Stefania Antoniazzi

On the relationship between human papilloma virus vaccine and autoimmune diseases

The human papilloma virus (HPV) vaccines were introduced to reduce the incidence of cervical cancer. The bivalent vaccine is effective against HPV-16, -18, -31, -33 and -45 while the quadrivalent vaccine is effective against HPV-16, 18, 31, 6 and 11 types. The immunisation, recommended for adolescent females, has led to high vaccine coverage in many countries. Along with the introduction of the HPV vaccines, several cases of onset or exacerbations of autoimmune diseases following the vaccine shot have been reported in the literature and pharmacovigilance databases, triggering concerns about its safety. This vaccination programme, however, has been introduced in a population that is at high risk for the onset of autoimmune diseases, making it difficult to assess the role of HPV vaccine in these cases and no conclusive studies have been reported thus far. We have thus analysed and reviewed comprehensively all case reports and studies dealing with either the onset of an autoimmune disease in vaccinated subject or the safety in patients with autoimmune diseases to define the role of the HPV vaccines in these diseases and hence its safety. A solid evidence of causal relationship was provided in few cases in the examined studies, and the risk vs. benefit of vaccination is still to be solved. The on-going vigilance for the safety of this vaccine remains thus of paramount importance.

Cardiovascular events associated with the long-term use of NSAIDs: a review of randomized controlled trials and observational studies

Introduction: An increased risk of cardiovascular thrombotic events in users of NSAIDs was first demonstrated for rofecoxib. This risk seems to be related to the COX-2 inhibitory potency and has been found with most NSAIDs except naproxen. Two main hypotheses have been advanced: an imbalance between COX-1-dependent platelet production of thromboxane and partly COX-2-dependent endothelial production of prostacyclin, and a COX-2-dependent increase in blood pressure. Areas covered: Clinical trials and observational studies providing information about cardiovascular risk associated with long-term use of NSAIDs were retrieved; 14 clinical trials and 16 observational studies mentioned a follow-up of at least 6 months. Expert opinion: Results are ambiguous: long-term exposure seemed associated with an increased risk of myocardial infarction or stroke with high-dose rofecoxib, and perhaps diclofenac, but less with other NSAIDs. In other studies, little or no increase in risk was associated with exposures shorter than 30 days. Since most NSAIDs are rarely used long term, there is little information on risks associated with long-term use. The relative risks or odds ratios associated with most drugs are mostly well below 2.

Acute Disseminated Encephalomyelitis Onset: Evaluation Based on Vaccine Adverse Events Reporting Systems

Objective To evaluate epidemiological features of post vaccine acute disseminated encephalomyelitis (ADEM) by considering data from different pharmacovigilance surveillance systems. Methods The Vaccine Adverse Event Reporting System (VAERS) database and the EudraVigilance post-authorisation module (EVPM) were searched to identify post vaccine ADEM cases. Epidemiological features including sex and related vaccines were analysed. Results We retrieved 205 and 236 ADEM cases from the EVPM and VAERS databases, respectively, of which 404 were considered for epidemiological analysis following verification and causality assessment. Half of the patients had less than 18 years and with a slight male predominance. The time interval from vaccination to ADEM onset was 2-30 days in 61% of the cases. Vaccine against seasonal flu and human papilloma virus vaccine were those most frequently associated with ADEM, accounting for almost 30% of the total cases. Mean number of reports per year between 2005 and 2012 in VAERS database was 40±21.7, decreasing after 2010 mainly because of a reduction of reports associated with human papilloma virus and Diphtheria, Pertussis, Tetanus, Polio and Haemophilus Influentiae type B vaccines. Conclusions This study has a high epidemiological power as it is based on information on adverse events having occurred in over one billion people. It suffers from lack of rigorous case verification due to the weakness intrinsic to the surveillance databases used. At variance with previous reports on a prevalence of ADEM in childhood we demonstrate that it may occur at any age when post vaccination. This study also shows that the diminishing trend in post vaccine ADEM reporting related to Diphtheria, Pertussis, Tetanus, Polio and Haemophilus Influentiae type B and human papilloma virus vaccine groups is most likely due to a decline in vaccine coverage indicative of a reduced attention to this adverse drug reaction.

