Pandemic 2009 influenza H1N1 virus vaccination: compliance and safety in a single hemodialysis center

Abstract

Background: Acceptance of vaccination against pandemic 2009 H1N1 influenza virus has been poor in some countries, perhaps because of concerns about safety of the new vaccine. Subjects and methods: We prospectively examined vaccination compliance and reasons for nonvaccination in the dialysis patients and the staff of a single hemodialysis unit, after on-site vaccination with a monovalent inactivated adjuvanted H1N1 vaccine. Safety profile was evaluated and compared to that of a control group without chronic kidney disease (CKD). Results: Vaccination acceptance among dialysis patients in our unit was 68% (110/161). Dialysis patients vaccinated against H1N1 had significantly higher compliance with vaccination for seasonal influenza and pneumococcus than those unvaccinated. Three out of 34 (9%) of the unit's staff received the vaccine. Fear of side effects was the main reason for not vaccinating in both groups, while several participants did not consider pandemic influenza a serious disease. At least one adverse reaction was observed in 37/110 (33.6%) of the vaccinated dialysis patients and in 22/42 (52.4%) of the non-CKD control group, p = 0.034. Local mild pain at injection site was the most common side effect of vaccination in both groups. All side effects were of short duration and no serious adverse reactions related to the vaccine or reactions of special interest occurred during the follow-up period. Conclusions: Our findings indicate that immunization against H1N1 virus in dialysis patients is safe and do not support the concerns about safety of the vaccine that was the main reason for nonvaccination in our study.

Keywords:

• acceptance
• dialysis
• Greece
• immunization
• influenza A (H1N1)
• on-site
• side effects

INTRODUCTION

On 11 June 2009, the World Health Organization (WHO) declared a worldwide pandemic of the novel influenza A (H1N1) virus.¹ Several specific pandemic vaccines have received international or national authorization worldwide. Healthcare workers and individuals with underlying chronic diseases like the dialysis patients were the initial targets for immunization in most of the guidelines released from governmental and other official organizations worldwide, with subsequent expansion of the vaccination program in the general population.^2–6 Results from an international survey for the first wave of pandemic H1N1 influenza in dialysis patients reported a hospitalization rate of 34% and a mortality rate of 5% of infected people, concluding that these patients should be included in first ranks of the priority list for the vaccine.⁷

However, citizen's confidence in the new vaccines was poor in many countries, mainly because of concerns about safety, affecting the compliance to the immunization strategy. As a result as of 24 January 2010 only 3.5% (363,000) of the Greek population had been vaccinated against the H1N1 pandemic virus and the situation was similar in other countries as well.⁸ Studies regarding seasonal influenza immunization, which is also recommended for healthcare workers and high-risk groups, show that perception of influenza as a potentially severe disease is positively associated with vaccination. On the other side, the main reasons for noncompliance are the supposition of low risk of infection, fear of side effects, and skepticism about the effectiveness of the influenza vaccination.^9,10 Regarding H1N1 studies, one survey in the general population found that the intent to get vaccinated decreased from 45 to 5% in the absence of proved efficacy and safety.¹¹ For specific populations, such as dialysis patients, data on compliance and safety are lacking. This indicates the need for particular studies in these groups of patients, because the H1N1 strain will be included in the 2010–2011 seasonal influenza vaccine.¹²

This report examines the compliance to vaccination against H1N1 2009 pandemic virus in dialysis patients and staff of a single hemodialysis unit, as well as the safety profile of a monovalent inactivated adjuvanted vaccine in this population.

SUBJECTS AND METHODS

Study population

The study took place at Kallithea, a middle socio-economic class area of Athens, Greece. All chronic dialysis patients hemodialyzed in our unit during the vaccination period (n = 161) were included in the study. All medical and nursing staff of the dialysis unit (n = 34) was included as well. A control group of 42 subjects without known chronic kidney disease (CKD) consisted of relatives and accompanying persons of dialysis patients who wanted to get vaccinated. The following information was collected: demographics (age, sex, and body mass index), current smoking status and associated comorbidities that increase risk for influenza-related complications, and considered indications for vaccination (diabetes mellitus, chronic cardiovascular disease, chronic lung disease, chronic liver disease, cancer, and so on).² In dialysis patients we also collected the following data from the medical files: cause of end-stage renal disease, dialysis vintage, dialysis adequacy (single-pool Kt/V), and the routine blood test results (mean of the measurements before and after the vaccination day). All biochemicals were analyzed by standard laboratory techniques and parathyroid hormone was measured by using an intact assay. All participants were questioned about whether they had been vaccinated against seasonal influenza and pneumococcus. The hospital scientific committee approved the study protocol and the participants gave informed consent.

