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\begin{document}

\title{Covid-19 Vaccine as a potential triggering factor for Anti-GBM disease,
A case report and systematic review}



\author[1]{Mohanad  Ahmed}%
\author[1]{Sabah  Mohamed}%
\author[1]{Rayan Sibira}%
\author[1]{Isra Eltazi}%
\author[1]{Hussein Al-hussein}%
\author[1]{Ahmad  Salih Abdulhadi}%
\affil[1]{Hamad Medical Corporation}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\maketitle
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\selectlanguage{english}
\begin{abstract}
COVID-19 vaccine side effects are still a hot area under study, Many
side effects have been identified, and others are still under study.
Herein, we are reporting a patient who developed Rapidly Progressive
Glomerulonephritis due to anti-GBM disease two days after receiving the
COVI-19 vaccine.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

The novel coronavirus 2019 (COVID-19) pandemic that has been causing
striking worldwide extensive morbidity and mortality during the past two
years was followed by heroic research and vaccine discoveries, altering
the course of the illness in a more benign direction. The worldwide
vaccination campaigns are of clear benefit. Still, adverse events that
were not previously observed during clinical trials are now sprouting
and should remain in focus and must be tracked and followed up
vigilantly. Interestingly, there has been an upward trend in reporting
cases of unmasking/reactivation of glomerular disease after receiving
mRNA vaccines.

Antiglomerular basement membrane (anti-DBM) disease is an autoimmune
vasculitis disease characterized by the production of autoantibodies
against type IV collagen present in basement membranes affecting both
kidneys and lungs. These autoantibodies cause capillaritis at the
mentioned sites, and patients usually succumb to rapidly progressive
glomerulonephritis and alveolar bleeding. Diagnosis is made by linking
clinical data and serologic testing, though renal biopsy is required for
confirmation {[}1{]}. Like most autoimmune diseases, anti-GBM disease
occurs in genetically predisposed individuals after a specific insult
such as an infection, drugs, environmental exposure, etc. {[}2{]}.

During the COVID era, accelerated vaccine production has been observed.
The different vaccines use different mechanisms to generate immunity.
Pfizer BNT162b2 and Moderna mRNA-1273 use a pioneer mechanism, a lipid
nanoparticle nucleoside-modified mRNA encodes SARS-CoV-2 spike (S)
protein which medicates host attachment and viral entry. AstraZeneca
uses a replication-deficient chimpanzee adenovirus vector containing the
SARS-CoV-2 S protein. It has been shown recently that vaccines,
specifically mRNA-based ones, are linked to the development of
glomerular disease {[}3{]}.

\textbf{Case Report/Case Presentation}

We are presenting a 26 years old male, previously healthy, working as a
labor in a building company. The patient was sent on 16th August 2021 to
our medical department from a field hospital complaining of cough,
hemoptysis, shortness of breath, and feeling fatigued for seven days
which increased in severity in the last two days. He mentioned no chest
pain or fever. On further questioning, he said he received the COVID-19
vaccine (Moderna) second dose on 14th August, while the first was given
on 17th July. Currently, he doesn't smoke, consume alcohol, or take any
medications. On examination, the patient looked in mild respiratory
distress. His vital signs showed a respiratory rate of 23 cycles/min,
pulse rate of 98 beats/min, and Blood pressure of 115/76 mmHg. He was
afebrile, and his Oxygen saturation was 96\% on room air. Chest
examination was significant for diffuse bilateral crackles with
scattered wheezes. Cardiovascular, abdomen, and neurologic exams were
unremarkable. The patient was started on salbutamol nebulization while
blood tests and chest X-rays were requested.

Initial lab results were significant for a Hemoglobin (Hb) of 5.6 gm/dl;
platelets count was 231,000/mcl; blood urea was 15 mmol/l; creatinine
was 641umol/l; potassium was 4.1 mmol/l, and bicarbonate was 18 mmol/l.
The chest X-ray showed bilateral diffuse airspace opacity and patchy
consolidative changes at both lung parenchyma with background lung
nodular shadow (Figure 1).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure1. Chest X-ray on initial presentation showed bilateral diffuse
airspace opacity and patchy consolidative changes at both lung
parenchyma.

