SCID is defined as a type of inborn error of immunity, which could be fatal if not diagnosed and treated in the first 2 years of life. It is the most severe disease among all IEIs, and HSCT is the only curative treatment option in most countries. When a patient receives HSCT within the first 3 months, the chance of success rises to 95% (1, 13). However, there are differences in SCID diagnostic criteria between different primary immunodeficiency societies (3, 20). In our 20-year follow-up, 49 (83%) of our 59 patients diagnosed with SCID according to the IUIS criteria and 18 (30.5%) according to the ESID criteria met the diagnostic criteria for definitive SCID and 20 (34%) for probable SCID. However, all of the patients, except one, presented with severe infection, and all those not receiving a transplant died before age 2 with severe infection, which means these cases were clinically consistent with SCID. Therefore, we believe that patients aged 2 or below presenting with severe clinical infection should be approached as SCID cases until the diagnosis of SCID is excluded. In our cohort, lymphocyte count was below 3000/mm³ in 56 (95%) of the SCID patients and in 5 (63%) of 8 CID patients according to the ESID criteria. Thus, it would be safety to accept lower threshold for lymphopenia as 3000/mm3 for children in the first two years of life in the countries with high ratio of consanguineous marriage, such as our country. If patients present with a severe infection under two years of age, even if the lymphocyte count is above 3000/mm3, they should be approached the cases as SCID until a definitive diagnosis. Thus, we suggest to use our algorithm to approach to the children under 2 years of age who presents with severe infections (Fig. 2).
In our study, the mean age at diagnosis was 5.99 ± 4.80 months, the median was 5.0 (0–24) months, and the mean delay in diagnosis was 3.3 months. In the study of Aluri et al. from India, the mean time to onset of symptoms was 2 months, and the mean age of diagnosis was 5 months (15). In another study conducted in China, the mean age at diagnosis was 7.10 ± 7.96 months and the mean age of onset of symptoms was 3.56 ± 3.91 months (16). Including of T-cell Receptor Excision Circle (TREC) test in newborn screening program in the USA, the patients were diagnosed at much earlier age like a month (earliest: 0 - latest: 304 days) (17). When we evaluated our cohort 10-year period, there was increase in patients’ numbers, however no significant difference was observed in the age at diagnosis. This suggests that the awareness of SCID is still not at desired levels in our country and the TREC test should be included among the newborn screening tests as soon as possible.
Consanguineous marriage ratio is high in our country and it causes increased frequency of OR-hereditary diseases. While the incidence of consanguineous marriage was 50% in the study of Metin et al, it was reported to be 76% by Ikinciogullari et al (13, 18). In our study, however, this rate was calculated as 90.9%. The most common SCID phenotype was T-B- (41–63%) in the studies from our country (12, 13, 18). Similar to these studies, we also found that the most common SCID phenotype was T-B- (55.9%). In the study by Fırtına et al., the most frequent detected mutations were RAG1/2 (29.1%), ADA enzyme deficiency (12.5%) and IL2RG mutation (12.5%) in patients with T-B- SCID, while JAK3 mutation (16.6%) in those with T-B + SCID(12). Metin et al., reported, the most frequent mutations in their series including 34 patients, were ADA deficiency (17.6%), RAG1/2 mutation (14.7%) and Artemis gene defect (14.7%) (18). Likewise, in the study of İkinciogulları et al., which included a larger cohort, RAG1/2(15.4%) and Artemis mutation (5.6%) were found to be the most common among T-B- SCID patients, while JAK3 mutation (6.8%) was the most common in T-B + SCID cases (13). In our study, genetic mutations were detected in 27 patients, and the most common genetic defects were ADA enzyme deficiency, RAG1/2 and Artemis deficiency in T-B-phenotype, and JAK3 deficiency was found most frequently in T-B + phenotype.
Recurrent or life-threatening infections is the most common reason for hospital admission in SCID cases. Infections due to both bacterial and viral agents and even opportunistic agents can be observed in these patients. Our patients were also admitted with recurrent infections including complaints of cough (29.05%), diarrhea (18.8%) and fever (18.8%). Patients with SCID may also present to hospitals with signs and symptoms other than infection. In a study conducted in Brazil, organomegaly was found in 34.4% of the patients, and growth retardation was found in 35.9% (19).In the study of Yao et al., 50% organomegaly and 38.64% growth retardation were found on physical examination at admission (16). Consistent with such studies, organomegaly, eczematous rash, oral moniliasis and tonsillar tissue hypoplasia were the most common findings at physical examination in our study. Growth retardation was other detected abnormal physical examination findings in the majority of our patients. For this reason, we think that SCID should be kept in mind in the patients younger than 2 years old with severe infection and growth retardation. In addition, when investigating the cause of organomegaly and eczematous rash in patients under 2 years of age, especially if lymphopenia is accompanied, SCID should definitely be taken into account.
The most common abnormal laboratory finding in SCID is lymphopenia, and some immunodeficiency foundation take into account the absolute lymphocyte count while others look at the absolute CD3 + T cell ratio as a diagnostic criterion for SCID. However, flow cytometric analysis may not be performed in every hospital, which shows to need multicenter studies to develop an algorithm including clinical and simple laboratory test to early diagnosis of these patients. In our study, lymphocyte count was found to be below 3000/mm³ in all, but three of 59 patients diagnosed with SCID according to ESID criteria. The mean lymphocyte count in all patients was 1489/mm3 (100–9200/mm3). While the mean lymphocyte count of the patients who were admitted under the age of one (n = 58) was 1505/mm3 (100–9200/mm3), it was 1378/mm3 (200–3400/mm3) in patients admitted between the ages of 1–2 (n = 9). For this reason, we believe that in countries with high ratio of consanguineous marriage, where increased frequency of AR inherited IEIs are common, we can minimize the number of patients going unnoticed by accepting the lymphocyte lower limit of 3000/mm3 until the age of 2.
Currently, HSCT stands out as the only curative therapy in most of SCID, and it should perform the earlier stage to achieve the higher the chance of success. Our cohort showed that out of 32 patients who could not undergo HSCT, all 26 patients with available data died, and 20 of 35 (60.6%) patients receiving transplantation survived. The mean survival time after HSCT was 38.46 ± 52.20 months, with a median of 12.00 (0-168) months. Bayram et al. reported that HSCT was performed in 61 of 72 their patients and that only 12 of them died, with an overall survival rate of 80.3% (14). In a cohort study conducted by İkinciogulları et al, the overall survival rate was 65.7%, similar to our findings, and this rate was found to be 54% for the first 10 years and 69% for the second 10 years (13).
In conclusion, SCID is a pediatric emergency and fatal unless the patients receive the curative treatment of HSCT within the first 2 years of life. Pleasing outcome could be obtained with early diagnosis and treatment. In countries with high ratio of consanguineous marriage, the TREC test should be included in newborn screening as soon as possible for early diagnosis and treatment of SCID. However, physicians should consider SCID in their diagnosis of young patients presenting with severe infection, oral moniliasis, eczematous rash and organomegaly, particularly those aged under 2 with a lymphocyte count below 3000/mm3, which will prevent many such cases go unnoticed and save lives.