Volpe v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 16-1422V

Filed: October 12, 2022

PUBLISHED

Special Master Horner

SHARON VOLPE,

Petitioner, Cause-in-Fact; Significant

v. Aggravation; Denial of

Entitlement; Influenza Vaccine;

SECRETARY OF HEALTH AND Undifferentiated Connective

HUMAN SERVICES, Tissue Disease (UCTD)

Respondent.

Jeffrey A. Golvash, Golvash & Epstein, LLC, Pittsburgh, PA, for petitioner.

Ryan Daniel Pyles, U.S. Department of Justice, Washington, DC, for respondent.

DECISION DENYING ENTITLEMENT 1

On October 28, 2016, petitioner filed a petition under the National Childhood

Vaccine Injury Act, 42 U.S.C. § 300aa-10-34 (2012), 2 alleging that the influenza (“flu”)

vaccine she received on November 8, 2013, caused her to suffer undifferentiated

connective tissue disease (“UCTD”). (ECF No. 1, p. 1.) Petitioner later amended her

petition to allege that she suffered significant aggravation of either Hashimoto’s

thyroiditis (“HT”) and/or UCTD. (ECF No. 25, p. 2.) For the reasons set forth below, I

conclude that petitioner is not entitled to compensation.

I. Applicable Statutory Scheme

Under the National Vaccine Injury Compensation Program, compensation

awards are made to individuals who have suffered injuries after receiving vaccines. In

1 Because this decision contains a reasoned explanation for the special master’s action in this case, it will

be posted on the United States Court of Federal Claims’ website in accordance with the E-Government

Act of 2002. See 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion of Electronic

Government Services). This means the decision will be available to anyone with access to the

Internet. In accordance with Vaccine Rule 18(b), petitioner has 14 days to identify and move to redact

medical or other information the disclosure of which would constitute an unwarranted invasion of privacy.

If the special master, upon review, agrees that the identified material fits within this definition, it will be

redacted from public access.

2Within this decision, all citations to § 300aa will be the relevant sections of the Vaccine Act at 42 U.S.C.

§ 300aa-10-34.

general, to gain an award, a petitioner must make a number of factual demonstrations,

including showing that an individual received a vaccination covered by the statute;

received it in the United States; suffered a serious, long-standing injury; and has

received no previous award or settlement on account of the injury. Finally – and the key

question in most cases under the Program – the petitioner must also establish a causal

link between the vaccination and the injury. In some cases, the petitioner may simply

demonstrate the occurrence of what has been called a “Table Injury.” That is, it may be

shown that the vaccine recipient suffered an injury of the type enumerated in the

“Vaccine Injury Table,” corresponding to the vaccination in question, within an

applicable time period following the vaccination also specified in the Table. If so, the

Table Injury is presumed to have been caused by the vaccination, and the petitioner is

automatically entitled to compensation, unless it is affirmatively shown that the injury

was caused by some factor other than the vaccination. § 300aa-13(a)(1)(A); § 300 aa-

11(c)(1)(C)(i); § 300aa-14(a); § 300aa-13(a)(1)(B).

In many cases, however, the vaccine recipient may have suffered an injury not of

the type covered in the Vaccine Injury Table. In such instances, an alternative means

exists to demonstrate entitlement to a Program award. That is, the petitioner may gain

an award by showing that the recipient’s injury was “caused-in-fact” by the vaccination

in question. § 300aa-13(a)(1)(B); § 300aa-11(c)(1)(C)(ii). In such a situation, of course,

the presumptions available under the Vaccine Injury Table are inoperative. The burden

is on the petitioner to introduce evidence demonstrating that the vaccination actually

caused the injury in question. Althen v. Sec’y of Health & Human Servs., 418 F.3d

1274, 1278 (Fed. Cir. 2005); Hines v. Sec’y of Health & Human Servs., 940 F.2d 1518,

1525 (Fed. Cir. 1991).

The showing of “causation-in-fact” must satisfy the “preponderance of the

evidence” standard, the same standard ordinarily used in tort litigation. § 300aa-

13(a)(1)(A); see also Althen, 418 F.3d at 1279; Hines, 940 F.2d at 1525. Under that

standard, the petitioner must show that it is “more probable than not” that the

vaccination was the cause of the injury. Althen, 418 F.3d at 1279. The petitioner need

not show that the vaccination was the sole cause of the injury or condition, but must

demonstrate that the vaccination was at least a “substantial factor” in causing the

condition, and was a “but for” cause. Shyface v. Sec’y of Health & Human Servs., 165

F.3d 1344, 1352 (Fed. Cir. 1999). Thus, the petitioner must supply “proof of a logical

sequence of cause and effect showing that the vaccination was the reason for the

injury;” the logical sequence must be supported by “reputable medical or scientific

explanation, i.e., evidence in the form of scientific studies or expert medical testimony.”

Althen, 418 F.3d at 1278; Grant v. Sec’y of Health & Human Servs., 956 F.2d 1144,

1148 (Fed. Cir. 1992). A petitioner may not receive a Vaccine Program award based

solely on his or her assertions; rather, the petition must be supported by either medical

records or by the opinion of a competent physician. § 300aa-13(a)(1).

In what has become the predominant framing of this burden of proof, the Althen

court described the “causation-in-fact” standard, as follows:

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Concisely stated, Althen’s burden is to show by preponderant evidence

that the vaccination brought about her injury by providing: (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. If Althen satisfies this burden, she is

entitled to recover unless the [government] shows, also by a

preponderance of the evidence, that the injury was in fact caused by

factors unrelated to the vaccine.

Althen, 418 F.3d at 1278 (citations omitted). The Althen court noted that a petitioner

need not necessarily supply evidence from medical literature supporting petitioner’s

causation contention, so long as the petitioner supplies the medical opinion of an

expert. Id. at 1279-80. That expert’s opinion must be “sound and reliable.” Boatmon v.

Sec’y of Health & Human Servs., 941 F.3d 1351, 1359-60 (Fed. Cir. 2019). The Althen

court also indicated, however, that a Program factfinder may rely upon “circumstantial

evidence,” which the court found to be consistent with the “system created by Congress,

in which close calls regarding causation are resolved in favor of injured claimants.” 481

F.3d at 1280.

Where a petitioner in an off-Table case is seeking to prove that a vaccination

aggravated a preexisting injury, petitioners must also establish three additional factors.

See Loving v. Sec’y of Health & Human Servs., 86 Fed. Cl. 135, 144 (Fed. Cl. 2009)

(combining the first three Whitecotton factors for claims regarding aggravation of a

Table injury with the three Althen factors for off table injury claims to create a six-part

test for off-Table aggravation claims); see also W.C. v. Sec’y of Health & Human Servs.,

704 F.3d 1352, 1357 (Fed. Cir. 2013) (applying the six-part Loving test). The additional

Loving factors require petitioners to demonstrate aggravation by showing: (1) the

vaccinee’s condition prior to the administration of the vaccine, (2) the vaccinee’s current

condition, and (3) whether the vaccinee’s current condition constitutes a “significant

aggravation” of the condition prior to the vaccination. Id. The Vaccine Act defines

“significant aggravation” as a “any change for the worse in a preexisting condition which

results in markedly greater disability, pain, or illness accompanied by substantial

deterioration of health.” 42 U.S.C. § 300aa-33(4).

In this case, petitioner alleges that the influenza vaccine she received on

November 8, 2013, significantly aggravated her Hashimoto’s thyroiditis (“HT”) and/or

undifferentiated connective tissue disease (“UCTD”). (ECF No. 25, p. 2.) Because

neither of these injuries are listed as a Table Injury relative to the influenza vaccine,

petitioner must satisfy the six-part Loving test.

II. Procedural History

Petitioner filed her petition pro se on October 28, 2016. (ECF No. 1.) This case

was originally assigned to then Chief Special Master Dorsey. (See ECF No. 3.)

Petitioner proceeded pro se while seeking representation, until September 8, 2017,

when petitioner’s counsel filed a motion to substitute attorney. (ECF No. 14.) After

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petitioner secured representation, she filed medical records on January 16, 2018. (ECF

Nos. 21, 22.) Thereafter, petitioner filed an amended petition on March 7, 2018, adding

her significant aggravation claim. (ECF No. 25.) On March 29, 2018, respondent filed

his Rule 4(c) Report recommending against compensation. (ECF No. 26.)

On October 4, 2018, petitioner filed updated medical records along with an

expert report from rheumatologist Lige Rushing, M.D., M.S., P.A. (ECF No. 36.)

Respondent filed a responsive expert report from rheumatologist Erin Wilfong, M.D.,

Ph.D., on March 5, 2019, and an additional report from immunologist Noel Rose, M.D.,

Ph.D., on May 6, 2019. (ECF Nos. 39, 43.)

This case was assigned to my docket on June 7, 2019. (ECF Nos. 49, 50.)

Petitioner then filed a report from immunologist James DeAngelo, D.O., on October 7,

2019. (ECF No. 52.) Respondent filed responsive reports from Drs. Wilfong and Rose

on December 20, 2019. (ECF No. 57.) Petitioner responded with two additional

supplemental reports from Dr. DeAngelo on March 21, 2020 (one responding to Dr.

Wilfong and one responding to Dr. Rose). (ECF No. 59.) Thereafter, the case was set

for the scheduling of an entitlement hearing; however, respondent also filed a further

report from Dr. Wilfong on July 13, 2020, and a further report from Dr. Rose on August

5, 2020. (ECF Nos. 65, 67.) On September 14, 2020, a two-day entitlement hearing

was scheduled to commence on September 20, 2021. (ECF No. 70.)

However, on October 14, 2020, respondent advised that Dr. Rose had recently

passed away. (ECF No. 71.) Respondent further indicated that he intended to retain an

immunologist to testify at the hearing. (Id.) Thus, on November 19, 2020, respondent

filed an additional expert report from immunologist Arnold Levinson, M.D. (ECF No.

72.) Petitioner filed a responsive report from Dr. DeAngelo on February 18, 2021.

(ECF No. 75.) Respondent filed his final expert report from Dr. Levinson on June 3,

2021. (ECF No. 80.) On July 30, 2021, petitioner filed her final responsive expert

report from Dr. DeAngelo. (ECF No. 86.)

A two-day entitlement hearing was held remotely on September 20th and 21st,

2021, via Webex. (See ECF Nos. 104-05, Transcript of Proceedings (“Tr.”), filed

11/02/2021.) Petitioner testified and also presented testimony from her two experts,

Drs. Rushing and DeAngelo. Respondent presented testimony from Drs. Wilfong and

Levinson. This case is now ripe for resolution of entitlement.

III. Factual History

a. Medical Records

i. Pre-Vaccination Records

Petitioner’s medical records document a history of mitral valve prolapse, lumbar

laminectomy, gastroesophageal reflux disease (“GERD”), headaches, facial numbness,

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Hashimoto’s thyroiditis, sciatica, and vertigo. (Ex. 2, pp. 36, 41-42; Ex. 3, p. 6; Ex. 6, p.

95; Ex. 10, pp. 45, 64, 66-67; Ex. 12, p. 23; Ex. 13, p. 25.)

Upon experiencing vertigo, petitioner was examined by neurologist Dr. Jeffrey

Farbman on June 26, 2013. (Ex. 6, pp. 94-96.) At a follow-up appointment on July 31,

2013, Dr. Farbman discovered petitioner’s anti-nuclear antibody (“ANA”) 3 positivity and

referred her to a rheumatologist. (Id. at 91.) Petitioner’s MRI revealed an abnormality,

which was interpreted as potentially the result of migraine headache sequelae, minimal

small vessel ischemic disease, a demyelinating disease, or vasculitis. (Id. at 90, 95.)

On August 15, 2013, petitioner presented to rheumatologist Dr. Kenneth Crane.

(Ex. 10, pp. 40-44.) Petitioner reported a history of headaches, dizziness, Hashimoto’s

thyroiditis, and positive ANA. (Id. at 41.) Dr. Crane did not find any evidence to support

a diagnosis of rheumatic disease and associated petitioner’s positive ANA with her

thyroiditis. (Id. at 44.) He noted left side facial numbness and the possibility of an

inflammatory rheumatic disease. (Id. at 44, 48.)

On September 4, 2013, petitioner saw Dr. Crane in follow up for her positive

ANA. (Ex. 10, p. 38.) Upon review of petitioner’s labs, Dr. Crane noted positive anti-

smith (“Sm”) antibodies and ribonucleoprotein (“RNP”) antibodies. (Id. at 38-39.)

Based on these results, Dr. Crane suspected systemic lupus erythematosus (“SLE” or

“lupus”). (Id.) He recommended repeat testing and a potential lumbar puncture if the

results remained positive. (Id.)

On September 20, 2013, Dr. Crane noted that petitioner’s follow up testing did

not reveal Sm antibody positivity, but that she did maintain positive RNP antibodies. He

wrote that positive ANA and RNP antibodies are commonly associated with connective

tissue disease, though petitioner did not report any symptoms related to such a disease.

Dr. Crane concluded that despite her elevated autoantibody levels, petitioner did not

warrant further treatment. (Ex. 10, p. 34.)

Petitioner sought a second opinion from another rheumatologist, Dr. Glenn

Wiener. (Ex. 3, p. 6.) On November 5, 2013, Dr. Wiener described his initial

examination of petitioner in a letter to Dr. Glick. Dr. Wiener wrote that petitioner

reported a history of chronic dizziness and lightheadedness over the previous four

years, an episode of a severe headache with vertigo in June 2012, chronic headaches

for the previous six years, tinnitus for several years, a meningioma of the brain, a mitral

valve prolapse with palpitations and acid reflux, recent right-side neck pain, Hashimoto’s

3 “ANAs are used to diagnose autoimmune diseases, including systemic lupus erythematosus (“SLE”).

Kathleen D. Pagana & Timothy J. Pagana, Mosby’s Manual of Diagnostic and Laboratory Tests, ch. 2, at

80 (6th ed. 2018). ANA has fluorescent patterns in cells. Id. at 82. “Different patterns are associated

with a variety of autoimmune disorders.” Id. Mosby’s states a positive ANA with a homogeneous pattern

is associated with SLE and mixed connective tissue disease (“MCTD”). Id. It also says that a positive

ANA with a speckled pattern is associated with SLE, scleroderma, RA, MCTD, Sjögren syndrome, and

polymyositis (“PM”). Id. As for anti-RNP antibodies, they are associated with MCTD, SLE, and

progressive systemic sclerosis (scleroderma). Id. at 81. MCTD is associated with ANA, anti-RNP

antibodies, RF, and ssDNA. Id.

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thyroiditis, and a lumbar laminectomy in 2001. (Id.) Dr. Wiener believed that

petitioner’s positive ANA “could be related to the recent diagnosis of autoimmune

thyroid disease which is my suspicion.” (Id. at 7.)

ii. Post-Vaccination Records

Petitioner received a flu vaccination in her left deltoid on November 8, 2013. (Ex.

1, p. 1.) On January 8, 2014, petitioner presented to Dr. Glick with a chief complaint of

bilateral shoulder pain lasting six weeks. (Ex. 2, p. 9.) On January 22, 2014, petitioner

returned to Dr. Glick for continuing pain / myalgias mostly in her upper arms. (Id. at 8.)

On February 5, 2014, Dr. Crane wrote to Dr. Glick explaining that he had seen

petitioner that day for her shoulder pain which had improved significantly with a Medrol

Dosepak. (Ex. 6, p. 61.) However, new laboratory studies had revealed leukopenia and

Dr. Crane was concerned that petitioner may have SLE. (Id.) On February 19, 2014,

Petitioner contacted Dr. Crane’s office reporting increased pain in both arms. (Ex. 10,

p. 26). She was started on prednisone. (Id.)

Petitioner next saw Dr. Crane on February 27, 2014. She reported continued

upper arm and shoulder pain, a rash on her breast, and a mouth sore. (Ex. 10, p. 23.)

