The opinion
In the United States Court of Federal Claims
OFFICE OF SPECIAL MASTERS
No. 12-254V
Filed: June 28, 2018
To Be Published
*************************************
MARK MILES, legal representative of a *
minor child, J.M., *
*
Petitioner, *
*
v. * Influenza (“flu”) vaccine; significant
* aggravation of minimal change
SECRETARY OF HEALTH * nephrotic syndrome; three strokes;
AND HUMAN SERVICES, * timing of onset of second relapse.
*
Respondent. *
*
*************************************
John F. McHugh, New York, NY, for petitioner.
Darryl R. Wishard, Washington, DC, for respondent.
MILLMAN, Special Master
DECISION1
On April 18, 2012, petitioner filed a petition under the National Childhood Vaccine
Injury Act, 42 U.S.C. § 300aa-10-34 (2012), alleging that influenza2 (“flu”) vaccine administered
to his son J.M. on October 1, 2009 caused J.M. to have a second relapse of his preexisting
nephrotic syndrome.3 Pet. Preamble and ¶ 2.
1
Vaccine Rule 18(b) states that all decisions of the special masters will be made available to the public unless they
contain trade secrets or commercial or financial information that is privileged and confidential, or medical or similar
information whose disclosure would constitute a clearly unwarranted invasion of privacy. When such a decision is
filed, petitioner has 14 days to identify and move to redact such information prior to the document’s enclosure. If
the special master, upon review, agrees that the identified material fits within the banned categories listed above, the
special master shall redact such material from public access.
2
Influenza virus is “any of a group of orthomyxoviruses that cause influenza, including at least three genera:
Influenzavirus A, Influenzavirus B, and Influenzavirus C. Antigenic variants are classified on the basis of their
surface antigens (hemagglutinin and neuraminidase) as H1N1, H2N2, etc. Serotype A viruses are subject to major
antigenic changes (antigenic shifts) as well as minor gradual antigenic changes (antigenic drift) and cause the major
pandemics. Serotype B viruses appear to undergo only antigenic drift and cause more localized epidemics.
Serotype C viruses appear to be antigenically stable and cause only sporadic disease.” DORLAND’S ILLUSTRATED
MEDICAL DICTIONARY 2062 (32nd ed. 2012) (hereinafter “Dorland’s”).
3
Nephrotic syndrome is a “general name for any of a large group of diseases involving defective renal glomeruli,
characterized by massive proteinuria and lipiduria with varying degrees of edema, hypoalbuminemia, and
hyperlipidemia.” Dorland’s at 1840.
On August 6, 2012, petitioner filed a petition which should have been titled as an
amended petition. It includes an extensive review of the medical records filed as of that date.
On October 23, 2012, petitioner filed a Supplemental Petition No. 2.
The parties attempted to settle this case but failed. The parties participated in mediation
but mediation failed.
A hearing was held on October 17 and 18, 2017. Testifying for petitioner were
petitioner, Dr. Albert Quan (J.M.’s treating pediatric nephrologist), and Dr. Joseph A. Bellanti
(expert immunologist). Testifying for respondent were Dr. Bernard S. Kaplan (expert pediatric
nephrologist) and Dr. Arnold I. Levinson (expert immunologist).
Petitioner filed his posthearing brief on December 22, 2017.
Respondent filed his posthearing brief on January 23, 2018.
Petitioner filed his reply brief on January 25, 2018.
FACTS
Prevaccination Records
J.M. was born on February 23, 2001. He is now 17 years old.
On April 19, 2001, when J.M. was two months old, his mother took him to Willow Bend
Pediatric. J.M. had head congestion, was sneezing a lot, and had a loss of appetite. Med. recs.
Ex. 1, at 43. He seemed sleepier than usual. Id. His head cold did not trigger minimal change
nephrotic syndrome.
On April 24, 2001, J.M. received his first DTaP, Hib, hepatitis B, and IPV vaccines.
Med. recs. Ex. 12, at 2. His first DTaP, Hib, hepatitis B, and IPV vaccinations did not trigger
minimal change nephrotic syndrome.
On June 12, 2001, J.M. went to Willow Bend Pediatrics with congestion and a hoarse,
rattling cough. Med. recs. Ex. 1, at 42. He had been fussy and up at night. He had eye drainage.
He had a low-grade temperature of 99.2 degrees. Dr. Michael J. Frank diagnosed J.M. with
bronchiolitis. Id. J.M.’s bronchiolitis did not trigger minimal change nephrotic syndrome.
On July 2, 2001, J.M. received his second DTaP, Hib, hepatitis B, and IPV vaccines.
Med. recs. Ex. 12, at 2. His second DTaP, Hib, hepatitis B, and IPV vaccinations did not trigger
minimal change nephrotic syndrome.
2
On February 9, 2002, J.M. was at Willow Bend Pediatrics because of congestion and cold
symptoms plus loose stools. Med. recs. Ex. 1, at 41. Dr. Frank diagnosed J.M. with bilateral
otitis media and bronchitis. Id. J.M.’s bilateral otitis media and bronchitis did not trigger
minimal change nephrotic syndrome.
On March 26, 2002, J.M. saw Dr. Kimberly F. Mehendale at Willow Bend Pediatrics,
with a history of cough and congestion for the prior two to three days. Id. Dr. Mehendale
diagnosed J.M. with an upper respiratory infection (“URI”). Id. J.M.’s URI did not trigger
minimal change nephrotic syndrome.
On April 16, 2002, J.M. received Varivax and Prevnar vaccinations at Willow Bend
Pediatrics. Id. His Varivax and Prevnar vaccinations did not trigger minimal change nephrotic
syndrome.
On May 24, 2002, J.M. received his third DTaP, Hib, hepatitis B, and IPV vaccines.
Med. recs. Ex. 12, at 2. His third DTaP, Hib, hepatitis B, and IPV vaccinations did not trigger
minimal change nephrotic syndrome.
On March 11, 2003, when J.M. was two years old, he went to Willow Bend Pediatrics
with congestion for two days. Id. at 48. He had moderate nasal congestion. Dr. Susan J. Sickler
diagnosed J.M. with an upper respiratory infection (“URI”). J.M.’s URI did not trigger minimal
change nephrotic syndrome.
On October 6, 2004, when J.M. was three years old, he was supposed to receive flu
vaccine, but because he had had a temperature of 101-103 degrees within the last 24 hours, the
nurse at Willow Bend Pediatrics did not vaccinate him. Id. at 63. His febrile illness did not
trigger minimal change nephrotic syndrome.
On December 24, 2004, J.M. went to Willow Bend Pediatrics and saw Dr. Mehendale,
complaining of yellow runny nose for five days, green rhinorrhea, and congestion. Id. at 62. Dr.
Mehendale wrote J.M. had green rhinorrhea and his symptoms were worsening. Id. J.M.’s
respiratory infection did not trigger minimal change nephrotic syndrome.
On July 12, 2005, when J.M. was four years old, he went to Willow Bend Pediatrics with
a urinary tract infection lasting two weeks with increased frequency. Id. at 61. Dr. Michael J.
Frank diagnosed him with spastic bladder. Id. His urinary tract infection did not trigger minimal
change nephrotic syndrome.
On August 8, 2005, J.M. went to Willow Bend Pediatrics and received DTaP, IPV,
MMR, and his second hepatitis A vaccinations. Id. at 46. His DTaP, IPV, MMR, and hepatitis
A vaccinations did not trigger minimal change nephrotic syndrome.
On November 20, 2006, J.M. received FluMist vaccine. Med. recs. Ex. 12, at 3. FluMist
did not trigger minimal change nephrotic syndrome.
3
On August 31, 2007, when J.M. was six years old, he went to Willow Bend Pediatrics
with puffy cheeks and eyes, and diarrhea. Med. recs. Ex. 1, at 60. He had mild suborbital edema
and thin mucosa. Id. His infection did not trigger minimal change nephrotic syndrome.
On September 6, 2007, J.M. went to Children’s Medical Center Dallas because he started
having swelling of his body about 12 days previously. Med. recs. Ex. 1, at 279. The history was
that J.M. had a new onset of edema, proteinuria, elevated creatinine, and hypoalbuminemia. Id.
at 29. The findings on J.M.’s renal ultrasound were consistent with the typical findings seen in
nephrotic syndrome, including large kidneys with increased echogenicity. Id. at 19-22. J.M. had
acute renal injury with serum creatinine concentrations of 0.8 to 1.6 mg/dl (normal being 0.3-0.7
mg/dl). Med. recs. Ex. 2, at 15-22. J.M. was started on prednisone,4 which he continued to take
until February 4, 2008. Id. at 25-36.
On October 11, 2007, Dr. Mouin G. Seikaly, J.M.’s first pediatric nephrologist, noted
J.M. had new-onset nephrotic syndrome, and a moderate amount of proteinuria. J.M. had not
completed a full six weeks of daily steroid therapy. Id. at 28. On November 2, 2007, J.M.
continued to have 30 mg/dl of proteinuria while on prednisone 40 mg every other day. Dr.
Seikaly stated his concern that J.M. might relapse once prednisone was tapered. He noted he
discussed with J.M.’s parents the use of Tacrolimus5 and CellCept6 therapy, and said J.M. would
benefit from starting CellCept if he did not tolerate tapering off prednisone. Id. at 31.
On December 19, 2007, J.M. was in remission and his steroid was slowly tapered. Id. at
33. On February 6, 2008, J.M. was in remission and fully off prednisone. Id. at 35.
On January 15, 2008, J.M. went to Willow Bend Pediatrics with a stuffy nose and fatigue
plus a fever of 101 degrees. Med. recs. Ex. 1, at 58. He had swollen mucosa, thick mucus, and a
congested cough. Dr. Frank diagnosed J.M. with bronchitis. Id. J.M.’s bronchitis did not trigger
a relapse of his nephrotic syndrome.
On March 26, 2008, J.M. was in remission, still off prednisone, but on Norvasc,7 5 mg
4
Prednisone is “a synthetic glucocorticoid derived from cortisone, administered orally as an anti-inflammatory and
immunosuppressant in a wide variety of disorders.” Dorland’s at 1509. Glucocorticoid is “any of the
corticosteroids (steroids produced by the adrenal cortex) that regulate carbohydrate, lipid, and protein metabolism
and inhibit the release of corticotropin. They also affect muscle tone and the microcirculation, participate in the
maintenance of arterial blood pressure, increase gastric secretion, alter connective tissue response to injury, impede
cartilage production, inhibit inflammatory, allergic, and immune responses, invoke shrinkage of lymphatic tissue,
reduce the number of circulating lymphocytes, and affect the functions of the central nervous system. Some exert
varying degrees of mineralocorticoid activity. In humans the most important ones are cortisol, cortisone, and
corticosterone.” Dorland’s at 789.
5
Tacrolimus is “a macrolide immunosuppressant of the calcineurin inhibitor group, derived from Streptomyces
tsukubasensis and having actions similar to those of cyclosporine.” Dorland’s at 1868. Cyclosporine “acts by
inhibiting activation of helper T lymphocytes.” Id. at 456.
6
CellCept is “trademark for preparations of mycophenolate mofetil.” Dorland’s at 325. Mycophenolate mofetil is
“an immunosuppressive agent used in conjunction with cyclosporine and corticosteroids. . . .” Id. at 1216.
7
Norvasc is “trademark for a preparation of amlodipine besylate.” Dorland’s at 1291. Amlodipine besylate is “a
4
twice daily. About that time, Norvasc was reduced and Cozaar8 started. Med. recs. Ex. 19, at 2.
On July 28, 2008, when J.M. was seven years old, he went to Willow Bend Pediatrics.
Med. recs. Ex. 1, at 45. Dr. Frank noted that J.M. was well, and J.M. received his second
Varivax vaccination. His nephrotic syndrome was accompanied by persistent hypertension. Id.
The second Varivax vaccination did not trigger a relapse of J.M.’s nephrotic syndrome.
On November 19, 2008, J.M. received flu vaccine. Med. recs. Ex. 1, at 3. No reaction
was recorded. His flu vaccination did not trigger a relapse of his nephrotic syndrome.
On March 4, 2009, J.M. saw Dr. Seikaly who noted that J.M. had stayed well and did not
have any swelling episodes and no complaints of headaches or dizziness. Med. recs. Ex. 16, at
12.
On June 15, 2009, Dr. Seikaly’s nurse practitioner Becky Nolde-Hurlbert noted J.M. had
proteinuria since June 10, 2009, swelling in his face and abdomen, and elevated blood
pressure. J.M. did not report any illness that could have triggered this first relapse of his
disease later characterized as recurrent nephrotic syndrome. Med. recs. Ex. 1, at 24-26, 36. J.M.
had not been ill to trigger this relapse although he did have some allergy issues. Med. recs. Ex.
16, at 14.
On June 22, 2009, J.M.’s parents phoned Willow Bend Pediatrics to report that a week
earlier, J.M. had a relapse of nephrotic syndrome and was back on high-dose steroids. Med. recs.
Ex. 1, at 1.
By June 29, 2009, J.M. was in remission while taking another course of prednisone. On
August 26, 2009, Dr. Seikaly noted that since J.M.’s last visit in March 2009, J.M. had not done
well because he had a relapse in June, requiring steroid therapy. At the August 26, 2009 visit,
J.M. was weaning off prednisone 25 mg every second day. He was also on Cozaar 25 mg daily.
His urine protein was 1+. Med. recs. Ex. 10, at 77. J.M. was again weaned off prednisone by
September 7, 2009. Med. recs. Ex. 16, at 14-16.
On August 17, 2009, J.M. went to Willow Bend Pediatrics for a physical examination.
Med. recs. Ex. 1, at 34. He was noted to have had a relapse of nephrotic syndrome two months
previously (June 2009). Id.
On August 26, 2009, J.M. saw Dr. Seikaly, who noted that since J.M.’s last visit in March
2009, he had not done well as he had a relapse in June 2009 which required steroid therapy. Id.
at 32. J.M.’s last relapse was in February 2008. (This is the only mention in the medical records
of a relapse in February 2008.) Id. Dr. Seikaly’s plan was for J.M. to wean off steroids. Id. at
25. He recommended checking J.M.’s urine for protein with illnesses to detect relapses early. If
calcium channel blocking agent used in the treatment of hypertension . . . .” Id. at 63.
8
Cozaar is “trademark for a preparation of losartan potassium.” Dorland’s at 427. Losartan potassium is “an
angiotensin II receptor antagonist, used as an antihypertensive. . . .” Id. at 1075.
5
proteinuria or edema returned, J.M.’s parents were to call the nephrology clinic. Id. He
discussed J.M.’s receiving H1N1 and seasonal flu vaccines. Id. at 25-26.
Postvaccination Records
On October 1, 2009, at 4:00 p.m., J.M. received flu vaccine. Med. recs. Ex. 1, at 2 (a
notation by J.M.’s pediatrician that he received “influenza (whole)”); Ex. 16, at 23. Entered on
August 26, 2009 was a notation from Dr. Seikaly that J.M. has an unspecified disorder of
immune mechanism. Med. recs. Ex. 16, at 22. This appears on the encounter date of October 1,
2009. Id.
On October 9, 2009, J.M. saw Dr. Seikaly, who noted J.M. had done well since his last
visit in August 2009 until the past two weeks when he had an increase in his urine protein and
developed edema. Med. recs. Ex. 10, at 72. The onset of J.M.’s increase in urine protein and
development of edema would therefore have begun before his October 1, 2009 flu vaccination.
However, petitioner’s affidavit states that, prior to his October 1, 2009 flu vaccination, J.M.’s
protein was negative for three weeks, but increased immediately and was markedly higher the
morning after his flu vaccination. Ex. 5, at 1-1, § 3. J.M. had nearly completed a steroid taper (5
mg orally every 48 hours) from his relapse in June 2009. J.M. reported vomiting several times
on October 13, 2009. He was hungry but unable to tolerate fluid or food. He did not have fever
and had normal stools. Med. recs. Ex. 2, at 3.
On October 10, 2009, J.M.’s mother telephoned Willow Bend Pediatrics to ask if J.M.
could receive flu shots since he was going on steroids. Med. recs. Ex. 1, at 4. The reply was that
the flu shot was okay, but not Flu Mist. J.M.’s mother agreed. Id.
On November 4, 2009, J.M.’s urine protein stayed mildly elevated. He was again
prescribed prednisone and weaned slowly. Id. at 9-10. When J.M. was weaned to 10 mg of
prednisone every 48 hours in December 2009, J.M. had his third relapse. Id. at 12; Med. recs.
Ex. 16, at 38. J.M. had his fourth relapse in March 2010. Med. recs. Ex. 7, at 1. He was weaned
off steroids by April 20, 2010. Med. recs. Ex. 4, at 5.
On February 24, 2010, RN Nolde-Hurlbert noted it was difficult to determine the exact
cause of J.M.’s relapse October 2009, but “anything that affects the immune system [ ] could be
a contributing factor. No cause and effect relationship [between flu vaccine and nephrotic
syndrome relapse] has been directly documented in the literature [;] there is only speculation.”
Med. recs. Ex. 16, at 42. Nurse Nolde-Hurlbert further noted, “In a child with Nephrotic
Syndrome it is difficult to determine the exact cause of a relapse[.] Causes include but [are] not
limited to: Spontaneous [ ] modulation of the immune system including infection. While the
timing of the relapse is close to vaccine administration[,] no cause and effect relationship can be
linked.” Id. at 43.
On May 9, 2010, J.M. had his fifth relapse. Med. recs. Ex. 4, at 7.
6
On May 13, 2010, J.M. saw his second pediatric nephrologist, Dr. Albert Quan. Med.
recs. Ex. 1, at 5. He recounts the history that J.M. had an initial onset of nephrotic syndrome in
September 2007 when he was six years old. Id. He was given prednisone and went into
remission. In June 2009, J.M. had his first relapse, was treated with prednisone again, and was
weaned off prednisone in September 2009. In October 2009, J.M. had another relapse after flu
vaccination. He was put back on prednisone and his urine protein became negative, but he was
not weaned off until April 20, 2010. Id. His course was remarkable for persistent proteinuria
and a prolonged course of prednisone. Id. J.M. was still on Cozaar. Id.
