Abstract: A 5-year-old girl had poor growth and unresolving pneumonia.
There was persistent collapse-consolidation of the right middle lobe. CT
thorax revealed bilateral bronchial wall thickening and dilatation.
Bronchoscopy showed numerous endobronchial mucosal nodules, consisting
of dense lymphoid infiltrates. Bacterial culture of the nodule biopsy
suggested endobronchial actinomycosis. She had T-cell lymphopenia.
Genetic test confirmed the diagnosis of activated phosphatidylinositol
3-kinase delta syndrome (APDS), an immunodeficiency condition.
Keywords:
Endobronchial nodules
Activated phosphatidylinositol 3-kinase delta syndrome (APDS)
Bronchial actinomycosis
Cobblestone airway
A 5-year-old Chinese girl had persistent cough for a few months
following an acute episode of pneumonia, despite multiple courses of
oral and intravenous antibiotics. The serial chest X-rays (CXR) showed
non-resolving consolidation of the right middle lobe (RML) (Figure 1a).
The inflammatory markers including white cell count, neutrophil count,
C-reactive protein, erythrocyte sedimentation rate and procalcitonin
were normal. Haemophilus influenzae and Moraxella
Catarrhalis were isolated from two respiratory specimens respectively,
and antibiotics had been given accordingly. The workup for pulmonary
tuberculosis was negative.
In retrospect, she had poor growth and recurrent wet cough since 3 years
old, recurrent snoring since infancy, and self-limiting febrile
illnesses 2-3 times per year. She did not have swallowing dysfunction.
On physical examination, she did not have respiratory distress, finger
clubbing, chest deformity, lymphadenopathy, hepatomegaly, or
splenomegaly. Her breath sound was normal. Her oral and dental condition
was good. There was bilateral grade 3 tonsillar hypertrophy. Her oxygen
saturation was normal.
The immunological workup showed T-cell and NK cell lymphopenia (table
1).
High-resolution computed tomography (HRCT) of the thorax revealed
diffuse bronchial wall thickening and RML collapse. There was mucus
plugging and bronchiectasis of both lower lobes. It also showed mosaic
attenuation of both lungs, suggestive of small airway disease. (Figure
1b)
Bronchoscopy found numerous whitish mucosal nodules from the trachea to
the bilateral major segmental bronchi, resembling cobblestone
appearance. The RML opening was completely obliterated by the nodules
(Figure 1d-e). On air injection, the RML bronchus opened and pus came
out.
The biopsy of the endobronchial lesions showed dense lymphoid
infiltrates and some polymorphs in the underlying stroma (Figure 1c).
The lymphoid cells included mixed populations of CD3+ and CD20+ cells.
There was no light chain restriction by immunostaining. There was no
granuloma or malignancy. Bacterial culture of the biopsy yieldedActinomyces odontolyticus , whereas the AFB culture was negative.
She was treated with intravenous benzylpenicillin (300,000 units/kg/day)
for four weeks, followed by oral amoxicillin (45mg/kg/day) for six
months. Her cough and snoring resolved, and she had better weight gain.
On follow-up bronchoscopy, the endobronchial nodules became remarkably
fewer and smaller (Figure 1f). The appearance in CT thorax also improved
notably.
We suspected she had inborn error of immunity, as she had T-cell and NK
cell lymphopenia, failure to thrive, endobronchial actinomycosis (not
typical in children), non-resolving pneumonia, and atypical
endobronchial appearance.
Genetic testing by next generation sequencing gene panel revealed de
novo nucleotide substitution c.3061G>A of exon 24 in thePIK3CD gene. This missense variant caused a substitution of a
glutamic acid residue with lysine at codon 1021 of the PIK3CDprotein (pGlu1021Lys), which is a hotspot mutation. The diagnosis of
activated phosphatidylinositol 3-kinase delta syndrome (APDS) was made.
She was put on long-term sirolimus and monthly immunoglobulin infusion.
