Faup v. Secretary of Health and Human Services ( 2020 )

In the United States Court of Federal Claims
OFFICE OF SPECIAL MASTERS
Filed: June 17, 2019
* * * * * * * * * * * * * *
LISA FAUP, on behalf of A.F., a minor, * No. 12-87V
*
Petitioner, * Special Master Sanders
*
v. *
* Entitlement; Diphtheria-Tetanus-acellular-
SECRETARY OF HEALTH * Pertussis (“DTaP”) Vaccine; Inactivated
AND HUMAN SERVICES, * Polio (“IP”) Vaccine; Systemic Juvenile
* Idiopathic Arthritis (“sJIA”); Althen
Respondent. * Causation
* * * * * * * * * * * * * *
Sylvia Chin-Caplan, Law Office of Sylvia Chin-Caplan, Boston, MA, for Petitioner.
Jennifer L. Reynaud, United States Department of Justice, Washington, D.C., for Respondent.
DECISION ON ENTITLEMENT1
On February 9, 2012, Lisa Faup (“Petitioner”) filed a petition on behalf of A.F., a minor,
pursuant to the National Vaccine Injury Compensation Program,2 42 U.S.C. §§ 300aa-10 to 34
(2012). Petitioner alleged that A.F. suffered from a “rheumatologic injury” as a result of the
Diphtheria-Tetanus-acellular-Pertussis (“DTaP”) and inactivated polio (“IP”) vaccines she
received on March 13, 2009. Pet. at 1, ECF No. 1. On October 5, 2012, Petitioner amended the
petition to allege that A.F.’s vaccines caused her to develop systemic3 juvenile idiopathic
arthritis4 (“sJIA”). Am. Pet. at 1, ECF No. 19.
1
This decision shall be posted on the United States Court of Federal Claims’ website, in accordance with
the E-Government Act of 2002, 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), a party has 14 days to identify and move to delete
medical or other information that satisfies the criteria in § 300aa-12(d)(4)(B). Further, consistent with the
rule requirement, a motion for redaction must include a proposed redacted decision. If, upon review, the
undersigned agrees that the identified material fits within the requirements of that provision, such material
will be deleted from public access.
2
National Childhood Vaccine Injury Act of 1986, Pub L. No. 99-660, 100 Stat. 3755 (“the Vaccine Act”
or “Act”). Hereinafter, for ease of citation, all “§” references to the Vaccine Act will be to the pertinent
subparagraph of 42 U.S.C. § 300aa (2012).
3
“Pertaining to or affecting the body as a whole.” Dorland’s Illustrated Medical Dictionary 1865 (32nd
ed. 2012) [hereinafter “Dorland’s”].
4
Juvenile idiopathic arthritis is a type of “rheumatoid arthritis [seen] in children, with swelling,
tenderness, and pain in one or more joints, which may lead to impaired growth and development,
limitation of movement, ankylosis, and flexion contractures.” Dorland’s at 150.
The undersigned held an entitlement hearing in this matter on March 13–14, 2018, in
Washington, D.C. After considering the record as a whole, and for the reasons explained below,
the undersigned finds that Petitioner has failed to show that A.F.’s condition was caused by the
alleged vaccines and is therefore not entitled to compensation under the Vaccine Act.
I. Procedural History
The undersigned detailed the procedural history of this case in the decision granting
interim attorneys’ fees and costs, issued on April 21, 2017. ECF No. 83.
Petitioner submitted medical records over the four months following the filing of her
petition. ECF Nos. 8, 10. Respondent filed his Rule 4(c) report on June 18, 2012. ECF No. 12.
Respondent argued that Petitioner’s claim should be dismissed because she could not show that
A.F. suffered from her condition for more than six months. Resp’t’s Report at 12–13, ECF No.
12. Respondent also alleged that Petitioner had not provided a medical theory causally linking
A.F.’s injuries with the vaccines she received on March 13, 2009. Id. During a subsequent
status conference, the special master assigned to the case at the time ordered Respondent to
submit a motion for summary judgment based upon the six-month severity requirement. ECF
No. 14. Respondent submitted this motion on August 17, 2012. ECF No. 15.
In his motion, Respondent argued that evidence that A.F. was treated by medication
beyond six months was not sufficient to satisfy the Vaccine Act’s six-month requirement. Id. at
8–10. On February 26, 2013, the presiding special master found that she could not rule on the
motion without “testimony from either a treating physician or an expert” on “whether A.F.’s
abnormal laboratory test results were indicative of ongoing problems with JIA; and . . . [on]
whether A.F.’s normal bone marrow biopsy constituted a surgical intervention under the Vaccine
Act.” Ruling Denying Mot. for Summary Judgment, ECF No. 23 at 8. Petitioner submitted an
expert report in response to the special master’s ruling on September 12, 2013, ECF No. 30, and
Respondent filed a responsive expert report on January 13, 2014. ECF No. 32.
On May 20, 2014, Respondent filed his second motion for summary judgment. ECF No.
34. This motion was denied in a ruling issued on January 15, 2015. Order Denying Mot. for
Summary Judgment, ECF No. 37. The presiding special master found that “the ongoing need for
medication to prevent symptoms and/or relapse of the alleged vaccine-caused illness constitutes
a residual effect or complication of that illness.” Id. at 6. Following this decision, the parties
submitted expert reports through June and August of 2015 regarding Petitioner’s theory of
causation. ECF Nos. 44 and 45. Petitioner submitted a second supplemental expert report on
February 5, 2016. ECF No. 51. Respondent submitted a responsive expert report on August 4,
2016. ECF No. 60.
On January 10, 2017, the undersigned was assigned to the case. Not. of Reassignment,
ECF No. 71. On February 8, 2017, Ms. Sylvia Chin-Caplan was substituted in as Petitioner’s
counsel. ECF No. 75. Petitioner immediately filed a motion for interim attorneys’ fees and costs
for the work performed by her former counsel, Mr. Ronald Homer. ECF No. 74. Petitioner then
submitted another expert report on February 13, 2017. ECF No. 76. On April 21, 2017, the
undersigned issued a decision awarding interim attorneys’ fees and costs to Petitioner’s former
2
counsel. ECF No. 83. On May 30, 2017, Respondent submitted another responsive expert
report. ECF No. 86.
An entitlement hearing was held in Washington, D.C., on March 13–14, 2018. ECF No.
91. Following the hearing, the parties submitted post-hearing briefs. See Minute Entry, dated
Mar. 14, 2018. Petitioner submitted her post-hearing brief on May 30, 2018, ECF No. 116, and
Respondent submitted his on August 3, 2018. ECF No. 118. Petitioner submitted a post-hearing
reply brief on September 4, 2018. ECF No. 119.
This matter is now ripe for adjudication.
II. Factual Background
A. Medical Records
A.F. was born on March 9, 2004, the oldest of a set of female triplets. Pet’r’s Ex. 1 at 1,
14, ECF No. 8-1. A.F. and her sisters were born prematurely at thirty-five weeks with no health
concerns. Id. at 22–23. At the age of seven weeks, A.F. underwent a cardiac evaluation for a
detected heart murmur. Id. at 27. She was diagnosed with an “innocent heart murmur” but was
“otherwise normal.” Id. at 28; see also Pet’r’s Ex. 28 at 10, ECF No. 65-5. On March 2, 2009,
A.F. was seen by her pediatrician for an otitis media5 and given a seven-day course of
amoxicillin.6 Pet’r’s Ex. 15 at 1, ECF No. 10-1; Pet’r’s Ex. 1 at 72. A.F.’s early medical history
was otherwise unremarkable, and she had all her early immunizations without incident. Pet’r’s
Ex. 1 at 2.
On March 13, 2009, A.F. received the DTaP and IP vaccinations at issue in this case.
Pet’r’s Ex. 1 at 2, 8; Pet’r’s Ex. 15 at 1. On March 20, 2009, Petitioner took A.F. to Island
Heights Pediatrics because she had been suffering from a maculopapular rash7 over the previous
three days. Pet’r’s Ex. 1 at 16; Pet’r’s Ex. 15 at 1. A.F. was afebrile and tested negative for
strep throat. Pet’r’s Ex. 1 at 16; Pet’r’s Ex. 11 at 2, ECF No. 8-11. She was given prednisone8
for the rash. Pet’r’s Ex. 15 at 1. On March 25, 2009, A.F. presented again to Island Heights
Pediatrics for abdominal pain, a swollen knee, and a recurring fever of up to 103 °F.9 Id. The
medical records reflect that A.F.’s primary care physician considered a diagnosis of Henoch-
Schönlein purpura10 (“HSP”). Id. Two days later, A.F. was seen by an allergist at the Allergy
5
Otitis media is defined as “inflammation of the middle ear.” Dorland’s at 1351.
6
Amoxicillin is defined as “a semisynthetic derivative of ampicillin effective against a broad spectrum of
gram-positive and gram-negative bacteria.” Dorland’s at 65.
7
A maculopapular rash consists of “both flat and raised skin lesions . . . [which] are usually red and can
merge together.” What Is a Maculopapular Rash? HEALTHLINE, https://www.healthline.com/health/skin/
maculopapular-rash (last visited May 30, 2019).
8
Prednisone is defined as “a synthetic glucocorticoid derived from cortisone, administered orally as an
antiinflammatory and immunosuppressant in a wide variety of disorders.” Dorland’s at 1509.
9
The record does not indicate whether A.F. was given any treatment by her parents during those three
days.
10
Henoch-Schönlein purpura is “a form of nonthrombocytopenic purpura, sometimes a type of
hypersensitivity vasculitis and sometimes of unknown cause, usually seen in children and associated with
3
and Asthma Center who could not determine whether A.F.’s rash was allergic or viral in nature.
Pet’r’s Ex. 3 at 2–4, ECF No. 8-3. The allergist advised Petitioner to take A.F. to the emergency
department. Id. at 3.
A.F. was admitted to the Robert Wood Johnson University Hospital later that day.
Pet’r’s Ex. 2 at 2, ECF No. 8-2. The emergency physicians admitted A.F. in order to rule out
HSP. Id. Petitioner recounted that A.F. had been suffering from her rash for ten days and “ha[d]
been having itchiness since then.” Id. The physicians noted that A.F. had “maculopapular rash
to her face, trunk, and extremities” that was “slightly raised” and experienced “mild difficult
walking due to discomfort [from itchiness].” Id. A.F. was discharged the same day with a
diagnosis of HSP. Id. at 1. A.F. was given a prescription for Benadryl11 and instructions to
follow up with her primary care physician. Id. at 1, 4, 13. On March 31, 2009, A.F. was taken to
Richmond Pediatrics for a rash, fever, joint pain, and loss of appetite. Pet’r’s Ex. 4 at 1, ECF
No. 8-4. The treating physician’s impression was that A.F. suffered from HSP. Id.
On April 8, 2009, A.F. presented again to Richmond Pediatrics for joint pain, swollen
wrists and hands, and a fever of 102–104 °F lasting several days. Id. at 2. The treating
physician’s impression was that A.F. suffered from HSP. Id. A.F. was referred to Dr. Yukiko
Kimura, a pediatric rheumatologist, by A.F.’s pediatrician, Dr. Ann Marie Grigoletto. See
Pet’r’s Ex. 5 at 1, 5, ECF No. 8-5. A.F. was seen by Dr. Kimura for an initial evaluation on
April 16, 2009. Id. at 5. Dr. Kimura reviewed A.F.’s medical history and noted that she was
having daily ankle, knee, and wrist pain. Id. at 1, 7. Dr. Kimura’s assessment was that A.F.
likely suffered from sJIA of unknown etiology. Id. at 9. Dr. Kimura advised Petitioner to give
A.F. Motrin12 or Naprosyn13 if her fever or joint pain continued. Id. A.F. saw Dr. Kimura again
on April 28, 2009, for persistent fever lasting several days and continued joint and abdominal
pain. Id. at 14. Dr. Kimura noted the symptoms but concluded that there had been “some
improvement” in A.F.’s sJIA without treatment and prescribed Naprosyn. Id. at 15.
A.F. continued to have symptoms of fever and rash through May of 2009. See id. at 18–
35. On May 13, 2009, a CT scan showed that A.F. suffered from hepatosplenomegaly.14 Pet’r’s
Ex. 7 at 1–2, ECF No. 8-7. Between May 21 and May 23, 2009, A.F. had a severe flare-up of
her rash and experienced high fever. Pet’r’s Ex. 5 at 34; Pet’r’s Ex. 1 at 20. On May 26, 2009,
A.F. underwent blood tests, which, according to Dr. Kimura, showed a possible episode of
macrophage activation syndrome15 (“MAS”). Pet’r’s Ex. 11 at 11; Pet’r’s Ex. 1 at 73. Because
symptoms including urticaria, erythema, arthropathy, arthritis, gastrointestinal symptoms, and renal
involvement.” Dorland’s at 1557.
11
Benadryl is the “trademark for preparations of diphenhydramine hydrochloride,” which is “an
angiotensin-converting enzyme inhibitor.” Dorland’s at 208.
12
Motrin is the “trademark for preparations of ibuprofen.” Dorland’s at 1182.
13
Naprosyn is the “trademark for preparations of naproxen,” which in turn is “a nonsteroidal
antiinflammatory drug . . . used in the treatment of pain, inflammation, arthritis, rheumatoid arthritis [and]
fever.” Dorland’s at 1232.
14
Hepatosplenomegaly is defined as the “enlargement of the liver and spleen.” Dorland’s at 847.
15
Macrophage activation syndrome is “a life-threatening complication of rheumatic disease that, for
unknown reasons, occurs much more frequently in individuals with systemic juvenile idiopathic arthritis .
. . and in those with adult-onset Still disease. Macrophage activation syndrome is characterized by
pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms and is thought to be caused by
4
MAS is “a hemophagocytic syndrome that can be life threatening in systemic JIA[,]” A.F.’s
pediatrician, Dr. Grigoletto, called Petitioner to advise her to take A.F. to hospital “to get the labs
repeated immediately.” Pet’r’s Ex. 1 at 73; Pet’r’s Ex. 5 at 30 (record of phone call).
Although A.F. was asymptomatic at that time, Petitioner took A.F. to the Children’s
Hospital of Philadelphia (“CHOP”) emergency department on May 28, 2009. Pet’r’s Ex. 1 at 73;
Pet’r’s Ex. 5 at 30; Pet’r’s Ex. 12 at 11, ECF No. 8-12. A.F. was admitted to the emergency
department “to get lab values.” Pet’r’s Ex. 12 at 14. The medical records note that A.F. had
been “misdiagnos[ed]” with HSP and that she spent the night in CHOP under observation. Id. at
11, 33. Rheumatology assessed A.F.’s condition and confirmed her diagnosis of sJIA. Id. at 26.
