Discussion
Common adverse effects of COVID-19 vaccination including local reactions, fever, myalgia, arthralgia and headache can be well tolerated in outpatient setting, but some conditions need inpatient care and somehow can be problematic or even fatal. Here in, we reported three cases of serious events of post COVID-19 AstraZeneca vaccination that hospitalized and managed successfully, including encephalopathy, CVST and LCV.
Causality assessment of adverse drug reaction (ADR) with COVID-19 vaccination based on ADR scales including Naranjo Probability Scale(10) and the WHO-UMC causality system(11) showed all discussed cases were categorized as probable but not definite cases caused by COVID-19 vaccination. Severity of ADR by COVID-19 vaccination for presented cases were evaluated by J Seigel and PJ Schneider study(12) and also Karch and Lasanga study(13), post vaccination encephalitis and VITT were classified as severe cases requiring intensive medical care which are life threatening reactions, while LCV categorized with moderate severity requiring special treatment with an increase in hospitalization by at least one day.
Encephalitis/encephalopathy is defined as inflammation of brain tissue provoked by an infection or an autoimmune response(14). The occurrence of encephalitis, according to several publicly existing databases (Welcome to GOV.UK (www.gov.uk), European Medicines Agency | (europa.eu), Paul-Ehrlich-Institut - Startseite (pei.de)), estimated to be 8 and 2 per 10 million injected shots following AstraZeneca and Pfizer-Biontech vaccines, respectively(15). Possible or confirmed diagnosis of encephalitis is determined by combination of clinical manifestations, laboratory tests, neuroimaging, and electroencephalographic studies(16). Our first case had the major criteria of encephalitis according to Venkatesan et al., presenting to medical attention with altered mental status lasting ≥24 h with no alternative cause stated, and one minor criteria of documented fever within the 72 hours prior or after presentation(16). The patient neuroimaging and CSF analysis weren’t compatible with encephalitis and EEG wasn’t performed for her, so the complete criteria for encephalitis cannot be fulfilled and encephalopathy after vaccination may be more likely. However, it doesn’t seem to be a just fever-related delirium due to patient’s age, past medical history and her clinical picture and a CNS related dysfunction is highly probable.
Previously reported post vaccination encephalopathy cases were all older than 50 years of age except for one 21 year old female, and were more common following ChAdOx1 nCov-19 administration(15)(17)(18). Fever and myalgia were commonly seen. Alike our patient, brain imaging was normal in all of these reports and no remarkable finding was seen(15)(17)(18). Two cases had abnormal findings in EEG, a 77years old male showed moderate diffuse slowing and another 77year old male presented generalized slow background in the theta range(17)(18). In terms of CSF analysis, in contrast with our patient, pleocytosis was a common finding being seen in 4 out of 5 cases and only one patient had normal WBC count with an elevated protean level(15)(17)(18).
VITT is well established side effect of AZ and many studies reported the post AZ vaccination VITT. A review by Franchini et al.(19) On previous VITT cases due to AZ vaccine showed thrombotic complications occurred 5-25 days after first dose of AZ vaccination and in majority of cases site of thrombosis was cerebral veins, while splenic vein thrombosis and pulmonary embolism were in second and third place. Our patient showed initial symptoms on first day after vaccination and admitted to hospital but discharged due to improvement of patient’s conditions. But on second admission, few days after discharge, CVST was detected on imaging and laboratory data confirmed the VITT by positive HIPA, PIPA, and anti-PF4 IgG ELISA tests.
Although vaccine-induced thrombotic thrombocytopenia (VITT) was first reported after AZ vaccination growing number of papers were recently published reporting the VITT with Johnson&Johnson(20)(21), Moderna(21)(22), and BioNTech/Pfizer(21)(23) vaccines. Due to positive anti-PF4 antibodies in both mRNA-based vaccines and vector-based vaccines it raises the question which component of vaccine is responsible to elicit response to PF4 proteins and VITT phenomenon?
LCV is a cutaneous small vessel vasculitis of dermal capillaries and venules and typically presents with a painful, burning rash predominantly in lower extremities. It is often idiopathic but can be associated with infections, neoplasms, or medications(24). However, relation between vaccination or immunization with vasculitis is not well determined, vasculitis precipitation has been reported secondary multiple vaccines including influenza virus, hepatitis B virus (HBV), Basil Calmette-Guerin (BCG), and Human papillomavirus (HPV)(25).
Skin vasculitis with cutaneous lesions have been reported during mild and fulminant COVID-19 disease(26). On the other hand, vasculitis was also reported after COVID-19 vaccination. A recent study by McMahon et al. on 417 cases of cutaneous reaction after mRNA COVID-19 vaccines, reported 0.7% and 2.9% of vasculitis after first dose of Moderna and BioNTech/Pfizer vaccines, respectively(27). Several case reports were also reported skin vasculitis following vector-based vaccines including AZ(28) and Johnson Johnson(29).