Primary Immunodeficiency Disorders in Pediatric Intensive Care

doi:10.21203/rs.3.rs-4437591/v1

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Primary Immunodeficiency Disorders in Pediatric Intensive Care

https://doi.org/10.21203/rs.3.rs-4437591/v1

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Inborn errors of immunity (IEI) are a heterogeneous group of genetic diseases characterized by impaired immune system function. This prospective study aimed to determine the frequency, characteristics, and clinical course of IEI patients admitted to the pediatric intensive care unit (PICU) and identify mortality-related factors. Over three years, 33 out of 753 PICU patients were diagnosed with IEIs, with an incidence of 4.39%. The most common disorders were immunodeficiencies with immune dysregulation (48.5%), followed by combined immunodeficiencies (24.2%). Severe viral infections (61%) and life-threatening infections (51.7%) were the most frequent warning signs. Only 31% of patients exhibited at least two Jeffrey Modell Foundation warning signs. The mortality rate was 58%, highlighting the need for early diagnosis and treatment. Newborn screening and family segregation studies are crucial to improving outcomes for IEI patients in intensive care settings.

Inborn errors of immunity

PICU

immune dysregulation

combined immunodeficiencies

outcomes

In recent years, there has been an escalating acknowledgment of inborn errors of immunity (IEI) as a diverse group of diseases characterized by quantitative and/or qualitative impairments in one or more immune system components.[1] The International Union of Immunological Societies (IUIS) updated the classification of IEIs in 2022, which encompasses a total of 485 recognized disorders.[2] Individual IEIs are deemed rare when considered collectively but are more prevalent than previously assumed. The IUIS 2019 update estimated a combined prevalence of at least 1/1000-1/5000 for IEIs.[3, 4]

Diagnosing IEIs can pose a challenge as patients often present as outwardly usual, and the sole method to confirm the presence of an IEI is through the manifestation of clinical immunodeficiency and subsequent testing for these defects. In some instances, a diagnosis can be established before the onset of clinical symptoms, mainly when there is a familial history of the disease and family members undergo screening. Nonetheless, routine screening is indispensable to ascertain these disorders' true incidence and population prevalence. Healthcare professionals must be aware of the relative frequency of these disorders in the absence of routine screening, as prompt diagnosis and treatment are vital for enhancing outcomes. Case reports have demonstrated that life-threatening infections in childhood can be the initial presentation of IEI.[5] However, there is limited knowledge regarding the prevalence of genetic variants of IEIs in patients with sepsis, and guidance is absent on genetic or immunological investigations following the first episode of sepsis.

In the pediatric intensive care unit (PICU), routine investigations for the presence of IEIs are not commonly undertaken, and data on the rates of referral of these patients to PICU are scarce. A significant number of patients with IEIs receive a diagnosis once they are admitted to the intensive care unit, and many succumb without a diagnosis. Early diagnosis, prevention of complications, and appropriate treatment are paramount in reducing mortality and morbidity in patients with IEIs. To further investigate IEIs, there is a need for studies that delineate indications for diagnosis, regular education, and heightened awareness among pediatric intensive care specialists. This study aims to review the frequency, characteristics, and clinical course of patients with IEIs admitted to the pediatric intensive care unit and identify mortality-related factors.

A prospective study was conducted at the Pediatric Intensive Care Unit of Antalya Education and Research Hospital, including patients admitted between January 2020 and December 2022. Patients aged between 1 month and 18 years admitted to the pediatric intensive care unit due to infection-associated complications or severe inflammations (neurologic or systemic) were our study population. Patients with chronic diseases (neuromuscular, respiratory, or cardiac), trauma cases, post-surgical cases, poisonings (drugs, chemicals, scorpion stings, or snake bites), and patients previously diagnosed with IEI were not included in the study population.