The rheumatology notes state that A.F.’s rash began on March 17, 2009, together with abdominal
pain and fever. Id. at 23. A.F.’s lab tests “showed some improvement,” and she had no issues
during her admission. Pet’r’s Ex. 1 at 73. A.F. was prescribed Mobic16 and Petitioner was
advised to continue giving her Naprosyn. Pet’r’s Ex. 12 at 18, 23. A.F. was discharged on May
29, 2009, without complications. Id. at 33. Dr. Kimura wrote that since her discharge, A.F. had
“continued to do well and seem[ed] [to have been] back to her pre-illness state.” Pet’r’s Ex. 1 at
73. Dr. Kimura also suspected that “the fever and rash episode that [A.F.] had [had] early in the
week may have been MAS which . . . spontaneously improved since she [was] asymptomatic . .
.” Id.
Despite the improvement of her symptoms, on June 4, 2009, A.F. underwent a bone
marrow evaluation to rule out leukemia or MAS before starting treatment with steroids. Pet’r’s
Ex. 1 at 65–66. The bone marrow “looked normal and showed no evidence of either malignancy
or MAS.” Id. That same day, Petitioner took A.F. to see Dr. Kimura for “occas[ional] joint
pain” and low-grade fever. Id. at 66. Dr. Kimura noted that A.F. had swelling in her left and
right ankles, an active rash, and low-grade fever. Id. at 66–67. She also wrote that A.F.’s sJIA
was still active and discussed steroid treatment with Petitioner. Id. at 67. Ultimately, Dr.
Kimura did not administer steroids at that time, instead increasing A.F.’s Mobic prescription. Id.
On June 16, 2009, Dr. Kimura saw A.F. for “some rash [and] occas[ional] joint pain,” absent
fever. Id. at 46. Dr. Kimura noted that A.F.’s sJIA was “somewhat better[,] but [her] arthritis
persist[ed].” Id. at 47. After discussing treatment options with Petitioner, Dr. Kimura decided to
begin A.F. on fifteen milligrams of methotrexate.17 Id.
On June 17, 2009, Petitioner took A.F. to see Dr. Thomas Lehman, a pediatric
rheumatologist, for an evaluation. Pet’r’s Ex. 6 at 1–2, ECF No. 8-6. Dr. Lehman reviewed
A.F.’s medical history and noted that “[s]he ha[d] had no recent fever or rash[,] her rash [was]
minimal, and [she] only [had] minor joint complaints.” Id. at 1. Dr. Lehman found that A.F.
the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages,
leading to widespread hemophagocytosis and cytokine overproduction.” Macrophage Activation
Syndrome, MEDSCAPE, http://emedicine.medscape.com/article/1380671-overview (last visited May 30,
2019).
16
Mobic is the “trademark for a preparation of meloxicam,” which in turn is “a nonsteroidal
antiinflammatory drug used in the treatment of osteoarthritis[.]” Dorland’s at 1126, 1171.
17
Methotrexate is defined as “a folic acid antagonist that acts by inhibiting synthesis of DNA, RNA,
thymidylate, and protein . . . It is also used as an antipsoriatic and antiarthritic in the treatment of severe,
recalcitrant, disabling psoriasis and severe rheumatoid and psoriatic arthritis.” Dorland’s at 1151.
5
“ha[d] [a] clearly documented systemic-onset [juvenile rheumatoid arthritis18] by history and by
laboratory findings.” Id. at 2. After discussing treatment options with A.F.’s family, Dr.
Lehman recommended they begin a low dose of prednisone and advised Petitioner to follow up
with A.F.’s primary care physician. Id. On June 18, 2009, Petitioner called Dr. Kimura to
discuss treating A.F. with prednisone. Pet’r’s Ex. 5 at 48. Dr. Kimura explained that
“prednisone would do nothing to protect [A.F.’s] joints” and that she did not want to put A.F. on
the drug. Id. Petitioner agreed and stated she would “fill the prescription for . . . [m]ethotrexate”
for A.F. to take over the next few days. Id.
A.F. was seen again by Dr. Kimura on July 14, 2009. Pet’r’s Ex. 1 at 43. Dr. Kimura
noted that A.F. was doing well, with no fever, only an occasional rash, and “no joint pain to
speak of.” Id. Dr. Kimura advised Petitioner to stop the Naprosyn and noted that A.F.’s sJIA
was “much better” on methotrexate. Id. at 44. A.F. had greatly improved by her next visit to Dr.
Kimura on August 27, 2009. Id. at 49. Dr. Kimura wrote that A.F. “ha[d] been great[,] [with] no
fever, rash, [or] joint pain.” Id. She noted that A.F. had only trace swelling in her ankles and a
low blood count. Id. at 50. Petitioner mentioned that A.F. had experienced nausea on
methotrexate once but was otherwise “doing well.” Id. at 49–50. Dr. Kimura did not decrease
A.F.’s dosage of methotrexate at that time. Id. at 51. A.F. continued to improve, and on
December 1, 2009, Dr. Kimura reduced A.F.’s methotrexate dose to 0.5 milligrams weekly. Id.
at 52–53.
A.F.’s sJIA symptoms continued to improve. On February 2, 2010, Dr. Kimura noted
that A.F. had no fever, pain, or rash. Id. at 55. Dr. Kimura again reduced A.F.’s methotrexate
dosage on April 6, 2010, to 0.15 milligrams weekly. Pet’r’s Ex. 5 at 64. On July 13, 2010, Dr.
Kimura wrote that A.F. was experiencing “no problems at all.” Pet’r’s Ex. 1 at 58. Dr. Kimura
also wrote that A.F. had stopped taking methotrexate completely six weeks earlier, without a
relapse in her symptoms.19 Id. at 58–59. A.F.’s lab results, however, continued to be abnormal.
Pet’r’s Ex. 5 at 78–79. Specifically, her white blood cell count and creatine levels were low, and
her lactate dehydrogenase20 levels were high. Id. Other than an indication that these results were
abnormal, no other discussion of the significance of these results is found in the medical records.
A.F.’s sJIA symptoms ultimately did not return, and her health has improved. Pet’r’s Ex. 18 at
4, ECF No. 18-1.
B. Petitioner’s Affidavit
Petitioner submitted one affidavit in this case. See Pet’r’s Ex. 18. Petitioner wrote that
prior to receiving the vaccines in question, A.F. had been “a very active child [who had] enjoyed
playing with her sisters, whether it was arts and crafts or running around at the playground.” Id.
18
Another term for JIA. Dorland’s at 150.
19
It is unclear on what precise date A.F. stopped taking methotrexate. The medical records do not specify
when this happened besides the July 13, 2010 notation from Dr. Kimura.
20
Lactate dehydrogenase “is an enzyme found in almost every cell of [the] body.” The lactate
dehydrogenase test “looks for signs of damage to the body’s tissues.” What Is a Lactate Dehydrogenase
(LDH) Test? WEBMD, https://www.webmd.com/a-to-z-guides/lactic-acid-dehydrogenase-test#1 (last
visited May 30, 2019).
6
at 1. She also wrote that “[b]y her fifth birthday, [A.F.] was riding her bike without training
wheels.” Id.
Petitioner wrote that A.F. received the DTaP and IP vaccines in question during a
physical exam on March 12, 2009, in order to “enroll in kindergarten in the fall[.]” Id. She also
wrote that A.F.’s health began to deteriorate “[w]ithin the next several days,” after developing a
rash and experiencing elbow and wrist pain. Id. Petitioner described how A.F.’s condition did
not improve despite multiple doctor’s visits and treatments. Id. at 2. Petitioner’s account of
A.F.’s symptoms and treatment was consistent with the medical record.
Petitioner described a time A.F.’s “body was covered in a rash, her joints remained
swollen, and [her] fever persisted. [A.F.] did not want to be touched because physical contact
was painful to her frail body.” Id. Petitioner also wrote that the “family helped [A.F. to] eat and
go to the bathroom because she had little strength to do so on her own.” Id.
Petitioner wrote that A.F.’s weekly methotrexate injections were “a traumatic experience
for [the] family[,]” because A.F. “hated receiving the injections, and [Petitioner’s] husband and
[she] had to hold her down to give her the medicine.” Id. Petitioner also wrote that A.F.’s
“sisters were always by her side showing their support, teary-eyed since they saw how painful
the injections were.” Id. She also described the side effects of methotrexate as “horrible,” which
left A.F. feeling “nauseous and fatigued following her injections, and [with] a compromised
immune system . . . .” Id. at 3–4.
Petitioner wrote that A.F.’s health has improved[,]” and she “can once again enjoy
activities with her sisters and friends, like riding bikes and playing in the schoolyard.” Id. at 4.
Petitioner also wrote that despite the progress made, the family “still worr[ies] that [A.F.’s]
symptoms will return.” Id.
III. Expert Review21
A. Petitioner’s Expert, Dr. Robert Sundel, M.D.
Dr. Sundel is a pediatric rheumatologist and is board certified in pediatrics and pediatric
rheumatology. Pet’r’s Ex. 21 at 1, ECF No. 30-2; Tr. 14:18–19. Dr. Sundel received his medical
degree from Boston University in 1982. Pet’r’s Ex. 21 at 1. His post-doctoral training includes
two years spent as a pediatric resident at the Babies Hospital at Columbia–Presbyterian Medical
Center in New York and one year spent as a research associate in cellular immunology at
Hadassah Medical Center in Jerusalem, Israel. Id. He also spent three years as an allergy/
immunology/rheumatology fellow at the Children’s Hospital in Boston, MA. Id. As a pediatric
rheumatologist, he has seen between one hundred and one hundred and fifty pediatric patients
with juvenile arthritis. Tr. 15:3–7.
21
The undersigned will not discuss Petitioner’s exhibit 20 because it specifically addressed the six-month
duration issue previously decided by the then assigned special master’s ruling issued on January 15, 2015.
See ECF No. 37.
7
Dr. Sundel’s clinical experience includes thirty years as an attending physician and then
as director at the Children’s Hospital in Boston, MA. Pet’r’s Ex. 21 at 2. He is the current Fred
S. Rosen Chair in Pediatric Rheumatology and Director Emeritus of Rheumatology at the Boston
Children’s Hospital, where he has been employed since 1989. Pet’r’s Ex. 21 at 1–2; Tr. 14:3–5.
In addition to his clinical experience, Dr. Sundel is an associate professor of pediatrics at
Harvard Medical School. Pet’r’s Ex. 21 at 1; Tr. 14:14–15. He has authored more than sixty
publications, including articles on the treatment of polyarticular juvenile rheumatoid arthritis and
of severe systemic onset juvenile rheumatoid arthritis. Pet’r’s Ex. 21 at 5–10; Tr. 14:18–20. Dr.
Sundel was admitted to testify as an expert in the field of pediatric rheumatology. Tr. 16:11–16.
Dr. Sundel submitted one expert report and two supplemental reports in this case. Pet’r’s
Ex. 20, ECF No. 30-1; Pet’r’s Ex. 23, ECF No. 44-1; Pet’r’s Ex. 24, ECF No. 51-1.
1. Dr. Sundel’s Expert Report
Dr. Sundel submitted his expert report on September 12, 2013.22 Pet’r’s Ex. 20. Dr.
Sundel opined that A.F. “developed systemic onset juvenile idiopathic arthritis after being
immunized with DTaP and [IP] vaccines.” Id. at 2, 4. He noted that A.F. exhibited “no
symptoms to suggest an infection, trauma, or other recognized antecedents of arthritis in
children.” Id. at 2. He did state, however, that A.F. had been treated “with amoxicillin for an ear
infection” eleven days prior to the vaccination in question. Id. at 2. Dr. Sundel also noted that
although some types of arthritis develop gradually, A.F.’s sJIA was “far more dramatic and
abrupt.” Id. He explained that A.F.’s “presentation is more commonly associated with
infections and other acute challenges to the immune system.” Id. He concluded that “in the
absence of alternative explanations for why [A.F.] developed arthritis, vaccine-associated
arthritis is the most plausible hypothesis.” Id. (citing Pet’r’s Ex. 20, Tab E,23 ECF No. 104-5;
Pet’r’s Ex. 20, Tab F,24 ECF No. 30-1).
Dr. Sundel also wrote that A.F.’s normal test results during the early stages of her disease
were likely due to the treatments she received at the time. Id. at 3. The use of
“immunosuppressive and immunomodulatory therapies,” he explained, “regularly allows
children . . . to achieve sustained, disease-free remissions in conditions that were inexorably
crippling in the past.” Id. He therefore argued that “a child [like A.F.] may have a normal
examination and laboratory tests when her arthritis is optimally controlled, even relatively soon
after the onset of [her] condition.” Id.
2. Dr. Sundel’s First Supplemental Expert Report
Dr. Sundel submitted his first supplemental report on June 15, 2015. Pet’r’s Ex. 23. Dr.
Sundel wrote that “the pathogenesis of arthritis [including sJIA] is generally not understood.” Id.
22
Dr. Sundel’s report primarily addressed the six-month duration issue upon which two special masters
ruled previously and which will not be discussed in this Opinion.
23
D.P.M. Symmons and K. Chakravarty, Can Immunisation Trigger Rheumatoid Arthritis? ANN. RHEUM.
DIS. 1993;52:843–44.
24
C.P. Howson and H.V. Fineberg, Adverse Events Following Pertussis and Rubella Vaccines. Summary
of a Report of the Institute of Medicine. JAMA 1992;267(3):392–96.
8
at 3 (citing Pet’r’s Ex. 23, Tab A,25 ECF No. 105-5). But, he agreed with Respondent’s expert
Dr. Rose that “the innate immune system is central to autoinflammatory disorders” like sJIA. Id.
at 4.
Dr. Sundel also explained that several theories exist on the triggers of sJIA, “though none
ha[ve] been incontrovertibly proven.” Id. Dr. Sundel wrote that one of these theories is
molecular mimicry, which involves the “cross[-]reactivity between bacterial antigens and
fragments of human proteins[.]” Id. He posited that A.F.’s sJIA was likely not the result of
molecular mimicry. Id. He explained that “the complex interaction of T- and B-cells necessary
to induce the antigen-specific response of molecular mimicry typically takes considerably longer
than the week between [A.F.’s] immunizations and the apparent onset of her systemic [JIA].” Id.
Dr. Sundel wrote that the Autoimmune/Autoinflammatory Syndrome Induced by
Adjuvants (“ASIA”) theory “has raised the possibility that triggering of arthritis and other forms
of autoimmunity may be the result of immune potentiation by additives to immunizations rather
than the vaccines themselves.” Id. at 3–4 (citing Pet’r’s Ex. 23, Tab D,26 ECF No. 44-1). He
noted that “arthritis has been associated with a variety of vaccines and a broad spectrum of
incubation periods . . . .” Id. at 4 (citing Pet’r’s Ex. 23, Tab G,27 ECF No. 44-1). But “[b]ecause
of this variety of potential triggers,” he continued, “a direct association with even the most
commonly implicated vaccines . . . has been elusive.” Id. (citing Pet’r’s Ex. 23, Tab H,28 ECF
No. 44-1). Dr. Sundel, nonetheless, argued that A.F.’s sJIA “is consistent with the much more
rapid response that may occur when an adjuvant triggers pathologic inflammation.” Id.
