Demographic Profile
Twenty patients with confirmed diagnosis of SCID were included for data analysis, of which sixteen were typical SCID, three were leaky-SCID, and one was Omenn Syndrome. A higher number of diagnoses were observed in 2020-2021; n=7, coinciding with the period of NUPAD-UFMG pilot NBS program for SCID.
The male to female ratio found was 4:1. The children were separated into two groups: early and late diagnosis. Only seven patients were diagnosed early, at birth. Of these seven, six were referred to the service from the NBS for SCID, and one due to a family history, all of them had the opportunity to curative treatment with HSCT. Thirteen children were diagnosed late by clinical presentation, five had severe infections at diagnosis and died within a few months, one lost the follow-up, one died while awaiting HSCT, and the other six were transplanted. The overall median age at diagnosis was 164 days (IQR: 47-233), with the oldest age being 633 days in a child diagnosed as leaky-SCID(P11), and the youngest age was 18 days in a patient from NBS. The median age at diagnosis in the group of early diagnosis patients was 41 days (IQR: 28-47; ranging from 18 to 50 days), contrasting with the median age of those patients diagnosed later, by clinical history, of 190 days (IQR: 175-349; ranging from 125 to 633 days) (p < 0.001). (Table 1) (Figure 1)
Consanguinity was present in more than half of the families where this data was available (8 out of 15 patients). History of early deaths in the family was found in 9 of 18 patients (50%), with only one family (P2) having been advised with genetic and immunological counseling (Table 2).
Vaccination
All patients received the Bacillus calmette-guérin (BCG) vaccine at birth, except for patient P2. Eighteen out of the twenty patients had records in their medical files regarding the presence or absence of alterations secondary to vaccination. Eight of these eighteen patients (44.4%) experienced some type of complication related to the BCG vaccine, with 5 (62.5%) having a loco-regional reaction (BCGitis) and 3 (37.5%) with disseminated disease (BCGosis). The six patients from the NBS started prophylaxis with Rifampicin and Isoniazid upon diagnosis, and only one (0,17%) patient presented a loco-regional reaction, treated with a quadruple regimen (Rifampicin, Isoniazid, Ethambutol, and Clarithromycin), without complications. Patients with later diagnosis had also received other live agent vaccines such as rotavirus and yellow fever, according to the vaccination schedule established by the Brazilian National Immunization Program. One patient (P14) had a severe encephalitis from Yellow Fever after this vaccination.
Laboratory, Phenotypic, and Genotypic Profile
Fifteen out of nineteen patients (78%) presented severe absolute lymphopenia in the blood count with lymphocytes < 2,500 cells/μL of blood at the time of diagnosis. One patient did not have a record of the absolute lymphocyte. Five patients had lymphocytes > 2,500 cells/μL, due to B or NK lymphocytosis or clonal expansion. (Table 2). Six out of nineteen patients (31.5%) presented hypogammaglobulinemia associated with lymphopenia at diagnosis, and one patient did not have a record of the immunoglobulin G (IgG) value. Out of the 9 patients who underwent TREC dosage, 8 had undetectable values, and one patient presented a result of 2.3 copies/μL of peripheral blood (normal range >25 copies/ μL).
The most prevalent phenotype was T-B+NK+ with 7 patients (35%), followed by T-BlowNK+ with 4 patients (20%), T-B+NK- with 3 patients (15%), T-B-NK+ with 2 patients (10%), and T-BlowNK- with 1 patient (5%). In three patients (15%), B lymphocytes and NK cells counts were not performed due to unavailability in the service and because of the severity of the condition at diagnosis.
Genetic analysis through next-generation sequencing revealed mutations in hemizygous in the IL2RG gene (4 patients), in homozygous in RAG1 (2), CD3δ (2), IL7R (1), in compound heterozygous ADA (1) and PNP (1). Three patients showed mutations in simple heterozygous (JAK3 (1), LIG4 (1), RMRP (1)) there do not explain the disease. One patient did not present a mutation in the genetic panel of 17 genes for SCID available at the service (IL2RG, JAK3, ORAI1, GATA2, RAG1, RAG2, LCK, ADA, PNP, CD3D, CD3G, CD3Z, CD3E, IL7R, LIG4, DCLRE1C, NHEJ1) and 5 patients were not submitted to genetic analysis due the unavailability of the test (Table 2).
Clinical Characterization of Patients and Final Outcome
The patients were divided into 2 groups: those with early diagnosis, at birth, and those with late diagnosis, from clinical presentation, to assess the impact of early diagnosis on the outcome of the disease. The age at diagnosis was also considered to evaluate whether the infection status before HSCT at different ages would have a direct impact on the survival of these patients after HSCT. After the diagnostic confirmation with lymphocyte immunophenotyping, antimicrobial prophylaxes were started according to the Latin American Consensus on the management of patients with SCID of 2019 (42).
