Knorr v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 15-1169V

(to be published)

************************* Special Master Corcoran

*

RAMONA KNORR, *

*

Petitioner, * Filed: December 7, 2018

*

v. * Decision; Influenza (“flu”)

* Vaccine; Microscopic Polyangiitis

SECRETARY OF HEALTH * (“MPA”); Granulomatosis with

AND HUMAN SERVICES, * Polyangiitis (“GPA”); Vasculitis

*

Respondent. *

*

*************************

Michael McLaren, Black McLaren Jones Ryland & Griffee, Memphis, TN, for Petitioner.

Sarah C. Duncan, U.S. Dep’t of Justice, Washington, DC, for Respondent.

DECISION DENYING ENTITLEMENT1

On October 9, 2015, Ramona Knorr filed a petition seeking compensation under the

National Vaccine Injury Compensation Program (“Vaccine Program”).2 Petitioner alleges that she

suffered from several injuries, including hearing loss, microscopic polyangiitis (“MPA”) (a form

of anti-neutrophil cytoplasmic antibody (“ANCA”)-positive vasculitis) with renal failure, and

polyneuropathy as a result of receiving doses of the influenza (“flu”) vaccine on November 7,

2012, and October 8, 2013, respectively.

1

This Decision has been formally designated “to be published,” and will be be posted on the Court of Federal Claims’s

website in accordance with the E-Government Act of 2002, 44 U.S.C. § 3501 (2012). This means the Decision will

be available to anyone with access to the internet. As provided by 42 U.S.C. § 300aa-12(d)(4)(B), however, the

parties may object to the Decision’s inclusion of certain kinds of confidential information. Specifically, under Vaccine

Rule 18(b), each party has fourteen days within which to request redaction “of any information furnished by that party:

(1) that is a trade secret or commercial or financial in substance and is privileged or confidential; or (2) that includes

medical files or similar files, the disclosure of which would constitute a clearly unwarranted invasion of privacy.”

Vaccine Rule 18(b). Otherwise, the Decision in its present form will be available. Id

2

The Vaccine Program comprises Part 2 of the National Childhood Vaccine Injury Act of 1986, Pub. L. No. 99-660,

100 Stat. 3758, codified as amended at 42 U.S.C. §§ 300aa-10 through 34 (2012) [hereinafter “Vaccine Act” or “the

Act”]. Individual section references hereafter will be to § 300aa of the Act (but will omit that statutory prefix).

An entitlement hearing was held on October 26-27, 2017. For the reasons stated below,

Petitioner has not demonstrated entitlement to compensation under the Vaccine Program.

Petitioner’s primary theory at hearing – that she began experiencing vaccine-induced symptoms

reflective of her vasculitis after the first dose of the flu vaccine in 2012 – relied on establishing

that those symptoms were in fact evidence of MPA, but Respondent effectively rebutted such

contentions, demonstrating that those symptoms were actually associated with a medically-

distinguishable form of vasculitis, granulomatosis with polyangiitis (“GPA”). Petitioner otherwise

has not demonstrated with reliable scientific and medical evidence that the second flu vaccine dose

she received in 2013 could be, or was, causative of her MPA, especially given the extent to which

her expert unpersuasively conflated that form of ANCA-positive vasculitis with GPA.

I. Factual Background

The record in this case consists of Ms. Knorr’s medical records, the testimony of multiple

experts, and one fact witness, plus the medical or scientific literature submitted by the parties in

support of their respective positions. I have reviewed the entire record as required by the Vaccine

Act.

November 2012 Flu Vaccination and Subsequent Symptoms

On November 7, 2012, Ms. Knorr received the flu vaccine at the office of her employer,

Presbyterian Homes of Tennessee, in Knoxville, Tennessee. Ex. 2 at 20. Prior to this time, it

appears that Mr. Knorr was relatively healthy, with no significant issues relevant herein – apart

from treatment for fluid in her right ear one year prior on October 17, 2011. Ex. 2 at 8. Earlier

records from July 2011 through September 2012 indicated unremarkable physical exams. See Ex.

2 at 1-2, 6-7, and 10-17 (detailing normal physical exams from July 2011 through September

2012). Ms. Knorr’s records also indicate a past history of attention deficit disorder (including

decreased concentration), depression, and stress. Ex. 2 at 6, 8, 11.

Five days post-vaccination, Ms. Knorr presented to her primary care physician (“PCP”),

Dr. Raye-Anne Ayo, with complaints of flu-like symptoms (including body aches, sore throat,

cough and congestion, nausea, and fever for one to two days). Id. Upon exam, Dr. Ayo found that

Ms. Knorr had enlarged tonsils and non-tender, enlarged lymph nodes. Id. Dr. Ayo also conducted

a lab screening for the flu virus, which was negative. Id. at 22. Dr. Ayo’s overall assessment

included flu-like symptoms, and she recommended that Ms. Knorr begin taking Tamiflu. Id. Office

notes from this visit make no mention of any hearing loss.

2

Hearing Loss in 2013 and Treatment

On January 19, 2013 (over two months post-vaccination), Ms. Knorr presented to the

Minute Clinic in Knoxville, Tennessee, complaining of bilateral ear pain with ear popping, and

that she had been experiencing such symptoms for approximately one month (or since the middle

of December). Ex. 3 at 1; Ex. 8 at 1-3. Ms. Knorr also complained of postnasal drainage,

congestion, and stuffiness. Ex. 8 at 1. Upon exam, her treating nurse practitioner, Mary Anne

Webster, noted that she had clear fluid in her left middle ear, and a bulging tympanic membrane

in her right ear. Id. at 2. The overall assessment included sinusitis and otitis media with effusion,

and Nurse Webster prescribed Amoxicillin. Id. Following this visit, Ms. Knorr returned to the

Minute Clinic roughly two weeks later on February 7, 2013, with continued complaints of bilateral

ear pain and nasal congestion. Ex. 3 at 2. Nurse Webster noted that Ms. Knorr now had red

eardrums with cloudy fluid on exam, and prescribed Augmentin. Consistent with Ms. Knorr’s visit

in January, the assessment remained acute otitis media, and included no mention of the flu vaccine

as having a connection. Id. at 3.

On February 25, 2013, Ms. Knorr took herself to Dr. Bond Almand, an ear, nose, and throat

(“ENT”) specialist at Blount Memorial Hospital in Maryville, Tennessee. Ex. 3 at 4. During this

visit, she reported a gradual, two-month history of hearing loss (with fullness and pressure) that

had not improved with antibiotics. Id. According to Ms. Knorr, her symptoms included occasional

ringing in the ear, as well as occasional pulsing, but no balance issues. Id. Upon examination, Dr.

Almand found no evidence of any ear infection or ear canal/drum injury, but an audiogram

conducted during the visit revealed profound mixed hearing loss in the right ear, and mild to severe

hearing loss in the left ear. Id. at 4. Dr. Almand’s overall assessment also included serous otitis

media and asymmetry in bone conduction threshold. Id. Following her visit with Dr. Almand, Ms.

Knorr presented to Blount Memorial for a follow-up MRI of the brain and ear canals. Id. at 6-7.

The treating radiologist noted no abnormalities in the brain, but did find “opacification of the

majority of the mastoids” in the ears, consistent with a combination of fluid and mucosal

thickening. Id. at 7.

Ms. Knorr next returned to her PCP, Dr. Ayo, on April 23, 2013, with continued complaints

of hearing loss (that she now reported began six months prior “with the flu”).3 Ex. 3 at 8. In

particular, Petitioner reported that she continued to experience congestion with general

improvement but no resolution, despite multiple rounds of antibiotic treatment. Id. Upon

examination, Dr. Ayo diagnosed Ms. Knorr with chronic otitis media (consistent with past

diagnoses), and chronic rhinitis. Id. at 9. Dr. Ayo also found evidence of fluid in the left ear and

Eustachian tube dysfunction in her right ear. Id. at 8-9. Allergy testing conducted during the visit

3

Notably, the record does not state whether the “flu” reference pertained to the vaccination or a wild virus infection.

See Ex. 3 at 8.

3

was positive for trees, weeds, and mold. These records contain no treater suggestions that the flu

vaccine Ms. Knorr received in November 2012 had any relationship with her hearing loss or related

symptoms.

Ms. Knorr subsequently presented to Dr. Elise Denneny, a second ENT specialist, on June

6, 2013, at Greater Knoxville Ear Nose & Throat Associates, in Knoxville, Tennessee, with

continued complaints of hearing loss in both ears. Ex. 3 at 18. Dr. Denneny’s notes reveal that Ms.

Knorr reported that she had experienced hearing loss after a “severe upper respiratory tract

infection,” rather than implicating the November 2012 vaccine. Id. at 19. Dr. Denneny observed

that Ms. Knorr’s audiogram (previously conducted by Dr. Almand) indicated bilateral hearing loss,

but her MRI (also conducted by Dr. Almand) showed no abnormalities in the cranial nerves. Id.

Dr. Denneny’s notes also indicated that Ms. Knorr reported “asymmetry in her smile[,]” although

the same notes do not set forth any diagnostic analysis of, or treatment recommendation for, this

symptom. Id. Dr. Denneny recommend that Ms. Knorr schedule a follow-up appointment for

placement of tympanostomy tubes4 to help with her hearing symptoms. Id.

Ms. Knorr’s next record is from July 2013, and primarily recounts her treatment for

seasonal allergies. Ms. Knorr began receiving allergy immunotherapy shots for allergic rhinitis on

July 29, 2013, at the Family Health Center in Knoxville, Tennessee. Ex. 3 at 20-26, 31-36.

Treatment records indicated that Ms. Knorr received approximately twenty injections during the

following two-month period. Id. No adverse reactions were noted in the accompanying office

notes.

In the interim, Ms. Knorr presented to her PCP, Dr. Ayo, on August 19, 2013, with

continued complaints of decreased hearing. Ex. 3 at 23. This record set forth Petitioner’s history

of hearing loss (via audiogram) and tube placement. Id. Ms. Knorr now reported that her tubes had

helped with draining fluid from the ears, but she also stated that her hearing loss had otherwise

worsened. Id. Upon examination, Dr. Ayo found that both ears were “clogged by cerumen[,]” or

wax, but her external auditory canals were normal. Id. Ms. Knorr’s overall assessment continued

to include decreased hearing loss and allergic rhinitis, pollen-induced (for which she was receiving

allergy shots). Id. at 24.

On September 27, 2013, Ms. Knorr presented (for a follow-up) to her ENT, Dr. Denneny

at Greater Knoxville Ear Nose & Throat. Ex. 3 at 28. According to this record, Ms. Knorr continued

to complain of hearing difficulties plus ear ringing, with onset of symptoms “gradual year(s) ago”

4

Tympanostomy tubes (or ear tubes) are used to prevent the accumulation of fluid behind the eardrum. Tympanostomy

tubes are typically surgically inserted into the eardrum using small, cylinder-shaped tubes made of plastic or metal.

See Tympanostomy Tubes, Mayo Clinic, https://www.mayoclinic.org/tests-procedures/ear-tubes/multimedia/img-

20199962 (last accessed on June 14, 2018).

4

and no known event preceded her hearing loss. Id. During this visit, Ms. Knorr described her

current state of hearing loss as “severe and unchanged” (and reported other new symptoms,

including ostalgia and light headedness). Id. Upon examination, Dr. Denneny noted bilateral gray

tympanic membranes in both ears and an occluded tympanostomy tube. Id. at 29. Overall, Dr.

Denneny’s follow-up assessment noted that Ms. Knorr was suffering from chronic serous otitis

media, bilateral hearing loss, and allergic rhinitis (consist with her overall health course and

statements of past treaters). Id. at 30.

October 2013 Flu Vaccine and Subsequent Symptoms

Ms. Knorr received a second flu vaccine on October 8, 2013, at her place of employment,

Presbyterian Homes of Tennessee, in Knoxville, Tennessee. Ex. 3 at 37. Specifically, Petitioner

was administered Fluarix – an inactivated, quadrivalent (meaning containing four wild flu virus

strains), and non-adjuvanted5 form of flu vaccine. Id.; see also Package Insert, FDA, May 2015,

filed as Court Ex. 1 (ECF No. 75-1). No adverse reactions were noted the day of vaccination.

Three days later, on October 11, 2013, Ms. Knorr returned to Greater Knoxville Ear Nose

& Throat, but this time presented to a different ear, nose, and throat (“ENT”) specialist, Dr. Richard

Desperio. Ex. 3 at 40. Consistent with her past statements, Ms. Knorr reported (for the second

time) a gradual onset of hearing loss beginning “year(s) ago,” without reference to any specific

prior event (such as vaccination), along with a worsening of symptoms since her last office visit.

Id. Dr. Desperio’s notes indicated that her latest audiogram showed a blocked right tube but no

fluid, along with an open left tube. Id. at 41. A hearing test returned decreased hearing levels. Id.

During this visit, Ms. Knorr also reported extreme tightness in her neck and tenderness/pain when

opening her mouth. Id. Dr. Desperio’s overall assessment remained chronic serous otitis media

(and also included cervicalgia6). Id. He advised Ms. Knorr to take Advil or Aleve for her pain, and

prescribed Xanax as well. Id. Office notes also indicated that Ms. Knorr scheduled a follow-up

appointment for six weeks later.

5

Adjuvants are used in some vaccines to create a stronger immune response to the disease being vaccinated against.

See Adjuvants Help Vaccines Work Better, CDC, https://www.cdc.gov/vaccinesafety/concerns/adjuvants.html (last

accessed on November 20, 2018). Aluminum salts, for example, have been used safely in vaccines since the 1930s.

Id. Not all vaccines contain adjuvants, however. Id. Typical non-adjuvanted vaccines include chickenpox, MMR,

rotavirus, seasonal flu, and yellow fever. Id.

6

“Cervical” is a general term used to describe the neck. Dorland’s Illustrated Medical Dictionary 333 (32nd ed. 2012)

(hereinafter Dorland’s). “Cervicalgia” refers to generalized neck pain. Symptoms can include muscle tightness,

spasms, headaches, and decreased ability to move the head. See Neck Pain, Mayo Clinic,

https://www.mayoclinic.org/diseases-conditions/neck-pain/symptoms-causes/syc-20375581 (last accessed on June

14, 2018).

5

One week post-vaccination, Mr. Knorr visited her PCP, Dr. Ayo, on October 15, 2013,

complaining of a four-day course of flu-like symptoms (including body aches, cough, subjective

fever, watery nasal discharge, and sore throat). Ex. 3 at 43. She specifically asserted that her

present symptoms were similar to those she experienced following her flu vaccine in November

2012. Id. Upon exam, however, Dr. Ayo noted that Ms. Knorr appeared healthy apart from

rhinorrhea and general malaise. Id. at 44. Her notes also indicated that Ms. Knorr was experiencing

temporomandibular joint dysfunction (“TMJ”) pain in the jaw and surrounding muscles. Id. Her

overall impression was that Ms. Knorr’s symptoms were flu-like and “seem[ed] related to

influenza vaccine.” Id. Dr. Ayo recommended that Ms. Knorr rest for a week and use a mouth

guard for her TMJ pain. Id.

On October 22, 2013, Ms. Knorr presented again to Dr. Ayo, now reporting a rash on her

neck, chest, and arms for the past week, plus a fever, arthralgia, and a dry cough (for two weeks).

Ex. 3 at 45. Dr. Ayo noted that Ms. Knorr received the flu vaccine earlier that month and had

reported flu-like symptoms a few days later, but she did not appear to opine as to any causal

connection between the vaccine and the present rash. Id. Dr. Ayo diagnosed Ms. Knorr with a

cough and rash, and prescribed antibiotics. Id. at 46. A lab workup conducted during the visit

showed increased platelets of 434 (reference range 130-400), but a normal erythematous

sedimentation rate (“ESR”) of 21 (reference range 0-32), which was not supportive of the

conclusion that she was at that time experiencing active inflammation. Id. at 51-52.

The lab results from October 2013, however, also revealed the presence of a number of

antibodies associated with the Epstein Barr virus (“EBV”). Ex. 3 at 50. Specifically, Petitioner

tested positive for Anti-Viral Capsid Antigen (“VCA”) IgM antibodies (3.9 on a reference range

of 0.0 to 0.8) and IgG antibodies (greater than 8 on the same range), and positive as well for the

EBV nuclear antigen (“EBNA”) antibody (also greater than 8 on the same range).7 Id. The

interpretation chart for this testing classified these results as most likely reflecting that Petitioner

was in the convalescent phase of a recent EBV infection (or mononucleosis). Id.

7

Immunoglobulin G (IgG) and Immunoglobulin M (IgM) are antibodies produced in response to infection, and their

titer levels can help monitor or detect immune deficiencies. IgM is an indicator of current infection, while IgG reflects

exposure to a past infection. Increased levels of IgG or IgM are indicia of hepatic diseases (including connective tissue

diseases and acute/chronic infections), while decreased levels are found in patients with primary/secondary immune

deficiencies. See Immunoglobulins (IgG, IgA, and IgM), Serum, Mayo Clinic Med. Laboratories,

https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/8156 (last accessed June 14,

2018).

6

Worsening and Attempts to Diagnose Etiology of Symptoms

Ms. Knorr’s condition seemed to worsen in the weeks following her October 22nd

appointment. She presented to the emergency room at Parkwest Medical Center in Knoxville,

Tennessee, on November 4, 2013, complaining of a rash, fever, and bilateral pain in her upper

extremities. Ex. 3 at 54. She specifically recounted at this time that she had received the flu vaccine

roughly three weeks prior and developed flu-like symptoms four days post-vaccination. Id. Upon

intake, the treating physician noted that Ms. Knorr had some weakness, difficulty adducting her

thumb, calf pain, headaches, scalp tenderness, and dyspnea upon exertion. Id. Ms. Knorr also

reported subjective chills and decreased fever, weight loss, and an aching jaw. Id. Given her host

of symptoms, Mr. Knorr was admitted to Parkwest Hospital from November 4-5, 2013, with

concerns for systematic inflammatory response syndrome (“SIRS”), neuralgia, elevated liver

function tests (“LFTs”), and a possible vasculitis-type process. Id. Initial lab testing conducted

during her hospitalization now showed an elevated ESR of 106 (reference range 0-20) – a

significant change from the reading obtained two weeks prior - an elevated C-reactive protein of

32.5 (normal 0-0.5), and positive EBV-VCA IgG. Id. at 55, 67-69. Additional testing was also

notable for a positive p-ANCA antibody titer.8 Id. at 87.

