RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA.
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1. NAME OF THE CANDIDATE: Dr. Jalaja Mary George
& ADDRESS Department of Pathology
St. John’s medical college
Sarjapur Road
Bangalore-560 034.
2. NAME OF THE INSTITUTION: St.John’s medical college
Bangalore-34
3. COURSE OF STUDY & : P.G.(M.D. PATHOLOGY)
SUBJECT
4. DATE OF ADMISSION TO : 16 April 2012
COURSE
5. TITLE OF THE TOPIC:
The spectrum of Primary immunodeficiencydisorders – Clinical and Laboratory profile
6. BRIEF RESUME OF INTENDED WORK
6.1 NEED FOR THE STUDY :
Immunity plays a vital role in prevention and control of infections.Immunodeficiency disorders
which are either inherited or acquired increase susceptibility to infections. Primary immunedeficiency diseases (PID) are rare and comprise a genetically heterogeneous group of disorders
that affect distinct components of the innate and adaptive immune system such as neutrophils, macrophages, dendritic cells, complement proteins, NK cells as well as T and B lymphocytes1.
The reason for missing the diagnosis of PID include low index of suspicion, very high rates of
infection in general population and non-availability of diagnostic facilities at most centers. In
India the occurrence of recurrent infection is very high and therefore the index of suspicion of
PID is very low, which results in death due to infections without diagnosis of root cause. This
study aims at reporting various primary immunodeficiencies diagnosed in children at a tertiary
care hospital with correlation of clinical features and laboratory profile
6.2 REVIEW OF LITERATURE:
6.2.1. Categorization and clinical manifestations:
The primary immunodeficiency diseases (PIDs) are rare disorders that reflect abnormalities in the
development, maturation or performance of cells required for immune function. Affected individuals
aresusceptible to repeatedinfections, allergies, autoimmune diseases, andmalignancies. The incidence
of these diseases varies andranges from 1:400 to 1:500 000 live births in the UnitedStates2.
PIDs can be broadly categorized in to 5 groups
1. Predominantly antibody deficiencies.
2.Combined immunodeficiencies.
3.Other well defined immunodeficiency syndromes.
4. Phagocytic disorders.
5. Complement deficiencies2.
The main clinical manifestations can be usual, chronic or recurrent infections such as
One or more systemic bacterial infections
More serious respiratory/documented bacterial infections
Serious infections occurring in unusual sites
Infection with unusual pathogen
Infection with common childhood pathogen but of unusual severity
Ten warning signs of PIDs have been promoted by various organizations in Europe and the United States to predict PID. The most current version of the 10 warning signs developed by the JeffreyModel Foundation Medical AdvisoryBoard is as follows:
1. ≥4 new ear infections within 1year;
2. ≥2 serious sinus infections within1 year;
3. ≥2months of oral antibiotic treatmentwith little effect;
4. ≥2 episodes of pneumonia within1 year;
5. Failure of an infant to gain weightor grow normally;
6. Recurrent, deep skin or organabscesses;
7. Persistent thrush in mouth or fungal infection on skin;
8. Need for intravenous antibiotics to clear infections;
9. ≥2 deep-seated infections, including septicemia; and
10. A family history of PID3.
6.2.2. Clinical studies
Many studies were conducted in Western countries on primary immunodeficiency disorders. A historical cohort study conducted by Avni Y Joshi et al. to describe the epidemiology of PIDs in Olmsted Country, Minnesota during a 31 year period from January1,1976,through December31,2006 using Rochester epidemiology project. During the 31 year study period 158 new cases of PIDs were diagnosed with an overall incidence rate of 4.6 per100,000 person years. The rate of PIDs from 2001 through 2006(10.3 per 100,000 person years) was nearly 5 times higher than that from 1976 through 1980(2.4 per 100,000 person years).Longer delay in diagnosis was significantly associated with increased morbidity and mortality4.
The study conducted by Felipe C Javier et al. on distribution of PIDs diagnosed in a pediatric tertiary care hospital revealed that specific antibody deficiency with normal immunoglobulins followed by IgG2 subclass deficiency was the most frequently diagnosed PID.It also indicates that immunodeficiency disorder should be considered in patients with other abnormalities like allergic and syndromic or chromosomal disorders that present with recurrent infections5.
