- Email: [email protected]
Vaccination strategies in pediatric inflammatory bowel disease
Vaccine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Vaccination strategies in pediatric inflammatory bowel disease Valeria Dipasquale, Claudio Romano ⇑ Unit of Pediatrics, Department of Human Pathology in Adulthood and Childhood ‘‘G. Barresi”, University of Messina, Messina, Italy
a r t i c l e
i n f o
Article history: Received 11 April 2017 Received in revised form 31 August 2017 Accepted 8 September 2017 Available online xxxx Keywords: Inflammatory bowel disease Vaccination Immunization Immunogenicity Safety Children
a b s t r a c t The incidence of pediatric inflammatory bowel disease (IBD) is rising, as is the use of immunomodulatory and biological drugs. IBD patients are vulnerable to infections owing to disease-related immunological alterations and drug-induced systemic immunosuppression. Although many infections are vaccinepreventable, vaccination coverage in IBD patients is insufficient. Current guidelines recommend that children with IBD follow the same routine immunization schedule as healthy children, avoiding live vaccines during immunosuppressive therapy. Immunization status should be checked at diagnosis, and patients should be immunized with the vaccines they need. Some studies have demonstrated a suboptimal immune response to vaccinations in IBD patients, but responsible mechanisms are poorly understood. In this manuscript, we provide a broad review of available data about vaccine coverage rates, immunogenicity and safety of both killed and live attenuated vaccinations in the pediatric IBD population; furthermore, we provide comprehensive information regarding current guidelines for immunization of children with IBD and their household contacts. A comprehensive search of published literature using the PubMed (http:// www.ncbi.nlm.nih.gov/pubmed/) database was carried out to identify all articles published in English from 1998 to March 2017, using the following key terms: ‘‘inflammatory bowel disease”, ‘‘vaccination”, ‘‘immunization”, ‘‘immunogenicity”, ‘‘safety” and ‘‘children”. Ó 2017 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunization rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunization strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Checking immunization status: how and when . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaccination immunogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Mechanisms impairing the response to vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Vaccination immunogenicity in adult patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Vaccination immunogenicity in pediatric patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Hepatitis A and hepatitis B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Pneumococcus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Human papillomavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.4. Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.5. Other inactivated vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.6. Varicella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.7. Measles, mumps, and rubella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
⇑ Corresponding author at: Unit of Pediatrics, Department of Human Pathology in Adulthood and Childhood ‘‘G. Barresi,” University of Messina, Via Consolare Valeria, Messina 98124, Italy. E-mail address: [email protected] (C. Romano). https://doi.org/10.1016/j.vaccine.2017.09.031 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
2
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx
Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors’ statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease (CD), ulcerative colitis (UC) and indeterminate colitis (IC), continue to rise in incidence and prevalence worldwide, both in the adult and pediatric populations [1]. IBDs are defined as multifactorial disorders characterized by chronic relapsing intestinal inflammation, with a peak onset during adolescence and young adulthood [2]. Treatment during the last decade has been based on immunomodulatory and biological drugs, such as anti-tumor necrosis factor alpha (TNF-a), that are being used increasingly often and earlier during the course of the disease [3,4]. Clinical studies, registries, and case series have highlighted the increased risk of infection, notably opportunistic infections, in young and adult patients with IBD [5–7]. An opportunistic infection is defined as a serious, often progressive infection, caused by microorganisms that have limited virulence, but can cause serious disease related to a predisposing pathologic condition or its treatment [8]. The challenges are not only in managing these diseases, but also in recognizing, preventing and managing infections. Prevention of infections is a major issue for public health, and vaccination has shown to be one of the most successful strategies against the spread of several infectious diseases [9]. Accordingly, the European Crohn’s and Colitis Organization (ECCO) recommends protection with vaccines for young and adult IBD patients, where appropriate and available [6]. In the present manuscript, we provide an upgraded review of literature regarding vaccination rates, immunogenicity and safety, and current guidelines for vaccination in children with IBD. To accomplish this, a comprehensive search of published literature using the PubMed MEDLINE database (1998– March 2017) was performed. The key terms ‘‘inflammatory bowel disease”, ‘‘vaccination”, ‘‘immunization”, ‘‘immunogenicity”, ‘‘safety” and ‘‘children” were used. 2. Immunization rate The most efficacious way to minimize vaccine-preventable infections is through vaccinations. A complete vaccination schedule is important in pediatric patients with IBD, who are at a higher risk of infection and severe or fatal complications than the general population [10]. Nonetheless, vaccination coverage in IBD adult and young patients is reported as below that of healthy children [10,11]. Incomplete childhood immunization can be distinguished as IBD-related or non IBD-related [12]. IBD-related reasons include use of immunosuppressive drugs and disease flare at the time of scheduled immunization, while non IBD-related reasons include parental refusal, lack of awareness of routine immunization, recent move from elsewhere with different immunization schedules, needle phobia. Many studies have demonstrated that both gastroenterologists and patients underuse the tool of vaccination in patients with IBD [10]. Primary care practitioners and gastroenterologists are often unaware of any existing recommendations, resulting in the lack of appropriate counseling [13,14]. Patients are frequently worried about vaccine-associated complications or low effectiveness, finally resulting in unsatisfying adherence to vaccination programs and seroprotection [15,16]. A survey of 36 IBD patients [11] has reported on provided reasons for the refusal of a recommended vaccination, which included the supposed unneces-
00 00 00 00
sity of vaccinating (52%), the fear of possible vaccine-related side effects or adverse reactions (25%), doubts about effectiveness (14%), the high cost of the vaccine (6%) and discouragement from medical care providers (37%). Another survey of pediatric gastroenterologists [17] concluded that the main barriers to vaccination are the lack of coordination of care with primary care practitioners (even if only 28% believed that primary care practitioners were solely responsible for immunizations), poor access to immunization records, and the inability to offer vaccinations in their immediate area, thereby being obliged to refer patients to overburdened public health clinics for vaccines, which are often located far from their offices or in other cities. In a recent prospective cohort study carried out over 2 successive influenza seasons, educational intervention and providing of influenza vaccine during clinic visits has been associated with improved influenza vaccination rates [18]. 3. Immunization strategies In 2013, the Infectious Disease Society of America published a ‘‘Clinical Practice Guideline for Vaccination of the Immunocompromised Host”, an evidence-based guideline for vaccination of immunocompromised adults and children [19]. They recommended vaccinating all IBD patients, following the same routine immunization schedule as in healthy children. Live vaccines can be used before the start of immunosuppressive therapy—at least 4 weeks before starting treatment in the case of the varicella vaccine, and 6 weeks before treatment begins in the case of the measles, mumps, and rubella (MMR) vaccine. In pediatrics, exclusive enteral nutrition is considered a valuable alternative for induction therapy and could therefore be used as a window allowing time to update vaccinations prior to prescribing immunosuppressive drugs [6]. If immunosuppressive therapy has already begun, guidelines recommend administering live vaccines after discontinuation for at least 3 months (only 1 month if corticosteroid monotherapy is being used). Fortunately, most children with IBD have already received live vaccines by the time of diagnosis, as live vaccines are routinely administered to young children, and IBD onset is less common in children younger than 5 years of age. Household contacts can safely receive inactivated vaccinations, as well as the MMR vaccine, without fear of harming or spreading the virus to the patient [20]. The varicella vaccine is also viable; if a vaccine-related rash develops and the patient is not immunized, it is enough to avoid close contact. Such a scenario does not indicate administration of varicella zoster immunoglobulin, as the secondary infection from the vaccine is expected to be mild [20]. The ‘‘cocoon strategy” refers to protecting vulnerable patients from infection due to close contact with those who have been vaccinated. Recently, a study investigated the ‘‘cocooning strategy” among patients with IBD for the first time, concluding that it is not sufficient to protect IBD patients [11]. 3.1. Checking immunization status: how and when The immunization status of the patient should ideally be checked at the time of IBD diagnosis, especially if there is no clear history of vaccination or wild-type infection [10]. According to the second ECCO Consensus (2014) on opportunistic infections in adult
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx
3
Table 1 Recommendations on vaccinations in pediatric IBD. Non-replicating vaccinations may be administered regardless of immunosuppressive drug use Live attenuated vaccinations may be considered if there are no plans to start immunosuppressive therapy in 4–6 weeks Live attenuated vaccines may be administered after at least 3 months-discontinuation (after 1 month-discontinuation in case of corticosteroids monotherapy) if immunosuppressive therapy has already been started Both live attenuated and non-replicating vaccines may be administered to household contacts; varicella vaccine recipients with vaccine-related rash should avoid contact with the immunosuppressed patient who is not immunized Immunization status should be checked at diagnosis, above all in case of unknown history of vaccination or wild-type infection Immunization status can be checked by verbal inquiring and/or antibody titers (MMR, hepatitis A and B virus, and varicella) Titers can be useful in the case of unknown history of vaccination or wild-type infection or to confirm adequate antibody levels Vaccine effectiveness may be lower in patients during immunosuppressive therapy MMR - measles, mumps, rubella.
