           In the United States Court of Federal Claims
                             OFFICE OF SPECIAL MASTERS
                                          No. 10-0197V
                               Originally filed March 17, 2016
                            Re-filed in redacted form July 11, 2013
                                       (To be published)


*************************
                                   *
H.L., on behalf of A.I.,           *
A.I., deceased,                    *
                                   *
                       Petitioner, *                  Vaccine Act Entitlement;
                                   *                  Causation-in-fact; Significant Aggravation;
                                   *                  FluMist Vaccine; Metabolic
                v.                 *                  Decompensation/Leigh Disease
                                   *
SECRETARY OF HEALTH AND            *
HUMAN SERVICES,                    *
                                   *
                       Respondent. *
                                   *
*************************


Robert J. Krakow, New York, New York, for Petitioner.
Justine Walters, U.S. Department of Justice, Washington, DC, for Respondent.

                                           DECISION

HASTINGS, Special Master.


       This is an action in which the Petitioner, H.L., seeks an award under the National
Vaccine Injury Compensation Program (hereinafter “the Program”1), on account of the death of
her daughter, A.I. For the reasons set forth below, I conclude that Petitioner is not entitled to an
award.




1
        The applicable statutory provisions defining the Program are found at 42 U.S.C. § 300aa-
10 et seq. (2012 ed.). Hereinafter, for ease of citation, all "§" references will be to 42 U.S.C.
(2012 ed.).
                                                 1
                                                 I

                        THE APPLICABLE STATUTORY SCHEME

        Under the National Vaccine Injury Compensation Program, compensation awards are
made to individuals who have suffered injuries after receiving vaccines. In general, to gain an
award, a petitioner must make a number of factual demonstrations, including showing that an
individual received a vaccination covered by the statute; received it in the United States; suffered
a serious, long-standing injury; and has received no previous award or settlement on account of
the injury. Finally – and the key question in most cases under the Program – the petitioner must
also establish a causal link between the vaccination and the injury. In some cases, the petitioner
may simply demonstrate the occurrence of what has been called a “Table Injury.” That is, it may
be shown that the vaccine recipient suffered an injury of the type enumerated in the “Vaccine
Injury Table,” corresponding to the vaccination in question, within an applicable time period
following the vaccination also specified in the Table. If so, the Table Injury is presumed to have
been caused by the vaccination, and the petitioner is automatically entitled to compensation,
unless it is affirmatively shown that the injury was caused by some factor other than the
vaccination. § 300aa-13(a)(1)(A); § 300aa-11(c)(1)(C)(i); § 300aa-14(a); § 300aa-13(a)(1)(B).

         In other cases, however, the vaccine recipient may have suffered an injury not of the type
covered in the Vaccine Injury Table. In such instances, an alternative means exists to
demonstrate entitlement to a Program award. That is, the petitioner may gain an award by
showing that the recipient’s injury was “caused-in-fact” by the vaccination in question. § 300aa-
13(a)(1)(B); § 300aa-11(c)(1)(C)(ii). In such a situation, of course, the presumptions available
under the Vaccine Injury Table are inoperative. The burden is on the petitioner to introduce
evidence demonstrating that the vaccination actually caused the injury in question. Althen v.
HHS, 418 F.3d 1274, 1278 (Fed. Cir. 2005); Hines v. HHS, 940 F.2d 1518, 1525 (Fed. Cir.
1991). The showing of “causation-in-fact” must satisfy the “preponderance of the evidence”
standard, the same standard ordinarily used in tort litigation. § 300aa-13(a)(1)(A); see also
Althen, 418 F.3d at 1279; Hines, 940 F.2d at 1525. Under that standard, the petitioner must
show that it is “more probable than not” that the vaccination was the cause of the injury. Althen,
418 F.3d at 1279. The petitioner need not show that the vaccination was the sole cause or even
the predominant cause of the injury or condition, but must demonstrate that the vaccination was
at least a “substantial factor” in causing the condition, and was a “but for” cause. Shyface v.
HHS, 165 F.3d 1344, 1352 (Fed. Cir. 1999). Thus, the petitioner must supply “proof of a logical
sequence of cause and effect showing that the vaccination was the reason for the injury;” the
logical sequence must be supported by “reputable medical or scientific explanation, i.e., evidence
in the form of scientific studies or expert medical testimony.” Althen, 418 F.3d at 1278; Grant v.
HHS, 956 F.2d 1144, 1148 (Fed. Cir. 1992).

        The Althen court also provided additional discussion of the “causation-in-fact” standard,
as follows:

       Concisely stated, Althen’s burden is to show by preponderant evidence that the
       vaccination brought about her injury by providing: (1) a medical theory causally
       connecting the vaccination and the injury; (2) a logical sequence of cause and


                                                 2
       effect showing that the vaccination was the reason for the injury; and (3) a
       showing of proximate temporal relationship between vaccination and injury. If
       Althen satisfies this burden, she is “entitled to recover unless the [government]
       shows, also by a preponderance of the evidence, that the injury was in fact caused
       by factors unrelated to the vaccine.”

Althen, 418 F.3d at 1278 (citations omitted). The Althen court noted that a petitioner need not
necessarily supply evidence from medical literature supporting petitioner’s causation contention,
so long as the petitioner supplies the medical opinion of an expert. (Id. at 1279-80.) The court
also indicated that, in finding causation, a Program fact-finder may rely upon “circumstantial
evidence,” which the court found to be consistent with the “system created by Congress, in
which close calls regarding causation are resolved in favor of injured claimants.” (Id. at 1280.)

        Where a petitioner in a cause-in-fact or “off Table” case is seeking to prove that their
vaccination aggravated a pre-existing injury, the court must also apply three additional factors
originating the standard for assessing aggravation claims in “Table” injury cases. See Loving v.
HHS, 86 Fed. Cl. 135, 144 (Fed. Cl. 2009)(combining the first three Whitecotton factors for
claims regarding aggravation of a Table injury with the three Althen factors for off table injury
claims to create a six-part test for off Table aggravation claims); see also W.C. v. HHS, 704 F.3d
1352, 1357 (Fed. Cir. 2013)(applying the six-part Loving test.). The additional Loving factors
require the Petitioners to demonstrate aggravation by showing: (1) the vacinee’s condition prior
to the administration of the vaccine, (2) the vacinee’s current condition, and (3) whether the
vacinee’s current condition constitutes a “significant aggravation” of the condition prior to the
vaccination. Id.

         Since Althen, the Federal Circuit has addressed the causation-in-fact standard in several
additional rulings, which have affirmed the applicability of the Althen test, and afforded further
instruction for resolving causation-in-fact issues. In Capizzano v. HHS, 440 F.3d 1317, 1326
(Fed. Cir. 2006), the court cautioned Program fact-finders against narrowly construing the
second element of the Althen test, confirming that circumstantial evidence and medical opinion,
sometimes in the form of notations of treating physicians in the vaccinee’s medical records, may
in a particular case be sufficient to satisfy that second element of the Althen test. Both Pafford v.
HHS, 451 F.3d 1352, 1355 (Fed. Cir. 2006), and Walther v. HHS, 485 F.3d 1146, 1150 (Fed. Cir.
2007), discussed the issue of which party bears the burden of ruling out potential non-vaccine
causes. DeBazan v. HHS, 539 F.3d 1347 (Fed. Cir. 2008), concerned an issue of what evidence
the special master may consider in deciding the initial question of whether the petitioner has met
her causation burden. The issue of the temporal relationship between vaccination and the onset
of an alleged injury was further discussed in Locane v. HHS, 685 F.3d 1375 (Fed. Cir. 2012), and
W.C. v. HHS, 704 F.3d 1352 (Fed. Cir. 2013). Moberly v. HHS, 592 F.3d 1315 (Fed. Cir. 2010),
concluded that the “preponderance of the evidence” standard that applies to Vaccine Act cases is
the same as the standard used in traditional tort cases, so that conclusive proof involving medical
literature or epidemiology is not needed, but demonstration of causation must be more than
“plausible” or “possible.” Both Andreu v. HHS, 569 F.3d 1367 (Fed. Cir. 2009), and Porter v.
HHS, 663 F.3d 1242 (Fed. Cir. 2011), considered when a determination concerning an expert’s
credibility may reasonably affect the outcome of a causation inquiry. Broekelschen v. HHS, 618
F.3d 1339 (Fed. Cir. 2010), found that it was appropriate for a special master to determine the


                                                 3
reliability of a diagnosis before analyzing the likelihood of vaccine causation. Lombardi v. HHS,
656 F.3d 1343 (Fed. Cir. 2011), and Hibbard v. HHS, 698 F.3d 1355 (Fed. Cir. 2012), both again
explored the importance of assessing the accuracy of the diagnosis that supports a claimant’s
theory of causation. Doe 11 v. HHS, 601 F.3d 1349 (Fed.Cir. 2010) and Deribeaux v. HHS, 717
F.3d 1363 (Fed. Cir. 2013), both discuss the burden of proof necessary to establish that a “factor
unrelated” to a vaccine may have caused the alleged injury.

         Another important aspect of the causation-in-fact case law under the Program concerns
the factors that a special master should consider in evaluating the reliability of expert testimony
and other scientific evidence relating to causation issues. In Daubert v. Merrell Dow
Pharmaceuticals, Inc., 509 U.S. 579 (1993), the Supreme Court listed certain factors that federal
trial courts should utilize in evaluating proposed expert testimony concerning scientific issues.
In Terran v. HHS, 195 F.3d 1302, 1316 (Fed. Cir. 1999), the Federal Circuit ruled that it is
appropriate for special masters to utilize Daubert’s factors as a framework for evaluating the
reliability of causation-in-fact theories presented in Program cases.

        The Petitioner in this case alleges that the influenza vaccination that A.I. received on
January 11, 2008, did not initially cause Leigh Disease, but rather, that the vaccination
significantly aggravated her pre-existing Leigh Disease, causing it to worsen. According to
W.C. v. HHS, 704 F.3d 1352 (Fed. Cir. 2013), “the National Vaccine Injury Compensation
Program *** allows certain petitioners to be compensated upon showing, among other things,
that a person ‘sustained, or had significantly aggravated’ a vaccine-related ‘illness, disability,
injury, or condition.’” Id. at 1355-56, quoting 42 U.S.C. § 300aa-11(c)(1)(C)) (emphasis added.)
In Whitecotton v. HHS, 81 F.3d 1099, 1103 (Fed. Cir. 1996), the U.S. Court of Appeals for the
Federal Circuit stated that “the statutory requirements to make out a prima facie significant
aggravation claim are analogous to those required to make out a prima facie initial onset claim.”
The Vaccine Act states that “[t]he term ‘significant aggravation’ means any change for the worse
in a preexisting condition which results in markedly greater disability, pain or illness
accompanied by substantial deterioration of health.” § 300aa-33(4).
       The elements of an off-Table significant aggravation case are set forth in Loving v. HHS,
86 Fed. Cl. 135, 144 (2009). There, the court combined the test from Althen, above, which
defines off-Table causation cases, with the test from Whitecotton v. HHS, 81 F.3d 1099, 1107
(Fed. Cir. 1996), which concerns on-Table significant aggravation cases. The resulting test has
six components, which are:

       (1) the person's condition prior to administration of the vaccine, (2) the person's
       current condition (or the condition following the vaccination if that is also
       pertinent), (3) whether the person's current condition constitutes a 'significant
       aggravation' of the person's condition prior to vaccination, (4) a medical theory
       causally connecting such a significantly worsened condition to the vaccination,
       (5) a logical sequence of cause and effect showing that the vaccination was the
       reason for the significant aggravation, and (6) a showing of a proximate temporal
       relationship between the vaccination and the significant aggravation.




                                                 4
Loving, 86 Fed. Cl. at 144; see also W.C. v. HHS, 704 F.3d 1352, 1357 (Fed. Cir. 2013) (holding
that “the Loving case provides the correct framework for evaluating off-table significant
aggravation claims”).


