LISA HAMILTON-FIELDMAN, Special Master.
On August 30, 2011, Tina Ramsay filed a vaccine claim under the National Vaccine Injury Compensation Program ("the Program")
The undersigned now finds that Petitioner has proven, by a preponderance of the evidence, that her sJIA was caused by her HPV vaccinations. The Clerk's Office is ordered to enter judgment in favor of Petitioner unless a motion for review is filed.
Petitioner was born on June 16, 1993. Petitioner's Exhibit ("Pet. Ex.") 1 at 1. Prior to administration of the first and second Gardasil vaccinations, Petitioner's medical history was unremarkable except for a tonsillectomy at age seven and migraine headaches and irritable bowel syndrome diagnosed at age twelve. Pet Ex. 3 at 11; Pet. Ex. 4 at 47-48. Petitioner asserts, and the records do not contradict, that she had no adverse reactions to any vaccination prior to administration of the Gardasil vaccine. See Petitioner's Post-Hearing Brief at 1.
Petitioner was administered the first Gardasil vaccine on March 19, 2008, when she was fourteen years old. Pet. Ex. 2 at 3-4. She was administered the second Gardasil vaccine on June 30, 2008, when she was fifteen years old. Pet. Ex. 3 at 11; Pet. Ex. 13 at 1.
The medical records are inconclusive regarding the precise date of onset of Petitioner's sJIA. According to an affidavit authored by Tina Ramsay, Petitioner "began having flu-like symptoms, such as sore throat, fever and aching all over her body" during the first week of November 2008. Pet. Ex. 9 at 1; see also Pet. Ex. 6 at 46 (reporting that "aches and pains" began "in the first part of November," followed by headache, red eyes, and fever). Petitioner did not seek medical attention, however, until November 13, 2008, when she presented to her primary care physician, Dr. Carl Brutkiewicz, with complaints of muscle aches, fever, and wrist pain, as well as "irritated eyes and headaches over the last week." Pet. Ex. 3 at 12; Pet Ex. 5 at 42. Her temperature was 99.1 degrees. Pet. Ex. 3 at 12. Dr. Brutkiewicz diagnosed Petitioner with allergies and prescribed Petitioner with Xyxal #10 (anti-allergy eyedrops). Id. Dr. Brutkiewicz would later describe her exam at this visit as "fairly unremarkable." Pet. Ex. 5 at 38.
On November 14, 2008, Petitioner's mother, Tina Ramsay, called in to Dr. Brutkiewicz's office and reported that Petitioner was "achy all over today," with a fever of 100.6 and headaches. Pet. Ex. 3 at 12. She was prescribed amoxicillin. Id. No rash was reported, either during this call or during the November 13, 2008 exam.
On November 16, 2008, Petitioner reported to Mobile Infirmary West with generalized rash and myalgia.
On November 20, 2008, Petitioner presented to the emergency department of South Alabama Hospital "[with complaints of] fever, myalgia for 8 days." Pet. Ex. 4 at 14. According to Petitioner's mother, Petitioner's fevers, rash, and myalgias had persisted after she was prescribed amoxicillin; her maximum temperature had been 104. Id. Upon exam, "patchy erythematous rash"
She followed up with Dr. Brutkiewicz on November 21, 2008. Pet. Ex. 3 at 12. Petitioner reported that her "diffuse aches" had continued despite medication. Id. Dr. Brutkiewicz noted that Petitioner had a temperature of 100.8, "moderate pharyngeal erythema," diffuse myalgias, and a fading macular rash on her upper extremities. Id. He diagnosed her with "probable viral syndrome with post viral _____." Id.
On November 24, 2008, Petitioner was admitted to Springhill Memorial Hospital (hereinafter "Springhill") for treatment of a "fibrile [sic] illness." Pet. Ex. 5 at 37. Upon admission, her temperature was documented at 103.2. Pet. Ex. 5 at 38. Her condition had "progressed to generalized aches and pains of all of her joints and extremities." Id. at 42. "[I]ntermittent macular rash on . . . her extremities and hands" was noted. Id. at 37, 42. Testing revealed that Petitioner's white blood cell count was elevated to 22,500; monospot, throat culture, DNAase B titer, ASO titer, Hepatitis B surface antigen, Hepatitis C antibody, Parvovirus B19 IgG/IgM, ANA profile, rheumatoid factor, and Mycoplasma
Several of Petitioner's treatment providers at Springhill noted that her condition was consistent with sJIA. Dr. Teresa Oglesby, a consulting rheumatologist, opined that, clinically speaking, her illness was consistent with a "postviral" event or with Still's disease. Id. at 29. Among other things, Dr. Oglesby observed that an elevated ferritin level was commonly associated with Still's. Id. at 25. Dr. Adrien Bodet, an infectious disease specialist, suspected either "1) [p]ost-infectious inflammatory [disease] or 2) [primary] immune [reaction] (Still's?)." Id. at 24. See also Pet. Ex. 5 at 41 (Dr. Sindel stated that "Still's disease [is still] a consideration").
After her discharge from Springhill, Petitioner followed up with Dr. Daren Scroggie, a pediatric rheumatologist. Pet. Ex. 6 at 45-47. Following a visit on December 1, 2008, Dr. Scroggie concluded that Petitioner "has a history consistent with systemic onset JIA, though she is still early on." Id. at 47; see also Pet. Ex. 3 at 10 (Dr. Brutkiewicz noting Dr. Scroggie's presumptive diagnosis of Still's disease on December 4, 2008). On December 8, 2008, Dr. Scroggie prescribed methotrexate.
Throughout 2009, Petitioner's physicians continued to treat her illness with methotrexate and steroids. See, e.g., Pet. Ex. 6 at 3, 44. In 2010, Petitioner's treaters also began referring to a diagnosis of Crohn's-related arthritis. See, e.g., Pet. Ex. 8 at 81. As Respondent concedes, "[these physician] notes lack sufficient clarity to establish the basis for a change from JIA to Crohn's as the diagnosis." Respondent's Rule 4 Report at 5; see also tr. 43-44 (Respondent declining to contest the accuracy of Petitioner's sJIA diagnosis).
