             In the United States Court of Federal Claims
                                     OFFICE OF SPECIAL MASTERS
                                           Filed: July 10, 2017

* * * * * * * * * * *                              *   *
CHASE BOATMON & MAURINA                                *         PUBLISHED DECISION
CUPID, parents of J.B., deceased,                      *
                                                       *         No. 13-611V
                                                       *
                  Petitioners,                         *         Special Master Gowen
                                                       *
v.                                                     *         Entitlement Decision; Diphtheria-
                                                       *         Tetanus-acellular Pertussis (DTaP)
SECRETARY OF HEALTH                                    *         Vaccine; Inactivated Polio Vaccine
AND HUMAN SERVICES,                                    *         (IPV); Haemophilus Influenzae (HiB)
                                                       *         Vaccine; Pneumococcal Conjugate
                  Respondent.                          *         (PCV) Vaccine; Rotavirus Vaccine;
                                                       *         Sudden Infant Death Syndrome (SIDS).
*    * *     *    *    *   *    *    *    *   *    *   *

Ronald C. Homer & Joseph M. Pepper, Conway, Homer P.C., Boston, MA, for petitioners.
Lara A. Englund & Ryan M. Pyles, United States Department of Justice, Washington, DC, for
respondent.1

                                         RULING ON ENTITLEMENT2

       On August 27, 2013, Chase Boatmon and Maurina Cupid (“petitioners”), as the
representatives of the estate of their deceased minor child, J.B., filed a petition under the
National Vaccine Injury Compensation Program (“Vaccine Act” or the “Program”),3 42 U.S.C. §
300aa-10 et. seq. (2012). Petitioners allege that as a result of receiving vaccinations for
1
 Mr. Homer is petitioners’ attorney of record, while his colleague Mr. Pepper appeared at the entitlement hearing.
Similarly, for respondent, Ms. Englund has always been the attorney of record, but Mr. Pyles appeared at the
entitlement hearing.
2
  Because this decision contains a reasoned explanation for the action in this case, the undersigned intends to post it
on the website of the United States Court of Federal Claims, pursuant to the E-Government Act of 2002, see 44 U.S.C.
§ 3501 note (2012). The court’s website is at http://www.uscfc.uscourts.gov/aggregator/sources/7. Before the decision
is posted on the court’s website, each party has 14 days to file a motion requesting redaction “of any information
furnished by that party: (1) that is a trade secret or commercial or financial in substance and is privileged or
confidential; or (2) that includes medical files or similar files, the disclosure of which would constitute a clearly
unwarranted invasion of privacy.” Vaccine Rule 18(b). “An objecting party must provide the court with a proposed
redacted version of the decision.” Id. If neither party files a motion for redaction within 14 days, the decision will be
posted on the court’s website. Id.
3
 The National Vaccine Injury Compensation Program is set forth in Part 2 of the National Childhood Vaccine Injury
Act of 1986, Pub. L. No. 99-660, 100 Stat. 3705, codified as amended, 42 U.S.C. §§ 300aa-1 to -34 (2012). All
citations in this decision to individual sections of the Vaccine Act are to 42 U.S.C. § 300aa.


                                                           1
Diphtheria-Tetanus-acellular Pertussis (“DTaP”), inactivated polio (“IPV”), haemophilus
influenzae (“HiB”), Pneumococcal Conjugate (“PCV”), and Rotavirus vaccinations on
September 2, 2011, J.B. passed away from Sudden Infant Death Syndrome (“SIDS”) on
September 3, 2011. See Petition (ECF No. 1); Amended Petition (ECF No. 15).

        After carefully analyzing and weighing all of the evidence and testimony presented in
this case in accordance with the applicable legal standards, the undersigned finds that petitioners
have met their legal burden. Petitioners have put forth preponderant evidence that the vaccines
J.B. received on September 2, 2011 actually caused or substantially contributed to his death from
Sudden Infant Death Syndrome. Furthermore, respondent has failed to put forth preponderant
evidence that J.B.’s death was in fact caused by factors unrelated to the vaccines. Accordingly,
petitioners are entitled to compensation.

    I.       BACKGROUND

             A. Procedural History

        Petitioners filed a petition for compensation pursuant to the Vaccine Act on behalf of
their deceased minor son, J.B., on August 27, 2013. Petition (ECF No. 1). They filed an
amended petition on February 6, 2014. Amended Petition (ECF No. 15). Petitioners filed the
expert report of Dr. Douglas C. Miller, a neuropathologist, along with the medical literature
referenced in his report, on May 20, 2014. Exhibit 13, 14 (ECF No. 21).4

       On September 9, 2014, respondent filed a Rule 4(c) report advising against
compensation. Rule 4(c) Report (ECF No. 28). That same day, he filed an expert report and
medical literature referenced therein from Dr. Brent Harris, a pathologist. Exhibit A (ECF No.
29). Respondent also filed an expert report and medical literature from Dr. Christine T.
McCusker. Exhibit C (ECF Nos. 30-32). Petitioners filed a supplemental report from Dr. Miller
on November 10, 2014. Exhibit 16 (ECF No. 35). Extensive and detailed medical literature was
submitted in support of all of the expert reports.5

        At numerous stages of this case, the undersigned encouraged the parties to pursue the
possibility of an informal resolution and/or to consider mediation. See, e.g., Order filed
December 9, 2014 (ECF No. 37). The parties ultimately did not settle the case. An entitlement
hearing was held on Thursday, August 6, and Friday, August 7, 2015, in Washington, D.C. Dr.
Miller testified on behalf of petitioners, and Dr. Harris and Dr. McCusker testified for
respondent. The case was well tried and involved detailed expert testimony from both sides. See

4
 On October 14, 2014, petitioners refiled the medical literature cited in Dr. Miller’s report, highlighting the specific
portions being relied upon to support causation. Petitioners’ Notice of Refiling Documents (ECF No. 34).
5
  I have read and digested all of the literature submitted in this case and will reference numerous but not all articles
in the course of this opinion. However, all articles have been considered in coming to a conclusion in this case.
More recent articles, particularly those by the same authors or groups, are referenced more frequently because they
incorporate, build upon, and update the earlier literature. Petitioners and Dr. Miller filed Exhibits 13-A through 13-
V and Exhibits 14 through 21. Respondent and Dr. Harris filed Exhibits A-1 through A-6. Respondent and Dr.
McCusker submitted Exhibits C-1 through C-20 and Exhibits D through G.


                                                           2
Transcript filed on September 9, 2015 (ECF Nos. 50, 52). Petitioners filed their post-hearing
brief on December 7, 2015. (ECF No. 61). Respondent filed his post-hearing brief on March 7,
2016. (ECF No. 63). Petitioners filed their reply to respondent’s post-hearing brief on March
28, 2016. (ECF No. 64). This matter is now ripe for adjudication.

           B. Standards for Adjudication

        The Vaccine Act established the Program to compensate vaccine-related injuries and
deaths. § 300aa-10(a). “Congress designed the Vaccine Program to supplement the state law civil
tort system as a simple, fair and expeditious means for compensating vaccine-related injured
persons. The Program was established to award ‘vaccine-injured persons quickly, easily, and
with certainty and generosity.’” Rooks v. Sec’y of Health & Human Servs., 35 Fed. Cl. 1, 7
(1996) (quoting H.R. Rep. No. 908 at 3, reprinted in 1986 U.S.C.C.A.N. at 6287, 6344).

        There are two avenues to compensation under the Program. The first is to demonstrate a
“Table injury,” that is, a specified injury within a specified period of time following
administration of a vaccine listed on the Vaccine Injury Table. § 300aa-14(a). A Table injury
creates a presumption of causation, which is only defeated if respondent shows that the injury
was caused by a factor or factors unrelated to the vaccine. In the present case, petitioners allege
that J.B. died suddenly of a cause that remained unexplained after a site investigation and
autopsy, often referred to as SIDS, shortly after receiving various vaccines listed on the Table.
The Table does not list SIDS occurring in any period of time after any vaccine.

        Therefore, petitioners must take the second avenue towards compensation: they must
establish an “off-Table injury,” meaning that the vaccine(s) were the cause in fact of the
vaccinee’s injuries. In Althen, the Federal Circuit established a three-prong test: petitioners must
establish (1) a medical theory causally connecting the vaccination and the injury; (2) a logical
sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a
proximate temporal relationship between vaccination and injury. Althen v. Sec’y of Health &
Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005).

        The legal standard is by a preponderance of the evidence.” §300aa-13(a)(1)(a). This
does not require “conclusive scientific evidence” or “certainty.” Moberly v. Sec’y of Health &
Human Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010). Instead, the standard has been interpreted
to mean that a fact is more likely than not. Id. at 1322 n.2. The Federal Circuit has observed that
this preponderance standard enables “the finding of causation in a field bereft of complete and
direct proof of how the vaccines affect the human body.” Althen, 418 F.3d at 1280. Petitioners
must establish each Althen prong by the preponderance of the evidence. Caves v. Sec’y of Health
& Human Servs., 100 Fed. Cl. 119, 132 (2011), aff. per curiam, 463 Fed. Appx. 932 (Fed. Cir.
2012).

        Each Althen prong may be satisfied by medical records or a medical opinion. Althen, 418
F.3d at 1279; see also Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1326 (Fed.
Cir. 2006) (noting that the same piece of evidence can support several Althen prongs).
Petitioners are not required to provide “objective confirmation” by way of “medical


                                                 3
documentation.” Id. at 1278. Such a requirement would “contravene the plain language of the
statute.” Id. at 1281.

        In determining whether a petitioner is entitled to compensation, a special master must
consider the entire record and is not bound by any particular piece of evidence. § 13(b)(1)
(stating that a special master is not bound by any “diagnosis, conclusion, judgment, test result,
report, or summary” contained in the record). Thus, a special master must weigh and evaluate
opposing expert opinions, medical and scientific evidence, and the evidentiary record in deciding
whether petitioners have met their burden of proof.

        Epidemiological studies, or the lack thereof, are not dispositive of the causation in fact
determination. Grant v. Sec’y of Health & Human Servs., 956 F.2d 1144, 1149 (Fed. Cir. 1992).
Indeed, petitioners are not required to present medical literature or epidemiological evidence to
establish any Althen prong. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1380
(Fed. Cir. 2009). However, the special master can consider [epidemiological evidence] in
reaching an informed judgment as to whether a particular vaccination likely caused a particular
injury…. Medical literature and epidemiological evidence must be viewed… not through the lens
of the laboratorian, but instead from the vantage point of the Vaccine Act’s preponderant
evidence standard.” Andreu, 569 F.3d at 1380.

        Under the second Althen prong, petitioners need to show that the vaccine(s) was “not
only a but-for cause of the injury but also a substantial factor in bringing about the injury.”
Shyface v. Sec’y of Health & Human Servs., 165 F.3d 1344, 1352-53 (Fed. Cir. 1999). They do
not need to show that the vaccine(s) was the “sole” or even the “predominant” cause. Id. at
1352. For example, in Shyface, the Federal Circuit affirmed that petitioners were entitled to
compensation, based on their expert’s testimony that the vaccine together with a bacterial
infection caused the child’s high fever and death (although the expert could not testify that the
vaccine was the “sole” or “predominant” cause. 165 F.3d at 1353.

         Showing a logical sequence of cause and effect between the vaccine(s) and the injury
will tend to show that the injury was not caused by an alternative cause. However, a petitioner is
not required to eliminate all possible alternative causes of the injury. See Walter v. Sec’y of
Health & Human Servs., 485 F.3d 1146, 1150 (Fed. Cir. 2007) (“the Vaccine Act does not
require the petitioner to bear the burden of eliminating alternative causes where the other
evidence on causation is sufficient to establish a prima facie case”). This standard permits the
use of “circumstantial evidence” and accomplishes Congress’s goal that “close calls regarding
causation are resolved in favor of injured claimants.” Althen, 165 F.3d at 1280.

        Once a petitioner fulfills the Althen test, the burden of persuasion shifts to respondent to
show that the alleged injury was caused by a factor unrelated to the vaccination. Knudsen, 35
F.3d 543 at 548; § 13(a)(1)(B). Respondent has the burden of demonstrating that “a factor
unrelated to the vaccination is the more likely or principal cause of the injury alleged. Such a
showing establishes that the factor unrelated, not the vaccination, was ‘principally responsible’
for the injury.” Deribeaux v. Sec’y of Health & Human Servs., 717 F.3d 1363, 1369 (Fed. Cir.
2013). Section 13(a)(2) specifies that factors unrelated “[do]not include any idiopathic,
unexplained, unknown, hypothetical, or undocumented causal factor, injury, illness, or

                                                  4
condition.” Close calls regarding causation must be resolved in favor of the petitioner. Althen,
418 F.3d at 1280; Knudsen, 35 F.3d at 551 (“If the evidence (on alternative cause) is seen in
equipoise, then the government has failed in its burden of persuasion and compensation must be
awarded.

                C. Summary of Relevant Facts

        J.B. was born on April 7, 2011, when his mother became pre-eclamptic and underwent a
Caesarean section. Exhibit 1 at 10. J.B. was born 4 weeks prematurely at 36 weeks gestation.
Exhibit 2 at 3. The mother’s medical records report no history of tobacco, alcohol, or illicit
drugs. Exhibit 1 at 3. At birth, J.B. was noted to be “well appearing, non-dysmorphic[,] alert
and in no acute distress.” Exhibit 2 at 9. His Apgar scores6 were 8 at 1 minute and 9 at 5
minutes. Exhibit 2 at 9. J.B. and his mother are both noted to be African-American. Exhibit 2
at 3, 25.

          On April 14, 2011, one week after birth, J.B. received his first Hep B vaccination.
Exhibit 2 at 82.7 At his two-week well baby visit on April 21, 2011, J.B. was “well appearing,
alert . . . a healthy appearing 2 [week] old with normal growth and development.” Id. at 79-81.
On June 7, 2011, J.B. – exhibiting a cough and a runny nose – was brought to the emergency
room. Id. at 73. He underwent a chest x-ray that revealed “no radiographic evidence of acute
cardiopulmonary disease.” Id.

        J.B.’s subsequent well-baby visits were scheduled to account for the fact of his being
born 4 weeks prematurely. On July 22, 2011, more than three months after J.B.’s birth, he had a
two-month well baby visit with his pediatrician, Laura Wright, M.D. Exhibit 3 at 8-10. Dr.
Wright’s evaluation was thorough and well documented. Id. J.B. had no feeding difficulties,
slept best at night, slept in his own room, and slept on his back. Id. at 8. He was noted to be a
“well child, almost 4 months but behind on [vaccinations]” with “normal growth and
development.” Id. at 10. J.B. received DTaP, IPV, PCV, rotavirus, and Hep B vaccinations at
this visit. Id. at 2, 8.

        On September 2, 2011, almost five months after J.B.’s birth, he had his four-month well
baby visit with Dr. Wright. Exhibit 3 at 5-7. He was nearly five months post-delivery, although
his gestational age was about four months given his early delivery. J.B. was sleeping up to seven
hours at a time, on his back, in a crib in his own room. Id. at 5. He was described as “healthy
appearing and cooperative . . . well-nourished and well developed.” Id. His chest and lungs
were normal with no adventitious8 sounds. Id. at 6.

6
  Apgar score is defined as “a numerical expression of the condition of a newborn infant, usually determined at 60
seconds after birth, being the sum of points gained on assessment of the heart rate, respiratory effort, muscle tone,
reflex irritability, and color.” Dorland’s Illustrated Medical Dictionary (32d ed. 2012) (“Dorland’s”) at 1682.
7
 Petitioners’ expert, Dr. Miller, stated that normally an infant receives the first Hep B vaccination a day after
delivery or just before going home. Exhibit 13 at 3. Dr. Miller characterized J.B. receiving the first Hep B
vaccination one week after delivery as “a little unusual [but…] likely inconsequential.” Id.
8
    Adventitious is defined as “accidental or acquired; not natural or hereditary.” Dorland’s at 34.


                                                             5
         J.B.’s heart rate was regular with normal heart sounds and no pericardial friction rubs.
Id. His reflexes were all 2/2 and his red reflex was normal. Id. His weight was 16 pounds, 8
ounces. Id. at 5. For infants of his age, his weight was stable at the 50th percentile, his height
was up at the 50th percentile, and his head circumference was at the 75th percentile. Id. Nasal
mucosa was normal, turbinates9 were normal, and nares10 were patent. Oropharynx was normal.
Id. at 6. He was recorded as not having a fever, nasal congestion, or cough and history of
wheezing. Id. at 5. He met numerous 4-month developmental milestones, including “head up 45
degrees, head up 90 degrees, sits – head steady.” Id. During this visit, J.B. received DTaP, IPV,
PCV, rotavirus, and Hep B vaccinations. Id. at 6; Exhibit 4 at 1. Dr. Wright completed her
records from this visit on September 2, 2011, at 10:45 a.m., suggesting that the appointment had
concluded by that time. Exhibit 3 at 7.

        J.B.’s father attested that during the well-baby visit, J.B. was “smiling and cooing like
normal.” Exhibit 11 at 1. However, later that day after J.B. received the vaccinations, he “was
not laughing or cooing like he normally did[,] he was not moving as much[, and] he seemed
quiet and withdrawn.” Id. That night, J.B. had a fever and he did not sleep well. Id. 11

       J.B.’s mother and father stated that on September 3, 2011, at 4:00 a.m., they gave J.B.
Advil,12 after which he went to bed in a supine position (on his back). Exhibit 8 at 2. When J.B.
woke up a few hours later, he was distant, very quiet, and would not eat. Exhibit 11 at 2. He
began running a fever again and was given another dose of Advil at approximately 8:00 a.m. Id.;


9
    Turbinate is defined as “any of the nasal conchae.*” Dorland’s at 1991.
10
     Nares is defined as “the external orifices of the nose; [also known as] nostrils.” Dorland’s at 1232.

11
     The following factual summary draws from:
        Exhibit 5 – Suffolk, Virginia Department of Fire & Rescue records of responding to the home on
           September 2, 2011.

          Exhibit 7 – Suffolk, Virginia Police Department records. This includes notes from the police’s response to
           the home on September 3, 2011, and the police department’s formal report on their response and a
           handwritten statement from J.B.’s mother, both completed on September 8, 2011.

          Exhibit 8 – Office of the Chief Medical Examiner, Tidewater District, Norfolk, Virginia, Records. This
           exhibit contains a summary of a child death reenactment with a doll, performed with J.B.’s parents in their
           home on September 8, 2011. Exhibit 8 at 3. The autopsy report was completed on November 2, 2011.
           Exhibit 8 at 1-2; 4-9.

          Exhibit 9 – Suffolk, Virginia Police Department records – photos of a bottle of Advil, taken on September
           8, 2011; J.B. following the autopsy, undated; and the crib, bedroom, and exterior of the home, taken on
           September 3, 2011.

J.B.’s mother and father were not present to testify at the entitlement hearing.
12
  A bottle of children’s Advil was taken into evidence. Exhibit 7 at 47. But see Exhibit 6 at 2, 5 (“aspirin”);
Exhibit 8 at 2 (“infant Tylenol”); Exhibit 8 at 4-6 (“over-the-counter acetaminophen”). To the extent that it makes
any difference it would seem most likely that it was the Advil that was given and the other notations were made
subsequently without that same attention to this detail that the site investigation utilized.


                                                             6
Exhibit 7 at 11. J.B.’s mother said that J.B. sat up and played with her nephews during the
morning. Exhibit 7 at 16.

        In the early afternoon, J.B. became fussy and his father put him down for a nap in his
bedroom, on the second floor of the house. Exhibit 7 at 3, 16; Exhibit 8 at 2. His father attested
that he placed J.B. supine with his head to the right. Exhibit 7 at 5; Exhibit 8 at 3. J.B. seems to
have had a pacifier in his mouth. Exhibit 7 at 16. He was placed in the middle of his crib, with a
blanket across his midsection. Exhibit 8 at 3. The crib also contained a “little crib pillow – very
flat,” but no clutter or toys. Exhibit 7 at 5; Exhibit 8 at 3. J.B.’s mother attested that the air
conditioning was always set at 76 degrees Fahrenheit. Exhibit 7 at 4. She indicated that J.B.
slept on his back and that he could roll over on his own, lift his head, and pull or push himself
up. Exhibit 7 at 5.

        After putting J.B. down for his nap, his father left the home to get lunch. Exhibit 11 at 2.
His mother remained in the home, but “heard [J.B.] fussing in crib” while she was cleaning and
on the phone. Exhibit 7 at 16. After some period of time, J.B.’s mother went upstairs and put
the pacifier in J.B.’s mouth. Id. (noting that J.B. “tend[ed] to cry when he spit the pacifier out”).
When she returned, she found J.B. on his right side, with his head turned slightly, and
unresponsive. Exhibit 7 at 17; Exhibit 8 at 2-3. She called J.B.’s father and said that J.B. was
not breathing. Exhibit 7 at 17; Exhibit 11 at 2. The father told her to call 911 and he headed
home. Exhibit 11 at 2.

        J.B.’s mother said that “approximately 50 minutes passed” between his father placing
J.B. down for a nap and when she found J.B. unresponsive. Exhibit 8 at 2. There was a “10-
minute window” between when his mother checked on J.B. and replaced his pacifier, and when
she returned to find him unresponsive. Exhibit 5 at 2. She informed the police that his nose and
mouth were not covered. Pet. Ex 7 p 5.