                                                 II

                                  PROCEDURAL HISTORY

        On April 1, 2010, Petitioner H.L. filed a petition through her attorney, Robert Krakow,
under the National Vaccine Injury Compensation Program, on behalf of her deceased daughter,
A.I. (ECF No. 1.) The petition alleged that A.I. was administered an influenza vaccine under
the brand name “FluMist” on January 11, 2008, and that that vaccine “significantly aggravated
[A.I.’s] metabolic and mitochondrial disorder leading to serious complicating medical problems
and causing her death on April 5, 2008.” (Id., ¶¶ 10, 11.) According to the Petition, A.I.’s
diagnosis at death was “Leigh’s encephalopathy syndrome,” respiratory failure, and sepsis. (Id.,
¶ 53.)
       At that time, Petitioner filed medical and other records marked as Exhibits 1 to 22. Also
on April 1, 2010, a notice was filed assigning the case to Special Master Golkiewicz. (ECF No.
2.)
        Respondent filed a “Rule 4 report” on June 30, 2010, contending that the Petitioner had
not met her burden of proving causation or significant aggravation. (ECF No. 8.) Although
Respondent did not dispute that A.I. suffered from the terrible condition known as “Leigh
Disease,” or that her death was ultimately attributable to it (id., p. 8), the government contended
that the facts of this case were not sufficient to justify a finding that the Leigh Disease was
caused or aggravated by A.I.’s vaccination, particularly in the absence of any causal connection
having been made by any of A.I.’s treating physicians (id., pp. 10-11).
        After a number of extensions of time, Petitioner filed an expert report by Dr. Frances D.
Kendall on January 1, 2012. (Ex. 24.) Shortly thereafter, the case was reassigned to Chief
Special Master Patricia Campbell-Smith. (ECF No. 29.) On July 17, 2012, Respondent filed an
expert report by Dr. Shawn E. McCandless. (Ex. A.)
       Subsequently, the case was reassigned to me on May 28, 2013, and I scheduled an
evidentiary hearing for July 26, 2013. Pre-hearing submissions were submitted by both parties
on July 3, 2013, as was a supplemental declaration by H.L. on July 19, 2013 (Ex. 93). At the
hearing, held on July 26, 2013, I heard testimony from H.L. as well as Drs. Kendall and
McCandless. (See Transcript of Proceedings (“Tr.”), ECF No. 70.)
        From that point forward, Petitioner requested a large number of extensions before finally
submitting a post-hearing brief on December 14, 2014. (ECF No. 114.) Respondent’s response
was filed on April 22, 2015 (ECF No. 123), followed by Petitioner’s reply brief on June 9, 2015
(ECF No. 127).
        The parties were subsequently permitted to file additional supplemental briefs, which
they did on August 3, 2015 (Respondent), and September 3, 2015 (Petitioner). (ECF Nos. 130,

                                                 5
133.) These briefs principally addressed the significance of the Federal Circuit’s decision in
Paluck v. HHS, 786 F.3d 1373 (Fed. Cir. 2015), which was raised for the first time in Petitioner’s
reply brief.2

                                                  III

                                               FACTS

       A.I. was born prematurely on December 7, 2001, at 29 weeks of gestation, and was not
discharged from the hospital until approximately two months later. (Ex. 1, p. 140.) During this
time she had feeding and breathing difficulties, pneumonia, and gastro-esophageal reflux
disorder (“GERD”). (Ex. 19, pp. 443-44.) Following her discharge, A.I. was seen regularly by
Brighton Pediatrics. She was generally described as doing “well” and as being “alert,” but her
premature birth was noted several times in the medical records. (See, e.g., Ex. 1, pp. 110-29.)
        In the course of her pediatric care, A.I. was treated for common infections on a number of
occasions. (Ex. 1, pp. 4-7.) At various points, she had conjunctivitis, upper respiratory
infections, bronchitis, otitis media, sinusitis, viral gastroenteritis, and other illnesses. (Id.) A.I.
developed fevers on multiple occasions, but was able to recover from those illnesses. (Id., pp.
65, 91, 107.) In January of 2003, A.I. was hospitalized with fever, diarrhea, and dehydration.
(Ex. 3, pp. 53-56; Ex. 14, p. 26.) Her records indicate a 103-degree fever on December 1, 2003,
at which point it was noted that she was falling and clumsy. (Ex. 1, p. 91.)
        In A.I.’s first year, her development was viewed as appropriate for her adjusted age, and
she was growing well. (Ex. 1, p. 110.) At about age 14 months, however, A.I. was observed to
have motor delay and possible speech delay. (Ex. 1, p. 102.) These delays were noted again at
16 months (Ex. 1, p. 98) and 18 months (Ex. 1, p. 94). At about 30 months, it was noted that A.I.
was a late walker and that she still fell down frequently. (Ex. 1, p. 83.) At about 35 months of
age, A.I. visited the pediatrician after falling and hitting her head. (Ex. 1, pp. 79-80.) At this
time her developmental delay was again noted, as was the fact that she appeared “wobbly” when
she walked. (Id.)
        In addition to mild illnesses and developmental concerns, A.I. had some surgeries. She
was also diagnosed with esotropia, an eye condition, and had corrective surgery for that
condition at 31 months. (Ex. 2, pp. 20-22.) At age 49 months, she had an adenoidectomy and
tube placement in her ears. (Ex. 8, p. 9.)
        On January 11, 2008, A.I., now six years old, saw her pediatrician following two days of
coughing, and a fever registering 102 degrees that morning. (Ex. 1, pp. 39-40.) By the time of
her exam, her fever had reduced to 100.3. (Id.) She was diagnosed as having an upper
respiratory infection, which had improved by her next visit on January 16, 2008. (Ex. 1, pp. 38,
40.) During the visit on January 11, 2008, A.I.’s pediatrician administered a FluMist vaccine,
recommended Tylenol for her fever, and prescribed donatussin. (Ex. 1, p. 40.)



2
        Paluck was decided on May 20, 2015, after Respondent had filed her brief, but before
Petitioner filed her reply.
                                                  6
        H.L. testified that after that point, A.I. began demonstrating unusual symptoms. In
particular, later in the evening on January 11, A.I. began experiencing “staring spells.” (Tr. 23-
26.) 3 Continuing to feel unwell, A.I. stayed home from school through January 18, 2008. (Ex. 5,
p. 95; Tr. 25, 28.)
        On January 22, 2008, A.I. collapsed three times during the school day, and was taken to
the emergency room at the Children’s Hospital. (Ex. 4, pp. 3-4.) Her parents reported that over
the previous week, A.I. had light sensitivity in her eyes, painful urination, and periods of
disorientation, which resolved with stimulation. (Ex. 6, p. 5.) A.I. was discharged the same day
with instructions to follow up with her pediatrician. (Ex 4, p. 4.)


3
         There is no documentation in the medical records directly supporting H.L.’s testimony
that A.I. experienced staring spells on the day of her FluMist vaccination. Ordinarily medical
records “warrant consideration as trustworthy evidence.” Cucuras v. Sec'y of Health & Human
Servs., 993 F.2d 1525, 1528 (Fed. Cir. 1993). Accordingly, where subsequent testimony
conflicts with contemporaneous medical records, special masters frequently accord more weight
to the medical records. See, e.g., Reusser v. Sec'y of Health & Human Servs., 28 Fed. Cl. 516,
523 (1993) (“[W]ritten documentation recorded by a disinterested person at or soon after the
event at issue is generally more reliable than the recollection of a party to a lawsuit many years
later.”). However, “it must be recognized that the absence of a reference to a condition or
circumstance is much less significant than a reference which negates the existence of the
condition or circumstance. Since medical records typically record only a fraction of all that
occurs, the fact that reference to an event is omitted from the medical records may not be very
significant.” Murphy v. HHS, 23 Cl. Ct. 726, 733 (Fed. Cl. 1991)(aff’d 968 F.2d 1226 (Fed. Cir.
1992)). Here, there is nothing in the records to either support or directly contradict H.L.’s
account of the staring spells that allegedly occurred immediately after A.I.’s vaccination. The
record for A.I.’s next medical exam on January 16 indicates that A.I.’s activity level was
“down,” but does not mention staring spells. (Ex. 1, p. 37.) I note, however, that H.L. testified
that at the time she witnessed A.I.’s staring spells, she did not have the vocabulary to describe it.
(Tr. 23.) But in any event, the record for A.I.’s next visit on January 28 does explicitly reference
the staring spells, and does so without any reference to when they began. (Ex. 1, p. 35.) Despite
the lack of any notation in the January 16 records, this later entry provides some corroboration of
H.L.’s account, although it does not specify when the staring spells occurred. (Also note that at
Ex. 1, p. 4, there seems to be a handwritten notation on 1/23/08 mentioning “staring spells”.) I
also find it noteworthy that H.L. was able to anchor her recollection of the staring spells to two
specific instances, one in which A.I. seemed to ignore H.L. when they returned home and it was
time to get out of the car, and one in which H.L. observed A.I. apparently ignoring her brother.
(Tr. 23-25.)

        Assessing these factors, I do find it strange that if A.I. actually experienced staring spells
on January 11, these would not have been reported at the January 16 visit. However, for
purposes of deciding this case at this time, I will assume that A.I. did experience her first staring
spells on January 11, as Petitioner asserts.



                                                  7
        However, while walking to the car in the emergency room parking lot, A.I. collapsed
again. (Ex. 3, pp. 31, 34; Ex. 4, p. 4.) A.I.’s father carried her back to the emergency room, and
A.I. was diagnosed with staring spells and “weakness.” (Ex. 3, p. 40; Ex. 6, p. 8.) The plan
remained for her to follow up with her pediatrician in two days. (Id.) The next day, A.I.’s
pediatrician noted that she was experiencing “drop attacks” and “staring spells,” and referred her
for an EEG. (Ex. 1, p. 4.) On January 24, 2008, an EEG was performed, which came back
normal.
        On January 28, 2008, A.I. was seen at her pediatrician’s office for a follow-up visit. (Ex.
1, p. 35.) The doctor’s impression was ataxia, weakness in legs, and probably mild Guillain-
Barré syndrome, and A.I. was referred to a pediatric neurologist. (Id., p. 36.) Two days later,
A.I. was seen by pediatric neurologist, Benjamin Ross. (Ex. 6, pp. 27-30.) Upon examination,
Dr. Ross concluded that Guillain-Barré was unlikely. (Ex. 6, p. 29.)
        On February 11, 2008, A.I. had an MRI of her brain, which was abnormal, and
suggestive of a possible mitochondrial disorder. (Ex. 19, p. 244; Ex. 6, pp. 31-32.) At Dr. Ross’
request, the family returned to his office on February 19, 2008, to discuss the results. (Ex. 6, pp.
31-32.) At this time, A.I. was no longer having sudden falls, but continued to have intermittent
staring spells and increased difficulty eating and drinking. (Id., p. 31.) Dr. Ross recorded
additional family history, and ultimately concluded that given A.I.’s abnormal MRI, recent
symptoms, and family history, the likely diagnosis was a mitochondrial disorder. (Id., p. 33.)
Specifically, Dr. Ross was concerned A.I. had “Leigh syndrome,” and recommended further
investigation. (Id.)
        On February 21, 2008, A.I. was evaluated by clinical geneticist Dr. Margarita Sifuentes
Saenz, and metabolic attending Dr. Janet Thomas, at the Children’s Hospital. Dr. Saenz noted
that in mid-January, shortly after A.I. received the FluMist vaccine, she began manifesting some
atypical behaviors, including staring spells, increased fatigue, increased loss of balance, and
drop-like attacks. (Ex. 3, pp.16-20.) Dr. Saenz and Dr. Thomas concluded that A.I.’s clinical
and other features were strongly indicative of Leigh syndrome, but apparently did not fulfill the
stringent diagnostic criteria. (Id., pp. 18-19.)
    [***********************************************
****************************************************
****************]
       On March 15, 2008, A.I. was taken by ambulance to the Children’s Hospital because she
had an episode of unconsciousness and difficulty breathing. (Ex. 14, p. 46.) At the emergency
room, her physician diagnosed A.I. with possible hypoxic seizures and respiratory distress, and
she was transported to Presbyterian/St. Luke’s Medical Center (PSL) on that the same day, for
overnight observation. (Id., pp. 42-43, 46.) At PSL, a sleep study was conducted, and came
back grossly abnormal. (Ex. 3, p. 48.) The study showed an apparent seizure, severe sleep-
disordered breathing manifested by prolonged obstructive hypoventilation, snoring, and labored
breathing with associated hypoxemia. (Ex. 6, p. 1.)
        After admission to PSL, A.I. exhibited progressive respiratory and swallowing
difficulties. A gastronomy tube was placed on March 21, 2008. (Ex. 20, p. 1.) Following the
surgery, A.I.’s neurologic status deteriorated, and she became unresponsive over time. (Id.)

                                                 8
MRI examinations showed a worsening of the lesions in the brain consistent with Leigh
syndrome. (Id.) Tragically, on April 5, 2008, A.I. passed away, with “Leigh Syndrome” being
the listed cause of death. (Id., pp. 1-3.) No autopsy was performed. (Id., p. 3.)

