Pediatric Nephrology

https://doi.org/10.1007/s00467-018-3900-z

ORIGINAL ARTICLE

Infusion reactions associated with rituximab

treatment for childhood-onset complicated nephrotic syndrome
Koichi Kamei 1 & Masao Ogura 1 & Mai Sato 1 & Shuichi Ito 2 & Kenji Ishikura 1

Received: 16 October 2017 / Revised: 21 January 2018 / Accepted: 23 January 2018

# IPNA 2018

Abstract
Background Infusion reaction (IR) is defined as an adverse event within 24 h after monoclonal antibody infusion. In non-Hodgkin
lymphoma, IR incidence following rituximab treatment is high (77–80%), but there are no data in complicated nephrotic syndrome.
Methods Records of rituximab infusions in patients with complicated nephrotic syndrome between February 2006 and
December 2014 at the National Center for Child Health and Development were reviewed. Rituximab was administered at doses
of 375 mg/m2. The severity of IR was evaluated using the Common Terminology Criteria for Adverse Events ver. 4.0.
Results For 309 rituximab infusions in 159 patients (male, 110; median age, 12 years), IR was observed in 165 infusions (53.4%).
Respiratory symptoms were most common (66% of all events). Ninety-five percent of the IR was observed within 3 h after
rituximab infusion initiation. Sixty-eight percent of the events were classified as grade 1 and others classified as grade 2. Only
18% required medical intervention. CD20 cell count in patients with IR was significantly higher than in patients without IR.
Incidence of IR was similar in subsequent rituximab treatment after B-cell recovery. Patients who experienced IR at first
rituximab treatment were more likely to experience recurrent IR with subsequent treatments compared to those not having IR
at initial treatment (odds ratio 3.64; p < 0.001).
Conclusions In patients with complicated nephrotic syndrome, respiratory symptoms were the major type of IR, mostly observed
within 3 h of infusion. Incidence of IR was lower and its severity milder in patients with complicated nephrotic syndrome than
those with lymphoma.

Keywords Rituximab . Infusion reaction . Complicated nephrotic syndrome . B-cell . Respiratory symptoms

Introduction (anaphylactic reactions) which are mediated by immunoglob-

Infusion reaction (IR) is defined as any adverse event occur-
ring within 24 h after the infusion of monoclonal antibody [1].
Its clinical manifestations resemble allergic reactions or hy-
persensitivity syndrome and include such symptoms as fever,
chills, headache, pain, nausea, itching, rash, cough, and ede-
ma. However, its mechanism is distinct from allergic reactions
* Koichi Kamei
kamei-k@ncchd.go.jp
1
Division of Nephrology and Rheumatology, National Center for
Child Health and Development, 2-10-1, Okura, Setagaya-ku,
Tokyo 157-8535, Japan
2
Department of Pediatrics, Yokohama City University Graduate
School pf Medicine, 3-9, Fukuura, Kanazawa-ku,
Yokohama, Kanagawa 236-0004, Japan
ulin E [1]. Sometimes, severe fatal symptoms, such as respi-
ratory distress or heart failure, may occur in IR.
The mechanism of IR caused by rituximab is not fully
understood, although the release of cytokines or chemokines
due to B-cell destruction is the most likely cause of this phe-
nomenon. Tumor necrosis factor-α and interleukin-6 were
reportedly elevated after rituximab infusions [2–4]. In patients
with non-Hodgkin lymphoma, the incidence of IR resulting
from rituximab treatment was reportedly 77–80% [5–12], a
much higher figure than that for other monoclonal antibodies,
while the incidence of severe IR (grade 3–4) was reportedly
4.4–10% [13, 14]. However, as the increase in IR risk corre-
lated with an increased population of B-cells and the presence
of splenomegaly and prior cardiovascular disease or respira-
tory dysfunction [15, 16], the clinical characteristics of IR
resulting from rituximab treatment in patients with nephrotic
syndrome might differ from those of patients with non-
Hodgkin lymphoma.