Tina Ramsay filed this vaccine petition on Petitioner's behalf on August 30, 2011. The case was initially assigned to Special Master Gary Golkiewicz. Medical records, including Exhibits 1 through 13, as well as a statement of completion, were filed between October 25, 2011 and December 28, 2011. On December 28, 2011, Petitioner filed an expert report authored by Dr. Michael McCabe. See Pet. Ex. 14. The references cited in Dr. McCabe's report were filed on January 6, 2012. See Pet. Ex. 15-36.
On March 20, 2012, Respondent filed a Rule 4 Report recommending against compensation because, Respondent argued, Petitioner had not established by a preponderance of the evidence that Petitioner had suffered a vaccine-related injury. Rule 4 Report ("Resp. Report") at 1, 6-14. Simultaneously, Respondent filed an expert report authored by Dr. Carlos Rose. See Respondent's Exhibit ("Resp. Ex.") A.
At a status conference held on March 29, 2012, Special Master Golkiewicz and "[t]he parties discussed how to address respondent's concerns regarding the proper medical diagnosis and whether Dr. McCabe . . . is qualified to address such an issue." See Order, filed March 30, 2012, at 1. Special Master Golkiewicz noted that "petitioner's expert's reasoning regarding a medically appropriate time frame between vaccination and onset of injury is problematic." Id.
On April 30, 2012, Petitioner filed a status report in which she stated that her treating rheumatologist, Dr. Peter Weiser, had agreed to write a letter clarifying Petitioner's diagnosis. Petitioner requested the opportunity to file Dr. Weiser's letter, as well as a supplemental expert report authored by Dr. McCabe. Both of these requests were granted. See Order, filed May 1, 2012, at 1.
On May 9, 2012, this case was reassigned to then-Chief Special Master Campbell-Smith.
Petitioner ultimately filed Dr. Weiser's letter on May 22, 2012; she filed Dr. McCabe's supplemental expert report on June 15, 2012.
On July 11, 2012, Chief Special Master Campbell-Smith convened a status conference during which she advised Petitioner to clarify the nature of Petitioner's injury, to "address the medical appropriateness of the four-month period between the onset of [Petitioner's] symptoms and her receipt of the vaccinations at issue," and "to address the impact, if any, of a clarified diagnosis of either sJIA or Crohn's disease" on Dr. McCabe's theory of causation. See Order, July 12, 2012, at 2-3. Among other things, Chief Special Master Campbell-Smith observed that the factual predicate underlying Petitioner's theory remained unclear. Id. at 2. She directed Petitioner to file clarifying opinions from Petitioner's treating gastroenterologist, Dr. Jeanine Maclin, "regarding the basis for the diagnostic impression that [Petitioner] has Crohn's disease;" from Dr. Weiser "clarify[ing] whether he attributes [Petitioner's] inflammatory condition to a diagnosis of sJIA or Crohn's disease;" and from Dr. McCabe regarding the timeliness of onset. Id. at 3. Petitioner ultimately filed clarifying opinions from Dr. Maclin and Dr. McCabe on October 9, 2012. See Pet. Exs. 39 (Dr. Maclin) and 40 (Dr. McCabe). Petitioner declined to file an additional report from Dr. Weiser.
During a status conference held on November 21, 2012, Chief Special Master Campbell-Smith began the process of scheduling an entitlement hearing. See Order, filed November 21, 2012, at 1-2. A pre-hearing order was issued on December 6, 2012. Petitioner filed three additional medical literature exhibits on November 30, 2012, see Pet. Exs. 41-43, and Respondent filed a final expert report authored by Dr. Rose, as well as supportive medical literature, on January 7, 2013. See Resp. Exs. G-J.
On March 4, 2013, this case was reassigned to the undersigned.
On June 7, 2013, Petitioner moved to continue the entitlement hearing that had been set for August 5, 2013 and August 6, 2013, as well as its associated pre-trial deadlines. Motion to Continue Entitlement Hearing and Pre-Trial Deadlines, filed June 7, 2013, at 1-2. Petitioner's counsel requested that the hearing be postponed pending appellate review of a decision denying entitlement in a similar case. See Koehn v. Sec'y of Health & Human Servs., 773 F.3d 1239 (Fed. Cir. 2014) (affirming denial of entitlement in a Gardasil/sJIA case that had been filed by Ms. O'Dell on the basis of Dr. McCabe's theory of causation). Id. Respondent objected to the requested continuance. Id. at 2. The undersigned ultimately denied Petitioner's motion to continue, noting that there are "distinctive factual and medical differences between this case and the Koehn case," and that Koehn's outcome was not binding on the undersigned. See Order, June 11, 2013, at 2.
On June 20, 2013, the undersigned granted Petitioner's motion to file a supplemental expert report, this time authored by Dr. Eric Gershwin. See Order, filed June 20, 2013; Motion, filed June 18, 2013. Petitioner filed Dr. Gershwin's expert report, as well as supportive medical literature, on June 26, 2013. See Pet. Exs. 44-65. Petitioner filed additional medical literature, as well as her experts' CVs, on July 12, 2013. See Pet. Exs. 66-83.
An entitlement hearing was held in Washington, D.C., on August 5th and 6th, 2013. Both parties' experts testified. At the close of the hearing, the undersigned granted Petitioner's counsel's request to file post-hearing briefs. Tr. 428-31. The parties simultaneously filed post-hearing briefs on September 3, 2013. This matter is now ripe for a ruling.
To receive compensation under the Vaccine Act, Petitioner must demonstrate either that: (1) she suffered a "Table injury" by receiving a covered vaccine and subsequently developing a listed injury within the time frame prescribed by the Vaccine Injury Table set forth at 42 U.S.C. § 300aa-14, as amended by 42 C.F.R. § 100.3; or (2) that suffered an "off-Table Injury," one not listed on the Table as a result of her receipt of a covered vaccine. See 42 U.S.C. §§ 300aa-11(c)(1)(C); Moberly v. Sec'y of Health & Human Servs., 592 F.3d 1315, 1321 (Fed. Cir. 2010); Capizzano v. Sec'y of Health & Human Servs., 440 F.3d 1317, 1320 (Fed. Cir. 2006).
Because Petitioner does not allege a Table injury in this case, she must prove that her injury was caused-in-fact by an covered vaccine. To establish causation-in-fact, Petitioner must demonstrate by a preponderance of the evidence that the vaccine was the cause of the injury. 42 U.S.C. § 300aa-13(a)(1)(A). Petitioners are required to prove that the vaccine was "not only [the] but-for cause of the injury but also a substantial factor in bringing about the injury." Moberly v. Sec'y of Health & Human Servs., 592 F.3d 1315, 1321-22 (Fed. Cir. 2010) (quoting Shyface v. Sec'y of Health & Human Servs., 165 F.3d 1344, 1352-53 (Fed. Cir. 1999)).