Dr. Crane’s impression was SLE, and he recommended Plaquenil and prednisone. (Id.

at 25.) Petitioner remained on prednisone but refrained from taking Plaquenil due to

potential side effects. (Id.)

A cervical MRI on March 5, 2014, showed a “[l]inear fluid signal in the central part

of the spinal cord compatible with hydrosyringomyelia” and “[m]ild/moderate cervical

spine degenerative changes.” (Ex. 14, p. 8.)

On March 19, 2014, petitioner presented to hematologist Dr. Ronald Slade for

consultation on using immunosuppressive therapy in the context of leukopenia. (Ex. 10,

p. 78.) Dr. Slade felt that petitioner could continue using immunosuppressive therapy

because her leukopenia was believed to be caused by her underlying autoimmune

disorder. (Id. at 80.)

On March 20, 2014, petitioner presented to orthopedist Dr. Richard Rabinowitz

for constant bilateral posterior neck pain lasting five months and radiating to her upper

arms. (Ex. 9, p. 17.) Her physical examination was normal, and her MRI and x-ray

were unremarkable. (Id. at 19.) Dr. Rabinowitz believed petitioner’s pain was due to a

degenerative disc and recommended physical therapy. (Id. at 20.)

On April 15, 2014, petitioner was evaluated by rheumatologist Dr. Rosalind

Ramsey-Goldman who recorded the following medical history:

Got a flu shot in 11/2013, ten days later developed myalgias in shoulders

and upper arms. Took advil and tylenol without relief. Rheumatologist then

recommended starting plaquenil, which she was nervous about starting

because of possible vision side effects. Was started on prednisone . . .

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without improvement in shoulder/arm pain, but then did get relief with

prednisone . . . which she has been taking for last 2 months. Muscle pain

in shoulders and upper arms, with morning stiffness for 1 hour, pain worse

at night. Now has pain in right forearm. Had repeat MRI of neck after

shoulder symptoms started, was told she had an osteophyte on C5 (has

discs with her but not report), unsure if causing symptoms. Has had low

WBC counts in the past, ever since she was kid. Intermittent,

spontaneously would be normal again. Normal differential. Saw a

hematologist 10 years ago and no etiology found. [Patient] is also

concerned because her total protein has increased on recent

testing . . . . Had painful occipital lymphadenopathy in fall 2013 that

resolved w/ medrol dosepak and antibiotics.

(Ex. 12, p. 23.) Petitioner also reported a “longstanding history of intermittent

leukopenia” and recent development of pain in her right forearm. (Id. at 23, 28.) Dr.

Ramsey-Goldman diagnosed petitioner with unspecified diffuse connective tissue

disease (“UCTD”). (Id. at 29.) She planned to taper petitioner’s steroids and monitor

the response. (Id. at 28-29.)

On May 14, 2014, petitioner presented for a neurosurgery consult by Dr. Richard

Broderick. (Ex. 14, pp. 2-4.) Dr. Broderick noted a medical history of bilateral shoulder

/ upper arm pain since November 2013 following petitioner’s flu vaccination and positive

ANA. (Id. at 2.) Petitioner reported that she experienced some relief of her joint pain

when taking prednisone but noticed right wrist and hand pain when reducing her

dosage. (Id.) Petitioner’s brain and cervicothoracic MRI were unremarkable and not

believed to contribute to her symptoms including her shoulder and wrist pain. (Id. at 4.)

On June 3, 2014, petitioner returned to Dr. Ramsey-Goldman to follow up on her

joint pain and reevaluate her prednisone tapering. Dr. Ramsey-Goldman noted a

history of Hashimoto’s thyroiditis and suspected UCTD characterized by positive ANA

and RNP, Raynaud’s, steroid-responsive myalgia, arthralgia, and leukopenia. (Ex. 12,

p. 22.) Petitioner reported increased joint and muscle discomfort while tapering

prednisone in addition to third PIP 4 swelling and a rash on her knuckles. (Id. at 19.) Dr.

Ramsey-Goldman recommended continued conservative treatment of petitioner’s

condition. (Id. at 22.)

Petitioner was discharged from physical therapy on June 19, 2014, after eighteen

visits with pain with external rotation only and strength of 4/5. (Ex. 9, p. 21.)

On August 27, 2014, petitioner presented to Dr. Brooke Belcher for an orthopedic

follow up for worsening carpal tunnel syndrome (“CTS”) and a bilateral upper extremity

EMG. (Ex. 9, p. 13.) Petitioner reported that her neck and arm pain was improving, but

that her bilateral hand pain, numbness, and tingling had been getting worse. (Id.)

Petitioner’s EMG revealed a severe bilateral median mononeuropathy. (Id. at 29.)

4PIP or proximal interphalangeal joint is “the interphalangeal joint located proximally on any digit.”

Proximal interphalangeal joint, DORLAND’S MEDICAL DICTIONARY ONLINE,

https://www.dorlandsonline.com/dorland/definition?id=83592 (last accessed July 26, 2022).

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On September 3, 2014, petitioner presented to orthopedist Dr. Matthew

Bernstein for an orthopedic follow up. (Ex. 9, p. 9.) Dr. Bernstein noted petitioner’s

history of Raynaud’s and mixed connective tissue disease and that petitioner’s CTS-

related numbness and tingling began two months previously. (Id.)

On October 1, 2014, petitioner returned to Dr. Ramsey-Goldman’s office for a

rheumatology follow up. She reported that her fingers were puffy and that her rings did

not fit. (Ex. 12, p. 12.) She also complained of worsening Raynaud’s and occasional

severe right knee pain. (Id.) The assessment was Raynaud’s phenomenon, myalgia,

arthralgia, and carpal tunnel syndrome, with UCTD suspected. (Id. at 17.) Dr. Ramsey-

Goldman believed that petitioner Raynaud’s symptoms could be exacerbated by a beta

blocker she was on, and that she had a possible scleroderma. (Id. at 18.) Her

recommended course of treatment was to continue wearing a splint and a trial course of

diclofenac with possible carpal tunnel steroid injections. (Id.)

On December 31, 2014, petitioner returned to Dr. Ramsey-Goldman for a follow

up. Dr. Ramsey-Goldman noted suspected UCTD characterized by positive ANA and

RNP, steroid-responsive arthralgia and myalgia, Raynaud’s, and intermittent

leukopenia. (Ex. 12, pp. 5-6.) Dr. Ramsey-Goldman also noted petitioner’s recent

onset of bilateral carpal tunnel syndrome and her lack of response to steroid injections

in November 2014. (Id. at 6.) Petitioner also reported swelling in her hands and

fingers. (Id. at 6, 11.) Dr. Ramsey-Goldman reaffirmed petitioner’s UCTD diagnosis

with limited scleroderma. (Id. at 11.) Dr. Ramsey-Goldman recommended continued

conservative treatment pending further evaluation of petitioner’s scleroderma. (Id.)

Relative to her scleroderma concern, petitioner was evaluated by rheumatologist

Dr. John Varga on March 18, 2015, and October 7, 2015. (Ex. 12, pp. 2-5.) Petitioner’s

history included diagnoses of Hashimoto’s thyroiditis, UCTD, CTS, and Raynaud’s. (Id.

at 2, 4.) Petitioner also reported chronic fatigue and facial / trigeminal neuropathy. (Id.

at 2-3.) Dr. Varga ruled out existing or developing proximal scleroderma. (Id. at 5.) Dr.

Varga recommended that petitioner continue with prednisone as needed and follow up

with rheumatology. (Id.)

On March 26, 2015, Petitioner saw Dr. Glick with new onset of discomfort and

numbness on the left side of her face, including the tongue and lips. (Ex. 2, p. 3.) Dr.

Glick prescribed a Medrol Dosepak, which offered some relief. (Id.)

In light of her new facial symptoms, petitioner returned to her neurologist, Dr.

Farbman, on April 8th and 20th, 2015. (Ex. 6, pp. 84-87.) Petitioner’s physical exam

was significant for abnormal facial sensation in left V1 through V3 distributions. (Id.)

Petitioner was prescribed Neurontin, which provided some relief. (Id.)

On May 4, 2015, petitioner presented to rheumatologist Dr. Sergey Furmanov,

reporting symptoms of painful numbness on the left side of her face and tongue, swollen

finger joints without pain, some hair loss, and Raynaud’s phenomenon. (Ex. 10, p. 19.)

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Dr. Furmanov noted that “UCTD seem[ed] to be the consensus,” based on petitioner’s

prior rheumatology records. (Id.) He noted that petitioner’s facial paresthesia “could be

related to UCTD in the absence of another explanation.” (Id. at 20.) Dr. Furmanov also

noted that brain and spinal MRI revealed no evidence of demyelination and was

therefore not contributing to petitioner’s ongoing syndrome. (Id. at 16, 19.) Dr.

Furmanov also noted evidence of PIP joint synovitis and Raynaud’s. (Id. at 16-17, 18,

19-20.) Dr. Furmanov’s concluded that petitioner’s facial paresthesia was UCTD

related. (Id.)

Petitioner was seen in follow-up by Dr. Furmanov on July 23, September 9, and

November 18, 2015. (Ex. 10, pp. 4, 10, 13.) On November 18, 2015, Dr. Furmanov

observed that petitioner’s PIP joints were still slightly swollen but not tender; she had

unchanged painful numbness on the left side of her face and tongue; her Raynaud’s

and mild hair loss were stable; and she awoke some nights with right knee pain that

would subside spontaneously. (Ex. 17, p. 22.) Dr. Furmanov’s assessment was: “1.

UCTD/mild inflammatory arthropathy at PIP joints improved on HCQ, off Prednisone. 2.

Facial paresthesia possibly related to UCTD. 3. Mild intermittent leukopenia,

transaminitis are likely related to the inflammatory disease #1, stable. 4. Intermittent

right knee pain.” (Id. at 23.)

On January 4, 2016, petitioner was referred to Ronald Shade, M.D., for

evaluation of her leukopenia, related to immunosuppressive therapy (Plaquenil)

prescribed for her autoimmune disorder. (Ex. 61, p. 88.) Dr. Shade noted that

petitioner had an undefined rheumatologic disorder and chronic mild leukopenia “which

has remained stable for at least a decade.” (Id.) He concluded that her mild leukopenia

was due to her underlying autoimmune disorder and ordered her to continue follow-up

management with her rheumatologist. (Id. at 90.)

On April 18, 2018, petitioner presented to Dr. Furmanov for a rheumatology

follow-up reporting that she was “feeling good on HCQ 300 mg QD [without] PIP or

other joint . . . pain/stiffness,” and that her right knee was “OK.” (Ex. 17, p. 1.) Her

fatigue had not improved, her eyes and lips were a “little dry,” though “no Raynaud’s.”

(Id.) Petitioner was not participating in Zumba classes and was busy with school. (Id.)

She reported that her left-side facial pain and numbness was stable on Neurontin and

Xanax. (Id.) Dr. Furmanov documented substantially similar follow up exams of

petitioner on October 11, 2018, May 29, 2019, October 10, 2019, April 15, 2020, and

December 2, 2020. (See Ex. 60, pp. 2, 6, 12, 17, 22.)

b. Petitioner’s Affidavit and Testimony

Petitioner filed an affidavit on August 9, 2021, describing the course and

character of her alleged injury. (Ex. 64.) She notes a medical history of mitral valve

prolapse, lumbar laminectomy, acid reflux, headaches, and Hashimoto’s thyroiditis

which was clinically stable due to prescribed Levothyroxine. (Id. at 1.) She states that

she began experiencing bilateral upper arm and shoulder pain approximately 10 to 14

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days after receiving her vaccination. (Id.) The pain was unlike any other she had felt

before, was worse at night and interrupted her sleep. (Id.)

She explains that when the pain did not subside, she was seen by her primary

care physician, Dr. Glick on January 8 and 22 of 2014. Her chief complaint was

bilateral shoulder pain lasting six weeks and beginning approximately two weeks after

her flu shot. (Id.) She was prescribed a Medrol pack and shoulder x-rays were taken

and returned negative. Petitioner notes that the Medrol pack provided temporary relief

but that her pain returned once she quit using the Medrol.

Petitioner explains that she was seen by her rheumatologist on February 5, 2014,

due to her persistent joint pain and recent history of bilateral shoulder pain. She states

that Dr. Crane suspected lupus and ordered additional bloodwork. She followed up with

Dr. Crane on February 27, 2014, and reported that her pain syndrome had progressed

to the midportion of her upper arms. She explains that she was told her pain could be

caused by SLE or Sjogren’s syndrome and was recommended treatment with Plaquenil

and prednisone. Petitioner states that she started treating with prednisone but refrained

from taking Plaquenil due to concerns over potential side effects. (Ex. 64, p. 1.)

Petitioner describes seeking a second opinion from rheumatologist Dr. Ramsey-

Goldman on April 15, 2014. On this examination, petitioner explains that Dr. Ramsey-

Goldman diagnosed her with UCTD based on her positive ANA and RNP, Raynaud’s

signs, and steroid-responsive arthralgia and myalgia. (Ex. 64, p. 2.) Petitioner affirms

that joint swelling was not a condition that she had ever experienced prior to her flu

vaccination. (Id.) Petitioner states that she was seen by Dr. Ramsey-Goldman on June

3, 2014, for a follow up on her UCTD. Petitioner had been tapering her prednisone use

and reported that her pain increased as she decreased her dosage. Petitioner explains

that the treatment plan was to continue tapering prednisone along with conservative

treatment of petitioner’s rheumatic disease. (Id.)

Petitioner explains that she was off prednisone by the time she was seen again

by Dr. Ramsey-Goldman on October 1, 2014. (Ex. 64, p. 2.) She explained that she

had new onset carpal tunnel syndrome and increased joint discomfort. She also

reported new onset of swelling in her fingers and hands, and right knee discomfort. She

was diagnosed with active rheumatic disease process with developing carpal tunnel.

Petitioner notes that carpal tunnel was not a condition she experienced prior to her

vaccination. (Id.)

Petitioner avers that she returned to Dr. Glick on March 26, 2015, with new

development of numbness and discomfort on the left side of her face, including her

tongue and lips. She was prescribed a Medrol dose pack, but it offered little relief.

Petitioner reports that this was another condition that she did not experience prior to her

vaccination. (Ex. 64, p. 2.)

Petitioner then explains that she was reevaluated by her neurologist, Dr.

Farbman, on April 8th and 20th, 2015, for her new facial symptoms and ongoing joint

10

pain. Her physical exam noted abnormal facial sensation and she was prescribed

Neurontin which provided some relief. Petitioner states that on June 19, 2015, she

started Plaquenil due to her elevated liver enzymes and the suspicion of autoimmune

hepatitis. (Ex. 64, p. 2.)

Petitioner sought further treatment for her facial paresthesia from her

rheumatologist Dr. Furmanov on May 4th and June 25th, 2015. Her primary complaint

was constant to moderate pain on her left side face along with swollen fingers and

Raynaud’s syndrome. She was advised to continue her Neurontin regimen. Dr.

Furmanov associated her facial symptoms with her underlying UCTD. (Ex. 64, p. 3.)

Petitioner concludes her affidavit stating that while her rheumatic condition has

improved over time, she continues to experience intermittent shoulder and upper arm

discomfort, carpal tunnel, and finger and hand swelling. Her facial symptoms remain

“fairly constant,” and her daily living activities and recreational hobbies have been

curtailed. She affirms that she believes her underlying UCTD was significantly

aggravated by her flu vaccination, that she has suffered the symptoms of her condition

for over six months, and that she has not received any compensation as a result of her

injuries. (Ex. 64, p. 3.)

Petitioner’s testimony during the hearing was largely consistent with her affidavit.

