Age: 26.0
Sex: F
Vaccine: HPV4
Symptoms: Laboratory test abnormal, Musculoskeletal pain, Myalgia, Neck pain, Neurological examination normal
Clinical narrative: It was reported in a published article, which was received via Novartis (MFR# S2011US00115). Shoulder pain is a common transient side-effect of vaccination. Infrequently, patients can developed prolonged shoulder pain and dysfunction following vaccination. A series of 13 cases are described in which persistent shoulder dysfunction and pain developed following immunization. Common clinical characteristics include absence of a history of prior shoulder dysfunction, previous exposure to vaccine administered, rapid onset of pain, and limited range of motion. The proposed mechanism of injury is the unintentional injection of antigenic material into synovial tissues resulting in an immune-mediated inflammatory reaction. Careful consideration should be given to appropriate injection technique when administering intramuscular vaccinations to reduce the risk of shoulder injury. The Vaccine Injury Compensation Program houses an Administrative database containing information on recent claims submitted to the Program. A query of the database was conducted to identify potentially relevant cases based on a claimed injury of "shoulder pain," "arm pain", "shoulder dysfunction", "frozen shoulder", "adhesive capsulitis", or "shoulder bursitis". "Brachial neuritis" was also included since this injury is frequently claimed  when the arm is involved regardless of the actual diagnosis. Case histories of all submitted medical records were reviewed in detail to verify vaccination date, symptom onset and clinical course. Cases consistent with a diagnosis of brachial neuritis or complex regional pain syndrome were excluded, as were cases of superficial localized soft tissue swelling with pain and/or superficial scarring. Two cases claiming arm pain were excluded because the onset of arm pain was reported many months following vaccination and record lacked sufficient documentation to verify any association between the onset of symptoms and vaccination. Following the review, 13 potential cases submitted between 2006 and 2010 were identified for inclusion in this report. A literature search was conducted using PubMed and search terms of "vaccination," with "shoulder," "shoulder dysfunction," "arm pain," "needle length," and "BMI." The literature search was limited to publications of a specific language. In the course of reviewing claims submitted from 2006 through 2010, the VICP identified 13 claims in which it appeared that vaccine administration led to significant shoulder pain and dysfunction. All individuals in this case series were adults, 85% were women, and, with one exception, all received either influenza vaccine or a tetanus-containing vaccine prior to the onset of symptoms. The mean body mass index (BMI) of patients in the case series was 27.2 (range 19.4-41.3). A history of prior immunization with the same vaccine was confirmed in 85% of the cases. Among patients in whom a history of previous vaccination was confirmed, the interval between vaccinations was no less than 10 years for those receiving tetanus-containing vaccines and no less than 11 months for influenza vaccine. One patient developed shoulder symptoms following administration of the third of a three dose series of human papillomavirus (HPV) vaccine which was administered three months following the second HPV vaccination. Shoulder pain was present in all patients. Onset of pain was reported as occurring less than 24 h after vaccination in 93% and occurred immediately following injection in 54% of the authors' cases. Forty-six percent of the patients voiced concerns regarding vaccine administration, specifically that the vaccination had been administered "too high" in the deltoid. The most common findings on examination were limited and painful range of motion. Skin and local injection site reactions were not reported and sensory symptoms such as tingling and numbness in the affected extremity were uncommon. Weakness was not a common finding in any of the cases during the initial examination and when found was attributed to pain. Deep tendon reflexes, when tested, were noted to be normal. Among the 39% of patients who underwent electrodiagnostic studies, none had findings suggestive of a neurological disorder such as brachial neuritis. When performed, MRI findings varied but included fluid collections in the deep deltoid or overlying the rotator cuff tendons (39%), bursitis, fluid "greater than typically seen" within the bursa, tendonitis, rotator cuff tears, and in one patient, subchondral changes in the humerus with overlying severe tendonitis and fluid accumulation. A complete rotator cuff tear was found in 15% of cases and, in one case, associated atrophy of the rotator cuff tendon was noted. Sixty-three percent of the MRIs performed in the author's case series were conducted within three months of the date of symptom onset and half were performed within six weeks of symptom onset. Routine X-rays of the shoulder were performed less frequently and did not provide helpful diagnostic information among patients in this series. The severity and duration of shoulder dysfunction varied among patients in this case series. More than half of the patients required at least one injection of a corticosteroid over time. Surgical intervention was performed in 31% of cases with half of those cases requiring a second surgical intervention. Review of the available records showed that shoulder symptoms persisted among the authors' cases from six months to many years. All patients had symptoms for at least six months. Less than one third of patients had complete recovery while the majority of patients in this series had continuing symptoms including persistent pain, limited range of motion, and pain on range of motion at last follow-up. The authors took these publications into consideration as the