VACCINATION IN CHILDREN WITH CHRONIC DISEASE

Susanna EspositoPediatric Highly Intensive Care Unit,

University of MilanFondazione IRCCS Ca’ Granda Ospedale

Maggiore Policlinico, Milan, Italy

MAIN PROBLEMS

• Influenza vaccination

• Pneumococcal vaccinations

• Booster doses in immunocompromised patients

CHILDREN AT HIGHER RISK FOR INFLUENZA COMPLICATIONS

• THOSE WHO HAVE CHRONIC PULMONARY (INCLUDING ASTHMA), CARDIOVASCULAR (EXCEPT HYPERTENSION), RENAL, HEPATIC, HEMATOLOGICAL OR METABOLIC DISORDERS (INCLUDING DIABETES MELLITUS)

• THOSE WHO ARE IMMUNOSUPPRESSED (INCLUDING IMMUNOSUPPRESSION CAUSED BY MEDICATIONS OR HIV)

• THOSE WHO HAVE ANY CONDITION (EG, COGNITIVE DYSFUNCTION, SPINAL CORD INJURIES, SEIZURE DISORDERS) THAT CAN COMPROMISE RESPIRATORY FUNCTION OR THE HANDLING OF RESPIRATORY SECRETIONS OR THAT CAN INCREASE THE RISK FOR ASPIRATION

• THOSE WHO ARE RECEIVING LONG-TERM ASPIRIN THERAPY WHO THEREFORE MIGHT BE AT RISK FOR EXPERIENCING REYE SYNDROME AFTER INFLUENZA INFECTION

MEDICAL EVENTS DURING DIFFERENT TIME PERIODS

(From Neuzil KM at al. J Pediatr 2000)

IMPACT OF ILI IN ADOLESCENTS WITH ONCOHEMATOLOGICAL PROBLEMS

(From Esposito S et al. Vaccine 2010)

IMPACT OF ILI OF CHILDREN WITH ONCOHEMATOLOGICAL PROBLEMS ON

HOUSEHOLDS(From Esposito S et al. Vaccine 2010)

INFLUENZA VACCINATION RATES IN ADOLESCENTS WITH HIGH-RISK

CONDITIONS (USA) (From Nakamura MM and Lee GM, Pediatrics 2008)

INFLUENZA VACCINATION RATES AMONG 5,286 ITALIAN CHILDREN AND

ADOLESCENTS(Esposito S et al., Vaccine 2006)

05

1015202530

Flu season2000-2001

Flu season2001-2002

Flu season2002-2003

High risk children Healthy children

%

VACCINATED HIGH-RISK CHILDREN (No.=72)

Why is your child vaccinated against influenza?

ANSWER FREQUENCYPediatrician’s recommendation

63 (87.5%)

Protection of parents 6 (8.3%)Protection of an elderly family members

2 (2.8%)

Previous serious influenza-like illness

1 (1.4%)

Esposito S et al., Vaccine 2006

UNVACCINATED HIGH-RISK CHILDREN (No.=202)

Why is your child not vaccinated against influenza?

ANSWER FREQUENCYLack of awareness 173 (85.6%)Inconvenience 11 (5.5%)Concern about side effects

18 (8.9%)

Esposito S et al. Vaccine 2006

PEDIATRICIANS’ OPINIONS CONCERNING INFLUENZA (No.=256)

If you do not recommend influenza vaccination in a child with chronic disease,

what are the reasons?

ANSWER FREQUENCYInfluenza infection not sufficiently severe

68 (26.6%)

Poor efficacy of influenza vaccines

149 (58.2%)

Concern about side effects

39 (15.2%)

Esposito S et al., Vaccine 2006

INFLUENZA AND ASTHMA: EFFICACY OF THE VACCINATION

(Kramarz P et al., J Pediatr 2000)

•

ASTHMA AND INFLUENZA VACCINATION(Am Lung Ass Asthma Clin Res Centers, N Engl J Med 2001)

2,032 patients with chronic asthma aged 3-64 years (712 < 14 anni)

Randomized 1:1 to receive TIV or placebo

Asthma exacerbation in the 2 weeks after enrollment:

TIV 28.8%PLACEBO 27.7%

Am Lung Ass Asthma Clin Res Centers, N Engl J Med 2001

Am Lung Ass Asthma Clin Res Centers, N Engl J Med 2001

CHARACTERISTICS OF ASTHMATIC CHILDREN WITH AND WITHOUT EGG ALLERGY

(Esposito S et al., Vaccine 2008)

No significant between-group difference

(Esposito S et al., Vaccine 2008)

CARDIORESPIRATORY PARAMETERS AND ADVERSE EVENTS IN THE 4 H AFTER INFLUENZA

VACCINATION

IMMUNOGENICITY OF MF59-ADJUVANTED SEASONAL INFLUENZA VACCINE IN CHILDREN WITH JIA TREATED WITH DIFFERENT

DRUGS (Dell’Era et al., Vaccine 2012)

INACTIVATED INFLUENZA VACCINE IN CHILDREN WITH CANCER

(Esposito S et al., Vaccine 2011)

• Susceptibility to influenza is greater during the first six months of discontinuation of chemotherapy than in normal children or those who have been off-therapy for more than six months

• Children with cancer seem to be able to generate a sufficient immune response to the influenza antigens contained in the vaccines when receiving chemotherapy

• Immune response is weaker than that of healthy children or children with cancer who have discontinued chemotherapy for more than one month

• The safety and tolerability of inactivated influenza vaccine have always seemed to be very good

IMMUNOGENICITY AND SAFETY OF INFLUENZA VACCINATION IN CHILDREN WITH IEM

(Esposito et al., Vaccine 2013)

GAPS RELATED TO INLUENZA VACCINATION IN HIGH-RISK CHILDREN

• Few epidemiologic studies on the impact of influenza in each of the high-risk groups

• Few data on the immunogenicity, safety and efficacy of influenza vaccination in each of the high-risk groups

• Absence of clear correlates of protection especially with new vaccines

• Few influenza vaccines are approved for high risk children

METANALYSIS OF STUDIES WHICH EVALUATED TELEPHONE RECALL SYSTEM TO INCREASE

INFLUENZA VACCINATION COVERAGE

Cochrane Database of Systematic Reviews, 2005

INTERVENTIONS TO IMPROVE INFLUENZA VACCINATION COVERAGE AMONG

CHILDREN WITH CHRONIC ASTHMA

%

Esposito et al., ESWI 2008

*p<0.05

Randomisation group Influenza vaccination in

previous season (2005-

2006),

No. (%)

Influenza vaccination with

intervention strategy

(2006-2007),

No. (%)

P value

Group A (n=71) 11 (15.5) 31 (43.7) <0.0001

Chemotherapy completion

<6 mos (n=27)

4 (14.8) 20 (74.1) <0.0001

Chemotherapy completion

6 mos-2 yrs (n=44)

7 (15.9) 11 (25.0) 0.422

Group B (n=64) 12 (18.8) 27 (42.2) 0.007

Chemotherapy completion

<6 mos (n=22)

4 (18.2) 17 (77.2) 0.0002

Chemotherapy completion

6 mos-2 yrs (n=42)

8 (19.0) 10 (23.8) 0.790

Group C (n=70) 19 (27.1) 34 (48.6) 0.014

Chemotherapy completion

<6 mos (n=25)

8 (32.0) 20 (80.0) 0.001

Chemotherapy completion

6 mos-2 yrs (n=45)

11 (24.4) 14 (31.1) 0.637

Cecinati V, Esposito S et al. Human Vacc 2010

TAKE HOME MESSAGES ON INFLUENZA VACCINATION

•Influenza vaccination has to be strongly recommended in high risk children and active recall systems appear useful to increase the coverage rate• Children with persistent asthma have significant benefits with the use of influenza vaccines, with no risk of asthma exacerbation• Studies on immunogenicity and safety of influenza vaccines are available also for other high-risk groups, but further research is needed in this area

Autorizzazioni all’uso di PCV13 nel bambino grande e nell’adolescente

In Europa dalla fine del 2012 è autorizzato in tutti i soggetti dai 6 ai 18 anni indipendentemente dall’ esistenza di condizioni di rischio

Negli USA da tempo registrato per l’uso fino a 5 anni nel bambino sano e fino a 71 mesi in quello a rischio, è oggi raccomandato (ACIP) in tutti i soggetti di età pediatrica (fino a 18 anni), anche in questo caso indipendentemente dalle condizioni di base del bambino