        J.B.’s mother called 911 at 2:39 p.m. Exhibit 7 at 35. She then attempted CPR. Exhibit
5 at 2; Exhibit 7 at 17. It appears that she removed him from the crib and placed him on his back
on the floor. Exhibit 7 at 9-10. Officer Anderson was the first to arrive, at 2:42 p.m. – just 3
minutes and 21 seconds after the call. Exhibit 7 at 7, 9, 11, 35. Upon entering the home and
going upstairs, the officer found J.B. lying on the bedroom floor, perpendicular to his crib. Id. at
9. J.B. was face up, with his eyes closed, and unresponsive. Id. He was still warm, but had no
pulse or breath. Id. J.B.’s mother was kneeling over him. Id. The officer performed chest
compressions until EMS arrived. Id.

       The first responders left with J.B. at 3:02 p.m. and arrived at the emergency department
of Harborview Medical Center at 3:08 p.m. Exhibit 7 at 36. J.B. was given oxygen under
pressure during transport, but PEA (pulseless electrical activity) was noted on the monitor.
Exhibit 5 at 1-2. Efforts at resuscitation were unsuccessful and J.B. was pronounced dead at the
hospital, on September 3, 2011, at 4:01 p.m. Exhibit 7 at 10.




                                                  7
        On September 5, 2011, a medical examiner, Dr. Jeffrey Gofton, completed an autopsy
report for J.B. Exhibit 8 at 4-6. The medical examiner noted that the scene reenactment
indicated that J.B. was placed to sleep on his back and was later found on his right side. Id. at 6.
Scene photographs indicated a crib with soft blankets and a flat soft pillow, but no clutter or toys
in the bed. Id. It was further noted that J.B. had no known medical problems, with regular infant
care and immunizations. Id. He had a well-baby check-up on the day prior to his death, during
which he received multiple vaccinations. Id. He had reportedly been fussy and had an
intermittent temperature that seemed to be controlled with Tylenol. Id. J.B. was reportedly
placed to sleep on his back and later found on his right side. Id. The medical examiner stated
that J.B.’s lungs exhibited congestion and pulmonary edema.13 Id. However, J.B. had no
traumatic injury, congenital abnormalities, or viruses such as influenza. Id. Both a cerebral
spinal fluid culture and a nasopharyngeal swab for viruses were negative. Id. J.B.’s brain
weighed 876 grams (normal is 620 plus or minus 71 grams). Id. There was no evidence of
epidural, subdural, or subarachnoid hemorrhage. Id. Serial sectioning showed normal
configuration and infantile myelination of the cerebrum. Id. The brainstem was normally
formed with no focal lesions. Id. at 5. Extensive drug testing was performed and was negative.
Id at 6. The medical examiner, based on the “absence of findings and the reported sleeping
position in a child with no anatomic or microscopic significant findings,” stated that “the cause
of death was SIDS and the manner was “natural.” Id. The parties agree that the characterization
of J.B.’s cause of death as SIDS is appropriate. Joint Prehearing Submission at 2.

        The parties’ experts in neuropathology – Dr. Miller for petitioners and Dr. Harris for
respondent – reviewed 21 slides from J.B.’s autopsy, including two of J.B.’s brain. Exhibit 13 at
4-5; Exhibit A at 5. The first brain slide is a cross-section of pons at the level of the locus
coeruleus (the upper pons), and the second slide is of two cingulate gyri with a portion of the
adjacent corpus callosum. Exhibit 13 at 5. These brain sections demonstrated no abnormalities.
Id. However, the medical examiner did not make slides from other parts of the brain, such as the
medulla or hippocampus. Id. Furthermore, he did not take any photographs of the internal
examination. Id. The parties’ experts agreed that the medical examiner did not collect all of the
data necessary to definitively analyze whether J.B. fit the Triple Risk Model of SIDS, introduced
in the following section. Tr. 42-43 (testimony of Dr. Miller); Tr. 334 (testimony of Dr. Harris).
The experts agreed that they would section considerably more of the brain in a possible SIDS
autopsy than the two frontal lobes and one area of the pons that were sectioned in this case. Dr.
Harris indicated that usually a SIDS autopsy should include samples of at least ten areas,
including the medulla and hippocampus, which can help to show hypoxic ischemic changes as
well as epilepsy related changes. Tr. 334. Both experts agreed, however, that in many SIDS
cases, brains are not examined with the precision that they would recommend or that Dr.
Kinney’s group at Harvard did in their studies (introduced in the following section). Tr. 346.




13
  Dr. Miller and Dr. Harris agreed that congestion in the brain and lungs and other organs is a very common and
non-specific finding at autopsy from which they would not draw any conclusion. Tr. 103 (Miller); Tr. 332-33
(Harris).

                                                        8
     II.     SUMMARY OF THE EVIDENCE

             A. Medical Literature

        The parties submitted voluminous literature to explain what is understood about sudden
infant death syndrome (“SIDS”), the potential role of inflammatory cytokines generated by
vaccines in acting as a necessary trigger, and the epidemiology of SIDS. Both parties submitted
various studies from Hannah C. Kinney, M.D., a neuropathologist at Harvard, and others on her
team which leads the research and current understanding of SIDS. The later articles tend to build
upon and incorporate the earlier articles. Studies by other authors on SIDS and related subjects
served to supplement and generally confirm that by Kinney et al.

        A review of the literature is critical to the determination of whether petitioners have
satisfied the Althen prongs (a reliable theory of how vaccines can cause death from SIDS, that
the vaccines did in J.B.’s particular case, and that there was a medically acceptable temporal
relationship between the vaccinations and J.B.’s death). This review is also necessary to
determine whether respondent has sufficiently rebutted petitioners’ theory by demonstrating that
J.B.’s death was caused by factors unrelated to the vaccine.

       SIDS is defined as “the sudden death of an infant under one year of age which remains
unexplained after a thorough case investigation, including performance of a complete autopsy,
death scene investigation, and review of the clinical history.”14 “Epidemiological studies link
SIDS with sleep periods, leading to the premise that SIDS occurs during sleep or transitions
between sleep and waking.” Id.

         SIDS is the leading cause of infant mortality in the United States, with an incidence of
0.53 per 1,000 infants.15 Research has revealed that infants put to sleep in the prone position,
i.e., with their heads facing downward, are twice as likely to experience SIDS. Id. Other risk
factors for SIDS related to the “sleeping environment” have been recognized, including “[being]
found face-down, head covered, sleeping on an adult mattress, couch or playpen, soft bedding,
[and] bed-sharing.” Id.

        In 1994, Dr. Hannah C. Kinney, Dr. James Filiano, and their colleagues synthesized
many neuropathological studies into their proposed Triple Risk Model.16 This model posits that
SIDS occurs when: (1) an infant in a critical development period; (2) possessing an underlying
vulnerability; (3) encounters an exogenous stressor. Id. The following Venn diagram has been
used to illustrate the Triple Risk Model:



14
 Filiano, J.J. & H.C. Kinney, Arcuate Nucleus Hypoplasia in the Sudden Infant Death Syndrome, 51 J.
Neuropathol. Exp. Neurol. 394 (1992), Exhibit 13-A at 394.
15
 Trachtenberg F.L., E.A. Haas, H.C. Kinney, C. Stanley & H.F. Krous, Risk Factor Changes for Sudden Infant
Death Syndrome After Initiation of Back-to-Sleep Campaign, 129 Pediatrics 630 (2012), Exhibit C-11 at 631.
16
  Filiano, J.J. & H.C. Kinney, A Perspective on Neuropathologic Findings in Victims of the Sudden Infant Death
Syndrome, 65 Biol. Neonate 194 (1994), Exhibit 13-B at 195 [also filed as Exhibit A-2].

                                                        9
Id. at 3, Figure 1. This model emphasizes the intersection of multiple factors in the pathogenesis
of SIDS. According to this model, SIDS occurs only when components of all three factors are
present simultaneously, which explains why all infants who are placed prone to sleep or who bed
share do not die of SIDS.17

                     1. First Risk Factor: Critical Development Period

         The first factor in the Triple Risk Model of SIDS is the critical development period,
which Kinney et al. initially defined as the first year of life.18 However, their more recent
literature tends to define it as the first six months of life.19 The peak incidence of SIDS deaths
has historically occurred between two and four months of age. A study by Trachtenberg,
Kinney, and others published in 2012 found slightly more younger and older infants succumbing
to SIDS than had been seen in earlier studies. In the groups studied, the percentage of SIDS
babies who were five months or more rose from 11.8% in the pre-Back-to-Sleep20 era, to 17.6%
in the 1996-2008 post-Back-to-Sleep era.21 Kinney and Thach wrote, “Given the wide array of
homeostatic functions modulated by the medullary 5-hydroxytrptamine system, sudden death
may result from a convergence of defects in protective response to homeostatic stressors during
sleep that are modulated by 5-hydroxytrptamine, probably in conjunction with related
neurotransmitters.”22


17
 Kinney, H.C. et al., The Brainstem and Serotonin in the Sudden Infant Death Syndrome, 4 Annu. Rev. Pathol.
Mech. Dis. 517 (2009), Exhibit 13-H at 521.
18
     Filiano & Kinney (1992), Exhibit 13-A at 394.
19
     See, e.g., Kinney et al. (2009), Exhibit 13-H at 521.
20
  The “Back to Sleep” campaign refers to a major public health effort to encourage parents to place their infants on
their backs to sleep, particularly during the first year of life as a means of reducing the incidence of SIDS.
21
     Trachtenberg, Kinney, et al. (2012), Exhibit C-11 at 634.
22
  Kinney, H.C. & B. Thach, The Sudden Infant Death Syndrome, 361 New England J. of Med. 795 (2009), Exhibit
A-4 at 6.


                                                             10
                    2. Second Risk Factor: Vulnerable Infant

        After Kinney et al. formulated the Triple Risk Model, the initial research was focused on
determining why particular infants were “vulnerable”, possibly because of environmental or
genetic factors. Exhibit 13-H at 5. Intrinsic risk factors include “male gender, African-
American race, poverty, adverse prenatal factors such as maternal smoking or alcohol use during
pregnancy, and genetic polymorphisms.” Id. It was also hypothesized as early as 1987 that most
likely SIDS was related to a brainstem abnormality in the neuroregulation of cardiorespiratory
control.23 These intrinsic factors when combined with the vulnerable developmental period of
the infant and a critical exogenous factor resulted in sudden infant death. As research
progressed over the following decades, the above intrinsic risk factors remained but a significant
emphasis was placed on the brainstem hypothesis, based upon the research of Dr. Kinney and
others. In 2009, Dr. Kinney explained: “To date the most robust evidence for a neurochemical
abnormality comes from research on the medullary 5-HT system,24 in that approximately 50-
70% of infants with SIDS appear to have abnormalities in this system. The medullary 5-HT
system, which is considered critical for the modulation and integration of diverse homeostatic
functions, is involved in ventilation and gasping, thermoregulation, autonomic control, response
to carbon dioxide and oxygen, arousal from sleep, and hypoxia-induced plasticity.25

         The 5-HT system refers to the serotonin system. “The caudal serotonergic (5-HT) system
is a critical component of a medullary “homeostatic network” that regulates protective response
to metabolic stressors such as hypoxia, hypercapnia and hyperthermia.”26 “Homeostasis refers to
the ability of an organism to maintain a constant internal environment, thereby allowing survival
over a wide range of external environmental conditions. It becomes self-sufficient at the
moment of birth as the fetus takes the first breath in the extra-uterine world and begins to adjust
instantaneously and independently to the myriad of changing metabolic demands. ... Receptor
systems that sense deviations in any internal milieu (e.g., oxygen and carbon dioxide, glucose,
and temperature levels) have been defined as well as the effector systems that are the final
common pathway in mediating adjustments. Major focus has been placed upon the brain as the
‘control center’ which sets the range at which a particular parameter namely CO2 is maintained,
and determines the protective response to deviations from this range namely hypercarbia.”27,28



23
     Kinney et al. (2009), Exhibit 13-H at 519.
24
   5-HT (5-hydroxytryptamine), also called serotonin, is defined as “a monoamine vasoconstrictor, synthesized in
the intestinal chromaffin cells or in central or peripheral neurons and found in high concentrations in many body
tissues, including the intestinal mucosa, pineal body, and central nervous system.” Dorland’s at 1699.
25
     Kinney & Thach (2009), Exhibit A-4 at 6.
26
  Kinney, H.C. et al., The Serotonergic Anatomy of the Developing Human Medulla Oblongata: Implications for
Pediatric Disorders of Homeostasis, 41 J. Chem. Neuroanat. 12 (2011), Exhibit 13-F at 182.
27
     Hypercarbia, also called hypercapnia, is defined as “excess of carbon dioxide in the blood.” Dorland’s at 887.
28
     Kinney et al. (2009), Exhibit 13-F at 183.


                                                           11
         The serotonergic system, primarily concentrated in the medulla oblongata, which is
called the caudal 5-HT system or the medullary 5-HT system, is now recognized as a key
component of the brain’s control system of homeostasis. Id. Dr. Kinney proposed that deficits
in the caudal 5-HT system will lead to imbalances in respiratory, cardiovascular, and/or
metabolic regulation – including in response to stress – in the pediatric age range, particularly in
the first days and months following birth. Id. As noted by the Kinney group in a 2011 article on
the serotonergic anatomy, “extensive experimental data implicate the caudal 5-HT system in
homeostasis and respiratory and autonomic regulation, including upper airway control,
respiration (including via modulation of the pre-Botzinger complex, the putative central rhythm
generator of respiration), autoresuscitation, central chemoreceptor responses to hypercapnia and
hypoxia, cardiovascular control, pain, motor function, and thermoregulation.” Id. The article
also notes that the medullary 5-HT system “interfaces with the cytokine system which is critical
to homeostasis in its mediation of ‘protective sickness’ behaviors and cellular defenses against
tissue damage.” Id.

        Dr. Kinney’s team’s research on the brainstem focused on a collection of neurons in the
ventral medullary surface known as the arcuate nucleus “based upon cytological and positional
homologies between the respiratory chemosensitive fields on the ventral medullary surface in
cats. Structural underdevelopment of the arcuate nucleus was subsequently observed in SIDS
cases.”29 As the research advanced, it was recognized that the “arcuate anomaly was similar to
that reported in infants with clinical insensitivity to CO2 and sleep related sudden death.” Id.
By 2009, Dr. Kinney reported, “Serotonergic neurons at the medullary ventral surface and in the
midline (raphe) are now known to be preferentially chemosensitive to CO2 and although they are
not the only central chemosensitive neurons they appear to play a critical potentially modulatory
role…A small but important population of 5-HT neurons is embedded within the human arcuate
nucleus suggesting that the putative dysfunction in chemosensitivity related to the arcuate
anomaly specifically involved these embedded 5-HT neurons.” Id. (emphasis added).

         “Serotonergic neurons are well-suited to a role as central respiratory chemo-receptors, as
they are closely associated with the basilar artery and its largest branches near the ventral surface
of the medulla namely they are in a position to directly monitor arterial PCO2.... 5-HT neurons
respond intrinsically to increased PCO230 with large increases in firing rate; this response is due
to a decrease in intracellular pH induced by hypercapnia. On average these neurons increase
their firing rate threefold in response to a decrease in pH of 7.4 to 7.2. Chemosensitivity
increases during postnatal development, with a blunted response to pH before postnatal date 12
in rats. Physiological delay in chemosensitivity is potentially relevant to SIDS because it
indicates that 5-HT neurons may be immature during the critical developmental period,
throughout which all infants are susceptible to hypercapnia.”31 Harper and Kinney state the data
now suggest that SIDS is associated with a brainstem (medullary) 5-HT deficiency rather than 5-

29
  Kinney et al. (2009), Exhibit 13-H at 522. Kinney defines chemosensitivity as “the ventilator response to a
change in carbon dioxide/pH as sensed by tissue chemoreceptors, which are composed of neurons and/or
astrocytes.” Id.
30
     PCO2 is defined as “the partial pressure of carbon dioxide.” Dorland’s at 2120.
31
     Kinney et al. (2009), Exhibit 13-H at 530.


                                                           12
HT overproduction.32 Of note, the medullary 5-HT profile differed between infants dying of
SIDS and those dying with known chronic oxygenation disorders, suggesting that chronic
hypoxia does not necessarily play a major role in the pathogenesis of the impairments in the 5-
HT tissue markers. Id.

         Harper & Kinney explained that the insufficient function of the 5-HT system, which is
necessary for breathing, leaves an infant vulnerable to a variety of crisis situations. These
include external airway obstruction, upper airway obstruction resulting from loss of tone in the
upper airway musculature in association with diaphragmatic movements, or importantly of
central apnea, which has occupied a central focus of attention. These are also proposed
mechanisms underlying the fatal event in SIDS. This failure can result from several components
of the breathing process, including impaired sensory transduction or integration of either carbon
dioxide or oxygen, or non-recruitment of gasping mechanisms, the final restorative mechanism
to low oxygen. In SIDS, a principal concern is the “loss of the wakefulness drive to breathe.”
Id. at 5. The waking state activates processes which maintain breathing, while during sleep those
influences are suppressed or not recruited. Thus, impaired central chemosensitivity to excess
carbon dioxide or inadequate oxygen contributed to by defects in the medullary serotonin
system, in addition to the normal reduction of the function of the 5-HT system during sleep, may
play a central role in SIDS, which occurs primarily during sleep. Id. at 4-5.

        Despite the emphasis on brainstem abnormality or underdevelopment, the other intrinsic
risk factors are thought to continue to play an important role in the multi-factorial analysis of
SIDS causation. Some of these factors may be related to the medullary 5-HT deficits described
above. Several intrinsic risk factors are apparent in J.B.’s case. First, prematurity is defined as
less than 37 weeks at birth33 and J.B. was born at 36 weeks. Male gender, as boys exceed girls in
SIDS deaths by a two-to-one ratio, and African-American race have also been called intrinsic
risk factors because they are over-represented among SIDS victims.34 Importantly, maternal
smoking and alcohol consumption during pregnancy are considered important risk factors but are
not relevant in this case, as J.B.’s mother did not smoke or drink during or after her pregnancy.

        Dr. Kinney has hypothesized that males may predominate among SIDS deaths because
males tend to be less responsive to the accumulation of carbon dioxide, and in the situation with
a defective medullary 5-HT system may be particularly impaired from responding to excess
carbon dioxide during sleep. Id. The predominance of males in the occurrence of SIDS appears
to be potentially related to the reduction of 5-HT binding in the medullary raphe compared to
females dying of SIDS, as well as the report that plasma levels of testosterone, but not estradiol,
are significantly higher in both male and female SIDS infants compared to age-matched controls.
Several studies in knockout mice and piglets also “underscore gender differences in brainstem-
mediated 5-HT function, with females’ brains apparently relying less on 5-HT neurons in
chemoreception and adapting more readily to the loss of 5-HT function. Id.

32
  Harper, R.M. & H.C. Kinney, Potential Mechanisms of Failure in the Sudden Infant Death Syndrome, 6 Curr.
Pediatr. Rev. 39 (2010), Exhibit C-12 at 7.
33
     Trachtenberg, Kinney, et al. (2012), Exhibit C-11 at 631.
34
     Kinney et al. (2009), Exhibit 13-H at 532.


                                                           13
        The role of African-American race in SIDS is less defined, other than statistically. Most
authors speculate that the statistical predominance of African-American children may represent
lower socioeconomic status resulting in inadequate medical care. If that be the case however,
J.B.’s race should not be an increased risk factor as he was receiving regular medical care with
comprehensive and well-documented well baby visits occurring in July and September. His first
set of vaccinations was somewhat late, but the second dose, those received on September 2,
2011, brought him up to date. His growth and functional milestones appeared to be normal. It is
also reported that 75% of white infants are placed to sleep in the supine position, while only 53%
of black infants are, and that there is greater incidence of bed sharing among black infants than in
other groups.35 J.B. was placed on his back and was in his own crib.

                    3. Third Risk Factor: Exogenous Stressor(s)

         The third and last factor is referred to as exogenous stressor[s] present at the time of
death.36 These stressors identified in the literature include “prone sleep position, face-down
position, covered face in the supine position, soft bedding, bed sharing, over-bundling, elevated
room temperature, and minor infection at the time of death.”37 Virtually every SIDS case
includes one or more exogenous stressors, implying that they act as “triggers” for SIDS.38
Studies also show that often multiple risk factors are present in a given SIDS case. Trachtenberg
et al. found that “at least 2 extrinsic risk factors” were present in a majority of 568 cases
reviewed. Id. at 632.

        Dr. Kinney has hypothesized that exogenous stressors “lead to asphyxia, hypoxia,
hypercapnia, or thermal imbalance requiring intact brainstem defense systems to protect against
lethal consequences.”39 Non-vulnerable infants are generally able to recover from these
conditions, but vulnerable infants are less able to recover and succumb to SIDS. Id. at 521.

