Introduction
Primary immunodeficiencies (PID) are a group of genetically based disorders that affect the immune system. Common variable immunodeficiency (CVID) is the most frequently observed antibody deficiency among congenital immune disorders. CVID is a heterogeneous disease characterized by hypogammaglobulinemia and an increased susceptibility to recurrent bacterial infections. Numerous studies have demonstrated that immunological and genetic defects play a role in the pathogenesis of CVID [1–4]. In PID, recurrent infections are often accompanied by various clinical manifestations including autoimmune disorders, autoinflammatory conditions, immune dysregulation defects, and malignancies [1, 2].
In addition to preventive measures for congenital immune deficiencies, immunoglobulin (IG) infusions, primarily containing immunoglobulin G (IgG), constitute the cornerstone of treatment. Human IG therapy can be administered as either intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG). IG therapy has shown highly effective outcomes in both primary and secondary immunodeficiencies. IG preparations are produced by fractionating the pooled plasma collected from thousands of donors [5]. These preparations are stabilized using agents such as human albumin, glycine, polyethylene glycol, or sugars such as sucrose, maltose, or glucose. Although IG therapies are primarily used as replacement treatments in patients with immunodeficiencies, they are also employed as immunomodulatory therapies in autoimmune and inflammatory conditions, often at different or even high doses. IG preparations used in therapy are manufactured by various companies worldwide and are available for clinical use [5, 6].
Both IVIG and SCIG replacement therapies improve the quality of life and overall survival of patients with primary antibody deficiencies [3]. Although IVIG therapy is generally well tolerated by patients, adverse effects may occur. As a result of the manufacturing process, reactions may develop against immunoglobulin aggregates or stabilizing agents present in the preparations [7]. Most of these adverse effects are mild and typically resolve with a reduction in the infusion rate. However, serious adverse events such as aseptic meningitis, renal failure, thrombosis, and anaphylaxis may also occur, potentially leading to significant morbidity and mortality [6, 8].
The adverse effects associated with IVIG can involve a wide range of organs, and patients should be closely monitored for such reactions. The adoption of individualized treatment approaches in the management of these side effects is crucial to ensure patient safety and adherence to therapy.
Aim
This study aims to determine the frequency, types and severity of adverse effects observed in adult patients receiving IVIG treatment due to PID; to evaluate which clinical and demographic factors are associated with these side effects and to reveal the effect of premedication practices on the development of side effects.
Material and methods
This retrospective cohort study was conducted at the Immunology and Allergy Diseases Clinic. Patients over the age of 18 who were diagnosed with PID and received at least one IVIG infusion between 1 January 2016, and 1 January 2024, at the Immunology and Allergy Diseases outpatient clinic were included in the study. Patients with incomplete information in their medical records were excluded from the study. The medical files and treatment records of patients who were diagnosed with immunodeficiency and received immunoglobulin therapy were reviewed to evaluate adverse effects and allergic reactions related to immunoglobulin treatment.
Data on age, sex, IVIG replacement indications, comorbidities, presence of atopy, concomitant medications, and family history were collected from patient files. For all patients included in the study, information related to their IVIG treatment, such as infusion dates, premedication practices, timing and type of adverse effects, and treatments administered in response to these effects, was recorded.
The IVIG dose was 400–600 mg/kg, which varied according to clinical indications. IVIG infusions were initiated at a slow rate (10 ml/h) and were gradually increased to a maximum rate of approximately 200 ml/h. Adjustments were made to individual dosages and infusion rates as necessary.
In this study, adverse effects related to IVIG therapy were classified into two main categories based on their time of onset, as defined in the literature: immediate and delayed. Immediate adverse effects generally occur during infusion or within the first 6 h of infusion. These reactions were further classified according to severity as mild, moderate, or severe. Mild adverse effects included headaches, fever, chills, and fatigue. These typically resolve with a reduction in the infusion rate or administration of antihistamines and analgesics. Moderate adverse effects included chest pain, dyspnoea, vomiting, arthralgia, and severe headache. In such cases, discontinuation of the infusion and symptomatic treatment may be necessary. Severe adverse effects include life-threatening reactions such as hypotension, anaphylaxis, bronchospasm, and altered consciousness. In these cases, infusion must be stopped immediately, and emergency medical intervention should be provided.
Delayed adverse effects emerge hours or even days after the infusion. These reactions may include severe headache or aseptic meningitis, acute kidney injury, haemolysis, and thromboembolic events such as deep vein thrombosis or pulmonary embolism. In such cases, infusion should be discontinued, and the IVIG treatment regimen should be reconsidered [6, 9].