Limiti di PP23

I polisaccaridi capsulari sono antigeni T indipendenti

Non creano una memoria immunologica La risposta immune alle dosi di richiamo può essere

non ottimale Gli eventi avversi locali sono significativi

particolarmente dopo dosi ripetute Non incide sullo stato di portatore L’efficacia nell’adulto e nell’anziano sembra

dimostrata nella prevenzione delle IPD ma non in quella delle CAP

L’effetto protettivo nel paziente a rischio non è completamente definito ma sembra modesto o nullo

The observed number of cases, the odds ratio comparing the risk groups and the non-risk groups, and the

estimated annual incidence of IPD per 100,000 in 2008-2009 in England

(From van Hoek AJ et al., J Infect 2012)

Annual average incidence of PCV13 type IPD in children aged 6-18 years, with and without

selected underlying immunocompromising conditions – USA 2007-2009

(From CDC. MMWR, June 28, 2013)

Incidence of IPD in patients with asthma (From Talbot MR et al., NEJM 2005)

Ragioni addotte per spiegare la maggiore incidenza di patologia pneumococcica negli

asmatici

A) Modificazioni anatomico-funzionalidell’albero respiratorio indotte dalla flogosi cronicaB) Riduzione delle difese indotta dalla terapia steroideaC) Immunocompromissione primitiva degli asmatici o, genericamente, dei soggetti atopici

Association between daily use (*) ofcorticosteroids and risk of colonization withS. pneumoniae among children with asthma

(From Zhang L et al., Respirology 2013)

(*) A mean dose of 400 g of beclomethasone or equivalent) for at least 30 days (mean duration 8.6 months)

Colonization at the first month of life in relation to asthma diagnosis, lung function and allergy

(From Bisgaard H et al., NEJM 2007)

Ministero della SalutePiano Nazionale Vaccini 2012-2014

Immunogenicità ed efficacia di PCV in soggetti a rischio

Immunogenicity of PCV afterPP23 compared to PCV alone

Age-specific annual IPD incidence in Norway for the different pneumococcal serotypes

after PCV7 and PCV13 (From Steens A et al., Vaccine 2013)

PCV7 serotypes PCV13 serotypes

Non PCV7 serotypes Non PCV13 serotypes

PCV7 PCV13

PCV7 PCV13PCV13PCV7

PCV7 PCV13

OROPHARYNGEAL VS NASOPHARYNGEAL SAMPLING IN HEALTHY ADOLESCENTS (Principi N et al., J Med Microbiol 2013)

TAKE HOME MESSAGES ON PNEUMOCOCCAL VACCINATION

• Patients with some chronic underlying diseases showedan incresed risk of IPD also in pediatic age

• Vaccination with PCV13 should be recommended in children with chronic disease >6 yrs of age, especially if immunocompromised

• Further data are needed in order to clarify whetherthere are differences in the risk of IPD and in immune response to PCV13 in relation to the chronicunderlying disease and its severity

• Further studies are needed to clarify the frequencyof pneumococcal colonization in children and adolescents with chronic disease

MAIN PROBLEMS FOR VACCINATIONS IN PATIENTS WITH CANCER

(Esposito S et al., Vaccine 2010)- Patients with cancer may be immunocompromised as a result of their primary underlying disease and/or the use of prolonged and intensive chemotherapy administered with or without irradiation - After the discontinuation of chemotherapy, they may continue to be immunosuppressed for some months

This suggests that they may partially or totally lose the protection offered by the vaccines

administered before the onset of cancer, and may not be able to adequately respond to

vaccine stimulation during the disease itself and for a certain time after the cessation of

chemotherapy

FACTORS WHICH INFLUENCE IMMUNE SYSTEM IN CANCER

- The age of the patient (i.e., in younger children time needed to reconstitute memory lymphocytes is longer than in the older ones)

- The type of cancer (i.e., ALL shows a shorter immune recovery than solid tumors)

- The intensity and duration of the chemotherapy (i.e., cell counts return to normal values in 3-6 mos after the end of chemotherapy)

IMMUNE SYSTEM FUNCTION IN CHILDREN WITH CANCER AND ITS THEORETICAL CONSEQUENCES

ON VACCINE IMMUNOGENICITY AND SAFETY(Esposito S et al., Vaccine 2010)

- Most children with cancer still seem to have aperfectly functioning immune system at the time ofdisease presentation