        As a result of their research, Dr. Kinney and her team proposed the Triple Risk Model to
explain the occurrence of SIDS. Dr. Kinney’s group then proposed the “Back to Sleep
Campaign” in the early 1990s in which they recommended that babies always be put to sleep on
their backs (supine) on a firm mattress, without pillows, blankets, toys, bumpers or other items
that could potentially obstruct breathing. The prone or face-down sleeping position was
considered to make an infant particularly vulnerable because an infant in the first six months of
life with one or more intrinsic defects may re-breathe excess carbon dioxide and lack the
corrective arousal mechanisms during sleep that would prevent a fatal outcome. Generally, the
accumulation of excess carbon dioxide in the body causes signaling to breathe, thereby exhaling

35
  Moon R.Y. et al., American Academy of Pediatrics – Task Force on Sudden Infant Death Syndrome, SIDS and
Other Sleep Related Infant Deaths: Expansion of Recommendations for a Safe Infant Sleeping Environment, 128
Pediatrics 1030 (2011), available at http://pediatrics.aappublications.org/content/128/5/1030.long.
36
     Trachtenberg, Kinney, et al. (2012), Exhibit C-11 at 631.
37
     Kinney et al. (2009), Exhibit 13-H at 521.
38
     Trachtenberg, Kinney, et al. (2012), Exhibit C-11 at 633.
39
     Kinney et al. (2009), Exhibit 13-H at 520.

                                                           14
carbon dioxide and inhaling room air containing oxygen. During sleep it is thought that excess
carbon dioxide normally causes a person to turn the head toward fresh air and become aroused
from sleep. When those mechanisms fail, the gasp reflex is triggered, which brings in oxygen
and resets the rhythm of breathing. In SIDS, the dominant theory is that all of these mechanisms
fail, leading to death.

        The Back to Sleep Campaign has succeeded remarkably in reducing the number of SIDS
deaths in the United States by approximately 50%.40 In the U.S., the rate was reduced from more
than 1 per 1,000 infants to 0.53 per 1,000, the current rate where it has plateaued. Id. However,
SIDS remains the leading cause of post neo-natal infant death in the United States, raising some
of the questions at issue in this case. Id. The emphasis has continued to be on the
cardiorespiratory failure explanation of SIDS. Research has indicated that prone sleeping
position increases the risk twofold or more. Id. They concluded that those not found prone
sleeping were subject to alternative SIDS risk factors. Id. at 635.

         The Trachtenberg article concluded that virtually all SIDS infants have at least one risk
factor, and the majority have at least one intrinsic risk factor and two extrinsic factors. Id. The
article also notes that the American Academy of Pediatrics risk reduction guidelines also include
recommendations against side-sleeping and bed-sharing, and suggest a separate but proximate
sleeping environment and pacifier use. Id. at 636. The data from the Trachtenberg study found a
decline in prone position sleeping from 84% in the pre-Back-to-Sleep era to 48.5% in the post-
era, but it also found that in the post-era 17.3% of SIDS infants were found on their sides while
22.6% were initially placed on their sides. Id. at 634, Table 2. Interestingly, 29% of the SIDS
babies in that study were found supine while 41.7% were placed on their backs, suggesting that
SIDS is not exclusively caused by prone sleeping. Id. at 632.

        The Trachtenberg and Kinney articles emphasize the belief in the medical community
that SIDS is multifactorial. As Trachtenberg noted, they were only able to evaluate which SIDS
risk factors are most common, not which factors raise the odds of SIDS most significantly. Id. at
635. The authors suggest that the number of risks is probably underestimated and that “the
majority of SIDS infants were subject to at least two extrinsic risk factors, suggesting that SIDS
occurs from the simultaneous occurrence of multiple factors, rarely just one.” Id. Additionally,
Dr. Kinney has noted that under the Triple Risk Model, only infants with an underlying
brainstem disease process die of SIDS, which explains why all infants who are placed prone to
sleep or who bed share do not die of SIDS.41 She states that SIDS essentially represents the
occurrence of “the biologic version of the perfect storm in which the chance combination of
multiple events is far more powerful than each individual event alone.” Id. at 539. She suggests
a possible scenario in which a child with the underlying brainstem deficit, during the critical
developmental period, is exposed to excess carbon dioxide while he is sleeping. This may be
based upon his sleeping position or he may have an issue with the laryngeal chemoreflex
stimulated by reflux of gastric contents or may have a mild infection with fever causing the
laryngeal chemoreflex induced apnea to be inordinately prolonged by mild hyperthermia” Id.

40
     Trachtenberg, Kinney, et al. (2012), Exhibit C-11 at 631.
41
     Kinney et al. (2009), Exhibit 13-H at 521.


                                                           15
(emphasis added). In this scenario, “if the infant’s ventilator response to the progressive
hypoxia and hypercapnia during the apnea is depressed, and if the hypoxic gasping and/or
arousal mechanism is abnormal, oxygen lack from uninterrupted apnea results. Ultimately, death
occurs within minutes to hours.” Id. (emphasis added).

        Respondent filed the article by Trachtenberg et al., which emphasized that they could
find no positive correlations between risk factors or risk clusters but it appeared that any
combination of risks together increased the odds of SIDS. The fact that most infants have at
least two extrinsic risk factors suggests that SIDS occurs as a result of the occurrence of multiple
factors and rarely just one.42 The Kashiwagi article43 filed by petitioners suggests that vaccines
provoke an inflammatory cytokine response similar to that provoked by a mild infection.
Petitioners theorize that these cytokines travel to the brainstem and further suppress the function
of the already impaired medullary 5-HT system in a subset of SIDS infants.

                         a. Cytokines, Mild Infection and Vaccines

        Relevant to this case, in a 2009 article in the New England Journal of Medicine, Kinney
and Thach stated, “A causal role for mild infection in sudden infant death is suggested by reports
that in approximately half of SIDS cases, the infants have a seemingly trivial infection around
the time of death, as well as mild tracheobronchial inflammation, altered serum immunoglobulin
or cytokine levels and the presence of microbial isolates at autopsy. In infants who die
unexpectedly of infection, the given organism may precipitate a lethal cytokine cascade or toxic
response.”44 The question arises as to whether the cytokine response stimulated by vaccination
can have the same effect as a mild or trivial infection in a baby who presumably has a defect in
the medullary 5-HT system.

        The role of cytokines stimulated by either mild infection or by vaccination is central to
petitioners’ theory in this case. Approximately 50% of SIDS babies have been found in multiple
studies to have had mild or even “trivial” infections, primarily of the upper respiratory tract at
the time of death. In this case, J.B. was documented the prior day as being healthy with patent
nares, normal turbinates, and clear chest, but during the 28 hours after the vaccine he was
reported to have a fever, which is generated by cytokine signaling. He also was distant, quiet,
and would not eat, according to his parents. The case raises the issue of whether inflammatory
cytokines stimulated by the innate response to the vaccines triggered the fever and his fussiness,
and ultimately suppressed his 5HT system sufficiently so that he could not process the carbon
dioxide in his system. The question of whether inflammatory cytokines stimulated by the innate
response to the vaccine could have been the trigger that led to his death was central to the
testimony and much of the literature submitted by the parties particularly in light of the clear
medical evaluation on the day of the vaccination and a fever within hours afterward.

42
     Trachtenberg, Kinney, et al. (2012), Exhibit C-11 at 7.
43
  Kashiwagi Y et al., Production of Inflammatory Cytokines in Response to Diphtheria-Pertussis-Tetanus (DPT),
Haemophilus Influenzae Type B (Hib) and 7-Valent Pneumococcal (PC7) Vaccines, 10 Hum. Vacc. Immunother.
677 (2014), Exhibit 17.
44
     Kinney & Thach (2009), Exhibit A-4 at 2.


                                                               16
         As Dr. Kinney and her colleagues explained in 2011: “Cytokines orchestrate immune
responses to microbial invasion and other insults and coordinate these responses with those of
other physiological systems, including the autonomic nervous system, in the protection of the
organism against tissue injury. They also mediate sickness behavior, including fever, anorexia,
excessive sleepiness, blunted arousal, deep rest respiration, and lowered heart rate, which is
thought to protect the organism during systemic illness by dampening excessive metabolic
demands and thereby speeding repair and recovery - a form of homeostasis.”45 “Cytokines
determine this sickness behavior by binding to endogenous cytokine receptors on neuronal
populations in the hypothalamus and/or brainstem that mediate respiration, autonomic function,
satiety, sleep, and arousal.” Id. at 190. The cytokines which act within the brain in response to
tissue injury are produced by astrocytes, and endothelial cells, microglia, and/or peripheral
immune cells which enter the brain in response to binaural signals of tissue damage.” Id.
(emphasis added). During infection, peripherally produced IL-6 may cross the blood brain
barrier and bind to IL-6 receptors on 5 HT neurons that mediate homeostasis in response to the
infectious stressor and potentially mediate sickness behavior. Id. at 191. The role of pro-
inflammatory cytokines in the pathology of SIDS is thought by multiple authors to be a
potentially critical factor in tipping the molecular balance in the underdeveloped brainstem
leading to death in infants in the vulnerable time period. IL-1β, IL-2, and IL-6 are pro-
inflammatory cytokines that have been studied in connection with SIDS leading to theories about
their potentially neuro-modulatory role in SIDS babies.

        Kadhim et al. described a distinct cytokine profile in a SIDS brain in a study comparing
SIDS brains with non-SIDS brains. The non-SIDS brains were from infants who died of known
causes, including AIDS, cirrhosis of the liver, mononucleosis, purulent meningitis, and
congenital heart disease with post-operative acidosis-shock. He found an over-expression of
interleukin 1β in arcuate and dorsal vagal nuclei in all SIDS victims. In arcuate nuclei, high
levels of interleukin 1β were detected in 17/17 SIDS brains vs. only 1 of 6 non-SIDS brains.46 In
dorsal vagal nuclei, interleukin 1β was also detected in high levels in 17 of 17 SIDS brains vs.
only 2 of 7 non-SIDS brains. Id. Kadhim found a “region-specific pattern of cytokine
expression in [the arcuate and dorsal vagal nuclei] of SIDS brains compared to non-SIDS
brains.” Id. at 1259. Kadhim theorized: “cytokines could exert neuromodulatory effects.
Infectious inflammatory conditions and injury to the brain could up regulate pro inflammatory
cytokines and produce functional alteration ... Cytokine/neurotransmitter interactions could
therefore modify vital CNS functions.” Id. Kadhim et al. further concluded that IL-1 causes
prolonged apnea and depresses respiration, and that the brain appears to be less effective than the
peripheral nervous system in inducing IL-1 antagonists to control IL-1 action.




45
     Kinney et al. (2011), Exhibit 13-F at 189.
46
  Kadhim, H. et al., Distinct Cytokine Profile in SIDS Brain: A Common Denominator in a Multifactorial
Syndrome?, 61 Neurol. 1256 (2003), Exhibit 13-L at 1256.


                                                      17
         In a second study from 2010, Kadhim focused on the expression of IL-2 in 28 autopsied
infants who died at less than one year of age.47 He described IL-2 as major immune-related
cytokine that was originally thought to be a T-lymphocyte growth factor but is now recognized
to have a wider spectrum of functions, targets and sources. Id. The study compared 18 SIDS
brains to those of infants who died of diverse severe pathological conditions including infectious,
hemodynamic, metabolic or other serious genetic conditions. In the severely ill children (non-
SIDS), they found that IL-2 was preferentially expressed in specific neuronal centers within the
brainstem (SNT-solitary nucleus tractus and TSNT-spinal trigeminal nucleus/tractus) in 10 of 10
cases of the fatally sick (non-SIDS) children and in the arcuate and dorsal vagal nuclei in 8 of 10.
“Examination of the brainstem in the SIDS group showed a topographically similar profile with
an equally intense immune reactivity within the very same neuronal circuits; precisely the
strongly expressed cytokine labeling of IL-2 in SNTT and/or TSNT was observed in 17 out of 18
cases that constituted the 2nd study group (SIDS). IL-2 was also notable in the arcuate nucleus
and dorsal vagus nucleus in 17 cases. These brainstem neuronal centers are known to be
intricately implicated in autonomic control of vital homeostatic functions namely
cardiorespiratory control mechanisms.”48 The authors concluded that it was not surprising to see
the intense IL-2 expression in the infants who were severely ill before they died, but the SIDS
victims are generally free from apparent potentially fatal conditions. “The SIDS victims often
have preceding mild infectious/inflammatory conditions (like coryza49/mild upper respiratory
infections, soft stools mild gastroenteritis, postvaccinal fever, etc.). Such trivial infections were
found to induce a hypertuned immune/inflammatory response including high levels of immune
inflammatory cytokines.” Id. at 122. (emphasis added). Kadhim reviewed the Triple Risk
Model, placing his study findings with regard to inflammatory cytokines in that framework;
“Such mild infectious inflammatory conditions (extrinsic environmental stressors), if contracted
in a vulnerable infant (intrinsic factors including prematurity and gene polymorphisms) during a
critical developmental period whereby brainstem command centers undergo rapid maturation
could provoke exaggerated immune responses with over expression of cytokines. We believe
that this hypertuned immune response is behind the high IL-2 immune-reactivity we detected in
situ in the brainstem of these victims.” Id. at 125. Kadhim also noted that while pro-
inflammatory cytokines have immune function, it is noteworthy here that cytokines have neuro-
modulatory effects whereby they can modify neurotransmission. Id.

        The role of mild infection was further discussed in an article by Rognum et al.50 The
Rognum group compared three groups of deceased infants. The group of 25 SIDS cases was
selected from those subjects in whom no explanation for death was found. A second group died
from known infectious causes and the third control group died primarily from violent causes

47
  Kadhim, H. et al., Interleukin-2 as a Neuromodulator Possibly Implicated in the Physiopathology of Sudden
Infant Death Syndrome, 480 Neurosci. Lett. 122 (2010), Exhibit 13-O at 123.
48
     Kadhim et al. (2010), Exhibit 13-O at 124.

 Coryza, also known as acute rhinitis, is defined as an “inflammation of the mucous membranes of the nose.”
49

Dorland’s at 423, 1639.
50
  Rognum, I.J., R.L. Haynes, A. Vege, M. Yang, T.O. Rognum & H.C. Kinney, Interleukin-6 and the Serotonergic
System of the Medulla Oblongata in the Sudden Infant Death Syndrome, 118 Acta Neuropathol. 519 (2009), Exhibit
13-N at 519-30.

                                                       18
such as drowning, suffocation or strangulation. Id. at 522. The IL-6 levels were significantly
higher in SIDS subjects than in controls. The IL-6 levels in SIDS infants with minor infection
were comparable to those infants who succumbed to severe infection. Id. at 520.

        Rognum et al. wrote: “We previously showed that IL-6 is elevated in the cerebrospinal
fluid of SIDS infants and that this elevation may be induced by a peripheral immune reaction.
Approximately one half of the SIDS cases we have studied show signs of a mild infection, but
IL-6 levels are comparable to those of infants succumbing to severe infection, suggesting an
overreaction to the slight infection.” Id.

         According to Rognum: “In addition to its pro-inflammatory properties, IL-6 exerts
effects outside the immune system. Non-immune cells including neurons can produce and
secrete IL-6 and express its receptor. Of critical relevance to the premise that cytokines interact
with central neurons to affect their function, IL-6 is shown to be important in neuronal
development in the modulation of neuronal signaling.” Id. “A major site of 5-HT cell bodies in
the human infant brainstem is in the arcuate nucleus, the putative site for central carbon dioxide
(CO2) sensitivity in humans and animal models. In this regard the synergistic effect of prone
sleeping and infection on SIDS risks may be a set up for CO2 accumulation, as both rebreathing
in the face down prone position and increased metabolism due to infection may increase CO2
levels. Death may be triggered if CO2 sensing regions in the brainstem, such as the arcuate
nucleus, are compromised and cannot mount an arousal response to protect the infant from the
dangerous situation. The arcuate nucleus is of particular interest in the study due to the previous
finding by others of high neuronal IL-1β immunoreactivity at this site in SIDS cases compared to
controls.” Id.

         Rognum et al. did identify one particular confounder to this theory in that they found that
the mean IL-6R (receptor) intensity grade in the arcuate nucleus was significantly higher in the
SIDS group than in the control group but the gp130 transducer was significantly higher in the
infection group but less so in SIDS relative to the controls. While Rognum et al. acknowledged
difficulty in grading the immunosensitivity of IL-6R and gp130 in this study due to its small size
as a major limitation in the study, the result led the authors to hypothesize that the increased
expression of IL-6R in the arcuate nucleus may be a compensatory mechanism as defective
arcuate neurons may require excessive IL-6 stimulation in order to respond to altered carbon
dioxide levels and there may be an inability in the SIDS babies to upregulate gp130 to mount an
effective response.51 Id. at 528. Nevertheless, the study concluded that abnormal IL-6R
expression was found in the arcuate nucleus of SIDS babies 44% of whom had mild infections
prior to death and thereby “provides evidence for aberrant interactions in SIDS infants between
Il-6 and the arcuate nucleus, a key medullary 5-HT related region involved in protective
responses to hypercapnia, potentially induced by the combined effect of prone position and mild
infection.” Id. at 529.


51
  Dr. Miller explained that gp130 is a second messenger in the cell that takes the message that the receptor has
bound something and does something with it to take (tell) the cell to do something else. This is a very common
mechanism in membrane signaling, that there’s a second messenger system that then tells the cell to do something.
Tr. p 32.


                                                        19
        Rognum et al. concluded: “The key finding in this study is abnormal IL-6R expression in
the arcuate nucleus in the SIDS cases, 44% of whom had signs of mild infection immediately
prior to death. Id. at 528. Rognum further noted that the arcuate nucleus contains 5-HT and
glutamatergic neurons that have been shown in animals to be critical to chemosensitivity. It is
also the site for several neurotransmitter abnormalities in SIDS, including in 5-HT, muscarinic
and kainite receptor binding. It is well documented that CO2 levels are elevated during severe
neonatal infection and, interestingly, even mild upper respiratory infection may increase CO2
levels in infants over 3 months of age. Animal studies indicate that the CO2 elevation can be
attributed to a hyper metabolic state induced by proinflammatory cytokines.” Id. at 527-28
(emphasis added).

        Kashiwagi studied the production of cytokines after vaccination in 61 vaccine recipients
with fever and 18 without fever within 24 hours of vaccination. Blood samples were taken
within 48 hours of vaccination in both groups. He reviewed the role of the innate immune
system in responding to vaccination noting that the activation of the innate immune system
including the enhanced production of inflammatory cytokines is indispensable for
immunogenicity and these cytokines may be related to the occurrence of adverse events.52 This
group found that cytokine production began about 6 hours after the stimulation by a single or
combination of vaccines and increased for 24 hours, showing the same level afterward. Id. at
679. They found that higher levels of IL-1β, IL-6, G-CSF53 and TNF-α were produced with the
concurrent stimulation by multiple vaccines than with the single vaccine in PBMC cultures
(peripheral blood mononuclear cells - obtained from young infants in this study). Id. at 679.
Higher levels of IL-6, IL-10, IL 12, G-CSF, IFNγ and TNFα in both the febrile and non-febrile
groups were found after vaccination and G-CSF was significantly higher in the febrile group. Id.
at 680. He noted that innate immune systems are not fully functional at the time of birth.
Kashiwagi’s group found that TLR (Toll-Like Receptors) stimulated the production of pro-
inflammatory cytokines (specifically IL-β, IL-6, and IL-8) which was markedly higher in
neonates than in adults. He also found that higher levels of IL-1β were produced in PBMC
cultures stimulated with PCV7 than with DPT or Hib. Hib induced higher levels of IL-6 and
TNF-α. IL-1β increased in PBMCs stimulated concurrently with Hib/PCV7 and DPT/Hib/PCV7
with similar patterns of TNF-α and G-CSF. However, when blood was drawn 48 hours post-
vaccination, IL-1β was not found. Id. Dr. Miller theorized that IL-1β rises rapidly and then
disappears by 48 hours whereas the other inflammatory cytokines have a longer half-life. Tr. 47

       Kashiwagi noted: “All effective vaccines induce the production of cytokines or
chemokines, which modulate immunogenicity and are also involved in inducing adverse events,
such as systemic febrile illness and immunotoxicity. In this standpoint, IL-6, IL-10, IL-12, G-
CSF, IFN-γ, and TNF-α were detected in both febrile and non-febrile groups after vaccination in
comparison with those in normal subjects.” Id. at 683. Inflammatory cytokine profiles after
vaccination were similar to the outpatient group infected with the influenza virus. Id.



52
     Kashiwagi, et al. (2014), Exhibit 17 at 678.
53
     G-CSF is granulocyte colony stimulating factor Dorlands at 767- It is now classified as another cytokine. Tr. 47.


