# In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

Filed: September 5, 2019

* * * * * * * * * * * * *

G.C. by her parent BRYNN CONTINO, * PUBLISHED

* Petitioner, * No. 15

- 773V

*

v. * Special Mas ter Gowen

*

SECRETARY OF HEALTH * Entitlement; Influenza (“flu”); AND HUMAN SERVICES, * Urticarial Vasculitis ; Bystander

* Activation. Respondent. *

* * * * * * * * * * * * *

Lawrence R. Cohan , Anapol Weiss, Philadelphia, PA, fo r petitioners. Darryl R. Wishard , United States Department of Justice, Washington, DC, for respondent.

RULING ON ENTITLEMENT 1

On July 23, 2015, Brynn Contino (“petitioner”), on behalf of her minor child, G.C., filed a petition in the National Vaccine I njury Compensation Program. 2 Petitioner allege s that G.C. developed urticarial/hypersensitivity vasculitis which was caused in fact by the influenza (“flu”)

vac cination received on December 3, 2013. Petition at Preamble. Based upon a full review of

all of the evidence and testimony presented, I find that petitioner is 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 po sted 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 inc lusion of

certain kinds of confidenti al information. Specifically, u nder Vac cine 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 sub stance 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 1 4 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

- 6 60, 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 re ach 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 outcom e. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 1 of 252

I. BACKGROUND

A. Procedural History

On July 23, 2015, petitioner file d her claim that G.C.’s December 13, 2013 flu

vaccination was the cause

- in

- fact of her developm ent of urticarial/hypersensitivity vasculitis. Petition (ECF No. 1). An initial status conference was held on September 1, 2015 . Scheduling Order (ECF No. 7). Respondent indicated that he would like to review an expert report from petitioner prior to d etermining on how to proceed. Id. Petitioner was ordered to file all medical records and an expert report. Id.

On October 28, 2015, petitioner filed medical records. 4 Petitioner’s (“Pet.”) Exhibit (“Ex.”) 5 ( ECF No. 9 ) . Then on November 18 and 19 , 2 015, petitioner filed her first expert report from Dr. Vera Byers 5 and supporting medical literature. Pet. Exs. 6

- 8(1) (ECF Nos. 10

- 12). On February 5, 2016, respondent filed his first expert report by Dr. Harry Schroeder, Jr. 6 and supporting medical lit erature. Respondent’s (“Resp.”) Ex. A (ECF No. 16).

4 With the petition, petitioner filed a Notice of Intent to File Medical Records via compact disc (“CD”). Exhibits 1

- 4

were filed via CD. ECF No. 1.

5 Dr. Vera Byers obtained a bachelor’s degree in microbiology in 1965, a M.A. in microbiology in 196 7, a nd a Ph.D in immunology in 1969, all from the University of California

- Los Angeles (UCLA) Pet. Ex. 7 at 1 ; Tr. 54. She completed a fellowship in protein chemistry at Abbott Laboratories from 1969

- 1971 and a fellowship in clinical immunology and allerg y f rom 1971

- 1973. Pet. Ex. 7 at 1. She testified that during this fellowship, she saw and treated rheumatology patients as well as those with genetic immunodeficiencies. Tr. 55. She obtained an M.D. in 1981, then completed a three

- year residency in int ern al medicine from 1981

- 1984, all from the University of

California

- San Francisco (UCSF). From 1984

- 1987, Dr. B yers work at Immunology Incorporated Medical Group in California, which was a private medical practice where she saw patients with rheumatology a nd allergy/immunology issues. Tr. 55; Pet. Ex. 7 at 3. Dr. Byers testified that she has diagnosed and treated patients with chronic urticaria and vasculitis. Tr. 58. Dr. Byers is currently the medical director and a consulting medical toxicologist fo r pharmaceutical companies at Immunology Inc. Pet. Ex. 7 at 2 . 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, petitioner pro ffered 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

urticarial vasculitis.

6 Dr. Harry Schroeder obtained a bachelor’s degree in chemistry in 1974 from Texas A&M University, a M.D. from Baylor College of Medicine in 1981 and a Ph.D. in cell biology in 1979 from Baylor College of Medicine. Resp. Ex. B. He testified that he did his residency at the U niversity of Kentucky in Lexington, Kentucky. Tr. 204. Dr. Schroeder then went to the University of Washington where he obtained training in medical genetics. Id. He is board certified in internal medical and clinical genetics. Id. From 1986

- 1988 he pursued training in immunology, molecular immunology at the Howard Hughes Institute in Seattle, Washington. Resp. Ex. B at 2; Tr. 204. Dr. Schroeder began a teaching career at the University of Alabama at Birmingham in 1988. Tr. 204. Dr. Schroeder

spen t a sabbatical year at the University of Cologne in Cologne Germany at the Institute of Genetics under the mentorship of Klaus Rajewsky. Tr. 204. He is currently a Director of the University of Alabama at Birmingham (“UAB”) in Immunology and Director of the T32 Training Program in Immunologic Diseases and Basic Immunology at UAB. Resp. Ex. A at 1. Dr. Schroeder also serves as an associate editor for the Journal of Immunology, for the Journal of Allergy and Clinical Immunology. Tr. 205; Resp. Ex. A at 1 . He is also the editor of the textbook, Clinical Immunology: Principles and Practices. Tr. 205. Dr. Schroeder testified that has never testified before the Vaccine Court, but reviewed five cases for the respondent. Tr. 211. Dr. Schroeder also testifi ed that he never treated any children with chronic urticaria. Tr. 219. In this case, respondent proffered and I accepted Dr. Schroeder as an expert in the area of immunology. Tr. 222. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 2 of 253

Additionally, the same day, r espondent filed his Rule 4(c) report recommending against compensatio n. Resp. Report (“Rept.”) (ECF No. 17). Respondent asserted that G.C.’s “symptom onset began in Septe mber 2013, on or about three months before her flu vaccination. G.C.’s symptom recurrence was relatively consistent both before and after vaccination....Thus, G.C.’s urticarial vasculitis has followed the normal course of the disease process, and the flu

va ccination neither caused nor aggravated the disease course.” Resp. Rept. at 5.

A Rule 5 status conference was held on February 24, 201 6. The parties were ordered to submit additional expert reports. Scheduling Order (ECF No. 18). Petitioner submitte d a supplemental expert report by Dr. Vera Byers on May 9, 2016. Pet. Ex. 12 (ECF No. 22). Respondent submitted a responsive report by D r. Harry Schroeder on July 25, 2016. Resp. Ex. J (ECF NO. 24).

After a status conference held on August 9, 2016, w here the undersigned reviewed the additional expert reports, the parties agreed to proceed simultaneously with litigative risk

settlement discussions and scheduling a date for an entitlement hearing. Scheduling Order (ECF No. 25). The parties engaged in unfruitful settlement discussions until December 16, 2016, at which point they reached an impasse and elected to proceed to an entitlement hearing scheduled for September 13, 2017. Resp. Status Report (ECF No. 32). Both parties briefed the case prior

to the hearing. Pet. Prehearing Submissions filed June 1, 2017 (ECF No. 34); Resp. Prehearing Submissions filed June 28, 2017 (ECF No. 35).

An entitlement hearing was held on September 13, 2017 and was continued on November 8, 2017 in Washington, D.C. Pet itioner, Ms. Brynn Contino offered fact testimony. Petitioner presented expert testimony from Dr. Vera B yers . Respondent presented exper t testimony from Dr. Harry Schroeder via video conference. The parties submitted post hearing

- briefs addressing key i ssues raised during the entitlement hearing and identifying the most relevant medical

literature submitted. See Pet. Post Hearing Brief ( “ Pet. Br ief ” ) ( ECF No. 63); Resp. Post Hearing Brief ( “ Resp. B rief ” ) (ECF No. 64); and Pet. Post Hearing Rebuttal Brie f (ECF No. 65).

This matter is now ripe for adjudication.

B. Summary of Relevant Facts

1. Medical Records from Birth to Influenza Vaccination on December 3, 201 3

G.C. was born on November 6, 2010. Pet. Ex. 1 at 5. On December 23, 2010, G.C.
present ed to the Frederick Memorial Hospital emergency department with three days of coughing and congestion, no fevers, but had vomited twice. Pet. Ex. 5 at 62. She tested negative for the flu virus, but positive for respiratory syncytial virus (“RSV”). Id. at 63. A deep nasal suction was performed with little improvement and she was placed on 1 Liter of oxygen,

then increased to 2 liters

. Pet. Ex. 1 at 175 . G.C. was t r ansported via helicopter to Johns Hopkins where she was admitted to the pediatric intens ive care unit (“ICU” ). Id. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 3 of 254

G.C. was admitted to Johns Hopkins from December 23

- 27, 2010. Pet. Ex. 3 at 6

- 10. Prior to discharge, she was weaned off oxygen support for 24 hours before she was sent home without any signs of respiratory distress. Id. a t 7.

The following year, G. C. was treated by Dr. James Lee on various occasions for coughs and upper respiratory infections. See Pet. Ex. 1(a) at 63, 127, 160

. However, she continued receiving her scheduled childhood immunizations. Pet. Ex. 1(a) at 12 & Pet. Ex. 1(b) at 187.

In February 2012, G.C. had a complete blood count test performed. Pet. Ex. 1(a) at 37. The test showed that her IgA, IgM and IgG subclasses were in normal range, but the total IgG

was low. Pet. Ex. 5 at 130

- 135. Then on Ma rch 9, 2012, G.C. underwent a b ilateral myringotomy and ventilation tube placement

. 7 Pet. Ex. 1(a) at 75; Pet. Ex. 5 at 144.

On April 2, 2012, Dr. Samuel Rosenberg assessed G.C. for coughing and recurrent otitis

media . Pet. Ex. 1(a) at 81. Her phy sical exam was normal. Id. He noted that “ her IgG was slightly reduced but the remainder of her immunoglobulins were normal and pneumococcal antibodies which showed elevation in several serotypes [are] indicative of good antibody response.” Id. After r eviewing her history and perform ing a physical exam, Dr. Rosenberg recommended G.C. use an inhaler with corticosteroids to treat any asthma component to her cough. Id. He stated that “IgG level was slightly reduced, but I do not feel that this is

represe ntative of any significant immun e system issue.” Id. Dr. Rosenberg also believed that the PE tubes placed in G.C.’s ears would “dramatically help with her recurrent respiratory symptoms.” Id.

