Research Article, J Biochem Physiol Vol: 8 Issue: 1

Retrospective Analysis of Demographics, Clinical Features, Labs and Inflammatory Biomarkers in Serum Sickness-Like Cases

Seda Tasdemir Salar¹, Alaaddin Yorulmaz^2*, Vildan Gungorer³ and Sukru Arslan⁴

¹Department of Child Health and Diseases Clinic, Tatvan State Hospital, Bitlis, Turkey

²Department of Pediatrics, Selcuk University Medical School, Konya, Turkey

³Department of Pediatrics, Division of Pediatric Rheumatology, Ankara City Hospital, Turkey

⁴Department of Pediatric Rheumatology, Bakircay University, Izmir, Turkey

*Corresponding Author:

Alaaddin Yorulmaz
Department of Pediatrics, Selcuk University Medical School, Konya, Turkey
E-mail: dralaaddiny@gmail.com

Received date: 07 January, 2025, Manuscript No. JBPY-25-158079; Editor assigned date: 09 January, 2025, PreQC No. JBPY-25-158079 (PQ); Reviewed date: 23 January, 2025, QC No. JBPY-25-158079; Revised date: 31 January, 2025, Manuscript No. JBPY-25-158079 (R); Published date: 07 February, 2025, DOI: 10.4172/jbpy.1000183.

Citation: Yorulmaz A, Salar TS, Gungorer V, Arslan S (2024) Retrospective Analysis of Demographics, Clinical Features, Labs and Inflammatory Biomarkers in Serum Sickness-Like Cases. J Biochem Physiol 8:1.

Copyright: © All articles published in Journal of Biochemistry and Physiology are the property of SciTechnol and is protected by copyright laws. Copyright © 2024, SciTechnol, All Rights Reserved.

Abstract

Keywords: Pediatric, Serum sickness-like reactions, Inflammatory biomarkers, Systemic inflammation, Neutrophil or lymphocyte ratio

Keywords

Pediatric; Serum sickness-like reactions; Inflammatory biomarkers; Systemic inflammation; Neutrophil or lymphocyte ratio

Abbreviations

Serum Sickness-like Reactions (SSLR); Red-cell Distribution Width (RDW); Neutrophil or Lymphocyte Ratio (NLR); Platelet or Lymphocyte Ratio (PLR); Alkaline Phosphatase (ALP); Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST); Systemic Inflammatory Index (SII); Area under the Curve (AUC); Receiver-operating characteristic Curve (ROC)

Introduction

Serum Sickness-like Reactions (SSLR) is Type 3 hypersensitivity reactions occurring in the presence of certain antigens. Symptoms generally begin 6 days to 21 days after the exposure to antigenic stimulation. The antigen that causes a Type 3 hypersensitivity reaction might be an exogenous foreign protein, drug, bacteria or virus. Typical clinical findings include fever (10% to 20%), erythematous rash (95%), polyarthritis or polyarthralgia (10% to 50%) and lymphadenopathy (10% to 20%). Patients might also develop muscle pain, chest pain, peripheral edema, difficulty breathing; Rarely, neurological and myocardial involvement, dyspnea with or without pulmonary infiltrations, hepatosplenomegaly, gastrointestinal symptoms, renal complications and serositis [1,2]. It has been reported that SSLR occurs at a rate of 0.06% to 0.5% in pediatric patients [3].

Although there are no laboratory findings or diagnostic criteria that are specific to Serum Sickness-like Reactions (SSLR), the diagnosis is made mostly based on anamnesis, clinical findings and physical examination results. Clinical findings of fever, rash, arthritis or arthralgia and lymphadenopathy without any other focus that occur 1 to 2 weeks after the exposure to the triggering agent support the diagnosis. In the laboratory, leukocytosis, increased erythrocyte sedimentation rate, lower CRP elevation and rarely, mild hematuria and proteinuria are detected in urine tests. Hypocomplementemia, which is the characteristic laboratory finding of true serum sickness, is not detected in SSLR [1,2,4]. There is no recommended and agreed-upon treatment modality for Serum Sickness-like Reactions. The treatment generally consists of eliminating the causative agent of SSLR and symptomatic treatment.