(Tr. 6-45.) On cross examination, petitioner acknowledged that she had experienced

facial numbness prior to her vaccination, in 2005, in 2011, and in 2013. (Id. at 40-41

(citing Ex. 10, pp. 48, 66; Ex. 9, p. 28.) However, she explained that it was a “totally

different facial pain,” she described “strange sensations . . . when I had

headache . . . almost like a tiny little numbness.” (Tr. at 41.) Petitioner testified, “It

wasn’t really a pain. And it could be on the left side or the right side.” (Id. at 43.) She

estimated that it occurred approximately once a year. (Id.) She explained that she

mentioned the numbness during the MRI “in case it was significant” though it “wasn’t

really anything that bothered me. I just mentioned it in case it was somehow relevant to

when I had a headache.” (Id. at 44.) According to petitioner, Dr. Glick advised her that

the facial numbness was a complication of her underlying headaches. (Id.) Petitioner

testified that the onset of her headaches preceded vaccination, and the headaches

occurred frequently enough to seek treatment, though it was “more of a remote history.”

(Id. at 42-43.) She testified that she did not experience a pattern of headaches post-

vaccination. (Id. at 43.) Petitioner testified that the pain she currently has is

significantly worse than any complaints of pain she may have had prior, in 2011 or

2015. (Id. at 45.)

11

IV. Summary of Experts’ Opinions

a. For Petitioner

i. Lige B. Rushing, Jr., M.D., M.S., P.A.

Petitioner has offered Dr. Rushing as an expert in rheumatology and internal

medicine. 5 Respondent does not object. (Tr. 53-54.)

Dr. Rushing concludes, accounting for petitioner’s preexisting Hashimoto’s

thyroiditis and elevated ANA, it is likely that she experienced a vaccine-mediated

reaction causing “arthralgia and myalgia, Raynaud’s rash, hair loss, and facial

paresthesia, and when coupled with positive ANA and RNP, led [petitioner’s] treating

rheumatologists to the post-vaccination consensus diagnosis of UCTD.” 6 (Ex. 18, p. 5.)

Dr. Rushing opines that the 10-to-14-day period of onset of petitioner’s post-vaccination

symptoms is within an appropriate medical timeframe to infer vaccine causation, and

that the absence of any other causes shows that petitioner’s vaccine is the necessary

cause of her symptoms. (Id.)

Dr. Rushing agrees that petitioner’s ANA and RNP bloodwork was representative

of an underlying connective tissue disease that was subclinical at the time of her

vaccination. (Tr. 65.) Dr. Rushing further indicates, however, that patients may be ANA

and RNP positive for “years and perhaps their entire life without ever demonstrating or

exhibiting clinical signs or symptoms of connective tissue disease.” (Id. at 66.) Dr.

Rushing opines that petitioner’s asymptomatic connective tissue disease significantly

worsened following her influenza vaccination on November 8, 2013. (Id. at 77.)

Specifically, he observed that petitioner developed pain in her shoulders and arms, and

subsequently developed Raynaud’s. (Id.) Furthermore, she developed swelling in her

hands and fingers, she had hair loss, and ultimately developed trigeminal neuropathy—

“a whole new set of symptoms which she didn’t have before the vaccine.” (Id.)

Whereas respondent’s experts discussed the possibility that petitioner’s condition

constitutes mixed connective tissue disease or “MCTD,” Dr. Rushing opines that

petitioner more likely suffers from UCTD. (Tr. 78-79.) According to Dr. Rushing, UCTD

is a “recognized diagnosis,” whereas mixed connective tissue disease is not. (Id. at 78.)

5

Dr. Rushing received his medical degree from Baylor University College of Medicine and completed his

residency and internship in internal medicine at Harris Hospital in Fort Worth, Texas. (Ex. 19.) He held a

fellowship in internal medicine and rheumatology at the Mayo Clinic in Rochester, Minnesota. He is

certified by the American Board of Internal Medicine, the American Board of Geriatrics, and the American

Board of Rheumatology. He has previously served as an affiliate physician at the Presbyterian Hospital

of Dallas, Texas and is currently engaged in private practice of internal medicine and rheumatology. He

is a member of the American Medical Association, the Texas Medical Association, the Dallas County

Medical Association, and the Mayo Alumni Association. (Id.)

6 Dr. Rushing also offers an alternative assessment that petitioner suffered polymyalgia rheumatica

(“PMR”). (Ex. 18, p. 6.) However, respondent’s experts disagreed (Ex. A, pp. 3-4; Ex. C, pp. 5-6) and

petitioner ultimately did not rely on that assessment. Accordingly, PMR will not be addressed further.

12

MCTD typically involves a set of symptoms that do not confirm an identified rheumatic

disease. In the case of UCTD, however, Dr. Rushing explains that “as the time goes by,

they do differentiate into identifiable, recognized connective tissue disorders, such as

scleroderma or lupus or rheumatoid arthritis.” (Id.) Dr. Rushing also suggested that

some rheumatologists may use these terms interchangeably, though he believes this is

inaccurate. Petitioner, Dr. Rushing opines, more likely suffers from undifferentiated

connective tissue disease because she did not exhibit enough signs or symptoms to fall

under any one, or multiple, categories of connective tissue disease. (Id. at 79.)

Apart from petitioner having been administered an influenza vaccine, Dr. Rushing

initially agreed that there was nothing unusual about petitioner’s transition from

subclinical to clinical connective tissue disease. (Tr. 101.) Asked whether, in his

experience, physicians are able to identify an environmental trigger to the clinical

presentation, Dr. Rushing testified “lots of times you cannot determine [the trigger].” (Id.

at 101-02.) He testified that the medical literature on mixed connective tissue diseases

suggests that “as high as 25 percent [of cases] you can’t identify a trigger.” (Id.) On

redirect, however, Dr. Rushing suggested that the abruptness of petitioner’s

presentation from subclinical to clinical was an “unusual occurrence” in the context of a

connective tissue disease that he has not seen in his own practice. (Tr. 104.)

Dr. Rushing’s report also included a theory of vaccine causation based on the

concept of “Autoimmune Syndrome Induced by Adjuvants” or “ASIA.” (Ex. 18, p. 4

(citing Nabeela Siddiqi et al., Polymyalgia Rheumatica and Autoimmune Inflammatory

Syndrome Induced by Adjuvants Following Administration of Influenza Vaccine, JCR 1

(2018) (Ex. 20); Alessandra Soriano et al., Predicting Post-Vaccination Autoimmunity:

Who Might Be at Risk?, 92 PHARMACOL. RES. 18 (2015) (Ex. 21)).) However, he later

opined during the hearing that ASIA syndrome is not relevant because petitioner’s

“vaccine didn’t contain any adjuvants.” (Tr. 89.) He agreed that his opinion “isn’t

predicated upon an ASIA analysis.” (Id.) Instead, Dr. Rushing deferred to petitioner’s

immunology expert, Dr. DeAngelo, regarding the theory on vaccine causation. (Id. at

81, 89.)

ii. James N. DeAngelo, D.O.

Petitioner has offered Dr. DeAngelo as an expert in allergy and clinical

immunology. 7 Respondent does not object. (Tr. 116-17.)

7 Dr. DeAngelo received his medical degree from the Philadelphia College of Osteopathic Medicine,

completed his internship in family medicine at Millcreek Community Hospital, his residency in internal

medicine at West Virginia University in Morgantown, West Virginia, and a fellowship in allergy and

immunology at the Cleveland Clinic Foundation in Cleveland, Ohio. (Ex. 24, p. 1.) He is licensed by the

State of Pennsylvania. (Id. at 2.) He currently serves as Chair of the department of Allergy and

Immunology at the Washington Hospital, and previously held positions as Director of the American

Osteopathic Board of Allergy and Immunology, item writer for the Association of Clinical Research

Professionals, Director of the Allergy and Immunology Subspecialty Board of the American Osteopathic

Board of Internal Medicine, a Level III Item Writer for the Allergy and Immunology Section of the National

Board of Osteopathic Medical Examiners, a Board Member of the American Osteopathic Board of Internal

Medicine, Subspecialty Board Writer for Allergy and Immunology at the American Osteopathic Board of

Internal Medicine, the District VIII Delegate for the Pennsylvania Osteopathic Medical Association’s

13

Dr. DeAngelo acknowledges that petitioner showed signs of predisposition to

autoimmunity prior to the vaccination at issue. (Ex. 42, p. 1.) However, he opines that

the concept of “autoimmune tautology” explains how several co-existent autoimmune

conditions can be found in the same individual, each with their own precipitant. (Id.) Dr.

DeAngelo opines that “the environmental trigger for each autoimmune disease must be

viewed independently of the overall predisposition to an autoinflammatory state.” (Id. at

2.) In that regard, he stresses that petitioner was asymptomatic prior to her vaccination

despite having elevated ANA and RNP antibodies and developed physical signs of

connective tissue disease within two weeks of vaccination. (Ex. 62, p. 2.)

Dr. DeAngelo acknowledges that the vaccine at issue in this case did not contain

an adjuvant and therefore petitioner’s illness “does not strictly fulfill the original definition

of ASIA, as described by Shoenfeld and Agmon-Levin in 2011.” (Ex. 23, p. 1.)

However, he suggests that it had many of the same characteristics, “suggesting a

similar vaccine antigen-based pathogenesis as contemplated in subsequent ASIA

medical literature.” (Id.) Citing this ASIA literature, Dr. DeAngelo opines that exposure

to the antigen within an inactivated flu vaccine can trigger the type of immune reactivity

that has been linked to autoimmunity without exposure to live virus. (Id. at 10 (citing

Yehuda Shoenfeld & Nancy Agmon-Levin, ‘ASIA’ – Autoimmunity/Inflammatory

Syndrome Induced by Adjuvants, 36 J. AUTOIMMUNITY 4 (2011) (Ex. C, Tab 2); Victoria

Furer et al., 2019 Update of EULAR Recommendations for Vaccination in Adult Patients

with Autoimmune Inflammatory Rheumatic Diseases, ANN. RHEUM. DIS. 1 (2019) (Ex.

29); Siddiqi et al., supra, at Ex. 20; N. Toplak et al., Autoimmune Response Following

Annual Influenza Vaccination in 92 Apparently Healthy Adults, 8 AUTOIMMUNITY REVIEWS

134 (2008) (Ex. 38); Abdulla Watad et al., Seasonality and Autoimmune Diseases: The

Contribution of the Four Seasons to the Mosaic of Autoimmunity, 82 J. AUTOIMMUNITY 13

(2017) (Ex. 39); Abdulla Watad et al., Autoimmune/Inflammatory Syndrome Induced by

Adjuvants (ASIA) Demonstrates Distinct Autoimmune and Autoinflammatory Disease

Associations According to the Adjuvant Subtype: Insights from an Analysis of 500

Cases, 203 CLIN. IMMUNOL. 1 (2019) (Ex. 40)).)

In the absence of an adjuvant, Dr. DeAngelo proposes that vaccine

hemagglutinins, either alone or in combination with host proteins, can induce an

autoinflammatory state. (Ex. 42, p. 3 (citing Maria Smatti et al., Viruses and

Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms, 11

VIRUSES 1 (2019) (Ex. 50); Timothy Z. Chang et al., Host- and Pathogen-Derived

Adjuvant Coatings on Protein Nanoparticle Vaccines, 2 BIOENGIN. & TRANSLATIONAL

MED. 120 (2017) (Ex. 46)).) He suggests that prior studies have shown increased levels

of autoantibodies in people who receive flu vaccines. (Ex. 23, pp. 7-8 (K. Perdan-

Pirkmajer et al., Autoimmune Response Following Influenza Vaccination in Patients with

Autoimmune Inflammatory Rheumatic Disease, 21 LUPUS 175 (2012) (Ex. 32); Toplak et

al., supra, at Ex. 38.)

House of Delegates, and as an intern delegate for western Pennsylvania to the Pennsylvania Osteopathic

Medical Association’s House of Delegates. (Id. at 2-3.) Dr. DeAngelo has also conducted 167 clinical

research trials, 73 of which where he served as the primary investigator. (Id. at 3-17.)

14

Explaining his citation to ASIA further, Dr. DeAngelo explained that several

proposed mechanisms may underlie the “broader ASIA umbrella.” (Ex. 54, p. 2.)

Specifically, he cites molecular mimicry, bystander activation, polyclonal activation,

superantigen stimulation, and haptenization. (Id.) Ultimately, he explains that he is not

relying on ASIA as “the mechanistic explanation” for petitioner’s condition. (Ex. 62, p.

1.) Rather, he relies on ASIA as “a category of immune-mediated diseases that arise or

worsen in a subset of genetically predisposed individuals . . . .” (Id.) That is, he cites

ASIA as representative of what he opines occurred in this case, “antigens contained in

the influenza vaccine set forth a cascade of events similar to what was originally

described as ASIA and mediated through superantigen formation and epitope

spreading.” (Id.)

In his final report, Dr. DeAngelo introduced a study by Brauner et al., which also

became a major focus of his testimony during the hearing. In Brauner et al., the authors

found that individuals with preexisting connective tissue disease, specifically, Sjogren’s

syndrome, exhibited B-cell hyperactivity following H1N1 inoculation. (Ex. 62, pp. 2-3

(citing Susanna Brauner et al., H1N1 Vaccination in Sjogren’s Syndrome Triggers

Polyclonal B Cell Activation and Promotes Autoantibody Production, 76 ANN. RHEUM.

DIS. 1755 (2017) (Ex. 63)).) This hyperactivity was “characterized by the

overexpression of a variety of immune-related genes, including those downstream of

the endosomal TLR signaling, and an enhanced capacity to undergo class switch and

plasma cell differentiation when triggered by endosomal TLR ligands.” (Id. at 3 (quoting

Brauner et al., supra, at Ex. 63).) Dr. DeAngelo opines that the Brauner results show

that untreated autoimmune patients are at a higher risk of autoimmune exacerbation

when receiving the flu vaccine. (Id.) Dr. DeAngelo further opines that although

petitioner was not diagnosed with Sjogren’s syndrome, her condition is nonetheless a

rheumatic disorder which causes systemic inflammation and autoimmune activation. 8

Thus, according to Dr. DeAngelo, “a solid immunologic and mechanistic parallel can be

drawn in the context of [petitioner’s] influenza vaccine and her untreated UCTD.” (Id.)

During the hearing, Dr. DeAngelo provided detailed testimony regarding several

figures contained within the Brauner paper (Figs. 2, 4, 5, and 6). (Tr. 163-83.) Dr.

DeAngelo concludes that “Brauner’s article[] basically suggest[s] that B cell function

from untreated patients goes through the toll-like receptors, and that is basically

supported by the fact that that response is aborted by the inhibition of the toll-like

receptors with hydroxychloroquine.” (Tr. 183.) Dr. DeAngelo stresses that “this doesn’t

happen in all untreated patients, but . . . not all of them go on to have . . . significant

flares of autoimmunity but they could.” (Id. at 184-85.) Brauner et al. shows “there’s

8 According to Dr. DeAngelo, there is significant overlap among connective tissue diseases. (Tr. 170.)

He testified, “Again, we get back to this autoimmune typology where, you know, you have one common,

you know, disease . . . autoimmune is equal to A is equal to B is equal to C.” (Id.) However, he clarified

that not all connective tissue diseases are comparable, but he confidently placed Sjogren’s,

dermatomyositis, polymyositis, mixed connective, undifferentiated connective, lupus, and possibly

rheumatoid arthritis, all in the same category. (Id.) In contrast, others, such as Reiter’s syndrome,

ankylosing spondylitis, and psoriatic arthritis tend to form their own group. (Id.) Dr. DeAngelo did not

offer any additional testimony regarding what characteristics or pathogenesis makes these diseases

comparable or distinguishable. (See id.)

15

certainly an increase in polyclonal stimulation.” (Id. at 185.) Over-stimulation creates a

risk for the unmasking of an underlying condition or aggravation of an existing condition.

(Id. at 187.)