In the fall of 2012, G.C. has the right ventilation tube r emoved. Dr. Lee stated that “an underlying acute otitis media with perforation was noted.” Pet. Ex. 1(a) at 76. Then in December 2012, a second myringotomy with an adenoidectomy was performed. Pet. Ex. 1(a) at 75.

In April 2013, G.C. was taken to se e Dr. Lee twice for a cough without fever. Pet. Ex. 1(a) at 102 & 104. He observed that her left ear tube appeared to be blocked by “opaque effusion,” but she did not have any rash or skin lesions. Id. at 102. He prescribed a course of

amoxicillin twic e a day for ten days. Id. at 103.

Ms. Contino testified that in late August 2013, G.C. developed a rash. Transcript (“Tr.”)

9. Ms. C ontino stated that hives were located on G.C.’s armpit, bottom half of her thighs and the

back of her knees. Id. Sh e described th e se hives as “raise d.” Tr. 10. Ms. Contino testified that

she treated the hives with Benadryl and the rash went away within an hour. Tr. 12 & 35. She

testified that a similar rash re

- appeared on G.C. in September 2013. Tr. 9

- 10. Ms. Con tino again

gave G.C. Benadryl and the rash resolved within an hour. Tr. 12. She described that G.C. was “uncomfortable because they were itchy

, ” but the rash did not affect G.C’s play or eating. Tr. 11

& 35.

7 A myringotomy and ventilation tube placement is a common procedure t hat surgically places small tubes in a child’s eardrum to help drain fluid out of the middle ear in order to reduce the risk of ear infections. Ear tubes are recommended for children who have persistent fluid buildup behind the eardrum. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 4 of 255

On September 13, 2013, G.C. was seen by D r. Lee for asse ssment of a rash on her cheek that began two days prior to the office visit. Pet. Ex. 1(a) at 98. Dr. Lee observed “well defined pink patches, only slightly raise d mostly along waistband, backs of thighs, ankles but also on abdomen, back o f hands and che ek.” Id. He stated that “[G.C.] seems unaffected

- well appearing/acting, not itching, rash is nontender, she was very cooperative with exam....seems to

b e more of an irritant dermatitis.” Id. Dr. Lee recommended Ms. Contino treat with Benad ryl as

necessary

. Id.

The next month, on October 3, 2013, G.C. was seen by allergist, Dr. Monika Ko r ff

, for

hives. Id. at 69

- 70. Ms. Contino reported that 2

- 3 weeks ago G.C. “woke up one morning and was covered in hives....After taking the Benad ry l for a day, the rash resolved.” Id. at 69. The rash reappeared three days later and was resolved by Benadryl. Id. Then, G.C. had another episode of rashes that resolved with Benadryl within 24 hours. Id. Dr. Ko r ff performed a physical exam of G.C. and f ound that her conjunctivae were clear, allergic shiners absent and her lungs have good breath sounds without wheezing or rhonchi. Id. at 70. Dr. Ko r ff assessed G.C. with dermatographic urticaria that “certainly explained the hives” and recommended t reati ng the symptoms with Benadryl during episodes versus daily use of a long acting antihistamine as prophylaxis. Id.

On October 21, 2013, G.C. saw Dr. Lee for constipation and difficult voiding. Pet. Ex. 1(a) at 96. Dr. Lee observed G.C.’s skin as “pin k, warm and dry.” Id. A urine sample was negative for protein. Id. Dr. Lee assessed G.C. with an abnormality of urination, noting G.C. was resistant on the toilet and opined that her voiding and constipation was attributable to toddler independenc e, ra ther than a medical issue. Id. at 97. A urina lysis was negative for p rotein in

G.C. ’ s urine. Id.

Dr. Lee saw G.C. on November 11, 2013 for complaints of an ongoing wet cough and congestion . Pet. Ex. 1(a) at 94. Upon physical exam, G.C. appeared “un happy, but non

- ill acting.” Id. Most notably, no skin rashes or lesions were observed. Id. Dr. Lee diagnosed G.C. with an acute upper respiratory infection of unspecified site an d was given a ten

- day course of

amoxicillin. Id at 95

.

On December 3, 2013, G.C. received her third flu vaccine. Pet. Ex. 1(a) at 12.

2. Medical History Post Flu Vaccination to Present

The family travelled from Maryland to Florida for a tr ip to Disney World on Saturday, December 7, 2013. Tr. 14. During the car trip, Ms . Contino noticed “smaller red blotchy
rashes” on G.C. that “started on her stomach area.” Id. On December 9, 2013, while in the amusement park

, G.C. refused to walk and complained that her legs really hur t . Tr. 15. Ms

. Contino testified that G.C.’s h ands , feet and lips began to swell. Id. She further testified that G.C. had between 60 to 80 bruises all over her body, including on her thighs, backside and

stomach. Tha t same night, Ms. Contino took G.C. to the emergency room of Florida Hospital.

Tr. 21 & Pet. Ex. 5. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 5 of 256

G.C. was treated at the emergency department of Florida Hospital for hives, a fever of 101 degrees Fahrenheit , bruising and swelling. Pet. Ex. 5 at 12, 16 & Pet. Ex. 2(a) at 7. The clinical impression of G.C. at the emergency room wa s G.C.’s symptoms were “most consistent with a viral exanthem” and she was given a steroid injection. Pet. Ex. 4 at 18. Upon discharge, she was given a prescription of pre dni solone and Benadryl. Id. Ms. Contino testified that G.C.’s swelling went down after the steroid treatment at Florida Hospital, but the bruising remained.

Tr. 25.

Ms. Contino testified that this was the first time that G.C. had developed bruising

a ssociated with a rash. Tr. 23. S he explained that G.C. experienced episodes of re current bruising and swelling in January 2014. Tr. 27.

On February 3, 2014, G.C. was seen by pediatric allergist, Dr. Glenn Si lber

. Pet. Ex. 1(a)

at 60. During that visit, Ms. Contino reported that G.C. continued to have rashes around three

times a week that lasted about six hours and some swelling occur ed with cold exposure

. Id. A physical exam revealed that G.C. had no rash and no dermatographism

. 8 Id. Ms. Contino

testified that she showed Dr. Si lber pictures she had taken of G.C. in Florida. T r. 27. Dr. Si lber assessed G.C. with “probable vasculitis

- doubt allergy with no pruritus” and recommended G.C.

seek treatment from a pedia tric rheumatologist. Id ; Tr. 27.

Ms. Contino testified that due to a four week wait for an appointment with a

rhe umatologist at Johns Hopkins

, she drove G.C. to the Cleveland Clinic

. Tr. 28. G.C. was seen by pediatric rheumatologist

, Dr. Andrew Zeft, on February 12, 2014

. Pet. Ex. 9 at 4 . His physical exam of G.C. was relatively normal, but he ordered a com plete blood count and immunoglobulin test. Id. Dr. Zeft opined that G.C.’s diagnosis was “most consistent with hemorrhagic edema of infancy triggered by influenza vaccination. Preceding urticaria may be idiopathic or potentially part of illness spectrum. No biopsy has been done on skin lesions to clarify leu kocytoclastic vasculitis pathology. Presentation is not consistent with urticarial
vasculitis.” Id. G.C.’s blood IgG, IgA and IgM levels were within normal limits. 9 Id. at 13. When Dr. Zeft spoke to G .C.’s mother on February 13, 2014 to relay the test results, G.C. had apparently developed “new dependant bruises.” Pet. Ex. 9 at 16. Dr. Zeft recommended to
recheck G.C.’s blood count and to consider d apsone. 10

On February 20, 2014, G.C. was evaluated by rheumatologist, Dr. Sangeela Sule

, at Johns Hopk ins Division of R heumatology . Pet. Ex. 2(a) at 4. Dr. Sule noted that two days after

8 Dermatographi s m (also spelled, “dermagraphism”) is a type of physical urticaria in which moderately firm stroking or scratching of the skin with a dull instrument produces a wheal with a red flare on each side. Dorland’s Illustrated Medical Dictionary 32 nd ed. (2012) ( hereinafter “ Dorland’s” ) at 499

.

9 Petitioner’s Pre

- Hearing Brief states that G.C.’s IgG level was below normal and cites to Petitioner’s Exhibit 1(a) at 37. However, this reference is to an immunoglobulin test result from 2012.

10 Dapsone is an antib a cterial and antifungal medication administered orally for the treatment of dermatologic noninfectious inflammatory diseases. It was also used to treat leprosy and malaria. Golusin, Z. et al., What do we know about diaminodiphenylsulfone? 53 Med. Pregl. 3 69

- 72 (2000). Available at https://www.ncbi.nlm.nih.gov/pubmed/11214480 (accessed on August 22, 2019). Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 6 of 257

G.C. received the flu vaccine, she had hives, her legs and feet were swollen, and bruising appeared. 11 Id. at 4. Dr. S ule developed a working diagnosis of “urticarial vas culitis” and

referred G.C. to dermatology for a biopsy to confirm the tentative diagnosis of urticarial

vasculitis. Id. at 6. Additionally, Dr. Sule wanted a repeat urinalysis and recommended a renal

ul trasound because of the two prior urine samples with eleva ted protein/creatinine ( “ pr/cr ” )

ratio s. Id. at 6.

G.C. returned to Johns Hopkins on March 19, 2014 for an evaluation by pediatric nephrologist, Dr. Cozumel Pruette. Id. at 7. Dr. Pruette not ed that the working diagnosis is
“urticarial vasculitis ” and there was concern that the proteinuria noted on previous urine samples may indicate possible renal involvement. Id. at 8. Dr. Pruette requested an additional first morning urine sample and a sk in biopsy. Id. at 8.