In the seminal case of Althen v. Secretary of the Department of Health and Human Services, the Federal Circuit set forth a three-pronged test used to determine whether a petitioner has established a causal link between a vaccine and the claimed injury. See Althen v. Sec'y of Health & Human Servs., 418 F.3d 1274, 1278-79 (Fed. Cir. 2005). The Althen test requires the petitioners to set forth: "(1) a medical theory causally connecting the vaccination and the injury;
(2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury." Id. To establish entitlement to compensation under the Program, a petitioner is required to establish each of the three prongs of Althen by a preponderance of the evidence. See id.
Specifically, under the first prong of Althen, Petitioners must offer a scientific or medical theory that answers in the affirmative the question "can the vaccine(s) at issue cause the type of injury alleged?" See Pafford v. Sec'y of Health & Human Servs., No. 01-0165V, 2004 WL 1717359, at *4 (Fed. Cl. Spec. Mstr. July 16, 2004). This may be accomplished in a number of ways. Id. "Reliability and plausibility of pathogenesis can be bolstered by providing evidence that at least a sufficient minority in the medical community has accepted the theory, so as to render it credible." Id. In addition, "epidemiological studies and an expert's experience, while not dispositive, lend significant credence to the claim of reliability; articles published in respected medical journals, which have been subjected to peer review, are also persuasive." Id. However, publication "does not necessarily correlate with reliability," because "in some instances well-grounded but innovative theories will not have been published." Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 593-94 (1993).
In addition to showing that the vaccine at issue can cause a particular injury, a petitioner must also prove that the vaccine actually did cause the alleged injury in a particular case. See Pafford, 2004 WL 1717359, at *4 (emphasis added); Althen, 418 F.3d at 1279. A petitioner does not meet this obligation by showing a temporal association between the vaccination and the injury; the petitioner must explain "how and why the injury occurred." Pafford, 2004 WL 1717359, at *4.
While a temporal association alone is insufficient to establish causation under the third prong of Althen, a petitioner must show that the timing of the injury fits with the causal theory. See Althen, 418 F.3d at 1278. For example, if the petitioner's theory involves a process that takes several days to develop after vaccination, an injury that occurred within a day of vaccination would not be temporally consistent with that theory. Conversely, if the theory is one that anticipates a rapid development of the reaction post-vaccination, the development of the alleged injury weeks or months post-vaccination would not be consistent with that theory. The special master cannot infer causation from temporal proximity alone. In fact, it has been held, that where a petitioner's expert views the temporal relationship as the "key" indicator of causation, the claim must fail. See Thibaudeau v. Sec'y of Health & Human Servs., 24 Cl. Ct. 400, 403-04 (Fed. Cl. Oct. 23, 1991); see also Grant v. Sec'y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992); Hasler v. United States, 718 F.2d 202, 205 (6th Cir. 1983) (stating that inoculation is not the cause of every event that occurs within a ten-day period following it).
A petitioner who demonstrates by a preponderance of the evidence that he suffered an injury caused by vaccination is entitled to compensation, unless the respondent can demonstrate by a preponderance of the evidence that the injury was caused by factors unrelated to the vaccination. See Althen, 418 F.3d at 1278; Knudsen v. Sec'y of Health & Human Servs., 35 F.3d 543, 547 (Fed. Cir. 1994).
Dr. Eric Gershwin received his medical degree from Stanford University in 1971. Pet. Ex. 67 at 1; tr. 5. He has been board-certified in internal medicine, rheumatology, and allergy and clinical immunology since 1974, 1978, and 1980, respectively. Pet. Ex. 67 at 2; tr. 7. He is currently a professor of medicine at the University of California School of Medicine in Davis, California; since 1982, he served as the school's chief of the Division of Rheumatology/Allergy and Clinical Immunology. Pet. Ex. 67 at 1; tr. 6-7.
Between 1960 and the date of the entitlement hearing, Dr. Gershwin had published 859 peer-reviewed articles. Pet. Ex. 67 at 13-82; tr. 10. He has also written numerous books, book chapters, and reviews. Tr. 7-10. Of particular note are Dr. Gershwin's role in editing the first published book on musculoskeletal diseases in children, and in publishing a peer-reviewed article on issues related to the roles of familial factors, environmental factors, and activating macrophages in juvenile arthritis. See generally Pet Ex. 67. Dr. Gershwin has published articles specifically on the role of pro-inflammatory cytokines in sJIA. See, e.g., Pet. Ex. 46.
At hearing, Dr. Gershwin was admitted as an expert in rheumatology and immunology. Tr. 11.
Dr. Gershwin declined to opine in favor of causation in this case, citing a lack of supportive epidemiological evidence. See generally Pet. Ex. 44; tr. 17, 30-31 (agreeing that "a vaccine [can] be a trigger in a genetically susceptible host" and that vaccines are a "risk factor" for Still's, but that he "would not write a vaccination produced a disease, like Still's disease, at all. . . . [There is] no evidence that it [can] produce [] a disease like Still's [in the absence of] a clear-cut epidemiologic analysis, which, of course, with an incidence of . . . less than one per hundred thousand, it's just not possible in Still's").
He agreed, however, that sJIA "is a disease caused by a genetic predisposition," that it needs "some environmental stimulus to set it off," and that a vaccine can constitute this environmental stimulus "in some people." Tr. 17, 40-41. According to an article of which Dr. Gershwin was a co-author, sJIA is "defined by arthritis with spiking fever persisting for more than 2 weeks and at least one of the clinical features of systemic inflammation: skin rash, lymphadenopathy,
sJIA is an autoinflammatory disease:
The uncontrolled activation — or "dysregulation" — of the innate immune response in sJIA patients results in continuous production — or "upregulation" — of certain types of proteins secreted by cells of the immune system. Tr. 15-16, 25-27, 35. These proteins are called proinflammatory cytokines. Id. at 16. Specific cytokines — including interleukin-1 ("IL-1), interleukin-6 ("IL-6"), and interleukin-18 ("IL-18"), among others — are associated with sJIA. Tr. 15-16.