                                                 IV

                                   ISSUES TO BE DECIDED

        In this case, Petitioner seeks a Program award, contending that A.I.’s death was “caused-
in-fact” by the “FluMist” vaccination administered to her on January 11, 2008. The issues to be
resolved in this decision can be narrowed considerably, in that both experts agree that A.I.
suffered from Leigh Disease (also known as “Leigh Syndrome”), an inborn metabolic disorder,
and that she ultimately died as a result of a metabolic decompensation, a common occurrence
among Leigh Disease patients. (Tr. 54, 121.) Moreover, both experts also agree that metabolic
decompensation can be caused by a fever or infectious illness, and that A.I. had such an illness in
January 2008 that likely contributed to the metabolic decompensation which ultimately led to her
death. (Tr. 56-59, 77, 99-100, 174-75.) The only significant disagreement is on the particular
question of whether the FluMist vaccine administered on January 11, 2008, additionally played
any causal role in triggering that metabolic decompensation. After careful consideration, I
conclude that Petitioner has failed to meet her burden.4
        Petitioner argues that the FluMist vaccine acted in concert with A.I.’s intercurrent illness,
creating a combined stress event that resulted in the cascade of symptoms leading to her death.
Petitioner’s argument is based on five main contentions raised by her expert, Dr. Kendall, which
are addressed in detail below. Briefly, these points are: A.I.’s decline was temporally related to
her vaccination; there is no evidence that A.I. experienced metabolic decompensation following
prior, more severe, illnesses, in the absence of the FluMist vaccination; post-marketing evidence
for the FluMist vaccine has specifically reported instances of this vaccine exacerbating
symptoms of mitochondrial encephalomyopathy (Leigh Disease); studies showing a link between
vaccines and autistic regression in patients with metabolic disorders demonstrate that vaccines
are metabolic stressors; and, studies showing that the wild flu virus is capable of causing cell
death (the process at work in a fatal metabolic decompensation such as A.I. experienced). Dr.
Kendall acknowledged that there is no direct scientific evidence that immunizations can cause
the type of metabolic decompensation at issue in this case (tr. 83, 86), but argued, in effect, that
the above points circumstantially demonstrate that the vaccine played a causal role in A.I.’s
death, by aggravating her pre-existing Leigh Disease.
        Respondent’s expert, Dr. McCandless, disagreed with each of these contentions. He
argued that Dr. Kendall presented studies that are mismatched to the facts of this case, and that
she sought to draw inferences from the articles that are not supported by the actual findings of
the studies. Dr. McCandless also took issue with the purported significance of postmarketing
experience, and stressed that the medical community overwhelmingly recommends flu
vaccinations to patients with inborn metabolic disorders. Dr. McCandless stressed that metabolic
4
        Petitioner has the burden of demonstrating the facts necessary for entitlement to an award
by a “preponderance of the evidence.” § 300aa-13(a)(1)(A). Under that standard, the existence
of a fact must be shown to be “more probable than its nonexistence.” In re Winship, 397 U.S.
358, 371 (1970) (Harlan, J., concurring).
                                                 9
decompensation can occur without any apparent trigger, and opined that in A.I.’s case the most
likely trigger, if any, was an upper respiratory infection that A.I. suffered prior to her FluMist
vaccination.
                                                 V

      SUMMARY OF EXPERT WITNESSES’ QUALIFICATIONS AND OPINIONS

       In this case, each side presented the expert reports and hearing testimony of one medical
expert. At this point, I will briefly summarize both the qualifications and the opinions of these
expert witnesses.

A. Petitioner’s expert

        1. Dr. Frances D. Kendall
         Petitioner has relied primarily on the expert report and testimony of Dr. Frances D.
Kendal. Dr. Kendall has been practicing with a special attention to mitochondrial diseases for 20
years. (Ex. 24, p. 1; Tr. 43-44.) She was trained at Harvard Medical School and Boston
Children’s Hospital before she started Horizon Molecular Medicine, a laboratory dedicated to the
molecular and enzymatic diagnosis of mitochondrial patients. (Tr. 43-44.) Her current practice,
Virtual Medical Practice, is devoted to the care of patients with mitochondrial and other rare
genetic disorders. (Ex. 24, p. 1; Tr. 44.)
        Dr. Kendall received her B.A. in 1982 from Temple University, and her M.D. in 1987
from UMDNJ-New Jersey Medical School. (Ex. 25, p. 1.) From 1987 to 1988, she interned at
the pediatrics department of Thomas Jefferson University Hospital. (Id.) She completed her
residency in pediatrics from 1988 to 1990 at that hospital, serving as Chief Resident from 1989 to
1990. (Id.) She completed a fellowship in genetics and metabolism at the Children’s Hospital
and Harvard Medical School from 1990 to 1993, while also completing a research fellowship in
genetics and metabolism at Tufts University from 1991 to 1993. (Id.) She has been an active
member of the Society of Inherited Metabolic Diseases since 1998. (Ex. 25, p. 2.)
          Dr. Kendall was an instructor in pediatrics at Harvard Medical School from 1993 to 1998.
(Id., p. 3.) She has been board-certified in pediatrics since 1990, and board-certified in medical
genetics since 1996. (Id., p. 1.) In 2008, Dr. Kendall was appointed an Assistant Professor at the
Emory University School of Medicine. (Id.) Dr. Kendall was the attending physician for the
IEM-PKU5 Program at the Children’s Hospital in Boston from 1993 to 1995, and was later the
assistant director of that program from 1996 to 1998. (Ex. 25, p. 2.) She was the director of the
mitochondrial disorders program at the Children’s Hospital from 1994 to 1998. (Id.) Dr. Kendall
also served from 1998 to 2001 as the director of the Medical Genetics and Metabolic Screening
Laboratory at Children’s Healthcare of Atlanta, where she currently serves as an attending
physician. (Id.) She lists seven articles on her curriculum vitae, as well as numerous lectures and
several reviews and abstracts. (Ex. 25, pp. 3-7.)


5
       IEM refers to “inborn errors of metabolism,” and PKU to phenylketonuria, a particular
form of IEM.
                                                 10
       2. Summary of Dr. Kendall’s opinion
       Dr. Kendall devoted much of her expert report to establishing that A.I. in fact had Leigh
Disease, a form of mitochondrial disorder, which involves a “homoplasmic 8993 mtDNA
mutation.” (Ex. 24, pp. 4-7.) Ultimately, Dr. Kendall argued that this left A.I. at risk for
metabolic decompensation, and that her infectious illness of January 10th and 11th, combined
with the added stress of her flu vaccination, “caused increased stress to her body and resulted in a
cascade of events that ultimately resulted in her demise.” (Tr. 53-55.) At the hearing in this case,
however, Dr. Kendall acknowledged that there is no direct scientific evidence that
immunizations can cause the type of metabolic decompensation at issue in this case. (Tr. 83,
86.)
        Rather, in her expert report Dr. Kendall argued that “recent studies have documented the
association of developmental regression and autism in patients with mitochondrial disease
following exposure to immunizations.” (Ex. 24, p. 7.) She posited that “[c]learly, the onset of
regressive clinical symptoms following immunizations in one subset of mitochondrial patients
provides precedent for the development of similar regression following vaccination in another
subtype of affected individuals, namely Leigh disease patients with the mtDNA 8993 mutation,
who have already been shown to regress with other stressors.” (Id.)
        On that basis, Dr. Kendall opined, coupling A.I.’s Leigh Disease diagnosis with the
temporal relationship between her vaccination and the onset of A.I.’s decompensation, that A.I.’s
decline, and ultimately her death, were the result of the flu vaccination’s significant aggravation
of her pre-existing Leigh Disease. (Ex. 24, p. 8.) In that regard, Dr. Kendall stressed that A.I.’s
medical history showed that she was able to tolerate previous illnesses and vaccinations without
difficulty. (Id.)
B. Respondent’s expert

       1. Dr. Shawn McCandless
        Respondent has relied primarily on the expert report and testimony of Dr. Shawn
McCandless. Dr. McCandless received a B.S. in Chemistry in 1984 from Westminster College,
and his M.D. from Temple University School of Medicine in 1988. (Ex. L, p. 1.) Dr.
McCandless completed his residency in pediatrics at the University of Wisconsin Hospital and
Clinics from 1988 through 1991. (Id.) He then completed a registrar in pediatrics from 1991 to
1992 at Gloucestershire Royal Hospital. (Id.) From 1996 to 1999, Dr. McCandless completed a
residency in medical genetics at the University Hospitals of Cleveland/Case Western Reserve
University. (Id.) He completed a fellowship in biochemical genetics from the same hospital.
(Id.)
        Dr. McCandless is currently an associate professor of genetics, pediatrics, and pathology
at Case Western Reserve University. (Ex. L, p. 1.) He is board-certified in both clinical
biochemical genetics and pediatrics. (Id., p. 2.) He is also a member of the Genetics and Birth
Defects Section of the American Academy of Pediatrics, and is currently on the board of
directors of the Society for Inherited Disorders of Metabolism. (Id., p. 3.) He lists 35 peer-
reviewed articles on his curriculum vitae, as well as numerous book chapters, reviews, and
presentations. (Id., pp. 5-8.)

                                                11
       2. Summary of Dr. McCandless’ opinion

        Dr. McCandless agreed with Dr. Kendall’s assessment to the extent of her conclusion that
A.I. suffered from a homoplasmic 8993 mutation consistent with Leigh Disease (Ex. A, p. 2), but
rejected Dr. Kendall’s further suggestion that A.I.’s immunization contributed to her significant
deterioration (id., p. 3; Tr. 174.) Rather, Dr. McCandless contended that “[t]he clinical course
described here is characteristic of the underlying condition [i.e., Leigh Disease],” and further
argued that “[t]he metabolic community has not been able to identify any clear association with
immunization and metabolic decompensation (acute metabolic illness) or neurological
deterioration.” (Ex A, p. 3.)

        Specifically, Dr. McCandless rejected Dr. Kendall’s suggestion that medical literature
supports the claim that immunization can lead to autistic regression, and further disputed Dr.
Kendall’s comparison of A.I.’s condition to cases of autistic regression. (Ex. A, pp. 3-4; Tr. 135-
37.) He noted that Dr. Kendall’s opinion proposes that in A.I.’s case “an immunization
contributed to the neurological deterioration in the underlying mitochondrial condition, rather
than the much better known, and more likely, association with the concurrent febrile illness that
was present before the immunization was given.” (Ex. A, p. 3.) In other words, Dr. McCandless
argued that while it is possible that A.I.’s infectious febrile illness, which already existed prior to
her FluMist vaccination, contributed to A.I.’s neurological deterioration, there is no reasonable
basis for the assertion that the FluMist immunization additionally contributed. (Ex. A, pp. 3-4;
Tr. 173-74.)

                                                  VI

                                 SUMMARY OF MY OPINION

        After reviewing the record of this case, I have found that Dr. Kendall’s view of the case
was quite unpersuasive, while Dr. McCandless’s opinion was far more persuasive. On the
whole, in contrast to Dr. McCandless’s coherent and sound testimony, Dr. Kendall failed to
persuade me that key pieces of evidence, upon which she relied, supported her contentions. I
find that Dr. Kendall overstated the significance of other pieces of information, such as the
FluMist postmarketing experience, and effectively admitted that certain aspects of her causation
opinion were speculative. As indicated above, there is much that these two experts agree upon.
Where they part, however, is where Dr. Kendall sought to make inferential leaps not supported
by the record in this case. Simply put, Dr. Kendall failed to convince me that any of the main
points she used to support her theory establish the specific propositions that she advanced. Her
testimony is therefore unpersuasive, and fails to meet Petitioner’s burden of demonstrating that it
is “more likely than not” that A.I.’s FluMist vaccination contributed to triggering the metabolic
decompensation that led to her death, or in any other way significantly aggravated the metabolic
condition (Leigh Disease) which was present in A.I. from her birth.




                                                  12
                                                VII
      DR. McCANDLESS WAS FAR MORE PERSUASIVE THAN DR. KENDALL
A. Dr. Kendall’s opinion was flawed in several respects.
         There were several severe deficiencies in Dr. Kendall’s presentation in this case. First,
the timing of A.I.’s metabolic decompensation, as alleged by Petitioner, makes it less likely that
the FluMist vaccine contributed to her injury, and more likely that the injury was a result of her
upper respiratory infection. Dr. Kendall also ineffectually argued that A.I.’s ability to tolerate
prior illnesses provides evidence of a causal role for her vaccination. Indeed, she effectively
acknowledged that her argument on that point is speculative. Moreover, Dr. Kendall greatly
overstated the significance of postmarketing information contained in the FluMist packaging.
Contrary to her assertion, FluMist is not contraindicated for those with Leigh Disease.

