Bucci v. Secretary of Health and Human Services ( 2019 )

In the United States Court of Federal Claims
OFFICE OF SPECIAL MASTERS
Filed: March 27, 2019
* * * * * * * * * * * * *
TIA BUCCI and NICHOLAS BUCCI, *
as parents of D.B., a minor, * PUBLISHED
*
Petitioners, * No. 11-513V
*
v. * Special Master Gowen
*
SECRETARY OF HEALTH * Entitlement; Hepatitis B (Hep B); Evans
AND HUMAN SERVICES, * Syndrome; Immune Thrombocytopenia
* (ITP); Hemolytic Anemia; Bystander
Respondent. * Activation.
* * * * * * * * * * * * *
Lawrence R. Cohan, Anapol Weiss, Philadelphia, PA, for petitioners.
Robert P. Coleman, United States Department of Justice, Washington, DC, for respondent.
DECISION1
On August 11, 2011, Tia Bucci and Nicholas Bucci (“petitioners”), on behalf of their
minor child, D.B., filed a petition in the National Vaccine Injury Compensation Program.2
Petitioners allege that D.B. developed Evans syndrome which was caused in fact by a Hepatitis
B (“Hep B”) vaccination received on March 4, 2009. Based upon a full review of all of the
evidence and testimony presented, I find that petitioners have not established that they are
entitled to compensation.3
1
In accordance with the E-Government Act of 2002, 44 U.S.C. § 3501 (2012), because this opinion contains a
reasoned explanation for the action in this case, this opinion will be posted on the website of the United States
Court of Federal Claims. This means the opinion will be available to anyone with access to the internet. As
provided by 42 U.S.C. § 300aa-12(d)(4)B), however, the parties may object to the published Decision’s inclusion of
certain kinds of confidential information. Specifically, under Vaccine Rule 18(b), each party has 14 days within
which to request 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). If neither
party files a motion for redaction within 14 days, the entire opinion will be posted on the website and available
to the public in its current form. Id.
2
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. 3755, codified as amended, 42 U.S.C. §§ 300aa-10 to 34 (2012)
(hereinafter “Vaccine Act” or “the Act”). Hereinafter, individual section references will be to 42 U.S.C. § 300aa of
the Act.
3
Pursuant to Section 300aa-13(a)(1), in order to reach my conclusion, I have considered the entire record including
all of the medical records, statements, expert reports, and medical literature submitted by the parties. This opinion
discusses the elements of the record I found most relevant to the outcome.
I. BACKGROUND
A. Procedural History
On August 11, 2011, petitioners filed their claim that D.B.’s March 4, 2009 hepatitis B
vaccination was the cause-in-fact of his development of Evans syndrome. Petition (ECF No. 1).
On October 31, 2011, respondent filed a Rule 4(c) Report recommending against compensation.
Respondent’s Report (“Resp. Rept.”) (ECF No. 7). Respondent asserted that “Evans syndrome
is an idiopathic illness with no known cause,” petitioners had not yet submitted a report from a
medical expert to establish that the Hepatitis B vaccine was the cause-in-fact of D.B.’s Evans
syndrome, and “without the requisite medical opinion support,” petitioners’ claim would fail. Id.
at 9.4
Subsequently, on December 9, 2011, petitioners filed one report from Dr. Marcel
Kinsbourne. Petitioners’ Exhibit (“Pet. Ex.”) 3 (ECF No. 9).5 On February 17, 2012, respondent
filed the first report of Dr. Joan Cox Gill. Resp. Ex. A (ECF No. 13). Following a Rule 5 status
conference on March 14, 2012, the special master assigned to the case directed the parties to
jointly explore the potential for settlement of the case rather than proceeding in a litigation
posture. Order (ECF No. 14). On September 20, 2012, petitioners filed the first report of Dr.
Vera Byers. Pet. Ex. 7 (ECF No. 21).
The parties engaged in unfruitful settlement discussions until June 16, 2014, at which
point they reached an impasse and requested an entitlement hearing, which the presiding special
master agreed to set. Joint Status Report on June 16, 2014 (ECF No. 38); Scheduling Order on
July 2, 2014 (ECF No. 39). Afterwards, the case was transferred to the undersigned. Order
Reassigning Case on September 8, 2014 (ECF No. 42). On September 29, 2014, respondent
filed the first report of Dr. Hayley Altman Gans. Resp. Ex. D (ECF No. 44). On March 27,
2015, petitioners filed the first report of Dr. Edwin Forman, Pet. Ex. 14, and Dr. Byers’s second
report, Pet. Ex. 16 (both at ECF No. 50). Both parties briefed the case prior to hearing.
4
As discussed below, Evans syndrome is a very rare condition, even by the standards of the Vaccine Program.
However, it has been the subject of at least three prior claims. See Isom v. Sec’y of Health & Human Servs., No. 97-
770V, 1998 WL 835519 (Fed. Cl. Spec. Mstr. Nov. 3, 1998) (denying entitlement); Cohen v. Sec’y of Health &
Human Servs., No. 94-353V, 1998 WL 408784 (Fed. Cl. Spec. Mstr. July 1, 1998) (denying entitlement); but see
Mason v. Sec’y of Health & Human Servs., No. 14-487V, 2017 WL 3814643 (Fed. Cl. Spec. Mstr. Aug. 4, 2017)
(approving the parties’ stipulation awarding compensation to petitioners). These claims were before other special
masters and did not involve the experts involved in the present claim. I have reviewed these past opinions on Evans
syndrome, but I do not discuss them in this opinion because I reached my own independent conclusion based on the
evidence submitted in this claim.
5
Dr. Kinsbourne’s primary specialty is neurology. His curriculum vitae lists some early experience with pediatrics
but does not mention immunology, hematology, oncology, or blood disorders. Pet. Ex. 4 (ECF No. 9-2). His report
does not address whether he is qualified to opine on these topics. Pet. Ex. 3. Petitioners’ prehearing brief provides
that they would rely in part on Dr. Kinsbourne’s opinion. Pet. Prehearing Brief at 5. However, they do not provide
any citations or specific points from the same. At the entitlement hearing, petitioners’ counsel provided that they
“chos[e] not to call Dr. Kinsbourne so as not to be repetitive.” Tr. 4-5. Petitioners’ posthearing brief does not cite
to or reference any specific points from Dr. Kinsbourne. Thus, while I have reviewed and considered Dr.
Kinsbourne’s opinion in this case, it is not discussed in this opinion because I found it to be less relevant than the
opinions of the other experts.
2
Petitioners’ Prehearing Submission filed July 18, 2016 (ECF No. 70); Respondent’s Prehearing
Submission filed September 12, 2016 (ECF No. 76).
On November 1-2, 2016, an entitlement hearing was held in Washington, D.C. Petitioner
Ms. Tia Bucci offered fact testimony. Petitioners presented expert testimony from Dr. Forman
and Dr. Byers. Respondent presented expert testimony from Dr. Gans and Dr. Gill. During a
post-hearing status conference, I set forth issues that the parties needed to address further in
supplemental reports from Dr. Byers and Dr. Gans, as well as in their post-hearing briefs. I also
encouraged further efforts at settlement. Post-Hearing Order on November 15, 2015 (ECF No.
85). On November 29, 2016, the entitlement hearing transcript was then entered on the docket.
On December 16, 2016, petitioners filed Dr. Byers’ third report. Pet. Ex. 27 (ECF No. 90). On
January 17, 2017, respondent filed Dr. Gans’s second report. Resp. Ex. W (ECF No. 92).
After the parties reengaged briefly in settlement discussions, on July 18, 2017, petitioners
filed their post-hearing brief (ECF No. 106). On September 22, 2017, respondent filed his post-
hearing brief (ECF No. 109).
Petitioners submitted a revised settlement demand to respondent. Joint Status Report on October
10, 2017 (ECF No. 110). They then reported that settlement was not feasible. Joint Status
Report on November 13, 2017 (ECF No. 112). Due to the complexity of the case and
involvement of an extremely rare condition, on June 12, 2018, I referred the parties to alternative
dispute resolution. Order Referring to ADR on June 12, 2018 (ECF No. 119). However, they
were unable to settle the case. Order Removing from ADR on October 18, 2018 (ECF No. 121).
This matter is now ripe for adjudication.
B. Summary of Relevant Facts
1. Medical Records from Birth to the Hepatitis B Vaccination on March 3,
2009
D.B. was born at term, by cesarean section due to maternal hypertension and fetal
distress, on August 27, 2008. Pet. Ex. 1 at 5, 1089. He received primary care at the PEDI Group
Practice in Boston, Massachusetts. Id. at 1076. On September 4, 2008, at the one-week well
child visit on September 4, 2008, Dr. Ronald Benz recorded that D.B. was a “[t]hriving baby.”
Id. at 1102. On September 16, 2008, at the two-week well child visit, Dr. Benz noted pus in
D.B.’s eye and assessed him with conjunctivitis. Id. at 1097. On October 9, 2008, Dr. Benz
assessed D.B. with oral thrush and an upper respiratory infection (“URI”). Id. at 1092-93. On
October 20, 2008, at the two-month well child visit, D.B. was again assessed with thrush. Id. at
1091. At this same visit, D.B. received his first vaccinations for diphtheria-tetanus-acellular
pertussis (“DTaP”), inactivated polio vaccine (“IPV”), hepatitis B (“hep B”), haemophilus
influenzae type B (“Hib”), pneumococcal conjugate vaccine (“PCV7”) and rotavirus. Id. Later
that evening, D.B.’s mother brought him to the emergency department of Massachusetts General
Hospital for complaints of irritability and discomfort. Id. at 2. D.B. was noted to be afebrile and
was discharged home with instructions to take Tylenol for continued irritability. Id. at 5-6. D.B.
received vaccinations without complication on December 17, 2008; January 7, 2009; and
3
February 18, 2009.6
2. Medical Records Postdating the Hepatitis B Vaccination on March 3,
2009
On March 4, 2009, D.B. returned to the pediatric practice to complete his six-month
routine vaccination schedule. Pet Ex. 1 at 1074. At this visit, he received Hep B and Prevnar
(PCV7) vaccinations at this visit. Id.
Three days post-vaccination, on March 7, 2009, D.B. and his mother returned to the
pediatric practice. Pet. Ex. 1 at 1073. Dr. Hey Jin Chong recorded the mother’s history that over
the past few nights, D.B. had been waking up multiple times crying and tugging on his ear. Id.
Dr. Chong observed that D.B. was afebrile and was not experiencing URI symptoms. Id. D.B.
had normal ear canals with tympanic membranes clear and mobile. Id. at 1074. Thus, Dr.
Chong ruled out ear infection. Id. at 1075. D.B. was not experiencing “excessive bleeding,
bruising, [or] lymphadenopathy.” Id. at 1074. However, he had a dime-sized bruise with
induration on his right thigh, at the vaccination injection site. Id. Dr. Chong’s assessment was
“most likely pain/ irritability” following the vaccinations and directed his mother to give Tylenol
and return to the clinic if D.B. developed a fever or URI symptoms. Id. at 1075.
Eleven days post-vaccination, on March 15, 2009, D.B. and his mother returned to the
pediatric practice. Dr. Avram Traum recorded a history of “easy bruising over the past week,
worse over last 2d. All over body, even with minor activity such as struggling in bath seat,
grabbing at legs to pull up.” Pet. Ex. 1 at 1071. Upon physical examination, Dr. Traum recorded
that D.B. had “[i]nnumerable ecchymoses over head, pinnae, legs, arm. Petechiae noted as
well”7 and “epistaxis seen from left nares.”8 Id. at 1072. D.B. was referred to Massachusetts
General Hospital for further evaluation. Id. at 729, 1072.
That same day, March 15, 2009, D.B. presented to the emergency room at Massachusetts
General Hospital. The emergency department triage/ screening record provides that D.B.’s
mother had observed both tiny red dots and bruises “this week.” Pet. Ex. 1 at 11-12.
6
At his routine well-child visit on December 17, 2008, D.B. received DTaP, IPV, Hep B, and Rotavirus
vaccinations. Pet. Ex. 1 at 1081. D.B.’s mother opted to split his vaccinations at this visit, so D.B. received his Hib
and PCV7 vaccinations two weeks later, on January 7, 2009. Id. at 1080. At his six-month well child visit, D.B.
received DTaP-IPV/HiB and Rotavirus vaccinations. Id. at 1079. Since his mother again opted to split his
vaccinations, D.B. completed his six-month vaccinations two weeks later, on March 4, 2009, when he received the
PCV7 and Hep B vaccinations (the latter being the vaccination at issue in this case). Id. at 1074.
7
An ecchymosis is “a small hemorrhagic spot, larger than a petechia, in the skin or mucous membrane forming a
non-elevated, rounded or irregular, blue or purplish patch.” Dorland’s Illustrated Medical Dictionary (32nd ed.
2012) [hereinafter “Dorland’s”] at 1829. A petechia is “a pinpoint, non-raised, perfectly round, purplish red spot
caused by intradermal or submucous hemorrhage.” Dorland’s at 1422. The pinna, also called an auricular, is “the
portion of the external ear not contained within the head; the flap of the ear.” Dorland’s at 179.
8
Epistaxis is “hemorrhage from the nose; also called nosebleed and nasal hemorrhage.” Dorland’s at 635.
4
Other hospital records noted that both parents were present. Those records provide
different descriptions of D.B.’s history. For example, a March 15, 2009 coagulation disorder
evaluation provides: “This lovely little boy was well until a few days ago, when he started to
show bruises on his bottom, arms, and on his left lower lip. Had received a DTaP on March 39,
and dad feels that his bruising began with this vaccination.” Pet. Ex. 1 at 1068. A March 16,
2009 nursing admit note provides: “[D.B.] is an adorable 6 month old male who presented to his
PCP with increased bruising over the past week. Received his 6 month immunization on 3/4/09
and since that time dad had noticed an increase in the amount of bruising on legs and back.” Id.
at 71. The discharge summary provides that D.B. presented with “1 week history of bruising,
which parents feel has become more pronounced within the 3 days [prior to admission].” Id. at
729. This record also notes that D.B. lived with his mother but not his father. Id.
The attending physician was a pediatric hematologist, Dr. Eric Grabowski. Pet. Ex. 1 at
8. He ordered bloodwork, which was timestamped March 15, 2009 at 6:15 p.m. Pet. Ex. 1 at
559, 1069. This bloodwork found 5,000 platelets/μl (low, compared to a reference range of
150,000 – 400,000 platelets/μl), which was diagnosed as thrombocytopenia. Pet. Ex. 1 at 559,
1069. The same bloodwork found that hematocrit (red blood cells) constituted only 30.9% of
whole blood, which was classified as mild normocytic anemia. Id. at 1069. A Coombs test was
positive. Id. at 730. Based on the combined findings of thrombocytopenia, anemia, and the
positive Coombs test, D.B. was diagnosed with Evans syndrome. Id.