Efficacy of vaccination against influenza in patients with multiple sclerosis: The role of concomitant therapies

Multiple sclerosis is a chronic progressive demyelinating disease affecting over 2.1 million patients worldwide. Patients affected by MS are exposed to an increased risk of infection from communicable diseases, which may lead to severe disease relapses. Studies have analysed the issue of vaccination of MS-affected patients. These studies, however, deal mostly with safety-related issues documenting that most vaccines have been proven to be safe in MS patients and that vaccination is not associated with an increased risk of relapses. By contrast, evidence on the efficacy is comparatively scant and not yet systematised in a comprehensive picture. This aspect is however important, as both MS and its treatment alter the immune responses, a situation that may be associated with a reduced vaccine efficacy. We have now reviewed the literature and assessed the effects of the therapy for MS on vaccine efficacy; we focused on the vaccine against influenza as for the other vaccines the information is still too scant. The majority of drugs appear not associated with a reduced response to vaccination against influenza, with the notable exception of mitoxantrone and glatiramer acetate. For a few drugs, among which natalizumab, information is not sufficiently clear and additional studies are needed to draw a definite conclusion. These results highlight the importance to evaluate the efficacy of vaccination in patients treated with immunosuppressant drugs.

Can HPV immunisation cause ADEM? Two case reports and literature review

Human papilloma virus (HPV) vaccination is widely used in order to decrease the incidence of cervical cancer cases worldwide.1 The safety profile of these vaccines, assessed during phase III studies, showed that both vaccines have a good profile of tolerability. Recently, however, Schäffer et al. provided the first report regarding the onset of acute disseminated encephalomyelitis (ADEM) 23 days following HPV vaccination in a 15-year-old woman.2 Further reports provided similar observations,3,4 indicating a possible relationship between HPV vaccination and ADEM. ADEM is an uncommon condition, usually preceded by an acute infection.5 In about 5% of ADEM cases, however, a precedent immunisation was described as the only risk factor.3 We report on two additional cases of patients, two girls aged 13 and 12 respectively, who developed ADEM following one primary and two booster administrations of HPV vaccine. In both patients’ medical history, blood and cerebrospinal fluid (CSF) analyses ruled out a possible infectious aetiology and autoantibody testing was negative for ANA, ANCA and AQP4-Ab. The 13-year-old Caucasian girl was hospitalised for a unilateral deficit of the second and third cranial nerves and objective signs of meningo-encephalitis 6 months after receiving the third dose of HPV vaccination (unknown manufacturer). Magnetic resonance imaging (MRI) of the brain revealed the presence of multiple ring-enhancing lesions located primarily in thalamic, pons and insula white matter. CSF was normal and we did not observe the presence of oligoclonal bands (OCBs). The long time interval between vaccine and disease onset is unusual in ADEM developed after vaccination, and does not necessarily argue for a causal relationship; however, we did not identify any other significant risk factor. Her clinical condition improved following steroids therapy and she was discharged fully recovered. The 12-year-old girl was hospitalised due to the onset of numbness of the left foot, ambulation difficulty, and speech disorder. Parents reported that she had been vaccinated with the third dose of vaccine against HPV (Quadrivalent) 15 days before. At the admission, both computed axial tomography (CAT) and MRI were negative. During hospitalisation, patient developed enuresis, faecal incontinence and dysphagia. MRI of the brain revealed the presence of multiple ring-enhancing lesions at subcortical levels, pons, trigeminal nuclei and mesencephalon. Spinal cord MRI revealed swelling from C4 to C6 without contrast enhancement. After 1 month from hospitalisation, a reduction in visual acuity was observed and MRI confirmed the previously observed lesion and identified new lesions in the subcortical white matter. MRI of the spinal cord showed extensive enhancing lesion from C1/2 to D1/2. Analysis of CSF revealed lymphocytic pleocytosis and excluded the presence of OCBs. A therapy with high dose steroids was started that led to improvement of the patient’s conditions. For a better evaluation of the relationship between HPV immunisation and ADEM, we analysed data from the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system that collects vaccine adverse drug reaction data from the USA and other countries. After causality assessment with World Heath Organisation criteria, we were able to identify 12 ADEM reports that could be classified as related to qHPV vaccination between 1 June 2006 and 30 July 2012. By considering these reports and the number of qHPV doses distributed within this period (46 million doses), the reporting rate was estimated to be 0.26/106 (CI 95%: 0.16/106–0.37/106). Despite known limitation of VAERS, these data strengthen our hypothesis of correlation between HPV immunisation and ADEM. These cases, taking together with pharmacovigilance data and literature findings, indicate the presence of a relationship between ADEM and HPV vaccination.

