Abramova NN, Avrusin IS, Kozlova OP, Firsova LA, Kuleshova AG, Kondratiev GV, Ivanov DO, Aleksandrovich YS, Kostik MM. Predictors of lethal outcome in patients with immunoinflammatory diseases hospitalized in the intensive care unit. World J Crit Care Med 2025; 14(3): 101890 [DOI: 10.5492/wjccm.v14.i3.101890]
Corresponding Author of This Article
Mikhail M Kostik, MD, PhD, Professor, Department of Hospital Pediatrics, Saint Petersburg State Pediatric Medical University, 2 Lytovskaya Street, Saint-Petersburg 194100, Russia, kost-mikhail@yandex.ru
Research Domain of This Article
Rheumatology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Natalia N Abramova, Yury S Aleksandrovich, Department of Anesthesiology, Resuscitation and Emergency Pediatrics, Saint Petersburg State Pediatric Medical University, Saint Petersburg 194100, Russia
Ilia S Avrusin, Anastasia G Kuleshova, Mikhail M Kostik, Department of Hospital Pediatrics, Saint Petersburg State Pediatric Medical University, Saint Petersburg 194100, Russia
Olga P Kozlova, Department of Clinical Mycology, Allergology, and Immunology, North-Western State Medical University Named after I.I. Mechnikov, Saint Petersburg 191015, Russia
Liudmila A Firsova, Department of Propaedeutics of Childhood Diseases, Saint Petersburg State Pediatric Medical University, Saint Petersburg 194100, Russia
Gleb V Kondratiev, Department of Oncology, Pediatric Oncology and Radiation Therapy, Saint Petersburg State Pediatric Medical University, Saint Petersburg 194100, Russia
Dmitry O Ivanov, Department of Neonatology, Saint Petersburg State Pediatric Medical University, Saint Petersburg 194100, Russia
Co-first authors: Natalia N Abramova and Ilia S Avrusin.
Author contributions: Abramova NN, Avrusin IS, and Kostik MM contributed to the conceptualization, writing, reviewing, and editing; Abramova NN and Avrusin IS contributed equally to this article as co-first authors of this manuscript; Ivanov DO, Aleksandrovich Yu S, and Kostik MM contributed to the methodology; Firsova LA and Kuleshova AG contributed to the software, resources, and data curation; Kondratiev GV, Firsova LA, and Kuleshova AG contributed to the validation; Avrusin IS and Kostik MM contributed to the formal analysis; Abramova NN and Kozlova OP contributed to the investigation and visualization; Avrusin IS, Aleksandrovich YS, and Kostik MM contributed to writing the first draft, funding, supervision, and project administration; All authors read and agreed to the published version of the manuscript.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Saint Petersburg State Pediatric Medical University, approval No. 03/09 22 March 2021.
Informed consent statement: Informed consent was obtained from all subjects involved in the study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mikhail M Kostik, MD, PhD, Professor, Department of Hospital Pediatrics, Saint Petersburg State Pediatric Medical University, 2 Lytovskaya Street, Saint-Petersburg 194100, Russia, kost-mikhail@yandex.ru
Received: September 30, 2024 Revised: January 20, 2025 Accepted: February 6, 2025 Published online: September 9, 2025 Processing time: 291 Days and 20.2 Hours
Abstract
BACKGROUND
Systemic immunoinflammatory diseases can affect multiple systems and organs. They have a severe course and severe complications, causing multiple organ failure and death. Quite often these patients are required to be hospitalized in the intensive care unit (ICU). Approximately 50% of patients with multisystem inflammatory syndrome associated with coronavirus disease 2019 in children and systemic lupus erythematosus need admission to the ICU.
AIM
To find early predictors of death in patients with immunoinflammatory diseases who are hospitalized in the ICU.
METHODS
The retrospective continuous cohort study included 51 patients (23 males, 28 females) with immunoinflammatory diseases, including multisystem inflammatory syndrome associated with coronavirus disease 2019 (n = 18), systemic rheumatic diseases (n = 24), and generalized infections (n = 9). The patients ranged in age from 7 months to 17 years old and were admitted to the ICU of the clinic of Saint Petersburg State Pediatric Medical University from 2007 to 2023.