To date, there have been no detailed reports of IR associat-
ed with rituximab treatment for complicated nephrotic syn-
drome. Here, we retrospectively investigated IR associated
with rituximab treatment using data from patients with com-
plicated nephrotic syndrome who were treated at our center
and analyzed the incidence, clinical characteristics, severity,
and risk factors.
Materials and methods
Study design and patient population
We reviewed the records of patients with complicated ne-
phrotic syndrome who were treated with rituximab be-
tween February 2006 and December 2014 at the
National Center for Child Health and Development.
Complicated (refractory) nephrotic syndrome was defined
as steroid-sensitive nephrotic syndrome with continuing
frequent relapses or steroid-dependent despite standard
immunosuppressant therapy and thus requiring continua-
tion of steroid therapy: or steroid-resistant nephrotic syn-
drome without complete remission despite standard im-
munosuppressant therapy [17]. IR was defined as all ad-
verse events occurring within 24 h after rituximab infu-
sion. We excluded cases of rituximab treatment during B-
cell depletion (i.e., second, third, or fourth weekly dose
for four doses), as the incidence of IR is reportedly much
lower during B-cell depletion. We also excluded patients
enrolled in the investigator-initiated multicenter clinical
trials of rituximab treatment in Japan, as the present trial
is based on a double-blind, randomized, placebo-
controlled study of rituximab [18].
Before rituximab administration, the following assess-
ments were made: complete blood counts, biochemical pa-
rameters (total protein, albumin, renal function, liver function,
electrolytes, C-reactive protein, etc.), peripheral B-cell count,
and hepatitis B and C virus titers. Chest X-rays and electro-
cardiograms were also performed. Rituximab was adminis-
tered at a dose of 375 mg/m2 (maximum dose of 500 mg).
To minimize the risk of IR, patients received oral acetamino-
phen (10 mg/kg; maximum, 300 mg) and chlorpheniramine
maleate (0.04 mg/kg; maximum, 2 mg), 30 min prior to ritux-
imab infusion. From August 2007, patients received intrave-
nous methylprednisolone (1–1.5 mg/kg) 30 min prior to ritux-
imab infusion to minimize the risk of IR. Rituximab was di-
luted to 1 mg/ml with saline and administered to patients at the
initial dose of 25 ml/h for 1 h. If patients experienced no IR,
the infusion rate was increased to 100 ml/h for the next 1 h and
200 ml/h until the end of infusion. In the event of an IR, the
attending physicians decreased the infusion rate or stopped
until the symptoms disappeared according to their severity.
Pediatr Nephrol
The physicians also administered medical interventions, such
as inhalation or steroid infusions, as clinically indicated.
Data collection and analysis
All IR data were collected from medical charts. We catego-
rized events according to their clinical characteristics and in-
vestigated their incidence, onset time, and medical interven-
tions if any. The severity of IR was categorized as grade 1 to 5
using the Common Terminology Criteria for Adverse Events
(CTCAE) ver. 4.0. We analyzed the risk factors by comparing
patients with and without IR. We also evaluated the frequency
of IR at subsequent rituximab treatments.
The data were analyzed with the JMP version 11.0
(SAS institute Japan Ltd., Tokyo, Japan). The Mann-
Whitney U test was used for continuous values and
Fisher’s exact test for categorical values. Statistical signif-
icance was established at P < 0.05.
Results
Patient characteristics and incidence of IR
We reviewed 309 rituximab infusions in 159 patients
(Fig. 1, Table 1). IR was observed in 165 infusions
(53.4%). Table 2 shows the details of all IR cases.
Respiratory symptoms such as sore throat and cough oc-
curred most frequently and comprised 75% of all 165 IR
cases and 66% of all 225 adverse events.
Onset time of IR
Figure 2 shows the onset times of IR. Median time of onset of all
225 events was 1 h, and 214 events (95%) were observed within 3 h
after the initiation of rituximab treatment. In 148 respiratory events,
420 infusions in 168 patients
36 infusions (1st~4th doses) in 9
patients were excluded as they
60 infusions (1st~4th doses) in
were enrolled in the multicenter
clinical trials. (There were no
15 patients were excluded as subsequent infusions.)
they were enrolled in the
multicenter clinical trials. (Their
15 infusions (2nd~4th doses)
subsequent infusions were
during B-cell depletion in 5
included.)
patients were excluded. (Their
1st and subsequent infusions were
included.)
309 infusions in 159 patients
(279 infusions at steroid sensitive;
30 infusions at steroid resistant)
(One patient received 1st infusion in the other institute.)
Fig. 1 Flow diagram of this study population. Rituximab infusions in the
multicenter clinical trials [18] and infusions during B-cell depletion were
excluded in this study, although subsequent infusions were included
Pediatr Nephrol