Premedication protocols were individualized based on the clinical condition of the patients, previous treatment experiences, and accompanying comorbidities. In our clinic, premedication was administered according to the clinical needs of patients prior to IVIG infusion. To reduce the side effects of intravenous administration and ensure hemodynamic stability, 100–150 ml isotonic solution was administered intravenously before IVIG infusion. To prevent allergic reactions, one ampoule (45.5 mg/ 2 ml) of pheniramine maleate was administered intramuscularly (IM) or intravenously (IV) approximately 30 min before the infusion. Methylprednisolone (0.5 mg/kg) was administered to reduce the risk of recurrence in patients with a history of reactions to previous infusions. Additionally, to prevent systemic side effects such as fever, headache, and myalgia, 500 mg of paracetamol was administered. For patients who reported gastric discomfort, 40 mg of lansoprazole was prescribed.
Statistical analysis
Statistical analyses were performed using the IBM SPSS version 23.0. Descriptive statistics for continuous variables were presented as mean ± standard deviation (mean ± SD), median, first quartile, third quartile, and minimum and maximum values. Categorical variables were expressed as frequencies and percentages. The Shapiro-Wilk test was used to assess the normality of the data distribution. Homogeneity of variances for binary comparisons was evaluated using the Levene’s test. Comparisons between two independent groups were made using the independent samples t-test when normality and homogeneity assumptions were met; otherwise, the Mann-Whitney U test was applied. Comparisons between categorical variables were evaluated using the Pearson χ2 test, and Fisher’s Exact χ2 test (for 2×2 tables) or the Exact Chi-square test (for non-2×2 tables) was used. Statistical significance was set at p < 0.05.
Results
Ninety patients were included in the study. A total of 6246 IVIG infusions were evaluated. The demographic characteristics of the patients are presented in Table 1.
Table 1
Demographic characteristics of the patients
| Parameter | Patients with adverse events | Patients without adverse events | Total | P-value | |||
|---|---|---|---|---|---|---|---|
| n | %a | n | %a | n | % | ||
| Gender | 0.0621 | ||||||
| Male | 38 | 76.0 | 23 | 57.5 | 61 | 67.8 | |
| Female | 12 | 24.0 | 17 | 42.5 | 29 | 32.2 | |
| Body mass index | 0.4262 | ||||||
| Underweight | 6 | 12.0 | 4 | 10.0 | 10 | 11.1 | |
| Normal weight | 30 | 60.0 | 18 | 45.0 | 48 | 53.3 | |
| Overweight | 10 | 20.0 | 14 | 35.0 | 24 | 26.7 | |
| Obese | 4 | 8.0 | 4 | 10.0 | 8 | 8.9 | |
| Age | 0.1653 | ||||||
| Mean ± SD | 39.42 ±14.35 | 44.05 ±16.17 | 41.48 ±15.27 | ||||
| Min.–max. | 20.0–75.0 | 23.0–77.0 | 20.0–77.0 | ||||
| Median (Q1–Q3) | 34.0 (30.0–46.25) | 40.0 (31.0–55.0) | 37.5 (30.0–51.0) | ||||
When comorbidities were examined, 60.0% of patients had chronic diseases. The rate was 57.5% among patients who experienced adverse effects and 62.0% among those who did not experience adverse effects. Among the comorbid conditions, hypothyroidism was the most common (12.2%), followed by hypertension (10.0%), autoimmune diseases (7.8%), diabetes mellitus (DM) (6.7%), and iron deficiency anemia (6.7%). Osteoporosis ranked fifth (5.6%).
There was no statistically significant difference between patients who experienced adverse effects and those who did not in terms of chronic diseases (p = 0.206, p = 0.504, p = 0.235, p = 0.400, p = 0.221, p = 1.000, and p = 0.377, respectively). Regarding allergic diseases, 18.9% of the patients had at least one allergic condition. The rate was 20.0% among those who experienced reactions, and 18.0% among those who did not. The distribution of PID diagnoses and patients’ use of IVIG are presented in Table 2.
Table-2
PID and IVIG use
[i] Mean – average. SD – standard deviation, Min – minimum, Max – maximum, Q1 – 1st quartile, Q3 – 3rd quartile, acolumn percentage, 1Pearson χ2 test, ²two independent groups t test. 1Pearson χ2 test. 4Fisher’s Exact test. PID – primary immunodeficiency, ICF – syndrome (Immunodeficiency, Centromeric region instability, and Facial anomalies syndrome), CVID – common variable immunodeficiency.
