dihydroxycholecalciferol [1,25(OH)2D3]. In tropical

climates, where the amount of sun exposure is high, the concentration of vitamin D3 is

increased(69). Hence patients from tropics, where sunlight is plentiful have more

37

circulating vitamin D available for extra-renal synthesis of [1,25(OH)2D3] than others

and may give rise to hypercalcaemia in the presence of tuberculosis(70).

Calcium is complexed to albumin in serum, however only the free or ionized calcium

is physiologically relevant(71). Hence. It is important that serum calcium be corrected

for the serum albumin, or, ideally, to use serum ionized calcium as criteria for

hypercalcemia(72).

In 1979, Abbasi et al. reviewed retrospectively the incidence of hypercalcemia in 79

consecutive patients admitted with diagnosis of active pulmonary tuberculosis in

USA. 22 (28%) patients developed hypercalcemia during the course of illness.

Hypercalcemia resolved with treatment in all the patients(73).

In 1980, Kitrou et al. studied the prevalence of hypercalcemia in 50 consecutive

patients admitted with diagnosis of active pulmonary tuberculosis in Greece. 24 (48%)

patients were detected to have hypercalcemia at admission. Majority of the patients

were asymptomatic, except for 2 patients(74).

In 1981, Sharma studied the prevalence of hypercalcemia in 94 patients with

tuberculosis in India. 16% patients had hypercalcemia(75).

38

In 1990, Lind et al. studied the prevalence of hypercalcemia in 67 patients and

reported 25% prevalence.

In 1993, Tan et al. studied the prevalence of hypercalcemia in 43 patients with

tuberculosis in Malaysia. Only 1(2.3%) out of 43 patients had hypercalcemia. This

was in stark contrast to previously reported incidence rates of hypercalcemia

(25-50%)(76).

In 1994, Chan et al. studied the prevalence of hypercalcemia in 34 patients with

tuberculosis in China. 15% patients had hypercalcemia(77).

In 1998, Liam et al. studied prospectively the incidence of hypercalcemia in 120

consecutive patients with tuberculosis in Malaysia. Elevated calcium level was

detected in 27.5 % of patients. Only 12% of these patients showed symptoms of

hypercalcemia(78).

In 2001, Roussos et al. studied prospectively the incidence of hypercalcemia in 88

consecutive patients admitted with active pulmonary tuberculosis in Greece. 22 (25%)

patients were detected to have hypercalcemia. Only 14% of these patients showed

symptoms of hypercalcemia(79).

39

Besides the above mentioned retrospective and prospective cases series, there are

numerous case reports of hypercalcemia with tuberculosis(60,80–85).

HYPOCALCEMIA

Hypocalcemia in tuberculosis is less reported as compared to hypercalcemia.

Majority of the cases are attributed to impaired intestinal absorption of calcium,

deficient intake of calcium, malnutrition and consequent hypoalbuminemia(86).

Poor exposure to sunlight results in vitamin D deficiency. Vitamin D deficiency

results in decreased intestinal absorption of calcium. In the event of disease, decreased

physical activity experienced by the patient due to the rest advised and consequence

less exposure to sunlight has been postulated be responsible for vitamin D deficiency

and hence hypocalcemia.

In 1990, Shirai et al. reported hypocalcemia in 69 (38%) out of 183 patients with

pulmonary tuberculosis in Japan(87).

In 1997, Ali-Gombe et al. reported hypocalcemia in 45 (44%) out of 102 patients with

pulmonary tuberculosis in Nigeria(88).

40

In 2004, Ijaz et al, studied calcium abnormalities in 152 patients with pulmonary

tuberculosis in Pakistan. 52 (38%) patients had hypocalcemia, while 7 (5%) patients

had hypercalcemia(89).

In 2014, Rohini et al, assessed calcium levels in 40 patients with tuberculosis before

initiation of treatment. The average calcium level was 1.2-fold less than matched

controls. The difference persisted at 2 months and disappeared at end of 6 months(90).

41

METHODOLOGY

This was a cross-sectional study conducted at the Christian Medical College, a tertiary

hospital in Vellore, Tamil Nadu over the years 2016-2017. This aim was to calculate

the prevalence of sodium and calcium abnormality in adults admitted with tuberculosis.

The study protocol was approved by the institutional review board with IRB Min No:

9975 dated 02.03.2016. Scanned copy of IRB is in annexure number -----. Patients were

recruited and data was collected from June 2016 to July 2017.

The study was performed as a cross sectional study, which is observational in

design. The aim was to obtain a representative sample by taking a cross section of the

population. All the measurements for a study participant were obtained at a single point

in time, although recruitment took place across a period of time. Samples were taken

randomly to minimize selection bias.

