Objective: To determine the clinico-demographic features and laboratory parameters of children with severe combined immunodeficiency (SCID).
Study Design: Case series.
Place and Duration of Study: Department of Paediatrics and Child Health, the Aga Khan University, Karachi, from July 2006 to July 2011.
Methodology: Thirteen infants who were discharged with a diagnosis of SCID were inducted in the study. Their clinicodemographic features and laboratory parameters were determined. Descriptive statistics has been used for computing frequency and percentage.
Results: The median age at diagnosis was five months; 5 infants presented within 3 months of life. Three-fourth (77%) were males. Most of the infants were severely malnourished (85%) at the time of presentation. More than two-thirds (69%) were products of consanguineous marriages. All subjects had severe lymphopenia {absolute lymphocyte count (ALC) ranging between 170 – 2280} and low T and B lymphocyte counts.
Conclusion: SCID should be considered in infants presenting with severe and recurrent infections. Low ALC (\u3c 2500/mm3), is a reliable diagnostic feature of SCID. These infants should be promptly referred to a facility where stem cell transplant can be done

Ali, Syed Asad

Khawaja, Ranish Deedar Ali

Saleem, Ali Faisal

Shaikh, Abdul Sattar

Zaidi, Anita Kaniz Mehdi

eCommons@AKU

eCommons@AKUDepartment of Paediatrics and Child Health Division of Woman and Child HealthAugust 2013Severe combined immune deficiency syndromeAli Faisal SaleemAga Khan UniversityRanish Deedar Ali KhawajaAga Khan UniversityAbdul Sattar ShaikhAga Khan UniversitySyed Asad AliAga Khan UniversityAnita Kaniz Mehdi ZaidiAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_women_childhealth_paediatrPart of the Immune System Diseases Commons, and the Medical Immunology CommonsRecommended CitationSaleem, A. F., Khawaja, R. D., Shaikh, A. S., Ali, S. A., Zaidi, A. K. (2013). Severe combined immune deficiency syndrome. Journal ofthe College of Physicians and Surgeons Pakistan, 23(8), 570-573.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_women_childhealth_paediatr/166570 Journal of the College of Physicians and Surgeons Pakistan 2013, Vol. 23 (8): 570-573INTRODUCTIONSevere combined immune deficiency syndrome (SCID)is an inherited immune disorder characterized by lack ofcellular and humoral immunity leading to severe andrecurrent infections. Clinical features include recurrentor persistent severe infections starting from the first fewmonths of life, which results in progressive failure tothrive and death during infancy if left untreated.1 Earlystem cell transplant therapy within the first 3 months oflife has upto 95% chance of success, however, thesuccess rate progressively decreases with the increaseage.2,3The global incidence of SCID is estimated to be 1 per40,000 – 75,000 newborns.4 There are no publisheddata regarding the incidence of SCID in Pakistan. SCIDis more common in countries where consanguineousmarriage rates are high;1,5 and Pakistan has one of thehighest reported consanguineous rate in the world withapproximately two thirds of all marriages beingconsanguineous.6An excellent screening test for SCID is the absolutelymphocyte count (ALC), which can be easily calculatedwith the help of routine complete blood count withmanual differentiation in an infant. A bedside calculationof ALC < 2500/mm3 in the neonatal period or infancyshould alert the physician towards the possiblediagnosis of SCID and further evaluation should bedone. Confirmatory tests include flow cytometry,which shows very low B and T cell subsets, lowimmunoglobulin levels, and mitogen stimulation assaythat detect abnormal or dysfunctional lymphocytes.7There is a complete dearth of knowledge regarding theincidence of SCID in Pakistan. With the high rate ofconsanguineous marriages, the incidence is likely tobe high. However, if children with SCID are to besuccessfully treated with early stem cell transplant, thehealth care community needs to be sensitized about theprevalence and early diagnosis of this disorder. The aim of this study was to describe the clinicalcharacteristics and laboratory features of SCID in infantsadmitted at the study centre.METHODOLOGYThis is a case series of infants with discharge diagnosisof SCID at the Aga Khan University Hospital (AKUH),Karachi, during five years (June 2006 till July 