A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases

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A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases Etsuro Nanishi a,*, Takayuki Hoshina a,d, Hidetoshi Takada a,b, Masataka Ishimura a, Hisanori Nishio a,c, Takahiro Uehara e, Yumi Mizuno f, Shunji Hasegawa g, Shouichi Ohga a,g, Masayoshi Nagao h, Maiko Igarashi i, Shuhei Yajima j, Yoshio Kusumoto k, Noriko Onishi l, Yoji Sasahara m, Takahiro Yasumi n, Toshio Heike n, Toshiro Hara a,o, on behalf of PID-Infection Study Group a

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan c Center for the Study of Global Infection, Kyushu University Hospital, Fukuoka, Japan d Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan e Department of Pediatrics, Kameda Medical Center, Kamogawa, Japan f Department of Pediatric Infectious Disease, Fukuoka Children’s Hospital, Fukuoka, Japan g Department of Pediatrics, Graduate School of Medicine, Yamaguchi University, Ube, Japan h Department of Pediatrics and Clinical Research, NHO Hokkaido Medical Center, Sapporo, Japan i Department of Pediatrics, Saiseikai Kawaguchi General Hospital, Kawaguchi, Japan j Department of Pediatrics, Hamamatsu Medical Center, Hamamatsu, Japan k Department of Pediatrics, Osaka General Medical Center, Osaka, Japan l Department of Pediatrics, Fujita General Hospital, Fukushima, Japan m Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan n Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan o Fukuoka Children’s Hospital, Fukuoka, Japan b

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Accepted 26 July 2016 Available online - - -

* Corresponding author. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Fax: þ81 92 642 5435. E-mail address: [email protected] (E. Nanishi). http://dx.doi.org/10.1016/j.jinf.2016.07.018 0163-4453/ª 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Nanishi E, et al., A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.07.018

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E. Nanishi et al.

KEYWORDS Primary immunodeficiency diseases; Respiratory syncytial virus; Rotavirus; Varicella-zoster virus; Influenza virus; Cellular immunodeficiency

Summary Objectives: Patients with primary immunodeficiency diseases (PID) are highly susceptible to various microorganisms. However, no population-based studies have been performed among common viral pathogens, such as respiratory syncytial virus (RSV), rotavirus (RV), varicella-zoster virus (VZV) and influenza virus (IV). The objective of this study was to reveal the clinical burden of these four infections among PID patients in Japan. Methods: We conducted a nationwide survey by sending questionnaires to 898 hospitals with pediatric departments throughout Japan. Results: Nine hundred ten PID patients from 621 hospitals were registered (response rate: 69.2%). Fifty-four of the patients were hospitalized due to these viral infections. The durations of hospitalization due to RSV and RV infections differed significantly in the PID patients with and without cellular immunodeficiency (12.0 vs 6.5 days, p Z 0.041; and 14.0 vs 6.0 days, p Z 0.031, respectively). There was no significant difference in the duration of hospitalization in PID patients with and without cellular immunodeficiency who were hospitalized with IV infections (7.3 vs 6.1 days, p Z 0.53). Conclusions: Special attention should be paid to PID patients with compromised cellular immunity who present with RSV and RV infection due to their high risk for severe disease. ª 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Introduction The primary immunodeficiency diseases (PID) are a heterogeneous group of inherited disorders that may involve one or multiple components of the immune system.1 In most PID patients, the immune response is insufficient to eliminate specific pathogens, which leads to increased rates of morbidity and mortality due to infections caused by various pathogens, including viral pathogens that are common in childhood, such as respiratory syncytial virus (RSV), rotavirus (RV), varicella-zoster virus (VZV) and influenza virus (IV). While the infectious diseases caused by these viruses are usually self-limited in healthy children, they can be fatal in immunocompromised children. In the present study, we focus on these four viruses because the infections can be rapidly diagnosed using antigen detection kits or based on the typical clinical findings in patients with VZV infection. RSV is one of the most common pathogens of lower respiratory tract infections (LRTIs) in childhood, and is considered to be highly pathogenic in PID patients. In 2013, new indications for the use of palivizumab in children with immunocompromised conditions and Down’s syndrome were approved in Japan.2 It is recommended that PID patients of 24 months of age, predominantly those with Tcell dysfunctions (e.g., severe combined immunodeficiency [SCID], DiGeorge syndrome, WiskotteAldrich syndrome and ataxia telangiectasia), receive palivizumab to prevent severe RSV infection. In 2014, the American Academy of Pediatrics (AAP) also updated the guidance for palivizumab prophylaxis and noted that the prophylactic administration of palivizumab might be considered for immunocompromised children of less than 24 months of age during the RSV season.3 However, these recommendations were based on the results of several clinical studies that were performed in a single center.4e10 Similarly, the reports on RV, VZV and IV infection among PID patients are limited.11e15 Although specific treatments and effective vaccines have been developed for VZV and IV in children with cancer, their efficacy has not been established in patients with PID.16e18 Moreover, the vaccines

against RV and VZV are live attenuated and have the potential to cause vaccine-related diseases in PID patients.19e22 To date, no population-based studies have been performed to clarify the incidence and actual severity of these viral infections in PID patients. The objective of the present study was to clarify the incidence and severity of the common viral infections caused by RSV, RV, VZV and IV in PID children.