The Gardasil vaccine, by design, stimulates both the innate and adaptive immune systems. Tr. 14. Like other vaccines, it is capable of precipitating autoimmune diseases. Tr. 30-31. Moreover, Dr. Gershwin testified that sJIA is a genetic disease and that it can be prompted by an environmental trigger. Tr. 16-17. According to Dr. Gershwin, studies have shown that the concordance of sJIA among identical twins is "quite low," "which means that although genetics are important, environment has to start it off. Id. at 17. There has to be something that takes a genetically predisposed person to produce inflammation." Tr. 17.
With respect to the instant case, Dr. Gershwin observed that Petitioner presented to her treatment providers in November 2008 with symptoms that included fever, headache, and sore throat; a high white blood cell count; and elevated C-reactive protein, all of which are consistent with a Still's presentation. Tr. 36-38. Dr. Gershwin agreed that the onset of her sJIA was in November 2008, and that Petitioner exhibited no signs and symptoms of the disease between March and November 2008. Tr. 44. Dr. Gershwin also observed that Petitioner's treatment regimen provides additional evidence that her injury was caused by upregulation of the cytokines associated with sJIA: Petitioner was successfully treated with steroids and methotrexate, both of which are drugs that inhibit the cytokines TNF-alpha, IL-6, and IL-1. Tr. 37-39; see also Pet. Ex. 6 at 34-36, 41.
Most importantly, Dr. Gershwin opined that four and a half months — the amount of time it took Petitioner's sJIA to manifest after the second Gardasil vaccine — is an appropriate interval between a triggering event and sJIA manifestation. Tr. 16-30. Dr. Gershwin testified that "[t]he protective response . . . to the HPV vaccination takes about seven months [from the first shot]." Tr. 18-19, 30 ("the precipitation of [sJIA] ends up being an immunological imbalance, which takes time to develop. . . . Because the latency time is a significant period of time, and something is happening during that time."). In support of this testimony, Dr. Gershwin pointed to the results of the Frazer study, which showed that, among subjects who had received three HPV vaccinations, peak immune response occurred at approximately seven months after the first vaccination. Tr. 19-20; Pet. Ex. 29.
According to Dr. Gershwin, Still's was likely to have eventually been triggered in someone with Petitioner's genetic predisposition. Tr. 41-42. There are multiple etiologies for the disease. Tr. 41. It is unlikely, however, that Petitioner's pre-existing IBS was the trigger, because IBS does not produce inflammation or cytokines. Tr. 42-43.
Dr. Gershwin acknowledged that, according to an article he co-authored in 2011 and that discussed "triggering factors" of sJIA, there has only been one case of "an exacerbation of systemic JIA" following vaccination. Lin at 5. In that case, onset occurred five days post-vaccination, and the vaccine at issue was live-attenuated rubella. Id. The individual studied had pre-existing Still's. Id.; tr. 45-47. The authors of the article contemplated molecular mimicry, rather than cytokines, as the initial mechanism of injury. Lin at 3 ("Vaccines, similar to infectious agents, may trigger autoimmune diseases through various mechanisms such as molecular mimicry of vaccine with self-antigens, antigen non-specific bystander activation and polyclonal lymphocyte activation during immune response to vaccine."). At hearing, Dr. Gershwin clarified that, even though the authors argued that the process was initiated by molecular mimicry, "the process of the inflammation, whether it's mimicry or not, it's still cytokines, absolutely, carved in concrete, inescapable in Still's." Tr. 52-54.
Dr. Michael McCabe earned a Ph.D. in Microbiology and Immunology from Albany Medical College in 1991. Pet. Ex. 66 at 2. He subsequently served as a postdoctoral research associate at the Karolinska Institute in Sweden, where he studied cell-signaling and regulation of the cell death process. Id., tr. 58-59. Between 1992 and 2000, he was an assistant professor of chemical toxicology and pharmaceutical sciences at Wayne State University. Pet. Ex. 66 at 2. Between 2000 and 2009, Dr. McCabe served as an associate professor in the University of Rochester School of Medicine's Department of Environmental Medicine. Id. at 1. Between 2009 and the date of the hearing, Dr. McCabe served as an "associate" at Robson Forensic, Inc., "an expert witness consulting firm providing litigation support, expertise, [and] opinions [] to the legal and insurance industries." Id.; tr. at 68. He has authored approximately 40 peer-reviewed articles and twelve book chapters, and is an editor of the Journal of Immunotoxicology. Pet. Ex. 66 at 4; 8-13. At hearing, Dr. McCabe was admitted as an expert in immunology. Tr. 74.
Dr. McCabe's theories regarding the immune system's response to the Gardasil vaccine — and its role in the etiology of sJIA — are essentially consistent with those of Dr. Gershwin. Unlike Dr. Gershwin, however, Dr. McCabe believes that there is sufficient evidence upon which to conclude that Petitioner's Gardasil vaccinations caused her sJIA.
According to Dr. McCabe, Gardasil, which is designed to stimulate both the innate and adaptive immune systems, produces "a dramatic, robust, sustained response." Tr. 79-80, 128, 181. One aspect of this response is an upregulation of cytokines, which "participate both in adaptive immune signaling, as well as innate immune signaling, as well as interactions between the adaptive and innate immune system." Tr. 128. In particular, the vaccine causes a marked upregulation of the proinflammatory cytokines IL 6, TNF-alpha, and IL 1. Tr. 128-30. In practice, "Gardasil elicits proinflammatory cytokines in nearly everyone [to whom] the vaccine is administered," and "[i]n some genetically susceptible individuals, that trigger, cytokine upregulation, is an environmental trigger contributing to the causation of the disease [sJIA]." Tr. 80; Pet Ex. 14 at 4 ("the cause of sJIA is thought to be multifactorial — with genetic susceptibility factors and environmental triggers working together in complex ways to initiate and perpetuate adaptive and/or innate immune activities resulting in tissue damage.").
