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
MAY 2019
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
HOSPITAL FOR CHILDREN EGMORE, CHENNAI
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
Date:
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.Rema Chandramohan, 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 valuable suggestions.
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 have seen the light of the day.
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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 IVIG- Intravenous immunoglobulin
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
12. ANNEXURES
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 presentation of many diseases.
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 transplantation (HSCT) are the treatment options available.
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, activation of lymphocytes and the effector phase.
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 the anatomical barriers.
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. Infections due to unusual organisms.
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 of PID.
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.
▪ Vitiligo may be present in autoimmune diseases.
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.
o In WAS, there will be thrombocytopenia and low mean platelet volume(MPV).
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 considering PID, if there is recurrent pneumonia in the same segment.
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.
▪ Extremely elevated IgE levels seen in hyper-IgE 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) It should be done in all cases of suspected PID.
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.
Avoid live vaccines in the PID child.
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
4. Type of organism
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 childhood infections.
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.
SCID is a medical emergency. Suspecting and diagnosing early will helps in early treatment. Avoid live vaccines in the child with suspected SCID.
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.
Definitive treatment options available are thymic transplantation and hematopoietic stem cell transplantation.
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 is 7.4-10.4 fL.
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 characteristic features of ataxia telengiectasia.
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.
The most common form is X-linked inheritance which is characterized by combined immune deficiency.
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.
Regular IVIG infusions will be helpful in many patients but type I X-linked hyper-IgM syndrome needs stem cell transplantation.
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 transplacentally acquired maternal IgG presents in the body.
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 for this disorder.
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.
Diagnosis is confirmed by reduced serum immunoglobulin levels of two isotypes and lymphocyte subset analysis.
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 Ulcerative colitis.
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 antimicrobials.
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 2. Leukocyte adhesion defect
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 gp-91phox, p-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 these patients. Liver abscess is more commonly due to Pseudomonas and Staphylococcus.
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 defective expression of CD11a/CD 18 in Flowcytometry. Antimicrobials are the main stay of treatment. Stem cell transplantation is the curative treatment.
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 pneumonia with pneumatoceles.
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 treatment.
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 immunological society guidelines. The different diseases were due to
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 granulomatous children were retrospectively studied over a period of 23 years.
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 the recruitment of leukocytes. 7 cases of LAD-I were diagnosed and studied
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 collected from the medical records and analyzed. All children found to have
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 and B-cell defects.[13].
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:
The aim of the study is to determine the “CLINICAL PROFILE AND OUTCOME OF PRIMARY IMMUNODEFICIENCY IN CHILDREN AT A TERTIARY CARE CENTRE IN SOUTH INDIA”
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 expression, complement levels will be done.
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 groups (3.3%).
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%
AGE CATEGORIZATION OF CASES
<6 months 6 months to1 year 1 to 5 years 5 to 10 years >10 years
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
AGE (in years)
AGE & GENDER DISTRIBUTION
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 respectively. (p>0.05)
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 AGE (in years)
AGE OF ONSET OF PID AND ITS
RELATION TO GENDER
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
Survivors Non-survivors
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
(n=23) 12 52.2 11 47.8
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 %)
SURVIVORS NON-SURVIVORS
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 %)
SURVIVORS NON-SURVIVORS
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
(n=24) 13 54.2 11 45.8
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 %)
SURVIVORS NON-SURVIVORS
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 %)
SURVIVORS NON-SURVIVORS
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 41.7 55.6 44.4
FAMILY H/O CONSANGUINITY AND OUTCOME (in %)
SURVIVORS NON-SURVIVORS
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 %)
SURVIVORS NON-SURVIVORS
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
(n=29) 17 58.6 12 41.4
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 outcome.(p>0.05)
