Clinical Profile and Outcome of Primary Immunodeficiency in Children at a Tertiary Care Centre in South India

CLINICAL PROFILE AND OUTCOME OF

PRIMARY IMMUNODEFICIENCY IN CHILDREN AT

A TERTIARY CARE CENTRE IN SOUTH INDIA

Dissertation submitted to

THE TAMILNADU

DR .M.G.R.MEDICAL UNIVERSITY

CHENNAI

With Partial fulfillment of the regulations For the award of the Degree of

MD PAEDIATRICS

(BRANCH VII)

INSTITUTE OF CHILD HEALTH AND

HOSPITAL FOR CHILDREN

MADRAS MEDICAL COLLEGE

CHENNAI

CERTIFICATE

This is to certify that the dissertation titled “CLINICAL PROFILE AND OUTCOME OF PRIMARY IMMUNODEFICIENCY IN CHILDREN AT A TERTIARY CARE CENTRE IN SOUTH INDIA’’ submitted by Dr.C.VASANTHARAJ to the Faculty of Paediatrics, THE

TAMILNADU DR.M.G.R MEDICAL UNIVERSITY, CHENNAI, in partial fulfillment of the requirements for the award of M.D. Degree (Paediatrics) is a

bonafide research work carried out by him under our direct supervision and

guidance.

PROF. Dr.R.JAYANTHI, MD.FRCP(Glasg)

DEAN

MADRAS MEDICAL COLLEGE, CHENNAI–03

PROF.DrA.T.ARASAR SEERALAR, MD.,DCH.,

DIRECTOR AND SUPERINTENDENT, INSTITUTE OF CHILD HEALTH AND HOSPITAL FOR CHILDREN

EGMORE, CHENNAI-08

PROF. Dr .REMA CHANDRAMOHAN MD, DCH, DNB. PGDDN, PGDEpi, FIAMS., PhD

PROFESSOR OF PEDIATRICS INSTITUTE OF CHILD HEALTH AND

HOSPITAL FOR CHILDREN EGMORE, CHENNAI

DECLARATION

This dissertation entitled “CLINICAL PROFILE AND OUTCOME OF PRIMARY IMMUNODEFICIENCY IN CHILDREN AT A TERTIARY CARE CENTRE IN SOUTH INDIA” is a bonafide work done by Dr.C.VASANTHARAJ at Institute of Child Health, Madras Medical

College during the academic year 2016-2019 under the guidance of

PROF Dr.REMA CHANDRAMOHAN MD., DCH., DNB., PGDDN., PGDEpi., FIAMS, PhD, Professor of Pediatrics, Institute of Child Health, Chennai-600008. This dissertation is submitted to The Tamil Nadu Dr. M.G.R.

Medical University, Chennai in partial fulfillment of rules and regulations for

the M.D. Degree Examinations in Paediatrics.

PROF. Dr .REMA CHANDRAMOHAN MD, DCH, DNB. PGDDN, PGDEpi, FIAMS., PhD

PROFESSOR OF PEDIATRICS INSTITUTE OF CHILD HEALTH AND

DECLARATION

I Dr.C.VASANTHARAJ, solemnly declare that the dissertation title “CLINICAL PROFILE AND OUTCOME OF PRIMARY IMMUNODEFICIENCY IN CHILDREN AT A TERTIARY CARE CENTRE IN SOUTH INDIA” has been prepared by me.

This dissertation is submitted to The Tamil Nadu Dr. M.G.R. Medical

University Chennai in partial fulfillment of rules and regulations for the

M.D. Degree Examinations in Paediatrics.

DR.C.VASANTHARAJ

Place: Chennai

SPECIAL ACKNOWLEDGEMENT

My sincere thanks to PROF.DR.R.JAYANTHI,MD.,FRCP(Glasg) Dean, Madras Medical College, for allowing me to do this dissertation and

utilize the institutional facilities.

ACKNOWLEDGEMENT

 It is with immense pleasure and privilege, which I express my heartfelt

gratitude, admiration and sincere thanks to Prof. Dr.A.T.Arasar Seeralar M.D, DCH, Director and Superintendent, ICH and HC for his guidance and support during this study.

 I am greatly indebted to my guide and teacher,

Prof.Dr.RemaChandramohan, MD,DCH.,DNB.PGDDN., PGDEpi., FIAMS., PhD., Professor of Paediatrics for her supervision, guidance and encouragement while undertaking this study.

 I am very thankful to Prof.Dr.S.Ezhilarasi, MD,DCH, Professor of Paediatrics for her support and encouragement for the study

 I am very thankful to Dr.S.Srinivasn,DCH, Registrar for the help and guidance in every stage of this study.

 I am very thankful to my assistant professor Dr.B.Sarath Balaji for his encouragement and guidance in every stage of this study

 I would like to thank my Assistant Professors Dr.G.Srinivasan, Dr.M.Karthikeyan, Dr.R.V.Dhakshayani, Dr.M.Thenmozhi for their valuable suggestions and support.

 I also thank all the members of the Dissertation Committee for their

 I also express my gratitude to all my fellow postgraduates for their kind

cooperation in carrying out this study and for their critical analysis.

 I thank the Dean and the members of Ethical Committee, Rajiv Gandhi

Government General Hospital and Madras Medical College, Chennai for

permitting me to perform this study.

 I thank all the parents and children who have ungrudgingly lent

themselves to undergo this study without which this study would not

CERTIFICATE –II

This is to certify that this dissertation work titled “CLINICAL PROFILE AND OUTCOME OF PRIMARY IMMUNODEFICIENCY IN CHILDREN AT A TERTIARY CARE CENTRE IN SOUTH INDIA.” of the candidate DR.C.VASANTHARAJ with registration number 201617016 for the award of M.D PAEDIATRICS in the branch of VII. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and

result shows 0 percentage of plagiarism in the dissertation.

ABBREVIATIONS

PID- Primary immunodeficiency

SCID- Severe combined immunodeficiency

CVID- Common variable immunodeficiency

WAS- Wiskott Aldrich Syndrome

CGD- Chronic Granulomatous Disease

LAD- Leukocyte Adhesion Defect

NBT- Nitro blue Tetrazolium test

DHR- Dihydrorhodamine assay

GvHD- Graft vs. Host Disease

HSCT- Hematopoietic Stem Cell Transplantation

S.No CONTENTS Page No.

1. INTRODUCTION 1

2. REVIEW OF LITERATURE 31

3. STUDY JUSTIFICATION 36

4. OBJECTIVES OF THE STUDY 37

5. MATERIALS AND METHODS 38

6. STATISTICAL ANALYSIS 40

7. OBSERVATION AND RESULTS 41

8. DISCUSSION 71

9. LIMITATIONS 77

10. CONCLUSION 78

11. BIBLIOGRAPHY

1

INTRODUCTION

Primary Immunodeficiency diseases (PID) are a group of disorders of immune dysfunction. This is due to the inborn error of innate and adaptive

immunity.