In support of his theory, Dr. McCabe relied heavily on a study of the cytokine responses elicited by the HPV-16 IL-1 viruslike particle (one of the components of the Gardasil vaccine)
According to Dr. McCabe, the Pinto study data have largely been confirmed by other medical literature. A 2007 study, the results of which were reported by lead author Garcia-Pineras, revealed a seven-fold increase in IL-6 production following three doses of Gardasil. Pet. Ex. 31 at 2;
Dr. McCabe also cited the Evans study, which examined individuals at zero-, four-, and 16-week intervals and showed "a dramatic increase" in IF-gamma and IL-5 as a function of vaccination, Pet. Ex. 33
Dr. McCabe conceded that none of the articles he cites studied arthritis or sJIA specifically; they assessed only the cytokine responses in their subjects. Tr. 169-71. Dr. McCabe also conceded that there are no published case reports, case control studies, or animal models that show a relationship between HPV vaccines and sJIA. Tr. 154. Moreover, neither the Meningococcus C nor the Measles-Mumps-Rubella ("MMR") vaccinations, both of which had been suggested as triggers and which were subject to prospective and retrospective studies, have been confirmed to trigger sJIA. Pet. Ex. 16,
Dr. McCabe disputed that the studies cited by Dr. Rose — including the Chao study, the Verstraeten study, and the Klein study — conclusively establish that Gardasil cannot play a causal role in the development of sJIA. See Pet. Ex. 79
Klein, also cited by Dr. Rose, suffers from the same deficiencies. Id. at 160. To enable researchers to draw any conclusions about the correlation between vaccination and sJIA, a study would have to include a million to a million and a half subjects. Tr. 152-53; Pet. Ex. 80;
Verstraeten, which was a study of over 68,000 participants, found that the administration of Cervarix — another HPV vaccine — did not increase the participants' relative risk for contracting lupus, sJIA, systemic lupus, Sjogren's syndrome, or rheumatoid arthritis. Verstraeten at 1. Dr. McCabe pointed out that Cervarix includes a different adjuvant than Gardasil; that it includes immunization against only two — rather than four, as in Gardasil — HPV strains; that it is inadequately powered; and that it did not examine sJIA specifically. Tr. 362-63.
sJIA is a multigenic disease that results from "an interaction between environmental and genetic factors." Tr. 118, 130. See also Pet. Ex. 83
Dr. McCabe testified that the term "idiopathic," when used in the context of sJIA, means "unique;" because it has an incidence of less than one in 100,000 people, all of whom have unique genetic and immunologic profiles, epidemiological analysis is difficult. Tr. 209-10. Therefore, the fact that there are no published case reports linking sJIA to the HPV vaccine, tr. 154, 248, is of limited relevance. Id. at 154.
Dr. McCabe identified the proinflammatory cytokines IL-1, IL-6, IL-18, and TNF — the upregulation of which Gardasil is designed to induce — as being involved in the development of sJIA.
Although "the complexity of interactions between genetic factors and unknown environmental triggers has not been completely unraveled," "a triggering role for infections and vaccinations [in the development of sJIA] has been suggested and likely exists." Pet. Ex. 14 at 4-5; see also tr. 111-17; Prakken at 4 ("[a] genetically susceptible individual might develop a deleterious and uncontrolled response towards a self-antigen on exposure to an unknown environmental trigger. . . . In juvenile idiopathic arthritis, infections and vaccinations have been suggested as two candidates"). Supportive data for this conclusion comes both from human population studies that implicate infection and from "mechanistic considerations." Pet. Ex. 14 at 4. "Infections and vaccinations activate the innate and adaptive immune processes required for functional immunity, which paradoxically can result in deleterious and improperly balanced immune processes causing self tissue damage characteristic of autoimmune/autoinflammatory disease." Id. The Gardasil vaccine contains a "spontaneous formation of non-infectious virus like particles [("VLPs")] that lack the HPV genome but resemble native virions;" administration of the vaccine "induce[s] high titers of neutralizing antibodies to" the L1 viral capsid proteins from four of the most common disease-associated HPV strains." Id. "In individuals immunized with HPV-L1 VLPs, high levels of both adaptive and innate immune cytokines are produced." Id. Many of the cytokines elicited are the pro-inflammatory cytokines that have been implicated in the etiology of sJIA. Id.
According to Dr. McCabe, the fact that studies have not linked sJIA with naturally-occurring HPV infections is "irrelevant." Tr. 75-79; see generally Pet. Ex. 22 (discussing the efficacy of HPV vaccines in prompting an immune response).
Dr. McCabe argued that Petitioner was genetically susceptible host for sJIA. Tr. 210. Applying the mechanisms he had identified, Dr. McCabe testified that the Gardasil vaccine "was an environmental trigger that, given her genetic and immunological susceptibility, caused her disease to manifest when it did." Tr. 154. More specifically, the vaccination "produced upregulation in [Petitioner's] adaptive and . . . innate immune response that included the production of proinflammatory cytokines; . . . her genetic susceptibility and immune susceptibility resulted in her presentation with symptoms that are well known and generally accepted by the scientific and medical community to be tied to inflammatory cytokines." Tr. 132; see also tr. 147-48 ("[Petitioner's] macrophages, which may [have] initially contain[ed] some [] control of secretion of cytokines, are being instructed, upon immunization with Gardasil, by her adaptive immune system to make proinflammatory cytokines," thereby "triggering the process."). The ongoing production of these pro-inflammatory cytokines triggered Petitioner's sJIA, which manifested clinically in November 2008. Tr. 131-32.
Dr. McCabe conceded that there is no direct evidence in Petitioner's medical record of an upregulation of cytokines after either the first or second vaccine. Tr. 182. However, Dr. McCabe observed that Petitioner's medical records contain no alternative explanation for her sJIA, either in the form of another vaccine or another infection. Tr. 195. He opined that while her immune system was capable of handling a mild infection, any infection capable of producing as robust an immune response as that elicited by the Gardasil vaccine would have had to be debilitating, and likely would have been documented. Tr. 210-11.
Dr. McCabe explained that none of Petitioner's treating physicians attributed her injury to the Gardasil vaccination because their primary goal was likely the treatment of her symptoms, not an assessment of causation, and because they lacked a way to test for upregulation of proinflammatory cytokines. Tr. 133, 196-97. Dr. McCabe also testified that, for the reasons set forth in subsection (b)(4), the 3.5 month interval between her first and second doses does not detract from the likelihood that the vaccine caused her sJIA, even though her vaccines were administered at different intervals than the intervals described in Pinto and other studies. Tr. 213-14.