During her stay at Parkwest Hospital, Ms. Knorr was evaluated by an infectious disease

physician, Dr. John Adams. Ex. 3 at 57. Dr. Adams observed Ms. Knorr to display generalized

weakness, numbness, calf pain, and reduced finger strength upon examination. Id. at 57-59. The

notes from his examination recount that Ms. Knorr had received a flu vaccine in October, but did

not opine as to a possible relationship between the vaccine and her current state. Id. at 57.

Following the consultation, Dr. Adams assessed Ms. Knorr with a “somewhat unusual syndrome

with an apparent initial viral syndrome which could have been Epstein-Barr virus reactivation”

followed by abnormal LFTs, although he expressed doubt that she was suffering from an active

infection, given her IgG and IgM measurements. Id. at 50, 59. Dr. Adams recommended a

neurological consultation. Id. While he opined that Ms. Knorr was suffering from a “clearly

evolving inflammatory process,” he was not convinced that her symptoms were related to

vasculitis, but more likely some form of acute demyelinating encephalomyelitis (or ADEM). Id.

Ms. Knorr was next seen by Dr. James Burns on November 4, 2013, for a neurology

consultation. Ex. 3 at 99. Dr. Burns recounted Ms. Knorr’s health course, noting that she reported

she was in excellent health prior to receiving a flu vaccine the prior year. Id. Thereafter, Ms. Knorr

8

Perinuclear antineutrophil cytoplasmic antibodies (“p-ANCA”) are used to evaluate patients suspected of having

autoimmune vasculitis (including GPA and MPA). See Test ID:ANCA, Mayo Clinic Med. Laboratories,

https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9441 (last accessed on June 14,

2018). P-ANCA antibodies are most closely associated with MPA, however. See A. Greco, et al., Microscopic

Polyangiitis: Advances in Diagnostic and Therapeutic Approaches, 14 Autoimm. Rev. 837, 840 (2015), filed as Ex.

C, Tab 2 (ECF No. 19-4).

7

had developed hearing loss (requiring tympanoplasty tubes) and a Bell’s palsy-type appearance

following vaccination, along with increased hearing loss following a second flu vaccination in

October 2013. Id. Similar to Dr. Adam’s evaluation, Dr. Burns noted that Ms. Knorr was

experiencing hand numbness and weakness (acute onset on day of admission), headaches, aching

in the calves/thighs/shoulders, rash, and elevated ESR. Id. Following the initial evaluation, Dr.

Burns ordered lab testing to measure Ms. Knorr’s anti-neutrophil cytoplasmic antibodies (or

ANCAs). Id. at 101. Ms. Knorr tested positive for p-ANCA antibodies and negative for c-ANCA

antibodies. Id. at 87. Dr. Burns ultimately raised concerns for the possibility of a vasculitis illness,

or a “neurologic reaction to vaccine such as an atypical Guillain-Barre-type presentation.” Id. at

101. He recommended that Ms. Knorr receive a full neurological evaluation at an alternate facility

with the appropriate capabilities. Id.

Ms. Knorr was transferred to Fort Sanders Regional Medical Center on November 5, 2013,

and remained hospitalized from November 5-12, 2013. Ex. 3 at 112. Upon discharge from

Parkwest, her overall assessment included a purpuric, balancing type rash, covering her upper

torso, arms, feet, and ankles. Id. at 112. The discharging physician indicated that her main

neurological abnormalities included decreased adduction of her thumb and index finger, decreased

flexion and extension strength in her forearms, as well as hyperflexivity in the upper and lower

extremities. Id. Lab testing noted in the record upon release indicated abnormal LFTs and elevated

platelet and white blood cell counts. Id. at 113.

During her stay at Fort Sanders, Ms. Knorr was seen by Dr. Darrell Thomas (a neurologist)

on November 5, 2013. Ex. 3 at 119. Dr. Thomas recounted a health history similar to that provided

to treaters at Parkwest. More specifically, Dr. Thomas noted that Ms. Knorr had presented to the

emergency room at Parkwest with acute onset pain and numbness in her arms and hands (along

with general sense of weakness, a rash, and history or hearing loss). Id. Upon exam, Dr. Thomas

found that Ms. Knorr displayed weakness in her fingers and wrist flexors, but no additional

concerning neurological symptoms. Id. at 119. Overall, Dr. Thomas assessed Ms. Knorr with

dysesthesias and weakness in the upper extremities, and described her condition “to be more of an

immune-mediated process probably precipitated by a flu shot.” Id. He excluded GBS as a possible

diagnosis (given Ms. Knorr’s normal reflexes and local distribution of weakness), but did not rule

out vasculitis or sarcoid. Id. Moving forward, Dr. Thomas ordered additional lab testing, an EMG,

and a lumbar puncture to test for infection or a carcinomatous-type process.

Ms. Knorr was seen by Dr. Amanda Miller for a rheumatology examination on November

6, 2013. Ex. 3 at 115. Similar to Dr. Thomas’s assessment, Dr. Miller indicated that Ms. Knorr had

experienced a systematic illness, “possibly a reaction to a flu vaccine, which would be the second

severe reaction . . . in two years.” Id. at 116. Dr. Miller suggested that Ms. Knorr might have some

form of vasculitis or other immunologic disease, but was not convinced her symptoms were

8

autoimmune in nature. Id. at 116. Dr. Miller found Ms. Knorr’s increased liver enzyme levels

(along with elevated platelet counts) to be significant and possibly a marker for an existing

inflammatory process. Id. Absent any identified infection or other cause (as indicated by Ms.

Knorr’s labs), Dr. Miller recommended a trial of high-dose steroids. Id.

An EMG/NCV conducted on November 7, 2013 was normal with no evidence of

neuropathy or plexopathy. Ex. 3 at 144. Spinal fluid studies also revealed no abnormalities. Id.

Upon discharge, Ms. Knorr’s treating physician diagnosed her with “weakness and dysesthesias

of the upper extremities following a flu vaccine, suspected inflammatory or autoimmune process.”

Id. at 145. Notes further indicated that “this appear[ed] to be the second serious reaction she has

had to flu vaccinations.” Id. The discharging physician recommended that Ms. Knorr begin therapy

for her physical symptoms and prescribed gabapentin. Id. at 147.

Vasculitis/MPA Diagnosis

Following her initial hospitalization, Ms. Knorr was seen in the rheumatology clinic at

Vanderbilt University Medical Center in Nashville, Tennessee, by Dr. Glenn Douglas on

November 19, 2013. Ex. 3 at 161. Ms. Knorr reported a health course similar to those referenced

above (including hospitalization for nerve pain and numbness beginning in October 2013). Id. Dr.

Douglas also included pneumonia, hearing loss, EBV infection, and a rash in her health history.

Id. Following an evaluation, Dr. Douglas diagnosed Ms. Knorr with ANCA-positive vasculitis

with possible renal involvement, as well as polyneuropathy (along with a rash). Id. He prescribed

Prednisone and Oxycodone (for pain), and recommended that Ms. Knorr schedule a follow-up

appointment in two weeks. Id.

Petitioner was subsequently hospitalized for vasculitis flares on three additional separate

occasions at Vanderbilt Medical Center in Nashville, from November 2013 through January 2014,

including: (1) November 27-December 1, 2013; (2) December 3-10, 2013; and (3) January 3-14,

2014. Ex. 3 at 164, 206; Ex. 4 at 27.

On November 27th, Ms. Knorr presented to Vanderbilt Medical Center with a history of

ANCA-positive vasculitis (including lower extremity swelling) and complaints of worsening

kidney involvement. Ex. 3 at 164. She was monitored and discharged with a diagnosis of lower

extremity swelling and blood in stool. Id. at 169. Ms. Knorr presented a second time on December

3rd with complaints of shortness of breath and fever related to her vasculitis diagnosis. Id. at 206.

Upon discharge on December 10, 2013, treating physicians concurred with prior determinations

that Ms. Knorr had ANCA-positive vasculitis with possible renal involvement – making the form

of vasculitis most likely MPA – and steroid induced-diabetes. Id. Following her December 2013

hospitalizations, Ms. Knorr presented a third time to Vanderbilt Medical Center after an

9

exacerbation of her vasculitis (including symptoms of pain, malaise, blurred vision, and

headaches). Ex. 4 at 27. Her diagnoses upon discharge continued to include MPA, renal failure,

neuropathic pain, and anemia of chronic disease. Id. Treaters recommended that she continue

physical therapy, and use Gabapentin and Cymbalta as needed. Id. at 28.

Mr. Knorr was hospitalized for a fourth flare-up from March 1-6, 2014, at the University

of Tennessee Medical Center in Knoxville, Tennessee. Ex. 4 at 192, 222. Her chief complaint

during this visit was fever and generalized weakness (associated with her MPA diagnosis roughly

four months prior). Id. at 192. Upon examination, the treating physician, Dr. Sahar Lotfi, noted

that Ms. Knorr displayed no acute distress (and stated she had been doing well overall), but

experienced an onset of lethargy and weakness two days prior. Id. Dr. Lotfi opined that Ms.

Knorr’s symptoms were related to her vasculitis diagnosis, steroid-induced hypoglycemia, and

renal failure (as well as the medication she was taking, including Prednisone). Id. In light of her

renal insufficiency, a right renal biopsy was conducted during her hospitalization which displayed

necrotizing and crescentic glomerulonephritis, consistent with ANCA-associated disease. Id. at

201, 222, 247. Ms. Knorr’s discharge summary indicated diagnoses of MPA, chronic kidney

disease, hypertension, and anemia. Id. at 222. Dr. Lofti also prescribed Cytoxan for her kidney

dysfunction.

Ms. Knorr next presented to a rheumatologist, Dr. Natalie Braggs, at Vanderbilt University

Medical Center on March 13, 2014. Ex. 4B at 15. Ms. Knorr recounted her recent diagnoses of

MPA and hospitalization for high fever and worsening kidney function. Id. Dr. Braggs noted that

Ms. Knorr reported that her kidney function had improved with IV Cytoxan. Id. According to Ms.

Knorr, she was still experiencing pain and numbness in her feet and hands, blurred vision, and

occasional shortness of breath (and cough). Id. at 15. Dr. Braggs’s overall assessment included

ANCA-vasculitis, steroid-induced diabetes, and neuropathy. Id. at 17. She recommended that Ms.

Knorr continue taking Prednisone (decreased to a lower dose), Cytoxan, and Gabapentin, and

follow-up as needed. Id. Relevant lab testing conducted during a lab follow-up showed a normal

C-reactive protein and ESR. Ex. 6 at 25-29.

During the following months, Ms. Knorr saw various additional treating physicians at

Vanderbilt Medical Center for follow-up appointments related to her vasculitis diagnosis and

kidney dysfunction (as well as additional on-going problems such as steroid-induced diabetes and

a vitamin D deficiency). See, e.g., Ex. 4B at 56-57 (4/15/2014 follow-up visit with Dr. William

Sullivan), 88 (5/20/2014 follow-up visit with Dr. Sullivan), 180 (6/17/2014 follow-up with Dr.

Williams). The records from these visits suggest that Ms. Knorr’s condition has seen steady

improvement with proper treatment and medication. See, e.g., Ex. 4B at 56, 87. Ms. Knorr has

continued to attend physical therapy for her hand/arm weakness. Id. at 118, 160; Ex. 6 at 2, 17-55.

10

II. Fact Witness Testimony

A. Ms. Ramona Knorr

Petitioner testified at hearing. Tr. at 6-59. Her testimony largely consisted of her own

recollections of her overall health history prior to receiving the flu vaccines on November 2012

and October 2013, respectively, as well as describing the symptoms that followed.

Ms. Knorr began by describing her overall condition prior to receiving her initial flu

vaccine in November 2012. At that time, she was extremely healthy, with no adverse health

problems or chronic ailments. Tr. at 12-13. She testified that she worked full-time as an

occupational therapist, attended school part-time, exercised occasionally, and cared for her three

children. Id. at 13.

Next, Ms. Knorr recounted her receipt of the flu vaccine on the day of November 7, 2012.

Tr. at 14. She noticed no adverse reaction to the vaccine the day it was administered. Id. Following

the vaccination, Ms. Knorr stated that she presented to her PCP, Dr. Ayo, four to five days later,

complaining of flu-like symptoms (including aches and pains). Id. at 15. However, she did not

recall experiencing hearing loss at that time. Id.

Ms. Knorr recalled going to a Minute Clinic at her local CVS roughly two months post-

vaccination, with worsening flu-like symptoms and ear pain/popping. Tr. at 16. Although she

categorized her symptoms as gradually increasing over the past months, she testified that she did

not return to her PCP or any other physician in the interim due to her busy schedule. Id. According

to Ms. Knorr, during this visit, she reported her hearing loss began shortly after her initial

presentation to Dr. Ayo on November 12, 2012 (likely around November 23rd-25th). Id. at 18.

Ms. Knorr expressed frustration that her hearing problems seemed to be getting worse,

despite her attempts to cure them (including antibiotics, and tube placement). Tr. at 19, 29-30. She

next recalled various appointments for hearing problems beginning in February 2013. Ms. Knorr

began with a February 2013 appointment with her ENT, Dr. Almand. Id. at 21. According to the

medical records, Ms. Knorr told Dr. Almand at this time that her symptoms began two-months (or

a “few” months) prior to her visit (which would place onset post-vaccination in December 2012).

Id. at 22-23. However, Petitioner characterized such statements to Dr. Almand as no more than

vague estimations. Id. at 23.

Ms. Knorr also discussed an appointment with a second ENT, Dr. Denneny, whose notes

indicated that her hearing loss symptoms actually began in June 2012 (pre-vaccination), and/or

11

followed a URI. Tr. at 32. Ms. Knorr disputed the accuracy of this record, but acknowledged that

statements concerning the URI were correct (which, according to Ms. Knorr, would place onset in

late November 2012). Id. Overall, despite the varying statements concerning the onset of hearing

problems, Ms. Knorr continued to maintain that her symptoms began in November 2012, a few

weeks following her initial flu vaccine on November 7th. Id. at 24.

By the summer of 2013, Ms. Knorr testified, she was having trouble working and keeping

up with her graduate school classes. Tr. at 26. She also recalled having an issue with her smile,

which she described as “like a Bell’s palsy sort of situation” or a “droopy smile.” Id. at 33, 34.

Despite these symptoms, no diagnosis of Bell’s palsy (or any other) was ever made, and Ms. Knorr

testified that these symptoms resolved on their own. Id. at 34.

Ms. Knorr next recalled her general health course following the October 2013 vaccination.

Tr. at 36. She presented to her PCP, Dr. Ayo, seven days post-vaccination with complaints of flu-

like symptoms (similar to her complaints with regard to her initial flu vaccination in November

2012. Ms. Knorr testified that Dr. Ayo prescribed Tamiflu and recommended that she get some

rest. Id. She was later diagnosed with Epstein Barr (or mono) in early November 2013 (although

she also noted she was diagnosed with mono as a teenager and did not feel as if she was

experiencing similar symptoms). Id. at 39. According to Ms. Knorr, her health course thereafter

continued to deteriorate during the following months, and she could no longer work. Id. at 38-39.

Finally, Ms. Knorr recounted her hospitalization for what now appears to be the early

manifestations of MPA. Ms. Knorr described her hospital course as “really, really rough.” Tr. at

43. She was in and out of Vanderbilt Hospital for four months with various symptomology and

flare-ups of MPA. Ms. Knorr testified that these flares ranged in severity and included symptoms

such as double vision, headaches, pain, and an inability to walk. Id. at 44. She also experienced

paralysis in her right hand, hair loss, and Prednisone-induced diabetes. Id. at 44, 46. According to

Ms. Knorr, her treatment course during this time included plasmapheresis, chemotherapy, spinal

taps, and rehab therapy. Id. at 44-45. To date, Ms. Knorr continues to have trouble walking, has

decreased sensation in her right hand, as well as balance issues and decreased fine motor skills. Id.

at 50-53. Ms. Knorr testified that she has not returned to work (given the general physical

demands), and continues to take azathioprine (immunosuppressant) and gabapentin (for nerve

pain). Id. at 48-50.

B. Petitioner’s Expert – Dr. Eric Gershwin

Dr. Gershwin is an immunologist who testified on behalf of Petitioner and offered three

expert reports in the case. Tr. 64-124, 156-58; Ex. 19, dated Feb. 17, 2016 (ECF No. 41)

(“Gershwin First Rep.”); Ex. 67, dated Aug. 11, 2016 (ECF No. 24-1) (“Gershwin Second Rep.”);

12

Ex. 96, dated Aug. 11, 2017 (ECF No. 42-1) (“Gershwin Third Rep.”). Dr. Gershwin opined that

Ms. Knorr’s initial flu vaccine in November 2012 (resulting in flu-like symptoms, hearing loss,

and Bell’s palsy-type symptoms), coupled with the second flu vaccine in October 2013

(exacerbating her hearing loss and resulting in additional flu-like symptoms), caused her MPA

vasculitis. Tr. at 93, 111, 153.

Dr. Gershwin received his bachelor's degree from Syracuse University in Syracuse, New

York, followed by his medical degree, which was completed at Stanford University in Stanford,

California. Ex. 66 at 1 (ECF No. 41) (“Gershwin CV”). He then completed his internship and

residency at Tufts–New England Medical Center in Boston, Massachusetts. Id. at 2. After

completing a fellowship in immunology with the National Institute of Health, Dr. Gershwin

became an assistant Professor in Rheumatology and Allergy at the University of California, School

of Medicine in Davis, California. Id. at 2. Along with maintaining a clinical practice, Dr. Gershwin

remains employed by the University of California, School of Medicine in Davis, California as the

Chief of the Division of Rheumatology/Allergy and Clinical Immunology. Gershwin CV at 1-2;

Tr. at 65. He currently serves as the editor-in-chief of the Journal of Autoimmunity as well as

several other publications focusing on autoimmunity. Tr. at 80; Gershwin CV at 5. Dr. Gershwin

also maintains a clinical practice (one day per week) at UC Davis and spends four to six weeks

conducting a rheumatology consult service. Tr. at 78.

To begin, Dr. Gershwin described vasculitis and provided a brief overview of its relevant

presenting symptoms. Tr. at 71. Dr. Gershwin defined vasculitis as “inflammation of the [blood]

vessel[s]” or an inflammatory response initiated by some injury. Id. at 72, 85. While Dr. Gershwin

acknowledged that genetic (or inherited) factors can play a role in its development, he opined that

vasculitis requires an environmental stimulus. Id. at 86. He characterized vasculitis as an all-

defining term, given the multiple types in existence, which he asserted differ mainly due to the

size of the vessel implicated, the presence of specific autoantibodies, as well as the presenting

location in the body (i.e. can be limited to the head and neck, for example, or spread through the

body). Id. at 72, 100, 102. It can also be associated with various environmental factors, including

viral illness or independent diseases such as lupus or rheumatoid arthritis. Id.

