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© Borgis - Postępy Nauk Medycznych 6/2016, s. 410-413
Alicja Sapała-Smoczyńska1, 2, *Teresa Jackowska1, 2, Piotr Hartmann1, 2, Bartosz Siewert3
An ordinary infection, an extraordinary patient [ndash] X-Linked Agammaglobulinemia (Bruton disease) case report**
Zwykła infekcja, niezwykły pacjent – opis przypadku agammaglobulinemii sprzężonej z chromosomem X (Brutona)
1Department of Pediatrics, Centre of Postgraduate Medical Education, Warsaw
Head of Department: prof. Teresa Jackowska, MD, PhD
2Department of Pediatrics, Father Jerzy Popiełuszko “Bielański” Hospital, Independent Public Health Care Institution in Warsaw
Head of Department: prof. Teresa Jackowska, MD, PhD
3Student Research Circle, Department of Pediatrics, Centre of Postgraduate Medical Education, Warsaw
Head of Circle: Piotr Hartmann, MD
Streszczenie
W pracy opisano przypadek pacjenta, który został przyjęty do oddziału pediatrii w trybie dyżurowym z powodu gorączki i wymiotów. W czasie hospitalizacji rozpoznano u niego agammaglobulinemię sprzężoną z chromosomem X (Brutona). W badaniach laboratoryjnych stwierdzono leukopenię z neutropenią, podwyższone stężenie wykładników stanu zapalnego, hipokaliemię. Stan chłopca poprawił się po nawodnieniu doustnym i dożylnym oraz suplementacji potasu. Jednak w badaniach kontrolnych wykładniki stanu zapalnego znacznie narosły. Empirycznie do leczenia włączono cefotaksym. Po kolejnych dwóch dniach z posiewu krwi wyhodowano Pseudomonas aeruginosa. Zmieniono leczenie na meropenem z amikacyną. W czasie hospitalizacji chłopiec skarżył się na ból podczas defekacji. W badaniu ultrasonograficznym jamy brzusznej uwidoczniono niewielką ilość płynu zapęcherzowo. Kontrolne badanie morfologii oraz wykładniki stanu zapalnego były prawidłowe. Ze względu na zakażenie uogólnione Pseudomonas aeruginosa, z obecnością ropnia okołoodbytniczego, wysunięto podejrzenie zaburzenia odporności humoralnej. Oznaczono poziom immunoglobulin, których stężenia były poniżej czułości metody. Chłopca przekazano do Poradni Immunologicznej z podejrzeniem agammaglobulinemii Brutona.
W przypadku zakażenia bakterią, która jest „nietypowa” dla dzieci bez zaburzeń odporności, konieczna jest dalsza diagnostyka celem wykluczenia zaburzeń odporności komórkowej i humoralnej.
Summary
In this article a case is presented in which a patient was admitted on an emergency basis to a paediatric department with fever and emesis. During hospitalization X-linked agammaglobulinemia (Bruton disease) was diagnosed. Laboratory testing revealed leukopenia with neutropenia, inflammatory markers elevation and hypokalemia. The general condition of the patient improved after performing oral and intravenous hydration, and potassium supplementation. However, control tests showed significant inflammatory markers elevation. Cefotaxime was included in the therapy on an empirical basis. After two subsequent days Pseudomonas aeruginosa was cultivated from blood culture. The treatment was switched to meropenem with amikacin. During hospitalization the boy complained about painful defecation. Abdominal cavity ultrasound examination revealed a slight amount of retrovesical fluid. The results of a full blood exam and inflammatory markers test were normal. Taking into consideration generalized Pseudomonas aeruginosa infection and the presence of perianal abscess, humoral immunity disorder was proposed. Immunoglobulins level were measured and their concentrations were below the sensitivity threshold of the method used. The patient was assigned to immunology outpatient clinic with the suspicion of Bruton agammaglobulinemia.
In the case of infection with the bacteria which is “unusual” for paediatric patients without immunity disorders, further diagnostics is necessary in order to rule out humoral and cellular immunity disorders.
Introduction
Bruton agammaglobulinemia is a disease linked to the X chromosome which belongs to the wide group of primary immunodeficiencies, which includes more than 240 diseases (1). The most common disease of this group is immunoglobulin A (IgA) deficiency, which appears, depending on the region, in 1/223 to 1/3230 cases, and more often in Caucasian race (1). X-Linked Agammaglobulinemia (XLA) was described for the first time in 1952 by Bruton (2), and for this reason, it is commonly referred to as Bruton agammaglobulinemia. XLA occurs very rarely [ndash] in 1/200 000 of live births (1).