Materials and methods Study design The present nationwide retrospective survey was conducted to investigate the severity of RSV, RV, VZV and IV infections among children with PID. Questionnaires were sent to hospitals with pediatric departments throughout Japan. The hospitals in the survey were selected in a similar manner to that which was used in our previous study in 2008, which was performed in accordance with The Nationwide Epidemiological Survey Manual for Patients with Intractable Diseases (2nd edition 2006, Ministry of Health, Labor, and Welfare of Japan).23,24 We previously found that more than 90% of pediatric PID patients received regular medical care in the hospitals with 300 beds.23 Thus, in the present study, we sent the first questionnaire to all of the university hospitals, pediatric training hospitals and hospitals with 300 beds. The present study was approved by the Institutional Review Board of Kyushu University (No. 24e145).

Delivery of the first questionnaire The first questionnaire was delivered to inquire about the total number of patients, the disease names (based on the PID classification of the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency)1 and the number of PID patients hospitalized for one of four viral infections (RSV, RV, VZV and IV) between January 2002 and December 2011. PID patients who were

Please cite this article in press as: Nanishi E, et al., A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.07.018

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Common viral infections in PID patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

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15 years of age were enrolled in the study on RSV and RV infections. All PID patients (regardless of age) were enrolled in the study on VZV and IV infections.

The delivery of the second questionnaire The second questionnaire was sent to the hospitals which reported that they had treated PID patients who were hospitalized due to the above-mentioned viral infections in the first questionnaire. The following information was recorded for each patient: (1) age and sex; (2) disease name, gene mutation, the age at diagnosis, history of therapy against PID and representative immunological data; and (3) other underlying diseases. The following information was recorded at the onset of each viral infection: (1) age, the diagnosis of the infection, the viral detection method and detailed laboratory data; (2) the history of preventive measures against viral infections (vaccine or palivizumab), the history of daily life in the day-care center, the presence of siblings and the probable route of the infection; and (3) the duration of hospitalization and length of ICU stay, the administration of any antimicrobial agents, and the outcome. Only the duration of the treatment against viral infection was recorded in the

Table 1

case of patients who required consecutive hospitalization for additional treatment (e.g. stem cell transplantation). The patients who died from viral infection were excluded from the assessment of the duration of hospitalization.

Classification of PID with and without cellular immunodeficiency We defined PID with cellular immunodeficiency based on international classification.1 PID which belongs to the categories of “Combined immunodeficiency” and “Combined immunodeficiency with associated or syndromic features” were classified as cellular immunodeficiency. In addition, other PID with subnormal results of lymphocyte stimulation test were also classified to cellular immunodeficiency.

Statistical analyses Based on the results of the questionnaires, we assessed the characteristics and severity of the four target infectious disorders. All of the statistical analyses were performed using the JMP Pro software program (ver. 11.0.0. SAS Institute, 2001, Cary, NC). Statistical significance was determined by a nonparametric analysis (a one-way ANOVA).

The reported number of PID patients and the number of the PID patients hospitalized for the target viral infections.

Category, diagnosis of PID

Hospitalized PID patients for each target viral infection, n (episodes) RSV

RV

Combined immunodeficiencies Severe combined immunodeficiencies 1 1 Others 3 1 Combined immunodeficiencies with associated or syndromic features WiskotteAldrich syndrome 1 DiGeorge anomaly 2 1 Hyper IgE syndrome 2 Ataxiaetelangiectasia Others Predominantly antibody deficiencies BTK deficiency 1 Common variable immunodeficiency 3 (7) 3 disorders Others 1 Diseases of immune dysregulation Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome Others Congenital defects of phagocyte number, function, or both X-linked chronic granulomatous disease 2 Others or undeterminated 2 Defects in innate immunity Anhidrotic ectodermal dysplasia with 1 immunodeficiency Others Complement deficiencies Undetermined Total 15 (19) 10

VZV

IV

1 2 2

1 4 2

4 7 4 1

6 4

7 10 (14)

2

3

1

9

Total 3 6

1

2

Total PID patients

1

1

20

97 45 52 201 67 66 51 13 4 394 175 124 95 21 2

1

19 164 145 19 24 1

54 (58)

23 5 3 910

5 2

PID, primary immunodeficiency diseases; RSV, respiratory syncytial virus; RV, rotavirus; VZV, varicella-zoster virus; IV, influenza virus.