The diagnosis of TB was based on one or more of the following criteria in the relevant

tissue or specimen: first, a positive smear for acid-fast bacilli; second, a positive culture

for Mycobacterium tuberculosis; third, a typical histology showing the central area of

caseation necrosis with epithelioid granulomas with or without positive staining for

acid-fast bacilli; fourth, typical imaging and clinical features suggestive of tuberculosis.

The study included both newly diagnosed patients as well as patients who are already

on treatment.

Blood samples were collected at the point of enrolment into the study for measurement

of sodium, calcium, albumin and serum osmolality by multichannel automated analyser.

42

On treatment naïve patients, baseline samples were collected prior to starting ATT.

Information regarding the type of tuberculosis, treatment details (including duration),

HIV status, co-morbid illnesses and outcome at discharge was documented.

The collected data was entered in clinical research form (CRF). The clinical research

form (CRF) was filled by the principal investigator. The copy of the CRF is in annexure.

Data from the CRF were entered into the epidata v 3.1 data entry software and then

exported to SPSS version 17, IBM Corporation for analysis.

PATIENT POPULATION

The study included all adult patients admitted with active tuberculosis in the general medicine

ward of Christian Medical College, Vellore between July 2016 and July 2017.

INCLUSION CRITERIA

1. Age 16 years or older

2. Patients admitted with diagnosis of tuberculosis, irrespective of whether the

patient is on treatment or not

43

CASE DEFINITIONS

A bacteriologically confirmed TB case is one from whom a biological specimen is

positive by smear microscopy, culture or WHO-approved rapid diagnostics (such as

Xpert MTB/RIF).

A clinically diagnosed TB case is one who does not fulfil the criteria for bacteriological

confirmation but has been diagnosed with active TB by a clinician or other medical

practitioner who has decided to give the patient a full course of TB treatment. This

definition includes cases diagnosed on the basis of X-ray abnormalities or suggestive

histology and extrapulmonary cases without laboratory confirmation.

Pulmonary tuberculosis (PTB) refers to any bacteriologically confirmed or clinically

diagnosed case of TB involving the lung parenchyma or the tracheobronchial tree.

Miliary TB is classified as pulmonary tuberculosis because there are lesions in the

lungs.

Extrapulmonary tuberculosis (EPTB) refers to any bacteriologically confirmed or

clinically diagnosed case of TB involving organs other than the lungs, e.g. pleura, lymph

nodes, abdomen, genitourinary tract, skin, joints and bones, meninges.

44

Disseminated TB is defined as tuberculous infection involving the blood stream, bone

marrow, liver, or 2 or more non-contiguous sites, or miliary TB.

EXCLUSION CRITERIA

1. Age less than 16 years

2. Women who are pregnant

3. Multi drug resistant tuberculosis

SETTING

This study was carried out in the general medical wards and intensive care unit of

Christian Medical College and Hospital, a tertiary hospital in Vellore, Tamil Nadu.

STUDY METHODS

All patients admitted with a diagnosis of tuberculosis and fulfilling the inclusion criteria

were enrolled after taking consent. The consent was taken directly from the patient. If

the patient was not able to sign, thumb impression was taken. In case the patient could

not give consent because of his general condition, consent was taken from the family

and subsequently from the patient after recovery.

45

Two millilitres of blood was drawn using all standard safety precaution and analysed

for sodium and calcium levels. To allow for protein binding of calcium, measured

total serum calcium concentration was corrected for serum albumin concentration. If

hyponatremia was present, serum osmolality was measured and clinical volume status

of the patient was documented. Urine spot sodium, random cortisol and TSH was

measured to further characterize the cause of hyponatremia.

CALCIUM CORRECTION:

In patients with hypoalbuminemia the corrected calcium levels was estimated using

the following formula

measured total serum calcium (mg/dL) + 0.8 (4−serum albumin (mg/dL)).

46

FLOW CHART

All patients admitted in

medical wards with diagnosis of TB

110 patients are enrolled

Sodium and Calcium levels

measured

If hyponatremia present,

mechanism is studied

47

HYPONATREMIA ALGORITHM

48

STATISTICS

SAMPLE SIZE CALCULATION

After literature review of similar studies which employed similar strategy, the

maximum proportion of patients with hyponatremia in tuberculosis was 0.51 (P) and

hypercalcemia in tuberculosis was 0.48. It is known that the true rate is unlikely to

exceed 50%. We wanted to estimate the prevalence to within 10 percentage points of

the true value, with 95% confidence.

Anticipated population proportion (p) 0.5

Confidence Interval (C.I) 95%

Z score for 95% C.I. 1.96

Absolute precision ( ) (40 – 60 %) 10%

The sample size (n) calculated with p = 0.5 and d = 0.1 was 100 with 95% confidence

interval.

49

STATISTICAL ANALYSIS

Data from the CRF was entered into epidata v 3.1 data entry software and then exported

to SPSS version 17, IBM Corporation for analysis. Pearson's chi-square test was used

to discover if there is a relationship between two categorical variables. All analysis was

performed by a biostatistician.