Case study
A patient aged 2 years and 4 months was admitted in an emergency to a paediatric department with fever and emesis, lasting for seven days. The patient complained about pain in the anus region which was linked to suppositories administration. Moreover, the boy had symptoms of upper respiratory tract infection, which was treated ambulatory and symptomatically. According to the patient’s mother, there were symptoms of gastroenteritis among house-dwellers at the time.
The paediatric patient was born as a first child in 38th week of pregnancy with weight of 2640 g, length of 50 cm and rated 10 points in Apgar score. In the first year of life the patient was vaccinated according to obligatory protective vaccination program. In the second year of life the patient was not vaccinated against measles, mumps and rubella due to the fact that he was disqualified by a neurologist. According to the patient’s mother, the reason was six cafe-au-lait spots on his trunk. Among the obligatory vaccinations, the patient received rotavirus, pneumococcus and varicella vaccinations. The patient has been hospitalized twice. The first hospitalization took place in the 6th week of life due to axillary and cervical lymph nodes enlargement, and anaemia. At the time only anti-anaemia treatment was recommended. Afterwards, the patient was hospitalized at the age of 1.5 years due to gastroenteritis. At that time high levels of inflammatory markers were observed. Due to the suspicion of infection of Salmonella etiology, a treatment with third-generation cephalosporin was performed. Also, a hard to heal skin lesion on the right shin was described, which was linked to an insect bite.
During the described (third) hospitalization, the paediatric patient was admitted in an average general condition. He was anxious, tearful and had fever with the temperature up to 38.9°C. Physical examination revealed redness inside the throat, enlarged palatine tonsils with mucous residue and large amount of mucous secretions in the nose. The skin in the anus region was reddened. On the skin of the left wrist a single cafe-au--lait lesion was noted as well as the scar on the right shin. Psychomotor development of the patient was found to be proper, as well as a family medical survey which showed no burden.
Laboratory testing performed at the admission day revealed leukopenia (3.0 thousands/μl) with neutropenia (0.13 thousands/μl), without anaemia and thrombocytopenia as well as increased concentration of acute phase protein (CRP – 74.2 mg/l) (laboratory standard) and procalcitonin (PCT – 3.64 ng/ml) (laboratory standard). After performing oral and intravenous hydration, the general health condition of the pediatric patient rapidly improved. Fever subsided and the patient became more lively.
In the second day of hospitalization performed control tests showed significant increase in inflammatory markers (CRP – 235.98 mg/l; PCT – 6.50 ng/ml). The blood sample taken at the admission showed growth of the bacteria which cause granulomas. Generalized infection was diagnosed and because of the presence of gastroenteritis symptoms among the house-dwellers of the patient, there was a Salmonella infection suspicion. Third generation cephalosporin (cefotaxime) was included in the treatment regimen.
A full blood exam performed in the third day of the hospitalization enabled to diagnose leukocytopenia and granulocytopenia (leukocytes – 12.0 thousands/μl; neutrophiles – 2.84 thousands/μl) and lowered level of inflammatory markers (CRP – 97.32 mg/l; PCT – 3.39 ng/ml). Bacteria cultured from the blood sample was identified as Pseudomonas aeruginosa (P. aeruginosa). A decision was made with regard to changing the antibiotic prescribed to cephalosporin with bactericidal effect against P. aeruginosa (ceftazidime). On the same day the paediatric patient began to report pain in the anus area during defecation. An ultrasound examination of the abdominal cavity confirmed the presence of perianal abscess (fig. 1).
Fig. 1. A slight amount of retrovesical fluid, up to 10 mm
Generalized infection with an abscess in the anus region (a perianal abscess) was diagnosed at that time. The decision was made to change the antibiotic from ceftazidime to carbapenem (meropenem) with aminoglycoside (amikacin), and use antifungal prophylaxis at the same time. Meropenem treatment was continued only for three days and subsequently switched to ceftazidime therapy consistent with an antibiogram and antibiotic de-escalation protocol (application of an antibiotic with narrowed antimicrobial spectrum).
In the following days the patient gradually felt better. A follow-up ultrasound examination (17th day of hospitalization) confirmed the area of pathological structure (the anus region), which resembled a residual lesion of inflammatory infiltrate.
Taking into consideration the location of the infection, leukopenia with neutropenia, as well as an increase in the concentration of P. aeruginosa in the blood, immunodeficiency was proposed. The diagnose range was extended which enabled to observe a significant deficiency of immunoglobulines of all the classes (Normal values by age: IgG – 5.2-13.60 g/l, IgM – 0.46-1.9 g/l, IgA – 0.45-1.35 g/l). The diagnosis included severe humoral immune deficiency syndrome in a paediatric patient with generalized infection and perianal abscess with complications. The patient was referred to immunology outpatient clinic in order to perform further diagnostics. Genetic tests enabled to diagnose X-linked agammaglobulinemia (Bruton disease).
