Age: 0.17
Sex: F
Vaccine: DTAPHEPBIP, HIBV, PNC13, RV1
Symptoms: Echocardiogram normal, Erythema, Haemoglobin normal, Immunoglobulin therapy, Kawasaki's disease
Clinical narrative: This is a literature report. In this report, the authors describe a girl who presented with classic KD shortly after receiving her routine 4 month vaccination series. The available literature exploring potential connections between immunizations and KD and other vasculitis, and the methodologic challenges that complicate analysis in this area, are subsequently reviewed. Briefly, the present patient was first admitted with fever, edema and erythematous-purplish rash of the extremities, 1 week after receiving PEDIARIX; (GlaxoSmithKline), Hib, PREVNAR 13 (Wyeth/Pfizer), and ROTARIX (GlaxoSmithKline) at age 2 months. At that presentation, she had poor perfusion, elevated leukocytes, platelets, and lactate, and underwent conventional infant rule-out sepsis management. Cerebrospinal fluid panel, urinalysis, and all cultures were normal/negative; the patient quickly improved with supportive care, was suspected to have viral sepsis, and was discharged after 2 days. The patient remained well through her routine 4 months well child visit. Twelve hours after receiving vaccines (again, PREVNAR 13, DTaP/IPV/HepB, and ROTARIX) at that visit, she developed a fever. This persisted until presentation on day of illness (DOI) 4, at which time she had a temperature of 39.4degreeC, heme-occult positive diarrhea, and an erythematous macular rash on her torso. By DOI 7 she had dry, cracked lips, intermittent non-purulent conjunctivitis, and edematous feet with red soles. KD was suspected based on standard criteria:2 laboratory data were notable for C-reactive protein 97.1 mg/L, hemoglobin 10.2 g/ dL, and albumin 2.8 g/dL; viral respiratory screen, urine and blood cultures were negative; echocardiogram and abdominal ultrasound were normal. With ongoing flares of body rash and feet swelling, and refractory >39degreeC fever, she was given i.v. immunoglobulin (IVIG) and aspirin on DOI 9. She defervesced during the IVIG infusion, the swelling resolved the next day, and besides a fading reticular rash, she was at her clinical baseline at discharge on DOI 11. Subsequently, she received all expected 6 months vaccines except ROTARIX, and MMR and Varicella vaccines at 12 months - all with no issues - and had remained otherwise well through 15 months of age. Prior case reports have temporally associated KD with various vaccines, including hepatitis B, yellow fever, pneumococcal polysaccharide vaccine (PPSV)23, influenza, and others.3-9 The present case had similarities to a case from country in 2012, in which a 20-monthchild began with fever the night after receiving her second rotavirus vaccine (Lanzhou lamb rotavirus vaccine; LLV), and had broader clinical and laboratory features diagnostic for KD, including coronary artery dilatation, by day 5 of illness.3 Two other cases in infants greater than or equal to2 months - an unusually young age for KD, given that <2% of vasculitis cases are seen in greater than or equal to3-month-olds - who also had refractory fever greater than or equal to 1 day after vaccination, similarly were suggestive of immunization as being a trigger for KD.3,4 Notably, KD was found at higher rates in those receiving ROTAEQ (Merck) in the 42 days after vaccination compared with placebo, in phase 3 of clinical trials: unadjusted RR, 4.9 (5/36,150 vs 1/35,536).10 Given concerns raised by these findings and separate case reports, several post-licensure studies have tracked both intussusception and KD rates closely after rotavirus vaccines were licensed and introduced into national immunization programs. 11-14 In an analysis led by an independent group, an increase in KD was reported to the Vaccine Adverse Events Reporting System (VAERS; comanaged by the Centers forDisease Control [CDC] and Food and Drug Administration [FDA]), in the first five quarters of post-marketing of RV5, with 11 cases being associated with use (or co-use) of this specific vaccine during this time period.11 Subsequent large studies from around the world, however, have not confirmed any definitive association of KD with rotavirus vaccines.12-16 In a comprehensive analysis of VAERS data from 1990 to 2007, KD symptom onset was not temporally clustered at any specific timepoint after ROTATEQ receipt; also, rates of KD reported in association with ROTATEQ (even at its highest level after the aforementioned phase 3 findings were included in an FDA label revision) were substantially lower than established background rates of disease. In independently published data from a phase 3 study of ROTARIX in three high-income countries, KD rates were equivalent in vaccine and placebo recipients. Similarly, in an industry-led integrated analysis of 28 randomized clinical trials from various global regions, which included >56 000 ROTARIX recipients and analyzed adverse events (AE) =31 days after vaccination, there was only one case of KD in each of the vaccine and placebo groups.14 Lastly, after both ROTATEQ and