Tetanus, Diphtheria, and Pertussis Vaccine Associated UveitisDavid M Hinkle1*, John R Chancellor2, Benjamin P Hale3, Frederick T Fraunfelder4 and Frederick W Fraunfelder5
2 UMass Memorial Eye Center, University of Massachusetts Medical Center, 281 Lincoln Street, Worcester, Massachusetts, USA
3 Geisinger Medical Center, 100 N Academy Ave, Danville, USA
4 Department of Ophthalmology, Casey Eye Institute, 3303 SW Bond Ave, Portland, USA
5 Mason Eye Institute, 1 Hospital Drive, Columbia, USA
Citation: Hinkle DM, Chancellor JR, Hale BP, Fraunfelder FT, et al. Tetanus, Diphtheria, and Pertussis Vaccine Associated Uveitis. J Basic Clin Pharma 2017;8:S92-S95
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There are many reports of the widely administered vaccines causing uveitis. We analyze data from spontaneous reporting and present a specific case report to evaluate a possible relationship between the tetanus, diphtheria, and pertussis vaccine formulations and the development of uveitis. Uveitis may be a rare adverse effect of vaccines, but awareness of this potential reaction is important to clinicians and should continue to be reported.
Uveitis; adverse effect of vaccines; tetanus; diphtheria; pertussis vaccine formulations
The tetanus, diphtheria, and cellular pertussis vaccines consist of a mixture of the detoxified toxins of tetanus, diphtheria, and pertussis and one or more of the following components of B. pertussis: filamentous hemagglutinin, fimbrial antigens, and pertactin [Table 1].[1,2] Three commonly administered formulations in the United States are the DTaP, Tdap, and Td vaccines (GSK Vaccines, Triangle Park NC; Merck and Co., Inc., West Point PA; and Sanofi Pasteur, Swiftwater PA). The DTaP vaccine is approved for children under the age of seven. Children should receive 5 total doses of the DTaP vaccine given at 2, 4, 6, and 15-18 months, and 6 years of age. The Tdap vaccine (which contains lower doses of diphtheria and pertussis) and Td (contains no pertussis components) are approved for adolescents and adults starting at age 11. It is recommended that individuals receive a Td vaccine every 10 years, and one dose of TdaP between ages 11 and 64. Tetanus toxoid (TT) vaccine was approved for adults and children, but it has been replaced by combination formulas; the last doses of TT expired in 2015. These vaccines stimulate the adaptive immune system and result in the development of memory B and T lymphocytes. The most common side effects include pain, redness or swelling at the injection site, fever, headache, fatigue, nausea, vomiting, diarrhea, body aches, and joint pain. Rare but serious adverse effects include high fever, seizures (0.5 in 100,000), and anaphylaxis (0- 1.3 in 1,000,000). Ocular complications are exceedingly rare and include a partial paralysis of accommodation, transient conjunctivitis, and possible papilledema or optic neuritis.[6-9] A connection between the DTaP, Tdap, Td, and TT vaccines and uveitis has not been described. We present here a case of bilateral, simultaneous anterior uveitis, optic papillitis and retinal vacuities associated with Tdap vaccine and 40 additional reports from the spontaneous reporting databases.