Although, on June 18, 2010, Dr. Quan recorded that J.M.’s first episode of nephrotic
syndrome promptly responded to prednisone, J.M. actually did not respond for about six weeks.
Id. at 4; see Med. recs. Ex. 2, at 33, 35. A renal biopsy did not show evidence of focal segmental
glomerulosclerosis (“FSGS”). J.M. had one globally sclerosed glomerulus9 out of a total of 25
glomeruli. Ultrastructural studies showed thin glomerular basement membranes. Med. recs. Ex.
4, at 35-36.
On June 25, 2010, Dr. Quan prescribed Prograf10 for J.M. Med. recs. Ex. 3, at 2.
On January 26, 2011, Dr. Quan recorded that J.M. had not experienced proteinuria or
edema since his office visit October 15, 2010. Id. Dr. Quan discussed the side effects of
Prograf, including hypertension, tremors, and renal injury. Id. at 3. The plan was to wean J.M.
off Prograf in the summer of 2011. Id. J.M.’s remission lasted 11 months while on Prograf. Ex.
5, at 2. Petitioner requested J.M.’s Prograf be discontinued to see how J.M. would respond
because of petitioner’s concern over the long-term effects of Prograf. Id. at 2-3.
By June 28, 2011, Dr. Quan noted J.M. had felt well since his last office visit and did not
have any relapses. The plan was to stop Prograf in five days after weaning J.M.’s dosage. Id. at
16-17. J.M.’s Prograf was stopped. Dr. Quan recorded in his notes that J.M. should update all of
his immunizations while he was off Prograf, stating J.M.’s October 2009 flu vaccination “may
have triggered the onset of his nephrotic relapse.” Med. recs. Ex. 12, at 74-81.
By the end of July, J.M.’s nephrotic syndrome relapsed and J.M. could not resume
prednisone because his nephrotic syndrome did not respond any more to prednisone.
On August 18, 2011, J.M. had a cardiovascular attack (“CVA”). He was not on Prograf.
Med. recs. Ex. 11. J.M. was admitted to Medical City Dallas Hospital. Id. at 73-80. J.M.
suffered three strokes resulting in complete paralysis on his left side. Med. recs. Ex. 10 at 82;
Ex. 5, at 3. He also had a syncopal episode while hospitalized, and was treated with anti-
epileptic medications. Id. at 48, 51-52. He received inpatient and rehabilitation services until
9
A renal glomerulus is “a globular tuft formed by capillaries in the kidney, the site of the filtration barrier between
the blood and the kidney; it projects into the expanded end of a renal tubule, and together with its surrounding
capsule (glomerular capsule) it constitutes a renal corpuscle.” Dorland’s at 787. “Sclerosed” means “hardened.”
Id. at 1680.
10
Prograf is “trademark for preparations of tacrolimus . . . .” Dorland’s at 1523. See n.4 supra for “tacrolimus.”
7
September 23, 2011. Id. at 47-53.
J.M. continued to see Dr. Quan, as well as doctors specializing in neurology and
hematology. In September 2011, Dr. Quan noted that J.M.’s CVA was secondary to his
nephrotic relapse in July 2011. Med. recs. Ex. 14, at 1. J.M. continued weekly physical,
occupational, and speech therapy. Id. at 4-9, 15-17. His hematologist noted in October 2011
that J.M. had made a remarkable recovery post-stroke, and recommended anticoagulation
therapy for six months. Med. recs. Ex. 9, at 39-40. J.M.’s neurologist noted in October 2011
that J.M. could communicate verbally with normal speech and ambulate independently, but had
residual left-sided weakness and concerns about mental processing speed. He had improving but
residual left hemiparesis. J.M. continued on anti-epileptics. Med. recs. Ex. 9, at 5-6.
As of March 2012, J.M.’s neurologist recorded that J.M. was off steroids and continued
taking antiepileptic medicine. Id. at 1-4. Dr. Quan noted that J.M. was receiving Prograf which
would help prevent future strokes. Med. recs. Ex. 14, at 19. Based on a neuropsychological
evaluation performed in June 2012, J.M. has cognitive deficits secondary to his CVAs. Med.
recs. Ex. 13, at 16-24.
On October 20, 2015, J.M. saw Dr. Kazi Majeed, a pediatric neurologist. Med. recs. Ex.
63, at 36. He was last seen in 2012. J.M. had residual spastic hemiparesis. J.M. had a right
cerebral infarct in August 2011. Tiny infarcts were also see in his left hemisphere. Testing for
hypercoagulability showed factor V Leiden mutation.11
Expert Reports
Dr. Albert H. Quan
Dr. Albert H. Quan, J.M.’s second treating nephrologist, submitted his first expert report
dated June 30, 2012. Ex. 7, at 1. In it, he gives a short summary of his medical qualifications
(petitioner did not file Dr. Quan’s C.V.). He has been board-certified in pediatric nephrology
since 1993. He is licensed to practice in Texas. He was Associate Professor of Pediatrics at the
University of Texas Southwestern Medical Center from 1993 to 2006. At the time of this letter,
he was the Medical Director of Pediatric Nephrology and Pediatric Renal Transplantation at
Medical City Children’s Hospital and the Medical Director of Pediatric Dialysis at Home Kidney
Care. Id. He became J.M.s’ treating nephrologist in May 2010. He states he reviewed J.M.’s
medical records and medical literature regarding nephrotic syndrome and vaccinations. Before
he became J.M.’s pediatric nephrologist, J.M. was a patient of Children’s Medical Center under
Dr. Seikaly’s care. Id.
Dr. Quan was under the mistaken impression that J.M. had received H1N1 flu vaccine
instead of the trivalent seasonal flu vaccine. Id. (Petitioner filed a new report to replace this
11
Factor V Leiden thrombophilia is an inherited disorder of blood clotting, i.e., an increased tendency to form
abnormal blood clots that can block blood vessels. https://ghr nlm nih.gov/condition/factor-v-leiden-thrombophilia
(last visited April 4, 2018).
8
report on April 4, 2013 as Ex. 20, minus Dr. Quan’s initial reference to H1N1 flu vaccine.) On
June 10, 2008, Dr. Quan did a kidney biopsy on J.M. which showed that J.M.’s nephrotic
syndrome was due to minimal change12 nephrotic syndrome (“MCNS”). Id. Dr. Quan explains
nephrotic syndrome as a kidney disease that occurs when large amounts of protein are lost
through urine (proteinuria), resulting in low blood protein levels (low serum albumin). Id. at 1-2.
Low serum albumin causes edema or swelling throughout the body. Id. at 2. Dr. Quan says that
the most common cause of nephrotic syndrome in children is MCNS. Id. While the exact
mechanism is unknown, “loss of urinary protein in MCNS is thought to be due to immune
system mediated injury to the kidney, which then results in massive losses of serum protein into
the urine with resulting low serum albumin levels.” Id. Dr. Quan supports this statement by
noting: (1) nephrotic relapse usually occurs during or after a viral illness when immune system
activity is markedly increased; (2) remission of nephrotic syndrome occurs with medicine that
suppresses the immune system; (3) infusion of T-cell (a type of immune cell) proteins from
patients with MCNS into normal mice induces nephrotic syndrome in them; (4) high levels of T-
cell protein, interleukin 13, when infused into rats causes massive proteinuria; and (5) nephrotic
syndrome can go into spontaneous remission during measles infection which is known to depress
cell-mediated (T-cell) immunity. Id. Dr. Quan states that these observations taken together
strongly support a role of the immune system in the development of nephrotic syndrome. Id.
Dr. Quan notes that, as early as the 1990s, case reports of nephrotic syndrome occurring
after vaccinations were published. Id. Since vaccinations stimulate the immune system, Dr.
Quan says it is plausible that such stimulation can lead to immune injury in the kidney followed
by nephrotic relapses. Id. He notes in these reports that the time interval between various
vaccinations and onset of nephrotic syndrome was consistent with an immune-system-mediated
type of reaction, mentioning onsets of two weeks and six weeks post-vaccination. Id. (Both
these intervals are far longer than the less than one day interval between J.M.’s vaccination and
the increase in protein in his urine.)
Dr. Quan also notes that in all nephrotic syndrome cases, use of prednisone (which is the
drug of choice for MCNS) was successful in treating the patients. Id. He admits that the risk of
nephrotic relapses after vaccinations, while very plausible, remains somewhat controversial. Id.
He states that very likely more study patients will be necessary to have the statistical power to
detect an increased risk of relapses after vaccination. Id.
To Dr. Quan, J.M.’s relapse of nephrotic syndrome “virtually immediately” after his flu
vaccination “strongly indicates a causal and temporal relationship” between vaccination and
relapse. Id. Before his flu vaccination on October 1, 2009, J.M. was clearly in remission for
about two months. He did not have a preceding viral illness and neither did his family. Id. Dr.
Quan states the most likely triggering event for J.M.’s nephrotic relapse in October 2009 was the
12
Minimal change disease is “subtle alterations in kidney function demonstrable by clinical albuminuria and the
presence of lipid droplets in cells of the proximal tubules; abnormalities of foot processes of the glomerular
epithelial cells are present but too subtle to be seen with light microscopy. It is seen primarily in children under age
6 but sometimes in adults with the nephrotic syndrome, and it may or may not progress to glomerulosclerosis or
glomerulonephritis.” Dorland’s at 539.
9
preceding flu vaccination, where vaccine-induced immune stimulation led to immune injury to
the kidney, followed by nephrotic syndrome. Id. at 3. He holds his opinion to a reasonable and
substantial medical probability. Id. (Petitioner filed the same report as Ex. 18, titling it as an
updated report, with no statement of a relapse in February 2008.)
Dr. Quan submitted his second expert report dated March 22, 2013. Ex. 21. He states
that a majority of patients with nephrotic syndrome have one to two or more relapses per year
and the frequency of such relapses decreases over time. Id. at 1. In more severe cases, patients
develop steroid dependent nephrotic syndrome which results in a relapse when the patient stops
taking steroids. In the most severe cases, patients develop steroid-resistant nephrotic syndrome
where even high-dose steroids fail to treat the nephrotic syndrome. Id. Then more powerful
immunosuppressive drugs such as Prograf, Ciclosporine, Cytoxan, or CellCept are used. Id.
Dr. Quan states that J.M.’s initial course was very favorable. Id. at 2. After he ceased
taking steroids on January 28, 2008, his remission lasted over 18 months until his first relapse on
June 10, 2009. Id. Steroid therapy for J.M.’s relapse was again successful and ceased on
September 13, 2009. His infrequent relapse rate and excellent response to steroids strongly
indicated his subsequent course would be uncomplicated with few relapses, if any. Id. After
J.M.’s relapse, however, he developed steroid-dependent nephrotic syndrome which became
steroid-resistant nephrotic syndrome, necessitating his taking Prograf for a year. Id. In August
2011, J.M. had another relapse of his nephrotic syndrome, followed by three cerebrovascular
strokes, which Dr. Quan terms “a severe complication.” Id. Dr. Quan does not explain how the
2011 relapse caused the three cerebrovascular strokes.
Dr. Quan states J.M.’s October 2009 relapse was diagnosed on the fourth day after he
received flu vaccine. Id. He does not mention that J.M.’s onset was either the morning of the
late afternoon vaccination on October 1, 2009, when he was five pounds heavier than on
September 30, 2009, or that J.M.’s protein in his urine was detected on October 2, 2009 within
16 hours of his flu vaccination. What Dr. Quan does mention in his report is that case reports
describing intervals between immunization and onset of nephrotic relapse show an onset as short
as five days to as long as six weeks or more. Id. He does not mention that J.M.’s onset is too
short to fit within the parameters in the case reports petitioner filed with Dr. Quan’s report.
Dr. Quan goes on to describe a theory of how prior vaccinations can alter the immune
system so that a subsequent vaccination can induce a relapse of nephrotic syndrome, citing the
Islek13 letter to the editor (which was also a reference in Dr. Quan’s first report). In Islek, a four-
year-old boy received hepatitis B vaccine on May 12, 1998, June 12, 1998, and November 12,
1998. He had nephrotic syndrome eight days after his third hepatitis B vaccination. Hepatitis B
vaccine was identical in all three doses and those doses were administered one month apart
between the first and second vaccinations, and five months apart between the second and third
vaccinations. Dr. Quan uses Islek to buttress his opinion that J.M.’s prior flu vaccination on
November 18, 2008, although it did not induce a nephrotic relapse, “likely further boosted his
13
Nephrotic syndrome following hepatitis B vaccination by I. Islek, et al., 14 PEDIATR NEPHROL 89-90 (2004),
describing a four-year-old boy whose eyelids swelled eight days after his third hepatitis B vaccination.
10
immunity and contributed to his vaccine induced relapse, similar to the hepatitis B induced
relapse.” Id. (Dr. Quan states it was November 18, 2008, but the informed consent form is
signed November 19, 2008, Ex. 1, at 3, although there is a notation in a doctor’s record for
December 18, 2008 that flu vaccine was administered that day. Id. at 1).
However, there are discrepancies between the Islek letter to the editor and J.M.’s case.
First, there is a gap of one year between J.M.’s 2008 and 2009 flu vaccinations unlike the
intervals of months between hepatitis B vaccinations the child in the Islek letter to the editor
received. Secondly, the contents of the 2008 and 2009 flu vaccines J.M. received were not
identical, unlike the three hepatitis B vaccines the Islek child received. According to the Centers
for Disease Control, the 2009-2010 flu vaccine contained a B/Brisbane/60/2008-like virus the
2008-2009 flu vaccine did not.14 Therefore, Dr. Quan’s attempt to link conceptually the
experience of the Islek child with three successive, identical hepatitis B vaccinations
administered months apart to J.M.’s receipt of two differing flu vaccines one year apart fails to
prove his point that the effect of the prior 2008 flu vaccination was to boost J.M.’s immunity
after the 2009 flu vaccination. Dr. Quan’s statement that J.M. had “heightened immunity”
because of the prior 2008 flu vaccination is not tenable based on the Islek letter to the editor. Id.
at 3.
Since petitioner did not file Dr. Quan’s C.V., there is no way to check his publications.
However, at the hearing, respondent’s counsel asked Dr. Quan if he ever published an article on
minimal change nephrotic syndrome. Dr. Quan responded that he had not.
Dr. Bernard S. Kaplan
On June 18, 2013, Dr. Bernard S. Kaplan, respondent’s expert pediatric nephrologist,
wrote his expert report. Resp’t’s Ex. A. Dr. Kaplan was the Chief of Pediatric Nephrology at
The Children’s Hospital of Philadelphia (“CHOP”) until he resigned in 2010. Id. at 1. He
continues to work in the Division of Nephrology three days a week, seeing new and old patients.
He is also Professor of Pediatrics and Medicine at The Perelman School of Medicine at the
University of Pennsylvania. He is board-certified in pediatrics and in pediatric nephrology. He
had been practicing pediatric nephrology for 35 years. He has studied and published papers and
chapters on nephrotic syndrome and co-edited a textbook in which nephrotic syndrome and
immunization of children with renal disease is discussed extensively. Dr. Kaplan has taught
these subjects to medical students, interns, residents, and renal fellows at CHOP. Id.
14
Respondent’s Exhibit T shows that the November 19, 2008 trivalent flu vaccine J.M. received contained
A/Brisbane/59/2007 (H1N1)-like virus; A/Brisbane/10/2007 (H3N2)-like virus; and B/Florida/4/2006-like virus (Med.
recs. Ex. 1, at 3). Exhibit T shows that the October 1, 2009 trivalent flu vaccine J.M. received contained
A/Brisbane/59/2007 (H1N1)-like virus; A/Brisbane/10/2007 (H3N2)-like virus; but the third component differed from
the third component of the 2008 trivalent flu vaccine, containing B/Brisbane/60/2008-like virus (Med. recs. Ex. 16,
at 23). Exhibit T also shows the components of the trivalent flu vaccines J.M. received on November 20, 2006. The
flu vaccine contained A/New Caledonia/20/99 (H1N1)-like virus; A/Wisconsin/67/2005 (H3N2)-like virus; and
B/Malaysia/2506/2004-like virus (Med. recs. Ex. 12, at 3). Petitioner testified that J.M. did not receive flu vaccine
in 2004 because he had had a fever within 24 hours of the proposed vaccination and the nurse cancelled the
vaccination.
11
In summarizing J.M.’s medical records, Dr. Kaplan noted J.M.’s onset of nephrotic
syndrome in September 2007, his first relapse in June 2009, his second relapse in October 2009,
his third relapse in December 2009, his fourth relapse in March 2010, his fifth relapse in May
2010, and his sixth relapse in June 2011, followed by a cerebrovascular accident (“CVA”) on
August 18, 2011 while in relapse and off Prograf. Id. at 1-3. Dr. Kaplan notes that J.M. had
idiopathic nephrotic syndrome as evidenced by edema, pleural effusions, proteinuria, and
hypoalbuminemia at the age of six in September 2007. Id. at 3. He comments that this first
episode resulted in acute renal failure with serum creatinine concentrations of 0.8 to 1.6 mg/dl.
J.M.’s kidney function was initially below normal which Dr. Kaplan said is quite unusual for
steroid-sensitive nephrotic syndrome at this state because the glomerular filtration rate is usually
above normal. In addition, Dr. Kaplan states, not only did acute renal failure complicate J.M.’s
initial course of nephrotic syndrome, but also J.M.’s first remission of nephrotic syndrome took
longer than usual to achieve. This caused so much concern to Dr. Seikaly, J.M.’s first pediatric
nephrologist, that he discussed using other agents to help induce a remission. Id. Dr. Kaplan
notes that J.M. required anti-hypertensive therapy from the beginning which is also unusual for a
patient with typical steroid-sensitive nephrotic syndrome. Id. To Dr. Kaplan, the factors of
acute renal failure, prolonged period to achieve remission, and hypertension suggest that J.M.’s
subsequent course of nephrotic syndrome might not be favorable. Id. at 4. Dr. Kaplan states this
unfavorable course was borne out by J.M.’s subsequent relapses and his becoming less steroid
sensitive. In addition, J.M. stayed in remission for almost a year on Prograf, but relapsed after
discontinuing Prograf. A kidney biopsy did not show any evidence of immune deposits that
might suggest J.M. had C1q nephropathy15 or IgM nephropathy.16 A CVA further complicated
J.M.’s course, but he has not progressed to end-stage renal failure. Id.