Recently, easy-to-measure and practical modalities that provide valuable data for the diagnosis and prognosis of various diseases have come to the attention. Novel markers that are associated with the inflammatory process are being reported for many disease groups. Complete blood count can be easily accessed and estimated quickly in the emergency department. Interdependent parameters (e.g., leukocytes, neutrophils, lymphocytes and neutrophil-lymphocyte ratio) in complete blood count have been examined in many studies as inflammatory markers. It is maintained that the hemogram parameters, Red-cell Distribution Width (RDW), Neutrophil or Lymphocyte Ratio (NLR) and Platelet or Lymphocyte Ratio (PLR) can be used in the diagnosis and follow-up of inflammation.

In the literature, there are very few studies that investigate the levels of NLR, PLR and RDW, which are considered indicators of systemic inflammation and have become used widely in the clinic, in SSLR patients. In the present study, the purpose was to examine whether there are any changes in these hematological parameters and their prognostic significance in patients diagnosed with SSLR and followed and treated in our clinic. It was also aimed to all together examine the demographic, clinical and laboratory findings of SSLR patients, convey their results and obtain results that might serve as a guide in diagnosis and treatment in this respect.

Materials and Methods

Recruitment of patients

The files of 122 patients, who were hospitalized and followed up with a diagnosis of SSLR in the Pediatric Healthcare and Diseases Clinic between September, 2016 and December, 2021 were examined all together. The records of the patients were recorded electronically. Those who were under the age of 18, who had complete data and came for regular follow-ups were included in the study and those who had other combinations of diseases or chronic diseases, who had discontinued their follow-ups in our clinic and whose data were missing were not included. The control group consisted of children who did not have any disease and were examined at the Pediatric Healthcare and Diseases Clinic.

Evaluation of the demographic and clinical characteristics

The patients were diagnosed with SSLR by anamnesis and clinical examination. All patients between the ages of 0 to 18 who had the disease were included in the study. The gender, age, duration of hospitalization, accompanying clinical findings, family history of atopy, previous infection and medication history of the patient were obtained from the hospital files. Arthralgia was diagnosed when there was only pain and no other inflammatory criteria. Arthritis was diagnosed with joint pain, swelling, tenderness, increased temperature, sometimes redness and limitation of joint movements.

Laboratory analyzes

Complete blood counts of the patients were performed with a Beckman Coulter LH780 brand device in the Biochemistry Laboratory of Selcuk University Faculty of Medicine Hospital and biochemistry samples were performed with Beckman Coulter AU5800 and Beckman Coulter AU680 brand devices in the Biochemistry Laboratory of Selcuk University Faculty of Medicine Hospital.

Complete blood count, C-reactive protein, erythrocyte sedimentation rate, serum electrolytes, blood glucose, urea and liver function test results of the patients were examined. The total protein, albumin, Calcium (Ca), Phosphorus (P), Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) results of the patients were also recorded.

The complete blood count results of the patients, which were routinely sent at the time of diagnosis, were evaluated. Hemoglobin (Hb), Red-cell Distribution Width (RDW), leukocyte, neutrophil, lymphocyte and platelet counts at the time of diagnosis were recorded. Then, Neutrophil or Lymphocyte Ratio (NLR), Platelet or Lymphocyte Ratio (PLR), RDW or Platelet Ratio (RPR) and RDW or Lymphocyte Ratio (RLR) were calculated and recorded. The SII values of the patients were calculated by using Neutrophil, Platelet, and Lymphocyte values according to the following formula.

Statistical analysis

The SPSS23.0 Package Program was used for statistical analysis of the data in the study. The categorical data are given with number percentage values and numerical data are given with prevalence measures such as mean, standard deviation and smallest and largest values. Pearson's Chi-Square Test was used for comparing the categorical data between independent groups. The suitability of the continuous numerical data for normal distribution was evaluated with the Kolmogorov-Smirnov Test. Whether there were differences between the groups in terms of the measured variables was evaluated with the t-test in independent groups and with the Mann-Whitney U-test if the necessary assumptions were not met. Receiver-operating characteristic Curve (ROC) curves were created in the patient group and the Area under the Curve (AUC) was calculated for each marker. The ROC curve cutoff point was determined by using the Youden Index and p<0.05 was accepted as the statistical significance level.

Results

A total of 64 (52.5%) of the patients were male, 58 (47.5%) were female and the Male or Female Ratio was 1.10. The age distribution of the patients varied between 14 months and 213 months (Mean ± SD: 99.83 ± 47.72 months), the median value was 89.50 months. When the average age distribution of the patients was examined according to gender, it was 96.00 months in boys and 112.17 months in girls. When the age distribution of the patients was analyzed statistically according to gender, no significant differences were detected (0.716).