D.B. was started on steroids, but his platelet count continued to drop despite the
treatment. Id. at 730, 1069. D.B. was transitioned to a high-dose steroid, prednisone, and his
platelet count increased initially to 23,000/μl by March 17, 2009, and then decreased slightly to
18,000/μl by March 18, 2009. Id. at 1059-61. A central venous line was placed for intravenous
medication administration and continued blood draws, and D.B. was started on intravenous
immunoglobulin (“IVIg”) treatment, after which his platelet count increased to 60,000/μl. Id. at
730-31. His hematocrit level decreased. Id. By March 21, 2009, his platelet count increased
further to 93,000/μl and his hematocrit was stable at 23.8 with “decreased evidence of hemolysis
as evidenced by decreasing LDH and reticulocyte count.” Thus, on March 21, D.B. was
discharged home with oral steroids and instructions to follow up with Dr. Grabowski at the
hematology clinic. Id. at 711-14.
On March 24, 2009, Dr. Grabowski saw D.B. for follow up. He recorded that labs from a
prior day, before D.B. began IVIg, showed platelets at 158,000/μl, hemoglobin at 9.9, and
hematocrit at 28.4. Pet. Ex. 1 at 1058. The same labs showed high serum IgG (at 1012 mg/dL),
the significance of which was “discussed with Dr. Mark Pasternack; neither of us can attribute
anything worrisome to it at the present time. Will repeat in 2-3 months.” Id. The same labs
showed normal IgA (18 mg/dL), IgM (52 mg/ dL), and serum protein pattern. Id.
9
This medical record contains at least two errors: first, that D.B. received a DTaP vaccination where he actually
received Hep B and Prevnar, and second, that the referenced vaccination(s) were on March 3, when they were
actually on March 4. Pet. Ex. 1 at 1074.
5
By April 3, 2009, D.B.’s hematocrit had increased to 36 but his platelet count dropped to
30,000/μl. He was readmitted to Massachusetts General, where he received additional IVIg and
was assessed with “Evans syndrome, stable hemolytic anemia but worsening thrombocytopenia.”
He was discharged the following morning. Pet. Ex. 1 at 714-15.
On April 10, 2009, D.B. returned to Massachusetts General with a several-day history of
acute otitis media, vomiting, diarrhea, irritability, and increased bruising. His platelets had
dropped below 5,000/μl. Pet. Ex. 1 at 683. D.B. underwent a normal CT scan to rule out
intracranial bleeding and a normal ultrasound to rule out intussusception. Id. at 687-88. D.B.’s
stool tested positive for rotavirus, and it was thought that the rotavirus was ramping up his
immune system and exacerbating his Evans syndrome. Id. at 688. His platelet count remained
below 5,000/μl for the first several days of his admission, and his hematocrit also dropped
acutely. Id. D.B. received two platelet transfusions and one red blood cell transfusion. Id. He
was started on 6-mercaptopurine, an immunosuppressant, in addition to his IVIg treatments. Id.
D.B.’s overall clinical picture improved as his rotavirus improved, and he was discharged on
April 17, 2009, with a platelet count of 9,000/μl, hemoglobin of 10.4, and a hematocrit of 30. Id.
at 688, 695.
On April 26, 2009, D.B. returned to Massachusetts General for irritability. Pet. Ex. 1 at
682. He was well appearing on arrival and his exam and lab work was reassuring. Id. His
inconsolability resolved and he was discharged that same day with instructions to follow up if his
condition worsened. Id. On May 31, 2009, D.B. returned to Massachusetts General again due to
increased bruising and fatigue while on a prednisone taper. Id. at 681. His exam was notable for
mild bruising on his lower legs. Id. He had a platelet count of 40,000/μl and hematocrit of 31.
Id. D.B was given prednisolone and discharged that same day with instructions to continue the
steroid until he followed up with his hematologist, Dr. Grabowski. Id. On June 30, 2009, D.B.
was readmitted for low platelet count, fatigue, irritability, and scattered petechiae. Id. at 675. He
was given a high dose of Solumedrol and discharged home that same day. Id.
After blood drawn from his central venous line grew gram-positive cocci, on July 3,
2009, D.B. was again admitted to Massachusetts General, where he was administered steroids.
On July 7, 2009, he was discharged home with instructions to continue the steroids. Pet. Ex. 1 at
50, 660.
On September 3, 2009, D.B. presented with irritability, abdominal pain, and fever. Pet.
Ex. 1 at 642. Blood cultures turned positive “pretty rapidly” for gram negative rods. Id. On
September 8, 2009, due to a large gallstone, his gallbladder was removed. Id. He was
discharged on September 10, 2009. Id. From September 21 – October 2, 2009, D.B. was
hospitalized again. He presented with persistent vomiting and diarrhea. Id. at 908. Despite new
bruises appearing on his lower extremities, D.B.’s platelet cell count remained steady during his
hospital course and he was discharged on his normal dosage of prednisone. Id. at 614.
Dr. Grabowski continued to monitor and manage D.B.’s care. He prescribed regular
infusions through D.B.’s central venous line of pentamidine (an antimicrobial medication
administered to people with poor immune function). Pet. Ex. 1 at 598. He also prescribed
regular infusions of rituximab (an antibody targeting B cells), but that had the secondary effect of
6
hypogammaglobulinemia. Id. at 598, 767. At Dr. Grabowski’s supervision, D.B. continued to
undergo IVIg treatments. Pet. Ex. 2 at 82. In July 2010, D.B. underwent a bone marrow biopsy
with the possibility of a transplant in mind. Pet. Ex. 1 at 777. His platelet levels remained
steady and manageable until December 2010, when they dropped to 16,000/μl in association with
an increase in bruising. Pet. Ex. 2 at 234. He was admitted overnight for observation and
received a pentamidine infusion and IV solumedrol. Pet. Ex. 2 at 234.
In 2011, D.B. continued to suffer from gastrointestinal issues, bruising, bacterial
infections, and chronic relapses. Pet. Ex. 2 at 138-230. In May 2012, D.B.’s mycophenolate and
low-dose prednisone were discontinued, causing a significant increase in fresh bruises. Pet. Ex.
9 at 51. After his platelet count subsequently dropped to 20,000/μl, Dr. Grabowski and D.B.’s
other physicians decided to start him on N-Plate.10 Id. D.B.’s platelets stabilized over the next
several months with his new regimen of N-Plate and IVIg. Id. at 58. D.B.’s bloodwork
generally remained stable but he experienced intermittent relapses coupled with gastroenteritis.
In December 2014, a repeat bone marrow biopsy yielded a diagnosis of bone marrow fibrosis,
which was believed to be a side effect of his prolonged N-plate use. Pet. Ex. 17(b) at 69. As a
result, Dr. Grabowski tapered down and then eliminated the N-plate. Id. By February 2015,
D.B. was completely weaned off the N-plate but he developed frequent nose bleeds, severe
abdominal pain, and gastrointestinal complications. He received frequent platelet transfusions.
Pet. Ex. 17(a) at 182. In July 2015, another bone marrow biopsy showed favorable results and
the N-plate was restarted. Pet. Ex. 17(a) at 130-31, 153-54.
Further medical records covering 2016 reflect that D.B.’s platelets and red blood cells are
consistently low. In April 2016, he had normal IgG (719 mg/dL), low IgA (13 mg/dL), and low
IgM (8 mg/dL). In May, June, and July 2016, IgG was low (at 530, 336, and 598 mg/dL,
respectively) but it does not appear that IgA and IgM were tested. D.B.’s care remained
supervised by pediatric hematologist Dr. Grabowski and D.B.’s diagnosis has remained Evans
syndrome with associated hypogammaglobulinemia. See generally Pet. Ex. 26.
3. Testimony of Petitioner Tia Bucci (D.B.’s Mother)
D.B.’s mother offered fact testimony at the entitlement hearing in November 2016. Tr. 6-
54, 135-39. Since approximately 2006, she has been employed as a licensed radiologic
technologist at Massachusetts General Hospital. Id. at 7. D.B. is her first and only child. Id. at
6. The mother testified that when D.B. was born, she was married to and living with his father,
petitioner Nicholas Bucci. Tr. 7. When D.B. was approximately two weeks old, his father left
10
The U.S. Food and Drug Administration (FDA) initially approved use of N-plate (romiplostim) to treat “low
blood platelet counts in adults with chronic (idiopathic) immune idiopathic thrombocytopenia (ITP) when certain
other medicines, or surgery to remove the spleen have not worked well enough.” See FDA, Postmarket Drug Safety
Information for Patients and Providers – N-Plate (romiplostim) information, available at
https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm280200 htm
(last accessed March 12, 2019). Petitioner Ms. Tia Bucci testified that in 2011, D.B. was “the first pediatric patient
to be accepted” by the FDA to receive N-plate. Tr. 39. Seven years later, the FDA officially and broadly approved
use of N-plate in pediatric patients 1 year of age and older with ITP for at least 6 months who have had an
insufficient response to corticosteroids, immunoglobulins, or splenectomy. See FDA, N-Plate Supplement 163
(dated December 14, 2018), available at
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process.
7
the home and did not see D.B. unless the mother was there. Id. at 7, 15-16. The mother recalled
that D.B. was generally a normal and healthy child for the first six months of life until he
received the hep B vaccination at issue on March 4, 2009. Id. at 8-9. That evening, D.B. was
fussy, crying and irritable. Id. at 9-10. He was also constantly sticking his fingers in his ear and
pulling and tugging on his ear. Id. at 10. The mother thought he had an ear infection. Id.
These issues persisted for several days until March 7, 2009, when the mother called the
pediatric practice and brought D.B. in for an appointment. Id. The mother recalled that at this
time, D.B. had a “very small, round, black and blue” mark “exactly at the injection site of the
Hep B vaccination.” Id. at 11. Additionally, D.B. had a “pink mark on the ear” which “looked
like his skin had just been irritated from him consistently sticking his finger in his ear and pulling
at his ear.” Id. The mother did not recall the pediatrician raising any concerns about these
findings. Id. She believed that D.B.’s fussiness, mark at the injection site, and mark on the ear
all resolved within one to two days after the March 7, 2009 pediatrics appointment. Id. at 11-12.
The mother recalled that on March 12, 2009, she had her first appearance in divorce
court, which represented “the beginning of the end of her marriage.” Tr. 17. Upon returning
home, she observed a purple bruise on D.B.’s right lower ankle. Id. She initially didn’t think
much of it because D.B. was just beginning to move around, crawl, and roll over. Id. at 18. On
March 13, she observed a couple more bruises on his shins. Id. On March 14, the bruising had
spread to his thighs, abdomen, and the upper extremity portion. Id. at 19. She called the
pediatric practice and spoke to a nurse practitioner who suggested that it was vascular and to
keep D.B. warm and observe him further. Id.
On March 15, 2009, upon waking up and attending to D.B., the mother observed that the
bruising had multiplied. She stated that the prior bruise at the vaccine administration site
observed on March 7 was significantly different from the bruises which began approximately
one week later. The latter were more significant in color, size, and depth. Tr. 14, 25-26.
Also on March 15, 2009, there were new “tiny red dots” resembling what could be
marked with a ballpoint pen, “all over his face down to his ankles.” Id. at 12-13, 19. She stated
that this was the first time she saw these dots, which were later referred to as petechiae. Id.
They were significantly different from the findings on D.B.’s ear observed back on March 7,
2009. Tr. 13.
The mother called and informed D.B.’s father that there might be something really wrong
with their child. Id. at 20-21. The mother brought D.B. to the pediatric clinic and was then
referred to Massachusetts General Hospital, where she was joined by the father, who had not
been living with or seeing D.B. regularly or without his mother for several months. Id. at 21-23.
Additionally, the mother did not have time at the hospital to share any details about D.B.’s post-
vaccination course with the father. Id. at 21-23. Thus, any history obtained from the father
would be inaccurate. See, e.g., id. at 31, 50-51. However, the father did remain at the hospital
and became more involved in D.B.’s life afterwards. See, e.g., id. at 30, 32, 47.
8
The mother testified, consistent with the medical records summarized above, that D.B.’s
diagnosis remains Evans syndrome. Id. at 38. He has received and continues to receive various
treatment for that condition. Id. His blood counts dictate his physical activity level. Id. If his
platelets fall below 40,000/μl, his physical activity must be restricted, for example, he cannot go
out for recess, play on the jungle gym, or participate in physical sports. Id. at 38-39.
II. LEGAL STANDARD11
The Vaccine Act was established to compensate vaccine-related injuries and deaths.
Section 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).
A petitioner must prove that he or she is entitled to compensation under the Vaccine
Program. A petitioner’s burden of proof is by a preponderance of the evidence. § 300aa-
13(a)(1). A petitioner may demonstrate entitlement in one of two ways. 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). In the
present case, petitioners do not allege a Table injury, nor would the record support such an
assertion.
Therefore, petitioners must demonstrate that the vaccine was the cause-in-fact of the
vaccinee’s injury. In order to prevail in an “off-Table Injury,” claim, a petitioner must meet the
three prong test provided by the Althen court: “(1) a medical theory casually connecting the
vaccine and injury; (2) a logical sequence of cause and effect showing the vaccination was the
reason for the injury; and (3) a showing of a proximate temporal relationship between the
vaccine and the 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).
11
Decisions of special masters (some of which I cite in this decision) constitute persuasive but not binding authority.
Hanlon v. Sec’y of Health & Human Servs., 40 Fed. Cl. 625, 630 (1998). Decisions from the Court of Federal
Claims are only binding in the same case on remand. Id. Federal Circuit decisions concerning legal issues are
binding on special masters. Guillory v. Sec’y of Health & Human Servs., 59 Fed. Cl. 121, 124 (2003), aff’d, 104
Fed. App’x 712 (Fed. Cir. 2004); see also Spooner v. Sec’y of Health & Human Servs., No. 13-159V, 2014 WL
504278, at *7 n. 12 (Fed. Cl. Spec. Mstr. Jan. 16, 2014).
9
The preponderance of the evidence standard, in turn, has been interpreted to mean that a
fact is more likely than not. See Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315,
1322 n.2 (Fed. Cir. 2010). Proof of medical certainty is not required. Bunting v. Sec’y of Health
& Human Servs., 931 F.2d 867, 873 (Fed. Cir.1991). Thus, petitioners must provide a reputable
medical or scientific explanation that pertains specifically to this case, although the explanation
need only be “legally probable, not medically or scientifically certain.” Knudsen v. Sec’y of
Health & Human Servs., 35 F.3d 543, 548-49 (Fed. Cir. 1994). Petitioners 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).
Petitioners cannot establish entitlement to compensation based solely on their assertions.