       1. The timing of the onset of A.I.’s neurodegenerative symptoms makes A.I.’s pre-
          existing infectious illness the more likely explanation of her decline.

         Dr. Kendall argued that the timing of the onset of A.I.’s metabolic decompensation is
consistent with her theory that it was caused by the FluMist vaccine. But as to A.I.’s metabolic
decompensation, Dr. Kendall’s written report was not specific in noting any specific particular
“first symptom.” Dr. Kendall simply asserted that “the onset of her regressive clinical
symptomology was temporally related to exposure to the influenza vaccine following which she
developed a neurodegenerative course followed by death.” (Ex. 24, p. 8.) At the hearing,
however, Dr. Kendall indicated that the first indication of A.I.’s decline was the staring spells
that she allegedly experienced the day of her vaccination. (Tr. 62-63.) According to Dr.
Kendall, the timing of those staring spells is a key component of her opinion that A.I.’s
metabolic decompensation was caused, at least in part, by the vaccination. (Tr. 63-64.) Dr.
Kendall, however, has offered no citation to any medical literature supporting her contention that
a mitochondrial decompensation could occur within hours of a vaccination, as a result of such
vaccination. Indeed, Dr. Kendall has not cited to any medical literature specifically addressing
the timing of mitochondrial decompensation at all.6
        Dr. McCandless, on the other hand, indicated that if, in fact, A.I. experienced staring
spells on the same day that she received her vaccination, that would indicate that the
decompensation was more likely a result of A.I.’s pre-existing infectious illness than the FluMist.
(Note that A.I.’s records show that she was diagnosed as having an upper respiratory infection
on January 11, 2008, the day that she received the vaccination to which Petitioner points). (Ex.

6
        As discussed below, Dr. Kendall relies chiefly on the Shoffner and Poling articles to link
vaccination to mitochondrial regression -- a reliance which I reject in Section VII(B)(1) of this
Decision below. With regard to timing, however, the Shoffner study is not more specific than to
say that the authors considered cases where regression occurred “within two weeks” of a febrile
episode. (See Ex. 24, Ref. 28, p. 2.) The study does not report that any subject experienced
regression immediately after immunization. And although the Poling subject was reported to
have regressed within 48 hours of immunization (see Ex. 24, ref. 27, p. 1), as described below,
that timing in the Poling case was consistent with the causal presumption for encephalopathy
under the Vaccine Injury Table, an injury not alleged in this case.
                                                13
1, pp. 39-40.) Citing to “The Otolaryngological Manfiestations of Mitochondrial Disease and the
Risk of Neurodegeneration With Infection” by Edmonds et al., published in The Journal of the
American Medical Association (Otolaryngology – Head & Neck Surgery) (Ex. 37), Dr.
McCandless persuasively argued that there should typically be a period of several days between
the time of an infectious insult and the onset of neurological consequences. (Tr. 172-73.) The
Edmonds article states that “The timing of the infection and the neurodegenerative event varied.
In a few patients (3/13), the neurologic setback occurred early in the course of infection. In most
patients (10/13), the neurologic event occurred 3 to 7 days after the onset of infection and
frequently appeared at a time when the infection was resolving.” (Id., p. 360.)
        Although the Edmonds paper noted that a minority of patients experienced neurologic
setbacks “early in the course of infection,” it also shows that if A.I.’s staring spells were a
consequence of her upper respiratory infection, she would fall among the majority of patients in
the Edmonds study who experienced neurodegenerative events several days after the onset of
infection, and as the infection was resolving.7 As noted, A.I.’s medical records show that she
was diagnosed with an upper respiratory infection on January 11, 2008, the same day she
received her vaccination. (Ex. 1, pp. 39-40.) The records indicate that A.I. had been coughing
for two days prior, and had had a fever of 102 degrees. (Id.) Although Dr. Kendall argued that
this was a mild illness, she appeared to accept the diagnosis of upper respiratory infection. (Tr.
73-74, 99-100.) By the time A.I. saw the doctor, however, it appeared that she was getting better
and her fever had gone down to 100.3 degrees. (Ex. 1, p. 40.) Both experts agree that the fever
had reduced enough that the vaccination was no longer contraindicated. (Tr. 58-59, 73, 204-07.)
Thus, consistent with the majority of the Edmonds subjects, it appears that the onset of A.I.’s
neurodegeneration occurred approximately two to three days following the onset of her infection,
as the infection was resolving. But the onset occurred only hours after vaccination, which would
likely be too soon to be related to the vaccination. Therefore, contrary to Dr. Kendall’s opinion,
it appears that the upper respiratory infection is a more likely explanation for A.I.’s
decompensation, based on the testimony of A.I.’s mother that A.I. experienced staring spells on
the day that she received the vaccination. 8
        Significantly, the Federal Circuit has cautioned against relying on isolated small-scale
studies as creating clear-cut periods of onset. Paluck v. HHS, 786 F.3d 1373, 1383-84 (Fed. Cir.
2015). Here, however, the Edmonds study remains the only evidence in this record regarding the
expected timing of a neurologic deterioration such as A.I. experienced. It is therefore a

7
       Moreover, I note that there is nothing in the Edmonds paper to suggest that “early in the
course of infection” would be as little as the several hours that occurred, according to Petitioner,
between A.I.’s vaccination and her staring spells, and Petitioner has not otherwise pointed to any
support for such a contention.
8
         If, alternatively, I were to find that the January 22 collapse, occurring 11 days post-
vaccination, was the first symptom, that would place A.I.’s neurodegenerative event on the far
side of the bell curve suggested by the Edmonds study, regardless of whether it was caused by
the vaccination or the upper respiratory infection. (Ex. 37, p. 361.) But I would still have to
reject the Petitioner’s causation claim in this case, for all of the other reasons stated in this
Decision.


                                                 14
significant, albeit not dispositive, piece of evidence supporting my conclusion that among these
two competing expert opinions, Dr. McCandless is more persuasive on this particular point. In
any event, Dr. Kendall cited no medical literature to substantiate her claim of a temporal
relationship between vaccination and decompensation. Thus, her claim of a temporal
relationship in A.I.’s case is unsupported and speculative, with or without reference to the
Edmonds study. In that regard it is important to note that even if a broad reading of the Edmonds
study indicated that an immediate neurologic deterioration following infection is possible, that
still would not mean that its findings could be extended to vaccinations or combinations of
metabolic factors other than infection. Such scenarios were simply not addressed in the study. 9

       2. A.I.’s ability to tolerate prior illnesses is not evidence of vaccine causation.

         Dr. Kendall found it unlikely that A.I.’s upper respiratory illness alone could have caused
her metabolic decompensation, without the vaccination. Looking at the specifics of A.I.’s
clinical history, Dr. Kendall argued that her theory is supported by the fact that A.I. did not
experience a metabolic decompensation after prior illnesses or vaccinations, contending that
A.I.’s ability to tolerate prior illnesses and vaccinations makes it more likely that the January 11
illness required the additional stress of the FluMist vaccination to overwhelm A.I.’s system. (Tr.
67, 73-74.) That is, Dr. Kendall argued that A.I. “was in a weakened state. Her body was
already stressed from the intercurrent illness [the URI] and then she was added another stressor
[the vaccination] on top of that.” (Tr. 67.) Dr. Kendall opined that a mild illness such as A.I.
experienced on January 11, which was short in duration and did not include excessive fever or
eating difficulty, would not ordinarily lead to metabolic decompensation on its own. (Tr. 73-74.)
        Dr. McCandless indicated, however, that the causes of metabolic decompensation are not
well understood, and stated his opinion that there is not always any identifiable precipitating
factor. (Tr. 138-39.) Significantly, Dr. McCandless further indicated that most Leigh Disease
patients do not decompensate with every illness, and that nobody is able to predict when an
illness will be a precipitating factor. (Tr. 139-40.) On cross-examination, Dr. Kendall
effectively conceded these points. (E.g., Tr. 99-100.) Specifically, Dr. Kendall testified that
metabolic decompensation is common after an infectious illness, and that absent the ability to
measure oxidative stress, she cannot say for sure whether A.I.’s January 11 illness alone was
sufficient to cause metabolic decompensation. (Id.) Moreover, she acknowledged not only that
Leigh Disease typically results in premature death (Tr. 95-96), but also conceded that metabolic
decompensation can occur without any known stressor (Tr. 100).



9
         One could argue that the Edmonds article provides some support for Dr. Kendall’s
position, in that a minority of subjects experienced deterioration “early in the course of
infection,” language which could conceivably be interpreted to be analogous to a
decompensation only hours after a vaccination in this case. (Ex. 37, p. 360.) Nonetheless, even
if I accept the presence of a temporal relationship in satisfaction of Althen Prong 3 based on
Petitioner’s filing of the Edmonds article, I would still find that the article is relevant to, and
supportive of, Respondent’s arguments going to Althen Prong 2. That is, the Edmonds article as
a whole suggests that the infection, rather than the vaccination, is a substantially more likely
explanation for A.I.’s deterioration.
                                                15
        Thus, Dr. Kendall’s assertion, that A.I.’s clinical history of tolerating prior illnesses and
vaccines likely indicates vaccine involvement in her ultimate decompensation, is essentially
speculation. The two experts agree that the significance of A.I.’s January 11 illness, or any of
her prior illnesses, is effectively unknowable. Most significantly, Dr. Kendall admitted not only
that she is unable to measure whether the January 11 illness would have been an insufficient
trigger, she also admitted that no identifiable trigger is even required.10
       3. FluMist postmarketing evidence regarding Leigh Disease is not evidence of vaccine
          causation.
       Dr. Kendall additionally cited the postmarketing information provided as part of the
FluMist packaging as further evidence that the FluMist vaccine in particular would have been
capable of causing A.I.’s metabolic decompensation. (Tr. 56-57.) Specifically, Dr. Kendall
noted that the packaging states that among the reported events occurring post-approval, there
occurred instances of “exacerbation of symptoms of mitochondrial encephalomyopathy (Leigh
Syndrome).” (Tr. 56-57; Ex. 30, p. 7.) Initially, Dr. Kendall contended that this notation was a
contraindication for the vaccination. (Tr. 84-85.) Ultimately, however, she acknowledged that
the package information regarding Leigh Disease was not a contraindication. (Tr. 106.)

10
        This also raises a broader question going to proximate causation. That is, even if the
FluMist vaccine could be considered a potential stressor as Dr. Kendall argues, given the nature
of Leigh Disease as a condition that almost invariably leads to metabolic decompensation and
ultimately premature death even in the absence of a stressor, it could be argued that FluMist
vaccination still would not necessarily constitute a “proximate cause” of A.I.’s death. (See, e.g.,
Shyface v. HHS, 165 F.3d 1344, 1352-53 (Fed. Cir. 1999) (noting that “but for” causation is
insufficient without a logical sequence of cause and effect showing that the vaccine substantially
contributed to the injury).) This would be a particularly challenging burden for the Petitioner in
this case, because there has been evidence in this case that A.I. demonstrated some pre-vaccine
neurodegenerative symptoms which may have been attributable to her Leigh Disease. (Tr. 143-
44.) However, because I have found that Petitioner has not met her burden of establishing that
the FluMist vaccine was even a plausible triggering event of A.I.’s metabolic decompensation, it
is not necessary to reach that question. In this regard, I stress that even if Dr. Kendall were able
to establish that A.I.’s January 11 upper respiratory infection lacked sufficient metabolic demand
to cause a decompensation on its own, this still would not lead to the conclusion that A.I.’s
FluMist vaccination was necessarily an additional contributing stressor. As described in Section
VII(B)(1) below, Dr. Kendall has not established that the vaccine itself had a material impact on
metabolic demand, and, in any event, as noted in this section, both experts agree that metabolic
decompensation in Leigh Disease patients can occur without any known stressor.