Dr. Sundel explained that as an autoinflammatory disorder, sJIA “is more consistent with
a process involving [Toll-like receptors29] and inflammasomes.30” Id. Adjuvants, he wrote,
“exert their immunomodulatory roles on diverse components of the immune response, . . .
including binding to [these] Toll-like receptors . . . and activating the inflammasome system to
stimulate innate immune responses.” Id. Because adjuvants have an effect on both the innate
and adaptive immune systems, he explained, they “may [also] augment the release of
chemokines31 and cytokines32 from cells of the adaptive immune system,” thus “perpetuati[ng] . .
. the immune response that leads to systemic arthritis.” Id.
25
C.K. Correll and B.A. Binstadt, Advances in the Pathogenesis and Treatment of Systemic Juvenile
Idiopathic Arthritis. PEDIATRIC RESEARCH 2013;75(1‐2):176–83.
26
Y. Shoenfeld and N. Agmon‐Levin, ‘ASIA’ – Autoimmune/Inflammatory Syndrome Induced by
Adjuvants. JOURNAL OF AUTOIMM. 2011;36(1):4–8.
27
Vaccine Adverse Event Reporting System, available at http://vaers.hhs.gov/index.
28
R.P. Chen et al., Epidemiology of Autoimmune Reactions Induced by Vaccination. JOURNAL OF
AUTOIMM. 2001;16:309–18.
29
Toll-like receptors are “microbial components [that] are detected by innate signaling pattern recognition
receptors” and which “are specialized for detect[ing] . . . different classes of pathogens.” See Notice of
Filing Resp’t’s Ex. I, Tab 6 at 1, filed on CD-ROM, ECF No. 47.
30
Inflammasomes are the “the control center of the innate immune system.” Tr. 35:1–2.
31
Chemokines are “a family of low molecular weight . . . cytokines that induce chemotaxis or
chemokinesis in leukocytes[.]” Dorland’s at 340.
32
Cytokine is the “generic term for nonantibody proteins released by one cell population . . . on contact
with specific antigen, which act as intercellular mediators, as in the generation of an immune response.”
Dorland’s at 466.
9
Dr. Sundel concluded that despite sparse data on the correlation between adjuvants and
vaccine-related complications, recent research supports the contention that aluminum adjuvants
play a role “particularly in young girls who develop arthritis shortly after an immunization,
typically a booster dose.” Id. at 5. Dr. Sundel referred to a study by Cerpa-Cruz et al.33 that
analyzed one hundred and twenty patients who developed a medical complication within fifty-
four days after receiving a vaccine at several health centers in Guadalajara, Mexico, from 2008
to 2012. Id. (citing Pet’r’s Ex. 23, Tab L, ECF No. 106-1). He noted that the characteristics of
forty-three of the patients “match [A.F.] very closely: [sixty percent] of those developing
reactions after receiving vaccinations were children, [fifty-eight percent] of whom were female.”
Id. Dr. Sundel also opined that although an aluminum adjuvant-related causation “cannot be
proven retrospectively,” his conclusion that A.F.’s sJIA is causally linked to the vaccines in
question “accords better with facts of the case and the impressions of the treating physicians than
any alternative theories.” Id.
3. Dr. Sundel’s Second Supplemental Expert Report
Dr. Sundel authored his second supplemental report on February 5, 2016. Pet’r’s Ex. 24.
In his report, Dr. Sundel reiterated his opinion that A.F.’s sJIA was caused by the aluminum
adjuvant found in the DTaP and IP vaccines she received, and that molecular mimicry was not
the likely process involved. Id. at 3, 5.
Dr. Sundel reaffirmed his conclusion that the short time interval between vaccination and
disease onset is appropriate. He argued that “[a]lthough the pathophysiology of juvenile arthritis
is still not understood,” there is greater consensus that sJIA is an autoinflammatory disorder that
is driven by the innate immune response. Id. at 2. He explained that “[a]utoinflammatory
disorders are distinct from autoimmune diseases [because] [t]hey involve evolutionarily older
and less adaptable methods of recognizing pathogens . . . rather than the infinitely mutable
lymphocyte antigen receptors of the adaptive immune system.” Id. Because these innate
responses depend on “preformed mechanisms,” he explained, they “typically occur more rapidly
than adaptive responses . . . .” Id. Dr. Sundel stated that “[t]his is consistent with the rapidity of
onset of Alexa’s symptoms” post vaccination, which would rule out molecular mimicry as a
possible causation mechanism. Id.
B. Petitioner’s Expert, Michael Gurish, Ph.D.
Dr. Gurish received a Bachelor of Science in Biology and a Bachelor of Arts in
Chemistry from the University of California at Irvine. Pet’r’s Ex. 30 at 3, ECF No. 82-4. He
also received a Doctor of Philosophy in Experimental Pathology (Immunology) from the
University of Utah. Id. Dr. Gurish is an associate immunochemist at Brigham and Women’s
Hospital in Boston, MA. Id. at 2; Tr. 95:18–21. He is also an associate professor of medicine at
Harvard Medical School, where he focuses on lymphocyte subsets in human rheumatic disease.
Id. Dr. Gurish undertook two post-doctoral fellowships: he studied the regulation of humoral
immunity at Brandeis University in Waltham, MA, and the molecular immunology of mast cells
at Brigham and Women’s Hospital and Harvard Medical School in Boston, MA. Pet’r’s Ex. 30
33
S. Cerpa‐Cruz et al., Adverse Events Following Immunization with Vaccines Containing Adjuvants.
IMMUNOL. RESEARCH 2013;56(2–3):299–303.
10
at 3. He is a member of the American Association of Science and the American Association of
Immunologists, and he has authored more than one hundred publications, including articles on
the cellular link between autoantibodies and inflammatory arthritis and the contribution of mast
cells to the initiation of autoantibody-mediated arthritis. Id. at 3, 8–15. Although Petitioner did
not move to admit Dr. Gurish as an expert in the field of immunology, he provided opinion
testimony in that area. See Tr. 94:12–123:15.
Dr. Gurish submitted one expert report in this case. Pet’r’s Ex. 29, ECF No. 76-1.
1. Dr. Gurish’s Expert Report
Dr. Gurish submitted his expert report on February 13, 2017. Pet’r’s Ex. 29. In his
report, Dr. Gurish provided a more in-depth introduction to the immune system. Dr. Gurish
explained that the innate immune system is the first responder to any potential pathogens by
“eliminat[ing] components that appear different from what is normally present.” Id. at 2. The
innate system “then drives a more pathogen-specific response by stimulating lymphocytes, the T
cells and B cells that compose the adaptive immune response.” Id. He also wrote that all
immune responses are “highly regulated and under constant surveillance” because they “can be
damaging to the host if not contained.” Id. He explained that any “[l]oss of specificity in the
components that are targeted by the immune response can lead to autoimmunity[.]” Id.
Dr. Gurish agreed with Dr. Sundel that the medical community has come to distinguish
between autoimmune and autoinflammatory response. Id. at 3. If the immune system
dysfunction involves “the adaptive arm [of the immune system] and effector functions of T and
or B cells[,]” it is referred to as autoimmune. Id. Conversely, a condition is autoinflammatory if
“the response principally involves innate cells, such as macrophages[,] as the effector cells[.]”
Id. Dr. Gurish stated that “[i]t is unlikely . . . that any reaction is exclusively an activation of one
or the other arm of the immune response” due to the overlapping interactions between the two.
Id. He noted, however, that “most cases of sJIA do not appear to be principally driven by the
adaptive arm of the immune system” because the immune system’s “response is dominated by
macrophages[.]” Id. at 4 (citing Pet’r’s Ex. 29, Tab F,34 ECF No. 107-8; Pet’r’s Ex. 23, Tab A;35
Pet’r’s Ex. 29, Tab D,36 ECF No. 107-6).
Dr. Gurish wrote that sJIA has a “genetic association with a particular human [major
histocompatibility complex (“MHC”)] Class II molecule.37” Id. at 4 (citing Pet’r’s Ex. 29, Tab
34
C. Macaubas et al., Distribution of Circulating Cells in Systemic Juvenile Idiopathic Arthritis across
Disease Activity States. CLINICAL IMMUNOL, 2010;134(2):206.
35
Correll & Binstadt, supra note 25.
36
P.A. Nigrovic, Autoinflammation and Autoimmunity in Systemic Juvenile Idiopathic Arthritis.
Proceedings of the National Academy of Sciences of the United States of America, 2015;112(52):15785–
86.
37
MHC molecules “are heterodimeric cell surface receptors that function to present antigen peptide
fragments to T cells responsible for cell-mediated immune responses.” MHC Class II molecules “present
exogenously derived antigenic peptides . . . to helper T cells.” MHC Class II, Alpha/Beta Chain, N-
Terminal, INTERPRO, http://www.ebi.ac.uk/interpro/ entry/IPR014745 (last visited May 30, 2019).
11
G,38 ECF No. 107-9). He explained that MHC Class II molecules direct antigens to
lymphocytes. Id. at 3. Because MHC Class II molecules vary from individual to individual, Dr.
Gurish concluded that sJIA has a genetic component. Id. at 3–4. Additionally, Dr. Gurish noted
that “alum has been shown to activate macrophages via the activation of and subsequent release
of the NLRP3 inflammasome39 and the polymerized downstream adapter molecule, ASC.40” Id.
at 4. He explained that the ASC and NLRP3 can leave their originating cell and activate other
macrophages, which “can lead to systemic macrophage activation.” Id. Dr. Gurish conceded
that it is unknown “whether this is the result of direct activation of the inflammasome by the
aluminum compounds, or . . . the result of cell damage caused by the vaccination that leads to the
release of activating damage-associated molecular patterns . . . that in turn activate the
inflammasome within the innate cells[.]” Id. He nonetheless argued that “the end result of using
[aluminum] adjuvant is activation of the innate cells, and the subsequent elaboration of cytokines
such as IL-1 and IL-6,” which are “two of the most important mediators of sJIA.” Id. Dr.
Gurish therefore concluded that “a recent immunization with a macrophage activating agent . . .
can lead to systemic distribution of activating components and subsequently, the appearance of
over[-]activated macrophages implicating the former in the production of the latter.” Id. at 4–5.
Dr. Gurish further elaborated on Dr. Sundel’s causation theory. Id. at 5. Dr. Gurish
wrote that A.F.’s immune system was in flux following her treatment for an ear infection and
noted two “critical factors” that show that the vaccination was the precipitating event for
developing sJIA. Id. The first factor involves the time frame, because the innate immune
response is activated within hours to days of exposure. Id. Dr. Gurish noted that A.F. began
experiencing symptoms two to four days after vaccination, which he argues matches the results
found in a study by Luján et al.,41 which showed that the acute phase of the ASIA syndrome in
commercial sheep occurred two to six days after “repetitive inoculation [with] aluminum-
containing adjuvants[.]” Id. (citing Pet’r’s Ex. 29, Tab J at 1, ECF No. 108-3). The second
factor is that aluminum is known to activate “innate cells, in particular macrophages, via
38
M.J. Ombrello et al., HLA-DRB1*11 and Variants of the MHC Class II Locus Are Strong Risk Factors
for Systemic Juvenile Idiopathic Arthritis. Proceedings of the National Academy of Sciences of the
United States of America, 2015;112(52):15970–75.
39
The NOD-like receptor pyrin containing domain 3 (“NLRP3”) inflammasome “associates with
Caspase-1 to form an inflammasome complex[, which] regulates cleavage of pro-inflammatory cytokines
like IL-1β, IL-18 and IL-33 into their active forms, thereby activating multiple inflammatory processes.”
See Pet’r’s Ex. 29, Tab K at 3, ECF No. 108-4, H. Bagavant et al., Alum, an Aluminum-based Adjuvant,
Induces Sjögren’s Syndrome-like Disorder in Mice. CLIN. AND EXPER. RHEUM. 2014;32(2):251–55.
Caspase-1 is defined as “a group of cysteine endopeptidases that cleave proteins on the C-terminal side of
aspartic acid residues as one of the final steps in apoptosis.” Dorland’s at 301.
40
ASC stands for apoptosis-associated Speck-like protein with a caspase recruitment domain. It is an
adaptor protein that “contains several . . . interaction domains so that it can act as a connector for
interaction between molecules and facilitate [the] activation of pathways after receptors have been
activated.” Dorland’s at 1531. “Inflammasome complexes are composed of a sensor protein connected
to caspase-1, an interaction that in most cases requires the adaptor ASC.” See Pet’r’s Ex. 29, Tab H at 2,
ECF No. 108-1, A. Baroja-Mazo et al., The NLRP3 Inflammasome Is Released as a Particulate Danger
Signal that Amplifies the Inflammatory Response. NATURE IMMUNOL., 2014;15(8):738–48.
41
L. Luján et al., Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA Syndrome) in
Commercial Sheep. IMMUNOL. RESEARCH, 2013;56(2):317–24.
12
inflammasome activation,” which leads to sJIA. Id. (citing Pet’r’s Ex. 24, Tab I,42 ECF No. 51-
1). Dr. Gurish also wrote that there is evidence that although an immune response may be
localized, “the response is really systemic even though it focuses at the site of the infection”
because “immune cells can reenter the blood stream and traffic to other places in the body,
especially to the site of the infection.” Id. at 7. Dr. Gurish noted that the study by Luján et al.
showed macrophages in the brain of sheep containing “white crystalline material,” which shows
that a substance such as aluminum could “become systemically dispersed.” Id. Dr. Gurish
concluded that although we do not know “what is driving the systemic innate response in
[sJIA,]” the “various factors within this case” indicate that A.F.’s condition was caused by the
DTaP vaccine. Id. at 7–8.
C. Respondent’s Expert,43 Dr. Carlos Rose, M.D., C.I.P.
Dr. Rose is a board-certified pediatric rheumatologist. Resp’t’s Ex. L at 3, ECF No.
101-1; Tr. 139:8–19. He received his medical degree from the University of Buenos Aires,
Argentina, in 1977. Resp’t’s Ex. L at 1. Dr. Rose’s post-doctoral training includes one year
spent as a pediatric resident at the Medical Center of Delaware in Newark, DE, and two years
spent as a rheumatology fellow at the National Institute of Rehabilitation, Rheumatology
Division, in Buenos Aires, Argentina. Resp’t’s Ex. L at 4–5. He was also a pediatric
rheumatology fellow for one year at the Children’s Hospital of Philadelphia in Philadelphia, PA,
and for two years at the Alfred I. duPont Institute in Wilmington, DE. Id.
Dr. Rose’s clinical experience includes almost thirty years as staff physician and head of
the division of rheumatology at the Nemours/Alfred I. duPont Hospital for Children in
Wilmington, DE. Id.; Tr. 139:12–14, 139:23–140:3. Currently, he is a staff physician,
researcher, and educator at the same institution, where he runs three half-day clinics per week
and chairs the Institutional Review Board. Tr. 139:14–16, 140:10–11. In addition to his clinical
experience, Dr. Rose is a professor of pediatrics at Thomas Jefferson University. Resp’t’s Ex. L
at 6; Tr. 140:3–5. He has authored more than one hundred and twenty publications, including
articles on juvenile idiopathic rheumatoid arthritis. Resp’t’s Ex. L at 6, 13–22; Tr. 139:18–22.