RESULTS
Thirteen patients (25.5%) died within 39 (17; 62) days after ICU admission. Patients with an unfavorable outcome were significantly older and were admitted to the ICU later than patients who survived (30 days vs 7 days, P = 0.013) and had a longer stay in the ICU (30 days vs 6 days, P = 0.003). The main predictors of the fatal outcome were age > 162 months [odds ratio (OR) = 10.7; 95% confidence interval (CI): 2.4-47.2], P = 0.0006], time to ICU admission > 26 days from the disease onset (OR = 12.0; 95%CI: 2.6-55.3, P = 0.008), preceding immune suppression treatment (OR = 6.2; 95%CI: 1.6-24.0, P = 0.013), invasive mycosis during the ICU stay (OR = 18.8; 95%CI: 1.9-184.1, P = 0.0005), systemic rheumatic diseases (OR = 7.2; 95%CI: 1.7-31.1, P = 0.004), and ICU stay over 15 days (OR = 19.1; 95%CI: 4.0-91.8, P = 0.00003). Multiple regression analysis (r2 = 0.422, P < 0.000002) identified two predictors of the fatal outcomes: Systemic rheumatic diseases (P = 0.015) and ICU stay over 15 days (P = 0.00002).
CONCLUSION
Identifying patients at high risk of an unfavorable outcome is the subject of the most careful monitoring and appropriate treatment program. Avoiding ICU stays for patients with systemic rheumatic diseases, close monitoring, and preventing invasive mycosis might improve the outcome in children with systemic immune-mediated diseases.
Core Tip: Systemic immunoinflammatory diseases are characterized by the simultaneous involvement of different organs and systems with a high risk of a fatal outcome. These patients are often required to be admitted to the intensive care unit (ICU). Early predictors of fatal outcomes after ICU admission may be modifiable to improve the outcomes. Older age, longer time before ICU admission, longer stay in the ICU, preceding immune suppression therapy, and development of invasive mycosis are predictors of unfavorable outcomes. Preventive measures should be set up to decrease the lethality in such patients.
Citation: Abramova NN, Avrusin IS, Kozlova OP, Firsova LA, Kuleshova AG, Kondratiev GV, Ivanov DO, Aleksandrovich YS, Kostik MM. Predictors of lethal outcome in patients with immunoinflammatory diseases hospitalized in the intensive care unit. World J Crit Care Med 2025; 14(3): 101890
Systemic immunoinflammatory diseases have severe courses and severe complications. They involve multiple organs and systems with possible multiple organ failure and death. Quite often these diseases can require hospitalization in the intensive care unit (ICU). Nearly half of the children with multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) (MIS-C) need ICU admission[1-4]. Mortality rates for MIS-C are around 1.5%-2.5% according to the data of different studies[5-9]. Among systemic rheumatic diseases (SRD), the most common causes of ICU admission belong to systemic lupus erythematosus (SLE) (48%), systemic vasculitis (16%), juvenile dermatomyositis (11%), and juvenile idiopathic arthritis (JIA) (8%)[10]. According to another study, SLE was the main reason for ICU admission in 62% of patients with rheumatic disease with a mortality rate of 15%[11]. Beil et al[12] observed that 25% of all patients with rheumatic disease admitted to the ICU were diagnosed with SLE (26.8%) and vasculitis (25.4%), with a mortality of 16.2% and 28.6%, respectively.
In a large retrospective cohort study by Chang et al[13], patients with SLE required ICU admission in 28% of cases. There are some ethnic differences in the course of SLE. Thus, Black children with SLE had a greater risk for ICU admission than non-Hispanic White patients[13]. In the study of Son et al[14], 10.4% of patients with SLE needed ICU admission, with in-hospital mortality of only 0.4%.
The generalized course of infectious diseases often requires hospitalization in the ICU. Sepsis remains a major cause of death while in intensive care, with a mortality of at least 38%[15]. Several epidemiological studies documented the gram-negative bacteria supremacy among ICU infection etiologies. Specifically, Klebsiella species are predominate, with Klebsiella pneumoniae being the most prolific. Furthermore, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii could similarly and severely impact ICUs. Among gram-positive bacteria, Staphylococcus aureus and Enterococcus species prevail[16-18]. Current data do not show a significant difference in in-hospital mortality between patients with and without bacteremia (25.6% vs 21.0%, P = 0.08)[19].
The majority of the studies have focused on specific diseases and infections, but simple indicators have not been evaluated in children with immunoinflammatory diseases before. To date, there are no established indicators for the course and prognosis of the disease in patients with immunoinflammatory disorders who require intensive care. This necessitates further investigation to find predictors of lethal outcomes in patients with immunoinflammatory diseases who have been hospitalized in the ICU.