In India, based on the findings of various studies, it may be concluded that family history plays a major role. To highlight a few, in a retrospective survey by Subbarayan et al, of 563 children who presented to two pediatric immunodeficiency centers, the strongest identifiers of PID were a family history of immunodeficiency disease, use of intravenous antibiotics for sepsis in children with neutrophil PID and failure to thrive in children with T-lymphocyte PID. With these 3 signs, 96% of patients with neutrophil and complement deficiencies and 89% of children withT-lymphocyte immunodeficiencies could be identified correctly. Family history was the only warning sign that identified children with B-lymphocyte PID3.
The result of a study conducted by Sumit Verma et al. in a tertiary care hospital in North India showed 27 children(M:F=3.5:1) with mean age of 5.4±4.6 years (2month to 16 years) to have PID. Thirteen children had chronic granulomatous disease,4 had SCID,4 had hypogammglobulinemia, 2 had Ataxia telangiectasia and one each had DiGeorge syndrome,Wiskott Aldrich syndrome, hyperIgM syndrome and leukocyte adhesion defect6.
6.2.3. Laboratory evaluation:
The initial evaluation of patients suspected to have an immunodeficiency disorder include enumeration of crucial cell populations and assessment of immunological competence. Flow cytometry using monoclonal antibodies to analyze and identify cells involved in immune function is useful in the diagnosis and management of many primary immunodeficiency disorders. It is a rapid and sensitive assay that has the advantage of evaluating several characteristics of a cell type. It has basically replaced previous tests, such as E-rosette formation for T-cell detection and identification of surface immunoglobulins for B-cell detection. Flow cytometry can be used to enumerate a particularcell type, evaluate function, or detect a particular geneproduct. Initial results, together with other available clinicaldata, help in making a decision on further testing,especially genetic testing.Flow cytometry is of limited value in the evaluation of a patient with complement deficiency2.
6.3 OBJECTIVES OF THE STUDY:
1. To study the occurrence of primary immunodeficiency disorders among patientsattending St. John’s Medical College Hospital.
2.To correlate the clinical and laboratory features of these patients for diagnosis and management.
6.4 MATERIAL & METHODS:
The study will be both retrospective andprospective. The retrospective study will cover the period
from January 2009 to December 2011.The prospective study will be conducted from January2012 toDecember 2013.The patients who will be seeking treatment fromSt.John’s Medical college,Bangalore will be included in the study.
7.1a.SOURCE OF DATA
The list of the patients diagnosed with primary immunodeficiency disorders in St.John's Medical College Hospital will be collected from the laboratory registers since 2009. Case records and laboratory investigations will be analyzed retrospectively and will be followed up for a period of one year. Newly detected cases also will be followed up for a duration of one year.
7.1b.SAMPLE SIZE
Approximately 30 patients.
Primary immunodeficiency disorders are a rare group of disorders. In the past 4 years, from 2008-2011, 15 patients have been screened and diagnosed.As the present study includes retrospective study from 2009 to 2011 and prospective study from 2012 january to 2013 december, the sample size has been kept as 30 after consultation with the HOD and faculty of pediatric department.
7.2 INCLUSION CRITERIA
Any one or more of the following clinical criteria will be used-
1. ≥4 new ear infections within 1 year;
2. ≥2 serious sinus infections within 1 year;
3. ≥2months of oral antibiotic treatment with little effect;
4. ≥2 episodes of pneumonia within 1 year;
5. Failure of an infant to gain weight or grow normally;
6. Recurrent, deep skin or organ abscesses;
7. Persistent thrush in mouth or fungal infection on skin;
8. Need for intravenous antibiotics to clear infections;
9. ≥2 deep-seated infections, including septicemia;
10. A family history of primary immunodeficiency disorders.
7.3EXCLUSION CITERIA
1.Patients on steroids.
2.Patients with acquired immunodeficiency.
The following algorithm will be used in the study.
Patients with any of the inclusion criteria
Assess on PS Increased WBC TC Normal NBT (Functional disorders)
Toxic Features Decreased
Complement Absolute Neutrophil Count
Assay Absolute Lymphocyte Count
(Complement deficiency)
T cell subset B cell subset
Decreased Normal
Immunoglobulin
(Antibody deficiency)
NBT Test -Nitro Blue Tetrazolium dye reduction Test.