Dr. Rose was admitted to testify as an expert in the field of pediatric rheumatology. Tr. 141:1–4.
Dr. Rose submitted one expert report and one supplemental report in this case. Resp’t’s
Ex. A, ECF No. 32-1; Resp’t’s Ex. G, ECF No. 45-1.
42
P. He et al., Advances in Aluminum Hydroxide-based Adjuvant Research and its Mechanism. HUMAN
VACCINES & IMMUNOTHERAP. 2015;11(2):477–88.
43
In addition to the reports of Dr. Rose and Dr. Whitton, Respondent filed a white paper authored by Dr.
Edward Cetaruk, which addressed the causation theory of ASIA. ECF No. 45-2. Dr. Cetaruk’s report
“wasn’t submitted specific to this case[]” and, by not testifying, he did not provide context or rebuttal to
Petitioner’s arguments. See Tr. 326:11–327:3. Furthermore, Petitioner and the undersigned did not have
the opportunity to cross-examine the expert. For these reasons, the undersigned gave less weight to his
report in deciding this case.
13
1. Dr. Rose’s Expert Report
Dr. Rose submitted his expert report on January 13, 2014, in response to Dr. Sundel’s
first expert report. Resp’t’s Ex. A. In his report, Dr. Rose primarily discussed the pathogenesis
of sJIA. He wrote that A.F. had had no similar reaction to all previous vaccinations she had
received, and her symptoms closely followed her ear infection. Resp’t’s Ex. A at 16. He posited
that it is therefore more likely than not that A.F.’s sJIA was caused by a viral infection rather
than the vaccines in question. Id.
Dr. Rose concurred with A.F.’s diagnosis of sJIA but disagreed that there was an
“absence of alternative explanations.” Id. at 7. He wrote that the vaccines were “not the only
event preceding the onset of [A.F.’s] clinical disease.” Id. at 8. Dr. Rose argued that a possible
viral infection A.F. experienced at the end of March 2009 and the ear infection she had eleven
days prior to the vaccination must also be considered as triggering factors. He explained that
“[t]he rash of systemic JIA is more commonly faint and many times not even noticed by the
patient or the parent.” Id. at 7. By contrast, Dr. Rose noted that the purpuric rash A.F. had on
March 27, 2009, “is unusual in [sJIA] except when the presentation of [sJIA] coincides with an
episode of [MAS].” Id. During testimony, he also clarified that “a significant component of that
. . . purpura[] is not seen in systemic JIA.” Tr. 162:10–12. Dr. Rose also argued that because
A.F.’s laboratory tests were negative for MAS on March 27, 2009, the purpuric rash could not
have been a sign of sJIA at that point but of a viral infection. Id. He also noted that “[t]he
lifetime risk of developing clinical MAS for a child with s[]JIA is about [ten percent] and of
subclinical MAS perhaps [thirty to forty percent].” Id. at 12. He therefore argued that there is an
“unquestionable link” between sJIA and MAS, with “some authors believ[ing] that the pathways
of MAS could be a core mechanism for all s[]JIA.” Id. at 12–13 (emphasis in original).
Dr. Rose stated that it is difficult to determine the environmental triggers that cause a
rheumatic disease. Id. at 11. He explained that the onset of sJIA “is bound to be temporally
associated with a multitude of events, all with more or less biological plausibility to
cause/trigger” it. Id. He also noted that “[c]hildren suffer an average of [eight] mild infections a
year and undergo multiple vaccinations during the period in which [sJIA] may be diagnosed.”
Id. In A.F.’s case, an ear infection was present, as was the ‘possibility of a[ viral] infection
concurrent with or preceding the onset of her” disease. Id. Dr. Rose argued that A.F.’s sJIA was
more likely than not caused by a combination of these factors and not the vaccines. Id.
Dr. Rose agreed with Dr. Sundel that sJIA is an autoinflammatory disease. Id. at 12. He
explained that unlike autoimmune diseases, autoinflammatory diseases involve the presence of
antibodies in the serum. Id. He also agreed that autoinflammatory diseases are linked to a
dysfunction in the innate immune system, whereas autoimmune diseases “are likely linked to
aberrations of the adaptive immunity.” Id. He did note that although both systems are constantly
at play, “the diseases resulting from malfunctioning of each of them are . . . differentiable.” Id.
This is because the innate immune system is designed to have the same rapid and predictable
response to any antigen, whereas the adaptive immune system’s response depends on knowledge
gained from “previous exposure [to a certain antigen] and genetic make-up.” Id. at 12–13.
14
Dr. Rose stated that there is a genetic link to sJIA; specifically, that it is “likely the result
of polymorphisms in genes of the ‘cytolysis pathway.’”44 Id. at 16. He explained that the actors
of the cytolysis pathway are linked to the innate immune system, which “remains ‘static’
throughout our lifespan in terms of recognition and response” to antigens. Id. at 16–17. Dr.
Rose therefore argued that A.F.’s polymorphic genes would have had the same “MAS-like or a
JIA[-]like response anytime she was exposed to” a vaccine containing aluminum adjuvant. Id.
Because A.F. had never had a similar reaction with any previous vaccination and because
“infections . . . are more likely to be associated with the onset of MAS [than vaccines],” he
opined that the triggering factor of A.F.’s sJIA and MAS was more likely than not a viral
infection. Id. at 17.
2. Dr. Rose’s Supplemental Expert Report
Dr. Rose submitted his supplemental expert report on August 14, 2015, in response to Dr.
Sundel’s first supplemental expert report. Resp’t’s Ex. G. Dr. Rose reiterated his conclusion
that A.F.’s sJIA was more likely than not caused by “her genetic make-up and the infectious
events occurring prior to the onset of her symptoms[,]” and not the vaccines in question. Id. at 6.
Although the cause of sJIA is unknown, he wrote, “viral triggers are well[]described for” MAS,
particularly in people like A.F. who are genetically predisposed to both MAS and sJIA. Id. at 2.
He explained that these viral triggers “are determinants of activation of the innate immune
system which in turn leads to” sJIA and MAS in those susceptible to developing MAS. Id. at 2.
Dr. Rose also wrote that Dr. Sundel “suggest[ed] that the mechanism for Alexa’s
systemic JIA is somewhat in line with the so-called ASIA syndrome.” Id. at 4. He argued,
however, that there are several flaws regarding this causation theory. Id. at 2–6. First, he
explained that the theory fails to address “the continued activation . . . of the innate immune
system that would be required to explain a chronic disease like [sJIA]”. Id. at 3. Second, he
stated that ASIA’s diagnostic criteria are inherently flawed, which renders them inapplicable to
medical practice. Id. at 4. Specifically, none of the ASIA criteria, Dr. Rose explained, have
been formally validated since the ASIA study was published in 2011. Id.
Lastly, Dr. Rose wrote that ASIA’s major criteria can be easily met by the general
population. Id. For instance, by the age of two months, most people have been vaccinated; the
term “infectious stimuli” is a catch-all criterion that most people would satisfy; and because there
is no specified interval between the introduction of an infectious stimulus and the onset of ASIA,
“any condition at any age can theoretically be called ASIA if the individual . . . suffers from the
‘typical’ clinical manifestations.” Id. Dr. Rose argued that ASIA is over-inclusive and “has not
been substantiated by any reliable medical or scientific evidence.” Id. It cannot, therefore, be
used to explain the cause of A.F.’s sJIA. Id.
D. Respondent’s Expert, Dr. J. Lindsay Whitton, M.D., Ph.D.
Dr. Whitton is an immunologist and he received his medical degree from the University
of Glasgow, Scotland, in 1979. Resp’t’s Ex. M at 1–2, ECF No. 101-2. He also received his
44
The cytolysis pathway refers to the “course . . . followed in the attainment of” the “dissolution or
destruction of a cell by rupture of the cell membrane with loss of cytoplasm.” Dorland’s at 466, 1397.
15
Doctor of Philosophy in Herpesvirus Transcription from the same university in 1984. Id. Dr.
Whitton’s post-doctoral training includes three years spent as a research fellow on herpesvirus
transcriptional control at the Medical Research Council in the United Kingdom and two years
spent as a senior research fellow at the Department of Immunology of the Scripps Clinic in La
Jolla, CA. Id. at 1. Dr. Whitton is currently a professor at the Department of Immunology and
Microbiology of the Scripps Research Institute in La Jolla, CA, where he has been employed
since 1989. Id. He is a member of the American Association of Pathologists, the American
Association of Immunologists, the American Society of Virology, and the American Society of
Microbiology. Id.
Dr. Whitton has been on the editorial board of several scientific journals, such as the
Journal of Virology and Viral Immunology, and has authored close to two hundred peer-
reviewed publications, including articles on vaccine-related research. Id. at 1, 4–14. Dr.
Whitton has also been a speaker at several symposia and events organized by, inter alia, the
World Health Organization, the European Union, and the Oregon Health & Science University.
Id. at 16–18. Dr. Whitton is currently working with Prof. Joe McCormick and Dr. Mike
Buchmeier to “construct[] Lassa virus45 DNA vaccines to test in primates.” Id. at 20. Dr.
Whitton was admitted to testify as an expert in the field of immunology. Tr. 200:2–6.
Dr. Whitton submitted one expert report and two supplemental reports in this case.
Resp’t’s Ex. I, ECF No. 45-3; Resp’t’s Ex. J, ECF No. 60-1; Resp’t’s Ex. K, ECF No. 86-1.
1. Dr. Whitton’s Expert Report
Dr. Whitton submitted his expert report on August 14, 2015, in response to the causation
theory proposed by Petitioner. Resp’t’s Ex. I. In view of Respondent’s belief that Petitioner’s
experts’ theory is based on ASIA, Dr. Whitton’s report provides an overview of the ASIA theory
and explains why it fails to link aluminum adjuvants and sJIA. Id. at 1. Dr. Whitton opined that
because there is no scientific “evidence to support the notion that adjuvants in current use trigger
any long-term systemic disease[,]” A.F.’s sJIA cannot be attributed to the vaccines she received.
Id. at 16.
Dr. Whitton first elaborated on Dr. Rose’s explanation of why a rapid response of the
innate immune system could not have triggered A.F.’s sJIA. He explained that the innate
immune system’s response is “non-antigen specific.” Id. It is “pre-programmed to mount a
certain response,” which “will be the same regardless of whether this is [its] . . . first encounter
with a [specific] stimulus, or [its] tenth.” Id. Conversely, the adaptive immune system is antigen
specific and “can learn from experience[.]” Id. Thus, “its response to a second encounter with a
specific antigen will be much more rapid, and biologically [] effective, than the first.” Id. Dr.
Whitton also stated that the responses of both the innate and the adaptive immune systems are
not “entirely separate” but are instead “inextricably linked.” Id. at 2.
Dr. Whitton then discussed the ASIA hypothesis in detail, articulating his main criticisms
of this theory. He wrote that the authors of the ASIA study argue that the interval between
45
Lassa virus is “an arenavirus . . . existing in several serologically distinct strains and distributed
throughout West and Central Africa.” Dorland’s at 2063.
16
“‘exposure to infection and the diagnosis of autoimmune disease’ . . . can be as long as many
years.” Id. at 8. But no reliable data were offered to support this contention and, by extending
the interval to years, he argued, it is “inevitable that all vaccinees will experience some episode
of ill-health.” Id. This, therefore, would mean that vaccination could be offered as the cause of
any possible adverse event even years later. Id.
Dr. Whitton agreed with Dr. Rose that the diagnostic criteria of the ASIA hypothesis are
flawed. Specifically, he noted that the “exposure to external stimuli” criterion is overbroad,
while the absence of a temporal constraint “is inconsistent with well[]established immunological
principles.” Id. at 13. This is because it “runs counter to what we know of the immune response,
which generally ‘peaks’ around [two] weeks after infection or vaccination, then declines over the
next [one to two] weeks.” Id. He also stated that the “appearance of ‘typical’ clinical
manifestations” criterion is over inclusive because the symptoms listed are common and non-
specific. Id.
Dr. Whitton also cast doubt upon ASIA’s “removal of inciting agent induces
improvement” criterion because infections that result in autoimmune diseases are “acute in
nature” and therefore, “the inciting agent is [inherently] removed.” Id. This runs counter to the
ASIA study authors’ contention that “acute infections . . . trigger long-term autoimmune
disease.” Id. Moreover, Dr. Whitton noted that the “appearance of . . . antibodies directed at the
suspected adjuvant” criterion would not apply in this case because there are no aluminum-
specific antibodies. Id. at 13–14.
Dr. Whitton concluded his criticism of the ASIA hypothesis by stating that it is an over-
inclusive and “highly speculative” theory. Id. at 14. For instance, the “other clinical
manifestations” criterion, he claimed, acts as a “fishing expedition” since any clinical
manifestation can potentially be explained by ASIA. Id. Dr. Whitton also stated that “many of
the statements made by [the ASIA study’s authors] are not supported by cited scientific
literature, and many of the papers that are cited appear to be extremely unreliable, or even
irrelevant.” Id.
2. Dr. Whitton’s First Supplemental Expert Report
Dr. Whitton submitted his first supplemental expert report on August 4, 2016, in which
he discussed the “biological plausibility” of the theory proposed by Dr. Sundel. Resp’t’s Ex. J at
1. Dr. Whitton opined that, based on the facts of this case and his knowledge of the function of
the immune system, the evidence presented to support the theory “is extremely weak.” Id. at 12.
In this report, Dr. Whitton explicitly stated that Petitioner’s causation theory is
“indistinguishable” from the ASIA hypothesis. Id. at 4. He argued that, like ASIA, Petitioner’s
causation theory fails for several reasons. First, Dr. Whitton wrote that one of the ASIA study
authors, Dr. Yehuda Shoenfeld, has conceded that “every attempt for an epidemiological study
has so far failed to deliver a connection” between autoimmune diseases and vaccines. Id.
Additionally, Dr. Whitton noted that the Reeves et al.46 article offered by Dr. Sundel to show that
46
See Pet’r’s Ex. 23, Tab F, ECF No. 105-9, W.H. Reeves et al., Induction of Autoimmunity by Pristine
and Other Naturally Occurring Hydrocarbons. TRENDS IN IMMUNOL. 2009;30(9):455–64.
17
adjuvants “can trigger a variety of autoimmune diseases” is inapposite because the study
involved pristane, which is not an adjuvant contained by any vaccine administered to humans
and cannot therefore be equated to aluminum adjuvant. Id. at 5. Dr. Whitton agreed with Dr.
Sundel that the Chen et al.47 article shows that scientific evidence demonstrating a causation link
between vaccines and autoimmune diseases remains “elusive.” Id.