G.C. had a skin biopsy performed on her left arm on March 27, 2014 that confirmed the diagnosis of urticarial vasculitis. Id. at 9

- 10. The biopsy was positive for granular deposition of IgM and C3 in superficial derma blood v esse ls. Pet. Ex. 3 at 4. The test was negative for IgA,

I g G and Fibrin. Id. Dr. Grant Anhalt noted that the “findings are seen in vasculitis.” Id. Dr. Max Fischer reviewed the biopsy results and changed G.C.’s diagnosis from “consistent with

urticari a; n egative for vasculitis” to “urticaria

- like reaction pattern.” Id . at 5.

O n April 3 , 2014, Dr. Sule called G.C.’s mother to confirm the biopsy findings and recommended G.C. begin 10 mg of prednisone and 15 mg A zathioprine 12 daily. Id. at 10. On Apr il 1 4, 2014, Dr. Puttgen saw G.C. to remove the suture. Dr. Puttgen stated that the differential diagnosis confirms vasculitis “which in the setting of the clinical presentation is consistent with urticarial vasculitis. The presentation in G.C. is somewh at u nusual as the lesions come and go in less than 24 hours often, more typical of standard urticaria.” She continued by stating, “However, coupled with the complaints of leg pain and proteinuria, a more systemic process does fit.” Pet. Ex. 2(a) at 10.

On April 25, 2014, Ms. Contino reported to Dr. Sule that G.C. was still experiencing intermittent hives associated with itching and pain

. Pet. Ex. 2(a) at 11. Dr. Sule requested that the pharmacy at Johns Hopkins compound A zathioprine to a form that G. C. w ould be able to take, instead of tablets. Id.

Drs. Sule, Puttgen and Pruette continued to manage and follow G.C. ’s health between April and February 2015. See Pet. Ex. 2(a) at 9

- 18 . G.C. continued to provide urine samples that showed abnormal urine p r /cr ratios, with individual numbers being within normal ranges.

Id. at 1 2.

11 Dr. Sule incorrectly states that G.C. received flu vaccine on December 5, 2015. G.C

. received a flu vaccine on December 3, 2013. See Pet. Ex. 1 (a) at 12.

12 Azathioprine is an immunosuppressant drug that is used to treat dermatomyositis, systemic lupus erythematosus, inflammatory bowel disease, vasculitis and rheumatoid arthritis. Acc e ssed at: https://www rheumatology.org/I

- Am

A/Patient

- Caregiver/Treatments/Azathioprine

- Imuran Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 7 of 258

On August 11, 2014, Dr. Pru e tt e spoke with Ms. Contino regarding G.C.’s recent urine

results showing increased pr/cr ratio. Id. at 13. Dr. P ruette recommended that G.C. remai n on Imuran and prednisolone given that G.C.’s proteinuria is “relatively stable, kidney function remains stable and she is clinically doing well.” Id. Ms. Contino inform ed Dr. Pruttgen that G.C. was still experiencing leg pain and wanted to speak with D r. Sule about decreasing the dose of prednisolone. Id.

Ms. Contino testified that throughout the spring of 2014 and into the fall of 2014 G.C. was in constant pai n. Tr. 37. G.C. would have pain primarily in her hip and legs, but occasionally in her a rms. Tr. 38. G.C.’s rash symptoms were more intermittent, but would appear if she got very hot, however, G.C.’s pain was constant. Tr. 37.

In September 2014, G. C. was seen by Dr. Jillian Kaskavage at Johns Hopkins Pediatric Rheumatology. Pet. Ex. 1( a) at 53. Ms. Contino reported that G.C. did not have any rash over the summer, but as the weather got cooler, G.C. had a rash appear at night, but was gone by the

m orning. Id. Additionally, G.C. was not complaining of any itchiness or pain. Id. Ms. C ontino

stated that G.C. experienced some pain in her lower extremities and observed G.C. grabbing her shins, however, no joint swelling was observed. Id. Dr. Kaskav age recommended G.C. continue

on A zathioprine for at least one year at 2 mg daily due to t he likely “renal involvement” and her continued abnormal urine pr/ c r ratio. Id at 54.

On December 17, 2014, Dr. Pruette saw G.C. for a follow

- up appointment. Pet . Ex. 1(a) at 46. Dr. Pruette reported that G.C.’s proteinuria trend had been improving s ince the steroids

were initiated. Id. Ms. Contino reported that G.C. still experienced leg pain, but no recent rash.

Id. Dr. Pruette again assessed G.C. with prot einuria associated with underlying urticarial

vasculitis. Id. She stated that G.C. respo nded favorably to the regimen of A zathioprine and

steroids and that there was no need for a kidney biopsy at that time. Id. at 49. Dr. Pruette

recommended that G.C. continue weaning her steroid dose and take MiraLAX to reduce her constipation. Id.

Fr om December 2014 through January 2015, G.C.’s doctors continued to wean her from prednisone and continued the course of A zathioprine at the current dose. Pet. Ex. 2(a) at 17. Then on February 16, 2015, G.C. experienced a recurrence of her urticarial va sc ulitis with multiple hives observed all over her body when she missed a dose of prednisone

. Id. at 18. Dr.

Sule recommended G.C. be treated with rituximab, 375 mg /m2 once a week for four weeks. Pet. Exs. 1(b) at 10 & Pet. Ex. 2 at 22

- 24.

On March 2 5, 2015, G.C. was brought into the Johns Hopkins clinic presenting with a red

rash on her face and abdomen but was alert and playful . Pet. Ex. 2 at 24. It was reported that again G.C. had missed a dose of prednisone. Id. Dr. Sule advised Ms. Contino to c ontinue to give G.C. prednisone and to make a follow up appointment in a few weeks. Id.

Dr. Mark Gorelik , pediatric rheumatologist, attended to G.C. on April 16 , 2015. Pet. Ex.

2 (b) at 25. Ms. Contino reported that as G.C. was weaning from the steroi ds, a rash reappeared on her face, but no other symptoms returned. Id. Ms. Contino also reported that G.C. was slightly more tired lately and irritable since the wean. Id. Upon physical exam, Dr. Gorelik Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 8 of 259

observed a small 1 cm erythematous rash over the left check. Id. at 26. He noted that G.C.’s symptoms are improving on A zathioprine, but she had a borderline abnormal urine pr/ c r ratio and suggested a follow up appointment in two months. Id. at 26. Ms. Contino called the clinic four days later, requ esting to speak to the doctor and that G.C. was experiencing back pain over the past month. Id. at 26. Dr. Pruette followed up with Ms. Contino the following day, reporting that G.C.’s lab results were “good/stable,” and i ndicated that continuing the ste roid wean would be appropriate. Id. at 27.

On May 20, 2015, Dr. Pruette reported to Ms. Contino that G.C.’s lab results showed an increase in her pr/cr ratio from the previous month. Pet. Ex. 2 (b) at 9 . Ms. Contino reported that G.C. has “significant sun sensitivity from the steroids,” but informed Dr. Pruette there were “no other skin complaints.” Id. Dr. Pruette and Ms. Contino agreed to continue G.C . on the current prednisolone dose, check G.C.’s creatinine and CD19/CD20 counts to assess for ongo ing effects

of recent R ituximab course and follow proteinuria. Id. The lab results from May 21, 2015 show that G.C.’s CD19/CD20 lymphocyte levels were at z ero. Id. at 45.

On August 10, 2015, G.C. was seen by Dr. Lee for a fever of 102 degrees and a s ore on her tongue. Pet. Ex. 10 at 6. Upon a physical exam, G.C. was irritable and excessively crying.

Id. Dr. Lee described G.C. as “uncomfortable and ac utely ill.” Id. at 11. Dr. Lee described a “yellow pustule [on] tip of tongue. Also

, more classi c cold sores inner mucus membrane and gingiva [is] generally inflamed.” Id. The next day, August 11, 2015 G.C. was hospitalized at Johns Hopkins for a rash that lasted 10 days, a fever of 102 degrees Fahrenheit and sores in her mouth for seven days. Pet . Ex. 6 at 4. G.C. was diagnosed with a viral exanthema and discharged on August 15, 2015. 13 Id

.

Ms. Contino testified that G.C. ’s mouth ulcers appeared m onthly. Tr. 49. G.C. went back to Dr. Lee in October 2015 with sores under her tongue, decreased appetite and difficulty sleeping. Pet. Ex. 10 at 10. G.C. had been prescribed cephalexin on August 12, 2015. Id. A physical exam confirmed a single ulcer on G.C.’s inner cheek area. Id. at 12. Dr. Lee prescribed lidocaine to apply to the affected ar ea of the mouth three times a day. Id.

Ms. Contino described the hives and bruising that appeared on G.C. after she received
the flu shot as “smaller” with a “purplish tint to them,” in addition to “lots of swelling and pain in her legs.” Tr. 33. P etitioner submitted into evidence multiple color photographs of G.C. taken in December 2013 that depicted rashes and extensive bruising. See Pet. Ex. 18(a) Further, she
testified that G.C.’s condition was much improved after receiving the rituximab treatm ent in March 2015. Tr. 38. However, G.C. continues to have mouth ulcers and continues to be on steroids because of her kidney involvement. Tr. 49

- 50 ; 340

. She testified that G.C. is still on steroids and has been consistently since April 2014. Tr. 340

. As recently as 2017, doctors at Kentucky Children’s Hospital are determining if G.C. can wean from the steroids because of concern that the steroids may be doing more harm to G.C.’s kidneys than the disease. Id.

13 Both Dr. Byers and Dr. Schroeder make reference to G.C. being hospitalized on August 11, 2015, however, those

records were never filed with the Court. Petitio n er’s Exhibit 10 provides the lab results from G.C.’s hospitalization at that time but does not provide any further information. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 9 of 2510

II. LEGAL STANDARD

The Vaccine Act provid es two avenues for petitioners to receive compensation. A petitioner may demonstrate a “Table” injury, 14 or that a vaccine listed on the Vaccine Table was

the cause

- in

- fact of any injury. In the present case, petitioner does not establish that she has

suf fered a Table injury.

To satisfy the burden of proving causation

- in

- fact, petitioner must “show by preponderant evidence that the vaccination brought a bout the injury by providing 1) a medical theory connecting the vaccination and injury; 2) a logical s equence of cause and effect showing that the vaccination was the reason for the injury; and 3) a showing of proximate temporal relationship

between vaccin ation and injury.” Althen v. Sec’y of Health & Human Servs., 418 F. 3d 1274, 1278 (Fed. Cir. 2005). Petitioner’s 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).