Dr. Gershwin went on to discuss some of the specific ANCA-associated vasculitis (or

“AAV”) sub-types (i.e. GPA and MPA), given their relevance in the present matter. Dr. Gershwin

defined ANCA-associated vasculitis as “a heterogeneous group of diseases that include the

presence of circulating ANCAs.” Gershwin First Rep. at 22. ANCAs are implicated in the

pathogenesis of AAV, although the process by which these antibodies are formed is not well-

understood (with genetic, environmental, or infection related-factors all considered possible

triggers). Id.; see R. Wijngaarden, et al., Hypotheses on the Etiology of Antineurtrophil

Cytoplasmic Autoantibody-Associated Vasculitis: The Cause Is Hidden, but the Result Is Known,

13

3 J. Am. Soc. Nephrol. 237, 237 (2008), filed as Ex. 53 (ECF No. 41) (“Wijngaarden”).

Wijngaarden discusses in depth some of the identified causes of ANCA-associated vasculitis,

including silica exposure, genetic predisposition, bacterial/viral infection (such as parvovirus

B19), and certain thyroid drugs. Wijngaarden at 237.

Dr. Gershwin defined Wegener’s granulomatosis (more accurately termed GPA) to be a

type of vasculitis mediated by a collection of white cells called granulomas9, or foreign body

reactions. Tr. at 72; see also Gershwin First Rep. at 22-23. GPA can be both acute (resulting in a

rapid onset), or indolent (resulting in a progression of symptoms over time). Tr. at 74-75. Dr.

Gershwin saw no reason to distinguish between GPA and Ms. Knorr’s MPA diagnosis given the

overlapping symptoms (although in so testifying he essentially acknowledged that some

differences existed), despite filing literature acknowledging expressly that MPA is

“distinguish[able] as a separate ANCA-associated vasculitis.” Wijngaarden at 237 (emphasis

added); see also Tr. at 308-09. He did, however, acknowledge that Petitioner’s MPA diagnosis

was medically accurate. Tr. at 74, 298.

For Petitioner’s causation theory, Dr. Gershwin maintained that Ms. Knorr’s vasculitis was

the result of immunological insult to her autonomic nervous system attributable to the flu vaccine,

occurring via the biologic mechanism of molecular mimicry and producing an inflammatory

response. Gershwin First Rep. at 22; Tr. at 143, 150. Dr. Gershwin described molecular mimicry

as an “antigen-specific phenomenon where there is activation of autoreactive B and T cells due to

antigen similarity between the host antigen and microbial antigen,” involving both amino acid

sequences as well as the secondary/tertiary structure of the presenting antigen (in this case, a

protein sequence from the flu vaccine). Gershwin First Rep. at 21-22. Antigens in the flu vaccine

mimicked self-structures in the body, producing a cross-reaction whereby antibodies produced in

response to the vaccine also attack those self-structures, resulting in an autoimmune illness. Tr. at

93-95, 143-44, 150-51. Dr. Gershwin’s opinion relied specifically on a lengthy block quote set

forth in a single cited item of literature. Gershwin First Rep. at 23 (citing T. Duggal, et al.,

Antineutrophil Cytoplasmic Antibody Vasculitis Associated with Influenza Vaccination, 38 Am. J.

Nephrology 174, 176-77 (2013), filed as Ex. 24 (ECF No. 41) (“Duggal”)); Tr. at 141.

To bulwark this proposed mechanism, Dr. Gershwin relied on various articles (not specific

to vasculitis) discussing molecular mimicry as a possible explanation for how infectious agents

can stimulate autoimmunity in an antigen-specific way. See, e.g., D. Wraith, et al., Vaccination

and Autoimmune Disease: What is the Evidence, 362 Lancet 1659 (2003), filed as Ex. 54 (ECF

No. 41); Y. Shoenfeld, et al., Vaccination and Autoimmune-‘Vaccinosis’: A Dangerous Liaison?,

9

Granulomas are areas of inflammation in the body tissue. See Granulomatosis with Polyangiitis, Mayo Clinic,

https://www.mayoclinic.org/diseases-conditions/granulomatosis-with-polyangiitis/symptoms-causes/syc-20351088

(last accessed on June 18, 2018).

14

14 J. Autoimm. 1 (2000), filed as Ex. 55 (ECF No. 41). Dr. Gershwin acknowledged, however,

that he could not identify homology (amino acid sequential similarity) between the viral

components of the version of the flu vaccine Petitioner received and a protein in the body that

would be the target of an autoantibody attack resulting in MPA, nor could he specify what

component of the vaccine was the antigenic mimic. Tr. at 119, 143, 151. At best, he could only

cite to an unspecified “ongoing NIH study” that implicates the importance of protein structure in

autoimmune cross-reactions (but did not file this study), and also opined the likely target antigen

to be the neutrophil cytoplasmic antigen, since it purportedly had such structural homology with a

flu vaccine component (again without filing anything in support). Id. at 143-45, 151; Gershwin

First Rep. at 22.

Alternatively, Dr. Gershwin proposed that viral RNA protein found in certain formulations

of the flu vaccine might contribute to the development of the ANCA autoantibodies. Tr. at 119,

143; Gershwin First Rep. at 23-24; see L. Jeffs, et al., Viral RNA in the Influenza Vaccine May

Have Contributed to the Development of ANCA-Associated Vasculitis in a Patient Following

Immunization, Clin. Rheumatol. (2015), doi 10.1007/s10067-015-3073-0, filed as Ex. 30 (ECF

No. 41) (“Jeffs I”). Jeffs I is a case control study involving a single patient (compared to eight

healthy controls and six ANCA controls) who developed ANCA-associated vasculitis two weeks

following receipt of a flu vaccine in Australia. Jeffs I at 1. In it, researchers isolated peripheral

blood samples from the fifteen patients and found evidence that the vaccinated index patient had

increased levels of PR3-ANCA in his blood, leading researchers to conclude that forms of the flu

vaccines also containing viral ribonucleic acid (RNA) might be able to stimulate production of this

particular ANCA autoantibody. Id. at 1-2, 8. Dr. Gershwin did not establish, however, that Fluarix

(the version of the vaccine Ms. Knorr received) is comparable to the tested versions of the flu

vaccine in Jeffs I, and Dr. Gershwin acknowledged in any event that he did not put much stock in

this mechanistic explanation for how ANCA production could be vaccine-stimulated. Tr. at 143

(“I think it’s less likely . . . [t]here is not likely to be much RNA there [in the vaccine], but I just

wanted to be complete”).

There are other problems with Jeffs I. First, it involved PR3-ANCA, an autoantibody more

commonly associated with GPA than MPA. See, e.g., A. Greco, et al., Microscopic Polyangiitis:

Advances in Diagnostic and Therapeutic Approaches, 14 Autoimm. Rev. 837, 840 (2015), filed

as Ex. C, Tab 2 (ECF No. 19-4) (“Greco”) (determining “PR3-ANCA usually cause a C-ANCA

pattern and are mainly associated with GPA[,]” while myeloperoxidase ANCA (“MPO-ANCA”)

are associated with MPA); L. Guillevin, et al., Microscopic Polyangiitis: Clinical Laboratory

Findings in Eighty-Five Patients, 42 Arthritis & Rheumatol. 421, 424, 428 (1999), filed as Ex. 50

(ECF No. 41) (“Guillevin”) (31 out of 51 MPA patients evaluated in study tested positive for anti-

MPO antibodies, where only 4 out of 51 tested positive for PR3). Second, an article with the same

primary author published in the same year as Jeffs I (and filed by Petitioner in this case) cautions

15

against overreliance on the possible implications of Jeffs I. See L. Jeffs, et al., Randomized Trial

Investigating the Safety and Efficacy of Influenza Vaccination in Patients with Antineutrophil

Cytoplasmic Antibody-Associated Vasculitis, 20 Nephrology 343, 345-51 (2015), filed as Exhibit

31 (ECF No. 41) (“Jeffs II”). Jeffs II specifically monitored thirty-one patients who already had

ANCA-associated vasculitis and concluded they were not likely to experience a relapse after

receipt of the flu vaccine. As part of its control grouping, the Jeffs II authors also analyzed 67

healthy patients and found no evidence that the flu vaccine could trigger the relevant ANCA-

associated antibodies necessary for disease onset. Id. at 343, 348-49. Since it is the Petitioner’s

theory that the earlier flu vaccine dose from 2012 played a role in causing her vasculitis after the

second dose, Jeffs II not only seems to limit the significance of Jeffs I, but calls into question the

entirety of the causation theory.10

In addition to molecular mimicry, Dr. Gershwin also suggested that the mechanism of

bystander activation could play a role in instigating an ANCA-associated vasculitis. As he

proposed, bystander activation results “in a release of previously sequestered self-antigens or

stimulat[ed] . . . innate immune response.” Gershwin First Rep. at 23; Tr. at 142. Dr. Gershwin’s

first report seems to define bystander activation (or what he also termed “polyclonal activation” at

hearing) as an immune mechanism initiated by a vaccine (or viral infection) which results in the

activation of T cells apart from any specific antigen stimulation directly caused by vaccination.

Gershwin First Rep. at 23; Tr. at 135, 149.

The literature ostensibly supporting this proposition, however, did not explain how

bystander activation could act as the predominant driver of an autoimmune process (as opposed to

a secondary process fueling an existing autoimmune reaction instigated by something else). See

M. Moro, et al., A Population Based Cohort Study to Assess the Safety of Pandemic Influenza

Vaccine Focetria in Emilia-Romagna, Italy—Part Two, 31 Vaccine 1438 (2013), filed as Ex. 35

(ECF No. 41); B. Ormen, et al., Attitudes and Side Effects Related to Pandemic Influenza A (H1N1)

Vaccination in Healthcare Personnel, 46 Mikrobiyol Bul. 57 (2012), filed as Ex. 36 (ECF No. 41)

(filed in Turkish language with English abstract); H. Reynolds, et al., A Prospective Observational

10

In addition, Jeffs I seems to possibly embrace a vaccine causation theory that has not been found scientifically

reliable (to date) in the Vaccine Program. Jeffs I noted that the examined case study reflected “another of the recently

proposed concepts of ‘Autoimmune/Inflammatory Syndrome Induced by Adjuvants’” or ASIA. Jeffs I at 8. But the

ASIA theory (which relies heavily on the proposition that adjuvants in a vaccine can overstimulate the immune system,

thereby precipitating an autoimmune reaction) has repeatedly been found to be unpersuasive and/or insufficiently

supported by present science to be reliable. See, e.g., Rowan v. Sec'y of Health & Human Servs., No. 10–272V, 2014

WL 7465661 (Fed. Cl. Spec. Mstr. Dec. 8, 2014); mot. for review den'd, 2015 WL 3562409 (Fed. Cl. 2015);

D'Angiolini v. Sec'y of Health & Human Servs., No 99–578V, 2014 WL 1678145 (Fed. Cl. Spec. Mstr. Mar. 27, 2014),

mot. for review den'd, 122 Fed. Cl. 86 (2015), aff'd, 645 F. App'x 1002 (Fed. Cir. 2016). More importantly, the version

of the flu vaccine Petitioner received does not contain an adjuvant – rendering ASIA completely irrelevant as a co-

explanatory mechanism. Dr. Gershwin himself specifically disavowed any faith in such a theory. Tr. at 141-42 (“I

personally do not believe that the adjuvants within a vaccine can cause an autoimmune disease”).

16

Safety Study on MF59 Adjuvanted Cell Culture-Derived Vaccine, Celtura During the A/H1N1

(2009) Influenza Pandemic, 30 Vaccine 6436 (2012), filed as Ex. 39 (ECF No. 41); Tr. at 143. At

hearing, Dr. Gershwin acknowledged that an existing autoimmune reaction (or infectious process)

must occur prior to the initiation of any polyclonal activation, but he did not identify what process

(if any) explained Ms. Knorr’s experience (unless it is assumed that Dr. Gershwin’s invocation of

bystander activation relied on his other mechanism of molecular mimicry occurring first). See Tr.

at 148-49.

Besides offering literature to support his theory, Dr. Gershwin cited reported cases of onset

of ANCA-associated vasculitis two to four weeks after receipt of the flu vaccine (and/or a flu wild

virus infection). Gershwin First Rep. at 23; Tr. at 112-13; Duggal (two cases of onset of ANCA-

associated vasculitis following flu vaccination, but concluding a causal role cannot be confirmed);

R. Birck, et al., ANCA-Associated Vasculitis Following Influenza Vaccination: Causal Association

or Mere Coincidence, 15 J. Clin. Rheumatol. 289-291 (2009), filed as Ex. 21 (ECF No. 41)

(“Birck”) (reporting three cases of onset of ANCA-associated vasculitis following flu vaccine, but

concluding that that it could not be determined if relationship was causal or due simply to chance);

B. Spaetgens, et al., Influenza Vaccination in ANCA-Associated Vasculitis, 24 Nephrol. Dial.

Transplant. 3258-59 (2009), filed as Ex. 44 (ECF No. 41) (“Spaetgens”) (case report detailing

temporal relapse of ANCA-associated vasculitis following flu vaccination); M. Uji, et al.,

Microscopic Polyangiits After Influenza Vaccination, 44 Intern. Med. 892-96 (2005), filed as Ex.

61 (ECF No. 41) (“Uji”) (case report detailing temporal onset of MPA in an 83-year-old patient

following flu vaccination); M. Konishi, et al., A Case of Microscopic Polyangiitis and Giant Cell

Arteritis after Influenza Vaccine, 34 Jpn. J. Clin. Immunol. 154 (2011), filed as Ex. 32 (ECF No.

41) (case report of 67-year-old patient who developed MPA and giant cell arteritis following a flu

vaccine); Wijngaarden at 2 (noting possible seasonal association between the flu wild virus and

MPA based on three case reports); see also T. Kwok, et al., Two Rare Cases of Retinal Vasculitis

Following Vaccination, 58 Scottish Med. J. E10-E12 (2013), filed as Ex. 34 (ECF No. 41)

(“Kwok”) (two case report study detailing onset of retinal vasculitis four weeks and two months

following flu vaccination).

Dr. Gershwin also noted the existence of reliable literature observing vasculitis relapse

following vaccination. See, e.g., J. Cannata, et al., Reactivation of Vasculitis After Influenza

Vaccination, 283 Br. Med. J. 526 (1981), filed as Ex. 63 (ECF No. 41); A. Kostianovsky, et al.,

Immunogenicity and Safety of Seasonal and 2009 Pandemic A/H1N1 Influenza Vaccines for

Patients with Autoimmune Diseases: A prospective, Moncentre Trial on 199 Patients, 30 Clin.

Exp. Rheumatol. S83 (2012), filed as Ex. 33 (ECF No. 41) (noting nineteen mild autoimmune

disease flares following flu vaccine administration); but see Jeffs II (flu vaccine likely safe for

existing cases of ANCA-associated vasculitis). He further submitted adverse event reports of

spontaneous vasculitis following immunizations across three international databases. See, e.g., P.

17

Felicetti, et al., Spontaneous Reports of Vasculitis as an Adverse Event Following Immunization,

34 Elsevier 6634, 6634-40 (2016), filed as Ex. 20 (ECF No. 41) (cataloging all reports of vasculitis

to EV,11 VAERS,12 and VigiBase13 between January 2003 and June 2014). Although Dr. Gershwin

categorized vasculitis as an uncommon or rare disease, he maintained that the literature cited above

supported a causal connection between the flu vaccine and vasculitis. Tr. at 112-13, 114, 121.

Dr. Gershwin next discussed the nature of autoimmune conditions and autoimmunity

generally, given the accepted principle that genetic and environmental factors can trigger

autoimmune disorders. Tr. at 94-96. He was unable to identify what specific suspected genetic

factors might be relevant to Ms. Knorr (beyond the somewhat conclusory assertion in his first

report that she likely had a “unique genetic predisposition”). Gershwin First Rep. at 24. Instead,

he emphasized possible environmental factors. Tr. at 96. Thus, given Ms. Knorr’s course of

symptoms (including hearing loss and Bell’s palsy) following the first flu vaccine, and then her

worsening hearing loss (and vasculitis diagnosis) following the second, a “striking” association

exists between Ms. Knorr’s vaccinations and her subsequent disease course. Id. at 97.

To bulwark his theory, Dr. Gershwin attempted to provide a close reading of Ms. Knorr’s

documented health course based upon the filed record. He concurred with her formal MPA

vasculitis diagnosis in November 2013, although he did point to a record suggesting a treater

expressed concerns about GPA. Tr. at 71, 88, 101, 117, 297; Gershwin Frist Rep. at 21; Ex. 18 at

666. Dr. Gershwin opined that Ms. Knorr experienced flu-like symptoms and hearing loss

following her receipt of the flu vaccine in November 2012, with additional flu-like symptoms and

a worsening of hearing loss following the second flu vaccine received in October 2013 – in turn

leading to the vasculitis diagnosis roughly a month later, in November 2013. Tr. at 89-91. The

second vaccine she received in October 2013 was essentially a “booster shot” that amplified her

aberrant immunologic reaction (already established as pathogenic in light of the first time she

received the flu vaccine), resulting in her “crescendo” of symptoms leading to her November

11

EudraVigilance (“EV”) is the European Medicines Agency (“EMA”) management system for reporting adverse

reactions to medications and drugs. EMA (along with the reporting system) is maintained by the European Union. The

database requires registration to access materials. As of June 15, 2018, the EMA’s website is currently under

construction (http://www.ema.europa.eu/).

12

The Vaccine Adverse Event Reporting System (“VAERS”) is a national warning system designed to detect safety

problems in U.S.-licensed vaccines. See About VAERS, VAERS, https://vaers hhs.gov/about html (last visited June

15, 2018). It is managed by both the CDC and the FDA. VAERS monitors and analyzes reports of vaccine related

injuries and side effects from both healthcare professionals and individuals.

13

VigiBase is a World Health Organization (WHO) database used to obtain case safety reports (ICSRs) of suspected

adverse effects of medicine, including vaccinations, collected between 1960-2017 from member countries. Currently,

110 contribute to the database. It is maintained by Uppsala Monitoring Centre in Uppsala, Sweden, on behalf of the

WHO. See What Is VigiBase?, UPS, https://www.who-umc.org/vigibase/vigibase/ (last accessed on June 15, 2018).

