This article is a commentary on:
Pituitary apoplexy and COVID-19 vaccination: a case report and literature review
Ach Taieb
Ben Abdelkrim Asma1,2- 1Department of Endocrinology, University Hospital of Farhat Hached, Sousse, Tunisia
- 2University of Sousse, Faculty of Medicine of Sousse, Sousse, Tunisia
- 3Laboratory of Exercise Physiology and Pathophysiology, University Hospital of Farhat Hached, Sousse, Tunisia
- 4Department of Internal Medicine, University Hospital of Charles Nicolle, Tunis, Tunisia
by Aliberti L, Gagliardi I, Rizzo R, Bortolotti D, Schiuma G, Franceschetti P, Gafà R, Borgatti L, Cavallo MA, Zatelli MC and Ambrosio MR (2022)
Evidences that SARS-CoV-2 Vaccine-Induced apoplexy may not be solely due to ASIA or VITT syndrome', Commentary on Pituitary apoplexy and COVID-19 vaccination: A case report and literature review
13:1035482. doi: 10.3389/fendo.2022.1035482
1 Introduction
The present commentary aims to discuss certain diagnostic and pathophysiological aspects of pituitary apoplexy in the case reported by Aliberti et al. (2022) (1).
The report states the occurrence of pituitary apoplexy following the third dose of Moderna vaccine. It is the fourth case, to date, to report this adverse event (2–4), the second to report it in a patient with a pituitary adenoma (4), and the first of its kind to confirm the persistent presence of traces of SARS-CoV-2 infection as confirmed by histopathological examination of a pituitary biopsy.
As a complement to the first and recently published review of pilot findings addressing SARS-CoV-2 vaccine-induced pituitary diseases (5), we will briefly discuss other interesting elements concerning this entity that will be highlighted by this report.
2 Pituitary adenoma patients are at a higher risk of vaccine-induced apoplexy
It is interesting to mention that before the case of Aliberti et al. (1), only Piñar-Gutiérrez et al. have reported pituitary apoplexy in a patient with a pituitary adenoma (4). The incident occurred 5 days after the first dose of AstraZeneca vaccine, and the MRI showed an adenohypophysis hemorrhage in association with a 10-mm intraglandular adenoma. Pituitary adenomas in men, if not prolactin- or growth hormone (GH)-secreting, are usually nonfunctional and large (>10 mm) (6). It is not uncommon to discover them following an event-induced apoplexy, as mentioned by the authors. In cases of apoplexy linked to vaccines, pituitary bleeding can be due either to vaccine-induced thrombophilia–thrombocytopenia (VITT) syndrome or to autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) syndrome (5). The ASIA syndrome can only be confirmed by a histopathological study. However, VITT has diagnostic criteria that have been recently updated to fit the context of post-vaccine thrombosis (7).
According to these recommendations, the presence of the following criteria is required to diagnose VITT syndrome:
1. COVID-19 vaccine at 4 to 42 days prior to symptom onset
2. any venous or arterial thrombosis
3. thrombocytopenia (platelet count <150 × 109/L)
4. positive Platelet factor 4 (PF4) heparin-induced thrombocytopenia (HIT) ELISA
5. elevated D-dimer (>4× upper limit of normal)
Upon reading the case of Aliberti et al. (1), several elements suggest that these two pathophysiological hypotheses are not easily applicable in this case. Firstly, several major criteria of VITT are not fulfilled: The patient had a rapid onset of the disease (on vaccination day) and a platelet count superior to 150 × 109/L (170 × 109/L). Secondly, the rapid onset of the disease cannot be explained by an inflammatory or an autoimmune mechanism as such processes require a longer time interval to have clinical consequences (8). In comparison, other cases of SARS-CoV-2 vaccine-induced pituitary diseases report a delay of a few days for the beginning of symptoms (3 days on average) (9).
The rapid onset of apoplexy suggests that the patient’s pituitary gland already has fragility or a pathological state that predisposes it to bleeding. Pituitary adenoma, which is due to a richly vascularized cellular hyperplasia, can be the cause of such a delicate state (6). Several authors have already mentioned the fragility of pituitary adenomas to chemical or physical stimuli, making the risk of hemorrhage a major one (10).
3 An alternative hypothesis to vaccine-induced thrombophilia–thrombocytopenia or autoimmune/autoinflammatory syndrome induced by adjuvants syndrome
The originality in the case presented by Aliberti et al. (1) is the existence of a histopathological proof of asymptomatic infection by SARS-CoV-2. Several authors have confirmed the involvement of this virus in endothelial damage, which seems to explain the persistence of the “long-standing COVID-19” state (11). Two articles have even proved the possibility of pituitary insufficiencies as sequelae in previously infected patients. Urhan et al. have identified a corticotropic insufficiency in nearly 10% of cases and a GH insufficiency in nearly 50% of cases in patients infected by COVID-19, without notable hypopituitarism manifestations (12). These disorders persisted for several months after the infection and even longer (up to 15 months), as mentioned by Yoshimura et al. in their analysis (13).
We can therefore assume that in patients with an adenomatous pituitary gland weakened by an asymptomatic infection, there is an increased hemorrhagic risk caused by the vaccine. In this case, the VITT syndrome or the ASIA syndrome could initiate hemorrhage and be expressed quite rapidly, even on the first day of injection, aggravated by the fragility of the pituitary gland. This is further supported by the SARS-CoV-2 nuclear protein expression next to pituitary vessels, in the presence of an evident lymphocyte infiltrate (1). Therefore, this pathophysiological hypothesis supports the rapidity of the onset of apoplexy in both cases reported by Aliberti et al. (1) and Piñar-Gutiérrez et al. (4) since the patients had, concomitantly, a pituitary macroadenoma.
