A 5-month-old girl was hospitalized in the context of failure to thrive, irritability and mild respiratory distress with a diagnostic suspicion of gastroesophageal reflux disease. Her neonatal history was unremarkable. Prior to this admission, at 3 months of age, the patient presented with a perianal skin infection that was treated with a course of amoxicillin PO. At 3 and a half months, she suffered from atypical pneumonia that required hospital admission, without significant clinical improvement despite treatment with amoxicillin for 8 days, and adding azithromycin for 5 days in combination with inhaled salbutamol and budesonide, and later escalation to cefixime. On the third day of hospitalization, there was worsening respiratory status, requiring oxygen therapy at 0.5 L/min. On physical examination, there was subcostal retraction and marked respiratory grunting, with normal pulmonary auscultation. Oropharyngeal candidiasis was also noted, as well as irritability. The chest radiograph (CXR) revealed bilateral ill-defined increased pulmonary density, more evident in central areas, with increased interstitial markings (Figure 1A). Blood tests indicated low hemoglobin (8.7 g/dL), leukopenia (2.6 × 10³/µL), lymphopenia (0.1 × 10³/µL) and C-reactive protein at 27.6 mg/L. A multiplex respiratory polymerase chain reaction (PCR) viral panel was negative. An immunological assessment was performed, showing generalized hypogammaglobulinemia. Lymphocyte subpopulation study demonstrated a significant defect in B and T cell populations. Mutations in the ADA (Adenosine Deaminase) gene c.46delG and c.632 G > A were detected in a genetic panel for inborn errors of immunity, confirming the diagnosis of Severe Combined Immunodeficiency (ADA-SCID). Due to persistent respiratory distress a bronchoscopy was performed on day 8 of hospitalization and revealed copious, milky-white material (Figure 1B). No microorganisms were isolated in the bronchoalveolar lavage (BAL). BAL cytology demonstrated eosinophilic extracellular periodic acid–Schiff (PAS)-positive lipoproteinaceous material resistant to PAS-diastase, consistent with pulmonary alveolar proteinosis (PAP). Enzyme replacement therapy with pegylated adenosine deaminase (PEG-ADA) was initiated immediately after diagnosis and the patient was discharged under this therapy 20 days later, following progressive improvement of respiratory distress. Two months later, radiological improvement was partial in CXR and BAL yielded a pale whitish material, with negative PAS staining at histopathological examination. A thoracic high resolution computed tomography (HRCT) was also done at this time (Figure 2A). At 4 months, a new CXR was performed, and further improvement was noted. Due to inability to find an HLA-matched donor for hematopoietic stem cell transplantation (HSCT), the patient was considered a candidate for autologous ex vivo lentiviral gene therapy, which was performed at 15 months of age. Following gene therapy, there was progressive recovery of the total cell count. A significant improvement was documented in a follow-up HRCT performed after 3 years of gene therapy (Figure 2B) and serial spirometry tests were normal. No evidence of recurrence of pulmonary alveolar proteinosis or SCID was observed after 6 years of follow-up. Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by the accumulation of surfactant in the alveoli, because of impaired clearance by dysfunctional alveolar macrophages. Specifically, in adenosine deaminase (ADA) deficiency the presence of toxic purine metabolites compromises macrophage function. The overall incidence of PAP is 7–10 cases per million. Most cases (90%) consist of autoimmune PAP (due to anti-GM-CSF antibodies), which affects adults and older children. In neonates and infants, it is an ultra-rare disease, and it is caused by congenital or secondary diseases, such as immunodeficiencies 1, 2. We describe a case of PAP secondary to ADA-SCID. ADA deficiency is one of the most frequent causes of SCID and about 44% of patients with ADA-SCID deficiency develop PAP. In fact, the frequency of PAP is significantly higher in ADA-SCID than in other forms of SCID, in which it is exceptional1. The symptoms of PAP vary by age and underlying etiology. In neonates and infants, it often starts with respiratory distress, tachypnea, hypoxemia and failure to thrive, as in our case. In young children its clinical presentation consists of chronic cough, exertional dyspnea, and poor weight gain 2. Regarding diagnosis, it is based on clinical and radiological suspicion and confirmation by BAL. Pulmonary biopsy is not recommended as a routine diagnostic method, given the high diagnostic yield of BAL (90.7%) and the lower accessibility and risks of biopsy 3. For identification of the specific etiology, current guidelines recommend targeted testing: GM-CSF antibody testing is essential for diagnosing autoimmune PAP and it is considered the first test to do. Nevertheless, autoimmune PAP is rare in infants and young children, so genetic analysis is prioritized to do in these age groups. Next-generation sequencing (NGS) panels are advised to identify mutations in surfactant protein genes or GM-CSF receptor genes 3. The treatment of PAP will vary depending on its cause. Related to ADA-SCID, enzyme replacement therapy with PEG-ADA is indicated as an initial and stabilizing measure until curative treatment is performed. Both HSCT from an HLA-matched donor and autologous ex vivo lentiviral gene therapy are considered the first-line treatment 4. We describe a case that was successfully treated with lentiviral gene therapy. This option has been demonstrated to be secure and effective in children with ADA-SCID. A recent 7-years follow-up study has reported an overall survival of 100%, and event-free survival of 95% in children who were treated with lentiviral gene therapy. Compared to HSCT, although its access is limited by manufacturing and regulatory constraints, and long-term monitoring is required, there is no risk of graft versus host disease (GVHD) and no immunosuppression is required 5. In conclusion, although the incidence of PAP in children is extremely low, it should be considered in those infants with persistent respiratory distress, particularly if an underlying immunodeficiency is suspected. ADA-SCID is the immunodeficiency most strongly associated with PAP, and its definitive treatment is essential for the sustained resolution of this condition. This case highlights the successful use of lentiviral gene therapy for ADA-SCID and it is the first report documenting its efficacy in PAP secondary to this immunodeficiency. Cristina de Manuel Gómez: conceptualization, methodology, validation, writing – review and editing, visualization, supervision, investigation. Patricio Gutiérrez Lucas: writing – original draft. Manuel Parrón-Pajares: supervision. Ana Méndez-Echevarria: supervision. The authors have nothing to report. According to institutional policy at Hospital Universitario La Paz, single case reports that do not involve experimental interventions are not submitted to, nor approved by, the Ethics Committee. Written informed consent was obtained from the patient's parents for the publication of this clinical case and any accompanying images. All procedures were conducted in accordance with the ethical standards of the responsible institutional committee and with the principles outlined in the Declaration of Helsinki. Patient confidentiality has been strictly preserved, and no identifying information is included in this report. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Gómez et al. (Fri,) studied this question.