Please cite this article in press as: Nanishi E, et al., A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.07.018

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The demographic and clinical characteristics of the patients hospitalized for respiratory syncytial virus (RSV) infection.

Age

Sex

Dx. of PID

Complication

1 2 3

0y 0y 0y 1y 6y 7y 8y 1y 1y 1y 1y 1y 2y 3y 3y 3y 4y 5y 7y

1m 4m 8m 10m

M M F

HIES SCID CVIDa

CHD

2m 2m 6m 7m 8m

M M M M M M M M M M M M

4 5 6 7 8 9 10 11 12 13 14 15

Treatment for PID

CHD, PH, PMR IVIG IVIG IVIG IVIG

CID MSMD CVID EDA-ID CVID DC deficiency DGA DGA XLA APDS APDS HIES

CHD, PH, BA, PMR BA, 21 trisomy SCT (at 9m) CS MDS, MAS CHD, epilepsy CHD

CS

BA, PMR Bronchiectasis, BA CLD, BA, PMR

IVIG IVIG

Type of RSV infection

Administration of Palivizumab

Duration of hospitalization, days

MV

ICU stay, duration

Outcome

Bronchitis Bronchitis Pneumonia Bronchitis Pneumonia Pneumonia Pneumonia Bronchitis Bronchitis Bronchitis Pneumonia Pneumonia Bronchitis Bronchitis Pneumonia Pneumonia Pneumonia Pneumonia Bronchitis

No No No Yes (CHD) No No No Yes (CHD) No No No No No No No No No No No

15 82 17 13 21 9 8 7 3 10 14 6 1 5 11 7 12 12 7

No No Yes No No No No No No No Yes No Yes No No No No No No

No Yes, 1days Yes, 8 days No No No No No No No Yes, 10days No Yes No No No No No No

IWS IWS IWS IWS IWS IWS IWS IWS IWS IWS IWS IWS dead IWS IWS IWS IWS IWS IWS

HIES, hyper IgE syndrome; (S)CID, (severe) combined immunodeficiency; CVID, common variable immunodeficiency; EDA-ID, anhidrotic ectodermal dysplasia with immunodeficiency; DC, dendritic cell; DGA, DiGeorge anomaly; APDS, activated PI3 kinase delta syndrome; MSMD, Mendelian susceptibility to mycobacterial diseases; XLA, X-linked agammaglobulinemia; CHD, congenital heart disease; PH, pulmonary hypertension; PMR, psychomotor retardation; BA, bronchial asthma; MDS, myelodysplastic syndrome; MAS, macrophage activation syndrome; CLD, chronic lung disease; IVIG, intravenous immunoglobulin; SCT, stem cell transplantation; CS, corticosteroid; MV, Mechanical ventilator; IWS, improved without sequelae. a The patient was also found to have cellular immunodeficiency based on the low level of lymphocyte blasts in a transformation test.

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E. Nanishi et al.

Please cite this article in press as: Nanishi E, et al., A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.07.018

Table 2

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Common viral infections in PID patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

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KruskaleWallis and Wilcoxon tests were used to analyze the continuous variables and the chi-squared and Fisher’s exact tests were used to analyze the categorical variables. All of the statistical tests were two-sided. p Values of <0.05 were considered to indicate statistical significance.

Results Response rate of questionnaires Six hundred twenty-one of the 898 hospitals (69.2%) replied to the first questionnaire and 910 PID patients were identified. Among them, 54 PID patients (58 episodes) from 40 hospitals were admitted for one of the 4 viral infections (RSV, n Z 15; RV, n Z 10; VZV, n Z 9; and IV, n Z 20). In the secondary survey, 38 (95.0%) of the 40 hospitals (55 of 58 episodes) replied to the questionnaire.

The distribution of the PID patients The diagnosis, the total number of PID patients, and the numbers of PID patients hospitalized for the 4 infectious disorders are shown in Table 1. Among 910 PID patients, the most common form of PID was predominantly antibody deficiency (n Z 394, 43.3%), followed by combined immunodeficiency with associated or syndromic features (n Z 201, 22.1%), congenital defects in the phagocyte number, function, or both (n Z 164, 18.0%) and combined immunodeficiency (n Z 97, 10.7%). The most common PID was Bruton’s tyrosine kinase (BTK) deficiency (n Z 175, 19.2%), followed by X-linked chronic granulomatous disease (n Z 145, 15.9%). The rate of hospitalization due to any 4 viral infections was highest in PID patients with combined immunodeficiency (n Z 9, 9.3%), followed by combined immunodeficiency with associated or syndromic features (n Z 16, 8.0%), predominantly antibody deficiency (n Z 20, 5.1%).