MATERIALS AND METHODS
Data sources and recruitment
The retrospective continuous cohort study included the data of 51 patients (23 males, 28 females) with systemic immunoinflammatory diseases including MIS-C (n = 18), systemic JIA (n = 5), SLE (n = 6), systemic vasculitis (n = 13), and systemic infections (n = 9). Patients range in age from 7 months up to 17 years old and were admitted to the ICU of the clinic of Saint Petersburg State Pediatric Medical University in the period from 2007 to 2023. Inclusion criteria included: (1) Patients with systemic immunoinflammatory diseases; (2) Age under 18 years; and (3) ICU admission. Exclusion criteria included: Patients with non-inflammatory diseases (e.g., diabetes and other endocrinopathies); accident trauma; or malignancy.
Data collection
In every patient, we evaluated the following data: (1) Demography: Date of birth, date of disease onset, date of ICU admission, date of death, gender, and diagnosis; (2) Outcomes: Death or recovery, time between ICU admission and death, development of invasive mycosis, and presence of hemophagocytosis; and (3) Treatment: Corticosteroid and biological treatment and intravenous immunoglobulin (IVIG).
Study design and measurements
This study was a retrospective continuous cohort study design. All patients for subsequent analysis were divided into the three nosological groups: MIS-C; SRDs (systemic JIA, SLE, and systemic vasculitis); and generalized infections. All patients were divided into two groups: Dead and recovered. The term intensive immune suppressive treatment (IST) means a high dose of corticosteroid treatment [e.g., corticosteroid treatment of prednisolone (1 mg/kg/day) at least 2 weeks with or without preceding pulse-therapy with methylprednisolone (at least 10 mg/kg) at least 3 days with or without biologic treatment with or without cyclophosphamide].
Statistical analysis
The analysis of the obtained data was performed using the STATISTICA software package, version 10.0 (StatSoft Inc., St. Tulsa, OK, United States). All continuous variables were checked by the Kolmogorov–Smirnov test, with no normal distribution identified. Quantitative indicators were described using the median (25th and 75th percentiles). Comparisons of qualitative indicators were made using the Pearson criterion χ2. Comparisons of quantitative indicators were made using the Mann-Whitney criterion. Sensitivity and specificity analyses were used to assess the ability of each feature to distinguish patients with dichotomous characteristics. For quantitative variables, critical values were calculated using area under the receiver operating curves with 95% confidence intervals, and odds ratio were calculated using a 2 × 2 table without taking into account the time of the event of interest. Sensitivity and specificity were assessed for each of the studied parameters.
Independent predictors of death as the event of interest were identified using binary logistic regression by including quantitative and qualitative indicators related to the dependent variable in the analysis. A prognostic model for the risk of a certain outcome was constructed using multivariate logistic regression. The independent variables were selected using stepwise direct selection with the Wald statistic as an exclusion criterion. All significant predictors were included in the following multiple regression analysis, excluding the duplicated factors, to avoid multicollinearity. The multicollinearity was assessed with correlation analysis and clinically meaningful overlapping. The statistical significance of the resulting model was determined using the χ2 test. Differences or connections were considered statistically significant at P < 0.05.
RESULTS
Demographic characteristics of patients with systemic immunoinflammatory diseases
The study included 51 patients hospitalized in the ICU with various immunoinflammatory diseases. The number of females (n = 28, 54.9%) was slightly higher than the number of males (n = 23, 45.1%). The median age of patients was 121 (60; 182) months. The study group included: MIS-C in children (18 patients; 35.3%); SRDs (24 patients; 47.1%); and generalized infections (9 patients; 17.6). The group of SRDs consisted of SLE (n = 8), systemic vasculitis (n = 12), and systemic JIA (n = 4). The median time between the onset of the disease and admission to ICU was 10.0 (6.0; 30.0) days with a range of 2-720 days. The data are presented in Table 1.
Table 1 Demographic characteristics, treatments, and outcomes of patients with immunoinflammatory diseases hospitalized in the intensive care unit.