The patients in the study population suspected of having IEIs based on their presenting complaints, medical history, physical examination, and laboratory results were evaluated. Patients at risk for IEI were further assessed and followed by a clinical immunologist. We examined 28 warning signs used for IEI diagnosis, including the 10 warning signs defined by the Jeffrey Modell Foundation (JMF) and additional warning signs described in the literature.[6–8]

Data encompassed age, gender, parental consanguinity, and indicative signs of IEIs in the medical history. Diagnoses were made by the European Society for Immunodeficiencies (ESID)[9] criteria, supplemented by laboratory test results and immunological and genetic findings. These diagnosed IEI patients were further categorized into subgroups based on IUIS classification.[2]

During the study period, there were 401 annual admissions in our PICU, and with the exclusion criteria, the study population averaged 251 patients per annum. Adhering to the ESID criteria, a definitive diagnosis of IEI was established for 33 patients. Among these, 17 (51.5%) had sepsis, 12 (36.4%) had acute respiratory failure, and 4 had neuroinflammatory disorders (Fig. 1a). The incidence of patients in this group under the care of a clinical immunologist and included in our study was 4.39%.

The selected 33 patients had an average age of 40.7 months. 72.2% were under 60 months old, and 57.5% were under 24 months old. Further, 20 (60.6%) were male, and 13 (39.4%) were female. Interestingly, 66.7% of the patients had a history of family kinship. A specific examination revealed that 48.5% of these instances were related to first-degree cousin marriages in parental unions (Fig. 1b-c).

From the 10 warning signs of primary immunodeficiency established by the Jeffrey Modell Foundation, it was determined that only 31% of patients presented with two or more warning signs. One-third of the cases did not exhibit any JMF warning signs. The most common accompanying warning signs were a history of severe viral infections (61%) and a history of life-threatening infections (51.7%). Sibling or cousin deaths were observed in 25% of the patients, and a history of more than two episodes of pneumonia per year was present in 22.5%.

Based on the diagnostic criteria set forth by the ESID and IUIS, 16 (48.5%) exhibited immunodeficiency with immune dysregulation, 8 (24.2%) had immunodeficiencies affecting cellular and humoral immunity, 2 (6.1%) presented with immunodeficiency with a predominant antibody deficiency, 5 (15.2%) had immunodeficiency with defects in innate immunity, 1 (3%) had immunodeficiency accompanied by autoinflammatory diseases, and 1 (3%) had immunodeficiency with bone marrow failure (Table 1 and Fig. 1d).

Table 1

Patient distribution according to IUIS classification
N (%)	Disease names	Gene	Homozygosity
1. Immunodeficiencies affecting cellular and humoral immunity	8 (%24.2)
	RAG Deficiency	RAG1, RAG2	Homozygote
	T- B- NK + SCID	None
	T- B + NK- SCID	None
	γc deficiency	IL2RG	Hemizygote
2. Predominantly antibody deficiencies	2 (%6.1)
	IgA Deficiency	None
	Transient Hypogammaglobulinemia	None
3. Immunodeficiencies with immune dysregulation	16 (%48.5)
	FHL2	PRF1	Homozygote
	FHL3	UNC13D	Homozygote
	Chediak Higashi Syndrome	LYST	Homozygote
	Griselli Syndrome	RAB27A	Homozygote
	IPEX Syndrome	FOXP3	Hemizygote
4. Defects in intrinsic and innate immunity	5 (%15.2)
	Acute necrotizing encephalopathy	RANBP2	Homozygote
	ISG15 Deficiency	ISG15	Homozygote
	RNA polymerase III deficiency	POLR3A	Heterozygote
	IFNAR2 deficiency	IFNAR2	Homozygote
	Herpes Encephalitis	IRF3	Heterozygote
5. Autoinflammatory disorders	1 (%3)
	SLC29A3 mutation	SLC29A3	Homozygote
6. Bone marrow failure	1 (%3)
	DKCB4 mutation	TERT	Homozygote