        Petitioner’s brief also makes much of one statement by Dr. McCandless that A.I.’s
overall clinical course was “atypical.” (ECF 137, p. 8.) However, Dr. McCandless further
addressed that same issue elsewhere in his testimony. For example, he explained that that A.I.’s
course in fact was “typical” except for the fact her major decompensation occurred later in her
life than is usually the case with Leigh Disease patients. (Tr. 123-24.) He added, moreover, that
while 75% of Leigh Disease patients experienced their major decompensation by age three, still
the other 25% experience their decompensation, like A.I., after age three. (Tr. 177.) Therefore,
he explained, to that extent A.I.’s case is not really “atypical” after all. (Id.)
                                                 16
Nonetheless, Dr. Kendall characterized it as “specifically warn[ing] physicians to avoid its use in
mitochondrial patients” (tr. 56), and further testified that it would make her “very cautious” (tr.
106).
         Dr. McCandless, likewise, indicated that the package insert would cause him to consider
the risk of administering the FluMist vaccine to a child with Leigh Disease. (Tr. 191.) He also
testified, however, that he would still perceive the risk to be low. (Id.) Dr. McCandless
explained that postmarketing experience is the result of a reporting requirement mandated by the
FDA to ensure that potential issues may be investigated where there are reports of a particular
occurrence after vaccination. (Tr. 166-69.) He argued that postmarketing information itself is
therefore not evidence of a causal connection.11 (Id.) Moreover, Dr. McCandless stressed that
postmarketing experience is distinct, and of lesser significance than, either contraindications or
warnings, and that, according to the package information, the FluMist vaccine is not
contraindicated for individuals with Leigh Disease. (Id.)
         In that regard, Dr. McCandless also stressed that, as a general matter, the medical
community as a whole largely agrees that vaccines should be routinely administered to
individuals with metabolic disorders. Specifically, Dr. McCandless agreed with the statement
made in “Attitudes Regarding Vaccination Among Practitioners of Clinical Biochemical
Genetics” by Barshop et al., published in Molecular Genetics and Metabolism, that “it is clear
that the general opinion held by practitioners in the field of clinical biochemical genetics favors
the full schedule of vaccination for their patients. The overwhelming majority feel that the
benefits of the current schedule outweigh the risks to individuals with undiagnosed metabolic
disease. Most have never observed any significant adverse event which was attributed to a
vaccine reaction.” (Tr. 154-55; Ex. 36, p. 2.12) He also cited “Immunization for Patients With
Metabolic Disorders” by Kingsley et al., published in Pediatrics. (Tr. 155-57.) The Kingsley
article indicates that a review of English language medical literature found that
“contraindications against immunizations were not found in the available infectious disease and
metabolic disease databases for inborn errors of metabolism.” (Ex. D, p. 11.) These articles
further support Dr. McCandless’s opinion that the postmarketing experience reported in the




11
        Accord, Werderitsh v. HHS, No. 99-319V, 2005 WL 3320041, at *8 (Fed. Cl. Spec. Mstr.
Nov. 10, 2005) (Special Master Sweeney stating that “Vaccine manufacturers must report
adverse events to the FDA, whether or not the adverse event is considered to be product-related.
[Citations omitted]. Further, ‘[a] report or information submitted by a licensed manufacturer ...
does not necessarily reflect a conclusion by the licensed manufacturer or FDA that the report or
information constitutes an admission that the biological product caused or contributed to an
adverse effect.’ [Citations omitted]. Thus, federal regulations specifically preclude the contents
of drug product labels, as reproduced in the PDR, from serving as admissions regarding
causation.”).
12
       This article was mistakenly identified in the hearing transcript as Exhibit 26.


                                                 17
FluMist package insert falls well short of constituting either a warning or a contraindication, and
is not good evidence of causation.13
        Most significantly, however, Dr. McCandless also pointed out that there is no monograph
or other information reporting on the details of the FluMist postmarketing information regarding
Leigh Disease. (Tr. 169.) Therefore, he argued, the packaging report of exacerbation of Leigh
Disease could be based on a very few, or even a single instance, of such an occurrence. (Tr. 168-
69.) In fact, Dr. McCandless suggested that based on the first appearance of this postmarketing
information in the FluMist packaging--that first appearance post-dated A.I.’s metabolic
decompensation--that it could theoretically refer solely to A.I.’s case. (Id.) While such a
suggestion is clearly speculative, the fact remains that absent more detailed information

13
         I note that to the extent that Dr. McCandless (and the articles he cites) are addressing risk,
this is therefore not evidence going directly to the issue of causation. For example, while the
Barshop article indicates that the great majority of clinicians believed the benefit of vaccinating
metabolic disorder patients to outweigh the risk, a small minority did report having seen at least
one instance of an adverse outcome attributable to a vaccine. (Ex. 36, pp. 1-2.) Thus, I do not
find that the articles in themselves disprove a causal connection, in that they do not dispute that
adverse events, whether vaccine-related or not, can happen, albeit rarely, soon after vaccination.
Rather, I find these articles to bear specifically on the significance of the postmarketing
information presented by Dr. Kendall. For example, in Christiansen v. HHS, 08-244V, 2012 WL
6766650 at *12 (Fed. Cl. Spec. Mstr. Dec. 20, 2012), faced with evidence that most pediatricians
would have disregarded a specific package contraindication, the special master discounted the
significance of that contraindication because it likely represented defensive medicine on the part
of the manufacturer, and “does not guide practice in the field.” In this case, these articles
convince me that Dr. McCandless’ opinion regarding the administration of the flu vaccine to an
individual with Leigh Disease is an accurate reflection of the medical community as a whole. In
fact, even Dr. Kendall indicated that a case like A.I.’s would be rare, and that she will continue
to immunize her patients who have mitochondrial disease even in light of the postmarketing
information. (Tr. 105-06.) It is highly unlikely that these attitudes would prevail if the
postmarketing information provided the type of stark warning that Dr. Kendall implies, as
opposed to being preliminary fact-gathering that does not necessarily indicate a causal
connection, as Dr. McCandless argues.
        Further, I note that Petitioner is correct in arguing that the mere fact that mitochondrial
specialists would have their mitochondrial disease patients vaccinated, as posing a lesser risk
than the absence of vaccination, does not necessarily prove that there is no risk in vaccination.
As Petitioner has argued, there still could be a small risk in vaccination, and a particular
vaccinee, such as A.I., might possibly be the rare victim of such a small risk. However, the
recommendation of specialists, including Dr. Kendall herself, that mitochondrial disease patients
be vaccinated, is at least some evidence contrary to Petitioner’s assertion that vaccination is a
likely cause of decompensation in mitochondrial disease patients. Further, in this case the burden
is not on Respondent to show that vaccines can never cause decompensation in a Leigh Disease
patient, but on the Petitioner to demonstrate that the vaccination in question “more likely than
not” did aggravate A.I.’s Leigh Disease. This burden has not been carried by Petitioner, for all
the reasons detailed in this Decision.

                                                  18
regarding the number of instances reported, the postmarketing information is simply not
informative of any causal connection. Indeed, without even knowing how many reported
instances there were, it is impossible to even credit it as suggesting any correlation or temporal
association at all.14

     B. Dr. Kendall’s opinion is not supported by the medical literature that she submitted.
        Dr. Kendall’s failure to establish a factual basis for the application of her causal theory is
reason enough to dismiss her opinion in this case. Nonetheless, I note also that her opinion is
unpersuasive for the additional reason that it is not well supported by the medical literature that
she submitted. That is, her opinion goes well beyond the findings of the studies she cited,
essentially engaging in speculation on multiple points underlying her theory.

        1. Dr. Kendall has not demonstrated how articles purporting to show a link
           between immunization and “autistic regression” are relevant to A.I.’s case.

        At base, Dr. Kendall’s theory is predicated on the idea that the FluMist vaccine created
“oxidative stress” (excess energy demand) that contributed materially to the event that triggered
A.I.’s metabolic decompensation. Although Dr. Kendall does not claim that the vaccine alone
was responsible for A.I.’s metabolic decompensation, absent evidence that a vaccine could have
a material impact on cellular energy demand, Dr. Kendall has no explanation for how the
vaccine could have played any role in A.I.’s death.
        In that regard, Dr. Kendall relied on a case study by Poling et al. titled “Developmental
Regression and Mitochondrial Dysfunction in a Child With Autism” (Ex. 24, Ref. 27 (ECF No.
26-8)) as evidence that “if mitochondrial dysfunction, from either a primary genetic abnormality
or secondary inhibition of oxidative phosphorylation by other factors, is present at the times of
infections and immunizations in young children that the added oxidative stresses from immune
activation on cellular metabolism are likely to be very critical for the highly energy dependent
central nervous system.” (Ex. 24, p. 7.) Dr. Kendall also cited “Fever Plus Mitochondrial
Disease Could be Risk Factors for Autistic Regression” by Shoffner et al., an article appearing in
the Journal of Child Neurology. (Ex. 24, Ref. 28 (ECF No. 26-9)(also filed as Respondent’s Ex.
K.) According to Dr. Kendall, this article shows, as a general proposition, how a stressor can
precipitate a decline in a mitochondrial disease patient. (Tr. 76.) Specifically, in her expert
report, Dr. Kendall cited the Shoffner article as further support for the proposition--introduced by
her with the Poling case study--that there is a link between immunization and “autistic
regression” among mitochondrial disease patients. (Ex. 24, p. 7.)
       Dr. McCandless criticized Dr. Kendall’s reliance on these articles, and in particular the
Poling case study, because, he argues, they are not comparable to A.I.’s case. (Tr. 160-62.)
Whereas the Poling subject experienced an autistic regression, it is undisputed that A.I. did not

14
        For example, as I will explain below with regard to the Poling case report, a single case
report is not strong evidence, because it could easily be the result of chance. I also note that in
the Christiansen case cited in footnote 13 above, the special master found a study cited by a
package insert to be unpersuasive, because it did not provide the necessary information on
background incidence necessary to interpret its results.


                                                  19
experience an autistic regression.15 (Tr. 88.) Moreover, it is also undisputed that A.I. had Leigh
Disease, a type of mitochondrial disorder which the Poling child did not have. (Id.) Indeed,
despite acknowledging this distinction (tr. 92-95), Dr. Kendall has come forward with no
evidence supporting the notion that autistic regression can be equated to metabolic
decompensation, making it difficult to draw any inferences from these articles regarding the
cause of A.I.’s condition. Rather, in her expert report, Dr. Kendall argued in a wholly
conclusory manner, and without apparent support, that “[c]learly, the onset of regressive clinical
symptoms following immunizations in one subset of mitochondrial patients provides precedent
for the development of similar regression following vaccination in another subtype of affected
individuals, namely Leigh Disease patients with mtDNA 8993 mutation, who have already been
shown to regress with other stressors.” (Ex. 24, p. 7.) Dr. Kendall simply has not substantiated
her assertion, either in her expert report or in her hearing testimony, that the regression in the
Poling case is at all similar to the metabolic decompensation experienced by A.I. 16