Rather, a vaccine claim must be supported either by medical records or by the opinion of a
medical doctor. § 300aa-13(a)(1). In determining whether petitioners are entitled to
compensation, the special master shall consider all material contained in the record, including
“any . . . conclusion, [or] medical judgment . . . which is contained in the record regarding . . .
causation.” § 300aa-13(b)(1)(A). The undersigned must weigh the submitted evidence and the
testimony of the parties’ offered experts and rule in petitioners’ favor when the evidence weighs
in their favor. See Moberly, 592 F.3d at 1325-26 (“Finders of fact are entitled—indeed,
expected—to make determinations as to the reliability of the evidence presented to them and, if
appropriate, as to the credibility of the persons presenting that evidence”); Althen, 418 F.3d at
1280 (“close calls” are resolved in petitioner’s favor).
Causation is determined on a case by case basis, with “no hard and fast per se scientific
or medical rules.” Knudsen v. Sec'y of Health & Human Servs., 35 F.3d 543, 548 (Fed. Cir.
1994). The Althen court noted that a petitioner need not necessarily supply evidence from
medical literature supporting petitioner's causation contention so long as the petitioner supplies
the medical opinion of an expert. Id. at 1279–80. The court also indicated that, in finding
causation, the fact-finder may rely upon “circumstantial evidence,” which the court found to be
consistent with the “system created by Congress, in which close calls regarding causation are
resolved in favor of injured claimants.” Id. at 1280.
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
condition.”
Regardless of whether the burden ever shifts to respondent, the special master may
consider the evidence presented by respondent in determining whether the petitioner has
established a prima facie case. Flores v. Sec’y of Health & Human Servs., 115 Fed. Cl. 157, 163
(2014) (citing Stone v. Sec’y of Health & Human Servs., 676 F.3d 1373, 1379 (Fed.Cir.2012)
(“[E]vidence of other possible sources of injury can be relevant not only to the ‘factors
10
unrelated’ defense, but also to whether a prima facie showing has been made that the vaccine
was a substantial factor in causing the injury in question.”)).
In Vaccine Act cases, expert testimony is usually evaluated according to the factors for
analyzing scientific reliability set forth in Daubert v. Merrell Dow Pharm., Inc., 509 U.S. 579,
594-96 (1993); see also Cedillo, 617 F.3d at 1339 (citing Terran v. Sec’y of Health & Human
Servs., 195 F.3d 1302, 1316 (Fed. Cir. 1999). “The Daubert factors for analyzing the reliability
of testimony are: (1) whether a theory or technique can be (and has been) tested; (2) whether the
theory or technique has been subjected to peer review and publication; (3) whether there is a
known or potential rate of error and whether there are standards for controlling the error; and (4)
whether the theory or technique enjoys general acceptance within a relevant scientific
community.” Terran, 195 F.3d at 1316 n.2 (citing Daubert, 509 U.S. at 592-95). In Vaccine
Program cases, these factors are used in the weighing of the scientific evidence actually
proffered and heard. Davis v. Sec'y of Health & Human Servs., 94 Fed. Cl. 53, 66–67 (Fed. Cl.
2010) (“uniquely in this Circuit, the Daubert factors have been employed also as an acceptable
evidentiary-gauging tool with respect to persuasiveness of expert testimony already admitted”),
aff'd, 420 F. App'x 923 (Fed. Cir. 2011). The flexible use of the Daubert factors to determine the
persuasiveness and/or reliability of expert testimony in Vaccine Program cases has routinely
been upheld. See, e.g., Snyder v. Sec'y of Health & Human Servs., 88 Fed. Cl. 706, 742–45
(2009).
Where both sides offer expert testimony, a special master's decision may be “based on the
credibility of the experts and the relative persuasiveness of their competing theories.”
Broekelschen v. Sec'y of Health & Human Servs., 618 F.3d 1339, 1347 (Fed. Cir. 2010) (citing
Lampe v. Sec’y of Health & Human Servs., 219 F.3d 1357, 1362 (Fed. Cir. 2000)). However,
nothing requires the acceptance of an expert's conclusion “connected to existing data only by the
ipse dixit of the expert,” especially if “there is simply too great an analytical gap between the
data and the opinion proffered.” Snyder, 88 Fed. Cl. at 743 (quoting Gen. Elec. Co. v. Joiner,
522 U.S. 146 (1997)). Weighing the relative persuasiveness of competing expert testimony,
based on a particular expert's credibility, is part of the overall reliability analysis to which special
masters must subject expert testimony in Vaccine Program cases. Moberly, 592 F.3d at 1325–26
(“[a]ssessments as to the reliability of expert testimony often turn on credibility
determinations”); see also Porter v. Sec'y of Health & Human Servs., 663 F.3d 1242, 1250 (Fed.
Cir. 2011) (“this court has unambiguously explained that special masters are expected to
consider the credibility of expert witnesses in evaluating petitions for compensation under the
Vaccine Act”).
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”).
11
III. EXPERT TESTIMONY
A. Petitioners’ Expert, Dr. Edwin Forman
Dr. Forman’s Qualifications
Petitioners submitted one report and hearing testimony from Dr. Forman. Pet. Ex. 14; Tr.
55-135. He obtained a bachelor’s degree from Brown University in 1956 and a medical degree
from the University of Pennsylvania in 1960. Pet. Ex. 15 at 3. Afterward, he practiced general
pediatrics in the United States Air Force for three years, then completed an internship and
residency in Pediatrics at Johns Hopkins Hospital, and a two-year fellowship in Pediatric
Hematology and Oncology at the United States Public Health Service in Chicago, Illinois. Id.;
Tr. 57. For approximately four decades, he practiced those specialties at Rhode Island Hospital
and taught them at Brown University, where he rose to the rank of full professor. Pet. Ex. 15 at
3. Brown University has established a chair in honor and recognition of Dr. Forman’s work with
children with blood disorders and cancers, as well as his work in biomedical ethics. Tr. 59.
Since 2009, Dr. Forman has been affiliated with Mount Sinai School of Medicine in New
York, where he is an attending physician and a full Professor of Pediatrics. He is board-certified
in pediatrics and pediatric hematology-oncology. He was elected as a member of the American
Pediatric Society and to the American Board of Pediatrics Committee on Hematology-Oncology,
which writes the certifying exam. Pet. Ex. 15 at 1-7; Tr. 57-59.
Dr. Forman estimated that he has worked with more than 150 patients with ITP and
approximately seven patients with Evans syndrome, most of whom he diagnosed himself. Tr.
60. As part of his regular practice, he endeavors to keep up with the literature published on
autoimmune diseases, and their suspected triggers, diagnosis, and treatment. Tr. 60. He has both
provided opinions and testified in a few prior cases in the Vaccine Program. Tr. 62.
I admitted Dr. Forman as an expert in pediatric hematology and oncology, particularly as
those areas relate to evaluation, diagnosis, and treatment of autoimmune diseases including
Evans syndrome and ITP. Tr. 62-63.
Dr. Forman’s Opinion Regarding Evans syndrome
Dr. Forman and the three other experts in this case all agreed that D.B.’s prevailing
diagnosis is Evans syndrome. Pet. Ex. 14 at 1; Tr. 64. Dr. Forman defined Evans syndrome as
autoimmune hematologic cytopenias (a reduction in the number of mature blood cells caused by
antibodies that destroy them) in at least two lines after exclusion of any known etiology.
Neutrophils are occasionally involved. However, the most common presentation as in D.B.’s
case, is that the two cell lines affected are platelets and red blood cells. Evans syndrome has two
diagnostic requirements: (1) bloodwork confirming two low blood cell counts and (2) a Coombs-
or direct-antibody test which shows that the patient’s gammaglobulin is binding to the red blood
cells, which confirms that the reduction in red blood cells is due to an autoimmune process.
However, Evans syndrome remains a diagnosis of exclusion of other autoimmune conditions.
See Pet. Ex. 14 at 1; Tr. 65-66, 69.12
12
See also Dorland’s at 1922.
12
The reduction in red blood cells is referred to as hemolytic anemia. Pet. Ex. 14 at 1; Tr.
65-66.13 Dr. Forman generally did not discuss its consequences.
The reduction in platelets is referred to as thrombocytopenia. This results in blood
leaking from numerous vessels close to one another, manifesting as spontaneous bruising
without trauma. This condition is referred to as immunologic thrombocytopenia purpura (ITP)).
Pet. Ex. 14 at 1; Tr. 65-66.14 Dr. Forman acknowledged that ITP can occur on its own (without
involvement of a second cell line). ITP generally has an acute onset, is benign, and resolves on
its own without treatment. Ninety percent of cases resolve within a year. Tr. 66. Dr. Forman
opined that in contrast to acute ITP, Evans syndrome is chronic and almost never spontaneously
remits. Evans syndrome is associated with increased morbidity and mortality. It has a “totally
different course and different management.” Tr. 66-67.
Dr. Forman opined that for both ITP and Evans syndrome, the first-line treatment is
intravenous gammaglobulin (IVIg), which “chemically paralyzes” the spleen, which normally
slows down circulation and enables phagocytes to pick off platelets and red cells coated with
gammaglobulin. Tr. 94. Through this mechanism, IVIg raises the cell count 70-80% of the time.
Tr. 94. It is less successful – perhaps 60% - in Evans syndrome. Tr. 94, 122-23. Dr. Forman
noted that other treatments include removing the spleen, which is less desirable because it makes
the patient more susceptible to infection, and N-plate which stimulates megacaryocytes, the
immature cells that turn into platelets. Tr. 95-96.
Dr. Forman agreed that Evans syndrome is a rare diagnosis, but he referenced a study
authored by Aladjidi et al.15 on all patients under 18 years old living in France and diagnosed or
followed up with autoimmune hemolytic anemia. There were 265 such patients. Detailed data
from each patient’s medical records was checked. Ninety-nine (37%) of the patients with
autoimmune hemolytic anemia also had ITP, which converted their diagnosis to Evans
syndrome. Pet. Ex. 21(f) at 2.
At the hearing, Dr. Forman (as well as counsel and the other experts) inadvertently
misstated that the Aladjidi article was of 265 patients diagnosed originally with ITP, of which
37% were also found to have hemolytic anemia leading to the diagnosis of Evans syndrome. Tr.
68-69. Id. at 1. This is significant because Dr. Forman went on to say that there are an
“incredible number” of patients with pediatric ITP. If ITP is “incredibl[y]” common and a
greater-than-expected number of patients with ITP also have hemolytic anemia and by extension
Evans syndrome, then Evans syndrome is more common than is currently recognized by the
medical community. Tr. 69. However, compared to ITP, there are fewer cases of hemolytic
anemia. Aladjidi’s finding that 37% of 265 patients with hemolytic anemia also have ITP and by
13
See also Dorland’s at 79.
14
See also Dorland’s at 1829.
15
N. Aladjidi et al., New Insights Into Childhood Autoimmune Hemolytic Anemia: A French National Observational
Study of 265 Children, 96 Haematologica 655 (2011) [Pet. Ex. 21(f)].
13
extension Evans syndrome suggests that Evans syndrome is more common than reported by
other articles – but not as common as Dr. Forman projects.
Dr. Forman opined that in common variable deficiency syndrome (CVID), the word to be
emphasized was “variable.” He described CVID as “an immune deficiency state or immune
dysfunction state . . . associated with a deficiency of immunoglobulins.” Tr. 87. There are three
important immunoglobulins involved here. IgG attacks germs and a low level of IgG is
associated with a significantly increased susceptibility to infection.” Tr. 87. IgA and IgM are
also involved. Tr. 87. At least two of these gammaglobulins must be low for a diagnosis of
CVID to be made. Tr. 87. Other immune deficiencies and other cases must be ruled out. Tr. 87.
Dr. Forman opined that CVID most often presents in the second or third decade of life and
perhaps only 10% of cases present in children. Pet. Ex. 14 at 3; Tr. 87. Dr. Forman stated that
there are “several different kinds” of CVID.” Tr. 88. However, he also said that CVID has “a
whole different course and different things to look for, like pulmonary involvement and early
treatment before it becomes lethal.” Tr. 88. Dr. Forman opined that IVIg, rituximab, and
immunosuppressants can prevent an accurate reading of a patient’s gammaglobulins, thus
preventing an accurate diagnosis of CVID. Pet. Ex. 14 at 316; Tr. 88-90, 121. Additionally, “[a]
diagnosis of CVID before the age of six years is particularly problematic because of the
immunologic immaturity and the persistence of hypogammaglobulinemia of infancy in some
children.” Pet. Ex. 14 at 3.17 “Most children present with a history of recurrent and significant
infections.” Pet. Ex. 14 at 3.
Dr. Forman first opined that “[CVID] usually doesn’t present this way, but it can evolve
into Evans Syndrome.” Tr. 88. Later in the testimony, when I asked for confirmation of this
course, Dr. Forman stated that usually, patients are diagnosed first with CVID “because
pulmonary symptoms are the first projection, and as they are followed, they can develop
autoimmunity against platelets, red cells, and even the neutrophils [culminating in a diagnosis of
Evans syndrome]. Now, can it happen the other way around? Can Evans be the first sign of
CVID? I don’t know. It’s possible.” Tr. 101-02.
Dr. Forman opined: “To presume that [D.B.] had an underlying condition that caused his
Evans syndrome would not be correct. Everyone carries some genetic mutations/variations, but
it takes a precipitant to bring the disease on. Thus, the precipitant is the cause of the clinical
situation.” Pet. Ex. 14 at 2. In other words, a precipitant or trigger needs to begin the
autoimmune process against the blood cells in Evans syndrome. At the entitlement hearing, Dr.
Forman offered the analogy that certain people have a genetic predisposition to develop lung
cancer, but they need a trigger, such as smoking, to initiate that process. (People who do not
have the genetic predisposition, but do smoke, are unlikely to develop lung cancer.) Both the
genetic predisposition and the trigger are necessary for the condition to develop. Tr. 71, 117.
16
Citing Vaccine Injury Table, 42 C.F.R. § 100.3(a).
17
Citing M. Hogan & N. Wilson, Common Variable Immunodeficiency in Children, Wolters Kluwer Health –
UpToDate May 27, 2014 [Pet. Ex. 20(h); P. Ogershok et al., Spectrum of Illness in Pediatric Common Variable
Immunodeficiency, 97 Ann. Allergy Asthma Immunol. 653 (2006) [Pet. Ex. 20(i)].
14
Dr. Forman’s Opinion Regarding Causation between Hepatitis B Vaccine
and Evans syndrome
Dr. Forman largely left the theory of causation to be addressed by Dr. Byers, the
immunologist retained by petitioners. However, he opined that in a small number of individuals
with an underlying vulnerability, “the measles vaccine can lead to ITP.” Pet. Ex. 14 at 2.18 He
opined that there were also numerous reports linking hepatitis B vaccine and hepatitis B
infections to Evans syndrome. Pet. Ex. 14 at 3.19 “Note: the antigens in the hepatitis B vaccine
are derived from the hepatitis B virus.” Pet. Ex. 14 at 3. On cross-examination, Dr. Forman
referenced one case report on hepatitis B vaccine and Evans syndrome in a 33-year-old man.
