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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e31821058bc
Original Articles: Gastroenterology

Leukocytapheresis in Pediatric Patients With Ulcerative Colitis

Tomomasa, Takeshi*; Tajiri, Hitoshi; Kagimoto, Seiichi; Shimizu, Toshiaki§; Yoden, Atsushi||; Ushijima, Kosuke; Uchida, Keiichi#; Kaneko, Hiroaki**; Abukawa, Daiki††; Konno, Mutsuko‡‡; Maisawa, Shun-ichi§§; Kohsaka, Takao||||; Kobayashi, Akio¶¶; and the Japanese Study Group for Pediatric Ulcerative Colitis

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*Departments of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan

Osaka General Medical Center, Japan

Saitama Children's Medical Center, Japan

§Juntendo University School of Medicine, Japan

||Osaka Medical College, Japan

Kurume University Medical Center, Japan

#Departments of Gastroenterology and Pediatric Surgery, Mie University Hospital, Japan

**Mirai Children's Clinic, Japan

††Miyagi Children's Hospital, Japan

‡‡Departments of Pediatrics, Sapporo Kosei General Hospital, Japan

§§Morioka Children's Hospital, Japan

||||Departments of Pediatrics, Tokyo West Tokushukai Hospital, Japan

¶¶Showa University, Toyosu Clinic, Japan.

Received 14 August, 2010

Accepted 10 January, 2011

Address correspondence and reprint requests to Takeshi Tomomasa, MD, Department of Pediatrics, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan (e-mail: tomomasa@gunma-u.ac.jp).

Financial support for the present study was provided by Asahi Kasei Kuraray Medical Co, Ltd, Tokyo, Japan.

The authors report no conflicts of interest.

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Abstract

Objective: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC.

Patients and Methods: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements.

Results: The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration.

Conclusions: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.

Leukocytapheresis (LCAP) has recently been developed in Japan as a possible treatment for active ulcerative colitis (UC). It is a form of extracorporeal therapy that removes leukocytes and blood platelets, which may be involved in inflammation, from the peripheral blood, by passage through a column housing a polyester fiber nonwoven fabric cloth rolled up into a cylindrical shape. The leukocyte adsorption principle of LCAP is attributed to the cells' adhesiveness and a sieving effect. It has been reported that 1 to 1.5 × 1010 leukocytes (granulocytes, monocytes, lymphocytes) and approximately 5 × 1011 blood platelets are removed during apheresis of 3 L of blood (1). LCAP has been shown to suppress inflammation by removing activated leukocytes that cause inflammation (2), normalizing platelet function by removing activated platelets (3,4), reducing the number of reactive oxygen-species–producing granulocytes (5), improving the effector T-cell/suppressor T-cell balance (6), and inhibiting proinflammatory cytokines (7,8).

In adult patients, LCAP has been reported to be more effective than increasing the steroid dose as a treatment for steroid-resistant disease (9–12), and may also be effective in steroid-free patients (13). The Japanese guidelines for the management of UC (14), which were developed by the Research Group for Intractable Inflammatory Bowel Disease, funded by the Japanese Ministry of Health, Labour, and Welfare, indicate LCAP for patients who fail to respond to 1 to 2 weeks of prednisolone (PSL) treatment at an adequate dose (30–40 mg/day).

Only a few retrospective case reports have been published on LCAP therapy in children (15,16), and its usefulness and safety in such patients are thus largely unknown. An additional problem is that the available columns are unsuitable for the treatment of pediatric patients with low body weights because of the large volume of extracorporeal circulating blood. A new column (model EI), which uses the same material as the EX column but with only half the volume, has recently been developed and is expected to increase the availability of LCAP for children. In the present study, we assessed the efficacy and safety of LCAP in pediatric patients with UC using the standard EX and the reduced-volume EI columns.

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PATIENTS AND METHODS

Study Design

The present study was a prospective open trial conducted at 21 participating institutions. The study protocol was reviewed and approved by the institutional review board of each participating institution. Age-appropriate patient consent or assent was obtained, in addition to informed parental consent.