Dr. Kaplan then defines idiopathic nephrotic syndrome, which is also called steroid-
sensitive nephrotic syndrome or minimal change nephrotic syndrome. Id. The condition’s
characteristics are clinical and laboratory features of nephrotic syndrome, normal renal histology
on light microscopy, no immunofluorescent deposits, and effacement of foot processes on
electron microscopy. Nephrotic syndrome is almost always steroid sensitive, but in some cases
may become resistant to steroids and thus require a calcineurin inhibitor or cyclophosphamide to
induce and maintain a remission. About 30 percent of patients relapse after stopping calcineurin
inhibitor and some have difficulty achieving subsequent remission with corticosteroids. Id. Dr.
Kaplan states that predicting with any certainty a patient’s long-term course with steroid-
sensitive nephrotic syndrome is impossible. Constantinescu and his co-authors note that more
15
C1q nephropathy is “a type of immune complex glomerulonephritis with deposits of complement component C1q;
signs and symptoms are similar to those of minimal change disease or mild focal segmental glomerulosclerosis.”
Dorland’s at 1242.
16
IgM nephropathy is mesangial proliferative glomerulonephritis. Dorland’s at 1242. Mesangial proliferative
glomerulonephritis is “glomerulonephritis characterized by diffuse glomerular proliferation of mesangial and
endocapillary cells and mesangial matrix, seen in patients with nephrotic syndrome; IgM deposits and complement 3
are often found in the mesangium.” Id. at 786. The mesangium is “the thin membrane that helps support the
capillary loops in a renal glomerulus.” Id. at 1138. The renal glomerulus is “a globular tuft formed by capillaries in
the kidney, the site of the filtration barrier between the blood and the kidney; it projects into the expanded end of a
renal tubule, and together with its surrounding capsule . . . constitutes a renal corpuscle.” Id. at 787.
12
than half of children with nephrotic syndrome have relapses which may be infrequent or
frequent. Dr. Kaplan notes that J.M. took a long time to respond to prednisone after his
diagnosis with nephrotic syndrome and also subsequently developed late steroid resistance. Id.
He states that immunosuppressive treatment is a viable option in nephrotic syndrome patients
who develop late steroid resistance. Id. at 5.
Dr. Kaplan states the etiology of idiopathic nephrotic syndrome is unknown. Medical
literature does not report an association between relapse of idiopathic nephrotic syndrome and
flu vaccine. Id. He states that scientific evidence does not exist to prove inactivated flu vaccine
or any other vaccine causes or precipitates nephrotic syndrome or a relapse of nephrotic
syndrome. He disputes the literature that Dr. Quan cites in his report. The Fernandes case report
of an increase in proteinuria in an adult with steroid-resistant nephrotic syndrome due to focal
segmental glomerulosclerosis differs from J.M.’s case because the Fernandes adult had
preexisting proteinuria for six months, and it is unclear whether the H1N1 vaccine induced the
increase. Id. Dr. Kaplan notes the Kimata case report of a five-year-old boy with idiopathic
nephrotic syndrome who attained remission without steroid treatment in response to influenza B
infection (not vaccination). Id. at 6. To Dr. Kaplan, the Kimata case report shows that any
presumed association between flu vaccination and relapse of nephrotic syndrome is likely
coincidental since the opposite (i.e., remission in the context of flu infection) may occur.
Dr. Kaplan states no evidence supports the assertion that flu vaccine alters the course of
nephrotic syndrome, making it less sensitive to steroid therapy or subject to more frequent
relapses or complications such as intravascular thrombi. He mentions the Zhu case control study
showing flu vaccine was associated with a reduced risk of thrombotic embolism. Id. He
discusses the Araya article which explores whether cytokines played a role in idiopathic minimal
lesion nephrotic syndrome and concluded that evidence was lacking. Id. at 7. The theory was
that T-cells increased glomerular permeability, but that was unproven. Then the theory was that
activated T-cells released a circulating factor that caused idiopathic minimal lesion nephrotic
syndrome and that resulted in no definitive conclusion. Thus, the pathogenetic cytokine has not
been identified and there is doubt whether there is Th2 dominance in the disease. Id.
Dr. Kaplan states more recent studies question the mechanism for steroid induction of
remission in idiopathic nephrotic syndrome. Id. Traditionally, the action of steroids was
assumed to induce remission in idiopathic nephrotic syndrome by immune suppression.
However, new studies by Clement show little is known about the mechanisms of steroids.
Greenbaum and his co-authors state that evidence now indicates nephrotic syndrome results from
podocyte17 dysfunction. The use of conventional immunosuppressive agents (such as
glucocorticoids and cyclosporine) which directly affect podocyte structure and function
challenges the immune theory of T-cell-caused childhood nephrotic syndrome. Id.
17
A podocyte is “a modified epithelial cell of the visceral layer of the glomerular capsule in the renal glomerulus; it
has a small perikaryon and a number of primary and secondary footlike radiating processes (pedicels) that
interdigitate with those of other podocytes and embrace the walls of glomerular capillaries.” Dorland’s at 1477.
The perikaryon is “the cell body as distinguished from the nucleus and the processes. . . .” Id. at 1413.
13
Dr. Kaplan thinks the case reports on which Dr. Quan relies to support causation from
vaccinations base their conclusions on pure coincidence. Id. at 8. Dr. Kaplan notes that J.M.’s
pre-vaccination course was not uncomplicated. He initially had acute renal injury which is an
uncommon occurrence in steroid-sensitive nephrotic syndrome. J.M.’s response to prednisone
took a long time in his initial episode of nephrotic syndrome. He had a relapse before his
October 1, 2009 flu vaccination. In addition, Dr. Seikaly treated him for hypertension. Dr.
Seikaly was also concerned that J.M. might relapse once Dr. Seikaly tapered his prednisone. Dr.
Seikaly’s concerns were realized and contrast with Dr. Quan’s statement in his report that J.M.’s
subsequent course would be uncomplicated with few relapses if any. Id. Dr. Kaplan did not
dispute that nephrotic syndrome often occurs in association with a viral illness, but he disputed
that flu vaccine was a viral illness because it is an inactivated virus, i.e., a killed flu virus. He
agrees that immunosuppressive agents do induce remissions but finds no connection to the idea
that killed virus induces a relapse. Id.
Dr. Kaplan states the timing of relapses in idiopathic nephrotic syndrome is chaotic and
unpredictable, occurring at any time with or without an antecedent viral infection. Id. He also
states there is no scientific or published evidence supporting the view that a prior flu vaccination
primes a recipient who has idiopathic nephrotic syndrome to have a relapse after a subsequent flu
vaccination. Id. at 9. Thus, there is no evidence that J.M.’s 2008 flu vaccination together with
his 2009 flu vaccination altered the course of his nephrotic syndrome. Lastly, Dr. Kaplan states
there is no evidence that flu vaccine leads to CVA. Id.
Dr. Kaplan’s C.V. shows, in addition to his professional responsibilities detailed in his
expert report, that he was on the editorial board of Pediatric Nephrology from 1992-2012, and is
a reviewer of the following journals: the Journal of the American Society of Nephrology, the
Journal of Infectious Diseases, Mayo Clinic Proceedings, American Journal of Medical Genetics,
American Journal of Kidney Diseases, Critical Care Medicine, Journal of Pediatrics, Clinical
Pediatrics, Nephron (A Journal of Nephrology), New England Journal of Medicine, Pediatric
Nephrology, Pediatric Emergency Care, Pediatrics, Developmental Pharmacology, Kidney
International, the European Journal of Pediatrics, and Clinical Genetics. Ex. B, at 3. He has
written 143 original papers as primary author or co-author. Id. at 6-15. He has written 92
chapters and reviews as primary author or co-author. Id. at 16-21. The topics of these papers,
chapters, and reviews include nephrotic syndrome and minimal change nephrotic syndrome.
Dr. Arnold I. Levinson
Dr. Arnold I. Levinson, respondent’s expert immunologist, submitted his first expert
report dated October 28, 2013. Ex. D. He is board-certified in internal medicine and allergy and
clinical immunology. Ex. D, at 1. Dr. Levinson states that bilateral pleural effusions 18 and
ascites19 complicated J.M.’s initial clinical course. Id. Dr. Levinson objects to Dr. Quan’s
opinion that flu vaccine caused J.M.’s October 2009 relapse because Dr. Quan did not explain
18
Bilateral pleural effusions means “the presence of fluid in the pleural spaces” in both lungs. Dorland’s at 596.
19
Ascites is “effusion and accumulation of serous fluid in the abdominal cavity.” Dorland’s at 163. Serous fluid is
“normal lymph of a serous cavity.” Id. at 720.
14
how flu vaccine immunologically stimulated injury to J.M.’s kidneys, resulting in nephrosis. Id.
at 5. Dr. Levinson does not accept the results of animal studies in humans with idiopathic
minimal change nephrotic syndrome. Id. He states there is no credible evidence that any viral
vaccination leads to a systemic immune response in test animals or in humans leading to a
minimal change nephrotic syndrome-like disease. Id. at 5-6. He takes issue with Dr. Quan’s
equating the immune effect of three successive hepatitis B vaccinations with yearly flu
vaccinations which “are changed year to year in anticipation of new viral epitopes that will be
introduced into the community in each successive year.” Id. at 6. With hepatitis B vaccinations,
“each of the three vaccines contains the same viral proteins.” Id. Thus, each successive hepatitis
B vaccination provides a sequential boost to the recipient’s immune response to hepatitis B virus.
In contrast, there is “no a priori reason to expect increasing immune responses” to each
successive year’s flu vaccination. Id. Dr. Levinson concludes that J.M.’s October 1, 2009 flu
vaccination neither caused nor significantly aggravated J.M’s minimal change nephrotic
syndrome, which relapsed on several occasions after its onset. Id. He also does not believe that
J.M.’s flu vaccination on October 1, 2009 caused or significantly aggravated J.M.’s relapse in
late July 2011.
Dr. Levinson’s C.V. shows he is Emeritus Professor of Medicine and Neurology at the
Perelman School of Medicine at The University of Pennsylvania School of Medicine. Ex. E, at
2. He used to be Chief of the Allergy and Immunology Section, Director of the Fellowship
Training Program in Allergy and Immunology, and Director of the Center for Clinical
Immunology. He currently serves as Associate Dean for Research. Id. at 1-2. He was author or
co-author of 11 articles and 42 editorials, chapters, and invited journal reviews. Id. at 9-20.
Dr. Joseph A. Bellanti
Dr. Joseph A. Bellanti, petitioner’s expert immunologist, submitted his first expert report
dated June 3, 2014. Ex. 25, at 1. He agrees with Dr. Quan that nephrotic relapse often occurs
after events such as viral illnesses and, more rarely, vaccinations. Id. at 2. He states every
relapse of an immune-mediated condition like nephrotic syndrome can cause additional injury
and lead to a course of illness that is more steroid-dependent and constantly relapsing. Id. at 3.
Dr. Bellanti considers J.M.’s third, fourth, and fifth relapses as continuations of his
second relapse. His opinion is that the October 1, 2009 flu vaccine probably triggered J.M.’s
sudden relapse of nephrotic syndrome. He finds it unsurprising that, having received two prior
flu vaccinations (in 2006 and 2008), J.M.’s reaction to his 2009 flu vaccination was rapid. Dr.
Bellanti’s basis for his lack of surprise about the rapid onset on J.M.’s nephrotic syndrome is that
J.M. had an anamnestic response to similar antigens due to prior priming or sensitizing J.M.’s
memory cells. Id. Dr. Bellanti agrees with respondent’s expert Dr. Kaplan that flu vaccine is not
equivalent to a viral illness, but Dr. Bellanti writes flu vaccine is designed to present viral
antigens to the immune system in a way similar enough to infection to cause the immune system
to develop protective antibodies and T-memory cells as if the body confronted an infection. Dr.
Bellanti states that it is generally understood that if an infection can trigger an immune-mediated
condition, then vaccinations against those infections probably also can initiate a similar response
15
although far less frequently. Id. Dr. Bellanti says that the longer J.M. was in a state of disease
instead of remission, the greater the likelihood of his developing thromboembolic complications.
Id. Thus, his opinion is that flu vaccine triggered J.M.’s relapse, resulting in his subsequent
strokes, and significant aggravation of his condition. He notes that receipt of prednisone and
Prograf are also associated adversely with strokes. Id.
Dr. Bellanti’s C.V. (Ex. 32) shows he is Director of the International Center for
Interdisciplinary Studies of Immunology at Georgetown University and Professor of Pediatrics
and Microbiology-Immunology School of Medicine at the same institution. Ex. 32, at 1. He lists
269 articles dating from 1961 to 2013 (Ex. 32, at 12-29), 200 abstracts dating from 1962 to 2008
(id. at 29-42), and 59 books or chapters in books dating from 1971 to 2012 (id. at 43-46).
Of his 269 articles from 1961 to 2013, Dr. Bellanti was co-author on just four articles
having anything to do with the kidney, and only one of those four concerned minimal change
nephrotic syndrome, which was published in 1981, i.e., 37 years ago.20
Of his 200 abstracts from 1962 to 2008, only one abstract concerned the kidney.21
Of his 59 books or chapters in books from 1971 to 2012, none concerns the kidneys
(although some of the books have very general titles without specifying chapter content).
Dr. Kaplan’s supplemental report
On July 17, 2014, Dr. Kaplan wrote a supplemental expert report in response to Dr.
Bellanti’s expert report. Ex. G. He comments that although Dr. Bellanti did not find a reference
for a 1+ urine protein for J.M. on August 26, 2009, it is in Exhibit 10, at 3. Id. at 1. This would
be 35 days before J.M. received flu vaccine on October 1, 2009. Dr. Kaplan contests Dr.
Bellanti’s statement that every relapse of an immune-mediated condition can cause additional
injury. Id. at 2. Dr. Kaplan states that there is no evidence that every relapse of nephrotic
syndrome can cause additional injury or result in more steroid dependency or become constantly
relapsing. Moreover, there is no evidence that J.M.’s third, fourth, and fifth relapses were the
20
Dr. Bellanti was third co-author of one article on acute kidney disease associated with prior streptococcal
infection, resulting in reduction of serum hemolytic complement: Acute glomerulonephritis associated with normal
serum ß1C-globulin, by L.U. Tina, et al., 115 AM J DIS CHILD 1:29-36 (1968). He was fourth co-author of an article
about abnormal microtubular structures in glomeruli and elevated serum-antibody levels in human diseases such as
systemic lupus erythematosus and experimental viral infections: Glomerular microtubules of systemic lupus
erythematosus, by T. Pincus, et al., 296 LANCET 7682:1058-61 (1970). He was fourth co-author of an article on
minimal change nephrotic syndrome and immunological parameters: Studies of immunological parameters in
minimal change nephrotic syndrome, L.U. Tina, et al., 46 ANN ALLERGY 1:34-36 (1981). He was sixth co-author of
a two-part article on ataxia telangiectasia which can result in renal failure: Ataxia telangiectasia: immunologically
mediated renal and hepatic failure, 55 ANN ALLERGY 4:539-40, 593-98 (1985). He was fourth co-author of an
article on lack of graft rejection in a renal transplant AIDS patient: Lack of graft rejection in a renal transplant
recipient with AIDS, J.E. Gootenberg, et al., 67 ANN ALLERGY 2:123-25 (1991).
21
Dr. Theodore Pincus and Dr. Bellanti presented Anti-DNA antibodies and virus-like structures in the renal disease
of systemic lupus erythematosus to the SOCIETY FOR PEDIATRIC RESEARCH, Atlantic City NJ, in May 1970. This
was subsequently published in 4 PED RESEARCH 435 (1970).
16
result of the flu vaccination he received on October 1, 2009. Dr. Kaplan states these multiple
relapses were from the disease process itself. Dr. Bellanti’s idea that these relapses were really a
continuation of J.M.’s second relapse makes no sense to Dr. Kaplan. Id.
Dr. Kaplan disagrees with Dr. Bellanti’s opinion that J.M.’s immune system mounted a
misdirected response to the vaccination that triggered a relapse of his nephrotic syndrome. Id. at
2-3. Dr. Kaplan calls this pure conjecture without any supporting evidence. He further
disagrees with Dr. Bellanti that the longer J.M. was ill rather than in remission, the more likely
he was to have thromboembolic complications. Id. at 3. Dr. Kaplan states the majority of
nephrotic syndrome cases manifest thrombosis during the first flare or within six months after
onset of the disease. Id. Contrary to Dr. Bellanti’s statement, prednisone is no longer considered
a predisposing factor in the development of thrombosis in nephrotic syndrome and there is no
evidence showing Prograf causes cerebral thrombosis. Id. He agrees with Dr. Bellanti that any
alleged relationship between flu vaccine and relapse of nephrotic syndrome is speculative and
unproven. Id.
Dr. Levinson’s supplemental report
On August 12, 2014, respondent’s expert immunologist wrote a supplemental report in
response to petitioner’s expert immunologist Dr. Bellanti. Ex. J. Dr. Levinson states that a
“major pillar” of Dr. Bellanti’s opinion is that since a wild virus can cause an autoimmune
disease, a viral vaccine can cause the same autoimmune disease. Id. at 1-2. The example upon
which Dr. Bellanti relies is measles virus both in the wild and in the vaccine, but Dr. Levinson
disputes the validity of this comparison, which Dr. Bellanti later admitted was a poor one. Id. at
2. First, measles vaccine contains live measles virus whereas flu vaccine is a killed virus
vaccine. Id. Therefore, it is impossible that live influenza virus infected any of J.M.’s body
tissues as could measles virus. Moreover, there is no evidence that flu virus infects any part of
the kidney, which is the target of tissue injury in minimal change nephrotic syndrome. Id.
Measles virus, on the other hand, can infect neurons and other cells within the brains of patients
who develop encephalitis. In addition, medical articles do not show that any wild flu virus
components share molecular motifs that the kidney expresses. Id. Dr. Bellanti posits J.M. had a
misdirected response, but Dr. Levinson says Dr. Bellanti did not show a misdirected response
occurred or resulted in J.M.’s relapse of nephrotic syndrome. Id. at 2-3.