Vaccination

Vaccinated participants received a dose of 0.5 mL of monovalent inactivated adjuvanted vaccine against influenza A/California/7/2009 (H1N1)v-like strain (Focetria, Lot No.: 0900301, Novartis Vaccines and Diagnostics S.r.l., Siena, Italy).¹³ The vaccine was administered by intramuscular injection into the deltoid muscle of the arm without vascular access in dialysis patients or of the nondominant arm in the control group. The vaccine was provided from the Hellenic Center of Disease Control (KEEΛ) through the national vaccination program. The vaccination took place in a designated area of the dialysis unit (on-site) so that the participants could receive the vaccine during their visit at our unit, whenever they wanted throughout the vaccination period. According to the national vaccination program, immunization of the high-risk groups started on 23 November 2009 and was expanded to the general population on 1 December 2009.^5,14 Vaccination in our unit started on 25 November 2009 and completed on 4 December 2009. The vaccination was free of charge for the whole Greek population.

Outcomes

Main outcome measures of the study were as follows: 1. Vaccination compliance and reasons for not vaccinating in dialysis patients and staff of our unit. During the vaccination period in our unit, unvaccinated subjects were questioned on selected pre-specified reasons for not vaccinating or they were given the option to explain other reasons, Table 1. They could give more than one answer. 2. Safety of vaccination. Subjects were observed for at least 1 hour after each injection. We prospectively collected solicited reports of local and systemic adverse events for the 7 days after immunization. Unsolicited reports of adverse events were collected for 1 month following vaccination. All solicited local adverse events were considered to be related to the H1N1 vaccine, whereas the investigator evaluated the relationship of solicited systemic and unsolicited adverse events with vaccination. Adverse events were graded as follows: none; mild (if they did not interfere with normal activities); moderate (if they resulted in interference with normal activities or necessitated medical attention); serious (if any reaction related to vaccination necessitated hospitalization).

Table 1.  Reasons for nonvaccination in dialysis patients (HDNV) and unit's staff expressed as actual number and percentage of respecting group. The reasons listed were all pre-specified, except the last one. The participants could give more than one reasons

	Dialysis patients n = 51	Staff unvaccinated n = 31
Fear of side effects, n (%)	39 (76.5%)	25 (80.6%)
Inadequately tested, n (%)	6 (11.8%)	9 (29%)
Efficacy doubts, n (%)	6 (11.8%)	5 (16.1%)
Not serious disease, n (%)	10 (19.6%)	12 (38.7%)
Allergy, n (%)	1 (2%)	0 (0%)
Severe illness, n (%)	6 (11.8%)	0 (0%)
Health system pressure, n (%)	1 (2%)	6 (19.3%)

Data analysis

For the description of the data, we used frequencies and percentages for nominal variables, and mean and SD for numerical variables. We performed unpaired t-test for comparison of means and chi-square test for comparison of proportions between variables. If any of the expected frequencies was <2 or if more than 20% of the expected frequencies were <5 in 2 × 2 tables, we used Fisher's exact test instead of chi-square. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for associated nominal variables. Probability values (p) less than 0.05 were considered to be significant.

RESULTS

Vaccination compliance among dialysis patients after on-site vaccination against H1N1 in our unit was 68% (110/161). The characteristics of dialysis patients who received the vaccine (HDV) and of those who did not (HDNV) are shown in Table 2. Dialysis patients who have been vaccinated against seasonal influenza and pneumococcus were more likely to get vaccinated against H1N1 (OR: 2.130, 95% CI: 1.085–4.183, p = 0.027 and OR: 2.313, 95% CI: 1.173–4.560, p = 0.014, respectively). Dialysis staff consisted of 6 doctors and 28 nurses. Their mean age was 35.71 ± 12.33 years, one of them suffered from chronic lung disease and one from cardiovascular disease, and only two had been vaccinated against seasonal influenza and pneumococcus. Three of them (9%) received the H1N1 vaccine. A control group of 42 subjects without kidney disease (CV) received the vaccine against H1N1 in our unit as well. They were younger, had less comorbidities and different vaccination history, compared to HDV patients (Table 2).