Table 3

The characteristics of the PID patients hospitalized for RSV infection The information on the 15 patients (19 episodes) who were hospitalized for RSV infection is summarized in Table 2. Among these patients, the male-to-female ratio was 14:1 and the median age at the onset of infection was 2.0 years (range, 0.08e8 years). All of the episodes were diagnosed using a rapid antigen detection test. With respect to the route of infection, RSV was transmitted nosocomially in 4 patients (21.1%), and by family members in 2 patients (10.5%). Two patients (10.5%) were thought to have acquired RSV in a day-care center. The route of infection in the remaining patients was unknown. The median duration of hospitalization was 10.5 days (range; 3e82). All patients developed LRTIs, 4 patients were admitted to an intensive care unit and 3 required mechanical ventilatory support. A two-year-old boy with dendritic cell deficiency and myelodysplastic syndrome died from respiratory failure and macrophage activation syndrome triggered by RSV infection.

The characteristics of the PID patients who were hospitalized for RV infection Detailed information was obtained for 9 of the 10 patients hospitalized for RV infection (Table 3). The male-to-female ratio was 3.5:1, and the median age at the onset of the infection was 1.5 years (range: 0.4e4 years). All of the patients were diagnosed using a rapid antigen detection test. All of the patients were under 5 years of age, and 56.0% of the patients were under 2 years of age. The rates of nosocomial and intrafamilial transmission were 22.2% and 11.1%, respectively. Transmission was associated with a day-care center in 33.3% of the cases. All of the patients received intravenous fluid administration during hospitalization, and the median duration of hospitalization was 7.5 days (range: 5e56 days). All of the patients improved without sequelae, except for a 14-month-old boy with

The demographic and clinical characteristics of the patients hospitalized for Rotavirus (RV) infection.

Pt. Age

Sex Dx. of PID

Complication

1 2

0y 5m 0y 8m

F M

3 4 5 6 7 8 9

0y 11m M 1y 2m M 1y 6m M 2y M 2y M 3y F 4y M

Enteritis SCT (at 5m) Enteritis IVIG Enteritis CoA, PMR Enteritis IFNg Enteritis Enteritis IVIG Enteritis CHD, PH, PMR IVIG Enteritis 21 trisomy Enteritis

SCID SCID (post SCT) WAS DGA CGD CGD CVID CVIDa CVID

LPD, GVHD

Treatment for PID

Type of History of Duration of ICU stay Outcome RV infection vaccination hospitalization, days No No

14 56

No No

IWS IWS

No No No No No No No

8 1 7 5 5 51 7

No Yes No No No No No

IWS dead IWS IWS IWS IWS IWS

SCID, severe combined immunodeficiency; SCT, stem cell transplantation; WAS, WiskotteAldrich syndrome; DGA, DiGeorge anomaly; CVID, common variable immunodeficiency; CGD, chronic granulomatous disease; LPDS, lymphoproliferative disease; GVHD, graft versus host disease; CoA, coarctation of the aorta; PMR, psychomotor retardation; CHD, congenital heart disease; PH, pulmonary hypertension; IVIG, intravenous immunoglobulin; IWS, improved without sequelae. a The patient was also found to have cellular immunodeficiency based on the low level of lymphocyte blasts in a transformation test.

Please cite this article in press as: Nanishi E, et al., A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.07.018

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IVIG, SCT (at 16y) IVIG GVHD Restrictive LD PMR CGD (post SCT) AT 17y 25y 8 9

M F

ML

SCID, severe combined immunodeficiency; WAS, WiskotteAldrich syndrome; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; CGD, chronic granulomatous disease; SCT, stem cell transplantation; AT, ataxia telangiectasia; IBD, inflammatory bowel disease; BA, bronchial asthma; T1DM, type 1 diabetes mellitus; NS, nephrotic syndrome; ML, malignant lymphoma; GVHD, graft versus host disease; LD, lung disease; PMR, psychomotor retardation; IVIG, intravenous immunoglobulin; SSSS, Staphylococcal scalded skin syndrome; CMV, cytomegalovirus; IWS, improved without sequelae.