Dr. DeAngelo furthermore explained that though Brauner involved the H1N1

seasonal flu vaccine, which is adjuvanted, petitioner “still would have responded one

way or the other to the vaccine.” (Tr. 191-92.) He opines that he “do[esn]’t see a

difference really in response.” (Id.) He further agreed that the authors of the Brauner

study did not limit the application of the study to untreated patients with autoimmune

rheumatic disease to the H1N1 Pandemrix vaccine. (Id. at 192-93.) Nowhere did the

authors caution specifically against using an adjuvant. (Id.)

Drawing a logical sequence of cause and effect, Dr. DeAngelo testified that

petitioner’s influenza vaccine “introduced the foreign antigens to her body. She already

had a hyper-excitable state.” (Tr. 203.) Dr. DeAngelo infers that petitioner “had higher

interferon alpha levels.” (Id.) He testified that:

All of the things that we saw in the Brauner study, she probably had all

these. We don’t have any evidence of that, of course, but she had a positive

ANA at 1 to 320. She had a positive RNP. The antigen came into the body.

The human body processed it, her antigen, in kind of a unique way. It may

have been a unique antigen that year. The RNA and the hemagglutinins

change every year when they make these viron vaccines. And we’ve seen

this with other vaccines, where one year you have febrile seizures in

children associated with a particular vaccine, and you don’t see it in other

years. So her body processed it in such a way that her body went through

a process of probable molecular mimicry associated with bystander

activation, epitope spreading, and then finally we saw the polyclonal B cell

activation as part of this process, and presumably by inference, polyclonal

T cell, but, I mean, I’m inferring that because the researchers didn’t really

look at that. And this was manifested in B cells that were clearly in the

plasmablast category, and they were transitioning to plasma cells producing

lots of antibodies, and I believe that those autoantibodies were

autoantibodies, and I think that’s largely responsible for some of her long-

term consequences, but I also feel that the type I interferons were playing

a very prominent role, as well as tumor necrosis factor and all of the other

mediators of inflammation which were turned on by the immunization

process.

(Tr. at 203-04.) Significant to Dr. DeAngelo’s opinion was that there was no antecedent

or precipitant event that would otherwise explain petitioner’s significant worsening. (Id.

at 204.) Dr. DeAngelo testified that there were no new medications introduced, no

respiratory virus, no history of gastroenteritis, and no history of any other sort of

infection prior to this. (Id.)

16

Seeking to establish a proximate temporal relationship between vaccination and

injury, Dr. DeAngelo explained that Figure 1 in Brauner et al., shows a rise in the

plasmablasts peaking at around ten days, and certainly within a fourteen-day timeframe.

(Tr. 207-08; Brauner et al., supra, at Ex. 63, p. 1757, Fig. 1.) Specifically, he explained

that it “take[s] a while for them to produce antibody, and then you see the concomitant

rise in IgG levels, which is also that same time period, and we’ve already showed in

[Figure 1E], we see the polyclonal stimulation is even more profound compared to the

healthy controls, because you see that coming on around day ten. And, of course, it

peaks much later, like at 45 days, but that would be expected.” (Id. at 208.) In

petitioner’s case, Dr. DeAngelo notes that her symptoms and clinical indicators

manifested within two weeks following her vaccination. He therefore concludes that

onset of petitioner’s rheumatic disease is consistent with the timeframe found in the

Brauner study for anticipated/expected rise in antibody response and polyclonal

activation of B cells following vaccination. (Ex. 62, p. 4.)

On cross-examination, Dr. DeAngelo acknowledged that “there’s no way to say

for certain what occurred. Something in the vaccine triggered the immune system, but I

don’t know what that something is in the Brauner article or in [petitioner’s] case.” (Tr.

212-13.) Dr. DeAngelo

believe[s] that it is an antigen within the vaccine, and whether that vaccine

had any homology, either after immune processing . . . [o]r it could have just

simply been that she was responding to the vaccine itself and producing

good antibodies to the influenza, but unfortunately, because she was so

predisposed, she had an overreaching response, and began to respond to

activate other already primed B cell clones. So [he] do[es]n’t really know

the exact process before the polyclonal activation.

(Tr. 213.) According to Dr. DeAngelo, vaccine hemagglutinins, either alone, or in

combination with host proteins, are enough to induce an autoinflammatory state in a

susceptible host. (Tr. 228 (quoting Ex. 42, p. 3).) Simply put, “there’s two different

ways,” and Dr. DeAngelo cannot be sure which process occurred. (Id. at 230.) He

explains that “nobody has done – and nobody would ever do . . . this basic bench

research here, to try and find out which host protein.” (Id.) He believes the

hemagglutinin is a foreign antigen, and “as we’ve seen following vaccination in this

susceptible population in the Brauner article, you see this rise of inflammatory mediators

and antibodies. That means something’s been recognized as bad. Whether that’s the

hemagglutinin or whether that’s the hemagglutinin and a self-protein, [he] cannot say

with any certainty.” (Id. at 230-31.)

Going a step further, Dr. DeAngelo testified that he “believe[s] it could happen

with any antigen, any foreign antigen, whether it’s a natural infection or a component.”

(Tr. 233-34.) In fact, he opined, “It doesn’t have to be flu. It could be – it doesn’t have

to be this strain. But different people respond differently to different strains and different

antigens.” (Id. at 234.) Dr. DeAngelo further agreed that any vaccine the CDC

recommends for routine use in humans can precipitate or cause unmasking of an

17

asymptomatic connective tissue disease. (Id. at 234-35.) On cross examination, he

agreed that any immunogenic protein from any virus or microbe can trigger a connective

tissue disease, in individuals who are already prone. (Id. at 235.)

b. For Respondent 9

i. Erin Wilfong, M.D., Ph.D.

Respondent has offered Dr. Wilfong as an expert in rheumatology. 10 Petitioner

does not object. (Tr. 257.)

Dr. Wilfong suggests that the more likely diagnosis for petitioner’s condition is

mixed connective tissue disease. She explains that “[m]ixed connective tissue disease

(MCTD) is characterized by the presence of high titer RNP antibodies, puffy

fingers/swollen hands, Raynaud’s phenomenon and synovitis (inflammatory arthritis),”

and “myositis (muscle inflammation) is also commonly present.” (Ex. A, p. 3.) Dr.

Wilfong notes that petitioner had an elevated AST/ALT, which suggests mild myositis,

exhibited puffy fingers, and was observed to suffer from synovitis. 11 (Id. at 4.)

Dr. Wilfong also explains that prior to her vaccination, there was already a

concern that petitioner had an emerging connective tissue disease. (Ex. A, p. 5.) She

notes that on June 26, 2013, petitioner was seen by her neurologist, complaining of

vertigo. (Id. (citing Ex. 6, pp. 94-96.) The neurologist ordered an autoimmune workup

to see if an autoimmune disease was contributing to her symptoms. Later, a letter to

petitioner’s neurologist from her rheumatologist stated that petitioner had positive Sm

9 As explained above, respondent presented three reports by Dr. Rose before his passing (Exs. C, I, and

P) and then an additional two reports from Dr. Levison (Exs. Q and S), who succeeded him in this case

and then ultimately testified at the hearing. Petitioner filed a total of five reports by Dr. DeAngelo (Exs.

23, 42, 43, 54, and 62) responding to all of these reports. Although Dr. Rose’s reports remain a part of

the record, his opinions will not be separately summarized given the availability of Dr. Levinson’s opinion.

10 Dr. Wilfong received her medical degree from Duke University School of Medicine in 2011. She

completed her residency in internal medicine at Johns Hopkins Hospital in 2014, a rheumatology

fellowship at the University of California, San Francisco in 2016, and is currently a Pulmonary & Critical

Care fellow at Vanderbilt University. (Ex. B, p. 1.) Dr. Wilfong is certified by the American Board of

Internal Medicine, and the American Board of Internal Medicine – Rheumatology. She is licensed to

practice in California and Tennessee. (Id. at 2.) Dr. Wilfong has participated in six different clinical

research studies and has published eight different pieces of medical literature on biochemistry and

rheumatology. (Id. at 5.)

11 Dr. Wilfong notes that there have been two sets of proposed diagnostic criteria for MCTD, but at the

time of writing, neither had been accepted by the American College of Rheumatology. (Ex. A, p. 3.) The

Alarcon-Segovia criteria are met if the patient shows an Anti-RNP at hemagglutination titer of greater than

or equal to 1:1,600, and at least three symptoms including swollen hands, synovitis, myositis, Raynaud’s

phenomenon, and acrosclerosis – one of which must be synovitis or myositis. (Id. at 4, Table 1.) The

Kahn criteria are met if the patient shows an RNP titer of greater than or equal to 1:1,200 and at least two

of clinical presentations of either swollen fingers, synovitis, myositis, or Raynaud’s phenomenon. (Id.) Dr.

Wilfong explains that petitioner’s RNP titer was at 214 AU/mL, which Dr. Wilfong opines satisfies both

versions of the serologic criteria.

18

and RNP antibodies. (Id. (citing Ex. 6, p. 63.) The rheumatologist expressed concern

that petitioner may be experiencing the early stages of SLE. (Id.)

According to Dr. Wilfong, during the preclinical phase in rheumatic disease,

“genetic and environmental risk factors interact, probably sequentially, to initiate and

propagate the development of autoimmunity, ultimately culminating in detectable tissue

inflammation and injury. Furthermore, disease-related biomarkers, particularly

autoantibodies, develop and evolve, initially in the absence of clinical signs and

symptoms of tissue injury.” (Ex. A, p. 4 (quoting Kevin Deane & Hani El-Gabalawy,

Pathogenesis and Prevention of Rheumatic Disease: Focus on Preclinical RA and SLE,

10 NAT. REV. RHEUMATOL. 212 (2014) (Ex. A, Tab 3)).) Dr. Wilfong notes that studies of

preclinical disease phases have most often been conducted on rheumatoid arthritis

(“RA”) and lupus (“SLE”) patients. Five months preceding her diagnosis petitioner

exhibited high RNP antibodies, which Dr. Wilfong opines places her in the preclinical

phase of MCTD. (Ex. A, p. 5.) Thus, she concludes the vaccination did not cause the

injury. 12 (Id. at 4.)

Dr. Wilfong’s testimony was largely consistent with her expert reports. (Tr. 252-

346.) Dr. Wilfong disagrees with petitioner’s testimony that she developed all of her

connective tissue disease symptoms post-vaccination. (Id. at 285.) Dr. Wilfong

stresses, “She already had the antibodies. She already had arthralgia. She had

morning stiffness noted. She had leukopenia prior to vaccination. Were these enough

that I would have said to her in the office, You definitely have a connective tissue

disease? No.” (Id.) However, she stresses that petitioner’s presentation was

suggestive of an emerging CTD prior to vaccination. (Id.) Dr. Wilfong opines that

petitioner showcased a “relatively typical progression.” (Id. at 286.)

Specifically, Dr. Wilfong opined that petitioner began exhibiting symptoms of an

emerging connective tissue disease in the summer of 2013. (Tr. 266.) She

acknowledged that petitioner complained of arthralgias back in 2010, and while

12 Dr. Wilfong cites several studies with respect to this discussion. In one RA study, 23% of patients had

detectable autoantibodies at least 10 years prior to onset. (Ex. A, p. 4 (citing Jeremy Sokolove et al.,

Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis, 7

PLOS 1 (2012) (Ex. A, Tab 4)).). Over time, the level of autoantibodies rose until the patient eventually

presented clinically. Another study found that the development of anti-CCP antibodies makes a patient

90% likely to develop clinical RA. (Id. (citing Deane & El-Gabalawy, supra, at Ex. A, Tab 3).) In an SLE

study of 130 patients, 78% were found to have anti-nuclear antibodies up to 9.2 years preceding their

diagnosis. (Id. at 5.) Positive ANA was on average detectable three years prior to diagnosis, and 79% of

patients with an RNP component to their SLE showed detectable RNP antibodies as early as 7.2 years

preceding diagnosis with an average detectability of .9 years preceding diagnosis. A longitudinal study by

Frandsen et al., followed up on patients with high-titer anti-RNP antibodies. Only 56 out of 151 patients

had been diagnosed with definitive connective tissue disease when the RNP antibodies were detected.

(Id. (citing P.B. Frandsen et al., Follow-Up of 151 Patients with High-Titer U1RNP Antibodies, 15 CLIN.

RHEUMATOL. 254 (1996) (Ex. A, Tab 5)).) By the end of the study, however, 127 patients had a definite

connective tissue disease, and an additional 21 had probable connective tissue disease. On average,

diagnosis was made 3.1 years after RNP antibody detection. (Id.) Dr. Wilfong uses these studies on

preclinical disease phase to conclude that based on her autoantibody levels, it’s likely that petitioner was

in the preclinical phase of MCTD prior to her flu vaccination. (Id.)

19

arthralgia may indicate joint pain, it doesn’t necessarily correspond to swelling and

inflammation. (Id.) Dr. Wilfong observed that petitioner’s headaches seemed to be

progressing during the summer of 2013 and recalled mention of muscular or migraine

headaches in February of 2013, and in March and during the summer. (Id. at 267.)

She explained that 30 to 35 percent of patients with MCTD will develop vascular

migraine headaches, compared to 12 percent of the general population or 18 percent of

women. 13 (Id.)

By August 2013, petitioner reported morning stiffness. (Tr. 268-69.) Dr. Wilfong

explains that morning stiffness is a diagnostic symptom for inflammatory arthritis—when

“overnight as people aren’t using their joints, their joints get stiffer, and in the morning,

they’re stiff for an hour or two, and the more they use their joints, the better they do.”

(Id. at 268.) The fact that morning stiffness was noted in Dr. Crane’s notes, according

to Dr. Wilfong, “is concerning that the [CTD] was definitely emerging by August of

2013.” (Id. at 268-69.) At the same time, petitioner’s RNP was found to be

exceptionally high titer. (Id. at 269.) Dr. Wilfong explains that “this is the

pathognomonic antibody for . . . mixed connective tissue disease, and so that’s

expected, given [petitioner’s] ultimate clinical course, but, again, it’s very concerning

that we are really hearing the first true clinical obvious manifestation of her MCTD.” (Id.)

Although petitioner reported post-vaccination bilateral shoulder pain, Dr. Wilfong

suggested that shoulder pain complicates CTD diagnosis. (Id. at 282.) She explained

that it is a common complaint among patients, but may be caused by rotator cuff

tendinopathy, for example, or myalgias or muscle pain which could be related to muscle

enzymes subsequently being elevated in petitioner’s mixed connective tissue disease.

(Id.)

Dr. Wilfong further opines that there is no evidence that vaccinations exacerbate

autoimmune rheumatic diseases. (Ex. A, p. 6.) Dr. Wilfong testified that for the

influenza vaccine to act at the triggering event, the antigen should cross-react with the

antibody of interest. (Tr. 302.) For connective tissue disease, the vaccine would either

have to trigger a specific release of the RNP antigen from self in the circulation, leading

to an increased amount of RNP antigen, or the influenza vaccine would need to have

epitopic overlap with RNP. (Id.) Dr. Wilfong stresses, “I’m not aware of . . . evidence

really supporting that.” (Id.) In contrast, Dr. Wilfong cites several epidemiologic studies

that she indicates show “there is substantial evidence that influenza vaccinations are

safe and do not exacerbate systemic rheumatologic conditions.” (Ex. A, p. 6; see also

Tr. 297; Soriano et al., supra, at Ex. 21; Perdan-Pirkmajer et al., supra, at Ex. 32; Carla

G.S. Saad et al., Immunogenicity and Safety of the 2009 Non-Adjuvanted Influenza

A/H1N1 Vaccine in a Large Cohort of Autoimmune Rheumatic Diseases, 70 ANN.