2011).Patients were identified by health informationmanagement system using coded discharge diagnosisof combined immunity deficiency (ICD9 CM 279.2). Thiscoding contains SCID.Features including the age on admission, gender,anthropometry, past admissions, family history of earlyCLINICAL PRACTICE ARTICLESevere Combined Immune Deficiency SyndromeAli Faisal Saleem1, Ranish Deedar Ali Khawaja2, Abdul Sattar Shaikh1, Syed Asad Ali1 and Anita Kaniz Mehdi Zaidi1ABSTRACTObjective: To determine the clinico-demographic features and laboratory parameters of children with severe combinedimmunodeficiency (SCID).Study Design: Case series.Place and Duration of Study: Department of Paediatrics and Child Health, the Aga Khan University, Karachi, from July2006 to July 2011.Methodology: Thirteen infants who were discharged with a diagnosis of SCID were inducted in the study. Their clinico-demographic features and laboratory parameters were determined. Descriptive statistics has been used for computingfrequency and percentage.Results: The median age at diagnosis was five months; 5 infants presented within 3 months of life. Three-fourth (77%)were males. Most of the infants were severely malnourished (85%) at the time of presentation. More than two-thirds (69%)were products of consanguineous marriages. All subjects had severe lymphopenia {absolute lymphocyte count (ALC)ranging between 170 – 2280} and low T and B lymphocyte counts.Conclusion: SCID should be considered in infants presenting with severe and recurrent infections. Low ALC(< 2500/mm3), is a reliable diagnostic feature of SCID. These infants should be promptly referred to a facility where stemcell transplant can be done.Key Words: Severe combined immune deficiency (SCID).   Absolute lymphocyte count (ALC).   Recurrent infections.   Infants.   Lymphopenia.1 Department of Paediatrics and Child Health, The Aga KhanUniversity Hospital, Karachi.2 Medical Student, The Aga Khan University, Karachi.Correspondence: Dr. Ali Faisal Saleem, Department ofPaediatrics and Child Health, The Aga Khan UniversityHospital, Stadium Road, P.O. Box. 3500, Karachi.E-mail: ali.saleem@aku.eduReceived: February 17, 2012;   Accepted: April 23, 2013.deaths and miscarriages, patient microbiological andimmunological profile (ALC, cluster of differentiation(CD) markers count; serum immunoglobulin levels; HIV)and duration of hospitalization were recorded. The ALCwas calculated from the first available complete bloodcount that could have been done prior to, or at the timeof hospitalization. Cases were diagnosed on the basis of clinical presen-tations and laboratory investigations; ALC < 2500/mm3,low serum immunoglobulin levels (according to age) andextremely low B and T cell subsets {suggestive clinicalpresentation - recurrent diarrhea, pneumonia andpyogenic infections; failure to thrive (FTT), family historyof sibling death due to recurrent infections, oral thrushand absence of lymphoid tissue}.1,8Descriptive statistics has been used for computingfrequency and percentage. The Ethical ReviewCommittee of the AKU granted an exemption for thisstudy (1950-Ped-ERC-11).RESULTSAmong the 13 SCID infants, the mean age was 143 ± 70days (median 154 days). Males (n = 10, 77%) werepredominant. Eleven (85%) were severely malnourished(weight/age < 3 SD). Fever (n = 7; 54%), respiratorydistress (n = 7; 54%), persistent cough (n = 5; 38%),poor oral intake (n = 4; 31%) and loose stools (n = 4;31%) were the presenting complaints. Parents of nineinfants had consanguineous marriage. More than half(n = 7, 54%) of the patients had family history of infantdeaths of undiagnosed cause while 3 (23%) had familyhistory of recurrent miscarriages. The ALC rangedbetween 170 – 2280/mm3 (Table I). CD counts andserum immunoglobulin levels were not available for 3patients. The diagnosis of these patients was made ontheir clinical presentation (recurrent infections andfailure to thrive), as well as supportive lab investigationsincluding low ALC, low lymphocyte subsets andimmunoglobulin levels. HIV status was checked for 5patients and found to be negative. Mean length ofhospitalization was 10.9 ± 10 days. Three children hadpositive bacterial cultures. Table II shows the spectrumof microorganisms isolated from blood, urinary,respiratory and from the stool of the patients.DISCUSSIONSCID is a genetic disease with severe abnormalities ofimmune function and