Immunity plays a vital role in control and prevention of infections in

childhood.

Affected individuals are predisposed to increased rate and severity of

infection, allergic diseases, autoimmune diseases, malignancy and immune

dysregulation. [1]

The prevalence of PID is approximately 1 in 10000 population.

The developing immune system and increase in exposure to pathogens makes the young children more vulnerable to recurrent infections.

An accurate and careful history is necessary to diagnose PID.

The age at presentation, infecting organisms, pattern of infection and

family history often provides clues to the diagnosis of PID and the types of

PID.

Diagnosis of PID is very difficult because the affected patients do not

have abnormal physical features and there is no screening test.

Extensive use of antibiotics in the recent era also masks the clinical

2

So these diseases are easily missed and many infants and children may

be dying without any diagnosis.

Children with recurrent infections and not responding to conventional

antibiotics need further evaluation for PID.

Environmental factors like indoor air pollution, cigarette smoking is

common nowadays and this can also increase the frequency of infections.

Poor nutrition, overcrowding can predispose to increase in pyogenic

infections and tuberculosis.

Recurrent infections due to this factor should be ruled out before

diagnosing PID.

Prompt and accurate diagnosis of PID in child can result in early

treatment and better outcome.

This also helps in guiding the family for appropriate genetic counselling.

Intravenous immunoglobulin and hematopoietic stem cell

3

IMMUNITY[2]

The two major components of the immune system are innate and adaptive immunity.

INNNATE IMMUNITY

This is the first line defense mechanism of our body which is primitive,

nonspecific and has no memory.

Macrophages, polymorphonuclear leukocytes, natural killer (NK) cells

are the cellular components of innate immune system.

Classical and alternate pathways of complement system possess innate

immunity.

ADAPTIVE IMMUNITY

This immunity is mainly due to specific memory which results in rapid

immune response when exposed to the same organism. This is highly evolved

immunity.

Lymphocytes, macrophages, antigen presenting cells are the components

of adaptive immune system. Adaptive immune system consists of specificity, diversity and immunologic memory.

The phases of adaptive immune system includes antigen recognition,

4

Adaptive immunity consists of humoral and cell mediated immunity.

Humoral immunity is mainly due to B cells and their products like

antibodies or gamma globulin.

This immune response is mainly against the extracellular

microorganisms and their secreted toxins.

Cell mediated immunity is mainly due to T lymphocytes and its differentiation. This mainly takes care of intracellular pathogens.

ORGANS OF IMMUNE SYSTEM[2]

Organs of immune system are classified into primary, secondary and

tertiary lymphoid organs.

Primary lymphoid organs are bone marrow and thymus where B cell

development and maturation occurs.

Secondary lymphoid organs are lymph nodes, spleen and aggregates of lymphoid tissue.

Tertiary lymphoid organs are liver, lungs and skin. Through these

organs infectious agents enters the body. Memory and effector immune cells

reside in these organs.

Skin and mucosa of respiratory, gastrointestinal and urogenital tracts are

5

Peptides and antimicrobial proteins which presents in tears and sebum,

acid secreted in stomach are the chemical barriers.

This barrier protects our body from the infections.

PRIMARY IMMUNODEFICIENCY DISEASES

These disorders can affect any of the major components of immune

system and leads to various diseases.

The immunodeficient child may presents with recurrent infections,

autoimmune diseases and also susceptible to malignancy.

High degree of clinical suspicion is needed in a child to suspect

immunodeficiency. The most common presentation is infection.

To suspect PID in following infections [1]

1. Recurrent infections like otitis media, recurrent pneumonia and sinusitis.

2. Persistent infections that is difficult to clear.

3. Complicated infections like lung abscess and empyema due to

progression of pneumonia.

4. Severe fulminant infections like fulminant infectious mononucleosis,

hemorrhagic chicken pox.

5. Unusual site infections like osteomyelitis, liver abscess.

6

Warning signs in suspecting PID [1]

▪ Two or more pneumonias within a year

▪ Two or more serious sinus infections within a year

▪ Eight or more ear infections in a year

▪ Two or more months of antibiotics without any effect

▪ Need for intravenous antibiotics

▪ Recurrent skin or deep organ abscess

▪ 2 or more deep seated infections

▪ Persistent oral thrush or anywhere after 1 year of age

▪ Failure to thrive

▪ Family history of PID

PID’s can present at any age of the child but most of the diseases will

present in the early age and some will present in the older age.

But sometimes age will give some important clue to think about the type

7

T cell defects and phagocytic defects will present within 3 months of life

whereas B cell defects will present after 6 months, because maternally

transmitted antibodies will protect them from infections.

Family history also gives some clue to our diagnosis.

We have to ask family history regarding intrauterine and neonatal deaths,

sibling deaths and presentation of the problems.

Males are most commonly affected by PID, because the PID related

genes are present on the X chromosome. So if a previously affected child is

male, we have to strongly suspect PID to be the cause.

PHYSICAL EXAMINATION[1]

▪ Physical examination will give valuable clues for our diagnosis. So

careful physical examination is very important.

▪ Look for BCG scar, if there is large ulceration, BCG adenitis, large

nodule at BCG site, suspect T cell defect.

▪ In Omenn syndrome and GvHD, skin rash may be seen.

▪ Eczema and petichiae may be seen in Wiskott Aldrich Syndrome.

▪ In Chediak-Higashi syndrome, Albinism may be seen.

8

▪ Typical facies, retained primary teeth and skin cold abscess may be

seen in hyper-IgE Syndrome.

▪ Gingivostomatitis is classically seen in phagocytic defects.

▪ Candidiasis may be seen in oral cavity and perianal region.

▪ Absence of lymph nodes and tonsils are clues for SCID.

▪ Lymphadenopathy may be seen in Auto immune lymphoproliferative

syndrome [ALPS].

▪ In disseminated BCGosis there will be organomegaly.

SUSPECTING PID IN INVESTIGATIONS[1]

 Simple investigations provide important clues for suspecting PID.

 The first simple investigation for suspecting PID is complete blood

count(CBC).

o In LAD, there will be extreme neutrophilic leukocytosis.

o In SCID, Absolute Lymphocyte count is less than normal for that age.

9

 In Chediak-Higashi syndrome, presence of large granules in WBC may

be seen.

 In congenital specific granule deficiency, absence of granules in

neutrophil on Peripheral Smear (PS) is seen.

 A very low absolute neutrophil count (ANC) suggests congenital

neutropenia.

 Always compare the values with the normal values for that age.

 SCID is suspected if the ALC is less than 4000 in an infant.

 We have to calculate the absolute values of neutrophils, lymphocytes

every time not only percentage.