The preponderance of the evidence standard re quires a petitioner to demonstrate that it is “more likely than not” that the vaccine caused her injury. 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). In particular, a petitioner must demonstrate that the vaccine was “not only [a] but for cause of the injury but also

a substantial factor in brin g ing about the injury.” Moberly, 592 F.3d at 1321 (quoting Shyface v. Sec’y of Health & Human Servs., 135 F.3d 1344, 1352

- 53 (Fed. Cir. 1999); Pafford v. Sec’y of Health and Human Servs., 451 F.3d 1352, 1355 (Fed. Cir. 2006). 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). A 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.” Althen, 418 F. 3d at 1280.

Establishing a sound and reliable medical theory connecting the vaccine to the injury often requires petitioners to present expert testimony in support o f his or her claim. Lampe v. Sec’y of Health & Human Servs., 219 F.3d 1357, 1361 (Fed. Cir. 2000). Ex pert testimony in the Vaccine Program is usually evaluated according to the factors set forth in Daubert v. Merrell Dow Pharm., Inc., 509 U.S. 579, 594

- 9 6 (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). Thus, for Vaccine Act claims, a “special master is entitled to require some indicia of reliability to support

the assertio n of the expert witness.” Moberly at 1324. The Daubert factors are used in weighing the reliability o f scientific evidence proffered. Davis v. Sec’y of Health & Human Servs., 94 Fed. Cl. 53, 66

- 67 (2010). Where both sides offer expert testimony, a spec ial master’s decision may be “based on the credibility of the experts and the relative persuasiveness o f their competing
theories.” Broekelschen v. Sec’y of Health & Human Servs., 219 F.3d 1339, 1347 (Fed. Cir. 2010) (citing Lampe v. Sec’y of Health & Hum an Servs., 219 F.3d 1357, 1362 (Fed. Cir. 2000).

14 A “Table” injury is an injury listed on the Vaccine Injury Table, 42 U.S.C. § 100.3, corresponding to the vaccine

received w ithin the time

- frame specified. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 10 of 2511

Once a petitioner has proven causation by preponder ant evidence, the burden shifts to respondent to show by a preponderance of the e vi d ence that the injury is due to factors unrelated

to the administratio n of the vaccine. Deribeaux ex rel. Deribeaux v. Sec’y of Health & Human
Servs., 717 F.3d 1363, 1367 ( Fed. Cir. 2013) (citing § 13(a)(1)(B)). Respondent has the burden of demonstrating that “a factor unrelated to the vaccination is the more likely or pri ncipal cause of injury alleged. Such a showing establishes that the factor unrelated, not the vaccinat ion, was ‘principally responsible’ for the injury. If the evidence or alternative cause is seen in equipoise, then the government has failed in its burd en of persuasion and compensation must be awarded. Knudsen, 35 F.3d at 551.

III. DISCUSSION

A. Diagnosis

The medical records establish that G.C. has been diagnosed with urticarial vasculitis. Pet. Ex. 2(a) at 10. The parties do not dispute G.C.’s ultimate diagnosis, but debate when the autoimmune condition began.

Respondent argued that G.C’s symptoms of manifested in the late summer or early fall of 2013, three months prior to the vaccination. Resp. Ex. A at 8; Resp. Brief at 8 . Petitioner argued

tha t G.C.’s rash and hives that appeared in the late summer/early fall of 2013 were part of a separate alle rgic response and that she did not develop symptoms associated with her

auto immune urticarial vasculitis until after the December 3 , 20 1 3 flu vaccinatio n.

1. Acute Urticaria

Urticaria

, better known as “hives,” is a common dermatologic condition that typica lly presents with intensely pruritic, well

- circumscribed, raised wheals ranging from several millimeters to several centimeters or larger in size. 15 Urt icaria is historically divided into acute and chronic disease, dependent on the disease duration. 16 Pet. Ex. 16(f) at 2. Urticaria that recurs within a period of less than six week is classified as acute; chronic urticaria becomes chronic if

disease activi ty continues for six weeks or longer. Id.

According to Nelson’s Pediatric Textbook , acute urticaria is often caused by an allergic IgE

- mediated reaction. 17 Pet. Ex. 16(t) at 1. However, acute urticaria can also result from non

IgE mediated stimulation of mast cells caused by viral agents including Epstein

- Barr and hepatitis B or physic al stimuli, such as a change in temperature. Id. at 1

- 2.

15 Paul Schaffer, Acute and Chronic Urticaria: Evaluation and Treatment, 95 Am. Family Physician 11 (June 1, 2017)

, https://www.aafp.org/afp/2017/0601/p717.html

16 Clive Grattan, The Urticarias: pathophysiology and manageme nt , 12 Clinical Medicine 2, 164

- 167 (2012). [Pet. Ex. 16(f)].

17 D onald Y.M. Leung and Stephen C. Dreskin

, Chapter 147: Urticaria (Hives) and Angioedema, 18 th ed. Nelson’s

Pediatrics Textbo ok , 979

- 82 [ Pet . Ex. 16(t)]. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 11 of 2512

Allergic acute urticaria is a “self

- limited process that occurs when an allergen activates

mast cells in the s kin.” Id. As explained in the Grattan article, “the mast cell plays a central role in most patterns of urticaria by releasing histamine which, in turn, acts on capillaries and cutaneous nerve endings to elicit the characteristic itchy red wheals.” Pet. Ex. 16(f) at 3. The stimulus for mast cell degranulation may be immunological. Id; Pet. Ex. 6 at 5; Pet. Ex. 8(c) at
1 18 ; and Pet. Ex. 17(e) at 1

. 19 The cross

- linking of two or more adjacent allergen

- specific immunoglobulin (“IgE”) molecule s bound to the high affinity IgE receptor (“FcεRI”) will initiate

a series of calcium

- dependent intracellular signaling events leading to incomplete degranulation in allergic urticaria. Pet. Ex. 16(f) at 3. This leads to the release of histamine, leukotrienes, platelet activating factor (PAF), enzymes such as tryptase and chymas e
, cytokines and chemokines. Pet. Ex. 16(l) at 2

. 20

Acute urticaria typically resolves within twelve hours and responds well to antihistamines. Pet. Ex. 6 at 5; Pet. Ex. 8(c) at 13; Pet. Ex. 16(f) at 1; Pet. Ex. 16(t) at 4.

2. Chronic Urticaria

Chronic urticaria is diagnosed when symptoms have been continuously or intermittently present for six weeks. See Pet. Ex 8(j) 21 ; Pet. Ex. 16(f); Pet. Ex. 17(e). Critical to the definition

of chronic urticaria in the medical articles submitted is the duration of the lesions. Najib and

Sheikh define chronic urticaria as “symptoms have been continuously or intermittently present for at least six weeks.” Pet. Ex. 8(j) at 1 (emp hasis added) . Chang, et. al, defines chronic spontaneous urticaria as the presentation of itchy wheal

- and

- flare skin reactions, angioedema or

both for a period of greater than six weeks. 22 Pet. Ex. 8(f) (emp hasis added)

. Grattan stat es that urticarial activity may be active for a few weeks, settle for another few weeks or months, then unpredictably return to what i t was prev iously. Id.

Causes for chronic urticaria can be physical, allergic, hereditary or autoimmune

. See Resp. Ex. A at 9; Pet. Ex. 6 at 5; Pet. Ex. 17(e) at 2; and Pet. Ex. 16(f) at 3. Between 30 and 50 percent of cases of chronic urticaria are autoimmune in nature. Pet. Ex. 8(j) at 1.

Both the experts agree that chronic urticaria resulting from an au toimmune disorder are due to the development of autoant ibodies directed against either the FcεRI receptor or the IgE on mast cells and basophils. Resp. Ex. A at 9; Pet. Ex. 6 at 6. T he autoantibodies directed against

18 Katherine Altman and Christopher Chan g
, Pathogenic Intracellula r and Autoimmune mechanisms in Urticaria and Angioedema, 45 Clinical Rev. Allerg. Immunol, 47

- 62 (2013) [Pet. Ex. 8(c)].

19 Gregory M. Metz and John S. Sundy

, Allergy and immunology p roblems and musculoskeletal specialists, Rheumatology Network (May 7, 2009), http://www rheumatologynetwork.com [Pet. Ex. 17(e)].

20 Allen P. Kaplan, MD, Urticaria and Angioedema: Synopsis, World Allergy Organizations (2014 ) [Pet. Ex. 16(l)].

21 Umer Najib M.D. and Javed Sheikh, M

. D.

, The Spectrum of Chronic Urticaria, 30 Allergy Asthma Proc., 1

- 10 (2009) [Pet. Ex. 8(j)].

22 Tse Wen Chang, Ph.D, et.al., The potential pha rmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria, 135(2) J. Allergy Clin. Immunol., 337

- 342 (201 4) [Pet. Ex. 8(f)]. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 12 of 2513

the IgE binding site on mast cells ca use the mast cells to spontaneously degranulate in abse nce of allergens. Pet. Ex. 6 at 6; Pet. Ex. 16(f) at 3 & Pet. Ex. 17(e) at 2

. According to the Metz article, approximately 40 percent of patients with chronic idiopathic urticaria have autoantibodies directed against a subunit of the FcεRI or to cell

- sur face IgE that may lead to IgE receptor cross

linking, leading to cell activation. Pet. Ex. 17(e) at 2.

The Altman article also indicates that the dysregulation of intracellular signaling pathways involving Syk, SHIP

- 1 or SHIP

- 2 in basophils and mast c ells may be another autoimmune mechanism of chronic urticaria. Pet. Ex. 8(c) at 1, 5; Resp. Ex. A at 9. SHIP

- 1 and

SHIP

- 2 are negative regulatory molecules that can dephosphorylate positive signaling mediators and control the activation and degranulation of mast cells and basophils , ultimately downregulating mast cell and basophil activation

. Id. Syk on the other hand promotes mast cell degranulation. Id. Altman cited a study in which the mast cel ls from patients with chronic

urticaria with an elevate d level of histamine release after stimulation were found to have lower

levels of SHIP

- 2 and increased levels of Syk. Pet. Ex. 8(c) at 4

- 5. Dr. Schroeder also endorsed

this mechanism for development of chronic urticaria. Resp. Ex. A at 9

.

