Currently, the awareness level of physicians and healthcare professionals about PID, and their experience with a clinical approach to a patient with PID are still insufficient. For this reason, the history, features, and physical examination findings from patients, as well as expert opinions were combined, and the “10 Warning Signs of Primary Immunodeficiency Diseases”, which has significantly contributed to the diagnosis of PID, was defined by the JMF [9]. In our study, the JMF scores of PID and SID patients calculated via these warning signs were statistically significantly higher compared with the control group. In addition, we found that parental consanguinity and a family history of tuberculosis, chronic diarrhea may also be warning signs of PID.
Every patient with suspected PID should be asked in detail for information related to the “10 warning signs” checklist during history taking. It has been proposed that PID should be investigated when ≥ 2 warning signs are present [10]. In our study, the JMF scores of both the PID and SID groups were significantly higher than the control group. The cut-off for JMF score in terms of PID and SID was determined to be 1.5, with a sensitivity of 92% and specificity of 93.5%. According to our study results, we hypothesize that the JMF criteria are a guiding tool not only for PID patients but also for SID patients. In addition, in a study by Reda et al., at least one of the 10 warning signs was observed in all PID patients, whereas 28% of patients without PID had no warning sign [11]. In our study, all patients in the SID group had warning signs of immunodeficiency, whereas two of our patients in the PID group had no warning sign. The reason for these two patients with a JMF score of zero being investigated was a history of chronic diarrhea. Considering this, we propose that a history of chronic diarrhea should be included in the warning signs of PID. We attribute the presence of JMF warning signs in all patients in the SID group to the fact that that they all had a more severe course that required IV immunoglobulin therapy.
Training programs aimed at increasing awareness of PID should target physicians who may discover a family history of PID, parental consanguinity, and a family history of early sibling deaths in societies where consanguineous marriages are common [11]. In a study from Egypt by Reda et al., 60% of PID patients had consanguineous parents [11]. In our country, the rate of parental consanguinity in PID patients has been found to be 14.3–37.5% [4]. In our study, the rate of parental consanguinity in PID cases was 41.8%. This rate was significantly higher compared with the control and SID groups, and we propose that parental consanguinity may be a warning sign of autosomal recessive-inherited PID for our region. According to a study conducted by Subbarayan et al. [6], one of the strongest identifiers of PID was a family history of immunodeficiency. In general, such a family history is 18 times more common in children with PID, compared to those without any identifiable PID. In our study, we determined a family history was 16.78 times more common in the PID patients compared with the control group. We propose that screening for PID would be important in the presence of a family history of PID, even when it exists alone.
In the Subbarayan et al. study, the most common of the 10 warning signs was the need for IV antibiotics. The second most common warning sign was a family history of PID (34%), followed by failure to thrive (31%) [6]. Similarly, in the study by Reda et al., the most common warning sign was the need for IV antibiotics (92%). In our study, as in these two studies, the most common warning sign was the need for IV antibiotics (82.9%). The second most common warning sign was having ≥ 2 lower respiratory tract infections in one year (64.3%), and the third was being on oral antibiotics for longer than two months with little effect (45.9%). Our findings confirm that the 10 warning signs may be used for the diagnosis of PID, although in a different order of frequency, and that different frequencies may be reported in different studies.
Frequent infections, a more severe course than expected, long-lasting infections, the occurrence of unexpected or severe complications due to infections, incomplete recovery with antibiotic treatment, the need for prolonged use of antibiotics, chronic courses of infectious diseases, and the occurrence of infections with unusual agents may also be associated with PID diseases [12]. Infections usually recover rapidly and without complications in children with a healthy immune system and no other risk factors [13]. In our study, among the JMF warning signs, frequent recurrent upper respiratory tract infections were significant in the PID group, and frequent recurrent lower respiratory tract infections and failure to thrive were significant in the SID group. This may be due to the high rate of antibody deficiency, and the presence of accompanying conditions (tracheostomy, epilepsy) in our SID patients.
Comprehensive evaluation of family history and clinical features may be helpful for the early diagnosis of PID disease [14,15]. However, absence of a family history of immunodeficiency does not exclude the presence of PID. Since the majority of PID diseases are inherited, the presence of a similar disease, as well as the age and sex of affected individuals are important. In the study by Yorulmaz et al., 3.8% of PID patients were found to have a family member with PID [4]. This was higher in the PID and SID groups in our study, with rates of 25.5% and 6.3%, respectively. These higher rates in our study may be due to asking not only about siblings and parents but also about the siblings of the parents and their children. In our study, the rate in the PID group was significantly higher than both the control and SID groups. A patient with a history of frequent infections and a family history of PID should be evaluated for PID.
In a study conducted by Yorulmaz et al. in Konya, the rate of sibling death among patients with combined immunodeficiency (CID) was 7.5% [4]. However, in the Reda study from Egypt, 21.7% of the patients had sibling deaths. This 3-fold higher rate in Egypt may be related to a higher rate of consanguineous marriages and the level of community and economic development. The highest rate of sibling death was determined to be 50% in those with CID [11]. Rates of early death in the family history were also evaluated in our study. According to the results, 66 (67.3%) of PID cases, 38 (59.4%) of SID cases, and 11 (5.5%) in the control group had a family history of early death. In our study, the reason for the high rate of a family history of early death may be the inclusion of questions about siblings of the parents and their children. Therefore, we think that an extended family history of early sibling death may be an important warning sign for the diagnosis of immunodeficient patients.
Worldwide, the mean duration of diagnostic delay between the onset of symptoms and diagnosis in PID diseases is 4.08 years. The biggest factor in an 8–10-year delay in the diagnosis of PID diseases after the onset of symptoms was the low level of physician awareness of these diseases [9]. In our study, the mean duration of diagnostic delay for the PID and SID groups was 21 months, with no significant difference between the groups. Given that a delay in diagnosis can significantly increase morbidity and mortality, we may conclude that the index of suspicion for PID on the part of physicians in our region is similar to that in other centers.
In the literature, PID diseases have been reported to be more common in males than in females [6]. The predominance of males results not from PIDs inherited in an autosomal recessive manner, but from X-linked PIDs. In our study of PID patients, 49% were female and 51% were male, with no statistically significant difference. We consider that this result was due to the high rate of consanguineous marriages in our study.
Antibody deficiencies are the most common subtype of PID [16]; they were also the most common PID group in our study. This is consistent with the European Society for Immunodeficiencies and the JMF databases, and our results are consistent with previous study results. However, given that the incidence of allergic, autoimmune, and hematological diseases, as well as the incidence of malignancies are high among PID patients, the medical history should be scrutinized in this respect [17]. Studies suggest the need for some additional warning signs to facilitate early diagnosis in such patients [18,19]. In our study, the rates of a family history of allergy, rheumatic diseases, and malignancy in the PID and SID groups were significantly higher than in the control group. Patients with immunodeficiencies may present with infectious diseases, and also with immune dysregulation diseases and malignancies; we consider that these diseases should also be considered as warning signs of immunodeficiency.
In conclusion, early diagnosis of PID will allow effective treatment of these diseases. We agree that the 10 warning signs of PID diseases defined by the JMF are important for the early diagnosis of PID. From our study results, a family history of parental consanguinity or tuberculosis may also be warning signs of PID, and a history of chronic diarrhea should be included. Studies from different immunology centers may clarify these additions. This approach will allow early diagnosis of PID and, thus, early and effective treatment, which will allow patients to reach adulthood before the development of organ injury.