18

hospitalization and vasculitis diagnosis. Id. at 92, 99, 117. Thus, taking her health course as a

whole (including her symptoms following both vaccinations), Dr. Gershwin proposed that Ms.

Knorr’s onset of hearing loss following her first flu vaccine was the initial symptom of vasculitis

(given the indolent nature of the disease, its presenting limited location in the head and neck, and

its apparent stabilization following the placement of hearing tubes). Id. at 91, 115-17.

In support of these contentions, Dr. Gershwin cited a host of articles purporting to show a

connection between hearing loss and vasculitis. Gershwin Third Rep. at 2; see S. Bakthavachalam,

et al., Hearing Loss in Wegener’s Granulomatosis, 25 Otol. & Neurotol. 833, 833-34 (2004), filed

as Ex. 98 (ECF No. 42-3) (“Bakthavachalam”) (56 percent of GPA patients in a 36-person study

developed documented hearing loss); N. Rasmussen, et al., Management of the Ear, Nose, and

Throat Manifestations of Wegener’s Granulomatosis, 13 Curr. Opin. Rheumatol. 3, 4 (2001), filed

as Ex. 99 (ECF No. 42-4) (“Rasmussen”) (30 percent of GPA patients in 124-person study

developed new deafness); K. Devaney, et al., Wegener’s Granulomatosis of the Head and Neck,

107 Ann. Otol. Rhinol. 439, 440 (1998), filed as Ex. 100 (ECF No. 42-5) (“Devaney”) (ear pain,

edema, and hearing deficit are clinical manifestations of GPA); G. Hoffman, et al., Wegener’s

Granulomatosis: An Analysis of 158 Patients, 116 Ann. Intern. Med. 488, 489 (1992), filed as Ex.

101 (ECF No. 42-6) (“Hoffman”) (90 percent of GPA patients in a 159-patient study presented

with nasal, sinus, tracheal, or ear abnormalities during initial consultation for treatment). Dr.

Gershwin relied on the above articles despite the fact that they solely involved Wegener’s/GPA

(consistent with his view that MPA and GPA were largely congruent for purposes of present

analysis).14

Dr. Gershwin next discussed Ms. Knorr’s symptom progression over time, endeavoring to

pinpoint specific clinical evidence for a vaccine-induced vasculitis injury (or an inflammatory

process more generally). As mentioned earlier, Dr. Gershwin maintained that Ms. Knorr’s

November 2012 manifestation of hearing loss (and subsequent treatment with tubes) represented

the onset of her vasculitis. Tr. at 129, 152. He disputed the contention (raised by Respondent) that

Ms. Knorr’s hearing problems were attributable to a bacterial infection. Id. at 119, 127, 132;

Gershwin Third Rep. at 1. Rather, Dr. Gershwin opined that the medical record did not establish

the existence of a bacterial infection at the time (which would be evidenced by severe pain, pus,

and the treatment determination to make immediate placement of tubes or employ intensive

antibiotics). Tr. at 120.

14

Notably, one article cited by Dr. Gershwin (seeking to define the typical presenting clinical symptoms of MPA)

specifically excluded patients with ear, nose, and throat symptoms from inclusion in the study. See L. Guillevin, et al.,

Microscopic Polyangiitis, 42 Arthritis & Rheumatism 421, 422 (1999), filed as Ex. 50 (ECF No. 41).

19

Dr. Gershwin also mentioned Ms. Knorr’s ESR levels taken in October 2013, which he

asserted increased four-fold in the time period following her second vaccination and her

hospitalization (thereby establishing a rapidly-progressive inflammatory process). Tr. at 107, 120.

Although Dr. Gershwin argued that an elevated ESR can be evidence of systematic inflammation,

however, he could not explain Ms. Knorr’s course of up and down rates (as her October 2013 ESR

levels - taken two weeks post-vaccination – were normal, when compared with those taken during

her hospitalization in November). Id. at 140. He further admitted that proof of an elevated ESR

alone could not advance his overall theory. Id. at 107. At the same time, Dr. Gershwin asserted

that Ms. Knorr’s other lab results (like increased platelet levels) lent further support for his overall

opinion that Ms. Knorr was experiencing some inflammatory process that could be linked to her

vaccination (and earlier onset vasculitis) – even though her initial ESR findings, taken closer-in-

time to the second vaccination, were not elevated. Id. at 139-140, 155; Gershwin Third Rep. at 1.

In addition, Dr. Gershwin addressed Petitioner’s smile asymmetry that a June 2013 record

tangentially mentions as occurring in the time between the two vaccinations at issue herein. He

proposed that this could have been evidence of Bell’s palsy, a form of neuritis or neuropathy of

the face (although it was never formally diagnosed as such). Tr. at 92, 97; see Ex. 3 at 18, 99; Tr.

at 33-34. If so, Dr. Gershwin found this symptom to be an important potential inflammatory

marker, and thus an additional indicator of an ongoing vasculitis initiated by her initial receipt of

the flu vaccine in November 2012. Tr. at 93.

Besides offering support for his own theory, Dr. Gershwin made efforts to rebut

Respondent’s proposed alternate explanations for Ms. Knorr’s symptoms. Tr. at 104; Gershwin

Second Rep. at 1-2. He acknowledged that Ms. Knorr’s treaters had included a possible EBV

infection as an explanation for her condition in her differential diagnosis in 2013 (given relevant

testing as early as October 2013 revealed the presence of some form of EBV infection, as noted

by treaters in contemporaneous records). Tr. at 104-05, 300. Dr. Gershwin maintained, however,

that these elevated titer levels simply indicated that Ms. Knorr’s immune system had previously

been active against the EBV virus (consistent with her medical record, which revealed she had

experienced EBV-mediated mononucleosis earlier in life), rather than that she was experiencing a

new infection. Id. at 106, 147, 150. Accordingly, any EBV infection she was experiencing had

been reactivated by something else – most likely the ongoing autoimmune vasculitis, which Dr.

Gershwin maintained had begun the year before – rather than that the reactivated EBV infection

was causing her vasculitis.

To support this proposition, Dr. Gershwin emphasized literature discussing how EBV-

related antibody titer measurements should be clinically interpreted, citing an article released by

the Centers for Disease Control (the “CDC”). See Epstein-Barr Laboratory Testing, CDC,

https://www.cdc.gov/epstein-barr/laboratory-testing.html (last accessed on June 15, 2018), filed

20

as Ex. 103 (ECF No. 47-1) (“CDC Article”). The CDC Article discussed the lab testing helpful in

identifying not only whether a person suffers from an EBV infection, but also when the infection

may have begun. CDC Article at 1. To do so, it reviewed the different kinds of antibodies that will

be observed when an EBV infection exists. VCA IgM antibodies appear early in an active EBV

infection but soon disappear, whereas EBNA antibodies are not seen during the acute phase of

infection but instead arise slowly, up to two to four months after symptoms onset. Id. An individual

experiencing a current or ongoing EBV infection should test positive only for anti-VCA antigen

antibodies, whereas finding antibodies to both anti-VCA IgM and EBNA supports the conclusion

that the initiating EBV infection likely occurred several months to years earlier. Id. at 2. Because

Petitioner’s testing revealed the latter, she was more likely than not experiencing a reactivated

infection, rather than a new one that could have caused her subsequent vasculitis. Tr. at 300-01.

He added that irrespective of these results, no treater ultimately concluded that an EBV infection

was causative of her MPA. Id. at 135, 299-301, 311, 313.

Moreover, even if Ms. Knorr had been suffering from an intercurrent, recent EBV

infection, Dr. Gershwin did not deem that as undermining his theory, because the EBV infection

would at best be a secondary stimulus resulting from a pre-existing process initiated by the flu

vaccine. Tr. at 103, 135, 148; Gershwin Second Rep. at 1-2. Dr. Gershwin thus characterized EBV

as a “polyclonal B cell activator,” with the measured antibodies attributable to the autoimmune

process he alleged Petitioner was then experiencing. Gershwin Second Rep. at 1-2; Wijngaarden

at 241 (concluding there is not much support for a viral trigger for ANCA-associated vasculitis);

P. Xu, et al., Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Associated with Epstein-

Barr Virus Infection: A Case Report and Review of the Literature, 42 Infection 591, 591-92 (2014),

filed as Ex. 85 (ECF No. 41) (“Xu”). Xu is a case report discussing the onset of ANCA-associated

vasculitis in a sixteen-year-old patient, where initial lab testing indicated a serum positive IgM

antibody against EBV, but concluding that more research is required before a causal association

could be determined. Id. at 594.15

Dr. Gershwin also attempted to rebut Respondent’s assertion that Ms. Knorr’s

immunotherapy allergy injections (or any diagnosed allergy for that matter) from the summer of

2013 may have played a role in her development of vasculitis, deeming the concept a “red herring.”

Tr. at 108, 130, 136, 315-16; Gershwin Second Rep. at 1. In his view, the relevant scientific

literature does not support the conclusion that allergy shots play any part in B cell immune system

stimulation, despite various submissions by Respondent proposing a possible association. Tr. at

15

Dr. Gershwin cited additional case reports similarly concluding that a causal relationship between EBV and

vasculitis-type diseases has yet to be determined. See P. Zoroquiain, et al., Leukocytoclastic Vasculitis as Early

Manifestation of Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma of the Elderly, 34 Am. J.

Dermatopathol. 330 (2012), filed as Ex. 87 (ECF No. 41); M. Yamazaki, et al., Transient Lupus Anticoagulant Induced

by Epstein-Barr Virus Infection, 2 Blood Coag. Fib. 771 (1991), filed as Ex. 88 (ECF No. 41).

21

110; see, e.g., A. Linneberg, et al., Allergen-Specific Immunotherapy and Risk of Autoimmune

Disease, 12 J. Allergy Clin. Iummonol. Pract. 161-67 (2012), filed as Ex. 69 (ECF No. 41)

(identifying case reports and concluding evidence to support idea that allergen-specific

immunotherapy as a trigger for autoimmune diseases is weak and speculative).16 On cross, Dr.

Gershwin asserted that he was the most qualified of the experts to opine on this particular topic,

given his background in allergy medicine. Tr. at 303. Relying on this expertise, he opined that

immunotherapy injections are not designed to stimulate the immune system, although he did allow

for the possibility that any antigen could itself be a stimulant. Id. at 304. Overall, however, he

testified that the literature suggests that immunotherapy-induced vasculitis is far too rare to be a

persuasive possible explanation for Petitioner’s MPA. Gershwin Second Rep. at 1.

Finally, Dr. Gershwin asserted that the onset of Ms. Knorr’s symptoms occurred three or

four days post-vaccination in November 2012, with it progressing thereafter in accordance with

the medical record. Tr. at 121, 125. He deemed her initial hearing loss to be the first manifesting

symptom, adding that it did not matter to his theory whether that loss was discovered at the time

he alleged or even in the winter of 2013. Id. at 306. He stressed, however, that his theory was

dependent on a finding that the autoimmune process in question began with the 2012 flu vaccine.

Id. at 153-54 (describing both vaccines as “integral” to his theory).

On rebuttal, Dr. Gershwin spent some time addressing distinctions drawn by Respondent’s

expert Dr. Oddis between MPA and GPA. In his view, the overlap between the two vasculitis

variants overshadowed any clinical or diagnostic differences (and therefore it did not matter if

some of the literature he relied upon to associate Ms. Knorr’s symptoms to her MPA, like hearing

loss, mostly related to GPA). Tr. at 296. He noted as well that some treaters had suggested

Petitioner was suffering from GPA/Wegener’s, as well as the fact that treatments for either variant

would be similar. Id. at 297-99; Ex. 18 at 740-42, 769 (internal medicine progress note indicating

that rheumatology consult suggested MPA diagnosis, but internist suggested possible

Wegener’s/GPA given renal laboratory abnormalities, and treated Petitioner the same given

similarities in treatment for both diseases).

16

Similarly, Dr. Gershwin offered a series of case reports concerning immunotherapy-induced vasculitis (indicating

the rarity of such a reaction) to bolster his assertions that Ms. Knorr’s injections did not causally contribute to her

symptoms. See, e.g., M. Branco-Ferreira, et al., Distal Digital Vasculitis Induced by Specific Immunotherapy, 53

Allergy 102 (1998), filed as Ex. 71 (ECF No. 41); G. Cabrera, et al., Digital Vasculitis Following Allergic

Desensitization Treatment, 20 J. Rheumatol. 1970 (1993), filed as Ex. 72 (ECF No. 41); L. Sanchez-Morillas, et al.,

Vasculitis During Immunotherapy Treatment in a Patient with Allergy to Cupressus Arizonica, 33 Allergol. &

Immunopathol. 333 (2005), filed as Ex. 75 (ECF No. 41); P. Phanuphak, et al., Onset of Polyarteritis Nodosa During

Allergic Hyposensitization Treatment, 68 Am. J. Med. 479 (1980), filed as Ex. 81 (ECF No. 41).

22

C. Respondent’s Experts

1. Dr. Lindsay Whitton

Respondent’s first expert, Dr. Whitton, submitted one written report and testified at

hearing, proposing that the flu vaccine has not been shown to cause vasculitis, and therefore

could not have caused Petitioner’s illness. See Whitton Expert Report, dated June 6, 2016, filed

as Ex. C (ECF No. 18-3) (“Whitton Rep.”); Tr. at 165-242. Dr. Whitton’s testimony mostly

pertained specifically to Petitioner’s causation theory as opposed to the veracity of her diagnosis

or its onset, although he did occasionally address the latter points.

Dr. Whitton is currently a professor in the Department of Immunology and Microbial

Science at the Scripps Institute in La Jolla, California, and has served in this capacity since 1998.

Tr. at 158. He received his medical degree from the University of Glasgow in Scotland. Tr. at

158-59; Whitton CV, filed as Ex. D (ECF No. 18-4) at 1. He also received a Ph.D. in molecular

biology from the University of Glasgow. Whitton CV at 1. His practice consists almost

exclusively of research related to viral immunology, although he also oversees a graduate

student program focused on virology and immunology. Tr. at 160-61. Eighty to ninety percent

of his research involves immune system responses to viruses, bacteria, and live virus vaccines.

Id. He has also served on the editorial board of various academic journals focused on virology.

Id. at 162. Dr. Whitton currently serves as an editor of Virology and has published roughly 35

papers on DNA vaccines. Id. Dr. Whitton does not see patients and is not currently licensed to

practice medicine in the United States. He does not hold any specialties in disease treatment.

With regard to Petitioner’s proffered medical theory, Dr. Whitton admitted that reliable

medical literature supports the existence of (rare) vaccine-induced injuries occurring via the

biologic mechanism of molecular mimicry. Tr. at 190, 204. However, Dr. Whitton took issue

with that mechanism’s applicability to this case, since it is so dependent on an adaptive immune

response (which typically requires a boosted or adjuvanted vaccine). Id. at 191-92. The Fluarix

form of the flu vaccine Petitioner received is not adjuvanted, diminishing the likelihood that

molecular mimicry would occur at all. Id. As a result, Ms. Knorr’s reliance on an innate immune-

mediated response in this case (Tr. at 126; Gershwin First Rep. at 23) rendered it even less likely

that the flu vaccine could have initiated an autoimmune process (even though he later admitted

an “adjuvant-free preparation[]” like the flu vaccine is still sufficiently immunogenic to

function). Id. at 236, 240. Despite his assertions, Dr. Whitton did acknowledge that an innate

response “may help facilitate or amplify the adaptive response[,]” although it does not appear

that this point altered his opinion in the instant case. See id. at 192.

23

Dr. Whitton was the first expert to note the importance of Petitioner’s specific diagnosis.

He stated that he agreed with Ms. Knorr’s final diagnosis of MPA, but disputed Dr. Gershwin’s

discussion of her diagnosis as interchangeable with Wegener’s granulomatosis (or GPA). Tr. at

166, 214, 241-42; Whitton Rep. at 5-6. Rather, in his view MPA is distinguishable from GPA,

given the presence of granulomatous inflammation specific to GPA. Tr. at 241. Head and neck

symptoms (as seen in Ms. Knorr’s case) are also more common in patients with GPA than MPA,

although hearing loss can precede both forms of the disease. Id. at 215. Dr. Whitton otherwise

agreed with Dr. Gershwin that the course of MPA can be indolent (and eventually progressive),

rather than strictly acute, and can be initiated by both genetic and environmental factors. Id. at

215. He also agreed that MPA is rare, although he disputed it was as uncommon as Dr. Gershwin

seemed to suggest. Id. at 206; Whitton Rep. at 9.

Based upon his review of Ms. Knorr’s health course, Dr. Whitton asserted that her

vasculitis was likely due to an alternate cause, such as a bacterial infection. At hearing, Dr.

Whitton also offered various explanations for a viral-induced trigger, including a pre-existing

ear infection or a reactivation of an EBV infection. Tr. at 165-70, 184-88; Whitton Rep. at 6.

Dr. Whitton further opined that Ms. Knorr’s onset of allergies and subsequent immunotherapy

injections could have played some role in her eventual MPA diagnosis, although he later

admitted her symptoms were not temporally congruent with the expected allergy season. Tr. at

174-75, 213; Whitton Rep. at 7.

To support the above, Dr. Whitton identified specific examples from the medical record.

Ms. Knorr reported an onset of hearing loss in January of 2013 (or possibly a few months prior

near the end of 2012). Tr. at 165-66. But in Dr. Whitton’s reading of the records, Petitioner was

likely experiencing a bacterial infection of the middle ear during this time. Id. at 167-69, 170;

Whitton Rep. at 8, 10. For support, he pointed to records from February 2013, indicating

complaints of ear pain, redness/cloudiness in the tympanic membrane, fluid in the ear, and

antibiotic treatment. Tr. at 167. The antibiotics she was prescribed likely eradicated the

infection, but she subsequently developed noninfectious serous otitis media causing her hearing

problems (and resulting the placement of tubes to equalize pressure in the ear). Id. at 170. Dr.

Whitton also took note of a medical record indicating that Ms. Knorr had been diagnosed with

fluid behind the ear pre-vaccination in 2011. Id. at 213. Taken together, Dr. Whitton attempted

to categorize Ms. Knorr’s hearing problems (or infection) as “chronic,” despite additional later

records indicating unremarkable findings. Id.