Dr. McCabe opined that "the expected interval between a vaccination and this autoinflammatory disease is predicted by the time period that measurable changes in the immune response are known to be elicited by the vaccine." Tr. 134-35. At least one study has shown that, among individuals who are administered a quadrivalent HPV vaccine at zero, two, and six months, over 99% of subjects experience a "robust" immune response within seven months. Pet. Ex. 26
According to Dr. McCabe, a vacinee's immune response starts to rise after administration of the first vaccine and continues to rise through the second, and possibly the third, dose of vaccine. Tr. 136-37. Dr. McCabe cited the Frazer study, which conclusively documents, among women who received three quadrivalent HPV doses, increased levels of antibody titers over a 5-year period:
Frazer at 4 (internal citations omitted); tr. 136-37. The results summarized in Frazer suggest that "vaccination induced a marked immune response, beginning approximately 1 month after the initial dose, peaking at approximately month 7, and thereafter declining to a stable plateau for 2.5 years after the last vaccine dose." Frazer at 4. Dr. McCabe's opinion, therefore, was that the timing of Petitioner's clinical presentation for sJIA — in November 2008, approximately seven months after she was administered the first dose of Gardasil — was temporally appropriate. Tr. 138-39.
Dr. McCabe disagreed with Dr. Rose that upregulation of proinflammatory cytokines occurs within 24 to 48 hours: "it takes days to mount a primary immune response, meaning an immune response where we're just looking at, focused on the proliferation of T cells." Tr. 140. Based on study data, Dr. McCabe testified that peak cytokine and antibody production occurs at approximately one month after the second vaccine dose. Tr. 191-93.
At hearing, Dr. McCabe gave two explanations for his theory that Petitioner experienced an acute innate system reaction almost five months after the administration of the second vaccine, and approximately four months after peak cytokine production. First, he explained that the second dose of the vaccination caused a more "sustained" and "robust" reaction. Tr. 184, 186 (noting that most, if not all, vaccines include a second dose as a booster to stimulate secondary responses). Acknowledging that studies have documented a slight "downtick" in antibody levels around a month after administration of the second HPV vaccine, Dr. McCabe pointed out that the overall increase in antibody titer is so large after the first and second vaccines that these slight decreases are relatively meaningless: "there is a large — a high level of both immunoglobulin antibody and cytokine that I'd expect to be present even after the peak, even after the second [immunization]," tr. 193-94; "to perseverate on the minor changes that occur in antibody titer between month three and month seven . . . you're missing that much of the potency, the robustness of the response, is occurring within the time frame of those first two immunizations." Tr. 188. He cited at least one study for the proposition that "the highest increments in . . . cytokine responses were seen after the second immunization (i.e., at month 2)." Pet. Ex. 32 at 9;
Second, Dr. McCabe explained that the production of cytokines was merely the initiation of Petitioner's immune response:
Tr. 194. As Petitioner clarified in her post-hearing brief, the analysis of temporal association involves two distinct processes: the development of sJIA and the development of immunity provided by Gardasil. Pet. Brief at 19-20; tr. 395-96.
Dr. McCabe also explained in detail why, notwithstanding the lack of a third Gardasil shot, the timing of onset of Petitioner's sJIA was plausible. Dr. McCabe testified that the first two shots provided an ongoing stimulus to Petitioner's adaptive and innate immune systems. Tr. 136-38, 185, 419-21. Any contribution of the third vaccine to the robustness of Petitioner's immune response would have been minor compared to the contributions of the first two vaccines. Tr. 189-90; see also tr. 139, Pinto (noting that, according to the Pinto article, the peak cytogram response occurs within the time frame of the second HPV immunization). Thus, even though there are no known studies documenting subjects' immune response in the absence of a third shot, the studies referenced by Dr. McCabe — which document almost-peak cytokine production approximately a month following administration of the second vaccine — are a sufficient basis, in his view, upon which to conclude that the timing of onset of Petitioner's sJIA was proximate to the administration of the first two Gardasil injections. Tr. 190-93.
Dr. McCabe did agree that in light of the timing of onset, he would have been less inclined to view the vaccine as causal if Petitioner had received only one dose of the vaccine. Tr. 182-83 (observing that, if Petitioner had received only one vaccination, the onset of her sJIA should have occurred in approximately two months).
Dr. Carlos Rose graduated summa cum laude from the University of Buenos Aires School of Medicine in 1977. Resp. Ex. B at 1. He completed his pediatric residency and pediatric rheumatology training at Thomas Jefferson University; he completed his fellowship training at the University of Pennsylvania. Tr. 222-23. Since 1994, he has been the chief of the Division of Rheumatology, in the Department of Pediatrics, at DuPont Hospital for Children in Delaware. Resp. Ex. B at 7; tr. 222. He has been a member of the American Board of Pediatrics since 1997 and of the American Board of Pediatric Rheumatology since 1998. Tr. 223; Resp. Ex. B. at 3-4.
At the time of the hearing, Dr. Rose testified that he spent approximately 30-40% of his time in clinical practice, treating clients "with mostly inflammatory conditions, including general arthritis . . . systemic among them, lupus, [and] typical pediatric rheumatology diseases." Tr. 223-24. He has spent a portion of his remaining time researching the mechanisms of autoinflammatory diseases and the measurement of cytokines. Tr. 225-27, 231-32. Although he had published numerous articles, none had been on the subjects of sJIA or Gardasil. Tr. 235.
At hearing, Dr. Rose was qualified as an expert in pediatric rheumatology. Tr. 236.
Dr. Rose agreed with Dr. McCabe that sJIA results from innate immune system dysfunction, and that it is characterized by the dysregulation of specific cytokines. Resp. Ex. A at 4 ("[B]ased on its clinical features and gene expression profile[, sJIA is] . . . one of the auto-inflammatory diseases likely associated with dis-regulation of cytokine networks likely IL-1 and IL-6 rather than the adaptive immune system") (internal citation omitted); tr. 241. Dr. Rose also agreed that sJIA is an auto-inflammatory, not an autoimmune, condition, and that it has many triggers. Tr. 241-42, 297. Dr. Rose did not agree, however, that the Gardasil vaccine played a role in the development of Petitioner's sJIA. Tr. 237. In almost 30 years of clinical practice in rheumatology, Dr. Rose has never seen a natural infection "associated with a pattern reminiscent of systemic JIA." Resp. Ex. A at 4.
Prior to the hearing, Respondent and Dr. Rose had espoused the theory that Petitioner's post-vaccine injury was, in fact, Macrophage Activation Syndrome ("MAS").
