Homozygous STAT-1 Loss of Function Presenting with Recurrent Respiratory Infections and <i>Pneumocystis jirovecii</i> Pneumonia

Background Autosomal recessive complete STAT-1 deficiency is a rare primary immunodeficiency characterized by predisposition to life-threatening viral and mycobacterial infections due to loss of STAT-1–dependent responses to type I/II interferons. We present a case of complete STAT-1 deficiency presenting with severe respiratory infections. Case A 5-week-old, ex–full-term female infant was admitted for RSV bronchiolitis with superimposed MRSA pneumonia and bacteremia requiring intubation. At 2 months, she required noninvasive ventilatory support for rhinovirus infection and treatment for aspiration pneumonia. At 4 months, she was treated for COVID-19 pneumonia. Her history prompted workup for immunodeficiency; she had normal T and B cells, immunoglobulins, and adequate titers to killed vaccines. Genetic testing revealed homozygous deletion in STAT1 (exons 7-9). Functional studies demonstrated absence of STAT-1 phosphorylation to interferon-gamma, supportive of complete STAT-1 deficiency. She was started on prophylactic IVIG and acyclovir and regularly screened for EBV, CMV, and HHV-6. At 5 months, she presented with fever, respiratory distress, and recurrent emesis with leukocytosis and elevated inflammatory markers without a clear source. Ultimately, Pneumocystis jirovecii pneumonia was diagnosed by PCR from bronchoalveolar lavage; she improved with trimethoprim-sulfamethoxazole. During infectious workup, Karius testing returned positive for Mycobacterium abscessus. Given high risk for mycobacterial infection, empiric treatment with azithromycin, amikacin, and linezolid was initiated. At 10 months, she underwent an alpha-beta T cell–depleted haploidentical peripheral blood SCT from her father. Planned conditioning regimen was rituximab, targeted dosing rATG, targeted busulfan, targeted fludarabine, and thiotepa. She had an anaphylactic reaction to Rituximab on Day -1; no further doses of rituximab were given. Graft-versus-host prophylaxis was tocilizumab and abatacept. Engraftment occurred on Day +13. Immediate post-transplant course was initially complicated by persistent host T cells, concerning for a high risk of immunological rejection, but she has since continued to have improvement of donor CD3 chimerism. She is currently Day +50 without signs of GVHD or viral reactivation and continues abatacept monthly. Discussion Complete STAT1 deficiency is a severe immunodeficiency that is historically fatal in early life without curative HSCT. Our case supports the need for early transplant before the acquisition of and complications due to severe infections.