Mimicking hypersensitivity pneumonitis as an uncommon initial presentation of chronic granulomatous disease in children
Liu et al. Orphanet Journal of Rare Diseases
Mimicking hypersensitivity pneumonitis as an uncommon initial presentation of chronic granulomatous disease in children
Hui Liu 0 2
Jinrong Liu 0 2
Huimin Li 0 2
Yun Peng 1
Shunying Zhao 0 2
0 Department of Respiratory Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health , Nanlishi Road 56, Xicheng District, Beijing , China
1 Imaging Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health , Nanlishi Road 56, Xicheng District, Beijing , China
2 Department of Respiratory Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health , Nanlishi Road 56, Xicheng District, Beijing , China
Dry cough, dyspenea and diffuse centrilobular nodules in both lungs of radiologic findings similar to hypersensitivity pneumonitis (HP) are rare initial presentation in chronic granulomatous disease (CGD). CGD is remarkable for increased susceptibility to bacterial and fungal infections as well as high sensitivity to inciting antigens such as Aspergillus species due to dysregulated inflammation. We identified three children who had an initial presentation mimicking HP and were subsequently diagnosed as CGD. All patients developed invasive pulmonary A. fumigatus infection (IPAI) following systemic glucocorticoid therapy. Two of the three patients were found to have mutations in NCF1 gene and one patient in NCF2 gene. As HP is uncommon in children, we should consider the possibility of CGD in children with HP, even in mimicking HP patients with suggestive inhalation history and negative fungal cultures. A prompt diagnosis of CGD is essential to enable initiation of prophylactic antibacterial and antifungal therapies.
Chronic granulomatous disease; Hypersensitivity pneumonitis; A; fumigatus; Glucocorticoid; Children
Letter to the editor
Chronic granulomatous disease (CGD) is characterized
by recurrent and severe bacterial and fungal infections
as well as excessive inflammation, which are most
prominent in gastrointestinal and genitourinary tracts, such
as granulomata mimicking Crohn’s disease [
An exuberant respiratory inflammation induced by the
exposure to inciting antigens and clinically manifested as
hypersensitivity pneumonitis (HP) or allergic
bronchopulmonary aspergillosis (ABPA) has also been described
in CGD [
]. However, HP as an initial presentation of
CGD is uncommon and has never been reported. Here
we review three children who had an initial presentation
mimicking HP, developed invasive pulmonary A.
fumigatus infection (IPAI) following systemic glucocorticoid
therapy and were subsequently diagnosed as CGD.
A 4-year-old boy was admitted to the hospital on
September 8, 2011 after 3 weeks of dry cough,
progressive dyspnea and fever. He lived in a fruit stall with
many rotten fruits inside. He had a history of pneumonia
at 3 months old. He also had a history of severe eczema
and seasonal rhinitis at one year old.
On admission, his oxygen saturation at rest was 92%,
and decreased to 86% after walking. Bilateral basilar rales
were noted on auscultation. Chest high-resolution CT
(HRCT) scan showed diffuse nodular opacities and slight
ground-glass (Fig. 1a). Cultures revealed no evidences
of mycobacteria, fungi and viruses. A specimen taken
from video-assisted lung biopsy of the right lower
lobe revealed bronchiolo centric lymphocytic, and
nonnecrotizing granulomas and no evidence of fungal or
bacterial elements (Fig. 2). Bronchoalveolar lavage fluid
(BALF) from his right middle lobe consisted of 46%
macrophages, 2% eosinophils and 52% T cells, with a
CD4+/CD8+ ratio of 0.62. Fungal and mycobacterial
cultures of BALF were negative, as were T-cell
interferonγ release assays for tuberculosis and polymerase chain
reactions for pneumocystis jirovecii. After exclusion of
infectious agents, diagnosis of mimicking HP probably due
to inhalation of rotten fruit elements was made.
Treatment with 1 mg/kg/day prednisone was initiated and
clinical symptoms improved after 3 days.
Three weeks after the beginning of tapered
prednisone, he developed fever and cough with purulent
sputum. HRCT found consolidation in left upper lobe and
cavity in right upper lobe (Fig. 2a). Sputum culture was
positive for A. fumigatus three times. Parenteral
voriconazole therapy for 2 months followed by oral
voriconazole was administered for 6 months until lung
lesions disappeared completely. In consideration of the
patient’s progressive course, he was referred to
immunological test. Dihydrorhodamine-1,2,3 (DHR) test showed
the absence of neutrophil oxidative burst consistent with
CGD. Gene mutation analyses revealed compound
heterozygous mutations (c.278A > T and c.475delA) in
NCF2 gene, indicating autosomal recessive CGD [
Continuous prophylactic treatment with
trimethoprimsulfamethoxazole and itraconazole were administered, and
no infection recurred in a follow-up period of 4 years.
An 8-year-old girl was admitted to the hospital on
February 15, 2015 because of high spiking fever and chills,
dry cough, progressive dyspnea and chest stuffy for
20 days. Twenty-four days ago she had burned decayed
cornhusks with her brother (case 3) for 4 h. She had a
history of severe eczema and seasonal rhinitis at 3 years old.