Principle-NBT is a pale yellow dye which is degraded to formazan,a deep blue dye when taken up by certain neutrophils,thus indicating the normal functioning of the neutrophils.
Flow cytometry is a technology that simultaneously measures, and then analyses multiple physical characteristics of single particles,usually cells,as they flow in a fluid stream through a beam of light,usually a laser.T cell and B cell subsetting is done by immunophenotyping.
As the sample size is small and consists ofheterogenous group of primary immunodeficiency disorders, descriptive statistics will be applied.
ST.JOHN’S MEDICAL COLLEGE HOSPITAL, BANGALORE-560034
Primary immunodeficiency disorder work up
Proforma
Date:
Name: OP./IP. No.
Father’s Name: Religion:
DOB/Age: Caste:
Sex: State of origin:
Occupation Socio economic status
Address
1. Reason for hospital visit/referral:
2. Age of onset of symptoms:
3. H/O Chronic/Recurrent infections: Yes/No
If Yes, How many times:
Site of infection:
Causative organism:
Received any antibiotics: Yes/No
If Yes, Oral/IV:
4. Persistent infections after receiving live vaccines:
5. Failure to gain weight/grow normally:
6. Any significant family history:
7. Family tree:
8. Drug history:
PHYSICAL EXAMINATION
Height: weight:
Pallor: Jaundice: Cyanosis: Clubbing:
Lymphnode: Skin & Hair:
CVS:
RS:
GIT:
CNS:
Musculoskeletal:
INVESTIGATIONS
CBC:
Absolute neutrophil count:
Absolute lymphocyte count:
NBT: Positive/Negative
Serum immunoglobulin levels:
Flow cytometry
Other investigations:
7.4 Does the study require any investigation or intervention to be conducted on patients or other than human beings or animals.
If so describe briefly;
The investigations done on these patients will be as part of standard care. If any additional investigations are required as part of the study, patients will not be charged.
7.5 Has ethical clearance been obtained from your institution
Yes
8. REFERENCES
1.Raif.S.Geha et al.The International Union of Immunological Societies (IUIS) Primary
Immunodeficiency diseases classification committee.J Allergy Clin Immunol. 2007;
120(4):
pp. 776-794.
2.Orieji C. Illoh.Current applications of flow cytometryin the diagnosis of primary
immunodeficiency diseases. Arch Pathol Lab Med.2004;128: pp. 23-31.
3.Subbarayan et al. Clinical features that identify children with primary immunodeficiency
diseases.Pediatrics. 2011;127: pp.810-816
4.Avni Y Joshi,Vivek N Iyer,John B Hagan,Jennifer L.St.Sauver and Thomas G. Boyce.
Incidence
and temporal trends of primary immunodeficiency:A population based cohort study.Mayo
Clin
Proc.2009;84(1): pp.16-22
5. Felipe C Javier,Cleveland M Moore,Ricardo U Sorensen.Distribution of primary Immune deficiency diseases diagnosed in a pediatric tertiary hospital.Ann Allergy Asthma
Immunol.2000;84: pp.25-30.
6. Sumit Verma,Pradeep Kumar Sharma,SindhuSivanandan,NidhiRana,SavithaSaini,
RakeshLodha
andS.K.Kabra.Spectrum of primary immune deficiency at a tertiary care hospital.Indian
Journal of
Pediatrics.2008;75(2):pp.143-148.
7.Ameratunga et al.The clinical utility of molecular diagnostic testing for primary immune
deficiency
disorders:a case based review.Allergy,Asthma and Clinical Immunology.2010;6:12.
- 9. SIGNATURE OF CANDIDATE:
- 10. REMARKS OF THE GUIDE:
- 11. NAME AND DESIGNATION OF
- 11.1 GUIDE:
- 11.2 SIGNATURE:
- 11.3 Co-GUIDE(if any):
- 11.4 SIGNATURE:
- 11.5 HEAD OF THE DEPARTMENT
- 11.6 SIGNATURE:
- 12.1 REMARKS OF THE CHAIRMAN:
- & PRINCIPAL
- 12.2 SIGNATURE:
1