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Patient Selection

The present study enrolled subjects between the ages of 8 and 16 years with steroid-resistant moderate-to-severe UC, including 1 fulminant case. UC was diagnosed on the basis of standard clinical and endoscopic criteria. A patient was regarded as steroid-resistant when the decrease in stool frequency/hematochezia score was ≤1 after at least 2 weeks of oral or intravenous steroid therapy (PSL ≥1 mg · kg−1 · day−1 or ≥40 mg/day), or if the score had increased by ≥1 at the end of the first week. Continuous use of preceding drugs (mesalazine, salazosulfapyridine, and azathioprine) was permitted on the condition that they had already been used for at least 2 weeks and that the dose was not changed or reduced during the period of the trial. Patients who were being treated with cyclosporine or steroid pulse therapy or who had participated in another clinical trial in the last 6 months were excluded.

Patients with the following conditions were excluded from the present study: toxic megacolon, serious kidney dysfunction or circulatory disorders, currently pregnant, currently breast-feeding, serious infection, a history of shock during extracorporeal circulation, a history of nafamostat mesilate hypersensitivity, prescribed an angiotensin-converting enzyme inhibitor, a blood platelet count <100,000/μL, and a white blood cell count <3000/μL.

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LCAP Treatment

During LCAP treatment, blood was continuously drawn from a cubital or femoral vein into the extracorporeal circuit by a blood pump, passed through the column, and then returned to a cubital or femoral vein on the opposite side of the inlet. In the present study, 2 types of columns with different volumes were used. The EX column used in clinical practice has a volume of 170 mL, whereas the recently developed EI column has a volume of 90 mL, approximately half the volume of the EX. The choice between the EX and EI columns depended on the patient's body weight. The EI column was used for patients with a body weight of 20 to 30 kg, and the EX column was used for patients weighing ≥40 kg. The investigator in charge decided which column to use for patients who weighed between 30 and 40 kg, based on each patient's general condition.

The volume of blood processed during a single treatment with either column was 30 to 50 mL/kg. Treatment was performed at a blood flow rate of 30 to 50 mL/min with the EX and 15 to 25 mL/min with the EI column. Nafamostat mesilate was used as the anticoagulant.

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Study Protocol

LCAP therapy was performed once per week for 5 consecutive weeks in moderate and severe cases. In the fulminant case, LCAP was performed twice during the first week, and then once per week for the next 4 weeks. LCAP therapy could be performed once per week for an additional 5 consecutive weeks from the sixth week onward, at the discretion of the investigator in charge.

The primary endpoint was a decrease in baseline (pretreatment) stool frequency/hematochezia score after 5 treatments. Presence or absence of remission, stool frequency before treatment and after 5 treatments, hematochezia, body temperature, abdominal pain, steroid dose, serum C-reactive protein level, erythrocyte sedimentation rate, hemoglobin concentration, fecal calprotectin, Lichtiger clinical activity index (CAI) (17), and Matts endoscopic score (Appendix A) (18) were assessed as secondary endpoints.

The stool frequency/hematochezia score was calculated as the sum of the diarrhea frequency score and visible fecal blood score using Lichtiger CAI. Severity of UC was defined according to the diagnostic criteria for Crohn disease and UC, modified Truelove criteria, published by the Ministry of Health, Labour, and Welfare (Appendix B) (14). Remission was defined as no fever, no abdominal pain, no blood in the stools, a normal frequency and consistency of bowel movements, and normal erythrocyte sedimentation rate (≤30 mm/h) and C-reactive protein (≤1.0 mg/dL) values (19).

In addition, we assessed the number of patients with improvements, defined as reductions in stool frequency/hematochezia score ≥2 points or reduction in Matts endoscopic score ≥1 grade. We also evaluated the decrease in PSL dose after LCAP therapy.

Most patients enrolled in the present study had moderate disease and only 4 had severe/fulminant disease as described below; thus, the effect of disease severity on the efficacy of treatment was not clearly demonstrated. We retrospectively classified the patients into 2 groups according to disease severity and PSL administration: group 1 (n = 15) included patients with moderate disease treated with oral prednisone and group 2 (n = 8) included patients with severe/fulminant disease (n = 4) or patients treated with intravenous steroids (n = 4), and compared stool frequency/hematochezia scores before and after LACP treatment between these 2 groups.

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Statistical Analysis

Last observation carried forward was used as a substitute for the next measurement after 5 treatments; however, if no supplementary data other than baseline data existed because of discontinuation or dropping out, the worst value of all of the subject's data was substituted. Numerical data were analyzed using Wilcoxon signed rank-sum test, and categorical data were analyzed using the Fisher exact test. Values of P < 0.05 were considered to be significant.

