Affiliation:
- Murugan Sudhakar, Senior Resident, Department of
Pediatrics1, Advanced Pediatrics Centre,
Postgraduate Institute of Medical Education and Research, Chandigarh-
160012.
- Manpreet Arora, Junior Resident, Department of
Pediatrics1, Advanced Pediatrics Centre,
Postgraduate Institute of Medical Education and Research, Chandigarh-
160012.
- Lesa Dawman, Assistant Professor, Department of
Pediatrics1, Advanced Pediatrics Centre,
Postgraduate Institute of Medical Education and Research, Chandigarh-
160012.
- Dharmagat Bhattarai, Senior Resident, Department of
Pediatrics1, Advanced Pediatrics Centre,
Postgraduate Institute of Medical Education and Research, Chandigarh-
160012.
- Pratap Kumar Patra, Senior Resident, Department of
Pediatrics1, Advanced Pediatrics Centre,
Postgraduate Institute of Medical Education and Research, Chandigarh-
160012.
- Ankur Kumar Jindal, Assistant Professor, Department of
Pediatrics1, Advanced Pediatrics Centre,
Postgraduate Institute of Medical Education and Research, Chandigarh-
160012.
- Ritambhra Nada, Professor, Department of
Histopathology2, Postgraduate Institute of Medical
Education and Research, Chandigarh- 160012.
- Amit Rawat, Professor, Department of Pediatrics1,
Advanced Pediatrics Centre, Postgraduate Institute of Medical
Education and Research, Chandigarh- 160012.
- Karalanglin Tiewsoh, Associate Professor, Department of
Pediatrics1, Advanced Pediatrics Centre,
Postgraduate Institute of Medical Education and Research, Chandigarh-
160012.
To the Editor,
X-linked agammaglobulinemia (XLA) is one of the commonest inborn error
of immunity that results in defective antibody
production1. XLA is characterized by
pan-hypogammaglobulinemia resulting in recurrent infections with
encapsulated bacteria (such as Streptococci, Staphylococci , andHaemophilus influenzae), enteroviruses (such as poliovirus,
echovirus, and coxsackievirus ), hepatitis viruses andGiardia 1. Citrobacter freundi is a
normal gut commensal that has mostly been reported as
healthcare-associated infection (HCAI) and also in immunocompromised
individuals2,3. Renal manifestations in patients with
XLA are extremely rare and limited to 2 cases of membranoproliferative
glomerulonephritis4 and 1 case of membranous
nephropathy.5 However, the pathophysiology of renal
manifestations in XLA is unclear. No case of thrombotic microangiopathy
(TMA) has been reported in these patients. Herein, we report a young boy
with XLA with myriad clinical manifestations of the disease including
TMA. A written informed consent was taken from the parents and approval
for the case report was obtained from the departmental review board.
An 8-year-old boy, presented with history of loose stools and vomiting
for 5 days. He also developed reduced urine output and periorbital
puffiness for 2 days prior to hospitalization. In the past, he was
symptomatic since the age of 9 months when he developed acute flaccid
paralysis with anterior horn myelitis. He was suspected to have
vaccine-associated paralytic poliomyelitis (VAPP) leading to sequalae of
thoraco-lumbar spine kyphoscoliosis (Figure 1A). However, stool
examination did not reveal vaccine derived poliovirus strain. He had had
5 episodes of pneumonia since the age of 2 years (Figure 1B, 1C, and 1D)
requiring IV antimicrobials; 1 episode of persistent diarrhoea caused byGiardia lamblia ; chronic bilateral ear discharge and 1 episode of
bacterial meningitis. At the age of 8, he developed septic arthritis of
the right elbow, and pus culture grew Streptococcus pneumoniae .
His family history revealed death of 3 maternal uncles and 3 maternal
grand uncles in early childhood due to repeated sino-pulmonary
infections, suggestive of an X-linked recessive pattern of inheritance
(Figure 2). On examination, he had hypertension (Blood pressure
[118/76 mm of Hg (between
95th-99th centile)], pallor,
absent tonsils and lymph nodes, and periorbital puffiness. He also had
kyphosis of thoracolumbar spine (Figure 1A) and contractures at
bilateral ankle joints and right elbow joint. Rest of the examination
was unremarkable.