Table 2.  Clinical characteristics of dialysis patients vaccinated against H1N1 (HDV), unvaccinated dialysis patients (HDNV), and control vaccinated group (CV). Blood tests were done only in dialysis patients. Unpaired t-test was used for comparison of means and chi-square test or Fisher's exact test (*) for comparison of proportions

	HDV n = 110	HDNV n = 51	p^a	CV n = 42	p^b
Age, years	69.8 ± 11.7	66.9 ± 14.7	ns	57.9 ± 16.8	<0.001
Dialysis vintage, months	49.2 ± 39.8	45.5 ± 50	ns	N/A	N/A
Cause of ESRD DN/GP/ID/HN/ADPKD/UN	31/13/6/16/14/30	14/7/10/5/3/12	ns	N/A	N/A
Male/female	57/53	27/24	ns	23/19	ns
Body mass index (kg/m^2)	25.6 ± 5.4	25.7 ± 4.6	ns	28.1 ± 4.6	0.009
Influenza vaccination	70 (64%)	23 (45%)	0.027	19 (45%)	0.039
Pneumococcus vaccine	74 (67%)	27 (47%)	0.014	9 (21%)	<0.001
Diabetes	39 (35%)	19 (37%)	ns	5 (12%)	0.004
Cardiovascular disease	66 (60%)	33 (65%)	ns	11 (26%)	<0.001
Chronic lung disease	7 (6%)	8 (16%)	ns*	4 (10%)	ns
Chronic liver disease	3 (3%)	0 (0%)	ns*	1 (2%)	ns*
Number of comorbidities	1.16 ± 0.84	1.41 ± 0.87	ns	0.55 ± 0.83	<0.001
Current smoking	25 (23%)	17 (34%)	ns	13 (31%)	ns
Hemoglobin (g/dL)	10.8 ± 1.27	10.2 ± 1.53	0.016	N/M	N/A
WBC count (×10^6/μL)	7.32 ± 2.46	8.49 ± 3.36	0.029	N/M	N/A
Lymphocytes (×10^6/μL)	1.57 ± 0.66	1.79 ± 1.43	ns	N/M	N/A
BUN (mg/dL)	62.5 ± 15.8	64.8 ± 18.1	ns	N/M	N/A
Creatinine (mg/dL)	6.8 ± 1.8	6.9 ± 2	ns	N/M	N/A
sp Kt/V	1.46 ± 0.28	1.38 ± 0.31	ns	N/M	N/A
Calcium (mg/dL)	8.90 ± 0.71	9.11 ± 0.83	ns	N/M	N/A
Phosphate (mg/dL)	4.97 ± 1.35	4.75 ± 1.44	ns	N/M	N/A
iPTH (pg/mL)	357 ± 268	318 ± 250	ns	N/M	N/A
Albumin (g/dL)	3.97 ± 0.35	3.76 ± 0.47	0.005	N/M	N/A

Notes: ADPKD, autosomic dominant polycystic kidney disease; BUN, blood urea nitrogen; DN, diabetic nephropathy; ESRD, end-stage renal disease; GP, glomerulopathy; HN, hypertensive nephrosclerosis; ID, interstitial disease; iPTH, parathyroid hormone; n, number; N/A, not applicable; N/M, not measured; ns, non statistically significant; sp Kt/V, single-pool Kt/V; UN, Unknown; WBC, white blood cells.

^aComparison between HDV and HDNV groups.

^bComparison between HDV and CV groups.