However, petitioners’ counsel objected to that line of questioning on the grounds that Dr.
Forman was not presented to discuss the medical literature on causation by hepatitis B.
Accordingly, Dr. Forman’s testimony on this subject was limited. Tr. 103-07. He also opined
that hepatitis B vaccine is one of many possible triggers for Evans syndrome. Tr. 112-14.
Dr. Forman’s Opinion Regarding Sequence of Cause and Effect
As discussed below, respondent’s expert Dr. Gans opined that she believed it was likely
that D.B.’s Evans syndrome was the first manifestation of what is actually CVID. Dr. Forman
largely disagreed. D.B.’s treating hematologist, Dr. Grabowski, observed that at the beginning
of his disease course, before IVIg was started, D.B.’s IgG was somewhat high and his IgM and
IgA were within normal limits, meaning that he could not be diagnosed with CVID. Tr. 88-92
(discussing Pet. Ex. 1 at 1058). Once D.B. was started on IVIg (on which he has remained for
years), subsequent tests of the gammaglobulins did not accurately represent what was produced
by D.B.’s own body and what was being delivered via IVIg. Dr. Forman also explained that
accurate gammaglobulin levels cannot be obtained until IVIg has been withdrawn for several
months. Dr. Forman acknowledged that Dr. Grabowski may have been “entertaining” that
diagnosis, which does have a late onset and might “possibly” start with the development of
18
Citing American Academy of Pediatrics, Red Book: Report of the Committee on Infectious Diseases (30th ed.
2009) at 544 [Pet. Ex. 20(a)]; V. Vlacha et al., Recurrent Thrombocytopenic Purpura After Repeated Measles-
Mumps-Rubella Vaccination, 97 Pediatrics 738 (1996) [Pet. Ex. 20(b)]; C. Black et al., MMR Vaccine and
Idiopathic Thrombocytopaenic Purpura, 55 Br. J. Clin. Pharmacol. 107 (2002) [Pet. Ex. 21(c)]; E. Miller et al.,
Idiopathic Thrombocytopaenic Purpura and MMR Vaccine, 84 Arch. Dis. Child 227 (2001) [Pet. Ex. 20(d)].
19
Citing P. Poullin & B. Gabriel, Case Report: Thrombocytopaenic Purpura After Recombinant Hepatitis B
Vaccine, 344 Lancet 1293 (1994) [Pet. Ex. 20(j)]; P. Finielz et al., Systemic Lupus Erythematosus and
Thrombocytopaenic Purpura in Two Members of the Same Family Following Hepatitis B Vaccine, 13 Nephrol. Dial.
Transplant 2421 (1998) [Pet. Ex. 20(k)]; E. Martinez & P. Domingo, Case Report: Evans syndrome Triggered by
Recombinant Hepatitis B Vaccine, 15 Clinical Infectious Diseases 1051 (1992) [Resp. Ex. P]; F. Ronchi et al.,
Thrombocytopaenic Purpura as Adverse Reaction to Recombinant Hepatitis B Vaccine, 78 Arch. Dis. Child 273
(1998) [Pet. Ex. 20(m)]; H. Nuevo et al., Thrombocytopaenic Purpura After Hepatitis B Vaccine: Case Report and
Review of the Literature, 23 Ped. Infect. Disease J. 183 (2004) [Pet. Ex. 20(n)]; A. Polat et al., Severe
Thrombocytopenia after Hepatitis B Vaccine in an Infant from Turkey, 26 Vaccine 6495 (2008) [Pet. Ex. 20(o)]; D.
Neau et al., Immune Thrombocytopenic Purpura after Recombinant Hepatitis B Vaccine: Retrospective Study of
Seven Cases, 30 Scand. J. Infect. Dis. 115-18 (1998) [Pet. Ex. 20(p)]; R. Maezono & A. Escobar, Thrombocytopenic
Purpura after Hepatitis B Vaccine, 76 J. Pediatr. (Rio J.) 395 (2000) [Pet. Ex. 20(q)]; K. Sakha et al., Hepatitis B
Vaccine and Infantile Idiopathic Thrombocytopaenic Purpura, 15 Med. J. of Islamic World Acad. Sci. 149 (2005)
[Pet. Ex. 20(r)]; A. Kalayci et al., Case Report: Evans syndrome Related to Hepatitis B Virus Infection: A Case that
Responded to Lamivudine Therapy, 32 J. Ped. Gastro. & Nutrition 493 (2001) [Pet. Ex. 25].
15
Evans syndrome. Dr. Grabowski and the other treating physicians have never diagnosed or
treated D.B. for CVID. Tr. 98-102, 96-110.
In his report, Dr. Forman stated that it would be incorrect to presume that D.B. had an
underlying genetic condition that caused his Evans syndrome. Pet. Ex. 14 at 2. There is no
specific verifiable genetic vulnerability associated with Evans syndrome and none was found in
D.B.
Dr. Forman noted that the hepatitis B vaccine’s reported possible side effects include
irritability, which is often associated with children pulling their ears, as well as earache. In this
case, D.B.’s mother reported a history of “ear pulling” and he was recorded to have a “red mark”
on the ear. Thus, it was more likely that the ear was irritated by D.B. himself and less likely that
this was a bruise representing an early sign of an autoimmune disease like ITP or Evans
syndrome. There was also no indication of an ear infection. Pet. Ex. 14 at 2; Tr. 78-82.
Dr. Forman testified that D.B.’s “dime-sized bruise with induration on the right thigh”
where the hepatitis B vaccination was administered was a typical vaccine reaction. He did not
believe this was unusual or suggestive of either ITP or Evans syndrome. Tr. 78-79. As
discussed below, respondent’s experts, Dr. Gans and Dr. Gill, attributed more significance to this
bruise, but it seemed that Dr. Forman had more experience in vaccinating a wide array of
children both with and without bleeding disorders and that his testimony about the common
occurrence of transient bruising after vaccination was more credible.
Dr. Forman also opined that D.B.’s fussiness, mark on the ear, and mark at the injection
site resolving within a few days was consistent with his understanding of benign post-
vaccination reactions. Tr. 82.
Dr. Forman opined that “acute ITP almost always begins with diffuse petechiae and/ or
purpura and/ or bleeding and not in a single spot.” Pet. Ex. 14 at 2.20 “The multiple bruises and
diffuse petechiae, with or without bleeding, are generally shocking enough for parents to bring
their child in for medical care within a day, as was the case here.” Id. at 2-3.
Dr. Forman opined that “in a minority of patients, there’s immunodysfunction in the
patient and in relatives.” Tr. 71. Dr. Forman opined that in this case, if respondent’s experts
were correct that D.B.’s mother had ulcerative colitis and endometriosis, that could be suggestive
that D.B. had inherited immunodysfunction. Tr. 70-71.21
Dr. Forman maintained that even if there were some evidence of immune dysfunction in
D.B. and/ or his mother, a trigger for the development of Evans syndrome would still be needed
and that the hepatitis B vaccine was the trigger in this case. Pet. Ex. 14 at 2; Tr. 71.
20
Citing Nelson Textbook of Pediatrics (18th ed. 2007) at 2082 [Pet. Ex. 20(e)]; Nathan and Oski’s Hematology of
Infants and Childhood (7th ed. 2007) at 1558-59 [Pet. Ex. 20(f)].
21
The mother insisted that the mention of ulcerative colitis in her medical record was in error. Respondent
contended that the mother’s diagnosed endometriosis is also an autoimmune condition. Petitioners disputed same
and the literature was equivocal. As her condition would provide at most a clue I elected not to do a collateral
analysis of the mother’s diagnoses or their significance.
16
Dr. Forman’s Opinion Regarding Timing
As noted above, Dr. Forman did not believe that D.B.’s post-vaccination irritability, mark
on the ear, and mark at the vaccination site represented the first manifestations of Evans
syndrome. Rather, Dr. Forman accepted the mother’s testimony that D.B.’s petechiae and
bruising began approximately eight days after the vaccination, on March 12, 2009. Dr. Forman
noted that these symptoms were consistent with Evans syndrome and that when they first
manifest, they are quite alarming to both parents and treating physicians. That occurred in this
case: the mother promptly called and then brought D.B. in to the pediatric practice, and the
physician ordered bloodwork. Tr. 73.
Dr. Forman opined that this temporal relationship was appropriate. Pet. Ex. 14 at 2. He
opined that from the moment antibodies are formed, the platelet count drops within twenty-four
hours. In many cases of Evans syndrome, a trigger is not identified. However, if a trigger for
Evans syndrome is identified, the time from the platelet count dropping to when the condition is
visibly apparent, e.g., bruising, is usually one to six weeks. This is a bell-shaped curve. The
peak is around 10-14 days.
For the aforementioned reasons, Dr. Forman opined that the hepatitis B vaccine D.B.
received on March 4, 2009, more likely than not caused the onset of his Evans syndrome with
onset approximately eight days afterwards. Pet. Ex. 14 at 2-422; Tr. 74-80, 85-86.
B. Petitioners’ Expert, Dr. Vera Byers
Dr. Byers’s Qualifications
Petitioners presented three expert reports and testimony from Dr. Byers. Pet. Exs, 7, 16;
Tr. 139-204; Pet. Ex. 27 (submitted post-hearing). She obtained a bachelor’s degree in
microbiology in 1965, a M.A. in microbiology in 1967, and a Ph.D. in immunology in 1969, all
from the University of California – Los Angeles. Pet. Ex. 8 at 1. She completed a fellowship in
protein chemistry at Abbott Laboratories from 1969-1971. Afterward, she completed a
fellowship in clinical immunology from 1971-1973, obtained an M.D. in 1981, then completed a
three-year residency in internal medicine from 1981-1984, all from the University of California -
San Francisco (UCSF). Id.
From 1988-1994, she was the director of the Positive Action Health Care HIV Clinic in
California. Pet. Ex. 8 at 3-4; Tr. 142-43. Dr. Byers testified that during her medical education
and her work at the HIV clinic, she did see patients with thrombocytopenia. Tr. 142-43. She has
treated approximately 30 children and adults diagnosed with CVID. Tr. 184. She has never
treated any children or adults with Evans syndrome. Tr. 184. She stated that she practiced
medicine for about twenty years, but she has not done so since at least 2006. Tr. 183.
Dr. Byers has devoted a significant portion of her career to consulting with several
biotech companies, some involved with developing vaccines. Pet. Ex. 8 at 2-4; Tr. 141-42. Dr.
Byers is currently medical director and a consulting medical toxicologist for pharmaceutical
22
Citing Vaccine Injury Table, 42 C.F.R. § 100.3(a).
17
companies at Immunology Inc. Pet. Ex. 8 at 2. She has been board-certified in internal medicine
since 1984, but she has never been board-certified in immunology. Id.; Tr. 139.
She has frequently served as an expert witness in civil litigation and in the Vaccine
Program, where she has previously been qualified as an expert in immunology. In this case,
petitioners proffered and I accepted Dr. Byers as an expert in the area of clinical immunology,
particularly as it relates to evaluating and determining whether particular vaccines can trigger
autoimmune diseases, including ITP and Evans syndrome.23
Dr. Byers’s Opinion Regarding Evans syndrome
Over the litigation of this case, Dr. Byers offered various explanations of the medical
conditions involved, of which she had limited treating or research experience. In her first report,
Dr. Byers suggested that D.B. had CVID which is an autoimmune disorder with many possible
manifestations, including ITP and Coombs-positive hemolytic anemia. Pet. Ex. 7 at 2-3. She
also said that “Evan[s] syndrome is really ITP, with a Coombs-positive anemia attached.” Id. at
5. Respondent’s expert Dr. Gans then raised the argument that ITP has different
pathophysiology and etiology; thus, its findings cannot be extrapolated to Evans syndrome.
Resp. Ex. D at 2-3 (discussed further below). Dr. Byers answered that this “doesn’t make much
difference.” Pet. Ex. 16 at 3. Dr. Byers stated that “most authors classify Evans syndrome as a
secondary form of ITP, along with ALPS, anti-phospholipid syndrome, and SLE, as [Dr. Byers]
did [in her first report].” Id. She opined that ITP and Evans syndrome are each very rare. They
are more difficult to compare because each study uses the “assay du jour” rather than the same
methods used in previous studies, which would help to evaluate the data as a whole. Id.24 Dr.
Byers opined that ITP and Evans syndrome each involves a “seriously dysregulated” immune
system. Id. Each condition is “very heterogeneous.” Id.25 “This heterogeneity carries through
all the papers and reviews attempting to characterize either of the syndromes and provide very
unconvincing evidence for either a difference or a characteristic profile for either disease.” Id.
Dr. Byers is not persuaded by Dr. Gans’s other distinctions between ITP and Evans. Id.26 For
23
In his post-hearing brief, respondent contends that Dr. Byers overstated or misrepresented certain qualifications.
Resp. Post-Hearing Brief at 16-17, citing Pet. Ex. 8. Respondent also criticizes Dr. Byers’s reliability. Respondent
cites to multiple past opinions by special masters finding Dr. Byers’s opinions to be confusing, speculative, or
unsupported. Resp. Post-Hearing Brief at 16-17. I take these points and will not comment on them, except to state
that in this case, I found Dr. Byers’s first two reports and her hearing testimony to be confusing. I directed her (as
well as Dr. Gans) to file an additional report. These were helpful in answering some of the specific questions I
raised. Had these issues been appropriately addressed before the hearing, I – and counsel - would have had the
opportunity to ask appropriate questions rising from those reports.
24
Citing W. Wang et al., Immunoregulatory Abnormalities in Evans Syndrome, 15 Am. J. Hematol. 381 (1983)
[Resp. Ex. I]; S. Savasan et al., Increased Lymphocyte Fas Expression and High Incidence of Common Variable
Immunodeficiency Disorder in Childhood Evans Syndrome, 125 Clin. Immun. 224 (2007) [Resp. Ex. J]; D. Teachey
et al., Unmasking Evans Syndrome: T-cell Phenotype and Apoptotic Response Reveal Autoimmune
Lymphoproliferative Syndrome (ALPS), 15 Blood 2443 (2005) [Resp. Ex. K].
25
Citing S. Savasan (2007) [Resp. Ex. J].
26
Citing D. Cines & V. Blanchette, Medical Progress: Immune Thrombocytopenic Purpura, 346 N. Eng. J. Med.
995 (2002) [Pet. Ex. 21(a)].
18
various reasons, which are in truth difficult to summarize, Dr. Byers opined that “the information
differentiating Evans from ITP is not convincing, and the appropriate name for the syndrome is
ITP-Evans.” Id.
At the hearing, Dr. Byers repeated the inadvertent characterization that Aladjidi et al.27
found that out of 265 pediatric patients diagnosed with ITP, 37% were also found to have
hemolytic anemia thereby converting their diagnosis to Evans syndrome. Tr. 169-70. From this
study, Dr. Byers extrapolated that the Vaccine Adverse Events Reporting System (VAERS)
included approximately 200 reports of hepatitis B vaccine and ITP, but “a substantial portion of
those” probably have Evans syndrome. Tr. 170. However, as discussed above in the summary
of Dr. Forman’s testimony, those patients’ original diagnosis was hemolytic anemia (the less
common condition) and were found to also have ITP. This undercuts both of petitioners’
experts’ opinions that Evans syndrome is more common than is currently recognized.