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RESULTS

Twenty-three patients ages 8 to 16 years were enrolled. Their backgrounds are shown in Table 1, and the patient disposition is shown in Figure 1. Eleven patients were treated using an EI and 12 using an EX column. LCAP treatment was discontinued and switched to another form of treatment in 1 patient because the abdominal pain and fever associated with UC became more severe during the first course of treatment.

Table 1
Table 1
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Figure 1
Figure 1
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Clinical Outcome

The stool frequency/hematochezia score decreased significantly, from 4.5 ± 1.2 before the series of LCAP therapy to 1.6 ± 1.9 after LCAP therapy (P < 0.01). The remission rate was 9/23 (39%) patients, and clinical improvements were noted in 19/23 (83%) patients. Stool frequency, hematochezia, and abdominal pain improved in 74%, 78%, and 63% of patients, respectively. There was no change in body temperature after treatment. Lichtiger CAI score also decreased significantly, from 9.9 ± 4.1 after the first LCAP to 5.4 ± 4.5 after the fifth LCAP (P < 0.01). Matts endoscopic score improved significantly from 0/0/12/4 (grade 1/2/3/4) before therapy to 4/9/2/1 (grade 1/2/3/4) after therapy (P < 0.01). The PSL dosage decreased in 18/23 (78%) patients, from 1.1 ± 0.4 mg/kg before therapy to 0.8 ± 0.5 mg/kg after therapy. Fecal calprotectin and the leukocyte count were also lower after therapy than before therapy (Table 2).

Table 2
Table 2
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The changes in stool frequency/hematochezia score and Lichtiger CAI score are shown in Figure 2. Both scores decreased in a similar manner with each treatment, with a correlation coefficient of r = 0.8986 (Fig. 3).

Figure 2
Figure 2
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Figure 3
Figure 3
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The changes in stool frequency/hematochezia score between baseline and after treatment using the EX and EI columns are shown in Figure 4. The stool frequency/hematochezia score decreased significantly, from 4.8 ± 1.3 before treatment to 1.5 ± 2.1 after treatment with EI, and from 4.3 ± 1.1 before treatment to 1.8 ± 1.9 after treatment with EX. Matts endoscopic score improved in both groups after treatment.

Figure 4
Figure 4
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The stool frequency/hematochezia scores before and after LACP treatment in group 1 were 3.9 ± 1.4 and 0.7 ± 1.7, and those in group 2 were 5.8 ± 1.0 and 2.0 ± 2.4, respectively.

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Adverse Effects

Adverse effects were reported in 14 of the 23 patients (61%): 5/11 (45%) with EI and 9/12 (75%) with EX. The most common adverse effects were a decrease in hematocrit in 6 patients (26.1%), pain at the infusion site in 5 patients (21.7%), and a decrease in red blood cell count in 3 patients (13.0%). None of the adverse effects were considered to be serious, and none necessitated discontinuation or interruption of treatment.

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DISCUSSION

Two types of cytapheresis therapy, LCAP and granulocyte/monocyte apheresis (GMA), have recently been developed for UC in Japan. Circulating granulocytes, monocytes, and lymphocytes are removed by LCAP using a Cellsorba column (Asahi Medical, Tokyo, Japan), whereas granulocytes and monocytes are removed by GMA using an Adacolumn (JIMRO, Takasaki, Japan), with little effect on lymphocytes. Cytapheresis therapy has been used to treat many adult patients with UC (9–13,20), and its efficacy and safety have been reported. Although a few reports have also suggested its usefulness in children (15,16,21–23), these were case reports with small numbers of patients, and most of them used GMA (21–23).

The present study was performed to determine the efficacy and safety of LCAP in steroid-refractory pediatric patients. The data showed a significant decrease in the stool frequency/hematochezia score, from 4.5 ± 1.2 before a series of LCAP therapy, to 1.6 ± 1.9 after LCAP therapy. Improvement, defined as a decrease in stool frequency/hematochezia score by ≥1 or a decrease in Matts endoscopic score by ≥1 grade, was achieved in 19 out of 23 patients (83%). In addition, laboratory parameters such as fecal calprotectin and white blood cell count were reduced after therapy. The results of a randomized multicenter trial in adult patients with moderate and severe steroid-resistant UC showed an improvement rate of 74% in the LCAP group, which was significantly higher than the 38% improvement rate in the intensive PSL therapy group, in which the dose of PSL was increased (9). Another double-blind study using sham columns found an improvement rate of 80% in the LCAP group, which was significantly higher than the 33% in the sham-column group (P < 0.05) (10). The improvement rates in children in response to LCAP shown in the present study suggest that this treatment has an efficacy similar to that demonstrated in adults.