FUNDING AND APPROVAL

The study protocol was approved by the institutional review board with IRB Min No:

9975 dated 02.03.2016 and the funding was provided by the FLUID grant of the

institutional review board.

50

RESULTS

STROBE figure

All patients admitted in

medical wards with diagnosis of TB

110 patients are screened

103 eligible

100 recruited for study

Ineligible for study (n=7)

MDR TB (n=4)

Pregnant (n=2)

Did not give consent (n=1)

Excluded (n=3)

Diagnosis revised (n=3)

51

BASELINE CHARACTERISTICS

Median age of patients was 38.5. 47% were females. 23% patients were diabetic and

12% were hypertensive. 92% of patients were treatment naïve at the time of

assessment of electrolyte status. 23% of the patients were diabetic and 12% were

hypertensive. 2% of patients were seropositive.

Variable n = 100

Age, median years (range) 38.5

Gender, n (%)

Male

Female

53

47

Treatment status, N (%)

on

off

8

92

Average treatment duration (days) 57.5

Diabetes mellitus 23

Hypertension 12

Seropositive 2

52

AGE DISTRIBUTION

Figure 1 Age distribution

N Minimum Maximum Mean Std. Deviation

Age of patient 100 16 75 38.57 16.968

53

Figure 2 Age stratification

Age Frequency Percent Valid Percent

Cumulative

Percent

16-29 43 43.0 43.0 43.0

30-49 27 27.0 27.0 70.0

50-75 30 30.0 30.0 100.0

Total 100 100.0 100.0

43

27 30

100

Age 16-29 30-49 50-75 Total

54

GENDER

Frequency Percent Valid Percent Cumulative Percent

Male 53 53.0 53.0 53.0

Female 47 47.0 47.0 100.0

Total 100 100.0 100.0

TREATMENT STATUS AT RECRUITMENT

Frequency Percent Valid Percent Cumulative Percent

Treatment naive 92 92.0 92.0 92.0

On 8 8.0 8.0 100.0

Total 100 100.0 100.0

8 (8%) patients were on treatment for tuberculosis at the time of recruitment with

mean duration of treatment of 57.5 days.

55

Figure 3 treatment duration

0 20 40 60 80 100 120 140

1

2

3

4

5

6

7

8

Treatment duration (days)

N Valid 8

Missing 92

Median 60.00

Minimum 10

Maximum 120

56

COMORBID ILLNESSES

HIV status

Frequency Percent Valid Percent

Cumulative

Percent

positive 2 2.0 2.0 2.0

negative 98 98.0 98.0 100.0

Total 100 100.0 100.0

Diabetes


Cumulative

Percent

yes 23 23.0 23.0 23.0

no 77 77.0 77.0 100.0

Total 100 100.0 100.0

Hypertension


Cumulative

Percent

yes 12 12.0 12.0 12.0

no 88 88.0 88.0 100.0

Total 100 100.0 100.0

57

TYPE OF TUBERCULOSIS

Figure 4 type of tuberculosis


Cumulative

Percent

pulmonary 20 20.0 20.0 20.0

CNS tuberculosis 32 32.0 32.0 52.0

extrapulmonary 12 12.0 12.0 64.0

disseminated 36 36.0 36.0 100.0

Total 100 100.0 100.0

20

32

12

36

100

pulmonary CNS tuberculosis extrapulmonary disseminated Total

58

SODIUM ABNORMALITY

Hyponatremia was detected in 43% of patients.

Figure 5 Sodium levels


Cumulative

Percent

hyponatremia 43 43.0 43.0 43.0

normal 57 57.0 57.0 100.0

Total 100 100.0 100.0

4357

100

HYPONATREMIA NORMAL TOTAL

Sodium levels

59

ETIOLOGY OF HYPONATREMIA

Distribution

The predominant mechanism of hyponatremia was syndrome of inappropriate anti-

diuretic hormone secretion (SIADH), which was present in 28 (65%) of cases with

hyponatremia. Hypovolemic hyponatremia was present in 6 (14%) of cases.

Hypervolemic hyponatremia was present in 5 (11%) of cases. There were two cases

with hypocortisolemia and one case each with hypothyroidism and

pseudohyponatremia.

Figure 6 Etiology of hyponatremia

65.1

7 14 11.6 2.3

100

Etiology of Hyponatremia

60

Frequency Percent Valid

Percent

Cumulative

Percent

SIADH 28 28 65.1 65.1

Euvolemic (other)* 3 3 7 72.1

Hypovolemic 6 6 14 86

Hypervolemic 5 5 11.6 97.7

Pseudohyponatremia 1 1 2.3 100

Total 43 43 100

Normal 57 57

Sample size 100 100

* hypocortisolemia/hypothyroidism

61

STATISTICAL ANALYSIS OF SODIUM LEVELS

Age

The samples were stratified into two age groups. The prevalence of hyponatremia was

slightly higher in the older (> 40) age group (45.7% vs. 40.7%). However, the

difference between age groups were not statistically significant (p=.235).