Moving to the summer of June 2013, Dr. Whitton addressed references to an undiagnosed

Bell’s palsy-type facial asymmetry. Tr. at 171, 173. In his view, the development of these

symptoms (along with the subsequent evidence from October 2013) suggested Ms. Knorr had

possibly experienced a “recurrence or reactivation” of an EBV infection she experienced earlier

24

in life. Id. at 172-73, 181-82, 320-324; Whitton Rep. at 6-7, 9; see B. Lazarus, et al., Recent

Advances in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, 28 Indian J. Neph.

86, 89 (2016) (“Lazarus”) (categorizing infections as a “second hit” inducer of autoimmunity in

the context of the pathogenesis of AAV). If so, then during such a reactivation, Ms. Knorr would

have developed anti-EBV IgM antibodies (which subsequent testing corroborated), making

them a plausible trigger for her MPA. Tr. at 188.

For support, Dr. Whitton cited case reports indicating an associative link between the

EBV virus and vasculitis, although he admitted he could not say for sure if EBV could actually

cause the disease or its relevant subtypes, given the state of the literature (and the speculation

inherent to case reports generally). Tr. at 188, 196; G. Teng, et al., Vasculitis Related to Viral

and Other Microbial Agents, 29 Best. Prac. Res. Clin. Rheumatol. 226, 236-37 (2015), filed as

Ex. C, Tab 3 (ECF No. 19-5) (“Teng”) (citing case reports); A. Schned, et al., Fatal Relapse of

ANCA-Associated Glomerulonephritis Triggered by Successive Epstein-Barr and Varicella

Zoster Virus Infections, 47 Am. J. Kidney Dis. 915-922 (2005), filed as Ex. C, Tab 8 (ECF No.

20-3) (“Schned”) (case report detailing relapse of GPA following EBV infection, but

determining that it cannot be stated with certainty that the EBV virus caused the relapse); C.

Casiraghi, et al., Epstein-Barr Virus and Autoimmunity: The Role of a Latent Viral Infection in

Multiple Sclerosis and Systematic Lupus Erythematosus Pathogenesis, 8 Future Virology 173

(2013), filed as Ex. C, Tab 5 (ECF No. 19-7) (attempting to link EBV to the development of

autoimmunity, but concluding that there is no clear evidence establishing EBV as a trigger).17

In making this argument, Dr. Whitton directly took on Dr. Gershwin’s assertions about the

significance of Petitioner’s EBV antibody titer test results, and whether they revealed her EBV

infection to be primary or a secondary/reactivated infection from some time in her prior medical

history. Tr. at 184-88, 196; Whitton Rep. at 2, 4, 6-7.18 Dr. Whitton admitted (as per the CDC

Article) that the testing at issue revealing presence of EBV antibodies was consistent with the

17

Dr. Whitton’s report also cited additional case reports acknowledging a possible association between the EBV virus

and vasculitis, but ultimately concluding that a causal relationship has yet to be determined. See Xu (filed by Petitioner

and Respondent); T. Daikeler, et al., Fever and Increasing cANCA Titre After Kidney and Autologous Stem Cell

Transplantation for Wegener’s Granulomatosis, 64 Ann. Rheum. Dis. 646 (2005), filed as Ex. C, Tab 7 (ECF No. 20-

2); R. Ranganath et al., Crescentic Glomerulonephritis and Leucocytoclastic Vasculitis Associated With Acute EBV

Infection, 16 Nephrology 617 (2001), filed as Ex. D (ECF No. 37-1); M. Yamaguchi et al., Anti-Neutrophil

Cytoplasmic Antibody-Associated Vasculitis Associated With Infectious Mononucleosis Due to Primary Epstein-Barr

Virus Infection: Report of Three Cases, 7 Clin. Kidney J. 45 (2014), filed as Ex. E (ECF No. 37-2).

18

Dr. Whitton also noted the contradiction between Dr. Gershwin’s embrace of bystander activation as a possible

mechanism under his causation theory and the actual facts of the case. If, he reasoned, bystander activation explained

the autoimmune process that allegedly caused Ms. Knorr’s MPA, then the same tests revealing the presence of

reactivated EBV antibodies should not have come out negative for the reactivation of other infections like

cytomegalovirus (a common infection that Ms. Knorr likely would have been exposed to in the past). Tr. at 186-87.

25

latter, although he maintained that convalescence for EBV can be prolonged (weeks to months),

thus allowing for the possibility that the EBV infection had begun sometime in 2013 (even if before

that October). Tr. at 217-18; see M. Paschale, et al., Serological Diagnosis of Epstein-Barr Virus

Infection: Problems and Solutions, 12 World J. Virol. 31, 31 (2012), filed as Ex. F (ECF No. 49-

1) (“Paschale”) (finding that the presence of VCA IgM and VCA IgG without EBNA-1 IgG

suggests an acute infection, while the presence of VCA IgG only and EBNA-1 IgG without VCA

IgM suggests a past infection, and the presence of all three may be detected simultaneously in a

recent infection or during a course of reactivation).19 He otherwise questioned Dr. Gershwin’s

view that a reactivated EBV viral infection could only induce expansion of pre-existing cells

responsible for creating ANCA antibodies (i.e., exacerbate an existing autoimmune process) – it

could just as easily directly cause the process in the first place. Tr. at 196.

Dr. Whitton also deemed significant Ms. Knorr’s receipt of immunotherapy allergy

injections during the summer of 2013, although he admitted that he was “not honestly utterly

certain about the composition of the . . . shots.” Tr. at 175; see also Whitton Rep. at 7. Such

allergy shots could be a possible trigger of vasculitis, via an adjuvant contained in the shots,

such as alum. Tr. at 175-76. (This argument was later greatly undercut when Dr. Whitton

admitted that immunotherapy injections are in fact not adjuvanted (Tr. at 249)). Dr. Whitton

further disputed Dr. Gershwin’s assertion that the injections were at best homeopathic in nature,

arguing that they could be dangerous because they involve “antibody-mediated disease,” and

could result in anaphylaxis. Id. at 176-77, 237. In support, Dr. Whitton cited to various case

reports purportedly evidencing an association between immunotherapy injections and vasculitis,

although he admitted he places little weight on case reports generally. Id. at 178; see, e.g., A.

Linneberg, et al., Allergen-Specific Immunotherapy and Risk of Autoimmune Disease, 12 Curr.

Opin. Allergy Clin. Immunol. 635-39 (2012), filed as Ex. C, Tab 10 (ECF No. 20-6) (evidence

to support immunotherapy-induced autoimmune diseases is weak and based on case reports).

Overall, Dr. Whitton could not opine for sure what caused Ms. Knorr’s vasculitis. Tr. at

207. Rather, he maintained that there were too many confounding factors in her health history

to conclude that the flu vaccines caused her injury. Id. Regardless, he insisted that Ms. Knorr’s

19

Respondent was later allowed to recall Dr. Whitton to clarify his views on the CDC Article – and specifically its

statements about what conclusions could be drawn about the nature of EBV antibody test results. See generally Tr. at

320-24. He claimed that these criteria (which Petitioner stressed suggested that the proper reading of her test results

revealing the presence of EBV antibodies was that the infection was resolved rather than intercurrent) had been

revisited – but in any event that he was not maintaining that Petitioner suffered from a primary/recent infection, but

rather that the antibodies had been reactivated due to prior exposure. Id.

26

vasculitis began no earlier than October 2013 (following her second vaccination), although he

somewhat revised this view in light of her Bell’s palsy-like symptoms, which he opined could

indicate onset of symptoms as early as June 2013. Id.

2. Dr. Chester Oddis

Respondent’s second expert, Dr. Oddis, submitted one written report and testified at

hearing. Similar to Dr. Whitton, Dr. Oddis proposed that the flu vaccine has not herein been shown

to cause Ms. Knorr’s vasculitis, but he also offered testimony illuminating the precise nature of

Petitioner’s illness that bears significantly on my ultimate determination of this case. See Oddis

Expert Report, dated July 1, 2016, filed as Ex. A (ECF No. 18-1) (“Oddis Rep.”).

Dr. Oddis is board-certified in internal medicine and rheumatology Tr. at 250; Oddis CV,

filed as Ex. B (ECF No. 18-2) (“Oddis CV”). He is presently a Professor of Medicine in the

Division of Rheumatology and Clinical Immunology in the School of Medicine at the University

of Pittsburgh. Tr. at 250. He received his undergraduate degree from the University of Pittsburgh

and his medical degree from Pennsylvania State University School of Medicine. Id. at 251. Dr.

Oddis specializes in the treatment of idiopathic inflammatory myopathies. Id. at 253-54. He has

also directed large clinical myositis trials and published extensively on the topic and its correlation

with autoantibodies. Id. at 254. In addition to his teaching duties, Dr. Oddis maintains a clinical

practice. Id. at 252. Dr. Oddis testified that he sees patients at the University of Pittsburgh clinic

weekly. Id. His clinical practice includes all rheumatologic diseases, including ANCA-vasculitis

and MPA. Id. at 253. At hearing, he estimated that he has treated roughly 100 patients with ANCA-

positive vasculitis (including MPA and GPA). Id.

Consistent with Drs. Gershwin and Whitton, Dr. Oddis agreed that Petitioner suffers from

MPA vasculitis. Tr. at 259; Oddis Rep. at 4. He did not, however, accept Dr. Gershwin’s assertion

that MPA and GPA (Wegener’s) were interchangeable, given important clinical distinctions

between the two, including the presenting antibody and evidence of granulomas in tissue –

distinctions born out in Petitioner’s presentation (since, as the record establishes above, Petitioner

did not have the antibodies associated with GPA, nor did she ever display granulomas). Tr. at 259-

60, 263.

To illustrate this point, Dr. Oddis embarked on an extended explanation of the distinctions

between the two ANCA-associated variants. He characterized MPA as a p-ANCA-antibody

disease targeting the myeloperoxidase antigen in the body; GPA, by contrast, is c-ANCA-mediated

and targets the proteinase 3 antigen. Tr. at 250, 289. With GPA, moreover, a tissue biopsy would

reveal the presence of immune-mediated granulomas, while MPA is not so characterized. Id. at

260-61. In addition, MPA typically presents in an “aggressive” and acute fashion, and is not

associated with a long progressive course. Id. at 289. Finally, while both GPA and MPA can

27

manifest adverse symptoms related to kidney and respiratory function, ENT dysfunction

(including hearing loss) is rarely associated with MPA. Id. at 261-62, 264, 295. This therefore

reduced the significance, in Dr. Oddis’s estimation, of the hearing loss evidence in the medical

record cited as proof that Petitioner suffered from MPA beginning sometime between the first and

second vaccinations (although he acknowledged that such symptoms could be secondary to

different forms of vasculitis regardless). Id. at 295.

Relying on this diagnostic distinction, Dr. Oddis maintained that Petitioner improperly

relied on literature specific to GPA to support her claim (due to the recognized clinical differences

between GPA and MPA, particularly with regard to ENT symptoms). See Guillevin at 422.

Guillevin in particular specifically studied patients with MPA, and in so doing excluded GPA

patients with ENT symptoms, such as the presence of granulomas in the ear. Id. at 291-93. Much

of the other literature cited by Dr. Gershwin as establishing a causal connection between vasculitis

and hearing loss related to patients diagnosed with GPA (not MPA). Tr. at 268; see generally

Bakthavachalam; Rasmussen; Hoffman. Ms. Knorr’s diagnosis, by contrast, clearly did not include

GPA, and the medical record revealed nothing that would support such an alternative diagnosis.

Tr. at 269.

Based on a review of Ms. Knorr’s health history, Dr. Oddis proposed that her hearing loss

likely began in early 2013, and could not be associated with any symptoms relating to her

subsequent 2013 MPA diagnosis. Tr. at 264, 267, 282, 295. He described her hearing loss as

unilateral, but allowed for the possibility that in some instances it presented as bilateral. Id. at 264,

283-84. Although he could not identify a specific cause of this hearing loss, Dr. Oddis opined that

the record suggested she likely had some form of an ear infection in early 2013. Id. at 266. In

addition, Ms. Knorr’s treaters diagnosed her with “serous otitis” in 2013, and proceeded as if the

otitis were infection-induced, despite a lack of record of evidence of pus or other more obvious

indicia of infection. Id. at 267, 284-85; Oddis Rep. at 5.

In addition (and consistent with Dr. Whitton’s testimony), Dr. Oddis opined that Ms.

Knorr’s health history included too many intervening factors to conclude that the flu vaccine was

casual of her vasculitis injury (such as chronic ear infection, allergies, and the allergy shots

treatment). Tr. at 267-68; Oddis Rep. at 5-6. Dr. Oddis specifically expressed concern with the

twenty-two immunotherapy injections Ms. Knorr received in the summer of 2013, which he opined

could not be discounted as a causal agent. Tr. at 267. Immunotherapy injections may stimulate the

immune system “in some fashion or form,” although Dr. Oddis later admitted that he could not say

what specifically the injections were meant to do. Id. at 269, 289. He also acknowledged that he

lacked sufficient expertise to opine on the topic. Id. at 289. Dr. Oddis did not, however, deem Ms.

Knorr’s Bell’s palsy-type symptoms (facial asymmetry) suggested in a June 2013 record to be of

any significance, given the lack of facial nerve involvement with MPA. Id. at 270.

28

With regard to Ms. Knorr’s October 2013 symptoms, Dr. Oddis observed the discrepancy

between her severe symptomology course and her “rock solid” ESR levels when first measured in

October 2013, not long after receipt of the second flu vaccine dose. Tr. at 271; Oddis Rep. at 5-6.

According to Dr. Oddis, a normal ESR is inconsistent with a typical MPA course unless the disease

process is “better under control.” Tr. at 272. As a result, he disputed that her vasculitis could have

begun close to the time of her vaccination. Id. Rather, he opined that early November 2013 – at

which time the record revealed her elevated ESR, coupled with a now “full blown phase” of

vasculitis (and pANCA-positive antibodies) – was the more likely onset date. Id. When cross-

examined, however, Dr. Oddis did allow for the possibility of MPA developing with an initially

normal ESR rate. Id.

Similar to Dr. Whitton, Dr. Oddis found significant the fact that Ms. Knorr’s lab results

revealed increased levels of EBV autoantibodies. Tr. at 274. Such results suggested to him that

Ms. Knorr had an active EBV infection in October 2013 that also may have played a causal role

in her development of MPA. Id. Dr. Oddis admitted that the literature cited by Respondent linking

an EBV infection to ANCA vasculitis consists mainly of case reports, although he opined that they

should be given some weight. Id. at 274-75; see also Xu. Even so, Dr. Oddis agreed that he lacked

the relevant expertise to opine as to an infectious disease alternative cause for Ms. Knorr’s injuries,

and he also declined to opine on the proper interpretation of the EBV antibody measurements set

in the CDC Article. Tr. at 287-88.

Dr. Oddis made some efforts to address the sufficiency of Petitioner’s “can cause”

showing. Tr. at 275. He testified that he knew of no evidence linking the flu vaccine to ANCA

vasculitis, and thus could not accept that the flu vaccine could have caused Ms. Knorr’s injuries

without more persuasive scientific and clinical evidence. Id. He did, however, admit that some

reliable literature suggested a seasonal correlation between the timing of flu vaccinations and onset

of MPA. Id. at 280-81; see Wijngaarden at 2. He again reiterated that overall he lacked the

expertise to opine on causation. Tr. at 279.

D. Post-Hearing Expert Reports

At my direction, the parties submitted post-hearing expert reports near the end of October

2018, to further clarify an issue I deemed to be inadequately addressed at hearing. In the process

of deciding the case, I had become concerned that Petitioner’s causation theory (which by Dr.

Gershwin’s admission relied heavily on linking the two flu vaccines to her MPA, with her

intervening ENT symptoms as proof of an initial vasculitis reaction) was deficient. However, the

obvious temporal association between the second vaccination and Petitioner’s MPA still allowed

for the possibility that her injuries were vaccine-caused – if the frame for considering her claim

were shrunk. I therefore asked them to address whether (and if so, how) the second flu vaccine

29

Petitioner received in October 2013 could be solely causal of her MPA. See Scheduling Order,

dated July 19, 2018 (ECF No. 66). Below is a brief summary of the filed responses.

1. Dr. Gershwin

Dr. Gershwin filed his supplemental report on August 30, 2018. See Post-Hearing Report,

dated August 11, 2018, filed as Ex. 104 (ECF No. 69-1) at 2-3 (“Gershwin Supp. Rep.”). Assuming

(as per my direction) that Ms. Knorr’s November 2012 vaccination played no role in the

developmental of her MPA symptoms, Dr. Gershwin opined that her second flu vaccine (received

on October 8, 2013) could alone be the trigger for her MPA.

In so maintaining, Dr. Gershwin again invoked the mechanism of molecular mimicry as

the most likely process for induction of Ms. Knorr’s MPA, with her symptoms progressing as

would be expected for a vaccine-induced reaction based on that process. Gershwin Supp. Rep. at

2. Under the assumed facts, Ms. Knorr’s symptom onset following her second vaccination

(approximately fourteen days) fell squarely within the timeframe he would expect for an immune

insult subsequent to a vaccine reaction, which in his opinion, could occur within thirty days

following vaccination. Id. at 2. For this conclusion Dr. Gershwin relied heavily on the documented

medical record, which he argued showed that Ms. Knorr had presented to treaters with concerns

for influenza-type symptoms on the 15th of October, which then progressed to more concerning

symptoms (including an increased SED rate and elevated C-reactive protein levels) between

October 22nd and her November 4th hospital presentation. Id. at 3.

Dr. Gershwin also offered two additional scientific articles in support of his opinion. See

R. Falk, et al., Clinical Manifestations and Diagnoses of Granulomatosis with Polyangiitis and

Microscopic Polyangiitis, Uptodate, filed as Ex. 105 (ECF No. 69-2); Y. Cao, et al., Polymorphism

and ANCA Disease Risk in White Populations: A Metaanalysis, 42 J. Rheumatology 292 (2015),

filed as Ex. 106 (ECF No. 69-3). These articles do not address how the flu vaccine can result in an

immunologic insult to the autonomic nervous system via Dr. Gershwin’s proposed mechanism,

however, or otherwise support causation as his prior testimony and reports proposed. Rather, they

seem to have been offered to supplement his argument that MPA and GPA are indistinguishable

for causation purposes.

Dr. Gershwin also offered a reply supplemental report aimed at further rebutting the

alternative cause based theories offered by Respondent’s experts (and revisited in their own post-

hearing reports). See Post-Hearing Report Reply, filed on Oct. 29, 2018 (ECF No. 73-1)

(“Gershwin Reply”). Consistent with earlier testimony, Dr. Gershwin again asserted that Ms.