Reasons for nonvaccination in dialysis patients and staff are shown in Table 1. Concern over vaccine side effects was the main reason for refusing vaccination in both groups. A lower percentage thought that the new vaccine was inadequately tested or questioned its efficacy. Several of them considered that pandemic influenza is not a serious disease. In some hospitalized dialysis patients the severity of their illness did not allow the vaccination. An interesting point to mention is that some of the subjects felt a significant pressure from health authorities to get vaccinated and thus refused the immunization as a form of “opposition.” This reason was spontaneously given by them.

Local and systemic reactions during the first 7 days following vaccination in both vaccinated groups are shown in Table 3. After immunization, at least one adverse event was reported by 33.6% of dialysis patients and by 52.4% of control subjects. Control subjects that experienced adverse events were younger than the respective dialysis patients (53.3 ± 18.6 vs. 68.9 ± 11.3 years, p = 0.001) and had less comorbidities (0.32 ± 0.78 vs. 0.97 ± 0.76, p = 0.003). The majority of the reactions were solicited and mild. Pain at the injection site was the most frequent local reaction reported. In general, it was not accompanied by redness or swelling and lasted less than 24 hours. All of the local reactions were mild in nature, generally self-limited, resolving within 48 hours, except one case in the CV group. This subject reported pain at injection site and swelling affecting an area >20 mm in diameter, and graded as moderate. She also had productive cough, but no fever. The symptoms resolved after 3 days. The most frequent systemic adverse event was malaise, especially in CV group. Headache, nausea, and diarrhea were also reported but all lasted less than a day. Upper respiratory symptoms were reported but without fever or chills, except one case in HDV group that resolved within 48 hours and one case in CV group that lasted 3 days. Nonproductive cough was reported by six dialysis patients and three control subjects (one reported productive cough). Three patients in HDV group and four subjects in CV group reported nasal congestion and sore throat. Three patients with side effects in HDV group (8.1%) and three (13.6%) in CV group reported use of paracetamol for relief of local or systemic symptoms (nonsignificant difference). No deaths, serious adverse events, or adverse events of special interest for H1N1 pandemic vaccines (neuritis, convulsions, anaphylaxis, encephalitis, vasculitis, Guillain–Barré syndrome, Bell's palsy, demyelinating disorders) attributable to the vaccine occurred during the month following vaccination.

Table 3.  Local and systemic adverse events related to vaccination within 7 days of follow-up in dialysis patients vaccinated against H1N1 (HDV) and control vaccinated group (CV), expressed as actual number and percentage of respecting group. Chi-square test or Fisher's exact test (*) was used for comparison of proportions

	HDV n = 110	CV n = 42	p
Local pain, n (%)	24 (21.8%)	11 (26.2%)	ns
Local swelling, n (%)	1 (0.9%)	1 (2.4%)	ns*
Local erythema, n (%)	1 (0.9%)	1 (2.4%)	ns*
Malaise, n (%)	3 (2.7%)	6 (14.3%)	0.014*
Myalgia, n (%)	2 (1.8%)	2 (4.8%)	ns*
Fever >37.5°C, n (%)	1 (0.9%)	1 (2.4%)	ns*
Chills, n (%)	1 (0.9%)	1 (2.4%)	ns*
Headache, n (%)	5 (4.5%)	3 (7.1%)	ns*
Diarrhea, n (%)	1 (0.9%)	2 (4.8%)	ns*
Nausea, n (%)	3 (2.7%)	3 (7.1%)	ns*
Conjunctivitis, n (%)	2 (1.8%)	0	ns*
Upper respiratory symptoms, n (%)	11 (10%)	5 (11.9%)	ns*
Subjects with symptoms, n (%)	37 (33.6%)	22 (52.4%)	0.034

Note: ns, non statistically significant.

Comparing the dialysis patients with post vaccination reactions and those without, the only significant difference was found in gender. Dialysis women were more likely to report side effects than men (OR: 2.355, 95% CI: 1.046–5.302, p = 0.037). Regarding the control group, vaccinated participants with adverse events were younger than those without (53.27 ± 18.59 vs. 62.9 ± 13.22 years), but this did not reach statistical significance.