 Baby’s lymphocytes may be falsely elevated by maternally transmitted

lymphocytes.

CHEST X-RAY (CXR)

1. Absence of thymus suggests SCID.

2. We have to suspect T cell defects, if CXR shows Pneumocystis Carnii

pneumonia.

3. We have to rule out congenital anomalies or foreign body before

10

NITROBLUE TETRAZOLIUM TEST [NBT]

It is the screening test for chronic granulomatous disease [CGD]. It

should be done in all cases of suspected CGD.

DIHYDRORHODAMINE ASSAY (DHR ASSAY)

All suspected CGD children who show a positive NBT test will be

confirmed by doing DHR assay.

SERUM IMMUNOGLOBULIN LEVELS[1]

▪ This is the initial screening test and the most basic test for evaluating an

antibody defect in various immunoglobulin isotypes.

▪ It gives quantitative estimation of IgA, IgG, IgM, IgE levels.

▪ Ig levels helps in differentiating various types of PID and should be

done in all children in whom we are suspecting PID.

▪ Serum Ig levels varies with age, so it should be compared with the

values normal for that age.

▪ Hypogammaglobunemia shows low Ig levels for that age.

▪ Elevated IgM but a low level of IgG is hallmark of hyper-IgM.

Syndrome.

11

▪ A variable serum Ig level is seen in common variable immunodeficiency

(CVID).

▪ Avoid doing serum Ig levels in recently transfused child and infants less

than 6 months of age.

▪ Serum Ig levels are elevated in children with ALPS.

▪ Hypergammaglobulinemia and extremely high ESR is seen in children

with HIV infection.

LYMPHOCYTE SUBSET ANALYSIS

Lymphocyte subset will provide important clue for diagnosing PID.

Flowcytometry is used to analyze the lymphocyte subset.

CD3,CD4,CD8(T cell markers),

CD19,CD20(B cell markers) and

CD16,CD56(NK cell markers)

12

ROLE OF PAEDIATRICIANS IN PID[1]

 The first step in diagnosing a primary immunodeficiency is to

suspect it.

 All recurrent infections in children should be given importance and

PID should be suspected in these children.

 A detailed history and thorough clinical examination helps in diagnosing PID.

 When we are suspecting a PID, a good CBC with differential count

and peripheral smear is the first investigation that should be done.

 Clinical presentation should be correlated with the CBC reports.

 CBC detects abnormalities in one or more lineages and it provides

a clue to arrive at a diagnosis.

 Transfuse irradiated blood and blood products to a child with SCID

because normal blood will cause transfusion associated GvHD

which is fatal.

13

CLASSIFICATION OF PID [1]

Based on immune components involved, PIDs have been classified into

▪ Defects of innate immunity

▪ Defects in cellular immunity

▪ Predominantly humoral or antibody deficiencies

▪ Other defined syndromes with immune deficiency

▪ Defects in functions/number of phagocytes

▪ Defects of immune dysregulation

▪ Complement deficiencies

▪ Auto inflammatory disorders

While evaluating any child with recurrent infections and suspected PID,

One can narrow down the type of PID based on the following points:

1. Age of presentation

2. Family history (pattern of inheritance)

3. Systems involved

14

CELLULAR AND COMBINED IMMUNODEFICIENCY[2]

Cellular and combined immunodeficiency consists of various diseases

which includes

1. Severe combined immunodeficiency(SCID)

2. DiGeorge anomaly

3. Wiskott Aldrich Syndrome

4. Ataxia-telengiectasia

5. Hyper-IgM syndrome

SEVERE COMBINED IMMUNODEFICIENCY[1][2][3]

This is the most fatal and severe form of inherited immunodeficiency. It

occurs 1 in 50000 live births. It is an inherited disorder of T-cell and B-cell

defects.

X-linked SCID is the most common form which is caused by mutations

in the common gamma chain. The other types are due to adenosine deaminase

deficiency and purine nucleoside phosphorylase deficiency.

Male children are most commonly affected. Children may be normal at

birth. The diagnosis may be significantly delayed because the complicated infections present in this child may not initially be distinguishable from routine

15

This presents with severe infections in infancy due to fungi, viruses and

intracellular pathogens.

The most common infections are pneumonia, persistent diarrhea,

disseminated BCGosis, candidiasis (oral, esophageal, perianal).

The most common organisms are Pneumocystis jirovecii, Mycobacteria,

Candida, cytomegalovirus, adenovirus, influenza virus and respiratory

synctitial virus.

Due to complications of various infections, these infants usually die

during the first year of life. Sometimes if such babies are left untreated they

may die within a few months.

Lymph nodes are not palpable and tonsillar tissue is usually absent.

Oral ulcers, skin rash, coarse facies and midline defects are the physical

features usually present in this child.

Family history in the form of previous sibling deaths, severe infections are highly suggestive of SCID.

Complete blood count is the screening test. Almost all the children have

severe lymphopenia, which is characteristic for SCID. Absolute lymphocyte

count is very helpful in diagnosing SCID. Flow cytometry is used to

differentiate the types of SCID with lymphocyte subset analysis.

16

The treatment of SCID is to treat the existing infections and

antimicrobials, antifungals and IVIG prophylaxis to be given to avoid further

infections.

Enzyme replacement therapy, gene therapy and stem cell transplantation

are the definitive treatment options available nowadays.

DIGEORGE SYNDROME[2][3]

A defect in the embryogenesis of third and fourth pharyngeal pouches

leads to this disorder. This is autosomal dominant and it is caused by the

deletion of 22q11.2 gene in the chromosome 22.

Hypertelorism, antimongoloid slant, low set ears, micrognathia, short

philtrum, bifid uvula, hypocalcaemic tetany, aortic arch anomalies, absent

thymus, congenital heart disease and developmental delay are the clinical

characteristics of this disorder.

T cell defects will present in 20-30% of patients which leads to infections which ranging from mild to severe infections requiring higher

antibiotics.

There is no cure for this condition. Supportive treatment with antibiotics

should be given and treatment for hypocalcaemia and cardiac defects are

helpful.

17

WISKOTT ALDRICH SYNDROME[2][3]

Mutations in the gene encoding for the WAS protein leads to this

disorder. The common gene involved is Xp11.22-23.

This disorder follows X-linked recessive inheritance. This protein is

present in the cytoplasm of lymphocytes and platelets.

The classical triad of WAS is eczema, recurrent infections and

thrombocytopenia with small platelets. Only one third of these patients present

with this classical triad.

Male child with recurrent infections, eczema and gastrointestinal bleed

with positive family history is suggestive of WAS.

Patients are highly susceptible to infections with pneumococci,

meningiococci and H.influenza, due to impaired response to the polysaccharide

antigens.