Dr. Whitton then criticized Dr. Sundel’s reliance on the Cerpa-Cruz et al.48 study to show
a causal link between vaccines and autoimmune diseases. Id. at 6. He noted that the authors
conceded that the study suffered from significant limitations, namely, its cross-sectional design;
small population size; inherent selection bias; and, most importantly, the lack of a control group,
without which there cannot be an appropriate comparison of the results. Id. These limitations,
Dr. Whitton argued, “render the [study’s] findings essentially meaningless.” Id.
Dr. Whitton provided the results of controlled studies of adjuvanted vaccines to show that
they have no deleterious effects on JIA. Id. at 7. He noted the study by Heijstek et al.49 which
found that “‘[t]he bivalent HPV16/18 . . . is immunogenic and well tolerated in JIA patients.’”
Id. He also stated that the safety of human papillomavirus vaccines in autoimmune diseases
including JIA has been confirmed “in at least two other studies[,]” while the hepatitis B,
meningococcus C, and adjuvanted influenza vaccines have also been found to be safe in patients
with JIA. Id. (citing Resp’t’s Ex. J, Tab 4,50 ECF No. 62-4; Resp’t’s Ex. J, Tab 5,51 ECF No. 62-
5; Resp’t’s Ex. J, Tab 6,52 ECF No. 62-6; Resp’t’s Ex. J, Tab 7,53 ECF No. 62-7; Resp’t’s Ex. J,
Tab 8,54 ECF No. 62-8). Dr. Whitton noted that “[t]he vaccines neither triggered JIA, nor [did
they] exacerbate[] existing JIA[]” in any of the studies he reviewed. Id. Indeed, he continued,
some vaccines are recommended in JIA patients because “the immune disruption [experienced
by] JIA sufferers may render them more susceptible to the related pathogens.” Id.
Dr. Whitton stated that A.F.’s sJIA could not have been triggered by the vaccines in
question because A.F. had tolerated all previous vaccines. Id. at 8. Dr. Whitton agreed with Dr.
Sundel that “adjuvants act, in general, by activating the innate immune system[.]” Id. He noted,
however, that “unlike the adaptive immune system, the innate response does not have significant
memory[]” because the innate immune system is designed to act rapidly. Id. He explained that
“every time [the innate immune system] encounters a given stimulus . . . its response will be very
47
See Chen et al., supra note 28.
48
See Cerpa‐Cruz et al., supra note 33.
49
See Resp’t’s Ex. J, Tab C, ECF No. 62-3, M.W. Heijstek et al., Immunogenicity and Safety of the
Bivalent HPV Vaccine in Female Patients with Juvenile Idiopathic Arthritis: A Prospective Controlled
Observational Cohort Study. ANN. RHEUM. DIS. 2014;73:1500–07.
50
P. Pellegrino et al., Immunogenicity and Safety of the Human Papillomavirus Vaccine in Patients with
Autoimmune Diseases: A systematic review. VACCINE 2015;33:3444–49.
51
S. Esposito et al., Immunogenicity, Safety and Tolerability of a Bivalent Human Papillomavirus
Vaccine in Adolescents with Juvenile Idiopathic Arthritis. EXPERT. REV. VACCINES 2014;13:1387–93.
52
Y. Nerome et al., The Safety and Effectiveness of HBV Vaccination in Patients with Juvenile Idiopathic
Arthritis Controlled by Treatment. MOD. RHEUMATOL. 2016;26:368–71.
53
E. Zonneveld-Huijssoon et al., Safety and Efficacy of Meningococcal C Vaccination in Juvenile
Idiopathic Arthritis. ARTHRITIS RHEUM. 2007;56:639–46.
54
L. Dell’Era et al., Immunogenicity, Safety and Tolerability of MF59-Adjuvanted Seasonal Influenza
Vaccine in Children with Juvenile Idiopathic Arthritis. VACCINE 2012;30:936–40.
18
similar.” Id. Dr. Whitton therefore argued that without such memory, A.F.’s innate immune
system could not have been “primed by previous vaccines.” Id. Dr. Whitton also explained that
sJIA requires a constant “‘driver’ of inflammation,” which is inapposite to the innate immune
system’s response to an adjuvant, which is local and short lived. Id.
Dr. Whitton argued that A.F.’s sJIA was triggered by her previous ear infection, whose
“[b]acterial DNA is a strong stimulator of the innate immune response . . . and abundant DNA is
made during a bacterial infection.” Id. at 11. The purpuric rash A.F. also had on March 27,
2009, “might have been reflective of an undiagnosed viral infection” since such rash is not a sign
of JIA or MAS. Id. Dr. Whitton concluded that A.F.’s condition was more likely than not
caused by a viral infection close in time to the vaccine administration. Id. at 11–12.
3. Dr. Whitton’s Second Supplemental Expert Report
Dr. Whitton submitted his second supplemental expert report on May 30, 2017, in
response to Dr. Gurish’s expert report. Resp’t’s Ex. K. In this report, Dr. Whitton reiterated his
critique of the ASIA hypothesis. Id. at 1–3. He also reiterated his conclusion that a viral
infection was the more likely trigger for A.F.’s sJIA rather than the vaccines she received. Id. at
13–15.
Dr. Whitton discussed in detail all the studies submitted by Dr. Gurish to support
Petitioner’s theory that an adjuvanted vaccine was the likely cause of A.F.’s sJIA. He first
discussed the Luján et al. study.55 He argued that the authors “appear to have reached their
conclusion before starting their analyses,” namely, that the ovine ASIA syndrome observed in
the study sheep was “related to adjuvants within the vaccines.” Id. at 4. Instead, Dr. Whitton
argued that given the high doses of aluminum to which the sheep had been exposed over a
prolonged period, “many of the findings can be attributed to aluminum intoxication.” Id. at 5.
Dr. Whitton also noted that the study was “extremely poorly . . . controlled” for three reasons:
(1) it failed to include a group that received only the adjuvant so any result comparison would be
rendered meaningless; (2) the group size of three sheep each was very small; and (3) the sheep
“received a smorgasbord of 14 vaccines” which made it “impossible to identify the responsible
vaccine component (if any).” Id. at 5–7. Finally, Dr. Whitton stated that the study is
inapplicable because, unlike in A.F.’s case, “no acute disease was observed.” Id. at 6.
Dr. Whitton also noted weaknesses in the study by Bagavant et al.,56 which Dr. Gurish
offered to support the idea that “vaccination with alum can indeed trigger an autoimmune
response.” Id. at 7. Dr. Whitton wrote that the concentration of aluminum administered to the
study mice was high. Id. at 8. Indeed, he noted, “when corrected for body weight, these mice
appear to have been given around . . . [nine hundred and twenty-four thousand times the dose
that is given in a human vaccine.” Id. “[G]iven the absence of any clear sign of
autoimmunity[,]” aluminum toxicity is “an adequate explanation” for the study findings rather
than the authors’ conclusion that the vaccines were to blame. Id. at 8–9. Additionally, Dr.
Whitton argued that the various routes of administration employed by the study authors do not
match the intramuscular route employed when administering vaccines to humans. Id. at 8. He
55
See Luján et al., supra note 41.
56
See Bagavant et al., supra note 39.
19
agreed with Dr. Gurish in his expert report, that based on the administration route used, “[t]he
bio-distribution will be different.” Id.; see also Pet’r’s Ex. 29 at 8 (noting that “a basic tenet of
immunology is that [the] route of exposure is critical to determining the ultimate reaction.”).
Dr. Whitton concluded by rebutting Dr. Gurish’s criticisms of Dr. Whitton’s previous
expert reports. He noted that Dr. Gurish agreed “that an ongoing driver is necessary” in
autoinflammatory disorders like sJIA. Id. at 12–13. This, he argued, puts it at odds with Dr.
Gurish’s contention that aluminum adjuvant triggered A.F.’s sJIA because the effects of
aluminum are local and short lived. Id. Dr. Whitton also argued that the “innate memory”
proposed by Dr. Gurish to explain why A.F. had no response to previous vaccinations fails for
two reasons. Id. at 13. First, he noted that studies on innate memory “suggest that only [two to
three] exposures are required to reach a maximal level[,]” which is much lower than the
seventeen previous vaccines A.F. had received, “many of which contained alum[.]” Id. at 13.
Second, he explained that the long-term effects of innate memory last days to weeks after
vaccination, whereas here A.F.’s previous DTaP vaccination was on April 10, 2006, i.e., almost
three years previously. Id. This time interval, he argued, “far exceed[s] the known duration of
‘innate training.’” Id.
E. Expert Testimony
1. Dr. Sundel’s Testimony
Dr. Sundel described sJIA as a “multifactorial” condition that requires “a susceptive area,
presumably genetic,” and “numerous triggers that seem to be able to push a child over,” usually
“low-grade inflammation that is controlled[.]” Tr. 27:10–18. He explained that at some point
“something increases the amount of inflammation in the child,” who cannot control it, and “it
explodes into a case of systemic JIA.” Tr. 27:18–21. Dr. Sundel noted that it was “a challenge
to diagnose” A.F.’s condition because “[t]here is not a single clinical manifestation, nor a single
laboratory test, nor a single imaging study that can make the diagnosis.” Tr. 19:24–20:5. He
explained that A.F. “had high markers of inflammation” and “specific tests for specific diseases
were all negative.” Tr. 19:22–20:1. He therefore argued that A.F.’s overall clinical presentation
and certain medical expertise were required to “rul[e] out all of the other possibilities” to
properly diagnose her with sJIA. Tr. 20:5–7.
Dr. Sundel testified that we know A.F. was unable to control her inflammation because of
the presence of MAS, which he described as a “cytokine storm.” Tr. 29:24–30:6. He explained
that during a cytokine storm “so many arms of the immune system are activated simultaneously,
[and] the body cannot handle that.” Tr. 30:8–10. He noted that when a child, like A.F., is
genetically predisposed, the aluminum adjuvant may stimulate the immune system to such a
degree as to enhance its response, thus leading to a cytokine storm. Tr. 34:21–35:4, 38:25–39:6,
39:19–40:8. Dr. Sundel also argued that the presence of MAS in A.F. is “further evidence that
she has systemic JIA, since [MAS is] so prevalent in that disease more than any other disease.”
Tr. 41:23–42:3.
Dr. Sundel noted that although A.F. was “genetically susceptible to systemic arthritis”
that was not enough to trigger the disease. Tr. 43:11–15. Rather, he argued, A.F.’s
20
inflammasomes and the rest of her innate immune system were triggered by a “concatenation” of
factors to cause her to develop sJIA. Tr. 43:3–9, 45:18–46:2. Dr. Sundel likened A.F.’s
condition to a “bubbling pot” created by a combination of her genetic predisposition and a
variety of environmental factors, with the vaccines being “a brick [thrown] into [the pot] and it
overflowed.” Tr. 53:9–25. He also equated the occurrence of A.F.’s condition to wildfires. Tr.
42:15–43:9. Although factors leading to wildfires, such as dry conditions or strong winds, can
be present in many different circumstances, wildfires happen only once the right conditions are
met. Id. In the same way, A.F. only developed sJIA due to “changes in her body:” (1) “her diet
was different [so] she had different bacteria in her gut[;]” (2) antibodies she had produced in
response to her earlier ear infection were present in her body; and (3) the amoxicillin she had
taken had “change[d] the bacteria in her intestine.” Tr. 43:18–25. Ultimately, Dr. Sundel argued
that DTaP vaccine was “the final blow” because the aluminum adjuvant “stimulated both
[A.F.’s] innate and adaptive immune system,” resulting in the cytokine storm. Tr. 44:2–9. Dr.
Sundel stated that, similar to a wildfire, the cause of a rare occurrence like A.F.’s condition could
only be discerned in retrospect due to the multivariate nature of the cause. Id. at 44:10–17.
On cross-examination, Dr. Sundel stated that he believes aluminum triggered A.F.’s
innate immune system because the data concerning aluminum show “that it . . . has this type of
an effect on the inflammasome and on the innate immune system.” Tr. 58:21–24. This immune
response is “normal” and occurs in any vaccine with aluminum. Tr. at 56:12–18. Dr. Sundel
noted that in A.F.’s case “the difference . . . was that she could not control” the innate system’s
inflammatory response. Tr. 59:9–10. When asked how much aluminum a person ingests daily,
Dr. Sundel replied that he did not know and reiterated that his “multi-hit hypothesis [is] that it
took a lot of inflammation to overwhelm [A.F.’s] controls and cause her to have a chronic
inflammatory disorder like systemic arthritis.” Tr. 78:1–12, 78:20–23. Finally, Dr. Sundel
disagreed that his causation theory of A.F.’s condition is analogous to the ASIA theory because
ASIA is “an overly broad generalization of what happens with vaccines[.]” Tr. 72:4–9. In fact,
Dr. Sundel rejected ASIA as “too broad for a theory that will have any use in clinical medicine,
or even in the legal system.” Tr. 84:20–22. Instead, he argued that his causation theory is
similar to “the more specific studies of things such as alum and IL-18” because, unlike ASIA,
those do not have the potential of encompassing almost all types of signs, symptoms, and
sequelae. Tr. 74:1–6.
The undersigned asked Dr. Sundel how he can base his theory of ASIA on the
pathogenesis of JIA when the pathogenesis is unknown. Tr. 86:1–2. Dr. Sundel explained that
although the pathogenesis is unknown, what we do know about the “development and
manifestations of [JIA] on a cellular level” is that it is an autoinflammatory disease where
inflammasomes, interferon, Interleukin-1 (“IL-1”),57 Interleukin-6 (“IL-6”),58 and Interleukin-18
57
Interleukin-1 is a “predominately macrophage-produced [cytokine] that mediates the host inflammatory
response in innate immunity . . . . At low concentrations, [it] principally acts to mediate local
inflammation,” whereas “at high concentrations [it] enters the blood stream and acts as an endocrine
hormone.” Dorland’s at 949.
58
Interleukin-6 is a “lymphokine produced by antigen- or mitogen-activated T cells, fibroblasts,
macrophages, and adipose and other cells that serves as a differentiation factor for B cells and thymocytes
and stimulates immunoglobulin production by B cells; it also induces hepatocytes to synthesize various
plasma proteins involved in the acute phase response.” Dorland’s at 949.
21
(“IL-18”)59 play an important role. Tr. 89:3–10. The undersigned then asked Dr. Sundel how he
distinguishes between a causal relationship and a byproduct with respect to IL-6 and IL-18. Tr.
86:12–14. Dr. Sundel stated that there is no evidence of a causal relationship due to a lack of
studies performed on such a rare disease. Tr. 86:18–87:2. Dr. Sundel also clarified that he does
not agree with ASIA because he does not know whether causation can be limited to the adjuvant.
Tr. 88:10–13. Dr. Sundel then explained the importance of the pre-vaccine ear infection. Tr.
88:16–90:17. Dr. Sundel stated that the ear infection activated A.F.’s innate and adaptive
immune systems and, although there were no signs of infection, the immune response was still
active and elevated. Id. at 88:21–90:7. In that context, he continued, the aluminum adjuvant
further activated A.F.’s immune system to such a degree that it “overwhelm[ed her body’s]
control mechanisms[,]” resulting in sJIA. Tr. 89:10–17. Under re-direct examination, Dr.
