Abbreviations
SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Covid-19,
coronavirus disease 2019; AESI, adverse events of special interest; AHA,
acquired hemophilia A; FVIII, factor VIII; aPTT, activated partial
thromboplastin time; rFVIIa, recombinant activated factor VII; aPCC,
activated prothrombin complex concentrate; ITP, Immune-mediated
thrombocytopenia; ICH, intracranial hemorrhage; AEFI, adverse events
following immunization; CARPA, complement activation pseudo-allergy;
PEG, polyethylene glycol; CLS, Capillary leak syndrome; PCLS, pulmonary
CLS; SCLS, systemic CLS; RRT, renal replacement therapy; TSH,
thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine; HA,
Hyaluronic acid; PCT, proximal convoluted tubules; ACE2,
angiotensin-converting enzyme 2; CT, computed tomography; EM, Erythema
multiforme; VAERS, vaccine Adverse Event Reporting System; DIC,
Disseminated intravascular coagulation; POBA, plain old balloon
angioplasty; DVT, Deep venous thrombosis; PTE, pulmonary
thromboembolism; VTE, venous thromboembolic disease; CTPA, computed
pulmonary tomography angiography; VITT, vaccine-induced immune
thrombotic thrombocytopenia; CVST, cerebral venous sinus thrombosis;
PF4, platelet factor 4; SAH, Subarachnoid hemorrhage; ICH, intracerebral
hemorrhage; SVT, Splanchnic vein thrombosis; BCG, Bacillus
Calmette-Guerin; HPV, human papillomavirus; KD, Kikuchi’s disease; SLE,
systemic lupus erythematosus; AAION, Arteritic anterior ischemic optic
neuropathy; AZOOR, acute zonal occult outer retinopathy; OCT, optic
coherence tomography; FA, Fluorescein angiography; ERG,
electroretinography; FAF, fundus autofluorescence; AMNR, Acute macular
neuro-retinopathy; PAMM, Paracentral acute middle maculopathy; CSR,
Central serous retinopathy; RPE, retinal pigment epithelium; RRD,
rhegmatogenous retinal detachment; POCUS, point-of-care ultrasound; VKH,
Vogt-Koyanagi-Harada; AMPPE, acute posterior multifocal placoid pigment
epitheliopathy; RF, Rheumatoid factor; EBV, Epstein-Barr virus; MI,
Myocardial infarction; PCI, Percutaneous coronary intervention; MIS-C,
multisystem inflammatory syndrome in children; TTE, Trans-thoracic
echocardiography; RT-PCR, reverse transcriptase-polymerase chain
reaction; GBS, Guillain-Barré syndrome; EMG/NCV, Electromyography and
nerve conduction velocity; DOACs, direct oral anticoagulants; CD,
Cluster of differentiation; TM, Transverse myelitis; NMO, neuromyelitis
optica; CSF, cerebrospinal fluid.
Introduction
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection has caused many complications, the invention of coronavirus
disease 2019 (Covid-19) vaccines has also brought about several adverse
events, from common side effects to unexpected and rare ones.1 Common vaccine-related side adverse reactions are
those manifested locally or systematically following any vaccine,
including Covid-19 vaccines. Local reactions include erythema,
tenderness, induration, and, rarely, abscess formation at the injection
site. In contrast, systemic side effects include fever, chills,
headache, cough, coryza, and rarely anaphylactic reactions.2 However, certain side effects, known as adverse
events of special interest (AESI), could manifest as autoimmune diseases
or involve various organs, such as renal, dermatologic, hematologic,
lymphatics, ocular, gastrointestinal, cardiovascular, and neurologic
systems, are unusual and need more evaluation. 1 Some
adverse events have never happened with other previously administered
vaccines (Figure 1). Examples are those related to the hyperthrombotic
condition induced by the Covid-19 vaccines that have been discussed in
several articles. 3 Among the reported side effects of
Covid-19 vaccines, some rare adverse events have been discussed here.
First, their proposed pathophysiology is described, and the possible
diagnostic approaches along with recommended treatment options are
demonstrated.