Some previous reports have suggested that some adverse effects of steroids are more serious in children than in adults (24,25). In the present study, the steroid dose was reduced in 18/23 (78%) patients, compared with the dose before LCAP therapy, suggesting that LCAP may be helpful in allowing a reduction in steroid dose in pediatric UC, thus mitigating the adverse effects of steroids.

The present study was performed as an uncontrolled study because the use of sham columns is ethically unacceptable in clinical trials involving children. Some reports, however, have shown improvements in the natural course of UC (26), and the results of the present study may therefore have included the effects of natural changes in the course of the disease. It should also be noted that the long-term effects of this therapy were not determined in the present study, and further studies are needed to explore this aspect.

In the present study, the effect of disease severity on the efficacy of LCAP was not clear. Previous studies have reported reduced or delayed efficacy of LCAP therapy in patients with deeply penetrating ulcers or in steroid-dependent patients, suggesting that not all patients with UC benefit from LCAP (12). Further clinical studies are needed to confirm the usefulness of LCAP therapy in children and to determine the type of pediatric patients in whom LCAP is indicated.

The usual recommended volume of extracorporeal circulating blood is 10% of the patient's total blood volume. The volume of extracorporeal circulating blood using the EX column is the sum of the column volume (170 mL) and the volume of the circuit. The volume in patients whose body weight is <30 kg may thus exceed 10%, making the treatment difficult to perform. In the present study we used the newly developed EI column (90 mL), the volume of which is half that of the EX. The flow rate of circulating blood also can be reduced with the EI to half that required with the EX. The results showed an improvement in 10/12 (84%) patients with UC, younger than 18 years of age, weighing 38 to 60 kg, and treated with EX, and in 9/11 (82%) patients younger than 18 years of age, weighing 21 to 36 kg, and treated with EI. This suggests that LCAP using a column with a smaller volume can be an effective treatment in patients with low body weight.

Adverse effects occurred in 14/23 (61%) patients. The nature of the adverse effects was similar to that previously reported for other types of apheresis treatment, and none of them were serious. An iron preparation was used in some patients to treat the most common adverse effect, anemia, manifested by a low hematocrit, and all of these patients recovered. The next most common adverse effect was pain at the infusion site. It is possible that the reported frequency of this effect was high because the study subjects were children, who are more afraid and less tolerant of injection pain.

Although several different types of CAI score (17,27,28) have been used as evaluation indices for UC in adult patients, we developed stool frequency/hematochezia score as a primary endpoint for use in the present study. The previous scores include several items that require subjective judgment, such as abdominal pain and feelings of well-being; however, we considered that the primary endpoint should not involve highly subjective items because the open-label nature of the study meant that the impressive appearance of an apheresis device may be associated with a considerable placebo effect. The Pediatric UC Activity Index (29) was not available at the start of this trial. We therefore developed a special score using the 2 main items from Lichtiger CAI, to produce a score that was as simple and objective as possible. This score was highly correlated with Lichtiger CAI (r = 0.8986).

In summary, by selecting an appropriate column for the patient's body weight, LCAP could be performed safely and effectively in pediatric patients with UC, despite a wide range of ages and body weights. The efficacy of the procedure was comparable to that performed in the adult population. The results of the present study suggest that LCAP can be a useful medical procedure for pediatric patients in the active phase of UC, and further studies are required to determine the types of pediatric patients best suited to LCAP therapy.

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REFERENCES

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Appendix A Matts score18
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Appendix B Classification of UC by severity14*
Table 1
Table 1
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Cited By:

This article has been cited 1 time(s).

Digestive Diseases and Sciences
Fecal Calprotectin in Pediatric Inflammatory Bowel Disease: A Systematic Review
Kostakis, ID; Cholidou, KG; Vaiopoulos, AG; Vlachos, IS; Perrea, D; Vaos, G
Digestive Diseases and Sciences, 58(2): 309-319.
10.1007/s10620-012-2347-5
CrossRef
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Keywords:

apheresis; calprotectin; children; prospective study; remission

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