Recurrent severe infections with fulminant course are more common in

WAS spectrum whereas bleeding manifestations are common in X-linked

thrombocytopenia.

Diagnosis is made clinically by the classical triad. Small platelets are

usually diagnosed by decrease in mean platelet volume (MPV). Normal MPV

18

Severe IgM deficiency is classically found in WAS. Due to deficient

expression of CD43 in lymphocytes, there will defective T signaling.

Diagnosis is confirmed by doing the genetic testing for WASP gene

expression.

Management of WAS is by treating the underlying infections with

antibiotics. Massive bleed will be treated with blood, FFP and platelet

transfusion.

IVIG therapy significantly decreases the infections, hospital admission

and will increase the quality of life. Hematopoietic stem cell transplantation is

the definitive curative treatment.

ATAXIA TELENGIECTASIA[2][3][5]

Mutations in the ATM gene located at 11q22-q23 leads to this disorder. This disorder follows X-linked recessive inheritance. ATM gene helps in

phosphorylation of proteins involves in DNA repair and cell-cycle control.

Progressive ataxia, telengiectasia, recurrent sinopulmonary infections,

chromosomal breakage, increased sensitivity to ionizing radiation is the

19

Telengiectasia commonly involves the bulbar conjunctiva but it is also

seen over the bridge of nose, the ears and on the exposed surfaces of the

extremities.

Recurrent sinopulmonary infections are due to the abnormalities in the

immunological function.

In more than 50% of these patients there will be decrease in the

immunoglobulin levels. Serum IgA, IgG2 subclass and IgE levels are usually reduced.

The degree of immunodeficiency is usually less profound than Wiskott

Aldrich syndrome. Lymphoreticular tumours and brain tumours are more

common.

Elevated alpha fetoprotein gives the clue in diagnosis. Diagnosis is

confirmed by ATM gene mutation. Death is most commonly due to infection or tumour dissemination.

HYPER-IGM SYNDROME[1][2]

This syndrome follows the X-linked inheritance or autosomal recessive

inheritance. Males are commonly affected.

20

There are multiple causes for this syndrome. The most common cause is

CD40 ligand defect.

Pneumonia is the most common infection. The common organisms

causing the pneumonia are Staphylococcus, Streptococcus, CMV, PCP,

Candida and Histoplasma.

Due to profound neutropenia in this child, there will be oral ulcers;

gingivitis, diarrhea and rectal ulcers are common.

The common organisms causing diarrhea are Cryptosporidium,

G.lamblia, Salmonella and E.histolytica.

The poor response to antimicrobials in this disorder results in recurrent

or prolonged diarrhea.

Taking boiled water or filtered water will prevent Cryptosporidium

infection. Nitazoxanide is approved for the treatment for diarrhea caused by

cryptosporidium.

Normal or high IgM levels with low IgG and IgA is the characteristic

feature of this syndrome.

Supportive treatment for the infections with antibiotics, antivirals and

antifungals will be helpful.

21

HUMORAL IMMUNODEFICIENCY[2]

This includes the following types

1. X-linked (Bruton) agammaglobulinemia

2. Common variable immunodeficiency (CVID)

3. Selective IgA deficiency

4. IgG subclass deficiency

5. Transient hypogammaglobulinemia of infancy

X-LINKED (BRUTON) AGAMMAGLOBULINEMIA[1][2][3]

This disorder of humoral deficiency is due to mutation in BTK

(Bruton’s Tyrosine Kinase) gene, located on the long arm of X-chromosome.

BTK is important for the maturation of Pre-B cells to mature B cells.

This leads to failure of B cell development and results in decreased

mature B cells in the peripheral circulation.

This in turn leads to decrease in the production of various immunoglobulin levels and severe hypogammaglobulinemia.

So the affected children are more susceptible to recurrent infections

which results in recurrent admission.

Children are asymptomatic up to 6 months of age because of the

22

The most common infection is recurrent sinopulmonary infections

which presents as otitis media, sinusitis, bronchitis and pneumonia.

The infections are most commonly caused by encapsulated organisms

like H.influenza type B, S.pyogenes, S.pneumoniae and Pseudomonas species.

Respiratory, urogenital and joint infections are also caused by

Mycoplasma. Gastrointestinal infections are most commonly caused by

G.lamblia and C.jejuni. Viral infections are also common in this disorder.

Autoimmune inflammatory diseases like inflammatory bowel disease

and arthritis are more common in this disease.

It is diagnosed by the reduction in all isotypes of immunoglobulin and

almost complete absence of peripheral B cells in circulation which is less than

2%.

T cell number and functions are normal. Flowcytometry helps in finding

BTK protein expression on monocytes.

The confirmatory test for Bruton’s agammaglobulinemia is to see for

defect in the BTK gene or BTK expression in genetic analysis.

Antibiotics and IVIG replacement therapy are the current treatment

facilities available. Stem cell gene therapy is a potential therapeutic approach

23

COMMON VARIABLE IMMUNODEFICIENCY (CVID)[1][2][3][4]

This disorder is due to the variable defects in T cell number and function

and also characterized by hypogammaglobulinemia.

This is defined as deficiency of any two immunoglobulins subtypes

most commonly IgG along with IgA/IgM and impaired antibody response.

CVID is most commonly presents sporadically but can also present as autosomal recessive and autosomal dominant inheritance.

Most common gene mutations encountered in CVID are Inducible co stimulator (ICOS), CD 19, CD 20, B cell-activating factor of tumor necrosis

factor family receptor (BAFF-R) and transmembrane activator.

The most common infections are sinopulmonary infections like

recurrent sinusitis, otitis media and bronchitis with pneumonia, gastrointestinal

infections, autoimmune diseases and malignancy.

The most common organisms in sinopulmonary infections are

S.pneumoniae, H.influenza and S.aureus. Gastrointestinal infections are due to

Giardia, Salmonella and C.jejuni.

The affected children show marked Lymphadenopathy and

hepatosplenomegaly.

24

Management includes antibiotics for recurrent infections and

antimicrobial prophylaxis to prevent further infections.

The mainstay of treatment is immunoglobulin therapy. Hematopoietic

stem cell transplantation is the definitive curative treatment.

SELECTIVE IgA DEFICIENCY[1][2][3]

This is one of the most common causes of immunodeficiency. Majority

of the patients are asymptomatic.

GI involvement is less in its deficiency inspite of IgA being the major

immunoglobulin in the intestinal mucosa. Compensated increase of IgM for the

lack of IgA in the intestinal mucosa is the believed mechanism for this less

GI involvement.

The most common infections are pulmonary and gastrointestinal infections. The most common organisms are pneumococci, meningiococci,

staphylococcus and Giardia.

The infections are more common if there is associated IgG deficiency.

Other associated diseases which are common in IgA deficiency are

chronic arthritis, Celiac disease and pernicious anemia, Crohn’s disease and

25

The treatment is supportive. Infections are treated with antimicrobials.