                                                           20
       Vege and Rognum reviewed the literature and their own work and noted that “in 1995
they found that half of the SIDS victims had elevated levels of interleukin-6 (IL-6) in their
cerebrospinal fluid (csf). The concentrations of IL-6 in SIDS infants were comparable to those
we found in infants dying from infectious diseases like meningitis and septicaemia.” They
concluded that there were two groups of SIDS infants—one with IL-6 levels similar to infants
dying of severe infections and another having low levels similar to those dying violent deaths.
They hypothesized that one group of SIDS deaths may be attributable to sleep position and
another to an uncontrolled inflammatory response to infection, predominantly occurring at night
when cortisol levels, another mechanism for controlling inflammatory responses, are low.54

        Others have studied cytokine expression in animals. Brambilla demonstrated in animal
studies that Interleukin 1 (IL-1) inhibited firing of excitatory or wakefulness producing neurons
in the dorsal raphe nucleus and enhanced activity of GABAergic or inhibitory neurons and, as
such, induces enhancement of NREM sleep.55

        Respondent submitted an article by Siljehav, Hofstetter et al. which sheds additional light
on the possible mechanism involved with apnea in infants occurring in response to infection.
These authors wrote: “Our data suggest that PGE256 induced by IL-1β as well as hypoxia
selectively modulates respiration-related neurons in the rostral ventrolateral medulla, including
the preBotzinger Complex via EP3R. Other neuromodulators, including PGE1, have been
shown to inhibit preBotC neurons and slow respiration-related rhythm and preBotC lesions may
disrupt anoxic gasping and evoke central apneas and ataxic breathing. Moreover, these
respiration-related neurons were recently shown to be critical for adequate response to hypoxia,
maintaining brainstem homeostasis with gasping and autoresuscitation and thus restoring oxygen
levels. PGE2-induced depression of this vital brainstem neuronal network, e.g., during an
infectious response, could result in gasping and autoresuscitation failure and ultimately death.”57
The model of the IL-1β induced respiratory depression and autoresuscitation failure via a PGE2
–mediated pathway was described. "During a systemic immune response, the proinflammatory
cytokine IL-1ß is released into the peripheral blood stream. It binds to its receptor (IL-1R)
located on endothelial cells of the blood brain barrier. Activation of IL-1R induces the synthesis
of PGH2 from arachidonic acid via COX-2 and the synthesis of PGE2 from PGH2 via the rate
limiting enzyme mPGES-1. PGE2 is released into the brain parenchyma and binds to the EP3R
located in respiratory control regions of the brainstem, e.g., nucleus tractus solitarius and rostral
ventrolateral medulla. This results in depression of central respiration-related neurons and


54
  Vege, A & T. Rognum, Sudden Infant Death Syndrome, Infection, and Inflammatory Responses, 42 FEMS
Immunol. Med. Microbiol. 3 (2004), Exhibit 13-Q at 5 and 8.
55
  Brambilla, D. et al., Interleukin-1 Inhibits Firing of Serotonergic Neurons in the Dorsal Raphe Nucleus and
Enhances GABAergic Inhibitory Post-Synaptic Potentials, 26 Eur. J. Neurosci. 1862 (2007), Exhibit 13-M at 1862.
56
  PGE2 is a symbol for a prostaglandin. Dorland’s at 1529. Prostaglandins are “any of a group of components
derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway; they
are potent mediators of numerous different physiologic processes.” Dorland’s at 1528.
57
  Siljehav, V. et al., mPGES-1 and Prostaglandin E2: Vital Role in Inflammation, Hypoxic Response, and Survival,
72 Pediat. Res. 460 (2012), Exhibit C-9 at 9897.


                                                        21
breathing, which may fatally decrease the ability to gasp and autoresuscitation during hypoxic
events." Id. at 9898.

         Stoltenberg58 experimented on piglets and concluded IL-1 stimulates the release of beta
endorphin and indicated that his group had shown that the level of beta-endorphin in cerebral
spinal fluid correlates strongly with the duration of apnea. Furthermore IL-1β stimulates GABA
transmission and hence increases the inhibitory postsynaptic function by opening of chloride
delective channels, and this will reduce the activity in the central respiratory neurons and may
produce hypoxia. He concluded that intravenous and intrathecal injections of interleukin 1β in
piglets' prolonged apnea and modified autoresuscitation. Such a mechanism may play a role in
depressing respiration in some infants dying of sudden infant death syndrome. Id. at 427.

        In a study looking at the role of vaccination in producing apnea, bradycardia and oxygen
desaturations in pre-term infants who received first DPT (whether whole cell or acellular
pertussis, inactivated polio and Haemophilus influenza B), Lee found elevations in apnea,
bradycardia and desaturations defined as cessation of respiration for 20 seconds, with a heart rate
less than 100 and oxygen saturation less than 85%. Almost half had adverse cardiorespiratory
events in the 72 hours post-vaccination which was statistically significantly higher than the
control group which did not receive a vaccination in the prior 72 hours.59

        Schulzke also studied apnea and bradycardia in pre-term infants, not on oxygen or
respiratory support but in the NICU when they received pentavalent or hexavalent vaccines.
Rate of increased apnea and bradycardia (defined the same as by Lee) was 13% in otherwise
stable infants. Infants received ventilatory support and recovered. Events occurred between 8
and 24 hours after vaccination with onset of fever between 6 and 24 hours post immunization. 60

        B. SIDS Epidemiology

       Although epidemiology is not required to demonstrate entitlement to compensation in the
Vaccine Program, the parties submitted multiple articles, primarily from European studies, which
looked at the question of the possible relationship between vaccination and the incidence of
SIDS, as well as several articles that reported on cases. Articles by Venneman61, Jonville Bera,
Traversa, VonKries, Goldman, and Kuhnert studied the question of vaccine causation in SIDS by
various methodologies all of which described their own limitations. Others by Ottaviani and

58
  Stoltenberg, L. et al., Changes in Apnea and Autoresuscitation in Piglets After Intravenous and Intrathecal
Interleukin-1β Injection, 22 J. Perinat. Med. 421 (1994), Exhibit 13-J.
59
  Lee et al., Frequency of apnea, bradycardia, and desaturations following first diphtheria-pertussis invactivated
polio-Haemophilus influenzae type B immunization in hospitalized preterm infants, BMC Pediatrics (2006), Exhibit
20 at 3-4.
60
  Schulzke, Apnea and bradycardia in preterm infants following immunization with pentavalent or hexavalent
vaccines, European Journal of Pediatrics (2005), Exhibit 21 at 432-35.
61
  Vennemann M.M. et al., Sudden Infant Death Syndrome: No Increased Risk After Immunization, 25 Vaccine 336
(2007), Exhibit C-17.


                                                        22
Zinka discussed individual cases of unexplained deaths occurring in close temporal proximity to
receipt of vaccinations.

        Goldman looked at VAERS data from 1990 to 2010 for hospitalizations and deaths after
vaccinations and found a statistically significant positive correlation between mortality and
receipt of five to eight vaccines compared to one to four.62 (J.B. received 7 counting DTaP as
three as the study did). Traversa conducted a large study using data from the Italian health
system where vaccines are offered for free and the belief is that 95% of children are vaccinated.
The study found a statistically significant relative risk for death in the first seven days after
vaccination for the first hexavalent vaccine (six vaccines) but not after subsequent doses.63

        Kuhnert did a review of studies from Germany, England, and New Zealand and critiqued
the case control methodology through the use of the self-controlled case series method (SCCS).
It concluded that the re-analysis using the latter method showed that the risk of SIDS was neither
increased or decreased in SIDS cases or controls during the early post-vaccination periods but
did “provide more detailed insights into the methodological pitfalls of such analyses using
conventional case control methods.”64 Dr. McCusker testified that the Kuhnert study looked at
three different studies and applied 39 statistical tests to them. She read the study as concluding
that despite the application of multiple statistical post hoc tests, they still did not see anything.
Tr. 236.

        Other papers submitted in evidence included Zinka65 reporting on six deaths in Germany
within 48 hours of receipt of hexavalent vaccines. Kries66 reported on a slight elevation in day
one in the first year of life after one particular hexavalent vaccine but a significant increase in
deaths in the second year of life after receipt of that vaccine. Ottaviani67 did a detailed case
study of one young child who died three hours after receipt of a hexavalent vaccine at 3 months
of age. He did a detailed autopsy identifying bilateral hypoplasia of the arcuate nucleus. He
concluded that this death could be consistent with the Triple Risk Model or be one of the SIDS


62
  Goldman, G.S. and N.Z. Miller, Relative Trends in Hospitalizations and Mortality Among Infants by the Number
of Vaccine Doses and Age, based on the Vaccine Adverse Event Reporting System (VAERS): 1990-2010, 31 Hum.
Exp. Toxicol. 1012 (2012), Exhibit 19 at 1016, Table 4.
63
 Traversa, G. et al., Sudden Unexpected Deaths and Vaccinations During the First Two Years of Life in Italy: A
Case Study, 6 PLoS One 1 (2011), Exhibit 13-U at 4.
64
  Kuhnert R. et al., Reanalyses of Case Control Studies Examining the Temporal Association Between Sudden
Infant Death and Vaccination, 30 Vaccine 2349 (2012), Exhibit C-20 at 2355.
65
 Zinka, B. et al., Unexplained Cases of Sudden Infant Death Syndrome Shortly After Hexavalent Vaccination, 24
Vaccines 5779 (2006), Exhibit 13-S.
66
  Kries, R. et al., Sudden and Unexpected Deaths After the Administration of Hexavalent Vaccines (Diphtheria,
Tetanus, Pertussis, Poliomyelitis, Hepatitis B, Haemophilus Influenza Type B): Is There a Signal?, 164 Eur. J.
Pediatr. 61 (2005), Exhibit 13-R.
67
  Ottoviani, G. et al., Sudden Infant Death Syndrome (SIDS) Shortly After Hexavalent Vaccination: Another
Pathology in Suspected SIDS?, 448 Virchows Arch. 100 (2006), Exhibit 13-T at 4.


                                                        23
“grey zone” cases in which it is difficult to establish if the pathological findings were sufficient
to cause death.

         Each of the studies contained considerable acknowledgment of its own methodological
deficiencies that may have affected the results. In different papers, these included inclusion
without autopsies, small samples, comparing SIDS victims to living children rather than
vaccinated SIDS to unvaccinated SIDS, as well as having no control group or having potential
underreporting as in VAERS. The Kuhnert paper which analyzed three other case control
studies including Venneman, said, “The small number of cases is a problem with the three case
control studies, particularly in view of the short time periods under investigation. This problem
is illustrated by the very broad confidence intervals of estimates that are only related to the
events of the first few days.”68

        Dr. Miller criticized several of the studies for failing to use cases that were verified by
autopsy, that the Vennemann study compared a new hexavalent vaccine to older vaccines rather
than asking the question as to whether vaccines regardless of new or old could be associated with
SIDS, and used data based on the number of vaccines sold rather than administered. Tr. 70-74.
He noted that the IOM concluded that the evidence that it reviewed was insufficient to accept or
reject causation. Tr. 387. In his report, Dr. Miller explained why it is difficult to do reliable
epidemiological studies of SIDS. He said, “[I]f the risk for SIDS is present only in those infants
who are already vulnerable because of a pre-existing brainstem abnormality, then no
retrospective (or prospective) epidemiological study not grounded in a thorough
neuropathological examination of all of the supposed SIDS cases would be likely to identify that
putative causal relationship.” Exhibit 13 at 5. He observed that J.B. would be one of those not
counted as he did not have a complete neuropathological autopsy. Id. at 6.

        Dr. McCusker criticized some studies as case reports or having no control group. She
looked to Kuhnert which incorporated Vennemann to argue that there was no significant finding
that SIDS occurred more often than chance. Tr. 228.

        The Vaccine Program does not require epidemiological evidence and the studies
presented contained multiple methodological flaws, and did not tend to shed much light on the
question at issue, that is, whether the death of the child in this case was caused or triggered by
the vaccinations received the day before. Thus the studies were read and considered and credited
to show that vaccines are generally safe, but were specifically unpersuasive as to whether they
are on rare occasions the exogenous factor resulting in the perfect storm in a child with a
defective arcuate nucleus or other 5HT structure during the vulnerable period of life. They were
also unpersuasive to reject causation as they frequently showed some temporal correlation to the
receipt of vaccines even if those correlations were not found to be statistically significant.




68
     Kuhnert et al. (2012), Exhibit C-20 at 2355.


                                                    24
        C. Expert Opinions

            1. Petitioners’ Expert Douglas C. Miller

        Dr. Douglas C. Miller earned his bachelor’s degree from Williams College and his
medical degree from the University of Miami School of Medicine in 1978.69 He received a
Ph.D. in Physiology and Biophysics from the University of Miami in 1980. Id. Dr. Miller was a
resident at Massachusetts General Hospital from 1980-1984, focusing in the areas of anatomic
pathology and neuropathology. Id. He currently serves as a clinical professor of pathology and
anatomical sciences, as well as the program director of pathology residency, at the University of
Missouri School of Medicine. Id. at 3. He also serves as an associate medical examiner for
Boone, Callaway, and Greene Counties in Missouri. Id.; Tr. 10. Dr. Miller has been a full-time
faculty member at the medical schools at Robert Wood Johnson in New Jersey, New York
University, and the University of Missouri. He has published over 150 articles in medical
journals and is the author of a textbook on neuropathology.

                          i. Althen Prong One: Medical Theory

        Dr. Miller, consistent with the dominant literature in the field, proposed the Triple Risk
Model of SIDS as the framework for his theory of causation.70 Tr. 19. As explained above, this
model first provides that SIDS can occur only when an infant is in a critical developmental
period (the first year of life). Tr. 20. Second, SIDS can occur only to an infant who is inherently
vulnerable in some way. Id. Third, the infant must encounter an exogenous stressor. Id.

        Dr. Miller explained the normal physiological process for handling carbon dioxide and
stimulating breathing. He said if the carbon dioxide levels rise above a normal threshold to an
abnormal threshold, a normal brainstem’s response – in this age group – is mediated by the
arcuate nuclei alone. The excess carbon dioxide stimulates other neuronal systems to alert the
cervical spinal cord motor neurons to tell the diaphragm and other muscles of respiration to
contract, at the same time signaling up through other mechanisms in the basal forebrain,
underneath the lower part of the frontal lobes, to wake up. In general, there is arousal and there
is deeper breathing to blow off the carbon dioxide, and if it is position-related, the infant would
also move so that homeostasis is restored. Tr. 29. He explained that this process is dependent on
serotonin, an excitatory neurotransmitter, which stimulates the cells to which it signals to fire
more rapidly to increase breathing or arousal. Tr. 28. That is in contrast to GABA, which is
inhibitory and balances the excitatory effect of serotonin. Id.

        Dr. Miller explained that the majority opinion in the medical community is based
principally but not exclusively on work done by Dr. Hannah C. Kinney, in a series of papers that
stretch back more than 25 or 30 years and has been verified by other people. She has shown that
“the medulla, the lowest part of the brainstem, in infants who have died of SIDS and have been
autopsied and have had the appropriate examinations is defective. In particular, it has a defect in

69
  Curriculum Vitae of Dr. Douglas C. Miller, Exhibit 14 at 1.
70
  Kinney, H.C. et al., Medullary Serotonergic Network Deficiency in the Sudden Infant Death Syndrome: Review of
a 15-Year Study of a Single Dataset, 60 J. Neuropathol. Exp. Neurol. 228 (2001), Exhibit 13-C.


                                                      25
a set of nuclei [or] groups of neurons, which use, as a neuro-transmitter a molecule called
serotonin … which is also known as 5-hydroxytryptophan and which is abbreviated as 5-HT.”
Tr. 19. He further explained that Dr. Kinney and others have shown various deficits in infants,
but the ones who die of SIDS have in common deficits in either the number of 5-HT neurons or
in receptors for serotonin on those neurons or various other associated abnormalities. All of
these suggest that the infants who die of SIDS usually die in their sleep and usually after an
episode of apnea – that is, the cessation of breathing with elevated carbon dioxide in the blood to
which they fail to respond normally. They fail to respond because the 5-HT system is the system
which, in that age group, allows for arousal and increased breathing to respond to that kind of a
danger. Since they fail to respond, they do not wake up, they do not breathe, and they die. Tr.
20.

        Dr. Miller theorized, consistently with the research of Dr. Kinney and others, that many
SIDS infants have “abnormalities of the medullary serotonergic synaptic systems governing
respiration and arousal from apnea.” Id. at 6. He said that “we have data that at least 70 percent
of infants who ultimately die of SIDS have a defective 5-HT system which is way over half and
thus statistically likely that [J.B.] was one of those.” Tr. 62. Dr. Miller said, “It’s really a
neurochemical question. These molecules (cytokines) are provoked by an immune response, an
innate immune response, originally in the periphery, but their effect in terms of SIDS is a
neurochemical effect, affecting synaptic transmission and neuronal activity of the 5-HT system
and maybe the GABA system in the medulla, and that’s a neurochemical synaptic effect.” Tr.
61. He stressed that the role of the cytokines in SIDS was in their capacity to modify normal
neurologic function rather than being purely immune in nature. He assumed that J.B. was an
immunologically normal child, who when given a vaccination would have had an appropriate
immune response, including the production of cytokines such as the ones identified by
Kashiwagi et al. Therefore, he would expect the level of cytokines to be transiently increased
after vaccination. Tr. 62. “These cytokines would have been circulating in his body after
vaccination and we have direct evidence that there was some cytokine-central nervous system
interaction in that he had fever. Then there is a logical chain of events that says cytokines
depressed the 5-HT system in a defective medulla leading to SIDS during sleep.” Tr. 62-63.

        Dr. Miller stated that research is still identifying all of the exogenous stressors for SIDS.
Tr. 44. He opined that one very well-recognized exogenous stressor for SIDS is mild infection.
Tr. 45. Some of the estimates indicate that 40 - 50% of SIDS victims have had a very recent or
current mild upper respiratory infection (URI) at the time of death. Tr. 45. He said that it is
explicit in the literature from Dr. Kinney’s laboratory and others that what happens with mild
infections is that the response to the infection involves the production of certain cytokines and
that those cytokines can act on the central nervous system. He presented a theory: that a mild
upper respiratory infection can act as a neurochemical stressor by prompting the upregulation of
cytokines, which he theorizes are detrimental in two ways. He said that an infection could
cause fever, an extrinsic risk factor, and can cause elevated IL-1β levels, which would further
depress a defective medullary 5-HT system. The system would then be incapable of responding
to excess carbon dioxide, resulting in death. Tr. 46.




                                                 26
         Dr. Miller cited several studies, including ones discussed above by Rognum, Kashiwagi,
Kadhim, Brambilla, Stoltenberg, and Froen, that addressed the issue of cytokine stimulation and
the function of cytokines entering the central nervous system. From these studies, Dr. Miller
concluded that either mild URIs or vaccinations upregulate the production of cytokines, and
these inflammatory cytokines, can “shut down” a structurally vulnerable 5-HT system and
completely prevent it from restoring an infant’s normal breathing. Tr. 35. In other words, the
cytokines and the structural defect in the serotonin system acting in concert during a vulnerable
period have the cumulative effect of causing SIDS by making the baby incapable of responding
to excess carbon dioxide.

         Dr. Miller noted that Kashiwagi found similar cytokine profiles in the recently-vaccinated
population and those suffering from influenza, and further that the cytokine profiles were similar
in post-vaccination babies whether they had a fever or not. Tr. 49. He explained that cells that
are injured by infection initially produce an innate immune response. The cells of the innate
immune system release cytokines which signal further activation of the adaptive immune system
to respond to the foreign antigen. He said that there is a wide range of things that the cytokines
produce, but the initial production is certainly peripheral where there is infection. Tr. 50. He
testified that there is a whole lot of evidence that cytokines, produced peripherally, interact with
the central nervous system and the easiest one to understand is the way fever is produced. He
explained that fever is mediated by the central nervous system and specifically by the
hypothalamus in the brain. The hypothalamus sets our body temperatures. It causes us to shiver
if we are in the cold and need to warm up, or to sweat when we are overheated. Tr. 50-51. He
further explained that if the fever was generated in response to an infection outside of the brain,
such as in the case of a URI, there would be no inflammation in the brain as the brain is not
infected, but there is still an interaction with the hypothalamus in the brain caused by cytokine
signaling that causes fever in response to an infection outside of the brain. Tr. 51-52. Dr. Miller
stated that he was not aware of any literature describing URI as a mechanical exogenous stressor
and that in his professional experience conducting autopsies, he had never seen a URI
“obstruction of the airway” that would be sufficient on its own to cause death. Tr. 46.

        Dr. Miller stated that vaccinations can be an extrinsic risk factor in SIDS, as they prompt
the upregulation of cytokines that, among other things, produce fever. Tr. 62-63. He testified
that, based on the literature, there is a scientifically-plausible mechanism for vaccinations acting
as the extrinsic risk factor in SIDS in much the same way as a mild infection. He explained that
when you get a vaccination or a whole group of them at once, as J.B. did, it evokes a response
which includes the production of cytokines, and that among those cytokines are IL-6, TNFα, and
IL-1β. The physiological studies have shown that these can raise body temperature by producing
fever, which is a risk factor, and they can inhibit the activity of 5-HT neurons in the medulla
causing prolonged apneas and interference with autoresuscitation. Tr. 54, 62-63. When the
vaccines are administered in the presence of the defects in the medulla, during the critical
developmental period, they are likely to have a similar effect as mild infection that may cause a
failure of the medullary response system and ultimately a death. Tr. 54.




                                                27
        Dr. Miller stated that mild upper respiratory tract infection is widely recognized to be an
exogenous stressor under the Triple Risk Model. However, he acknowledged that there is not
wide recognition, or a generally accepted theory, that vaccinations are an exogenous stressor. He
stated that the Institute of Medicine concluded “the evidence is insufficient to say that there is an
effect or there isn’t an effect.” Tr. 55. The Kinney research team has not studied the relationship
between vaccination and SIDS. Tr. 60. Dr. Miller pointed to “multiple reports of similar cases
of SIDS following various neonatal or infant vaccinations, mostly stressing the close temporal
relationships between vaccination, increased cytokine production, and death from apparent SIDS
as seen with this case.”71 He said that these individual cases and small case series show a
“suspicious association between the timing of vaccination and the timing of SIDS deaths.” Tr. at
55.

