Introduction
Henoch-Schönlein purpura (HSP) is a systemic small-vessel vasculitis characterized by purpuric rash, arthritis, nephritis, and gastrointestinal symptoms. It is the most common cause of non-thrombocytopenic purpura in childhood, with a community incidence of approximately 13.5-18/100,000 (1,2). HSP is reported to be triggered by infectious agents (e.g., beta-hemolytic streptococci), drugs, food, and insect bites (1,3-6). The most common, prominent sign is non-thrombocytopenic palpable purpura, particularly on the lower extremities. Severe early gastrointestinal system (GIS) and late renal system involvement are the primary factors contributing to the mortality and morbidity of HSP (7).
Although the exact etiopathogenesis of HSP is still unclear, research has focused on the potential roles of tumor necrosis factor (TNF), free oxygen radicals, leukotrienes, prostanoids, vascular cell adhesion molecules, and the C5b-9 terminal complement complex. The complement system is known to be activated by various antigenic stimuli. Activated neutrophils release free oxygen radicals and proteinases, which damage the vascular wall and tissues. Studies have shown that proinflammatory cytokines also play a role in activating the complement system. Increased levels of TNF-a and interleukin (IL)-6 have been observed in children during the acute phase of HSP as compared to healthy controls (2,8-10). This study aimed to investigate whether IL-6 and mean platelet volume (MPV) levels were associated with GIS and renal system involvement in HSP patients.
Materials and Methods
This retrospektif cohort study was performed on HSP patients under 18 years of age at Ankara Child Health and Diseases Hematology and Oncology Training and Research Hospital in Turkey and approved by the local ethical committee, performed according to the Declaration of Helsinki and Good Clinical Practice guidelines Declaration of Helsinki and Good Clinical Practice guidelines (13.3.2011-2011/51). We obtained written informed consent from all participants. The HSP diagnosis was based on the EULAR/PRINTO/PRES criteria (11).
Data Collection and Analysis
Patient clinical and demographic data were collected, including age, sex, the season of disease onset, and the presence and type of infection before the attack. Systemic involvement in each patient was evaluated from the medical history, physical examination, and laboratory tests. Normal MPV, CRP, and IL-6 levels were designated as 6.9-10 fL, 0-1.8 mg/dL, and <5.4 pg/mL, respectively. IL-6 levels were measured via immunoluminometric assay.
HSP nephritis patients were classified by the initial clinical presentation into five grades using a modified Meadow classification: grade 1, microscopic hematuria; grade 2, persistent mild proteinuria (<20 mg/m2/h) and/or hematuria; grade 3, nephritic syndrome (hematuria, low glomerular filtration rate, oliguria, hypertension, edema); grade 4, nephrotic syndrome (proteinuria >40 mg/m2/h, hypoalbuminemia, hyperlipidemia, edema); and grade 5, mixed nephritic-nephrotic syndrome. Indications for renal biopsy were persistent proteinuria, persistent hematuria, nephrotic or nephritic syndrome, or hematuria with renal failure (12). Renal biopsies were graded in increasing severity from I to V according to the International Study of Kidney Disease in Children classification system (13).
Statistical Analysis
We compared the data of the patient groups regarding their demographic, clinical characteristics and outcomes. All statistical analyses were performed using SPSS version 18.0 (SPSS, Inc., Chicago, IL, USA). Descriptive statistics were used to summarize the participants’ baseline characteristics, including medians, and interquartile ranges for continuous variables and frequency distributions for categorical variables. P-values were calculated using the chi-square or Fisher’s exact tests for categorical variables and the Student’s t-test or Mann-Whitney U tests for continuous variables according to the normality assumption to evaluate the relationship between urinary protein content and serum factor and renal impairment in HSP patients. A p-value of <0.05 was regarded as indicative of statistical significance.
Results
A total of 85 patients between 2-17 years of age (median age: 8 years) were included in the study, of which 46 (54.1%) were male and 39 (45.9%) were female (Table 1). All patients had the typical purpuric rash, with 5 (5.8%) showing scalp edema and 61 (71.8%), 63 (74.1%), and 27 (31.8%) displaying joint, GIS, and renal involvement, respectively (Table 1). Of the 27 patients with HSP nephritis, 7 (25.9%) were grade 1, 14 (51.8%) were grade 2, and 6 (22.2 %) were grade 4 according to the modified Meadow’s criteria. The six children assigned as grade 4 underwent renal biopsy, which classified 5 (83.3%) of them as grade 2 and confirmed 1 (16.6 %) as grade 4.
C-reactive protein (CRP) and IL-6 levels were increased in 34 (40%) and 38 (53.5%) of the patients, respectively, while 40 (47.1%) patients had decreased MPV. At the time of diagnosis, when leucocyte count and serum IL-6, CRP, and MPV levels were evaluated, only the serum leukocyte count and CRP level were positively correlated (r=0.223; p=0.03). Urinary protein content did not correlate (p>0.05) with leucocyte count or serum IL-6, CRP, and MPV levels. Although patients with and without joint involvement showed significant differences in the rate of leukocytosis (p=0.01) and CRP levels (p=0.02), these parameters did not significantly differ (p=0.05) for patients with or without renal or GIS involvement.