Table 1 Patient characteristics Table 2 Details of 225 events observed in 165 infusions

No. of patients 159 No. of No. of Details No. of

Male sex 110 (69.2) infusions events of events events
with IRa of IRb
Age at NS onset (years) 4 (2–8)
Biopsy findings Respiratory 124 (75%) 148 (66%) Sore throat 75
MGA 125 (78.6) Cough 38
FSGS 29 (18.2) Dyspnea 21
DMP 3 (1.9) Wheezing 11
Unknown 1 (0.6) Hoarseness 3
Not performed 1 (0.6)
No. of RTX infusions 309 Skin 25 (15%) 25 (11%) Facial flush 13
Age at RTX treatment (years) 12 (7–16) Itching/urticaria 7
State of NS at RTX treatment Other rash 5
Complete or partial remission 279 (90.3)
No remission 30 (9.7) Cardiovascular 20 (12%) 22 (10%) Hypertension 13
Immunosuppressive agent at RTX treatment Palpitation 3
CsA 45 (14.6) Tachycardia 2
CsA + MMF 83 (26.9) Hypotension 2
CsA + MZR 66 (21.4) Bradycardia 1
Tac 6 (1.9) Premature ventricular 1
contraction
Tac + MMF 6 (1.9)
Tac + MZR 2 (0.6) Digestive 18 (11%) 18 (8%) Abdominal pain 11
MMF 53 (17.2) Vomiting 4
MZR 17 (5.5) Nausea 3
None 31 (10.0)
Steroid treatment at RTX treatment 285 (92.2) Others 12 (7%) 12 (5%) Fever 7
RAS blockade use at RTX treatment 95 (30.7) Headache 5
ACE-I 39 (12.6)
ARB 48 (15.5) More than one symptoms were observed in one infusion in several cases
ACE-I and ARB 8 (2.6) IR infusion reactions
a
CD20 cells at RTX treatment (%) 13.1 (7.6–21.3) Data represents incidents of each symptoms in 165 infusions
b
CD20 cells at RTX treatment (/mm3) 232.2 (105.3–388.2) Data represents incidents of each symptoms in 225 events
mPSL infusion prior to RTX infusion 298 (96.4)
antihistamine or antihypertensive agent, oxygenation, inhala-
Data are presented as median (interquartile range) or number (%) tion) (CTCAE grade 2). No grades 3–5 events were observed,
NS nephrotic syndrome, MGA minor glomerular abnormalities, FSGS and all patients completed their rituximab infusions. None of the
focal segmental glomerulosclerosis, DMP diffuse mesangial prolifera- patients experienced any severe life-threatening event.
tion, RTX rituximab, CsA ciclosporine A, MMF mycophenolate mofetil,
MZR mizoribine, Tac tacrolimus, RAS blockade renin-angiotensin system
blockade, ACE-I angiotensin converting enzyme inhibitor, ARB angioten- Comparison of patient demographics with and
sin receptor blockade, mPSL methylprednisolone without IR events

the median time of onset was also 1 h, and 146 events (99%) were We compared the characteristics of patients with and without
observed within 3 h after the initiation of rituximab treatment. IR (Table 3). The CD20 cell count and the percentage of
CD20 cells in the lymphocytes at rituximab infusion were
Severity of IR and medical intervention significantly higher in patients with, than in those without, IR.

In 225 IR events, 153 events (68%) required neither a decrease
nor discontinuation of rituximab infusion or medical interven-
tion (CTCAE grade 1). Thirty-one events (14%) required a de-
crease or temporary discontinuation of rituximab infusion with-
out medical intervention (CTCAE grade 2). Forty-one events
(18%) required medical intervention (treatment with a steroid,
The number of rituximab infusions and the incidence
of IR
Seventy-nine patients received additional rituximab treatment
after B-cell recovery during the study period. The incidence of
IR was similar in subsequent rituximab treatments (Table 4).