         Summarizing his theory and review of the literature, Dr, Miller testified that the papers
cited, including Kadhim, Kashiwagi, Rognum, Stoltenberg, and Froen, “verify the importance of
the 5-HT system and its interactions with the GABA system in the medulla in terms of response
to apnea or other respiratory-related insults.” Tr. 34. Second, “they showed that there’s an
altered cytokine profile in SIDS cases versus non-SIDS cases, dying of other things, like
drowning or trauma.” Id. Third is the specific information on IL-1β, in that it inhibits the 5-HT
system. Id. Therefore, in the context of SIDS, this suggests that if there is an elevated level of
IL-1β to which the 5-HT neurons are exposed in an infant who already has too little 5-HT
activity because of a defective brainstem, this additional cytokine effect would shut down the
system such that it would not respond to other external stressors such as prone sleeping, nicotine,
infection or fever. Tr. 34-35.

        Dr. Miller addressed this analysis in terms of the cytokine reaction generated by vaccines.
He said that we know that when a child gets a vaccine or a whole group of vaccines all at once,
as occurred in this case, it evokes a response which includes the production of cytokines; that
among those cytokines are IL-6, TNFα, and IL-1β. Those levels go up in the blood. We know
that IL-1β can inhibit the activity of the 5-HT neurons in the medulla. If you take an infant who
has a defective medulla with a defective 5-HT system already, you put in a stress situation with
elevated carbon dioxide or low oxygen, and there is a vaccination which further shuts down the
5-HT system, and you can get a complete failure of response and therefore a death. He
concluded that the mechanism is plausible. Tr. 54.

                           ii. Althen Prong Two: Logical Sequence of Cause and Effect

       Dr. Miller then applied his theory to J.B.’s specific case. As an initial matter, he agreed
with the decision to classify J.B.’s death as SIDS. Exhibit 13 at 1. Under the Triple Risk Model,
Dr. Miller opined that J.B. was in the critical developmental period. Tr. 44. Statistically, he was
inherently vulnerable. Dr. Miller opined that Kinney et al. have found that a significant
proportion – up to 70% – of SIDS infants have abnormalities in the arcuate nuclei and other
sections of the medulla. Exhibit 13 at 3. Dr. Miller said that there is also a Japanese study in

71
  Vege & Rognum (2004), Exhibit 13-Q; Kries et al. (2005), Exhibit 13-R; Zinka et al. (2006), Exhibit 13-S;
Ottoviani et al. (2006), Exhibit 13-T; Traversa et al. (2011), Exhibit 13-U; Institute of Medicine, Adverse Effects of
Pertussis and Rubella Vaccines (1991), Exhibit 13-V.


                                                          28
which that number went as high as 90 percent. Tr. 38. He testified that it is statistically most
likely that J.B. also had this medullary 5 HT defect based on the Kinney data and other studies,
even though it was not confirmed because the medical examiner did not sample that section of
the brain. Exhibit 13 at 4-6; Tr. 37-38. Dr. McCusker agreed that “according to the Triple Risk
theory, the brain problem must exist [in J.B.’s case].” Tr. 206.

        A great many autopsies of SIDS infants outside of the research context do not section all
of the necessary areas of the brain or view them histopathologically, which is typical of medical
examiner autopsies. Tr. 16. Respondent’s expert pathologist, Dr. Harris, acknowledged that
based on Dr. Kinney’s research, the majority of SIDS babies and up to 70% in some of her
studies had an abnormality of the 5-HT system. Tr. 346. However, “[d]etection of these
abnormalities requires special immune-histochemical research techniques not generally available
for a ‘routine’ autopsy.” Id. Dr. Miller testified that even in some autopsies where no structural
abnormality was found in Dr. Kinney’s research, when the full histochemistry was performed,
there were still receptor binding deficits, such as in the IL-6 and gp130 studies. Tr. 41-42.
Unfortunately, the types of tools she used including autoradiography and immunohistochemistry
are not generally available for autopsies. Tr. 42-43.

        Dr. Miller discussed the logical sequence of cause and effect between vaccines
administered on September 2, and J.B.’s death on September 3. He opined that the vaccines
acted as a critical external stressor in this case. He noted that J.B. was a “healthy infant…
developing normally.” Exhibit 13 at 4. He was “immunologically normal.” Tr. 62. Therefore,
after receiving vaccinations, his body mounted an innate immune response including the
production of cytokines. Exhibit 13 at 6; Exhibit 16 at 1; Tr. 63. Those cytokines circulated in
J.B.’s body, specifically into the central nervous system. Exhibit 13 at 6; Tr. 63. These
peripheral cytokines interacted with the hypothalamus to provoke fever the night after the
vaccinations, and the following day (before J.B.’s death). Exhibit 13 at 6; Exhibit 16 at 1; Tr.
62-64. “Those cytokines then acted in the brainstem which was already deficient in
serotoninergic drive for respiratory effort, leading to an apneic episode from which he did not
recover, i.e., SIDS.” Exhibit 13 at 6; see also Tr. 62 (the cytokines “depress[ed the] 5-HT
system in a defective medulla, leading to SIDS during sleep”).

        He opined that there was “no other demonstrable inciting event” for J.B.’s death. Exhibit
13 at 1. There was no evidence of the fever being related to anything other than J.B.’s
vaccinations. Tr. 66. The autopsy did not identify any other infectious processes. Tr. 66.72

        Dr. Miller was asked whether the pillow in J.B.’s crib increased the risk of SIDS. Tr. 87.
Dr. Miller was not sure whether J.B.’s head was on the pillow. Id. He said, “If the pillow was
by his feet, I don’t think it’s a risk factor.” Id. A review of the investigation files indicates that
there was no evidence as to whether or not his head was on the pillow. The only relevant
evidence was that it was “a little crib pillow-very flat” and that his mother told the police that his
nose or mouth were not covered when she found him about ten minutes after replacing his
pacifier. Exhibit 7 at 5.

72
   Dr. Miller noted that there was bacterial growth and food particles in J.B.’s lungs and epithelial cells in the upper
airways. He opined that this was not evidence of a separate infectious process. He agreed with the medical examiner
that these were terminal or resuscitative events. Tr. 17-18; 66; 352-53.

                                                          29
        On cross-examination, Dr. Miller stated that J.B. was placed on his back but was found
on his side, which demonstrates that he was able to “move around.” Tr. 92. However, J.B. did
not pass away until “something else intervened.” Tr. 85. Based on his theory and the temporal
association, Dr. Miller opined that the vaccines were the intervening factor that caused J.B.’s
death. Tr. 85; Exhibit 7 at 5. He said that he looks at SIDS cases individually and that it was his
diagnosis that the vaccines contributed substantially to the death of J.B. in this case. Tr. 106-08.

                      iii. Althen Prong Three: Timing

        With regard to timing, Dr. Miller stated several reports “have noted an elevated risk for
SIDS within the first 48 hours following immunization, although this is not statistically
significant.” Exhibit 13 at 5. He stated that J.B. died within this 48-hour “window of elevated
risk” following vaccination. Id.

       Dr. Miller also stated that the available evidence is that foreign antigens, like those
contained in vaccinations, activate the production of cytokines “within hours” and that
production “peaks within 2 to at most 4 days.” Exhibit 16 at 1. Thus, a vulnerable infant who
receives vaccinations is most likely to suffer a fatal event if one is to occur “within the first 48
hours to at most 4 days.” Id. Dr. Miller opined that J.B.’s death was “well within this vulnerable
period.” Id.

           2. Respondent’s Expert Dr. Christine McCusker

         Dr. Christine McCusker earned a Masters in Molecular Virology in 1988, followed by an
M.D. in 1993, at McMaster University, in Hamilton, Ontario. Exhibit D at 1. Her residency
training was in pediatrics, at Montreal Children’s Hospital, McGill University, from 1993-1996.
Id. at 2. She was then a clinical fellow in allergy and immunology at McGill University from
1996-1999. Id. Dr. McCusker is board certified in pediatrics. Id. She is currently the division
director of pediatric allergy, immunology, and dermatology at the Montreal Children’s Hospital
at McGill University Health Center and is the director of the Clinical Immunology Lab. Tr. 122.
She has a wet lab that studies developmental immunology, which has peer-reviewed funding. Id.
She also runs a clinical research program that uses databases to follow patients with primary
immunodeficiency. Id. In addition, she sees pediatric patients at McGill Children’s emergency
room and at several allergy, immunology, and general pediatrics clinics. Tr. 124. Dr. McCusker
also teaches medical students in the areas of immunology, dermatology, and malignant
hematology. Id.

                 i.    Althen Prong One: Response to Petitioners’ Medical Theory

        Like petitioners’ expert Dr. Miller, Dr. McCusker accepted Dr. Kinney’s formulation of
the Triple Risk Model. Dr. McCusker agreed with Dr. Miller on the critical development period,
and that an infant may be “vulnerable” because of a brain defect, premature birth, male gender,
and/ or African American race. Dr. McCusker disagreed with Dr. Miller’s opinion that upper
respiratory infection, and by extension, vaccines, act as neurochemical exogenous stressors
within the Triple Risk Model.


                                                 30
        Dr. McCusker spent considerable time explaining why upper respiratory infection and
other exogenous stressors, such as “being placed or found in a prone/ side-sleep position, found
face down, head covered, sleeping on an adult mattress, couch, or playpen, soft bedding, bed-
sharing, and signs of upper respiratory tract infection,” are mechanical. Specifically, each one
impedes an infant’s ability to exhale carbon dioxide and inhale fresh oxygen, thereby increasing
the risk of SIDS. Tr. 127-28.73

        She opined that the prone sleep position is more widely recognized as an exogenous
stressor for SIDS, but that the side-sleep position poses just as much risk. Tr. 131. She stated
that breathing depends on “drop[ping] the diaphragm down and creat[ing] a negative airspace,
[in which] the air comes rushing in.” Tr. 130. An infant’s body is not fully developed, so it uses
“more than just the diaphragm” and “a lot of abdominal muscle to breathe.” Id. An infant lying
supine with the head back breathes most easily. Id. In contrast, an infant in either the prone or
side-sleep position has more difficulty dropping the diaphragm and exhaling carbon dioxide. Id.
Dr. McCusker also opined that the side-sleep position compresses “at least half your rib cage.”
Tr. 132. She stated that an infant’s rib cage is “soft” and “very pliable.” Therefore, it does not
take much to influence the infant’s ability to exchange air. Id. She also noted that an infant’s
breath is much more shallow and rapid than an adult’s, and therefore the diffusion of exhaled
carbon dioxide is less than in adults and rebreathing is more likely. Id. Theoretically, this means
that an infant is at greater risk of re-inhaling expelled carbon dioxide. Id. Dr. McCusker
acknowledged that the Back to Sleep Campaign previously advised parents to avoid all risk
factors for SIDS, and that early research emphasized avoiding prone sleeping. Id. at 132-33.
However, she said more recent studies looking “a little bit more closely” indicate that “prone and
side-sleeping have equal risk.” Tr. 134. She also stated that an infant learns to roll from the
supine position to the side or prone position, but “usually not until somewhere between four and
six months.” Tr. 134-35. She did acknowledge, however, that the American Academy of
Pediatrics does say that once a child is able to roll from his back to his side or to prone, then the
parent should not disturb them. They should just have nothing else in the crib that could
obstruct breathing. Tr. 135.

        She also stated that gastroesophageal reflux is an exogenous stressor. Tr. 137.
Specifically, an infant’s airway and esophagus are linked at the back of the throat. Id. An infant
may regurgitate and inhale at the same time, and therefore stop breathing momentarily. Id. at
138. If the infant neither swallows nor expels the food, his breathing will become obstructed and
he will not recover. Id.

        Dr. McCusker stated that bundling is an exogenous stressor and suggested several
possible reasons why. Id. at 135. First, she opined that bundling decreases an infant’s arousal,
which helps the infant go back to sleep, but may increase the incidence of SIDS. Id. at 136.
Second, a bundled infant may be less able to roll out of the prone or side-sleeping position. Id.
Third, bundling may be an exogenous risk factor by leading to hyperthermia. Id. It should be
noted that there is no evidence of bundling in this case, as J.B.’s father said he placed him on his
back with a blanket across the midsection, but there was no indication that he was wrapped or
bundled.


73
     Trachtenberg, Kinney, et al. (2012), Exhibit C-11.

                                                          31
        Dr. Miller stated that hyperthermia was a term encompassing both high ambient
temperature and fever. But Dr. McCusker disagreed. She testified that hyperthermia was high
ambient temperature, and hyperpyrexia was fever. She stated that older literature listed both
hyperthermia and hyperpyrexia as exogenous risk factors for SIDS. Tr. at 201, 287. However,
she opined that newer literature, such as an article by Trachtenberg, lists hyperthermia as a risk
factor for SIDS, but not fever. Tr. at 201, 287, 290. She agreed with this distinction. She
reasoned that an infant experiencing hyperthermia tries to cool himself down. Tr. 289. To do so,
the infant takes short, shallow breaths, which increase CO2 levels, which trigger the pathway to
SIDS. Tr. 288, 295. She cited an article by Harper and Kinney, which provides that
“vasodilation associated with overheating makes compensation for low blood pressure more
difficult.”74 Dr. McCusker opined that fever is not a risk factor for SIDS. Specifically, she said
in fever the body fasciculates or shivers – it makes small muscle movements that create friction,
which generates heat inside the body. Id. at 184. The body cannot make these movements
during deep REM sleep. Therefore, it stays in NREM sleep. Id. at 184-85. She opined that an
infant generating or maintaining a fever, who does not descend into REM sleep, is less
susceptible to SIDS. Id. at 202. It should be noted that nowhere in the submitted literature was
an explicit distinction made between hyperthermia and hyperpyrexia, including in Trachtenberg
or the Harper & Kinney article. Dr. McCusker is correct that in a 1992 article by Dr. Kinney,
she mentioned “infection, fever and hyperthermia” as exogenous stressors.75 Later articles
generally reference hyperthermia and overheating. However, in a 2009 article, Dr. Kinney
described a SIDS scenario in which in part she describes “an infant may be slightly febrile due to
an otherwise trivial upper respiratory tract infection (3) as a consequence, the apnea component
of the LCR is inordinately prolonged by mild hyperthermia,”76 This reference would appear to
suggest that the term hyperthermia may be more broadly inclusive.

        Unlike Dr. Miller, Dr. McCusker characterized mild upper respiratory infection as a
purely mechanical extrinsic risk factor for SIDS. Tr. at 127-28. She opined that an infant is
accustomed to breathing through the nose, which enables uninterrupted bottle or breast-feeding.
Id. at 138-39. When the nose is congested, she said, the infant still exerts significant effort to
breathe through the nose, which elevates carbon dioxide. Id. at 139. If and when the infant
finally resorts to breathing through the mouth, that is less effective and also increases the risk of
respiratory distress. Id. at 140-43.

        Dr. McCusker then spoke about cytokines. She asserted that cytokines serve a variety of
positive functions in the healthy human brain. Id. at 145-58.77 Researchers initially theorized
that cytokines found in the brain, including IL-6, IL-1β, and tumor necrosis factor-alpha (TNF-
alpha), had traveled there through the cerebrospinal fluid, to respond to inflammation in the
brain. Id. at 151-52. However, research beginning in the late 1990s indicates that the brain itself

74
     Harper & Kinney (2010), Exhibit C-12 at 3.
75
     Filiano & Kinney (1992), Exhibit 13-A at 401.
76
     Kinney et al. (2009), Exhibit 13-H at 539.
77
 Besedovsky, H.O. and A. del Ray, Central and Peripheral Cytokines Mediate Immune-Brain Connectivity, 36
Neurochem Res. 1 (2011), Exhibit C-3.


                                                     32
produces cytokines. Id. at 152. Dr. McCusker cited articles reporting that inflammatory
cytokines such as IL-6 and IL-1β regulate pain sensitivity, memory consolidation, stress, fever,
and sleep. Id. at 152-56.78 Ron-Harel wrote, “Pro-inflammatory cytokines are abundantly
expressed in healthy brain and are involved in the regulation of many physiological functions
such as pain sensitivity, memory consolidation and neural plasticity. Elevation in brain cytokine
levels is considered part of the adaptive response to external stimuli. Exposure to acute
psychological stressors by induction of adrenalin, noradrenalin and dopamine induces an
increase in brain proinflammatory cytokines which modulate the neuroendocrine and behavioral
response to the stressor. Id. at 3. She also cited an article by Moidunny et al. suggesting that
cytokines including IL-6 may play a neuroprotective role in the brain after stroke or head trauma.
Id. at 157.79 Moidunny was studying the role of IL-6 in reducing glutamate excitotoxicity in
stroke and head trauma with the goal of further research to identify additional pharmacological
protection with IL-6 from glutamate neurotoxicity in these patients. Moidunny does not discuss
SIDS or the role of peripheral cytokines in this article.

        Dr. McCusker also cited to an article by Chen Miller, which discusses the role of
Tryptophan Hydroxylase 2 which is a rate limiting enzyme in 5-HT biosynthesis. The article
discusses advances in understanding Tryptophan Hydroxylase TPH and TPH2 which are critical
for the initiation of the synthesis of 5-HT (serotonin) which modulates the stress response by
interacting with the hormonal hypothalamic pituitary adrenal axis and neuronal sympathetic
nervous system. The TPH2 mRNA expression is abundant in the raphe nuclei or regions
containing raphe nuclei such as the pons and medulla, while it is detectable in a number of other
regions including the cortex, hypothalamus, thalamus, hippocampus, amygdala and cerebellum.
TPH2 gene expression is sensitive to stressful events including hemorrhage and hypoxia and
involves neuronal and hormonal mechanisms. The article hypothesizes about the role of TPH2
and serotonin in response to stimulating events such as hypotensive hemorrhage, hypoxia and
adverse events experienced in early life or as an adult, and a possible role in such conditions as
PTSD but it was not clear how this paper directly addresses the issue of respiratory depression in
SIDS. 80

       Dr. McCusker argued that the various animal studies cited by Dr. Miller were not
relevant to cytokines’ effect in infant brains in vivo. Id. at 162-87. First, she stated that the
Brambilla article,81 which showed that IL-1β depressed serotonin in rats’ brain tissue, was not

78
  Ron-Harel, N. et al., Brain Homeostasis is Maintained by “Danger” Signals Stimulating a Supportive Immune
Response Within the Brain’s Borders, Brain Behav. Immun. (2011), Exhibit C-1; Su, Y. et al., Predator Exposure-
Induced Cerebral Interleukins are Modulated Heterogeneously in Behavioral Asymmetry, 135 Immunol. Let. 158
(2011), Exhibit C-4; Kinney et al. (2011), Exhibit 13-F.
79
  Moidunny, S. et al., Interleukin-6-Type Cytokines in Neuroprotection and Neuromodulation: Oncostatin M, but
not Leukemia Inhibitory Factor, Requires Neuronal Adenosine A1 Receptor Function, 114 J. Neurochem. 1667
(2010), Exhibit C-2.
80
  Chen, G.L. & G.M. Miller, Advances in Tryptophan Hydroxylase-2 Gene Expression Regulation: New Insights
into Serotonin-Stress Interaction and Clinical Implications, 159B Am. J. Med. Genet. B. Neuropsychiatr. Genet.
152 (2012), Exhibit C-15.
81
  Brambilla, D. et al., Interleukin-1 Inhibits Firing of Serotonergic Neurons in the Dorsal Raphe Nucleus and
Enhances GABAergic Inhibitory Post-Synaptic Potentials, 26 Eur. J. Neurosci. 1862 (2007), Exhibit 13-M.

                                                        33
relevant to sleeping infants. Id. at 185. Specifically, the Brambilla study submerged rats’ brain
tissue in “super-physiologic doses” of IL-1β for an extended period of time; and kept it isolated
in petri dishes, which would not reflect what happens to a vulnerable infant in a “crisis
situation.” Id. at 186-87.

        Similarly, Dr. McCusker opined that the Stoltenberg and Froen articles,82 which reported
that very young piglets did not recover from apnea as quickly when they received super-
physiological doses of cytokines, had limited significance. Id. at 162-63. The articles reported
this effect only in piglets younger than fifteen days old; in a previous study, cytokines did not
have any effect on older piglets. Id. at 163. Dr. McCusker opined that pigs’ and infants’
respiratory systems develop at similar paces; therefore, piglets younger than fifteen days old
could be compared only to infants under one month old. Id. at 164. Furthermore, she argued
that Froen induced extremely high cytokine levels that would not occur naturally in infants. Id.
at 171. On rebuttal, Dr. Miller responded to this criticism, by saying that pigs’ brains are very
different from human brains. Pigs are born with much more myelin than adult brains; they are
much more mature than our brains. The piglets are walking and do things early in piglet life that
humans take up to a year or more to do. Thus, this model is not an irrelevant model for a 4-
month-old in terms of brain development. He noted correctly that what Stoltenberg and Froen
were looking at was brain physiology or pathophysiology. They were not looking at respiratory
development in terms of pulmonary or bronchial development or vascular or cardiac
development. They were looking at the responsive neurons in the brain. Tr. 358.

        Dr. McCusker also argued that studies of cytokine levels in human brains were only
observational, and did not support Dr. Miller’s theory. She stated that the Rognum article83
found similar IL-6 levels in SIDS infants with and without minor infections. She argued that if
infection upregulates cytokine levels, the data between these two groups should be different. Id.
at 173-74.