Knorr’s EBV infection was best categorized as a “reactivation” of a prior resolved infection

(resulting from a non-specific activation of the immune system – presumably caused by the flu

vaccine). Gershwin Reply at 2. Dr. Gershwin relied on articles previously submitted with his

earlier reports, but also cited one new piece of literature. See N. Obel, et al., Serological Findings

30

in Patients with Serological Evidence of Reactivated Epstein-Barr Virus Infection, 104 APMIS

424 (1996), filed as Ex. 108 (ECF No. 73-2) (simultaneous positive results for IgM and IgG-EBNA

indicates a reactivation of latent EBV infection). He also again opined that Petitioner’s

immunotherapy injections played no role in her health course given the lack of scientific evidence

causally connecting immunotherapy with vasculitis. Gershwin Reply at 1.

2. Dr. Whitton

Dr. Whitton’s post-hearing report acknowledged that Ms. Knorr’s MPA likely began

between October and November 2013 (consistent with his earlier reports), but maintained that the

October 2013 flu vaccine she received was only temporally related to the onset of her MPA. See

Post-Hearing Report, filed as Ex. G (ECF No. 71-1) (“Whitton Post-Hearing Rep.”).

Dr. Whitton again contended that there is no verifiable scientific support for a causal

relationship between flu vaccines and any form of vasculitis. Whitton Post-Hearing Rep. at 4. He

also repeated his view that Ms. Knorr’s prior EBV infection was the more likely cause of her MPA,

characterizing the antibody titer test results as reflecting either a “late primary infection” or

“reactivation” of latent EBV. Id. at 2 (citing Ex. 3 at 50, 52); Paschale at 33. Moreover, Dr. Whitton

contented that the above conclusion is strengthened by the existence of case reports associating

the EBV virus with the onset of vasculitis (and other autoimmune diseases generally). Whitton

Post-Hearing Rep. at 3-4. He cited two case reports in support of EBV-induced vasculitis (both of

which had already been filed in the matter). See generally R. Ranganath, et al., Crescentic

Glomerulonephritis and Leucocytoclastic Vasculitis Associated with Acute EBV Infection, 16

Nephrology 617 (2011), filed as Ex. G, Tab 2 (ECF No. 71-3); M. Yamaguchi, et al., Anti-

Neutrophil Cytoplasmic Antibody-Associated Vasculitis Associated with Infectious Mononucleosis

Due to Primary Epstein-Barr Virus Infection: Report of Three Cases, 7 Clin. Kindney J. 45 (2014),

filed as Ex. G, Tab 3 (ECF No. 71-4).

3. Dr. Oddis

Respondent filed one final post-hearing report from Dr. Oddis. See Post-Hearing Report,

filed as Ex. H (ECF No. 71-5). In it, Dr. Oddis opined that flu vaccine Ms. Knorr received in

October 2013 played no role in her onset of MPA (either in isolation or in the context of her first

vaccination in 2012). Id. at 2. Similar to the post-hearing report offered by Dr. Whitton, Dr. Oddis’s

report attributed Ms. Knorr’s MPA to an EBV reactivation or even the multiple immunotherapy

injections (received between August and September 2013) as the more likely antecedent triggers.

Id. In support, Dr. Oddis cited to case reports (previously filed in the matter) revealing an

associative link between the EBV virus and onset of vasculitis, and contended that in most cases

of ANCA-associated vasculitis, there is no identifiable cause. Id. He otherwise asserted that Dr.

31

Gershwin had provided no additional evidence that the flu vaccine can cause ANCA-associated

vasculitis (or did so in this case). Id. at 1.

Procedural History

Ms. Knorr filed her Petition on October 9, 2015. Pet. at 1. Almost eight months later, after

most records in the case had been filed, on July 8, 2016, Respondent filed his Rule 4(c) report

denying that Ms. Knorr was entitled to compensation. ECF No. 17. The Statement of Completion

was then filed on February 8, 2016. ECF No. 11.

Thereafter, the parties began filing expert reports. Petitioner filed an initial expert report

from Dr. Gershwin on February 19, 2016. ECF No. 41. Respondent filed an initial expert report

from Dr. Whitton on June 6, 2016, 2016. ECF No. 18-3. Following a request to supplement the

record with additional expert support, Respondent filed a second expert report from Dr. Oddis on

July1, 2016 (ECF No. 18-1). Thereafter, Petitioner filed a supplemental report from Dr. Gershwin

on August 11, 2016. ECF No. 24-1. Given the issues identified the expert reports, I scheduled this

matter for hearing on October 26-27, 2017, to determine entitlement. ECF No. 23. Prior to the

hearing, Petitioner filed a second supplemental report by Dr. Gershwin on August 11, 2017. ECF

No. 96.

The entitlement hearing was held as scheduled on October 26-27, 2017. That hearing

included testimony from the experts identified above (along with testimony from Petitioner).

Following the hearing’s conclusion, the parties submitted post-hearing briefs on November 29,

2017, and December 6, 2017, respectively. ECF Nos. 56-57. Thereafter, as noted above I contacted

the parties and requested that they file supplemental expert reports addressing whether (were I to

find that the first flu vaccine dose was not causal of Petitioner’s MPA) the second dose from

October 2013 could be solely causal, and if so how. All experts weighed in on this topic, and the

parties also filed brief additional statements explaining their positions. ECF Nos. 72, 74. The

matter is ripe for adjudication.

Applicable Law

A. Petitioner’s Overall Burden in Vaccine Program Cases

To receive compensation in the Vaccine Program, a petitioner must prove either: (1) that

he suffered a “Table Injury” – i.e., an injury falling within the Vaccine Injury Table –

corresponding to one of the vaccinations in question within a statutorily prescribed period of time

or, in the alternative, (2) that his illnesses were actually caused by a vaccine (a “Non-Table

Injury”). See Sections 13(a)(1)(A), 11(c)(1), and 14(a), as amended by 42 C.F.R. § 100.3; §

11(c)(1)(C)(ii)(I); see also Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1321 (Fed.

32

Cir. 2010); Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1320 (Fed. Cir. 2006).20

In this case, Petitioner does not assert a Table claim.

For both Table and Non-Table claims, Vaccine Program petitioners bear a “preponderance

of the evidence” burden of proof. Section 13(1)(a). That is, a petitioner must offer evidence that

leads the “trier of fact to believe that the existence of a fact is more probable than its nonexistence

before [he] may find in favor of the party who has the burden to persuade the judge of the fact’s

existence.” Moberly, 592 F.3d at 1322 n.2; see also Snowbank Enter. v. United States, 6 Cl. Ct.

476, 486 (1984) (mere conjecture or speculation is insufficient under a preponderance standard).

Proof of medical certainty is not required. Bunting v. Sec’y of Health & Human Servs., 931 F.2d

867, 873 (Fed. Cir. 1991). In particular, a petitioner must demonstrate that the vaccine was “not

only [the] but-for cause of the injury but also a substantial factor in bringing about the injury.”

Moberly, 592 F.3d at 1321 (quoting Shyface v. Sec’y of Health & Human Servs., 165 F.3d 1344,

1352-53 (Fed. Cir. 1999)); Pafford v. Sec’y of Health & Human Servs., 451 F.3d 1352, 1355 (Fed.

Cir. 2006). A petitioner may not receive a Vaccine Program award based solely on his assertions;

rather, the petition must be supported by either medical records or by the opinion of a competent

physician. Section 13(a)(1).

In attempting to establish entitlement to a Vaccine Program award of compensation for a

Non-Table claim, a petitioner must satisfy all three of the elements established by the Federal

Circuit in Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005): “(1)

a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause

and effect showing that the vaccination was the reason for the injury; and (3) a showing of

proximate temporal relationship between vaccination and injury.” Althen, 418 F.3d at 1278.

Each of the Althen prongs requires a different showing. Under Althen prong one, petitioners

must provide a “reputable medical theory,” demonstrating that the vaccine received can cause the

type of injury alleged. Pafford, 451 F.3d at 1355-56 (citations omitted). To satisfy this prong, a

petitioner’s theory must be based on a “sound and reliable medical or scientific explanation.”

Knudsen v. Sec’y of Health & Human Servs., 35 F.3d 543, 548 (Fed. Cir. 1994). Such a theory

must only be “legally probable, not medically or scientifically certain.” Id. at 549.

Petitioners may satisfy the first Althen prong without resort to medical literature,

epidemiological studies, demonstration of a specific mechanism, or a generally accepted medical

20

Decisions of special masters (some of which I reference in this ruling) constitute persuasive but not binding

authority. Hanlon v. Sec’y of Health & Human Servs., 40 Fed. Cl. 625, 630 (1998). By contrast, Federal Circuit rulings

concerning legal issues are binding on special masters. Guillory v. Sec’y of Health & Human Servs., 59 Fed. Cl. 121,

124 (2003), aff’d 104 F. App’x 712 (Fed. Cir. 2004); see also Spooner v. Sec’y of Health & Human Servs., No. 13-

159V, 2014 WL 504728, at *7 n.12 (Fed. Cl. Spec. Mstr. Jan. 16, 2014).

33

theory. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1378-79 (Fed. Cir. 2009) (citing

Capizzano, 440 F.3d at 1325-26). Special masters, despite their expertise, are not empowered by

statute to conclusively resolve what are essentially thorny scientific and medical questions, and

thus scientific evidence offered to establish Althen prong one is viewed “not through the lens of

the laboratorian, but instead from the vantage point of the Vaccine Act’s preponderant evidence

standard.” Id. at 1380. Accordingly, special masters must take care not to increase the burden

placed on petitioners in offering a scientific theory linking vaccine to injury. Contreras v. Sec’y of

Health & Human Servs., 121 Fed. Cl. 230, 245 (2015) (“[p]lausibility . . . in many cases may be

enough to satisfy Althen prong one” (emphasis in original)), vacated on other grounds, 844 F.3d

1363 (Fed. Cir. 2017). But this does not negate or reduce a petitioner’s ultimate burden to establish

his overall entitlement to damages by preponderant evidence. W.C. v. Sec’y of Health & Human

Servs., 704 F.3d 1352, 1356 (Fed. Cir. 2013) (citations omitted).21

The second Althen prong requires proof of a logical sequence of cause and effect, usually

supported by facts derived from a petitioner’s medical records. Althen, 418 F.3d at 1278; Andreu,

569 F.3d at 1375-77; Capizzano, 440 F.3d at 1326; Grant v. Sec’y of Health & Human Servs., 956

F.2d 1144, 1148 (Fed. Cir. 1992). In establishing that a vaccine “did cause” injury, the opinions

and views of the injured party’s treating physicians are entitled to some weight. Andreu, 569 F.3d

at 1367; Capizzano, 440 F.3d at 1326 (“medical records and medical opinion testimony are favored

in vaccine cases, as treating physicians are likely to be in the best position to determine whether a

‘logical sequence of cause and effect show[s] that the vaccination was the reason for the injury’”)

(quoting Althen, 418 F.3d at 1280). Medical records are generally viewed as particularly

trustworthy evidence, since they are created contemporaneously with the treatment of the patient.

Cucuras v. Sec’y of Health & Human Servs., 993 F.2d 1525, 1528 (Fed. Cir. 1993).

However, medical records and/or statements of a treating physician’s views do not per se

bind the special master to adopt the conclusions of such an individual, even if they must be

considered and carefully evaluated. Section 13(b)(1) (providing that “[a]ny such diagnosis,

conclusion, judgment, test result, report, or summary shall not be binding on the special master or

court”); Snyder v. Sec’y of Health & Human Servs., 88 Fed. Cl. 706, 746 n.67 (2009) (“there is

nothing . . . that mandates that the testimony of a treating physician is sacrosanct – that it must be

accepted in its entirety and cannot be rebutted”). As with expert testimony offered to establish a

theory of causation, the opinions or diagnoses of treating physicians are only as trustworthy as the

reasonableness of their suppositions or bases. The views of treating physicians should also be

21

Although decisions like Contreras suggest that the burden of proof required to satisfy the first Althen prong is less

stringent than the other two, there is ample contrary authority for the more straightforward proposition that when

considering the first prong, the same preponderance standard used overall is also applied when evaluating if a reliable

and plausible causal theory has been established. Broekelschen v. Sec’y of Health & Human Servs., 618 F.3d 1339,

1350 (Fed. Cir. 2010).

34

weighed against other, contrary evidence also present in the record – including conflicting opinions

among such individuals. Hibbard v. Sec’y of Health & Human Servs., 100 Fed. Cl. 742, 749 (2011)

(not arbitrary or capricious for special master to weigh competing treating physicians’ conclusions

against each other), aff’d, 698 F.3d 1355 (Fed. Cir. 2012); Caves v. Sec’y of Dept. of Health &

Human Servs., No. 06-522V, 2011 WL 1935813, at *17 (Fed. Cl. Spec. Mstr. Apr. 29, 2011), mot.

for review den’d, 100 Fed. Cl. 344, 356 (2011), aff’d without opinion, 475 Fed. App’x 765 (Fed.

Cir. 2012).

The third Althen prong requires establishing a “proximate temporal relationship” between

the vaccination and the injury alleged. Althen, 418 F.3d at 1281. That term has been equated to the

phrase “medically-acceptable temporal relationship.” Id. A petitioner must offer “preponderant

proof that the onset of symptoms occurred within a timeframe which, given the medical

understanding of the disorder’s etiology, it is medically acceptable to infer causation.” de Bazan

v. Sec’y of Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for

what is a medically acceptable timeframe must also coincide with the theory of how the relevant

vaccine can cause an injury (Althen prong one’s requirement). Id. at 1352; Shapiro v. Sec’y of

Health & Human Servs., 101 Fed. Cl. 532, 542 (2011), recons. den’d after remand, 105 Fed. Cl.

353 (2012), aff’d mem., 2013 WL 1896173 (Fed. Cir. 2013); Koehn v. Sec’y of Health & Human

Servs., No. 11-355V, 2013 WL 3214877 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for review

den’d (Fed. Cl. Dec. 3, 2013), aff’d, 773 F.3d 1239 (Fed. Cir. 2014).

B. Law Governing Analysis of Fact Evidence

The process for making determinations in Vaccine Program cases regarding factual issues

begins with consideration of the medical records. Section 11(c)(2). The special master is required

to consider “all [] relevant medical and scientific evidence contained in the record,” including “any

diagnosis, conclusion, medical judgment, or autopsy or coroner’s report which is contained in the

record regarding the nature, causation, and aggravation of the petitioner’s illness, disability, injury,

condition, or death,” as well as the “results of any diagnostic or evaluative test which are contained

in the record and the summaries and conclusions.” Section 13(b)(1)(A). The special master is then

required to weigh the evidence presented, including contemporaneous medical records and

testimony. See Burns v. Sec’y of Health & Human Servs., 3 F.3d 415, 417 (Fed. Cir. 1993) (it is

within the special master’s discretion to determine whether to afford greater weight to

contemporaneous medical records than to other evidence, such as oral testimony surrounding the

events in question that was given at a later date, provided that such determination is evidenced by

a rational determination).

Medical records that are created contemporaneously with the events they describe are

presumed to be accurate and “complete” (i.e., presenting all relevant information on a patient’s

35

health problems). Cucuras, 993 F.2d at 1528; Doe/70 v. Sec’y of Health & Human Servs., 95 Fed.

Cl. 598, 608 (2010) (“[g]iven the inconsistencies between petitioner’s testimony and his

contemporaneous medical records, the special master’s decision to rely on petitioner’s medical

records was rational and consistent with applicable law”), aff’d, Rickett v. Sec’y of Health &

Human Servs., 468 F. App’x 952 (Fed. Cir. 2011) (non-precedential opinion). This presumption is

based on the linked propositions that (i) sick people visit medical professionals; (ii) sick people

honestly report their health problems to those professionals; and (iii) medical professionals record

what they are told or observe when examining their patients in as accurate a manner as possible,

so that they are aware of enough relevant facts to make appropriate treatment decisions. Sanchez

v. Sec’y of Health & Human Servs., No. 11-685V, 2013 WL 1880825, at *2 (Fed. Cl. Spec. Mstr.

Apr. 10, 2013); Cucuras v. Sec’y of Health & Human Servs., 26 Cl. Ct. 537, 543 (1992), aff’d, 993

F.2d at 1525 (Fed. Cir. 1993) (“[i]t strains reason to conclude that petitioners would fail to

accurately report the onset of their daughter’s symptoms.”).

Accordingly, if the medical records are clear, consistent, and complete, then they should

be afforded substantial weight. Lowrie v. Sec’y of Health & Human Servs., No. 03-1585V, 2005

WL 6117475, at *20 (Fed. Cl. Spec. Mstr. Dec. 12, 2005). Indeed, contemporaneous medical

records are generally found to be deserving of greater evidentiary weight than oral testimony –

especially where such testimony conflicts with the record evidence. Cucuras, 993 F.2d at 1528;

see also Murphy v. Sec’y of Health & Human Servs., 23 Cl. Ct. 726, 733 (1991), aff’d per curiam,

968 F.2d 1226 (Fed. Cir. 1992), cert. den’d, Murphy v. Sullivan, 506 U.S. 974 (1992) (citing United

States v. United States Gypsum Co., 333 U.S. 364, 396 (1947) (“[i]t has generally been held that

oral testimony which is in conflict with contemporaneous documents is entitled to little evidentiary

weight.”)).

However, there are situations in which compelling oral testimony may be more persuasive

than written records, such as where records are deemed to be incomplete or inaccurate. Campbell

v. Sec’y of Health & Human Servs., 69 Fed. Cl. 775, 779 (2006) (“like any norm based upon

common sense and experience, this rule should not be treated as an absolute and must yield where

the factual predicates for its application are weak or lacking”); Lowrie, 2005 WL 6117475, at *19

(“[w]ritten records which are, themselves, inconsistent, should be accorded less deference than

those which are internally consistent”) (quoting Murphy, 23 Cl. Ct. at 733)). Ultimately, a

determination regarding a witness’s credibility is needed when determining the weight that such

testimony should be afforded. Andreu, 569 F.3d at 1379; Bradley v. Sec’y of Health & Human

Servs., 991 F.2d 1570, 1575 (Fed. Cir. 1993).