When the application years of the patients who were included in the study were examined, it was found that 33 (27.0%) applied to the hospital most frequently in 2017 and 32 (26.2%) patients in 2019. When the application months of the patients who were included in the study were examined, it was found that 17 (13.9%) patients most frequently applied to our hospital in February and December, followed by July with 16 (13.1%) patients. When the clinical findings of the patients who were included in the study were examined, 110 (90.20%) had arthralgia, 100 (82.0%) had a skin rash, 79 (64.8%) had arthritis, 45 (36.90%) had lymphadenopathy, 42 (34.4%) had fever and 17 (13.90%) had abdominal pain.

A total of 23 (18.9%) of the patients who were included in the study had a family history of allergy and 86 (70.5%) patients had a history of infection before the disease. Among these, 10 had acute gastroenteritis, 2 had soft tissue infections, 2 had urinary tract infections and the remaining 72 had upper respiratory tract infections. One of the patients had a history of Scarlet Fever and one had a history of Influenza A. Prior to the diagnosis, 60 (49.18%) of the patients had a history of drug use and 49 of these patients (81.60%) had a history of antibiotic use. Among the patients who used antibiotics, the priority was a history of using amoxicillin-clavunate, with 29 (59.18%) patients. It was also found that 3 (2.4%) patients were diagnosed with Acute Gastroenteritis and had a history of Metronidazole use.

There was evidence of pleural effusion in 1 (0.8%) patient and pericardial effusion in 1 (0.8%) patient. Eight (6.4%) patients were admitted to our hospital with signs of hematuria. Lumbar puncture was performed for one (0.8%) patient considering meningococcemia and was evaluated as normal. It was learned that 12 (9.8%) patients had bone marrow aspiration to exclude leukemia because of bone pain. The complete blood count values of the patients who were included in the study were compared with those of the control group.

The total leukocyte count was 10.84 ± 5.41 in the patient group and 9.27 ± 2.16 in the control group. When the leukocyte count of the patients was compared statistically between the patient and the control groups, no significant differences were detected (p:0.184). Statistically significant differences were detected in the Neutrophil Count, Lymphocyte Count, NLR, PLR, RLR, AST/ALT Ratio, SII, and AST/PLT ratios of the patients compared to the control group.

The comparison of complete blood count values of the patients who were included in the study to the control group is given in [Table 1].

Table 1: The comparison of complete blood count values of the patients who were included in the study to the control group; Note: WBC: White Blood Cell; PC: Platelet Count; RDW: Red cell distribution width; NC: Neutrophil Count; LC: Lymphocyte Count; NLR: Neutrophil-Lymphocyte Ratio; PLR: Platelet-Lymphocyte Ratio; RPR: RDW/Platelet Ratio; RLR: RDW/ Lymphocyte Ratio; SII: Systemic Inflammatory Index (SII=NÃ?T/L).

When the complete blood count values of the patients who were included in the study were examined according to the presence of arthritis, the total leukocyte count (WBC) was 11.21 ± 6.17 in those without arthritis and 10.65 ± 4.99 in those with arthritis. When the WBC value was compared according to the presence of arthritis, it was not found to be statistically significant (p:0.881). The comparison of the hemogram values of the patients according to the presence of arthritis is given in [Table 2].

Table 2: The comparison of the hemogram values of the patients according to the presence of arthritis; Note: ESR: Erythrocyte Sedimentation Rate.

When the patients were examined in terms of systemic involvement 6 (4.9%) patients had systemic involvement. When the prognoses of the patients were evaluated, it was found that the prognosis of 6 (4.9%) patients was poor. During their follow to ups relapse was detected in 13 (10.7%) patients. Anti-tuberculosis treatment was started in one (0.8%) patient. When additional findings of the patients were evaluated 2 (1.6%) patients had Erythema nodosum 7 (5.7%) patients had hematuria 1 (0.8%) patient had glomerulonephritis 1 (0.8%) patient had hepatosplenomegaly and 1 (0.0%) patient had hematuria. Pericardial effusion was detected in 8 patients and proteinuria was detected in 1 (0.8%) patient.