|DTaP||Daptacel||DTaP||Sanofi||Inactivated Bacterial/IM||2002||Tetanus and diphtheria toxoids and acellular pertussis vaccine|
|DTaP||Infanrix||DTaP||GlaxoSmithKline||Inactivated Bacterial/IM||1997||Tetanus and diphtheria toxoids and cellular pertussis vaccine|
|DT||Generic||DT||Sanofi||Inactivated Bacterial/IM||1978||Pediatric formulation through age 6|
|DTaP, Polio||Kinrix||DTaP-IPV||GlaxoSmithKline||Inactivated Bacterial and Viral/IM||2008||Licensed for 5th (DTaP) and 4th (IPV) booster at 4-6 years|
|DTaP, hepatitis B, Polio||Pediatrix||DTaP-HepB-IPV||GlasoSmithKline||Inactivated Bacterial and Viral/IM||2002||Licensed for doses at 2, 4, and 6 months (through 6 years of age). Not licensed for boosters|
|DTaP, Polio, Haemophilus influenza type b||Pentacel||DTaP-IPV/Hib||Sanofi||Inactivated Bacterial and Viral/IM||2008||Licensed for 4 doses at 2,4, 6, and 15-18 months|
|Tetanus, (reduced) Diphtheria||Decavac||Td||Sanofi||Inactivated Bacterial Toxoids/IM||1955||Adult formulation (age 7 and older)|
|Tetanus, (reduced) Diphtheria||Tenivac||Td||Sanofi||Inactivated Bacterial Toxoids/IM||2003||Adult formulation (age 7 and older)|
|Tetanus, (reduced) Diphtheria||Generic||Td||Massachusetts Biological Labs||Inactivated Bacterial Toxoids/IM||1967||Adult formulation (age 7 and older)|
|Tetanus,(reduced)Diphtheria, (reduced) Pertussis||Boostrix||Tdap||GlaxoSmithKline||Inactivated Bacterial/IM||2005||Tetanus, diphtheria toxoids and pertussis vaccine. Minimum age = 10 years|
|Tetanus,(reduced)Diphtheria, (reduced) Pertussis||Adacel||Tdap||Sanofi||Inactivated Bacertial/IM||2005||Tetanus, diphtheria toxoids and acellular pertussis vaccine. Age 10 through 64 years|
|Tetanus Toxoid||Generic||TT||Sanofi||Inactivated Bacterial Toxoids/IM||1970||Used for adults or children. Discontinued April 2013. Last doses expired January 2015.|
Table 1: Various tetanus, diphtheria, and pertussis vaccine formulations
Spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland OR), the World Health Organization’s Uppsala Monitoring Center (Uppsala, Sweden) and Food and Drug Administration (Bethesda, MD) were collected on uveitis associated with tetanus-based vaccine formulations between December 1993 and February 2016. A Medline literature search was performed using keywords “uveitis,” “iritis,” “iridocyclitis,” “diphtheria,” “tetanus,” and “pertussis.” Data was reviewed on the spontaneous reports and collected for age, gender, adverse drug reaction (ADR), time between vaccination and ADR and de-challenge data. A case report from 2012 is presented.
A 38 year old female with a history of migraine headaches developed jaw and frontal head pain and sought care at an emergency department where her intraocular pressure was noted to be elevated. Past medical history revealed vaccination with Tdap (Adacel Sanofi Pasteur Inc, Swiftwater, PA) 2 weeks prior to onset of symptoms. Uncorrected visual acuity was 20/20 each eye. Intraocular pressure was 24 in both eyes. Conjunctival injection was present in both eyes. The cornea demonstrated post LASIK changes and inferior keratic precipitates in both eyes. The anterior chamber reaction was graded as 3+cell in both eyes. Trace vitreous cells were present in both eyes and fluorescein angiography demonstrated late hyperfluoresence of the optic discs. Serologic work-up disclosed evidence of prior exposure to Epstein Barr virus. Magnetic resonance imaging of brain and orbits with gadolinium contrast was unremarkable. Physical examination and additional serologic evaluations were performed by her primary care physician and a rheumatologist, however no underlying cause for her uveitis was discovered. Repeat fluorescein angiography demonstrated perivenular leakage adjacent to the optic disc in both eyes [Figure 1]. She was treated with oral prednisone 60 mg daily with a gradual taper over 4 months. Prednisone was discontinued and uveitis symptoms have not recurred after an additional 27 months.
There were a total of 41 cases of ocular inflammation following administration of DTaP, Tdap, and Td vaccines [Table 2]. Fourteen cases were classified as uveitis (6 uveitis, 4 iritis, 2 iridocyclitis, 1 choriditis, 1 chorioretinitis). An additional 27 cases of “eye inflammation” were reported; however, there was insufficient data to determine if these were cases of uveitis. The majority of patients (61%) were female. The median age of patients was 8.5 years with a range of 2 months to 67 years. The median time from Vaccination to onset of ocular symptoms was 1 day (range 0-74 days). In total, 21 patients received the DTaP vaccine, 4 received the Tdap vaccine, 12 received the Td vaccine, and 4 received tetanus vaccine. Six patients also received other vaccines concurrently.