Autoimmune complications
Acquired hemophilia A
Acquired hemophilia A (AHA) is a very rare autoimmune-hematologic
disorder within the immune system that is aroused by a trigger to
produce auto-antibodies against clotting factor VIII (FVIII inhibitor)4. It is suggested to be associated with predisposing
factors, such as autoimmune diseases, drugs, pregnancy, infections, and
malignancy. AHA major presentations include bruise or ecchymosis in the
skin, mostly in the extremities, but it may progress to muscles and
mucosal layers. However, joint involvement is not included despite the
hereditary type 5. Recently, few case reports have
introduced SARS-CoV-2 mRNA vaccines as a possible trigger for AHA
without other predicting conditions 6-8. There are
also several reports on exhibiting AHA following SARS-CoV-2 infection5. Presumed pathophysiology can be the antigenic
mimicry of SARS-CoV-2 and FVIII, leading to uncontrollable degradation
of FVIII. Autoimmune response may be conducted by various underlying
causes such as certain genetic polymorphism and activation of previously
existing autoimmune B/T cells 9. Laboratory confirming
evidence include prolonged activated partial thromboplastin time (aPTT),
decreased level of FVIII, and elevated FVIII inhibitor4. Mentioned cases diagnosed with vaccination caused
AHA within days to weeks following receiving first/second doses of
Moderna (mRNA1273) or Pfizer-BioNTech (BNT162b2) vaccines5,6,8,9. Cases were mostly discharged after a few days
of treatment. AHA treatment methods consist of two major issues: 1)
homeostasis normalization. First, it is important to complete the
coagulation cascade with recombinant activated factor VII (rFVIIa) and
activated prothrombin complex concentrate (aPCC); and 2) immune
suppressive therapy should be conducted by corticosteroids (high dose
prednisone mostly), cyclophosphamide, and rituximab (in refractory
cases) 4.
Immune-mediated thrombocytopenia
Immune-mediated thrombocytopenia (ITP) is an autoimmune disorder in
which platelets destroy by autoantibodies. Etiology mostly includes
autoimmunity, but it can also occur secondary to viral infections and
even vaccination. In the past years, after the beginning of the Covid-19
vaccination, several ITP cases have been reported, mainly following mRNA
vaccines 10. In terms of de novo ITP, which happens
within days, hypothesized pathophysiology encompasses molecular mimicry
and cross-reaction of antibodies against vaccine components and
platelets antigens. 9 Albeit, in case of a flare-up of
pre-existing ITP occurring in hours, the underlying mechanism amplifies
prior immune response 9. It is worth noting that the
measured incidence of secondary ITP after vaccination has been lower
than expected ITP in the general population so far. 11However, since the exact differentiation of coincidental ITP and ITP
related to vaccination is not possible right now, immediate treatment
should be performed to prevent severe outcomes 11.
Patients present with mild to severe symptoms due to platelets count. In
moderate thrombocytopenia, symptoms generally include petechiae,
purpura, bruising, and mucosal bleeding. 12 Platelet
count under 5,000/µL is life-threatening with a high risk of
intracranial hemorrhage (ICH). 12 Treatment typically
consists of IV fluids, corticosteroids, IVIG, platelet transfusion,
rituximab, and thrombopoietic agents (e.g., romiplostim, eltrombopag).12 A better approach has been suggested to start the
initial treatment with corticosteroids (e.g., dexamethasone,
methylprednisone) and IVIG. 12 Further, if the
platelets count did not rise, other agents could be added. Since
rituximab response in about 8 weeks and alter the body’s reaction to the
vaccine, it should be excluded from initial treatment12.
Anaphylaxis
There are two types of adverse events following immunization (AEFI)
after receiving vaccines; non-allergic reactions are normal expected
immune responses to including pain in the injection site, nausea, fever,
chill, and fatigue, while allergic reactions are caused by body
hypersensitivity to vaccines’ adjuvant (not an active ingredient) such
as excipients. Allergic reactions may involve any body part and can
exhibit mild-severe symptoms in different patients, including flush,
pruritus, facial edema, tachycardia, laryngeal edema, and diarrhea13. Anaphylaxis is perceived as an allergic AEFI with
a very low incidence among vaccine receivers (1 in a million doses) and
a higher rate in women, which is increasingly garnering attraction these
days 14. Underlying pathophysiology has been proposed
to be IgE-mediated type one hypersensitivity 15.