Assuming that sJIA was, in fact, an accurate diagnosis, Dr. Rose's opinion was that a November 2008 viral infection — evidenced by a sore throat, fever, achiness, and irritated eyes — is the most likely cause of Petitioner's sJIA. Tr. 303, ("the preceding and most immediate viral infection could be a good alternative explanation for the triggering aspects"), 328-29.
Dr. Rose also pointed out that there are no case-control prospective epidemiologic studies addressing sJIA following HPV vaccination. Resp. Ex. A at 5. Indeed, Dr. Rose cited several studies for the proposition that, statistically speaking, administration of the HPV vaccine did not increase vaccinees' risk for developing autoimmune diseases. See generally tr. 287-94; Verstraeten (finding, based on a study of over 68,000 participants, that administration of Cervarix — another HPV vaccine — did not increase the participants' relative risk for contracting lupus, sJIA, systemic lupus, Sjogren's syndrome, or rheumatoid arthritis); Chao (finding, based on a study of 189,000 recipients of the HPV vaccine, that the vaccine presented no increased risk for sJIA); Klein (finding, based on a study of the same population, that there was no increase in emergency room visits or hospitalizations, both of which one would expect to see in a patient with sJIA);
Dr. Rose's position was that none of the studies cited by Dr. McCabe supports his argument that the HPV vaccine (or HPV virus-like particles) causes "the massive amount of cytokine production that you need sustained . . . in a person with systemic JIA day after day." Tr. 276. For the Gardasil vaccine to have caused her injury, Petitioner would have had to have "suffered an extraordinary powerful [sic] cytokine response to the vaccine (not noticed clinically . . . during the days immediately following the inoculation) and that the normal mechanisms of control of the cytokine response are ineffective." Resp. Ex. G at 3-4. The medical literature cited by Petitioner's experts, therefore, does not support a causative link, because it does not document a sustained pattern of cytokine upregulation in response to vaccination. Id. Dr. Rose argues that such a pattern is essential to show that the Gardasil can cause sJIA. Id.
With regard to the timing of onset of Petitioner's sJIA, Dr. Rose described as "baseless" Dr. McCabe's theory that a plausible time frame for onset should be assessed with reference to the timing of measurable changes in the immune response. Resp. Ex. G at 3. According to Dr. Rose, the body's immune response to a vaccine, as documented by sero-conversion and T cell response, has no pathological implication. Id. The production of pro-inflammatory cytokines does not always result in disease; such production is a normal, protective response that vaccines are designed to elicit, not evidence of disease onset. Id.
Dr. Rose testified that, if the cytokine upregulation caused by Petitioner's second Gardasil dose had, in fact, triggered her sJIA, she would have manifested the disease almost immediately. sJIA patients who take a daily dose of anakinra
The Supreme Court has recognized that a novel theory that is relatively unexamined by the relevant scientific community may not be as persuasive as a theory that has been thoroughly peer-reviewed. This is so because "submission to the scrutiny of the scientific community . . . increases the likelihood that substantive flaws in methodology will be detected." Daubert, 509 U.S. at 593-94 (clarifying that the lack of publication is a "relevant, though not dispositive, consideration in assessing . . . scientific validity"). However, special masters have also recognized that a theory's novelty is not dispositive in determining its scientific validity. Cedillo v. HHS, No 98-916V, 2009 WL 331968, at *111 (Fed. Cl. Spec. Mstr. Feb. 12, 2009) ("At times novel theories can be persuasive"). See also Daubert, 509 U.S. at 593 ("in some instances well-grounded but innovative theories will not have been published.")(internal citations omitted).
In the instant case, the undersigned finds that Drs. Gershwin and McCabe have set forth a novel, but nevertheless reliable and plausible theory by which two Gardasil vaccinations can cause sJIA. Several aspects of Petitioner's experts' theory — that Gardasil is designed to elicit proinflammatory cytokines, and that sJIA is triggered by the same type of cytokine upregulation that the Gardasil vaccine is designed to induce — are essentially uncontested by Respondent. Dr. Rose also did not dispute, as discussed by Dr. Gershwin, that sJIA is an autoinflammatory disease, and that it occurs in genetically predisposed individuals exposed to an environmental trigger. Thus, most of the mechanism of causation put forth by Petitioner's experts was not disputed. Dr. Rose did, however, disagree that the Gardasil vaccine can trigger sJIA, because he has never seen a natural HPV infection associated with sJIA, and because there is a dearth of supportive epidemiological evidence. Resp. Ex. A at 4-5; see generally tr. 225-300.
The undersigned finds that the lack of an association between sJIA and naturally occurring HPV infections is not dispositive. As Dr. McCabe pointed out, natural infections do not produce the same sustained immune response, or the same upregulation of proinflammatory cytokines, as does the vaccine. Tr. 77-79. This conclusion is supported by the Pinto study, which found that "[t]he cellular immune responses (lymphoproliferation and cytokine levels) after healthy individuals are immunized with []vaccine are consistently higher than those previously reported in the context of natural infection. In fact, T cell responses to HPV antigens in natural HPV infection have been difficult to measure." Pinto 2 at 10 (citations omitted).
The undersigned often relies on epidemiological evidence such as that cited by Dr. Rose in this case. However, particularly in the Prong One context, its persuasiveness is tempered by the fact that, while it may show that a vaccine has not caused a particular injury, at least to a statistically relevant extent, it cannot show that the vaccine cannot cause that particular injury. The Chao study, which followed subjects until 180 days after they had received a third quadrivalent HPV vaccine (Gardasil), did not specifically study sJIA. See generally Chao; tr. 150-51. Moreover, the study only included 189,000 subjects, and the incidence of sJIA in the general population is less than 1 in 100,000; as such, the study is "underpowered and is not able to be applied to an analysis of . . . the increased risk attributable to . . . developing sJIA following vaccination." Tr. 151-52. During the hearing, Dr. Rose appeared equivocal, at best, about his assertion that the studies he cited were "sufficiently powered" to be statistically useful. For example, when asked whether the Verstraeten study was sufficiently powered, Dr. Rose testified, "I did not do my power calculations. I'm sorry. That was the only thing I had at the time. I thought it was a good number. I saw they didn't see the signals. I wasn't in the peer review, I'm not an epidemiologist." Tr. 363-64. In light of the rarity with which sJIA presents, the undersigned finds that the lack of supportive epidemiological evidence is not dispositive in this case
Finally, the undersigned finds that the reliability of Dr. Rose's methodology, particularly as it relates to his definition and description of Petitioner's injury, was somewhat compromised by his insistence that Petitioner's actual injury was MAS, not sJIA, and that sJIA and Crohn's disease are mutually exclusive diagnoses.