ROTARIX were introduced into the national immunization programs of country and country, analyses of billing data, and mandatory reporting of postvaccine AE (respectively), found no association of KD with either rotavirus vaccine.15,16 In part due to concerns raised by the ROTATEQ phase 3 experience, PREVNAR 7 and subsequently PREVNAR 13 have had similar monitoring and investigations for associations with KD. In a postlicensure analysis from Company of >65 000 children, although an unadjusted analysis found a statistically significant increase in KD hospitalization incidence in PREVNAR 7 recipients compared with historical controls, there was no association after adjusting for potential confounding variables (e.g. sex, race, length of follow up etc.); nevertheless, worth noting from that study is that the overall adjusted RR of 1.61 approached statistical significance (95%CI: 0.93-3.00, P = 0.0831), but also that KD episodes occurred at a median >100 days after the first use of PCV7, and typically after the third or fourth dose. A later study assessed AE associated with PCV13 immediately after its introduction, through the Vaccine Safety Datalink Project, and found an adjusted RR of 1.97 greater than or equal to 28 days after PCV13 vaccination compared with historical controls who had received PCV7 (95%CI: 0.79-4.94).18 Given this persistent signal, FDAs program is maintaining ongoing surveillance for KD associated with PCV13.19 Also, retrospective analyses of various vaccine safety databases (VSD) have examined the association of vaccines, other than RV and PCV, with KD and also with other vasculitis diagnoses. In the previously cited review of VAERS data from 1990 to 2007, the proportional reporting ratio of KD for PEDIARIX was elevated compared with other vaccinesincluding in the time period before the ROTATEQ FDA label revision - but again this (highest, approx. 2.44/100 000) was lower than background KD incidence rates. In a review of VSD data (prior to ROTATEQ introduction) from 1996 to 2006, verified KD patients were less likely than non-KD controls to have received any vaccine in the 42 days prior, raising the possibility of a transient protective effect (against KD) of immunization.20 Most recently, an analysis of electronic health data of <6- yearolds from 2008 to 2012 (during which time PCV but not RV were part of the routine schedule), incidence of KD greater than or equal to28 days after any immunization stage was 12.8/100 000 person-years (95%CI: 5.7-28.4), which fell within the wide range of available age-related background KD rates.21 There are noteworthy limitations, however, to these studies and to the investigation of vaccine associations in general, including that AE capture in safety databases is mainly by voluntary reporting, which may lead to underestimations; that such reports are symptom rather than diagnosis focused; and that vasculitides lack standard diagnostic definitions.The lack of a standardized KD case definition has been highlighted by the Brighton KD Study Group, who recently proposed criteria for diagnostic certainty levels (definite, complete and incomplete; probable; and possible) to improve the data collection and analysis of KD surveillance and research. Last, epidemiologists have long noted that there are social and medical attributes associated with both the avoidance of vaccinations and the increased risk of AE, and that if these confounders are not adequately controlled for in studies, the association of AE with vaccines may be underestimated. The current patients first presentation after vaccination, with widespread rash and edema, was consistent with vasculitis; her second met the criteria for KD, and the prompt response to IVIG corroborated this diagnosis. The rapidity of symptoms after the second round of vaccinations suggested the possibility of antigen sensitization with her previous exposure and an immune-mediated phenomenon. It is worth noting that the patients personal contacts all lacked any illnesses around the time of diagnosis, and there were no other KD cases in the present hospital for 4 weeks before or after. Given an absence of issues after the 6 month immunizations when ROTARIX was omitted, we suspect that this vaccine was the precipitating agent; nevertheless, an independent or combined effect with a concomitantly received immunization remains possible. In conclusion, vaccines may potentially be associated with vasculitides, including KD, in individual children, and ongoing, systematic surveillance of such events is warranted, particularly for newer immunizations. Sender's Comments: There is a plausible time association between the vaccination with PREVENAR 13 and the occurrence of Kawasaki disease and vasculitis. Based on the information currently available, the Company however considers the administration of concomitant vaccines especially rotavirus vaccine might have played a major contributory role in triggering the onset of the event. The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to Regulatory Authorities, Ethics Committees and Investigators, as appropriate.