4 Summary and conclusions
In summary, the case of Aliberti et al. (1) gives insight or helpful information for the understanding of SARS-CoV-2 post-infectious pituitary lesions by confirming the existence of persistent endothelial damage even in asymptomatic patients or after recovery. This damage to the adenomatous pituitary gland could further weaken it and cause hemorrhage upon exposure to the COVID-19 vaccine. This case emphasizes the need for clinicians to be aware of pituitary involvement in genuine COVID-19 infections. The two cases of Aliberti et al. (1) and Piñar-Gutiérrez et al. (4) should prompt greater caution when vaccinating patients with pituitary adenomas because of the additional risk of apoplexy that could be caused by the vaccine (5). Currently, this remains true as the need for COVID vaccination persists, at least seasonally, in the years to come. Other cases could emerge in the future and may better explain the interrelation that might exist between pituitary ACE-2 receptors, the coronavirus, and the anti-COVID-19 vaccine.
Author contributions
AT drafted the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Aliberti L, Gagliardi I, Rizzo R, Bortolotti D, Schiuma G, Franceschetti P, et al. Pituitary apoplexy and COVID-19 vaccination: A case report and literature review. Front Endocrinol (2022) 13. doi: 10.3389/fendo.2022.1035482
2. Zainordin NA, Hatta S, Ab Mumin N, Shah FZM, Ghani RA. Pituitary apoplexy after COVID-19 vaccination: A case report. J Clin Trans Endocrinol Case Rep (2022) 25:100123. doi: 10.1016/j.jecr.2022.100123
3. Roncati L, Manenti A. Pituitary apoplexy following adenoviral vector-based COVID-19 vaccination. Brain Hemorrhages (2022) 4(1):27–29. doi: 10.1016/j.hest.2022.04.002
4. Piñar-Gutiérrez A, Remón-Ruiz P, Soto-Moreno A. Case report: Pituitary apoplexy after COVID-19 vaccination. Med Clin (Engl Ed) (2022) 158(10):498–9. doi: 10.1016/j.medcli.2021.09.028
5. Taieb A, Mounira EE. Pilot findings on SARS-CoV-2 vaccine-induced pituitary diseases: A mini review from diagnosis to pathophysiology. Vaccines (2022) 10(12):2004. doi: 10.3390/vaccines10122004
6. Capatina C, Inder W, Karavitaki N, Wass JAH. MANAGEMENT OF ENDOCRINE DISEASE: Pituitary tumour apoplexy. Eur J Endocrinol (2015) 172(5):R179–R90. doi: 10.1530/EJE-14-0794
7. Favaloro EJ, Pasalic L, Lippi G. Review and evolution of guidelines for diagnosis of COVID-19 vaccine induced thrombotic thrombocytopenia (VITT). Clin Chem Lab Med (2022) 60(1):7–17. doi: 10.1515/cclm-2021-1039
8. Taieb A, Sawsen N, Asma BA, Ghada S, Hamza E, Yosra H, et al. A rare case of grave’s disease after SARS-CoV-2 vaccine: Is it an adjuvant effect? Eur Rev Med Pharmacol Sci (2022) 26(7):2627–30. doi: 10.26355/eurrev_202204_28500
9. Ach T, Kammoun F, Fekih HE, Slama NBH, Kahloun S, Fredj FB, et al. Central diabetes insipidus revealing a hypophysitis induced by SARS-CoV-2 vaccine. Therapies (2022) 10(12):2004. doi: 10.3390/vaccines10122004
10. Khaldi S, Saad G, Elfekih H, Ben Abdelkrim A, Ach T, Kacem M, et al. Pituitary apoplexy of a giant prolactinoma during pregnancy. Gynecol Endocrinol (2021) 37(9):863–6. doi: 10.1080/09513590.2021.1938527
11. Oikonomou E, Souvaliotis N, Lampsas S, Siasos G, Poulakou G, Theofilis P, et al. Endothelial dysfunction in acute and long standing COVID-19: A prospective cohort study. Vasc Pharmacol (2022) 144:106975. doi: 10.1016/j.vph.2022.106975
12. Urhan E, Karaca Z, Unuvar GK, Gundogan K, Unluhizarci K. Investigation of pituitary functions after acute coronavirus disease 2019. Endocrine J (2022) 69(6):649–58. doi: 10.1507/endocrj.EJ21-0531
Keywords: COVID-19, SARS-CoV-2, vaccine, apoplexy, hypophysitis, pituitary adenoma
Citation: Taieb A, Asma BA and Mounira EE (2023) Evidences that SARS-CoV-2 Vaccine-Induced apoplexy may not be solely due to ASIA or VITT syndrome', Commentary on Pituitary apoplexy and COVID-19 vaccination: A case report and literature review. Front. Endocrinol. 14:1111581. doi: 10.3389/fendo.2023.1111581
Received: 22 December 2022; Accepted: 05 January 2023;
Published: 25 January 2023.
Edited by:
Lucio Vilar, Federal University of Pernambuco, BrazilReviewed by:
Katherine Araque, Corcept, United StatesCopyright © 2023 Taieb, Asma and Mounira. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ach Taieb, ach.taieb@gmail.com