Secondly, Dr. Bellanti attributes a less than 24-hour development of relapse of nephrotic
syndrome after J.M. received flu vaccine on October 1, 2009 to an anamnestic response, but Dr.
Levinson asks to what did an anamnestic immune response respond. Id. at 3. Dr. Levinson
states Dr. Bellanti’s arguments lack substance. Id.
Dr. Bellanti’s supplemental report
Dr. Bellanti submitted his supplemental report dated October 10, 2014. Ex. 28. He
reviewed the reports respondent’s experts Dr. Kaplan and Dr. Levinson wrote. Dr. Bellanti
agrees with respondent’s experts that Dr. Bellanti’s explication in his initial written opinion of a
17
causative relationship between measles virus and encephalitis and between measles vaccine and
encephalitis was not (as Dr. Bellanti put it) “an ideal choice for an example” because measles
vaccine is an attenuated viral vaccine, whereas flu vaccine (the vaccine in J.M.’s case) is a killed
virus vaccine. Id. at 1. But Dr. Bellanti still adheres to the belief that the known effects of
natural disease are relevant in evaluating what a vaccine can theoretically cause. Id. He cites the
Institute of Medicine (“IOM”) publication, ADVERSE EVENTS ASSOCIATED WITH CHILDHOOD
VACCINES: EVIDENCE BEARING ON CAUSALITY 28 (K.R. Stratton, et al., eds., National Academy
Press 1994), for the same point. Id. at 2.
Dr. Bellanti then uses what he describes as a better example than measles virus and
measles vaccine for the principle that, since viruses cause disease, viral vaccines can cause the
same disease: influenza and upper respiratory infections can cause or trigger Guillain-Barré
syndrome (“GBS”); therefore, flu vaccine can also cause GBS. Id. Dr. Bellanti states he agrees
with Dr. Kaplan that a viral illness such as influenza can trigger nephrotic syndrome (“and
logically can also trigger a relapse of nephrotic syndrome.”). Id. He ties J.M.’s third, fourth, and
fifth relapses to his second relapse on the basis that weaning J.M. off steroids became impossible
after the second relapse. Id. at 3. Dr. Bellanti identifies the timing of J.M.’s second relapse as
the day after his flu vaccination on October 1, 2009. Id. Dr. Bellanti states he suspects that the
immune-mediated reaction involved both the innate and adaptive immune systems. Id.
Dr. Quan’s supplemental report
On January 2, 2015, Dr. Quan wrote a supplemental expert report in response to
respondent’s expert nephrologist Dr. Bernard Kaplan. Ex. 40. Dr. Quan begins by giving a
timeline of events. For October 1, 2009, he states that J.M. received flu vaccine and, four to five
days later, he experienced his second nephrotic relapse. Id. at 1. (This is not accurate.) After
resuming prednisone, J.M. was put on Prograf until mid-June 2011. By August 2011, J.M. had
his third nephrotic relapse. Id. After J.M.’s CVA, he restarted prednisone and Prograf and went
into remission two weeks later. Id. at 2. Dr. Quan states that J.M. remains in remission on both
medications. Id. Dr. Quan relates J.M.’s steroid dependence, third nephrotic relapse and CVA
to his flu vaccination. Id.
Dr. Quan disagrees with Dr. Kaplan’s opinion that J.M. had third, fourth, fifth, and sixth
relapses. Dr. Quan’s opinion is that J.M. never truly went into remission after his 2009 flu
vaccination. Id. He also disagrees with Dr. Kaplan that an elevation in serum creatinine from
0.8 to 1.6 mg/dl was indicative of acute renal failure. Id. Dr. Quan attributes J.M.’s elevation of
creatinine to mild dehydration due to a concurrent viral illness and lower blood volume due to
low blood albumin level. Id. Dr. Quan opines that 10 percent or more of children can take up to
six to eight weeks of prednisone before going into remission, as J.M. did. J.M.’s disease was
steroid sensitive and, thus, Dr. Quan concludes that J.M.’s early disease course did not indicate
poor outcome. Id.
Finally, Dr. Quan reviews Dr. Kaplan’s statement that current thinking on the
pathogenesis of minimal change nephrotic syndrome may have changed and now focuses on
18
non-immune etiologies. Id. Dr. Quan admits that some new studies do indeed indicate other
possible mechanisms leading to nephrotic syndrome, particularly involving the podocyte, a cell
central to the glomerular basement membrane, which is the filter of the kidney. He gives an
example of high levels of a podocyte-secreted protein (ANGPTL4) within the podocyte (versus
in circulation) can lead to nephrotic syndrome, citing Jiang. (Petitioner filed the Jiang article as
Exhibit 49. It is mostly in Mandarin with an abstract in English.)
Dr. Quan says many studies continue to implicate a role for the immune system in the
development of nephrotic syndrome, e.g., elevation of lymphokine interleukin-13 in CD-4 and
CD-8 T-cells during a nephrotic relapse and reduction of interleukin after prednisone therapy. In
an animal study, researchers induced loss of urinary protein in mice by injecting CD 34+ T-cells
into them, which Dr. Quan finds consistent with a role for immature immune cells in the
development of nephrotic syndrome.
Dr. Quan concludes his supplemental report by asking:
So, where does the truth about the cause of minimal change
nephrotic syndrome lie? Does the immune system play a major
role or can this role be relegated to other causes? The actual truth
may lie in the fact that nephrotic syndrome may have different
underlying causes in different patients. Newer mechanisms of
nephrotic syndrome, therefore[,] do not preclude an important role
for the immune system in many patients. However, such
differences in the underlying causes to the nephrotic syndrome
may explain why a “one size fits all” conventional treatment
regimen is not effective in all patients.
Id. at 3.
Dr. Quan concludes that J.M. was in the low-risk category of minimal change nephrotic
syndrome before his 2009 flu vaccination which abruptly and severely altered his nephrotic
syndrome. Id. at 3-4. He attributes J.M.’s CVA to hypercoagulability (increased risk of
development of blood clots), which is a well-known complication of nephrotic syndrome. Id. at
4. He states that hypercoagulability results in urinary loss of clotting proteins which leads to a
risk of inappropriate formation of blood clots. He also states it is biologically plausible that a
vaccine adverse event can cause a more severe nephrotic syndrome leading to a CVA. Id.
Dr. Quan quotes from Dr. Bellanti’s expert report that “’if a viral infection [such as
influenzae] can trigger an immune mediated condition [such as nephrotic syndrome], then the
vaccine [influenza immunization] for those infections are [sic] probably also capable of initiating
a similar deleterious response [nephrotic syndrome].’” Id.
Dr. Kaplan’s supplemental report
19
On September 21, 2015, Dr. Kaplan wrote a supplemental report in response to Dr.
Bellanti’s October 10, 2014 expert report and Dr. Quan’s January 2, 2015 expert report. Ex. L.
Dr. Kaplan states “there is absolutely no evidence that influenza or influenza vaccine induce[s]
nephrotic syndrome.” Id. at 1. He quotes Dr. Bellanti’s statement that any alleged relationship
between flu vaccine and relapse of nephrotic syndrome is “speculative and unproved.” Id. Dr.
Bellanti also wrote that the definition of a medical theory is that it is speculative and unproved.
Id.
Dr. Kaplan finds it inconceivable that flu vaccine caused J.M.’s episode of venous
thrombosis several years later, as Dr. Quan suggests in his report. Id. Dr. Kaplan notes that
although J.M.’s nephrotic syndrome course changed after flu vaccination on October 1, 2009,
J.M. did subsequently enter full remission. Id. at 4. Dr. Kaplan states there is no evidence that
flu vaccine altered J.M.’s course as this pattern occurs in patients who were previously sensitive
to steroid treatment. Id. Dr. Kaplan disagrees with Dr. Quan’s assertion that J.M. did not have
acute renal failure during his initial presentation of nephrotic syndrome. He calls Dr. Quan’s
attention to the KDQUO Guidelines on Acute Renal Injury,22 pointing out that even mild,
reversible acute kidney injury (“AKI”) has important clinical consequences including increased
risk of death. Id. Contrary to Dr. Quan’s opinion, Dr. Kaplan notes that the medical records
prove that J.M.’s elevation in serum creatinine from 0.8 to 1.6 mg/dl constitutes acute renal
failure. J.M. took longer than usual to achieve his first remission (which occurred before the flu
vaccination at issue). Id.
Dr. Kaplan notes that J.M.’s time to respond to prednisone differed from 90 percent of
patients with nephrotic syndrome. Id. According to the Siegel23 article, if someone does not
relapse within three years of onset of nephrotic syndrome, his prognosis is good. But J.M. had
two relapses within three years of his initial episode. Therefore, complete resolution was
unlikely. Even after 15 years post-onset, 20 percent of relapsing patients continue to have
relapses, according to Siegel. Id.
Dr. Kaplan cites the conclusion of the Kim24 article that a higher incidence of initial and
subsequent steroid resistance in minimal change nephrotic syndrome suggests the syndrome may
not be as benign as earlier studies indicate. Id. Dr. Kaplan adds that J.M. was at increased risk
for relapses because early indicators in his course showed his prognosis might be poorer. Id. at
4-5. Dr. Kaplan clarifies his statement denying a medical literature association of flu vaccine
and idiopathic nephrotic syndrome by stating no report in the world literature describes an
association between minimal change nephrotic syndrome and flu vaccine in children. Id. at 5.
Dr. Kaplan states the problem with describing a supposed pathogenesis of minimal change
nephrotic syndrome is that it involves speculation. No pathogenetic evidence or epidemiological
22
Kidney Disease: Improving Global Outcomes (KDIGO), Acute Kidney Injury Work Group. KDIGO Clinical
Practice Guideline for Acute Kidney Injury, 2 KIDNEY INTER SUPP 1-138 (2012). Ex. Q.
23
Long-term follow-up of children with steroid-responsive nephrotic syndrome, by N.J. Siegel, et al., 81 J PEDIATR
2:251-58 (1972). Ex. R.
24
High incidence of initial and late steroid resistance in childhood nephrotic syndrome, by J.S. Kim, et al., 68
KIDNEY INTER 1275-81 (2005). Ex. S.
20
support links flu vaccine to relapses of minimal change nephrotic syndrome, subsequent steroid
resistance, or venous thrombosis. Id. Dr. Kaplan emphasizes Dr. Quan’s admission that the
truth about the cause of minimal change nephrotic syndrome is unknown, by quoting Dr. Quan’s
statement in Exhibit 40, at 3, that “nephrotic syndrome may have different underlying causes in
different patients.” Id.
Dr. Kaplan concludes that before J.M. received flu vaccine on October 1, 2009, he had
acute renal failure, responded late to steroid therapy, and had two relapses (the first on June 10,
2009, the second around the time of the October 1, 2009 flu vaccination) within three years of
the onset of his minimal change nephrotic syndrome on September 6, 2007, putting J.M. in a
high-risk category. Id. After his second nephrotic relapse, J.M.’s clinical course was “abruptly
and severely altered.” Id. After J.M.’s second relapse, he became steroid-dependent and
remained on steroids continuously for eight months until June 20, 2010 when he went on Prograf
to which he responded. Id. But, Dr. Kaplan says evidence is lacking that flu vaccine either
caused this second relapse or altered the course of J.M.’s minimal change nephrotic syndrome.
Id. He cites the Kim article stating, “An important new finding in our study was the surprisingly
high number of patients who developed late steroid resistance during subsequent relapses despite
being initially steroid responsive.” Id. at 5-6.
Dr. Kaplan continues in his conclusion that when in June 2011, J.M. was weaned off
Prograf, he had his third nephrotic relapse, followed two months later in August 2011 by his
cerebrovascular accident. Id. at 6. Dr. Kaplan attributes the cause of J.M.’s CVA to
hypercoagulability (increased risk of development of blood clots due to urinary loss of clotting
proteins), which is a well-known complication of nephrotic syndrome. Dr. Kaplan states there is
absolutely no plausible link between J.M.’s second relapse and the thrombosis following his last
relapse. Id.
Articles
Among the medical articles petitioner filed to which Dr. Quan referred in his initial
expert report (Ex. # 7) was a Letter to the Editor entitled Nephrotic syndrome following hepatitis
B vaccination, by I. Islek, et al., 14 PEDIATR NEPHROL 89-90 (2004), describing a four-year-old
boy whose eyelids swelled eight days after his third hepatitis B vaccination. Id. Although the
authors admit that causal relationship between minimal change nephrotic syndrome and hepatitis
B vaccine is not easily established and the development of minimal change nephrotic syndrome
after hepatitis B vaccination might be coincidental in this case, the timing of minimal change
nephrotic syndrome after hepatitis B vaccination in this case strongly favored an immune-
mediated side effect of vaccination. Id. This eight-day interval between vaccination and
swelling contrasts with J.M.’s onset of increased protein within 16 hours of his October 1, 2009
flu vaccination and with the onset of edema the same day as his October 1, 2009 flu vaccination.
Another of petitioner’s filings was one of Dr. Quan’s references in his initial expert
report (Ex. # 7), a case report entitled Minimal change nephrotic syndrome in an 82 year old
patient following a tetanus-diphtheria-poliomyelitis-vaccination, by C. Clajus, et al., 10 BMC
21
NEPHROL 21-25 (2009). (Respondent also filed this as Ex. C, Tab 4.) The onset interval between
Td/polio (REVAXIS) vaccination and edema was four weeks. Id. at 22. The authors state that
the clinical findings and course of minimal change nephrotic syndrome in this 82-year-old
female patient were typical for the disease. Id. at 23. The authors recount other articles in which
a vaccine recipient had minimal change nephrotic syndrome. A woman suffered the syndrome
10 days after smallpox vaccination. Id. They report a woman who had minimal change
nephrotic syndrome four months after pneumococcal vaccination. Id. They report a woman who
had minimal change nephrotic syndrome four days after flu vaccination. Id. They report a three-
year-old boy who had minimal change nephrotic syndrome 17 days after hepatitis B vaccination.
Id. They report a four-year-old boy who had minimal change nephrotic syndrome eight days
after hepatitis B vaccination. These intervals contrast markedly with J.M.’s increased protein
within 16 hours of flu vaccination. The authors note the variety of time intervals in these case
reports, stating:
The time until the onset of symptoms varies in all described cases
from days to months, which could be explained by the different
time it took for the respective vaccine to trigger an immune
response. Nephrotic syndrome occurred after the second
administration of the vaccine which suggests that the last
administration has boosted a pre-existing immune response from
the first vaccination.
Id. at 24.
Another of petitioner’s filings of Dr. Quan’s references in his initial expert report (Ex. #
7) and in his supplemental expert report (Ex. # 40) as Exhibit 45 was a case report including one
of a man who developed Guillain-Barré syndrome (“GBS”) and nephrotic syndrome, the former
within two weeks of flu vaccination, and the latter within three weeks of flu vaccination. Dr.
Bellanti also referred to this case report as Exhibit 31 in his supplementary report (Ex. # 28).
Respondent’s expert Dr. Kaplan referred to this case report as Exhibit, Tab 5, in his expert
report: Guillain-Barré syndrome coexisting with pericarditis or nephrotic syndrome after
influenza vaccination, by C-D Kao, et al., 106 CLIN NEUROL NEUROSURG 136-38 (2004). The
authors emphasized the three-week onset of nephrotic syndrome after flu vaccination as creating
suspicion of a causal relationship. Id. at 137. This three-week interval contrasts with J.M.’s
onset of increased protein within one-half day of vaccination.
One of Dr. Quan’s references in his second expert report (Ex. # 21) was a case report
involving a 61-year-old woman who received haemophilus influenzae type B (“HiB”),
diphtheria-tetanus toxoid (“Dt”), and PPV 23 (pneumococcal or Pneumovax) vaccinations one
year after having a stem-cell transplant for acute myelogenous leukemia. She had progressive
weight gain, edema and fatigue five days after immunization. Fourteen days after immunization,
she had anasarca25 and was discovered to have acute renal failure and nephrotic proteinuria:
Minimal-change nephrotic syndrome in a hematopoietic stem-cell transplant recipient, by B.D.
25
Anasarca is “generalized massive edema.” Dorland’s at 75.
22
Humphreys, et al., 2 NATURE CLIN PRACTICE NEPHROL 9:535-39 (2006). The undersigned notes
that this woman’s edema preceded her proteinuria. The woman in the case report was diagnosed
with minimal change disease (“MCD”). Id. at 536. The authors list immunization as one of the
causes of MCD. Id. at 538. They note that case reports have linked MCD to influenza,
pneumococcal, and hepatitis B vaccines. Id. at 537. They associate the woman’s MCD to “an
allergic reaction to vaccination.” Id. They say, “We speculate that vaccination itself triggered
the hypersensitivity reaction.” Id. The authors found significant to their speculation the five-day
onset between the woman’s three vaccinations and her MCD. Id. Since the woman was a
recovering cancer patient, the authors “propose that simultaneous immunization with three
different vaccines might have resulted in hyperstimulation of the recovering immune system,
leading to dysregulated T-lymphocyte activation and, subsequently, MCD.” Id. However, the
authors also say, “we cannot rule out the possibility that the association between vaccination and
MCD is co-incidental, because all HSCT [hematopoietic stem-cell transplant] recipients receive
immunizations after successful engraftment and, to our knowledge, no other case of MCD has
been reported in this context.” Id. at 538. This 14-day interval until the patient had proteinuria
contrasts with J.M.’s 16-hour interval after vaccination.
Petitioner filed as Exhibit 27, an article entitled Cerebral sinovenous thrombosis and
idiopathic nephrotic syndrome in childhood: report of four new cases and review of the
literature, by J. Fluss, et al., 165 EUR J PEDIATR 709-16 (2006). The authors state nephrotic
syndrome is a common renal disorder in children characterized by severe proteinuria,
hypoalbuminemia, and edema. Id. at 709. Most childhood nephrotic syndrome is attributable to
minimal change glomerulopathy. Id. Nephrotic syndrome is associated with a hypercoagulable
state and thrombosis in both children and adults. Id. The hypercoagulable state is due to urinary
loss of anticoagulants, increased platelet aggregability, and intravascular volume depletion. Id.
at 709-10. Thrombosis is either venous or, less commonly, arterial and may be more frequently
associated with steroid-resistant nephrotic syndrome. Id. at 710. The authors note that cerebral
sinovenous thrombosis is infrequent in nephrotic children, whereas renal vein thrombosis is the
common site of thrombosis. Id.