        Dr. McCusker opined that cytokines play a protective role. Specifically, they maintain
homeostasis in the body. She stated that cytokines carry messages (e.g., that an infant’s
breathing is disrupted) to receptor cells, which contain gp130 molecules, which are supposed to
respond to those messages (e.g., by prompting the infant to arouse or gasp). Id. at 174-77. Dr.
McCusker noted that the Rognum article reported that SIDS brains showed increased binding of
IL-6 to neurons in the arcuate nucleus, but no corresponding increase in expression of gp130 (a
“signal transducer” for the 5-HT system).84 She said that if the lack of a corresponding increase
in gp130 is physiologically important, which “is a big if,” it would imply that the increased IL-6
would not be doing anything. Tr. 175



82
  Stoltenberg et al. (1994), Exhibit 13-J; Froen, J.F. et al., Adverse Effects of Nicotine and Interleukin-1β on
Autoresuscitation After Apnea in Piglets: Implications for Sudden Infant Death Syndrome, Pediatrics (April 2000),
Exhibit 13-K.
83
     Rognum, Kinney et al. (2009), Exhibit 13-N; Kadhim et al. (2010), Exhibit 13-O.
84
     Rognum, Kinney et al. (2009), Exhibit 13-N.


                                                          34
         As Dr. Miller mentioned, Rognum suggested that IL-6 may have “aberrant interactions”
with the arcuate nucleus, leading to SIDS. However, Rognum also suggested another theory:
that the “increased expression of the IL-6R in the arcuate nucleus may be a compensatory
mechanism as defective arcuate neurons may require excessive IL-6 stimulation in order to
respond to altered CO2 levels.” Id. at 528 (emphasis added). Kinney cited this theory, writing:
“The expression of IL-6 is elevated in the arcuate nucleus in SIDS infants, which may reflect a
compensatory mechanism whereby defective arcuate 5-HT neurons require excessive cytokine
stimulation to respond to infection-induced hypercapnia.”85 Dr. McCusker adopted and
elaborated on this theory suggesting that IL-6 mounts a protective response. Tr. 157. She cited
an article by Moidunny, which states that some IL-6 cytokines have “neuroprotective properties”
and that IL-6 requires gp130 receptor subunits to be activated for signaling.86 When a stressor –
such as inadequate oxygen or hypoxia - occurs, the cytokines bind to the 5-HT system, which
expresses gp130 molecules to prompt a response – such as prompting the body to turn over or
gasp. Tr. 155-56, 161, 175-77, 241. Dr. McCusker opined that these responses can be “quite
rapid, within hours or days.” Tr. 180-81. Based on these findings, Dr. McCusker suggested that
SIDS infants have potentially protective IL-6 molecules in the brain, but in SIDS infants hey fail
to prompt the upregulation of gp130 molecules. Thus the IL-6 is ineffective. Tr. 176

        Dr. McCusker stated that neither the Kinney team nor the AAP lists vaccinations as a risk
factor for SIDS. Id. at 144. Dr. Miller testified to a conversation that he had with Dr. Kinney
who told him that she did not want to study vaccines because she did not want to testify and did
not want to be involved in vaccine controversies. Tr. 60. Dr. McCusker acknowledged that
medical literature has reported a temporal association between vaccination and infant death in
certain cases. Specifically, the Ottaviani study reported that a three-month-old white female
infant received a hexavalent vaccine, lost consciousness one hour later, did not recover upon
resuscitation, and passed away a few hours later.87 Dr. McCusker highlighted that Ottaviani
suggested the case might fall into a “SIDS ‘gray zone’” because it was “difficult to establish
whether the pathological findings [were] sufficiently severe to have caused the death.” Id. Dr.
McCusker noted that Ottaviani published another study of five infants displaying those same
pathological abnormalities; however, that study did not mention vaccinations.88 Therefore, she
suggested that the vaccination in the first Ottaviani case was temporally associated with, but did
not cause, that infant’s death despite the fact that the author stated that in this case the sudden
death in a child with arcuate hypoplasia could have been triggered by the hexavalent vaccine or
could have been a gray zone case where it is difficult to determine if the pathological findings
were sufficient to cause the death. Tr. at 103. It should be noted that the gray zone study
focused on the neuropathology and histopathology of five specific SIDS victims to identify the
possible brainstem abnormalities. The victims were chosen for study with no reference to
vaccines or other specific causal pattern. The case report involving the child who died three

85
     Kinney et al. (2011), Exhibit 13-F at 195.
86
     Moidunny et al. (2010), Exhibit C-2 at 1668.
87
     Ottoviani et al. (2006), Exhibit 13-T at 101-02.
88
  Ottoviani G. et al., Sudden Infant Death Syndrome “Gray Zone” Disclosed Only by a Study of the Brainstem on
Serial Sections, 33 J. Perinat. Med. 165 (2005), Exhibit C-16 at 6.


                                                        35
hours after receipt of the hexavalent vaccine was published subsequently to the gray zone study
and mentions it as the group’s prior work. It does hypothesize that the death could have been
triggered by the vaccination or fall into the gray zone category.89

        Dr. McCusker’s comments in her report about the literature submitted by petitioners
caused some concern, in that they could be read as misleading. Exhibit C at 7-8. Dr. McCusker
stated that in the study by Rognum et al., “although [in SIDS infants] there was increased
intensity staining for IL-6R, it was not different from those dying of infectious causes.” Exhibit
C at 7 (discussing Exhibit 13-N). However, Dr. McCusker did not note that at most the SIDS
infants had mild infections, which would not be expected to cause elevated cytokines in the
brain, while the other group had severe infections which would be expected to cause elevated
cytokines in the brain and that “the mean IL-6R intensity grade in the arcuate nucleus was
significantly higher in the SIDS group than in the control group.” 90 [the control group died of
“primarily violent causes.”] Id. at 521.

        Of greater concern was Dr. McCusker’s characterization of the article by Kadhim et al.
Exhibit C at 7-8 (discussing Exhibit 13-O). She stated: Kadhim et al. “examined IL-2 levels in
SIDS versus non-SIDS brains and showed no difference in expression in IL-2 and they
hypothesize that IL-2, like the cytokines IL-1β, TNFα, and IL-6, may be expressed in normally
functioning brains of infants.” Exhibit C at 7-8. Kadhim et al. actually stated; “SIDS victims
often have preceding mild infectious/ inflammatory conditions (like coryza/ mild upper
respiratory infections, soft stools/ mild gastroenteritis, post-vaccinal fever, etc.)”91 They
compared the brains of SIDS infants to those of infants who died of severe infectious/
inflammatory conditions. Id. at 123. They found that IL-2 levels were unexpectedly comparable
in the two groups. Id. Kadhim said, “the comparable (equally intense) expression of IL-2 in
SIDS infants was rather unexpected as SIDS victims have no obvious or detectable serious health
conditions before death and that autopsies show no obvious cause for their demise. (as per
definition). However, this high expression in SIDS would corroborate the tenet that SIDS
victims experience hyperimmune reactions with ‘exaggerated cytokine response to the often
reported preceding mild/trivial infectious/inflammatory conditions. Upregulated cytokines exert
serious effects on many biological systems including the turnover, release, and transmission of
neurotransmitters; cytokines therefore act as neuro-modulators that could modify neural,
neuroimmune, and neuroendocrine functions, and can modify synaptic transmissions.” Id. at
125. The authors further concluded, “Thus various biological stressors such as infectious
inflammatory, ischemic or anoxic, and hyperimmune conditions, and metabolic disorders induce
IL-2 which is preferentially expressed in vital brainstem neuronal centers. IL-2 and other
subsequently triggered cytokines in downstream immune inflammatory mediators interact with
neurotransmitters and/or their receptors and modify their function. The resulting neuronal
molecular disequilibrium tips the delicate molecular balance causing dysfunction in those vital



89
     Ottoviani et al. (2006), Exhibit 13-T at 103.
90
     Rognum, Kinney et al. (2009), Exhibit 13-N at 521.
91
     Kadhim et al. (2010), Exhibit 13-O at 122.


                                                          36
brainstem centers in producing disturbed homeostasis with potentially drastic effects on target
organs systems and eventual death.” Id.

        Dr. McCusker reviewed the epidemiological papers submitted and noted that an article
by Kuhnert found a decreased incidence of SIDS in days 1-3 after vaccination, then increased
incidences of SIDS in days 4-7, 8-14, and 15-21. Tr. 229-35.92 Furthermore, she stated that
other studies did not find any temporal association between vaccination and SIDS. First, an
article by Jonville-Bera et al. did not find a heightened risk of SIDS in French infants vaccinated
at three months old.93 Second, Toro et al. found that the incidence of SIDS in two-month-old
children in Hungary decreased when that country instituted vaccinations at that age. Id. at 7.94
Third, Vennemann et al. did not find an increased risk of SIDS with vaccination.95 In Dr.
McCusker’s opinion, “large studies, designed to unmask rare events, have shown no link
between vaccination and SIDS and have at least in some studies demonstrated a vaccine
protective effect for SIDS.” Exhibit C at 7.

        At trial, Dr. McCusker added that the Kries study cited by petitioners did not support
their case. Specifically, SIDS is defined as a syndrome that only affects children “under one year
of age.”96 However, Kries et al. did not find an association between vaccination and death in
children under one year old. They found an increased incidence of SIDS only in children
vaccinated during the second year of life. Id. Therefore, she said this study does not support
petitioners’ theory about vaccination and SIDS. Tr. at 257.

                       ii.    Althen Prong Two: Response to Petitioners’ Opinion of a Logical
                              Sequence of Cause and Effect

        Dr. McCusker stated that there was “no evidence” that vaccinations contributed to J.B.’s
death from SIDS on September 3, 2011. Exhibit C at 8; Tr. 126. She did not dispute that J.B.
was in the critical development period. She agreed that “according to the triple-risk theory, the
brain problem must exist” for an infant to succumb to SIDS. Tr. 206.

        She agreed that vaccines “increase cytokine circulation.” Tr. 195. She also stated that
Kashiwagi et al. showed that 24-48 hours after vaccination, a child will have elevated cytokines,
whether or not he has a fever. Tr. 199. “Cytokine elevation in this model is independent of
fever.” Id. Dr. McCusker stated that J.B. had a fever, and because he was generally healthy and
had no signs of upper respiratory infection, the fever could be attributed only to his vaccinations.
Tr. 204-05. The fever was “an indication that [J.B.] was responding… to the vaccine.” Tr. 238.

92
     Kuhnert et al. (2012), Exhibit C-20.

 Jonville-Bera A., et al., Sudden Unexpected Death in Infants Under 3 Months of Age and Vaccination Status – A
93

Case Control Study, 51 Br. J. Clin. Pharmacol. 271 (2001), Exhibit C-18.
94
  Toro K. et al., Change in Immunization Schedule and Sudden Infant Death Syndrome in Hungary, 42 FEMS
Immunol. and Med. Microbiol. 119 (2004), Exhibit C-19.
95
     Vennemann et al. (2007), Exhibit C-17.
96
     Kries et al. (2005), Exhibit 13-R at 1.

                                                      37
        She stated that J.B. had a fever on September 3, 2011, but after he was given Advil that
morning at approximately 8:00 a.m., his fever resolved. Exhibit C at 4; Tr. 204-05, 237. She
also stated that a non-steroidal would last for eight hours. Tr. 192. She stated that “if IL-1β
mediated respiratory depression [occurred] in the case of J.B., the Advil he was given would
have acted to counter this effect, suggesting that this mechanism was not involved in his death
from SIDS.” Exhibit C at 5, 8.

         Her theory was that J.B. ‘was put down for his nap, he rolled over, he started rebreathing,
and he died of a sudden infant death due to hypercapnia… independent of any cytokines.” Tr.
206. She opined that there were several recognized exogenous stressors in J.B.’s case: formula
feeding, side sleeping, soft bedding, and a pillow under his head. Exhibit C at 5; also Tr. 128-29.
In her report, Dr. McCusker stated that J.B. “was found on his side with his face down on a
pillow.” Exhibit C at 4 (citing Exhibit 7 at 6). (The sixth page of this exhibit is a confirmation of
faxing the record.) However, the preceding page is a handwritten scene investigation form. It
states that J.B.’s crib had a “little crib pillow.” Exhibit 7 at 5. J.B. was found “on side with head
downward.” Id. The form also indicates that neither J.B.’s nose nor his mouth was covered. Id.

        At the hearing, Dr. McCusker first testified that J.B.’s “face was downward according to
the reports.” Tr. 128. On cross-examination, she could not identify where in the record it said
that his face was down on a pillow. Tr. 265. She thought “he was found with his head down.
There was a pillow in the bed, which is clear from the photos. So, it would be easy to
hypothesize that he was at least found face down in the general vicinity of a pillow, and one
would wonder what the pillow was doing in the bed if it wasn’t for under his head.” Tr. 266.
She noted that the photos of the crib showed a pillow on one end of the bed and diapers and
wipes on the other end. Tr. 266 (discussing Exhibit 9 at 8-9). She opined that J.B.’s head would
have been on the end of the bed where the pillow was. Tr. 266-67. Dr. McCusker
acknowledged, however, that she did not know whether J.B. was actually found with his head on
the pillow. Tr. 267. She also agreed that J.B.’s crib was taken down shortly after his death, after
which law enforcement and J.B.’s parents participated in a death scene reenactment. Tr. 267-68.
That reenactment does not mention the pillow or any other elements that were in the crib. Tr.
268.

       The undersigned asked Dr. McCusker about the “mechanical effect” of the sleep position
she assumed that J.B. was found in. Tr. 269. Dr. McCusker stated that side-sleeping, a pillow
under the head, “the lack of tight bed sheets,” and the “disarray” in the crib all together present
“the same risk factors as prone” sleeping. Tr. 269-72. The undersigned commented that these
facts were not completely clear from the record. Tr. 272.

                iii.   Althen Prong Three: Response to Petitioners’ Timing Argument

        Dr. McCusker stated that she understood Dr. Miller’s testimony to be that “the
upregulation of the serotonin through the TPH2 and 1433 system… would not be an
instantaneous event and that it would take time and presumably more than 24 hours’ time.” Tr.
180. She stated that “the production of increasing cortisol that occurs following a stimulus and




                                                 38
upregulation through IL-6 is actually quite rapid, within hours, not days.” Tr. 181.97 But she
also stated that Kashiwagi et al. showed that a child will have elevated cytokine levels in the
blood 24-48 hours after vaccination. Tr. 198.

             3. Respondent’s Expert Dr. Brent Harris

        Dr. Brent A. Harris earned a Masters in Biology from Hahnemann University in 1988.
Exhibit A at 1. He then earned a M.D. and a Ph.D. in Pharmacology from Georgetown
University in 1995. Id. He then obtained post-doctoral training at Stanford Medical School,
where he was a resident in Anatomic Pathology from 1995-1999, chief resident from 1997-1998,
and a neuropathology fellow from 1997-1999. Id. Dr. Harris is board certified in anatomic
pathology and neuropathology and is a Fellow of the College of American Pathologists. Id. He
is currently an Attending Pathologist, Associate Professor in Neurology and Pathology, and
Director of Neuropathology at Georgetown University Medical Center. Id. He also serves as a
Neuropathology Consultant for the Chief Medical Examiner, the National Institutes of Health,
Howard University Hospital, the Washington, DC Veterans Administration Hospital, and the
American International Pathology Laboratory. Id.

                     i.    Althen Prong One: Response to Petitioners’ Theory

         Dr. Harris agreed with the other experts that the Triple Risk Model is a generally
accepted and reliable model of SIDS. Tr. 345. He could not say whether all extrinsic risk
factors are mechanical or whether some of them may be neurochemical. Id. at 346. However, he
testified that he would want to see conclusive proof before he would list vaccines as a risk factor
in a medical report that he wrote. Tr. 348. He was aware of studies finding that vaccinations
induce the production of cytokines in the brain, but not of any studies finding that those
cytokines have a detrimental effect. Exhibit A at 6.

                    ii.    Althen Prong Two: Response to Petitioners’ Opinion of a Logical
                           Sequence of Cause and Effect

       Dr. Harris agreed with the characterization of J.B.’s death as SIDS and that under the
Triple Risk Model, J.B. was in the critical development period. Exhibit A at 6. It cannot be
confirmed whether J.B. had a brain defect rendering him “vulnerable” because the autopsy did
not sample that section of the brain. Exhibit A at 6.

        Dr. Harris opined that if vaccinations are found to be an exogenous stressor, they
“certainly cannot be proven in J.B.’s death.” Exhibit A at 6. He stated that there were “no
pathologic findings in the brain or other organs in this case that indicate a vaccine-related death.”
Exhibit A at 7; see also Tr. 328. J.B.’s brain was found to have metabolic glia, which are not
fully understood. Exhibit A at 6-7. Dr. Harris also opined: Induction of cytokines after

97
  This may not be an accurate characterization of Dr. Miller’s opinion. A review of the transcript did not find a
clear statement from Dr. Miller about the timing of cytokine production. But in his expert report, Dr. Miller actually
opined that cytokine production would begin “within hours” and would peak “within 2 to at most 4 days.” See
section above (citing Exhibit 16 at 1).


                                                         39
vaccination is a recognized physiological response involved in the immune process. The primary
immune surveillance cells in the brain are microglia.These cells when activated by circulating
molecules or direct invasion in the brain by organisms change their morphology and produce a
host of cytokines in response. Over-activation of these cells in J.B.’s brain is a non-specific
finding that could be related to the prior day’s vaccination and/ or infection.” Exhibit A at 6. Dr.
Harris testified that the “circulating molecules” that activate microglia can be either
lipopolysaccharides from bacteria or “circulating cytokines,” although this is not completely
understood. Tr. 342.

                iii.   Althen Prong Three: Response to Petitioners’ Timing Argument

       Dr. Harris agreed with Dr. McCusker’s opinion that cytokine signaling “doesn’t happen
immediately but happens over a period of time.” Tr. 343. He did not otherwise address the
timing for the cytokine response or whether it fit the case of J.B.

   III.    ANALYSIS

               A.      Summary of the Arguments

        The parties agree that the sole issue to be resolved is “whether the vaccines that J.B.
received on September 2, 2011 caused or substantially contributed to his death.” Joint
Prehearing Submission at 2. Pursuant to Althen, petitioners must show by a preponderance of
the evidence a reasonable theory as to how the vaccine could cause the harm at issue, a logical
but not scientifically certain explanation of how it did, and show the timing was appropriate
given the theory of causation. The Federal Circuit has observed that this preponderance
standard enables “the finding of causation in a field bereft of complete and direct proof of how
the vaccines affect the human body.” Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274,
1280 (Fed. Cir. 2005). The standard permits the use of “circumstantial evidence” and
accomplishes Congress’s goal that “close calls regarding causation are resolved in favor of
injured claimants.” Id. (citing Knudsen v. Sec’y of Health & Human Servs., 35 F.3d 543, 549
(Fed. Cir. 1994) (“to require identification and proof of specific biological mechanisms would be
inconsistent with the purpose and nature of the vaccine compensation program”)).

        To address the issue in the case, several questions must be addressed. The specific
questions for decision are whether inflammatory cytokines generated by a mild infection are
likely the critical exogenous stressor in many cases of SIDS when mild infection is also present.
The second question is whether the same cytokines are stimulated by the innate immune
response to vaccines and whether they are likely to be the exogenous stressor in some SIDS
cases, particularly, as in this case, when the child was thoroughly examined by a physician the
day before he died and found to be completely healthy, and there was no evidence of viral
infection by nasal swab at autopsy.

       Petitioners’ theory is essentially that a high percentage of SIDS infants, almost 50% in
most studies, have no history of a serious illness in the days and weeks prior to death, but have a
mild infection or fever at the time of death. In most instances, the mild infection was an upper



                                                40
respiratory infection, although one author listed post-vaccinal fever among the conditions.98 In
this case, J.B., a nearly five-month-old African American boy, who had been born at 36 weeks,
died of unknown causes while napping in the early afternoon one day after receiving his
scheduled four-month vaccines. He had a well-documented physical examination the prior day,
performed by an M.D. pediatrician who had performed a similar examination about five weeks
prior. J.B. was documented to be healthy, with no signs or symptoms of illness. He had patent
nasal passages and clear lungs, and he was progressing well in terms of growth and milestones.
His pediatrician noted that he was able to raise his head, hold it steady and roll over. In the 28-
hour period following vaccination, at 4 a.m. and again at 8 a.m., his mother noticed that he had a
mild fever and gave him children’s Advil. He seemed to be fine and playing normally during
the morning, but was fussy and started running a fever again in the early afternoon. Exhibit 8 at
2. His father then put him in his crib for a nap. He was put in the crib on his back, with a
blanket over his midsection. He was using a pacifier. There was a small, flat, crib pillow in the
bed. The air conditioning in the house was set at 76 degrees. His mother checked on him and
replaced his pacifier during his nap. She came back about ten minutes later, noticed that he had
rolled onto his side with his head tilted slightly downward, and he was not breathing. There is no
evidence that his breathing passages were in any way obstructed or that his face was down in the
bed or pillow when his mother found him. She called 911. Police and emergency medical
personnel responded within minutes. J.B. was transported to the hospital when he could not be
revived on scene. He was pronounced dead at the hospital.