and pediatric IBD, at the time of diagnosis the immunization status should be primarily checked for routinely administered vaccines, such as tetanus, diphtheria, poliomyelitis [6]. The survey by Lester et al. [17] reported that only about half of gastroenterologists routinely ascertain the patient’s vaccination status at the time of IBD diagnosis, while the other half assess it later at follow-up visits, or before starting immunosuppressive treatment. According to the respondents to the survey, the most commonly used investigative tool in this regard was verbal inquiry about immunization status; only 9% of those asked routinely obtained serology. Drawing titers may be useful in assessing whether titers are at an adequate level, or if there is no clear history of vaccination or wild-type infection. Investigators usually obtain a blood sample from the patient before and after inoculation of a vaccine, and compare the antibody titer levels in order to verify seroconversion, that can be defined the development of antibodies after vaccination in an individual who was previously seronegative. When the antibody level reaches, or exceeds, the minimum threshold considered protective against wild-type infection, seroprotection takes place. During patient follow-up, the following immunizations are recommended: annual influenza vaccine, pneumococcal vaccine (every 5 years), tetanus booster vaccine (every 10 years), and Human papillomavirus (HPV) vaccine (in adolescents) [5]. Recommendations on vaccinations in pediatric IBD are summarized in Table 1. 4. Vaccination immunogenicity It is reported that IBD patients have an appropriate immune response to vaccines, but it may be lower in patients on immunosuppressive therapy, especially TNF-a inhibitors. Hence, a major concern regarding vaccination of IBD patients is the ability of the immune system, often medically suppressed, to mount an effective immune response [20,21]. IBD patients considered to be immunosuppressed are those assuming 6-mercaptopurine (6-MP), azathioprine, methotrexate, biologics, tacrolimus, cyclosporine, or highdose systemic corticosteroids (20 mg/day, or 2 mg/kg/day if <10 kg, of prednisone or its equivalent if used for at least 14 days); those on aminosalicylate monotherapy are not considered immunosuppressed. Patients who are severely malnourished are also considered immunosuppressed [20,22,23].
(NOD2, TLR4), in autophagy (ATG16L1, IRGM, VAMP3), in intestinal barrier function (DLG5, MUC1), and in the activation and proliferation of lymphocytes (HLA, IL23R, IL10, IL10R, IL2RA, ERAP2, CPEB4, TNFSF11, SMAD3) [24,25]. Certain human leukocyte antigen (HLA) haplotypes have been associated with an increased risk of vaccination failure [25]. However, whether these genetic factors determine defective antigen presentation or recognition by immune cells remains unknown. Most studies assessing the immune response to vaccination in IBD patients have found a defective humoral response, involving the B-lymphocyte switching [26] and/or the development of IgG precursors [27], as mechanisms of impairment. Furthermore, a specific antibody deficiency (SAD) may occur against a specific antigen in IBD, regardless of class switching recombination [28]. Other studies have found an association between suboptimal immunogenicity and older age, lower albumin levels, pancolitis disease pattern, IBD duration of 110 months or more, and active IBD [29]. The genetic and immunological peculiarities of patients with IBD, together with the effect of immunomodulatory and immunosuppressive therapies, concurrently affect the ability of the immune system to react properly to vaccine antigens [25], but further studies are warranted. 4.2. Vaccination immunogenicity in adult patients In the adult IBD population, the immune response to hepatitis B [30] and A [31], influenza [21,32], and pneumococcal vaccines [33] have been found impaired, while the immune response to HPV vaccine seems to be similar to that observed in the general population [25]. Data on the immunogenicity of tetanus vaccine are conflicting [27,34,35]. Studies assessing the response to measles-mumpsrubella, varicella, and herpes zoster vaccines are scarce [25]. 4.3. Vaccination immunogenicity in pediatric patients
4.1. Mechanisms impairing the response to vaccine
Few studies have been carried out to investigate immune response to vaccines in pediatric IBD patients [10]. Interestingly, most of them have been carried out on IBD patients who have already been put on immunomodulatory and/or biological treatment. The available data on immunogenicity and safety of both inactivated and live attenuated vaccines for young and adolescent patients with IBD will be reported in the following section and summarized in Table 2.
The mechanisms of immune response impairment to vaccination in IBD are unclear. The immunological alterations generated by the disease and immunomodulatory drugs can impair the immune response to vaccinations in IBD patients. The cellular and molecular mechanisms responsible are not yet completely understood, and many hypotheses have been carried out. Many of the genetic mutations and polymorphisms associated with an increased risk of developing IBD have also been involved in recognition of intestinal microbiota by the innate immune system
4.3.1. Hepatitis A and hepatitis B Two recent pediatric studies (age range from 2–3 to 17– 18 years) concluded that the hepatitis A virus vaccine in children and adolescents with IBD is immunogenic (seroconversion rates of 97%–100% vs. 100% in healthy controls) and well tolerated (no worsening of disease activity) [36,37]. Similarly, a study on children and adolescents age 3–17 years showed that the hepatitis B virus (HBV) vaccine has a satisfying seroconversion in pediatric patients with IBD who had not been immunized against HBV (seroconver-
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
4
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx
Table 2 Vaccination immunogenicity and safety in pediatric inflammatory bowel disease. References
Research design
Population characteristics
Vaccine
Seroconversion rate
GMTs
Factors and/or mechanisms associated with a lower response
Serious adverse events
Radzikowski et al. [36]
Prospective
66 IBD (25 CD, 41 UC) children on treatment
HAV
97% (64/66)
Lower than controls
Steroid therapy
None
Moses et al. [29]
Prospective
100 IBD (91 CD, 9 UC) children on treatment
HBV
76% (26/34 who received booster dose) 56% (49/87 already vaccinated)
NR
Infliximab therapy Older age, lower albumin levels, pancolitis
None
Urgancy et al. [37]
Prospective
47 IBD (14 CD, 25 UC) children on treatment
HAV HBV
100% (23/23 who received 2-dose HAV) 70% (33/47) 50% (7/14 who received booster dose)
NR
– NR NR
None
Fallahi et al. [28]
Prospective
18 IBD (6 CD, 12 UC) children on treatment
PPV23
NR
Lower than controls
Defective B cell switching, specific antibody deficiency
NR
Banaszkiewicz et al. [26]
Prospective
122 IBD (72 CD, 50 UC) children on treatment (group B) or not (group A)
PCV13
90.4% (110/122)
Lower in group B
Immunosuppressive therapy
None
Jacobson et al. [42]
Prospective
33 IBD (26 CD, 2 UC, 2 IC) girls on treatment 15 IBD vaccinated (13 CD, 2 UC) girls on treatment
HPV4
100% (types 6, 11, 16) 96% (type 18)
Similar to controls
–
None
Retrospective
100% (types 6, 11, 16) 93% (type 18)
Mamula et al. [43]
Prospective
51 IBD (45 CD, 6 UC) children
Trivalent influenza vaccine
NR
Lower against B strain
Immunomodulatory and biological therapy
None
Lu et al. [44]
Prospective
146 IBD (96 CD, 47 UC, 3 IC) children, 126 on treatment
Trivalent influenza vaccine
95%, 89%, 39% respectively against H1N1, H3N2, B strains
Lower against B strain
NR
None
deBruyn et al. [46]
Prospective
60 IBD (26 CD, 24 UC, 10 IC) children, 42 on treatment
Trivalent influenza vaccine
98%, 95%, 85% respectively against H1N1, H3N2, B strains
Lower against B strain
Immunosuppressive therapy
None
deBruyn et al. [21]
Prospective
137 IBD (115 CD, 21 UC, IC) children on infliximab
Trivalent influenza vaccine
67% vs 66%, 43% vs 49%, 69% vs 79% respectively against H1N1,H3N2, B strains, at the time of infliximab infusion (69/137) and midway between infusions (68/137)
NR
–
None
Lu et al. [48]
Case series
6 IBD (5 CD, 1UC) children on treatment
Varicella
5/6
–
–
None
IBD - inflammatory bowel disease, CD - Crohn’s disease, UC - ulcerative colitis, IC - indeterminate colitis, HAV - hepatitis A virus, HBV - hepatitis B virus, HPV - human papillomavirus.