development. Infants with SCIDusually appear normal and healthy at birth but within1 – 2 months, the transplacentally acquired immunity(immunoglobulin) starts waning, and infants developSevere combined immune deficiency syndromeTable I: Demographic and immunological profile of SCID patients.Patient Age at Gender     Anthropometry CD4/CD8 Absolute CD3 CD4 CD8 CD19 CD 56 IgG IgM IgA HIV presen- ratio lymphocyte (2800- (1700- (800- (1000- (300- statustation Wt. Lgt. FOC count 3500) 3500) 1100) 1700) 800) checked(days) (ALC)*1 177 F ∆ - - Reversed 393 - - - - - 0.07 0.36 0.11 No2 49 M - - - Maintained 747 - - - undetectable - 0.07 6.26 0.94 No3 82 M - - - -- 297 Severely Severely Severely undetectable Relatively 0.23 3.07 0.13 Yesdecreased decreased decreased increased4 195 M ∆ - - Reversed 2100 Severely Severely Severely Mildly low - 0.66 0.07 0.33 Yesdecreased decreased decreased5 184 M ∆ - - -- 413 31 - - 2 - - - - No6 90 M ∆ ∆ ∆ Reversed 282 Severely 290 543 undetectable 15 - - - Nodecreased7 90 F ∆ - ∆ -- 1400 - - - - - 0.07 1.91 0.23 Yes8 150 M ∆ - - Maintained 393 - - - - - 0.6 0.1 94 No9 240 M ∆ - - Maintained 340 180 203 144 1 46 0.07 0.44 0.06 Yes10 37 M ∆ ∆ ∆ Maintained 170 195 41 18 13 28 3.51 0.11 0.13 No11 120 M ∆ - - Maintained 2280 430 255 196 143 4 - - - No12 150 M ∆ - - Reversed 1270 37 31 27 9 800 - - - No13 268 F ∆ - - Reversed 478 31 23 30 364 9 - - - YesM = male;   F = female;   CD = Cluster of differentiation;   *ALC = calculated from the first ever complete blood count;   Wt. = weight;   Lgt. = length;   FOC = Fronto-occipital circumference;∆ = < 3 SD - severely malnourished.Table II: Microorganisms isolated in SCIDS patients.Patient Blood isolates Urinary isolates Respiratory isolates Stool isolates3 – Candida albicans – Campylobacter jejuniEscherichia coliAeromonas species7 – – – Campylobacter jejuni9 Staphylococcus epidermis – – –10 Acinetobacter species – Escherichia coli –11 Acinetobacter species Candida tropicalis Klebseilla pneumoniae Candida tropicalis –Journal of the College of Physicians and Surgeons Pakistan 2013, Vol. 23 (8): 570-573 571severe and recurrent life threatening infections.9,10The median age of diagnosis worldwide is reported to be4 – 7 months of age.4,11 Median age of diagnosis in thiscohort was 5 months.Male infants were predominant in this cohort. The slightmale predominance has been reported previously in theliterature with M:F ratio varying from 1.5 – 2:1 (12, 13).X-linked SCID is the most common form and accountsfor approximately 46%.7 One possible explanation of thehigh male predominance in this cohort could be X-linkedSCID. The X-linked affected patients have no T cells orNK cells in the peripheral blood, but have normalnumber of B cells. Their immunoglobulin levels are lowor undetectable with absent lymph nodes and tonsils.8,10Among the 10 male patients in this cohort, parents ofeight had consanguineous marriages and had very lowALC; undetectable to very low NK cells and markedlylow serum immunoglobulin levels. While not formallytested, it is probable that many of these had X-linkedvariation of SCID.FTT is one the common clinical presentation of infantswith SCID. Recurrent gastrointestinal and respiratoryinfections are the basic reason of FTT in SCID patients.Shah has found 100% FTT in their SCID patients caseseries from India.9 Majority of the present study subjectswere severely malnourished.Consanguinity increases the risk of rare inheriteddisorders.5,14 Subbarayan et al. retrospectively reviewedthe clinical features of children diagnosed as primaryimmunodeficiency at their immunology centres(Manchester and New Castle) and found that 33%(111/334) of children with B and T cell immunodeficiencywere Pakistani in origin.1 This was a significant over-representation compared to the proportion of Pakistani-origin children in their catchment area.SCID is a medical emergency. The best screening testfor SCID is to check the ALC in all neonates and infants.However, this represents a challenge in a country wherethe majority of births take place at home and newbornsare not seen by physicians. In this environment, perhapsa strategy of screening young infants from familieshaving early sibling death may pick-up a substantialSCID cases. The ALC of < 2500/dL should alert thephysician towards the possibility of SCID and childshould be referred for confirmation (flow cytometry andimmunoglobulin