IWS IWS 15 10 Yes (once) Unknown

10 5 15 No Yes (once) Unknown T1DM, NS

IPEX syndrome CGD WAS 5y 5y 17y 5 6 7

M M M

IBD

WAS SCID SCID (post SCT) 11m 2y 3y 2 3 4

M M M

SCID 4m 1

F

BA

SCT (at 1m) IVIG Cyclosporine A IFNg Chemotherapy

Chikenpox Chikenpox Visceral varicella (reactivation) Zoster (reactivation) Chikenpox

No No No

20 30 5

Bacteremia

CMV infection

IWS IWS IWS

IWS IWS IWS

SSSS (MRSA) 138 No

Duration of hospitalization, days History of vaccination Type of VZV infection Treatment for PID Complication Dx. of PID

Cellular immunity was impaired in 62.7% of the patients who were hospitalized for the target infectious disorders. To find the roles of cellular immunity against each of the viral infections in humans, we analyzed the clinical characteristics of the target infectious diseases in the PID patients with and without cellular immunodeficiency (Table 6). The patients who underwent hematopoietic stem cell transplantation (HSCT) were excluded from this analysis. PID patients with cellular immunodeficiency required significantly longer hospital stay than those without cellular immunodeficiency for the treatment of RSV and RV infections (12.0 vs 6.5 days, p Z 0.041, and 14.0 vs 6.0 days, p Z 0.031, respectively). Among 10 patients with cellular immunodeficiency, 2 patients had received palivizumab

Sex

The comparison of the variables associated with each of the viruses in the PID patients with and without cellular immunodeficiency

Age

Detailed information was obtained from 18 of the 20 patients hospitalized for IV infection (Table 5). The maleto-female ratio was 3.7:1, and the median age at the onset of the infection was 8.0 years (range; 1.4e34). All of the patients were diagnosed using a rapid antigen detection test; two were also diagnosed by viral isolation. Seventy-nine percent of the patients with IV infections were >6 years of age. The rate of nosocomial transmission was 5.3%. Transmission from family members was observed in 26.3% of the cases. The median duration of hospitalization was 5.5 days (range: 4e21). Fifteen patients were hospitalized for LRTIs. The remaining three patients were diagnosed with upper respiratory infections (n Z 2) and gastroenteritis (n Z 1). One patient required mechanical ventilatory support. All of the patients improved without sequelae.

Pt.

The characteristics of the PID patients who were hospitalized for IV infection

The demographic and clinical characteristics of the patients hospitalized for varicella-zoster virus (VZV) infection.

The information of the 9 patients who were hospitalized due to VZV infection is summarized in Table 4. The maleto-female ratio was 3.5:1, and the median age at the onset of infection was 5.0 years (range: 0.3e25 years). Four patients were diagnosed by a blood DNA quantitation method, and two were diagnosed by a serology test; the remaining two were diagnosed based on the clinical findings. Two cases were caused by VZV reactivation; both patients were 17 years of age. The rates of nosocomial and intrafamilial transmission were both 28.6%. In 28.6% of the cases, the transmission was associated with a daycare center. The median duration of hospitalization was 15.0 days (range: 5e138). A four-month-old girl with SCID who had encephalitis and retinitis during primary varicella eventually developed vision loss. The development of VZV infection led to the diagnosis of SCID in two patients (Patient Nos. 1 and 3).

Complication of VZV infection

The characteristics of the PID patients who were hospitalized for VZV infection

Chikenpox, encephalitis, retinitis Chikenpox Chikenpox Chikenpox

Outcome

DiGeorge syndrome who died from hypovolemic shock on the first day of illness from RV infection.

Table 4

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

E. Nanishi et al. Vision loss

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Common viral infections in PID patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

Table 5

7

Demographic and clinical characteristics of the patients hospitalized for influenza virus (IV) infection.

Pt. Age

Sex Dx. of PID

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1y 5m 1y 8m 4y 4y 6y 6y 7y 8y 8y 8y 10y 13y 16y 17y

M M F M M M F M M M M F M F

15

17y

M

16 17 18

23y 32y 34y

M M M

CGD CVID CVIDa XLA DGA XLA DGA DGA HIES XLA XLA DGA WAS WHIM syndrome IgG2 subclass deficiency XLA HIES XLA

Complication

CHD, PH, PMR

Treatment Type of virus, Vaccination in Duration of MV for PID type of the season hospitalization, IV infection day

Outcome

IFNg IVIG

CHD CHD CHD, BA CLD, BA, PMR IVIG IVIG CHD, PMR CN CHD, PH (on HOT) IVIG Bronchiectasis IVIG IVIG

A, A, A, A, A, A, A, A, A, B, B, A, A, A,

bronchitis bronchitis pneumonia pneumonia pneumonia pneumonia bronchitis enteritis bronchitis pneumonia pneumonia URI pneumonia bronchitis

No Unknown Yes Unknown Unknown Unknown Unknown Yes No Unknown No Unknown Unknown Yes