When the treatments of the patients were examined, it was found that 104 (85.2%) patients were given Methylprednisolone 3 (2.5%) patients were given antihistamines. and 14 (11.5%) patients were given nonsteroidal anti-inflammatory drugs. The patients who were included in the study were treated as inpatients. The hospitalization period of the patients was 3 to16 days (Mean ± SD: 5.14 ± 3.20 days). When hospitalization periods were examined according to gender it was found to be 5.74 ± 2.58 days in boys and 5.04 ± 2.02 days in girls. When the hospitalization periods of the patients were compared statistically according to gender no significant difference was detected (p:0.136). The comparison of the hospitalization periods of the patients according to clinical data is given in [Table 3].

Table 3: The comparison of the hospitalization periods of the patients according to clinical data.

In the correlation analysis of the patients’ length of stay a weak and positive correlation was detected with NLR, SII and AST or ALT Ratios (p:0.014, r:0.241, p:0.022, r:0.225, p:0.002, r:0.395. respectively). The correlation analysis results of the patients are given in [Table 4].

Table 4: The correlation analysis results of the patients.

ROC curve was used for hematological biomarkers to evaluate the diagnostic levels of SSLR patients. The area under the curve obtained for NLR was 0.839 (95% CI: 0.538to0.656). According to the ROC analysis results of the present study it was found that NLR, PLR, RLR, RLR and SII values were statistically high in diagnosis. When the cutoff value of the NLR levels was taken as 1.36 the sensitivity was calculated as 77.00% and the specificity as 83.30% (p<0.001). ROC analysis results for the diagnostic value of SSLR patients are given in [Table 5].

Table 5: ROC analysis results for the diagnostic value of SSLR; Note: AUC: Area Under the curve; 95%CI: 95% Confidence Ä°nterval; +LR: Positivity Likelihood Ratio.

Discussion

Although there are no diagnostic criteria regarding SSLR it is diagnosed with findings of fever, rash, arthritis, arthralgia, lymphadenopathy and myalgia. Which develop 6 to 21 days after exposure to an agent that might trigger the disease and cannot be attributed to any other cause [5]. Some viral diseases with rash hypersensitivity vacuities acute meningococcal or gonococcal infection, lyme disease, acute rheumatic fever, systemic juvenile idiopathic arthritis, kawasaki and other types of drug reactions should be considered in the differential diagnosis. SSLR should be suspected when urticarial rash is accompanied by systemic findings. Unlike classical serum sickness which presents with similar clinical characteristics. SSLR is triggered by drugs (most often by β lactam antibiotics). However vaccines and infectious agents may also cause the development of SSLR [6].

The incidence of SSLR in children does not have definitive data because there are not many studies conducted in this field to date. This is mostly because of the lack of knowledge of some healthcare professionals regarding this reaction and its clinical presentation. For this reason SSLR may often be easily confused with other rash diseases [5]. In this study the purpose was to uncover exemplary data about the etiology risk factors, treatment and prognosis of the disease. We think that with increased studies to be conducted on SSLR, its frequency will be noticed and new studies will clear on predisposing factors risk factors and many issues.

Among the risk factors the most common therapeutic agents include antibiotics (cephalosporin, clarithromycin, ciprofloxacin, penicillin and minocycline) anticancer agents. Anticonvulsants, antidepressants, antidysrhythmics, antihypertensives and Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) [7,8]. It was found that 30% of SSLR cases were associated with drugs and 60% of the cases caused by drugs were antibiotics [9]. In the present study 60 (49.18%) of the patients had a history of drug use before diagnosis and 49 of these (81.60%) had a history of antibiotic use, with this rate it was found that the rate of drug and antibiotic use was included in the history at a higher rate than in existing epidemiological studies.

SSLR mostly occurs after taking oral antibiotics. It was identified among antibiotics. Especially after ingestion of Cefaclor and its frequency was reported to be 1% to 2% after the exposure [3]. In a previous study conducted in Australia in children under the age of 6, the risk of developing this reaction after taking Cefaclor was found to be 0.4% [10]. In a similar study that was conducted in the United States, the risk was found to be 0.2% [3]. In the present study it was found that it occurred in 29 (59.18%) patients after oral Amoxicill into Clavunate exposure. We think that this difference occurred because of the variability of commonly preferred antibiotics at the country level.

Serum to sickness like reactions may also be observed after infections (some viral infections such as streptococcal infections, tuberculosis, hepatitis) medications and vaccination [11,12]. Infectious agents were also reported to be potential triggers of SSLR [13]. In the present study 86 (70.5%) of the patients had a history of infection before the disease and 23 of these (18.9%) had a family history of allergy. Although there is no valid study in the literature conducted on the risk of infections in the development of SSLR, the results of the study suggest that infections might increase this risk but more studies are needed to prove this.