level).The good feature of HSCT therapy for SCID is its easyacceptance in the recipient. Pre-requisites for SCIDtransplantation require only human leukocyte antigenmatching (related or unrelated donor).15 The biggestchallenge is the unavailability of transplant centresand cost of transplantation in developing countrieslike Pakistan. None of these patients could receivetransplantation due to late presentation, lack of trans-plant set up in neonates at that time, and financialconstraints of parents.To the best of authors' knowledge, this is the first studyof any kind about SCID in Pakistan. This study had a fewlimitations. This is a retrospective chart review ofinpatients only and not the outpatients, therefore, thetrue burden of SCID seen in the hospital is likely to bemore than the report based on this inpatient case series.The true confirmatory tests, including molecular testingand mitogen stimulation assay could not be donebecause of lack of facilities. However, using the currentcriteria of severe lymphopenia and extremely low B andT cell subsets, the likelihood that our diagnosis wascorrect is very high.CONCLUSIONSCID is an important cause of early infant deaths in acountry with one of the highest rates of consanguinity.Increased awareness and educating health careproviders regarding SCID may lead to earlier diagnosisand potential therapy. Systemic studies documenting thecontribution of serious inherited disorders to infantmortality in Pakistan are also needed.Acknowledgement: Dr. Ali Faisal Saleem receivedresearch training support from the National Institute ofHealth’s Fogarty International Centre (1 D43 TW007585-01).REFERENCES1. Subbarayan A, Colarusso G, Hughes SM, Gennery AR, SlatterM, Cant AJ, et al. Clinical features that identify children withprimary immunodeficiency diseases. Pediatrics 2011; 127:810-6.2. Patel NC, Chinen J, Rosenblatt HM, Hanson IC, Krance RA,Paul ME, et al. Outcomes of patients with severe combinedimmunodeficiency treated with hematopoietic stem celltransplantation with and without pre-conditioning. J Allergy ClinImmunol 2009; 124:1062-9; e1-4.3. Chan A, Scalchunes C, Boyle M, Puck JM. Early vs. delayeddiagnosis of severe combined immunodeficiency: a familyperspective survey. Clin Immunol 2011; 138:3-8.4. Cossu F. Genetics of SCID. Ital J Pediatr 2010; 36:76.5. Saggar AK. Consanguinity and child health. Paediatr ChildHealth 2008; 18:244-9.6. National Institute of Population Studies (NIPS). PakistanDemographic and Health Survey 2006-07. Islamabad: NationalInstitute of Population Studies and Macro International Inc;2008.7. Kobrynski LJ. Combined immune deficiencies in children.J Infus Nurs 2006; 29:206-13.8. Fuleihan R. Immunology. In: Kliegman RM, Behrman RE,editors. Essentials of pediatrics. 5th ed. New Delhi: WB Saunders,2006.p. 376-78.9. Shah I. Severe combined immunodeficiency. Indian Pediatr2005; 42:819-22.10. Adeli MM, Buckley RH. Why newborn screening for severeAli Faisal Saleem, Ranish Deedar Ali Khawaja, Abdul Sattar Shaikh, Syed Asad Ali and Anita Kaniz Mehdi Zaidi572 Journal of the College of Physicians and Surgeons Pakistan 2013, Vol. 23 (8): 570-573Severe combined immune deficiency syndromeJournal of the College of Physicians and Surgeons Pakistan 2013, Vol. 23 (8): 570-573 573combined immunodeficiency is essential: a case report.Pediatrics 2010; 126:e465-9.11. Baumgart KW, Britton WJ, Kemp A, French M, Roberton D.The spectrum of primary immunodeficiency disorders inAustralia. J Allergy Clin Immunol 1997; 100:415-23.12. Fasth A. Primary immunodeficiency disorders in Sweden:cases among children, 1974-1979. J Clin Immunol 1982; 2:86-92.13. Naidoo R, Ungerer L, Cooper M, Pienaar S, Eley BS. Primaryimmunodeficiencies: a 27-year review at a tertiary paediatrichospital in cape town, South Africa. J Clin Immunol 2011; 31:99-105.14. Borhany M, Pahore Z, Ul Qadr Z, Rehan M, Naz A, Khan A,et al. Bleeding disorders in the tribe: result of consanguineousin breeding. Orphanet J Rare Dis 2010; 5:23.15. Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW,Roberts JL, et al. Hematopoietic stem-cell transplantation forthe treatment of severe combined immunodeficiency. N Engl JMed 1999; 340:508-16.

Severe combined immune deficiency syndrome

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Severe combined immune deficiency syndrome

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