Asymptomatic individuals do not require any treatment.

Frequent monitoring is needed in some patients because they may

progress to CVID later.

IgG SUBCLASS DEFICIENCY[2]

This subclass deficiency will result in infections in some patients and

some may remain asymptomatic.

IgG has four subclass and it protects against different infections.

IgG1- protects against bacteria like tetanus and diphtheria.

IgG2- protects against encapsulated organisms like pneumococci and

H.influenza.

IgG3- protects against viral infections.

IgG4-protects against parasites.

This is diagnosed by decreased immunoglobulin levels of subclass. But

sometimes these levels may be normal or elevated.

Treatment is mainly treating the underlying infections with appropriate

26

TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY[2]

Physiological hypogammaglobulinemia is a normal entity which

presents in infants between 3-6 months of age where the production of

immunoglobulin has not yet begun.

This is mainly due to the catabolism of transplacentally acquired

maternal IgG.

After 6 months of age, the child becomes normal. In some infants this

hypogammaglobulinemia will be prolonged up to 18-24 months of age and this

condition is termed as transient hypogammaglobulinemia of infancy.

B-cell numbers will be normal in this condition. So in this condition the

immunoglobulin levels are interpreted with the normal values for that age.

IVIG therapy may be needed. The long-term prognosis is excellent

because these children recover over time.

PHAGOCYTIC DEFECTS

These defects are due to decrease in number or function of phagocytes.

This includes

1. Chronic Granulomatous Disease

27

CHRONIC GRANULOMATOUS DISEASE (CGD)[1][2][3][6]

This disorder is due to the defect in the generation of superoxide radical

due to the reduced activity of NADPH oxidase.

This defective production of reactive oxygen species in phagocytes

results in defective killing of phagocytosed organisms.

This disorder follows X-linked recessive inheritance in most patients. Others are due to mutations in the gene encoding for g91phox, 47 phox,

p-67phox and p-22 phox.

Catalase producing organisms like Staphylococcus, Aspergillus,

Pseudomonas and Candida are more commonly causing infections in the child

with CGD.

Recurrent life threatening infections are common in these children since

infancy. The most common infections are prominent lymphadenitis, persistent

pneumonia, tuberculosis, gastrointestinal infections, multiple liver abscesses and osteomyelitis of small bones of the hands and feet.

Inflammatory processes and granuloma formation are the hallmarks of

CGD. Granulomatous lesions can involve any part of GI tract.

Pneumonia may take weeks to months to resolve after multiple

antibiotics. Aspergillus pneumonia is the most common cause of mortality in

28

Non specific manifestations like diarrhea, abdominal pain, constipation

and failure to thrive are present in majority of the patients.

Nitro blue Tetrazolium Test (NBT) is the screening test for CGD. It is

confirmed by dihydrorhodamine test (DHR) on flow cytometry.

Treatment is supportive. Long term cotrimoxazole and itraconazole

prophylaxis improves the management. Interferon gamma is useful in severe

infections. Stem cell transplantation and gene therapy is the curative treatment.

LEUKOCYTE ADHESION DEFECT (LAD)[1][2][3][7]

This is due to phagocytic defect which results in defect in the

recruitment of neutrophils to the site of inflammation.

This disorder is due to the defective expression of CD11a/CD18. Infants

present with omphalitis and delayed umbilical cord separation. Recurrent

bacterial infections are most common. Skin and mucosal membrane is usually

involved.

Bronchopneumonia, septicemia and aseptic meningitis are the life

threatening infections which occur in these patients. The most common

organisms are S.aureus, Gram negative enteric organisms and fungi.

This is diagnosed by neutrophilic leukocytosis in CBC and with the

classical history of delayed cord separation. Diagnosis is confirmed by

29

COMPLEMENT COMPONENT DEFICIENCY[2]

Recurrent bacterial infections are more common in deficiency of the

early complement components (C2-C4) whereas the Neisseria infections are

more common in later component deficiency (C5-C9).

Hereditary angioneurotic edema is due to the deficiency of C1 esterase

inhibitor. This presents with recurrent non-itchy swellings in the body and also

like anaphylaxis.

C2/C4 or C1q deficiency may lead to systemic lupus erythematosus.

Plasma infusions may be helpful in complement deficiencies.

Tranexemic acid and danazol are used as prophylactic therapy which

results in significant improvement in C1 esterase inhibitor deficiency.

Airway compromise and laryngeal involvement needs synthetic C1

esterase inhibitor for better outcome.

HYPER-IGE SYNDROME[1][2][3]

This disorder is due to the mutation of STAT3 protein which follows

autosomal dominant inheritance.

The most common infection is respiratory infection. Also presents with

recurrent cold staphylococcal abscesses, retained primary dentition and

30

S.aureus is the most common organism causing pneumonia.

Pneumatoceles predispose to secondary infections with Aspergillus,

Pseudomonas and atypical Mycobacteria.

Diagnosed with classical clinical features and elevated serum IgE

concentration more than 2000 IU/ml. Antimicrobials is the mainstay of

31

REVIEW OF LITERATURE

1. Sumit Verma et al conducted a study of clinical manifestations and laboratory profile of various primary immunodeficiency disorders in children at

a tertiary care hospital in New Delhi. Case records of 27 children diagnosed to

have primary immunodeficiency disorders over a period of 24 months were

studied and evaluated. Common mode of presentation, age of onset, infectious

agents caused the infections were studied. The different types of disease

diagnosed were severe combined immunodeficiency, chronic granulomatous

disease, ataxia telengiectasia, hypogammaglobulinemia, DiGeorge syndrome, hyper IgM syndrome, leukocyte adhesion defect and Wiskott Aldrich

syndrome. Recurrent diarrhea, recurrent pneumonia, deep seated abscesses,

otitis, meningitis and disseminated TB were the commonest manifestations in

this study. Infectious agents were isolated. Family history of sibling deaths was

elicited.[8]

2. Madkaikar M et al conducted a study of frequency, clinical manifestations

and disease complications of different primary immunodeficiency in a tertiary care hospital in Mumbai. Case records of 159 patients were retrospectively

reviewed over a period of 3 years and evaluated. The records of the patients

identified to have primary immunodeficiency diseases were evaluated. They

were classified into eight different subgroups according to the international

32

phagocytic defects, immune dysregulation, combined T and B cell deficiency,

predominant antibody deficiency and others. The distribution pattern of PID

varied significantly from those reported by Western countries.[9]