Type III immune complex type hypersensitivity reaction occurs as a result of the antibody formed against a soluble antigen forming an immune complex by binding with the antigen and activating the complement system. Immune complexes are formed as a result of antigen to antibody fusion. The antigen might be bacteria, viruses, drugs or other exogenous factors. Immune complexes are frequently detected in the vascular wall synovial membrane of the joints glomerular basement membrane in the kidney and choroidal plexus in the brain. Events begin when the immune complex activates the complement system. Anaphylatoxins (C3a, C4a, C5a) which are the complement degradation products cause localized mast cell degranulation and increase in local vascular permeability. Complement degradation products also cause neutrophils to gather in the area neutrophils bind to the immune complex, resulting in tissue damage with the contribution of the membrane attack complex. Type III Reactions can be local or systemic [14]. The mechanism by which drugs or other agents trigger SSLR seems to be different from classical SS because SSLR is not associated with antigen to antibody complex formation and complement blood levels are generally normal [15].

Usually the rash appears before the other findings typically beginning in the anterior lower trunk, periumbilical or axillary region and spreading to the upper trunk and extremities [16,17]. Rashes begin in the joint areas of the hands and feet on the palmar or plantar face and might spread [18]. It is reported in the literature that the rash can appear with very variable characteristics (e.g morbilliform, urticarial with pale center annular plaques or erythema multiformtolike lesions). Urticaria is the most common skin rash and might be itchy. Unlike the classical one lesion do not fade within 24 hours to 36 hours and tend to remain stable in SSLR. In the differential diagnosis the variable characteristics of the rashes might bring to mind many diseases. Cases in which lumbar puncture was performed are available in the literature because rashes were confused with meningococcemia [19]. Lumbar puncture was performed in 1 patient included in the study considering meningococcemia in the differential diagnosis and the result was negative. In the literature the frequency of rash among clinical findings is reported to be 95%. In our country Yorulmaz et al. reported that erythematous rash was present in 89.9% of the patients included in their study [19]. In the present study this rate was recorded as 82%.

The frequency of associated fever in patients varied between 30 to 75% [19,20]. Fever is usually >38.5Ë?C, rises suddenly during the day returns to normal naturally and is not accompanied by chills. Although fever increases and decreases throughout the day it does not show specific changes depending on the time of day and weakness usually accompanies the fever period. The frequency of fever was found to be 34.4% in the present study.

The presence of joint involvement which is characterized by arthralgia, joint swelling and limitation of movement is also needed to diagnose SSLR. Joints are usually affected bilaterally but may also be unilateral. Hand and foot joints are the most commonly affected joints. Less frequently knee and elbow joints might also be involved [21]. Purple discoloration and edema might also be observed in the skin surrounding the joints [14]. Joint inflammation lasts for several days in children with SSLR and the resulting pain leads to limitation of movement. Parents usually report that their children avoid walking or have abnormalities in joint movements [22]. Joint involvement usually appears after the rash and disappears before the rash disappears. Arthritis and arthralgia are distinctive characteristics of SSLR with a benign course when compared to other rheumatic joint involvements [1,23]. The frequency of arthritis reported in the literature is 51.7% and the frequency of arthralgia is 37.9% but the frequency of arthritis was found to be quite high in the present study with a rate of 64.8% and an arthralgia rate of 90.2%.

Although very rare clinical findings of SSLR might include myocardial and neurological involvement shortness of breath in the presence of pulmonary infiltration or effusion and gastrointestinal system involvement as well as hepatosplenomegaly, renal complications and serositis. In the study conducted by Yorulmaz et al., abdominal pain was detected in 17% of the patients, pulmonary involvement in 4 patients, pleural effusion in 3% and pericardial effusion in 3% and hematuria in 3% of patients, while 13% of the patients had abdominal pain in the present study [19]. Pleural effusion and pericardial effusion were detected in only 1 (0.8%) patient and 8 patients (6.4%) were admitted to our hospital with signs of hematuria. It was learned that bone marrow aspiration was performed in 12 (9.8%) patients to exclude leukemia because of bone pain.