The median (minimum-maximum) IL-6 levels in patients with renal, GIS, or joint involvement were 5.6 pg/mL (0-30 pg/mL), 5.7 pg/mL (0-45 pg/mL), and 6.8 pg/mL (0-45 pg/mL), respectively. Patients without renal, GIS, or joint involvement had IL-6 levels of 6.5 pg/mL (0-45 pg/mL), 4 pg/mL (0-16.8 pg/mL), and 1 pg/mL (0-39 pg/mL), respectively. The median (minimum-maximum) MPV levels in patients with renal, GIS, or joint involvement were 7.4 fL (5.4-9.1 fL), 6.9 fL (5.3-9.3 fL), and 6.9 fL (5.3-10 fL), respectively. Patients without renal, GIS, or joint involvement had MPV levels of 6.8 fL (5.3-10 fL), 7.2 fL (5.4-10 fL), and 7 fL (5.9-9 fL), respectively (Figure 1). IL-6 and MPV levels did not significantly differ (p>0.05) between patients with and without renal, GIS, or joint involvement (Table 2). Furthermore, these levels were not significantly different (p>0.05) when considering the grade of renal involvement (Table 3).
Of the 85 patients, 11 (12.9%) received supportive care, 33 (38.8%) received non-steroidal anti-inflammatory drugs (NSAIDs), 30 (35.8%) were treated with steroids, and 8 (9.4%) received both steroids and NSAIDs. One patient with severe renal involvement was treated with pulse steroid and pulse cyclophosphamide. The two remaining patients had severe GIS involvement and were treated with pulse steroid and plasmapheresis or with pulse steroid, pulse cyclophosphamide, and plasmapheresis.
Discussion
HSP is an acute, systemic vasculitis of unknown etiology, although several studies have implicated cytokines in its pathogenesis (14-16). The role of IL-6 in HSP renal, GI, and joint involvement has been of particular interest (17-21). IL-6 which is a cytokine important for inducing the fever response, stimulates the production of acute-phase proteins and induces leukocytosis, fever, and angiogenesis, can be released from vascular endothelial cells to initiate and propagate the inflammatory response. Once the inflammatory mechanisms are activated, IL-6 facilitates autoimmune phenomena and amplifies acute inflammation (22). Besbas et al. (17) reported a significant increase in TNF, IL-6, and IL-1 levels in HSP-patient skin specimens. Serum IL-6 levels were also found to be significantly higher during the acute stage of HSP and lower in patients with glomerulonephritis or gastrointestinal hemorrhage (23). Interestingly, Rostoker et al. (20) observed that the serum IL-6 levels of HSP patients did not correlate with proteinuria. In our study, IL-6 levels were increased in 53.5% of the HSP patients; however, there was no significant prognostic relationship between the serum IL-6 level at the initial diagnosis and GIS or renal involvement. These findings may reflect differences between serum and local tissue concentrations of IL-6. Serum concentration is likely not representative of cytokine production rate or local tissue concentration. Moreover, serum cytokine levels are influenced by a variety of interactions involving cytokines, their specific receptors, the soluble receptor fraction, and antagonists (18,24,25).
HSP is characterized by inflammation of small blood vessels via leukocytic infiltration of tissue, hemorrhage, and ischemia. Platelet activation plays a major role in the pathophysiology of diseases presenting with thrombosis and inflammation (26). Platelet volume is known to be correlated with platelet activation and function, with smaller platelets displaying decreased functional capabilities (27,28). Although there are limited studies investigating the role of MPV in HSP etiopathogenesis, decreased MPV levels have been suggested to be involved in HSP-related inflammation (29). Makay et al. (30) reported that low MPV levels could contribute to gastrointestinal bleeding in HSP. MPV has also been suggested to be a useful marker for identifying active disease in HSP patients (31). However, other studies did not observe similar dependencies, and findings concerning the importance of MPV in other inflammatory diseases are conflicting (10,32). Our study found no relationship between decreased MPV levels and GIS or renal involvement in HSP patients.
Study Limitations
Several limitations affect the generalizability of our findings. As the study was performed in a single center, the number of participants was limited. Additionally, there was no healthy control group. Finally, we were unable to evaluate IL-6 levels in sequential blood samples during the follow-up period and upon completion of the treatment.
Conclusion
In conclusion, this study found no prognostic relationship between MPV or serum IL-6 levels at the initial diagnosis and GIS or renal involvement in HSP. Due to the possibility of differences between serum and local tissue concentrations of IL-6, physicians should take account the clinical status of patients than laboratory results.
Ethics
Ethics Committee Approval: Ankara Child Health and Diseases Hematology and Oncology Training and Research Hospital in Turkey and approved by the local ethical committee, performed according to the Declaration of Helsinki and Good Clinical Practice guidelines Declaration of Helsinki and Good Clinical Practice guidelines (2011/51, 3.03.2011).
Informed Consent: We obtained written informed consent from all participants.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Surgical and Medical Practices: K.A., Concept: K.A., Design: K.A., N.Ç., Data Collection or Processing: K.A., Analysis or Interpretation: K.A., N.Ç., Literature Search: K.A., N.Ç., Writing: K.A., N.Ç.
Conflict of Interest: All the authors declare no competing interest in this manuscript.
Financial Disclosure: The authors declare that we have not received any financial support to perform this study.