3. Soheila et al conducted a study of the clinical features, treatment modalities,

disease complications and outcome of patients with primary immunodeficiency

in children in Iran. Case records of 59 patients with primary immunodeficiency diseases were retrospectively studied over a period of seven years and reports

were collected and analyzed. They collected the clinical, laboratory and

epidemiological data including family history and personal history based on the

review of patients medical records. The WHO criteria were used to diagnose

the primary immunodeficiency diseases. Common age, sex, mode of

presentation and types of immunodeficiency were studied. The different types

of diseases diagnosed included were phagocytic disorders, T-cell or combined deficiency and also antibody deficiency. Deaths were significant in the

consanguineous marriage group. Sibling deaths were also elicited.[10]

4. Rawat A et al conducted a study of clinical profile of infections in children

diagnosed with chronic granulomatous disease in a tertiary care hospital in

North India. The difference between the infections in developed countries and Western countries were also studied. Case records of 38 children with chronic

33

Common organisms caused the infections and common organs involved were

studied and compared with other studies. Some infections due to unusual

organisms were also isolated. The most common organisms isolated were

pseudomonas species and staphylococcus aureus. Autosomal recessive CGD

presented later with lesser number of infections whereas X-linked CGD

presented earlier with more number of infections. But mortality was similar in both CGD and decreased after antifungal and antibiotic prophylaxis.[6]

5. Suri D et al conducted a study of clinical and molecular profile and outcome

of Wiskott Aldrich Syndrome in a tertiary care hospital in North India.

Prospective study was done and 8 patients were diagnosed with Wiskott

Aldrich syndrome over a period of 5 years. The most common mode of

presentation, age and mutational analysis were studied. The common infections

encountered in this study were recurrent pneumonia and diarrhea, but eczema was variable. Small platelet with thrombocytopenia was the main clue for the

diagnosis. The different modalities of treatment used in these children were

intravenous immunoglobulin, stem cell transplantation and cotrimaxole

prophylaxis.[11].

6. Madkaikar M et al conducted a study of clinical profile of Leukocyte Adhesion Defect (LAD-I) a rare inherited immunodeficiency due to defect in

34

over a period of 3 years. Common manifestations, infections, delayed cord

separation were studied. Recurrent infections of skin and mucous membrane

were commonly present in these children. CD18 and CD11 expression was

studied in all of these patients and found to have been grossly reduced or

absent.[7]

7. Yao CM et al conducted a study of clinical manifestations and immunological features of severe combined immunodeficiency (SCID) in

children in China. Retrospective study of 44 cases over a period of 7 years

were studied and analyzed. Clinical manifestations, treatment and outcome of

SCID patients were studied. Males were affected more than female children.

Most children presented with X-SCID and only one patient had family history

of SCID. Children were treated with stem cell transplantation. Transfusion

associated graft vs host reaction occurred in children. BCG complications were noticed after BCG vaccination. Most patients were misdiagnosed before

referral to that centre.[12]

8. Barbara Piatosa et al conducted a study of clinical profile of common

variable immunodeficiency (CVID) in a tertiary care hospital in Poland.

Retrospective study was done with 49 patients who were diagnosed to have probable CVID over a period of 16 years. Clinical and laboratory profile were

35

significantly reduced immunoglobulin levels and poorly responded to

vaccination. The common presentations in the children were otitis media,

recurrent respiratory tract infections, recurrent diarrhea, granuloma formation,

hepatomegaly and splenomegaly.[4].

9. Fasth A et al conducted a study of clinical profile of primary

immunodeficiency disorders in children in Sweden. 201 cases were reported over a period of 6 years. The data of 174 children were analyzed. The different

types of diseases are studied and evaluated. Boys were commonly affected. The

most common disorders were antibody deficiencies, phagocytic disorders and T

and B-cell disorders. The highest mortality was documented for combined T

36

STUDY JUSTIFICATION

 Primary immunodeficiency disorders do occur in our country but the

exact prevalence is not known.

 We should have a high index of suspicion for immunodeficiency.

 Children presenting with infections due to unusual organisms, atypical

course of infections, poor response to conventional treatment and

increased complications following infections should be evaluated for

primary immunodeficiency.

 Awareness about these disorders may improve the diagnosis and help in

appropriate management of primary immunodeficiency.

 There is a need to share experience and data on these rare conditions and

treatment options at a national and international level so that both

patients and families afflicted with these ominous disorders are guided

well.

37

AIM AND OBJECTIVES OF THE STUDY:

AIM /OBJECTIVES:

38

MATERIALS AND METHODS

METHODOLOGY-

 STUDY DESIGN: Prospective observational study.

 STUDY PLACE: General Paediatric ward and other wards in ICH.

 STUDY PERIOD: December 2017 to September 2018.

 STUDY POPULATION: Children in the study age group admitted in general paediatric ward and other wards, satisfying the inclusion criteria.

 SAMPLE SIZE: The study intends to cover all the children presents with complaints in the inclusion criteria during the study period.

Inclusion criteria: Children with

4 or more new ear infections within a year

2 or more serious sinus infections within a year

2 or more pneumonias within a year

2 or more antibiotics with little effect

Need for intravenous injections to clear infections

Failure to thrive

Recurrent deep, skin or organ abscess

39

Persistent thrush in mouth or fungal infection on skin

2 or more deep seated infections including septicemia

A family history of PID

Exclusion criteria: Children with

HIV infection

On cancer chemotherapy

On chronic steroid ingestion

Infection secondary to congenital malformations

PROCEDURE:-

All children who meet the inclusion criteria are included in the study

and informed consent will be obtained from the parents. Detailed history with

anthropometric details, vital signs, clinical examination and detailed systemic

examination will be done.

Investigations like complete blood count, peripheral smear study,

absolute eosinophil count, CRP, Blood culture, urine routine, urine culture and

sensitivity, pus culture and sensitivity, Bronchoalveolar lavage(BAL),CXR,

USG abdomen and KUB, CT, Mantoux, TB workup, Immunoglobulin profile,

flow cytometry, NBT, DHR assay, CD11a/CD18 expression, WAS protein

40

STATISTICAL ANALYSIS

Data will be entered in excel sheet. Statistical analysis of data will be

performed by statistical software SPSS.

ETHICS:

Written informed consent was obtained from all parents and institution

review board clearance was obtained.

41

OBSERVATION AND RESULTS

The prospective observational study was conducted among patients

attending the Department of Paediatrics, Institute of Child Health, Egmore, Chennai for evaluation and treatment.

Table 1. Age description of the study population (n=30)

AGE DESCRIPTION

(in years)

Minimum Maximum Mean SD Median IQ Range

0.17 11 2.34 2.44 1.31 0.64, 4

The mean age of the study population was 2.3 years ± 2.4 SD and the

median age was 1.31 years (IQR=0.64 - 4) [Table 1].

42

Table 2. Age categorization of the cases

Age categories Frequency Percentage χ2 p-value

<6 months 5 16.7

16.6 .002

6 months to1 year 7 23.3

1 to 5 years 14 46.7

5 to 10 years 3 10.0

>10 years 1 3.3

Total 30 100.0

Non-parametric chi-square test used; p-value<.05 is significant.