sion rates of 70% vs. 90% in healthy controls); patients who had not seroconverted showed a good response after a booster dose administration (seroconversion rates of 50% vs. 60% in healthy controls) [37]. Several cases of HBV reactivation have been reported in adult IBD patients with latent HBV infection who had been treated using TNF-a inhibitors; such reactivation resulted in severe hepatitis and/ or liver failure [38]. No similar cases in pediatric IBD have been reported. Before the start of immunosuppressive therapy, it is important to check whether patients are seronegative for HBV infection. In cases of seronegativity, the three-dose vaccine series should be administered; the titers should then be re-checked 1 month after completion of the series. In cases of inadequate response, patients should be vaccinated with a double dose [20,39]. In a prospective study involving 100 children and young adults (age range 5–18 years) who had been treated for IBD using TNF-a inhibitors, 87% of the patients had already been immunized; however, only half of them had immunity. Booster immunization showed to be effective, with a seroconversion rate of 76% [29]. 4.3.2. Pneumococcus There are two different types of pneumococcal vaccine: the pneumococcal polysaccharide vaccines (PPVs), which include 23
Streptococcus pneumoniae serotypes (PPV23), and the pneumococcal conjugate vaccines (PCVs), which include 10 (PCV10) or 13 (PCV13) Streptococcus pneumoniae serotypes, calculated based on the chemical coupling of Streptococcus pneumoniae polysaccharides to carrier proteins. Even though the specific labeling details may differ by country, both PCV10 and PCV13 are licensed for vaccination of infants and children from 6 weeks to 5 years of age against the respective vaccine serotypes of Streptococcus pneumoniae. All patients with IBD, aged 2 years, who are receiving immunosuppressive therapy and who have not previously received PCV or PPV23, should receive a dose of PCV, followed by a dose of PPV23 at least 8 weeks later. A second dose of PPV23 is recommended 5 years later. Patients who have previously been vaccinated with PPV23 should be given a PCV dose 1 year after their last PPV23 [6]. Until last year, few data existed regarding PPV in adult patients with IBD [26]. Banaszkiewicz et al. [26] published the first study assessing the immune response to the PCV13 vaccine in pediatric patients aged 5–18 years with IBD; they demonstrated that PCV is immunogenic in this group of patients, with no significant differences in the rate of adequate vaccine response between patients with IBD and controls (seroconversion rates 90.4% vs. 96.5%, respectively). Safety was satisfactory too, with
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx
no serious adverse events occurring during the study. The serological response to PCV13 is probably better than that to PPV23. However, this position was not confirmed in a randomized study by Kantsø et al. [40], who found that adult patients with IBD who have received PCV13 have higher post-vaccination titers than those who have received PPV23. In the results of a study investigating the specific antibody response against PPV in children (mean age, 10.7 ± 4.2 years) with IBD [28], half of the participants were hyporesponsive to PPV and had a SAD against PP antigen. Therefore, vaccination may not be sufficient in this group of patients, and they may benefit from other preventive methods such as PCV administration and long-term antibiotic therapy. Interestingly, high pre-vaccination pneumococcal geometric mean titers (GMTs) for all PCV 13 serotypes were found in children and adolescents between 5 and 18 years of age with IBD, suggesting that they previously acquired natural protection against pneumococcus [41]. 4.3.3. Human papillomavirus HPV vaccine is a 3-dose series vaccine recommended between 11 and 12 years of age. It immunizes against HPV, which is responsible for approximately 75% of cervical cancers and 90% of genital warts. In a study by Jacobson et al. [42], girls and young women aged 9–26 years receiving immunosuppressive therapy for IBD showed excellent immune response to the HPV4 quadrivalent vaccine (against HPV types 16, 18, 6, and 11), with 100% seropositivity. There were no serious adverse events or worsened disease activity related to the vaccination. 4.3.4. Influenza The influenza vaccine is available as an inactivated, intramuscularly administered form for children age 6 months and older, and as a live attenuated, intranasally administered form, for children age 2 years and older [39]. The inactivated form of the influenza vaccine is recommended to all IBD patients every year [10]; according to the Centers for Disease Control and Prevention (CDC), when available, also the swine-origin H1N1 influenza viruses combination vaccine is specifically recommended for this group of subjects [39]. Pediatric IBD data demonstrate that there is good safety and tolerance to this vaccine, without serious adverse events or worsened IBD activity [21,43,44]. The vaccine is usually immunogenic, especially to the two A strains of influenza. However, the immune response in immunocompromised patients may vary [21]: pediatric data on the influenza vaccine in IBD suggest that both seroprotection and seroconversion occur, although there might be a slightly lower efficacy in patients prescribed biologics than in those not receiving immunosuppressive therapy and in healthy controls [21,43–46]. Importantly, vaccine timing relative to infliximab infusion does not seem to affect the achievement of serologic protection [21]. Uptake of the influenza vaccine is still low in patients with IBD, despite an increased risk of complications from infection. If influenza infection is certain or suspected, the recommendation is to withhold immunosuppressive therapy until infection resolution [10], and to use antiviral medications, such as oseltamivir, if clinically indicated, regardless of the patient’s immunosuppression status [10]. 4.3.5. Other inactivated vaccines No data currently exist regarding the diphtheria-tetanuspertussis, Haemophilus influenzae type B, meningococcal, and inactivated poliovirus vaccines in children with IBD [10]. 4.3.6. Varicella The varicella vaccine is a 2-dose regimen and is typically administered at 12–18 months of age, and one to three months after the first dose. The varicella vaccine is currently not recommended in patients with IBD on immunosuppressive therapy, since
5
it is live [10,19]. However, this group of patients often receive immunosuppressive treatments throughout childhood, the period in which varicella exposure is common, and major complications from wild-type infection have been described [47]. In contrast, the vaccine itself has not been linked to complications in children affected by IBD [48]. Notably, most of pediatric patients at diagnosis of IBD seem to have either a history of chickenpox or received at least 1 vaccine dose [48,49]. Researchers should weigh the benefits of vaccination against the risks of vaccine-associated adverse events. That said, there is a paucity of data regarding immune response to the varicella vaccine in pediatric patients with IBD. A good response was found in a case series consisting of six children and adolescents with IBD who were given the varicella vaccine during treatment with either 6-MP or TNF-a inhibitors. A positive immunity after vaccination (seroconversion) was documented in all but one [48]. Similarly, in a retrospective study involving 10 IBD patients (age range from 1 to 19 years) with a negative or unknown titer who were immunized before beginning immunosuppression, the response was promising [49]. 4.3.7. Measles, mumps, and rubella No data exist on the immunogenicity of the MMR vaccine in pediatric IBD patients [10]. 5. Conclusions The monitoring of vaccination schedules is an important aim in pediatric patients with IBD at diagnosis and before the start of immunomodulatory therapies (steroids, immunosuppressive and biological therapies). In a pediatric population, around 80% of patients will start steroids at diagnosis and 40% thiopurines and anti-TNF-a therapy within 1 year of diagnosis. Pediatric gastroenterologist sensitivity should be heightened to ensure an adequate vaccination program and monitoring. Funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Financial disclosure The authors have no financial relationships relevant to this article to disclose. Conflict of interest The authors have no conflicts of interest relevant to this article to disclose. Contributors’ statement Valeria Dipasquale: Dr. Dipasquale, conceptualized and designed the study, drafted the initial manuscript, and approved the final manuscript as submitted. Claudio Romano: Dr. Romano, carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. References [1] Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review [e42;
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
6
[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]