Laboratory investigations showed anemia (haemoglobin: 62g/L, N:115-145);
thrombocytopenia (platelet counts 38x109/L; N:150-400)
and total leucocyte count 7.54 x109/L
(Neutrophils-78%, Lymphocytes- 12%, Monocytes- 9%, Eosinophil- 1%)
with absolute lymphocyte count of 0.9 x109/L (N:
1.88-2.48). Urine examination showed 2 + albumin and microscopic
hematuria (-20 red blood cells/high power field). He had deranged renal
function [blood urea- 301 mg/dl (N: 14-36); serum creatinine- 8.3
mg/dl (N: 0.2-1); serum sodium- 129 meq/L (N: 135-145) and elevated
serum potassium levels (7.4 meq/L, N: 3.5-5). Lactate dehydrogenase was
elevated (1939 IU/L, N: <450IU/L) and blood smear examination
showed > 25% schistocytes. Alternate complement pathway
assay i.e AH 50 activity was 17% (N: 30 – 113%). Anti-complement
factor H antibodies was not estimated as the IgG was very low. Kidney
biopsy showed features suggestive of TMA (Figure 3A). Urine culture
showed growth of Citrobacter freundi (>
105/colony forming units) that was sensitive only to
colistin and polymyxin B. He also had pan-hypogammaglobulinemia (IgG:
0.046 g/L, N: 0.44-1.09; IgA- 0.026 g/L, N: 0.04-0.2 and IgM- 0.031 g/L,
N: 0.04-0.24); absent B lymphocytes (0.15%, N: 4-15%) and reduced flow
cytometric expression of Bruton tyrosine kinase (Btk) protein on CD14+
monocytes (Figure 3B) when compared to healthy unrelated control (Figure
3C). Btk expression in mother also showed reduced expression, suggestive
of carrier state (Figure 3D). He was diagnosed to have XLA withCitrobacter freundi infection induced TMA. He underwent 2 cycles
of haemodialysis and was initiated on intravenous methylprednisolone
pulse therapy (30 mg/kg/dose daily for 5 days) followed by tapering
doses of oral prednisolone (initial dose 1 mg/kg/day), intravenous
ceftriaxone and intravenous immunoglobulin (1 gm/Kg). He showed prompt
clinical improvement in the form of improving urine output, renal
function tests, and evidence of haemolysis on peripheral smear. He was
discharged with a plan to continue giving replacement IVIg therapy (400
mg/kg/month), azithromycin prophylaxis (250 mg 3 times a week) and
tapering doses of oral prednisolone.
Diagnosis of XLA was suspected in the index child because of strong
X-linked recessive family history; repeated sino-pulmonary infections;
suspected enteroviral myelitis, Giardia lamblia gastroenteritis,
and pneumococcal septic arthritis. His diagnosis was delayed till
7 years of age which is not unusual in developing countries because of
lack of awareness about these diseases. In our previously published
experience on XLA, a median delay of 3.25 years (range 0.16-16 years)
was reported7.
Citrobacter freundi is a normal commensal in the intestinal
tracts of humans and animals3. It may cause serious
infections in neonates and immunocompromised individuals. These include
neonatal meningitis, urinary tract infection (UTI), bloodstream
infections (BSI), gastroenteritis, and respiratory tract
infections2,3. Citrobacter sp. was isolated
from 9.4% of healthcare-associated UTI, usually following urinary
catheterization and genitourinary instrumentation and C. freundiwas a common subspecies to be isolated2. The index
child did not undergo urinary catheterization or any genitourinary
instrumentation, hence it was unlikely to be a health care associated
infection (HCAI). Tschape et al8 reported hemolytic
uremic syndrome (HUS) in a cluster of immunocompetent children from a
nursery and kindergarten following consumption of sandwich that was
found to be contaminated with C. freundi . Index case had
diarrhoea and C. freundi was isolated from urine. Any infection
including UTI has been found to precipitate HUS.9,10In the index case, C. freundi infection is the potential cause
for diarrhoea and UTI that precipitated HUS.
Autoimmune and inflammatory complications have infrequently been
reported in patients with XLA. These include arthritis, encephalitis,
cytopenias and inflammatory bowel disease. It has been postulated that
defective B cell tolerance and myeloid cell function in patients with
XLA may drive these autoimmune complications. However, exact
pathogenesis is still not known. Index patient had TMA which is a
complement mediated disease. It may be hypothesized that an immune
dysregulatory state triggered by C. freundi infection in the
index patient lead to overactivation of alternative complement pathway
and TMA.
To conclude, we report a spectrum of clinical manifestations of XLA in a
young boy whose diagnosis got missed for several years despite having
characteristic clinical manifestations of the disease. Renal involvement
is rare in XLA. However, infections may trigger TMA in these patients.
Conflict of interest: None