DISCUSSION

The vaccination compliance of dialysis patients in our unit (68%) was higher than the national vaccination program (3.5%) and two other dialysis units in the same area with the same range of patients treated (47% and 9%, personal communication). This may be attributed to the accessibility and flexibility of on-site vaccination offered in our unit. Easy access to the vaccine improves vaccination rates among high-risk groups and healthcare workers in studies for seasonal influenza.^15–17

Fear of vaccine side effects was the main reason for refusing vaccination in our study both in dialysis staff and in patients. This concern was not exclusively because of inadequate testing of the new vaccine as fewer participants responded so. Many of the participants did not perceive the pandemic influenza as a serious disease. In fact, the months previous to vaccination health departments focused public health messages on the risks for infection and severe illness, in an effort to increase coverage with H1N1 vaccine. However, at the time the vaccination started in Greece, experience from other countries revealed that pandemic influenza was not as serious as initially believed. All these resulted in controversial discussions in mass media with confusing messages reaching the public and the subsequent poor compliance of the population. Thus, it is not surprising that some of the participants in our study, especially those from the staff, denied vaccination to express their opposition to the pressure to get vaccinated.

The side effect profile of the H1N1 vaccine in our study is consistent with that in studies in non-CKD subjects. After immunization with an unadjuvanted H1N1 vaccine, at least one local adverse event was reported by 56.3% of subjects, and at least one solicited systemic adverse event was reported by 53.8% of subjects.¹⁸ In another multicenter placebo controlled trial, 12,000 subjects received different formulations of the H1N1 vaccine and the adverse reactions reported were mild or moderate and self-limited. Severe adverse reactions (mainly fever) occurred in 0.6%.¹⁹ As of November 2009, 65 million people had been vaccinated and the adverse events so far reported were mainly mild and transient local and systemic symptoms.²⁰ One study used both adjuvanted and nonadjuvanted H1N1 vaccines and reactions (mainly pain) were more common with the adjuvanted vaccine than with the nonadjuvanted one.²¹ The safety profile in our study is consistent with that presented in Focetria's Summary of Product Characteristics; most of the reactions are mild in nature and of short duration and their incidence in subjects over 60 years of age is generally lower as compared to the 18–60 years old population.¹³ In addition, we found that fewer dialysis patients experienced symptoms than the control subjects. A previous study found that 22% of hemodialysis patients developed symptoms after seasonal influenza vaccination comparing to 56% of the control group.²² The impaired immunity of dialysis patients and their advanced age may account for these findings.

Our study has certain limitations. First, it is not a randomized placebo controlled trial. As vaccination was recommended from health authorities we considered unethical to not vaccinate those who wanted to. However, we recorded systemic symptoms of short duration, similar to the symptoms reported by vaccinated dialysis patients, in the dialysis patients who did not receive the vaccine as well. Although not directly comparable, 21.6% (11/51) of the HDNV patients reported upper respiratory symptoms or diarrhea or malaise during the vaccination period in our unit, with no significant difference respecting to the HDV group (data not shown). Second, the sample size is small to detect rare adverse events or events of special interest and disease-specific side effects. Third, we have not included peritoneal dialysis patients in our study, as we do not offer peritoneal dialysis in our center. Fourth, we did not examine reasons for compliance that could have provided some more insight into why individuals accept or refuse vaccination and we did not examine the other dialysis units, to better understand the effect of on-site immunization. Fifth, we cannot generalize our findings, especially those of compliance, in other populations. Finally, we did not examine the immunogenicity of the vaccine and its effectiveness in preventing disease.

On the contrary, our study has some advantages too. It is the first one that examines compliance and safety of the new vaccine in dialysis patients. In addition, all patients of our unit were included, covering the whole spectrum of ESRD, and were compared to controls recruited from the same background. Finally, all the participants received the same type of the vaccine and from the same lot, minimizing confounding from manufacturing process.

In conclusion, our findings indicate that vaccination against H1N1 pandemic 2009 virus in dialysis patients is safe and do not support the concerns about safety of the vaccine that was the main reason for not vaccinating in our study. Further studies are needed to better examine the safety profile and effectiveness of different forms of the new vaccines in the dialysis population.

Acknowledgments

The authors thank Drs Fotis Makris, Georgios Triantafyllis, and Paraskevi Daggounaki for the information provided respecting the other dialysis units.

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.