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx quiz e30]. Gastroenterology 2012;142(1):46–54. https://doi.org/10.1053/ j.gastro.2011.10.001. Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423–39. https://doi.org/10.1002/ibd.21349. Corica D, Romano C. Biological therapy in pediatric inflammatory bowel disease: a systematic review. J Clin Gastroenterol 2017;51(2):100–10. https:// doi.org/10.1097/MCG.0000000000000696. Romano C, Syed S, Valenti S, et al. Management of acute severe colitis in children with ulcerative colitis in the biologics era. Pediatrics 2016;137(5): e20151184. https://doi.org/10.1542/peds.2015-1184. Nuti F, Civitelli F, Cucchiara S. Long-term safety of immunomodulators in pediatric inflammatory diseases. Paediatr Drugs 2014;16(5):343–52. https:// doi.org/10.1007/s40272-014-0084-2. Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2014;8(6):443–68. https://doi. org/10.1016/j.crohns.2013.12.013. Ardura MI, Toussi SS, Siegel JD, et al. NASPGHAN clinical report: surveillance, diagnosis, and prevention of infectious diseases in pediatric patients with inflammatory bowel disease receiving tumor necrosis factor-a inhibitors. J Pediatr Gastroenterol Nutr 2016;63(1):130–55. https://doi.org/10.1097/ MPG.0000000000001188. Symmers WS. Opportunistic infections. The concept of ‘opportunistic infections’. Proc R Soc Med 1965;58:341–6. Rosen MJ, Dhawan A, Saeed SA. Inflammatory bowel disease in children and adolescents. JAMA Pediatr 2015;169(11):1053–60. https://doi.org/ 10.1001/jamapediatrics.2015.1982. Lu Y, Bousvaros A. Immunizations in children with inflammatory bowel disease treated with immunosuppressive therapy. Gastroenterol Hepatol (NY) 2014;10(6):355–63. Waszczuk K, Waszczuk E, Mulak A, et al. A ‘cocoon immunization strategy’ among patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2015;27(3):249–53. https://doi.org/10.1097/MEG.0000000000000280. Soon IS, deBruyn JC, Wrobel I. Immunization history of children with inflammatory bowel disease. Can J Gastroenterol 2013;27(4):213–6. Banaszkiewicz A, Klincewicz B, Łazowska-Przeorek I, GrzybowskaChlebowczyk U, Ka˛kol P, Mytyk A, et al. Influenza vaccination coverage in children with inflammatory bowel disease. Influenza Other Respir Viruses 2014;8(4):431–5. https://doi.org/10.1111/irv.12236. Yeung JH, Goodman KJ, Fedorak RN. Inadequate knowledge of immunization guidelines: a missed opportunity for preventing infection in immunocompromised IBD patients. Inflamm Bowel Dis 2012;18(1):34–40. https://doi.org/10.1002/ibd.21668. Melmed GY, Ippoliti AF, Papadakis KA, et al. Patients with inflammatory bowel disease are at risk for vaccine-preventable illnesses. Am J Gastroenterol 2006;101(8):1834–40. https://doi.org/10.1111/j.1572-0241.2006.00646.x. Narula N, Dhillon AS, Chauhan U, Marshall JK. An audit of influenza vaccination status in adults with inflammatory bowel disease. Can J Gastroenterol 2012;26 (9):593–6. Lester R, Lu Y, Tung J. Survey of immunization practices in patients with inflammatory bowel disease among pediatric gastroenterologists. J Pediatr Gastroenterol Nutr 2015;61(1):47–51. https://doi.org/10.1097/ MPG.0000000000000730. Huth K, Benchimol EI, Aglipay M, Mack DR. Strategies to improve influenza vaccination in pediatric inflammatory bowel disease through education and access. Inflamm Bowel Dis 2015;21(8):1761–8. https://doi.org/10.1097/ MIB.0000000000000425. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58 (3):309–18. https://doi.org/10.1093/cid/cit816. Wasan SK, Baker SE, Skolnik PR, Farraye FA. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol 2010;105(6):1231–8. https://doi.org/10.1038/ajg.2009.733. deBruyn J, Fonseca K, Ghosh S, Panaccione R, Gasia MF, Ueno A, et al. Immunogenicity of influenza vaccine for patients with inflammatory bowel disease on maintenance infliximab therapy: a randomized trial. Inflamm Bowel Dis 2016;22:638–47. https://doi.org/10.1097/MIB.0000000000000615. Sands BE, Cuffari C, Katz J, et al. Guidelines for immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004;10(5):677–92. American Academy of Pediatrics. Varicella-zoster infections. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red book: 2009 report of the committee on infectious diseases. Elk Grove Village (IL): American Academy of Pediatrics; 2009. p. 714–27. Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 2011;140:1704–12. https://doi.org/10.1053/ j.gastro.2011.02.046. Marín AC, Gisbert JP, Chaparro M. Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease. World J Gastroenterol 2015;21(40):11273–81. https://doi.org/10.3748/wjg.v21.i40.11273. Banaszkiewicz A, Targon´ska B, Kowalska-Duplaga K, et al. Immunogenicity of 13-valent pneumococcal conjugate vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2015;21(7):1607–14. https://doi.org/10.1097/MIB.0000000000000406.
[27] Brogan MD, Shanahan F, Oliver M, Stevens RH, Targan SR. Defective memory B cell formation in patients with inflammatory bowel disease following tetanus toxoid booster immunization. J Clin Lab Immunol 1987;24:69–74. [28] Fallahi G, Aghamohammadi A, Khodadad A, Hashemi M, Mohammadinejad P, Asgarian-Omran H, et al. Evaluation of antibody response to polysaccharide vaccine and switched memory B cells in pediatric patients with inflammatory bowel disease. Gut Liver 2014;8(1):24–8. https://doi.org/10.5009/ gnl.2014.8.1.24. [29] Moses J, Alkhouri N, Shannon A, et al. Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab. Am J Gastroenterol 2012;107(1):133–8. https://doi.org/10.1038/ ajg.2011.295. [30] Altunöz ME, S ß enatesß E, Ye A, et al. Patients with inflammatory bowel disease have a lower response rate to HBV vaccination compared to controls. Dig Dis Sci 2012;57:1039–44. https://doi.org/10.1007/s10620-011-1980-8. [31] Park SH, Yang SK, Park SK, et al. Efficacy of hepatitis A vaccination and factors impacting on seroconversion in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(1):69–74. https://doi.org/10.1097/01. MIB.0000437736.91712.a1. [32] Hiroko M, Watanabe K, Morimoto K, et al. Booster doses of the trivalent influenza vaccine do not elicit a significant immune response in patients with inflammatory bowel disease: a prospective randomized controlled trial. Gastroenterology 2014;146(Suppl. 1):1039–44. S-80. [33] Melmed GY, Frenck R, Barolet-Garcia C, et al. TNF blockers and immunomodulators impair antibody responses to pneumococcal polysaccharide vaccine (PPV) in patients with inflammatory bowel disease (IBD). Gastroenterology 2008;134(4 Suppl. 1):A68. [34] Stevens R, Oliver M, Brogan M, Heiserodt J, Targan S. Defective generation of tetanus-specific antibody-producing B cells after in vivo immunization of Crohn’s disease and ulcerative colitis patients. Gastroenterology 1985;88:1860–6. [35] Nielsen HJ, Mortensen T, Holten-Andersen M, Brünner N, Sørensen S, RaskMadsen J. Increased levels of specific leukocyte- and platelet-derived substances during normal anti-tetanus antibody synthesis in patients with inactive Crohn disease. Scand J Gastroenterol 2001;36:265–9. [36] Radzikowski A, Banaszkiewicz A, Łazowska-Przeorek I, et al. Immunogenecity of hepatitis A vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2011;17(5):1117–24. https://doi.org/10.1002/ibd.21465. [37] Urganci N, Kalyoncu D. Immunogenecity of hepatitis A and B vaccination in pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2013;56(4):412–5. [38] Fuchs I, Abu-Shakra M, Sikuler E. Hepatitis B and C reactivation with tumor necrosis factor inhibitors: synopsis and interpretation of screening and prophylaxis recommendations. Isr Med Assoc J 2013;15(6):303–7. [39] ACIP Childhood/Adolescent Immunization Work Group, Akinsanya-Beysolow I, Jenkins R, Meissner HC. Centers for Disease Control and Prevention (CDC). Advisory Committee on Immunization Practices (ACIP) recommended immunization schedule for persons aged 0 through 18 years–United States, 2013. MMWR Suppl. 013;62(1):2–8. [40] Kantsø B, Halkjær SI, Thomsen OØ, et al. Immunosuppressive drugs impairs antibody response of the polysaccharide and conjugated pneumococcal vaccines in patients with Crohn’s disease. Vaccine 2015;33(41):5464–9. https://doi.org/10.1016/j.vaccine.2015.08.011. [41] Banaszkiewicz A, Targon´ska B, Kowalska-Duplaga K, Karolewska-Bochenek K, Sieczkowska A, Gawron´ska A, et al. Serotype specific pneumococcal status prior to PCV 13 administration in children and adolescents with inflammatory bowel disease. Pol J Microbiol 2016;65(1):89–91. [42] Jacobson DL, Bousvaros A, Ashworth L, et al. Immunogenicity and tolerability to human papillomavirus-like particle vaccine in girls and young women with inflammatory bowel disease. Inflamm Bowel Dis 2013;19(7):1441–9. https:// doi.org/10.1097/MIB.0b013e318281341b. [43] Mamula P, Markowitz JE, Piccoli DA, Klimov A, Cohen L, Baldassano RN. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5(7):851–6. https://doi.org/ 10.1016/j.cgh.2007.02.035. [44] Lu Y, Jacobson DL, Ashworth LA, et al. Immune response to influenza vaccine in children with inflammatory bowel disease. Am J Gastroenterol 2009;104 (2):444–53. https://doi.org/10.1038/ajg.2008.120. [45] Romanowska M, Banaszkiewicz A, Nowak I, et al. Immunization against influenza during the 2005/2006 epidemic season and the humoral response in children with diagnosed inflammatory bowel disease (IBD). Med Sci Monit 2010;16(9):CR433–9. [46] deBruyn JC, Hilsden R, Fonseca K, et al. Immunogenicity and safety of influenza vaccination in children with inflammatory bowel disease. Inflamm Bowel Dis 2012;18(1):25–33. https://doi.org/10.1002/ibd.21706. [47] Leung VS, Nguyen MT, Bush TM. Disseminated primary varicella after initiation of infliximab for Crohn’s disease. Am J Gastroenterol 2004;99 (12):2503–4. https://doi.org/10.1111/j.1572-0241.2004.41389_7.x. [48] Lu Y, Bousvaros A. Varicella vaccination in children with inflammatory bowel disease receiving immunosuppressive therapy. J Pediatr Gastroenterol Nutr 2010;50(5):562–5. https://doi.org/10.1097/MPG.0b013e3181bab351. [49] Ansari F, Baker RD, Patel R, et al. Varicella immunity in inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011;53(4):386–8. https://doi.org/ 10.1097/MPG.0b013e31821e1917.
