To the Editor,

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare disorder of immune dysregulation due to a defect in the XIAP gene, also known as the baculoviral IAP-repeat-containing protein 4 (BIRC4) [1]. XIAP deficiency has historically been classified as X-linked lymphoproliferative (XLP) syndrome type 2. BIRC4 is an important regulator inhibiting apoptosis by hindering pro-apoptotic caspases, particularly those for invariant natural killer T cells and mucosal-associated invariant T cells. BIRC4 is also responsible for the activation of the NLRP3 inflammasome, the lack of which leads to overproduction of proinflammatory cytokines. This chronic state of inflammation leads to hemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), immunodeficiency, autoimmunity, and lymphoproliferation [1]. In particular, XIAP-deficient patients often have recurrent HLH triggered by Epstein-Barr virus (EBV), and their IBD is very early onset and refractory [1]. The only curative treatment for XIAP is stem cell transplant [1].

Multisystem inflammatory syndrome in children (MIS-C) is a complication of COVID-19 characterized by fevers and elevated markers of inflammation (Table 1) [2]. In a 2021 study by Dr. Janet Chou et al. performing whole-exome sequencing on 18 otherwise healthy children with MIS-C, two patients were found to have XIAP deficiency [1]. However, no cases of MIS-C have been reported in XIAP-deficient patients post-transplant. Here within, we present a 27-month-old male with XIAP deficiency who developed a post-SARS-CoV-2 atypical inflammatory syndrome after stem cell transplant.

Table 1 Laboratory values for the patient compared to MIS-C diagnostic criteria
Full size table

Our patient had an uncomplicated birth and initial hospital stay. At 4 weeks of age, he had streaks of blood in his stool which persisted despite maternal dietary changes. At 6 weeks, he was hospitalized for parainfluenza virus and had an episode of otitis media and several upper viral respiratory tract infections over the next few months. At 6 months, formula was introduced but bloody stools persisted despite multiple changes to hypoallergenic and hydrolyzed formula. He was hospitalized at 7 months and again at 8 months for profusely bloody stools. At 8 months of age, he was diagnosed with IBD by endoscopy/colonoscopy. His IBD was refractory to standard treatments, and he failed to thrive. He underwent commercial Sanger sequencing and was found to have a novel hemizygous variant in XIAP (c.978-2A > G), an intronic mutation affecting the acceptor splice site in intron 3. Pathogenicity was confirmed by absent XIAP protein expression on flow cytometry, and he was diagnosed with XIAP deficiency at 10 months of age. He underwent matched unrelated donor stem cell transplant at 16 months with fludarabine (30 mg/m2/day D-11 to D-7)-based reduced intensity conditioning including anti-thymocyte globulin (2.5 mg/kg/day D-5 to D-2), thiotepa (8 mg/kg/day D-7), melphalan (140 mg/m2/day D-6), and rituximab (375 mg/m2/day D-12). He engrafted neutrophils on day 20 and was hospitalized for 6 weeks post-transplant (PT). His PT course was complicated by sinusoidal obstructive syndrome (2 weeks PT, treated with defibrotide 6.25 mg/kg BID × 4 days), graft versus host disease (GVHD grade 1/2, 3 weeks PT, treated with prednisone 1 mg/kg tapered over 1 month and topical corticosteroids), hypogammaglobulinemia (patient still on replacement immunoglobulin), and low mixed chimerism despite multiple donor lymphocyte infusions (DLIs). He has received 3 DLIs to date with the first 7 months PT and the last 10 months PT with doses CD3 + 1 × 105–107 cells/kg. His PT infectious history is significant for recurrent Clostridium difficile colitis (4–11 months PT), human herpesvirus 6 viremia (10 months PT), human metapneumovirus upper respiratory tract infection (3 months PT), and enterovirus enteritis (10 months PT). One-month PT, his chimerism was 99% (89% T cells). He developed a post-SARS-CoV-2 atypical inflammatory syndrome at 11 months PT when his chimerism was at its nadir of 7.3% (13.4% T cells). He had no history of HLH or EBV infection. There was no contributory family history.

At 27 months of age, he presented to the emergency room with a diffuse maculopapular rash, fever, conjunctivitis, red tongue, peeling lips, swollen neck/inguinal lymph nodes, and loose stools. At the time, he was not on immunosuppression and had just finished a steroid course for GVHD. Blood cultures were positive for coagulase negative staph and stool cultures positive for Clostridium difficile. He also had pancytopenia. His fevers persisted for a total of 10 days, and further work-up was consistent with a post-SARS-CoV-2 atypical inflammatory syndrome such as MIS-C (Table 1). The patient had a very high titer of COVID antibodies so unlikely due to passive infusion of replacement IVIG for his hypogammaglobulinemia though his replacement IVIG was not tested for COVID antibodies. Additionally, his last dose of IVIG was several weeks prior and likely had asymptomatic COVID infection several weeks prior when multiple family members tested positive for COVID. He had no evidence of COVID pneumonia on imaging during his admission and no prior symptoms consistent with this. He had dramatic improvement in his clinical status and defervesced after treatment with intravenous immunoglobulin (IVIG, 2 g/kg) and methylprednisolone (2 mg/kg/day) given on day 10 of fever. However, his inflammatory markers remained elevated for a few days post-treatment but normalized within 7 days. Of note, his EBV PCR (158 copies/mL) was positive for the first time during this admission, peaking at 1500 copies/mL a month later and down trending, but still positive for months later. His EBV PCR was negative just 2 weeks prior to this admission. His last DLI prior to this episode was 2 weeks prior at CD3 + 1 × 107 cells/kg.