On the Association between Human Papillomavirus Vaccine and Primary Ovarian Failure

Dear Sir, We have read the interesting series of case reports recently published by Colafrancesco et al. on your journal. The reports deal with the occurrence of primary ovarian failure occurring in three young girls few days after the vaccination with human papillomavirus vaccine. The reports by Colafrancesco et al., along with a previously reported case, rise an important concern in term of safety for this vaccine. Primary ovarian failure is estimated to affect 1/ 10,000 women under the age of 20 and etiology may include genetic mutations, autoimmune diseases, and environmental causes. However, in a significant amount of cases, no precise cause can be identified. Concerns about supposed adverse effects of vaccine occur regularly, especially after the implementation of a new vaccine in young healthy adolescent. Spontaneous reports of suspected drug reactions represent an important source of new information for monitoring the safety of a newly introduced vaccine, but many of these are simply a coincidence in time with the administration of the vaccine. To define further the association between primary ovarian failure and HPV vaccine, we carried out an analysis using the major national surveillance databases for adverse event following the administration of vaccines or drugs. In this analysis, we considered the adverse event following HPV vaccine coded as ‘premature ovarian failure’, ‘premature ovarian insufficient’, ‘premature menopause’, and ‘primary ovarian failure’. We retrieved four cases from the Vaccine Adverse Event Reporting System (VAERS) database, one case from the Australian database, and two cases from the European database of suspected adverse drug reaction reports. We assessed the reporting rates (RRs) of 0.065/ 1,000,000 doses for this adverse effect considering the number of quadrivalent HPV vaccine doses distributed in United States from June 1, 2006 through July 30, 2012 (46 million) and the VAERS domestic reports in the same time frame (three reports). A similar evaluation of qHPV vaccine doses (7 million of doses) and reports from the Australian TGA database yielded a RRs of 0.14/1,000,000 doses. We also carried out an evaluation of the number of hospital discharges with a diagnosis of premature ovarian failure (ICD-9 code 256.31) or other ovarian failures (ICD-9 code 256.39) using the United States National Inpatient Sample database (NIS). We did not observe any increase in the number of hospital discharge with these diagnoses in patients aged 1–17 years after the introduction of the HPV vaccine. Similarly, we did not observe significant increases in the number of hospital discharges retrieved from the children inpatient database for patients aged 15–17 before and after the introduction of this vaccine. The absence of a significant increase in primary ovarian failure in a population that has been largely exposed to the HPV vaccine, as well as the low number of reports to the regulatory agencies, argues against a causal relationship between the vaccine and this disease. Despite these observations, we cannot exclude that HPV vaccine had a role in the pathogenesis of the condition described by Colafrancesco et al., especially considering the possibility that a rare and unrecognized mutations acted as risk factor in these patients. As correctly stated by the authors, the fact that two of the three patients were blood relatives could indicate the presence of a rare risk factor capable of determining such adverse event following HPV vaccination. Further analysis is required to identify the presence of possible risk factors for this adverse event and define their prevalence among the population exposed to the HPV vaccine.