RHEUM. DIS. 1068 (2011) (Ex. A Tab 10); S. van Assen et al., EULAR

Recommendations for Vaccination in Adult Patients with Autoimmune Inflammatory

Rheumatic Diseases, 70 ANN. RHEUM. DIS. 414 (2011) (Ex. A, Tab 12); Mathilde Puges

et al., Immunogenicity and Impact on Disease Activity of Influenza and Pneumococcal

13 Dr. Wilfong further explained that trigeminal neuralgia is an inflammation of the sensory neuron of the

trigeminal nerve—which is associated with MCTD, though the attack can last for weeks to months, and

then abate completely for months to years. (Tr. 267.)

20

Vaccines in a Systemic Lupus Erythematosus: A Systematic Literature Review and

Meta-Analysis, 55 RHEMATOL. 1664 (2016) (Ex. J); Zhengfa Liao et al., Immunogenicity

and Safety of Influenza Vaccination in Systemic Lupus Erythematosus Patients

Compare with Healthy Controls: A Meta-Analysis, PLOS ONE 1 (2016) (Ex. C, Tab 14).)

Turning to Brauner et al., Dr. Wilfong testified that the study is “not broadly

generalizable.” (Tr. 313.) Dr. Wilfong observed that the authors did in fact measure T

cell frequency and found that there was no difference in the overall number of T cells,

the frequency of CD4 or CD8 T cells, or activated T cells using CD62L as the marker.

(Id. at 314.) She stressed that Brauner et al., found no differences in serum cytokines,

such as interferon gamma, interleukin 4, or interleukin 17, in the sera of these patients.

(Id.) Dr. Wilfong testified, that the figures in the Brauner article that Dr. DeAngelo relied

upon showed elevated cytokines relative to the control, without statistical comparisons

for the increase on day one, day ten, day 15, day 45, compared to zero. (Id. at 314-15.)

Therefore, Dr. Wilfong challenges the idea that the study showed statistically different

increases in cytokines, compared to the baseline for Sjogren’s syndrome. (Id.) Dr.

Wilfong also questions extrapolation of these results to vaccine efficacy “because there

was actually no difference in any of the recorded clinical parameters, and the authors

mention that caution is warranted in the abstract, but they don’t actually discuss it

anywhere in the discussion.” (Id. at 315-16.) Dr. Wilfong also questioned the relevance

of the Brauner article because, in her opinion, Sjogren’s syndrome is not an appropriate

model for B cell dysregulation with mixed connective tissue disease and RNP-positive

disease. (Tr. 316.) She explained that B cell dysregulation is a hallmark in Sjogren’s

syndrome more than in any other CTD. (Id.)

In contrast, Dr. Wilfong cites Zhou et al., which showed that, in clinical trials of

vaccination in Sjogren’s patients compared to healthy controls, patients had higher

antibody levels. (Tr. 317; Xingyu Zhou et al., Immune Responses After Influenza

Vaccination in Patients of Primary Sjogren’s Syndrome, 60 RHEUMATOLOGY 224 (2021)

(Ex. W).) However, Dr. Wilfong testified that Zhou et al., did not find any difference in

systemic adverse reactions, local injection site reactions, or changes in clinical or

laboratory parameters in disease activity out to three months. (Id.) Ultimately, Dr.

Wilfong stresses that Brauner et al. sought “to understand how B cells respond to

vaccine[s] and conduct an in-detail, in vitro study evaluating the effects of B cells and

linking the hyperactive state of B cells to proinflammatory cytokine exposures and

changes in intracellular signaling proteins.” (Tr. 318.) She concludes, “That was their

stated goal, not vaccine safety.” (Id.)

On cross examination, Dr. Wilfong testified Brauner et al. did not show any

evolution of new autoantibodies. (Tr. 332.) Nor did the authors find any epitope

spreading. (Id.) She stressed that polyclonal B cell activation alone does not correlate

with disease activity. (Id. at 332-33.) She disagrees with the authors conclusion that

“caution is warranted when considering vaccination in nontreated autoimmune patients.”

(Id. at 334.) Dr. Wilfong does not dispute the authors’ finding of

hypergammaglobulinemia as well as polyclonal B cell activation. (Id. at 344-45.) Even

still, Dr. Wilfong stresses that Brauner et al. used an adjuvanted vaccine. (Id.)

21

ii. Arnold I. Levinson, M.D.

Respondent has offered Dr. Levison as an expert in immunology. 14 Petitioner

does not object. (Tr. 356-57.)

As a threshold issue, Dr. Levinson opines that the ASIA concept is not very

useful and that it “tell[s] us nothing about a causal relationship between vaccine

administration and the disorders that have been reported to the Shoenfeld ASIA

registry, including MCTD.” (Ex. Q, pp. 4-5.) As the name implies, “the supposed

unifying construct” of ASIA is that siliconosis, gulf war syndrome, MMF and other “post-

vaccination phenomena” are all caused by the “untoward actions of adjuvants on the

immune system.” 15 (Id.) Dr. Levinson explains that acceptance of ASIA has waned

over time because it uses an “extremely nonspecific description of clinical features and

[a] very loose definition of the temporal relationship between alleged adjuvant exposure

and onset of disease manifestations.” (Id. at 4.) He notes that recent publications have

challenged the soundness and the utility of these concepts, based “largely on the lack of

specificity of the disorder’s diagnostic criteria and the imprecisely described temporal

relationship between vaccine exposure and onset of symptoms.” (Id. (citing David

Hawkes et al., Revisiting Adverse Reactions to Vaccines: A Critical Appraisal of

Autoimmune Syndrome Induced by Adjuvants (ASIA), 59 J. AUTOIMMUNITY 77 (2015)

(Ex. C, Tab 12); Rohan Ameratunga et al., Evidence Refuting the Existence of

Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA), 5 J. ALLERGY.

CLIN. IMMUNOL. PRACT. 1551 (2017) (Ex. C, Tab 9)).) He notes that critics have argued

that the ASIA diagnostic criteria “would likely encompass all patients with any

autoimmune disorder as well as a large proportion of the general population who have

the prescribed non-specific symptoms.” (Id.) Importantly, Dr. Levinson stresses that

ASIA has not been defined by an underlying biological mechanism, and therefore,

14 Dr. Levinson received his medical degree from the University of Maryland in 1969, completed his

internship in internal medicine at Baltimore City Hospital in 1970, and has held fellowships in

immunobiology, immunology, and allergy at Johns Hopkins Hospital, the University of Pennsylvania

School of Medicine, and the University of California, San Francisco Medical Center. (Ex. R, p. 1.) Dr.

Levinson has served as an assistant professor of medicine and pediatrics at the Uniformed Services

University of Health Sciences, as an associate professor of medicine and neurology at the University of

Pennsylvania School of Medicine, as a full professor of Medicine and Neurology at the University of

Pennsylvania, as associate dean for research at the University of Pennsylvania School of Medicine, and

now as an emeritus professor of medicine and neurology. (Ex. R, p. 1.) He is certified by the American

Board of Internal Medicine and the American Board of Allergy and Clinical Immunology and licensed by

the state of Pennsylvania. (Id. at 2.) Dr. Levinson has served as editor for the Journal of Allergy and

Clinical Immunology and the Journal of Clinical Immunology. (Id. at 4.) He has also published 46 pieces

of peer-reviewed medical literature on allergy, immunology, and neurology. (Id. at 18-21.)

15Dr. Levinson clarifies that adjuvants are “considered by immunologists to be agents that boost specific

T and B cell immune responses to co-administered antigens.” (Ex. Q, p. 4.) Adjuvants boost the immune

response by “directly stimulating innate immune responses, which subsequently promote the

development of antigen-specific adaptive . . . responses in the lymph nodes that drain the site of

antigen/adjuvant exposure.” (Id.) The most commonly used adjuvants in vaccines approved for

administration in the United States are aluminum salts. However, as Dr. DeAngelo likewise

acknowledges, Dr. Levinson stresses that petitioner’s vaccination did not contain any adjuvants. (Id.)

22

including it as a clinical entity “provides no clear exposition of the biologic processes

responsible for the pathogenesis of [ASIA].” (Id. at 4-5.)

Dr. Levinson explains that the literature Dr. DeAngelo relies on to show an

association between autoimmune disease and the flu vaccine are simply temporal

associations but do not find a causal link. (Ex. Q, p. 6.) Additionally, Dr. DeAngelo

“further muddies the water by saying that the medical literature he discussed actually

indicates that flu vaccination with adjuvanted or unadjuvanted vaccines induces more

frequent and ‘severe reactions’ in patients with autoimmune disease.” (Id.) Dr.

Levinson explains that if Dr. DeAngelo is suggesting that the vaccines exacerbate

clinical autoimmune disease, he has misinterpreted the literature because there is

“absolutely no epidemiological data that support his contention,” and that if this were

true, the European League Against Rheumatism (“EULAR”) would not recommend

administration of the flu vaccine to patients with rheumatic disease. (Id.)

Dr. Levinson questions why Dr. DeAngelo raised the concept of autoimmune

tautology because there is no disagreement that petitioner suffered from more than one

autoimmune disease, specifically Hashimoto’s thyroiditis and MCTD. (Ex. Q, p. 6.)

According to Dr. Levinson, this concept does not shed any light on the medical theory,

logical sequence of cause and effect, or accepted timing of onset linking the flu vaccine

to MCTD. (Id.) Dr. Levinson also notes that Dr. DeAngelo’s reliance on literature

regarding monogenic autoinflammatory diseases is misguided because “these disorders

are pathogenically quite different from the polygenic autoimmune disorders,” that

petitioner suffered from. (Id. at 7.)

Dr. Levinson is critical of Dr. DeAngelo’s reliance on studies by Smatti et al., and

Chang et al., to demonstrate that vaccine hemagglutinins can produce an

autoinflammatory state without any adjuvant. (Ex. Q, p. 7.) According to Dr. Levinson,

Smatti et al., examined live viral infections, rendering comparison to vaccination as false

equivalency given that viruses replicate in vivo, thereby augmenting the magnitude of

the viral antigen encountered. (Id.) Smatti et al. did examine two inactivated flu

vaccines (Pandemrix and Focetria), both adjuvanted, which is counter to Dr. DeAngelo’s

reliance on the paper. (Id.) Chang et al. dealt with the mechanisms by which IgM

coated ovalbumin-modified nanoparticles enhanced the immune response of mice to

ovalbumin. Dr. Levinson explains that this is a very specialized experiment model that

deals with a solid phase antigen which measured the immune response to the antigen,

and not the induction of an autoimmune response. (Id.) Thus, according to Dr.

Levinson, none of the literature cited by Dr. DeAngelo shows how an inactivated,

adjuvant-free soluble flu antigens can “somehow be adjuvanted by a host protein and

give rise to an autoimmune response.” (Id. at 8.)

Dr. Levinson’s testimony was largely consistent with the opinions expressed in

his expert reports. (Tr. 349-408.) Generally speaking, Dr. Levinson testified that

molecular mimicry is a term that refers to “sharing of antigenic determinates or what we

call epitopes, particularly molecular epitopes or motifs on exogenous antigens and self

antigens.” (Tr. 361.) In the abstract, molecular mimicry involves the sharing of

23

epitopes. (Id.) However, Dr. Levinson testified that most proposed cases of molecular

mimicry do not translate into clinical tissue destruction. (Id. at 361-62.) Despite proof

that there is epitope sharing on an exogenous antigen and a self-antigen, other features

must be present “in terms of licensing or weaponizing that abstract molecular mimicry.”

(Id. at 362.) The other features include antigen presentation, profound tissue

inflammatory milieu, quantitative and qualitative features of T cells or B cells that

engage in an inflammatory reaction. (Id.) Dr. Levinson stresses that we must consider

the status or integrity of the immunoregulatory mechanisms that are in place to

suppress this type of reactivity that might occur as a response to molecular mimicry.

(Id.)

With respect to Brauner et al., Dr. Levinson stresses that the study again

involved an adjuvanted H1N1 vaccine. (Tr. 370-71.) Furthermore, the adjuvant at issue

is AS03, an adjuvant system containing squalene, alpha-tocopherol, polysorbate 80.

(Id.) Squalene, he explains, is a component of shark tincture, while alpha-tocopherol is

an “iso form of vitamin E,” which is immune-stimulating, and polysorbate 80 is an

emulsifying agent. (Id.) Dr. Levinson suggests that this is a powerful adjuvant that

markedly increases antigen uptake and presentation in the draining lymph node,

particularly when it’s administered as part of a vaccine. (Id. at 371.) He explains that

AS03 stimulates powerful B and T cells—creating a much higher magnitude of antibody

response. (Id.) Importantly, there was no control for this adjuvant in Brauner et al. (Id.

at 371-72.) Additionally, Dr. Levison notes that Brauner et. al. offers no evidence of

exacerbation of underlying disease, i.e., Sjogren’s syndrome, or the nonspecific

symptoms of rheumatic autoimmune disease (other than fever). (Id. at 374.)

Subsequent to the Brauner article, Zhou et al., studied patients with Sjogren’s

syndrome to determine if, in fact, immunization with a flu vaccine, this time,

unadjuvanted seasonal H1N1 flu vaccine, affected immune parameters and whether the

vaccine led to an exacerbation of clinical disease. (Tr. 376.) Dr. Levinson emphasized

the fact that Zhou et al. used established disease activity indices to study patients at

baseline and as late as three months post-vaccination. (Id.) The authors observed

some changes in T cell subsets, post-vaccination. (Id.) Notably, they did not see the

kinds of results seen in the earlier Brauner study, with regard to the B cell activation.

(Id.) In particular, Dr. Levinson observed that Zhou et al., did not see increased

numbers of plasmablasts or memory B cells in among the patients. (Id. at 377.) Nor did

they see evidence of polyclonal B cell activation in the patients’ serum. (Id.) As Dr.

DeAngelo testified, on occasion results in these studies will show evidence of the

activation of the complement system, and C3 and C4 will “sometimes go down.” (Id.) In

Zhou et al., however, no such results were found. On cross examination, Dr. Levinson

acknowledged that Zhou et al. did not differentiate between patients who were treated

with immunotherapy versus those that were not—which he explained is a shortcoming

of the study. (Tr. 394.) In response, Dr. Levinson stressed that Zhou et al. conducted

the study in response to the Brauner study. (Id.) He stressed that the authors focused

on cellular activation in vitro. (Id.)

24

V. Discussion

a. Diagnosis

Petitioner’s experts opine that petitioner more likely than not suffers from UCTD.

(Tr. 78-79.) In his prehearing brief, respondent concurs that more likely than not,

petitioner’s diagnosis includes a connective tissue disease. (ECF No. 96, p. 15.)

However, respondent’s experts favor a diagnosis of MCTD. (Ex. A, p. 7; Ex. Q, p. 2; Tr.

257-66.) 16 Yet, as Dr. Levinson observes, “the terms MCTD and UCTD are often used

interchangeably to diagnose an autoimmune rheumatic condition that fails to meet the

criteria of a distinct condition such as systemic lupus erythematosus or polymyositis.”

(Ex. Q, p. 2). Furthermore, Dr. Wilfong testified that, “this is an argument of semantics,

whether we’re going by classification criteria [or] diagnostic criteria . . . [h]er clinical

symptoms are the same and . . . how exactly we classify or diagnose her is really

irrelevant to causation or her clinical course.” (Tr. 265-66.)

Thus, based on my review of the relevant medical literature and expert opinions

in this case, it is not necessary to parse whether petitioner’s condition is better

characterized as UCTD or MCTD. Although petitioner must specify her injury and

shoulder the burden on causation, the function of a special master is not to ‘diagnose’

vaccine-related injuries. See Andreu v. Sec’y of Health & Human Servs., 569 F.3d

1367, 1382 (Fed. Cir. 2009); Stillwell v. Sec’y of Health & Human Servs., 118 Fed. Cl.

