A five-month-old boy presented with paroxysmal cough and slight wheezing after a cold. The cough did not improve after oral medication and aerosol inhalation treatment at a local clinic. On the contrary, the cough worsened, and was accompanied by dyspnea, cyanosis, wheezing, and elevated work of breathing. The patient was diagnosed with pneumonia accompanied by respiratory failure. Thus, assisted breathing with a ventilator was provided for the patient, and ceftazidime was administered. The wheezes slightly improved after the interventions. However, the respiratory function did not completely improve. Therefore, the patient was transferred to our hospital. The parents of the boy were both non-consanguineous and healthy, and no previous history of genetic disease was declared.
The initial physical examination revealed the following: body temperature of 37.2°C, pulse of 142/min, breathing at 58/min, 86% percutaneous oxygen saturation (oxygen flow rate, 5 L/min; oxygen inhalation with mask), and weight of 7 kg. The patient’s consciousness was clear with shortness of breath. Furthermore, fine moist rales and wheezes were auscultated in both lungs.
The laboratory examination results revealed normal white blood cells (including neutrophils, lymphocytes, monocytes, platelets and red blood cells). However, the high-sensitivity C-reactive protein, procalcitonin, erythrocyte sedimentation rate, and enzyme tests related to the hepatic, renal and myocardial tissues were unremarkable. The serum immunoglobulin tests revealed a significant decrease in IgA and IgG levels, while the IgM level was normal (Table 1). The chest computerized tomography (CT) revealed bilateral diffuse patchy and ground-glass opacities, with a “crazy paving”-like appearance, suggesting bilateral interstitial pneumonia (Fig. 1A). Therefore, the patient was initially diagnosed with interstitial pneumonia with respiratory failure.
Table 1. Clinical and genetic characteristics of patients with XHIGM with PAP with the CD40LG mutation
Patient no.
|
Present patient
|
Patient 2(6)
|
Patient 3(7)
|
Patient 4(8)
|
Age of onset (months)
|
5
|
5
|
12
|
9
|
Age at diagnosis (months)
|
7
|
5
|
60
|
36
|
Delay in diagnosis (months)
|
2
|
0
|
48
|
25
|
Predominant infections
|
Pneumonia
|
Pneumonia
|
Pneumonia/diarrhea
|
Pneumonia
|
Organisms isolated
|
Fungi
|
No
|
Klebsiella pneumoniae
|
Pneumocystis jirovecii
|
Other manifestations
|
NA
|
No
|
Recurrent anemia
|
No
|
IgG (mg/dl)
|
81 (800-1600)
|
<80 (139-655)
|
308 (490-1 610)
|
40 (100-560)
|
IgA (mg/dl)
|
<7 (70-330)
|
8 (4-62)
|
65 (40-200)
|
150 (360-920)
|
IgM (mg/dl)
|
57 (50-220)
|
108 (17-69)
|
314 (50-200)
|
480 (400-1 280)
|
Neutropenia
|
Yes
|
NA
|
No
|
Yes
|
Chest CT
|
Ground-glass density images in both lungs
|
Diffuse ground glass opacities, reticular interstitial thickening, and consolidation
|
Ground-glass density images in both lungs
|
Ground-glass density images in both lungs
|
Pathology
|
BAL material PAS (+)
|
BAL material PAS (+)
|
Lung biopsy revealed PAS (+)
|
BAL material PAS (+)
|
Mutations/domains
|
c.516T>A, p.Tyr172Ter/TNFH
|
c.608G>C, p.Arg203Thr/TNFH
|
IVS3-1 G>A, E4 skip (del 347-409)/TNFH
|
c.511 dup A, p. Ile171Asn∗30/TNFH
|
Treatment given and outcomes
|
Recovery on WLL, IVIg, cotrimoxazole, and HSCT
|
Improved on steroids, IVIg and WLL
|
Improved on IVIg, cotrimoxazole,
|
Improved on WLL, methylprednisolone, IVIg
|
Follow-up (months)
|
42
|
12
|
96
|
36
|
Abbreviations: BAL, bronchoalveolar lavage; HSCT, hematopoietic stem cell transplantation; IVIg, intravenous immunoglobulin; NA, not available; PAS, periodic acid-Schiff; TNFH, tumor necrosis factor homology domain; WLL, whole-lung lavage.
The blood cultures used to identify causative microbes (including mycoplasma, bacteria, tuberculosis and adenovirus) were negative. Fungal infection was suspected due to the G-test result of 195.5 pg/mL (reference value: <10 pg/mL). Pulmonary lesions were remarkably alleviated after the administration of voriconazole (Fig. 1B). On the 11th day after admission, the alveolar lavage fluid was obtained via fiberoptic bronchoscopy, which appeared milky (Fig. 1D). The examination results for the periodic acid-Schiff (PAS) stain and diastase-PAS stain were found to be positive in the alveolar lavage fluid (Figs. 1E and 1F), which is consistent with the pathological characteristics of PAP. Hence, the boy was diagnosed with PAP and immunodeficiency. Next, the causes of immunodeficiency and PAP, including the secondary and genetic causes, were further investigated. Polymerase chain reaction and culture tests for Pneumocystis jirovecii, Mycobacterium tuberculosis, bacteria, and fungi infection, and the polymerase chain reaction and alveolar lavage fluid culture tests were performed, all results were negative. Trio whole-exon sequencing was subsequently performed using next-generation sequencing (Kangxu Medical Laboratory, Beijing, China). The results identified a CD40LG hemizygote nonsense mutation (NM_000074 c.516T > A, p. Tyr172Ter). Furthermore, the Sanger sequencing verified that this mutation was inherited from the patient’s asymptomatic mother (Fig. 2A). Thus, this variant was considered to be the cause of the disease, based on the American College of Medical Genetics and Genomics guidelines (PVS1 + PM2) (5). Finally, the patient was diagnosed with CD40LG-mutated- XHIGM with PAP.
A monthly intravenous immunoglobulin infusion combined with oral sulfonamides was administered. The lung lesions completely disappeared after nine months of treatment (Fig. 1C). After obtaining an informed consent, the patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the 10th month of the clinical course (HLA match, China Marrow Donor Program, HLA 10/10, donor blood type O/RH+, recipient blood type O/RH+). The conditioning regimen consisted of busulfan, cyclophosphamide, anti-thymocyte globulin, and graft-versus-host disease prophylaxis with cyclosporine A and methotrexate. The supplementation with immunoglobulin was stopped, because the serum immunoglobulin levels returned to the normal range after myeloid engraftment on day 52. The condition of the patient was good after discharge. The patient was followed up until July 2022 (at the age of four years and nine months old). The patient presented with normal growth and development comparable to the patient’s peers, and had no recurrence of PAP or infection. The serum immunoglobulin and chest CT were also normal. The clinical course of the patient is summarized in Fig. 3.