Petitioner filed as Exhibits 30 and 44 a Letter to the Editor to which Dr. Quan referred in
his supplemental report (Ex. # 40). Dr. Bellanti also referred to this Letter to the Editor as
Exhibit 30 in his supplementary report (Ex. # 28). Respondent also filed it as Exhibit N:
Minimal change disease following influenza vaccination and acute renal failure: just a
coincidence?, by S. Gutiérrez, et al., 32 NEFROLOGIA (MADR.) 3:414-15 (2012). A 44-year-old
man received flu vaccine and, 18 days later, had edema in his face and legs, and cervical
lymphadenopathy. Id. at 415. Renal biopsy showed severe acute tubular injury. Id. The authors
posit various theories of how minimal change disease occurs. Id. at 415. They conclude that the
immune response after flu vaccine generated MCD possibly due to hypersensitivity syndrome
while admitting the pathogenic bases are still controversial and debatable. Id. This 18-day
interval until the patient had edema and lymphadenopathy contrasts with J.M.’s 16-hour interval
after vaccination for proteinuria.
Petitioner filed as Exhibit 41 an article to which Dr. Quan referred in his supplemental
23
report (Ex. # 40): Volume regulation in children with early relapse of minimal-change nephrosis
with or without hypovolaemic symptoms, by J.G. Vande Walle, et al., 346 LANCET 148-52
(1995). The authors note three different presentations in early relapse of minimal change
nephrotic syndrome in children. The first presentation occurred in children who already showed
sodium retention before they manifested overt hypoproteinemia. Id. at 151. They already
showed sodium retention while renal plasma flow was high. This finding supported the idea that
an intrarenal defect is involved in sodium retention in minimal change nephrotic syndrome
children as well as in adults. Id. They opined that nephrotic edema cannot be explained solely
by hypovolemia.26 “In all cases, sodium retention has a primary renal component, and may
precede overt hypoproteinaemia.” Id.
Petitioner filed as Exhibit 42 a report from The International Study of Kidney Disease in
Children to which Dr. Quan referred in his supplemental report (Ex. # 40): The primary
nephrotic syndrome in children. Identification of patients with minimal change nephrotic
syndrome from initial response to prednisone, 98 J PED 4:561-64 (1981). The authors looked at
response or nonresponse during eight weeks of steroid treatment of minimal change nephrotic
syndrome. Id. at 564. Almost 94 percent of those who responded to steroid treatment had
already responded to steroid treatment by four weeks.
Petitioner filed as Exhibit 43 a case report to which Dr. Quan referred in his supplemental
report (Ex. # 40): Minimal change nephrotic syndrome in a 65-year-old patient following
influenza vaccination, by J.T. Kielstein, et al., 54 CLIN NEPHROLOGY 3:246-48 (2000). A 65-
year-old woman received flu vaccine on January 13, 1999. Six to eight hours later, she had a
cough, severe headaches and left-sided ear aches. Four days later, she had leg edema, weight
gain, and hypertension. Lab evaluation showed hypoproteinemia. Id. at 246. The authors
thought this case illustrated a potential way in which stimulation of the immune system may
relate to the manifestation of MCNS. Id. at 248. The four-day interval contrasts with J.M.’s 16-
hour interval after vaccination. Id.
Petitioner filed as Exhibit 46 a Letter to the Editor to which Dr. Quan referred in his
supplemental expert report (Ex. # 40). Dr. Bellanti also referred to this Letter to the Editor as
Exhibit 29 in his supplementary report (Ex. # 28). Respondent filed this as Ex. C, Tab 3, after
Dr. Kaplan’s expert report (Ex. C) and as Ex. M after Dr. Kaplan’s supplemental report (Ex. L):
Relapse of Nephrotic Syndrome Following the Use of 2009 Influenza A (H1N1) Vaccine, by P.
Fernandes, et al., 56 AMER J OF KIDNEY DIS 1:185-86 (2010). A 50 year-old woman with
steroid-resistant nephrotic syndrome received H1N1 vaccine and, one week later, had a relapse
of her nephrotic syndrome. Id. at 185. The authors regarded her relapse as an adverse reaction
to the H1N1 vaccine. Id. This one-week interval contrasts with J.M.’s 16-hour interval after
vaccination.
Petitioner filed as Exhibit 47 an article to which Dr. Quan referred in his supplemental
expert report (Ex. # 40): Podocyte secreted Angiopoietin-like 4 mediates proteinuria in
glucocorticoid sensitive nephrotic syndrome, by L.C. Clement, et al., 17 NAT MED 1:117-22
26
Hypovolemia is “abnormally decreased volume of circulating blood in the body. . . .” Dorland’s at 908.
24
(2011). The authors state the major manifestations of nephrotic syndrome include proteinuria,
hypoalbuminemia, edema, hyperlipidemia, and lipiduria. Id. at 117. Minimal change disease is
usually glucocorticoid sensitive. The authors state, “Despite recent identification of key
structural proteins in the glomerular capillary loop, many disease mechanisms in nephrotic
syndrome remain unresolved.” Id.
Petitioner filed as Exhibit 48 an article to which Dr. Quan referred in his supplemental
expert report (Ex. # 40): Th1 and Th2 Cytokine mRNA Profiles in Childhood Nephrotic
Syndrome: Evidence for Increased IL-13 mRNA Expression in Relapse, by H-K Yap, et al., 10 J
AM SOC NEPHROL 529-37 (1999). The authors state the “current understanding” (this article is
19 years old) of the pathogenesis of idiopathic nephrotic syndrome of childhood is probably due
to a primary immune disturbance. Id. at 529. They thought it conceivable that interleukin-13 is
an important regulatory cytokine that both CD4+ and CD8+ cells produce from patients with
nephrotic relapse. Id. at 536. Their laboratory was investigating the immunoregulatory actions
of interleukin-13 on monocytes from patients with relapse of nephrotic syndrome. Id.
Petitioner filed as Exhibit 49 an article to which Dr. Quan referred in his supplemental
expert report (Ex. # 40): Interleukin-13 expression before and after pulse treatment with
methylprednisolone in children with steroid-responsive nephrotic syndrome, by H-K Jiang, et al.,
9 CHIN J CONTEMP PEDIATR 6:533-36 (2007). Most of the article is in Mandarin, but the abstract
is in English. The authors conclude from testing serum concentration and mRNA expression of
interleukin-13 in children with steroid-responsive nephrotic syndrome that those levels
increased, but methylprednisolone pulse therapy could inhibit the expression of protein and
mRNA of interleukin-13 in those patients. Id. at 533.
Petitioner filed as Exhibit 50 an article to which Dr. Quan referred in his supplemental
expert report (Ex. # 40): A Humanized Mouse Model of Idiopathic Nephrotic Syndrome
Suggests a Pathogenic Role for Immature Cells, by A-L Sellier-Leclerc, et al., 18 J AM SOC
NEPHROL 2732-39 (2007). After experiments with mice, the authors conclude that “it is
tempting to propose that cells that are responsible for albuminuria are undifferentiated cells
undergoing differentiation into T cells.” Id. at 2736. They continue, “However, one cannot rule
out the hypothesis that immature cells of other lineages may be responsible for albuminuria.” Id.
Petitioner filed as Exhibit 51 an article to which Dr. Quan referred in his supplemental
expert report (Ex. # 40): Epidemiology and Risk Factors for Thromboembolic Complications of
Childhood Nephrotic Syndrome: A Midwest Pediatric Nephrology Consortium (MWPNC)
Study), by B.A. Kerlin, et al., 2009 J PEDIATR 1:105-10 (2009). The authors state that nephrotic
syndrome is most commonly idiopathic and that thromboembolism occurs in 1.8% to 5% of
children with idiopathic nephrotic syndrome. Id. at 105. The median age for diagnosis of
nephrotic syndrome was 6.5 years of age. Id. at 106. The authors state that relapsing necrotic
syndrome is common in childhood. Id. at 108. One of the most commonly identified risks of
thrombosis is Factor V Leiden. Id. at 109.
Petitioner filed as Exhibit 52 a case report on two children to which Dr. Quan referred in
25
his supplemental expert report (Ex. # 40): Case Reports. Cerebrovascular Complications in
Children with Nephrotic Syndrome, by M. Igarashi, et al., 4 PEDIATR NEUROL 6:362-65 (1988).
The authors state arterial thrombosis is much less common than venous thrombosis and has been
reported primarily in children. Id. at 365.
Petitioner filed as Exhibit 103 an article entitled Unraveling the immunopathogenesis of
glomerular disease, by B.L. Dickinson, 169 CLIN IMMUNOL 89-97 (2016). Dickinson states the
target of injury in glomerular disease is the filtration barrier, i.e., a structure composed of three
parts: (1) a fenestrated endothelium, (2) the glomerular basement membrane (“GBM”), and (3)
an epithelium comprised of unique epithelial cells called podocytes. Id. at 89-90. The
endothelium is the first barrier and is permeable to cytokines, chemokines, antibodies,
complement proteins, and other molecules. Id. at 90. The second layer, the GBM, prevents the
passage of molecules, large anionic proteins, and cells into the subepithelial space. Id. The third
layer is a single layer of podocytes, which are specialized polarized epithelial cells with slit
diaphragms located between interdigitating foot processes. Id.
Dickinson then discusses innate immunity, stating that macrophages and neutrophils are
the major effector cells of the innate immune system. Id. They detect pathogens and stimulate
the release of proteases and reactive oxygen species to clear an infection, but which also causes
collateral damage to tissues such as the glomerulus. Id. She notes that while macrophages are
present in most tissues and function as sentinels throughout the body where the sites are
vulnerable to infection, i.e., the skin and mucosal tissues of the respiratory, gastrointestinal, and
urogenital tracts, macrophages are excluded from the glomerulus in the steady state. Id.
Neutrophils are not normally found in healthy tissues but where there is inflammation, they
capture, engulf, and kill pathogens and then die by apoptosis. Id. In contrast to the rapid
response of the innate immune system, the adaptive immune response is much slower, evolving
over five to seven days. Id. at 91. T and B lymphocytes and their soluble mediators make up the
adaptive immune system. Id. Dickinson notes that early antibodies produced within weeks of
exposure to an antigen during a primary immune response have a lower affinity for antigen than
antibodies produced a month later, which exhibit a one-hundred fold increase in affinity. Id. at
93. She states that dendritic cells are innate immune cells and constitute the major antigen-
presenting cells of the immune system. Dendritic cells also play a role in glomerular disease.
She states glomerular disease is most often viewed as a manifestation of autoimmunity, the
development of which depends on dendritic cells activation of autoreactive T cells with
subsequent activation of autoreactive B lymphocytes. Id. In discussing alternatives to
corticosteroids for treating glomerular disease, she mentions monoclonal antibodies, such as
rituximab, which is specific for the B cell antigen CD20 and Belimumab, among other
monoclonal antibodies. Id. at 95. She opines that dendritic-cell-based vaccines may one day be
used to treat or prevent glomerular disease. Id.
Petitioner filed as Exhibit 104 an article entitled Childhood nephrotic syndrome--current
and future therapies, by L.A. Greenbaum, et al., 8 NAT REV NEPHROL 445-58 (2012).
(Respondent also filed this article as Ex. C, Tab 17.) The authors state that although edema and
proteinuria were clinical symptoms for more than 2,000 years, only in 1484 has nephrotic
26
syndrome been described and only named as such in 1929. Id. at 445. Before glucocorticoids or
antibiotics were available, 67 percent of children with nephrotic syndrome died. The mortality
rate dropped in 1939 with the advent of sulfonamides.27 The mortality rate dropped to 35
percent in 1944 following the use of penicillin. In the 1950s, the mortality rate fell to nine
percent after the introduction of adrenocorticotropic hormone (“ACTH”)28 and cortisone, which
caused a marked reduction in proteinuria in many patients. Id.
The authors state, “Although glucocorticoids have continued as the mainstay of therapy
for nephrotic syndrome for more than 50 years, neither the target cell nor the mechanism of
action of these agents in nephrotic syndrome has been clearly determined. Furthermore,
although the majority of treatments found to be effective in treating nephrotic syndrome have
been immunosuppressive, a minority have been thought to act by nonimmune mechanisms, and a
few actually through immunostimulation.” Id. The authors state that nephrotic syndrome is
“clearly not a single disease.” Id. They divide children with nephrotic syndrome into two
groups: (1) corticosteroid-resistant, and (2) corticosteroid-sensitive, but note that the specific
medications used for both groups are virtually identical. Id. They note that over the past decade
(i.e., between 2002 and 2012), extensive research “has highlighted the crucial importance of the
podocyte as a site of cellular injury in nephrotic syndrome.” Id. The authors review drugs that
have been traditionally used, but then switch to newer drugs, such as rituximab.29 Id. at 447.
They note that reports of rituximab inducing remission of nephrotic syndrome “have led to a re-
evaluation of the inter-relationship between nephrotic syndrome and the immune system.” Id. at
448. They continue:
Although most historical evidence has suggested involvement of T
cells, the effectiveness of rituximab in nephrotic syndrome implies
a potential role of B cells in the development of nephrotic
syndrome. However, the novel finding in 2011 that rituximab
binds directly to an acid sphingomyelinase-like phosphodiesterase
3b (SMPDL3B) on the surface of podocytes suggests an even more
direct mechanism of action for this drug in nephrotic syndrome.
Id. The authors mention the successful use of galactose30 in treating nephrotic syndrome in its
27
A sulfonamides is “an organic compound containing the –SO2NH2 group . . .; any of a class of drugs, the sulfa
drugs, which are derivatives of sulfanilamide, competitively inhibiting folic acid synthesis in microorganisms and
formerly bacteriostatic against gram-positive cocci (streptococci and pneumococci), gram-negative cocci
(meningococci and gonococci), gram-negative bacilli (Escherichia coli and shigellae), a wide variety of other
bacteria, and some protozoa. Because many strains of bacteria have developed resistance to sulfonamides,
particularly to agents used singly, they have largely been supplanted by more effect and less toxic antibiotics, and
when used are generally combined with another sulfonamide or other antimicrobial agent.” Dorland’s at 1802.
28
ACTH acts like corticotropin, “a 39-amino-acid anterior pituitary hormone, one of the derivatives of pro-
opiomelanocortin; it acts primarily on the adrenal cortex, stimulating its growth and the secretion of corticosteroids.”
Dorland’s at 422.
29
Rituximab is “a chimeric murine/human monoclonal antibody that binds the CD 20 antigen; used as an
antineoplastic in the treatment of CD20-positive, B-cell non-Hodgkin lymphoma . . . .” Dorland’s at 1650.
30
Galactose is “an aldohexose epimeric with glucose at the 4 carbon but less soluble and less sweet, occurring
naturally in both D- and L- forms (the latter in plants); it is a component of lactose and other oligosaccharides,
27
ability to alter glomerular permeability and decrease this permeability activity after IV
administration to patients. Id. at 449. They mention testing of adalimumab, a monoclonal anti-
tumor necrosis factor antibody, which has been associated with both remission and induction of
nephrotic syndrome. Id.
The authors discuss the use of thiazolidinediones, a drug approved to treat type 2 diabetes
mellitus, a therapeutic in nephrotic syndrome because it has beneficial effects on the kidneys. Id.
at 450. Thiazolidinediones reduce proteinuria, microalbuminuria, podocyte injury, vascular
injury, inflammation, and fibrosis in both diabetic and non-diabetic nephropathy. The success of
the treatment is thought to be through direct renal protective effects, partially because of the
direct action of thiazolidinediones on podocytes. Id. Among the known molecular effects of
thiazolidinediones is their ability to decrease the glomerular production of transforming growth
factor (“TGF”)-ß, which is a key mediator of renal injury. Id. The authors state, “Of potential
relevance to nephrotic syndrome, cultured podocytes treated with thiazolidinediones mimicked
some podocyte responses to glucocorticoids, or had additive effects with them.” Id. The authors
suggest that use of thiazolidinediones to treat nephrotic syndrome “might enable a reduction in
glucocorticoid exposure or improvement in their efficacy.” Id. at 451. They conclude:
In summary, thiazolidinediones slow the progression of glomerular
diseases, and have also been shown to directly protect podocytes.
Such findings suggest that thiazolidinediones might, therefore,
have considerable potential as a therapy for nephrotic syndrome,
even though the mechanisms of action are only partially
understood.
Id.
The authors note the increased p38 MAPK activation in biopsied podocytes from adults
with various forms of nephrotic syndrome. Id. Cell injury in podocytes involves both p38
MAPK and MK2. Id. Protein kinase C alpha (“PKCɑ”) loss has podocyte-protective effects in
mice. Id. PKCɑ seems to be a regulator of podocyte survival and proteinuria and might play an
important role in several glomerular diseases. Id. at 452. Inhibiting PKCɑ is a potential strategy
to protect podocytes in glomerular disease. Inhibiting PKCɑ, p38MAPK, and MK2 (all of which
affect the same signaling pathway at different levels) seems “an exciting potential strategy to
treat nephrotic syndrome in both children and adults” to the authors. Id.
The authors move on to Notch signaling which affects among other things a loss of
mature podocyte characteristics. “Indeed, the severity of glomerular injury has been suggested
to depend on Notch-regulated balance between podocyte death and regeneration provided by
progenitor cells.” Id. They state Notch signaling seems to play a key role during nephrogenesis
but is mostly silent afterwards. Reactivation of Notch signaling in podocytes is associated with
renal injury. They see an opportunity to treat nephrotic syndrome by inhibiting the Notch
pathway in mature podoctyes, thus treating the podocyte injury associated with nephrotic
cerebrosides and gangliosides, and various glycolipids and glycoproteins.” Dorland’s at 754.
28
syndrome. One method is use of ƴ-secretase-mediated cleavage of the Notch receptor. Id.