Human papillomavirus vaccine in patients with systemic lupus erythematosus.

To the Editor: Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide.1 Although usually transient and asymptomatic, HPV infection can result in cervical cancer in some predisposed women,1 and thus, many programs have been developed to foster HPV immunization. People who are at a particularly high risk for cervical cancer include those affected by systemic lupus erythematosus because of intrinsic immunological defiance and immunosuppressive treatments.2 In view of the higher risk of cervical cancer, guidelines urge HPV vaccination of these patients during adolescence.3 One concern about HPV vaccination in patients with systemic lupus erythematosus is the possible reactivation of the disease triggered by viral antigens or adjuvants contained in the vaccine.4 Although a recent case-control study did not find any increased risk of flares in a group of 50 patients,4 factors such as the variability in immunological response5 and the possible presence of genetic predisposing factors may limit the ability of studies to detect rare adverse events.5 Several case reports have described a possible correlation in predisposed patients,6,7 and 100 cases have been reported in pharmacovigilance databases in Europe, United States, and Australia.8–10 In the view of this limited knowledge, we assessed whether the number of hospitalizations for lupus in the United States increased after introduction of the HPV vaccination in 2006, using data from the National Hospital Discharge Survey, the National Inpatient Sample, and the Kids’ Inpatient Sample. We examined data on patients (all ages and ≤17 years of age) with first-line diagnosis of systemic lupus erythematosus at hospitalization or emergency department admission, in accordance with the codes in the International Classification of Disease, 9th

Two cases of hallucination in elderly patients due to a probable interaction between flu immunization and tramadol

Annual vaccination against influenza (FluV) is indicated forindividuals at risk of developing medical complicationsbecause of underlying pathological conditions [1]. Most ofthese patients are likely to be exposed to drug treatmentsoccasionally characterised by a narrow therapeutic index.The possible effects of FluV on the metabolism of thesedrugs have not been investigated in detail [2].We report on an adverse drug reaction (ADR) in two elderlypatients, a woman and a man aged 85 and 84 years, respective-ly, highly homogeneous in terms of pathological manifesta-tions, who developed hallucinations after the administration ofFluV (Vaxigrip® and Intanza®, respectively). Both patients atthe moment of vaccination had been receiving treatment withtramadol for several months due to chronic lumbar pain.The female patient had tolerated tramadol (100 mg/day)well, and no interactions were evident with the concomitanttherapy (Table 1). Six days after vaccination she developedhallucinations resulting in equilibrium imbalance and a majorfall. Neurological examinations carried out in the EmergencyDepartment (ED), including computed axial tomography(CAT) scan, did not reveal organic causes. The neurologistsuspecting the iatrogenic nature of the hallucinations,suspended the tramadol treatment and the hallucinationsdisappeared within 36 h. The following day, the patient de-cided to take 100 mg of tramadol and once again developedhallucinations with confusion and amnesic episodes. She wasadmitted again to the ED, and a second neurological examalso did not reveal any organic cause for the symptoms.Tramadol treatment was suspended and the hallucinationsdisappeared once again, this time within 48 h.In the male patient tramadol (25 mg/day) had also beenwell tolerated; no interactions were evident with the con-comitant therapy (Table 1). Five days after vaccination thepatient was hospitalised for hallucinations, psychomotoragitation, hypotension and malaise. Tramadol withdrawalled to an improvement in the severity of the hallucinations,which completely disappeared in 2 days. The neurologicalexaminations including CAT scan did not reveal possibleorganic causes.The Naranjo ADR probability scale indicates a “proba-ble” relationship between the female patient’s developmentof ADRs and therapy with tramadol, and a “possible” rela-tionship for the male patient. In both patients tramadol waswell tolerated, and ADRs developed in both cases only afterimmunisation against influenza. Both patients denied usingherbal remedies.Tramadol is inactivated by cytochrome P450 (CYP) 3A4and CYP2B6 [3, 4] and metabolised by CYP2D6 to itsactive metabolite M1. FluV decreases CYP3A4 activity,with peak inactivation occurring 7 days after vaccination[5, 6]. This reduction in CYP3A4 activity is greater inelderly people [5] and is consistent with the time course of