47, 56 (2014); 42.U.S.C. § 300aa-11(c). Given that the diagnosis stated by petitioner’s

treating rheumatologists was UCTD and given Dr. Wilfong’s testimony that “how exactly

we classify or diagnose [petitioner] is really irrelevant to causation,” the causation-in-fact

analysis will be addressed in the context of UCTD. (Tr. 266.)

b. Petitioner’s Medical Theory (i.e., Althen Prong One / Loving Prong

Four)

The most extensively debated aspect of this case is the validity of petitioner’s

theory of causation explaining how petitioner’s flu vaccination could have significantly

aggravated her condition. This presents a threshold issue in this case. Accordingly, I

will address petitioner’s theory of causation first. Having found that petitioner did not

meet her burden of proof on this point, I will then more briefly address the remaining

elements of the six-part Loving test discussed above.

Petitioner’s burden under the first Althen prong / fourth Loving prong is to

provide, by preponderant evidence, “a medical theory causally connecting the

vaccination and the injury.” Althen, 418 F.3d at 1278. Such a theory must only be

“legally probable, not medically or scientifically certain.” Knudsen v. Sec’y of Health &

Human Servs., 35 F.3d 543, 548-49 (Fed. Cir. 1994). Petitioners in the Vaccine

Program are not charged with demonstrating the “exact process” or precise mechanism

underlying their alleged vaccine injury. Kottenstette v. Sec’y of Health & Human Servs.,

861 F. App’x 433, 441 (Fed. Cir. 2021); Knudsen, 35 F.3d at 548. Moreover, scientific

16 Dr. Rose suggested a differential diagnosis of UCTD or MCTD. (Ex. C, p. 8.)

25

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.” Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1380

(Fed. Cir. 2009). However, to satisfy this prong, petitioner’s theory must be based on a

“sound and reliable medical or scientific explanation.” Knudsen, 35 F.3d at 548;

Boatmon, 941 F.3d at 1359.

As explained above, much of the discussion within the experts’ reports focused

on the ASIA concept. Dr. DeAngelo explained that several proposed mechanisms may

underlie the “broader ASIA umbrella,” citing mechanisms such as molecular mimicry, 17

bystander activation, polyclonal activation, superantigen stimulation, 18 and

haptenization. (Ex. 54, p. 2.) Ultimately, however, he explains that he is not relying on

ASIA as “the mechanistic explanation” for petitioner’s condition. Rather, he relies on

ASIA as “a category of immune-mediated disease that arise or worsen in a subset of

genetically predisposed individuals.” (Ex. 62, p. 1.)

17 Though molecular mimicry is a generally accepted scientific concept, and is frequently invoked in

Vaccine Program cases, mere mention of this theory does not constitute a preponderant showing.

McKown v. Sec’y of Health & Human Servs., No. 15-1451V, 2019 WL 4072113, at *50 (Fed. Cl. Spec.

Mstr. July 15, 2019) (stating that “merely chanting the magic words ‘molecular mimicry’ in a Vaccine Act

case does not render a causation theory scientifically reliable, absent additional evidence specifically

tying the mechanism to the injury and/or vaccine in question”). In his reports, Dr. DeAngelo did initially

purport to demonstrate molecular mimicry by citations to studies by Borba et al. and Shah et al. (See,

e.g., Ex. 54, p. 6.) Because he ultimately testified that he cannot rely on molecular mimicry, it is not

necessary to address this at length. However, I note that Dr. DeAngelo’s reliance on these two studies is

unpersuasive. Borba et al. focuses on sarcoidosis, Sjogren’s syndrome, UCTD, and silicone implant

incompatibility as classic examples of ASIA. (Vania Borba et al., Classic Examples of the Concept of the

ASIA Syndrome, 10 BIOMOLECULES 1 (2020) (Ex. 56).) ASIA is addressed separately below; however, Dr.

DeAngelo fails to explain how this study supports molecular mimicry between components of the flu

vaccine and any tissue implicated in UCTD. Shah et al. suggested that SARS-CoV-2 infection can

potentially lead to an array of rheumatological and autoimmune manifestations via molecular mimicry,

“bystander killing,” epitope spreading, viral persistence and formation of neutrophil extracellular traps.

(Sanket Shah et al., Autoimmune and Rheumatic Musculoskeletal Diseases as a Consequence of SARS-

CoV-2 Infection and Its Treatment, 40 RHEUMATOL. INT’L. 1539 (2020) (Ex. 58).) Dr. Levinson, however,

explains that “[t]here is no evidence presented that the supposed mimicking SARs CoV-2 epitopes

function as T or B cell immunogenic epitopes.” (Ex. S, p. 3.) Furthermore, there is no evidence

presented “that any of the cross-reactive sequences on human proteins actually represent immunogenic

epitopes and, more importantly, are the targets of an adaptive immune attack as a consequence of SARs

CoV-2 infection.” (Id.)

18 Dr. DeAngelo also proposed superantigen formation as another possible cause for polyclonal activation

in this case. (Tr. 241.) In response, Dr. Wilfong testified that superantigen formation is not a reliable

theory of causation to establish that the flu vaccine more likely than not can cause connective tissue

disease or a similar rheumatic autoimmune disease. (Id. at 378.) According to Dr. Wilfong,

superantigens “turn on a load of T cells, in the case of a T cell superantigen, or B cells, in the case of a B

cell superantigen.” (Id. at 379.) According to Dr. Wilfong, the antigens that are present in a seasonal

influenza flu vaccine are conventional antigens. (Id.) Specifically, she testified that “I’m not aware of any

evidence that a viral flu hemagglutinin or neuraminidase has any kind of superantigen potential, so I don’t

see how [Dr. DeAngelo] go[es] from flu vaccine antigen to superantigen activity in vivo.” (Id. at 379-80.)

Superantigens, according to Dr. Wilfong, induce roughly 60 percent of T cells or 30-60 percent of B cells.

(Id. at 379.) In contrast, conventional antigens induce only .0001 or one in 10,000, T cells. (Id.)

26

Thus, Dr. DeAngelo ultimately opined that his theory relies on polyclonal

activation, further explaining that “you have to have some sort of stimulus. And you

have to have an antigenic stimulation to get polyclonal activation.” (Tr. 212.) He

indicated that other possible mechanisms that occur before polyclonal stimulation

include epitope spreading and molecular mimicry. (Id.) However, he testified that “the

only one I can confirm is that from the literature that I’ve reviewed is that there’s

definitely evidence here from the Brauner article that, at least in Sjogren’s syndrome

and by inference other connective tissue disease, that you see polyclonal activation.”

(Id.) Dr. DeAngelo explained that “there’s no way to say for certain what occurred.

Something in the vaccine triggered the immune system, but I don’t know what that

something is in the Brauner article or in [petitioner’s] case.” (Tr. 212-13.) According to

Dr. DeAngelo, “because [petitioner] was so predisposed, she had an overreaching

response, and began to respond to activate other already primed B cell clones” though

he admitted, “I don’t really know the exact process before the polyclonal activation.” (Id.

at 213.)

Examining this theory of causation requires several separate discussions. First,

the analysis below addresses whether Dr. DeAngelo is persuasive in relying on the

above-referenced Brauner article to evidence polyclonal B cell activation occurring in

the context of this vaccine and injury. Second, a subsequent analysis addresses by

what basis Dr. DeAngelo suggests that the flu vaccine can act as the antigenic stimulant

that he indicates is necessary to begin that process. Finding that Dr. DeAngelo is not

persuasive on either point, the third and final analysis examines whether Dr. DeAngelo

is persuasive in invoking ASIA “as a category of immune-mediated disease” to

nonetheless support vaccine-causation as a matter of epidemiology.

1. Polyclonal B Cell Activation

Dr. DeAngelo opines that “[a]utoimmune diseases such as UCTD are believed to

be the result of aberrant B and T cell dysfunction directed against self-antigens.” (Ex.

23, p. 10 (citing Watad et al., supra, at Ex. 40).) In that regard, he opines that

petitioner’s alleged vaccine-injury resulted from polyclonal B cell activation. (Tr. 212-

13.) As noted above, Dr. DeAngelo sought to draw support for this mechanism primarily

from a study by Brauner et al. (Tr. 163-200; Brauner et al., supra, at Ex. 63.) Brauner

et al., found that individuals with preexisting connective tissue disease, specifically

Sjogren’s syndrome, exhibited B-cell hyperactivity following H1N1 vaccination.

(Brauner et al., supra, at Ex. 63.) This hyperactivity was “characterised by the

overexpression of a variety of immune-related genes, including those downstream of

the endosomal TLR signaling” with an enhanced capacity to undergo class switching

and plasma cell differentiation when triggered by endosomal TLR ligands. (Id. at 1758.)

Dr. DeAngelo opines that these results show that untreated autoimmune patients are at

a higher risk of autoimmune exacerbation when receiving the flu vaccine. (Ex. 62, p. 3.)

However, Brauner et al. acknowledge that the symptoms in Sjogren’s patients in

their study did not correspond or correlate to their B cell findings. Despite the markedly

increased B cell responses observed in the Sjogren’s patients, Brauner et al. “noted no

27

significant differences between patients and controls with regard to the recorded clinical

parameters fever, fatigue, myalgia and arthralgia.” (Brauner et al., supra, at Ex. 63, p.

1762.) These manifestations, according to the authors, “represent common symptoms

of both Sjogren’s syndrome and adverse reactions to vaccination.” (Id.) Notably,

however, similar frequencies of affected individuals were observed after vaccination in

both groups. (Id.) In his testimony, Dr. DeAngelo suggested that the only symptom that

showed a significant increase was the frequency of fever. (Tr. 157.) According to Dr.

DeAngelo, the study finding regarding disease activity (depicted at Figure 2) is “kind of

irrelevant, simply because it’s looking at symptoms that would be associated with like

lupus or mixed connective tissue disease” while Sjogren’s patients typically suffer dry

eyes and dry mouth, exocrine dysfunction in the pancreas or lungs, or even respiratory

symptoms. (Id. at 165.) However, Brauner et al. explained that they monitored

“common clinical signs of disease activity” which included fever, fatigue, myalgia, and

arthralgia, parameters which are now part of the Sjogren’s syndrome disease activity

scores (known as ESSPRI and ESSDAI). (Brauner et al., supra, at Ex. 63, p. 1756.)

Despite Dr. DeAngelo’s criticism that these symptoms are irrelevant to Sjogren’s

syndrome, Brauner et al. confirmed that these symptoms are indeed part of the

Sjogren’s syndrome disease activity scores. Therefore, the fact that Brauner et al.

noted no significant difference between patients and controls with regard to the clinical

parameters is significant and undercuts the authors own caution against vaccination.

Additionally, studies conducted both before and after Brauner further confirm that

post-vaccination findings have not been pathogenic. The Brauner authors report, “[i]n

contrast to previous studies reporting less vigorous immune responses to vaccination in

patients with autoimmune rheumatic disease, we found that untreated patients with

autoimmune [primary Sjogren’s syndrome] developed higher levels of vaccine-specific

IgG antibodies than matched controls.” (Brauner et al., supra, at Ex. 63, p. 1762.) In

one of the prior studies, in 2006 Holvast et al., measured antibody titers against

influenza viruses in patients with quiescent lupus 30 days post influenza vaccination. (A

Holvast et al., Safety and Efficacy of Influenza Vaccination in Systemic Lupus

Erythematosus Patients with Quiescent Disease, 60 RHEMATOL. 224 (2021) (Ex. V).)

The authors included four patient groups: (1) no drug treatment; (2) hydroxychloroquine

treatment; (3) azathioprine treatment; and (4) prednisone treatment. (Id. at 913.) The

patients were vaccinated with Influvac, a subunit vaccine in October and November

2003. (Id. at 914.) Sera of the patients was tested against three vaccine strains, H3N2,

A/H1N1, and B/Hong Kong. (Id.) Results (shown in Figure 1) using the validated

disease activity indexes (“SLEDAI scores”) showed no evidence of disease

exacerbation or increase in patient perception of disease activity. (Id. at 916.) These

results, according to Holvast et al., are consistent with previous studies in which clinical-

and laboratory-assessed lupus disease activity did not increase post-vaccination. (Id.)

Overall, Holvast et al., stress that influenza vaccination is safe in SLE patients.

In direct response to Brauner’s study, Zhou et al. designed a study to monitor

clinical features and serological responses in patients with primary Sjogren’s syndrome

who received China’s domestic quadrivalent influenza vaccine, a live attenuated

vaccine containing H1N1, H3N2, and the Yamagata lineage. (Zhou et al., supra, at Ex.

28

W, p. 225.) Zhou et al.’s results demonstrated that Sjogren’s patients developed higher

levels of vaccine-specific IgG antibodies than the healthy controls, consistent with

Brauner et al. (Id. at 226-28.) Importantly, however, the robust immune responses to

vaccination “[were] not accompanied by an increase in disease-specific serological

immune responses.” (Id.) Moreover, influenza vaccination did not aggravate disease

severity or any other significant adverse effects. 19 (Id.)

Further to this, Dr. Levison raised the use of an adjuvanted H1N1 vaccine as a

significant limitation in the Brauner study. (Tr. 370.) He stresses that the H1N1 vaccine

examined in Brauner was adjuvanted with AS03, an adjuvant system containing

squalene, alpha-tocopherol, polysorbate 80. (Id. at 370-71.) Squalene, he explains, is

a component of shark tincture; while alpha-tocopherol is an “iso form of vitamin E” which

is in and of itself immune-stimulating, and polysorbate 80 as an emulsifying agent. (Id.)

Taken together, Dr. Levinson stresses that this is a powerful adjuvant that markedly

increases antigen uptake and presentation in the draining lymph node, particularly when

it’s administered as part of a vaccine. (Id. at 371.) He explains that AS03 stimulates

powerful B and T cells—creating a much higher magnitude of antibody response. (Id.)

Importantly, Dr. Levinson stresses that there was no control for this adjuvant in Brauner

et al. (Id. at 371-72.)

Moreover, the authors themselves discuss additional reasons that their

hypothesis is tied to the specific vaccine formulation they studied, the 2009 pandemic

split vaccine – which suggests that their results may not be generally applicable, as Dr.

DeAngelo suggests. (Brauner et al., supra, at Ex. 63, p. 1762.) Brauner et al.

acknowledge that “[i]t is therefore possible that RNA present in the split-virus Pandemrix

vaccine used in our study may contribute to the increased plasma cell differentiation

and antibody production detected in patients by stimulating patients by stimulating B cell

endosomal TLRs.”20 (Id.)

In light of all of the above, Dr. DeAngelo’s reliance on Brauner et al. is

unpersuasive.

2. Hemagglutinin

As explained above, Dr. DeAngelo acknowledges that he is unable to explain

what process precedes the polyclonal activation he posits; however, he observed that

the process requires “some sort” of preceding antigenic stimulus. (Tr. 212.) In that

19 The authors also observed a significant increase of Th17 cells in patients with Sjogren’s. (Holvast et

al., supra, at Ex. V, p. 229.) Despite the increase in Th17 cells, the authors stress that the Sjogren’s

patients’ overall disease activity did not change. (Id.) To explain this increase, Zhou et al. suggest that

vaccines induce stable, long-term Th17 memory responses, and therefore these results are not

pathogenic in Sjogren’s. (Id.)

20

Brauner et al. discuss another study showing that TLR7 was required for optimal antibody production

post-immunization with the 2009 pandemic split vaccine in mice. (Id.) Those authors suggested that this

was likely due to TLR7 recognition of viral RNA present in the split vaccine. (Id.)

29

regard, Dr. DeAngelo suggested that “the inclusion of an adjuvant may not be

necessary for an unregulated autoinflammatory response in a susceptible host such as

[petitioner].” (Ex. 42, p. 3.) He cites a literature review by Smatti et al., which found that

“the literature supports the contention that viruses modify the clinical picture of

autoimmune diseases,” and suggests that “distinct antigen formulations may contribute

to the varying rates of autoimmunity observed in different studies exploring the

frequency of vaccine-associated autoimmunity.” 21 (Id. (citing Smatti et al, supra, at Ex.