In the cohort of immunodeficiency disorders associated with immune dysregulation, sixteen previously healthy patients were diagnosed with hemophagocytic lymphohistiocytosis (HLH). HLH diagnosis was established in these patients based on meeting at least 5 out of 8 diagnostic criteria for HLH. All patients presented with fever, cytopenia, and elevated ferritin levels. Hemophagocytosis was observed in ten patients. Genetic analysis was performed for eight patients, revealing specific abnormalities: three patients had perforin 3 deficiency, one patient had UN13D deficiency, one patient was diagnosed with Chediak-Higashi syndrome, one patient presented with Griscelli syndrome, and one patient had an IFNAR2 gene mutation. Additionally, one patient was diagnosed with IPEX syndrome. Genetic analysis could not be conducted for eight patients.

In the cohort of patients presenting with severe combined immunodeficiency, a RAG1 mutation was identified in two individuals, a RAG2 mutation in one individual resulting in Omenn syndrome, and an IL2RG gene mutation in one individual resulting in γc deficiency. Among these patients, three exhibited T- B + NK + SCID phenotype, while one displayed T- B- NK + SCID phenotype.

In the subset of immunodeficiency disorders associated with defects in the innate immune system, one patient was diagnosed with Acute Necrotizing Encephalopathy (RANBP2 mutation), one with ISG15 deficiency (ISG15 mutation), one with RNA polymerase III deficiency (POL3RA mutation), and one with an IRF3 gene mutation; identified in a patient with herpes simplex encephalitis. Interestingly, a patient who developed HLH was diagnosed with IFNAR2 deficiency. Among patients with predominant antibody deficiency, two individuals were diagnosed with selective IgA deficiency and transient hypogammaglobulinemia of infancy.

Furthermore, an SLC29A3 gene mutation was identified in a patient presenting with an autoinflammatory disease subgroup. Conversely, a DKCB4 gene mutation was detected in a patient manifesting an immunodeficiency disorder accompanied by bone marrow failure (Fig. 1f).

Overall, 33 patients had a mean (standard deviation-SD) PRISM score of 8.3 (5.09), and the PRISM predictive death rate was 3.7%. Mechanical ventilation was required in 20 cases (64%), with a mean (SD) duration of 16.25 (14.9) days. Furthermore, inotropic support was required in 16 cases (51.6%), and 18 cases (58%) in the case group did not survive to discharge (Fig. 1e).

Recent advances in understanding the immune system and increasing awareness of IEI have highlighted that this group of diseases is not as rare as previously believed. While individual IEIs may be considered rare when examined in isolation, collectively, they present a significant health burden. When all subgroups are considered, it has been demonstrated that approximately 1% of the population may be affected by IEI. The exact prevalence remains to be discovered due to the absence of a national neonatal screening and registry program and insufficient data on patients with IEI.

In a study conducted by Galal et al. in 2019, the prevalence of IEI was reported to be approximately 1 in 10,000 in Australia, North America, and Europe.[10] In 2007, Boyle and Buckley conducted a study in the United States where they randomly called 10,000 households and screened approximately 27,000 individuals. They identified individuals with a diagnosis of IEI and reported a prevalence of 1 in 2,000 in the pediatric population and 1 in 1,200 in the general population [4]. A study conducted by the JMF in 2018 found that the number of patients with IEI under follow-up increased by 35.4%, and the number of newly diagnosed patients with IEI increased by 21.8% worldwide compared to 2013. [11]

According to the IUIS 2019 Update, IEIs affect approximately 1 in 10,000 to 1 in 50,000 births. Still, with the discovery of new primary immunodeficiency disorders, it is more likely that the community prevalence is at least 1 in 1,000 to 1 in 5,000. [12] Recently, in a study investigating community-acquired sepsis cases due to bacterial pathogens using whole-exome sequencing (WES), 35 variants potentially causing IEI were identified among 176 patients.[13] Ödek et al. found that 3.7% of patients admitted to the PICU were patients with IEI who required PICU care based on a 10-year study of 51 IEI patients in the Pediatric Allergy and Immunology clinic.[14]

In a multicenter study in western France, Flatrès et al. investigated children with severe bacterial infections admitted to intensive care units and identified primary immunodeficiencies in 12% of the studied population.[15] This high rate may be attributed to the selective inclusion of patients from specific clinics rather than a comprehensive analysis of all patients, potentially leading to overestimating the prevalence of primary immunodeficiencies in the general population with severe bacterial infections.