         Under the first leg of the Triple Risk Model, petitioners theorize that J.B. likely had a
defective or under-developed serotonin system in the arcuate nucleus or other medullary area,
which unfortunately was not examined or sectioned at autopsy. He was clearly within the
vulnerable risk period for SIDS in that he was between four and five months old and, given his
pre-maturity, only about four months based on dates of conception. He had several intrinsic
risk factors in that he was born at 36 weeks, he was male and he was African American, all of
which groups are overrepresented among SIDS deaths – blacks more than whites and Hispanics,
boys more than girls, and preterm babies more than term babies. As noted above, at birth, J.B.
had Apgar scores of 8 at one minute and 9 at five minutes. He had grown to 16 pounds and was
well within the average ranges for height, weight and head circumference. He appeared to be
meeting expected milestones as documented by his pediatrician. He was receiving good medical
care and did not appear to be affected by issues associated with poverty, which is often
speculated to account for the overrepresentation of African American babies in the SIDS
statistics. He was a boy and it has been suggested, as noted above, that boys are more dependent
than girls on an effective serotonin system for sensing the accumulation of carbon dioxide and
responding appropriately to clear it.

        Also, J.B. was put to bed on his back. At J.B.’s two last appointments, Dr. Wright noted
that he slept on his back. The available evidence indicates that he rolled onto his side but was
not prone. His mother described in the police reenactment that he had turned to his right side
and his head was turned slightly downward. Nothing in the notes of the reenactment indicated
that the baby’s mouth or nose were in or close to the bedding, and in her police interview his
mother noted that his nose and mouth were not covered. His father indicated that he had a fever
when he was put down for his nap.
98
     Kadhim et al. (2010), Exhibit 13-O at 122.

                                                  41
        Thus, petitioners theorize that he did have a fever during the night, early morning and
before his nap. Dr. Miller testified that the fever documents the effect of inflammatory
cytokines, likely IL-1 and/or IL-6 signaling from the periphery to the hypothalamus to cause the
fever. They also theorize that the fever elevates body temperature, which is another risk factor
for SIDS. According to petitioners’ theory, because J.B. had no evidence of illness or infection
prior to vaccination, it is therefore highly likely that the fever was generated by the vaccines,
which likely caused a cascade of cytokines to cross the blood brain barrier and further suppress
the function of the already underdeveloped medullary serotonin system during sleep. This
caused his death to occur within about 28 hours of the administration of the four-month vaccines.
        Respondent disagrees, saying that J.B. was premature, an African American boy, and was
side sleeping, all of which are risk factors for SIDS. Citing the principle of Occam’s Razor, he
argues that it is unnecessary to consider anything beside these known risk factors and that the
proximate timing to the administration of the vaccines can be explained by coincidence given
that the peak time period of the occurrence of SIDS deaths coincides with the timing of the two
month and four month vaccine administration schedules. He further argues that there has not
been epidemiology to substantiate a causal relationship between vaccines and SIDS. Dr.
McCusker argued that the role of mild infection in relation to SIDS deaths is one of obstructing
airways rather than one of chemosensitivity, and she discussed her experience of suctioning the
noses of infants brought into the emergency room with upper respiratory infections.

        Dr. Miller and Dr. Harris agreed that an ideal autopsy would have sectioned the ventral
medulla and that that was not done in this case. They also agreed that the type of histological
examination that was done by Dr. Kinney and others would be unlikely to be done in a standard
autopsy. Tr. 339. They agreed that there is not definitive proof of defective medullary
structures.

                    B.       Althen Prong One

         After extensive review of the literature in the field of SIDS causation and listening to the
testimony of the experts in this case, I think it is clear that the Triple Risk Model is broadly
accepted as the general structure for understanding SIDS, even if the lack of comprehensive
autopsies do not allow the medical profession to say that SIDS always has a deficient medullary
serotonin system, as demonstrated in up to 75% of the cases examined by Dr. Kinney and her
group.99 She has said that “the most compelling hypothesis is that SIDS is related to a brainstem
abnormality in the neuroregulation of cardiorespiratory control.”100 She further observed,
“according to the Triple Risk Model, only infants with an underlying brainstem disease process
die of SIDS, which explains why all infants who are placed prone to sleep or who bed share do
not die of SIDS. They do not have the underlying vulnerability.” Id. at 521. Dr. Miller opined
that it is likely that J.B. had this defect based on the data from these studies. Tr. 37. Dr.
McCusker agreed, “according to the triple-risk theory that the brain problem must exist.” Tr.
206. The “brain problem” described in the triple-risk literature is that in the respiratory control
center in the medulla. As such, it is reasonable to conclude that the petitioners have shown by a

99
     Kinney & Thach (2009), Exhibit A-4 at 6.
100
      Kinney et al. (2009), Exhibit 13-H at 519.


                                                   42
preponderance of the evidence that an infant who has died of unknown causes, and in whom
autopsy has ruled out other causes, had the inherent brainstem vulnerability. I do conclude that
J.B. did.

        There is also no disagreement that the Back to Sleep Campaign convincingly
demonstrated the danger of prone sleeping. By persuading parents to place babies on their backs
to sleep during the vulnerable risk period, the campaign brought about an approximate 50%
reduction in the rate of SIDS. Side-sleeping has also been recognized as having an elevated
relative risk for SIDS, but the reason for this is not entirely clear. Dr. McCusker stated at some
length her understanding of the mechanics of breathing in an infant. Essentially, she explained
that the diaphragm drops down creating negative pressure within the lung relative to the
atmosphere, at which point air rushes in. She suggested that the stomach muscles which the
baby uses to help drop the diaphragm are compressed, as are the soft ribs in infants who are
prone or side-sleeping, which reduces the gas exchange. Tr. 129-32. Dr. Miller disagreed with
her explanation of respiratory physiology in that he did not find persuasive the notion that side-
sleeping in a four-month-old is going to inhibit the ability to have inspiratory motion in the
diaphragm, which creates the negative pressure in the lungs. Rather, he said the literature in
SIDS has emphasized the pocket of air and re-inhaled carbon dioxide. Tr. 354.

         The policy statement by the American Academy of Pediatrics, which was repeatedly
referenced by Dr. McCusker but not marked as an exhibit, says that the risk of side-sleeping is
similar in magnitude to prone sleeping (2.0 vs. 2.6).101 The statement appears to focus on the
risk of turning if the infant is placed on his side. “The risk of SIDS is exceptionally high for
infants who are placed on their sides and found on their stomach. The side sleep position is
inherently unstable, and the probability of an infant rolling to the prone position from the side
sleep position is significantly greater than rolling prone from the back.” Id. at 7. Interestingly ,
the same report addresses the issue of children who are able to roll over, which it notes generally
occurs at 4-to-6 months of age, and that as they age it is more likely that they will roll. The
Academy recommends, “If the infant can roll from supine to prone and from prone to supine, the
infant can then be allowed to remain in the sleep position that he or she assumes.” Id. at 8.

        In this case, J.B. was placed supine and he rolled to his side, but not prone. It would
appear from this policy statement that the greatest concern with side sleeping is when the infant
is placed on its side and can easily roll to the prone position. The fact that the Academy
recommends allowing the baby to remain in the position to which he rolls after being placed
supine suggests that it is likely that a baby who can roll probably also has developed the ability
to raise and turn his head.

         All of the experts in this case appeared to agree that at least the predominant thinking in
medicine as to the cause of SIDS is explained by the Triple Risk Model. Although as Dr. Harris
testified we do not know with certainty that the medullary serotonergic network deficiency is
always present because a great many autopsies, such as the one in this case, are not adequate to

  Moon R.Y. et al., American Academy of Pediatrics – Task Force on Sudden Infant Death Syndrome, SIDS and
101

Other Sleep Related Infant Deaths: Expansion of Recommendations for a Safe Infant Sleeping Environment, 128
Pediatrics 1030 (2011), available at http://pediatrics.aappublications.org/content/128/5/1030.long.


                                                     43
document that deficiency, it was also recognized that as Dr. Kinney stated in a 2009 paper, “only
infants with an underlying brainstem disease process die of SIDS.”102 Dr. McCusker agreed that
according to the triple risk theory the brain problem must exist. Tr. 206. There has also not been
significant debate about the statistical relevance of the other intrinsic risk factors. The success of
the Back to Sleep Campaign in educating the public about the danger of prone sleeping has been
remarkable in reducing SIDS deaths by half. But the other half still occur. The question
remains as to what extrinsic risk factors come to play at that “fatal intersection of vulnerability,
critical period and stressor.”103 The literature strongly suggests that SIDS is likely to be multi-
factorial. Some cases are likely to be caused by continued prone sleeping, but others are likely
caused by other factors. Mild infections, often described as “trivial” infections, appear to be a
factor as they have been reported to be present in nearly 50% of SIDS deaths, raising the
question of what it is about mild, otherwise non-life threatening infections that appear to interact
with the impaired medullary serotonin system during the vulnerable period to cause the “perfect
storm” that results in an unexplained death of a child?

         Dr. Miller, relying on multiple pieces of research described in the SIDS literature, opined
that it is likely that the cytokine signaling triggered in the immune system by mild infection
interacts with the underdeveloped 5-HT system in the brainstem, during sleep when the
excitatory function of serotonin is reduced, to further suppress the function of the brainstem to
cause a cardio-respiratory crisis. The further issue raised is whether, in the absence of a mild
infection, can the multiple vaccines administered together – in this case the day before – trigger
the same cytokines as does a mild infection with the same fatal result? Dr. Miller concluded
that they do.

        Petitioners refer to the significant number of SIDS deaths that document the co-
occurrence of mild or trivial infections which appear to stimulate a cytokine response similar to
that generated by severe infections with adverse or repressive effects on the 5-HT system for
chemosensitive response to hypercarbia, leading to failure to arouse and failure to initiate a
gasping reflex and ultimately death. Petitioners are not the first to suggest this theory. Dr.
Kinney has written, “A causal role for mild infection in sudden infant death is suggested by
reports that in approximately half of SIDS cases, the infants have a seemingly trivial infection
around the time of death, as well as mild tracheobronchial inflammation and altered serum
immunoglobulin or cytokine levels and the presence of microbial isolates at autopsy. In infants
who die unexpectedly of infection, the given organism may precipitate a lethal cytokine cascade
or toxic response.”104 Another article by her group explained the likely mechanism: “During
infection, peripherally produced IL-6 may cross the blood brain barrier and bind to IL-6
receptors on 5-HT neurons that mediate homeostasis in response to the infectious stressor and
potentially mediate sickness behavior. …We found ubiquitous expression of IL-6 receptors and
gp130 neurons in all regions in the infant medulla, including those effector nuclei critical to
respiratory and autonomic control, and those that contain 5-HT source neurons. Serotonergic

102
      Kinney et al. (2009), Exhibit 13-H at 521.
103
      Filiano & Kinney (1994), Exhibit 13-B at 197 [also filed as Exhibit A-2].
104
      Kinney & Thach (2009), Exhibit A-4 at 2 (emphasis added).


                                                           44
neurons in the caudal 5-HT system, including in the raphe obscurus and arcuate nucleus, express
IL-6Rs on somata and processes, indicating the site of IL-6/5 HT interaction.”105

        Various authors have identified the presence of IL-1β, IL-6, and IL-2, which are all pro-
inflammatory cytokines, in elevated levels in the infant medulla in SIDS. Stoltenberg studied the
effects of injection of IL-1β in piglets, and theorizes that in addition to cytokines being
transported to the brain by retrograde axonal transport, his findings suggested an equally
important alternative route in the immune-stimulation of the brain, inducing hypoxia and sudden
infant death. He said that it has been shown that IL-1β is internalized by blood brain barrier
endothelial cells, which implies that this cytokine passes through the blood brain barrier at the
endothelial rather than the ependymal or blood cerebrospinal fluid part of the brain barrier. He
found in his experiments with piglets that IL-1 stimulates the release of β-endorphin and the
level of β-endorphin in CSF correlates strongly with the duration of apnea. Further, he found
that “IL-1β stimulates GABA-transmission and hence increases the inhibitory postsynaptic
function by opening of chloride-delective channels, and this will reduce the activity in the central
respiratory neurons and may produce hypoxia.”106 Dr. McCusker referred to an article by
Besedovsky for the proposition that cytokines are produced in the brain, suggesting that
cytokines active in the brain necessarily originate in the brain. However, on review of the
article, Besedovsky also noted that some cytokines such as IL-1 and IL-6 are produced both
peripherally and within the brain.107 He postulated that tripartite synapses possess the cellular
and molecular components to function as a “relay system” capable of receiving and integrating
peripheral immune signals with central neural signals. Id. at 5.

         One of the best understood functions of cytokines in the case of infection and vaccination
is the triggering of fever. When this occurs, cytokines from the periphery at the site of the
infection travel to the brain, in particular to the hypothalamus, which then causes fever. As J.B.
had a fever in the day following vaccination after having a completely clear medical examination
the day before, Dr. McCusker agreed with Dr. Miller that in order for fever to have occurred
there had to be a hypothalamic signal, which is mediated by endogenous pyrogens, i.e. IL-6 or
TNFα. Tr. 286. The literature also recognizes IL-1 and others which are known pyrogens as
well. She also agreed that in the absence of an infection, the only thing we can attribute the fever
to is the vaccine. Tr. 205.

        After identifying a plausible mechanism for the means of activation of cytokines in the
medullary brainstem from a peripheral source, the next key question is why does mild or trivial
infection appear to occur in conjunction with SIDS? It is not the infection itself which causes
death, as by its mild nature it is not life threatening. Whether the infection is mild or severe, it
triggers the innate immune response, which in turn triggers the release of cytokines. As Dr.
McCusker explained, cytokines are small molecules that are released by different cell types
originally described in immune cells. They are viewed primarily as communication molecules,

105
      Kinney et al. (2011), Exhibit 13-F at 191.
106
      Stoltenberg et al. (1994), Exhibit 13-J at 427.
107
  Besedovsky, H.O. and A. del Ray, Central and Peripheral Cytokines Mediate Immune-Brain Connectivity, 36
Neurochem Res. 1 (2011), Exhibit C-3 at 1.


                                                        45
because they are released by one cell and bind to another through a series of signaling steps. Tr.
145. Dr. Miller explained that cytokines are messenger molecules that have a lot of different
effects which were first identified as products of the innate immune system, but are seen
elsewhere as well, including the brain. IL-6 binds with 5-HT and IL-1 has been shown in
animals to inhibit 5-HT firing. Tr. 30. There was no disagreement between the experts or in the
literature that cytokines are released by the innate immune response to infection, whether it be
mild or severe.

        The Siljehav-Hofstetter article filed by respondent provides an additional theoretical basis
for the role of cytokines in SIDS. The authors found that IL-1β stimulates a prostaglandin
(PGE2) with receptors in the rostral ventrolateral medulla. They explained that once stimulated
by IL-1β, PGE2 induced depression of this vital brainstem neuronal network, e.g., during an
infectious response, that could result in gasping and autoresuscitation failure and ultimately
death.”108

        Dr. Miller found further support in the work of Kadhim, who found overexpression of IL-
1β in the arcuate nuclei in 17 of 17 SIDS brains studied, but only in 1 of 6 non-SIDS brains.109
Kadhim noted that cytokines could exert neuromodulatory effects in the ascending reticular
activating system, which is involved in the arousal reflex. He noted that IL-1 causes prolonged
apneas and depresses respiration and the brain appears to be less effective than the periphery in
inducing IL-1 antagonist to terminate IL-1β actions. He hypothesized that the particular pattern
of neuronal cytokine he detected might therefore overturn a subtle equilibrium in a molecular
chain involving vital brain centers, causing SIDS. Id. at 1259.

        In a second study involving SIDS brains, Kadhim’s group noted that SIDS victims often
have preceding mild infections and that cytokines have neuromodulatory effects whereby they
can modify neurotransmission. In this study, they compared the brainstems of SIDS victims to
those of infants who died of diverse severe pathological conditions, mainly infectious,
hemodynamic, metabolic, severe congenital, or other serious conditions. They found that IL-2,
another inflammatory cytokine, was preferentially expressed in specific neuronal centers within
the brainstem. In this study, they found equally intense immune reactivity within the arcuate and
dorsal vagal nuclei in fatally sick infants, as with SIDS victims who had no obvious or detectable
serious health condition before death. They hypothesized that a hyperimmune response to mild
infection in the SIDS babies may result in a molecular disequilibrium which tips the delicate
molecular balance, causing dysfunction in those vital brainstem centers and producing disturbed
homeostasis with potentially drastic effects on target organs/systems and eventual death.110




108
      Siljehav (2012), Exhibit C-9 at 9897.
109
      Kadhim et al. (2003), Exhibit 13-L at 1256.
110
      Kadhim et al. (2010), Exhibit 13-O at 122-26.


                                                      46
       Brambilla also provided some support for this theory by demonstrating in animals that
IL-1 inhibited firing of neurons that promoted wakefulness in the dorsal raphe nucleus and
enhanced activity of GABAergic neurons which are inhibitory and induce enhancement of
NREM sleep.111

        Rognum further compared brains of SIDS victims to those of babies who died of severe
infections and to another group who died from drowning, suffocation, strangulation, or other
violent causes. They found that the SIDS babies had higher cytokines in the medullary
brainstem than did those who died of violent causes but their levels were not as high as those that
died of infectious causes. In a small section of their study, the Rognum group found elevations
of IL-6R in the arcuate nucleus in the SIDS and infection groups relative to the controls.
However, they found that the gp130, which is necessary for IL-6 to function, did not rise as high
above the controls as did the infection group, although it was higher than in those dying violent
deaths. This caused them to speculate that the IL-6R might be reactive to an excess carbon
dioxide crisis rather than its cause. Thus significant evidence has been produced to show that
cytokines are abundantly present in the medullary brainstem of SIDS infants relative to those
dying of other causes which strongly suggests a hyperimmune response to mild infection in these
children well out of proportion to the mild or trivial infection that they had. The presence of
these cytokines also appears likely to suppress the 5-HT response to the accumulate of carbon
dioxide in the body and the ultimate failure of the respiratory response system.

         The next important question is whether the vaccines can play the same cytokine
generating role as mild infection in a child who does not have an infection. If, as his father
described, the child developed symptoms such as a fever, crankiness and not being himself, signs
of cytokine activation, and had no evidence of infection, could one or more of the seven
vaccines he received the day before have generated a cytokine cascade that caused him to be
unable to respond to elevated carbon dioxide in his system, whether it was produced by
rebreathing or metabolically? Dr. Miller’s thesis was that the main role for mild inflammation as
a risk factor for SIDS is thought to be in elevating cytokines. He said that is explicit in multiple
articles that have been submitted. Then, if vaccines produce the same cytokine responses as very
mild upper respiratory infections, which is what is demonstrated by Kashiwagi, it would seem
logical to impute both having the same effect on the central nervous system. Tr. 370.

       Indeed, Kashiwagi conducted testing with multiple vaccines and studied the cytokine
response. He found that there was a more significant response in children who received three or
four vaccines at one time than in those who received fewer, and he found that higher IL-1β
production was noted in young infants, but decreased at around 2 years or older.112

        He also examined the cytokine profiles in 61 serum samples obtained from recipients
who exhibited febrile illness within 24 hours of being vaccinated and 18 serum samples from
recipients without febrile illness. The samples were taken within 48 hours of vaccination in both
groups. These were compared to each other and to cytokine profiles of ten normal subjects

111
      Kinney et al. (2009), Exhibit 13-H.
112
      Kashiwagi et al. (2014), Exhibit 17 at 680.


                                                    47
without vaccination. “Higher levels of IL-6, IL-10, IL-12, G-CSF,113 and IFN-α were detected in
both the febrile and non-febrile vaccination subjects in comparison with those in normal
subjects.” Id. at 680.

        The Lee and Schulzke studies of multiple vaccine administration to premature infants,
referenced above, found an elevation in the rate of apnea, bradycardia, and, in the Lee study,
oxygen desaturations (Schulzke did not look at desaturations). Both authors hypothesized that
the adverse events may be related to the immune response to the vaccines, particularly as Lee
found there was no difference in the rate of adverse events between whole cell pertussis and
acellular pertussis. 114 Schulzke noted that the adverse events occurred within 6 to 24 hours of
vaccination.115 While not studying SIDS, these studies focused on premature infants in a
controlled environment – a hospital – where the mechanism that is hypothesized to occur in
SIDS could be rapidly recognized, addressed, and treated. It seems quite likely that the same
sequence occurring post-administration of multiple vaccines may be what occurs in the
uncontrolled environment of the home when the child and often the parents are sleeping, or at
least not in the same room with the child when the combination of events leading to the fatal
sequence occurs.

        Dr. Miller’s theory, consistent with many of the articles in the literature, is that SIDS is
multifactorial. Multiple factors come together at the fatal moment that causes the perfect storm
leading to death. He theorizes that the cytokines triggered by the vaccines in the initial innate
immune response to the vaccines travel to their receptors in the arcuate nucleus and suppress the
serotonin function in a child whose functionality in that area is already impaired by an
underdeveloped or defective 5-HT system while he is asleep, which further reduces 5-HT
function. The input of the cytokines stimulated by the vaccines causes the lack of response to
elevation of carbon dioxide that converts a recoverable event to a fatal one. Whether the vaccine
generated cytokines cause additional metabolic activity generating fever and additional
production of carbon dioxide, or whether they caused the neurons in the brainstem to be unable
to respond to rebreathed or accumulated carbon dioxide, it is probable that they played an
important role in causing the death of this infant.