No. of events
100
80
60
40
20
㻜 lymphoproliferative disease [19]. In that study, most of the
0 3 6 9 12 15 18 21
Hours after initiation of rituximab infusion
Fig. 2 Onset time for all 225 events. Black boxes represent respiratory
events, and white boxes represent other symptoms. Mean ± standard
deviation of time of onset is as follows, respiratory symptoms (148
events); 1.2 ± 1.1 h. Skin symptoms (25 events); 1.6 ± 1.0 h.
Cardiovascular symptoms (22 events); 2.3 ± 3.7 h. Digestive symptoms
(18 events); 0.6 ± 0.6 h. Other symptoms (12 events); 1.9 ± 1.3 h
Risk of IR at subsequent rituximab treatments
in patients with or without IR at initial treatment
Seventy-six patients received 130 additional rituximab treat-
ments. In these 76 patients, IR was observed in 48 patients
during their initial treatment. These 48 patients received 81
additional rituximab infusions, in 55 (68%) of which an IR
occurred. The 28 patients who did not experience an IR at the
initial treatment received 49 subsequent rituximab infusions,
in 18 (37%) of which an IR occurred. Patients who experi-
enced IR with the first rituximab treatment were more likely to
experience recurrent IR with subsequent treatments compared
to those who did not have IR at the initial treatment (odds ratio
3.64; p < 0.001).
Discussion
We reviewed IR cases associated with rituximab treatment for
complicated nephrotic syndrome at our center. The incidence
of IR was much lower in patients with complicated nephrotic
syndrome (53.4%) than in patients with non-Hodgkin lym-
phoma (77–80%) [5–12]. Moreover, no patients experienced
grades 3–5 events in our study, although the incidence of
Table 3 Comparison of patient
demographics with and without
IR events
Male gender
Age at RTX infusion (years)
Complete or partial remission of NS at RTX treatment
RAS blockade use at RTX treatment
CD20 cells at RTX treatment (%)
CD20 cells at RTX treatment (/mm3)
mPSL infusion prior to RTX infusion
Data are presented as median (interquartile range) or number (%)
IR infusion reaction, RTX rituximab, NS nephrotic syndrome, RAS blockade renin-angiotensin system blockade,
mPSL methylprednisolone
Pediatr Nephrol
grades 3–5 events was reportedly 4.4–10% in patients with
non-Hodgkin lymphoma[13, 14]. In our study, two thirds of
all IR was grade 1, and the rate of events requiring medical
intervention was only 18%. In a recent retrospective study of
IR with rituximab, the rate was 39.2% and most cases were
low grade, which is similar to our experience in non-
24 diseases were not lymphoproliferative. Based on this study
and our own results, we speculate that the lower B-cell popu-
lation was the chief reason for the milder severity of IR in non-
lymphoma patients than patients with non-Hodgkin lympho-
ma, although more data are needed to clarify the pathophysi-
ology and risk of IR in the future.
The baseline B-cell count in patients with IR was signifi-
cantly higher than in patients without IR. This result is under-
standable given the suspected mechanism of IR in rituximab
treatment. Legeay et al. showed that a higher absolute lym-
phocyte count before infusion was associated with a greater
risk of IR [19]. Our data also showed that patients who expe-
rienced IR were more likely to experience it again in subse-
quent treatments, possibly because they had a higher B-cell
count than those without IR.
In non-Hodgkin lymphoma, the incidence of IR gradually
decreased with repeated administration of rituximab as the
population of tumor cells (B-cells) gradually decreased [1,
4–12]. However, at our institution, rituximab for complicated
nephrotic syndrome is usually administered in a single dose
which depletes the peripheral B-cell count. Rituximab is re-
administered when the B-cell count recovers and the patient
experiences a relapse. This is why we suspect that the inci-
dence of IR did not decrease in subsequent rituximab treat-
ments in this study. Indeed among eight patients at our center
who received rituximab during the period of B-cell depletion
(i.e., second, third, or fourth weekly dose for four doses), IR
was observed three times in 24 infusions (13%), which was
much lower incidence. Legeay et al. also showed that the rate
of IR was only 2.7% in subsequent doses [19].
Our study found that respiratory symptoms, such as sore
throat, cough, dyspnea, and wheezing, were the major types of
IR (+) (n = 165) IR (−) (n = 144) P value
115 (69.7) 101 (70.1) 1.00
11 (7–15) 12 (7–16) 0.35
152 (92.1) 130 (90.3) 0.29
44 (26.7) 51 (36.4) 0.11
15.4 (8.3–23.1) 11.1 (6.8–18.3) 0.01
276 (125–510) 197 (96–355) 0.03
6 (3.6%) 5 (3.5%) 1.00
Pediatr Nephrol
Table 4 The number of RTX infusion and the incidence of IR
RTX infusion No. of infusion Infusions with IR (%)
1st 144 83 (57.6)
2nd 74 40 (54.1)
3rd 26 12 (46.2)
4th 7 4 (57.1)
5th 18a 8 (44.4)
6th 16 8 (50.0)
7th 13 6 (46.2)
8th 8 2 (25.0)
9th 3 2 (66.7)
IR infusion reaction, RTX rituximab
a
Fifteen patients received RTX once weekly for four doses in the
investigator-initiated multicenter clinical trials at their first treatment
[18]. Their four infusions (1st–4th) were excluded from this study. This