The authors discuss inhibiting cytokines, although “no single cytokine has been shown to
have a direct causative role in nephrotic syndrome. . . .” Id. at 453. Interleukin (“IL”)-13 can be
a target for inhibition as a potential effective therapy. An IL-13 antibody (lebrikizumab) is
effective to treat asthma and might be effective in nephrotic syndrome. Id. The authors move on
to a discussion of a cellular stress response called stress-induced disturbance of protein folding in
the endoplasmic reticulum, called the unfolded protein response (“UPR”) which they say has a
pathogenic role in some forms of nephrotic syndrome. Id. They then focus on oxidative stress,
which is involved with nephrotic syndrome and other kidney diseases. Id. at 454. Developing
improved or targeted strategies to reduce podocyte oxidative stress would be appropriate to
attenuate podocyte injury in nephrotic syndrome. They note dietary supplementation with the
antioxidants probucol31 and Vitamin E in children with nephrotic syndrome has provided modest
evidence supporting this approach. Id. The authors conclude:
For more than 50 years, glucocorticoids have been the mainstay of
therapy for children with nephrotic syndrome. Despite this, neither
their target cell nor the mechanism of action in nephrotic syndrome
is clearly known. . . . [Because of the partial effectiveness of these
drugs and their marked adverse effects,] new therapies to treat
nephrotic syndrome are urgently required. Several currently
available drugs developed for other purposes are now being
employed in the treatment of nephrotic syndrome, and have the
potential to become standard therapies in the future. In addition,
the recognition of the crucial role of podocyte injury in nephrotic
syndrome has led to many new studies that have identified several
important molecular pathways that are able to regulate podocyte
injury. Development of drugs able to regulate these pathways
offers hope for the availability of targeted and effective treatments
for nephrotic syndrome in the future.
Id.
Petitioner filed as Exhibit 105 a case report entitled Membranous Nephropathy and
Severe Acute Kidney Injury Following Influenza Vaccination by C. Patel and H.H. Shah, 26
SAUDI J KIDNEY DIS TRANSPL 6:1289-93 (2015). A 60-year-old woman received the 2009 H1N1
flu vaccine and two weeks later went to the emergency room with fever, intermittent nausea and
vomiting, and lower extremity edema. Id. at 1290. She said that onset was “soon after being
immunized.” Id. She had seen her PCP one day before her ER visit because of worsening
bilateral lower extremity edema. She was given furosemide and metolazone for edema,
amlodipine and clonidine for hypertension, and prednisone for her membranous nephropathy and
acute kidney injury. Id. at 1291. She achieved complete remission after one relapse. Id. at
31
Probucol is “an anticholesteremic, used especially as an adjunct to diet for the reduction of elevated serum
cholesterol in primary cholesterolemia. . . .” Dorland’s at 1516.
29
1292. The authors thought that the woman’s abrupt onset of nephrotic syndrome suggested the
flu vaccine activated her immune system. It was unclear to the authors why their patient
relapsed. She responded well to the second round of corticosteroids. Id. They suggest further
studies to investigate the exact pathogenesis of flu vaccine-induced membraneous nephropathy.
Id. at 1293.
Petitioner filed as Exhibit 106 a case report entitled Can influenza H1N1 vaccination lead
to the membranous glomerulonephritis?, by A. Kutlucan et al., 55 INDIAN J PATHOL MICROBIOL
2:239-41 (2012). The authors describe the case of a 56-year-old man who received monovalent
influenza A (H1N1) vaccine and developed a flu-like illness diagnosed as membranous
glomerulonephritis (“MGN”) 23 days after vaccination. Id. at 239. The patient was put on
prednisolone, acetylsalicylic acid, atorvastatin, and lysinopryl. Treatment lasted three months
and ended. Id. The authors note that studies show the immunogenic response to H1N1 vaccine
develops on the 23rd day after vaccination. Id. at 240. The authors found significant that the
“emergence of the [MGN] illness and development of [the] immunogenic effect of the [H1N1]
vaccine” on the 23rd day post-vaccination was simultaneous. Id. The authors state the precise
reason for the MGN and renal involvement following H1N1 vaccination was unclear, but thought
it possible that a disposition to autoimmune renal disease might cause MGN. Id.
Petitioner filed as Exhibit 107 a case report: Serious Adverse Reactions Associated with
Over-the-counter Drugs, 293 PHARMACEUTICALS & MED DEVICES 16-17 (August 2012).32 A
boy under the age of 10 received flu HA (hemagglutinin) vaccine. The prior year, when he
received flu HA vaccine, he developed fever and swelling at the vaccination site. When he
received the current flu HA vaccine, eight hours after vaccination, his left axilla (armpit) swelled
and the vaccine site also swelled down to the elbow. He had swollen lymph nodes in the left
axilla and swelling on the left upper arm (vaccine site). One day after vaccination, he had fever
in the 38 degree range Celsius (100.4 degrees Fahrenheit). His left axilla swelling was less. Id.
at 16. Three days later vaccination, he had generalized swelling again and his weight increased.
Id. at 16-17. He also had an increase in his urine protein. Id. at 17. He was diagnosed with
nephrotic syndrome from which he recovered 21 days after vaccination. Id.
Exhibit C, Tabs 1-8, consist of the articles to which Dr. Kaplan referred in his expert
report (Ex. C). Exhibit C, Tab 1, is an article entitled Predicting First-Year Relapses in Children
With Nephrotic Syndrome, by A.R. Constantinescu, et al., 105 PEDIATRICS 3:492-95 (2000).
The authors intended to find what could predict the chance of relapse in children with idiopathic
nephrotic syndrome. Id. at 492. They found the earliest predictor of a relapsing course could be
the number of days it took the patient to enter remission after treating with prednisone. Id. at
494. Patients who took longer to respond tended to have frequent relapses or were steroid-
dependent. Id. A majority of patients will respond within the first three weeks after beginning
steroid therapy. Id.
Exhibit C, Tab 6, is a case report entitled Close association between proteinuria and
32
NEPHROTIC SYNDROME, www.pmdma.go.jp/english/safety/info-services/drugs/medical-safety-
information/0001.html (last visited April 12, 2018).
30
regulatory T cells in patients with idiopathic nephrotic syndrome, by T. Kimata, et al., 28
PEDIATR NEPHROL 667-69 (2013). The authors discuss whether or not circulating regulatory T
cells (“Tregs”) are increased or decreased when a child with idiopathic nephrotic syndrome is
exposed to a viral infection. The answer depended on the type of viral infection. Measles
infection suppresses T cells. Id. at 667. But the five-year-old child who was the subject of the
case report had influenza B virus which increased his regulatory T cells. Id. at 667, 669. Thus,
the authors considered the influenza B virus infection to have caused the child to have a
remission of nephrotic syndrome. Id. at 669. Previous reported exacerbations of nephrotic
syndrome were associated with influenza A virus, including pandemic H1N1 viral infection. Id.
Exhibit C, Tab 7, is an article entitled Association of influenza vaccination with reduced
risk of venous thromboembolism, by T. Zhu, et al., 102 THROMB HAEMOST 1259-64 (2009). The
authors discovered that flu vaccine can reduce the risk of venous thromboembolism. Id. at 1261.
They thought flu vaccination might lower the risk of thrombosis in some unknown ways other
than by preventing flu infection. Id. at 1262.
An article to which Dr. Kaplan refers in his supplemental expert report (Ex. G) is
Measles in the Nephrotic Syndrome, by A.H. Rosenblum, et al., 35 J PEDIATR 5:574-84 (1949).
The authors state, “The clinical picture of the nephrotic syndrome is studded with remissions and
exacerbations.” Id. Of seven cases of nephrotic syndrome in which the children contracted wild
measles virus, three showed marked and lasting improvement, three showed transient
improvement, and one showed no response. Id. at 584. The authors state that “in some cases of
the nephrotic syndrome a remission follows infection with measles.” Id.
Attached to Dr. Bellanti’s supplementary report (Ex. # 28) is a page (also marked as Ex.
#28) from the IOM’s ADVERSE EVENTS ASSOCIATED WITH CHILDHOOD VACCINES: EVIDENCE
BEARING ON CAUSALITY 28 (K.R. Stratton, et al., eds., National Academy Press 1994), including
the following under the heading “Biologic Plausibility:”
All of the vaccine-adverse event associations assessed in this
report have some biologic plausibility, at least on theoretical
grounds. That is, a knowledgeable person could postulate a
feasible mechanism by which the vaccine could cause the adverse
event. Actual demonstration of biologic plausibility, however, was
based on the known effects of the natural disease against which the
vaccine is given and the results of animal experiments and in vitro
studies. Only demonstrated biologic plausibility was considered
by the committee in reaching its causality judgments. [emphasis in
original].
Attached to Dr. Bellanti’s supplementary report (Ex. # 28) as Exhibit 35 is a case report
entitled Fulminant Cerebral Infarctions With Membranous Nephropathy, by S. Chaturvedi, 24
STROKE 3:473-75 (1993). The author states that nephrotic syndrome has been associated with
both venous and arterial thromboses. Id. at 473. He describes the case of a 37-year-old woman
31
who died from fulminant multifocal thromboses and whose autopsy showed left hemispheric and
right cerebellar infarction plus membranous nephropathy. Id. She had membranous
glomerulonephritis. Id. at 474. The author comments that “the reported cases of cerebral
infarction and nephrotic syndrome have lacked a unifying hematologic factor.” Id. at 475.
Attached to Dr. Bellanti’s supplementary report (Ex. # 28) as Exhibit 36 (and also filed as
Exhibit 39) is a case report entitled Cerebral Infarction in Patients With Nephrotic Syndrome, by
E.E. Marsh, et al., 22 STROKE 1:90-92 (1991). The authors describe two cases involving men
with nephrotic syndrome who had cerebral arterial strokes. Id. at 90. The authors attribute their
isolated cerebral arterial infarcts to a hypercoagulable state related to nephrotic syndrome. Id. at
92. They state the mechanism by which nephrotic syndrome causes a hypercoagulable state is
unclear. Id.
Attached to Dr. Bellanti’s supplementary report (Ex. # 28) as Exhibit 37 is a case report
entitled Cerebral Infarction as a Complication of Nephrotic Syndrome: A Case Report with a
Review of the Literature, by Y.W. Yun, et al., 19 J KOREAN MED SCI 2:315-19 (2004). The
authors focus on a 53-year-old man who had cerebral arterial infarction associated with focal
segmental glomerulosclerosis. Id. at 316.
Affidavits
On June 10, 2012, petitioner signed an affidavit. Ex. 5. Petitioner is a “trained
immunization pharmacist.” Id. at 1. He notes that J.M.’s urine is monitored daily each morning
using Multistix to test for proteins in his urine, which would indicate a relapse of his nephrotic
syndrome. Id. The day after J.M. received flu vaccine on October 1, 2009, his urine protein
levels were markedly higher. Id. at 2.
Calendars
Exhibit 15 consists of three months, August – October 2009, in which J.M.’s blood
pressure, whether he had protein in his urine, and weight are recorded. In the months of August
and September 2009, J.M. did not have any protein in his urine as none is noted. Id. at 1, 2. On
September 30, 2009, J.M. weighed 119 pounds. Id. at 2. On October 1, 2009, J.M. weighed 124
pounds, for a gain of five pounds in one day. Id. On October 2, 2009, the morning after
vaccination that occurred the afternoon of October 1, 2009, petitioner measured J.M.’s protein in
the morning (Ex. 17, at 1 [petitioner’s timeline]). J.M. had +3 in the Multistix testing for protein
in his urine. Med. recs. Ex. 15, at 3. Since the interval between the late afternoon vaccination
and the next morning when petitioner measured J.M.’s urine for protein is approximately 16
hours, J.M.’s rise in protein occurred within less than one day of flu vaccination. By October 29,
2009, J.M. weighed 147 pounds or 28 pounds more than he weighed on September 30, 2009. Id.
He had a reading of +2 in the Multistix testing for protein in his urine on October 31, 2009. Id.
VAERS Report
32
On January 17, 2012, petitioner completed a Vaccine Adverse Event Reporting System
(“VAERS”) form, stating that J.M. received flu vaccine at 2:30 p.m. on October 1, 2009 and had
an adverse event at 7:30 a.m. on October 2, 2009 when elevated protein levels in his urine were
detected. Ex. 16, at 1.
TESTIMONY
On October 17, 2017, the first day of the two-day hearing, petitioner testified first. Tr. at
4. Petitioner is a pharmacist. Id. He described J.M. as a well child with rare illnesses. Id. at 5.
In 2007, J.M. developed nephrotic syndrome for which he took enalapril33 but switched to
prednisone. Id. In addition, he took Norvasc or one of the other ACE inhibitors.34 Id. J.M.
went into remission and had zero proteinuria in the beginning of February 2008. Id. at 6.
Petitioner kept track of J.M.’s proteinuria with a dipstick with a Multistix. Id. He and his
wife checked J.M.’s proteinuria daily until four years before trial. Id. J.M. was negative on the
dipsticks from February 2008 until June 2009. Id. Early in 2009, the family had been on a
vacation and J.M. had a little bump in urine protein. Id. Through a phone consultation with the
nephrologist Dr. Seikaly’s office and through his nurse practitioner, they decided J.M. might
have a relapse. Id. at 7. The proteinuria went to zero within two weeks. After that, Dr. Seikaly
decided to use a prolonged protocol and J.M. used prednisone for an additional two months or
two and one-half months. Id.
They saw Dr. Seikaly in August 2009 and he felt the taper of prednisone was working.
Id. They spoke on August 14, 2009, and Dr. Seikaly mentioned J.M. receiving vaccination
because of the 2009 pandemic. Id. at 8. Dr. Seikaly wanted J.M. to receive both the trivalent flu
vaccine and the H1N1 monovalent vaccine. Id. The day after Thursday, October 1, 2009, the
dipstick showed that proteins had climbed. Id. at 9. By the following Monday, J.M.’s protein
was more of an issue as was his puffiness. Id. Petitioner brought J.M. in to see the doctor and
the staff did not find any viruses, bacteria, or infections that could have triggered it. Id. at 9-10.
The staff told him they suspected it was probably related to the vaccine, but they thought it
would probably go away. Id. at 10. They started J.M. on another round of prednisone about a
week afterwards. J.M. was on prednisone for about two months, but every time he tapered to 10
mg or between 10 and 20 mg, he had another relapse and the proteinuria returned. Id.
J.M. did not go into full remission until well after the strokes, i.e., sometime in 2013 or
2014. Id. at 11. J.M. went off steroid treatment when Dr. Quan tapered him down and in May
2010, Dr. Quan had a biopsy done. From the biopsy, Dr. Quan diagnosed J.M. with minimal
change nephrotic syndrome. Dr. Quan switched J.M. to tacrolimus, whose brand name is
Prograf. Id. Prograf is not a steroid, but lowers the immune response. Id. at 12. In late June
2011, Dr. Quan started to taper Prograf and J.M. started to have a bump in his proteinuria. The
family was on vacation in Dallas and J.M. had a stroke in the hotel room. Id. at 12. In the
33
Enalapril is “an angiotensin-converting enzyme inhibitor with antihypertensive and vasodilator actions.”
Dorland’s at 611.
34
ACE inhibitors are “angiotensin-conserving enzyme” inhibitors. Dorland’s at 940.
33
hospital, J.M. had two more strokes. Id.
On cross-examination, petitioner stated that after J.M. received flu vaccine on November
19, 2008 when he had been in remission for over nine months, he did not have a bump up in his
protein. Id. at 15-16. Before J.M. was diagnosed with nephrotic syndrome in late August or
early September 2007, petitioner noticed J.M. had a general swelling which seemed a little odd.
Id. at 16. Dr. Frank did a full checkup on J.M. and thought he was having some kind of allergic
generalized reaction. Id. at 17. He prescribed antihistamines. Two days later, on a Sunday,
J.M.’s parents took him to several different emergency rooms where personnel eventually
figured out that J.M. probably had nephrotic syndrome and sent him to Children’s Hospital
where he was admitted on September 6, 2007. Id.
Initially, J.M. was on prednisone for five months, from September 6, 2007 to January 28,
2008. Id. at 18. J.M. was also placed on hypertensives on which he stayed even when he
stopped taking prednisone in January 2008. Id. at 19. After J.M.’s first relapse of nephrotic
syndrome in June 2009, he was on prednisone from June 15 to September 13, 2009, about three
months. Id. at 23. In June 2009, J.M. had a little puffiness in his first relapse. Id. He called Dr.
Seikaly and told him that J.M. had swelling in his face and abdomen. Id. at 24. He also had
weight gain and an increase in blood pressure. Id. J.M. is no longer on antihypertensives or
renal medication. Id. at 24-25.
When petitioner measured J.M.’s protein, weight, and blood pressure, it was always in
the mornings between 7:30 a.m. and 7:45 a.m. Id. at 25-26. That was the weekday routine, but
on weekends, it might be a little bit later. Id. at 26. His wife would keep track of the
information as she printed out the calendars. Id. He would do the readings and give that
information to his wife who put it on the calendar. Id. at 27. A lot of times, he would enter the
information because she was at work. Id. The information on the calendar was created
contemporaneously. Id. For protein testing, he used Multistix. Id.
J.M.’s last day on prednisone before the October 1, 2009 flu vaccination was September
13, 2009. Id. at 28. J.M.’s weight from September 13 through September 30, 2009 was stable in
the 119- to 120-pound range. Id. J.M. received flu vaccine at 3:30 to 4:00 p.m. after school on
October 1, 2009. Id. at 29. On October 1, 2009, J.M.’s weight was 124 pounds. Id. J.M.’s
weight increased five pounds between September 30th and October 1st. Id. Petitioner agreed.
Id. It was a fairly rapid onset. Id. The five-pound weight gain occurred before vaccination since
petitioner recorded J.M.’s weight around 7:30 or 7:45 a.m. Id. at 30.
Petitioner then made various statements to explain away the significance of J.M.’s having
gained five pounds from the day before (September 30, 2009) and that his five-pound gain
occurred before he received flu vaccine in the afternoon of October 1, 2009. Petitioner first said
scales can be plus or minus five pounds or so. Id. He then said he could not say whether he
weighed J.M. in the morning on that day. Id. at 31. He said, “It’s too far back.” Id. He said he
did not necessarily do any weighing in the morning. He said he sometimes weighed J.M. in the
evening. Id. He said J.M. could have been wearing different clothes that day. Id. at 31-32.