After the hearing, I directed Dr. Byers to submit a supplemental expert report clarifying
her opinions on Evans syndrome and the other issues in this case. At one point, she opined:
“Evans syndrome is usually thought to be a peripheral disease, in other words it’s not a lack of
the ability of the bone marrow to produce the immature precursor cells, but rather the antibodies
that erroneously bind to the mature circulating cells.” Pet. Ex. 27 at 4 (emphasis added).
However, further down on the same page, Dr. Byers seems to contradict herself by
stating that Evans syndrome and other chronic blood disorders do not just involve an attack on
the mature circulating cells in the periphery, but also involve an attack on the immature precursor
cells:
The underlying pathology of acute ITP, which is one component of Evans
syndrome is acknowledged to be antibodies directed against mature platelets
which tag them as targets to be removed by the spleen. The other component is
also antibody-mediated, but the antibodies are now directed against red blood
cells. The two components can present together as happened here or occur
following one or the other. The question here is what causes chronic ITP or
hemolytic anemia. Several reviews feel the difference is that acute ITP or
hemolytic anemia is due only to antibodies removing the mature cells from the
peripheral circulation, but chronic disease is also associated with both immune-
mediated platelet destruction and destruction of the platelet precursors called
megacaryocytes by cytotoxic T lymphocytes. In other words, there is both
activation of auto-reactive T and B cells, and attack on both the mature cells and
their precursors.”
Pet. Ex. 27 at 4 (emphasis added).
27
Aladjidi et al. (2011) [Pet. Ex. 21(f)].
19
In support of this formulation of chronic ITP, Dr. Byers submitted two articles by
Robert McMillan and colleagues.28 McMillan observes that many patients with chronic
ITP produce antibodies against more than one glycoprotein, which has been “attributed to
epitope spreading.” Pet. Ex. 28(j) at 4 (not elaborating on the concept of epitope
spreading). The 2007 review and a 2009 follow-up review both report that chronic ITP
patients not only have decreased platelets, but also morphological damage to the
megacaryocytes. Pet. Ex. 28(j); Pet. Ex. 28(m). These articles provide some support for
a distinction between the physiology of acute and chronic ITP, with chronic ITP bearing
more similarity to Evans syndrome, possibly rooted in immune attack on the
magacaryocytes. Respondent’s expert Dr. Gans did not respond specifically to these
articles but acknowledged during the hearing that chronic ITP had more similarity to
Evans syndrome and may share some of the same pathways. Tr. 268-69.
While Dr. Byers’s contradictory statements regarding the pathophysiology of
Evans syndrome and chronic ITP may reflect some of the uncertainty in the medical
community about these conditions, her statements also reflect a lack of commitment or
understanding of her own causation opinion, which is not helpful to petitioners’ case.
Dr. Byers’s Opinion Regarding Causation between Hepatitis B Vaccine
and Evans syndrome
Dr. Byers initially pointed to molecular mimicry as a causal mechanism in her first
report. Pet. Ex. 7 at 4-5, 7. However, in her second report, she abandoned molecular mimicry
because she was unable to find any common epitope between the hepatitis B vaccine and either
the platelets or the red cells. Additionally, upon further consideration, she recognized that Evans
syndrome involves antibodies attacking at least two blood cell lines – in this case, both platelets
and red blood cells. She recognized that a single antigen in the hepatitis B vaccine was unlikely
to have sequence homology with two blood cell lines. Pet. Ex. 16 at 1-2; see also Tr. 159-60,
63-64, 67. Indeed, respondent submitted a 2005 review article providing:
Despite the frequency of haemopoietic cell-specific autoantibodies in patients
with Evans syndrome, there is very little information about the identity of target
antigens. Early work showed that the autoantibodies are specific to their target
cells and as shown by absorption and elution, do not cross-react. (Pegels et al.
1982). Alterations in serum immunoglobulin levels in Evans syndrome have been
reported in a number of studies but these are neither consistent or specific (Wang
28
Citing R. McMillan, The Pathogenesis of Chronic Immune Thrombocytopenic Purpura, 44 Semin. Hematol. S3-
11 (2007) [Pet. Ex. 28(j)]; D. Nugent et al., Pathogenesis of Chronic Immune Thrombocytopenia: Increased Platelet
Destruction and/ or Decreased Platelet Production, 146 Br. J. Hematol. 585 (2009) [Pet. Ex. 28(m)].
20
et al., 1983, Wang et al. 1988, Savasan et al. 1997) and the number of circulating
B cells appears to be in the expected range (Pegels et al. 1982).29
Thus, Dr. Byers opined that there were “many proven mechanisms by which vaccines
induce autoimmune diseases,” including inflammation which releases inflammatory cytokines,
antigen spreading, and binding of immune complexes. Pet. Ex. 16 at 2. In her conclusion, she
simply indicated that she had “listed several accepted mechanisms of action by which
vaccines/infections can induce ITP-Evans, and vaccines which can do it, including Hepatitis B.”
Id. at 3.
At the entitlement hearing and in her third, post-hearing expert report, Dr. Byers focused
on bystander activation. Regarding this theory, she opined that autoreactive immune cells are
present in every mammal. Pet. Ex. 27 at 1. They play a beneficial role in controlling growth and
differentiation in all organ systems and normally, they are tightly controlled by regulatory
immune cells. Pet. Ex. 27 at 1, 6-7.
Different immune cells are designed to protect against foreign antigens. The body’s first
line of defense, the innate immune system, is made up of cells that quickly identify the category
of antigen presented (e.g., virus, bacterium, mold). The innate system can react quickly but with
limited specificity. Pet. Ex. 27 at 1. It activates proinflammatory cytokines, which attract and
recruit additional cells like macrophages and dendritic cells to aid in the inflammatory response.
Pet. Ex. 27 at 1. The innate immune response eliminates the vast majority of the foreign
antigen’s load at this stage. Pet. Ex. 27 at 1. The proinflammatory cytokines also activate the
adaptive immune system’s B and T cells. Over the course of days or weeks, the B and T cells
undergo genetic recombination and develop highly specific receptors that recognize the unique
tertiary structure of the specific antigen presented. Pet. Ex. 27 at 1-2. After the antigen is fully
cleared, the adaptive immune system retains long-term specific memory so that it can react more
quickly to that specific foreign antigen if and when it presents again. Pet. Ex. 27 at 2.
Dr. Byers cited an article by Tough et al.30 reporting that in mice infected with influenza
virus, a cytokine called interferon 1 mediates the proliferation of T cells that are not specific to
the flu. Pet. Ex. 27 at 2 (citing Pet. Ex. 28(n)). Upon activation and proliferation, the number of
circulating T cells exceeds the number of viral cells. Pet. Ex. 28(n). Dr. Byers cited additional
papers on the proposition that viral and bacterial infections can be associated with the over-
proliferation of T cells. Pet. Ex. 27 at 2.31 Dr. Byers opined that in individuals that have a
29
A. Norton & I. Roberts, Management of Evans syndrome, 132 Brit. J. Hematol. 125 (2005) [Resp. Ex. F], citing
W. Wang et al., Evans syndrome in Childhood: Pathophysiology, Clinical Course, and Treatment, 10 Am. J. Ped.
Haematol. 330 (1988) [Resp. Ex. H]; W. Wang et al., Immunoregulatory Abnormalities in Evans syndrome, 15 Am.
J. Hematol. 381 (1983) [Resp. Ex. I]; S. Savasan et al., Increased Lymphocyte Fas Expression and High Incidence of
Common Variable Immunodeficiency Disorder in Childhood Evans syndrome, 125 Clinical Immunology 224 (2007)
[Resp. Ex. J].
30
D.F. Tough, Induction of Bystander T Cell Proliferation by Viruses and Type I Interferon in Vivo, 272 Science
1947 (1996) [Pet. Ex. 28(n)].
31
Citing G. Lertmemongkolchai et al., Bystander Activation of CD8+T Cells Contributes to the Rapid Production of
IFN-y in Response to Bacterial Pathogens, 166 J Immunol. 1097 (2001); doi 10.4049/jimmunol.166.2.1097 [Pet.
21
genetic susceptibility, the introduction of a foreign antigen can activate dormant
autoreactive T and B cells which trigger autoimmune disease.32 Pet. Ex. 27 at 2.
Respondent’s expert Dr. Gans criticized the theoretical nature of bystander activation
saying that it had only been shown in vitro and argued that any stimulus could initiate the
immune response. While it is not addressed in Dr. Byers’s reports, following the hearing,
petitioners also filed a study by van Aalst et al. published in 2017.33 In this study, van Aalst et
al. reported that bystander activation does not depend on strong T cell receptor (TCR) ligation,
but on signals derived from the ongoing response directed against the vaccine antigen or
adjuvant at hand. Pet. Ex. 29 at 1. They observed that in mice, the introduction of either
adjuvanted or non-adjuvanted vaccine antigens was associated with a response specific to the
vaccine as well as the bystander activation of non-vaccine-specific CD4+ T cells. Pet. Ex. 29 at
1, 6. Van Aalst et al. noted that their study did not demonstrate that the activated non-vaccine-
specific cells had a functional effect. Pet. Ex. 29 at 7. They hypothesize that the immune system
may have multiple checkpoints that prevent the activated cells from becoming functional.
Additionally, epidemiologic evidence has not been shown. However, they indicate that
bystander activation is one proposed mechanism by which vaccination might be involved in both
acute and chronic autoimmune diseases. Pet. Ex. 29 at 1.
Dr. Byers relied on the Agmon-Levin article which validates the bystander activation
theory as a biological mechanism because “enhanced cytokine production promotes the
expansion of autoreactive T cells whose prior number had been insufficient to produce an overt
disease.” Pet. Ex. 27 at 3.34 She said that each individual person has autoreactive T and B cells
that are controlled by regulatory cells. Tr. 166; Pet. Ex. 27 at 3-4. However, some individuals
have a genetic predisposition that can trigger these autoreactive T and B cells. Tr. 166; Pet. Ex.
27 at 3-4. The Atassi 2008 study, cited by Dr. Byers, provides scientific support that
autoantibodies are known to exist and can be contributory in autoimmune diseases. Pet. Ex. 27
at 3-4.35
Dr. Byers opined that both infections and vaccines can cause bystander activation
resulting in autoimmune diseases. Pet. Ex. 27 at 3-4. She stated: “In the case of polyclonal
activation of B cells, the increased B cell proliferation, antibody production, and generation of
Ex. 28(h)]; K. Murali-Krishna et al., Counting Antigen-Specific CD8 T Cells: A Reevaluation of Bystander
Activation during Viral Infection, 8 Immunity 177 (1998) [Pet. Ex. 28(k)].
32
A. Nogai, Lipopolysaccharide Injection Induces Relapses of Experimental Autoimmune Encephalomyelitis in
Nontransgenic Mice via Bystander Activation of Autoreactive CD4 +Cells, 175 J Immunol. 959 (2005) [Pet. Ex.
28(l)]; B.J. Vilen & J.A. Rutan, The regulation of autoreactive B cells during innate immune responses, 41 Immunol
Res. 295; doi: 10.1007/s12026-008-8039-8 (2008) [Pet. Ex. 28(o)]; Y.D. Dai et al., Antigen Processing by
Autoreactive B Cells Promotes Determinant Spreading, 2 Cell. & Molec. Immunol. 169 (2005) [Pet. Ex. 28(e)].
33
S. van Aalst et al., Bystander activation of irrelevant CD4+T cells following antigen-specific vaccination occurs
in the presence and absence of adjuvant, 12 PLoS One; doi.org/10.1371/journal.pone.0177365 (2017). [Pet. Ex. 29].
34
N. Agmon-Levin et al., Influenza Vaccine and Autoimmunity, 11 IMAJ 183 (2009) [Pet. Ex. 28(a) at 3].
35
M. Zouhair-Atassi & P. Casali, Molecular Mechanisms of Autoimmunity, 41(2) Autoimmunity 123 (2008); doi
10.1080/08916930801929021 [Pet. Ex. 28(b) at 3-4].
22
circulating immune complexes also damages self-tissues. In the case of Evans syndrome, the
major pathology was the buildup of antibodies on both platelets and red cells which were then
removed by the spleen.” Pet. Ex. 27 at 3. Thus, Dr. Byers opined that unlike molecular
mimicry, bystander activation could cause an autoimmune response against two lines of blood
cells as seen in Evans syndrome. Namely, bystander activation could activate autoreactive T and
B cells directed against two lines of blood cells. Id.
Dr. Byers said that the innate immune system, in the initial response to the hepatitis B
antigen, produces pro-inflammatory cytokines which then stimulate what she called rogue B
cells and T cells that have different specificities. They attack the invader but then perceive that
the platelets and red cells are also invaders and continue to attack. She agreed with respondent’s
experts that normally the regulatory cells would come in and tamp down the immune reaction
once the invasion is eliminated but because of a likely genetic susceptibility in these children, it
does not do so and the immune response then spins out of control.
While Dr. Byers focused on bystander activation, she opined that she was not “going to
completely discount epitope spreading” or separately, “TLR activation” as part of the bystander
activation process, as theories explaining how the hepatitis B vaccine can cause Evans syndrome.
Tr. 160-61. Indeed, even following my post-hearing order requesting supplemental reports to
clarify the experts’ opinions, Dr. Byers concluded: “my opinion as to the cause of the Evans (ITP
and hemolytic anemia) syndrome would remain – the [hepatitis B] vaccine was a cause or
substantial contributory factor, and the mechanism of action was either by bystander activation
or epitope spreading.” Pet. Ex. 27 at 5 (emphasis added). However, epitope spreading was not
particularly explained by Dr. Byers or summarized in petitioners’ pre- or post-hearing brief.
This appeared to be a supplemental theory that was not sufficiently detailed to be evaluated.
Thus, I have not endeavored to summarize that additional theory to the extent that it was offered
in this case.
Dr. Byers’s Opinion Regarding Sequence of Cause and Effect and Timing
Dr. Byers opined that D.B. was perfectly healthy before receiving the hepatitis B vaccine
(and Prevnar). He developed the first manifestations of Evans syndrome approximately eight
days later, which progressed rapidly over the next three days. Dr. Byers opined that certain
vaccinations are known to trigger certain autoimmune conditions. In D.B.’s case, she did not
identify any alternative causes such as infection. Thus, she concluded that there was a logical
sequence of cause and effect. She also believed that there was an acceptable temporal
relationship. Tr. 113-14.