The first li ne of treatment for chronic urticaria are first or second generation H1

- receptor antagonists (antihistamines). Pet. Ex. 8(j) at 6. These drugs include Benadryl (first generation), Zyrtec (second gene ration) or Claritin (second generation). Id. at 6

- 7. If the patient’s symptoms do not respond to the H1

- antagonists alone, then corticosteroids can be considered. Id. at 7; Pet. Ex. 16(t) at 4. In autoimmune chronic urticaria that is unresponsive to first

- and

- second line

treatments immunomodulatory drugs m ay be used, such as cyclosporin

, D apsone , and intravenous immune globulin

. Pet. Ex. 8(h) at 2

. 23

3. Urticarial Vascu litis

Urticarial vasculitis is a subgroup of the larger vasculitides disorders characterized by inflammation of blood vessels leading to ti ssue or end

- organ inj ur y. 24 Resp. Ex. I at 2. Vasculitis may be triggered by an infectious agent or may be a compli cation of primary autoimmune dysregulation and/or immunosuppressive therapy, among other disorders. Id. Urticarial

v asculitis primarily aff

ects the small vessels of the skin

. 25 Pet. Ex. 16(q) at 2. A small number

of individuals with chronic urticaria ma y have urticarial vasculitis. 26 Overall, vasculitis in children is rare. Resp. Ex. I at 2. Patients with vasculitis and urticaria are consi dered a sub

population of chronic spontaneous urticaria. Pet. Ex. 16( l ) at 2. According to the Najib article,

23 M arcus Mauer et. al, Omalizumab for the Treatment of Chronic Idiopathic or Spontaneous Urticaria, 386 N. Eng. J. Med., 924

- 35 (2013) [Pet. Ex. 8(h)].

24 C aterina Bonetto et al., Vasculitis as an adverse event following immunizatio n

- Systemic literature review, Vaccine 2015 [Resp. Ex. I].

25 What is Urticarial Vasculitis? Vasculitis Foundation, accessed on August 13, 2019: https://www.vasculi tisfoundation.org/education/forms/urticarial

- vasculi tis/

26 S. J. Deacock, An Approach to the patient with urticaria, Clin. Exp. Immunol (2008); doi: https://www.ncbi.nlm.nih.go v/pmc/articles/PMC2492902/#b71 Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 13 of 2514

“urticarial vasculitis is considered to be an extreme form of chronic urticaria.” Pet. Ex. 8(j) at 4.

Non

- blanching lesions can last for more than 24 hours and leave residual marks. Id. Vasculitic

lesion s have different features from typical urticaria, including a burning or painful sensation instead of pruritus, abdominal pain and fever. Pet. Ex. 17(e) at 6.

According to the article by J ennette and Falk

, 27 “urticaria can be a manifestation of small

vessel vasculitis, especially when there is an immune

- complex deposition with extensive complement activation.” Pet. Ex. 16(k) at 6. The article also distinguishes urticarial vasculitis

from al lergic urticaria, stating, “vasculitic urticaria lasts for more than a day, may evolve into purpuric lesions and may be accompanied by hypocomplementemia.” Id. The article by Russell

and Gibson 28 clarifies that hypocomplementemic urticarial vasculitis (“H UV”) is frequently associated with systemic lupus erythematosus (“SLE”) like systemic findings, often with multiorgan involvement. Pet. Ex. 16(w) at 3.

A skin biopsy is performed to confirm vasculitis. Id. A predominantly dermal interstitial

neutro philic infiltrate has been shown to be more frequent in HUV. Id. at 5. Skin biopsies from patients with immune

- complex mediated vasculitis reveal significant neutrophilic infiltrates. 29
Pet. Ex. 16(q) at 5. Immunofluorescence evaluation may be used beca use of the difficu lty identifying a lesion of the ideal age. Id. Russell and Gibson note that “especially in patients with widespread, recurrent crops of palpable purpura, knowledge of the age of lesions can be extremely difficult.” Id. When evaluating the vasculitic lesion by immunofluorescence, prominent IgM c an be suggestive of SLE. Id. at 6. Strong deposition of C3 in either blood vessels or the basement membrane zone is more suggestive of HUV. Id. at 5.

The treatment for vasculitis depends on the severity of the symptoms of the patient. Pet. Ex. 16(w) at 6. The use of anti

- inflammatory drugs and antihistamines are used to treat symptomatic complaints. Id. However, for recurrent or chronic symptoms utilizing immune
suppressant medication, l ike azathioprine or cyclosporine may be effective. Id. Azathioprine has been shown to be effective in preventing clinical recurrence, either on its own or with low

- dose continued prednisone. Id. at 7.

In this case, G.C. had a skin biopsy performed on Mar ch 27 , 2014 that confirmed

vasculitis. Pet. Ex. 3 at 2. The biopsy demonstrated “subtle dermal edema with a sparse perivascular and interstitial infiltrate consisting of neutrophils, eosinophils and lymphocytes, with a mild predominance of neutrophil s. Pet. Ex. 3 at 5. Direct immunofluorescence revealed granular deposition of IgM and C3 in superficial dermal blood vessels. Id. at 4. Dr. Sule began treating G.C. with 10 mg of prednisone and 15 mg of azathi o pr i ne on April 3, 3014 after reviewing the path ology report from the biopsy . Pet. Ex. 2 at 10.

27 J. Charles Jennett e, M.D. and Ronald J. Falk, M.D., Small

- Vessel Vasculitis, 337 New England Jour. Of Medicine,

1512

- 1517 (1997) [Pet. Ex. 16(k)].

28 James P. Russell, M.D. and Lawrence E. Gibson, M.D., Primary cutaneous small vessel vasculitis: approach to diagnosis and tr eatment, 45 International Journal of Dermatology, 3

- 13 (2006) [Pet. Ex. 16(w)].

29 Durga P. Misra and Vikas Agarwal, Innate immune cells in the pathogenesis of primary systemic vasculitis , 36

Rheumatol Int. 169

- 182 (2016) [Pet. Ex. 16(q)]. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 14 of 2515

Additionally, G.C. was referred to the Harriet Lane Kidney Center for evaluation of proteinuria. 30 Dr. Pruette stated that there was a concern for possible kidney involvement. Pet.

Ex. 3 at 5. Dr. Prue tte noted that kidney involvement is rare, but has been “described as more
severe when noted in children with urticarial vasculitis.” Id.

B. Classification of G.C.’s Condition Before and After the Vaccination

The petitioner contend ed that th e hives G.C . experienced in August and S ept ember 2013

were “ merely allergic in nature

. ” Pet. Brief at 23. Petitioner argue d that the symptoms and

treatment of G.C. ’ s hives in the fall of 2013 differe d dramatically from the symptoms and

treatment o f G.C. ’ s skin cond ition that began occu r ring five d ays after she received the flu

vaccination. Id. Res pondent argued that G.C. ’ s post

- vaccination diagnosis was the natural progression of her pre

- vac cination symptomology and disease process. Resp. Brief at 14. Respondent stated that “

... it is less importa nt for the S pecial Master t o try to define what type of

urticaria G.C. had before the vac cination. The important point is that [G.C ] had urticaria before

the vaccination, and was later diagnosed with [chronic urticaria ] and [urticarial va sculitis] after

vaccin ation. ” Id.

The respondent is asking the Court to simply accept his assertion that G .C. ’ s pre

vac cination symptoms were the beginning of her urticarial vasculitis without further inquiry as to

the differences between the nature, dur ation an d treatment of G.C. ’ s symptoms before and after

the vaccination. Yet , answering the question as to what type of urticaria G.C. had prior to the

vaccination is critical to resolving this case

, particularly when the difference is distinguishing

be tween a common s kin condition, hives

, and an aut oimmune condition, urt icarial vasculitis.

Dr. Byer’s opin ed that the intermittent hives G.C. experienced four mon ths prior to the vaccination were “consistent with an allergic, IgE mediated condition.” Dr. Byers state d that the hives were “mild,” “only lasted one day at a time,” and, “resp onded to Benadryl.” Pet. Ex. 6 at 6; Pet. Ex. 12 at 2.

Dr. Byers testified that in the summer of 2013, G.C. ’s urticaria met the classification for acute urticaria. Tr. 75. She stated that the three episodes of hives G.C. had prior to the vaccine

were readily treated within hours with Benadryl which resolved the rash. Tr. 78; 136. Dr. Byers explained that hives are “basically limited to the epidermis, which is the top layer of skin...primarily caused by vasodilation.” Id. G.C.’s hives prior to the va ccine were mild and required no treatment beside Benadryl . Pet. Ex. 12 at 2. There was no edema or bruising. Id. Further, Dr. Byers observed that the location of the hives prior to the vaccine was in G.C.’s armpit, back of the legs and the stomach and the rash was not accompanied by edema. Tr. 80 &

135. There are no other me dical records that document any skin lesion, rash or hives between

mid

- September 2013 and the December 9, 2013 emergency room visit at Florida Hospital.

Dr. Schro e der , on the o ther hand, opined that the hives G.C. experienced in the fall of

2013 was the first appearance of chronic urticaria, G.C.’s autoimmune condition and it naturally progressed after the vaccination . Resp. Ex. A at 8, 10 ; Resp. Ex. J at 3

- 4. In responding to Dr.

30 Proteinuria is excessive serum proteins in the urine, such as in renal disease, after strenuous exercise, and with dehydration. Dorland’s at 1535. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 15 of 2516

Byers’ opinion that G.C.’s initial hives was acute urticaria cased by all ergens, Dr. Schro e der stated, “ Most importantly, with the exception of the febrile episode five days post vaccination that resolved within a week and which her physicians judged due to a viral exanthem, the rash

which was the most visible manifestation of her vasculitis was the same prior to and after the administration of the influenza vaccine.” Resp. Ex. A at 11 (emphasis added). After reviewing the medical records, Dr. Schro e der concluded, “The records indicate that the skin manifestations

occurred eve ry two to three weeks before the vaccination and every two to three weeks after the
vaccination.” Id. at 12.