There is limited data on the frequency of IEI patients admitted to the PICU in the literature, and no studies specifically address the frequency of patients receiving their initial diagnosis during PICU admission. We aimed to find an answer to the question, "Are patients with Inborn Errors of Immunity in pediatric intensive care units not being diagnosed, and are many of them losing their lives without a diagnosis?" In our study, the frequency of patients with a definitive diagnosis of IEI whom a clinical immunology specialist followed was determined to be 4.3% during the study period. This frequency information has yet to be reported previously. A study conducted in Europe involving 2,212 patients demonstrated that symptoms of the disease appeared before the age of 10 in 34% of the patients. Severe IEI diseases, such as severe combined immunodeficiency and Omenn syndrome, tend to manifest in early life, leading to more frequent admissions to the pediatric intensive care unit and lower survival rates for patients under 6 months of age. [16] In our study, the case group had an average age of 40.7 months. It was observed that 72.2% of the case group were under 60 months old, and 57.5% were under 24 months old. Considering IEI in patients under 60 months of age who present with severe clinical manifestations and do not have any other known underlying diseases is essential for timely diagnosis.

In our study, 66.7% of patients diagnosed with IEI had a history of consanguinity between parents. Consanguinity primarily consisted of first-degree cousin marriages, representing 48.5% of cases. According to 2022 data from official sources in our country, the prevalence of first-cousin marriages is 8.3%, while the incidence is reported as 5.2%.[17] The documentation of consanguinity should always be included in the medical history of patients admitted to the pediatric intensive care unit, as it serves as a suggestive sign for IEIs, among many other genetic diseases.

When considering the frequency of IEIs in pediatric intensive care units according to the IUIS classification, disorders associated with immunodeficiency with immune dysregulation were the most common, followed by severe combined immunodeficiencies. This finding is remarkable, as primary immune dysregulatory disorders are high in our region.[8][18][19] New diagnostic algorithms are required for IEIs presenting with immune dysregulation. Remarkably, the frequency of severe combined immunodeficiency highlights the necessity of newborn screening for Immunodeficiencies affecting cellular and humoral immunity.

A noteworthy finding in our study was the high frequency of HLH cases among patients without any pre-existing medical conditions, suggesting a non-secondary etiology. Elevated serum ferritin levels were present in all patients diagnosed with HLH. This result emphasizes the need for a heightened index of suspicion for HLH among pediatric intensive care patients. Serum ferritin levels could serve as a useful screening tool in this setting. Increased vigilance is warranted to identify HLH cases, particularly in previously healthy children presenting with unexplained cytopenias and fever. Early recognition and prompt diagnostic workup are crucial, as HLH can rapidly progress to a life-threatening condition if left untreated.

We did not identify any patients with congenital phagocyte number or function defects. This absence may be due to the tendency of these IEIs to exhibit clinical symptoms before reaching acute life-threatening stages, thus allowing for diagnosis before intensive care unit admission.

In our study, another notable subgroup comprised immunodeficiencies characterized by defects in innate immunity, accounting for 15.2% of our patient cohort. These conditions are typically rare, with limited case reports and newly identified genetic mutations. Within our patient population, mutations in the RANBP2, ISG15, POL3RA, IRF3, and IFNAR2 genes were identified. Identifying these rare diseases within our pediatric intensive care unit is noteworthy, as they are still being elucidated with limited case reports and newly discovered genetic mutations. Such disorders often follow autosomal recessive inheritance patterns and are more prevalent in populations with a high rate of consanguineous marriages. Therefore, increased awareness and more thorough investigations of patients with suspected primary immunodeficiency disorders will increase the number of studies on these rare diseases.