C. Respondent’s Expert Dr. Hayley Gans
1. Dr. Gans’s Qualifications
Respondent submitted two reports and testimony from Dr. Gans. Resp. Ex. D; Tr. 209-
341; Resp. Ex. W (post-hearing). She obtained a bachelor’s degree in biochemistry from
Connecticut College in 1987 followed by a M.D. from the SUNY Health Science Center at
Syracuse in 1991. Resp. Ex. E. Dr. Gans then completed an internship and residency in
Pediatrics at Stanford University School of Medicine, followed by a fellowship in Pediatric
23
Infectious Diseases at Stanford. Id. at 1. Dr. Gans is board certified in Pediatrics and Pediatric
Infectious Diseases. Tr. 212. She explained that there is a board for allergy/immunology, in
which she did not do a residency. There is not a stand-alone board for immunology. Id. Dr.
Gans is currently an Assistant Professor of Pediatrics at Stanford. Resp. Ex. E at 2. She works
as a consultant in pediatric infectious disease. Tr. 213. She has treated children with ITP, CVID,
and Evans syndrome, and she has diagnosed both CVID and Evans syndrome. Tr. 213-18. I
admitted Dr. Gans as an expert in pediatrics, pediatric infectious diseases, immunology, and
vaccines insofar as all of those subjects relate to Evans syndrome. Id. at 216, 220.
2. Dr. Gans’s Opinion Regarding Evans syndrome
Dr. Gans, like all of the other experts in this case, agreed that D.B’s correct diagnosis is
Evans syndrome. Resp. Ex. D at 2; Tr. 222-23. She acknowledged that there was currently no
genetic test for this condition. Tr. 298. She agreed that the diagnosis depends on a finding of
decreased counts in at least two blood cell lines, a positive Coombs- or direct-antibody test, and
the exclusion of other immune conditions. She opined that Evans syndrome is a very rare
condition that is still being studied, but that the current limited understanding of this condition is
relevant to the likelihood of vaccine causation. See, e.g., Resp. Ex. D at 2; Tr. 222-23.
Dr. Gans opined that children with Evans syndrome have clinical similarities with other
immunodeficiencies but their immune systems act differently. Either acute ITP or hemolytic
anemia, presenting alone, generally responds to first-line treatments and resolves within months
to a year. Tr. 249; Resp. Ex. W at 2. Dr. Gans allowed that these conditions may require a
trigger. See, e.g., Resp. Ex. W at 4, 5.
In contrast, Evans syndrome does not respond to the same first-line treatments and is
chronic and relapsing. Tr. 249; Resp. Ex. W at 2. Additionally, some children with Evans
syndrome go on to develop other immune conditions such as common variable immune disorder
(“CVID”) and autoimmune lymphoproliferative syndrome (“ALPS”). Resp. Ex. D at 2; Tr. 224.
In recognition of the more difficult course of Evans syndrome, scientists are currently
working to understand its pathophysiology. Tr. 226-27.
By way of introduction, Dr. Gans explained that the immune system, when functioning
typically, should recognize a foreign antigen, respond effectively to eliminate the foreign
antigen, and then dampen the response and return the body to homeostasis. Tr. 230; Resp. Ex. W
at 5. She described that this occurred through a regulatory pathyway in which activated immune
cells express a cell surface protein called Fas ligand, which is recognized by T cells that possess
a cell surface protein called Fas. When the Fas and Fas ligand cells combine, the activated
immune cells die (termed apoptosis), the immune response ceases, and the body returns to
homeostasis. Tr. 231; Resp. Ex. W at 2.
Dr. Gans opined that dysfunction in this regulation of the immune system explains Evans
syndrome. There are very few patients diagnosed with Evans syndrome. However, when
studied, those patients seem to have inherent defects or irregularities in the immune system,
including T and B cells. Resp. Ex. D at 2; Resp. Ex. W at 1. For example, a study by Wang et
24
al.36 found that subjects with Evans syndrome showed increased T suppressor cells and
decreased T helper cells. The subjects had a markedly decreased T4:T8 cell ratio. When
compared to subjects with chronic ITP, the subjects with Evans syndrome had no significant
difference in T4 but they had a higher percentage in T8 and a lower T4:T8 ratio. Additionally,
among the six subjects with Evans syndrome, two subjects had diminished IgG, five subjects had
diminished IgA, and two subjects had diminished IgM. Resp. Ex. D at 2 (citing to Resp. Ex. H
at 1).
Dr. Gans connected these findings to a possible defect in the Fas-Fas ligand pathway in
patients with Evans syndrome. She cited a study by Teachey et al., 37 which found that 58%
(7/12) of patients with Evans syndrome also had ALPS.38 Additionally, 50% (6/12) had
defective Fas-mediated apoptosis. Id. Teachey et al. described Fas-mediated apoptosis as part of
the normal down regulation of the immune system.39 They describe the keynote finding in ALPS
is a disorder of T cell dysregulation caused by defective Fas mediated apoptosis.40 Teachey et al
state:
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of disrupted
lymphocyte homeostasis caused by defective Fas-mediated apoptosis. As part of the
normal down regulation of the immune response, activated T lymphocytes upregulate
expression of Fas ligand. (Nagata and Golstein, (1995). Fas and Fas ligand interact
through the Fas-activating death domain (FADD) to trigger the caspase cascade, leading
to proteolysis, DNA degradation, and apoptosis. Patients with ALPS have a defect in this
apoptotic pathway, leading to chronic lymphoproliferation and autoimmune
manifestations.
Resp. Ex. BB at 205.
Teachey et al. also found that no patient with ITP or autoimmune hemolytic anemia alone
had both double negative T cells and defective Fas-mediated apoptosis, which is the criteria for
ALPS. Two patients with ITP were described with defects in Fas-mediated apoptosis but did not
have double negative T cells. Resp. Ex. K at 2447. Teachey et al. went on to say that
autoimmunity is the second most common clinical manifestation of ALPS after
lymphoproliferation with autoimmune destruction of blood cells being the most common
presentation of autoimmunity in ALPS, affecting over 70% of patients. Resp. Ex. BB at 2.
Teachey et al. noted: “[L]aboratory testing [of the Fas-Fas ligand pathway] is labor-
intensive and expensive to perform, requiring multiple controls, including positive and negative
controls from both the patient and a normal control to be analyzed in tandem. Accordingly, it is
36
W. Wang et al., Immunoabnormalities in Evans syndrome, 15 Am J. Hematol. 381 (1983) [Resp. Ex. H].
37
D.T. Teachey et. al, Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune
lymphoproliferative syndrome (ALPS), 105 Blood 2443 (2005) [Resp. Ex. J].
38
D.B. has never been diagnosed with ALPS.
39
D.T. Teachey et al., Advances in the management and understanding of autoimmune lymphoproliferative
syndrome (ALPS), 148 Br. J. of Haematol. 205 (2009) [Resp. Ex. BB].
25
only performed in a handful of research laboratories in the world.” Resp. Ex. BB at 4.
Dr. Gans also cited a study by Savasan et al.41 on seven patients with Evans syndrome
followed over five years. Seventy-one percent (5/7) developed CVID. Those patients displayed
an increased expression of Fas-antigen on B lymphocytes and increased Fas-mediated apoptosis,
resulting in the decreased level of antibodies in patients with CVID. Resp. Ex. J at 225. The five
patients who went on to develop CVID had increased spontaneous lymphocyte Fas expression
and enhanced Fas-mediated apoptosis. Id. These findings were suggestive of persistent immune
activation in some patients with Evans syndrome. Id. Savasan also noted that previous research
concluded that up to 11% of patients with CVID may develop some form of autoimmune blood
disorder including Evans syndrome. However, as demonstrated in the study by Savasan et al.,
Evans syndrome may precede development of the CVID phenotype. Pet. Ex. J at 5.
Like the other experts, Dr. Gans discussed the presence of CVID in D.B. In her first
report, she opined that “D.B. developed Evans syndrome as part of an underlying
immunodeficiency which was eventually defined as [CVID].” Resp. Ex. D at 3. But she also
acknowledged that D.B.’s treating physicians never made that diagnosis and that it is extremely
difficult to diagnose in young children. Tr. 271-72, 294 (discussing Pet. Ex. 26). Dr. Gans
opined that D.B. is receiving IVIg for hypogammaglobulinemia, which is the treatment for
CVID. Tr. 272. It is interesting to note that multiple authors including Norton say that the first
line treatment for Evans syndrome is IVIg. Resp. Ex F at 128. Despite this debate over whether
D.B. has CVID, in Dr. Gans’s last report, she stated that “the presence or absence of CVID in
D.B. is not important for casualty [sic; presumably “causality”], but as with ALPS, represents an
entity that appears to develop over time in some individuals who carry a diagnosis of Evans
syndrome.” Resp. Ex. W at 4.
Dr. Gans explained why Teachey and Savasan reported different findings in the context
of Evans syndrome:
In summary, at the core of the immune issue in individuals with Evans syndrome
is a defect in the regulation of immune activation, and this is in part through
defects expressed in the Fas-Fas ligand pathway. This leads to (1) the incomplete
destruction of activated cells that are recognizing self and the production of
autoantibodies against the cells of the hematopoietic system which are most
vulnerable to these dysregulated cells [resulting in ALPS, as reported by Teachey
et al.] and (2) an overstimulated immune state due to inability over time to
deactivate the system which in turn creates the body to produce more immune
cells, and the cells produced in the B lymphocyte category than express Fas ligand
(given the high numbers this level is observed to be higher) and are cleared
leading to hypogammaglobinemia and CVID [as reported by Savasan et al.] This
may seem paradoxical, but is observed in immune-activated states since the body
is making more cells in an attempt to correct the defect and some of these are
defective giving rise to (1) and some are not defective but over-expressed giving
41
S. Savaşan et al., Increased lymphocyte Fas expression and high incidence of common variable immunodeficiency
disorder in childhood Evans syndrome, 125 Clin. Immunol. 224 (2007) [Resp. Ex. X].
26
rise to (2).
Resp. Ex. W at 2-3; see also Tr. 232. Dr. Gans also allows that the immune regulatory system
“has been an area of active investigation for years and is not entirely understood,” and its
“complexity . . . is phenomenal.” Resp. Ex. W at 3.
Dr. Gans opined that while Evans syndrome is rare, the hematopoietic (blood) system is
in fact the most common location for autoimmunity to occur. Resp. Ex. W at 3. “Likely this
represents the fact that the endovascular (or circulatory system) plays an important role in
preventing autoimmunity.” Id. More specifically:
It is believed that in individuals with immune dysregulation, the abnormal
immune cells (such as B and T cells with abnormalities in the Fas ligand system,
such as with Evans syndrome) circulate in the blood but the intravascular surfaces
act as a barrier preventing these dysregulated cells from entering other tissues and
thus in turn preventing broad tissue autoantibodies. In contrast, the intravascular
antigens (red cells and platelets) remain exposed to the dysregulated immune
cells, causing autoimmunity to be directed at these cells more commonly.
Id. at 3-4.42
Dr. Gans opined that individuals develop Evans syndrome as a result of the inherent
defects in the immune regulatory system discussed above. She opined that this pathophysiology
does not include an external antigenic stimulation as a source for the autoimmune phenomenon
associated with the disorder. Anything – a virus, an infection, or “the Grandma’s kiss” – can
conceivably stimulate the immune system. Tr. 262. However, the key failure and cause of
Evans syndrome is that once the antigen is cleared, the immune cells are not cleared from the
body and they look for something else to attack, and the blood cells are most vulnerable to that
attack. Tr. 298-99.
Dr. Gans acknowledged that in her patients diagnosed with Evans syndrome, when they
get an infection, “their syndrome definitely gets worse.” However, she did not take that to mean
that an infection or other specific antigen is necessary for Evans syndrome to develop. Tr. 262;
see also Tr. 266, 298-99, 303; Resp. Ex. W at 6.
3. Dr. Gans’s Opinion Regarding Causation between the Hepatitis B
Vaccine and Evans syndrome
Dr. Gans conceded that a vaccine could trigger an adaptive immune response. Tr. 277,
320. However, as discussed above, she opined that a foreign antigen such as a vaccine is not the
cause of Evans syndrome. Rather, the cause is the failure to clear the immune response once the
foreign antigen is cleared.
42
Citing J.C. Turbyville & V.K. Rao, The Autoimmune Lymphoproliferative Syndrome: A Rare Disorder Providing
Clues about Normal Tolerance, 9 Autoimmun. Rev. 488 (2010) [Resp. Ex. AA].
27
Dr. Gans acknowledged that there has been one case report associating Evans syndrome
with hepatitis B vaccine43 and another associated with hepatitis B infection.44 Resp. Ex. D at 3.
However, she opined: “These cases are less likely to represent true Evans syndrome since the
cytopenias in these cases were very responsive to first-line therapies which is not the case for
true Evans syndrome.” Id.45; see also Tr. 265-67.
4. Dr. Gans’s Opinion Regarding Sequence of Cause and Effect
Dr. Gans opined that D.B. would have developed Evans syndrome at some point during
his childhood independent of the vaccine. Resp. Ex. D at 4. As discussed above, Dr. Gans
opined that Evans syndrome is not caused by an immune response to a vaccination; but instead it
is the failure of the immune system to deactivate that causes Evans syndrome. Resp. Ex. W at 2.
Dr. Gans’s Opinion Regarding Timing
In contrast to petitioners’ experts, Dr. Gans concluded retrospectively that D.B’s first
manifestations of Evans syndrome were recorded three days after the hepatitis B vaccination.
Resp. Ex. D at 3. She opined that D.B.’s irritability was “likely [his] usual reaction to vaccines,”
based on his earlier history. Id. However, based on her retrospective knowledge of his later
diagnosis of Evans syndrome, she characterized the mark on the pinna of his ear as “bruising.”
Id. She opined: “[T]he bruising on the pinna with manipulation and at the site of his
immunization is suggestive of low platelets. At this point, the platelet count was not likely low
enough to result in the spontaneous bruising that subsequently developed on [D.B.’s] body but
would be at a level that trauma would be required to cause bruising.” Id. Dr. Gans opined that
these symptoms were too soon after the vaccination to infer causation. Id.; Tr. 265.
D. Respondent’s Expert Dr. Joan Cox Gill
Dr. Gill’s Qualifications
Respondent submitted one expert report and testimony from Dr. Gill. Resp. Ex. A; Tr.
342-407. She obtained a bachelor’s degree in science from St. Norbert College in 1965 followed
by an M.D. from the Medical College of Wisconsin in 1976. Resp. Ex. B. Dr. Gill then
completed an internship and residency in Pediatrics at Milwaukee Children’s Hospital, followed
by a fellowship in Pediatric Hematology-Oncology at the Medical College of Wisconsin and the
Blood Center of Southeastern Wisconsin. Id. at 1. Dr. Gill was board certified in Pediatrics and
Pediatric Hematology/Oncology. Tr. 244; Resp. Ex. B at 4. At the time of the hearing, Dr. Gill
was a Professor of Medicine, Pediatrics, and Population Health – Epidemiology at the Medical
College of Wisconsin, and an Investigator at the Blood Center of Southeastern Wisconsin. Resp.