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Vaccination strategies in pediatric inflammatory bowel disease Valeria Dipasquale, Claudio Romano ⇑ Unit of Pediatrics, Department of Human Pathology in Adulthood and Childhood ‘‘G. Barresi”, University of Messina, Messina, Italy
a r t i c l e
i n f o
Article history: Received 11 April 2017 Received in revised form 31 August 2017 Accepted 8 September 2017 Available online xxxx Keywords: Inflammatory bowel disease Vaccination Immunization Immunogenicity Safety Children
a b s t r a c t The incidence of pediatric inflammatory bowel disease (IBD) is rising, as is the use of immunomodulatory and biological drugs. IBD patients are vulnerable to infections owing to disease-related immunological alterations and drug-induced systemic immunosuppression. Although many infections are vaccinepreventable, vaccination coverage in IBD patients is insufficient. Current guidelines recommend that children with IBD follow the same routine immunization schedule as healthy children, avoiding live vaccines during immunosuppressive therapy. Immunization status should be checked at diagnosis, and patients should be immunized with the vaccines they need. Some studies have demonstrated a suboptimal immune response to vaccinations in IBD patients, but responsible mechanisms are poorly understood. In this manuscript, we provide a broad review of available data about vaccine coverage rates, immunogenicity and safety of both killed and live attenuated vaccinations in the pediatric IBD population; furthermore, we provide comprehensive information regarding current guidelines for immunization of children with IBD and their household contacts. A comprehensive search of published literature using the PubMed (http:// www.ncbi.nlm.nih.gov/pubmed/) database was carried out to identify all articles published in English from 1998 to March 2017, using the following key terms: ‘‘inflammatory bowel disease”, ‘‘vaccination”, ‘‘immunization”, ‘‘immunogenicity”, ‘‘safety” and ‘‘children”. Ó 2017 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunization rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunization strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Checking immunization status: how and when . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaccination immunogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Mechanisms impairing the response to vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Vaccination immunogenicity in adult patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Vaccination immunogenicity in pediatric patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Hepatitis A and hepatitis B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Pneumococcus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Human papillomavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.4. Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.5. Other inactivated vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.6. Varicella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.7. Measles, mumps, and rubella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
⇑ Corresponding author at: Unit of Pediatrics, Department of Human Pathology in Adulthood and Childhood ‘‘G. Barresi,” University of Messina, Via Consolare Valeria, Messina 98124, Italy. E-mail address: [email protected] (C. Romano). https://doi.org/10.1016/j.vaccine.2017.09.031 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
2
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx
Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors’ statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease (CD), ulcerative colitis (UC) and indeterminate colitis (IC), continue to rise in incidence and prevalence worldwide, both in the adult and pediatric populations [1]. IBDs are defined as multifactorial disorders characterized by chronic relapsing intestinal inflammation, with a peak onset during adolescence and young adulthood [2]. Treatment during the last decade has been based on immunomodulatory and biological drugs, such as anti-tumor necrosis factor alpha (TNF-a), that are being used increasingly often and earlier during the course of the disease [3,4]. Clinical studies, registries, and case series have highlighted the increased risk of infection, notably opportunistic infections, in young and adult patients with IBD [5–7]. An opportunistic infection is defined as a serious, often progressive infection, caused by microorganisms that have limited virulence, but can cause serious disease related to a predisposing pathologic condition or its treatment [8]. The challenges are not only in managing these diseases, but also in recognizing, preventing and managing infections. Prevention of infections is a major issue for public health, and vaccination has shown to be one of the most successful strategies against the spread of several infectious diseases [9]. Accordingly, the European Crohn’s and Colitis Organization (ECCO) recommends protection with vaccines for young and adult IBD patients, where appropriate and available [6]. In the present manuscript, we provide an upgraded review of literature regarding vaccination rates, immunogenicity and safety, and current guidelines for vaccination in children with IBD. To accomplish this, a comprehensive search of published literature using the PubMed MEDLINE database (1998– March 2017) was performed. The key terms ‘‘inflammatory bowel disease”, ‘‘vaccination”, ‘‘immunization”, ‘‘immunogenicity”, ‘‘safety” and ‘‘children” were used. 2. Immunization rate The most efficacious way to minimize vaccine-preventable infections is through vaccinations. A complete vaccination schedule is important in pediatric patients with IBD, who are at a higher risk of infection and severe or fatal complications than the general population [10]. Nonetheless, vaccination coverage in IBD adult and young patients is reported as below that of healthy children [10,11]. Incomplete childhood immunization can be distinguished as IBD-related or non IBD-related [12]. IBD-related reasons include use of immunosuppressive drugs and disease flare at the time of scheduled immunization, while non IBD-related reasons include parental refusal, lack of awareness of routine immunization, recent move from elsewhere with different immunization schedules, needle phobia. Many studies have demonstrated that both gastroenterologists and patients underuse the tool of vaccination in patients with IBD [10]. Primary care practitioners and gastroenterologists are often unaware of any existing recommendations, resulting in the lack of appropriate counseling [13,14]. Patients are frequently worried about vaccine-associated complications or low effectiveness, finally resulting in unsatisfying adherence to vaccination programs and seroprotection [15,16]. A survey of 36 IBD patients [11] has reported on provided reasons for the refusal of a recommended vaccination, which included the supposed unneces-
00 00 00 00
sity of vaccinating (52%), the fear of possible vaccine-related side effects or adverse reactions (25%), doubts about effectiveness (14%), the high cost of the vaccine (6%) and discouragement from medical care providers (37%). Another survey of pediatric gastroenterologists [17] concluded that the main barriers to vaccination are the lack of coordination of care with primary care practitioners (even if only 28% believed that primary care practitioners were solely responsible for immunizations), poor access to immunization records, and the inability to offer vaccinations in their immediate area, thereby being obliged to refer patients to overburdened public health clinics for vaccines, which are often located far from their offices or in other cities. In a recent prospective cohort study carried out over 2 successive influenza seasons, educational intervention and providing of influenza vaccine during clinic visits has been associated with improved influenza vaccination rates [18]. 3. Immunization strategies In 2013, the Infectious Disease Society of America published a ‘‘Clinical Practice Guideline for Vaccination of the Immunocompromised Host”, an evidence-based guideline for vaccination of immunocompromised adults and children [19]. They recommended vaccinating all IBD patients, following the same routine immunization schedule as in healthy children. Live vaccines can be used before the start of immunosuppressive therapy—at least 4 weeks before starting treatment in the case of the varicella vaccine, and 6 weeks before treatment begins in the case of the measles, mumps, and rubella (MMR) vaccine. In pediatrics, exclusive enteral nutrition is considered a valuable alternative for induction therapy and could therefore be used as a window allowing time to update vaccinations prior to prescribing immunosuppressive drugs [6]. If immunosuppressive therapy has already begun, guidelines recommend administering live vaccines after discontinuation for at least 3 months (only 1 month if corticosteroid monotherapy is being used). Fortunately, most children with IBD have already received live vaccines by the time of diagnosis, as live vaccines are routinely administered to young children, and IBD onset is less common in children younger than 5 years of age. Household contacts can safely receive inactivated vaccinations, as well as the MMR vaccine, without fear of harming or spreading the virus to the patient [20]. The varicella vaccine is also viable; if a vaccine-related rash develops and the patient is not immunized, it is enough to avoid close contact. Such a scenario does not indicate administration of varicella zoster immunoglobulin, as the secondary infection from the vaccine is expected to be mild [20]. The ‘‘cocoon strategy” refers to protecting vulnerable patients from infection due to close contact with those who have been vaccinated. Recently, a study investigated the ‘‘cocooning strategy” among patients with IBD for the first time, concluding that it is not sufficient to protect IBD patients [11]. 3.1. Checking immunization status: how and when The immunization status of the patient should ideally be checked at the time of IBD diagnosis, especially if there is no clear history of vaccination or wild-type infection [10]. According to the second ECCO Consensus (2014) on opportunistic infections in adult
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx
3
Table 1 Recommendations on vaccinations in pediatric IBD. Non-replicating vaccinations may be administered regardless of immunosuppressive drug use Live attenuated vaccinations may be considered if there are no plans to start immunosuppressive therapy in 4–6 weeks Live attenuated vaccines may be administered after at least 3 months-discontinuation (after 1 month-discontinuation in case of corticosteroids monotherapy) if immunosuppressive therapy has already been started Both live attenuated and non-replicating vaccines may be administered to household contacts; varicella vaccine recipients with vaccine-related rash should avoid contact with the immunosuppressed patient who is not immunized Immunization status should be checked at diagnosis, above all in case of unknown history of vaccination or wild-type infection Immunization status can be checked by verbal inquiring and/or antibody titers (MMR, hepatitis A and B virus, and varicella) Titers can be useful in the case of unknown history of vaccination or wild-type infection or to confirm adequate antibody levels Vaccine effectiveness may be lower in patients during immunosuppressive therapy MMR - measles, mumps, rubella.