She remains free of pneumonia, frequent infection, or atypical
infection.
Discussion
In the literature, there is limited information about the condition of
diffuse endobronchial nodules, or ‘cobblestone airway’, especially in
children.
In adults, there are reports about its association with chronic
eosinophilic pneumonia, Churg-Strauss syndrome, hypereosinophilic
syndrome, lymphoma, Sjögren’s syndrome, pulmonary sarcoidosis,
neurofibromatosis type 1, and tracheobronchopathia osteochondroplastica.
In children, some reports suggest that it is caused by mucosal
irritation resulting from factors like gastro-esophageal reflux (GERD)
or pulmonary infection. Contrastingly, Dave et al described that
tracheal cobblestoning in otherwise healthy children is common, and not
associated with GERD or respiratory infection1.
Meanwhile, some authors reported that diffuse endobronchial nodules were
seen in individuals with APDS and actinomycosis respectively.
In a series of 53 individuals with APDS2, five (9%)
had mucosal nodular lymphoid hyperplasia in the lower airway visualized
as cobblestone-like plagues or polyps. Biopsy specimens from the mucosal
lesions showed follicular hyperplasia. The most common findings in CT
thorax in this series are air-space opacity, tree-in-bud opacities,
bronchial wall thickening, bronchiectasis, mosaic attenuation, and
mediastinal lymphadenopathy.
Thoracic actinomycosis, occurring mostly in adults, usually presents as
slowly progressive chronic pneumonia or chest wall mass. Despite this,
Kalai et al described an adult case of bronchial actinomycosis with
diffuse mucosal nodules in the lower airway3.
In our case, the CT and endoscopic appearance improved significantly
following targeted antibiotic therapy against actinomycosis, even before
the diagnosis of immunodeficiency was made. We believe that both APDS
and actinomycosis contributed to the pathogenesis of the diffuse
endobronchial nodules.
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined
immunodeficiency syndrome. One cause is a gain-of-function mutation inPIK3CD , a phosphoinositide 3-kinase (PI3K) gene encoding p110δ.
PI3Ks are enzymes involved in cellular functions. Class IA PI3Ks involve
in lymphocyte signaling by activating protein kinase B (PKB, also known
as AKT) in the PI3K/AKT/mTOR/S6K pathway, which plays a major role in
controlling lymphocyte proliferation, differentiation, functioning, and
survival. This group of PI3Ks comprise of a catalytic (variants include
p110α, β and δ) and a regulatory subunit (variants include p85α, p85β
and p55). PI3Kδ, a class IA isoform comprising of p110δ and p85α, is
expressed predominantly in leukocytes. Mutations in PIK3CD result
in the hyperactivation of the PI3K/AKT/mTOR/S6K signaling pathways in
the leukocytes, causing aberrant differentiation of B cells and T cells.
These lymphocytes have abnormal proliferation, poor functioning and die
earlier than usual.
The hallmark of APDS is low naive CD4 and CD8 T cells. Affected
individuals usually have recurrent sinopulmonary infections,
bronchiectasis, lymphadenopathy, nodular lymphoid hyperplasia in mucosal
tissues, increased incidence of EBV and CMV infections, autoimmunity,
lymphoma, neurodevelopment delay and growth
retardation4,5.
Management options include antibiotic prophylaxis, immunoglobulin
replacement, immunosuppressive therapies (such as steroids and
rituximab), mTOR inhibition with sirolimus, and hematopoietic stem cell
transplantation. Targeted therapies like selective PI3Kδ inhibitors are
under development.
In the past, many APDS cases were diagnosed some years after the initial
presentation, when complications and structural damages had already been
established. Some patients remained undiagnosed until adolescence and
adulthood. With advances in genetic testing, APDS (and many other
conditions of inborn error of immunity) can be diagnosed timely. Early
recognition of the disease presentation and prompt referral for
immunological and genetic evaluation help to improve the outcome of
these children.