Invasive pneumococcal infection after allogeneic hematopoietic cell transplantation for <scp>NEMO</scp> deficiency

The incidence of invasive pneumococcal disease (IPD) in children has decreased due to widespread vaccination; however, caution remains warranted in immunocompromised children. Allogeneic hematopoietic cell transplantation (HCT) is performed to reduce susceptibility to infections in certain cases of inborn errors of immunity. Nevertheless, IPD can still occur post-HCT, and its mechanisms remain unclear. We report a case of IPD in a patient with nuclear factor-kappa B essential modulator (NEMO) deficiency who developed IPD despite improved immunocompetence and pneumococcal vaccination after HCT. The patient was diagnosed with NEMO deficiency at 5 months of age owing to the variant c.768 + 5G>A in IKBKG.1 He presented with anhidrotic skin, sparse hair, Pneumocystis jirovecii pneumonia, elevated immunoglobulin M (IgM), and decreased IgG. Graft failure occurred after the first HCT at 1 year of age. A second HCT was performed at age 2 (Mori et al., JJPHO, 2022, in Japanese). This course was uneventful, with no signs of graft-versus-host disease (GVHD). Complete donor chimerism and normalization of lymphocyte subsets were confirmed at 1 year post-HCT. Subcutaneous Ig injections were discontinued at 10-month post-HCT, immunosuppressive medications at 13 months, prophylactic antibiotics at 14 months, and the 13-valent pneumococcal conjugate vaccine (PCV13) was administered at 16 months. Following completion of Ig replacement, serum IgG2 levels were 86.2–147 mg/dL (within the normal range). Seventeen months after HCT, the patient was admitted due to a 1-week-long fever without prior antibiotic treatment. At admission, the patient's temperature was 39.1°C, heart rate was 153 bpm, blood pressure was 82/53 mmHg, respiratory rate was 60 breaths/min, and SpO2 was 88% under room air. Blood tests indicated a white blood cell count of 29,200/μL, hemoglobin 9.2 g/dL, platelet count 31.6 × 104/μL, CRP level 19.09 mg/dL, IgG 761 mg/dL (535–1340 mg/dL), and IgG2 112 mg/dL (58.5–292.1 mg/dL). The pneumococcal-specific IgG2 antibody titer was 14.1 μg/mL (protective threshold >0.25–0.35 μg/mL). Other postvaccination antibody titers, T/B/NK cell subsets, and complement levels were not evaluated. Computed tomography revealed multiloculated fluid accumulation in the left lung. The patient was treated with meropenem, vancomycin, and micafungin, and he underwent chest drainage. Penicillin-sensitive Streptococcus pneumoniae was detected in the blood and pleural fluid cultures, prompting a switch to cefotaxime. The infection continued and required surgical debridement, additional Ig supplementation, and intrapleural urokinase administration, which ultimately improved the patient's condition (Figure 1). The identified S. pneumoniae serotype was 33F, which was not included in PCV13. This case reflects the impact of non-PCV13 serotypes in IPD. The proportion of IPD from non-PCV13 serotypes has increased with PCV13 use. Serotype 33F is highly invasive and is associated with severe outcomes,2 potentially contributing to the patient's condition. In Japan, the introduction of PCV20, which includes the serotype 33F, is expected to enhance prevention. Furthermore, serotype-independent pneumococcal vaccines offer hope for broader protection against IPD. This case also highlights the potential for severe IPD even after immune recovery post-HCT, raising the possibility of insufficient immune recovery associated with NEMO deficiency post-HCT or its complications. Most clinical symptoms of NEMO deficiency are cured post-HCT, except colitis3; in our case, immune recovery was inferred from complete donor chimerism and normalization of lymphocyte subsets. For IgG2, which is crucial for pneumococcal defense by promoting opsonization, recovery can take up to 2 years post-HCT,4 and IPD due to selective IgG2 deficiency can take up to 18-month post-HCT (Sakagawa et al., J Jpn Pediatr Soc, 2023, in Japanese). In our case, however, IPD occurred despite normal IgG2 levels, suggesting that quantitative recovery alone was insufficient. Our case required further Ig supplementation despite sufficient IgG2 levels as well as intrapleural urokinase administration to dissolve the fibrin clot and promote lung expansion. Additionally, CRP elevation may remain relatively modest even under severe IPD (Figure 1), likely due to the residual impairment in CRP response associated with NEMO deficiency post-HCT, warranting careful monitoring. Moreover, in the general post-HCT context, late-onset pneumococcal infections can occur around 16-month post-HCT, with potential complications including chronic GVHD.5 Patients with NEMO deficiency remain at risk of IPD even after immune recovery post-HCT. Vaccination with pneumococcal vaccines covering a wide range of serotypes after appropriate Ig supplementation post-HCT may help prevent IPD. All authors have reviewed the final version to be published and have agreed to be accountable for all aspects of the work. Concept and design: T.Y., Y.K. Acquisition, analysis, or interpretation of data: T.Y., Y.K. Drafting of the manuscript: T.Y., Y.K. Critical review of the manuscript for important intellectual content: All authors. Informed consent was obtained from the patient's parents for publication of this case report. We would like to thank Editage (www.editage.jp) for English language editing. Hirokazu Kanegane has received lecture honoraria from Takeda Pharmaceutical Co., Ltd. The other authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.