Sundel stated that the incidence rate for sJIA in the United States is 0.5 per one hundred
thousand children, which classifies it as a “orphan disease” by the federal government, i.e., rare.
Tr. 90:16–91:8. Because the disease is rare, it would be very difficult to study in children. Tr.
90:13–17.
2. Dr. Gurish’s Testimony
Dr. Gurish agreed with Dr. Sundel and distanced himself from the ASIA hypothesis
during testimony. Tr. at 127:22–128:7. Dr. Gurish stated that although “the ASIA hypothesis is
intriguing in the sense that someone is trying to understand these adverse events on a very global
scale . . . it’s hard to make predications based on this global hypothesis . . . .” Id. Dr. Gurish,
also agreed with Dr. Sundel’s characterization of a causal theory similar to a wildfire. Tr.
112:20–25, 130:6–11.
During his testimony, Dr. Gurish stated that aluminum has the ability to trigger the type
of immune system reaction that, if uncontrolled, results in sJIA. Tr. 105:5–106:15. Dr. Gurish
explained that aluminum “activates . . . macrophage[s] and induces the formation of
inflammasomes.” Tr. 105:24–106:2. Once this occurs, inflammasomes produce cytokines,
which result in “increased . . . phagocytosis.60” Tr. 106:9–11. Dr. Gurish then cited to the
studies by Luján et al.61 and Bagavant et al.62 as evidence that aluminum activates the innate
immune system. Id. at 108:17–112:9. Dr. Gurish clarified that the mice used in the Bagavant et
al. study were genetically susceptible to develop Sjögren’s syndrome, and he would view the
aluminum introduced in the study as a trigger for the development of this condition. Tr. 109:21–
110:10, 111:2–22. Dr. Gurish also agreed with Dr. Sundel that A.F.’s prior ear infection and
59
Interleukin-18 is a cytokine whose serum “levels are increased in active s-JIA. Thus, serum IL-18
levels are increasingly used as a biomarker for s-JIA diagnosis and of its therapeutic response in s-JIA . . .
. Serum IL-18 levels are even further increased in patients with s-JIA-related MAS . . . .” See Pet’r’s Ex.
24, Tab O at 2, ECF No. 107-2, M. Shimizu M et al., Interleukin-18 for Predicting the Development of
Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis. CLINICAL IMMUNOL.
2015;160:277–81.
60
Phagocytosis is the “process by which certain living cells called phagocytes ingest or engulf other cells
or particles.” ENCYC. BRITTANICA, https://www.britannica.com/science/phagocytosis (last visited May
30, 2019).
61
See Luján et al., supra note 41.
62
See Bagavant et al., supra note 39.
22
antibiotic treatment were contributing factors to A.F. developing sJIA rather than the cause. Tr.
113:12–114:15.
Dr. Gurish reiterated his argument that aluminum can move throughout the immune
system after vaccination via aluminum-containing translocating macrophages. Tr. 106:25–
107:20. Dr. Gurish cited to the studies by Khan et al.63 and Flarend et al.64 to show that
aluminum has been found to translocate in animals. Tr. 116:22–118:12, 120:12–121:12.
Specifically, he stated that the Khan et al. study showed that aluminum can translocate to the
brain via macrophages, while the Flarend et al. article showed that aluminum that had been
injected intramuscularly in rabbits was later found in the spleen and kidneys. Id.
In a similar fashion as Dr. Sundel, upon cross-examination, Dr. Gurish distanced himself
from ASIA. He agreed with Dr. Sundel that although an “intriguing” theory, ASIA is too
overbroad to use effectively. Tr. 127: 24–128:5. He also acknowledged the flaws in the Cerpa-
Cruz et al.65 study mentioned during Dr. Sundel’s cross-examination. Tr. 126:19–127:18. He
nevertheless found it to be “suggestive evidence” as a retrospective study despite the inherent
design flaws. Id. The undersigned asked Dr. Gurish about whether he defined an adverse event
following vaccination as an isolated incident or the result of a multifactorial culmination of
events. Tr. 129:12–130:5. Dr. Gurish answered that “it is a multifactorial system that’s come
together in a negative fashion to produce this adverse event, but there are multiple factors that
needed to come together at the right time to lead to the event.” Tr. 130:6–11. Dr. Gurish also
noted that it would be very difficult to design a study to test this hypothesis on humans because
“we don’t have a way of distinguishing all these different factors.” Tr. 131:7–19. The
undersigned asked whether, in a study based upon Dr. Sundel’s hypothesis, one would have to
work from one factor, i.e., the vaccine, and then “compare the other factors, as long as they all
have the same adverse event,” i.e., autoinflammation. Tr. 132:12–16. Dr. Gurish agreed, with
the caveat that each individual in the study may present with a “subtly” or “dramatically
different” form of the disease. Tr. 132:19–24.
3. Dr. Rose’s Testimony
Dr. Rose testified that A.F.’s “two viral insults, one before the [sJIA], and one before the
MAS[]” were the cause of her condition. Tr. 157:8–15. He first noted that A.F.’s two cell
counts from the end of March 2009 are not consistent with A.F. having sJIA at that time. Tr.
148:7–11. He explained that A.F.’s cell count from March 24, 2009, “suggests a viral infection,”
while the one from March 26 is “typical . . . of a patient on steroids[, e.g., A.F.]” Tr. 147:10–13,
147:23–148:6. Dr. Rose argued that although we cannot know the exact onset of A.F.’s sJIA,
her cell counts show that “beyond question [A.F.] was experiencing a viral insult[]” at the end of
March 2009. Tr. 148:13–16.
63
Pet’r’s Ex. 29, Tab M, ECF No. 108-6, Z. Khan et al., Slow CCL2-dependent Translocation of
Biopersistent Particles from Muscle to Brain. BMC MEDICINE 2013;11(1):99.
64
Pet’r’s Ex. 29, Tab L, ECF No. 108-5, R. Flarend et al., In Vivo Absorption of Aluminium-containing
Vaccine Adjuvants Using 26Al. VACCINE 1997;15.
65
See Cerpa‐Cruz et al., supra note 33.
23
Dr. Rose argued that by April 2009, A.F. was already suffering from “a garden-variety
systemic onset JIA.” Tr. 149:14–17. At that point, he explained, A.F. had her second viral
infection in the form of a dry cough. Tr. 150:10–151:8. And, once again, he continued, she had
“an abnormal response to a viral infection” with her erythrocyte sedimentation rate (“ESR”)66
rate normalizing, even though she had sJIA. Id. This time, however, A.F. developed MAS. Tr.
151:9–11. Dr. Rose explained that thirty to forty percent of sJIA patients have a lifetime risk of
developing MAS, of whom “[ten] percent are clinically diagnosable and the other [twenty] or
[thirty] are subclinical.” Tr. 153:3–9. He then cited to the Ravelli et al.67 study which showed
that because patients with sJIA “have slightly abnormal variants of the[ familial HLH] genes[,]”
they are prone to developing MAS. Tr. 155:25–156:7. He explained, when gamma interferon is
released as a response to a viral infection, it “activates the macrophages, and this activation
persists . . more macrophages are recruited, more cytokines are released, and you enter this
situation of the cytokine storm[.]” Tr. 156:8–23. Dr. Rose argued that this shows the important
role viral infections play in an individual like A.F. who has sJIA and is genetically predisposed
to developing MAS. Tr. 157:8–15.
Dr. Rose then testified that the aluminum-adjuvanted vaccine did not cause A.F.’s sJIA
and MAS. He explained that a genetic cause is more plausible because aluminum is an
environmental factor. Tr. 157:25–158:2. Environmental factors are more difficult to pinpoint
because “they’re very hard to control[] and . . . they’re happening all the time [because] they are
in the atmosphere.” Tr. 158:2–5. In A.F.’s case, Dr. Rose argued, we already know A.F. was
predisposed to sJIA and she suffered two viral infections. Tr. 158:6–22. He concluded that it is
more likely than not that these were the causes of her sJIA and not the aluminum adjuvant in the
DTaP vaccine. Id. Dr. Rose also noted that A.F. could not have had sJIA as early as March
2009 because she had no “abnormal response to th[e] vaccine[,]” e.g., fever, which would be
evidence of “a clinical and relevant activation of the innate immune system.” Tr. 160:1–13.
On cross-examination, Dr. Rose reiterated that A.F.’s fever, joint pain, rash, and elevated
C-reactive protein (“CRP”)68 on March 24, 2009, were caused by a virus and not her sJIA. Tr.
162:3–15; 191:2–7. He explained that MAS “is overwhelmingly a post-viral phenomenon” and
it is “highly suggestive of carrying [specific] genes that make [an individual] have an abnormal
response to viral infections.” Tr. 188:19–21. It is therefore more likely, he continued, that
A.F.’s fever and rash at that time were caused by a virus. Tr. 188:21–189:1. Dr. Rose also noted
that A.F.’s treating physicians at that time must have also thought that she had a viral infection
because they kept on testing her for a virus. Tr. 162:18–22; 162:25–163:3. He explained that
even though all the tests came back negative, doctors can only “test for the most common and the
most likely that [they] have a test for.” Tr. 163:9–14; 171:17–18. He also pointed out that
66
The ESR is “the rate at which erythrocytes precipitate out from a well[]mixed specimen of venous
blood.” The ESR “is increased in . . . active inflammatory disease.” Dorland’s at 1594.
67
See Resp’t’s Ex. F, ECF No. 33-4, A. Ravelli et al., Macrophage activation syndrome as part of
systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment, GENES AND
IMMUNITY 2012;13:289–98.
68
The CRP “is a blood test marker for inflammation in the body” that “is classified as an acute phase
reactant, which means that its levels will rise in response to inflammation.” C-Reactive Protein CRP
Test, Ranges, Symptoms, and Treatment, MEDICINENET, https://www.medicine net.com/c-
reactive_protein_test_crp/article.htm#what_is_c-reactive_protein_crp (last visited May 30, 2019).
24
A.F.’s normal white blood cell count coupled with an elevated ESR and CRP is “the result of a
viral infection” that was perhaps associated with a vasculitis. Tr. 167:14–18. This would also
explain why A.F. had purpura. Tr. 192:17–193:7.
4. Dr. Whitton’s Testimony
Dr. Whitton testified that although aluminum triggers the innate immune system, which
produces cytokines, “the duration of that triggering is short.” Tr. 202:1–4. He explained that
triggering merely “limit[s] the number of . . . minor adverse effects that often occur after
vaccination,” the most common of which are “erythema, swelling or hardness of the skin, and
pain and fever.” Tr. 202:8–14. He also noted that these adverse effects are “short-lived[; t]hey
occur usually within the first [twenty-four] to [forty-eight] hours and they dissipate fairly rapidly
thereafter.” Tr. 202:15–20.
Dr. Whitton stated that there is no evidence that the “tiny” amount of aluminum
distributed in the body is pathogenic or disease causing. Tr. 203:19–20. In support, he cited to
the 2007 study by Didierlaurent et al.,69 which showed that the effects of aluminum are limited
temporally and spatially. Tr. 204:1–6. He also noted several differences between aluminum
adjuvants and viruses in terms of their impact on the innate immune system. First, unlike
adjuvants which cannot replicate, a virus is “a highly replicating organism who[se] nucleic acid
components multiply into the certainly many, many millions.” Tr. 209:16–22. Viruses, he
explained, can therefore “trigger a variety of different sensors[,]” thus resulting in a “profound
innate immune response[.]” Id. Moreover, unlike adjuvants whose amount does not increase in
the body, “the amount of viral nucleic acid, and therefore the amount of material capable of . . .
ongoing stimulation of the innate immune system, is rising for several days.” Tr. 209:22–
210:10. He explained that this results in a more prolonged response. Tr. 209:22–23.
Dr. Whitton also testified that aluminum adjuvants could not cause sJIA because their
effect on the innate immune system diminishes as they are eliminated by the body. Tr. 207:1–7.
On the other hand, he argued that viral infections are a more likely cause because sJIA requires
“a persistent driver [that continues to replicate in order] to evolve and clinically manifest.” Tr.
Tr. 209:22–210:10; 211:10–12; 214:4–6. Because aluminum “adjuvant can’t multiply[,]” it does
not constitute a “persistent driver.” Id. Dr. Whitton explained that in A.F.’s case, her genetic
susceptibility “to developing hyper responses as a result of deficiency,” will be “most strongly
[triggered], without any question, [by a] virus infection.” Tr. 213:7–13. He added that “alum
has never been shown to cause macrophage activation syndrome.” He therefore argued that the
most likely cause of A.F.’s MAS and sJIA is a virus that cannot be shut down due to A.F.’s
genetic susceptibility. Tr. 213:17–214:3.
On cross-examination, Dr. Whitton testified that he based his opinion that A.F.’s sJIA
was the result of a viral infection on the inclusion of the phrase “viral syndrome” in A.F.’s
medical records, the testimony from the other three experts, and his own knowledge of
immunology. Tr. 217:21–25; 221:14–19. He explained that “of the two options, option one
69
See Resp’t’s Exhibit J, Tab 19, ECF No. 63-9, A.M. Didierlaurent et al., AS04, an Aluminum Salt- and
TLR4 Agonist-Based Adjuvant System, Induces a Transient Localized Innate Immune Response Leading
to Enhanced Adaptive Immunity, THE JOURNAL OF IMMUNOL. 2009; 183: 6186–97.
25
being alum-triggered . . . sJIA and . . . MAS[] and option two being that a virus infection
triggered it,” a viral infection is “a plausible interpretation and more plausible than a reaction to
alum because a reaction to alum should not be substantially different in somebody who is lacking
cytotoxic activity[.]” Tr. 221:19–222:12. Dr. Whitton also noted that A.F.’s genetic deficiency
in her cytotoxic activity “may have played a role in prolonging the innate immune response to
viral nucleic acids which otherwise would have been cleared had that infection occurred in”
people without said deficiency. Tr. 230:20–24.
IV. The Applicable Legal Standard
To receive compensation under the Vaccine Act, Petitioner must demonstrate either that:
(1) A.F.’s injury is a “Table Injury” and therefore resulted from the receipt of a covered vaccine
or vaccines within the time frame prescribed by the Vaccine Injury Table set forth at § 14, as
amended by 42 C.F.R. § 100.3; or (2) A.F.’s injury is an “off-Table Injury,” one not listed on the
Table, that resulted from her receipt of a covered vaccine. See § 11(c)(1)(C); Moberly v. Sec’y of
Health & Human Servs., 592 F.3d 1315, 1321 (Fed. Cir. 2010); Capizzano v. Sec’y of Health &
Human Servs., 440 F.3d 1317, 1319–20 (Fed. Cir. 2006). Petitioner’s claim that A.F.’s vaccines
caused her injury does not fall within the Vaccine Table. Thus, it must be proven that her
vaccines were the cause-in-fact of her injury.