50).) Thus, in his reports Dr. DeAngelo cites a study by Chang et al. to opine that host-

derived proteins can, in certain circumstances, have an adjuvant effect, and therefore,

“the vaccine hemagglutinins, either alone or in combination with host proteins, is

enough to induce an autoinflammatory state in a susceptible host.” (Id. (citing Chang et

al., supra, at Ex. 46); Tr. 230.)

During his testimony, Dr. DeAngelo testified that there are “two different ways”

that hemagglutinins can induce autoinflammation, though he admitted “I’m not sure

which way.” (Tr. 230.) Dr. DeAngelo explained that “hemagglutinin is a foreign antigen”

and “as we’ve seen following vaccination in this susceptible population in the Brauner

article, you see this rise of inflammatory mediators and antibodies.” (Id.) According to

Dr. DeAngelo, “that means something’s been recognized as bad. Whether that’s the

hemagglutinin or whether that’s the hemagglutinin and a self-protein, I cannot say with

any certainty.” (Id. at 230-31.)

Chang et al. studied the mechanisms by which IgM coated ovalbumin-modified

nanoparticles enhanced the immune response of mice to ovalbumin. 22 (Chang et al.,

supra, at Ex. 46.) Chang et al. observed enhanced T-cell activation and complement

production by the particles after absorbing the proteins. (Chang et al., supra, at Ex. 46,

pp. 127-28.) While this group coated the nanoparticles used in these experiments with

murine IgM to enhance complement fixation and antigen responses, Dr. Wilfong

stresses that these nanoparticles were also coated in recombinant ovalbumin, which is

not a mouse-derived protein and is one of the most common adjuvants used in murine

vaccination studies. (Ex. O, p. 2.) Moreover, Figure 2B demonstrates that the addition

of murine IgM (host protein) to the ovalbumin nanoparticles fail to increase the immune

response. (Chang et al., supra, at Ex. 46, p. 124.) Thus, Dr. Wilfong is persuasive in

explaining that Chang et al. does not show a host protein acting as the adjuvant in this

experiment.

21 Dr. Rose suggested the Smatti study makes a “strong case” that several infectious agents may lead to

particular diseases. (Ex. P, p. 2.) However, Dr. Rose explained that “[t]he only well documented example

of multiple autoimmune diseases associated with the same infection is Epstein-Barr virus infection,” which

has not been linked to UTCD. (Id.) Dr. Rose stressed that the Smatti study focused on living, infectious

organisms. (Id.) The most cited example of a non-viable vaccine producing an autoimmune disease was

during the 1970’s swine flu epidemic when the flu vaccine was linked to an increased occurrence of GBS.

However, Dr. Rose explained that these cases of GBS only lasted a few weeks, and “not at all like the

chronic inflammatory disease” UCTD. (Id.)

22Dr. Rose explained that “[n]anoparticles are highly sensitive to size and surface, and [therefore] their

use in vaccines is still speculative.” (Ex. P, p. 3.)

30

3. Epidemiological Evidence and the ASIA Concept

Even in the absence of an identified autoantibody, or evidence of polyclonal B

cell activation, an epidemiological association between undifferentiated connective

tissue disease and the flu vaccine could still potentially support a causal theory. In that

regard Dr. DeAngelo cites to ASIA as an identification of a relevant category of vaccine-

triggered immune-mediated diseases even if it does not provide mechanistic evidence

of causation. Here, however, the epidemiological evidence filed in this case fails to

demonstrate a causal link between the flu vaccine and the onset or aggravation of

UCTD.

As a general matter, it is true that petitioners in the Vaccine Program are not

required to present epidemiological evidence to establish their causation burden under

Althen. Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1325 (Fed. Cir.

2010). However, “[n]othing in Althen or Capizzano requires the Special Master to

ignore probative epidemiological evidence that undermines petitioner’s theory.” D’Tiole,

726 F. App’x at 811 (citing Andreu, 569 F.3d at 1379 (“Although Althen and Capizzano

make clear that a claimant need not produce medical literature or epidemiological

evidence to establish causation under the Vaccine Act, where such evidence is

submitted, the Special Master can consider it in reaching an informed judgment as to

whether a particular vaccination likely caused a particular injury.”) (emphasis added));

Grant v. Sec’y of Health & Human Servs., 956 F.2d 1144, 1148-49 (Fed. Cir. 1992)

(considering negative epidemiological studies).

Respondent cites a number of studies demonstrating the safety of the flu vaccine

and the lack of a causal link with onset or aggravation of UCTD. A study conducted by

Saad et al. (2011), evaluated 1668 patients with autoimmune rheumatic disease,

including 69 with MCTD, which found no major relapses triggered by influenza

vaccination. (Saad et al., supra, at Ex. A, Tab 10.) The study’s main hypothesis was to

evaluate the safety of the flu vaccine in connective tissue disease patients, while the

safety and disease stability was investigated secondarily. (Id.) The SLE disease index,

a calculation used to gauge disease activity, did not increase after vaccination in the

study. (Id. at 1071.) This strongly suggests that the flu vaccine had no impact on the

subjects’ disease course, and furthermore, that the vaccine does not lead to connective

tissue disease flares.

A review by the European League Against Rheumatism (2011) concluded that flu

vaccination did not cause SLE flares, systemic sclerosis, or granulomatosis with

polyangiitis, ultimately recommending inactivated flu vaccinations to rheumatic disease

patients. (van Assen, supra, at Ex. A, Tab 12.) Dr. Wilfong relies on these studies to

opine that “there is substantial evidence that influenza vaccinations are safe and do not

exacerbate systemic rheumatologic conditions.” (Ex. A, p. 6.) Another review, Liao et

al. (2016), combined data from clinical trials, including 13 studies with data on FELDAI

scores, for a total of 1,106 patients, including low, moderate and stable disease

courses. (Liao et al., supra, at Ex. C, Tab 14, p. 5.) Trivalent, bivalent, and univalent

influenza vaccines were used in the studies. (Id.) The authors concluded that “[t]here

was [a] lack of direct evidence[] to verify that influenza can trigger exacerbation and

31

induce serious events.” (Id. at 11.) Some patients with serious adverse events had

other baseline diseases. (Id.) Liao et al. highlight the fact that influenza vaccines

produce immunological responses during the first few weeks following vaccination. (Id.)

If the vaccination triggered disease exacerbation, the authors stress that “it would be

expected to happen particularly during this early period.” (Id.) Yet, in their review, the

duration between vaccination and occurrence of adverse events was greater than four

weeks in some reported cases. (Id.)

Subsequently, van Assen et al. (2011) conducted a review of the reports that

formed the basis for the EULAR review. (S. van Assen et al., Vaccination in Adult

Patients with Auto-Immune Rheumatic Diseases, 10 AUTOIMMUNITY REVIEWS 341 (2011)

(Ex. A, Tab 11).) The authors questioned whether vaccines cause significant harm to

patients with autoimmune inflammatory rheumatic disease, generally, and specifically,

in those with unstable disease and those using immunomodulating agents. (Id. at 345.)

Upon their review, van Assen et al., reported no increase in disease activity among

rheumatoid arthritis and lupus patients following influenza vaccination. (Id.) Other

studies in lupus patients found either no flare or mild flares (up to 35%). (Id.) However,

the authors caution that these studies did not include disease-controls, making their

interpretation difficult. (Id.) Likewise, no flares were reported in Wegener

granulomatosis or systemic sclerosis patients post influenza vaccination. (Id.) Of note,

in all of the aforementioned studies the authors note that inactivated influenza vaccines

were used. The authors furthermore acknowledge that many case series and case

reports regarding the side effects of vaccination in autoimmune inflammatory rheumatic

disease have been published, though they were excluded from this review since the

“these cannot distinguish natural course of the underlying AIIRD from possible adverse

effects caused by vaccination.” (Id.)

Lastly, Puges et al. (2016), presented a literature review on the immunogenicity

of influenza and pneumococcal vaccines in systemic lupus erythematosus. (Puges et

al., supra, at Ex. J.) The influenza study contained three studies with a combined 1,598

patients and 800 controls that integrated SLEDAI scoring. (Id. at 1666.) Patients

received an inactivated trivalent vaccine containing three viral strains, AH1N1, AH3N2

and B. (Id. at 1665.) In this study 594 patients were systematically scored. (Id. at

1670, Fig. 6.) The results from this study revealed that the change in SLEDAI score

pre-and-post influenza vaccination was 0.6, not reaching statistical significance. (Id.)

According to Dr. Wilfong, the change in SLEDAI score associated with any increased

treatment for lupus is 1.5. (Tr. 297-98.) “And so there’s no evidence for this very large

meta-analysis that influenza vaccination was associated with increased disease activity

in lupus.” (Id. at 298.)

Addressing these studies, Dr. DeAngelo notes that they primarily center around

the recommendation from large committees, such as the EULAR’s conclusion that

vaccination did not cause disease flares in SLE, systemic sclerosis, or granulomatosis

with polyangiitis. (Ex. 23, p. 9 (citing van Assen et al., supra, at Ex. A, Tab 12).) He

explains that such conclusions assume that all connective tissue diseases and patients

are the same, and that, in the case of the 2011 EULAR article, the authors noted that

“[m]ore research is needed, particularly regarding the incidence of vaccine-preventable

32

infectious diseases and the safety of vaccination in patients,” with autoimmune

inflammatory rheumatic diseases (“AIIRD”). (Id. (quoting van Assen et al., supra, at Ex.

A, Tab 12).) Dr. DeAngelo criticizes respondent’s reliance on van Assen and Puges et

al. in particular because they assume that “all connective tissue diseases and patients

are the same.” (Id.) During the hearing, however, Dr. DeAngelo suggested that the

results of the Brauner et al. study would be the same in patients with undifferentiated

tissue disease, despite the fact that Brauner et al.’s study involved patients with

Sjogren’s syndrome. (Tr. 190.) According to Dr. DeAngelo, some connective tissue

diseases are “tightly linked.” (Id.) On direct examination, petitioner’s counsel inquired:

Q: . . . Do you believe the outcome of [Brauner et al.] would have been any

different with the connective tissue disease being the subject disease as

opposed to --

A: None of the ones that I believe are tightly linked -- that would be your

lupus, [MCTD], [UCTD], dermatomyositis, polymyositis, that group -- lupus,

scleroderma, CREST, that group, I think the results would be the same.

Would it be the same with ankylosing spondylitis, psoriatic arthritis, and

Reiter’s syndrome? Probably not, but, you known, I mean, who knows?

(Id.)

The literature filed in this case indicates that the essence of undifferentiated

connective tissue disease is “the existence of conditions characterized by the presence

of clinical and serological manifestations suggestive of autoimmune diseases but not

sufficient to make a diagnosis of a defined CTD.” (M. Mosca et al., Undifferentiated

Connective Tissue Diseases (UCTD), 6 AUTOIMMUNITY REVIEWS 1, 1 (2006) (Ex. 65).)

To that end, there is obvious overlap between the clinical manifestation of

undifferentiated tissue disease and other connective tissue diseases, an overlap that Dr.

DeAngelo himself endorses. Dr. DeAngelo cannot use the distinction between these

related conditions as both a sword and a shield. If Dr. DeAngelo’s preferred Brauner

study is relevant despite examining Sjogren’s symptoms, then the epidemiology cited by

respondent’s experts is also relevant. Conversely, if the broader epidemiology is

distinguishable, then Dr. DeAngelo’s reliance on Brauner et al. is similarly suspect. 23

Considering all of this, the epidemiologic evidence when considered as a whole

preponderates against a finding that the flu vaccine can cause or aggravate

undifferentiated connective tissue disease.

To the extent petitioner urges that ASIA literature counsels otherwise as a matter

of epidemiology, I have reviewed this literature and do not find that it bolsters

petitioner’s theory of causation. Dr. Levinson’s critique of the concept is well taken. I

have also previously addressed the merits of ASIA based on reports and testimony of

its originator and concluded that it is not sound and reliable as a theory of causation

under Althen prong one. J.F. v. Sec’y of Health & Human Servs., No. 13-799V (Fed. Cl.

23Notable in that regard Dr. Wilfong opines that B cell dysregulation is thought to be a hallmark of

Sjorgren’s syndrome more so than other connective tissue diseases. (Tr. 316.)

33

Spec. Mstr. Sept. 9, 2022). Other special masters have also been critical of the

concept. E.g., Decker v. Sec’y of Health & Human Servs., No. 15-71V, 2020 WL

7889059, at *32 (Fed. Cl. Spec. Mstr. Dec. 14, 2020); Phillips v. Sec’y of Health &

Human Servs., No. 16-906V, 2020 WL 7767511, at *21 (Fed. Cl. Spec. Mstr. Nov. 23,

2020); Salerno v. Sec’y of Health & Human Servs., No. 16-1280V, 2020 WL 3444163,

at *11 (Fed. Cl. Spec. Mstr. May 29, 2020); Pearson v. Sec’y of Health & Human Servs.,

No. 16-9V, 2019 WL 3852633, at *13 (Fed. Cl. Spec. Mstr. Jul. 31, 2019); Suliman v.

Sec’y of Health & Human Servs., No. 13-993V, 2018 WL 6803697, at *27 (Fed. Cl.

Spec. Mstr. Nov. 27, 2018) (“No special masters have ever found ASIA or ASIA-like

theories to be persuasive”). Despite earlier reports filed in this case, petitioner clarifies

that she is “not advocating . . . ASIA as the mechanistic explanation for Petitioner’s

onset and/or aggravation of her asymptomatic/subclinical UCTD.” (ECF No. 97, p. 13.)

c. Significant Aggravation (Loving prongs one through three)

Assuming arguendo that petitioner did prove a medical theory demonstrating that

her flu vaccination could have caused or aggravated her UCTD, the remainder of the

Loving test queries whether petitioner would be able to show that it did do so in this

particular case. The threshold question in that remaining analysis is whether

petitioner’s condition was, in fact, significantly aggravated. To demonstrate significant

aggravation, the Vaccine Act requires a “change for the worse in a preexisting

condition,” and “markedly greater disability, pain, or illness accompanied by substantial

deterioration of health.” 42 U.S.C. § 300aa-33(4). Under the Loving test, petitioner

demonstrates this by showing (1) her condition before the vaccination, (2) her current

condition, and (3) that her current condition constitutes a significant aggravation of her

prior condition. There are two cases, Locane and Sharpe, that illustrate the Federal

Circuit’s significant aggravation analysis with regard to the evolution of a petitioner’s

clinical course. Locane v. Sec’y of Health & Human Servs., 685 F.3d 1375 (Fed. Cir.

2012); Sharpe v. Sec’y of Health & Human Servs., 964 F.3d 1072 (Fed. Cir. 2020).

In Locane, petitioner alleged her Crohn’s disease, an inflammatory bowel

disease, was significantly aggravated by the Hepatitis B vaccine. Locane, 685 F.3d at

1377-78. The special master determined that petitioner failed to preponderantly prove

her significant aggravation claim “because the course of her disease was not affected

by the vaccination.” Id. at 1378. The Federal Circuit affirmed, explaining that the

special master considered “the relevant evidence of record, [drew] plausible inferences

and articulated a rational basis for the decision.” Id. at 1381-82. The Court further

indicated that petitioner was “given ample opportunity to develop her significant

aggravation claim but ‘failed to present persuasive evidence that separates [her]

problems from an expected course of Crohn's disease.’” Id. at 1382.

In Sharpe, petitioner alleged L.M. had a preexisting “seizure disorder” and the

administration of the several childhood vaccines at her six-month wellness check-up

significantly aggravated L.M.’s pre-existing condition. Sharpe, 964 F.3d at 1076-77.