Parameter
n = 51
Demographics
Sex, males
23 (45.1)
Age, months, median (25%; 75%)
121 (60; 182)
Disease groups
MIS-C
18 (35.3)
Systemic rheumatic diseases
24 (47.1)
Infections
9 (17.6)
Time to ICU admission from the diagnosis of the disease, days, median (25%; 75%)
10.0 (6.0; 30.0)
Treatment
Preceding IST
14 (27.5)
IST started in ICU
29 (56.9)
Follow-up IST in ICU
43 (84.3)
Outcomes
Duration of stay in ICU, days, median (25%; 75%)
6.0 (4.0; 17.0)
Total hospital staying, days, median (25%; 75%)
24.0 (16.0; 44.0)
Lethal outcome
13 (25.5)
Days before death, median (25%; 75%)
39 (17; 62)
There were no significant differences in sex distribution between the studied subgroups, but fewer males were observed in patients with SRDs. Patients with generalized infectious diseases were much younger than patients with MIS-C and SRDs with a median age of 41 (19; 60) months, 106 (64; 137) months, and 175 (115; 193) months, respectively (P = 0.001). The shortest time since hospital admission to ICU hospitalization in patients with MIS-C was 6 (4; 10) days, followed by the patients with generalized infectious diseases at took 7 (7; 8) days and patients with SRDs at 30 (3; 28) days (P = 0.00001). The data are presented in Table 2.
Table 2 The features, treatment, and outcomes of the patients with different immune-mediated diseases admitted to the intensive care unit.
Parameter
MIS-C (n = 18)
SRD (n = 24)
Infections (n = 9)
P value
Demography
Sex, males
11 (61.1)
8 (33.3)
4 (44.4)
0.201
Age, months, median (25%; 75%)
106 (64; 137)
175 (115; 193)
41 (19; 60)
0.001
Time from the hospital to ICU admission, days, median (25%; 75%)
6 (4; 10)
30 (3; 28)
7 (7; 8)
0.00001
Preceding IST
2 (11.1)
10 (41.1)
2 (22.2)
0.083
Treatment
New IST
16 (88.9)
9 (37.5)
4 (44.4)
0.003
Follow-up IST
18 (100.0)
19 (79.2)
6 (66.7)
0.051
Intravenous immunoglobulin
5 (27.8)
11 (45.8)
4 (44.4)
0.465
Biological treatment
3 (16.7)
3 (12.5)
2 (22.2)
0.784
Outcomes
Total hospital staying, days, median (25%; 75%)
17 (14; 26)
28 (19; 68)
32 (25; 50)
0.013
Duration of stay in ICU, days, median (25%; 75%)
6 (4; 10)
7 (4; 23)
9 (5; 24)
0.534
Invasive mycosis
0 (0)
6 (25)
0 (0)
0.022
Fatal outcome
1 (7.7)
10 (41.7)
2 (15.4)
0.028
Time since ICU admission to dearth, days, median (25%; 75%)
46 (46; 46)
25 (9; 62)
57 (39; 75)
0.544
Treatment of patients with systemic immunoinflammatory diseases
Intensive IST before the ICU admission was administered in 14 patients (27.5%). Among them, 2 patients with MIS-C received tocilizumab, 2 patients with generalized infection received corticosteroids, and 10 patients with rheumatic disease received corticosteroids and biologic and nonbiologic disease-modifying anti-rheumatic drugs. The total duration of the stay in the hospital was 24.0 (16.0; 44.0) days. The data are presented in Table 1. Preceding IST before ICU admission (P = 0.083) was administered predominantly in patients with SRD (n = 10, 41.1%), followed by patients with generalized infections (n = 2, 22.2%) and with MIS-C (n = 2, 11.1%). The data are in Table 2.
Main outcomes of the studied population
The longest stay at the hospital (both in the ICU and pediatric department) was observed in patients with SRD and generalized infection, but the ICU stay was similar in all studied groups. During ICU admission 29 patients (56.9%) started immune suppression therapy, and 43 patients (84.3%) received systemic immune suppression therapy during the follow-up. The patients with MIS-C received high-dose intravenous corticosteroids (n = 46, 88.5%), IVIGs (n = 20, 38.5%), and biologic treatment (n = 8, 15.4%) with tocilizumab (n = 6), anakinra (n = 1), and rituximab (n = 2). Two patients (22.2%) with generalized infections received anakinra (n = 1) and tocilizumab (n = 1) due to the development of macrophage activation syndrome.