Initial management included transfusion to two units of packed red blood
cells, starting antibiotics to cover the possibility of community
acquired pneumonia while the admission process was initiated.

Ultrasound scan of both kidneys showed normal size and no evidence of
obstruction. The next day, the patient laboratory tests showed no
improvement in his renal parameters, and he started to feel more
shortness of breath. Computed tomography (CT) scan of the chest was done
(figure 2), followed by bed Bedside bronchoscopy, and the presence of
pulmonary hemorrhage was confirmed.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2. CT of the chest showing Bilateral diffuse consolidation with
centrilobular nodules, in keeping with alveolar space disease

The patient was started on pulse steroids, and an anti-glomerular
basement membrane antibodies test was sent. On 19th August 2021,
echocardiography was done and reported as normal, followed by an
ultrasound-guided kidney biopsy on the same day.

Although the patient was started on steroids, he continued to
deteriorate. His oxygen requirement increased, Renal parameters
worsened, and he developed lower limb edema, followed by decreased urine
output. At this point, the patient was shifted to the intensive care
unit, central line inserted and the nephrology team started him on
regular hemodialysis. On 20th August, the report of anti-GBM antibody
was released. It was positive (titter = 550.0 U/mL). Plasmapheresis
started and planned to be continuous with weekly measuring the antibody
titter till it becomes negative. In addition to that, the patient was
started on Cyclophosphamide 100 mg daily, and the plan was to continue
for a total of three months. On 23rd August, the biopsy result was
reported as Crescentic glomerulonephritis, consistent with Anti-GBM
disease (Figure 3).

\textbf{Pathological Finding:}

Kidney biopsy (Figure.3, A-C) showed 24 glomeruli, 23 glomeruli show
extra capillary cellular crescents, but none show fibro cellular/fibrous
crescents. The crescents are temporally homogenous at the same age and
stage and fill the space delineated by Bowman's capsule (Figure.3, A-B),
some show rupture of Bowman's capsule. Some glomeruli show active
periglomerular inflammation (Figure.3, A). Mild tubular atrophy and
interstitial fibrosis were also noted (10-15\% of the cortical tissue),
associated with moderate multifocal interstitial inflammatory infiltrate
composed of lymphocytes and occasional eosinophils. Direct
immunofluorescent microscopy showed linear staining of IgG (Figure.3,
C), complement component C3, and light chains (kappa and lambda) along
the glomerular basement membrane. These findings of Crescentic
glomerulonephritis are consistent with Anti-Glomerular Basement Membrane
(GBM) glomerulonephritis.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 3 (A) Uniform cellular crescents with periglomerular inflammation
(H\&E, x200).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 3 (B) Remnants of GBM surrounded by cellular crescents, which
fill the space delineated by Bowman's capsule (Jones silver stain,
x200).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

Figure 3 (C) Strong linear ribbon-like appearance IgG (2+) in the GBM,
the glomerulus is compressed by a crescent, which does not stain (Direct
immunofluorescence on frozen kidney tissue, x200).

The patient was kept on plasmapheresis, hemodialysis, Cyclophosphamide
while steroids were switched to oral with tapering down after five days
of intravenous pulse steroids.

A few days later, the patient showed significant improvement in his
clinical condition and laboratory tests. His renal function improved,
and symptoms were resolved, so hemodialysis frequency was reduced. His
weekly titter of anti-GBM antibody was steadily declining with
plasmapheresis. After three weeks, the measured titter dropped from 500
U/mL to 7 U/mL. Plasmapheresis was stopped while he was kept on regular
hemodialysis three times per week in addition to Cyclophosphamide 100 mg
daily.

\textbf{Discussion:}

Since the start of the covid-19 vaccination, the temporal association
between the vaccine and the development of de novo or relapse of
glomerular diseases, including anti-GBM, has been studied {[}4{]}.
However, the pathogenesis of vaccine-associated glomerular disorders has
not been fully elucidated. On checking the literature, we found a
minimal number of reported cases of de novo anti-GBM disease following
COVID-19 vaccine ''in particular mRNA vaccines'' {[}5,6,7{]}.