Out of a total of 6246 IVIG infusions, adverse reactions were observed in 363 cases. Among the treatment approaches implemented for patients experiencing these side effects, the most frequently preferred intervention was a reduction in the infusion rate (37.5%), followed by complete discontinuation of therapy (27.5%), administration of antihistamines (Avil) (22.5%), oxygen therapy (12.5%), corticosteroid treatment (Prednol) (10%), fluid replacement therapy (10%), and use of adrenaline (2.5%). In addition, the incidence of adverse reactions during the first IVIG administration was 15%. These findings underscore the importance of close monitoring of adverse effects during IVIG infusions and the necessity of appropriate intervention protocols that are readily available. Among the 363 patients, 75.2% (n = 273) experienced side effects within the first 6 h of infusion, which were classified as early reactions. In the remaining 24.8% (n = 90), side effects developed 6 h post-infusion and were categorized as late reactions. IVIG-related adverse effects were classified by severity, according to the total number of infusions. The classifications are listed in Table 3.
Table 3
Classification of IVIG side effects by severity (total infusions: n = 6246)
Discussion
This study aimed to investigate the adverse effects associated with IVIG therapy in patients with PID, and to identify the factors that influence the management of these effects. Various adverse reactions related to IVIG therapy have been frequently reported in the literature, and our study provides valuable information regarding the management and prevention of these effects.
No statistically significant relationship was found between demographic factors (such as sex, age, and body mass index) and the frequency of adverse effects, which is consistent with similar findings reported in the literature. Previous studies have indicated that demographic characteristics are not decisive predictors of adverse reactions [10–12].
In a study conducted in Iran, 1,231 IVIG infusions in 71 patients with primary immunodeficiency were evaluated. Among the most observed immediate adverse reactions, mild reactions including chills, fever, flushing, myalgia, nausea, headache, and anxiety were reported in 131 infusions. Moderate reactions such as vomiting, chest pain, and wheezing were observed in 19 infusions. Additionally, 2 patients experienced severe adverse reactions that required hospitalization and close medical monitoring [13]. In another study conducted by Dashti-Khavidaki et al., 3,004 IVIG infusions administered to 99 patients with primary immunodeficiency (PID) were evaluated. Mild adverse effects were observed in 172 infusions, with fever, chills, and headaches being the most frequently reported. These reactions were successfully managed by reducing the infusion rate. On the other hand, moderate adverse effects such as nausea, vomiting, chest pain, and wheezing were reported in 41 infusions. These were addressed with medications such as antihistamines, corticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs), and treatment was continued at a slower infusion rate. Additionally, 2 patients experienced severe adverse reactions in the form of anaphylaxis during IVIG therapy, and their treatment regimens were modified after appropriate medical intervention [9]. In another study conducted by Bichuetti-Silva et al. in 2014, 1,765 infusions were evaluated in 117 patients with primary immunodeficiency (PID), and adverse effects were identified in 38 infusions. In this study, 31 reactions were classified as mild, 4 as moderate, and 3 as severe. The most reported symptoms were fatigue, headaches, and abdominal pain. Reported severe events included throat tightness and seizures. The authors emphasized that the incidence of adverse reactions during and after IVIG therapy was generally low [14, 15]. Another study involving 363 patients with primary immunodeficiency examined the adverse effect profiles of 22,667 IVIG infusions. The study reported that mild adverse reactions were most frequently observed, with myalgia, chills, headache, fever, and hypotension being the most common side effects of IVIG therapy. These reactions affected nearly half of the patients, particularly during the initial infusions, highlighting the importance of close monitoring of patients receiving IVIG therapy, particularly at the beginning of treatment [10]. Souayah et al. examined 420 patients who received IVIG for neurological reasons. The reactions were reported to be mild in nature, with 95% of adverse reactions observed [16]. In a study conducted by Manlhiot et al., 1056 IVIG infusions administered to 38 patients with juvenile dermatomyositis were evaluated for adverse effects. Mild symptoms were the most frequently observed side effects, and the patients generally tolerated IVIG therapy well [17]. In another study involving 109 patients with refractory autoimmune blistering skin diseases, the most reported adverse reactions were fever (29.4%) and headache (29.4%) [12]. Other studies have also reported that the most common adverse effects associated with IVIG administration are mild symptoms, including flu-like symptoms, nausea, fatigue, fever, chills, malaise, drowsiness, and headache [6, 18–20]. In our study, among the 6,246 IVIG infusions, the most frequently observed adverse effects were mild in severity (n = 248, 4%), followed by moderate (n = 108, 1.74%), and severe reactions (n = 7, 0.12%). The most frequently reported adverse effects included fear, panic, anxiety (n = 79, 1.27%), nausea and vomiting (n = 29, 0.47%), chills and shivering (n = 35, 0.56%), and headaches (n = 7, 0.11%). These findings indicate that IVIG therapy is generally safe and well-tolerated [21].