43
E. Martinez & P. Domingo, Case Report: Evans syndrome Triggered by Recombinant Hepatitis B Vaccine, 15
Clinical Infectious Diseases 1051 (1992) [Resp. Ex. P].
44
A. Kalayci et al., Case Report: Evans syndrome Related to Hepatitis B Virus Infection: A Case that Responded to
Lamivudine Therapy, 32 J. Ped. Gastro. & Nutrition 493 (2001) [Pet. Ex. 25].
45
Citing P. Mathew et al., Evans syndrome: Results of a National Survey, 19 J. Ped. Hem. Oncol. 433 (1997) [at
Resp. Ex. C at 1-5].
28
Ex. B at 2. Dr. Gill has worked with patients with ITP and autoimmune hemolytic anemia,
among other blood disorders. Tr. 346. She diagnosed and treated four or five cases of Evans
syndrome in her career, and she treated two patients who went on to develop the manifestations
of CVID, though she did not diagnose those patients. Tr. 346, 351. I admitted Dr. Gill as an
expert in pediatrics, hematology, and immunology insofar as those topics relate to Evans
syndrome. Tr. 347, 351.
Dr. Gill’s Opinion Regarding Evans syndrome
Dr. Gill opined that there is good evidence that the MMR vaccine (not at issue in this
case) causes ITP. In fact, this has been added to the Vaccine Injury Table. Tr. 349. With regard
to the hepatitis B vaccine, almost all of the literature consists of case reports and those are almost
all consistent with acute opposed to chronic ITP. Tr. 349-50.
Dr. Gill opined that acute ITP is probably caused by an antigen (for example, an upper
respiratory infection) triggering an immune response which then cross-reacts with platelets. As
the immune system clears that antigen, the antibody response goes away. The ITP subsides and
does not recur. Tr. 350.
Dr. Gill opined that in contrast, chronic ITP and by extension, Evans syndrome does not
have a precipitating event. Dr. Gill testified, consistently with Dr. Gans, that in a patient
destined to develop one of these conditions, once the immune system is stimulated, it never turns
off. The response is not regulated and the system does not return to homeostasis. Once the
trigger is eliminated, the immune system attacks self. Dr. Gill opined that the immune stimulant
can be many things – possibly including inhaled air, or food. Tr. 383-85. When asked whether a
cold or virus could serve as that trigger, she said no. However, a cold or virus could suppress the
bone marrow, causing the patient’s platelet count to drop so low that he would become
symptomatic. Tr. 386-87. Dr. Gill then had the following exchange:
Petitioners’ counsel: All right. So the cold could have been the insult that caused the - -
A: The manifestation - -
Q: - - the Evans to be - -
A: of the disorder.
Q: But in this case there was no cold.
A: No, right, yeah, but that’s - - you know - -
The Court: But by the same token, could the vaccine be enough to suppress the bone
marrow?
A: You know, I don’t know. I think it’s a really good question, I think it’s a possibility,
but I honestly don’t know the answer to that.
Tr. 387-88. Additionally, in response to my questioning, Dr. Gill stated that she did not know
why the immune system, once stimulated by a foreign antigen and not regulated back down,
attacks specifically the two blood cell lines. She also did not know why in some patients the
attack on both cell lines began simultaneously and in others they are attacked sequentially. Tr.
388-90.
29
3. Dr. Gill’s Opinion Regarding Causation between the Hepatitis B Vaccine
and Evans syndrome
In terms of the mechanisms of the immunology in Evans syndrome, Dr. Gill testified that
the Hepatitis B vaccine has a single antigen, the hepatitis B surface antigen. Tr. 356. The
antibody that would attach to this antigen would also have to attach to both the platelets and the
red cells. But she testified that it has been clearly shown that the antibodies that are present on
the platelets do not bind to the red cells and vice versa. Tr. 357.
Dr. Gill indicated that she generally would like to see epidemiology to draw conclusions
about causation. She observed that the Vaccine Adverse Events Reporting System (VAERS) is
voluntary and the cases are not fully worked up; nonetheless, VAERS data may sometimes
provide a signal.
She agreed with the other experts that Evans syndrome is a very rare disease. She did an
interesting calculation on the witness stand that demonstrated the difficulty with epidemiology in
rare diseases. Specifically, the incidence of ITP is about 1.5 per 100,000 children and Evans
would be about 1 in 10,000,000 (ten million) children. Therefore, a study would need at least a
million children to pick up one case of Evans syndrome. Thus, respondent’s submitted study by
O’Leary et al.46 in the Journal of Pediatrics, evaluating the risk of ITP after vaccination based on
data from 1.8 million children and adolescents, was not sufficiently powered to draw any
conclusions. Tr. 405-06.
Dr. Gill generally agreed with Dr. Gans that there was not a logical sequence of cause
and effect or an acceptable temporal relationship in D.B.’s case. Thus, her opinions on those
topics will not be repeated here.
IV. DISCUSSION
A. Althen Prong One
Legal Standard
Under Althen prong one, the causation theory must relate to the injury alleged. Thus, a
petitioner must provide a “reputable” medical or scientific explanation, demonstrating that the
vaccine received can cause the type of injury alleged. Pafford v. Sec’y of Health & Human
Servs., 451 F.3d 1352, 1355-56 (Fed. Cir. 2006) (citations omitted). The theory must be based
on a “sound and reliable medical or scientific explanation.” Knudsen v. Sec’y of Health &
Human Servs., 35 F.3d 543, 548 (Fed. Cir. 1994). It must only be “legally probable, not
medically or scientifically certain.” Id. at 549.
In Althen, the Federal Circuit noted that “while [that petitioner’s claim] involves the
possible link between [tetanus toxoid] vaccination and central nervous system injury, a sequence
hitherto unproven in medicine, the purpose of the Vaccine Act’s preponderance standard is to
46
S.T. O’Leary et al., The Risk of Immune Thrombocytopenic Purpura after Vaccination in Children and
Adolescents, Pediatrics (2012), doi: 10.1542/peds.2011-111 [Resp. Ex. R].
30
allow the finding of causation in a field bereft of complete and direct proof of how vaccines
affect the human body.” Althen, 418 F.3d at 1280 (emphasis added). Accordingly, the first
Althen prong may be satisfied without resort to medical literature, epidemiological studies,
demonstration of a specific mechanism, or a generally accepted medical theory. Andreu, 569
F.3d at 1378-79 (citing Capizzano, 440 F.3d at 1325-26)). Special masters, despite their
expertise, are not empowered by statute to conclusively resolve what are essentially thorny
scientific and medical questions, and thus scientific evidence offered to establish Althen prong
one is viewed “not from the lens of the laboratorian, but instead from the vantage point of the
Vaccine Act’s preponderant evidence standard.” Id. at 1380. Accordingly, special masters must
take care not to increase the burden placed on petitioners in offering a scientific theory linking
vaccine to injury. Contreras v. Sec’y of Health & Human Servs., 121 Fed. Cl. 230, 245 (2015),
vacated on other grounds, 844 F.3d 1363 (Fed. Cir. 2017). But this does not negate or reduce a
petitioner’s ultimate burden to establish his overall entitlement to damages by preponderant
evidence. W.C. v. Sec’y of Health & Human Servs., 704 F.3d 1352, 1356 (Fed. Cir. 2013)
(citations omitted).
Evans syndrome
As summarized by Drs. Forman and Gans, Evans syndrome (ES) is an autoimmune
disorder characterized by hemolytic anemia, thrombocytopenia and often neutropenia which can
occur simultaneously or sequentially. It was first reported in 1951 but continues to be a disorder
that is not well understood. With the exception of two,47 almost all of the studies submitted in
this case48 included very small numbers of patients reflecting the rarity of the disease. Even with
such small numbers, there was also significant variation in the presentations.
Ages of patients ranged from the first year of life to well into adulthood. For example,
49
Wang reported on ten patients with onset ranging from nine to fifteen years old with a median
of 7.5 years old. In a separate study, Mathew et al.50 reported on 42 patients with onset ranging
from 2 months to 26 years old, with a median of 7.7 years old.
The typical presentation varies. For example, in Mathew’s study of 42 patients, at their
initial presentation, 32 had ITP, 28 had hemolytic anemia, 10 had neutropenia and 6 had
pancytopenia. Resp. Ex. Q.
The subsequent course also varies. For example, Wang et al. found that 7 out of 10
patients had recurrences of hemolytic anemia (up to 22 episodes total). Nine out of 10 patients
had recurrences of thrombocytopenia (up to 20 episodes total). Resp. Ex. Y at 5.
47
P. Mathew et.al. (1997) [Resp. Ex. Q] (42 patients in the United States and Canada); N. Aladjidi et al. (2011) [Pet.
Ex. 21(f)] (265 patients in France).
48
See, e.g., W. Wang (1988) [Resp. Ex. H] (10 patients); W. Wang et al. (1983) [Resp. Ex. I] (6 patients). S.
Savasan (2005) [Resp. Ex. X.] (7 patients); D. Teachey et al. (2005) [Resp. Ex. Y] (12 patients).
49
W. Wang (1988) [Resp. Ex. H].
50
P. Mathew et.al. (1997) [Resp. Ex. Q].
31
Furthermore, it appears that Evans syndrome sometimes presents as part of a separate
autoimmune disease – most frequently systemic lupus erythematosus (SLE). This is not
considered a true Evans syndrome.51
Both parties’ experts agreed that Evans syndrome is generally chronic and involves
exacerbations and remissions with response to treatment being variable even within individual
patients having the need to resort to second and third line treatments. See, e.g., Tr. 65-67 (Dr.
Forman), 226-27 (Dr. Gans). Evans syndrome is usually treated first with steroids and/or IVIg.
Second and third line treatments include various immunosuppressants, chemotherapy,
splenectomy and stem cell transplants. All appear to have variable rates of success with
splenectomy falling out of favor as the improvement tends to be short-lived.
The enormous variability in Evans syndrome, particularly the onset ranging from infancy
to adulthood, raises the question of whether a trigger is needed. This may have been the
principal debate between the parties’ experts in this case. Respondent’s expert Dr. Gans argued,
and Dr. Gill agreed, that Evans Syndrome is generally considered to be caused by a defective
immune regulatory system which will develop at some point in life regardless of a specific
trigger. Dr. Forman and Dr. Byers seemed to agree that Evans syndrome involves a failure of the
immune regulatory system but contended that a trigger was necessary.
As noted in a relatively recent review article by Norton et al.,52 there have not been
studies on whether there is any association between vaccination and Evans syndrome. There
have been articles associating vaccination (and infection) with the development of hemolytic
anemia or ITP (in separate cases). Norton provides: “Taken together these reports suggest that
immunizations may provide a trigger for the development of disease in susceptible individuals
and may also lead to a sustained increased risk in some of them.” Resp. Ex. F at 2. Thus,
petitioners’ expert Dr. Byers tried to analogize hemolytic anemia and ITP, as each presents on its
own, to Evans syndrome. She recognized a distinction between acute ITP (which is monophasic
and generally resolves within a short period of time) and chronic ITP (which is recurrent and
more resistant to treatment). However, she seemed to contend that chronic ITP could be similar
to Evans syndrome, except that the latter would involve two cell lines. Pet. Ex. 16 at 3-4; Pet.
Ex. 27 at 3.
Dr. Gans contended that Evans syndrome is unique. She noted that compared to ITP and
hemolytic anemia, Evans syndrome is associated with “increased expression of Fas on both B
and T cell lymphocytes with higher Fas-induced activated T lymphocyte apoptosis.” Resp. Ex.
D at 1.53 Dr. Gans also recognized that there are cases of chronic ITP. Resp. Ex. D at 1.
However, she maintained that compared to chronic ITP, Evans syndrome had a distinctive
profile including “increased T suppressor and decreased T helper cells and subsequent
diminished Ig production.” Resp. Ex. D at 2.54 Dr. Gans also found it more significant that ITP
51
W. Wang (1988) [Resp. Ex. H]; D. Teachey et al. (2005) [Resp. Ex. Y]
52
A. Norton & I. Roberts (2005) [Resp. Ex. F].
53
Citing S. Savasan (2005) [Resp. Ex. X.]; D. Teachey et al. (2005) [Resp. Ex. Y].
54
Citing W. Wang et al. (1983) [Resp. Ex. I].
32
involves one cell line and Evans syndrome involves two cell lines. Therefore, although Dr. Gans
agreed that ITP (at least the acute form) may be the result of an autoimmune response to an
antigen, she opined that ITP was dissimilar to Evans syndrome. Resp. Ex. D at 1-2; Resp. Ex. W
at 1-2. However, her distinction between Evans syndrome and chronic ITP was not as clear and
she acknowledged that at least some cases of chronic ITP had at least some of the same immune
pathways occurring with Evans syndrome. Tr. 268-69.
As discussed above and repeated here because of the significance to the case, Dr. Gans
opined that Evans syndrome is the result of immune dysregulation. A normal immune system
can mount an effective response eliminating a foreign antigen, but afterwards, Fas and Fas ligand
surface proteins connect and cause apoptosis, ending the immune response and returning the
system to homeostasis. However, studies suggest that in patients with Evans syndrome, the Fas-
Fas ligand pathway is aberrant, leading to an attack on the self. Tr. 231-32; Resp. Ex. W at 2-3,
5. Dr. Gans also opined that while Evans syndrome is rare, the hematopoietic (blood) system is
in fact the most common location for autoimmunity to occur. Resp. Ex. W at 3. “Likely this
represents the fact that the endovascular (or circulatory system) plays an important role in
preventing autoimmunity.” Id.
As discussed above, Evans syndrome (requiring low counts in two blood cell lines) can
overlap with either ALPS (requiring the presence of double negative T cells and defective Fas-
mediated apoptosis; see studies by Teachey et al.) or CVID (requiring low counts in two
gammaglobulin lines, sometimes including attacks on the blood cells, see studies by Savasan et
al.).55 These findings appear at least somewhat paradoxical. Indeed, a review of the literature
and the expert testimony suggests that Evans syndrome is not fully understood. The medical
community and the experts in this case agree that in Evans syndrome, the two different cell lines
(i.e., the red blood cells and platelets) are being attacked by different immune cells which are not
cross-reactive.56 The available studies suggest that it is quite likely that Evans syndrome
involves a defect in the regulatory arm of the immune system, possibly involving a defect in the
Fas-Fas ligand pathway which can manifest in several different ways. First, a failure in Fas-
mediated apoptosis may result in chronic lymphoproliferation. In other patients, an enhanced
Fas-mediated process may result in decreased B and T cells. The authors of these studies also
consistently say that the etiology of Evans syndrome is unknown.57 For example: “Although
55
In this case, the experts devoted significant time debating whether D.B. developed CVID and whether that was the
cause or residual effect of his Evans syndrome. Petitioners’ expert Dr. Byers initially opined that he had CVID
which has many manifestations including hemolytic anemia, ITP, and “ITP-Evans.” Pet. Ex. 7 at 2-3. But over the
course of litigation, she amended that opinion. Later, Dr. Byers – and Dr. Forman - observed that D.B.’s
gammaglobulin levels were normal at the outset of his disease and that subsequent tests could not be read accurately
because he was receiving infusions of gammaglobulin by way of IVIg treatment. Additionally, there is no indication
that D.B. was ever tested for abnormalities in the Fas-Fas ligand pathway. Pet. Ex. 27 at 5-6. Respondent’s expert
Dr. Gans continued to suspect that D.B. had CVID. However, she opined that “the presence or absence of CVID in
D.B. is not important for casualty [sic; presumably “causality”], but as with ALPS, represents an entity that appears
to develop over time in some individuals who carry a diagnosis of Evans and are followed over time.” Resp. Ex. W
at 4. Thus, I will not make a determination whether or not D.B. developed CVID.