- After the start of chemotherapy, the immunesystem is rapidly and significantly compromised

- Most of the drugs used to treat malignancies have anegative effect on humoral and cellular immunity,and the damage to the immune system is related toboth the dose and the duration of administration

- There seems to be a significantly increased risk ofsevere adverse events, particularly when liveattenuated vaccines are administered

PERCENTAGE OF CHILDREN WITH CANCER WITH RESIDUAL PROTECTION DUE TO PREVIOUS

IMMUNISATION AT DIFFERENT TIMES AFTER THE CESSATION OF CHEMOTHERAPY - I

Authors

Periodofevaluation

Tetanus(%)

Diphtheria(%)

Pertussis

(%)

Polio(%)

Hib*

(%)Measles

(%)Mumps

(%)Rubella

(%)

Mustafa et al. [1998]

0-12 mos

off-ther

80 88 59 100 n.e. n.e. n.e. n.e.

Zignolet al. [2004]

0-72 mos

off-ther

86 n.e. n.e. 93 n.e. 75 72 76

Ercanet al. [2005]

3-6 mos

off-ther

20 34 34 n.e. n.e. 29 29 n.e.

PERCENTAGE OF CHILDREN WITH CANCER WITH RESIDUAL PROTECTION DUE TO PREVIOUS

IMMUNISATION AT DIFFERENT TIMES AFTER THE CESSATION OF CHEMOTHERAPY - II

Authors

Periodofevaluation

Tetanus

(%)

Diphtheria(%)

Pertussis(%)

Polio(%)

Hib*

(%)Measles

(%)Mumps

(%)Rubella

(%)

Nilsson et al. [2002]

2-12 yrs off-therap

y

n.e. n.e. n.e. n.e. n.e. 60 n.e. 72

Ek et al.[2005]

1-6 mos off-

therapy

33 17 n.e. n.e. 100 n.e. n.e. n.e.

Kosmidis et al. [2008]

18 mos off-

therapy

n.e. n.e. n.e. 63 n.e. 87 80 80

Vaccine Patients who have not started or not completed the vaccination schedule

at the time of cancer diagnosis

Patients who have completed the vaccination schedule at the time of

cancer diagnosis

Inactivated vaccineHexavalent vaccine Administration of the primary

schedule in patients off-therapy for 3 mos

Booster dose in patients off-therapy for 3 mos

Pneumococcal and meningococcal vaccines

Administration of the primary schedule in patients off-

therapy for 3 mos

Booster dose in patients off-therapy for 3 mos, but more studies are

required

Inactivated influenza

Two doses if ever vaccinated or aged <9yrs;

otherwise, one dose regardless of chemotherapy

Booster dose regardless of chemotherapy

Hepatitis A Two doses separated by at least 6 months regardless of chemotherapy in presence

of epidemiological risk

Booster dose regardless of chemotherapy in the presence of

epidemiological risk

Vaccine Patients who have not started or not completed the vaccination schedule

at the time of cancer diagnosis

Patients who have completed the vaccination schedule at the time of

cancer diagnosis

Live attenuated vaccineMMR Two doses separated by at

least 3 months in patients who have not received any

dose and have been off-therapy for 6 mos

Booster dose in patients who have been off-therapy for 6 mos

VZV vaccine Two doses separated by 3 months in patients in

continuous remission for at least one year, with a

lymphocyte count of >700/µL and a platelet count of

>100,000/µL; if still being treated in an epidemic

period, they should stop drug administration one week before and for one week after vaccination

Booster dose in patients in continuous remission for at least one year, with a lymphocyte count of >700/µL and a platelet count >100 x 103/µL; if still

being treated in an epidemic period, they should stop drug administration one week before and for one week

after vaccination

VACCINES NOT ALREADY STUDIED IN PATIENTS WITH CANCER

- MF-59 adjuvanted influenza vaccine

- Live influenza vaccine

- PCV10 and PCV13

- Men A, C, Y, W vaccines

- HPV vaccines

TAKE HOME MESSAGES ON VACCINATION IN CHILDREN WITH CANCER

• An increase in vaccination coverage represents a priority in patients with cancer

• General suggestions cannot cover all children with cancer and all vaccines

• More information is needed about children who have received only some of the doses of the usually recommended vaccines

• Further studies are required concerning the use of new vaccines