is the reason why the number of patients of fifth dose was higher than that
of fourth dose
IR events. Approximately two thirds of all events were respira-
tory. The symptoms of upper respiratory infection have been
shown to be induced by cytokines and chemokines from lym-
phocytes [20, 21]. Thus, an increase in cytokines and chemokines
due to B-cell destruction may readily account for the respiratory
symptoms resembling an upper respiratory infection.
Another fact which became apparent in our study was that
most events occurred within 3 h after the initiation of a ritux-
imab infusion, possibly demonstrating that most peripheral B-
cells are depleted within several hours after the initiation of a
rituximab infusion. Previous reports have also shown that tu-
mor necrosis factor α levels peak 1 h after a rituximab infusion
[3]. As most events were observed within 3 h of infusion and
no life-threatening events occurred, we posit an observation
time of three to 4 h as sufficient for rituximab treatment in
patients with nephrotic syndrome.
This study has some limitations. First, all adverse events
during 24 h after the initiation of rituximab were recorded as
IR in this study. IR caused by cytokines or chemokines during
the period of B-cell depletion is difficult to distinguish from
allergic/anaphylactic reactions mediated by immunoglobulin
E, raising the possibility that some allergic/anaphylactic reac-
tions were included in our analysis. Second, although none of
our patients experienced a life-threatening adverse event, the
body of data in this study was not sufficient to exclude the
possibility of severe adverse events. Severe late adverse
events such as agranulocytosis [22], Pneumocystis jirovecii
pneumonia [23], interstitial pneumonia [24, 25], and progres-
sive multifocal leukoencephalopathy due to JC virus reactiva-
tion [26, 27] have been reported with rituximab treatment.
Hence, we have to concede that rare but severe adverse events
may occur with rituximab treatment.
In conclusion, we were able to ascertain the principal as-
pects of IR resulting from rituximab treatment for complicated
nephrotic syndrome. The IR incidence and severity were
much milder in patients with complicated nephrotic syndrome
than those with non-Hodgkin lymphoma. Respiratory symp-
toms were the major type of event, and most cases of respira-
tory complication were observed in the first 3 h after initiation
of infusion. Patients who experienced IR showed a higher B-
cell count than those without IR and were more likely to
experience IR again at subsequent rituximab treatments.
Rituximab treatment for complicated nephrotic syndrome is
generally safe, although more data are necessary to assess the
possibility of rare but severe late adverse events.
Compliance with ethical standards
Conflict of interest KK has received lecture fees from the Chugai
Pharmaceutical Co., Ltd. SI has received lecture fees and/or grants from
the Chugai Pharmaceutical Co., Ltd.; Zenyaku Kogyo Co., Ltd.; Asahi
Kasei Pharma; Novartis Pharma K.K.; and Astellas Pharma Inc. KI has
received lecture fees from the Asahi Kasei Pharma; Chugai
Pharmaceutical Co., Ltd.; Zenyaku Kogyo Co., Ltd.; and Novartis
Pharma K.K. and a consultant fee from Ono Pharmaceutical Co., Ltd.
Ethical approval The design and execution of this study were in accor-
dance with the ethical standards of the Declaration of Helsinki. The pro-
tocol was approved by the Ethics Committee of the National Center for
Child Health and Development (no. 1505).
Informed consent For this type of study, formal informed consent is not
required.
References
1. Vogel WH (2010) Infusion reactions: diagnosis, assessment, and
management. Clin J Oncol Nurs 14:E10–E21
2. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A
(1999) Cytokine-release syndrome in patients with B-cell chronic
lymphocytic leukemia and high lymphocyte counts after treatment
with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8).
Blood 94:2217–2224
3. Bienvenu J, Chvetzoff R, Salles G, Balter C, Tilly H, Herbrecht R,
Morel P, Lederlin P, Solal-Celigny P, Audhuy B, Christian B,
Gabarre J, Casasnovas O, Marit G, Sebban C, Coiffier B, Groupe
d’Etude des Lymphomes de l’Adulte (2001) Tumor necrosis factor
alpha release is a major biological event associated with rituximab
treatment. Hematol J 2:378–384
4. Byrd JC, Murphy T, Howard RS, Lucas MS, Goodrich A, Park K,
Pearson M, Waselenko JK, Ling G, Grever MR, Grillo-Lopez AJ,
Rosenberg J, Kunkel L, Flinn IW (2001) Rituximab using a thrice
weekly dosing schedule in B-cell chronic lymphocytic leukemia
and small lymphocytic lymphoma demonstrates clinical activity
and acceptable toxicity. J Clin Oncol 19:2153–2164
5. Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg
J, Grillo-Lopez A, Levy R (1994) Phase I clinical trial using esca-
lating single-dose infusion of chimeric anti-CD20 monoclonal an-
tibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.
Blood 84:2457–2466
6. Maloney DG, Grillo-López AJ, Bodkin DJ, White CA, Liles TM,
Royston I, Varns C, Rosenberg J, Levy R (1997) IDEC-C2B8:

results of a phase I multiple-dose trial in patients with relapsed non-
Hodgkin’s lymphoma. J Clin Oncol 15:3266–3274
7. Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ,
Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK,
Wey K, Royston I, Davis T, Levy R (1997) IDEC-C2B8
(Rituximab) anti-CD20 monoclonal antibody therapy in patients
with relapsed low-grade non-Hodgkin's lymphoma. Blood 90:
2188–2195
8. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS,
Williams ME, Heyman MR, Bence-Bruckler I, White CA,
Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire
BK (1998) Rituximab chimeric anti-CD20 monoclonal antibody
therapy for relapsed indolent lymphoma: half of patients respond
to a four-dose treatment program. J Clin Oncol 16:2825–2833
9. Davis TA, White CA, Grillo-López AJ, Velásquez WS, Link B,
Maloney DG, Dillman RO, Williams ME, Mohrbacher A, Weaver
R, Dowden S, Levy R (1999) Single-agent monoclonal antibody
efficacy in bulky non-Hodgkin’s lymphoma: results of a phase II
trial of rituximab. J Clin Oncol 17:1851–1857
10. Piro LD, White CA, Grillo-López AJ, Janakiraman N, Saven A,
Beck TM, Varns C, Shuey S, Czuczman M, Lynch JW, Kolitz JE,
Jain V (1999) Extended Rituximab (anti-CD20 monoclonal
antibody) therapy for relapsed or refractory low-grade or follicular
non-Hodgkin's lymphoma. Ann Oncol 10:655–661
11. Davis TA, Grillo-López AJ, White CA, McLaughlin P, Czuczman
MS, Link BK, Maloney DG, Weaver RL, Rosenberg J, Levy R
(2000) Rituximab anti-CD20 monoclonal antibody therapy in
non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J
Clin Oncol 18:3135–3143
12. Lenz HJ (2007) Management and preparedness for infusion and
hypersensitivity reactions. Oncologist 12:601–609
13. Schwartzberg LS, Stepanski EJ, Fortner BV, Houts AC (2008)
Retrospective chart review of severe infusion reactions with ritux-
imab, cetuximab, and bevacizumab in community oncology prac-
tices: assessment of clinical consequences. Support Care Cancer 16:
393–398
14. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah
R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F,
Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus ritux-
imab compared with CHOP alone in elderly patients with diffuse
large-B-cell lymphoma. N Engl J Med 346:235–242
15. Kunkel L, Wong A, Maneatis T, Nickas J, Brown T, Grillo-López
A, Benyunes M, Grobman B, Dillman RO (2000) Optimizing the
use of rituximab for treatment of B-cell non-Hodgkin's lymphoma:
a benefit-risk update. Semin Oncol 27(6 Suppl 12):53–61
16. Chung CH (2008) Managing premedications and the risk for reac-
tions to infusional monoclonal antibody therapy. Oncologist 13:
725–732
Pediatr Nephrol
17. Ishikura K, Matsumoto S, Sako M, Tsuruga K, Nakanishi K, Kamei