A review of the medical records, the expert t estimony and medical literature, the

persua sive testimony of Ms. Contino

, and the photographic e vidence petitioner submitted into

the record

, demonstrates that G.C.’s condition prior to the vaccination and after the vaccination were distinctly different in presentation and symptomology.

When G.C. was evaluated at her pediatrician’s office for a r ash on September 13, 2013, G.C.’s skin condition was described as “well defined pink patches, only sl (slightly) raised mostly along waistband, backs of both thighs, ankles, but also on abdomen, b ack of hands and cheek (R).” Pet. Ex. 1(a) at 98. Dr. Lee noted that “G.C. seems unaffected

- well appearing/acting, not itching, rash is nontender, she was cooperative with exam.” Id. Dr. Lee recommended Benadryl and an oatmeal bath as necessary

. Id. G .C. saw Dr. Lee again on October 21, 2013 for unspecified co nstipation. Id. at 97. Her skin appeared “pink, warm, dry,”

and there was no mention of a rash. Id. In the medical record from the visit with Dr. Korff on October 3, 2014 states, “About 2

- 3 w eeks ago [ G.C. ] woke up one more morning and was

covered in hives. She was seen by the pediatrician and placed on Benadryl. After taking the Benadryl for a day, the rash resolved. Then 3 days later the hives reappeared and Benadryl again helped. She ha d another episode after that which again resolved with Benad ryl.” Pet. Ex. 1 at

69

- 70. Dr. Korff did not report any active hives, lesions or other skin markings on her physical exam of G.C., aside from noting that G.C. is dermatographic. Id. at 70. Dr. Korff diagnosed G.C. with dermatographic urticaria and reco mmended symptomatic treatment with Benadryl during episodes. Id. at 70. Ms. Contino testified that G.C. did not experience any additional hives in September, October, November and in December pr ior to the flu vaccine. Tr. 336.

The medical records ar e also consistent with Ms. Contino’s testimony. She described the hives that appeared in the fall of 2013 as “red and large,” and “covered a very large area on [G.C.’s] armpit, on her stomach and the backs of her legs.” Tr. 8. Ms. Contino testified that based on the recommendation of the pediatrician, she gave G.C. Benadryl and the hives “went away within an hour.” Tr. 12. She testified that between late August and early September 2013,

she tre ated G.C.’s hives with Benadryl and they resolved within an hour each time. Id. Ms.

Contino also testified that G.C.’s last episode of hives in the fall of 2013 occurred in late September. Tr. 13. She testified that G.C. did not experience another epis ode of hives from late September to the time of vaccination on December 3, 2013. Id.

After the vaccination, Ms. Contino’s description of G.C.’s hives changed dramatically. She testified that five days after the flu vaccination small red spots began to appear on G.C. Tr. 14, 337. Then G.C.’s legs began to swe ll and her feet began to turn purple. Tr. 337. G.C.

refused to w alk while in Disney World. Id. Ms. Contino stated that the rashes began to spread to Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 16 of 2517

her cheeks and up and down her legs. Tr. 15. Additionally, G.C. developed “60

- 80 bruises all

over her body,” that appeared purplish. Tr. 16. Ms. Contino rushed G.C. to the emergency room on the evening of December 9 th where she was given steroids and Benadryl. Tr. 343.

When the family returned home from Florida, the purplish bruise s, swelling in he r hands and feet and joint pain would return “a couple of times a week.” Tr. 342. Ms. Contino testified that G.C. did not have any symptoms of pain, swelling, or bruising associated with the hives that appeared in September. Tr. 342, 34 4. She stated th at beginning with the event in Florida G.C’s leg and joint pain was so bad that she would only lay in bed and cry. Tr. 338. Ms. Contino

testified that G.C.’s symptoms of joint pain and swelling were so serious that she drove all the

way from Maryland to the Cleveland Clinic to get G.C. seen as soon as possible. Id. I t was not until a skin biopsy was performed on March 27 , 2014 that G.C. was definitively diagnosed with

urticarial vasculitis. 31 See Pet

. Ex. 3 at 1.

Dr. Schroeder was focused solely on t he recurrence of G.C. ’ s hives and did n ot acknowledge that the post

- vaccine hives were accomp anied by joint pain, bruising and swelling and kidney issues that began in December and con tinuing thereafter. His opinion that “ the rash

which was the most visib le manifestation of [G.C. ’ s] vasculitis was the same to and after the administration of influenza vaccine, ” is contradicted by both the medical evidence and the convincing testimony of Ms. Contino.

When G.C. was treated for hives in the fa ll of 2013, th e medical records did not include any notation that G.C. was experiencing any of the symptoms associated with vasculitis. It was only after the vaccination did G.C. begin to complain about joint pain, experience significant swelling and dev elop bruises. See Pet. Ex. 3 at 4,7; Pet. Ex. 9 at 16. Both the medical records and Mrs. Contino’s testimony are clear that the rash G.C. experienced in the fall of 2013 responded almost immediately to Benadryl. See Pet. Ex. 1(a) at 69 , 98; Tr. 335.

During the heari ng, Dr. Schro e der acknowledged that some of the symptoms G.C. experienced in the fall of 2013 were different than the symptoms that presented after the

vaccination. He conceded that G.C. did not have any leg or feet swelling in September 2013, as

she did e xperience on December 9, 2013. Tr. 301. Dr. Schroeder also conceded that G.C. did not experience bruising in September or early October, as she did after the vaccination. Tr. 302. In fact, Dr. Schro e der stated, “the symptomatology that [G.C] had in Dec ember was different

t hen the symptomatology that she had befo re and after. I don’t recall there being any reports in the case...when she was having the active vasculitis where she had difficulty walking...general swelling, et cetera, or that she had a fever. Everything was focused on her skin.” Tr. 308 (emphasis adde d). When questioned whether he agreed if the symptoms of pain, history of bruising, history of swelling was suggestive of something different than urticaria, Dr. Schro e der stated, “Yes. Yes. Tha t’s what I said. There’s a difference about what happened in December versus what happened before and after. I agree with that.” Tr. 311

- 12. However, Dr. Schroeder attempted to disting uish the symptom s of bruising, joint pain and swelling that G.C. exp erienced in December as unique

, one

- time event caused by a virus

.

31 A biopsy for this condition can only be done on an active lesi on and because of the episodic nature of the disease and the difficulty in scheduling an immediate appointment at Johns Hopkins when a flare occurred the biopsy was not done until March 27, even though Dr. Sule’s working diagnosis was urticarial vasculitis before that time. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 17 of 2518

A s explained above, vasculitis is often accomp anied by joint pain or swelling and can have ren al involvement

. T he record well est abli shes that G.C. ’ s symptoms of joint swelling,

b ru isin g and pain , in addition to the hives, continued regularly until she was diagn osed with

ur ticarial vasculitis and treated accordingly. The newly appear ing vasculitic symptoms of bruising, swelling and joint pain was the reason that Ms. Contino drove G.C. f rom Ma ryland to

the Cleveland Clinic. It was th e accompanying symptoms of joint pain, swelling, and bruising

that caused Dr. Si lber and the doctors at Johns Hopkins to suspect vasculiti s and order a biopsy

to confirm the diagnosis

. See Pet. Ex. 1(a) at 6 0 ; Pet. Ex. 2(a) at 6.

Based on the medical records, the opinions of the experts and the testimony of Ms. Contino, I conclude that it is more likely than not that the hives G.C. experie nced in the fall of

2013 should be classified as an allergic IgE

- me diated response and what she experienced five days post

- vaccination was the initial presentation of G.C.’s autoimmune urticarial vasculitis

which continued thereafter

.

A. Althen Prong One: Medical Theory

1. Legal Standard

Under Althen prong one, the causati on 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, 451 F.3d at 1355

- 56 (Fed. Cir. 2006). Th e theory need only be “legally probable, not medically or scientifically certain.” Id. at 1380 (quoting Knudesn, 35 F.3d at 548). However, the theory still must be based on a “sound

and r eliable medical or scientific explanation.” Knudsen at 548. The F ederal Circuit explained

in Althen 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 preponder ance standard is to 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).

2. Discussion

The experts agree that the causes of chronic urticaria can be autoimmune. Pet. Ex. 6 at 5; Resp. Ex. A at 9. Petitioner submitted an article by Altman and Chang titled, Pathogenic Intracellular and Autoimmune Mechanisms in Urticaria and Angioedema, which Dr. Schroeder stated provided “a good review of our curren t understanding of the pathogenesis of urticaria.” Resp. Ex. A at 9. Additionally, both the experts agree that the G.C.’s underlying urticarial vasculitis is the product of an autoimmune process. Resp. Ex. A at 12; Pet. Ex. 6 at 8; and Pet.

Ex. 12 at 2. The main disagreement between the experts is the nature of the urticaria that G.C. experienced prior to the vaccination and the urticaria G.C. experienced post

- vaccination. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 18 of 2519 a. Expert s’ Opinion on Causation

Dr. Byers opined that through bystander activati on the flu vaccine caused G.C.’s

urticaria l vasculitis which initially appeared after the flu vaccination

. Pet. Ex. 6 at 8; Tr. 118

- 119. The Agmon

- Levin 32 article, which Dr. Byers’ quoted in her fi rst report and during hearing testimony explains bystander activation:

“Bystander activation is a situation where enhanced cytokine production promotes the expansion of autoreactive T cells, whose prior number has been insufficient to produce an

overt dis ease. In the case of polyclonal activation of B cells, the increased B cell proliferation, antibody production and the generation of circulating immune complexes may eventually damage self

- tissues.”

Pet. Ex. 8(b) at 2; Tr. 118

- 119. Dr. Byers also submit ted an article by Fujinami et al 33

., that

described the role of bystander activation in the production of autoimmune disease. Pet. Ex. 16(e). The article describes the stimulation of antigen presenting cells that could potentially activate pre

- primed auto reactive T

- cells which then initiate autoimmune disease by bystander

activation. Pet Ex 16 ( e ) at 2

.

Dr. Byers testified that every individual is born with dormant autoreactive immune cells.