authors analyzed the authors' case series to determine whether the injuries could be caused by vaccine administration. Since it is usually not possible to attribute causation from a case series, the authors took proposed set of nine criteria of "viewpoints" into consideration in determining whether a causal relationship might exist between vaccine administration and shoulder dysfunction in some cases. The clinical details of the patients in this series together with the published research literature on this subject meet many of suggested criteria for a causal relationship including specificity, temporal association, biological plausibility, coherence, and experimental evidence. Of the patients in the authors' series, none had a history of symptomatic shoulder problems prior to vaccination. They all received a vaccine to which they had previously been exposed. They all experienced the rapid onset of shoulder pain (range: immediate to four days) following vaccination. They all developed shoulder symptoms limited to the vaccinated shoulder. They all had symptoms and physical findings consistent with a local immune-mediated inflammatory musculoskeletal shoulder injury. One of the authors' cases provided additional evidence to support vaccine administration as a causal element in this type of injury. In this case, surgeons replicated the path of vaccine administration by inserting a needle into the deltoid area at the location identified by the patient as the injection site during reparative arthroscopic shoulder surgery. The path of the needle led through an area containing an inflamed and scarred bursa and thickened tissue around a damage tendon. Beneath the tendon the needle came into contact with abnormally friable bone on the greater tuberosity of the humerus that gave way with pressure from the needle. The authors believe it is likely that this patient as well as the other patients in the authors' series developed shoulder pain and dysfunction through the mechanism proposed and demonstrated experimentally. Although shoulder dysfunction due to mechanical or overuse injury is always a diagnostic consideration, the rapid onset of pain with limited range of motion following vaccination in the authors' series of patients is consistent with a robust and prolonged immune response within already-sensitized shoulder structures following injection of antigenic substance into the subacromial bursa or the area around the rotator cuff tendon. The authors believe that this type of phenomenon is not due to a specific vaccine but results from injection of a vaccine antigen to which a person has previously been sensitized as a result of previous naturally occurring infection or past vaccination. This concept is consistent with the vaccines which were given in this case series, namely influenza and tetanus vaccines which are given repeatedly over time and HPV vaccine which is given as a series of injections. The authors confirmed that almost all of the authors' cases had received at least one dose of the same vaccine in the past. The two cases for which prior vaccination could not be confirmed by the medical records included one case of influenza vaccine administration and one case involving administration of a tetanus-containing vaccine. It is likely than an adult patient would have received a prior tetanus-containing vaccination at some point in their lifetime. Although it is possible that an adult may receive a first-time influenza vaccine, it is unlikely that an adult would not have had exposure to influenza virus or an influenza infection in the past. The immune response to both vaccines and infections wanes over time and may explain some of the variation in severity and duration of symptoms in the authors' case series. In general, chronic shoulder pain with or without reduced shoulder joint function can be caused by a number of common conditions including impingement syndrome, rotator cuff tear, biceps tendonitis, osteoarthritis and adhesive capsulitis. In many cases, these conditions may cause no symptoms until provoked by trauma or other events. Authors reviewed a series of shoulder ultrasound and MRI studies obtained in asymptomatic persons past middle age and found partial or complete rotator cuff tears in 39% of those individuals. Therefore, some of the MRI findings in the authors' case series, such as rotator cuff tears, may have been present prior to vaccination and became symptomatic as a result of vaccination-associated synovial inflammation. Other findings such as fluid collections, localized tendon inflammation, and bursitis are more consistent with the vaccine needle over-penetration mechanism proposed here. The fact that six patients in the authors' case series vaccine administration "too high" in the shoulder indicates that in some of the authors' cases the injury may have been the result of improper injection techniques. Given that 62% of the authors' cases were overweight or obese based upon BMI and that no case was considered underweight, needle length alone may not have been the cause of injection into tissues other than the deltoid. Ultrasound findings revealed that the subacromial bursa can extend over 2.36 in. laterally from the acromion in some cases. Therefore, the authors agree with that avoiding the top third of the deltoid would help to reduce the risk of penetrating the bursa. In addition, while patients are often seated for vaccinations, the standing position of the provider administering the injection may also contribute to injecting inadvertently high into the deltoid. A seated patient may help to reduce the risk of injury during a syncopal episode, but an awareness of proper injection technique on the part of the vaccine administrator should also be emphasized. Thus, concurrent seating positions for both the administrator and the receiver may minimize the risk of the injection being "too high". Additional considerations for possible future study would include the benefit