New IST in the ICU was administered to all remaining patients with MIS-C (n = 16, 88.9%), patients with generalized infections (n = 4, 44.4%), and patients with SRD (n = 9; 37.5%, P = 0.003). Follow-up (death or discharge from the ICU) IST was administered to all MIS-C patients (100%), 19 patients with SRD (79.2%), and 6 patients with generalized infection (66.7%, P = 0.059). The median length of stay in the ICU was similar between groups (P = 0.534), but the total hospital stay was the shortest in patients with MIS-C [17 (14; 26) days] and longer in patients with SRD [28 (19; 68) days] and patients with infections [32 (25; 50) days, P = 0.013]. The data are in Tables 1 and 2.
Analysis of fatal outcomes in patients hospitalized in the ICU
A fatal outcome was recorded in 13 children (25.5%) during a period of 39 (17; 62) days after admission to the ICU. The shortest time from ICU admission to death was observed in patients with SRD, but the data were not significant (Figure 1). The mortality rates were 1/18 (7.7%) in patients with MIS-C, 10/24 (41.7%) in patients with SRD, and 2/9 (22.2%) in patients with generalized infections (P = 0.028). Among patients with SRDs admitted to the ICU, the highest mortality was observed in SLE (4/8; 50.0%), followed by systemic vasculitis (4/12; 33.3%) and JIA (1/4; 25.0%; P = 0.642). Six patients (11.8%) (SLE: 4; antineutrophil cytoplasmic antibody vasculitis: 1; and JIA: 1) who stayed in the ICU for an extended time developed invasive mycosis during the follow-up. The main reasons for death were septic shock and disseminated intravascular coagulation. The data are in Table 2.
Figure 1 Cumulative survival of patients with different groups of immune-mediated diseases hospitalized in the intensive care unit (LogRank test, P = 0.840).
MIS-C: Multisystem inflammatory syndrome associated with coronavirus disease-19 in children; SRD: Systemic rheumatic diseases; ICU: Intensive care unit.
Fatal outcomes were more common in older children (P = 0.031). The majority of deaths were related to SRD (P = 0.028). The patients with fatal outcomes had a longer time before ICU admission, had IST administration prior to admission into the ICU (53.9% vs 18.4%, P = 0.013), and had further developed invasive mycosis during the ICU stay (30.8% vs 5.3%, P = 0.014). The detailed data are presented in Table 3. The following predictors of fatal outcomes were identified: Age over 162 months (P = 0.0006); time to ICU admission over 26 days from diagnosis (P = 0.0005); prior IST (P = 0.013); invasive mycosis during ICU stay (P = 0.0005); overall hospital stay > 37 days (P = 0.001); SRDs (P = 0.004); and ICU stay over 15 days (P = 0.00003). Detailed data, including sensitivity, specificity, and odds ratio analyses, were presented in patients with the above-mentioned signs who were at risk of lethal outcomes. The data are in Table 4. All significant predictors were included in the following multiple regression analysis, excluding the duplicated factors, to avoid multicollinearity. The multiple regression analysis (Table 5) identified two predictors of fatal outcomes: SRDs (vs other diseases) and ICU stay over 15 days (r2 = 0.422, P < 0.000002).
Table 3 Comparison of patients with immune-mediated diseases with lethal outcomes and survivors.
Parameter
Dead (n = 13)
Alive (n = 38)
P value
Sex, males
5 (38.5)
18 (47.4)
0.578
Age, months, median (25%; 75%)
175 (165; 192)
102 (57; 162)
0.031
Nosological groups
-
-
0.028
MIS-C
1 (7.7)
17 (44.7)
0.016
Systemic rheumatic diseases
10 (76.9)
14 (36.8)
0.013
Infections
2 (15.4)
7 (18.4)
0.059
Time to ICU from the hospital admission, days, median (25%; 75%)
30 (13; 100)
7 (6; 18)
0.013
Preceding intensive IST
7 (53.9)
7 (18.4)
0.013
Newly started IST in ICU
5 (38.5)
24 (63.2)
0.121
Follow-up IST
12 (92.3)
31 (81.6)
0.359
Overall glucocorticosteroids
12 (92.3)
33 (81.6)
0.359
IVIG
6 (46.2)
13 (35.1)
0.481
Outcomes
Invasive mycosis
5 (38.5)
1 (2.6)
0.0005
Total hospital staying, median (25%; 75%)
46 (21; 90)
24 (16; 30)
0.052
Duration of stay in ICU, days, median (25%; 75%)
30 (9; 46)
6 (4; 10)
0.003
Table 4 Predictors of fatal outcomes in patients with immune-inflammatory diseases hospitalized to intensive care unit.