5 4 21 4 5 13 4 5 5 8 4 6 7 7

No No Yes No No No No No No No No No No No

IWS IWS IWS IWS IWS IWS IWS IWS IWS IWS IWS IWS IWS IWS

Unknown

6

No

IWS

A, bronchitis No A, pneumonia Unknown A, bronchitis Yes

6 6 4

No No No

IWS IWS IWS

A, URI

CGD, chronic granulomatous disease; CVID, common variable immunodeficiency; XLA, X-linked agammaglobulinemia; DGA, DiGeorge anomaly; HIES, hyper IgE syndrome; WAS, WiskotteAldrich syndrome; WHIM, warts. hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis; CHD, congenital heart disease; PH, pulmonary hypertension; PMR, psychomotor retardation; BA, bronchial asthma; CN, chronic nephritis; HOT, home oxygen therapy; IVIG, intravenous immunoglobulin; URI, upper respiratory infection; IWS, improved without sequelae. a The patient was also found to have cellular immunodeficiency based on the low level of lymphocyte blasts in a transformation test.

administration for RSV prophylaxis, and 3 patients required ICU stay and/or mechanical ventilation for the treatment of RSV infection. In addition, 1 patient with cellular immunodeficiency died of RSV infection. One patient with cellular immunodeficiency required ICU stay and died of RV infection. On the other hand, the duration of hospital stay for the treatment of IV was not significantly different between the two groups (7.3 vs 6.1 days, respectively; p Z 0.53). A statistical analysis on the laboratory data and the clinical courses of VZV infection between patients with and without cellular immunodeficiency could not be performed because only 1 patient developed VZV infection in PID patients without cellular immunodeficiency.

Discussion In the present study, we found that the duration of hospitalization due to RSV and RV infections was longer in the patients with impaired cellular immunity than in other PID patients. Patients with cellular immunodeficiency seemed to have severe RSV and RV infections, because 3 required ICU stay and/or mechanical ventilation in the course of RSV infection and 2 died of RSV or RV infection among cellular immunodeficiency patients, in contrast to the PID patients without cellular immunodeficiency. Although PID patients have been assumed to be susceptible to developing severe viral infections, no surveillance studies have been performed in other countries. The

number of patients hospitalized for these viral infections in the present study was somewhat lower than expected. This study achieved a high response rate (initial survey: 69.2%; secondary survey: 95.1%), and the number of reported PID patients was similar to our previous survey,23 which supports the quality of the present study. Cellular immunity plays a more critical role in the control of various viral infections than humoral immunity. The T-cell mediated immune response is involved in protection against RSV-associated illnesses.25 CD4þ T-cells play a crucial role in maintaining the balance between effector and regulatory immune responses in the RSVinfected lung.26 Immunocompromised patients, such as SCID and HSCT recipients are considered to have a higher risk of fatal RSV disease, and a close relationship has been suggested to exist between the clinical severity of RSV and decreased cellular immune function.4,5,27 In a mouse model of primary RV infection, both CD8þ T-cells and Bcells were found to play an important role in viral clearance and the former cells were found to respond more quickly and efficiently.28e30 Previous case series and case control studies on RV infection have suggested that the periods of clinical symptoms and viral shedding are prolonged in patients with T cell immunodeficiency.11,12,31 The results of our present study strongly supported these reports. It was reported that the duration of hospitalization correlated not only with the viral load but also with the mortality of the patients with viral infections. It has been used as a parameter which reflects the severity of

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The demographic, laboratory and clinical variables in relation to each virus infection in the PID patients with and without cellular immunodeficiency.

Cellular immunodeficiency

RSV þ

e

Number (episode) Gender, % malec Age at the onset of infection, yeard WBC count, /mld

10 (14) 90 (9/10) 3.0 (0.08e8)

4 100 (4/4) 1.6 (1.2e3)

11,425 (4600e36,400) 6755 (2362e34,398) 2006 (252e8191) 2.20 (0.04e18.8) 14 (2/14)

8900 (5900e27,100) 0.83 4725 (3649e14,715) 3737 (1664e9729) 0.39 (0.3e4.7) 0 (0/4)

0.67 0.20 0.24 1

12.0 (5e82)

6.5 (3e10)

21 (3/14)

7.1 (1/14)

Neutrophil count, /mld Lymphocyte count, /mld CRP level, mg/dLd History of preventive measuresa, %c Duration of hospitalization, dayb,d ICU stay and/or mechanical ventilation, %c Mortality, %c

p

RV

p

þ

e

4 50 (2/4) 1.0 (0.4e3)

4 100 (4/4) 2.0 (1.5e4)

12,455 (10,40e17,900) 6093 (3955e15,126) 4056 (1969e6554) 0.975 (0.05e3.3) 0 (0/4)

13,000 (6000e15,200) 9264 (3420e10,944) 2564 (566e5542) 0.31 (0.05e5.68) 0 (0/4)

0.77 0.38 1 e

0.04 14.0 (8e51)

6.0 (5e7)