When witness testimony is offered to overcome the presumption of accuracy afforded to

contemporaneous medical records, such testimony must be “consistent, clear, cogent, and

compelling.” Sanchez, 2013 WL 1880825, at *3 (citing Blutstein v. Sec’y of Health & Human

36

Servs., No. 90-2808V, 1998 WL 408611, at *5 (Fed. Cl. Spec. Mstr. June 30, 1998)). In

determining the accuracy and completeness of medical records, the Court of Federal Claims has

listed four possible explanations for inconsistencies between contemporaneously created medical

records and later testimony: (1) a person’s failure to recount to the medical professional everything

that happened during the relevant time period; (2) the medical professional’s failure to document

everything reported to her or him; (3) a person’s faulty recollection of the events when presenting

testimony; or (4) a person’s purposeful recounting of symptoms that did not exist. La Londe v.

Sec’y of Health & Human Servs., 110 Fed. Cl. 184, 203-04 (2013), aff’d, 746 F.3d 1334 (Fed. Cir.

2014). In making a determination regarding whether to afford greater weight to contemporaneous

medical records or other evidence, such as testimony at hearing, there must be evidence that this

decision was the result of a rational determination. Burns, 3 F.3d at 417.

C. Analysis of Expert Testimony

Establishing a sound and reliable medical theory often requires a petitioner to present

expert testimony in support of his claim. Lampe v. Sec’y of Health & Human Servs., 219 F.3d

1357, 1361 (Fed. Cir. 2000). Vaccine Program expert testimony is usually evaluated according to

the factors for analyzing scientific reliability set forth in Daubert v. Merrell Dow Pharm., Inc., 509

U.S. 579, 594-96 (1993). See Cedillo v. Sec’y of Health & Human Servs., 617 F.3d 1328, 1339

(Fed. Cir. 2010) (citing Terran v. Sec’y of Health & Human Servs., 195 F.3d 1302, 1316 (Fed. Cir.

1999). “The Daubert factors for analyzing the reliability of testimony are: (1) whether a theory or

technique can be (and has been) tested; (2) whether the theory or technique has been subjected to

peer review and publication; (3) whether there is a known or potential rate of error and whether

there are standards for controlling the error; and (4) whether the theory or technique enjoys general

acceptance within a relevant scientific community.” Terran, 195 F.3d at 1316 n.2 (citing Daubert,

509 U.S. at 592-95).

The Daubert factors play a slightly different role in Vaccine Program cases than they do

when applied in other federal judicial for a (such as the district courts). Daubert factors are usually

employed by judges (in the performance of their evidentiary gatekeeper roles) to exclude evidence

that is unreliable and/or could confuse a jury. In Vaccine Program cases, by contrast, these factors

are used in the weighing of the reliability of scientific evidence proffered. Davis v. Sec’y of Health

& Human Servs., 94 Fed. Cl. 53, 66-67 (2010) (“uniquely in this Circuit, the Daubert factors have

been employed also as an acceptable evidentiary-gauging tool with respect to persuasiveness of

expert testimony already admitted”). The flexible use of the Daubert factors to evaluate the

persuasiveness and reliability of expert testimony has routinely been upheld. See, e.g., Snyder, 88

Fed. Cl. at 742-45. In this matter (as in numerous other Vaccine Program cases), Daubert has not

been employed at the threshold, to determine what evidence should be admitted, but instead to

determine whether expert testimony offered is reliable and/or persuasive.

37

Respondent frequently offers one or more experts of his own in order to rebut a petitioner’s

case. Where both sides offer expert testimony, a special master’s decision may be “based on the

credibility of the experts and the relative persuasiveness of their competing theories.”

Broekelschen v. Sec’y of Health & Human Servs., 618 F.3d 1339, 1347 (Fed. Cir. 2010) (citing

Lampe, 219 F.3d at 1362). However, nothing requires the acceptance of an expert’s conclusion

“connected to existing data only by the ipse dixit of the expert,” especially if “there is simply too

great an analytical gap between the data and the opinion proffered.” Snyder, 88 Fed. Cl. at 743

(quoting Gen. Elec. Co. v. Joiner, 522 U.S. 146 91997)); see also Isaac v. Sec’y of Health &

Human Servs., No. 08-601V, 2012 WL 3609993, at *17 (Fed. Cl. Spec. Mstr. July 30, 2012), mot.

for review den’d, 108 Fed. Cl. 743 (2013), aff’d, 540 Fed. App’x 999 (Fed. Cir. 2013) (citing

Cedillo, 617 F.3d at 1339). Weighing the relative persuasiveness of competing expert testimony,

based on a particular expert’s credibility, is part of the overall reliability analysis to which special

masters must subject expert testimony in Vaccine Program cases. Moberly, 592 F.3d at 1325-26

(“[a]ssessments as to the reliability of expert testimony often turn on credibility determinations”);

see also Porter v. Sec’y of Health & Human Servs., 663 F.3d 1242, 1250 (Fed. Cir. 2011) (“this

court has unambiguously explained that special masters are expected to consider the credibility of

expert witnesses in evaluating petitions for compensation under the Vaccine Act”).

D. Consideration of Medical Literature

Both parties filed medical and scientific literature in this case – Petitioner a total of over

80 separate articles - but not every filed item factors into the outcome of this decision. While I

have reviewed all of the medical literature submitted in this case, I discuss only those articles that

are most relevant to my determination and/or are central to Petitioner’s case – just as I have not

exhaustively discussed every individual medical record filed. Moriarty v. Sec’y of Health &

Human Servs., No. 2015-5072, 2016 WL 1358616, at *5 (Fed. Cir. Apr. 6, 2016) (“[w]e generally

presume that a special master considered the relevant record evidence even though he does not

explicitly reference such evidence in his decision”) (citation omitted); see also Paterek v. Sec’y of

Health & Human Servs., 527 F. App’x 875, 884 (Fed. Cir. 2013) (“[f]inding certain information

not relevant does not lead to – and likely undermines – the conclusion that it was not considered”).

ANALYSIS

I. Overview of Medical Concepts

Prior to conducting the Althen analysis integral to the resolution of Vaccine Act claims, it

is necessary to evaluate Petitioner’s diagnosis – and the ramifications of it to her claim. There is

no dispute that Petitioner was properly diagnosed in the fall of 2013 with MPA, a form of ANCA-

38

associated vasculitis. Petitioner does not have GPA, and has not been shown to have had it at any

time relevant to her claim. She did not bear one of the primary indicia of a GPA diagnosis: large-

sized granulomas. Tr. at 293. In addition, she tested positive for the p-ANCA antibodies

(associated with MPA rather than GPA). Ex. 3 at 87.

In addition to the above, Respondent’s expert, Dr. Oddis, was persuasive in demonstrating

that there is a meaningful diagnostic distinction between GPA and MPA. Dr. Oddis was the only

expert testifying in this case with some demonstrated individual expertise in the relevant

disease/illness.22 He established that MPA is not associated with ENT problems to the extent GPA

is, just as GPA has other distinct clinical criteria. Dr. Oddis’s opinion, moreover, was not only the

product of his own experience in the field, but was corroborated in literature filed in this case. See,

e.g., Greco at 839 (“[e]ye and ENT manifestations are not considered clinical symptoms of MPA

. . . .”). Indeed, Petitioner’s own literature stressing the significance of ENT symptoms in an

ANCA-associated vasculitis diagnosis consistently addressed the GPA variant, and stressed the

degree to which such ENT symptoms are associated only with GPA. See, e.g., Rasmussen at 8

(“[w]ith the [diagnostic] nomenclature, a clear distinction was made between [MPA and GPA]

according to presence (WG)23 or absence (MPA) of granulomatous involvement of the respiratory

tract”); Bakthavachalam; Devaney; Hoffman.

Despite the above, Dr. Gershwin proposed that the distinction between GPA and MPA was

irrelevant for purposes of resolving entitlement. I grant his point that the MPA/GPA distinction is

not so total that it fully defeats Petitioner’s causation theory. Nevertheless, the distinction

negatively impacts large aspects of Petitioner’s case, as discussed in more detail below.

II. Petitioner Has Not Carried Her Burden of Proof

A. Petitioner Has Not Established That Her Symptoms Before October 2013 Were

More Likely Than Not Related to Her Subsequently-Diagnosed Vasculitis

22

By contrast, Dr. Gershwin (despite his demonstrated immunologic credentials) clearly lacks specialized expertise

on the subject of vasculitis. Indeed, he has previously been criticized for opining on vasculitis without a sufficient

grounding in the subject. See, e.g., Schoeberlein v. Sec’y of Health & Human Servs., No. 14-697V, 2018 WL 945843,

at *1 (Fed. Cl. Spec. Mstr. Jan. 11, 2018) (“Dr. Gershwin’s relative unfamiliarity with GPA appeared to affect his

opinion as he changed/revised/clarified his written reports during his oral testimony. Overall, Dr. Gershwin’s

presentation and demeanor reduced his credibility.”). I have taken into account his points on these topics nevertheless,

but I give his assertions on them less weight given his lack of demonstrated training or consistent familiarity with

vasculitides generally.

23

Rasmussen, a 17-year-old article, refers to GPA by its more classic term “Wegener granulomatosis” or WG.

Rasmussen at 3.

39

Based upon my review of the medical record, and in light of the established distinction

between MPA and GPA, I do not find that Petitioner successfully established that her demonstrated

ENT symptoms (beginning in late 2012 or early 2013, and then recurring throughout 2013 up to

the time she received a second flu vaccine dose) were connected to the more acute symptoms she

experienced after that second dose, which were ultimately the basis for her MPA diagnosis.

Dr. Oddis’s reading of the medical record was persuasive in suggesting that Petitioner’s

MPA began in late October/early November 2013, and that her prior symptoms were not

reasonably associated with that form of vasculitis. In addition, evidence such as the normal ESR

that Petitioner first presented with – followed by a much higher, abnormal ESR level from around

the time treaters suspected Ms. Knorr suffered from MPA after she tested positive for ANCA

antibodies – was consistent with Dr. Oddis’s view that MPA commonly presents in an acute but

nonprogressive fashion. See Tr. at 261-62, 264, 267-69 271-72, 282, 294-95; Oddis Rep. at 5-6.

No treater ever diagnosed Petitioner with GPA either (and the record does not suggest that her

ENT symptoms would support such a diagnosis, given the absence of relevant clinical criteria such

as granulomas or the particular autoantibodies more closely associated with GPA).

There is also a lack of credible evidence that Petitioner’s MPA began before October 2013,

even if I accept Dr. Gershwin’s argument that the chronic ENT symptoms could still be associated

with MPA. Dr. Gershwin did not (at least in the context of Ms. Knorr’s health history after the

November 2012 vaccination) persuasively establish that her ENT symptoms could be deemed

evidence of early vasculitis, given his overall lack of specific expertise with the condition coupled

with his overreliance on literature describing GPA symptoms. See, e.g., Bakthavachalam;

Rasmussen; Devaney; Hoffman.

I acknowledge that the existing record does not clearly establish an etiology for Ms.

Knorr’s demonstrated persistent hearing and inner ear symptoms,24 nor did Respondent succeed in

offering a persuasive alternative explanation for these symptoms with preponderant evidence.25

24

Both sides also attempted to define as significant the allusion in Petitioner’s medical records from June 2013 to a

possible Bell’s palsy-related symptom occurring between her two vaccinations (Ex. 3 at 18, 99), but neither was

persuasive. The one-time reference to a crooked smile is too ambiguous to give it the significance either side urges,

and subsequent records do not corroborate it as meaningful to Petitioner’s diagnosis. Indeed, Dr. Oddis was persuasive

in establishing that such a facial neuropathic symptom would be a presenting clinical feature of MPA. Tr. at 270.

25

I do not find, however, that the first flu vaccine plausibly explains these symptoms – regardless of whether they

were related to her vasculitis or not. Although the record reveals Petitioner experienced flu-like symptoms within a

week of vaccination in November 2012, her ENT symptoms did not begin until approximately a month later (based

on her report of them starting a month before her January 2013 doctor’s visit). Ex. 3 at 1; Ex. 8 at 1-3. The initial post-

vaccination symptoms have not persuasively been related to Petitioner’s December or January onset of ear infection

symptoms. And although infection has not been preponderantly established as an alternative explanation for

Petitioner’s symptoms, it has not been effectively rebutted by Petitioner either, thus weakening her showing that the

vaccine best explains those symptoms. See, e.g., Parsley v. Sec’y of Health & Human Servs., No. 08-781V, 2011 WL

40

But the disposition of Petitioner’s claims does not require Respondent to do so. Rather, to the

extent Petitioner’s theory depended on linking the two flu vaccines to her MPA, relying on the

intervening ENT symptoms to do so, she was tasked (as part of her overall evidentiary burden)

with providing a plausible explanation for the linkage – and the explanation she offered did not

meet that test. Petitioner did not otherwise establish that the November 2012 flu vaccine could

cause her ENT symptoms even if they were not related to her subsequent vasculitis (and indeed

largely did not attempt to do so). Accordingly, I do not find on this record that Petitioner’s theory

could succeed based on connecting the prior vaccination to the October 2013 vaccination and

subsequent MPA.

B. Petitioner’s First Flu Vaccine Was Not Likely Causal of Her MPA

As already noted, Petitioner’s overall theory relied heavily on associating the November

2012 flu vaccine she received with her subsequent ENT symptoms, which Dr. Gershwin argued

evidenced nascent vasculitis. See, e.g., Tr. at 91-92, 99, 115-17, 153; Gershwin Third Rep. at 2.

But in so maintaining, he cited literature discussing GPA symptoms. See, e.g., Bakthavachalam at

833-34; Rasmussen at 4; Devaney at 440; Hoffman at 489. In contrast, Respondent persuasively

established that such symptoms are not as commonly associated with MPA, Petitioner’s actual

diagnosis. In addition, the record is unhelpful to Petitioner on this point; testing does not support

GPA as an alternative diagnosis for Petitioner, and no treaters ever proposed that her ENT

symptoms reflected the onset of Petitioner’s vasculitis. At best, treaters speculated (based on what

she reported to them) that she had experienced a prior reaction to the flu vaccine that may have

recurred in 2013. But such treater views appear to have been the product of reaction to her reported

medical history rather than an informed view based on objective proof, like examination or test

results.

Accordingly, Petitioner has not established with preponderant evidence that her November

2012 flu vaccine caused her MPA diagnosed a year later.

C. Petitioner Has Not Preponderantly Established

That the October 2013 Flu Vaccine Caused Her MPA

Because I have determined that Petitioner’s initial ENT symptoms were not related to her

subsequently-diagnosed MPA,26 and that the 2012 flu vaccine dose was not otherwise causal of

2463539, at *14 (Fed. Cl. Spec, Mstr. May 27, 2011) (citing de Bazan v. Sec’y of Health & Human Servs., 539 F.3d

1347, 1353-54 (Fed. Cir. 2008)).

26

As a result, Petitioner lacks a viable claim that the second flu vaccine significantly aggravated an existing case of

MPA that had already begun (whether or not the earlier vaccine had anything to do with it). Loving v. Sec’y of Health

& Human Servs., 86 Fed. Cl. 135, 144 (2009) (setting forth prongs required to successfully establish significant

41

those symptoms or her MPA, Petitioner is left with establishing that the October 2013 dose was

enough to cause this form of ANCA-associated vasculitis. In an attempt to provide Petitioner the

fullest opportunity possible to prove her case, I offered her the chance to propose an alternative

causation theory based solely on the second vaccine dose. Although there is record evidence that

supports this alternative causation theory, I nevertheless conclude that Petitioner has not met the

preponderant, “more likely than not” test for establishing entitlement, for the reasons set forth

below.

1. Althen Prong One - Petitioner has proposed that the mechanistic process of

molecular mimicry between components of the flu vaccine and self structures could initiate MPA,

and Dr. Gershwin relied on the same mechanism when proposing a causation theory limited to

Petitioner’s 2013 vaccination.27 Petitioner’s Prehearing Submission, dated July 14, 2017, at 9;

Gershwin Supp. Rep. at 2-3. As a general matter, such a theory has been successfully offered in

other Program cases involving molecular mimicry between protein components in a vaccine (here,

the flu vaccine) and human peptides, resulting in a cross-reaction where antibodies produced in

reaction to the vaccine mistakenly attack self-structures, causing harm.28 The question is whether

this theory is scientifically plausible when invoked in the context of ANCA-associated vasculitis.

The first significant limitation to applying such a mechanism in this case is a lack of reliable

medical or scientific literature associating the flu vaccine with MPA. For molecular mimicry to be

a credible mechanistic explanation for how the flu vaccine could cause MPA, there should be some

evidence that the ANCA antibodies that drive the resulting vasculitis are produced as a result of

vaccination – and it is reasonable to require a petitioner to offer some evidence in support of such

a contention when evaluating the success of the claimant’s prong one showing. See, e.g., W.C. v.

Sec’y of Health & Human Servs., 704 F.3d 1352, 1361 (Fed. Cir. 2013) (upholding special master’s

rejection of molecular mimicry theory where petitioner provided no persuasive evidence

establishing that a specific peptide in the vaccine at issue was capable of cross-reacting with

specific proteins in the body); Hunt v. Sec’y of Health & Human Servs., 123 Fed. Cl. 509, 523-34

(2015) (discussing W.C.; special master properly denied entitlement where petitioner could not

aggravation). It does not appear that Petitioner intended to plead or prove such a claim, however. See Petitioner’s

Prehearing Submission, dated July 14, 2017, at 1, 8, 9-10 (ECF No. 35).

27

While petitioners need not prove a particular mechanism as part of their Althen first prong showing, where they

propose a theory and attempt to substantiate it, a special master may reasonably evaluate if they have successfully

done so, and weigh that showing as part of the overall evidentiary weighing that applies to each Althen prong. Althen,

418 F.3d at 1278.

28

The flu vaccine, for example, has been associated with a number of autoimmune conditions (like GBS), and has

been shown to be able to initiate such a process via the biologic mechanism of molecular mimicry. See, e.g., Tompkins

v. Sec’y of Health & Human Servs., No. 10-261V, 2013 WL 3498652, at *22 (Fed. Cl. Spec. Mstr. June 21, 2013)

(“[t]he molecular mimicry theory is the one most widely accepted for the agents most frequently accepted as causal”),

mot. for review den’d, 117 Fed. Cl. 713 (2014).

42

show the “particular parts” of the vaccine implicated as having cross-reactivity potential under a

molecular mimicry/bystander activation theory). Here, however, Dr. Gershwin admittedly could

not identify the antigenic source in the flu vaccine for this autoimmune process, and cited no

medical or scientific literature involving experimentation on this subject. See Tr. at 119, 143, 151.