Anti-GBM is a rare disease with a bimodal distribution. The majority of
the young patients present with pulmonary manifestations, while most of
the elderly patients present with renal involvement {[}8.9{]}. Comparing
our patient to the previously reported cases, all reported cases were
elderly females who presented with hematuria and acute kidney injury
following the COVID-19 vaccine. However, our patient was a young male,
presented with symptomatic pulmonary hemorrhage and renal impairment
simultaneously.

The duration between exposure to the vaccine and the incidence of
anti-GBM disease varied between days to weeks {[}5,6,7{]}. At the same
time, its symptoms started two days after the second dose of Moderna
vaccine in our reported patient. Although we were unable to find other
triggers, they cannot be excluded entirely. All reported cases,
including our patient, showed a negative association with Antineutrophil
cytoplasmic antibodies (ANCA). In all patients, the symptoms started
after the second dose of the vaccine, and they were all asymptomatic
after the first dose.

The outcome of the reported cases showed no specific pattern. Despite
receiving steroid cyclophosphamide and plasmapheresis, our patient's
renal function did not improve, and he remained dialysis-dependent.

Table 1: Cases of De Novo Anti GBM disease post mRNA COVID-19 vaccines\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllll@{}}
\toprule
\begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Report\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Age/gender\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Type of vaccine\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Dose\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Days from Vaccine to onset\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
De novo or relapse\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Symptoms on presentation\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
ANCA association\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Treatment\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Other triggers\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
Outcome\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Japan\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
F, 70 YO\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2\textsuperscript{nd}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
9 days\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
De Novo\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
AKI, Hematuria\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-ve\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
S,PLX,IV CYP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Centipede bite\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Remission\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
USA\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
F, older\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Moderna\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2\textsuperscript{nd}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
14 days\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
De Novo\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
AKI, hematuria\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-ve\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
S,PLX,CYP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
HD dependent\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Singapore\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
F, 60 YO\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Pfizer\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2\textsuperscript{nd}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
1 day\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
De Novo\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
AKI, Hematuria,NRP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-ve\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
S,PLX,O CYP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
N/A\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Qatar\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
M, 26 YO\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Moderna\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2\textsuperscript{nd}\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
2 days\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
De Novo\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Hemoptysis, AKI\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-ve\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
S,PLX,O CYP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
HD dependent\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

** S: Steroid, PLX: plasmapheresis, CYP: cyclophosphamide, O:oral , IV:
intravenous, AKI: Acute kidney injury, NRP : nephrotic range proteinuria

\textbf{Conclusion;}

This case report suggests that COVID-19 vaccines could be related to the
development of anti-GMB disease. However, further information and
studies are needed to establish and confirm this relation.

\textbf{Statements}

Statement of Ethics

The patient had given his written informed consent to publish her Case.

Disclosure Statement

All authors declared no conflict of interest.

Acknowledgment

All authors acknowledge Qatar National Library for the financial
support.

Author Contributions

\begin{enumerate}
\tightlist
\item
  Ahmed S Abdulhadi: Overall supervision and guiding.
\item
  Mohanad A E Ahmed: Corresponding author, Writing the case report,
  abstract and conclusion, language review and correcting language
  errors, submission to a journal.
\item
  Sabah E A Mohamed: writing the discussion.
\item
  Esra Z M Eltazi : writing the discussion.
\item
  Hussein N Al Hussein : writing the Introduction.
\item
  Rayan M Sibira : preparing pathology slides and writing pathology
  report.
\end{enumerate}

\textbf{References (Numerical)}

\begin{enumerate}
\tightlist
\item
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\item
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\item
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\item
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\item
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\item
  Tan, Hui Zhuan, et al. ''Is COVID-19 vaccination unmasking
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\item
  Sacker, Allan, Vanderlene Kung, and Nicole Andeen. ''Anti-GBM
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\item
  Savage, C. O., et al. ''Antiglomerular basement membrane antibody
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\item
  Levy, Jeremy B., et al. ''Long-term outcome of anti--glomerular
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\end{enumerate}

\selectlanguage{english}
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