However, there are a few other explanations as well. For example,
complement activation pseudo-allergy (CARPA) is mostly instigated
through C3a and C4a components without the involvement of IgE. Direct
interaction of double-stranded RNA applied in vaccines and mast cells is
also possible, but it is reported to be unlikely due to a lack of
evidence in previous in vitro studies 16. For an
IgE-mediated allergy, there should be prior contact with the allergen.
To further decipher, polyethylene glycol (PEG) or Macrogol and
polysorbate 80 have been reported as the most suspected component for
vaccine-related anaphylaxis. PEG2000 has been utilized in SARS-CoV-2
mRNA vaccines as an excipient to facilitate mRNA delivery into cells.
Note that it has a widespread application in medications and foods.
Moreover, polysorbate 80 is a PEG-derived molecule with a lower weight
recruited in many vaccines and medications 13. Their
similar structures lead to a cross-reactivity. It is worth noting that
most of the reported cases had a prior allergy to foods, drugs, or
vaccines 17.
Anaphylaxis mainly occurs in the first 15 minutes after vaccination.
Symptoms mainly encompass sensation of throat closure, upper airway
swelling, nausea-vomiting, tachycardia, difficulty breathing without
wheeze or stridor, angioedema, hypotension, and dry cough17. Diagnosis is primarily clinical and needs
immediate actions because it can be potentially fatal despite its very
low incidence. Treatment includes urgent intra-muscular injection of
epinephrine (0.01 mg/kg) and assessing airway, breathing, circulation,
and mental status at the same time. 13 Epinephrine
injection repeats every 5-15 minutes if the symptoms stay resilient up
to the maximum allowed dose of 0.5 mg in adults (0.3 mg in prepubertal
children). 13 Antihistamine and glucocorticoids are
second-line drugs mainly for skin and mucosal reactions. Note that PEG
or polysorbate have been added to some of this medication which should
not use as a treatment in patients with suspected allergy to these
components 13.
Capillary leak syndrome
Capillary leak syndrome (CLS) is the leakage of fluids in the vessels
into the extravascular space. There are two types of classification for
this disease; 1) idiopathic with unknown cause and secondary to
underlying causes, 2) pulmonary CLS (PCLS), which mainly involves the
lung and pleura, and systemic CLS (SCLS), which rarely consists of lungs
edema 18,19. Predisposing factors for secondary CLS
include hematologic malignancies, medical treatment, and viral
infections 20. In the last year, several case reports
of developing pulmonary or systemic CLS following SARS-CoV-2 infection
and vaccination 18,21. Precise pathophysiology has yet
needed to be elucidated. However, the assumed mechanism is dysregulation
in inflammatory response leading to cytokine storm (i.e., viral sepsis).19 High levels of pro-inflammatory agents in addition
to a hypoxic condition, pathogens’ invasion, and immune cells’ activity
injure the epithelial-endothelial integrity causing permeability in the
vascular wall and extravasation of exudative fluids.19 It has been demonstrated that hypoalbuminemia is a
frequent finding in Covid-19 cases, representing the severity of injury
to the epithelial-endothelial barrier 19. Both PCLS
and SCLS have been reported after SARS-CoV-2 infection so far18. However, CLS cases following Covid-19 vaccination
had a previously diagnosed SCLS or suspicious history of SCLS symptoms21,22. SCLS generally leads to anasarca, hypotensive
shock, hemoconcentration, hypoalbuminemia, monoclonal gammopathy,
compartment syndrome, and multiple organ failure in more severe cases21. It is worth noting that the diagnosis of SCLS is a
diagnosis of exclusion (other causes of shock) 20. Lab
data predominantly encompass hypoalbuminemia and increased level of
creatinine, lactate dehydrogenase, creatine kinase, aspartate
aminotransferase. 18 The interval between vaccine
administration and appearance of symptoms was about 1-2 days.18 For treatment, it has been suggested that the
underlying conditions and ongoing damages should be managed. For
