Boatmon v. Secretary of Health and Human Services

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 en

This text is long and has been trimmed here. Open the source document for the complete record.