15
         For example, Dr. McCandless noted that while the mechanism of autistic regression is
not known, regression caused by mitochondrial decompensation in a case of Leigh Disease
results in nerve loss visible on MRI. (Tr. 137-38.) In that regard, it is noteworthy that A.I. was
in fact found to have abnormal MRI findings (Ex. 19, p. 244; Ex. 6, pp. 31-32), whereas MRI
studies of the Poling subject following regression were interpreted as normal (Ex. 24, Ref. 27, p.
1).
16
        Indeed, in her post-hearing brief, Petitioner surprisingly included a motion to “compel”
me to accept Respondent’s concession in the Poling Vaccine Act case, as decisive in this case,
on the basis of “judicial estoppel,” despite explicitly conceding that “the nature of the regression
in the instant case is different on a factual basis.” (ECF No. 114, pp. 91-92.) This issue has
already been extensively and persuasively addressed by two other special masters in Vernacchio
v. HHS, No. 08-504V, 2015 WL 1396357 (Fed. Cl. Spec. Mstr. Mar. 6, 2015), and in R.K. v.
HHS (Fed. Cl. Spec. Mstr. Sep. 28, 2015) (“Ruling on Motions”) (not yet published or on Court
website), aff’d, 2016 WL 552481 (Feb. 12, 2016). As indicated in Vernacchio and R.K.,
Respondent cannot be compelled to concede Vaccine Act cases based on the Table Injury
concession in the Poling case for a number of reasons. But in any event, Petitioner’s
acknowledgment of the factual difference between the cases renders the request moot. Although
Petitioner is seeking only to have the general theory of injury (i.e., Althen Prong 1), supposedly
conceded in Poling, to be conceded in this case, such a concession in Poling would not be
relevant to this case. Establishing a theory that a vaccine can cause injury “X” is not the same as
proving that it can cause injury “Y,” absent some evidence showing that injuries X and Y share
sufficient commonality. And, as indicated herein, Dr. Kendall has not substantiated her claim
that the regression in Poling is similar to the decompensation in this case. Indeed, Petitioner has
admitted that the nature of the Poling regression is different than the decompensation that A.I.
suffered. Thus, it cannot be said that Respondent is taking inconsistent positions in the two
cases, a requirement for invoking judicial estoppel. See, e.g., Vernacchio, 2015 WL 1396357 at
*5. This issue garnered further attention in this case, in post-hearing sur-reply briefs filed by the
parties, in relation to the Federal Circuit’s apparent indication in Paluck v. HHS, 786 F.3d 1373
(Fed. Cir. 2015) that Respondent had conceded “on appeal” the theory that vaccines can
aggravate mitochondrial disorders. (ECF No. 127, pp. 2-3.) Respondent disputes that
characterization. (ECF No. 130, p. 1.) In fact, the Paluck court indicated that Respondent “does
                                                 20
        Moreover, any reliance by Dr. Kendall on these Poling and Shoffner articles, as evidence
that immunizations in and of themselves can lead to such results, would be misplaced. As Dr.
McCandless pointed out, the Shoffner article concludes that “[i]n our patients with mitochondrial
disease and autistic spectrum disorders, the vaccines did not appear related to the neurologic
regression.” (Ex. K, p. 4; Tr. 162-64.) Moreover, as a single case report, the Poling article’s
suggestion of a temporal relationship is not in itself strong evidence of a causal connection, since
it could easily be the result of pure chance.17
         I am, of course, mindful of the recent Federal Circuit decision in Paluck v. HHS, 786
F.3d 1373, 1383-84 (Fed. Cir. 2015), in which the panel relied in part on the Poling case report.
In that case, however, the Federal Circuit’s actual consideration of the Poling report was limited
to noting that, despite describing a young girl experiencing an apparent regression following
vaccination, the report does not purport to establish any definitive timeframe for the onset of a
causally-related neurological regression. (Id.) Any discussion of the significance of the Poling
report with respect to the validity of the Paluck petitioner’s theory of causation was unnecessary,
because, as noted above, the court of appeals believed that the Respondent had effectively
conceded the plausibility of the petitioner’s “general causation” theory for purposes of the appeal
in that case. Indeed, the Federal Circuit’s decision in Paluck does not address the validity of the
petitioner’s causation theory in that case, but rather whether the special master had properly
construed that theory for purposes of determining whether the Paluck child had a medical history
consistent with the expected timeframe stated by the theory. In this case, unlike the appellate
posture presented in Paluck, Respondent clearly is vigorously contesting Petitioner’s “general
causation” theory.
       Nonetheless, it is noteworthy that the Court of Federal Claims cautioned in Paluck that
although “case reports ‘do not purport to establish causation definitively, and this deficiency
does indeed reduce their evidentiary value’, *** ‘the fact that case reports can by their nature
only present indicia of causation does not deprive them of all evidentiary weight.’” See Paluck
v. HHS, 104 Fed. Cl. 457, 475 (2012) (quoting Campbell v. HHS, 97 Fed. Cl. 650, 668 (2011)).

not meaningfully dispute” the petitioner’s general causation theory “on appeal” in that case.
Paluck, 786 F.3d at 1380. That statement would seem to indicate that the court recognized that
Respondent had disputed the theory in the courts below, but was accepting the Court of Federal
Claims judge’s finding for purposes of the Federal Circuit appeal in that case. In any event,
regardless of whether the Federal Circuit accurately characterized Respondent’s position in that
case or not, nothing in the Federal Circuit Paluck opinion indicates that Respondent can be
compelled to concede any other case and, even if it did, this case remains factually distinct.
17
        Petitioner mentioned in her brief (ECF 114, p. 80, fn. 31) a certain statement made by a
special master previously assigned to this case, Patricia Campbell-Smith (now Chief Judge of
this Court), who seemed to indicate skepticism concerning Dr. Kendall’s use of the Poling and
Shoffner articles. (See Order issued on 9-21-12, ECF No. 37, p. 2.) Petitioner protested that
Special Master Campbell-Smith had made that observation before the expert hearing in this case.
(ECF 114, p. 80, fn. 31.) However, it is simply the case that after the evidentiary hearing in this
case, in which I heard Dr. Kendall explain her interpretation of the Poling and Shoffner articles, I
reached, on my own, an analysis of Dr. Kendall’s reliance on those articles that was similar to
that of Special Master Campbell-Smith.
                                                21
In that regard, I note that I am not entirely discounting the evidentiary value of the Poling report.
Importantly, however, as described in Section VII(A)(2) above, Dr. Kendall admitted that
metabolic decompensation in Leigh Disease patients can occur without any known stressor. This
testimony dramatically undercuts her reliance on a single case study to establish vaccine
causation, even if that case were similar to this case (which it is not). It is also significant that
another study filed into the record of this case attempted to screen for cases similar to the Poling
case, and yet found that the only case similar to Poling, among its cohort population of 25
subjects, was the Poling case itself, suggesting a distinct possibility that the temporal association
demonstrated in Poling was due to chance. (See Weissman et al., “Mitochondrial Disease in
Autism Spectrum Disorder Patients: A Cohort Analysis,” PLoS One: 3(11) (Nov. 2008) (Ex.
33).) 18
         Moreover, the Poling child at age 19 months reportedly experienced a severe neurologic
episode within 48 hours of a DTaP vaccination, and another within five to 15 days of an MMR
vaccine. (Ex. 24, Ref. 27, p. 1 (factual presentation).) Those neurological episodes occurred,
therefore, within the periods for a DTaP Table Injury encephalopathy (72 hours) and a measles
Table Injury encephalopathy (five to 15 days). See 42 C.F.R. § 100.3(a)(II)(B) and
(a)(III)(B)(2011) (Vaccine Injury Table identifying encephalopathy as an associated injury for
DTaP and measles vaccines and setting forth the time periods required). The Poling child was
eventually diagnosed with both autism and a mitochondrial disorder. (Ex. 24, Ref. 27, p. 2.) It is
noteworthy, then, that the Poling child experienced encephalopathy within the Table Injury time

18
        Petitioner filed the Weissman paper into the record of this case, though she did not
present it as part of her case-in-chief. In post-hearing briefs, however, Petitioner stressed an
isolated statement in the paper that “there might be no difference between the inflammatory or
catabolic stress of vaccinations and that of common childhood diseases, which are known
precipitants of mitochondrial regression.” (See, e.g., ECF No. 133, pp. 5-6 (quoting Ex. 33 at 4).)
Petitioner argues that this constitutes evidence “supportive of causation, even if it does not
‘prove’ causation.” (ECF No. 133, p. 6.) This argument is incorrect and misleading. The
Weissman study is not a study of vaccines, and does not itself contain any data supportive of the
quoted suggestion that vaccinations are “known” precipitants of mitochondrial regression. That
statement was included in a discussion of the Poling case. (See Ex. 33, p. 4, Refs. 12, 36.)
Moreover, the suggestion of the statement, that there may be no difference between vaccines and
infections in terms of precipitating mitochondrial regression, cites to the above-discussed
Edmonds study. (See Ex. 33, p. 4, Ref. 37.) And, significantly, the Edmonds study did not
address vaccinations, suggesting that the Weissman citation to Edmonds was merely for the
proposition that childhood illnesses can cause decompensation. (See Ex. 37.) Thus, the
Weissman paper itself does not contribute any additional relevant data to this record. And in any
event, to the extent that Petitioner would argue that the statement contained in the Weissman
paper constitutes additional evidence of causation in itself, it is incredibly weak evidence. The
statement upon which Petitioner relies says only that vaccines “might” have a metabolic impact.
Such a statement expresses at best that the connection is merely possible, not probable. In that
regard it is worth stressing that the study authors indicated in the same passage that the temporal
relationship present in the Poling case does not prove causation, and that “large, population-
based studies will be needed to identify a possible relationship of vaccination with autistic
regression in persons with mitochondrial cytopathies.” (Ex. 33, p. 4.)


                                                 22
for two different vaccinations (Ex. 24, Ref. 27, p. 1), thus carrying a presumption of causation
under the Vaccine Injury Table. The same cannot be said of A.I. in this case.


        During her testimony, Dr. Kendall additionally cited statements made in an article
submitted by Respondent that, she argued, supported her contention. Specifically, Dr. Kendall
cited statements from “Immunization Recommendations for Children With Metabolic Disorders:
More Data Would Help” by Brady et al., appearing as a commentary in Pediatrics. (Ex. C.)
Those statements are that “[v]accines may also cause metabolic changes that mimic, but typically
less severely, the metabolic changes associated with inflammation and infection” (Tr. 71; Ex. C,
p. 810), and that “[t]ransient metabolic changes associated with fever or anorexia may tip the
balance in the child whose clinical status is fragile or not well controlled” (Tr. 71; Ex. C, p. 811).
         Dr. McCandless argued, however, that the Brady article, as is the case with the Shoffner
article, indicates only that immunizations “may” cause fever or anorexia, which in turn may have
a metabolic impact. (Tr. 200.) Dr. McCandless noted that it is well-known that fever increases
metabolic demand by approximately ten percent per degree Centigrade per 24 hour period. (Tr.
201.) Significantly, even Dr. Kendall indicated that she believed the ability of infectious
illnesses to cause metabolic decompensation was related to qualifiers such as excessive fever,
dehydration, or anorexia. (Tr. 73-74.) Moreover, I stress that the Brady article itself clearly
states that the metabolic changes at issue are those “associated with fever or anorexia.” (Ex. C,
p. 811.) To the extent that the wording of the article suggests that the vaccine itself has been
shown to mimic the metabolic changes that can be caused by inflammation and infection, Dr.
McCandless argued, the vaccine might mimic the immunological impact of an infection, but
there is no evidence establishing that it mimics metabolic consequences. (Tr. 197.) He also
contended that that particular statement in the Brady article is not supported by its accompanying
reference. (Id.)
        Ultimately, I find that the Poling, Shoffner, and Brady articles do not provide persuasive
evidence that a vaccine--as opposed to a fever or infection--can contribute to a regression or
decompensation in a patient with mitochondrial disease. On cross-examination, Dr. Kendall
made an important concession concerning this point, acknowledging that the Shoffner study in
particular was concerned with fever, not immunizations, and that it did not conclude that there
was any causal relationship between vaccines and autistic regression. (Tr. 90.) In this regard, I
note that although A.I. was experiencing a fever around the time of her vaccination, it is
undisputed that that fever predated the vaccination.19

19
        That is, A.I.’s records indicate that she had a fever of 102 degrees on the morning of the
January 11 exam where she received her FluMist vaccination, but that it had reduced to 100.3
degrees by the time of her exam. (Ex. 1, pp. 39-40.) Both experts agree that the fever had
subsided to the point that A.I.’s treating physician believed it was appropriate to administer the
FluMist vaccination, which is contraindicated for severe illness, but not for mild illness. (Tr. 58-
59, 73, 204-07.) I also note that A.I.’s medical record for the follow-up visit on January 16, 2008,
indicates, based on parental reporting, that she had an additional fever of about 101 degrees two
days earlier, i.e., on or about January 14, or three days post-vaccination. (Ex. 1, p. 37.) No
indication of the duration of that fever is given, and her temperature was 97.3 degrees at the time
of that visit. (Ex. 1, p. 38.) H.L. specifically testified, however, that A.I. did not experience any
                                                 23
        Significantly, Dr. Kendall admitted that she is not aware of any reliable study attributing
acute metabolic decompensation to a flu vaccine among patients with Leigh Disease (tr. 86), and
also more generally that there is no evidence that a vaccine alone can cause the type of metabolic
decompensation at issue in this case (tr. 83). Moreover, Dr. Kendall acknowledged that the
oxidative stress that she alleges to be created by the vaccine cannot even be measured. (Tr.
99.)20 Petitioner has therefore failed to show that it is probable that A.I.’s vaccination could have
acted as an additional stressor contributing to her decompensation.
        Similarly, Petitioner pointed (ECF 114, p. 74; ECF 127, p. 10) to an article by Klein et
al., “Evaluation of Immunization Rates and Safety Among Children With Inborn Errors of
Metabolism,” published in Pediatrics (Ex. M). Petitioner notes that the Klein article stated at
one point that this study “did identify some evidence of increased frequencies of hospitalizations
among 1- to 4-year-old children in the sickest IEM group during the 2 weeks after vaccination.
This suggests that there may be a subset of more fragile children with IEMs who are at increased
risk for adverse events during the immediate postvaccination period.” (Ex. M, p. 1145.) The
Klein authors, however, immediately added, after the language quoted above, that “this finding
should be interpreted cautiously.” (Id.) More importantly, the Klein authors went on to
conclude that the “overall finding” of their study was that “children with IEMs [inborn errors of
metabolism] received immunizations in a manner comparable with healthy children (id.), and
that “[o]verall, vaccinating children with IEMs did not seem to place them at increased risk for
postimmunization emergency-department visits or hospitalizations during the 30 days after
vaccination” (id.).
       Thus, when the Klein article is considered in its entirety, it supports Dr. McCandless’
opinion in this case, not that of Dr. Kendall (as Dr. McCandless testified, see Tr. 151-54).