K, Saito H, Fujinaga S, Hamasaki Y, Chikamoto H, Ohtsuka Y,
Komatsu Y, Ohta T, Nagai T, Kaito H, Kondo S, Ikezumi Y,
Tanaka S, Kaku Y, Iijima K, Japanese Society for Pediatric
Nephrology (2015) Clinical practice guideline for pediatric idio-
pathic nephrotic syndrome 2013: medical therapy. Clin Exp
Nephrol 19:6–33
18. Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, Miura K,
Aya K, Nakanishi K, Ohtomo Y, Takahashi S, Tanaka R, Kaito H,
Nakamura H, Ishikura K, Ito S, Ohashi Y, Rituximab for
Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study
Group (2014) Rituximab for childhood-onset, complicated, fre-
quently relapsing nephrotic syndrome or steroid-dependent ne-
phrotic syndrome: a multicentre, double-blind, randomised,
placebo-controlled trial. Lancet 384:1273–1281
19. Legeay C, Bittencourt H, Haddad E, Spiesser-Robelet L, Thépot-
Seegers V, Therrien R (2017) A retrospective study on infusion-
related reactions to rituximab in a heterogeneous pediatric popula-
tion. J Pediatr Pharmacol Ther 22:369–374
20. Henriquez KM, Hayney MS, Xie Y, Zhang Z, Barrett B (2015)
Association of interleukin-8 and neutrophils with nasal symptom
severity during acute respiratory infection. J Med Virol 87:330–337
21. Pitrez PM, Brennan S, Sly PD (2005) Inflammatory profile in nasal
secretions of infants hospitalized with acute lower airway tract in-
fections. Respirology 10:365–370
22. Kamei K, Takahashi M, Fuyama M, Saida K, Machida H, Sato M,
Ogura M, Ito S (2015) Rituximab-associated agranulocytosis in
children with refractory idiopathic nephrotic syndrome: case series
and review of literature. Nephrol Dial Transplant 30:91–96
23. Sato M, Ito S, Ogura M, Kamei K, Miyairi I, Miyata I, Higuchi M,
Matsuoka K (2013) Atypical Pneumocystis jiroveci pneumonia
with multiple nodular granulomas after rituximab for refractory
nephrotic syndrome. Pediatr Nephrol 28:145–149
24. Chaumais MC, Garnier A, Chalard F, Peuchmaur M, Dauger S,
Jacqz-Agrain E, Deschênes G (2009) Fatal pulmonary fibrosis after
rituximab administration. Pediatr Nephrol 24:1753–1755
25. Keir GJ, Maher TM, Ming D, Abdullah R, de Lauretis A,
Wickremasinghe M, Nicholson AG, Hansell DM, Wells AU,
Renzoni EA (2014) Rituximab in severe, treatment-refractory in-
terstitial lung disease. Respirology 19:353–359
26. Sano Y, Nakano Y, Omoto M, Takao M, Ikeda E, Oga A,
Nakamichi K, Saijo M, Maoka T, Sano H, Kawai M, Kanda T
(2015 ) Rituximab-asso ciated progressive multifocal
leukoencephalopathy derived from non-Hodgkin lymphoma: neu-
ropathological findings and results of mefloquine treatment. Intern
Med 54:965–970
27. Sokol J, Lisá L, Zeleňáková J, Balhárek T, Plameňová I, Staško J,
Kubisz P (2017) Rituximab-associated progressive multifocal
leukoencephalopathy. Vnitr Lek 63:60–64