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\begin{document}

\title{Drug induced vasculitis , Thiazide or COVID-vaccine ? : A case report
and literature review}



\author[1]{Manoochehr Hekmat}%
\author[1]{ Sepideh Jafari Naeini}%
\author[1]{Zahra Abbasi}%
\author[1]{Sahar Dadkhahfar}%
\affil[1]{Shahid Beheshti University of Medical Sciences}%


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  \date{May 24, 2024}


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\begin{abstract}
A middle-aged woman with history of the administration of COVID-19
vaccine and valve replacement surgery before her symptoms, was admitted
with bilateral palpable purpuric lesions in the lower extremities and
headache . Based on the initial diagnosis of vasculitis , corticosteroid
therapy was initiated and resolved the skin lesion%
\end{abstract}%



\sloppy


\textbf{Drug induced vasculitis , Thiazide or COVID-vaccine ? : A case
report and literature review}

Manoochehr Hekmat \textsuperscript{1} , Sepideh Jafari
Naeini\textsuperscript{2*} , Zahra Abbasi \textsuperscript{3}, Sahar
Dadkhahfar \textsuperscript{4}

1 Department of cardiovascular surgery , Shahid Modarres Hospital ,
Shahid Beheshti university of medical sciences , Tehran , Iran

2 Cardiovascular research center , Shahid Beheshti university of medical
sciences , Tehran , Iran

3 Department of Internal medicine , Shahid Modarres Hospital , Shahid
Beheshti university of medical sciences , Tehran , Iran

4 Skin research center , Shahid Beheshti university of medical sciences
, Tehran , Iran

*Corresponding author : Sepideh Jafari Naeini

Cardiovascular research center , Shahid Beheshti university of medical
sciences , Tehran , Iran

Tel: 00982123515 , Email: sdnaeini@yahoo.com

Abstract

A middle-aged woman with history of the administration of COVID-19
vaccine and valve replacement surgery before her symptoms, was admitted
with bilateral palpable purpuric lesions in the lower extremities and
headache . Based on the initial diagnosis of vasculitis , corticosteroid
therapy was initiated and resolved the skin lesion .

keywords : vasculitis, warfarin , COVID-19 vaccines ,thiazides

Key clinical message : Drug induced vasculitis should be considered in
the setting of vasculitis after the initiation of a new medication or
the administration of COVID vaccines.

Introduction

Drug induced vasculitis (DIV) can be presented with a broad spectrum of
clinical signs and symptoms . As an inflammatory process in blood
vessels , it may affect different organs with localized or systemic
manifestations . Initial diagnosis should be made after the exclusion of
infectious diseases ( especially parasitic infections ), autoimmune
collagen vascular diseases and different related neoplasms (1, 2). Here
,we present a case of drug induced vasculitis with a specific initial
presentation and course .

Case Presentation

A 55 year-old woman was admitted with progressive palpable purpura in
both lower extremities and pruritus without systemic symptoms such as
arthralgia or myalgia (Figure 1). Her symptoms had been initiated 3 days
before admission and some of her lesions were hemorrhagic. Concomitantly
, she had complained of a vague headache during the days prior to being
hospitalized. She had a history of mitral and aortic valve replacement
(mechanical valve) 1 week prior and injection of a COVID-19 vaccine
(Sinopharm BIBP COVID-19 vaccine) 3 weeks prior to the onset of symptoms
and hypothyroidism. She was discharged after cardiac surgery with
warfarin , hydrochlorthiazide (HCTZ) ( 25 mg once daily ) , propranolol
, levothyroxine and pantoprazole

On admission, she was completely alert with stable vital signs (blood
pressure =120/75mmHg , pulse rate= 80 /minute , respiratory rate =14 per
minute without fever .Laboratory tests revealed creatinine =1.4 mg/dl ,
total bilirubin=1.6mg/ dl , direct bilirubin =0.2 mg/ dl , white blood
cells=7300/cm3 , International normalized ratio (INR) =3.7 ,negative
serology and polymerase chain reaction (PCR) for COVID-19 infection ,
qualitative C-reactive protein (CRP) =2+ and thyroid stimulating hormone
(TSH) = 16.4 mIU/ml . All the rheumatologic tests, including antinuclear
antibody (ANA) , Antineutrophil cytoplasmic antibodies (ANCA) ,
Rheumatoid factor (RF), Anti RO , anti double stranded DNA (anti ds DNA)
, Anti-CCPs (cyclic interlineated peptides) were negative and complement
levels were normal.

Echocardiography demonstrated normal biventricular size and function
with a large pericardial effusion (about 30 mm) posterior to the left
ventricle without a compressive effect . A spiral brain computed
tomography ( CT) scan was performed, which showed evidence of acute and
subacute foci of subdural hematoma adjacent to the left temporal lobe .

As a result , we had to transiently hold the administration of the
anticoagulant regimen until the next CT scans confirmed the
stabilization of the hemorrhagic area without expansion (48 hours and 5
days later).

Rheumatology and dermatology consultations were requested and the
initiation of corticosteroid therapy was recommended based on the
diagnosis of vasculitis . The patient refused to undergo skin biopsy and
methylprenosiolone 1 gr/ day was initiated based on the clinical
scenario, which led to rapid improvement of the lesions (Figure 2 )
.Oral prednisolone was continued and tapered over the next 2 months and
colchicin 1 mg /d was initiated and continued for 2 months . The patient
did not show any complications and the next brain CT showed elimination
of the hemorrhagic focus . She received a second dose of sinopharm 2
months after the first dose without complications and underwent drainage
of a massive pericardial effusion 3 months later .