Pharmacovigilance knowledge in family paediatricians. A survey study in Italy

Drugs prescription in children correlates with a high risk of developing unknown or rare adverse drug reactions (ADRs). In the absence of appropriate clinical trials in the paediatric population, the spontaneous reporting of suspected ADRs is an important means to promote reasonable warning signals. In this context, family paediatricians (FPs) play a crucial role although a general poor compliance in their ability of reporting of ADR is widely described. To understand the reasons beyond this situation we performed a survey, the first of its kind in Italy, to evaluate FPs knowledge, feeling and compliance in ADR reporting. A total of 552 FPs evenly distributed throughout the Italian territory provided a feedback to the survey. Knowledge of pharmacovigilance (PV) resulted to be poor, mainly due to the absence of adequate training in academy; despite this, the majority of FPs declared to be interested to PV and aware of its positive impact on their clinical practice. Yet, FPs reported a poor compliance to the reporting of ADRs. A very high variability in ADRs reporting however, was observed among the regions, possibly because of variability of regional educational programmes dedicated to PV.

On the possible interaction between vaccines and drugs

Dear Sirs, Reduction in the hepatic cytochrome P450 system activity has been described after a vaccination in previous studies [1, 2]. While the mechanism behind such reduction was explained as the consequence of the activity of inflammatory cytokines on the mRNA level of hepatic cytochromes [3], it is unclear what effect this interaction may have in the clinical practice. To date, only few reports describe significant changes in drug pharmacokinetics after the administration of a vaccine [4, 5], and small cohort studies reported contrasting results in patients treated with drugs that may be influenced by this interaction [6, 7, 10–12]. Moreover, it is unclear how the effects of vaccines on hepatic cytochrome P450 system activity affect patients who present risk factors such as age or genetic predisposition [1, 2]. To explore this issue further, we used the Vaccine Adverse Event Reporting System (VAERS) database, which collects information about adverse events following the administration of vaccines and is useful to detect rare vaccine-related adverse events [8]. We carried out a search of all reports consistent with a vaccine–drug interaction resulting in an adverse drug reaction, in a detectable increase of drug serum level, or in a change of drug-related biomarkers such as the International Normalized Ratio (INR). As the patients were treated with more than a single drug in many of the cases, we considered only those cases in which there was no mention of recent therapy variation, or there was an explicit statement about the absence of variations. As highlighted in Table 1, we retrieved and validated 28 reports. Among these, 12 were related to an increase of INR, and ten described an increase of serum level of phenytoin, carbamazepine and theophylline (Table 1). The remaining six cases described an adverse drug reaction attributed to an interaction between the vaccine and the drugs (Table 1). As expected, considering previous observations [1], we found that most of the cases occurred in elderly patients and within the first weeks after vaccine administration. Aitken et al. recently observed that human CYP2C8, 2C9, 2C18, 2C19, 2B6, and 3A4 mRNA expression is downregulated by inflammatory cytokines [3], which are also released as result of a vaccination [1, 2]. As one or more of these hepatic cytochromes metabolizes phenytoin, theophylline and carbamazepine, a reduction in their expression due to vaccination may explain the increased level of these drugs that we observed after vaccination. In agreement, other studies showed an increase in phenytoin serum level after vaccination with pertussis vaccine [10] and successive studies confirmed this finding in other drugs such as theophylline [11, 12]. The increased INR we observed with warfarin may also be explained by the vaccination. Warfarin is metabolized primarily by CYP2C9, and a reduction in the activity of this hepatic cytochrome may result in an increase of INR [9]. The reduced activity of this enzyme due to genetic polymorphisms [9], as well as the presence of other variants that may affect the cytokines response to vaccination, may create a subgroup of patients at higher risk for this interaction than the ones observed in our analysis. Paolo Pellegrino and Carla Carnovale contributed equally to this work.