Tr. 123; Pet. Ex. 23 at 4. She testified that the body contains anti

- self lymphocytes, including CD4 T cells, CD8 T cells , and B cells that are slowly replicating, but under control of T

re gulatory cells. Tr. 119. She explained that these cells can be activated by the innate immune systems response to an antigen. Tr. 122

- 124. When the cells of the innate immune system ar e activated they react with the antigen, but also release cytokines. Id. Macrophages and dendritic cells first respond to an incoming antigen and produce a blast of cytokines. Pet. Ex. 23 at 9. The enhanced cytokine production activate the adaptive imm une system’s B and T cells that are antigen specific. Pet. Ex. 23 a t 6, 8; Tr. 124

- 127. In addition to the antigen

- specific T and B cells, the dormant autoreactive T and B cells are also activated and may start to generate

autoantibodies. Pet. Ex. 23 at 8; Tr. 126

- 127.

Dr. Byers referred to an article by van Alst et al. 34 to further explain that in bystander activation, T cells unrelated to an antigen presented can be activated without classical T

- cell receptor (TCR) ligation, but rather via cytokines like IL

- 2 as a result of the excessive activation of cells during t he classical response. Pet. Ex. 17(a); Tr. 130

- 31.

Dr. Byers explained that the third flu vaccine G.C. received on December 3, 3013 caused a sudden inflammatory response in her skin b y the release of pro

- inflammatory cytokines. Pet.

Ex. 6 at 8. She explained t he flu vaccination stimulated the innate immune system in G.C.,

32 Nancy Agmon

- Levin et. al., Infl uenza Vaccine and Autoimmunity, 11 IMAJ 183

- 185 (2009) [Pet. Ex. 8(b)].

33 Robert S. Fujinami et al., Molecular Mimicry, bystander activation, or viral persistence: Infections and autoimmune disease, 19(1) Clinical Microbiology Reviews, 80

- 94 (2006) [Pet. Ex. 16(e)].

34 Susan van Alst et al., Bystander activation of irrelevant CD4+T cells following antigen

- specific vaccination occurs in the presence and absence of adjuvant. 12(5) PLoS One, e0177365 (2017) [Pet. Ex. 17(a)]. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 19 of 2520

generating pro

- inflammatory cytokines which signaled activation and replication of cytotoxic T

cells or B cells s pecific to the flu vaccine, but also of heterologous T or B cells wh ich attacked

the cells in the vascular walls. Tr. 130

- 33. She testified that heterologous T or B cells would be activated to produce anti

- IgE receptor antibodies that would bind to the m ast cells causing episodic degranulation. Tr. 133. This anti

- IgE r eceptor antibody caused the clinical manifestation observed in G.C. Pet. Ex. 6 at 8. Additionally, antigen

- antibody complexes are

involved in the vasculitis. Id. The antigen

- antibody c omplexes embed themselves in the vessels, fixing complement and prod uce the vasculitis. Id.

The respondent and Dr. Schro e der first argue d that there are no epidemiological studies connecting the flu vaccine to vasculitis. Dr. Schro e der referred to th e Bonetto et al. article to support the assertion that existing medical literature does not allow establishing a causative link

between vaccination and vasculitis. In Bonetto et al

. , the authors conduct ed a systemic medical

literature review of 75 studies that included c ase reports, controlled trials and retrospective/observational studies that related to vasculitis following immunization. Resp. Ex. I

at 2. However, the article also states that “standard diagnostic criteria for vasculitis are limited

and rarely applied; therefore, it is not possible to draw any conclusion on causality based on the
current data.” Id. at 8. The article notes that the vaccine most often reported to precede

vasculitis is the influenza vaccine. Id. at 9. Further , the articl e states that th e authors of 43 case reports considered that a link between vasculitis and vaccination was possible or likely, hypothesizing that the mechanism may involve immune complex deposition in the blood vessel

wall. Id.

Furthermore , an editoria l by Zafrir et al

. 35 observed that the most common autoimmune phenomena described following the flu vaccine were different vasculitic disease s . Pet. Ex. 17(c) at 2. The authors note that the 33 case reports of post

- influenza vaccination vascul itides report ed are rare compared with the amount of influenza vaccines administered yearly but pose a possible link between the vaccination and autoimmunity. Id. Dr. Schroeder argued that the higher case reports involving the flu vaccine and vasculitis was due to th e high frequency in which the flu vaccine is administered. Tr. 280; Resp. Ex. J at 6

.

Dr. Schro e der conceded that bystander activation is a means by which autoantibodies can be produced, leading to an autoimmune disease. Tr. 213

- 214. He arg ued that for bystander

activation to work

, the specific autoimmune antibodies would have had to have been present

before hand. Tr. 253. However, the essence of the bystander activation theory is that non

specific dormant autoimmune cells can be activate d in the lymp h nodes by the cytokines stimulated in response to the foreign antigen. Dr. Byers testified that there were likely quiescent B cells p resent for some time and it was the massive release of cytokines that activated those autoreactive B cells to start spewi ng out her IgM antibodies which were then seen in the biopsy.

Tr. 350 . Dr. Byers explained that after G.C. received the flu vaccine, the IgM anti

- IgE receptor antibodies produced the rash and also produce d the antigen

- antibody complexes, that embedded

t hemselves into the vessels, fixing complement, which is what led to the vasculitis. Tr. 351 ; Pet.

Ex. 6 at 8.

35 Yaron Zafrir et al., Post

- Influenza Vaccination Vasculitides: A Possible New Entity, 15 Journal of Clinical Rheumatology, 269

- 270 (2009) [Pet. Ex. 17(c)]. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 20 of 2521

Then Dr. Schroeder argued that bystander activation is a less efficient process for generating B cells

. Tr. 253. He testified that “had t he reaction occurred a month after the
vaccination...there would have been time.” Tr. 254. He opined that five days was too fast for a bystander activation to be the mechanism for triggering G.C. urticarial vasculitis. T r. 256. However, he did not account for the fact that G.C’s immune system had likely been primed by prior flu vaccines

, as this was her third flu vaccination.

After review of the testimony and the medical literature I conclude that bystander

activation i s a reasonable and reputable theory that is recognized in the literature and can explain the role of the vaccine in triggering the occurrence of autoimmune vasculitis in this case.

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

1. Legal Standard

To satisfy Althen prong two, petition er 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 at 1278. Even if the vaccination can cause the injury, petitioner must show “that it did so in [t his] particular case.” Hodges v. Sec’y of Health & Human Servs., 9 F.3d 958, 962 n.4 (Fed. Cir. 1993).

Proof of Althen prong two requires a logical explan ation 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 v. Sec’y of Health &
Human Servs., 440 F.3d at 132 6.

2. Discussion & Conclusion

Dr. Byers offered the theory of bystander activation to explain how the third flu vaccine G.C. received can cause urticarial vasculitis. Dr. Byers also opined that this theory fit the present

case because the clinical manife station s of the allergic acute urticaria G.C. experienced prior to

the vaccination w as markedly di fferent from the symptoms she experienced after receiving the

vaccination. Pet. Ex. 12 at 2.

Dr. Byers explained that the rash and hives accompanied by bruising and swelling that G.C. experienced after the vaccination was more consistent with a vasculit is. Tr. 349 ; Pet. Ex.

12 at 2. Dr. Schro e der, on the other hand, argued that there was “ no pro of that the skin
manifestations before and after vaccination were different....there is no documentation in the medical records that distinguishes the rashes befo re and after vaccination from each other.” Resp. Ex. A at 12

.

Dr. Schroeder’s assessment tha t G.C.’s skin manifestations” were the same before and

after the vaccine was limited to the presentation of the urticaria and failed to consider the ongoing vas culitic symptoms G.C. experienced post

- vaccination

. The vasculitic symptoms of joint pain, swelling and bruising first manifested five days after the flu vaccine and continued with some regularity. Tr. 338. However, Dr. Schroeder apparently disregarded Ms. Contino’s Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 21 of 2522

reports of joint pain, swelling and reoccurring bruises to phys icians, leading him to an unduly restrictive description of G.C.’s post

- vaccination condition. During cross

- examination, Dr. Schroeder acknowledged that the medical records relat ing to G.C.’s hives from September and

October do not indicate that G.C. expe rienced any swelling, bruising or joint pain in association with presentation of the hives . Tr. 300

- 02. He testified, “All I have is a description of a rash,

and the fact that t hey were treating her for urticaria. So I presume that she had an urticarial rash, if they were treating her for urticaria. She had an urticarial rash before, she had an urticarial rash after, right? And so it seems to me that it’s the same condition.” Tr. 313

. However, it was evident from the course of treatment and diagnosti c assessments of G.C. at the Cleveland Clinic and Johns Hopkins that the physicians were considering something considerably different than Benadryl responsive hives.

In his fi rst report, Dr. Schroeder offered two alternative explanations as to why G.C. experienced markedly different symptoms five days after the vaccine compared to the symptoms she experienced in the fall. First, Dr. Schroeder associated the different symptoms G.C. experienced in December to the change in temperature from Maryland to Fl orida. He explained that the “...the episode on December 8, 2013 occurred during travel from Maryland to Florida in December, a period where the temperature differential between th ese two states i s exacerbated.” Resp. Ex. A at 8

- 9. Dr. Schroeder then attr ibuted the different symptomology to a viral

infection. H e stated that “At Florida Hospital, her symptoms were judged by her emergency room physicians to be most consistent with a viral exanthema.” Id. at 9. He continued by stating, “...these particular s ymptoms with fever resolved and did not recur. Instead, the patient

returned to the pattern of a rash alone occurring every two to three weeks that held sway since September of 2 013.” Id (emphasis added). When Dr. Schroeder was asked by the C ourt if giv en the knowledge of the full history of the development of this condition

, which the emergency

room doctor did not have , wheth e r he still attributed the different symptomology tha t appeared in G.C. in Florida to a viral exanthem, he responded, “I can’t say to be frank.” Tr. 309.

