MPO-ANCA associated vasculitis with mononeuritis multiplex following influenza vaccination

In this report, we described a patient with MPO-ANCA vasculitis with renal involvement and mononeuritis multiplex two weeks after seasonal influenza vaccination. Since the patient showed overlapping sets of clinical features it was difficult to diagnose the exact subtype of AAV [10, 11]. Currently, a handful of AAV cases have been reported in temporal association with influenza vaccination [12, 13, 14, 15, 16, 17]. Recently, The Brighton Collaboration Vasculitis Working Group published a systematic literature review on adverse events following immunization (AEFI) suggesting an association between influenza vaccination and vasculitis, however no evidence is found to confirm this association yet [18]. The temporal relationship with the influenza vaccine could have been completely coincidental in our case. Several other etiological factors, such as exposure to silica, viral or bacterial infections, medication and genetic susceptibility have also been correlated to AAV [19, 20].

Vasculitic neuropathy is characterized by a necrotizing vasculitis involving the small arterioles of peripheral nerves. Mononeuritis multiplex is a painful, asymmetrical, asynchronous sensory and motor peripheral neuropathy involving isolated damage to at least two separate nerve areas. It can be distributed bilaterally, distally and proximally throughout the body, as we describe in our patient [21]. Hadden et al. reported several case reports with vasculitic neuropathy after influenza vaccination [22]. Mononeuritis multiplex was not proven histopathologically in our patient. However, the progressive neurological impairment was highly suggestive of mononeuritis multiplex, especially in combination with the results of the performed EMG as well as the histopathological proven renal vasculitis (level 2 evidence according to The Brighton Collaboration Vasculitic Peripheral Neuropathy Working Group) [22].

The exact etiology of post-influenza vaccination vasculitis is unknown. Several possible underlying mechanisms have been postulated, such as molecular mimicry, autoimmune syndrome induced by adjuvants (ASIA) and viral ribonucleic acid (RNA). In molecular mimicry, a microbial/foreign antigen shares structural similarities with self-antigens. Prolonged inflammatory responses to these foreign antigens can therefore induce autoimmunity syndromes in predisposed individuals [23, 24, 25]. A second possible mechanism is ASIA. Adding an adjuvant to a vaccine antigen leads to several advantages, including dose sparing and the introduction of a more rapid, broader and strong immune response. However, disadvantages of these adjuvants have been described as well. The pathogenesis of the ASIA syndrome is founded on the hypothesis that an exposure to an adjuvant may trigger the development of an autoimmune disease [26, 27]. The influenza vaccination our patient received was the third vaccination in three years. The first two years he had no complications after the vaccination. In 2011, his first influenza vaccine contained 4 viral types: A/California/7/09 A (H1N1), A/Perth/16/2009 (H3N2), A/Victoria/2010/2009 and B/Brisbane/60/08. In 2012, his second influenza vaccine contained the same California type, but also contained B/Victoria/361/2011 (H3N2) and B/Wisconsin/1/2010. His third vaccination consisted of the same California and Victoria types and of B/Massachussets/02/2012. Unfortunately, we were not able to obtain information on whether these vaccines were adjuvanted or not. According to the ASIA criteria defined by Alijotas-Reig, our patient met three major criteria, including exposure to an external stimulus, minimum latency time of days and muscle weakness [28]. Recently, another possible mechanism has been proposed regarding influenza vaccines containing viral RNA which may increase the production of Proteinase 3 (PR3-ANCA) and thus further contribute to the development of AAV following influenza vaccination [17].

Several clinical trials have investigated the relapse rate of AAV after influenza vaccination. Overall, influenza vaccination does not seem to increase the relapse rate in patients with pre-existent AAV in remission [29, 30]. Furthermore, the disease free survival was lower in patients not vaccinated [30]. A recent report showed no changes in auto-antibody levels after influenza vaccination in a small group of healthy individuals [29]. However, one study found silent auto-antibody formation after influenza vaccination in healthy individuals, but this did not reach statistical significance and none of the participants had clinical symptoms of systemic autoimmune disease [31].

In this report we described another case suggesting a temporal relationship between influenza vaccination and AAV with mononeuritis multiplex. However, existing literature does not support a causative link between vaccination and vasculitis yet. Further research is needed to evaluate this potential causal relationship, especially given the extent of influenza vaccinations administered to the peak age incidence population on an annual basis. In general, seasonal influenza vaccinations are considered to be safe, however, clinicians should be aware of this rare phenomenon.

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