of abducting the arm a few degrees laterally so that the bulk of the bursa is protected by the acromion process and possibly exploring alternate injection sites in patient's with little shoulder muscle mass. There is a notable absence of children in the authors' case series despite the fact that they have exposure to a broad range of vaccine antigens in the first decade of life. A number of factors may explain their lack of representation in this case series. The thigh is the preferred site of vaccination in toddlers and infants thus eliminating the risk of shoulder injury in this group. In older children and adolescents, the subacromial bursa may not be as developed or as extensive as those in adults. Vaccine administration in older children may more commonly include techniques such as "bunching" of the subcutaneous and deltoid tissue prior to vaccination thus increasing the distance between the skin and subacromial bursa. Children, as a group, have a much lower likelihood of pre-existing asymptomatic shoulder injuries which might be aggravated as a result of an inflammatory reaction related to vaccination. Finally, annual influenza vaccination, the most common vaccine associated with shoulder injury in this series, may have been more selectively encouraged for children at higher risk for influenza-related complications in past years thus reducing the possibility of vaccine-related shoulder injury in children by chance alone. The authors' study is limited by the absence of a control group to allow comparison of outcomes. Additionally, patients submitting petitions to the Vaccine Injury Compensation Program may not be representative of the general public, leading to the possibility of a reporting bias similar to that which might be seen with the Vaccine Adverse Event Reporting System (VAERS). The strength of the authors' case series is that the medical records in VICP petitions are typically voluminous and comprehensive, allowing detailed analysis of each case. Thus, although there is no specific diagnostic test for shoulder dysfunction due to vaccine needle over-penetration, the authors are able to describe clinical qualifications and aids to diagnosis for this entity allowing identification of possible cases of shoulder injury related to vaccine administration (SIRVA). The medical literature supports the possibility that a vaccine can be unintentionally injected into structures underlying the deltoid muscle due to inappropriate needle length and/or injection technique. The research literature supports the potential for inducing a prolonged immune-mediated inflammatory reaction if a vaccine antigen is injected into synovial tissue structures underlying the deltoid muscle. The authors' clinical case series provides additional evidence supporting the report that vaccine administration in the upper third of the deltoid area can have long-lasting consequences unrelated to the specific vaccine administered. Commonalities of history and physical examination among patients in the authors' case series may be helpful in identifying patients who may have developed shoulder pain and dysfunction as a result of inadvertent vaccination into the bursa or other tissues beneath the deltoid muscle. Soft tissue atrophy including tendon atrophy or rupture is a recognized side effect of corticosteroid injection. In situations where recent vaccination is suspected as a possible cause of shoulder pain the authors suggest consideration of non-invasive imaging such as MRI or high resolution musculoskeletal ultrasonography, prior to steroid injection to define any pre-existing anatomic abnormalities. Non-invasive imaging might assume greater importance if symptoms persist and additional steroid injections are being considered. The risk of vaccine administration-related shoulder injury may be reduced by giving careful consideration to appropriate needle length based on individual patient characteristics such as gender and body mass index. Care should be taken to insure that the needle is not inserted into the upper third of the deltoid muscle. Follow-up information was received from a physician indicating that there was a 26 year old female patient that on an unspecified date received the first dose of GARDASIL (lot #, expire date and route not reported). 3 months prior to the third dose of GARDASIL, the patient received the second dose of GARDASIL (lot #, expire date and route not reported). The physician reported that on an unspecified date, less than 24 hours following GARDASIL third dose administration into the left arm the event began. A phone call note at 13 days following vaccination documented pain at the site of injection since the day of vaccination. Symptoms included constant pain in the shoulder, upper arm, and neck; painful shoulder limiting activities of daily living. At day 14 after vaccination, there was tenderness of the shoulder muscles with limited range of motion on exam. Motor and sensory testing was normal although motor testing was painful. Injection of the shoulder from an anterior approach with steroids provided some relief. Diagnoses per treating physician at that time included adhesive capsulitis with possible rotator cuff tendonitis or bursitis and local tissue inflammation from injection. The patient was prescribed physical therapy with little progression as of 83 days following vaccination. X-rays of the shoulder 2 days after that was normal. Additional injection of the shoulder was performed from a posterior approach on the 100th day following vaccination. Pain recurred one year later with normal neurological exam with inconsistent exam for strength due to variable effort. There were signs of impingement and mild limitation in range of motion and the patient was referred to physical therapy. The outcome was reported as not resolved by the physician, as of the last records they had. This is one of several reports received from the same source. Additional information is not expected.