Predictors
Se
Sp
OR (95%CI)
RR (95%CI)
P value
Age > 162 months
76.9
76.3
10.7 (2.4-47.2)
5.6 (1.8-17.9)
0.0006
The time between onset of disease and ICU admission > 26 days
66.7
85.7
12.0 (2.6-55.3)
5.2 (1.9-14.5)
0.0005
Preceding IST
53.8
83.8
6.2 (1.6-24.0)
3.3 (1.4-8.1)
0.013
Invasive mycosis
38.5
97.4
18.8 (1.9-184.1)
4.7 (2.3-9.7)
0.0005
Hospital stay > 37 days
61.5
84.2
8.5 (2.1-35.2)
4.2 (1.7-10.8)
0.001
Stay in ICU for > 15 days
69.2
89.5
19.1 (4.0-91.8)
6.6 (2.4-17.8)
0.00003
Systemic rheumatic diseases: Yes
76.9
68.4
7.2 (1.7-31.1)
4.4 (1.4-14.1)
0.004
Table 5 The final predictors of the fatal outcome (multiple regression analysis data).
Predictor
β
SE
P value
Intercept
0.013
0.066
0.847
ICU stay > 15 days
0.525
0.011
0.00002
Systemic rheumatic diseases (vs other diseases)
0.251
0.01
0.015
DISCUSSION
The main predictors of fatal outcomes in patients with immunoinflammatory diseases were identified: Age over 162 months; more than 26 days of illness before admission to ICU; SRDs; and ICU stay over 15 days. Prior IST and invasive mycosis development were additional factors in the fatal outcomes in our groups of patients. In these groups, patients with SRDs, especially SLE, had the worst outcome. This fact may explain the association between older age and fatal outcomes because adolescents and young adults usually have the most severe SLE[20].
SRDs with severe courses usually require intensive IST with prolonged high-dosing corticosteroids, cyclophosphamide, and biologic treatment, especially with B-cell depletion (rituximab or similar)[21,22]. In previously published literature, it was shown that age and severity of the disease were associated with 28-day mortality in patients with rheumatic diseases. Also, administration of glucocorticoid treatment before staying in the ICU was an unfavorable sign for outcomes[23]. It is well known that systemic corticosteroids are a major factor for infection comorbidity, including invasive mycosis[24-26]. Patients with severe rheumatic diseases usually require intensive corticosteroid treatment in combination with other immune suppressive drugs. Immune disturbances, based on the pathogenesis of the SRDs, are also factors of higher susceptibility to infection. Some monogenic forms of SLE are caused by the genetic variants in the complement genes, which result in higher susceptibility to infection, such as pneumococcus, meningococcus, Hаemophilus influenzae type B infection, etc. [27].
Severe disease course associated with major organ involvement requires a longer stay in the ICU and is associated with a high risk of nosocomial infection[28,29]. Of course, there is also a reverse relationship whereby healthcare-associated infections lead to an increase in the length of hospital stay[30,31]. Barnett et al[32] reported that bloodstream infections especially methicillin-resistant Staphylococcus aureus are associated with an increased risk of death and longer hospital stay. According to previous studies, increased length of ICU stay and major organ involvement on admission were identified predictors of unfavorable outcomes in patients with rheumatic disease[33]. In our study, similar results were observed. Staying in the ICU for more than 15 days was an independent predictor of a fatal outcome, which might reflect the disease severity and the risk of secondary nosocomial infection. Interestingly, Cattalini et al[34] did not find any differences in mortality in the ICU, in the hospital, and after 180 days between patients with and without rheumatic diseases.
More than half of the patients with MIS-C require ICU admission, and the mortality rate is approximately 2%. Several studies propose criteria for the severe life-threatening course of this disease[2,4,35]. de Farias et al[35] showed factors associated with mortality in children with critical COVID-19 and MIS-C. Among children with COVID-19 the mortality rate was 6.1%, and in the MIS-C group the mortality rate was 6.8%. The mortality was associated with higher levels of vasoactive inotropic score, presence of acute respiratory distress syndrome, and higher levels of erythrocyte sedimentation rate and thrombocytopenia, which reflected the intensive hemophagocytosis and cytokine storm syndrome[36].