The most scientifically robust evidence that Petitioner offered in connection with this

assertion, Jeffs I, proposed only that some form of viral RNA found in certain versions of the flu

vaccines could contribute to the development of a particular ANCA antibody. But Dr. Gershwin

did not establish that the versions of the flu vaccines evaluated in Jeffs I were comparable to the

Fluarix version at issue herein – while admitting he personally did not find this particular theory

all that persuasive in any event. Tr. at 143. He also did not show that the antibody at issue in Jeffs

I is relevant to MPA – and in fact literature filed in this case suggests it is mainly GPA-associated.

See, e.g., Greco at 840; Guillevin at 424. And there is nothing post-Jeffs I in the literature filed in

this case suggesting that this theory has found corroboration (indeed, Jeffs I’s authors seem to

disavow Petitioner’s entire theory that the second flu vaccine could cause an acute upswing in the

severity of her vasculitis that was brought on in the prior year). Jeffs II at 343, 347-48, 349-50.

Dr. Gershwin offered some general scientific evidence suggesting the flu vaccine has been

associated with vasculitis in other regards, but it too fails to link with other elements of his

causation theory. See, e.g., Wijngaarden at 238; Spaetgens at 1. Spaetgens, for example, is a case

report involving a patient with active glomerulonephritis (a syndrome characterized by rapid renal

failure that can accompany ANCA-associated vasculitis) who suffered a relapse following flu

vaccine administration. Spaetgens at 1. Spaetgens’s authors opined that by activating antigen-

presenting cells expressing proteinase-3 (once again, the GPA-associated antibody discussed in

Jeffs I), the flu vaccine caused a secondary exacerbation of the existing glomerulonephritis, via

nonspecific B and T cell stimulation (akin to bystander activation). Id. Spaetgens, however, not

only runs counter to other literature filed in this case (e.g., Jeffs II) suggesting that the flu vaccine

likely does not exacerbate vasculitis, but it also embraces a secondary pathologic mechanism that

requires some initial autoimmune instigating process that has not been identified as occurring

herein. And Dr. Gershwin has been criticized for proposing bystander activation as a primary

mechanism for explaining an alleged link between the flu vaccine and vasculitis. See Schoeberlein

v. Sec’y of Health & Human Servs., No. 14-697V, 2018 WL 945843 (Fed. Cl. Spec. Mstr. Jan. 11,

2018) (denying entitlement where petitioner alleged a flu/GPA injury).

Petitioner otherwise heavily relies on case reports associating forms of the flu vaccine with

different types of vasculitis – but this category of evidence poses problems large and small. It is

well recognized that case reports are deserving of some evidentiary weight. Paluck v. Sec’y of

Health & Human Servs., 104 Fed. Cl. 457, 475 (2012) (noting that although “case reports ‘do not

purport to establish causation definitively, and this deficiency does indeed reduce their evidentiary

43

value’ . . . ‘the fact that case reports can by their nature only present indicia of causation does not

deprive them of all evidentiary weight’”) (quoting Campbell v. Sec’y of Health & Human Servs.,

97 Fed. Cl. 650, 668 (2011)). However, substantial authority also notes that case reports are not

robust evidence favoring causation (even under the Program’s comparatively lenient

preponderance evidentiary standard). W.C. v. Sec’y of Health & Human Servs., No. 07-456V, 2011

WL 4537887, at *13 (Fed. Cl. Spec. Mstr. Feb. 22, 2011) (“case reports are generally weak

evidence of causation because case reports cannot distinguish a temporal relationship from a causal

relationship”), mot. for review den’d, 100 Fed. Cl. 440 (2011), aff’d, 704 F.3d 1352 (Fed. Cir.

2013); Caves v. Sec’y of Health & Human Servs., No. 07-443V, 2010 WL 5557542, at *14 (Fed.

Cl. Spec. Mstr. Nov. 29, 2010) (“case reports do[] not help [petitioners] meet [their] burden of

demonstrating a persuasive and reliable theory causally connecting” vaccine to injury), mot. for

review den’d, 100 Fed. Cl. 119 (2011), aff’d, 463 F. App’x 932 (Fed. Cir. 2012); Shepperson v.

Sec’y of Health & Human Servs., No. 05-1064V, 2008 WL 2156748, at *11 (Fed. Cl. Spec. Mstr.

Apr. 30, 2008) (a single case report is not “sufficiently probative to begin the evidentiary climb to

a preponderance”); Muchnik v. Sec’y of Health & Human Servs., No. 90-703V, 1991 WL 217673,

at *4 (Fed. Cl. Spec. Mstr. Oct. 10, 1991) (“[f]or petitioner to establish causation in fact by a

preponderance of the evidence in any given case requires something more than case reports . . .

.”). There is accordingly risk in overreliance on case reports, especially where (as here) other prong

one causation proof is ambiguous or lacking.

Beyond such general failings as a category of evidence, the specific case reports at issue

are not individually all that helpful to Petitioner. Uji, for example, describes one patient’s onset of

MPA symptoms seven days following a flu vaccination (a timeframe comparable in certain

respects to that of this case). Uji at 892. The explanatory section contained therein, however, is

speculative, characterizing the flu vaccine’s relationship to MPA as only a “possible association.”

Id. at 895. The remainder of Petitioner’s case reports are equally speculative. See, e.g., Duggal at

1 (two-patient study noting a “causal role of vaccines in AAV cannot be confirmed with these case

reports”); Birk at 290 (three patient “case series cannot reliable differentiate between spontaneous

of vaccination triggered vasculitis disease activity”). And it is this kind of case report evidence

that larger review articles rely on when mentioning a possible association between the flu vaccine

and any form of vasculitis – not independent research. See, e.g., Wijngaarden at 238, 246 (citing

three case reports, including Uji). By contrast, other potential causes of ANCA-associated

vasculitis discussed in review articles like Wijngaarden have far more facially-valid scientific

support. Id. at 239-44, 246 (discussing scientific research supporting role of silica or

microbial/bacterial infections as playing a causative role in pathogenesis of ANCA-associated

disease); see also Teng (discussing potential role of Hep B and Hep C infection as trigger for

vasculitis generally); Lazarus (discussing causal role of staph or E. coli infection as trigger for

ANCA-associated vasculitis).

44

Such spotty evidence for Petitioner’s causation theory could have been imbued with greater

heft if an expert with sufficient grounding in ANCA-associated vasculitis, or expertise studying

the flu vaccine’s capacity to cause an autoimmune injury, had offered opinions in this case,

allowing that expertise to bind these less-probative evidentiary items into a greater whole. But

Petitioner relied solely on Dr. Gershwin, and he was unable to accomplish this task.

Unquestionably Dr. Gershwin was qualified to opine on immunologic matters, and his

demonstrated expertise on such fronts required me to take seriously his opinion. But that opinion

was ultimately rooted in topics in which he is less well-versed, such as the disease in question –

something that was underscored in his unpersuasive insistence (rebutted by Dr. Oddis) that I should

ignore distinctions between GPA and MPA. Indeed, even when directed to evaluate causation

based solely on the October 2013 vaccine (and thus to take note of my likely finding that

Petitioner’s earlier symptoms were not consistent with her subsequent diagnosis), he continued to

so assert, without also offering any additional evidence that would strengthen his underlying claim

about how the flu vaccine might produce MPA-associated antibodies. See, e.g., Gershwin Supp.

Rep. at 2-3.29 At bottom, an expert who has no direct experience studying the pathogenesis of

ANCA-associated vasculitis will generally not be overly persuasive in opining on that very subject.

Overall, I do not find that Petitioner’s “can cause” evidentiary showing was sufficient. The

concept that a vaccine could cause MPA is hardly beyond the pale, and may in the future be more

successfully established with some additional scientific or medical evidence providing a more

reliable basis for concluding that production of the ANCA antibodies central to this form of

vasculitis (rather than to GPA) are promoted by the flu vaccine, or that the immune-stimulating

properties of vaccination generally are enough to promote their existence in genetically-susceptible

individuals. But Petitioner offered mechanisms that were not reliable, relied on case reports rather

than verifiable research or scientifically-derived data, and utilized an expert whose reach exceeded

his grasp given the nature of the injury at issue in this case.

2. Althen Prongs Two and Three – My finding on the weakness of Petitioner’s

modified causation theory based only on the October 2013 vaccination makes it unnecessary to

discuss at length Petitioner’s showings under the other two Althen prongs. See, e.g., Veryzer v.

Sec’y of Health & Human Servs., No. 06-522V, 2011 WL 1935813, at *17 (Fed. Cl. Spec. Mstr.

29

The low weight I ultimately am assigning to Dr. Gershwin’s opinion and testimony was not the product of the

effectiveness of Dr. Whitton’s rebuttal testimony. Dr. Whitton (like Dr. Gershwin, a credentialed expert whose

testimony is often of great utility in Program cases) did effectively point out certain deficiencies in Petitioner’s theory

(for example, that the state of the medical literature does not support a link between the flu vaccine and AAV (relying

on Wijngaarden, Teng, and Lazarus). In this case, however, he devoted more time trying (in vain, as discussed below)

to establish alternative causes for Petitioner’s condition or to explain her ENT symptoms, and like Dr. Gershwin his

testimony frequently veered into matters that fell outside his immediate expertise. Because it is ultimately a petitioner’s

burden to prove causation, however, Dr. Gershwin’s inability to unify the disparate items of proof offered into a single

persuasive causation theory is what causes me to determine that the first Althen prong has not been met.

45

Apr. 29, 2011), mot. for review den’d, 100 Fed. Cl. 344 (2011). I will nevertheless briefly consider

Petitioner’s success in establishing each.

First, Ms. Knorr has not successfully demonstrated with preponderant evidence that the

October 2013 flu vaccine likely caused any symptom she experienced – although there is

considerably more probative evidence on this prong than on the first, “can cause” prong, making

it a closer question.30

The medical record does establish that a few days after vaccination, Petitioner began to

experience flu-like symptoms that she believed were comparable to how she felt after the flu

vaccine the year before, followed by an inflammatory process later than same month that

eventually led to the onset of her MPA. But this ultimately only establishes a temporal association

(vaccine followed by illness), which black letter law in the Vaccine Program establishes as an

insufficient basis for the conclusion that the vaccine in fact caused her injury. See, e.g., Lalonde v.

Sec’y of Health & Human Servs., 746 F.3d 1334, 1341 (Fed. Cir. 2014) (“a temporal correlation

alone is not enough to demonstrate causation”). There is also some treater opinion suggesting the

vaccine was a possible trigger for her symptoms, but it seems to be attributable to views expressed

to the treater by the Petitioner, rather than to reflect the treater’s reasoned view. See, e.g., Ex. 3 at

116, 118. The record references to the flu vaccine as “causing” her MPA are otherwise too

conclusory to give much weight, or (like Petitioner’s initial theory) rely on associating her earlier

ENT symptoms with her subsequently-diagnosed vasculitis. Nevertheless, this kind of evidence

supports Petitioner’s claim.

In addition, there also appears to be no clearly-identified possible alternative infectious

explanation for Petitioner’s MPA (other than her chronic ENT symptoms, which could have been

viral in nature, although no clear etiology for them has been established either). Tr. at 153 (Dr.

Gershwin admitting that he would more closely scrutinize causation (given the facts) in light of

any pre-existing viral illness Petitioner may have had during the preceding year). The proposal

that an EBV infection caused Ms. Knorr’s MPA was certainly not established with preponderant

evidence. At best, the record demonstrates that Petitioner experienced some kind of reactivation

of an EBV infection that October (something treaters also found significant), but I cannot conclude

from the record what reactivated it – or more importantly, whether an EBV infection could cause

MPA in the first place, given Respondent’s reliance on the same weakly probative kind of evidence

(case reports) that I critique above in my Althen prong one discussion. See, e.g., Xu; Daikeler;

30

I do not find, however (as discussed below), that Petitioner’s Althen two showing was sufficiently a “close call”

such that it should be decided in her favor based on the Vaccine Program’s goals. I am merely stating that (in

comparison to prong one) Petitioner made a stronger Althen two showing in light of the medical record.

46

Schned; Ranganath; Yamaguchi; Tr. at 188; see also Whitton Rep. at 6-7.31 Petitioner was,

however, more persuasive than Respondent in her argument that her allergy shots were unlikely

related to the more severe symptoms she later experienced. See Tr. at 175-76, 249.

But the lack of a persuasive alternative explanation for the cause of Petitioner’s MPA does

not amount to Petitioner having carried her burden of proof. See, e.g., Grant v. Sec’y of Health &

Human Servs., 956 F.2d 1144, 1149-50 (Fed. Cir. 1992) (“evidence showing an absence of other

causes does not meet petitioner’s affirmative duty to show actual or legal causation”). On the

contrary, the record does not allow for the conclusion of something central to a finding in

Petitioner’s favor: that the October 2013 flu vaccine resulted in the production of the ANCA

antibodies necessary for the illness. The many intervening factors, from the EBV reactivation

infection to Petitioner’s ongoing ENT symptoms, further muddy the waters (even though they have

not persuasively been demonstrated to explain her MPA). At best, the record suggests that

Petitioner experienced a variety of flu-like symptoms (and/or a continuation of her prior

unexplained ENT and hearing problems) within one to two weeks after the second vaccination.

Initial testing did not reveal an immediate, existing inflammatory process (given the normal ESR),

but hinted at a possible EBV infection reactivation. See Ex. 3 at 50. By November 2013 her

symptoms had become something that looked like MPA, as subsequent testing (and input by

treaters with experience specific to vasculitis) confirmed, with the inflammatory process she was

experiencing becoming far more active and alarming. This is generally consistent with the course

of MPA – but not corroborative of the conclusion that the MPA was vaccine-caused.

Given the above (and taking into account my prior finding that the Petitioner has not

established in this case that the flu vaccine “can cause” MPA), I cannot conclude that the October

2013 flu vaccine caused Petitioner’s actual case of MPA. Beyond the temporal association, the

record is too ambiguous as to what could have been the source of her illness (an intercurrent

infection; the reactivated EBV infection; her chronic otitis media), and there is not enough

evidence that would suggest Petitioner had more than a transient reaction to the vaccine.

31

The parties spent an unnecessary amount of time quibbling over the proper interpretation of the CDC Article and

whether Petitioner’s EBV titers supported a finding that her infection was ongoing/new, convalescent, or merely an

old reactivated infection. See Tr. at 217-18, 320-24. Based on the scientific support offered of both experts, the

literature suggests that Petitioner’s EBV antibody titers most likely were not evidence of an acute (or new) infection,

but could reflect a reoccurrence (rendering it an inconclusive trigger) – a point Dr. Whitton ultimately seems to have

accepted. See id. at 217-18, 320-24; Whitton Post-Hearing Rep. at 2. Dr. Gershwin’s arguments that a reactivated

infection could not be pathogenic and/or was most likely a product of Petitioner’s ongoing vasculitis were not

particularly persuasive, but Respondent’s larger point about the significance of the EBV infection was itself not carried

by sufficient preponderant evidence to conclude it could be an “alternative cause” for her MPA. See, e.g., Hazelhurst

v. Sec’y of Health & Human Servs., No. 03-654V, 2009 WL 332306, at *18 (Fed. Cl. Spec. Mstr. Feb. 12, 2009)

(discussing evidentiary standards for establishing an alternative cause), mot. for review den’d, 88 Fed. Cl. 473 (2009),

aff’d, 604 F.3d 1343 (Fed. Cir. 2010).

47

In so finding, although I have acknowledged the existence of evidence favoring Petitioner’s

position, I do not find that this presents a close case that should be resolved in her favor. See Althen,

481 F.3d at 1280. Petitioner’s weaker showing on the first Althen prong simply makes it far more

difficult for me to find that the mere temporal association between the October 2013 vaccine and

illness onset is proof of a “logical sequence of cause and effect.” Without having successfully

established how the flu vaccine could cause MPA, I cannot look at this record and conclude it did

so here – as there is little that can be pointed to from the record establishing that the flu vaccine

was causing Petitioner’s MPA . See, e.g., Hunt v. Sec’y of Health & Human Servs., No. 12-232V,

2015 WL 1263356, at *23 (Fed. Cl. Spec. Mstr. Feb. 23, 2015) (finding a petitioner who has not

established the “can cause” prong, cannot “as a matter of logic” establish the “did cause” prong)

(citing Veryzer v. Sec’y of Health & Human Servs., 100 Fed. Cl. 344, 352-53 (2011), aff’d without

op., 475 F. App’x 765 (Fed. Cir. 2012)), mot. for rev. den’d, 123 Fed. Cl. 509 (2015); see also

Caves, 100 Fed. Cl. at 145 (categorizing Althen prong one as “logically antecedent” to Althen

prong two).

I do, however, find that the third Althen prong has been met. As I have determined, Ms.

Knorr’s hearing and ENT-related symptoms from late 2012 into 2013 are not likely precursor

symptoms of her later-diagnosed MPA – rendering this timeframe largely irrelevant. But in

response to my invitation, Petitioner proposed alternatively that her symptoms following the

second vaccination could alone reasonably be connected to the form of vasculitis she has

experienced, given the acute nature of onset which has been successfully demonstrated to be a

hallmark of MPA (as confirmed by Dr. Oddis). Tr. at 289; see E. Ntatsaki, et al., Epidemiology of

ANCA-Associated Vasculitis, 36 Rheum. Dis. Clin. N. Am. 447, 453 (2010), filed as Ex. C, Tab

12 (ECF No. 20-7) (dominant feature of MPA is “rapidly progressive renal failure”).

The evidence in this case about the actual onset of Petitioner’s symptoms accords with the

timeframe proposed under Petitioner’s theory, and the many case reports she filed (despite their

unpersuasive character in establishing causation) involve onset in a time period of days to months

after vaccination, consistent with her own experience - although close inspection of those case

reports reveals that onset varies depending on the type of vasculitis experienced. See, e.g., Birck

at 289-90 (onset of two to three weeks for GPA injury); Duggal at 175 (onset of two days to four

weeks for AAV injury); Kwok at E11 (onset of four weeks to two months). The above is sufficient

to support the conclusion that Petitioner’s MPA began in a medically appropriate timeframe

consistent with her causation theory. Of course, the fundamental deficiencies in that same theory

mean that the reasonableness of a timeframe based upon it cannot save the claim.

48

CONCLUSION

Ms. Knorr has credibly established that the health problems she has unquestionably

suffered (including but not limited to her MPA) have negatively impacted her daily life, and I have

genuine sympathy for her struggles. She has also offered probative evidence in support of her

claim – particularly with respect to linking the second flu vaccine dose to her vasculitis. But the

preponderant test has not been met. Here, the evidentiary record does not support her contention

that any of the flu vaccine dose

This text is long and has been trimmed here. Open the source document for the complete record.