Table 2 and Figure 1 show the categorization of age for the cases

included. Majority of the patients were belonging to the ages 1-5 years

(46.7%). Those who were aged above 10 years were the least among the study

43

Figure 1

This variation of these distribution was statistically significant as

derived by Non-parametric chi-square test.[p<.05]

Table 3. Age and gender distribution

Gender

Age (in years)

p-valuea

Age (in years)

p-valueb

Mean SD Median IQ

Range Males

(n=22) 2.0 1.8

.36

1.2 0.58,

3.1

.42 Females

(n=8) 3.3 3.6 1.4 1.1, 5.5

a-Independent t-test used; b- Mann Whitney U test used; p-value <0.05 is significant;

17%

23%

47%

10%

3%

44

Figure-2

Table 3 (and figure 2) shows the relationship between age and sex. The

female children who were diagnosed with the disease (PID) were elder (2.0

years ± 1.8 SD ) than the male population.

Though this difference was not statistically significant as demonstrated

by Independent t-test for mean and Mann Whitney U test for median comparisons.(p>0.05)

0 1 2 3 4

MALE FEMALE

2

3.3

A

G

E

(i

n

y

ea

rs

)

45

Table 4. Description of Age of Onset

AGE DESCRIPTION

(in years)

Minimum Maximum Mean SD Median IQ Range

0.17 9 1.65 2.03 0.79 0.31,

2.25

Age of onset of symptoms related to PID was described in table 4 and compared between the genders and presented in table 5 and figure 3.

Where the male children had a slightly delayed presentation of symptoms

(1.7 years ± 2.2 SD and median 0.87 years, IQR = 0.33-2.2) than their

counterpart (1.5 years ± 1.8 SD and median 0.71 years, IQR = 0.25-3.2).

And this difference was not statistically significant as demonstrated by

Independent t-test for mean and Mann Whitney U test for median comparisons

46

Figure-3

Table 5. Age of Onset in relationship with the sex of the subjects

Groups

Age (in years)

p-valuea

Age (in years)

p-valueb

Mean SD Median IQ

Range Males

(n=22) 1.7 2.2

.78

0.87 0.33, 2.25

.66 Females

(n=8) 1.5 1.8 0.71

0.25, 3.21

a-Independent t-test used; b- Mann Whitney U test used; p-value <0.05 is significant;

1.4 1.5 1.6 1.7 MALE FEMALE 1.7 1.5 A G E (i n ye ar s)

47

Table 6. Distribution of outcome Outcome

groups Frequency Percentage χ2 p-value

Survivors 17 56.7

.53 .46

Non-survivors 13 43.3

Non-parametric chi-square test used; p-value <.05 is significant

Figure-4

In table 6 (and figure 4) the proportion of children who progressed to

life or death during the course of admission was described. Although the

majority were survivors (56.7%) this difference was not statistically

significant.(p>0.05)

57% 43%

DISTRIBUTION OF OUTCOME

48

Table 7. Relationship of presenting history with outcome

Presenting history

Outcome

χ2 p-value Survivors

(n=17)

Non-survivors (n=13)

No % No %

LBW

yes (n=4) 2 50.0 2 50.0

.084 .77

No (n=26) 15 57.7 11 42.3

Developmental history Normal

(n=28) 15 53.6 13 46.4

1.6 .20

Delayed

(n=2) 2 100.0 0 0.0

Immunized till date

Yes (n=30) 17 56.7 13 43.3

-- --

No (n=0) 0 0.0 0 0.0

Recurrent diarrhea Present

(n=10) 7 70.0 3 30.0

1.08 .12

Absent

(n=20) 10 50.0 10 50.0

FTT Present

(n=23) 13 56.5 10 43.5

.001 .97

Absent

(n=7) 4 57.1 3 42.9

Rashes Present

(n=7) 5 71.4 2 28.6

.81 .36

Absent

49

Delayed cord separation Present

(n=2) 2 100.0 0 0.0

1.6 .20

Absent

(n=28) 15 53.6 13 46.4

Ear discharge Present

(n=11) 7 63.6 4 36.4

.34 .55

Absent

(n=19) 10 52.6 9 47.4

Pearson Chi-square used; p-value <0.05 is significant

Figure-5a

RECURRENT DIARRHOEA

NO RECURRENCE

70

50 30

50

RELATION OF RECURRENT

DIARRHEA WITH OUTCOME (in %)

50

Figure-5b

Other significant history presented by the children in the past like

history of LBW, Developmental milestones, Immunization history, Recurrent

diarrheal episodes, FTT, Rashes, Delayed cord separation and ear discharge

and its relation with the outcome were presented in table 7 and figures(5a-b)

None of the above parameters had a significant effect on the outcome as

demonstrated by Pearson's chi-square test. (p>0.05)

NORMAL CORD SEPARATION

DELAYED CORED SEPARATION

100

53.6

0

46.4

DELAYED CORD SEPARATION AND

OUTCOME (in %)

51

Table 8. Relationship of presenting illness with outcome

Presenting illness Outcome χ2 p-value Survivors (n=17) Non-survivors (n=13)

No % No %

Pneumonia Present

(n=30) 17 56.7 13 43.3

-- --

Absent

(n=0) 0 0.0 0 0.0

Meningitis Present

(n=1) 1 100.0 0 0.0

.79 .37

Absent

(n=29) 16 55.2 13 44.8

Candidiasis Present

(n=6) 4 66.7 2 33.3

.30 .58

Absent

(n=24) 13 54.2 11 45.8

Lymphadenopathy Present

(n=1) 0 0.0 1 100.0

1.35 .24

Absent

(n=29) 17 58.6 12 41.4

SSTI Present

(n=6) 4 66.7 2 33.3

.30 .58

Absent

52 Tuberculosis

Present

(n=8) 5 62.5 3 37.5

.15 .69

Absent

(n=22) 12 54.5 10 45.5

Osteomyelitis Present

(n=1) 1 100.0 0 0.0

.79 .37

Absent

(n=29) 16 55.2 13 44.8

Pearson Chi-square used; p-value <0.05 is significant

Figure-6a

PNEUMONIA NO PNEUMONIA

56.7

0 43.3

0

H/O PNEUMONIA AND OUTCOME

(in %)

53

Figure-6b

In table 8 (and figure 6a and 6b ), the relationship of other common

systemic diseases like history of pneumonia, meningitis, candidiasis,

lymphadenopathy, SSTI, Tuberculosis and Osteomyelitis with the outcome was

presented.