|Age||Gender||Drug||Start Date||Onset Date||Time to Onset (days)||Dechallenge||Side|
|0.279 50||Male Female||Tetanus/diphtheria/pertussis/ polio/hep b tetanus/diphtheria||12/7/07 10/17/08||1||Eye Inflamed Iritis|
|0.5 1.3||Female Female||Tetanus/diphtheria/hep b/ pertussis/polio tetanus/diphtheria/pertussis||1/7/04 5/10/04||1/15/04 5/11/04||8 1||Eye Inflamed Eye Inflamed|
|0.5 12||Male Male||Tetanus/diphtheria/hep b/ pertussis/polio tetanus/diphtheria/pertussis||9/13/06 1/5/07||9/14/06 3/20/07||1 74||Eye Inflamed Iritis and Iridocyclitis|
|52||Female Female||Tetanus/diphtheria/hep b/ pertussis/polio tetanus/diphtheria/pertussis||8/14/07 2/19/07||8/16/07 3/5/07||2 14||Eye Inflamed Iritis|
|4 39||Female Female||Pertussis & tetanus/diphtheria/ polio
|1/9/03 1/21/04||1/19/03 1/30/04||10 9||Uveitis Uveitis|
Table 2: Spontaneous reports of eye inflammation and uveitis following vaccination with various tetanus, diphtheria, and pertussis vaccine formulations between 1993 and 2016
Post marketing surveillance systems suffer from underreporting, incomplete information, and lack of follow-up. These systems, however, provide an early signal of a possible adverse reaction by revealing information on the temporal relationship between vaccine administration and the development of the side-effect, pattern of presentation, and dechallenge and rechallenge data that may suggest possible, probable, or certain causation of an adverse vaccine event. Spontaneous reports may give the first signal that a vaccine is causing an adverse reaction, because clinical trials in the premarketing phase of vaccine development do not expose millions of subjects to a vaccine. Uveitis may follow vaccination against several bacteria and viruses. Varicella-zoster vaccine (Zostavax, Merck, Whitehouse Station, NJ) has been associated with exacerbation of pre-existing uveitis and de novo cases. Live, attenuated bacillus Calmein-Guerin (BCG) has also been associated with uveitis. HPV vaccination (Gardasil, Merck, Whitehouse Station NJ) was possibly associated with uveitis in 23 cases. One adolescent woman developed bilateral anterior uveitis 2 weeks after administration of the HPV vaccine; rechallange with the second and third vaccination in the series led to recurrent uveitis on both occasions. Studies have also been presented suggesting a probable link between MMR, Influenza, and Hepatitis B vaccines and uveitis.  The pathogenesis of uveitis following DTap, Tdap, Td, and tetanus vaccination cannot be explicitly elicited by surveillance data alone. Interestingly, most cases occurred shortly after administration of the first dose. This suggests one possible mechanism may include an immune-mediated delayed-type hypersensitivity reaction. Antigenic mimicry may be possible in certain patients that experience crossreactivity between host proteins and the components of the vaccine. The vaccine is designed to simulate an immune response and release of proinflammatory cytokines, and this response could inadvertently lead to activation of preexisting auto reactive T and B cells. The inflammatory response may also damage native tissues and lead to release of potentially auto reactive hidden antigens. Antigenic complementarity might occur if the various vaccine protein components stimulated B and T cells that, in turn, recognized one another as antigens.
In addition, data shows that pertussis toxin is capable of inducing experimental autoimmune uveitis in mice. In the study, pertussis toxin enhanced production of the Th1 cytokines IFN-y and TNF-alpha. The authors hypothesized that experimental autoimmune uveitis may be based upon pertussis-induced disruption of the blood eye/brain barrier and enhancement/activation of inflammatory cells. These mechanisms have also been proposed as potential causes of uveitis after administration of other vaccines.[10-15] 161 Clinicians should be aware of the association of uveitis following DTaP, Tdap, Td, and tetanus vaccination. If vaccine-associated adverse ocular event is suspected, reporting the case to the National Registry of Drug-Induced Ocular Side Effects (available at: www.eyedrugregistry.com) or the Vaccine Adverse Event Reporting System (VAERS) (available at vaers.hhs.gov) could help track these adverse events in the future.
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