To establish causation-in-fact, Petitioner must demonstrate by a preponderance of the
evidence that the vaccines were the cause of A.F.’s injury. § 13(a)(1)(A). Petitioner is required
to prove that the vaccines were “‘not only [the] but-for cause of the injury but also a substantial
factor in bringing about the injury.’” Moberly, 592 F.3d at 1321–22 (quoting Shyface v. Sec’y of
Health & Human Servs., 165 F.3d 1344, 1352–53 (Fed. Cir. 1999)). To do so, Petitioner must
provide evidence demonstrating a logical sequence causally linking the vaccination and the
injury. Shyface, 165 F.3d at 1352–53 (quoting Grant v. Sec’y of Health & Human Servs., 956
F.2d 1144, 1148 (Fed. Cir. 1992)). The vaccines received, however, need not be the
predominant cause of the injury. Shyface, 165 F.3d at 1352. Rather, the vaccines “must be a
substantial factor in bringing about the harm.” Id.
In Althen v. Sec’y of Health & Human Servs., the Federal Circuit set forth a three-
pronged test used to determine whether a petitioner has established a causal link between a
vaccine and the claimed injury. See 418 F.3d 1274, 1278 (Fed. Cir. 2005). The Althen test
requires a petitioner to set forth: “(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 a proximate temporal relationship between vaccination and
injury.” Id. To establish entitlement to compensation under the Program, a petitioner is required
to establish each of the three prongs of Althen by a preponderance of the evidence. See id.
(internal citations omitted).
Specifically, under the first prong of Althen, a petitioner must offer a scientific or medical
theory that answers in the affirmative the question “can [the] vaccine(s) at issue cause the type of
injury alleged?” See Pafford v. Sec’y of Health & Human Servs., No. 01-0165V, 2004 WL
1717359, at *4 (Fed. Cl. Spec. Mstr. July 16, 2004) aff’d sub nom. Pafford ex rel. Pafford v.
Sec’y of Dep’t of Health & Human Servs., 64 Fed. Cl. 19 (2005), and aff’d sub nom. Pafford v.
26
Sec’y of Health & Human Servs., 451 F.3d 1352 (Fed. Cir. 2006). This may be accomplished in
a number of ways. “Reliability and plausibility of . . . pathogenesis can be bolstered by
providing evidence that at least a sufficient minority in the medical community has accepted the
theory, so as to render it credible.” Id. Additionally, “epidemiological studies and an expert’s
experience, while not dispositive, lend significant credence to the claim of plausibility.” Id.
Medical literature published in respected medical journals is also persuasive. Id. “However,
publication ‘does not necessarily correlate with reliability,’ because ‘in some instances well-
grounded but innovative theories will not have been published.’” Id. (quoting Daubert v.
Merrell Dow Pharm., Inc., 509 U.S. 579, 593–94 (1993) (emphasis in original)). Furthermore, a
petitioner is not required to present medical literature or epidemiological studies to prove her
burden. Grant, 956 F.2d at 1149; Andreu v. Sec’y Health & Human Servs., 569 F.3d 1367, 1380
(Fed. Cir. 2009). However, to the extent medical literature and epidemiological studies are
provided, these are subject to critique by Respondent’s experts, and the special master will
consider them when deciding whether the petitioner has met her burden of proof.
In addition to showing that the vaccine at issue can cause a particular injury, a petitioner
must also, under Althen’s second prong, prove that the vaccine actually did cause the alleged
injury in a particular case. See Pafford, 2004 WL 1717359, at *4; Althen, 418 F.3d at 1278. A
petitioner does not meet this obligation by showing only a temporal association between the
vaccination and the injury; the petitioner “must explain how and why the injury occurred.”
Pafford, 2004 WL 1717359, at *4 (emphasis in original) (internal citations omitted).
Although a temporal association alone is insufficient to establish causation, under the
third prong of Althen, a petitioner must show that the timing of the injury fits with the causal
theory. See Althen, 418 F.3d at 1278. The special master cannot infer causation from temporal
proximity alone. See Thibaudeau v. Sec’y of Health & Human Servs., 24 Cl. Ct. 400, 403–04
(Fed. Cl. 1991); see also Grant, 956 F.2d at 1148 (“‘[T]he inoculation is not the cause of every
event that occurs within the ten[-]day period. . . . Without more, this proximate temporal
relationship will not support a finding of causation.’” (quoting Hasler v. United States, 718 F.2d
202, 205 (6th Cir. 1983))).
Petitioners who demonstrate by a preponderance of the evidence that they suffered an
injury caused by vaccination are entitled to compensation, unless Respondent can demonstrate
by a preponderance of the evidence that the injury was caused by factors unrelated to the
vaccination. See Althen, 418 F.3d at 1278; Paluck v. Sec’y of Health & Human Servs., 786 F.3d
1373, 1386 (Fed. Cir. 2015) (citing de Bazan v. Sec’y of Health & Human Servs., 539 F.3d 1347,
1352 (Fed. Cir. 2008) (holding that it is not a petitioner’s burden “to rule out possible alternative
causes” (internal citations omitted))); Knudsen v. Sec’y of Health & Human Servs., 35 F.3d 543,
547 (Fed. Cir. 1994). Under the Vaccine Act, the government’s burden is to prove by a
preponderance of the evidence that a substantial factor unrelated to the vaccine caused the injury.
42 U.S.C. § 300aa–13(a)(1)(B). This is identical to the burden of proof a petitioner bears to
establish his prima facie case. Id. § 300aa13 (a)(1)(A). The Federal Circuit has stated that “the
standards that apply to a petitioner’s proof of actual causation in fact in off-table cases should be
the same as those that apply to the government’s proof of alternative actual causation in fact.”
Knudsen, 35 F.3d at 549.
27
V. Discussion
A. Experts
Petitioner and Respondent both provided two experts, one each qualified to testify in the
areas of rheumatology and immunology. Dr. Sundel, for Petitioner, and Dr. Rose, for
Respondent, are board-certified pediatric rheumatologists. Dr. Sundel has impressive credentials
with more than sixty relevant publications and experience treating over one hundred and fifty
juvenile arthritis patients. Qualifications notwithstanding, Dr. Sundel’s expertise was undercut
by his vague and inconsistent causation theory. Dr. Sundel testified that “really it’s confusing”
and it “needs to be understood better, [but he] think[s] it is a reasonable hypothesis[.]” Tr.
85:14–15; 83:6–11. Dr. Sundel concluded that “[n]ew information on the role that aluminum
adjuvants appear to play in the development of autoimmunity following vaccinations . . . accord
well [with] the demographic, epidemiologic and chronologic characteristics of the events” that
can result in vaccine-caused sJIA. Pet’r’s Ex. 23 at 5. Despite this clear assertion that sJIA is an
autoimmune syndrome induced by adjuvants, Dr. Sundel did not refer to his theory by the ASIA
acronym well known in the program. In fact, during cross-examination, Dr. Sundel stated, “I’m
not invoking ASIA at all. I don’t think that’s relevant.” Tr. 60:23–24. Dr. Sundel’s rejection of
ASIA is contradicted by his filed medical literature. When asked for his “best evidence that an
aluminum salt adjuvant can trigger pathologic inflammation[]” or another adverse event, Dr.
Sundel referenced the Cerpa-Cruz et al.70 study. Tr. 82:1–18. Cerpa-Cruz et al. is a study
designed to test the ASIA theory. The authors wrote, “[o]ur results suggest that vaccines
containing adjuvants may be associated with an increased risk of autoimmune/inflammatory
adverse events following immunization.” Pet’r’s Ex. 23, Tab L at 4. If Dr. Sundel believes that
ASIA is “too broad for a theory that will have any use in clinical medicine, or even in the legal
system[,]” it is unclear why he would rely on papers by Dr. Shoenfeld, one of the leading
proponents of ASIA, and Cerpa-Cruz et al., who set out to test the veracity of ASIA. Tr. 84:20–
22; see Pet’r’s Ex. 23, Tab D; Pet’r’s Ex. 23, Tab L. Dr. Sundel praised Dr. Shoenfeld’s work
while acknowledging that it needs to be understood better. Tr. 83:2–10. He ultimately
conceded, “[i]t’s not proof, I acknowledge that.” Tr. 83:10–11.
By contrast, during testimony, Dr. Rose expanded on the opinion he expressed in his
reports, namely, that a viral infection, rather than the vaccines, caused A.F.’s sJIA. Dr. Rose
believed that Dr. Sundel was asserting an ASIA-based theory. He briefly critiqued the ASIA
theory but focused on how A.F.’s manifestations of sJIA and MAS were consistent with the
more commonly seen viral-induced sJIA. Dr. Rose’s application of his clinical knowledge of
sJIA to A.F.’s case was persuasive evidence that he was able to recognize and explain what
happened to her.
Dr. Gurish, Petitioner’s immunochemist, is an acclaimed researcher and professor.
Although he was not admitted to testify as an expert in immunology, Dr. Gurish exhibited his
expertise in the area through his written report and testimony. He was less helpful, however,
beyond providing a general overview of the immune system and responses. He agreed with
Respondent’s expert Dr. Whitton that the Cerpa-Cruz et al.71 study was not without flaws. He
70
See Cerpa‐Cruz et al., supra note 33.
71
Id.
28
also testified that he “would echo Dr. Sundel’s opinion that while the ASIA hypothesis is
intriguing . . . it also is disruptive . . . [and] it’s hard to make predictions based on this global
hypothesis.” Tr. 127: 24–128:5. Dr. Gurish did not explain how he had narrowed Dr.
Shoenfeld’s ASIA theory. He did not explain away holes in the causation theory that relate to its
vague symptoms or unspecific triggers. He was less persuasive for many of the same reasons as
Dr. Sundel.
Dr. Whitton is a more persuasive immunology expert because he has had more than
twenty years of experience as a professor of immunology, together with outstanding credentials
in immunology, virology, and vaccines. He also offered incisive critiques of the ASIA theory
and Dr. Sundel’s ASIA-like theory of autoimmunity as related to the function of the immune
system.
B. Althen Prong One
Petitioner has failed to prove by a preponderance of the evidence her theory causally
connecting A.F.’s DTaP and IP vaccinations to her sJIA. Dr. Sundel constructed this theory
based on the medical community’s current understanding that sJIA is an autoinflammatory
disease, the general principles of the innate immune system, and the accepted premise that the
DTaP and IP vaccines are designed to elicit an immune response. Dr. Sundel concluded that
even though “[d]ata looking at the potential role of adjuvants on development of complications
after vaccinations are still sparse[,]” aluminum adjuvants are a contributing factor of arthritis in
young girls after vaccination, “typically a booster dose.” Pet’r’s Ex. 23 at 5.
Petitioner’s medical theory can best be described by Dr. Sundel’s assertion, “was it the
IP[ vaccine], was it the DTaP, was it alum? I don’t really know, but I do know the combination
was not good for her.” Tr. 88:5–9. Despite his critique that ASIA is overbroad and in need of
additional study, his stated theory is based on the role of adjuvants in the development of adverse
events. It is ASIA and it fails now for the same reasons it has previously failed: the diagnostic
criteria proposed by the ASIA study’s authors are both vague and flawed. See, e.g., Resp’t’s Ex.
G at 4; Resp’t’s Ex. I at 8, 13–14.
The validity of the ASIA theory has been repeatedly called into doubt in the program.
See D’Angiolini v. Sec’y of Health & Human Servs., 122 Fed. Cl. 86, 102 (2015) (upholding
special master’s “determin[ation] that ASIA does not provide[] a biologically plausible theory
for recovery”), aff’d, 645 Fed. Appx. 1002 (Fed. Cir. 2016); Garner v. Sec’y of Health & Human
Servs., No. 15–063V, 2017 WL 1713184, at *8 (Fed. Cl. Spec. Mstr. Mar. 24, 2017) (observing
that the ASIA theory “is, at a minimum, incomplete and preliminary—and therefore unreliable
from an evidentiary standpoint”); Johnson v. Sec’y of Health & Human Servs., No. 10–578V,
2016 WL 4917548, at *7–9 (Fed. Cl. Spec. Mstr. Aug. 18, 2016) (rejecting Dr. Shoenfeld’s
expansive medical theory that “any adjuvant [is] capable of causing any autoimmune disease,”
finding it “overbroad, generalized, and vague, to the point that it could apply to virtually
everyone in the world who received a vaccine containing an adjuvant and then at some time in
their lives developed an autoimmune disease”); Rowan v. Sec’y of Health & Human Servs., No.
10–272V, 2014 WL 7465661, at *12 (Fed. Cl. Spec. Mstr. Dec. 8, 2014) (rejecting the ASIA
theory because it “is not a proven theory” and no “persuasive or reliable evidence” supports it).
29
The primary reason for ASIA’s rejection is its “changing and imprecise” diagnostic criteria,
which are unable to “distinguish between afflicted and un-afflicted patients.” D’Angiolini, 122
Fed. Cl. at 102. The “major” criteria include “dry mouth,” “arthralgia” (simple joint pain), and
“myalgia” (simple muscle pain); the “minor” criteria include “[o]ther clinical manifestations”
and “autoimmune disease.” Id.; see also Resp’t’s Ex. G at 4; Resp’t’s Ex. I at 8, 13–14. More
importantly, only “two major or one major and two minor criteria” are necessary for diagnosis.
D’Angiolini, 2014 WL 1678145, at *58. This does very little to “separate people with the
disease from people without the disease.” Id. at *59. In fact, Dr. Yehuda Shoenfeld, one of the
ASIA study authors, has conceded that “every attempt for an epidemiological study has so far
failed to deliver a connection” between autoimmune diseases and vaccines.72 Resp’t’s Ex. J at 4.
These flaws remained unaddressed by Dr. Sundel and Dr. Gurish. Their expert reports do
not add precision to the ASIA criteria, elaborate on the role of aluminum or specify how much is
needed, provide any further support from scientific or medical experts in the field, or add any
additional evidence to support the theory. They simply repeat what has already been rejected in
the cases cited above. In fact, Petitioner’s experts implicitly acknowledged the lack of success
ASIA has had in the program by trying to distance themselves from the name during their
testimony without distinguishing their medical theory from ASIA’s premise.
And, despite distancing himself from ASIA during testimony, Dr. Sundel relied on
medical literature that discussed autoimmune/autoinflammatory syndromes induced by adjuvants
to support his hypothesis. He relied upon the study by Cerpa-Cruz et al.73 to show a causal link
between vaccines and autoimmune diseases. Petitioner is correct that the authors of the report
conclude that their “results suggest that vaccines containing adjuvants may be associated with an
increased risk of autoimmune/inflammatory adverse events following immunization.” Pet’r’s
Ex. 23, Tab L at 4. However, this study suffers from serious limitations. As Dr. Whitton
explained in his reports, the study included no control group, its population size was small, and
there was an inherent selection bias. Resp’t’s Ex. J at 6. Additionally, as conceded by Dr.