and pediatric IBD, at the time of diagnosis the immunization status should be primarily checked for routinely administered vaccines, such as tetanus, diphtheria, poliomyelitis [6]. The survey by Lester et al. [17] reported that only about half of gastroenterologists routinely ascertain the patient’s vaccination status at the time of IBD diagnosis, while the other half assess it later at follow-up visits, or before starting immunosuppressive treatment. According to the respondents to the survey, the most commonly used investigative tool in this regard was verbal inquiry about immunization status; only 9% of those asked routinely obtained serology. Drawing titers may be useful in assessing whether titers are at an adequate level, or if there is no clear history of vaccination or wild-type infection. Investigators usually obtain a blood sample from the patient before and after inoculation of a vaccine, and compare the antibody titer levels in order to verify seroconversion, that can be defined the development of antibodies after vaccination in an individual who was previously seronegative. When the antibody level reaches, or exceeds, the minimum threshold considered protective against wild-type infection, seroprotection takes place. During patient follow-up, the following immunizations are recommended: annual influenza vaccine, pneumococcal vaccine (every 5 years), tetanus booster vaccine (every 10 years), and Human papillomavirus (HPV) vaccine (in adolescents) [5]. Recommendations on vaccinations in pediatric IBD are summarized in Table 1. 4. Vaccination immunogenicity It is reported that IBD patients have an appropriate immune response to vaccines, but it may be lower in patients on immunosuppressive therapy, especially TNF-a inhibitors. Hence, a major concern regarding vaccination of IBD patients is the ability of the immune system, often medically suppressed, to mount an effective immune response [20,21]. IBD patients considered to be immunosuppressed are those assuming 6-mercaptopurine (6-MP), azathioprine, methotrexate, biologics, tacrolimus, cyclosporine, or highdose systemic corticosteroids (20 mg/day, or 2 mg/kg/day if <10 kg, of prednisone or its equivalent if used for at least 14 days); those on aminosalicylate monotherapy are not considered immunosuppressed. Patients who are severely malnourished are also considered immunosuppressed [20,22,23].
(NOD2, TLR4), in autophagy (ATG16L1, IRGM, VAMP3), in intestinal barrier function (DLG5, MUC1), and in the activation and proliferation of lymphocytes (HLA, IL23R, IL10, IL10R, IL2RA, ERAP2, CPEB4, TNFSF11, SMAD3) [24,25]. Certain human leukocyte antigen (HLA) haplotypes have been associated with an increased risk of vaccination failure [25]. However, whether these genetic factors determine defective antigen presentation or recognition by immune cells remains unknown. Most studies assessing the immune response to vaccination in IBD patients have found a defective humoral response, involving the B-lymphocyte switching [26] and/or the development of IgG precursors [27], as mechanisms of impairment. Furthermore, a specific antibody deficiency (SAD) may occur against a specific antigen in IBD, regardless of class switching recombination [28]. Other studies have found an association between suboptimal immunogenicity and older age, lower albumin levels, pancolitis disease pattern, IBD duration of 110 months or more, and active IBD [29]. The genetic and immunological peculiarities of patients with IBD, together with the effect of immunomodulatory and immunosuppressive therapies, concurrently affect the ability of the immune system to react properly to vaccine antigens [25], but further studies are warranted. 4.2. Vaccination immunogenicity in adult patients In the adult IBD population, the immune response to hepatitis B [30] and A [31], influenza [21,32], and pneumococcal vaccines [33] have been found impaired, while the immune response to HPV vaccine seems to be similar to that observed in the general population [25]. Data on the immunogenicity of tetanus vaccine are conflicting [27,34,35]. Studies assessing the response to measles-mumpsrubella, varicella, and herpes zoster vaccines are scarce [25]. 4.3. Vaccination immunogenicity in pediatric patients
4.1. Mechanisms impairing the response to vaccine
Few studies have been carried out to investigate immune response to vaccines in pediatric IBD patients [10]. Interestingly, most of them have been carried out on IBD patients who have already been put on immunomodulatory and/or biological treatment. The available data on immunogenicity and safety of both inactivated and live attenuated vaccines for young and adolescent patients with IBD will be reported in the following section and summarized in Table 2.
The mechanisms of immune response impairment to vaccination in IBD are unclear. The immunological alterations generated by the disease and immunomodulatory drugs can impair the immune response to vaccinations in IBD patients. The cellular and molecular mechanisms responsible are not yet completely understood, and many hypotheses have been carried out. Many of the genetic mutations and polymorphisms associated with an increased risk of developing IBD have also been involved in recognition of intestinal microbiota by the innate immune system
4.3.1. Hepatitis A and hepatitis B Two recent pediatric studies (age range from 2–3 to 17– 18 years) concluded that the hepatitis A virus vaccine in children and adolescents with IBD is immunogenic (seroconversion rates of 97%–100% vs. 100% in healthy controls) and well tolerated (no worsening of disease activity) [36,37]. Similarly, a study on children and adolescents age 3–17 years showed that the hepatitis B virus (HBV) vaccine has a satisfying seroconversion in pediatric patients with IBD who had not been immunized against HBV (seroconver-
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
4
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx
Table 2 Vaccination immunogenicity and safety in pediatric inflammatory bowel disease. References
Research design
Population characteristics
Vaccine
Seroconversion rate
GMTs
Factors and/or mechanisms associated with a lower response
Serious adverse events
Radzikowski et al. [36]
Prospective
66 IBD (25 CD, 41 UC) children on treatment
HAV
97% (64/66)
Lower than controls
Steroid therapy
None
Moses et al. [29]
Prospective
100 IBD (91 CD, 9 UC) children on treatment
HBV
76% (26/34 who received booster dose) 56% (49/87 already vaccinated)
NR
Infliximab therapy Older age, lower albumin levels, pancolitis
None
Urgancy et al. [37]
Prospective
47 IBD (14 CD, 25 UC) children on treatment
HAV HBV
100% (23/23 who received 2-dose HAV) 70% (33/47) 50% (7/14 who received booster dose)
NR
– NR NR
None
Fallahi et al. [28]
Prospective
18 IBD (6 CD, 12 UC) children on treatment
PPV23
NR
Lower than controls
Defective B cell switching, specific antibody deficiency
NR
Banaszkiewicz et al. [26]
Prospective
122 IBD (72 CD, 50 UC) children on treatment (group B) or not (group A)
PCV13
90.4% (110/122)
Lower in group B
Immunosuppressive therapy
None
Jacobson et al. [42]
Prospective
33 IBD (26 CD, 2 UC, 2 IC) girls on treatment 15 IBD vaccinated (13 CD, 2 UC) girls on treatment
HPV4
100% (types 6, 11, 16) 96% (type 18)
Similar to controls
–
None
Retrospective
100% (types 6, 11, 16) 93% (type 18)
Mamula et al. [43]
Prospective
51 IBD (45 CD, 6 UC) children
Trivalent influenza vaccine
NR
Lower against B strain
Immunomodulatory and biological therapy
None
Lu et al. [44]
Prospective
146 IBD (96 CD, 47 UC, 3 IC) children, 126 on treatment
Trivalent influenza vaccine
95%, 89%, 39% respectively against H1N1, H3N2, B strains
Lower against B strain
NR
None
deBruyn et al. [46]
Prospective
60 IBD (26 CD, 24 UC, 10 IC) children, 42 on treatment
Trivalent influenza vaccine
98%, 95%, 85% respectively against H1N1, H3N2, B strains
Lower against B strain
Immunosuppressive therapy
None
deBruyn et al. [21]
Prospective
137 IBD (115 CD, 21 UC, IC) children on infliximab
Trivalent influenza vaccine
67% vs 66%, 43% vs 49%, 69% vs 79% respectively against H1N1,H3N2, B strains, at the time of infliximab infusion (69/137) and midway between infusions (68/137)
NR
–
None
Lu et al. [48]
Case series
6 IBD (5 CD, 1UC) children on treatment
Varicella
5/6
–
–
None
IBD - inflammatory bowel disease, CD - Crohn’s disease, UC - ulcerative colitis, IC - indeterminate colitis, HAV - hepatitis A virus, HBV - hepatitis B virus, HPV - human papillomavirus.