On admission, her oxygen saturation at rest was 93%,
and decreased to 84% after walking. Bilateral basilar rales
were noted on auscultation. HRCT scan showed the
presence of bilaterally diffuse centrilobular nodules and
slight ground-glass (Fig. 1b). BALF from her right
middle lobe consisted of 41% macrophages, 3% eosinophils
and 56% T cells, with a CD4+/CD8+ ratio of 0.65. Fungal
and mycobacterial cultures of BALF were negative. The
diagnosis of mimicking HP was made. A treatment of
1 mg/kg/day prednisone was initiated, and clinical
symptoms improved after 2 days.
As prednisone being tapered after 3 weeks, she
developed fever, racking cough with purulent sputum and
chest stuffy. Repeated HRCT showed multi-nodules
bilaterally distributed along bronchi and part of
multinodule fused into pieces more in upper lung (Fig. 2b).
Specific IgG antibody to A. fumigatus was positive. Both
culture of sputum and BALF from right middle lobe
found A. fumigatus. Amphotericin liposome B was taken
for 2 months followed by oral voriconazole for one
year. The nodes disappeared and the pieces shrank.
In consideration of the fact that his brother had a
history of perianal abscess and was diagnosed as CGD
by means of an abnormal DHR test, she was referred
to DHR test, which was consistent with CGD.
Sequencing of genomic DNA revealed homozygous
mutation (c.541delG) in NCF1 gene, indicating autosomal
recessive CGD [
]. Continuous prophylactic antibiotic
treatment was administered, and no symptoms
A 5-year-old boy with high spiking fever and chills, dry
cough and progressive dyspnea was admitted to the
hospital at the same time with his sister (case 2). He had the
same exposure to decayed cornhusks. He had a history
of perianal abscess and severe eczema at 3 months old,
and no history of previous pneumonia, asthma, or
On admission, his oxygen saturation at rest was 95%,
and decreased to 87% after walking. Bilateral basilar rales
were noted on auscultation. HRCT revealed bilaterally
diffuse ill-defined centrilobular nodules and slight
ground-glass (Fig. 1c). Lymphocytosis of 50% with a
CD4+/CD8+ ratio of 0.73, 48% macrophages and 2%
neutrophils were shown in BALF. Fungal and
mycobacterial cultures for BALF were negative. The diagnosis of
mimicking HP was made. Treatment with 1 mg/kg/day
oral prednisone was initiated and clinical symptoms
improved after 3 days. A slow taper of prednisone was
continued after 3 weeks.
Despite the lack of aggravated symptoms, specific IgG
antibody to A. fumigatus was positive and his chest
HRCT revealed a nodular consolidation with halo sign
in left upper lobe (Fig. 2c). Oral voriconazole was taken
for 4 months. The halo disappeared and the
consolidation shrank. In consideration of his history of perianal
abscess, he was referred to DHR test, and the result was
consistent with CGD. He was subsequently confirmed to
have the same NCF1 gene mutation as his sister.
Prophylactic antibiotic treatment was continuously administered.
No extra symptoms occurred anymore.
The clinical data relating to HP and IPAI of the 3
cases are summarized in Table 1. Antecedent history
and genetic tests for CGD are summarized in Table 2.
In CGD patients, hypersensitivity to Aspergillus clinically
manifested as HP and ABPA occurs after exposure to a
variety of antigens, and is characterized by the
constitutional symptoms and non-necrotizing granulomas in
walls of alveoli and airways. However, HP as the first
manifestation of CGD is rare in children.
Our cases illustrate that they had the clinical
presentations similar to HP, including the history of exposure to
potential inciting antigens, lymphocytosis in BALF,
compatible image features, poorly formed granulomas on
lung biopsy in one patient (case 1), and a favorable
response to systemic glucocorticoids. However, these
patients did not fully meet the diagnostic criteria for HP
published by Venkatesh and Wild [
Lung biopsy in one patient (case 1) revealed
nonnecrotizing granulomatous pneumonitis with variable
airspace organization. It is necessary to rule out the
pulmonary granulomatous process related to the underlying
CGD. Granulomas in patients with CGD are typically
small, containing central neutrophil micro-abcesses
surrounded by epithelioid histiocytes and giant cells and
spreading in airways or lung parenchyma [
Unlike CGD, the granulomas of our patient were loosely
formed and relatively larger, spread through airway to
lymph tract, and did not contain central micro-abcesses,
similar to the adult CGD patient reported by Katsuya
and colleagues .
Recently, Esenboga et al. reported that a 16-year-old
patient atypically presented with chronic HP caused by close
contact with pigeons and exposure to their allergens
before the diagnosis of CGD caused by homozygous deletion
mutation in NCF1 [
]. Like the present cases, the patient
recovered by allergen avoidance combining with the use
of anti-inflammatory drug. Meanwhile in another study
that followed up 33 patients with X-linked CGD for
10 years, four patients developed interstitial lung disease
(ILD). Two of the four patients, one 20 years old and
the other 23 years old, were diagnosed with HP through
CT images and histopathological examination, probably
caused by breathing in dust in a plant and an unknown
antigen, respectively [
]. However, the clinical symptoms
in the two patients were mitigated only by allergen
avoidance, suggesting that CGD patients are more
susceptible to hyperinflammation resulting from
inhalation of antigens.