In children with SSLR the development of skin rash and arthralgia may range from a few days to several weeks after exposure to the triggering agent. Clinical characteristics typically appear approximately 7 to 10 days after the treatment is completed in antibiotic to induced SSLR [24]. Several studies confirm that up to 80% of pediatric patients with SSLR exposed at least once to the same drug were free of prior reactions. No studies are reporting the relapse rate for SSLR in these patients. However, evidence suggests that those who experience an SSLR condition and are subsequently exposed to the same drug again develop earlier reactions and show more severe symptoms than the previous reaction [16,22].

There are no specific laboratory findings for SSLR and generally include leukocytosis. Slightly increased erythrocyte sedimentation rate and rarely proteinuria and hematuria [25,26]. A series of cases of 29 children with SSLR 46.0% of whom had leukocytosis 76.0% had high erythrocyte sedimentation rates and 83.3% had low complement levels [21]. Leukocytosis was detected in 10 of 29 patients and increased erythrocyte sedimentation rate in 17 in the study conducted by Yorulmaz et al. [19]. Also it must not be forgotten that hypoalbuminemia develops in patients with edema and although it is not common findings might develop depending on the organ involved in systemic involvement. In the present study increased leukocytosis was detected in 48 (39.3%) patients elevated ESR in 89 (72.9%) patients and increased CRP values in 66 (54.1%).

Neutrophils, lymphocytes, monocytes and platelets play important roles in inflammatory processes. Increasing attention has been paid to the roles of markers in the inflammatory response, including inflammatory cytokines, inflammatory cells and platelets [27]. A decrease in the number of circulating lymphocytes, neutrophilia and thrombocytosis occurs in systemic inflammation. Neutrophils play a central role in the host response to acute and chronic infections. Neutrophilia occurs by delayed apoptosis. demargination of neutrophils and stimulation of stem cells through growth factors. Increased neutrophil count at a high NLR value occurs because of increased inflammation but low lymphocyte count occurs because of poor general health status increased cortisol levels due to physiological stress and increased apoptosis. Neutrophils which are activated by tissue destruction release some enzymes such as myeloperoxidase acid phosphatase and elastase. Changes occur in the proportions of circulating leukocytes during the inflammatory response. Neutrophilia is accompanied by relative lymphopenia.

As indices of systemic inflammation to determine systemic inflammation in various chronic inflammatory diseases, NLR and PLR have recently been identified as potentially useful biomarkers for the differential diagnosis or prognostic prediction of diseases [27]. NLR and PLR can be an important measure of systemic inflammation because they are cost to effective and calculated easily. There are no studies in the literature conducted on NLR and PLR levels in SSLR. In the present study it was found that NLR levels were significantly elevated in SSLR patients when compared to the healthy control group. When ROC analysis was made for the NLR values for the diagnostic value of patients with SSLR when the cutoff value was set as 1.36 an AUC of 0.839 (0.789 to 0.889), sensitivity of 77.00% and specificity of 83.30% were detected. In the present study we think that this may be a good biomarker in predicting SSLR and prognosis. Advanced studies are needed on this subject.

PLR is a novel biomarker proposed as an ideal indicator of systemic inflammation [28]. In the present study PLR levels were found to be statistically and significantly higher in patients with SSLR when compared to the control group. When ROC analysis was used for the PLR value for the diagnostic value of patients with SSLR and when the cut to off value was set as 110.31, the AUC was found 0.799 (0.748 to 0.850), the sensitivity was 72.10% and the specificity was 77.10%. We think that PLR might be a good biomarker in predicting patients with SSLR and predicting their prognosis. RDW is a measure of the variability of erythrocyte size in peripheral blood and is an indicator of the deterioration occurring during the differentiation and maturation of erythrocytes as a result of chronic inflammation and oxidative stress [29,30]. It is reported in the literature that RDW is a marker of chronic inflammation and RDW increases with inflammation [31]. In the present study we did not detect any statistical significance between the control groups in terms of RDW of patients with SSLR.