sion rates of 70% vs. 90% in healthy controls); patients who had not seroconverted showed a good response after a booster dose administration (seroconversion rates of 50% vs. 60% in healthy controls) [37]. Several cases of HBV reactivation have been reported in adult IBD patients with latent HBV infection who had been treated using TNF-a inhibitors; such reactivation resulted in severe hepatitis and/ or liver failure [38]. No similar cases in pediatric IBD have been reported. Before the start of immunosuppressive therapy, it is important to check whether patients are seronegative for HBV infection. In cases of seronegativity, the three-dose vaccine series should be administered; the titers should then be re-checked 1 month after completion of the series. In cases of inadequate response, patients should be vaccinated with a double dose [20,39]. In a prospective study involving 100 children and young adults (age range 5–18 years) who had been treated for IBD using TNF-a inhibitors, 87% of the patients had already been immunized; however, only half of them had immunity. Booster immunization showed to be effective, with a seroconversion rate of 76% [29]. 4.3.2. Pneumococcus There are two different types of pneumococcal vaccine: the pneumococcal polysaccharide vaccines (PPVs), which include 23
Streptococcus pneumoniae serotypes (PPV23), and the pneumococcal conjugate vaccines (PCVs), which include 10 (PCV10) or 13 (PCV13) Streptococcus pneumoniae serotypes, calculated based on the chemical coupling of Streptococcus pneumoniae polysaccharides to carrier proteins. Even though the specific labeling details may differ by country, both PCV10 and PCV13 are licensed for vaccination of infants and children from 6 weeks to 5 years of age against the respective vaccine serotypes of Streptococcus pneumoniae. All patients with IBD, aged 2 years, who are receiving immunosuppressive therapy and who have not previously received PCV or PPV23, should receive a dose of PCV, followed by a dose of PPV23 at least 8 weeks later. A second dose of PPV23 is recommended 5 years later. Patients who have previously been vaccinated with PPV23 should be given a PCV dose 1 year after their last PPV23 [6]. Until last year, few data existed regarding PPV in adult patients with IBD [26]. Banaszkiewicz et al. [26] published the first study assessing the immune response to the PCV13 vaccine in pediatric patients aged 5–18 years with IBD; they demonstrated that PCV is immunogenic in this group of patients, with no significant differences in the rate of adequate vaccine response between patients with IBD and controls (seroconversion rates 90.4% vs. 96.5%, respectively). Safety was satisfactory too, with
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx
no serious adverse events occurring during the study. The serological response to PCV13 is probably better than that to PPV23. However, this position was not confirmed in a randomized study by Kantsø et al. [40], who found that adult patients with IBD who have received PCV13 have higher post-vaccination titers than those who have received PPV23. In the results of a study investigating the specific antibody response against PPV in children (mean age, 10.7 ± 4.2 years) with IBD [28], half of the participants were hyporesponsive to PPV and had a SAD against PP antigen. Therefore, vaccination may not be sufficient in this group of patients, and they may benefit from other preventive methods such as PCV administration and long-term antibiotic therapy. Interestingly, high pre-vaccination pneumococcal geometric mean titers (GMTs) for all PCV 13 serotypes were found in children and adolescents between 5 and 18 years of age with IBD, suggesting that they previously acquired natural protection against pneumococcus [41]. 4.3.3. Human papillomavirus HPV vaccine is a 3-dose series vaccine recommended between 11 and 12 years of age. It immunizes against HPV, which is responsible for approximately 75% of cervical cancers and 90% of genital warts. In a study by Jacobson et al. [42], girls and young women aged 9–26 years receiving immunosuppressive therapy for IBD showed excellent immune response to the HPV4 quadrivalent vaccine (against HPV types 16, 18, 6, and 11), with 100% seropositivity. There were no serious adverse events or worsened disease activity related to the vaccination. 4.3.4. Influenza The influenza vaccine is available as an inactivated, intramuscularly administered form for children age 6 months and older, and as a live attenuated, intranasally administered form, for children age 2 years and older [39]. The inactivated form of the influenza vaccine is recommended to all IBD patients every year [10]; according to the Centers for Disease Control and Prevention (CDC), when available, also the swine-origin H1N1 influenza viruses combination vaccine is specifically recommended for this group of subjects [39]. Pediatric IBD data demonstrate that there is good safety and tolerance to this vaccine, without serious adverse events or worsened IBD activity [21,43,44]. The vaccine is usually immunogenic, especially to the two A strains of influenza. However, the immune response in immunocompromised patients may vary [21]: pediatric data on the influenza vaccine in IBD suggest that both seroprotection and seroconversion occur, although there might be a slightly lower efficacy in patients prescribed biologics than in those not receiving immunosuppressive therapy and in healthy controls [21,43–46]. Importantly, vaccine timing relative to infliximab infusion does not seem to affect the achievement of serologic protection [21]. Uptake of the influenza vaccine is still low in patients with IBD, despite an increased risk of complications from infection. If influenza infection is certain or suspected, the recommendation is to withhold immunosuppressive therapy until infection resolution [10], and to use antiviral medications, such as oseltamivir, if clinically indicated, regardless of the patient’s immunosuppression status [10]. 4.3.5. Other inactivated vaccines No data currently exist regarding the diphtheria-tetanuspertussis, Haemophilus influenzae type B, meningococcal, and inactivated poliovirus vaccines in children with IBD [10]. 4.3.6. Varicella The varicella vaccine is a 2-dose regimen and is typically administered at 12–18 months of age, and one to three months after the first dose. The varicella vaccine is currently not recommended in patients with IBD on immunosuppressive therapy, since
5
it is live [10,19]. However, this group of patients often receive immunosuppressive treatments throughout childhood, the period in which varicella exposure is common, and major complications from wild-type infection have been described [47]. In contrast, the vaccine itself has not been linked to complications in children affected by IBD [48]. Notably, most of pediatric patients at diagnosis of IBD seem to have either a history of chickenpox or received at least 1 vaccine dose [48,49]. Researchers should weigh the benefits of vaccination against the risks of vaccine-associated adverse events. That said, there is a paucity of data regarding immune response to the varicella vaccine in pediatric patients with IBD. A good response was found in a case series consisting of six children and adolescents with IBD who were given the varicella vaccine during treatment with either 6-MP or TNF-a inhibitors. A positive immunity after vaccination (seroconversion) was documented in all but one [48]. Similarly, in a retrospective study involving 10 IBD patients (age range from 1 to 19 years) with a negative or unknown titer who were immunized before beginning immunosuppression, the response was promising [49]. 4.3.7. Measles, mumps, and rubella No data exist on the immunogenicity of the MMR vaccine in pediatric IBD patients [10]. 5. Conclusions The monitoring of vaccination schedules is an important aim in pediatric patients with IBD at diagnosis and before the start of immunomodulatory therapies (steroids, immunosuppressive and biological therapies). In a pediatric population, around 80% of patients will start steroids at diagnosis and 40% thiopurines and anti-TNF-a therapy within 1 year of diagnosis. Pediatric gastroenterologist sensitivity should be heightened to ensure an adequate vaccination program and monitoring. Funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Financial disclosure The authors have no financial relationships relevant to this article to disclose. Conflict of interest The authors have no conflicts of interest relevant to this article to disclose. Contributors’ statement Valeria Dipasquale: Dr. Dipasquale, conceptualized and designed the study, drafted the initial manuscript, and approved the final manuscript as submitted. Claudio Romano: Dr. Romano, carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. References [1] Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review [e42;
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031
6
[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]