The combination of HP/ABPA features has been
described in 2 CGD patients with a gradually progressive
course over many years [
]. Interestingly, case 2 had the
ABPA features of elevated total serum IgE (3000 IU/mL).
However, in ABPA patients, acute course or exacerbation
may present nodular pulmonary infiltrates, centrilobular
nodules and bronchiectasis on HRCT [
in BALF is uncommon in ABPA.
HP hypersensitivity pneumonitis, IPAI invasive pulmonary A.fumigatus infection, HRCT high-resolution computer tomography, BALF bronchoalveolar lavage fluid,
AM Alveolar macrophages, Lym lymphocytes, Neu neutrophils, Eos eosinophils, FEV1 forced expiratory volume in one second, FVC forced vital capacity, DLCO
decreased lung diffusion of carbon monoxide
CGD chronic granulomatous disease, DHR dihydrorhodamine-1,2,3, Igs immunoglobulins, NK natural killer
The mechanisms underlying this hyperinflammation
are still under investigation. A plausible explanation is
that the reduced ROS cannot adequately inhibit the
production of inflammatory cytokines [
], and that this
ROS deficit in CGD allows for the continuous
production of inflammatory cytokines, resulting in immune
dysregulation or hyperinflammation. Thus, one of the
effective therapeutic approaches for such
hyperinflammation is the use of corticosteroids or
immunosuppressive drugs [
]. Indeed, infliximab, a chimeric antibody
against tumor necrosis factor-α (TNFα), has shown
therapeutic efficacy for refractory CGD colitis, as TNFα
is thought to play a critical role in granuloma formation
Although the symptoms of HP were improved rapidly
after systemic corticosteroid treatment, the present
patients suffered worsening disease after 3 weeks’ treatment,
and the clinical, radiological and positive A. fumigatus
culture findings are consistent with the diagnosis of IPAI,
which is a major life-threatening infection among CGD
]. There are several reasons for the
occurrence of IPAI. Firstly, patients with CGD are prone to
develop characteristic invasive fungal infections due to
Aspergillus specie. Secondly, prolonged steroids
therapy makes a contribution to occurrence of IPAI by
increasing the patient’s susceptibility to infection.
Thirdly, the risk of Aspergillus infections in the
present patients is higher than that of other pathogens
infections because of the exposure to rotten fruits or
decayed cornhusks which are considered as Aspergillus
spores-rich environment. The occurrence of IPAI
makes it easier to diagnose CGD, but which would be
detected much earlier in the inflammatory period.
There are two previous reports of 10 patients who
developed fulminant mulch pneumonitis (FMP) as
emergency presentation of CGD [
]. Unlike our series,
the 10 patients presented acute, rapid, often fatal,
invasive aspergillosis symptoms after an identifiable exposure
to organic material; culture results were positive for
Aspergillus before systemic treatment of glucocorticoids,
and 5 of the 10 patients died despite the treatment of
antifungals and steroid. Based on the disease duration
of the present patients, similar inflammatory responses
characterized by lung granuloma formation,
lymphocytosis in BALF and Aspergillus specific IgG antibodies
could be viewed as the subacute end of the acute FMP
spectrum caused by inhalation of variable doses of
The incidence of HP is probably much higher in CGD
patients, especially in children. CGD should be first
excluded by diagnostic DHR testing before steroids therapy
in patient with newly diagnosed HP or mimicking HP.
Furthermore, it should be noted that the combined
application of antifungal drugs and steroids or other
anti-inflammatory drugs is more appropriate from the
beginning of the treatment in HP patients with suspected
CGD, especially in patients with a history of fungal
CGD should be considered in children with HP, even
in mimicking HP patients with suggestive inhalation
history and negative fungal cultures before steroids
therapy. A prompt diagnosis of CGD is essential to
enable initiation of prophylactic antibacterial and
ABPA: Allergic bronchopulmonary aspergillosis; BALF: Bronchoalveolar lavage
fluid; CGD: Chronic granulomatous disease; DHR: Dihydrorhodamine-1,2,3;
HP: Hypersensitivity pneumonitis; HRCT: High-resolution computer tomography;
IPAI: Invasive pulmonary A.fumigatus infection; TNFα: Tumor necrosis factor-α
We would like to thank all of the patients and their families for their kind
The study received no funding.
Availability of data and materials
Please contact author for data requests.
HLiu supervised the patient care, conceptualized and designed the report,
collected the data, and drafted the initial manuscript; JL supervised the
patient care, collected the data and revised the article; HLi supervised the
patient care and collected the data; YP supervised the radiological images;
SZ supervised the patient care, conceptualized the report, and reviewed and
revised the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The research was approved by the Ethics Committee of Beijing Children’s
Hospital. All patient guardians gave informed consent to the study.
Consent for publication
All patient guardians gave informed consent to the publication of this study.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional affiliations.
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