56
See, e.g., A. Norton & I. Roberts (2005) [Resp. Ex. F at 2].
57
A. Norton & I. Roberts (2005) [Resp. Ex. F at 1].
33
Evans syndrome appears to be a disorder of immune regulation, the exact pathophysiology is
unknown. Most studies have involved small numbers of patients . . . However, taken as a whole,
there is evidence to support abnormalities in both cellular and humoral immunity in Evans
syndrome.”58 And: “The etiology of Evans remains speculative at this time. Wang et al. noted
abnormalities of lymphocyte subsets and immunoglobulin synthesis, supporting the concept of
aberrant immunoregulation in this condition.”59 Alterations in serum immunoglobulin levels in
Evans syndrome have been reported in a number of studies, but these are neither consistent nor
specific. Moreover, the number of circulating B cells appears to be in the expected range.60 The
literature appears to be in agreement that the underlying pathology of Evans syndrome is
unknown but respondent’s experts suggest that Evans occurs because of the failure of the
immune system to regulate itself resulting in multiple dysregulated pathways with the end result
being autoimmune damage to different cell lines circulating in the blood where the cells are most
exposed to autoimmune attack.
The literature on Evans, for the most part, does not examine the potential role of triggers.
It is unclear why the studies do not examine potential triggers for onset of Evans syndrome;
however, it is clear that the pathophysiology of the disease is not entirely apparent.
Even if the conclusion is that the disease is solely a function of regulatory failure, it is not
at all clear why that failure in some instances results in depressed immune cells, in others
excessive lymphocytes and in others is simply described by damage to the platelets and red cells
with different antibodies on the cells. It is not clear why if the immune cells are depressed, they
continue to attack the platelets and red cells. Nor is it clear why the onset of the disease occurs
at such varying ages, although Dr. Gans theorized that this is just a function of different
maturational processes of the immune system. Tr. 259.
Bystander Activation
As summarized above, Dr. Byers’s initial opinion was that molecular mimicry between
the hepatitis B vaccine and the self can cause Evans syndrome.
Dr. Byers then recognized that Evans syndrome involves reduced counts in two separate
cell lines which are attacked by different autoantibodies that do not cross-react.61 She
acknowledged that it was unlikely for the hepatitis B vaccine, having only a single antigen, to
have sufficient similarity with both cell lines to result in molecular mimicry with two separate
cell lines. Tr. 163-64. She did maintain that they were “fairly closely related cells of the
hematopoietic lineage.” Tr. 165.
Dr. Byers shifted her focus to a theory of bystander activation, which is discussed in
more detail above. Put simply, bystander activation depends on a foreign antigen entering the
58
A. Norton & I. Roberts (2005) [Resp. Ex. F at 2].
59
P. Mathew et.al. (1997) [Resp. Ex. Q at 1].
60
A. Norton & I. Roberts (2005) [Resp. Ex. F at 2], citing to W. Wang (1988) [Resp. Ex. H]; W. Wang et al. (1983)
[Resp. Ex. I]; other citations omitted as not filed in this case.
61
See A. Norton & I. Roberts (2005) [Resp. Ex. F].
34
body and activating the non-specific innate immune system, which releases non-specific
inflammatory cytokines, which activate dormant B and T cells directed against part(s) of the self.
Specific to this case, Dr. Byers opined that a hepatitis B vaccine can activate the immune system
to attack the hepatitis B antigen, but also activate bystander immune cells which attack the red
blood cells and platelets.
Conclusion on Althen Prong One
While bystander activation is a recognized theory of autoimmunity that has been
proposed by many authors, I could find no reference to it in any of the literature regarding Evans
syndrome. While the pathophysiology of Evans syndrome appears to be far from certain and not
completely understood, it does appear that the predominant thinking does not implicate the
activation of previously dormant autoreactive cells that produce antibodies specific to the blood
cells. Rather, the predominant thinking focuses on malfunction of the regulatory system. The
most recent submitted studies on Evans syndrome and related conditions are by Teachey et al.
documenting a subgroup of twelve patients expressing resistance to Fas-mediated apoptosis
leading to ALPS,62 and by Savasan et al. documenting a subgroup of seven patients expressing
increased Fas-activated lymphocyte apoptosis leading to CVID.63 Thus, the focus of the Evans
literature has been almost entirely on the regulatory arm of the immune system and not on the
effector side of it.
Bystander activation or other types of autoimmune activation as triggering mechanisms
for Evans syndrome were generally not discussed in the literature on Evans syndrome. Norton et
al. do reference that a number of authors have investigated the role of various childhood
immunizations in the development of ITP or hemolytic anemia. Norton et al. provide that:
“Taken together, these reports suggest that immunizations may provide a trigger for the
development of disease in susceptible individuals and may also lead to a sustained increased risk
in some of them.” However, Norton et al. also make clear that none of these studies was on
Evans syndrome.64 Petitioners submitted one case study on the onset of Evans syndrome
following hepatitis B vaccine65 and another following hepatitis B virus,66 but these do not
explain the multiplicity of antigens that would be required or address the problem of chronicity
in Evans as opposed to the most common forms of ITP and hemolytic anemia. To wit, in the
case involving the hepatitis B vaccine, the patient (a 33-year-old man with bone marrow-
documented erythroid hyperplasia and megakaryocytic thrombocytopenia) had a good recovery
after two months treatment with methylprednisolone. Resp. Ex. P at 1.
At this point, a role for vaccines as triggers in this puzzling and very rare disease cannot
be entirely discounted. However, the evidence presented in this case is insufficient to establish a
62
D. Teachey et al. (2005) [Resp. Ex. K, also filed as Resp. Ex. Y]; see also D. Teachey et al. (2009) [Resp. Ex.
BB].
63
Savasan (2007) [Resp. Ex. J, also filed as Resp. Ex. X].
64
A. Norton & I. Roberts (2005) [Resp. Ex. F at 2].
65
E. Martinez & P. Domingo (1992) [Resp. Ex. P].
66
A. Kalayci et al. (2001) [Pet. Ex. 25].
35
reliable theory in the face of the dominant thinking in the literature to the effect that an activation
of the immune system causing an elevation of immune cells is not counteracted after the threat
has been eliminated and the system returned to homeostasis.
It appears that the leading theory is this inherent failure of immune regulation that allows
the multifaceted attack on different elements of the hematologic system, in this case the platelets
and red cells simultaneously. While Dr. Byers demonstrated through the literature general
theories of autoimmunity, which could conceivably play a role in this disease, Dr. Gans was
better able to tie the analysis of this rare syndrome to the research that has been done on the
disease itself and to explain its implication for treatment of patients with the condition whom she
manages. Although the mechanism or pathophysiology is far from certain and the studies to date
have produced paradoxical results, leaving many questions about the cause of the disease, the
research does focus on the regulatory arm of the immune system and does not appear to have
addressed theories like bystander activation to explain this difficult and chronic disease.
Accordingly, I have concluded that the evidence of bystander activation is too speculative
to establish a theory of vaccine causation in the face of the relatively defined theory of immune
dysregulation in this case. Accordingly, petitioners have not carried their burden to establish by a
preponderance of the evidence that bystander activation is a theory under which the hepatitis B
vaccine can cause Evans syndrome, accordingly, the claim fails Althen prong one.
B. Althen Prong Two
Legal Standard
To fulfill Althen prong two, petitioner must show, by a preponderance of the evidence, "a
logical sequence of cause and effect showing that the vaccination was the reason for the
injury." Althen, 418 F.3d at 1278. This prong is sometimes referred to as the “did it cause” test;
i.e., in this particular case, did the vaccine(s) cause the alleged injury. Broekelschen, 618 F.3d at
1345.
Proof of Althen prong two requires a logical explanation as to how the vaccine did cause
the injury in the petitioner. “’A logical sequence of cause and effect’ means what it sounds
like—the claimant’s theory of cause and effect must be logical.” Capizzano, 440 F.3d at 1326.
The proof need not rise to the level of scientific certainty, but rather to the Vaccine Act’s
preponderance standard under the system created by Congress, in which close calls regarding
causation are resolved in favor of injured claimants.’” Andreu, 569 F.3d at 1378. A physician
may rely on the close temporal proximity between a vaccination and an injury in concluding that
there is a logical sequence of cause and effect between the vaccine and the injury. Capizzano,
440 F.3d at 1326.
Discussion & Conclusion
Dr. Gans speculated that D.B.’s mother had endometriosis which was an autoimmune
condition and therefore may have put D.B. in a higher risk category for developing an
autoimmune condition himself. Dr. Gans also opined that D.B.’s pre-vaccination history of
prolonged thrush suggested that his immune system was not responding optimally. Resp. Ex. D
36
at 3. While Dr. Gans’s retrospective “unifying diagnosis” – in which she put together multiple
factors such as the mother’s possible autoimmune endometriosis, the dime-sized bruise and the
longerthan expected thrush coupled with the knowledge of the ultimate diagnosis of Evans
syndrome – is not unreasonable and may tend to show that the Evans syndrome was present prior
to the vaccination, those factors were somewhat speculative and were otherwise explained by Dr.
Foreman. Accordingly, I have not accorded that alternative diagnosis significant weight in
coming to my conclusion in this case.
If petitioners’ theory of bystander activation or epitope spreading appeared to be
sufficiently reliable, then prong two, a logical sequence of cause and effect, likely would have
been fulfilled. However, as I have concluded that the evidence was insufficient to satisfy prong
one, there is no need to make further finding on this part of the Althen criteria.
C. Althen Prong Three
Legal Standard
Althen prong three requires establishing a “proximate temporal relationship” between the
vaccination and the injury alleged. Althen, 418 F.3d at 1281. That term has been equated to the
phrase “medically-acceptable temporal relationship.” Id. A petitioner must offer “preponderant
proof that the onset of symptoms occurred within a timeframe which, given the medical
understanding of the disorder’s etiology, it is medically acceptable to infer causation.” de Bazan
v. Sec’y of Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for
what is a medically acceptable timeframe must also coincide with the theory of how the relevant
vaccine can cause an injury (Althen prong one). Id. at 1352; Shapiro v. Sec’y of Health &
Human Servs., 101 Fed. Cl. 532, 543 (2011), recons. den’d after remand, 105 Fed. Cl. 353
(2012), aff’d mem., 2013 WL 1896173 (Fed. Cir. 2013); Koehn v. Sec’y of Health & Human
Servs., No. 11-355V, 2013 WL 3214877 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for review
den’d (Fed. Cl. Dec. 3, 2013), aff’d, 773 F.3d 1239 (Fed. Cir. 2014).
Discussion & Conclusion
After careful consideration and review of the medical records as well as the mother’s
testimony (which I found to be credible, persuasive, and limited to her personal recollections), I
conclude that D.B. did not have bruising on the ear three days post-vaccination. The medical
records sometimes refer to a “mark” on the ear and also report a history of ear-pulling.
Additionally, petitioners’ expert hematologist Dr. Forman, who has clinical experience
vaccinating young patients and was familiar with their common reactions to hepatitis B vaccine,
opined that post-vaccination irritability could have led to this pulling of the ear, which could lead
to some discoloration.
D.B. did have a bruise at the vaccination site three days afterwards. However, Dr.
Forman opined that bruising at the vaccination site would be a common finding and not
necessarily evidence of a platelet deficiency. As noted above, I found this opinion to be credible
based on Dr. Forman’s significant clinical experience vaccinating children and adults in various
states of health and his comparison of this bruise to the later, more widespread bruising in D.B.
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I also found credible the mother’s recollection that the deeper, more widespread bruises
on D.B.’s legs, which were consistent with her later understanding of Evans syndrome, began on
March 12, 2009. The mother credibly related her observation of these first bruises to her first
appearance in divorce court on that same day, which was tied to a significant change in her life.
Both Dr. Forman and Dr. Byers supported the onset as being on or about March 12 with
the full presentation by March 15, 2009. and Dr. Gans agreed that the appearance of bruising and
petechiae would appear quite quickly.
My post-hearing order provided: “The undersigned will find that March 12 was the first
date of a visible presentation of Evans syndrome. This leaves open the issue of how long it
would take to develop a sufficiently low platelet count to produce the level of bruising seen on
March 12. However, the likelihood is that the undersigned would conclude that the timing was
appropriate.” Scheduling Order entered November 15, 2016 (ECF No. 85). As the experts
tended to agree that the clinically evident signs of bruising and petechiae could occur quite
quickly once the condition became operative, I think it is reasonable to conclude that an onset
date of March 12, 2009, is reasonable.
Accordingly, I conclude that if petitioners had presented an acceptable theory to fulfill
Althen prong one, they likely would have satisfied Althen prong three because the temporal
relationship between the Hep B vaccination on March 4, 2009, and the onset of Evans syndrome
approximately eight days later appears to be medically acceptable, at least in comparison to
accepted time periods for autoimmune onset of other conditions.
V. CONCLUSION
I appreciate the frustration that D.B., his parents, and his treating physicians must feel in
trying to manage this very rare disease with its elusive pathophysiology and inconsistent
response to treatment. I have great sympathy for what they have experienced. I have also been
frustrated in trying to understand the possible cause. However, after carefully reviewing the
testimony and the submitted literature, I unfortunately must conclude that the state of knowledge
about Evans syndrome is insufficient to be able to conclude that the hepatitis B vaccine played a
causal role in D.B.’s condition and that the evidence presented by respondent through the
testimony and the literature, in favor of an immune regulatory defect to explain the disease, more
likely than not explains the condition. Therefore, petitioners have not established entitlement to
compensation in the Vaccine Program and their claim must be and is DISMISSED. In the
absence of a motion for review filed pursuant to RCFC Appendix B, the Clerk of the Court is
directed to enter judgment forthwith.67
IT IS SO ORDERED.
s/Thomas L. Gowen
Thomas L. Gowen
Special Master
67
Entry of judgment is expedited by each party’s filing notice renouncing the right to seek review. Vaccine Rule
11(a).
38