As described in more detail above, the rashes and hives G.C. experienced in the fall of

2013 were sho rt

- lived and resolved quickly when given Benadryl. See Pet. Ex. 1(a) at 98; Tr. 9

- 10. A physical examination of G.C. on September 13, 2013 found her “well appearing/acting, not itching, rash is nontender.” Pet. Ex. 1 at 98. It was recommended that the rash be treated with Benadryl and an oatmeal bath. Id. When assessed the next month by Dr. Korff, she diagnosed G.C. with dermatographic urticaria and recommended treating the symptoms with Benadryl versus daily use of a long acting antihistamine. Pet. Ex. 1(a) at 70. Ms. Contino

testified that the hiv es in the fall were not accompanied by fever, extreme pain or bruising. Tr. 8;

10

- 13.

Five days after G.C. received the flu vaccination on December 3, 2013, G.C. began to

exhibit hives and rashes across her abdomen and thighs. Pet. Ex. 2 at 7; Tr. 14

- 5. Six days after receiving the vaccine, G.C,’s hives and rash spread across her body, accompanied by pain, a fever of 101 degrees and bruises accompanying the rash. Pet. Ex. 4 at 16

- 17; 23

- 24; Tr. 14

- 24. At the emergency room in the Florida Hospital, G.C. was treated with steroids that reduced the swelling in G.C.’s legs , but the bruises remained . Tr. 20

- 21. Ms. Contino explained that G.C.’s symptoms of swelling and joint pain, along with the rashes and bruises reappeared about a month

after the flu vacc ine and continued a few times a week. Tr. 338

- 43. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 22 of 2523

During the hearing, Dr. Byers explained that in the fall of 2013, the medical professional s that treated G.C. for hives did not suspect any systemic in volvement. Tr. 136. Instead, G.C. was

treated wit h Benadryl and the urticaria resolved within a few hours. Id. However, when G.C. saw Dr. Silber on February 3, 2014 for recurrent rash and joint pain, he suspected a systemic disease, diagnosed G.C. with “probable vasculitis” and recommended G.C. see a p ediatric rheumatologist. Pet. Ex. 1 at 60.

At the Cleveland Clinic, based on the report ed symptoms by Mrs. Contino and the photographs Ms. Contino presented to Dr. Zeft, G.C. was diagnosed with “hemorr hagic edema of infancy (a form of vasculitis) trigg ered by influenza vaccination. Preceding urticaria may be idiopathic or potentially part of an illness spectrum.” Id. at 58. Dr. Byers explained that Dr. Zeft’s diagnosis of “hemorrhagic edema of infanc y” was the second time in the medical records

that a medical professional was considering vasculitis as an explanation for G.C.’s symptoms.

Tr. 93

- 94. She explained that “hemorrhagic edema of infancy,” is small vessel vasculitis. Id.

Dr. Zeft recommend ed a complete blood count with differential, a urin alysis, complement metabolic panel to test for C3 or C4 and a serum immunoglobulin test, specifically looking for elevated IgA. Pet. Ex. 1 at 58; Tr. 94. At Johns Hopkins, Dr. Sule became concerned with

G.C.’s elevated protein/creatine ratio and recommen ded G.C. undergo a skin biopsy and repeat urinalysis. Pet. Ex. 2 at 3. The skin biopsy performed on March 27, 2014 confirmed the

ultimate diagnosis of urticarial vasculitis. Id. at 10.

From then on, G .C. has been treated with steroids and immunosuppr essive drugs. Tr. 41 ; see also Pet. Ex. 2 at 10

- 18. G.C. continues to experience leg and joint pain, along with rash

flare

- ups and mouth ulcers . Pet. Ex. 15 at 4 ; Tr. 49

- 50

, 343

.

While the “history of present illness,” in the medical records from the Cleveland Clinic and the first two appointments from Johns Hopkins somewhat confused the occurrences of the acute urticaria G.C. experienced in the fall of 2013, all three records are consistent in noting that after G.C. received a flu vaccination, she exp erienced bruising, swelling and joint pain that continued after seeking treatment at the emergency room of Florida Hospital. See Pet. Ex. 2 at 4, 7; Pet. Ex. 9 at 3. T aken as a whole

, the evidence indicates that G.C. did not simply experience a
“rash alo ne,” after she returned from Florida, as asserted by Dr. Schroeder, but instead G.C’s rashes post

- vaccination were accompanied with joint pain, bruising and swelling, all of which

were absent in the fall of 2013. A dditionally, post

- vaccination, G.C. consi stently had abnormal pr/cr ratio which was concerning to physicians to Johns Hopkins and was indicative of systemic

involvement

. See Pet. Ex. 2(a) at 12.

Following the theory propos ed by Dr. Byers , an extensive review of the medical records

and after he aring the compelling testimony of Mrs. Contino

, I conclude that the petitioner has set forth a logical cause and effect relationship between the flu vaccination and G.C.’s urticarial

v asculitis. G.C.’s symptoms post

- vaccine are consistent with the medical literature describing symptoms of autoimmune vasculitis, and more importantly, those symptoms are distinct from the symptoms that G.C. experienced in the fall of 2013. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 23 of 2524

C. Althen Prong Three

1. Legal Standard

Althen prong three requires establishing a “proximate temporal relationship” b etween the vaccination and the injury alleged. Althen 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 s ymptoms 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 & Hu man Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for w hat is medically acceptable timeframe must also coincide wit h the theory of how the relevant vaccine can cause an injury (

Althen prong one). Id. at 1352.

2. Discussion and Conclusion

Petitioner argued that there was an acceptable temporal relationship be tween G.C.’s flu

vaccination on December 3 , 2014 and the onset of the first symptoms of urticarial vasculitis five days later, on December 8 , 2014.

With respect to the temporal rela tionship between the vaccine and onset of G.C.’s symptoms, Dr. Byers opi ned that the onset of three to twenty

- one days is an appropriate medical onset of symptoms based upon the relevant medical literature. Pet. Ex. 6 at 8 ; Tr. 109

- 112.

As such, Dr. Byers contend ed that the temporal association of three to five days is a lso supported by medical literature. She cited to an article by Felicetti et al. 36 to support the proposition that vasculitides have been reported as an adverse event following vaccina tion, with more frequent reports in association with influenza vaccines than with any other vaccine in three international vaccine reporting databases, including VAERS. Pet. Ex. 16(d) at 3. This article also notes that across the three databases, vasculi tides appear to be more frequently reported in the pediatric population, among females and with a time to onset within 10 days from the

vaccination. Id. at 6. Dr. Byers also referred to a case report by Cao and Sun 37 where an elderly gentleman presented to an emergency room five days after receiving the flu vaccine with

exten sive rash, fever and joint pain in his hips, knees and ankles. Pet. Ex. 16(b) at 2. He was diagnosed with leucocytoclastic vasculitis. Id. An other case report by Liu et al. 38 indicated the onset of painful erythematous eruptions on the patient’s trunk, arms and thighs three days after receiving an H1N1 flu vaccination. Pet. Ex. 16(o).

Further, Dr. Byers assert ed that five days is particularl y medically appropriate because

this was the third flu vaccine G.C. had received. Tr. 87. The Agmon

- Levin art icle states that a

36 Patrizia Felicetti et al., Spontaneous reports of vasculitis as an ad verse event following immunization: A descriptive analysis across three international databases, 34 Vaccine 6634

- 6640 (2016) [Pet. Ex. 16(d)].

37 Sissi Cao and Dongemi Dongemi

, Leucocytoclastic vasculitis following influenz a vaccination, BMJ Case Rept. (20 17), doi: 10.1136/bcr

- 2016

- 217755 [Pet. Ex. 16(b)].

38 Po

- Yu Liu et al., Cutaneous Vasculitis Following Influenza Vaccination , 49 Inter. Med. 2187

- 2188 (2010) [Pet. Ex. 16(o)]. Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 24 of 2525

second exposure to the same antigen might elicit a response within a shorter period. Pet. Ex. 8(b) at 2.

Additionally, thi s court has previously awarded entitlement where the petitioner’s onset of symptoms of urticarial vasculitis be gan only a few days after the flu vaccination. Mc E lroy v. Sec’y of Health & Human Servs., No. 11

- 679, 2012 WL 1739873 at *4 (Fed. Cl. Spec. Mstr

. Apr. 13, 2012). In that case, the petitioner received the flu vaccine on October 25, 2008 and on November 6, 2008, complained of a travelling urticaric rash on her trunk and extremities for two weeks , putting onset almost immediately after the vaccinati on. Id (emphasis added).

Respondent’s expert, Dr. Schro e der, opined that the hives G.C. experienced in the fall of 2013 was the beginning stages of chronic urticaria. Resp. Ex. A at 10 ; Tr. 224

. He testified that in the fall of 2013, G.C’s hives could not be classifie d as “chronic urticaria” because the hives

had not yet presented for six weeks. Tr. 225. He also asserted that the urticarial symptoms that predated the vaccination were no different in presentation than the symptoms G.C. experienced

after the vaccination

, aside for the “severe episode of skin manifestations,” that occurred in

Florida

. Resp. Ex . A at 8. However, as discussed in greater detail above, the hives G.C. experienced in the fall appeared to be different in both symptomology and mechan ism of

activation . The post

- vaccination skin manifestations were accompanied by bruises, swelling, join t pain and kidney issues that were not present during the late summer and early fall episodes. The August/September episodes appeared to be an allergic r eaction, responsive to Benadryl and

the post

- vaccination condition being autoimmune

, requiring immunomo dification drugs and ongoing steroid treatment.

T he post

- vaccination condition appears to be autoimmune as opposed to allerg ic and five days is frequently period for onset for autoimmune conditions. T here appears to be a preponderance of the evidence th at G.C. experienced the initial presentation of her urticarial vasculitis within a medically appropriate timeframe following the flu vaccine on December 3,

2013.

VI. CONCLUSION

After a review of the entire record, I conclude that petitioner has establ ished a reliable theory that the flu vaccination G.C. received on December 3, 2013 was the cause

- in

- fact of her urticarial vasculitis. Accordingly, petitioner is entitled to compens ation. A separate damages

order will be issued.

IT IS SO ORDERED.

s/Thomas L. Gowen

Thomas L. Gowen Special Master Case 1:15-vv-00773-UNJ Document 66 Filed 09/05/19 Page 25 of 25