fever during this time period (January 11 – 15). (Tr. 25-26.) But even assuming that A.I. in fact
experienced a fever on January 14, it appears to be of little to no significance in that it post-dates
the onset of A.I.’s metabolic decompensation (the January 11 staring spells) as alleged by
Petitioner. (See Section VII (A)(1) above.) Moreover, neither expert specifically addressed the
fact of this later fever about January 14. In fact, at no point has the Petitioner alleged that any of
A.I.’s fevers were attributable to her FluMist vaccination.
20
         I note that Petitioner filed a medical article purporting to show that a live attenuated
FluMist vaccine does produce measurable evidence of oxidative stress in subsequent breath tests.
(See Philips, et al., “Effect of influenza vaccination on oxidative stress products in breath,” J.
Breath Res. 4 (2010) (Ex. 35).) Petitioner’s counsel questioned Dr. McCandless about this
article on cross-examination. (Tr. 213-15.) Dr. McCandless acknowledged that the study
showed a physiological difference between vaccinated and unvaccinated individuals, but
indicated that he could not opine on whether there were any metabolic differences. (Id.) In any
event, Dr. Kendall never offered any testimony regarding this article, nor did she cite it in her
expert report. Significantly, however, even if I accept that this study establishes that the FluMist
vaccine is capable of producing measurable oxidative stress, that still does not mean that it
produces material or injurious levels of oxidative stress. Dr. Kendall’s testimony is that she is
not aware of any study attributing metabolic decompensation to the flu vaccine. (Tr. 86.)


                                                  24
       2. Dr. Kendall has not demonstrated that articles purporting to show that the wild flu
          virus can lead to cell death are relevant to A.I.’s case.

        In addition to the above, Dr. Kendall also cited four articles that, she says, in combination
show a potential mechanism whereby the wild flu virus acts to cause mitochondrial death,
leading to cell death, leading to clinical symptoms. (Tr. 65.) That is, according to Dr. Kendall
these articles “simply demonstrate pathophysiology in terms of what the influenza virus actually
does in cells and in mitochondria.” (Tr. 66.) Dr. Kendall stressed that she formed her opinion of
this case prior to being aware of these studies, based on her clinical experience, but noted that
these studies are consistent with her opinion, and that they provide a plausible basis for
explaining how A.I.’s metabolic decompensation might have occurred.21 (Tr. 65-66.) These
articles are “Influenza Virus Induces Apoptosis via BAD-Mediated Mitochondrial
Dysregulation” by Tran et al. (Ex. 67); “Human Influenza A Virus (IAV) Decreases
Mitochondrial Respiration of Infected MDCK Cell” (Abstract) by Derakhshan et al. (Ex. 69)22;
“Activated THP-1 Cells Depress Mitochondrial Respiration in HEP G2 Cells Infected With
Influenza B Virus” by Schwarz et al. (Ex. 72); and “Influenza Virus PB1-F2 Protein Induces
Cell Death Through Mitochondrial ANT3 and VDAC1” by Zamarin et al. (Ex. 75).
        Dr. McCandless questioned Dr. Kendall’s reliance on the Tran and Zamarin articles, both
because they are not directly related to the specific mitochondrial function at issue in Leigh
Disease (respiration), and because their focus is on viral reproduction rather than on the impact
on the mitochondria. As a result, Dr. McCandless argued, one cannot extrapolate what energy
demand the virus may be placing on the cell from these studies, as Dr. Kendall implicitly sought
to do.23 (Tr. 216-18; 220-21.)



21
        In presenting these four articles Dr. Kendall seems to be suggesting that these articles
further support her theory that the FluMist vaccine itself created a significant amount of
metabolic stress, as discussed above. However, this suggestion simply was not persuasive, for
the reasons discussed.
22
        What has been submitted as Exhibit 69 relative to the Derakhshan article is merely an
abstract. It is a very brief one-page summary of a larger article that is not in evidence. In fact,
Respondent’s expert indicated that there was insufficient information provided for him to form
any opinion on the article, which Petitioner’s counsel characterized as “fair.” (Tr. 218.) Thus Ex.
69 is of extremely limited, if any, evidentiary value.
23
       Moreover, I would go a step further and note also that the Tran article appears to be
looking at the role that BAD-regulated mitochondria in healthy cells play in viral replication
once infection has occurred. If, as the article seems to suggest, a BAD deficiency interferes with
the “mitochondria-dependent apoptotic pathways” to the detriment of the infecting virus, then it
seems reasonable to question whether the results of this study can even be carried over to
already-dysfunctioning mitochondria, regardless of Dr. McCandless’s other criticisms. In other
words, the study’s findings appear to be predicated on the presence of well-functioning
mitochondria, something which is clearly not present for a patient with Leigh Disease.


                                                 25
         Dr. McCandless also argued that the Schwarz study is not useful because the result is, in
effect, artificial. That is, Dr. McCandless pointed out that the study was conducted with
something called HepG2 cells, which are self-replicating cells used by laboratories that originate
from human liver cells but are, in fact, distinct.24 (Tr. 158-59.) Dr. McCandless argued that a
cell culture study of this type is essentially of little value in determining what actually happens in
live humans, because “what you can do in cell culture *** that you can’t do in a person is that
you can add a particular chemical, you can add a particular transcription factor [to see how the
molecules in the cell react],” but “there are literally dozens of steps to go from that to what
happens in a human being, what happens in an organism.” (Tr. 159.)
         Having read these three articles, I agree with Dr. McCandless’ assessment. But
regardless of those criticisms, I also find it dispositive that all three of these studies are looking at
the wild flu virus as opposed to the type of attenuated strain contained in a FluMist vaccine. Dr.
Kendall candidly acknowledged that this was a limitation on her reliance on these papers, and
that she did not know if the outcome would be the same with an attenuated virus. (Tr. 101-02.)
That is, although Dr. Kendall testified that she believed that an attenuated flu vaccine could lead
to clinical symptoms, she conceded that the vaccine should produce an immune response without
an infection. (Tr. 66-67.) Indeed, Dr. Kendall posited that vaccines mimic less severely the
metabolic changes associated with inflammation and infection. (Tr. 103.) Nonetheless she
testified that she “surmises” that the vaccine in question placed additional stress on A.I.’s system
based on A.I.’s subsequent clinical presentation of metabolic decompensation. (Tr. 99.) Yet I
must stress that there has been no suggestion in this case that A.I.’s FluMist vaccine generated
any infection.
        Thus, even if these articles did demonstrate a mechanism whereby the wild influenza
virus could lead to acute metabolic decompensation as Dr. Kendall argues, by her own admission
they still would not be informative as to whether the same can be said of an attenuated flu
vaccine such as FluMist, where actual infection is not expected. This is critical, because, as
described above, both experts agree not only that metabolic decompensation can be triggered by
a number of different stressors, including a viral infection or other intercurrent illness (tr. 99-100,
139), but also that A.I. was recovering from such an illness at the time she received the FluMist
vaccination. (tr. 56-58, 73, 174-75). And there is no evidence that A.I.’s FluMist vaccine created
an actual infection, as opposed to merely an immune response, following her vaccination.
Therefore, even accepting Dr. Kendall’s reading of the articles,25 they still would not support that
part of Dr. Kendall’s opinion that is actually controverted in this case--i.e., that the FluMist
vaccine in particular played any role in A.I.’s metabolic decompensation. 26


24
         The article itself describes HepG2 cells as “a well-differentiated continuous human liver
cell line derived from a hepatoblastoma.” (Ex. 72, p. 2.)
25
       I also found that the fourth article, by Derakhshan et al., also did not offer substantial
support to Dr. Kendall’s theory.
26
        I note that Dr. Kendall made a point of stressing that her opinion is based primarily on
her clinical experience and is not entirely reliant on the four articles discussed in this section.
(Tr. 65.) She also acknowledged, however, that absent what she argues is suggested by these
                                                   26
C. Summary regarding Dr. Kendall’s causation opinion
        In this case, Dr. Kendall candidly acknowledged that there is no direct evidence
establishing that immunizations can trigger metabolic decompensation in patients with Leigh
Disease. (Tr. 83, 101.) In and of itself, this is not fatal to Petitioner’s claim. It is possible to
establish a cause-in-fact claim circumstantially, and I give Dr. Kendall credit for forthrightly
acknowledging the circumstantial nature of her opinion. Nonetheless, Dr. Kendall’s testimony in
favor of a circumstantial theory was flawed in several regards.
        Overall, for all the reasons discussed above, Dr. Kendall failed to persuade me that key
pieces of evidence she presented regarding her contentions actually supported her position. As
explained above, though she set out to establish that A.I.’s vaccination contributed to A.I.’s
decline by showing that FluMist is contraindicated for patients with Leigh Disease, that A.I.’s
prior clinical history is significant in that she tolerated previous illnesses well, and that the timing
of A.I.’s metabolic decompensation pointed to vaccine causation, she failed to show that any of
these contentions are, “more likely than not,” correct.
        Furthermore, Dr. Kendall contended that the Poling and Shoffner studies supported her
opinion that vaccines are in themselves metabolic stressors capable of causing a metabolic
decompensation, when in fact those studies do not establish that proposition. She also asserted
that the Tran, Zamarin, and Schwarz articles presented a plausible mechanism explaining A.I.’s
neurological deterioration, despite acknowledging that she did not know whether the impact of
an attenuated strain such as found in the FluMist vaccine would be the same as the wild flu virus
studied in those papers.
        Thus, on the whole, I found that Dr. Kendall’s testimony was far less persuasive than that
of Dr. McCandless. (See, e.g., Cedillo v. HHS, 617 F.3d 1328, 1339 (Fed. Cir. 2010) (holding
that special masters may properly conclude under a Daubert analysis that “there is simply too
great an analytical gap between the data and the opinion proffered.”); Caves v. HHS, 100 Fed.
Cl. 119, 134 (2011), aff’d, 463 Fed.Appx. 932 (2012)(quoting Gen. Elec. Co. v. Joiner, 522 U.S.
136 (1997) for the proposition that “Daubert does not require a trial court ‘to admit opinion
evidence that is connected to existing data only by the ipse dixit of the expert.’”); see also
Hennessey v. HHS, 2009 WL 1709053, at * 42 (Fed. Cl. Spec. Mstr. May 29, 2009) (“When
experts disagree, many factors influence a fact-finder to accept some testimony and reject other
contrary testimony. Objective factors, including the qualifications, training, and experience of
the expert witnesses and the extent to which their proffered opinions are supported by reliable
medical research, other testimony, and the factual basis for their opinions, are all significant in
determining what testimony to credit and what to reject.”).)




articles, she does not otherwise know the mechanism at work in A.I.’s case, and that these
articles were deliberately presented as a plausible explanation for A.I.’s condition. (Tr. 66.)


                                                  27
                                                VIII


                   PETITIONER’S CASE FAILS THE LOVING /ALTHEN TEST
        In this part of my Decision, I will explain how this case fits specifically within the
interpretive standards set forth in the Althen and Loving decisions. The short answer is that I find
that Petitioner’s case clearly does not satisfy the standards presented in either Althen or Loving.
    In this regard, as previously noted, Petitioner has argued that A.I.’s FluMist vaccination
significantly aggravated a preexisting mitochondrial disorder, known as Leigh Disease.
Accordingly, I will analyze Petitioner’s case under the six-part Loving/Althen test for “significant
aggravation” claims.
A. Analysis of a “significant aggravation” issue is guided by the ruling in Loving.