         Dr. McCusker disagreed. She argued that the presence of the various intrinsic risk factors
together with a flat pillow in the bed and side-sleeping to which the child turned after being
placed supine was sufficient to explain the death. She argued that the role of mild infection was
that it caused obstruction in the nasal passages in infants who are “obligate nose breathers” (Tr.
138) and mucous in the nose would obstruct the breathing of the child sufficient to cause death.
She referred to infants she sees in the emergency room with upper respiratory tract infections
who need to be suctioned which then brings down their carbon dioxide level. Tr. 139-40. Dr.
Miller disagreed. He stated that he had never seen a SIDS autopsy where the death was

113
   G-CSF is an abbreviation for granulocyte colony stimulating factor. It is another cytokine which mobilizes and
recruits neutrophils to the site of inflammation from the marginal pool. Kashiwagi et al. (2014), Exhibit 17 at 693.
114
  Lee, J. et al., Frequency of Apnea, Bradycardia, and Desaturations Following First Diphtheria-Tetanus-
Pertussis-Inactivated Polio-Haemophilus Influenzae Type B Immunization in Hospitalized Preterm Infants, 6 BMC
Pediatr. 20 (2006), Exhibit 20.
115
      Schulzke (2005), Exhibit 21 at 3.

                                                         48
attributed to nasal passage obstruction by mucous and that he had never seen any literature to
support that concept. Tr. 355.

         The literature certainly suggests that Dr. McCusker’s interpretation of the role of mild
infection was too limited in that she ignored the entire concept of brainstem chemosensitivity in
response to carbon dioxide accumulation. Dr. Kinney wrote, “Serotonergic neurons at the
medullary ventral surface and in the midline (raphe) are now known to be preferentially
chemosensitive to CO2 and although they are not the only central chemosensitive neurons they
appear to play a critical potentially modulatory role. … A small but important population of 5
HTE neurons is embedded within the human arcuate nucleus suggesting that the putative
dysfunction in chemosensitivity related to the arcuate anomaly specifically involved these
embedded 5 HT neurons.”116 In an article in the New England Journal of Medicine, Kinney
wrote, “the arousal from sleep that is triggered by abnormal levels of carbon dioxide and oxygen
is essential for the initiation of protective airway responses. … Arousal involves a progressive
activation of specific subcortical to cortical brain structures and consists of ascending and
descending components that mediate cortical and subcortical arousal respectively.”117 The
importance of the chemosensitive role in the stimulation of breathing, arousal, and ultimately
gasping in response to the accumulation of excess carbon dioxide appears critical to all of the
triple risk hypotheses. A stuffy nose does not explain the inability of the neurons in the arcuate
nucleus to modulate breathing rhythm and respond to excess carbon dioxide by initiating
breathing, particularly when there was no evidence of mucous congestion in the nose the day
before at the medical exam, in the report of the parents, or at the autopsy. The role of cytokines
stimulated by vaccines administered approximately 28 hours before seems much more likely to
play a critical role, similar to that of mild infection in causing the ultimate convergence of the
multiple factors leading to death. The inhibition of the 5-HT response, beyond its initially
impaired level with which the child had lived to that date, seems more likely to be caused by the
cytokine response to the multiple vaccines than to a stuffy nose or the side-sleeping position to
which he had turned, particularly when there was no evidence of nasal congestion or of the
breathing passages being obstructed. Exhibit 7 at 5. In fact the evidence was to the contrary.

        Dr. McCusker, citing to the Imeri article118 on sleep in general, also testified that fever
would tend to push the child out of REM sleep and into NREM, which she argued would make
him more arousable. A review of the Imeri article, which discusses the immune system and
sleep in general, and not specifically in infants, does indeed discuss the role of fever and the
generation of shivering in NREM sleep and that during the course of most infections there is an
increase in the amount of time spent in NREM sleep and a decrease in the amount of REM sleep.
Id. However, it also discusses the role of IL-1 and the generation of GABAergic inhibitory
cytokines. Id. at 205. Imeri also acknowledged the role of peripherally generated cytokines in
the regulation of sleep. Imeri concluded that at present we know little about these mechanisms


116
      Kinney et al. (2009), Exhibit 13-H at 522.
117
      Kinney & Thach (2009), Exhibit A-4 at 5.
118
  Imeri L. & M.R. Opp, How (and Why) the Immune System Makes Us Sleep, 10 Nat. Rev. Neurosci. 199 (2009),
Exhibit C-6 at 201.


                                                    49
by which cytokines inhibit REM sleep and argued that it is important because REM sleep is
disrupted in many pathologies that involve altered cytokine concentrations. Id.

         Dr. Miller hypothesized two roles for fever – overheating and travel of cytokines to the
brain in the mechanism of SIDS. Dr. McCusker agreed with cytokine signaling as relevant to the
production of fever but disagreed that fever was the equivalent of hyperthermia in the SIDS
literature. On the witness stand she drew a sharp distinction between environmental
hyperthermia and overheating secondary to fever, which she called hyperpyrexia. The literature
was unclear on this point. But the significant importance of fever to this case was in
demonstrating the travel of peripheral cytokines stimulated by the vaccines across the blood
brain barrier to the hypothalamus. Fever is the most obvious manifestation of the signaling of
cytokines from the peripheral location of the vaccinations to the brain. The SIDS literature
suggests that production of inflammatory cytokines IL-6, IL-10, IL-12, and IFNγ in response to
DPT, Hib, and PCV7 were detected in both febrile and non-febrile groups, with febrile illness
appearing 12-16 hours post vaccination.119 NREM sleep is also implicated in SIDS. A
distinctive feature of 5-HT neurons is that they exhibit differential firing rates according to the
level of arousal, with increased firing during waking, decreased firing during NREM, and almost
complete absence of firing during REM. Given the relationship of the firing of raphe 5-HT
neurons to arousal, the medullary 5-HT system is postulated to modulate and integrate
homeostatic function according to the level of arousal.120 Thus, particularly in the deeper levels
of NREM sleep, the 5-HT system is also functioning at lower levels, potentially contributing to
the multi-factorial causal picture.

        After review of all of the above, I have concluded that petitioners have presented a
reasonable and reliable theory of vaccine causation involving the role of inflammatory cytokines
acting as an extrinsic stressor in a baby with a brainstem deficit during the vulnerable time
period. It is particularly important to note that the literature indicates that SIDS is likely caused
by a multi-factorial process. Dr. Kinney wrote in the New England Journal of Medicine in 2009,
“Current evidence suggests that SIDS involves a convergence of stressors that probably results in
the asphyxia of a vulnerable infant who has defective cardiorespiratory or arousal defense
systems during a critical developmental period when immature defense mechanisms are not fully
integrated. Thus our current understanding of the pathogenesis of SIDS reflects the simultaneous
juxtaposition of multiple events that, when taken individually, are far less powerful than the
result of their chance combination.”121 In another 2009 article she wrote; “We now
conceptualize SIDS as the biologic version of the perfect storm, in which the simultaneous and
chance combination of multiple events is far more powerful than any individual event alone.”122



119
      Kashiwagi et al. (2014), Exhibit 17 at 680.
120
  Kinney, H.C., Brainstem Mechanisms Underlying the Sudden Infant Death Syndrome: Evidence from Human
Pathologic Studies, 51 Dev. Psychobiol. 223 (2009), Exhibit 13-E at 226.
121
      Kinney & Thach (2009), Exhibit A-4 at 7.
122
      Kinney et al. (2009), Exhibit 13-H at 539.


                                                    50
       I have concluded that the petitioners have demonstrated by a preponderance of the
evidence that the vaccines can and likely did play a critical role in this child’s death by
stimulating the production of inflammatory cytokines that suppressed the respiratory response
system and caused the vulnerable infant to be unable to respond in the normal way to the
accumulation of carbon dioxide in his system. Accordingly, petitioners have satisfied the
requirement of Althen Prong One by presenting a reasonable explanation of how the vaccine
could cause or substantially contribute to the child’s death.

           C.        Althen Prong Two

        Althen Prong Two requires the demonstration of a logical cause and effect as to how the
vaccine caused the harm, in this case the sudden unexplained death of J.B. Under Althen Prong
Two, petitioners must prove that there is a “logical sequence of cause and effect showing that the
vaccination was the reason for the injury.” Capizzano, 440 F.3d at 1324 (quoting Althen, 418
F.3d at 1278).

         Dr. Miller testified that it was his diagnosis that J.B. died of SIDS and that the vaccines
were a substantial contributing factor to his death. Tr. 126. Having accepted the theory of a
causal role of vaccine stimulated cytokines as an exogenous factor converging with the first two
prongs of the Triple Risk Model, the question of logical cause and effect requires a review of the
likely mechanism and comparing it to the operative facts of the case. Kashiwagi in particular
found that cytokines began to be produced 6 hours after stimulation and increased until 24 hours,
showing the same level thereafter. Higher levels of IL-1B, IL-6, G-CSF, and TNFα were
produced in that study by the concurrent stimulation of three vaccines than by one alone.123 J.B.
received seven vaccines at his 4 to 5 month well baby visit with his pediatrician on September 2,
2011. He was carefully examined and documented to be in entirely good health the day before.
Overnight, he developed a mild fever, consistent with cytokine signaling from the vaccination
site to the brain. In the early afternoon of September 3, he died during his nap.

        Dr. Miller discussed the logical sequence of cause and effect explaining how he believed
the vaccines acted as an exogenous stressor which caused J.B. to succumb to SIDS. He noted
that J.B. was a “healthy infant… developing normally.” Exhibit 13 at 4. He was
“immunologically normal.” Tr. 61. Therefore, after receiving vaccinations, his body mounted
an innate immune response including the production of cytokines. Exhibit 13 at 6; Exhibit 16 at
1; Tr. 62. Those cytokines circulated in J.B.’s body, going to the central nervous system.
Exhibit 13 at 6; Tr. 62. These peripheral cytokines interacted with the hypothalamus to provoke
fever the night after the vaccinations and during the following day (before J.B.’s death). Exhibit
13 at 6; Exhibit 16 at 1; Tr. 62-64. “Those cytokines then acted in the brainstem which was
already deficient in serotoninergic drive for respiratory effort, leading to an apneic episode from
which he did not recover, i.e., SIDS.” Exhibit 13 at 6; see also Tr. 62 (the cytokines “depress[ed
the] 5-HT system in a defective medulla, leading to SIDS during sleep”).




123
      Exhibit 17 at 679.


                                                51
        He opined that there was “no other demonstrable inciting event” for J.B.’s death. Exhibit
13 at 1. There was no evidence of the fever being related to anything other than J.B.’s
vaccinations. Tr. 66. The autopsy did not identify any other infectious processes. Tr. 66.124

        On cross-examination, Dr. Miller stated that J.B. was placed on his back but was found
on his side, which demonstrates that he was able to “move around.” Tr. 92. However, J.B. did
not pass away until “something else intervened.” Tr. 85. Based on his theory and the temporal
association, Dr. Miller opined that the vaccines were the intervening factor that caused J.B.’s
death. Tr. 85.

         An innate immune response to either mild infection or to a vaccine is likely to be fast
and begins the process of immune attack of a foreign antigen. Part of that response is the
triggering of cytokines to signal further response in the immune system. The triggering of the
innate immune system by vaccination is necessary and fundamental to producing the adaptive
response and immune memory which vaccines are designed to produce. After review and
consideration of all of the testimony and the literature submitted, I have concluded that Dr.
Miller has presented a reasonable and persuasive theory that the cytokine cascade triggered by
the innate response to the vaccine antigens is similar to the cytokine response to a mild infection,
and that the inflammatory cytokines had an immune modulatory effect on J.B.’s impaired
medullary 5-HT system causing a prolonged apneic event resulting in his death. As such, the
progression from vaccination to an unexplained death within approximately 28 hours is logical.

        This logical progression is also consistent with reports of at least mildly elevated SIDS
deaths in some studies such as Traversa, which found a 2.0 relationship in the first 7 days.125
Goldman reported a statistically significant increase in deaths when 5 to 8 vaccines were
administered simultaneously as opposed to 1 to 4.126 Ottaviani127 and Zinka128 reported on SIDS
deaths within 48 hours of receiving vaccinations. Other studies, such as Kuhnert129, found
neither a protective effect nor elevated risk, but Kuhnert noted that the small number of cases is a
problem with the three case control studies he reviewed, particularly in view of the short time
periods under investigation. According to Kuhnert, this problem was illustrated by the very
broad confidence intervals of estimates that were related to the first few days. Id. at 2355.




124
   Dr. Miller noted that there were bacterial growth and food particles in J.B.’s lungs and epithelial cells in the
upper airways. He opined that this was not evidence of a separate infectious process. He agreed with the medical
examiner that these were terminal or resuscitative sequelae. Tr. 17-18; 66; 352-53.
125
      Traversa et al. (2011), Exhibit 13-U at 8.
126
      Goldman & Miller (2012), Exhibit 19 at 1016.
127
      Ottoviani et al. (2006), Exhibit 13-T.
128
      Zinka et al. (2006), Exhibit 13-S.
129
      Kuhnert et al. (2012), Exhibit C-20.


                                                         52
         The statistical prevalence of boys, African Americans and premature babies among the
victims of SIDS also seems to be clear and causes their inclusion as intrinsic risk factors. I think
it is reasonable to question in this case whether the influence of prematurity would still be a
likely factor, given that he had nearly reached the age of five months and appeared to be
developing very well. It is also reasonable to question whether the statistical prevalence of
African Americans should be a significant factor, as it is often speculated that this may be a
function of socioeconomic status and poor medical care. This child appeared to have been living
in a two-parent household, with attentive parents, was well-nourished, and was receiving good
medical care. The role of his male gender may well have been important, as Dr. Kinney has
reported a greater reduction in 5-HT-1A in the medullary raphe in males compared to females
dying of SIDS.130

         Given that Dr. Miller’s thesis and that of much of the literature for the Triple Risk Model
is that SIDS results from the convergence of multiple factors, it seems likely that his male gender
may well have been a contributing intrinsic factor that may have amplified the effect of the
cytokine response to the vaccines on the day that he died. But, his gender, his race, and his
prematurity – all intrinsic factors – do not explain his death without the interaction with a critical
extrinsic factor, which I have concluded was likely the cytokines triggered by the vaccines which
depressed his 5-HT system sufficiently that he did not respond when carbon dioxide became
elevated in his system.

        The evidence for J.B.’s death occurring as a result of his having turned to his side without
a causal input from another significant extrinsic factor such as the vaccine stimulated cytokines
suppressing his response system is weak in this case. As noted above, the Academy of Pediatrics
recommends leaving a child in the assumed position when he has rolled from his back
presumably because it is also likely that he can push up and lift his head by the time he can roll.
This capability was documented in J.B’s case by his pediatrician. Although there was a flat
pillow and a light blanket in the bed, J.B.’s mother told the police investigators that his head was
not covered and that his head was turned downward only slightly. The scene investigation noted
her report that J.B.’s mouth and nose were not covered. Exhibit 7 at 5. It was described that he
had been put to sleep in the middle of the bed. Thus, there is no evidence in this case that the
baby’s breathing passages were obstructed or that he was breathing into an air pocket. The
possibility of rebreathing carbon dioxide in that position cannot be ruled out, but seems less
likely based upon this evidence derived from the extensive interviews and the site re-enactment
performed by the responding police. Thus, even if the side- sleeping position did cause some
rebreathing of carbon dioxide, I have concluded from the evidence that it is most likely that the
cytokines stimulated by the vaccines caused suppression of the already impaired medullary
serotonin system with the consequent failure to chemically sense elevated carbon dioxide, which
caused the ultimate failure to arouse and to breathe normally thus substantially contributing to
the death of J.B

       The emphasis of the Triple Risk Model on prone sleeping has had a powerful impact in
reducing SIDS deaths by approximately 50%. But there remains a significant number of SIDS
deaths each year, some of which are likely related to continued prone-sleeping and some to side-
sleeping. But the co-occurrence of mild infection in the statistics in nearly 50% of cases raises a
130
      Kinney et al. (2009), Exhibit 13-H at 532.

                                                   53
significant issue about the operative extrinsic risk factor or factors in the remaining cases,
including many that are found supine. In this case, an apparently perfectly healthy child was
found dead a day after vaccination, having had a mild fever in the interim without evidence of
infection. He was not prone sleeping but had turned to his side, with no evidence that his
breathing passages were in any way impaired. Significant literature introduced demonstrates that
the triggering of inflammatory cytokines in response to vaccines is similar to that raised in
response to mild infection. J.B.’s post-vaccinal fever provided confirmation of responsive
cytokine activity. The cause and effect between the vaccines, the cytokines triggered by the
vaccines, and their co-occurrence with other intrinsic and/or extrinsic risk factors in the presence
of a defective or underdeveloped brainstem seems likely to have produced the perfect storm that
resulted in J.B.’s death. Thus, I am persuaded that petitioners have proved prong two.

           D.        Althen Prong Three

        Under Althen prong three, petitioners must provide “preponderant proof that the onset of
symptoms occurred within a timeframe for which, given the understanding of the disorder’s
etiology, it is medically acceptable to infer causation-in-fact.” De Bazan, 539 F.3d at 1352. The
acceptable temporal association will vary according to the particular medical theory advanced in
the case. See Pafford, 451 F.3d at 1358. A temporal relationship between a vaccine and an injury,
standing alone, does not constitute preponderant evidence of vaccine causation. See, e.g., Veryzer
v. Sec’y of Health & Human Servs., 100 Fed. Cl. 344, 356 (2011) (explaining that “a temporal
relationship alone will not demonstrate the requisite causal link and that petitioner must posit a
medical theory causally connecting the vaccine and injury”).

        Dr. Miller stated that the available evidence is that foreign antigens, like those contained
in vaccinations, activate the production of cytokines “within hours” and that production “peaks
within 2 to at most 4 days.” Exhibit 16 at 1. Thus, a vulnerable infant who receives vaccinations
is most likely to suffer a fatal event if one is to occur “within the first 48 hours to at most 4
days.” Exhibit 13 at 5. Dr. Miller opined that J.B.’s death was “well within this vulnerable
period.” Id.

         In this case, the timing of the innate immune response to the multiple scheduled
vaccinations that J.B. received on September 2, to his death the following afternoon appears
entirely appropriate for an innate immune response in the vulnerable risk period for SIDS. It is
also consistent with reports of at least mildly elevated SIDS deaths in some studies and reports of
deaths that occur within the first several days after the vaccination. In this case, one day post-
vaccination is appropriate timing, in that inflammatory cytokines stimulated during the innate
immune response to the vaccine antigens are likely to be active in close proximity to the
stimulating event. As Dr. Miller stated, an adverse event that can be caused by the inflammatory
cytokine response to vaccine antigens would be likely to occur within a few days of the
vaccination. The cytokine response has been shown by Kashiwagi131 to occur within 6 to 24
hours of the vaccination, and the very essence of the innate immune response is one that occurs
rapidly after the invasion by a foreign antigen. As noted above, that rapid innate immune
response is necessary to initiate the ultimate adaptive immune response necessary to achieve the

131
      Kashiwagi et al. (2014), Exhibit 17 at 679.


                                                    54
design purpose of vaccination. The close temporal relationship of the child’s death to the receipt
of seven vaccines is reasonable and consistent with the theory of neuro-modulation in the arcuate
nucleus by the cytokine response to the vaccines. Accordingly, I am persuaded that prong three
of Althen has been satisfied.

       IV.      CONCLUSION

        In this case, I have concluded that petitioners have presented sufficient evidence and
testimony to entitle them to compensation in the Vaccine Program. I have not concluded that
vaccines present a substantial risk of SIDS. In fact, the evidence is to the contrary. The vast
majority of vaccine recipients do not succumb to SIDS. Under the multi-factorial analysis of the
Triple Risk Model, it is theorized that the ultimate fatal event may occur when multiple factors
converge during this vulnerable period to cause death when one stressor acting alone may not
have. As Dr. Kinney wrote, “Current evidence suggests that SIDS involves a convergence of
stressors that probably results in the asphyxia of a vulnerable infant who has defective
cardiorespiratory or arousal defense systems during a critical developmental period when
immature defense mechanisms are not fully integrated. The convergence of these factors appears
to be far more powerful than any one taken individually.”132 Thus, even if J.B. were rebreathing
some carbon dioxide on this occasion, it was likely the combination with the cytokines that
caused depression of the 5-HT system that caused his death by blunting the normal
chemosensitive response to excess carbon dioxide. The multi-factorial analysis, including
vaccines as an extrinsic risk factor, meets the Shyface standard that the vaccine need not be the
sole or even predominant factor but must be a “but for cause” and a substantial factor in causing
the death. Shyface, 165 F.3d at 1352. In this case, I have concluded, after review of the
evidence, that it is more likely than not that the vaccines played a substantial causal role in the
death of J.B. without the effect of which he would not have died. The role of inflammatory
cytokines as neuro-modulators in the infant medulla has been well described and is likely the
reason for a significant number of SIDS deaths occurring in conjunction with mild infection. I
have concluded that it is more likely than not that the vaccine-stimulated cytokines had the same
effect in this vulnerable infant during sleep.

        Accordingly, petitioners are entitled to compensation. A separate damages order
will issue.

                  IT IS SO ORDERED.
                                                        s/ Thomas L. Gowen
                                                        Thomas L. Gowen
                                                        Special Master




132
      Kinney et al. (2009), Exhibit 13-H at 539.

                                                   55