.

62

Gender

The samples were stratified by gender. A higher percentage (50.9%) of male patients

presented with hyponatremia, as compared to female patients (34%) . The difference

between age groups approached statistical significance, but were still > 0.05 (p=.088).

63

Diabetes and Hypertension

The samples were stratified by comorbid illnesses (diabetes and hypertension). 23% of

the patients were diabetic and 12% were hypertensive. There wasn’t any statistical

significance (p=0.594 and 0.253, respectively) between the presence of comorbid

illnesses and development of hyponatremia.

65

Treatment status

The samples were stratified by whether the patient was on treatment for tuberculosis

at the time of recruitment. 8% of patients were on treatment for tuberculosis at the

time of recruitment with mean duration of treatment of 57.5 days. There wasn’t any

statistical significance (p=0.722) between the group which was on treatment and the

treatment naïve group in relation to development of hyponatremia.

66

DISTRIBUTION OF HYPONATREMIA ACROSS TYPES OF TUBERCULOSIS

50% of cases of pulmonary tuberculosis had hyponatremia on admission. 47% of

cases of central nervous system and disseminated tuberculosis presented with

hyponatremia. Hyponatremia was seen only in 1 case of extrapulmonary tuberculosis.

Figure 7 Hyponatremia across types of tuberculosis

20

32

12

36

100

10 15 1 17

43

PULMONARY CNS TUBERCULOSIS EXTRAPULMONARY DISSEMINATED

HYPONATREMIA ACROSS TYPES OF TUBERCULOSIS

n hyponatremia

n hyponatremia p value

Pulmonary 20 10 (50%) 0.0162

CNS tuberculosis 32 15 (47%) 0.0178

Extrapulmonary 12 1 (03%)

Disseminated 36 17 (47%) 0.0159

100 43

67

The lower prevalence rate of hyponatremia in extrapulmonary tuberculosis (3%) was

statistically significant when compared to pulmonary (50%), central nervous system

(47%) and disseminated tuberculosis (47%).

DISTRIBUTION OF SIADH ACROSS TYPES OF TUBERCULOSIS

Out of 43% cases of hyponatremia, 28% were attributed to SIADH. 80% of cases of

CNS tuberculosis and 70% cases of pulmonary tuberculosis had SIADH as

predominant mechanism of hyponatremia. SIADH was responsible for 53% of cases

of hyponatremia in disseminated tuberculosis.

Figure 8 SIADH across types of tuberculosis

10

15

1

17

43

7

12

0 9

28

PULMONARY CNS TUBERCULOSIS EXTRAPULMONARY DISSEMINATED

SIADH across types of tuberculosis

hyponatremia SIADH

68

hyponatremia SIADH

Pulmonary 10 07 (70%)

CNS tuberculosis 15 12 (80%)

Extrapulmonary 1 0

Disseminated 17 09 (53%)

43 28

The difference between pulmonary, CNS tuberculosis and disseminated tuberculosis

were not statistically significant.

p value

Pulmonary vs. CNS tuberculosis 0.653

Pulmonary vs. disseminated 0.448

CNS tuberculosis vs. disseminated 0.147

69

CALCIUM ABNORMALITY

Hypercalcemia was detected in 4 (4%) of patients. Hypocalcemia was detected in 1

(1%) patients.

Figure 9 Calcium levels

Calcium status


Cumulative

Percent

Valid hypocalcemia 1 1.0 1.0 1.0

normal 95 95.0 95.0 96.0

hypercalcemia 4 4.0 4.0 100.0

Total 100 100.0 100.0

1

95

4

100

HYPOCALCEMIA NORMAL HYPERCALCEMIA TOTAL

Calcium levels

70

STATISTICAL ANALYSIS OF CALCIUM LEVELS

Age

The samples were stratified into two age groups. 3 (75%) out of 4 cases of

hypercalcemia was seen in the younger (<40) age group. The difference of prevalence

of hypercalcemia between the age groups was not statistically significant (p=0.354).

The only case of hypocalcemia was also seen in the younger (<40) age group. The

difference of prevalence of hypocalcemia between the age groups was not statistically

significant (p=0.389).

71

Gender

The samples were stratified by gender. 3 (75%) out of 4 cases of hypercalcemia were

males. The prevalence of hypercalcemia was not statistically different between males

and females (p=0.289). The only case of hypocalcemia was a female patient. The

prevalence of hypocalcemia was not statistically different between males and females

(p=0.359).

Diabetes and Hypertension

The samples were stratified by comorbid illnesses (diabetes and hypertension). 23% of

the patients were diabetic and 12% were hypertensive.