There is possibly an association between XIAP deficiency and a post-SARS-CoV-2 atypical inflammatory syndrome as demonstrated by this patient case and the two previously described cases with MIS-C [3]. However, what is interesting about this XIAP deficient case is that the post-SARS-CoV-2 atypical inflammatory syndrome occurred post-transplant. Prior studies have shown that XIAP-deficient patients have better long-term survival with reduced intensity conditioning transplants as opposed to myeloablative conditioning transplants [1], which is why a reduced-intensity regimen was used for our patient. However, reduced-intensity regimens are associated with reduced chimerism as demonstrated in our patient. We hypothesize that this reduced chimerism causes a persistent low level immune dysregulation that can become overactivated post-COVID infection. There is existing evidence that patients with XIAP deficiency have persistent immune dysregulation post-transplant. Ono et al. looked at 10 patients with XIAP deficiency who underwent stem cell transplant and 5 of which developed HLH post-transplant [1]. Interestingly, these patients did have high mixed chimerism unlike our patient, indicating that although we cannot rule out low chimerism as a risk factor for persistent immune dysregulation, high chimerism is still not enough to protect against recurrent HLH.

It is also interesting that the patient had activation of EBV when he was diagnosed with post-SARS-CoV-2 atypical inflammatory syndrome, and his EBV could also have been a contributing cofactor for this. There is evidenced by Gold et al. suggesting that COVID-19 can cause EBV reactivation and can contribute to the long-term effects of SARS-CoV-2 infection [4]. In our patient, we hypothesize that a combination of his low chimerism and SARS-CoV-2 infection made him susceptible to EBV activation, and our patient demonstrates that immunodeficient patients need to be closely monitored for EBV after SARS-CoV-2 infection. Another possibility is that the C. difficile colitis could have triggered an inflammatory response.

There is also the possibility that the patient had HLH triggered by EBV. The patient met 4/8 criteria for HLH including fever, anemia, thrombocytopenia, hypertriglyceridemia, and elevated ferritin; however, 5/8 are required for diagnosis. The patient’s impressive lymphadenopathy and normal liver enzymes pointed more towards MIS-C than HLH, and the patient’s rapid improvement with steroids and IVIG is also more favorable to MIS-C. Work-up for HLH would have been pursued if the patient did not clinically improve on therapy. MIS-C is however unusual for the patient’s age as MIS-C is more typical in older school age children, and our patient was only 27 months at diagnosis. However, there is a precedence in infants with immune dysregulation in Down syndrome having early-onset atypical inflammatory syndrome post-SARS-CoV-2 infection similar to MIS-C [2]. Therefore, it is possible that XIAP deficiency could also cause an early-onset post-SARS-CoV-2 atypical inflammatory syndrome, which luckily in our patient was not severe. Furthermore, there is published data of an association between the combination of human leukocyte antigen A*02, B*35, and C*04 alleles and MIS-C [5]. Phenoty** from the patient and donor is not consistent with this combination, though they both had A*02. Although the clinical observation of systemic inflammation in a patient of XIAP deficiency is interesting, there is no molecular and cellular level mechanistic evidence linking XIAP to the development of post-COVID multisystem inflammation as described in this and the previous report. Caution is needed in the interpretation of the case.

Another differential diagnosis for the patient’s symptoms is GVHD. Preceding the patient’s acute illness, he was receiving DLIs for his low chimerism, and the lymphocyte dose was recently increased. This could have precipitated acute GVHD that would have also been treated with the IVIG and steroids. There is also a paucity of data on whether COVID-19 infection can trigger GVHD, and we cannot rule out that the patient’s presentation was a combination of factors.

The patient is currently 3 years of age and has evidence of persistent immune dysregulation with an elevated IL-18 level of 2129 pg/mL (normal 89–540 pg/mL) and low XIAP expression at 2–19% (normal 89–100%). A second transplant will likely be needed, but the decision has made to defer for now.

Previously published studies have reported that MIS-C might occur in patients with defect in the innate immune system affecting the interferon pathway [3]. XIAP deficiency may put patients at risk for a post-SARS-CoV-2 atypical inflammatory syndrome due to the inborn error in innate immunity, and this case is concerning that transplant may not mitigate that risk. Additionally, COVID-19 might activate EBV infection in this vulnerable post-transplant population. COVID-19 vaccination and COVID-19 monoclonal antibody infusion if infected or as prophylaxis are important considerations in these patients.

In conclusion, we believe that this report highlights that there is a spectrum of inflammatory syndromes likely triggered by viral infections in hosts with an underlying inborn error of immunity. There are overlap** features between our patient and MIS-C triggered by SARS-CoV-2 and HLH triggered by EBV or other causes. However, this case highlights a unique atypical inflammatory syndrome not classic for either of these diagnoses. Recognizing atypical inflammatory syndromes in patients with inborn errors of immunity is important as we need more data on serum markers, diagnostic criteria, and treatment regimens for these patients.