34
Petitioner added, “And like I said a 5-pound weight gain is not really that big of a difference.”
Id. at 32. When respondent’s counsel informed petitioner that a five-pound weight gain for a
person J.M.’s size was a five percent increase in weight, petitioner said, “No. If I – if he’s
wearing shoes and everything. I don’t recall exactly how he [sic] measured that. If that – if
that’s the basis of the whole thing, then I don’t know – I don’t know.” Id. Petitioner said he did
not know if J.M. weighed himself on October 1, 2009. Id. at 33. J.M. would get on the scale and
tell petitioner what the number was. Id. at 34. Petitioner said he did not know if J.M. were
wearing shoes on that day. Id. at 33. He said, “I can tell you right now, I can lose five, 10
pounds with taking off my clothes.” Id. Petitioner finally said that the five-pound weight gain
could be inaccurate. Id. at 35.
The undersigned asked petitioner at that point if it would not be important to have
consistency in weighing J.M. Id. at 36. Petitioner responded, “[W]ell, no. Because we’re not
doing clinical data.” Id. The undersigned asked petitioner why he and his wife were weighing
J.M. Id. at 37. He responded, “[I]f there’s a drastic change in the weight, then there’s definitely
something the doctors would want to do . . . .” Id. The undersigned asked petitioner what
“drastic” meant to him and he replied, “A rapid change or a quick change.” Id. at 38. The
undersigned asked how much of a change and petitioner said a ten-pound weight gain. Id.
Petitioner admitted he had no recollection of a prior five-pound weight gain in J.M. either before
August 2009 or after October 2009. Id. at 38-39.
By October 29, 2009, J.M.’s weight had reached 147 pounds. Id. at 33. In other words,
he had gone from 119 pounds on September 30, 2009, to 124 pounds on October 1, 2009, to 147
pounds on October 29th for a total of a 28-pound weight gain in one month.
Respondent’s counsel asked petitioner if J.M. had any fever or local reaction to the flu
vaccine he received in the late afternoon of October 1, 2009. Id. at 40-41. Petitioner said there
was “nothing really outstanding or noticeable, but that very well could have happened. . . . I
don’t think [J.M.] had anything that was significantly noticed but it’s possible there was.” Id. at
41.
On redirect, petitioner went back into explaining why a five-pound weight gain was
meaningless:
And, again, part of – part of the weight has to do with clothing and
such, and, you know, kids wear big shoes some days and they
don’t wear big shoes other days. It just kind of – kind of varies on
basis of the scale’s accuracy as well as other things.
Id. at 51. Petitioner also testified that both Dr. Seikaly and his nurse practitioner Becky told him
that the likely trigger of J.M.’s nephrotic syndrome relapse was the flu vaccination. Id. at 52.
Dr. Albert Quan, J.M.’s treating pediatric nephrologist, testified next. Id. at 53. He has
been practicing nephrology since 1989. He was a faculty member at the University of Texas
35
Southwestern Medical Center from 1993 to 2005. Id. Since January 2006, he has been a clinical
nephrologist at a local hospital in Dallas. Id. at 53-54. He has been J.M.’s treating nephrologist
since the middle of 2010. Id. at 54.
Dr. Quan defined nephrotic syndrome as “a group of disorders whereby the kidney leaks
out a lot of protein from the body, the blood primarily, into the urine.” Id. This results in low
protein in the body, leading to a lot of edema, swelling all over the body, and high cholesterol
and high lipid levels. In children, one particular condition is known to cause the majority of
nephrotic syndrome disorders. It is called minimal change disease or minimal change nephrotic
syndrome. Id. It is easily treatable with steroids or prednisone. Id.
Dr. Quan said that after J.M.’s initial course, starting in September 2007, he had a slightly
longer period of steroids than most people. Id. at 55. But J.M. did respond to the steroids and
was in remission until over a year later when he had his first relapse in June 2009. Id. Dr. Quan
said many patients with nephrotic syndrome have relapses. Id. Typically, a relapse follows
some kind of viral illness, a cold or flu or something of that nature. Id. at 56. He said many (he
also said most) children relapse within six months of onset. Id. He considered J.M. lucky to
have not have a relapse until over a year and one-half after onset. Id.
Dr. Quan testified there was nothing unusual about J.M.’s first relapse in June 2009. Dr.
Seikaly put him on prednisone again, which is the usual treatment. Id. He went into remission
on June 23, 2009, 13 days after restarting steroids, which Dr. Quan said is very typical, i.e., to go
into remission within a couple of weeks of restarting steroids. Id. at 56-57. Then, Dr. Seikaly
weaned J.M. off steroids and, by late August or early September 2009, he was off them. Id. at
57. Dr. Quan deemed J.M. an infrequent relapser of nephrotic syndrome, and patients like that
typically have a very good prognosis. Id.
Dr. Quan said that after J.M. relapsed in October 2009, his nephrotic syndrome changed
from what it had been before. Id. After the second relapse, when Dr. Seikaly attempted to wean
J.M. off steroids, J.M. relapsed again, whereas before October 2009, he was able to wean J.M.
off steroids. Id. In December 2009, when J.M. was tapering steroids, he had a relapse in January
2010. Id. at 57-58. Dr. Quan considered all of J.M.’s subsequent relapses just a sustained
relapse rather than a new relapse. Id. at 58. When J.M. became Dr. Quan’s patient, he put him
on Prograf which got him under good control, and he was able to be weaned off steroids for
about a year. Id. at 58-59. Dr. Quan had J.M. on Prograf until June 2011. Id. at 59. A couple of
months later, in August 2011, J.M. had a relapse, and Dr. Quan put him back on steroids.
Shortly thereafter, he had a stroke and two other strokes. Dr. Quan put J.M. back on prednisone
and Prograf. Id. In nephrotic syndrome, someone can lose certain proteins that favor clotting in
the blood and Dr. Quan believes that is what happened to J.M. Id. The incidence of strokes in
children with nephrotic syndrome is not very common. Id. at 60. It is more common in adult
forms of nephrotic syndrome which are caused by different diseases, usually with membranous
nephropathy which occurs with certain types of cancers. Id. at 61. J.M. had a relatively atypical
course. Id.
36
Dr. Quan said a prolonged relapse that the doctor cannot get under control means J.M.
was continuing to lose protein in his urine which would tip the balance toward clotting in his
blood. Id. When J.M. got off Prograf in June 2011, Dr. Quan thought he was going to do well
and not have any further relapses. Id. at 62. Unfortunately, by August 2011, he relapsed which
at that point was related to his stroke. Id. Most nephrotic syndrome patients get some kind of
illness, a viral illness, typically a cold or flu, before they relapse. Id. at 62-63. Presumably, he
said, the immune system is upregulated at that point and, then, somehow, makes the kidney
membrane more permeable so that the patient loses protein in the urine leading to nephrotic
syndrome. Id. at 63. It makes sense, Dr. Quan said, that if someone’s immune system is
upregulated through immunization, a similar effect can also occur. This has been reported in the
medical literature. Id. Any vaccine could do that. Id.
Dr. Quan thought that temporally and plausibly, more likely than not, “flu vaccine led to
J.M.’s new onset of his latest relapse that finally led to his stroke.” Id. at 64. A poorly
controlled nephrotic syndrome has a higher risk of stroke or any other type of clotting
complication. Id. Most of the time, doctors can control a relapse of nephrotic syndrome. Id.
Prior to October 1, 2009, J.M. had had only the onset of nephrotic syndrome and one relapse a
year and one-half later. Id. at 64-65. He would have considered J.M. to be under good control
with just steroids and to have a good prognosis. Id. at 65.
When petitioner’s counsel asked Dr. Quan what the effect of the flu vaccination would
have been on J.M. if he started relapsing before he received the flu vaccine on October 1, 2009,
Dr. Quan said:
That would be impossible to say exactly. I think I would venture
to say that, if he was ready to relapse again, that the flu shot might
make that worse. But, again, there’s no evidence that that’s going
to be the case.
Id. at 66. Practitioners generally do not immunize patients who are in the middle of tapering
steroids on a relapse during the time they are tapering. Id. at 67. They wait until the tapering is
done and the patient has cleared from the relapse. Dr. Quan thinks that most nephrologists think
that an immunization can be a risk factor in causing a relapse. Id.
Dr. Quan testified that J.M. has not had any more relapses since the one that led to his
stroke in 2011. Id. at 67-68. Dr. Quan saw J.M. two or three months before the hearing and he
continued to do well without any nephrotic syndrome relapses at all. Id. at 68. The strokes
however have left sequelae. Id. Dr. Quan said there was nothing in his medical records other
than the flu vaccination that can be identified as causing the change from few relapses and
steroid sensitive to steroid dependent and long-term immunosuppression with steroids and
Prograf. Id.
On cross-examination, respondent’s counsel asked Dr. Quan if he had written any
publications on nephrotic syndrome in general. Id. at 69. Dr. Quan said he had not. In addition,
37
he has not written on minimal change nephrotic syndrome specifically.
The first time Dr. Quan saw J.M. was May 13, 2010. Id. at 70. Dr. Quan agrees that
weight gain is a sign or symptom of a relapse of nephrotic syndrome. Id. at 74-75. He reiterated
his prior testimony that, if the relapse occurred before vaccination, there is no evidence of which
he is aware that vaccination would have made the relapse worse. Id. at 75. He repeated,
“There’s no way to prove that the flu vaccine made anything worse or not.” Id. at 76. The
undersigned then asked Dr. Quan if the flu vaccination altered J.M.’s course if his relapse began
before the vaccination. He replied, “I don’t – I don’t know that I can answer that accurately. . . .
So the effect of the flu vaccine exactly on his relapse at that point, I can’t say with – with
complete honesty. I don’t know.” Id. at 78.
Respondent’s counsel asked Dr. Quan if he considers a five-pound one-day weight gain
in a 119-pound boy to be a significant weight gain. Id. at 79. Dr. Quan said yes. Dr. Quan
continued Dr. Seikaly’s practice of putting J.M. on hypertensives even when he was in
remission. Id. at 80. He did this because he was concerned about J.M.’s blood pressure levels.
Id. When Dr. Quan weaned J.M. off Prograf in June 2011, he wanted J.M. to catch up with all
his immunizations. Id. at 85. Dr. Quan knows that J.M. has a factor V Leiden mutation which is
associated with an increased risk of blood clots. Id. When J.M. had his strokes in August 2011,
Dr. Quan reinitiated his prednisone and Prograf. Id. at 86. Dr. Quan weaned him off Prograf in
March 2013 and off prednisone in 2012. Id. at 86-87.
Dr. Quan stated that pieces of data, such as using immune suppressants to treat any
relapses occurring after viral illnesses, strongly suggest that the immune system may play an
important role in nephrotic syndrome. Id. at 91. Dr. Quan agreed that the onset of J.M.’s
proteinuria was less than 24 hours after flu vaccination, much shorter than the onset of nephrotic
relapse or syndrome in the case reports filed with his reports. Id. at 94. The morning after his
late afternoon flu vaccination, J.M. had a protein count in his urine of plus 3. Id. at 96.
Although Dr. Quan put the onset of J.M.’s relapse in his January 2, 2015 report (Ex. # 40) as four
to five days, he agrees that it actually occurred within 24 hours of vaccination. Id. at 97. Most
of the onsets of relapses in the case reports to which Dr. Quan referred in his reports occurred
longer than within a day after vaccination. Id. at 100.
At this point, on redirect, petitioner’s counsel showed a Japanese government document
warning that flu vaccine can cause nephrotic syndrome, a document not admitted into evidence
that Dr. Quan, respondent’s counsel, respondent’s experts, and the undersigned had never seen.
Id. at 103. Respondent’s counsel objected because the time period for submitting exhibits in the
case had long passed. Id. at 103-04. Respondent’s counsel also objected to six new medical
articles referenced in Dr. Bellanti’s forthcoming PowerPoint presentation, none of which was
part of the record. Id. at 104. The undersigned did not permit petitioner’s counsel to ask Dr.
Quan questions about a document he had never seen, but did permit petitioner’s counsel to save
the document for Dr. Bellanti. Id. at 105.
On redirect, Dr. Quan said that normally weight gain and elevation in protein go hand in
38
hand because the loss of protein in urine leads to onset of edema and weight gain. Id. at 107. He
does not think that the weight gain occurring earlier or a day later changes the fact that before the
vaccination, J.M. was a well-controlled patient, infrequently relapsing, and then after the
vaccination, he became a frequent relapser. Id. at 108. That J.M. has a factor V Leiden mutation
does not affect his opinion that one of the complications of nephrotic syndrome is abnormal
clotting. Id. at 109. The factor V Leiden could have added some additional risk, but it was not
the only risk factor for J.M.’s clotting problem. Id.
As for any vaccination being an immune stimulator causing a nephrotic syndrome
relapse, one would need to see this happen more often. Id. He thinks the immune stimulation is
more important than the identity of the vaccine. Id. at 110.
On recross, Dr. Quan said that he would not consider the five-pound weight gain before
the flu vaccination on October 1, 2009 to be indicative of a relapse in J.M.’s nephrotic syndrome
when the protein in his urine on the same day was negative. Id. at 112, 113. Dr. Quan said he
looks at the trend, not a one-day measurement of weight. Id. at 115. Dr. Quan agreed that the
trend starting the morning of October 1, 2009 was his weight started to increase up to 147
pounds on October 29, 2009. Id. Dr. Quan agreed that J.M. had a trend of weight gain starting
before he received flu vaccine, saying, “That’s what it would seem to be; right.” Id. at 115-16.
Dr. Joseph A. Bellanti, petitioner’s expert immunologist, testified next. Id. at 118. He is
a professor of pediatrics and microbiology immunology emeritus and director of the International
Center for Interdisciplinary Studies of Immunology at Georgetown University Medical Center.
Id. at 119. He has held many national presidencies of national organizations: the Society for
Pediatric Research, the American College of Allergy & Immunology, the American Association
of Medical Laboratory Immunologist, and Interasma. Id. at 120. He has published over 400
scientific articles in peer-reviewed journals, including many books. His most recent textbook of
immunology is Immunology IV, Clinical Applications in Health and Disease, published in 2012.
Id.
Dr. Bellanti testified that there is little dispute that the 2009 flu vaccination was causally
related to the development of J.M.’s unfortunate downhill medical course. Id. at 122, 123.
J.M.’s infrequent relapse rate pre-vaccination and excellent response to steroids indicated to his
nephrologist that J.M.’s subsequent course would be uncomplicated with few relapses, if any.
Id. at 124.
Dr. Bellanti reviewed J.M.’s flu vaccinations. Id. The first flu vaccine he received was
the live attenuated intranasal flu vaccine (FluMist) on November 20, 2006. On November 19,
2008, he received his first inactivated flu vaccine. On October 1, 2009, he received his second
inactivated flu vaccine. Id. This last vaccination led to his relapse on October 2, 2009. Id. at
125. Following this flu vaccination, J.M. developed steroid-dependent or steroid-resistant
nephrotic syndrome. Id.
Dr. Bellanti began an explication of the immune system, stating it is everywhere and
39
constantly looking for foreignness. Id. at 128. The immune system has three functions: defense,
homeostasis, and surveillance. Id. Dr. Bellanti said he was not calling J.M.’s disease an
autoimmune disease, but “there are components of the immune system that are directed against
renal tissue. So in a sense, you might consider it an autoimmune expression of the immune
system.” Id.
Dr. Bellanti then divided his discussion of the immune system into three parts: (1) the
innate system, (2) the adaptive system, and (3) the immune system and disease. Id. at 129. The
innate system consists of many inflammatory cells, mediator cells, and complement natural killer
cells. If foreignness can be removed at that point, the immune system does not have any further
role. Id. But most of what people encounter involves the adaptive system which involves the T-
cell and B-cell systems. Id. at 130. The B-cell system in its differentiated form makes five
classes of immunoglobulins: IgG, IgA, IgM, IgD, and IgE. Id. The T-cell system has many
daughter cells which have different functions: Th1, Th17, Th2, T-reg cells. Those T cells can be
divided into two universes, the Th0 cells which is the helper population, the CD4+, and the
CD8s, the killer cells that kill virally-infected cells and tumors. Id.
Dr. Bellanti said the immune response responds to an action and to a reaction. Id. at 131.
Cytokines are molecules that cause the cells of the immune system to talk to one another. Id. at
132. Foreignness produces proinflammatory cytokines. Id. at 131-32. Some cytokines promote
inflammation, while others neutralize inflammation (the anti-inflammatory cytokines). When the
proinflammatory and anti-inflammatory cytokines are in balance, the individual is healthy. Id. at
132. Vaccinations can cause a disequilibrium when there are too many proinflammatory
cytokines produced and not enough anti-inflammatory cytokines to counterbalance. Id.
People are born with the innate system. Id. The innate system consists of phagocytic
cells which include macrophages, polymorphonuclear leukocytes, eosinophils, and dendritic
cells. Id. at 133. A group of cells are called mediator cells, which are mast cells and basophils.
Id. These cells get fired off with atopic or allergic disease by procuring mediators such as
histamine and globulins and others, the natural killer cells which help fight cancer and viral
infection complement, involved in neutralizing bacteria, combining with antibodies, making
complexes, and putting holes in cells with bactericidal activity. Id. at 134. There are also innate
T cells. Id.
Dr. Bellanti said that injury occurs not only from adaptive immunity, but also from innate
immunity. Id. Innate immunity responses occur within minutes, hours, or days. Adaptive
immunity takes a few weeks to be stimulated. Id. Dr. Bellanti said, “So as we’ll see in the case
of J.M., there is evidence that innate immune injury may be playing a role in the pathogenesis of
his condition.” Id.
Dr. Bellanti described the adaptive system as consisting of T cells (Th1, Th17, Th2, Th3,
Tr1) and B cells which interact with each other. Id. at 135. The Th2 cell interacts with the B cell
to make gamma globulins. IgG is made of four subclasses. At birth, the baby receives the
transfer of IgG from the mother which falls rapidly during the first months of life. Then the baby
40
make his or her own gamma globulins. Id. IgM appears first. Id. Then IgG, IgE, and IgA
appear later. Id. at 136.