In a study conducted by Tcheurekdjian et al., 447 IVIG infusions administered to 65 patients with primary immunodeficiency were evaluated, and it was observed that adverse events most frequently occurred within the first 24 h following IVIG infusion [11]. Similarly, in our study, most of the observed adverse reactions occurred within the first 24 h of IVIG infusion.
Although rare, anaphylaxis is one of the most severe and potentially life-threatening reactions that may occur during IVIG administration. In cases of anaphylaxis, several strategies have been recommended to prevent recurrence, including switching to SCIG products in patients receiving low doses of IgG, using an IVIG preparation with minimal IgA content, administering premedication prior to IVIG infusion, and delivering IVIG at a slower infusion rate [22]. Anaphylaxis may develop in patients with selective IgA deficiency and CVID who produce IgE antibodies against IgA following immunoglobulin therapy [9, 23–25]. In our study, two patients had a history of anaphylaxis during IVIG therapy. In one of these patients, since SCIG therapy was declined, the treatment was switched to an IVIG preparation with low IgA content. SCIG therapy was initiated for another patient who experienced anaphylaxis. Both patients continued immunoglobulin therapy without further complications.
In a study conducted by Kemmotsu et al., 384 children who received IVIG therapy for Kawasaki disease were evaluated. Among these patients, aseptic meningitis developed in 4 children within 48 h after IVIG administration. Two patients improved following intrathecal steroid therapy, whereas the other two recovered under clinical observation without additional intervention [26]. Similarly, Bharath et al. retrospectively reviewed the medical records of 1,324 patients who received 11,907 IVIG infusions for various indications. Among these, aseptic meningitis was observed in 8 cases [27]. In our study, aseptic meningitis developed in 1 patient approximately 10 h after receiving the first dose of IVIG among the 6,246 infusions. The patient recovered without steroid treatment and was managed solely with hydration therapy.
SCIG is a safer and more tolerable treatment option in terms of adverse reactions [28]. However, our retrospective study only considered the adverse effects of intravenous immunoglobulin (IVIG) administration; SCIG side effects were not included in our analysis. There were several reasons why patients who developed IVIG-related adverse reactions were not switched to SCIG in our study. The most significant limiting factors to switching to SCIG were patient reluctance and home environments unsuitable for regular subcutaneous infusions. Many patients prefer not to use SCIG due to concerns about injection liability and potential local reactions. Furthermore, there is insufficient space, equipment, and supportive training to administer weekly infusions under sterile conditions at home. Therefore, our current protocols focused on premedication strategies and IVIG dose adjustments [29, 30].
In the comparison between patients who received premedication and those who did not, the frequency of adverse events was significantly lower in the premedication group. Publications in the literature also recommend that premedication be administered to patients who experience mild, moderate, or severe adverse effects, based on the severity of their previous reactions. Premedication, along with dose adjustments and reduction of infusion rates, has been reported to have potential benefits in reducing adverse reactions associated with IVIG therapy [16, 31, 32]. In a study conducted by Côté [33] et al. on children receiving IVIG for various indications, it was emphasized that children who received corticosteroids as premedication experienced fewer adverse effects [33]. In our study, the incidence of adverse events was significantly lower in patients who received antihistamines as premedication than in those who did not receive any premedication. Patients who had previously experienced mild, moderate, or severe adverse reactions to IVIG were administered premedication tailored to the nature of their symptoms. Notably, these patients did not report any adverse effects during subsequent IVIG infusion after premedication was administered. Based on these findings, we believe that the low incidence of adverse events in our patients was attributable to premedication.
Conclusions
Previous studies on the adverse effects of IVIG have predominantly focused on paediatric populations, and data specifically addressing patients with PID remain limited. Therefore, the focus of our study on adult patients represents a significant contribution in filling this knowledge gap.
Moreover, the strength of our study is further enhanced by the large number of IVIG infusions evaluated over a relatively long period of 8 years in a broad patient cohort. Although IVIG therapy is generally well tolerated by patients, our findings suggest that certain adverse reactions can be prevented through appropriate premedication.
Based on our results, we recommend that premedication should be tailored according to the severity of previously experienced adverse effects (mild, moderate, or severe), that patients should be thoroughly informed and psychologically prepared prior to IVIG administration, and that the first dose should be closely monitored for potential reactions.
The main limitations of our study were the relatively small sample size and unequal distribution of patients receiving different IVIG preparations. Therefore, larger-scale prospective studies are required to validate and expand upon our findings.