The special master denied petitioner’s significant aggravation claim because L.M.’s

genetic mutation, and not the vaccination, was the sole, substantial cause of L.M.’s

seizure disorder. Id. at 1080. The Circuit found the special master’s analysis “required

34

[p]etitioner to prove the expected outcome for a child with a DYNC1H1 gene mutation

and to show that L.M.’s current, post-vaccination condition was worse than that

expected outcome.” Id. at 1081. The Circuit stated, “a court should consider all

evidence in the record, including evidence of other possible sources of injury. There is,

however, a fine line between a court properly considering evidence in the

record . . . and improperly placing the burden on the petitioner to prove that her

significantly aggravated condition was not caused by her gene mutation.” Id. at 1082.

The Court distinguished the special master’s decision from Locane stating, in Locane

“the special master did not require the petitioner to prove that her significantly

aggravated condition was not caused by her preexisting condition. Instead, the special

master found that the petitioner’s condition ‘was not affected by the vaccination.’” Id.

In this case, petitioner contends that prior to her influenza vaccination she

demonstrated no objective signs or symptoms of active connective tissue disease.

(ECF No. 97, p. 16 (citing Ex. 10, p. 34; Ex. 3, p. 7).) Petitioner contends that in the

two-week window following administration of her influenza vaccine, she experienced a

“clinically symptomatic event,” demonstrated by bilateral shoulder/arm

arthralgia/myalgia, which progressed and worsened over the weeks/months that

followed to include rash, Raynaud’s syndrome, swollen hands and PIP joints,

forearm/knee pain, synovitis, hair loss, and facial paresthesia—eventually leading to a

diagnosis of UCTD. (ECF No. 97, p. 16 (citing Ex. 12, pp. 5-6, 19; Ex. 10, pp. 5, 11,

14); see also Tr. 66-78; 119-149.)

Respondent’s experts did not dispute the overall decline in petitioner’s post-

vaccination health. (Tr. 323-24; 384-86.) Rather, respondent’s experts suggested that

petitioner’s increase in symptoms post-vaccination was the natural and expected

disease course—in which her vaccination played no significant role. (Id. at 284-86.) Dr.

Wilfong opined that petitioner began exhibiting symptoms of an emerging connective

tissue disease in the summer of 2013. (Id. at 266.) Dr. Wilfong testified that petitioner’s

providers became worried about an emerging CTD in June of 2013, when an ANA and

sudden CRP were observed. (Id. at 268.) By August 2013 petitioner reported morning

stiffness. (Id.) Dr. Wilfong explains that morning stiffness is a diagnostic symptom for

inflammatory arthritis—when overnight as patients are not using their joints, “their joints

get stiffer, and in the morning, they’re stiff for an hour or two, and the more they use

their joints, the better they do.” (Id.) The fact that morning stiffness was noted in Dr.

Crane’s notes, according to Dr. Wilfong, “is concerning that the [CTD] was definitely

emerging by August 2013.” (Id. at 269.) At the same time, petitioner’s RNP was found

to be exceptionally high titer. (Id.) Dr. Wilfong explains that this is the “pathognomonic

antibody for . . . mixed connective tissue disease, and so that’s expected, given

[petitioner’s] ultimate clinical course, but, again, it’s very concerning that we are really

hearing the first true clinical obvious manifestation of her MCTD.” (Id.)

Dr. Wilfong testified that she relies upon two studies, one on rheumatoid arthritis

and another on systematic lupus erythematous, to describe the presence of the

preclinical phase. (Tr. at 277 (citing Deane & El-Gabalawy, supra, Ex. A, Tab 3;

Melissa Arbuckle et al., Development of Autoantibodies Before the Clinical Onset of

35

Systemic Lupus Erythematosus, 349 N. ENGL. J. MED. 1526 (2003) (Ex. A, Tab 1)).)

Based on these studies, Dr. Wilfong observes that the interval time from the positive

RNP test to the onset of symptoms, was .2 years, or approximately two-and-a-half

months, “which is very close actually to the Petitioner’s course.” (Id. at 278.) The

studies suggest that “the antibodies accumulate, and then there’s a tipping point,”

though Dr. Wilfong explains that “we don’t really understand what causes that tipping

point . . . what causes somebody to transform from true preclinical with antibodies but

no symptoms to starting to get their symptoms and they’re more characteristic

symptoms.” (Id. at 278-79.)

Ultimately, Dr. Wilfong disagreed with petitioner’s testimony that she developed

all of her CTD symptoms post-vaccination. (Tr. 285.) Dr. Wilfong stresses that “she

already had the antibodies. She already had arthralgia. She had morning stiffness

noted. She had leukopenia prior to vaccination. Were these enough that I would have

said to her in the office, You definitely have a connective tissue disease? No.” (Id.)

However, she stresses that petitioner’s presentation was suggestive of an emerging

CTD prior to vaccination. (Id.) Based on her clinical experience, she stresses that

“[t]his is what patients do . . . they start with some vague complaints and then start

accumulating one symptom after another over time.” (Id. at 285-86.) Dr. Wilfong opines

that petitioner showcased a “relatively typical progression” of CTD. (Id.)

In contrast, Dr. Rushing agreed petitioner had preexisting UCTD (Tr. 64-66), but

opined that it was entirely asymptomatic prior to vaccination and significantly worsened

following her influenza vaccination on November 8, 2013. (Tr. 77.) Specifically, he

observed that petitioner developed pain in her shoulders and arms, and subsequently

developed Raynaud’s. (Id.) Furthermore, she developed swelling in her hands and

fingers, she had hair loss, and ultimately developed trigeminal neuropathy—“a whole

new set of symptoms which she didn’t have before the vaccine.” (Id.) However, I asked

Dr. Rushing, “Apart from the fact of her having had a flu vaccine, is there anything

unusual about Ms. Volpe’s transition from subclinical to clinical connective tissue

disorder or disease?” (Tr. 101.) Consistent with Dr. Wilfong’s opinion that petitioner

followed a “relatively typical progression,” Dr. Rushing initially answered that no, he is

not aware of anything unusual in petitioner’s transition from subclinical to clinical

disease. 24 (Id.) I also asked Dr. Rushing whether the standard of care for CTD

includes screening for environmental triggers and, if so, how often in Dr. Rushing’s

experience an environmental trigger is identified. (Id.) He testified that a complete

evaluation and history is part of the standard of care, but that “[l]ots of times you cannot

determine [the trigger].” (Id. at 102.) He testified that the medical literature on mixed

and undifferentiated connective tissue diseases suggests that “as high as 25 percent [of

24 On redirect, however, petitioner’s counsel re-asked essentially the same question, but offering the

specific prompt “do you deem it unusual for someone to be subclinical as you deemed Ms. Volpe to be

and then to present with the degree of symptomology that she did in such a short period of time?” (Tr.

104.) At that point, Dr. Rushing offered the opinion that the rapidity of petitioner’s transition to overt

UCTD was unusual. (Id. at 104-05.) Respondent objected to petitioner’s counsel’s leading of the witness.

(Id. at 105.) Dr. Rushing did not attempt to reconcile his testimony on redirect examination with this prior

testimony.

36

cases] you can’t identify a trigger.” (Id.) Dr. Rushing suggested that among that 25

percent, an environmental trigger is “probably undiscovered,” rather than absent, but

could not give “an absolute answer on that.” (Id.)

In light of the above, I do not find preponderant evidence on this record that

petitioner’s vaccination significantly aggravated her condition. On the whole, Dr.

Wilfong is more persuasive in explaining that petitioner had overt signs of an emerging

connective tissue disease prior to the vaccination at issue and followed a “typical

progression” of the condition. Dr. Rushing likewise agreed that the general progression

of petitioner’s condition was not unusual, but to the extent he opined it was unusually

rapid post-vaccination, this was based on his assumption that petitioner was

asymptomatic pre-vaccination. I have not required petitioner to prove that her post-

vaccination condition was worse than the expected outcome. Instead, I find that the

evidence taken as a whole shows that the course of her UCTD was not likely to have

been affected by the vaccination. This finding is consistent with Locane. It is also

further reinforced by the discussion of the treating physician opinions below.

d. Logical sequence of cause and effect showing the vaccination was

the cause or aggravation of petitioner’s injury (Althen Prong Two /

Loving Prong Five)

The second Althen prong / fifth Loving prong requires proof of a logical sequence

of cause and effect showing that the vaccine was the reason for the injury, 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 v. Sec’y of Health & Human Servs., 440

F.3d 1317, 1326 (Fed. Cir. 2006); Grant, 956 F.2d at 1148. However, medical records

and/or statements of a treating physician 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. See 42 U.S.C. §300aa-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) (stating that “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”). Here, I find that there is not preponderant evidence that petitioner’s treating

physicians concluded that her flu vaccination caused or significantly aggravated of her

preexisting UCTD.

The medical record closest to supporting petitioner’s contention is Dr. Ramsey-

Goldman’s note from April 15, 2014. (Ex. 12, p. 23.) Dr. Ramsey-Goldman noted

petitioner “[g]ot a flu shot in 11/2013, ten days later developed myalgias in shoulders

and upper arms.” (Id.) However, Dr. Ramsey-Goldman did not ultimately opine as to

the cause of petitioner’s symptoms. Dr. Ramsey-Goldman also explained that petitioner

underwent a repeat MRI on her neck and shoulder after her symptoms started, and was

told she had an osteophyte on C5, though she was “unsure if [it] was causing

symptoms.” (Id.) In context, Dr. Ramsey-Goldman’s discussion of petitioner’s MRI

findings more strongly suggests her consideration of a mechanical cause for petitioner’s

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shoulder pain. Similarly, on May 14, 2014, petitioner presented to Dr. Broderick, who

also noted “patient states that 10 days after, she received a flu shot. She started

experiencing bilateral shoulder and bilateral arm pain.” (Ex. 14, p. 2.) Dr. Broderick

concluded that petitioner’s cervical spine MRI showing a bulging disc are not a major

contributing factor to her right shoulder and right wrist symptoms although “an EMG of

the bilateral upper extremities [could] distinguish between a neurological versus

rheumatological problem.” (Id. at 4.) Dr. Broderick made no other mention of

petitioner’s vaccination. (See id. at 2-4.)

Upon my review of petitioner’s medical records, no other physicians attributed or

contemplated vaccine causation for petitioner’s UCTD. While treating physician records

are given significant weight, “[a] treating physician’s recognition of a temporal

relationship does not advance the analysis of causation.” Isaac v. Sec’y of Health &

Human Servs., No. 08-601V, 2012 WL 3609993, at *26 (Fed. Cl. Spec. Mstr. July 30,

2012); see also Devonshire v. Sec’y of Health & Human Servs., No. 99-031V, 2006 WL

2970418, at *19 (Fed. Cl. Spec. Mstr. Sept. 28, 2006) (medical expert’s “post hoc ergo

prompter hoc reasoning . . . has been consistently rejected by the Court and is

‘regarded as neither good logic nor good law’”) (quoting Fricano v. U.S., 22 Cl. Ct. 796,

800 (1991) (emphasis in original)).

In support of a logical sequence of cause and effect, petitioner stresses that her

treating rheumatologists agreed that she demonstrated no objective signs or symptoms

of active connective tissue disease prior to vaccination, and thus did not recommend

any therapy or treatment. (ECF No. 97, p. 16 (citing Ex 10, p. 34 (“no signs or

symptoms” of MCTD); Ex. 3, p. 7 (“positive ANA could be related to the recent diagnosis

of autoimmune thyroid diseases”)).) As discussed above, petitioner contends that she

suffered a “clinically symptomatic event” of newly developed bilateral shoulder / arm

arthralgia / myalgia, which progressed over the following weeks and months, leading to

the diagnosis of UCTD and immunosuppressant therapy program. (Ex. 12, pp. 5-6, 19;

Ex. 10, pp. 5, 11, 14). The records cited by petitioner in support of Althen prong two /

Loving prong five document petitioner’s worsening undifferentiated connective tissue

disease. (Ex. 12, pp. 5-6 (noting petitioner “was asymptomatic”); id. at 22 (“agree[ing]

with the assessment of suspected CTD with minimal sxs”); Ex. 10, p. 5 (assessing facial

paresthesia, intermittent leukopenia, intermittent knee pain); id. at 11 (same); id. at 14

(noting mild hair loss).) However, none of these records suggest that petitioner’s

symptoms were caused or significantly aggravated by her flu vaccination.

Lastly, petitioner contends that “[t]here is no evidence or recent illness, infection,

and/or other environmental factor to otherwise explain this sudden and dramatic onset

of symptomatic connective tissue disease.” (ECF No. 97, p. 16.) In this Program,

however, absence of another cause is not persuasive evidence in support of petitioner’s

burden to show causation. See D.G., 2019 WL 2511769, at *183 (“[T]he Federal Circuit

in Grant state[]d [that] petitioner’s burden is to prove vaccine causation with affirmative

evidence. Saying since there is no other cause, it has to be the vaccine is not

affirmative proof.”) (citing Grant, 956 F.2d at 1149).

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To the extent petitioner could otherwise support an Althen prong two / Loving

prong five showing based on expert opinion, the same issues that render petitioner’s

experts less persuasive with respect to Loving prongs one through four likewise prevent

them from effectively opining with respect to any logical sequence of cause and effect to

suggest her vaccine caused or aggravated her condition.

e. Proximate temporal relationship between vaccination and injury

(Althen prong three / Loving prong six)

The third Althen prong / sixth Loving 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. Id.; 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., 503 Fed. Appx. 952 (Fed. Cir. 2013); Koehn v. Sec'y of Health & Human Servs.,

No. 11-355V, 2013 WL 3214877, at *26 (Fed. Cl. Spec. Mstr. May 30, 2013), aff'd, 773

F.3d 1239 (Fed. Cir. 2014).

Petitioner alleges that she meets the medically acceptable temporal relationship

between flu vaccination and significant aggravation. (ECF No. 97, p. 16.) Dr.

DeAngelo relies on the Brauner study, which evidenced an increase in IgG response

and polyclonal activation of B cells occurred within 1-3 weeks after vaccination. (Id.

(citing Ex. 62, p. 4; Brauner et al., supra, at Ex. 63, p. 3).) Petitioner contends that her

symptomatic rheumatic disease first manifested approximately two weeks following

administration of her influenza vaccine. (ECF No. 97, p. 17 (citing Ex. 2, pp. 7-9; Ex.

12, pp. 23, 26-29; Ex. 64, p. 1).) Therefore, petitioner alleges that her onset of

rheumatic disease expression is consistent with the timeframe espoused in Brauner for

an anticipated / expected rise in antibody response and polyclonal activation of B cells

following vaccination. (ECF No. 97, p. 17.) However, I have concluded that the results

of Brauner et al. are not broadly applicable to petitioner’s case, for reasons enumerated

above. Without more, petitioner fails to preponderantly establish a proximate temporal

relationship between her vaccination and her UCTD.

In any event, even if the onset of petitioner’s post-vaccination symptoms could

arguably be consistent with an immunologic injury broadly, demonstration of a temporal

relationship alone is insufficient to prove causation. A temporal relationship between a

vaccine and an injury, standing alone, does not constitute preponderant evidence of

vaccine causation. See, e.g., Veryzer v. Sec’y of Health & Hu man Servs., 100 Fed. Cl.

344, 356 (2011) (explaining that “a temporal relationship alone will not demonstrate the

requisite causal link and that petitioner must posit a medical theory causally connecting

the vaccine and injury”).

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VI. Conclusion

Petitioner has my sympathy for the pain and suffering she endured and the

symptoms she suffers from presently. However, for all the reasons discussed above,

after weighing the evidence of record within the context of this program, I cannot find by

preponderant evidence that the flu vaccine caused or significantly aggravated

petitioner’s undifferentiated connective tissue disease. Accordingly, this claim is

DISMISSED. 25

IT IS SO ORDERED.

s/Daniel T. Horner

Daniel T. Horner

Special Master

25In the absence of a timely-filed motion for review of this Decision, the Clerk of the Court shall enter

judgment accordingly.

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