Based on the foregoing analysis, the undersigned finds that Petitioner has demonstrated by a preponderance of the evidence that the Gardasil vaccine can act as a trigger and cause sJIA.
Petitioner was administered the first Gardasil vaccine on March 19, 2008, and the second Gardasil vaccine on June 30, 2008. Pet. Ex. 2 at 3-4; Pet. Ex. 3 at 11. Four months after the administration of the second vaccine, she presented to medical treatment providers with clinical markers of elevated proinflammatory cytokines; namely, persistent fever, myalgia, rash, and joint pain. Pet. Ex. 4 at 14; Pet. Ex. 7 at 36-38; tr. 131-32. Tests for infectious and systematic autoimmune diseases were all negative. Pet. Ex. 4 at 54; Pet. Ex. 5 at 160-68. Blood tests in December 2008 were consistent with an ongoing systemic inflammatory process. Pet. Ex. 5 at 11-16. Her ferritin, CRP, sedimentation rate, and white blood cell counts were elevated, all of which were consistent with sJIA. Tr. 13, 17, 338-44. Petitioner was successfully treated with steroids and methotrexate, both of which are drugs that inhibit the cytokines TNF-alpha, IL-6, and IL-1. Tr. 37-39; Pet. Ex. 6 at 34-36, 41.
The undersigned finds these records to be sufficient evidence of an uncontrolled activation of Petitioner's genetically susceptible innate immune system, including elevated serum levels of acute phase reactants, including C-reactive protein, as well as serum complement components, ferritin, and elevated leukocytes and platelets accompanied by a rising erythrocyte sedimentation rate, which occurred in November and December 2008. Pet. Ex. 6 at 4, 82, 86; Pet. Ex. 5 at 16, 162-65; tr. 36-37 (Dr. Gershwin opining that Petitioner's symptoms and test results in November and December 2008 were reflective of the uncontrolled activation of her innate immune system that ultimately resulted in sJIA). Although there is no direct evidence of an upregulation of Petitioner's inflammatory cytokines, the medical record contains ample circumstantial evidence in the form of her clinical symptoms, her blood test results, and her favorable response to cytokine-suppressing drugs.
Dr. Rose's argument that Petitioner's sJIA may have been triggered by a viral infection is compromised by Respondent's decision not to pursue it under an alternative causation theory. Standing alone, Dr. Rose's unembellished theory does not undermine the reliability of Petitioner's prima facie case. The undersigned finds plausible Dr. McCabe's theory that Petitioner's immune system was capable of handling a mild infection (as it had many times in the past), notwithstanding her genetic predisposition to sJIA; Petitioner's immune system was more likely to, and did, produce a "dramatic" response to the Gardasil vaccination, which is designed to produce such a response. Tr. 79-80, 210-11. Any viral infection capable of producing a comparable response would have had to be debilitating, and would likely have been specifically documented. Tr. 210-11.
Finally, the undersigned finds that the absence of a third Gardasil vaccine does not compromise Petitioner's theory under Althen Prong 2. Whether or not a third "booster" vaccination is administered, the first two Gardasil vaccinations are, by design, likely to prompt a robust, sustained immune response. Tr. 22-23. This immune response is near its peak after the second dose. Frazer at 4; tr. 188-90 (opining that any contribution of the third vaccine to the robustness of the immune response would have been minor compared to the first two vaccines; "to perseverate on the minor changes that occur in antibody titer between month three and month seven . . . you're missing that much of the potency, the robustness of the response, is occurring within the time frame of those first two immunizations."); see also Pinto 2 at 6-7, which found that the further increases in cytokine levels from post-dose two to post-dose three of the vaccine "were, for the most part, small and nonsignificant."
Accordingly, the undersigned finds, by a preponderance of the evidence, that Petitioner's Gardasil vaccinations played a causative role in the development of her sJIA.
Both of Petitioner's experts testified that four and a half months after the second Gardasil vaccination — and seven to eight months after the first vaccination — are appropriate intervals between vaccination and onset. Tr. 16-30, 134-45. Dr. Gershwin opined that the protective response to the Gardasil vaccination takes about seven months after administration of the first shot. Tr. 18-19. Dr. McCabe cited numerous articles for his opinion that a vaccinee's peak immune response is likely to occur around seven months after the first Gardasil vaccination. Tr. 138. In light of the undersigned's finding that development of sJIA is triggered by the upregulation of the same cytokines as those peaking in response to the Gardasil vaccine, it is reasonable to conclude that the timing of onset of Petitioner's sJIA would be consistent with the peak cytokine responses documented in the studies cited by Petitioner. See, e.g., Pinto 2 at 1 ("The strongest cytokine responses at month 7 were observed in individuals with high antibody titers at month 2, suggesting that neutralizing antibodies generated by initial vaccination may augment T cell responses to subsequent booster vaccinations."). See generally Prakken, Pinto, Pinto 2, Garcia-Pineras, and Evans.
Dr. Gershwin's testimony that there may be a significant period of time between the incidence of cytokine dysregulation and the "breakthrough" that leads to clinical manifestation of sJIA, tr. 26-28, 30, and that this latency period may last months, tr. 19-20, 50, was also persuasive on the temporal issue.
The undersigned finds that Dr. Rose's Althen Prong 3 theory — that onset should have occurred much earlier — simply lacks substantiation in the record. The undersigned acknowledges Dr. Rose's argument that sJIA patients who miss doses of their cytokine inhibitors generally experience symptoms within 12 hours. However, that timing is associated with the recurrence of sJIA, where the manifestation threshold is already met, and is therefore inapposite.
The undersigned finds that Petitioner has proven, by a preponderance of the evidence, that there is a proximate temporal relationship between Petitioner's Gardasil vaccinations and the onset of her sJIA.
For the reasons set forth above, the undersigned finds that Petitioner has shown by medical records and competent medical opinion that her medical condition was "more likely than not" vaccine-caused, and that she is entitled to compensation. This case is now ready to proceed to damages.