3 (75%) out of 4 cases of hypercalcemia were non-diabetic. The only case of

hypocalcemia was a non-diabetic. There wasn’t any statistically significant difference

72

between the presence of diabetes and development of hypercalcemia (p=0.932) or

hypocalcemia (p=0.583).

All cases of hypercalcemia were non-hypertensive. The only case of hypocalcemia

was a non-hypertensive. There wasn’t any statistically significant difference between

the presence of hypertension and development of hypercalcemia (p=0.453) or

hypocalcemia (p=0.715).

73

Treatment status

The samples were stratified by whether the patient was on treatment for tuberculosis

at the time of recruitment. 8% of patients were on treatment for tuberculosis at the

time of recruitment with mean duration of treatment of 57.5 days. 3 (75%) out of 4

cases of hypercalcemia were treatment naïve. The only case of hypocalcemia was

treatment naïve. There wasn’t any statistically significance difference between the

treatment naïve group and the group which was on treatment in relation to

development of hypercalcemia (p=0.205) or hypocalcemia (p=0.766).

74

OUTCOME OF ILLNESS

Mortality rate was 5%.

Figure 10 Outcome at discharge

Outcome at discharge


Cumulative

Percent

Valid alive 95 95.0 95.0 95.0

dead 5 5.0 5.0 100.0

Total 100 100.0 100.0

95

5

100

ALIVE DEAD TOTAL

Outcome at discharge

75

OUTCOME IN RELATION TO THE SODIUM STATUS

4 (9.3%) patients with hyponatremia expired during the course of illness. The

mortality rate among patients with hyponatremia was slightly higher (9.3% vs. 1.8%)

than those patients without hyponatremia. The difference was not statistically

significant (p=0.162).

76

OUTCOME IN RELATION TO THE CALCIUM STATUS

1 (25%) patient with hypercalcemia expired during the course of illness. The

mortality rate among patients with hypercalcemia (25%) as compared to normal

calcium level (4.2%) was not statistically significant (p=0.482). This was due to the

low number of patients with hypercalcemia (4%) as compared to normal calcium

levels.

There was no mortality in the hypocalcemia group.

77

DISCUSSION

The primary objective of the study was to calculate the prevalence of sodium and

calcium abnormality in adult patients admitted with diagnosis of tuberculosis.

The prevalence of hyponatremia detected in the study was 43%. This is much higher

than the prevalence rates detected in studies done in USA (11%)(45) and Greece

(18%)(44). However, the rate was comparable with the study done by Jafari et al. in

Iran (51%)(52). Tuberculosis can induce hyponatremia by various mechanisms

including, infection of adrenal gland (adrenal insufficiency)(34,35), infection of

hypothalamus or pituitary gland(36,37), inappropriate ADH secretion via pulmonary

infection(38,39) and secondary hyperaldosteronism(40). 50% of cases of pulmonary

tuberculosis had hyponatremia on admission. 47% of cases of central nervous system

and disseminated tuberculosis presented with hyponatremia. Hyponatremia was seen

only in 1 case of extrapulmonary tuberculosis. This is consistent with previous studies

were pulmonary and CNS involvement predisposed to hyponatremia. Hypernatremia

was not detected in any patients.

The data was statistically analysed. There was no significant difference in

hyponatremia when the samples were stratified by age, gender, co-morbid illnesses.

The samples were also analysed to see of the initiation of treatment made any

78

significant differences in the prevalence of hyponatremia, however the results were

non-significant.

The prevalence of hypercalcemia detected in the study was 4%. This is much lower

than the prevalence rate detected in a study done previously in India (16%)(75).

However, the rate was comparable with a study done by Tan et al. in Malaysia

(1%)(76). The highest prevalence rate was detected in a study done by Kitrou et al. in

Greece(48%) (74). Hypercalcemia in association with high serum calcitriol (1,25-

dihydroxycholecalciferol [1,25(OH)2D3]) levels has been reported in

tuberculosis(61,62). Dysregulated production of 1,25(OH)2D3 by activated

macrophages trapped in pulmonary alveoli and granulomas are likely the source of

high calcitriol levels(63). In patients with pulmonary TB, T-lymphocytes and alveolar

macrophages obtained by bronchoalveolar lavage have been shown to produce 1,25-

dihydroxycholecalciferol [1,25(OH)2D3](64).

The prevalence of hypocalcemia detected in the study was 1%. This is much lower

than the prevalence detected in previous studies (38-44%)(87–89). Majority of the

cases of hypocalcemia in tuberculosis are attributed to impaired intestinal absorption

of calcium, deficient intake of calcium, malnutrition and consequent

hypoalbuminemia(86). Poor exposure to sunlight results in vitamin D deficiency,

which results in decreased intestinal absorption of calcium. In the event of disease,

decreased physical activity experienced by the patient due to the rest advised and

79

consequence less exposure to sunlight has been postulated be responsible for vitamin

D deficiency and hence hypocalcemia.