By the time J.M. developed nephrotic syndrome in 2007, he was six years old and his
gamma globulins, that is, his immune system, were fairly well developed but not completely. Id.
Gell & Coombs developed the four mechanisms of immunologic injury in 1963. Type I is where
IgE binds to a mast cell and, when coupled with antigen, releases mediators. Id. Type II is the
cytotoxic reaction when antibody can kill a cell, usually in the presence of a complement. 35 Id.
at 136-37. Type III is when immune complexes composed of antigen-antibody and complement
produce inflammation and serum sickness-like immune complex inflammatory disease. Id. at
137. Type IV is when the T cell damages by way of its subsets. Id. Dr. Bellanti said this
classification suffers because it is based entirely on components of the adaptive immune system,
without taking into consideration injury by the innate system. Id. Dr. Bellanti said we need a
new system. He suggests a new system in chapter 17 of his book because many diseases we are
now recognizing do not fit within the response of the classic Gell & Coombs adaptive system.
We need to look at the innate system. Id. The innate system has immediacy of action so that
when foreign configuration hits these cells, mediators are rapidly released, some of which have
been described in the pathogenesis of the nephrotic syndrome. Id. at 141.
Dr. Bellanti stated:
Nephrotic syndrome does not fit nicely into the Gell & Coombs.
It’s not a Type I IgE. It’s not – at least we’re not sure it doesn’t –
the cytotoxic IgG is Type II. Immune complexes may be involved
in certain forms of the nephrotic syndrome, but the type we’re
talking about with J.M., the idiopathic or the minimal change
disease, MCD, has been a mystery since I was a resident in
Buffalo. You know, we were wondering what is this nephrotic
syndrome. It sometimes occurs after a stinging bee or a Dilantin
drug or an infection. It didn’t fit neatly into this Gell & Coombs,
and that’s the point that I wish to make.
Id. at 141-42.
The undersigned responded to Dr. Bellanti:
SPECIAL MASTER MILLMAN: Well, I -- when I was reviewing
for this hearing, I vaguely recall that the concept even of what is
the pathogenesis or the pathological manifestation of nephrotic
syndrome is changing as we speak.
35
Complement “is now used to refer to the entire functionally related system comprising at least 20 distinct serum
proteins, their cellular receptors, and related regulatory proteins that is the effector not only of immune cytolysis but
also of other biologic functions including anaphylaxis, phagocytosis, opsonization, and hemolysis.” Dorland’s at
393.
41
THE WITNESS: As we speak.
...
SPECIAL MASTER MILLMAN: [T]hat concept of what
underlies nephrotic syndrome is not that it’s immune mediated,
that it’s some kind of I don’t know what to call it. What is it? Do
you have a word for this? What is this word?
THE WITNESS: It’s a – a complex pathogenesis involving many
mediator systems and toxic components that are released during
infection, during challenge with a drug, with a bee sting. It doesn’t
necessarily have to be a vaccine. But vaccine is one of them.
Id. at 142-43.
Dr. Bellanti testified that J.M. had an immediate response occurring within the first 24
hours which persisted with all of his recurrences, either with challenge with viral infection or flu
vaccine “or whatever.” Id. at 153. J.M. had a continuum of damages which the innate immune
system initiated but the adaptive system perpetuated. Id.
Dr. Bellanti said that the reason we call nephrotic syndrome a “syndrome” and not a
“disease” is that a disease has a single etiology, but a syndrome has many etiologies. Id. at 153-
54. Nephrotic syndrome refers to a group of kidney disorders involving loss of protein through
the kidneys, called proteinuria, leading to low protein levels in the blood, predominantly called
hypoalbuminemia, causing water to be drawn into soft tissues, called edema. Id. at 154.
The nephrotic syndrome that J.M. has does not have too many inflammatory cells. Id. at
155-56. J.M. has primary nephrotic syndrome, which means nephrotic syndrome in the absence
of systemic disease. Id. at 157. The reason that Dr. Quan diagnosed J.M. with minimal change
disease after J.M.’s biopsy in 2010 was that there was minimal inflammation. Id. at 158. Dr.
Bellanti stated that flu vaccine promotes a tremendous outpouring of cytokines and other
substances that can contribute to chronicity in rare cases. Id. at 159. Circulating factors could be
involved after flu vaccination. Id. at 162-63. Antigen-antibody complexes could also be
involved but they are less likely because they would cause more inflammatory involvement
rather than a mixed minimal change disease. Id. at 163.
Dr. Bellanti stated that J.M. received three flu vaccines: the first, intranasal flu vaccine,
on November 20, 2006; the second, inactivated flu vaccine on November 19, 2008; and the third,
the “punitive vaccine,” an inactivated flu vaccine on October 1, 2009, which led to the relapse of
nephrotic syndrome beginning on October 2, 2009. Id. at 164. Dr. Bellanti attributes J.M.’s
quick reaction to the 2009 flu vaccine to an anamnestic response since J.M. received two prior
flu vaccines in 2006 and 2008. Id. at 165. The third flu vaccine in 2009 constituted a
rechallenge. Id.
Dr. Bellanti said the normal immune response does not give someone kidney disease. Id.
42
at 166. Why is J.M.’s case different? Dr. Bellanti said probably genetics played a major role
and doctors have not begun “to scratch the surface on that.” Id. Dr. Bellanti agreed that J.M. did
not have any systemic signs of a cytokine reaction to flu vaccination. Id. at 168. J.M. did not
have fever or arthralgia. Id. Dr. Bellanti said that something happened to J.M. that was
localized, not systemic. Id. at 169. “There’s not a systemic cytokine storm as we sometimes see.
It’s a localized thing that’s going on.” Id. The damage was localized to J.M.’s kidneys. Id.
Dr. Bellanti said that, if J.M. were beginning a relapse before receiving flu vaccine on
October 1, 2009, the flu vaccine would only increase his susceptibility. Id. at 189.
On cross-examination, Dr. Bellanti agreed that it is hard to predict which children will be
steroid resistant and which will be steroid dependent. Id. at 219.
The undersigned asked Dr. Quan if there were a natural course of minimal change
nephrotic syndrome. Id. at 224-25. Dr. Quan responded, “But you don’t really know, nobody
has a crystal ball to tell you exactly how well they’re going to do. There are certain factors that
increase or decrease the risk of certain things happening and that’s the best you can do.” Id. at
225. Dr. Quan also said that minimal change nephrotic syndrome is a different disease in adults
than in children. Id. at 232. The underlying reason for the difference in adults compared to
children is that there is a different cause of minimal change nephrotic syndrome in adults than
the cause in children. Id.
Dr. Bellanti admitted on cross-examination that all of the studies to which he referred in
his expert reports and testimony concerned nephrotic syndrome in adults except for one which
dealt with children who had minimal change nephrotic syndrome and thrombosis, but were not
vaccinees. Id. at 233, 234. He agreed that minimal change nephrotic syndrome in adults is
different than in children. Id. at 233. None of the studies to which Dr. Bellanti referred in his
expert reports and testimony concerning nephrotic syndrome had onset within 24 hours. Id. at
234.
Although Dr. Bellanti stated that flu vaccine led to J.M.’s relapse, causing more
proteinuria and more hypercoagulability due to loss of urinary proteins, he also admitted that
J.M. could spontaneously lose enough protein in his urine to achieve hypercoagulability. Id. at
242. It could occur independently from flu vaccination or flu vaccination could cause it. Id. In
fact, other medications that J.M. took could play a role. Id.
On the second day of the hearing, counsel returned with information about the
components of the 2008 and 2009 flu vaccinations J.M. received. J.M. also previously had an
intranasal flu vaccination on November 20, 2006. Id. at 270. That vaccine plus the two
inactivated flu vaccines (in 2008 and 2009) were all similar, containing two A viruses consisting
of H1N1 and H3N2 plus a B virus. Id. Petitioner stated that J.M. never received flu vaccine
before the intranasal flu vaccination on November 20, 2006. Id. at 276.
Since Dr. Bellanti’s explanation for the quickness of J.M.’s 3+ proteinuria the morning of
43
October 2, 2009 was an anamnestic response due to his having received flu vaccine in 2008, the
issue was whether the difference in the B virus component of the 2008 flu vaccine compared to
the B virus component of the 2009 flu vaccine was an impediment to the theory Dr. Bellanti
espoused in explanation of the quick interval between 3:30 or 4:00 p.m. on October 1, 2009 and
the proteinuria the morning of October 2, 2009. Dr. Bellanti said J.M. had a hypersensitivity
response. Id. at 267. In Dr. Bellanti’s opinion, having two out of the three flu vaccine
components in 2008 and 2009 identical was sufficient for J.M. to have an anamnestic response
the day after his October 1, 2009 flu vaccination. Id. at 277. He thought a year between the two
vaccinations was appropriate for an anamnestic response to happen in that length of time. Id. at
278. He said immunological memory lasts a long time. Id. at 279.
Dr. Bellanti also thought J.M.’s 2006 intranasal flu vaccination played a role in the quick
interval between his 2009 flu vaccination and his proteinuria within a day of vaccination even
though the 2006 intranasal flu vaccine did not have any components identical to the 2008 killed
flu vaccine or the 2009 killed flu vaccine. Id. Dr. Bellanti explained that when he was at Walter
Reed Army Institute of Research, Dr. Tommy Francis and other workers with flu vaccine spoke
about “original immunologic sin” that was imprinted the first time someone was exposed to a
virus. Id. at 279-80. In this view, every time someone is exposed to a new virus, there is some
molecular mimicry or cross-reactivity to give that person an anamnestic response. Id. There is
sharing of epitopes36 so that whether the virus comes from Brisbane, Australia, Uruguay, or
Florida, there is enough similarity with those antigenic epitopes to stimulate the anamnestic
response. Id. In Dr. Bellanti’s opinion, there was sufficient identity among the two A flu strains
and one B flu strain to which J.M. was exposed in the intranasal vaccine of 2006, the killed virus
vaccine in 2008, and the killed virus vaccine in 2009 to cause an anamnestic response in 2009
based on the prior two vaccines. Id. at 280.
The undersigned asked Dr. Bellanti why, after J.M. had the onset of nephrotic syndrome
in September 2007 and went into remission in August 2008, he did not have a relapse when he
received flu vaccine on November 19, 2008, since he already received flu vaccine on November
20, 2006. Id. at 285-86. Dr. Bellanti said “We obviously don’t know the precise answer,” but
offered an opinion based on what we know about these vaccines. Id. at 286. Someone hopefully
obtains protective immunity when he or she receives flu virus intranasally because the vaccine
stimulates the IgA, not the IgG, and the secretions. Id. at 287. As it turns out, however, Dr.
Bellanti noted, the Centers for Disease Control no longer recommends intranasal attenuated
vaccine because it does not have the “punch” they hoped it would have. Id. Dr. Bellanti
surmised that J.M.’s intranasal flu vaccine was alone not sufficient to give enough of an
anamnestic response when he received his first inactivated flu vaccine in 2008. Id. The
36
An epitope is an “antigenic determinant.” Dorland’s at 637. An antigenic determinant is “a site on the surface of
an antigen molecule to which a single antibody molecule binds; generally an antigen has several or many different
antigenic determinants and reacts with antibodies of many different specificities.” Id. at 502. An antigen is “any
substance capable, under appropriate conditions, of inducing a specific immune response and with reacting with the
products of that response, that is, with specific antibody or specifically sensitized T lymphocytes, or both. Antigens
may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells;
however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant …
combines with antibody or a specific receptor on a lymphocyte.” Id. at 103.
44
induction of memory cells J.M. obtained was largely from the 2008 flu vaccination. Id. at 289.
J.M. was sensitized to the epitopes that are part of the killed virus in the flu vaccine. Id. Dr.
Bellanti said unfortunately flu vaccine is only 50 to 70 percent effective, but it does give some
benefit to blunting the disease. Id.
Dr. Bellanti recalled that Dr. Quan said that viruses, such as the common cold and other
respiratory viruses, trigger many cases of nephrotic syndrome. Id. at 290. Too much of an
immune response may trigger a relapse. Id. at 291. That could explain flu vaccine causing a
relapse, but in the case of measles virus, you might see improvement. Id. With measles,
someone gets anergy, i.e., too little response, but for the most part, infections heighten the
immune response. Id. at 292.
Dr. Bernard Kaplan testified for respondent. Id. at 294. He is retired. Id. Before he
retired in June 2016, he spent eight years at the Children’s Hospital of Philadelphia. Id. at 295.
His medical career started in Johannesburg, and proceeded to Montreal where he trained in
pediatric nephrology. Id. at 296. He eventually came to the Children’s Hospital of Philadelphia
in 1987 where he was chief of nephrology. Id. at 297. He spent almost 30 years there. Id.
Some 40 or 50 of his 400 articles are on glomerular disorders. Id. at 299.
Dr. Kaplan went to Montreal to work with Dr. Keith Drummond who had worked with
Dr. Robert Good in Minnesota. Id. at 299. Dr. Good was a famous immunologist who opened
up the field of immunopathology. Id. Dr. Drummond and Dr. Good with others showed immune
deposits in post-streptococcal glomeruloneuritis and in Goodpasture syndrome. Id. But they
were unable to show any immune pathology in minimal change nephrotic syndrome. Id. at 300.
Because they were unable to show any evidence of immune pathology in minimal change
nephrotic syndrome, the group in Minnesota and Dr. Drummond’s lab started to study the
biochemical structure of the basement membrane to try to understand whether there was an
alteration in the biochemistry of the basement membrane. Id. Using rats, they administered
puromycin or two anticancer agents, daunorubicin and Adriamycin, to see if there were structural
change in isolated glomeruli. Id. There were biochemical changes. Id. In patients with
infections such as congenital syphilis, thyroid disease, and candida infection, they saw syphilis
bacterium and immune complexes in the kidney, thyroid antigen in the kidney, and candida
antigen in the kidney. Id. at 300-01. But none of these patients had minimal change nephrotic
syndrome. Id. at 301. Their disorders were completely different from minimal change nephrotic
syndrome. The only aspect they had in common with minimal change nephrotic syndrome was a
lot of protein in the urine. Id.
When Dr. Kaplan lived in Montreal, he saw children with minimal change nephrotic
syndrome and wondered if mercury contamination due to the forestry industry near the St.
Lawrence River were related to the children’s nephrotic syndrome. Id. at 301-02. The link
between mercury exposure and nephrotic syndrome had occurred in women who used mercury
for cosmetic reasons in Africa, but Dr. Kaplan could not show an association in the Montreal
children. Id. at 302. In Montreal, he worked with cancer patients who had nephrotic syndrome,
but they were adults with a different form of nephrotic syndrome, i.e., the membranous form,
45
than children had. Id.
Dr. Kaplan mentioned that clots are extremely uncommon in people with nephrotic
syndrome. Id. at 303. Prednisone does not cause renal venous thrombosis or any thrombi. Id.
An imbalance between coagulant factors and anticoagulant factors can occur in nephrotic
syndrome. Id. Clotting occurs more frequently in adults. Id. at 303-04. Children with nephrotic
syndrome usually do not have proteinuria for a long time, which in theory explains why clots are
relatively rare in children. Id. Adults with membranous nephrotic syndrome may have nephrotic
syndrome for months or years because there still is not a good treatment for it. Thus they are
more likely to get clots. Id. Both in the adult literature, and especially in the pediatric literature,
one hardly ever sees arterial clots such as occurred in J.M. Id. at 304-05. In the pediatric
literature, the ratio of venous to arterial clots is 20 to 1. Id. at 305. In adults, the ratio of venous
to arterial clots is 3 to 1. There are other reasons why adults may have clots, such as
arteriosclerosis, smoking, and obesity. Id.
Dr. Kaplan then said he became “profoundly interested” in the genetic basis of nephrotic
syndrome because the hospital had a number of families where the mother and child had
nephrotic syndrome or two children had nephrotic syndrome and they were minimal change
nephrotic syndrome. Id. Other patients had focal sclerosis. By collaborating with people at
Harvard, they were able to show in some of their patients with focal sclerosis that they had a
mutation in a gene for podocin and for alpha-actinin 4. Id. Saying he had great respect for Dr.
Bellanti, Dr. Kaplan identified a misstatement Dr. Bellanti made during the first day of testimony
when he said the genetic causes of nephrotic syndrome occur in neonates and infants and not in
older people. Id. at 305-06. This is a very old idea which has now been completely shown to be
wrong. Id. at 306. There have been 20 mutations shown so far and they occur in older children
and adults as well. Id. at 306. These mutations are in proteins that help to control the podocyte,
which is an extraordinary cell that sits on the outer surface of the basement membrane and
controls the basement membrane. Id.
Dr. Kaplan said that the podocyte has interdigitating processes that are like rafts of
nephrin and podocin, which impede the passage of albumin. Id. at 306-07. If there is a
disruption in the apparatus, albumin can pass through and nephrotic syndrome can occur. Id. at
307. In minimal change nephrotic syndrome, it is predominantly albumin that is lost since
damage to the kidney is miniscule as light microscopy demonstrates. This compares with the
membranous form of nephrotic syndrome and other forms in which immune complexes disrupt
the architecture of the foot processes, causing massive leakage of all kinds of protein, not just
albumin. Id. Dr. Kaplan has been involved in the care of hundreds of children with nephrotic
syndrome, including many hundreds of children with minimal change or steroid-sensitive
nephrotic syndrome. Id. at 310. He has also seen thousands of relapses. Id.
Dr. Kaplan’s opinion is that the October 1, 2009 flu vaccine did not significantly
aggravate J.M.’s minimal change nephrotic syndrome. Id. at 313. His opinion also is that the
October 1, 2009 flu vaccine did not significantly aggravate J.M.’s minimal change nephrotic
syndrome so as to cause his strokes 22 months later. Id. The percentages of different types of
46
nephrotic syndrome differ in children versus adults. Id. at 314. The majority of patients who
were stero
This text is long and has been trimmed here. Open the source document for the complete record.