0 (0/4)

1

25 (1/4)

0 (0/4)

1

25 (1/4)

0.28 0.31

0.43 0.15 0.77

IV

Q10

p

þ

e

9 56 (5/9) 8.0 (4e32)

9 100 (9/9) 8.0 (1.4e34)

11,300 (1200e15,200) 6387 (808e13,344) 749 (262e11,339) 1.26 (0.1e9.57) 75 (3/4)

6600 (2900e22,500) 0.43

0.08 0.72

0.46 0.29 0.89 0.48

0.03 6.0 (4e21)

5.0 (4e13)

0.37

0 (0/4)

1

11 (1/9)

0 (0/9)

1

0 (0/4)

1

0 (0/9)

0 (0/9)

e

Data are expressed as % (n) or median (range). PID, primary immunodeficiency; RSV, respiratory syncytial virus; RV, rotavirus; VZV, varicella-zoster virus; IV, influenza virus; WBC, white blood cell; CRP, C-reactive protein. a Patients without written vaccination or palivizumab status were excluded. b Patients who died during hospitalization were excluded. c Pearson’s chi-square test was used to analyze the categorical variables. d Wilcoxon rank sum test was used to analyze the continuous variables.

Q9

YJINF3792_proof ■ 9 August 2016 ■ 8/11

3693 (1392e20,250) 1164 (522e2268) 1.67 (0e34.48) 25 (1/4)

E. Nanishi et al.

Please cite this article in press as: Nanishi E, et al., A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.07.018

Table 6

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Common viral infections in PID patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

infections.32e34 Therefore, it is suggested that the prolonged duration of hospitalization correlated with the impaired viral clearance or severity of the viral infections in PID patients with cellular immunodeficiency in this study. We could not sufficiently evaluate the correlations between cellular immunity and the severity of the disease (e.g. requirement for mechanical ventilation, ICU stay, sequelae and mortality), due to the limited sample size. Cell-mediated immune responses are considered to play a major role in the host defense against VZV infection.13 In the present study, the duration of hospitalization in patients with VZV infection with and without cellular immunodeficiency were 17.5 days (n Z 6, range; 10e138) and 5.0 days (n Z 1), respectively. However, we were unable to assess the association between cellular immunity and the duration of hospitalization in the patients with VZV infection due to the small sample size. In contrast to the other viral infections, there was no difference in the duration of hospitalization for IV infection in the PID patients with and without cellular immunodeficiency. Local mucosal and systemic antibodies as well as cytotoxic T-cell responses are considered to play an important role in the host defense against IV infection.35e38 The number of patients with severe influenza was surprisingly low in the present study. In Japan, early diagnosis and the provision of antiviral treatment within 48 h after the onset of influenza are widely applied in patients presenting with IV infections39,40; this might have contributed the low severity and the low rate of mortality in the PID patients of the present study. X-linked agammaglobulinemia (XLA) was the most frequently reported PID in the present study. The numbers of XLA patients hospitalized with the target viruses were as follows: RSV (n Z 1); RV (n Z 0), VZV (n Z 0), and IV (n Z 6). These results suggest a low correlation between impaired humoral immunity and the development of severe RSV, RV and VZV infection. The only XLA patient who developed an RSV-LRTI had not received regular intravenous immunoglobulin replacement. Although the concentration of RSV specific antibody in gammaglobulin preparations is low, immunoglobulin replacement may be effective at least in part against RSV-LRTI. The prevention of viral infections is important for PID patients. To prevent severe RSV infection, infants with PID (who predominantly have T-cell dysfunctions) can receive palivizumab during the epidemic period.2 However, PID patients over 24 months of age were also prone to developing severe LRTIs in the present study (Table 2). It is difficult to determine the age to which palivizumab prophylaxis should be continued. Although researchers have developed vaccines against various viral infections, PID patients with impaired cellular immunity cannot mount sufficient immune reactions against these viruses. Moreover, the patients with impaired cellular immunity should not receive live attenuated vaccines such as the RV and VZV vaccines due to the risk of developing of vaccine-related diseases.19,20 Nosocomial infections, transmission from a family member and transmission associated with a day-care center were responsible for most of the infections in the present study. Thus, universal vaccination, which would be useful for achieving herd immunity, could further protect PID patients.