Discussion

Leukocytoklastic vasculitis (small vessel vasculitis with neutrophil
infiltration ) due to different medications has been reported to be the
cause of 1/3 of cases of cutaneous vasculitis (1, 3-5) . Drug induced
vasculitis (DIV ) can involve different size vessels but is less
established in large vessels, such as the aorta. Although not very
prevalent , concomitant involvement of cerebral vasculature has also
been reported (4). The diagnosis of DIV should be made by exclusion of
other probable causes as it is mentioned before (1) .

Although warfarin has been considered to be the potential cause of
vasculitis (6, 7) , we were not able to discontinue it in our patient
due to the necessity of its administration following mechanical valve
replacement . Absence of the recurrence of the symptoms after the
discontinuation of corticosteroids made it less likely to consider
warfarin as the probable cause of vasculitis because based on previous
reports , and contrary to our study, clinical symptoms have relapsed in
most cases after reinitiating warfarin (3) . Another potential cause for
the occurrence of vasculitis is the use of thiazides, which has been
known for many years (1) .Although our patient received a low dose of
hydrochlorthiazide (HCTZ) (25mg once daily ), drug induced vasculitis
due to HCTZ could not be ruled out . Finally, we were curious whether
the administration of COVID vaccines could result in vasculitis
.Although there have recently been some reports about the use of mRNA
based COVID vaccines as a cause of leukocytoclastic vasculitis (8-12) ,
the role of inactivated whole virus vaccines such as Sinopharm , Sinovac
(CoronaVac) and COVAXIN (Bharat Biotech) should not be overlooked
(13-15) .

By discontinuing thiazides and receiving an immunosuppressive regimen ,
the patient showed significant improvement and all the lesions
disappeared early after the initiation of corticosteroids . Hemorrhagic
stroke responded well to this treatment and resolved gradually .She was
admitted three months later for the drainage of a massive pericardial
effusion without any complications.

Conclusion :

Irrespective of low prevalence , drug induced vasculitis should be
considered in the presence of vasculitis of unknown origin .Recently
,multiple cases of COVID vaccine induced vasculitis have been reported,
which necessitates further evaluation for the diagnosis of the
underlying cause.

Conflict of interest : None declared

Funding :None

Authors contributions :

SJ , MH : Data gathering, Editing the text

ZA , S D : Editing the text

SD , ZA : Writing the text

Ethical statement and acknowledgement:

Written informed consent was obtained from the patient who participated
in this study. This case report did not receive any funding. Authors had
access to all source data for this case report.

Data availability statement :

The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.

References :

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vasculitis: an overview and dermatological clues for clinical and
histopathological diagnosis - part I. An Bras Dermatol
2020;95(3):355-71.

2. Radi\selectlanguage{polish}ć \selectlanguage{english}M, Martinovi\selectlanguage{polish}ć \selectlanguage{english}Kaliterna D, Radi\selectlanguage{polish}ć \selectlanguage{english}J. Drug-induced vasculitis: a
clinical and pathological review. Neth J Med 2012;70(1):12-7.

3. Hsu CY, Chen WS, Sung SH. Warfarin-induced leukocytoclastic
vasculitis: a case report and review of literature. Intern Med
2012;51(6):601-6.

4. Misra D, Patro P, Sharma A. Drug-induced vasculitis. Indian J
Rheumatol 2019;14(5):3-9.

5. Altomare M, Jaulent C, Hacard F, Nicolas JF, Berard F, Nosbaum A.
Drug-induced cutaneous leukocytoclastic vasculitis: a series of 5 cases.
World Allergy Organ J 2020;13(8).

6. Jumean K, Arqoub AA, Hawatmeh A, Qaqa F, Bataineh A, Shaaban H.
Warfarin-induced leukocytoclastic vasculitis and proteinuria. J Family
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7. Elantably D, Mourad A, Elantably A, Effat M. Warfarin induced
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Thrombolysis 2020;49(1):149-52.

8. Bostan E, Zaid F, Akdogan N, Gokoz O. Possible case of mRNA COVID-19
vaccine-induced small-vessel vasculitis. Journal of Cosmetic Dermatology
2021;n/a(n/a).

9. Cavalli G, Colafrancesco S, De Luca G, Rizzo N, Priori R, Conti F,
Dagna L. Cutaneous vasculitis following COVID-19 vaccination. The Lancet
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10. Shakoor MT, Birkenbach MP, Lynch M. ANCA-Associated Vasculitis
Following Pfizer-BioNTech COVID-19 Vaccine. Am J Kidney Dis
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11. M\selectlanguage{ngerman}ücke VT, Knop V, Mücke MM, Ochsendorf F, Zeuzem S. First
description of immune complex vasculitis after COVID-19 vaccination with
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12. Dicks AB, Gray BH. Images in Vascular Medicine: Leukocytoclastic
vasculitis after COVID-19 vaccine booster. Vasc Med
2021:1358863x211055507.

13. Bencharattanaphakhi R, Rerknimitr P. Sinovac COVID-19
vaccine-induced cutaneous leukocytoclastic vasculitis. JAAD Case Rep
2021;18:1-3.

14. Kharkar V, Vishwanath T, Mahajan S, Joshi R, Gole P. Asymmetrical
cutaneous vasculitis following COVID-19 vaccination with unusual
eosinophil preponderance. Clinical and Experimental Dermatology
2021;46(8):1596-7.

15. Fernández P, Alaye ML, Chiple MEG, Arteaga J, Douthat W, Fuente J,
Chiurchiu C. Glomerulopathies after vaccination against COVID-19. Four
cases with three different vaccines in Argentina. Nefrologia 2021.\selectlanguage{english}
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