We found that the most common accompanying warning signs in patients diagnosed with IEIs were a history of severe viral infections (61%) and life-threatening infections (51.7%). The high frequency of severe viral infections and sepsis history among patients with IEIs is noteworthy, as it underlines the fact that pneumonia and sepsis are the predominant reasons for admission to the intensive care unit, emphasizing the significance of viral infections in this demographic.

When evaluating the presence of the 10 warning signs defined by the JMF, it was determined that only 9 patients (31%) had two or more warning signs, while one-third did not exhibit any of the JMF warning signs. Therefore, the JMF 10 warning signs may be inadequate in the intensive care setting, and the recognition of inborn errors of immunity could be enhanced by considering additional indicators such as severe viral infections and elevated ferritin levels. These findings should be regarded as additional warning signs for physicians in the intensive care setting.

Studies related to primary immunodeficiency patients followed in pediatric intensive care units are limited, resulting in limited data on mortality rates. In one study, it was reported that 23% of patients with inborn errors of immunity followed in the pediatric intensive care unit died due to sepsis and septic shock. [5] In our study, the case group had a mean (SD) PRISM score of 8.3 (5.09), and the PRISM predictive death rate was 3.7%. However, 18 cases (58%) in the case group did not survive to discharge. Among these patients, mechanical ventilation was required in 20 cases (64%) in the intensive care setting, with a mean (SD) duration of 16.25 (14.9) days. Furthermore, inotropic support was required in 16 cases (51.6%). Although the high mortality rate can be attributed to the severity of the HLH patients, who constituted most of the cases, it emphasizes the importance of early diagnosis.

As a point of limitation, we could not perform genetic analysis in all suspicious cases due to time constraints preventing thorough investigation. However, our study will contribute positively to the literature by revealing the frequency of IEI with genetic and immunologic subtypes and providing mortality data in the pediatric intensive care unit population.

In conclusion, being the first to assess the prevalence of newly diagnosed IEI in PICU, our findings reveal variations in the frequency of specific IEI subgroups between patients followed in clinics and those admitted to the PICU. These results provide valuable insights into the frequency of occurrence and clinical presentations of IEI in critically ill children.

Considering the suspicion of primary immunodeficiency in PICU patients presenting with sepsis and pneumonia is crucial. However, given the limitations in early diagnosis opportunities, mortality rates remain high for these patients in intensive care settings. Therefore, implementing newborn screening programs and conducting family segregation studies should be considered routine approaches for early diagnosis, which can be life-saving by enabling patients to receive a diagnosis before requiring pediatric intensive care.

Acknowledgments

Disclosure of Conflicts of Interests

No conflict of interest exists.

Author Contributions

F.C., A.O., and S.C. performed the experiments and analyses. F.C., A.O., E.O., H.S.K., and S.A. provided clinical patient care, clinical data, and patient materials. F.C. wrote the manuscript. F.C., A.A., and S.B. conceptualized and coordinated the study and provided laboratory resources. All authors critically reviewed the manuscript and agreed to its publication.

Funding

This work was partially supported by a grant from the Marmara University Scientific Research Project Coordination Unit (ADT-2022-10661) to S.B.

Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics approval

This study was performed in accordance with the principles of the Declaration of Helsinki. The local Ethics Committee of the University of Medical Science (11.08.2022.15/8)

Consent to participate.

Informed consent was obtained from all individual participants included in the study.

Consent for publication.

The manuscript does not contain any person's data.

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No competing interests reported.

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Primary Immunodeficiency Disorders in Pediatric Intensive Care

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