9 This study is associated with several limitations. First, the present study only included in patients. Although we might have underestimated the total episodes of hospitalization, severe cases are less likely to be missed in an epidemiological study.41 Second, different criteria for hospitalization and discharge among the institutions may have caused a bias in the duration of hospitalization. Third, most of viral infections were diagnosed by rapid antigen detection tests such as immunochromatographic tests. Although viral isolation and polymerase chain reaction detection are generally used as the standard methods, the diagnostic performance, especially the specificity of the rapid antigen tests, is sufficiently high.42e44 Fourth, our classification of cellular immunodeficiency was heterogeneous. In addition, some of the patients had other underlying diseases, such as congenital heart disease, which is a well-known risk factor for various viral infections. We could not quantify the impact of underlying disease due to the limited sample size. Finally, we could not evaluate the accuracy of the diagnosis of PID. On the other hand, PIDJ (Primary Immunodeficiency Database in Japan) system has been working for the genetic diagnosis and the diagnostic consultation for doctors who see the PID patients in Japan.45 We believe that the diagnosis of PID was done with high accuracy. In conclusion, this is the first nationwide survey to elucidate the incidence and severity of RSV, RV, VZV and IV infection among PID patients. Although the number of fatal cases was lower than expected, PID patients with cellular immunodeficiency were at a high risk of longer hospitalization due to RSV, RV and VZV infections. The early diagnosis, treatment and prevention of viral infections are required in patients with impaired cellular immunity.

Funding This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (22249043, THa) and a grant from AbbVie Inc. (THa).

Conflict of interest Dr. Hara has an investigator-initiated grant from AbbVie Inc.; the other authors have indicated they have no potential conflicts of interest to disclose. The sponsor had no control over the planning, interpretation, writing, or publication of this work.

Contributors’ statement EN conceptualized and designed the study; designed the data collection instruments; carried out the initial analyses; drafted the initial manuscript. MIs and HN designed the data collection instruments; reviewed and revised the manuscript. THo, HT and THa conceptualized and designed the study; interpreted the data; critically reviewed and revised the manuscript for important intellectual content. TU, YM, SH, SO, MN, MIg, SY, YK, NO, YS, TY, and THe

Please cite this article in press as: Nanishi E, et al., A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.07.018

Q5

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10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

obtained data; reviewed and revised the manuscript. All of the authors approved the final manuscript as submitted.

Acknowledgments

Q4

The PID-Infection Study Group (in addition to the named authors) are as follows: Chie Kobayashi (University of Tsukuba, Tsukuba, Japan); Takashi Ishige (Gunma University Graduate School of Medicine, Maebashi, Japan); Kanako Kudo (Chiba University Graduate School of Medicine, Chiba, Japan); Kyouko Suzuki (Juntendo University Urayasu Hospital, Urayasu, Japan); Shohei Ogata (Kitasato University School of Medicine, Sagamihara, Japan); Masako Kikuchi (Yokohama City University Hospital, Yokohama, Japan); Yachiyo Kurihara (St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan); Ryo Niiya, and Tomohiro Katsuta (St. Marianna University School of Medicine, Kawasaki, Japan); Yutaka Saikawa (Kanazawa Medical University, Uchinada, Japan); Hisao Yoshida (Osaka University Graduate School of Medicine, Suita, Japan); Yuko Ishizaki (Kansai Medical University Takii Hospital, Moriguchi, Japan); Akira Hayakawa (Kobe University Graduate School of Medicine, Kobe, Japan); Toshihiko Shirakawa (Nagasaki University Hospital, Nagasaki, Japan); Toshihiko Mori (NTT East Japan Sapporo Hospital, Sapporo, Japan); Yutaka Suzuki (Hachinohe City Hospital, Hachinohe, Japan); Hideo Tsuda (Fukui Prefectural Hospital, Fukui Japan); Tomoko Sato, and Tomoko Waragai (Jusendo General Hospital, Koriyama, Japan); Satoru Kumaki (Sendai Medical Center, Sendai, Japan); Osamu Komiyama (National Hospital Organization Tokyo Medical Center, Tokyo, Japan); Masumi Seto (Osaka Saiseikai Senri Hospital, Suita, Japan); Ryo Kadoya, and Noriko Ohbuchi (Yamaguchi Red Cross Hospital, Yamaguchi, Japan); Hiroko Kozan (Takamatsu Red Cross Hospital, Takamatsu, Japan); Hiroyuki Shimizu (Yokohama City University Medical Center, Yokohama, Japan); Tomoyuki Imagawa (Kanagawa Children’s Medical Center, Yokohama, Japan); Yoshiyuki Yamada (Gunma Children’s Medical Center, Shibukawa, Japan); Takuya Hara, and Takuro Ohno (Oita Prefectural Hospital, Oita, Japan); Eiji Ota (Nakatsu Municipal Hospital, Nakatsu, Japan); Hiroyuki Toda (Hachinohe Red Cross Hospital, Hachinohe, Japan). The authors would like to thank the support of the Japanese Research Group on Primary Immunodeficiency Diseases, which is supported by Japan’s Ministry of Health, Labor and Welfare. The authors also would like to thank Junji Kishimoto (Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan) for the support on the statistical analysis.

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