   The Vaccine Act states that “[t]the term ‘significant aggravation’ means any change for the
worse in a preexisting condition which results in markedly greater disability, pain or illness
accompanied by substantial deterioration of health.” §300aa-33(4).
        The elements of an off-Table significant aggravation case were set forth in Loving v.
HHS, 86 Fed. Cl. 135, 144 (2009). The United States Court of Appeals for the Federal Circuit
acknowledged that “the Loving case provides the correct framework for evaluating off-table
significant aggravation claims,” in W.C. v. HHS, 704 F.3d 1352, 1357 (Fed. Cir. 2013). Thus,
the Federal Circuit Court of Appeals, which sets binding precedent for decisions by the Office of
Special Masters, endorsed the use of a six-part test for significant aggravation, which was first
elaborated in Loving. A petitioner must prove by preponderant evidence that a vaccination
caused significant aggravation by showing:
       (1) the person’s condition prior to administration of the vaccine, (2) the person’s current
       condition (or the condition following the vaccination if that is also pertinent), (3) whether
       the person’s current condition constitutes a ‘significant aggravation’ of the person’s
       condition prior to vaccination, (4) a medical theory causally connecting such a significant
       worsened condition to the vaccination, (5) a logical sequence of cause and effect showing
       that the vaccination was the reason for the significant aggravation, and (6) a showing of a
       proximate temporal relationship between the vaccination and the significant aggravation.
W.C., 704 F.3d at 1357.


B. Analysis of this case, under the six-part Loving/Althen test


    In this Section, I will discuss whether Petitioner has satisfied the six-part Loving test to
establish the existence of vaccine-related significant aggravation of a preexisting condition.

   1. What was A.I.’s condition prior to the administration of the vaccination in question?

       During her childhood, A.I. had experienced developmental delay. (Ex. 1, pp. 94, 98,
102.) On January 11, 2008, when she received her FluMist vaccination, she had an upper

                                                 28
respiratory infection. (Id., pp. 39-40.) She also was already afflicted, since birth, with a
mitochondrial disorder known as Leigh Disease. However, on January 11, beyond the upper
respiratory illness, she did not seem especially ill.

   2. What was A.I.’s condition soon after the vaccination in question?

        Tragically, in the three months after January 11, 2008, A.I.’s condition worsened terribly,
and eventually she died, as set forth on pp. 7-9 above. Her decompensation and death were
related to her Leigh Disease.

   3. A.I.’s condition and death in the three months post-vaccination legally constitutes a
      “significant aggravation” of her prior condition.

        In part 3 of the Loving/Althen formulation set forth in W.C. and quoted above, one
question posed is whether the vaccinee’s condition soon after the vaccination in question
constitutes a “significant aggravation” of the vaccinee’s condition prior to vaccination. W.C.,
704 F.3d at 1357. (I understand “significant aggravation,” in this context, to simply mean a
“significant worsening,” without any implication as to the cause of the worsening.) As to that
question, my conclusion is that A.I.’s condition in the three months post-vaccination obviously
was “significantly worse” than her condition appeared immediately prior to the vaccination in
question. Therefore, following the standard set forth in Loving and W.C., A.I.’s condition during
those three months and her death do amount to a “significant aggravation” of her Leigh Disease
(though the worsening has definitely not been shown to have been related to her vaccination).
   4. Petitioner has failed to establish Prong 4 of Loving/Prong 1 of Althen.


    As discussed above, Prongs 4, 5, and 6 of the Loving test are, in effect, the same as Prongs 1,
2, and 3 of the Althen standard. Under Prong 4 of Loving and Prong 1 of Althen, a petitioner
must provide a medical theory demonstrating that the type of vaccine in question can cause a
significant worsening of the type of preexisting condition of the vaccinee. In this case, however,
for the reasons stated at length above, the Petitioner has failed to show that the vaccination in
question can aggravate the type of mitochondrial disorder from which A.I. suffered.

           a. Relationship between Althen Prongs 1 and 2 (Loving Prongs 4 and 5)
         One interpretive issue with the Althen test concerns the relationship between the first two
elements of that test. The first two prongs of the Althen test, as noted above, are that the
petitioners must provide “(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.” Initially, it is not absolutely clear how the two prongs differ from each other. That
is, on their face, each of the two prongs seems to require a demonstration of a causal connection
between “the vaccination” and “the injury.” However, a number of Program opinions have
concluded that these first two elements reflect the analytical distinction that has been described
as the “can cause” vs. “did cause” distinction. That is, in many Program opinions issued prior to
Althen involving “causation-in-fact” issues, special masters or judges stated that a petitioner
must demonstrate (1) that the type of vaccination in question can cause the type of injury in
question, and also (2) that the particular vaccination received by the specific vaccinee did cause

                                                 29
the vaccinee’s own injury. See, e.g., Kuperus v. HHS, 2003 WL 22912885, at *8 (Fed. Cl. Spec.
Mstr. Oct. 23, 2003); Helms v. HHS, 2002 WL 31441212, at *18 n. 42 (Fed. Cl. Spec. Mstr. Aug.
8, 2002). Thus, a number of judges and special masters of this court have concluded that Prong
1 of Althen is the “can cause” requirement, and Prong 2 of Althen is the “did cause” requirement.
See, e.g., Doe 11 v. HHS, 83 Fed. Cl. 157, 172-73 (2008); Nussman v. HHS, 83 Fed. Cl. 111, 117
(2008); Banks v. HHS, 2007 WL 2296047, at *24 (Fed. Cl. Spec. Mstr. July 20, 2007); Zeller v.
HHS, 2008 WL 3845155, at *25 (Fed. Cl. Spec. Mstr. July 30, 2008). And, most importantly,
the Federal Circuit confirmed that interpretation in Pafford, ruling explicitly that the “can it?/did
it?” test, used by the special master in that case, was equivalent to the first two prongs of the
Althen test. Pafford v. HHS, 451 F.3d 1352, 1355-56 (Fed. Cir. 2006). Thus, interpreting the
first two prongs of Althen as specified in Pafford, under Prong 1 of Althen a petitioner must
demonstrate that the type of vaccination in question can cause the type of condition in question;
and under Prong 2 of Althen that petitioner must then demonstrate that the particular vaccination
did cause the particular condition of the vaccinee in question.
        Moreover, there can be no doubt whatsoever that the Althen test ultimately requires that,
as an overall matter, a petitioner must demonstrate that it is “more probable than not” that the
particular vaccine was a substantial contributing factor in causing the particular injury in
question. That is clear from the statute itself, which states that the elements of a petitioner’s case
must be established by a “preponderance of the evidence.” § 300aa-13(a)(1)(A). And, whatever
is the precise meaning of Prongs 1 and 2 of Althen, in this case the overall evidence falls far short
of demonstrating that it is “more probable than not” that the vaccine that A.I. received
contributed to the causation of her tragic death.
           b. Petitioner has failed to establish Prong 1 of Althen (Loving Prong 4) in this
              case.
         As explained above, under Prong 1 of Althen a petitioner must provide a medical theory
demonstrating that the type of vaccine in question can cause the type of condition in question.
Petitioner’s theory in this case is that metabolic demand placed on A.I.’s system by her FluMist
vaccination, coupled with her upper respiratory infection, caused a metabolic decompensation
that ultimately, through a cascade of neurologic cell death, resulted in her death. For all of the
reasons described above, however, Petitioner has failed to make this showing. That is,
Petitioner’s reliance on certain postmarketing evidence was shown to be ineffectual. (Section
VII(A)(3) above.) Petitioner’s reliance on the Poling and Shoffner articles, among other articles,
and on the Paluck opinion, was also shown to be without merit. (Section VII(B)(1) above.)
Petitioner additionally sought to establish that the flu virus is capable of causing cell death, but
failed to demonstrate that the type of attenuated viral strain contained in the FluMist vaccine at
issue would have the same effect on the body as an infection from a wild flu virus. (Section
VII(B)(2) above.) Thus, Petitioner was unable to explain persuasively how the FluMist vaccine
might have caused or contributed to the type of decompensation that A.I. sustained. Petitioner
has therefore failed to meet her burden under the first Althen prong.27

27
        In this case, it does not matter whether Petitioner’s burden under Prong 1 of Althen is
merely to show that her “general causation” theory is “plausible,” or to show that it is “more
probable than not.” I find that Petitioner did not establish Althen Prong 1/Loving Prong 4 under
either standard of proof, for all the reasons set forth above.
                                                 30
     5. Petitioner has failed to establish Prong 2 of Althen (Loving Prong 5) in this case.
        Under Prong 2, the Petitioner needs to show that it is “more probable than not” that A.I.’s
FluMist vaccine did cause A.I.’s own death. But this she has failed to do. Again, for all the
reasons discussed above, Petitioner has failed to demonstrate that A.I.’s vaccine created
additional metabolic demand, or that it created any after-effect that in turn created such demand.
Moreover, Petitioner admitted that even if a vaccine could create metabolic demand, such
metabolic demand cannot be measured in a clinical setting. And in any event, for that same
reason, Petitioner’s expert conceded that she was unable to opine that the upper respiratory
infection, which A.I. was experiencing at the time of her vaccination, was not itself capable of
causing A.I.’s injury regardless of the vaccination. In that regard, it was also significant that the
only medical literature cited by either expert that addressed the timing of such deterioration
(Edmonds, et al.) better supported Respondent’s theory of the case than Petitioner’s. For all of
these reasons, I find that Petitioner has failed to establish that it is more likely than not that A.I.’s
FluMist vaccine did aggravate A.I.’s own Leigh Disease. Thus, Petitioner has also failed to meet
her burden under the second Althen prong.

     6. Petitioner has failed to establish Prong 3 of Althen (Loving Prong 6) in this case.
         Since I have explained why Petitioner has failed to satisfy both the first and the second
prongs of Althen, I need not discuss why Petitioner’s case also fails to satisfy the third prong.
However, I will note that, as described in Section VII(A)(1) above, I found that the timing of
A.I.’s first symptom of neurodegeneration (i.e., the staring spells), as alleged by Petitioner
herself, made the vaccination an unlikely explanation for A.I.’s metabolic decompensation. That
is, the evidence did not make it appear likely that the vaccine could have caused that symptom in
less than a single day. Therefore, Petitioner failed to establish a proximate temporal relationship
between the vaccination and A.I.’s metabolic decompensation, and thus failed to satisfy the third
Althen prong.

     7. Summary: Petitioner has failed the Loving/Althen test.
   To obtain a Program award under the Loving/W.C. test, a petitioner must succeed in
demonstrating all four of Prongs 3, 4, 5, and 6 of Loving. However, in this case, as explained
above, Petitioner has succeeded on Prong 3, but failed to demonstrate Prongs 4, 5, and 6.
Therefore, Petitioner has failed to demonstrate entitlement to an award in this case.

C. This is not a close case.
        As noted above, in Althen the Federal Circuit indicated that the Vaccine Act involves a
“system created by Congress, in which close calls regarding causation are resolved in favor of
injured claimants.” 418 F.3d at 1280. Accordingly, I note here that this case ultimately is not a
close case. For all the reasons set forth above, I found that Dr. Kendall’s theory was not at all
persuasive, while Respondent’s expert was far more persuasive.28

28
        Petitioner argued in one of her briefs (ECF 114, pp. 86-90), that Respondent failed to
carry “Respondent’s burden” of demonstrating that A.I.’s decompensation and death were
caused by “factors unrelated to the administration of the vaccine.” See § 300aa-13(a)(1)(B).
Petitioner is mistaken. Petitioner never carried her burden of demonstrating that the vaccination
                                                   31
                                                 IX
                                          CONCLUSION
       The record of this case demonstrates plainly that Petitioner and her family have been
through a tragic ordeal. Petitioner has my deepest sympathy on account of the tragic loss of her
daughter.
          However, I must decide this case not on sentiment, but by analyzing the evidence.
Congress designed the Program to compensate only the families of those individuals whose
injuries or deaths can be linked causally, either by a Table Injury presumption or by a
preponderance of “causation-in-fact” evidence, to a listed vaccine. In this case, the evidence
advanced by the Petitioner has fallen far short of demonstrating such a link. Accordingly, I
conclude that the Petitioner in this case is not entitled to a Program award as a result of A.I.’s
death.29



                                                             /s/ George L. Hastings, Jr.
                                                                George L. Hastings, Jr.
                                                                Special Master




aggravated A.I.’s Leigh Disease, or harmed her in any way. Therefore, no burden relating to a
“factor unrelated” ever passed to Respondent in the first place.

        In any event, as explained above, I conclude that Dr. McCandless did show it to be “more
probable than not” that A.I.’s tragic decompensation and death likely were caused by a
combination of (1) her inborn Leigh Disease and (2) the infectious illness that afflicted A.I. just
prior to the vaccination in question.
29
        In the absence of a timely-filed motion for review of this Decision, the Clerk of the Court
shall enter judgment accordingly.
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