The data was statistically analysed. There was no significant difference in

hypercalcemia or hypocalcemia when the samples were stratified by age, gender, co-

morbid illnesses. The lower prevalence rate of hyponatremia in extrapulmonary

tuberculosis was statistically significant when compared to pulmonary, central

nervous system and disseminated tuberculosis.

There were three secondary objectives

To assess the mechanism of hyponatremia.

The predominant mechanism of hyponatremia in our study was syndrome of

inappropriate anti-diuretic hormone secretion (SIADH), which was present in 65% of

cases with hyponatremia. Hypovolemic hyponatremia was present in 14% of cases.

Hypervolemic hyponatremia was present in 11% of cases. There were two cases with

hypocortisolemia and one case each with hypothyroidism and pseudohyponatremia.

There are only a few studies which have been done previously which evaluated the

etiology of hyponatremia concurrently while studying the prevalence rates. In one of

80

the first reports, Weiss et al., in 1965, reported hyponatremia resulting from SIADH in

4 patients with pulmonary tuberculosis. Singh et al., in 1994, reported hyponatremia

in 65% of the 22 patients admitted with tubercular meningitis. All patients had

SIADH. The findings in our study was consistent with these studies with SIADH

being the main mechanism of hyponatremia.

To assess relationship between type of tuberculosis and electrolyte abnormality

Hyponatremia was attributed to SIADH in 70% and 80% cases of pulmonary and

CNS tuberculosis, respectively. There were no cases of SIADH in extrapulmonary

tuberculosis. This is consistent with the data reported in previous studies. The

prevalence of SIADH was not statistically significant among pulmonary, central

nervous system and disseminated tuberculosis.

Hypercalcemia was seen in four cases. Three of those cases were disseminated

tuberculosis. The only case of hyponatremia detected in the study was also

disseminated tuberculosis. The results were not statistically significant among

pulmonary, central nervous system, extrapulmonary and disseminated tuberculosis.

To assess outcome at discharge in relation to electrolyte abnormality

81

Five of the recruited patients expired during the course of illness (one case of

pulmonary tuberculosis and four cases of disseminated tuberculosis). Four of these

patients had hyponatremia and one had hypercalcemia. These differences were not

statistically significant.

LIMITATIONS

The study had the following limitations. As the exposure and outcome were assessed

simultaneously, temporal relationship between them cannot be established. As

measurements were obtained at a single point in time, trends in outcome could not be

monitored over time. As the study is not longitudinal by design, new cases of

hyponatremia which developed over time could not be measured..

CONCLUSIONS

The primary objective of the study was to calculate the prevalence of sodium and

calcium abnormality in adult patients admitted with diagnosis of tuberculosis.

Hyponatremia was detected in 43% of patients. Hypernatremia was not detected in

any patients. Hypercalcemia was detected in 4% of patients. Hypocalcemia was

detected in 1% patients.

82

The predominant mechanism of hyponatremia was syndrome of inappropriate anti-

diuretic hormone secretion (SIADH), which was present in 65% of cases with

hyponatremia. SIADH was responsible for 70% and 80% of cases of hyponatremia in

pulmonary and CNS tuberculosis respectively.

Early detection and treatment of underlying electrolyte abnormality can potentially

reduce mortality and morbidity associated with tuberculosis and reduce duration of

hospitalization. Further research into the prevalence of potassium, magnesium and

chloride abnormalities can add to the lacunae of knowledge. Longitudinal studies can

be used to assess the incidence of electrolyte abnormality which develop over the

course of illness.