Out of the seven patients diagnosed at birth, only 1 (P16) had been hospitalized before diagnostic confirmation, at 30 days of life, due to difficult-to-treat acute otitis media, requiring intravenous antibiotic therapy. During follow-up, even with the use of appropriate prophylaxes, 5 of 7 patients (71.4%) were admitted to the ward to treat infectious events (Table 3), requiring parenteral antibiotic therapy, without serious complications. Five out of the seven also presented confirmed infection by RT-PCR for COVID-19 with mild symptoms. Patient 18 developed drug-induced hepatitis at 7 months, it was not possible to return to antimicrobial prophylaxes after repeated attempts, opting for rigorous observation and maintained prophylaxis only with intravenous human immunoglobulin until HSCT was performed (Table 3).
All patients in this group underwent curative treatment with HSCT. The median age of patients at HSCT was 380 days (IQR: 251-571; ranging from 185 to 623 days) and the median time between diagnosis and transplantation was 330 days (IQR: 226-524; ranging from 167 to 582 days) (Table 6). The earliest HSCT was performed at 6 months of life (185 days) and the latest at 1 year and 8 months (623 days). One patient (P19) had failure to thrive since birth and had been hospitalized on two occasions previously (Table 3). This patient underwent HSCT at 9 months, but succumbed to complications in the immediate post-HSCT period. As the patient underwent HSCT in another service, it was not possible to access details of the clinical evolution. Patient P15 underwent HSCT at 11 months of life (348 days), after treatment of acute CMV gastroenteritis and was successful in the procedure. However, a year after the transplant, he presented an acute respiratory infection, without a defined agent, evolving with respiratory failure and death at 1 year and 11 months. Therefore, in this group of patients with early diagnosis, 5 out of 7 patients (71.4%) were successful in HSCT and are alive and well, all with more than 3 years of follow-up (Table 3). Although no patient underwent transplantation before 3.5 months of life, it was observed that the 2 patients who did not present infectious episodes before the procedure are alive with more than 3 years of age. Among the 5 patients who had infectious episodes before HSCT, only three survived (60%). (Table 3)
Thirteen out of the twenty patients studied (65%) were diagnosed later, due to clinical presentation. Of these thirteen, six (46%) presented with severe infection at diagnosis, requiring admission to an intensive care unit (ICU) and leading to death during the first hospitalization (Table 4). The remaining eight of the thirteen patients diagnosed late received their diagnosis during the investigation of not immediately fatal infectious conditions. Of these eight, one patient (P4) died during a second severe infectious episode and. another patient (P7) discontinued follow-up at the service after diagnosis, making it impossible to access the outcome data. The other six patients in this group underwent HSCT (P2, P6, P8, P11, P12, P13). Of this six, two died after the procedure and four (66%) are alive at the last evaluation, with a median follow-up time of 9 years (ranging from 7 years and 6 months to 16 years) (Table 5).
The median age of patients at HSCT was 539 days (IQR: 400-1022; ranging from 328 to 3294 days), with no significant difference from the early diagnosis group (380 days; p = 0.234). (Table 6). The earliest HSCT was performed at 12 months of life (335 days), and the latest at 9 years (2851 days) (Table 5). The median time between diagnosis and the transplant was 322.5 days (IQR: 225-426; ranging from 96 to 2851 days), similar to the median found in the early diagnosis group (330 days; p=0.731) (Table 6).
Clinical Outcome
The percentage of survivors of the study population was 47.3% (9 out of 19 patients, excluding one patient who was lost to follow-up), with a median follow-up time of 7 years (ranging from 3 to 15 years). As no patient in this cohort underwent HSCT before 3.5 months of age to assess the direct impact of early transplantation on survival, we evaluated the impact of early diagnosis (at birth or by positive family history) on survival.
The 2-years overall survival (OS) of this population was 45.3% (95% CI 22.3-68.2%) (Figure 2a). Comparing the 2-year OS between the early diagnosis group at 71.4% (95% CI 37.8-100%) and the late diagnosis group at 29.2% (95% CI 1.9-56.4%), we found a trend towards a statistically significant difference between the two groups (p=0.053), showing that early diagnosis can directly impact the survival of patients with SCID (Figure 2b).
The percentage of survivors within patients who had the opportunity to undergo HSCT was 69.2% (9 out of 13 patients). Comparing the 2-year OS of these patients, we observed very similar rates between the two groups, 71.4% (95% CI 37.8-100%) for patients in the early diagnosis group vs. 60% (95% CI 17-100%) for patients in the late diagnosis group (p=0.774), suggesting that early diagnosis alone may not directly impact survival after HSCT (Figure 2c).
Evaluating the influence of previous infections before HSCT on clinical outcome, we observed a great difference in the percentage of survivors between patients who underwent transplantation without prior infection and those who underwent transplantation after experiencing infectious conditions. In patients who did not present an infection before HSCT, we found a survival percentage of 100% (2 out of 2 patients), while in those who had an infectious episode before HSCT, we found a survival percentage of 60% in the early diagnosis group and 66.6% in the late diagnosis group. However, a statistical comparison was not possible due to the small number in each group and because the late diagnosis without any infection group had no representatives.