HK J Paediatr (new series) 2003;8:15-20 Original Articles X-linked Agammaglobulinaemia in Hong Kong Chinese RCM LOBO, GCF CHAN, TL LEE, AKS CHIANG, HK HO, SY HA, YL LAU Abstract We reviewed retrospectively eleven Chinese children diagnosed with X-linked agammaglobulinaemia (XLA) and managed at the Department of Paediatrics & Adolescent Medicine of Queen Mary Hospital from 1987 to 2002. All of the eleven children had presenting signs and symptoms before fourteen months old, but diagnosis was delayed in most patients with the median age of diagnosis at 5.8 years (range 1.3-14.3 years). The respiratory tract was the most commonly affected site of infection (76%) before diagnosis. Haemophilus influenzae was the most commonly isolated microorganism before and after diagnosis. Intravenous immunoglobulin (IVIG) was given in all patients with a median dose of 700 mg/kg four weekly in order to achieve the pre-infusion IgG level within the normal reference range as well as control of clinical infections. The incidence of documented infections before IVIG replacement was 31 per 100 patient-months which decreased to 7.6 per 100 patient-months after IVIG replacement (p<0.0001). The height and weight centiles of the children also increased after IVIG replacement (p<0.01). Bronchiectasis was noted in three out of the eleven children who were diagnosed to have XLA late at 6, 12 and 14 years old. Adequate IVIG replacement could decrease the frequency of infections and normalize growth in children with XLA. It might prevent bronchiectasis if started early in life, which depends on early diagnosis of XLA. Key words Agammaglobulinaemia; Bronchiectasis; Growth; Immunodeficiency Introduction Dr. Bruton in the early 1950's and has remained as a prototype for primary immunodeficiency diseases (PID).1 X-linked agammaglobulinaemia (XLA) is an X-linked It is caused by a mutation of the Btk gene at the long arm recessive B cell disorder which was first described by (q 22) of X chromosome leading to the dysfunction of Bruton's tyrosine kinase (Btk), which interferes with the development and function of B cells and their progeny.1-3 Department of Paediatrics and Adolescent Medicine, The Major consequence of the defect appears to be an arrest at University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China the stage of development of pre-B cells to B cells. Individuals affected have pre-B cells in their bone marrow GCF CHAN ( 陳志峰 ) MD, FRCP(Edin) TL LEE ( 李子良 ) MBBS, FHKAM but few to absent B cells in their blood and lymphoid tissue. AKS CHIANG ( 蔣國誠 ) MBBS, PhD, FHKAM The plasma cells, which are producers of serum HK HO ( 何學工 ) MBBS, FHKAM immunoglobulins and derived from B cells, are also absent SY HA ( 夏修賢 ) MRCPATH, FRCP(Edin) YL LAU ( 劉宇隆 ) MD, FHKAM in the peripheral circulation and tissue. Individuals born with XLA are usually asymptomatic in their first six months Department of Paediatrics, Dr. Fe del Mundo Medical Center Foundation, Inc., 11 Banawe Quezon City, Philippines of life, and as maternally acquired immunoglobulins disappear during the second six months of life, symptoms RCM LOBO ( 林爐敏 ) MD, DPPS start to manifest. However, delayed manifestation is not Correspondence to: Prof YL LAU uncommon with 20% of the patients having their first Received July 30, 2002 infection after their first birthday.4 Intravenous 16 XLA in Chinese immunoglobulin (IVIG) had replaced intramuscular Statistical Analysis injection of immunoglobulin as the standard form of Comparative analysis of incidences of infections and treatment in the 1980's. In spite of IVIG replacement, organ dysfunction before and after IVIG replacement were complications though preventable have been observed to both calculated by Fisher Exact Test. The impact of IVIG set in.5 The objective of this study is to investigate the impact replacement on the height and weight centiles was analyzed of IVIG replacement on the frequency of infections and by Wilcoxon Rank Sum Test. growth in our patients with XLA. Results Methods Patients Patients All eleven patients are alive and had a total of 1017 The outpatient and inpatient records of eleven children months of follow up from 1987 to 2002 with a median diagnosed with XLA at the Department of Paediatrics & follow up of 7 years (range 1.6-15 years). The median age Adolescent Medicine of Queen Mary Hospital between at diagnosis was 5.8 years (range 1.3-14.3 years). On their 1987 and 2002 were reviewed. At the time of analysis all last follow up the median age was 14.9 years (range 6.8- are alive with a median age of 14.9 years (range 6.8-24.1 24.1 years). years). The diagnosis of XLA was based on history, serum immunoglobulin levels by nephelometric studies and Laboratory Examinations lymphocyte subset enumeration by flow cytometry. All eleven patients' serum immunoglobulins (IgG, M, Identification of the Btk gene mutations was reported A) were found to be very low with virtually absent B cells previously.6 Patient outcome was documented by in the peripheral blood (Table 1). Btk mutations in most of comparing height and weight percentile measurements our patients were published previously.6 before diagnosis and at their last follow up after a period of regular IVIG infusion. The dosage of the IVIG was adjusted Infections in order to achieve the pre-infusion serum IgG level within The median age of first infection was documented at 12 the normal reference range as well as control of clinical months (range 6-14 months). More than 76% of the infections. Oral prophylactic antibiotics were prescribed documented infections was attributable to the respiratory for varying periods of time for those who have adequate tract, with 59.8% and 16.4% due to an upper and lower serum IgG levels but still with respiratory infections. tract infection respectively (Table 2a). For the severe Bronchiectasis, a well-known complication of XLA,7 was infections, lower respiratory infections (45%) were the most documented by high-resolution computerized tomography common followed by gastrointestinal infections (16%) (HRCT). (Table 2a). Haemophilus influenzae was the commonest bacteria isolated at 34% (3/9), followed by Pseudomonas Infections and Prophylaxis sp. 22% (2/9). The clinical presentations of infections were reviewed retrospectively from the medical records. Each episode of Treatment, Effects and Complications infection identified was tabulated according to organ Our patients received a median dose of 700 mg/kg (range location and the causative organisms isolated. Documented 500-1000 mg/kg) per infusion of intravenous immuno- infection was defined as all signs or symptoms experienced globulin every 4 weeks. Some received intermittent oral by the patients attributable to an infectious process septrin prophylaxis because of the frequency of their necessitating symptomatic medical interventions. Severe respiratory infectious episodes despite adequate IVIG infection was defined as an occurrence of an infectious replacement but none of them received long term antibiotic process, that required hospitalization with intravenous prophylaxis. There were 253 documented infections before antibiotic infusion, and with or without surgical or ancillary starting IVIG and only 75 documented infections after radiological interventions (e.g. X-ray, CT scan or MRI). regular IVIG replacement (Tables 2a & 2b). The reduction The influence of long term IVIG was evaluated by was significant from an incidence of 31 infections per 100 comparing the incidence of infections before and after the patient-months (PM) to 7.6 infections per 100 PM start of IVIG replacement. (p <0.0001). The incidence of severe infections decreased Lobo et al. 17 Table 1 Immunoglobulin levels and B-cell percentage in peripheral blood Patients Ig G mg/dl Ig A mg/dl Ig M mg/dl B-cell percentage (1)1 <200 <12 18 0.5% (1)2 <70 <13 <7 0.0% (1)3 <69 <12 12 0.1% (2)4 <75 <13 <7 0.0% (2)5 <75 <13 26 0.0% 6 <200 4.2 33 0.4% 7 <100 12 7 0.0% 8 <75 <13 <7 0.1% 9 <200 <16 15 0.0% 10 <200 50 34 0.2% 11 <73 20 42 0.0% (1)1, (1)2 and (1)3 are maternal cousins (2)4 and (2)5 are brothers Table 2a Localization of documented infections and isolated organisms (before IVIG) Location of infections Documented infections Severe infections Isolated organisms URI (tonsillitis, 160 59.8% 3 6.8% tonsillar abscess, stomatitis, parotitis, rhinitis) LRI (pneumonia, bronchitis, 39 16.4% 18 41% Mycobacterium tuberculosis, bronchiectasis, pleuritis, Pseudomonas sp. TB) GII Enteritis 9 6.7% 6 13.7% Salmonella sp. Intra abdominal abscess 1 0.7% 1 2.3% Conjunctivitis 10.7% Skin abscess and dermatitis 4 3.0% 3 6.8% Meningitis 1 0.7% 1 2.3% H. influenzae UTI 2 1.5% 1 2.3% Arthritis 4 3.0% 4 9.0% H. influenzae Septicemia 4 3.0% 4 9.0% B. fragiles, H. influenzae, Pseudomonas sp., Strep. pneumoniae Otitis media, externa 4 3.0% 2 4.5% Sinusitis 2 1.5% 1 2.3% TOTAL 253 100.00% 44 100.00 % URI: upper respiratory infection LRI: lower respiratory infection GII: gastrointestinal infection UTI: urinary tract infection 18 XLA in Chinese Table 2b Localization of documented infections and isolated organisms (after IVIG) Location of infections Documented infections Severe infections Isolated organisms URI (tonsillitis, tonsillar 41 55% 1 5% H. influenzae abscess, stomatitis, parotitis, rhinitis) LRI (pneumonia, bronchitis, 7 9% 7 37% H. influenzae bronchiectasis, pleuritis, TB) GII Enteritis 11 15% 8 42% Campylobacter j. (5), Salmonella sp. (2) Giardia lamblia Intra abdominal abscess 1 1% 1 5% Conjunctivitis 00 00 Skin abscess and dermatitis 8 11% 0 0 Meningitis 00 00 UTI 00 00 Arthritis 11%00 Septicemia 00 00 Otitis media, externa 3 4% 2 11% H.