83

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89

ANNEXURE 1: IRB APPROVAL

93

ANNEXURE 2: FLUID GRANT FUND LETTER

94

ANNEXURE 3: CLINICAL RESEARCH FORM

96

ANNEXURE 4: CONSENT FORM

98

ANNEXURE 5: PATIENT INFORMATION SHEET

100

ANNEXURE 6: EXTRA TABLES/FIGURES

Serum osmolality


Cumulative

Percent

Valid hypoosmolar 42 42.0 97.7 97.7

isoosmolar 1 1.0 2.3 100.0

Total 43 43.0 100.0

Missing 57 57.0

Total 100 100.0

Volume status


Cumulative

Percent

Valid hypovolemic 6 6.0 14.3 14.3

euvolemic 31 31.0 73.8 88.1

hypervolemic 5 5.0 11.9 100.0

Total 42 42.0 100.0

Missing 58 58.0

Total 100 100.0

101

Urine spot sodium


Cumulative

Percent

Valid less than 20 6 6.0 14.3 14.3

more than 20 36 36.0 85.7 100.0

Total 42 42.0 100.0

Missing System 58 58.0

Total 100 100.0

Vitamin D levels


Cumulative

Percent

Valid normal 1 1.0 1.0 1.0

insufficient 15 15.0 15.0 16.0

not known 84 84.0 84.0 100.0

Total 100 100.0 100.0

102

ANNEXURE 7: THESIS DATA

Section-1

ID HID AGE SEX Ty

Tb

Rx Rx HIV DM HTN NA SNA VNA

1 692462b 18 1 1 0 2 2 2 1 1 2

2 677690g 58 1 1 0 2 1 1 1 1 2

3 531959g 52 1 1 1 60 1 1 2 1 2

4 519716f 54 1 1 0 2 1 1 1 1 2

5 530269g 45 1 4 1 70 1 2 2 1 1 2

6 736267g 20 1 1 0 2 1 2 2

7 532939g 27 1 2 0 2 2 2 1 1 2

8 534025g 32 2 2 0 2 1 2 2

9 530652g 23 2 4 1 20 2 2 2 2

10 534274g 21 2 2 0 2 2 2 1 1 2

11 534035g 21 2 2 0 2 2 2 1 1 2

12 659195g 31 2 2 1 60 2 2 2 1 1 1

13 530372g 24 2 1 0 2 2 2 2

14 530905g 21 2 4 1 10 2 2 2 2

15 786470g 38 1 1 0 2 2 2 1 1 1

16 524923g 18 2 2 0 2 2 2 2

17 540957g 69 1 1 0 2 1 2 1 1 2

18 704847c 73 2 1 0 2 1 2 1 1 2

19 559294d 61 1 2 0 2 1 2 2

20 733292g 28 1 4 0 2 2 2 1 1 2

21 888703f 66 2 4 0 2 2 2 2

22 743548g 25 2 3 0 2 2 2 2

23 514248g 21 2 4 1 120 2 2 2 2

24 192275d 35 1 4 0 2 2 2 2

25 450006c 63 1 1 0 2 1 1 2

26 548421g 16 1 4 0 2 2 2 1 1 2

27 604447g 52 1 1 0 2 2 2 2

28 557138g 56 1 2 1 60 2 1 1 1 1 2

29 853023g 48 2 2 0 2 2 2 2

30 246567f 44 1 2 0 2 1 2 2

31 778167g 18 2 4 0 2 2 2 1 1 2

32 559110g 25 2 2 0 2 2 2 2

33 872916g 44 1 1 0 2 1 2 2

34 532962g 19 1 3 0 2 2 2 2

35 349855a 29 1 3 0 2 2 2 2

36 546063g 42 1 4 0 2 1 2 1 1 2

37 408598g 26 2 4 0 2 2 2 2

38 561068g 30 2 2 0 2 2 2 1 1 2

39 804834g 37 2 4 0 2 2 2 1 1 1

40 777358c 42 1 4 0 2 2 1 1 1 3

41 825966g 28 2 4 0 2 2 2 2

42 546665g 19 1 2 1 60 2 2 2 2

43 547882g 31 1 2 0 2 2 2 1 1 2

44 524275f 56 1 2 0 2 1 2 1 1 2

45 750168g 19 2 4 0 2 2 2 2

103

46 746187g 25 1 4 0 2 2 2 2

47 532031g 27 1 2 0 2 2 2 1 1 2

48 193953b 74 1 3 0 2 1 1 2

49 527689g 39 2 2 0 2 2 2 1 1 2

50 530276g 25 1 4 0 2 2 2 1 1 1

51 697024g 69 1 3 0 2 1 1 2

52 530280g 53 1 1 0 2 1 2 1 1 3

53 715053g 42 2 1 0 2 2 2 2

54 524109g 70 2 2 0 2 2 2 2

55 523840g 27 2 4 0 2 2 2 1 1 2

56 526482g 67 1 4 0 2 2 2 1 1 2

57 527241g 19 1 2 0 2 2 2 1 1 1

58 527050g 66 1 3 0 2 1 2 2

59 527199g 23 1 2 0 2 2 2 2

60 641414g 49 1 4 0 2 2 1 1 1 3