During MIS-C outbreaks we faced restricted access to IVIG and anakinra. We were forced to use high doses of intravenous corticosteroids as the first-line treatment and used tocilizumab in severe cases[37]. The severity of MIS-C in our patients was related to a higher frequency of hypotension/shock, myocardial neurological, and respiratory systems involvement as well as the frequency of macrophage activation syndrome[4]. High hemophagocytic activity, measured by the H-score (> 91) was associated with myocardial involvement, hypotension/shock, and ICU admission in the national multicentral MIS-C cohort[38].
A corticosteroid sparing treatment plan with early biologic intervention with a short course of intravenous corticosteroids looks like a promising tool with superiority above the conventional treatment of a high dose of oral corticosteroids in SLE[39,40]. Decreased corticosteroid overload leads to less frequency of generalized infections in immune-compromised patients[41].
The risk factors of invasive mycosis in patients with rheumatic disease are: (1) Neutropenia < 500 cell/μL (< 0.5 × 109/L) during 10 or more days; (2) Prolonged use of corticosteroids ≥ 0.3 mg/kg/day (prednisolone) > 3 weeks in the previous 60 days; and (3) Treatment with T cell suppressor drugs within the past 90 days and/or treatment with B cell suppressor drugs[42]. The high degree of disease activity, especially SLE, is an independent risk factor for the development of invasive mycosis[43]. Several authors note such risk factors as pericardial disease, hypocomplementemia, lymphopenia, concomitant bacterial infections, and cytomegalovirus viremia were negative predictors for invasive aspergillosis in SLE patients[44].
Patients with SRDs were more likely to have an extended period between disease diagnosis and ICU admission compared with patients with MIS-C and generalized infections. A longer duration before ICU admission corresponded with increased IST and a higher risk of infection complications. In previous years, the severe course of the disease was the main reason for the fatal outcome in patients with SRDs, due to lack of modern IST, but now the first reason is an infection. Better disease control is associated with higher immune suppression and risk of infection complications. To assess the systemic inflammation in patients with inflammatory diseases there is also a convenient tool called the systemic immune-inflammatory index, which can be used as an early predictor of inflammatory complications of different diseases, including infections, rheumatic diseases, and autoimmune endocrine diseases[45-47]. Close monitoring of these predictors could modify the outcomes. It is necessary to avoid long ICU stays for patients with SRDs to decrease the risk of nosocomial infection. Patients with risk factors should be under the suspicion of invasive mycosis and urgent diagnostics in the cases of a fever of unknown origin or any lung involvement in the ICU are required.
Limitations
The retrospective nature of the study may introduce biases. The exclusion of certain patient groups and the small number of the cohort may also lead to bias. With a sample size of only 51 patients, the findings may lack statistical power and may not be generalizable to broader populations. A small sample size increases the risk of type II errors, where true effects may not be detected. The lack of clear definitions or standardization could lead to inconsistencies in data collection and analysis, ultimately impacting our conclusions. Establishing standardized criteria and definitions would enhance the clarity and reproducibility. The absence of a control group makes it difficult to determine whether the predictors identified are specific to the ICU population or if they are general risk factors applicable to all patients with these diseases. Including a control group would provide a clearer understanding of the specificity of the predictors. The missing data and heterogeneous population (specific types of disease and different ages) could influence the study results. In our study, we did not evaluate the confounding variables that could influence outcomes, such as the presence of comorbidities, variations in treatment protocols over time, or differences in healthcare access. These factors could skew the results and interpretations. A more comprehensive analysis that accounts for these confounders would provide more robust and reliable findings.
CONCLUSION
Identifying patients at high risk of an unfavorable outcome is necessary to reassess the treatment plans and treat the modifiable risk factors to decrease the mortality rates in children. Avoiding extended ICU stays for patients with SRDs, close monitoring, and preventing invasive mycosis might improve the outcome in children with systemic immune-mediated diseases. Avoiding long and high doses of corticosteroids and following infection control, especially the mycotic infection, might improve the mortality rates in patients with SRDs.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Critical care medicine
Country of origin: Russia
Peer-review report’s classification
Scientific Quality: Grade C, Grade C, Grade C
Novelty: Grade B, Grade C, Grade C
Creativity or Innovation: Grade B, Grade C, Grade C
Scientific Significance: Grade B, Grade C, Grade C
P-Reviewer: Byeon H; Li ZL; Tovani-Palone MR S-Editor: Bai Y L-Editor: A P-Editor: Xu ZH
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