As evidenced by Pearson's chi-square test none of them were found to

vary significantly in influencing the outcome.(p>0.05)

MENINGITIS NO MENINGITIS

100

55.2

0

44.8

H/O MENINGITIS AND OUTCOME

(in %)

54

Table 9. Relationship of familial characteristics with outcome

Familial characteristics Outcome χ2 p-value Survivors (n=17) Non-survivors (n=13)

No % No %

h/o Consanguinity

Present (n=12) _{7 58.3 5} 41.7

.02 .88

Absent (n=18) _{10 55.6 8} 44.4

Family h/o Sibling deaths

Present (n=3) 2 66.7 1 33.3

.13 .71

Absent (n=27) 15 55.6 12 44.4

h/o TB contacts

Present (n=1) _{1 100.0 0} 0.0

.79 .37

Absent (n=29) _{16 55.2 13} 44.8

Antenatal h/o mother

Uneventful

(n=30) 17 56.7 13 43.3 _{-- --}

No (n=0) _{0 0.0 0} 0.0

Pearson Chi-square used; p-value <0.05 is significant

Figure- 7a

h/o CONSANGNUITY NO h/o

58.3

55.6

41.7 44.4

FAMILY H/O CONSANGUINITY AND

OUTCOME (in %)

55

Figure-7b

Table 9 (and figure 7a and 7b) shows the relationship of familial characteristics

with the outcome and was evaluated using Pearson's chi-square test.

No associations of history of consanguineous marriage among parents,

family history of PID, history of TB contact among family members,

significant antenatal history were found to be significantly associated with the

outcome.(p>0.05)

FAMILY h/o NONE

66.7

55.6

33.3

44.4

FAMILIAL PID AND OUTCOME

(in %)

56

Table 10.Relationship of general examination findings with outcome

General examination features Outcome χ2 p-value Survivors (n=17) Non-survivors (n=13)

No % No %

Facies

Normal

(n=30) 17 56.7 13 43.3

-- --

Abnormal

(n=0) 0 0.0 0 0.0

Eczema

Present (n=0) _{0 0.0 0} 0.0

-- --

Absent

(n=30) 17 56.7 13 43.3

Abscess

Present (n=2) 1 50.0 1 50.0

.03 .84

Absent

(n=28) 16 57.1 12 42.9

Pallor

Present

(n=23) 11 47.8 12 52.2

3.1 .07

Absent (n=7) 6 85.7 1 14.3

Clubbing

Present (n=3) _{1 33.3 2} 66.7

.73 .39

Absent

(n=27) 16 59.3 11 40.7

Lymph nodes enlarged

Present (n=1) 0 0.0 1 100.0

1.35 .24

Absent

57

Tonsils enlarged

Present

(n=26) 15 57.7 11 42.3

.08 .77

Absent (n=4) _{2 50.0 2} 50.0

Short stature

Present

(n=11) 6 54.5 5 45.5

.03 .85

Absent

(n=19) 11 57.9 8 42.1

Underweight

Present

(n=27) 16 59.3 11 40.7

.73 .39

Absent (n=3) 1 33.3 2 66.7

Pearson Chi-square used; p-value <0.05 is significant

Table 10 shows the relationship of general examination findings with

the outcome and was evaluated by application of Pearson's chi-square test.

No associations of abnormal facies, eczematous lesions, abscesses, pallor, clubbing, enlarged lymph nodes, enlarged lymph nodes, short stature or

underweight were found to be significantly associated with the

58

Table 11. Relationship of systemic abnormality with outcome

Systemic examination

Outcome

χ2 p-value Survivors

(n=17)

Non-survivors (n=13)

No % No %

CNS examination

Normal (n=29) 16 55.2 13 44.8

.79 .37

Abnormal

(n=1) 1 100.0 0 0.0

CVS examination

Normal (n=30) 17 56.7 13 43.3

- -

Abnormal

(n=0) 0 0.0 0 0.0

Heart Rate (beats per minute)

Normal 4 57.1 3 42.9

.001 .99

Tachycardia 13 56.5 10 43.5

RS examination

NVBS (n=1) 1 100.0 0 0.0

.79 .37

Crepts/ Ronchi

(n=29) 16 55.2 13 44.8

Respiratory rate (breaths per minute)

Normal (n=2) 2 100.0 0 0.0

.79 .37

Tachypnea

(n=28) 15 53.6 13 46.4

Per abdomen examination Soft/Normal

(n=21) 13 61.9 8 38.1

.78 .37

Abnormal

(n=9) 4 44.4 5 55.6

59

Figure-8a

Figure-8b

Table 11 and figures (8a-b) shows the relationship of systemic

examination findings with the outcome and was evaluated by application of Pearson's chi-square test. There is no significant association.

NVBS CREPS/RONCHI

RS EXAMINATION

100

55.2 0

44.8

RS EXAMINATION FINDINGS AND OUTCOME

(in %)

SURVIVORS NON-SURVIVORS

NORMAL TACHYPNEA

RESPIRATORY RATE

100

53.6

0

46.4

RESPIRATORY RATE AND

OUTCOME

(in %)

60

Table 12. Relationship of lab parameters with outcome

Lab parameters

Outcome

χ2 p-value Survivors

(n=17)

Non-survivors (n=13)

No % No %

Haemoglobin (gm%)

Normal (n=8) 7 87.5 1 12.5

4.2 .04

Low (n=22) 10 45.5 12 54.5

Total count (cells/mm3)

Normal (n=8) 5 62.5 3 37.5

.25 .87

Low (n=8) 4 50.0 4 50.0

High (n=14) 8 57.1 6 42.9

Platelets (cells/mm3)

Normal (n=22) 13 59.1 9 40.9

.19 .65

Low (n=8) 4 50.0 4 50.0

ESR (per hour)

Normal (n=26) 14 53.8 12 46.2

.63 .42

Raised (n=4) 3 75.0 1 25.0

CRP Positive

(n=24) 13 54.2 11 45.8 _{.30 .58}

Negative (n=6) 4 66.7 2 33.3

Peripheral smear

Normal (n=8) 6 75.0 2 25.9

1.4 .22

Obtunded

(n=22) 11 50.0 11 50.0

61

Figure-9a

Figure-9b

NORMAL HB ANEMIC

87.5

45.5

12.5

54.5

RELATIONSHIP OF HEMOGLOBIN

LEVELS WITH THE OUTCOME

(in %)

SURVIVORS NON-SURVIVORS

NORMAL LOW HIGH

TOTAL COUNT

62.5

50 57.1

37.5

50

42.9

TOTAL COUNT AND OUTCOME

(in %)

62

Figure-9c

None of the lab parameters was associated were found to be associated

with the outcome except that of Hemoglobin.

Majority of the anemic individuals were dead as a consequence of PID

(p<0.05), whereas no other parameters differed between the groups [Table 12,

figure 9a-c].

NORMAL LOW

PLATELETS

59.1

50 40.9

50

THROMBOCYTOPENIA AND

OUTCOME (in %)