RPR is a biomarker used in various diseases. However we could not find any studies in the literature conducted on SSLR patients. In the present study no statistically significant differences were detected in the RPR levels in patients with SSLR when compared to the healthy control group. RLR is also used as an inflammation biomarker. It was found in the present study that the RLR level was statistically and significantly higher in patients with SSLR when compared to the healthy control group. When ROC analysis was used for the RLR value for the diagnostic value of patients with SSLR when the cut to off value was set as 5.07, the AUC was found to be 0.821 (0.768 to 0.874), the sensitivity was 65.60% and the specificity was 53.10%. No studies conducted with children were detected in the literature investigating the relationship between SII and SSLR. In the present study it was found that the SII level was significantly higher in patients with SSLR than in healthy controls. To investigate the diagnostic value of patients with SSLR when the cut to off value was taken as 504.59 in the ROC Analysis for the SII value, the AUC was found to be 0.818 (0.767 to 0.869) the sensitivity was 70.50% and the specificity was 83.80%.

There are 2 stages of treatment in SSLR [32]. The first step is to terminate the exposure to the agent that is considered to cause the reaction. If the agent cannot be stopped because of any reason there are studies suggesting using plasmapheresis to eliminate it [33]. Second to line treatment is symptomatic treatment. Although SSLR is generally a self to limiting reaction without sequelae, it might take several days or even weeks for symptoms to resolve completely. In such a case medical treatment might be necessary as well as immediate discontinuation of the drug considered to be the causative agent [6,19].

There are no valid guidelines for the medical treatment of children with SSLR since there are not enough studies that evaluate the effectiveness and safety of these treatments. For this reason dosage and duration of treatment often depend on the severity of symptoms and the experience of healthcare staff [14]. Antihistamines and nonsteroidal anti-inflammatory drugs are used to relieve the symptoms of joint pain and itching. In the present study, nonsteroidal anti-inflammatory drugs were used and antihistamine treatment was applied to 18 (15%) patients, and clinical findings completely regressed.

When symptoms are more severe and long-lasting the use of short to term oral corticosteroids is recommended (e.g. prednisone or intravenous methylprednisolone) [6,19]. In a previous study, dramatic improvement was achieved in patients after steroid treatment which was generally administered in variable doses (prednisolone treatment was administered at a dose of 0.5 to 1 mg/kg for approximately 4 weeks) [34]. It was noted that methylprednisolone is administered in low doses in some centers [35-37]. Administering prednisolone at a dose of 40 to 60mg/day for 2 weeks, the symptoms of SSLR by continuing prednisolone at a dose of 20 mg administered every 12 hours for a total of 5 days [2]. In the present study, Methylprednisolone was administered at a dose of 10 mg/kg for the first 3 days and then at a dose of 5 mg/kg for the next 3 days to 104 patients (85%). The patients were discharged with oral prednisolone treatment at a dose of 1 mg/kg and a 4 to week taper schedule after the regression of clinical findings. During follow to ups it was observed that the clinical findings of 90% of the patients disappeared completely and the acute phase values decreased to the normal range.

The prognosis for SSLR is generally good and the average recovery time of patients without any sequelae is 5 to 7 days. As a result of our study with the treatment protocol applied to patients who were diagnosed with SSLR in our clinic, full recovery was achieved in 90% of the patients and no recurrence was observed. A total of 13 (10%) patients with recurrence showed improvement with symptomatic treatment in our clinic follow to ups. As a result of the follow to ups of the patients, Juvenile idiopathic arthritis was diagnosed in 6 (4.91%) patients and familial mediterranean fever in 5 (4.0%) patients. This suggests that other rheumatological diseases must also be considered carefully in the differential diagnosis. We also think that patients who are diagnosed with SSLR might be prone to other rheumatological diseases. Although there is no clinical study on SSLR similar to ours to compare the results with we recommend the steroid treatment protocol applied in our unit considering the success of the treatment.

Conclusion

NLR and PLR values were elevated in SSLR patients, showing that these parameters can be used as important inflammation markers in the diagnosis and follow to up of the disease, High NLR and TLR values in SSLR patients will contribute to these values being used as a reference in future studies. However, studies on this subject with a larger number of patients and clinical evaluation parameters are needed. In our present day, the increasing number of antigenic stimuli and the widespread use of antibiotics cause SSLR to be detected often. As studies conducted on this subject increase, clinicians will recognize this reaction better and a common treatment modality will emerge in the future. The researchers aimed to define this condition, which is quite common, in light of available data, raise awareness among physicians, ensure better recognition, and provide a helpful resource in making the correct diagnosis. There is a need for more comprehensive studies to be conducted on SSLR to create a common treatment protocol.

Declarations

Ethics approval

The approval was obtained from the Selcuk University Faculty of Medicine Non Interventional Clinical Research Ethics Committee before the study was commenced (26-07-2017/230).

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