61 520456g 17 2 4 0 2 2 2 2

62 521230g 56 2 4 0 2 1 1 2

63 948855f 23 2 2 0 2 2 2 1 1 2

64 523562g 27 2 4 0 2 2 2 2

65 355943g 52 1 3 0 2 2 2 2

66 512271g 52 1 2 0 2 2 2 1 1 2

67 514297g 40 1 2 0 2 2 2 1 1 2

68 634996g 22 2 3 0 2 2 2 2

69 614041g 23 1 4 0 2 2 2 2

70 489734g 22 2 2 0 2 2 2 2

71 510896g 55 2 3 0 2 1 1 1 1 3

72 511175g 46 1 1 0 2 2 2 1 1 2

73 512082g 41 2 1 0 2 2 2 2

74 487726g 16 1 4 0 2 2 2 2

75 503287g 50 2 4 0 2 1 2 1 1 3

76 505653g 42 2 4 0 2 2 2 1 1 1

77 499139g 22 2 4 0 2 2 2 2

78 771826g 20 1 2 0 2 2 2 2

79 712991d 27 2 4 0 2 2 2 1 1 2

80 773419g 65 1 4 0 2 2 2 1 1 2

81 773470g 35 1 1 0 2 2 1 1 1 2

82 455635f 24 1 2 0 2 2 2 1 1 2

83 543979g 50 2 3 0 2 2 2 2

84 557020g 32 2 2 0 2 2 2 2

85 819870g 57 1 4 0 2 2 2 2

86 864505g 44 1 3 0 2 2 2 2

87 656654g 43 2 2 0 2 2 2 2

88 559867g 35 2 4 0 2 2 2 2

89 549769g 22 2 4 0 2 2 2 1 1 2

90 557018g 25 2 2 0 2 2 2 2

91 558027g 28 2 2 0 2 2 2 2

92 557820g 46 2 4 0 2 2 2 1 1 2

93 546627g 19 2 1 0 2 2 2 2

94 542844g 21 1 2 0 2 2 2 2

95 544485g 75 2 3 0 2 2 2 2

96 447268f 40 1 2 0 2 2 2 2

97 546931g 68 1 4 0 2 1 2 2

104

98 547378g 61 1 1 0 2 2 2 2

99 764241g 59 2 4 0 2 1 1 2

100 545993g 55 1 1 0 2 2 2 2

Section-2

ID THY CORT UNA CHF NF CR EXR RF DI ENa Ca VD OUT

1 2 2 2 2 2 1 2 3 1

2 2 2 2 2 2 1 2 3 1

3 5 2 3 1

4 2 2 2 1 2 1 2 3 1

5 2 2 2 2 2 1 2 3 1

6 2 3 1

7 9 9 2 2 2 1 2 3 1

8 2 3 1

9 2 3 1

10 2 2 2 2 2 1 2 3 1

11 2 2 2 2 2 1 2 3 1

12 2 2 2 2 2 3 2 2 1

13 2 3 1

14 2 3 1

15 1 2 2 2 1 2 2 3 2 3 1

16 2 3 1

17 2 2 2 2 2 1 2 2 1

18 2 2 2 2 2 1 2 3 2

19 2 3 1

20 2 1 2 2 2 2 2 3 1

21 2 3 1

22 2 3 1

23 3 2 2

24 2 3 1

25 2 2 1

26 2 2 2 2 2 1 2 2 1

27 2 3 1

28 2 2 2 2 2 1 2 2 1

29 2 3 1

30 2 3 1

31 2 2 2 2 2 1 2 3 1

32 2 3 1

33 2 3 1

34 2 3 1

35 2 3 1

36 2 2 2 2 2 1 2 3 1

37 2 3 1

38 2 2 2 2 2 1 2 3 1

39 1 2 2 2 1 2 2 3 2 3 2

40 2 1 2 4 2 3 2

41 2 3 1

42 2 3 1

43 2 2 2 2 2 1 2 3 1

44 2 2 2 2 2 1 2 3 1

45 2 3 1

105

46 3 2 1

47 2 2 2 2 2 1 2 3 1

48 2 3 1

49 2 2 2 2 2 1 2 3 1

50 1 2 2 2 1 2 2 3 2 3 2

51 2 3 1

52 2 1 2 4 2 2 1

53 2 3 1

54 2 3 1

55 2 2 2 2 2 1 2 3 1

56 1 2 2 2 2 2 2 3 1

57 1 2 2 2 1 2 2 3 2 3 1

58 3 1 1

59 2 3 1

60 1 2 2 2 2 2 2 4 2 3 1

61 2 3 1

62 2 3 1

63 1 2 2 2 2 2 2 3 1

64 2 3 1

65 2 3 1

66 2 2 2 2 2 1 2 2 1

67 2 2 2 2 2 1 2 3 1

68 2 2 1

69 2 3 1

70 2 3 1

71 2 1 2 4 2 3 1

72 2 2 2 2 2 1 2 3 1

73 2 3 1

74 3 2 1

75 1 2 2 2 2 2 2 4 2 3 1

76 2 2 2 3 2 3 1

77 1 2 1

78 2 3 1

79 2 2 2 2 2 1 2 3 1

80 2 2 2 2 2 1 2 3 1

81 2 2 2 2 2 1 2 3 1

82 2 2 2 2 2 1 2 3 1

83 2 3 1

84 2 2 1

85 2 2 1

86 2 3 1

87 2 2 1

88 2 3 1

89 2 2 2 2 2 1 2 3 1

90 2 3 1

91 2 3 1

92 2 2 2 2 2 1 2 3 1

93 2 3 1

94 2 3 1

95 2 3 1

96 2 3 1

97 2 3 1

106

98 2 3 1

99 2 3 1

100 2 3 1

A study of clinical profile, etiopathogenesis and outcome...

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