Gurish in his testimony, the study’s authors themselves stated that the study’s retrospective
design and lack of control group make it impossible to “prove causal correlation between vaccine
and clinical manifestation.” Pet’r’s Ex. 23, Tab L at 5. This lessens the credibility of the
authors’ contention that there is a correlation between sJIA alone and the various vaccines
analyzed. Therefore, the study does not provide persuasive support, under the preponderant
standard, for the contention that aluminum-adjuvanted vaccines can cause sJIA.
Dr. Gurish discussed the studies by Luján et al.74 and He et al.75 to show that aluminum
adjuvant can be a contributing factor in autoimmune and autoinflammatory diseases via the
72
It is worth noting that ASIA is a study without an International Classification of Diseases, Ninth
Revision (“ICD–9”) code, which “is designed to promote international comparability in the collection,
processing, classification, and presentation of mortality statistics.” NAT’L CTR. FOR HEALTH STAT.,
https://www.cdc.gov/nchs/icd/icd9.htm (last visited May 30, 2019); see also Resp’t’s Ex. K at 2.
Moreover, the study’s criteria have not been substantiated by any reliable medical or scientific evidence.
See Resp’t’s Ex. G at 4.
73
See Cerpa‐Cruz et al., supra note 33.
74
See Luján et al., supra note 41.
75
See He et al., supra note 42.
30
activation of macrophages. Pet’r’s Ex. 29 at 5. He noted that the onset of A.F.’s sJIA four days
after vaccination matches the findings of the Luján et al. study. Id. at 7–8. He explained that,
like in those findings, the aluminum adjuvant contained in the DTaP vaccine was dispersed in
A.F.’s body by entering her blood stream via macrophages, which resulted in a systemic immune
response. Id. However, this study is not persuasive evidence for two reasons. First, as Dr.
Whitton explained, it involved the administration of high doses of aluminum in sheep over a
prolonged period of time. Resp’t’s Ex. K at 5, 8. Indeed, the study’s authors noted that “[t]he
content of aluminum hydroxide-based adjuvant in each dose of vaccine is of paramount
importance[.]” Pet’r’s Ex. 24, Tab I at 7. They explained that a vaccine with a low content of
adjuvant “cannot induce immune response effectively[,]” whereas, one with a “[h]igh aluminum
hydroxide content can suppress immune reactions because it can suppress the release of the
antigen.” Id. It is disingenuous to compare a single adjuvanted vaccine to aluminum hydroxide
content so high that the study’s authors were concerned about possible cytotoxicity.76 Id. The
study’s findings could be better explained by aluminum toxicity rather than an acute response to
a small amount of aluminum adjuvant. Second, as noted by Dr. Whitton, the sheep were given a
combination of fourteen different vaccines. It is therefore impossible to determine whether a
specific vaccine, if any, was responsible for adjuvant-related complications. Id. at 5–7. Dr.
Whitton’s critiques effectively render the study and its findings inapposite because it cannot link
sJIA with a specific vaccine and/or adjuvant.
Dr. Gurish also relied upon the study by Bagavant et al.77 to show that aluminum
enhances autoimmune response in individuals with a specific genetic disposition to Sjögren’s
syndrome—an autoimmune disease. Tr. 109:21–110:10. This study, too, fails to persuade. As
noted by Dr. Whitton, “when corrected for body weight, the[ study] mice appear to have been
given around . . . [nine hundred and twenty-four thousand] times the dose that is given in a
human vaccine.” Resp’t’s Ex. K at 8. Given the high dose administered and the absence of
autoimmunity in the mice, this study’s findings could also be explained by aluminum toxicity
rather than the vaccination. Importantly, again, the study’s authors admitted the study’s
limitations. Pet’r’s Ex. 29, Tab K at 6. They acknowledged that the mice were dosed using
routes of administration other than the intramuscular route used when administering vaccines to
humans. Id. And, as conceded by Dr. Gurish, bio-distribution differs based on the
administration route used, which “is critical to determining the ultimate reaction.” Pet’r’s Ex. 29
at 8. Because this study administered much higher doses of aluminum using vaccination routes
other than those routinely used in humans, it fails to provide support that aluminum-adjuvanted
vaccines can cause sJIA.
Petitioner has presented a theory that she is unable to distinguish from ASIA. She has
correctly identified ASIA’s previously identified shortcomings but failed to present any new
evidence to overcome these persuasive critiques. In sum, Petitioner has failed to provide a
reputable medical theory and therefore has failed to satisfy her burden under Althen prong one.
76
Cytotoxicity is “the degree to which an agent possesses a specific destructive action on certain cells or
the possession of such action.” Dorland’s at 467.
77
See Bagavant et al., supra note 39.
31
C. Althen Prong Two
Neither party disputes that A.F. developed sJIA after she received the DTaP and IP
vaccines. However, that chronology of events alone is not sufficient under the preponderant
standard. Both Dr. Sundel and Dr. Rose agree that the triggers of sJIA are unknown.
Dr. Sundel based his conclusion that A.F.’s sJIA was vaccine induced on the short time
period between vaccination and onset of A.F.’s sJIA and on “the absence of alternative
explanations” for her sJIA. See Pet’r’s Ex. 20 at 2. Nevertheless, Dr. Sundel stated that his
causation theory “is a theory only, because nobody knows what the cause of systemic JIA is.”
Tr. 53:1–2. He also conceded that the Chen et al.78 study he submitted in support of his theory
shows that “a direct association with even the most commonly implicated vaccines . . . has been
elusive[]” because of the wide range of potential triggers. Pet’r’s Ex. 23 at 3–4. Petitioner’s
theory does not explain the roles any of the non-adjuvanted vaccines played in the development
of A.F.’s sJIA. In fact, Dr. Sundel is unable to say which, if any, of those vaccines were needed
for A.F.’s symptoms to manifest. He does not apply his theory to the specific vaccinations that
A.F. received.
Dr. Gurish expanded on Dr. Sundel’s theory, explaining that the innate immune response
is activated within hours to days of exposure to aluminum adjuvant. Pet’r’s Ex. 29 at 5. He
applied this timing sequence to A.F. and noted that she developed a maculopapular rash two to
four days after vaccination, which was followed by abdominal pain, a swollen knee, and a
recurring fever of up to 103 °F. These initial symptoms, he argued, match both the ASIA criteria
and data from several studies, in particular, those by Luján et al.79 and Bagavant et al.80 Id.
Nevertheless, as discussed in Althen prong one above, ASIA’s diagnostic criteria are
unclear. First, the “exposure to external stimuli” major criterion is overbroad. Any exposure
A.F. had, be it the previous otitis media, her consequent amoxicillin treatment, a viral infection,
her vaccinations, or even another unidentified environmental trigger, could have activated her
innate immune system’s response. Second, the “appearance of ‘typical’ clinical manifestations”
major criterion is overbroad because the symptoms listed are common and non-specific. A.F. or
any otherwise healthy person with “typical” symptoms of sJIA, like fever and swollen joints,
could potentially be diagnosed with sJIA.
Third, as Dr. Whitton explained, the “removal of inciting agent induces improvement”
major criterion is in conflict with the [ASIA] study authors’ claim that “acute infections . . .
trigger long-term autoimmune disease.” Resp’t’s Ex. I at 13. This is because infections that
result in autoimmune diseases are “acute in nature” and the inciting agent in question is quickly
removed once the immune system has mounted its response. In this case, A.F.’s condition would
have therefore improved shortly after her immunization once the aluminum was eliminated from
her system. A.F., however, continued to suffer from a rash, fever, and joint pain, as well as loss
of appetite and swollen wrists and hands, for weeks after receiving the vaccines. Lastly, the
“other clinical manifestations” minor criterion is a catch-all standard. Any clinical
78
See Chen et al., supra note 28.
79
See Luján et al., supra note 41.
80
See Bagavant et al., supra note 39.
32
manifestation, e.g., myalgia, fever, arthralgia or arthritis, weakness, fatigue, sleep disturbances,
and gastrointestinal, respiratory and skin disorders, can essentially be explained by ASIA.
Therefore, all of A.F.’s symptomology could potentially be explained by ASIA and linked
causally to the adjuvant contained in any vaccine, including those in question. Petitioner has
failed to provide preponderant evidence establishing that ASIA (or the ASIA-like theory
proposed by Dr. Sundel) can be applied to any specific case generally, or A.F.’s specifically.
Dr. Sundel also testified that A.F.’s sJIA was the result of a confluence of events. He
likened A.F.’s condition to a “bubbling pot” created by a combination of her genetic
predisposition and a variety of environmental factors, with the vaccines being “a brick [thrown]
into [the pot] and it overflowed.” Tr. 53:9–25. It appears Dr. Sundel may be making a Shyface
argument, namely, that the vaccines in question were “‘a substantial factor in bringing about the
injury,’” but this also fails. Shyface, 165 F.3d at 1352. In Shyface, the Court affirmed the special
master’s findings that petitioners’ minor child would not have died but for the DPT vaccination,
and that the DPT vaccine contributed to his death by causing him to experience an exceptionally
high fever. 165 F.3d at 1353. The Court also agreed with the special master that the concurrent
sepsis was not the predominant cause of the child’s death. Id. Although petitioners did not
prove that the DPT vaccine was the only or predominant cause of their child’s death, the
statutory requirements were “met upon proof of the substantial factor criterion.” Id. Unlike
Shyface, Petitioner in the instant case has not shown that A.F. would not have developed sJIA
but for the vaccines she received. A.F. was genetically predisposed to developing both MAS and
sJIA. See, e.g., Resp’t’s Ex. G at 2; Tr. 34:21–35:4, 38:25–39:6, 39:19–40:8. It was therefore
highly likely that A.F. would develop sJIA at some point in her life.
Additionally, Respondent’s experts argued persuasively that the facts of this case are
more consistent with an alternative cause. Specifically, Respondent’s experts proposed that,
rather than the aluminum-adjuvanted vaccines, a viral infection was the most likely contributing
factor for A.F.’s sJIA. See, e.g., Resp’t’s Ex. A at 7–8; Resp’t’s Ex. J at 11–12. Dr. Whitton
explained that because the effects of the small amount of aluminum contained in the vaccines in
question are localized and short lived, A.F.’s sJIA could not have been caused by her vaccines.
Resp’t’s Ex. K at 12. Rather, A.F.’s genetic predisposition and MAS, which are both commonly
triggered by viral infections, support the need for “an ongoing driver” that gives rise to sJIA. Id.;
Tr. 213:7–15; see also Resp’t’s Ex. A at 17. Dr. Rose also explained that because of A.F.’s
genetic predisposition to sJIA—which is linked to the innate immune system via the cytolysis
pathway—a similar MAS-like or JIA-like response would have occurred after every vaccination
with an aluminum adjuvant. Resp’t’s Ex. A at 16–17. Because this did not occur, it is more
likely that a viral infection triggered A.F.’s sJIA. Id. Dr. Gurish also agreed that “an ongoing
driver is necessary . . . .” Pet’r’s Ex. 29 at 7. As explained by Dr. Whitton, the innate immune
system’s response is rapid and short lived. Resp’t’s Ex. I at 16. It is therefore logical to assume
that a constant inflammation stimulus would be required in sJIA and thus, in A.F.’s case.
Finally, Dr. Rose stated that because laboratory results were negative for MAS on March 27,
2019, the only other likely explanation for A.F.’s purpuric rash is a viral infection. Id. at 6.
Given A.F.’s genetic predisposition and the symptoms she exhibited at that time, it is more likely
that this viral infection was the substantial factor that triggered her sJIA than the vaccines in
question.
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It should be noted that in her post-hearing reply, Petitioner stated that Respondent’s
experts have not offered any medical literature to support their contention that a constant
stimulus of inflammation is required. Pet’r’s Post-Hrg Reply at 6, ECF No. 119. She therefore
argued that “such conjecture should not be accepted without the indicia of reliability that
literature provides.” Id. It appears that Petitioner is arguing that Respondent should be held to a
higher standard than that for petitioners. Nevertheless, the standards “that apply to the
government’s proof of alternative actual causation” are the same as those that apply to
Petitioner’s proof of actual causation. Knudsen, 35 F.3d at 549. The undersigned did not hold
Petitioner’s assertions to a higher standard, and she will not do so for Respondent.
In sum, Petitioner has failed to demonstrate “a logical sequence of cause and effect
showing that the vaccination was the reason for the injury.” Althen, 418 F.3d at 1278. She did
not provide evidence that the vaccines A.F. received caused or were a substantial factor in
causing her sJIA. By contrast, Respondent’s experts demonstrated that a viral infection was the
more likely cause for A.F.’s sJIA. For those reasons, Petitioner has failed at Althen prong two.
D. Althen Prong Three
A.F. received the DTaP and IP vaccines on March 13, 2009. Both experts agree that
onset occurred sometime before April 16, 2009. They disagree on whether A.F.’s sJIA
developed in mid- to late March or in early April 2009.
Petitioner bases her theory on circular reasoning and concludes that because A.F.’s
injury is vaccine induced, the onset of A.F.’s symptoms establishes the appropriate time frame
for a vaccine-related injury. Dr. Sundel’s proposed time frame for disease onset was four to five
days post vaccination. Tr. 19:13–17. He based this time frame on the contemporaneous medical
records and Dr. Kimura’s ultimate diagnosis of sJIA. Id. Dr. Rose stated that he had “no doubts
that at the beginning of April [2009] A.F. had s[]JIA,” but he opined that the purpuric rash she
had on March 27, 2019, was not the result of sJIA, nor did she “have diagnosable MAS” at that
time. Resp’t’s Ex. A at 6. He explained that, based on laboratory results, the more likely cause
of the rash on March 27, 2019, was a viral infection, which would place the onset for sJIA in
early April 2009. Id. at 6–7. As explained in the analysis for Althen prong two, based on the
preponderant standard, A.F.’s sJIA was more likely caused by a viral infection. The time frame
proposed by Dr. Rose is therefore more appropriate.
Additionally, none of the medical literature offered by either party discusses a medically
appropriate time frame for vaccine-caused sJIA. The broader deficiencies with Petitioner’s
theory (which did not otherwise establish that the DTaP and IP vaccines could cause sJIA),
however, render the undersigned unable to find that the timing at issue in this case of the alleged
vaccine-induced sJIA has been shown to be medically acceptable. Therefore, the undersigned
finds that Petitioner has not met her burden under Althen prong three.
VI. Conclusion
A decision on entitlement to compensation in the Vaccine Program cannot be made based
on the nature and severity of the disease alone. It must reflect a thorough analysis of the
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evidence and a thoughtful balance against the applicable legal standards based upon probative
weight and persuasiveness. Petitioner has not established that A.F.’s DTaP and IP vaccines more
likely than not caused her to develop sJIA.
Accordingly, the undersigned DENIES Petitioner’s claim and DISMISSES this
petition. In the absence of a timely filed motion for review filed pursuant to Vaccine Rule 23,
the Clerk of Court is directed to ENTER JUDGMENT consistent with this decision.81
IT IS SO ORDERED.
s/Herbrina D. Sanders
Herbrina D. Sanders
Special Master
81
Entry of judgment can be expedited by each party’s filing of a notice renouncing the right to seek
review. Vaccine Rule 11(a).
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