V. Dipasquale, C. Romano / Vaccine xxx (2017) xxx–xxx quiz e30]. Gastroenterology 2012;142(1):46–54. https://doi.org/10.1053/ j.gastro.2011.10.001. Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423–39. https://doi.org/10.1002/ibd.21349. Corica D, Romano C. Biological therapy in pediatric inflammatory bowel disease: a systematic review. J Clin Gastroenterol 2017;51(2):100–10. https:// doi.org/10.1097/MCG.0000000000000696. Romano C, Syed S, Valenti S, et al. Management of acute severe colitis in children with ulcerative colitis in the biologics era. Pediatrics 2016;137(5): e20151184. https://doi.org/10.1542/peds.2015-1184. Nuti F, Civitelli F, Cucchiara S. Long-term safety of immunomodulators in pediatric inflammatory diseases. Paediatr Drugs 2014;16(5):343–52. https:// doi.org/10.1007/s40272-014-0084-2. Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2014;8(6):443–68. https://doi. org/10.1016/j.crohns.2013.12.013. Ardura MI, Toussi SS, Siegel JD, et al. NASPGHAN clinical report: surveillance, diagnosis, and prevention of infectious diseases in pediatric patients with inflammatory bowel disease receiving tumor necrosis factor-a inhibitors. J Pediatr Gastroenterol Nutr 2016;63(1):130–55. https://doi.org/10.1097/ MPG.0000000000001188. Symmers WS. Opportunistic infections. The concept of ‘opportunistic infections’. Proc R Soc Med 1965;58:341–6. Rosen MJ, Dhawan A, Saeed SA. Inflammatory bowel disease in children and adolescents. JAMA Pediatr 2015;169(11):1053–60. https://doi.org/ 10.1001/jamapediatrics.2015.1982. Lu Y, Bousvaros A. Immunizations in children with inflammatory bowel disease treated with immunosuppressive therapy. Gastroenterol Hepatol (NY) 2014;10(6):355–63. Waszczuk K, Waszczuk E, Mulak A, et al. A ‘cocoon immunization strategy’ among patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2015;27(3):249–53. https://doi.org/10.1097/MEG.0000000000000280. Soon IS, deBruyn JC, Wrobel I. Immunization history of children with inflammatory bowel disease. Can J Gastroenterol 2013;27(4):213–6. Banaszkiewicz A, Klincewicz B, Łazowska-Przeorek I, GrzybowskaChlebowczyk U, Ka˛kol P, Mytyk A, et al. Influenza vaccination coverage in children with inflammatory bowel disease. Influenza Other Respir Viruses 2014;8(4):431–5. https://doi.org/10.1111/irv.12236. Yeung JH, Goodman KJ, Fedorak RN. Inadequate knowledge of immunization guidelines: a missed opportunity for preventing infection in immunocompromised IBD patients. Inflamm Bowel Dis 2012;18(1):34–40. https://doi.org/10.1002/ibd.21668. Melmed GY, Ippoliti AF, Papadakis KA, et al. Patients with inflammatory bowel disease are at risk for vaccine-preventable illnesses. Am J Gastroenterol 2006;101(8):1834–40. https://doi.org/10.1111/j.1572-0241.2006.00646.x. Narula N, Dhillon AS, Chauhan U, Marshall JK. An audit of influenza vaccination status in adults with inflammatory bowel disease. Can J Gastroenterol 2012;26 (9):593–6. Lester R, Lu Y, Tung J. Survey of immunization practices in patients with inflammatory bowel disease among pediatric gastroenterologists. J Pediatr Gastroenterol Nutr 2015;61(1):47–51. https://doi.org/10.1097/ MPG.0000000000000730. Huth K, Benchimol EI, Aglipay M, Mack DR. Strategies to improve influenza vaccination in pediatric inflammatory bowel disease through education and access. Inflamm Bowel Dis 2015;21(8):1761–8. https://doi.org/10.1097/ MIB.0000000000000425. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58 (3):309–18. https://doi.org/10.1093/cid/cit816. Wasan SK, Baker SE, Skolnik PR, Farraye FA. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol 2010;105(6):1231–8. https://doi.org/10.1038/ajg.2009.733. deBruyn J, Fonseca K, Ghosh S, Panaccione R, Gasia MF, Ueno A, et al. Immunogenicity of influenza vaccine for patients with inflammatory bowel disease on maintenance infliximab therapy: a randomized trial. Inflamm Bowel Dis 2016;22:638–47. https://doi.org/10.1097/MIB.0000000000000615. Sands BE, Cuffari C, Katz J, et al. Guidelines for immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004;10(5):677–92. American Academy of Pediatrics. Varicella-zoster infections. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red book: 2009 report of the committee on infectious diseases. Elk Grove Village (IL): American Academy of Pediatrics; 2009. p. 714–27. Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 2011;140:1704–12. https://doi.org/10.1053/ j.gastro.2011.02.046. Marín AC, Gisbert JP, Chaparro M. Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease. World J Gastroenterol 2015;21(40):11273–81. https://doi.org/10.3748/wjg.v21.i40.11273. Banaszkiewicz A, Targon´ska B, Kowalska-Duplaga K, et al. Immunogenicity of 13-valent pneumococcal conjugate vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2015;21(7):1607–14. https://doi.org/10.1097/MIB.0000000000000406.
[27] Brogan MD, Shanahan F, Oliver M, Stevens RH, Targan SR. Defective memory B cell formation in patients with inflammatory bowel disease following tetanus toxoid booster immunization. J Clin Lab Immunol 1987;24:69–74. [28] Fallahi G, Aghamohammadi A, Khodadad A, Hashemi M, Mohammadinejad P, Asgarian-Omran H, et al. Evaluation of antibody response to polysaccharide vaccine and switched memory B cells in pediatric patients with inflammatory bowel disease. Gut Liver 2014;8(1):24–8. https://doi.org/10.5009/ gnl.2014.8.1.24. [29] Moses J, Alkhouri N, Shannon A, et al. Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab. Am J Gastroenterol 2012;107(1):133–8. https://doi.org/10.1038/ ajg.2011.295. [30] Altunöz ME, S ß enatesß E, Ye A, et al. Patients with inflammatory bowel disease have a lower response rate to HBV vaccination compared to controls. Dig Dis Sci 2012;57:1039–44. https://doi.org/10.1007/s10620-011-1980-8. [31] Park SH, Yang SK, Park SK, et al. Efficacy of hepatitis A vaccination and factors impacting on seroconversion in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(1):69–74. https://doi.org/10.1097/01. MIB.0000437736.91712.a1. [32] Hiroko M, Watanabe K, Morimoto K, et al. Booster doses of the trivalent influenza vaccine do not elicit a significant immune response in patients with inflammatory bowel disease: a prospective randomized controlled trial. Gastroenterology 2014;146(Suppl. 1):1039–44. S-80. [33] Melmed GY, Frenck R, Barolet-Garcia C, et al. TNF blockers and immunomodulators impair antibody responses to pneumococcal polysaccharide vaccine (PPV) in patients with inflammatory bowel disease (IBD). Gastroenterology 2008;134(4 Suppl. 1):A68. [34] Stevens R, Oliver M, Brogan M, Heiserodt J, Targan S. Defective generation of tetanus-specific antibody-producing B cells after in vivo immunization of Crohn’s disease and ulcerative colitis patients. Gastroenterology 1985;88:1860–6. [35] Nielsen HJ, Mortensen T, Holten-Andersen M, Brünner N, Sørensen S, RaskMadsen J. Increased levels of specific leukocyte- and platelet-derived substances during normal anti-tetanus antibody synthesis in patients with inactive Crohn disease. Scand J Gastroenterol 2001;36:265–9. [36] Radzikowski A, Banaszkiewicz A, Łazowska-Przeorek I, et al. Immunogenecity of hepatitis A vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2011;17(5):1117–24. https://doi.org/10.1002/ibd.21465. [37] Urganci N, Kalyoncu D. Immunogenecity of hepatitis A and B vaccination in pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2013;56(4):412–5. [38] Fuchs I, Abu-Shakra M, Sikuler E. Hepatitis B and C reactivation with tumor necrosis factor inhibitors: synopsis and interpretation of screening and prophylaxis recommendations. Isr Med Assoc J 2013;15(6):303–7. [39] ACIP Childhood/Adolescent Immunization Work Group, Akinsanya-Beysolow I, Jenkins R, Meissner HC. Centers for Disease Control and Prevention (CDC). Advisory Committee on Immunization Practices (ACIP) recommended immunization schedule for persons aged 0 through 18 years–United States, 2013. MMWR Suppl. 013;62(1):2–8. [40] Kantsø B, Halkjær SI, Thomsen OØ, et al. Immunosuppressive drugs impairs antibody response of the polysaccharide and conjugated pneumococcal vaccines in patients with Crohn’s disease. Vaccine 2015;33(41):5464–9. https://doi.org/10.1016/j.vaccine.2015.08.011. [41] Banaszkiewicz A, Targon´ska B, Kowalska-Duplaga K, Karolewska-Bochenek K, Sieczkowska A, Gawron´ska A, et al. Serotype specific pneumococcal status prior to PCV 13 administration in children and adolescents with inflammatory bowel disease. Pol J Microbiol 2016;65(1):89–91. [42] Jacobson DL, Bousvaros A, Ashworth L, et al. Immunogenicity and tolerability to human papillomavirus-like particle vaccine in girls and young women with inflammatory bowel disease. Inflamm Bowel Dis 2013;19(7):1441–9. https:// doi.org/10.1097/MIB.0b013e318281341b. [43] Mamula P, Markowitz JE, Piccoli DA, Klimov A, Cohen L, Baldassano RN. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5(7):851–6. https://doi.org/ 10.1016/j.cgh.2007.02.035. [44] Lu Y, Jacobson DL, Ashworth LA, et al. Immune response to influenza vaccine in children with inflammatory bowel disease. Am J Gastroenterol 2009;104 (2):444–53. https://doi.org/10.1038/ajg.2008.120. [45] Romanowska M, Banaszkiewicz A, Nowak I, et al. Immunization against influenza during the 2005/2006 epidemic season and the humoral response in children with diagnosed inflammatory bowel disease (IBD). Med Sci Monit 2010;16(9):CR433–9. [46] deBruyn JC, Hilsden R, Fonseca K, et al. Immunogenicity and safety of influenza vaccination in children with inflammatory bowel disease. Inflamm Bowel Dis 2012;18(1):25–33. https://doi.org/10.1002/ibd.21706. [47] Leung VS, Nguyen MT, Bush TM. Disseminated primary varicella after initiation of infliximab for Crohn’s disease. Am J Gastroenterol 2004;99 (12):2503–4. https://doi.org/10.1111/j.1572-0241.2004.41389_7.x. [48] Lu Y, Bousvaros A. Varicella vaccination in children with inflammatory bowel disease receiving immunosuppressive therapy. J Pediatr Gastroenterol Nutr 2010;50(5):562–5. https://doi.org/10.1097/MPG.0b013e3181bab351. [49] Ansari F, Baker RD, Patel R, et al. Varicella immunity in inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011;53(4):386–8. https://doi.org/ 10.1097/MPG.0b013e31821e1917.
Please cite this article in press as: Dipasquale V, Romano C. Vaccination strategies in pediatric inflammatory bowel disease. Vaccine (2017), https://doi.org/ 10.1016/j.vaccine.2017.09.031