Discussion
XLA is characterized by the deficiency of immunoglobulins of all the classes (IgA, IgG, IgM), and a lack of B cells in peripheral blood (1). In the year 1993 XLA was shown to be a result of a mutation in the gene coding tyrosine kinase, called Bruton’s tyrosine (Btk) (3, 4). The BTK gene was located on the Xq21.3-22 region. Thus far more than 600 BTK gene mutations have been described, which cause a lack of Btk protein expression (5, 6). BTK expression analysis may be used to detect disease carriers (7). XLA diagnosis is based on BTK gene mutation establishing, which may also be useful in prenatal diagnosis. Btk is essential for proper B cells growth in the bone marrow. Inhibition of the growth occurs in the phase of differentiation from pro-B cells to pre-B cells which immobilizes immature lymphocytes in the bone marrow and results in a lack of immunoglobulins production.
This disorder is diagnosed in early childhood (8-10). Boys with XLA usually start to suffer from the disease after the sixth month of life, because until that time antibodies received from the mother through placental transfer fulfil the protective role. It is also important to consider a family medical history, as the age of diagnosis is significantly lower (2.59 years on average) in the case of patients with positive family medical history, in opposition to those, whose family medical history was negative (5.37 years on average) (p < 0.001) (11).
The main symptoms are (1, 8-10, 12):
– recurrent respiratory tract infections (ears, nose, conjunctivae, sinuses, lungs),
– digestive tract infections (Giardia lamblia), causing abdominal pain, diarrhea, body mass loss, growth restriction,
– inflammation of bones and joints,
– skin and hair follicles infections.
Physical examination revealed very small palatine tonsils and lymph nodes of normal size despite recurrent infections. The first-line therapy is a substitutive therapy with intravenous or preferably subcutaneous immunoglobulin preparations (1).
We present this case due to unusual course of the disease. Among 10 diagnostic criteria helpful in diagnosis of primary immunodeficiencies established by an expert panel of European Society for Immunodeficiencies (ESID) and Jeffrey Modell Foundation (13, 14), the paediatric patient met only one (recurrent deep skin and organ abscess), which was diagnosed at the first time during the hospitalization when the suspicion was made. Nine remaining diagnostic criteria were absent. The boy received an antibiotic only once due to salmonellosis suspicion, but this was linked to dietetic mistake in his family. At present, almost 2.5 years old boy has the body mass increase (50th centile) and height increase (50th centile) at normal levels. Family medical history regarding primary immunodeficiencies was negative.
In conclusion, in the case of severe infection, especially caused by bacteria “unusual” for children without immune disorders history (P. aeruginosa), as well as with leukopenia and neutropenia, it is necessary to perform adequate diagnosis to rule out immune disorder (15).

**Supported by the Centre of Postgraduate Medical Education in Warsaw grant number 501-1-20-19-16
Piśmiennictwo
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7. Futatani T, Miyawaki T, Tsukada S et al.: Deficient Expression of Bruton’s Tyrosine Kinase in Monocytes from X-linked Agammaglobulinemia as Evaluated by a Flow Cytometric Analysis and Its Clinical Application to Carrier Detection. Blood 1998; 91: 595-602.
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11. Winkelstein JA, Marino MC, Lederman HM et al.: X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 2006; 85: 193-202.
12. Fernandes A, Guedes M, Vasconcelos J et al.: X-linked agammaglobulinemia: experience in a Portuguese hospital. An Pediatr (Barc) 2015; 82: 166-171.
13. Glocker E, Ehl S, Grimbacher B: Common variable immunodeficiency in children. Curr Opin Pediatr 2007; 19: 685-692.
14. Arkwright PD, Gennery AR: Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century. Ann N Y AcadSci 2011; 1238: 7-14.
15. Pietrucha B, Heropolitańska-Pliszka E, Klaudel-Dreszler M et al.: Wybrane zagadnienia z immunologii klinicznej – niedobory przeciwciał i niedobory komórkowe (część I). Ped Pol 2011; 86: 548-558.
otrzymano: 2016-05-04
zaakceptowano do druku: 2016-05-25

Adres do korespondencji:
*Teresa Jackowska
Department of Pediatrics Centre of Postgraduate Medical Education
ul. Marymoncka 99/103, 01-813 Warszawa
tel. +48 (22) 864-11-67
tjackowska@cmkp.edu.pl

Postępy Nauk Medycznych 6/2016
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