example, albumin administration may even exacerbate the edema because
vascular permeability is present continuously. 18Therefore, agents preserving epithelial-endothelial integrity can be
beneficial, including solnatide, FX06, and Bβ15-42. Vasopressors (e.g.,
norepinephrine, vasopressin, and epinephrine), antibiotics, volume
replacement, high dose of corticosteroid, IVIG (1 g/kg) are also
pivotal. In the case of compartment syndrome, fasciotomy, and in the
case of acute renal injury, renal replacement therapy (RRT) may be
needed. 18 Moreover, prophylaxis with IVIG has been
proposed as prevention in patients with prior SCLS who undergo
vaccination. 18
IgA vasculitis and leukocytoclastic vasculitis
(hypersensitivity vasculitis)
Another worrisome issue following Covid-19 vaccination is the
probability of new-onset emergence or exacerbation of pre-existing
autoimmune diseases 23. There have been rare reports
of IgA vasculitis reactivation, previously known as Henoch-Schönlein
Purpura, following the Covid-19 vaccination 24-26. IgA
vasculitis causes skin, joints, intestines, and kidneys’ small blood
vessels to inflate and bleed. The pathogenesis underlying IgA vasculitis
is yet to be known completely. However, the role of genetic,
environmental factors, vaccines, malignancies, and infections have been
reported 27. The most common feature of the disease is
the presence of purplish, especially on the buttocks and lower legs.
Elevated CRP, ESR, Urea, Creatinine, serum amyloid A levels, IgM, IgA,
and anti-spike IgG could suggest IgA vasculitis associated with Covid-19
vaccination. Methylprednisolone, Deflazacort, and Paracetamol were
prescribed in the mentioned cases27,28. Similarly,
cases of leukocytoclastic vasculitis were reported following Covid-19
mRNA-based vaccines. Histopathological evaluations and direct
immunofluorescence analysis helped make the diagnosis of
leukocytoclastic vasculitis. Prednisolone taper was prescribed for the
mentioned cases 29-31.
Urticarial vasculitis
Urticarial vasculitis following Covid-19 vaccination has been reported.
Urticarial vasculitis is an inflammatory skin disorder manifested by the
presence of urticarial rashes lasting more than a day and healing with
hyperpigmentation. Covid-19 vaccine-induced urticarial vasculitis is
characterized by elevated red rashes on the skin, which are itchy.
Elevated CRP and histopathological evaluations also help the diagnosis
of the disease. In this case, oral indomethacin, levocetirizine tablet,
and topical calamine lotion could be prescribed 32.
Cutaneous vasculitis
Cutaneous vasculitis is an inflammatory disease that affects dermal
blood vessel walls. The skin is normally involved. Cutaneous vasculitis
can reflect a cutaneous component of systemic vasculitis, a
skin-dominant or skin-limited expression or variant of systemic
vasculitis, or be a single-organ vasculitis per se. The diagnosis is
often based on physical examination and skin biopsy33. The occurrence of a peculiar post-Covid-19
vaccination maculopapular rash characterized by lymphocytic vasculitis
as the main histological finding was recently reported. The rash
responded to systemic antihistamine and local steroid therapy34.
Rheumatoid arthritis and reactive arthritis
There have been reports of a rheumatoid arthritis flare-up following the
Covid-19 vaccination. Moreover, rheumatoid arthritis exacerbation has
also been reported after the Covid-19 vaccination35,
which had been previously observed following tetanus, rubella, hepatitis
B, and influenza vaccines36. The mechanism underlying
this flare-up could be possibly attributed to the molecular mimicry or
non-specific adjuvant effect. Elevated ESR and CRP levels with abnormal
ultrasound evaluation of the swollen limb and arthrocentesis were
suggestive for the flare-up of rheumatoid arthritis in these cases.
Intra-articular steroids could be prescribed in these
cases37. Besides, a case of reactive arthritis has
been reported following the SARS-CoV-2 vaccine in a 23-year-old woman
treated with intra-articular betamethasone35,38.
IgA nephropathy
IgA nephropathy has been similarly reported following Covid-19 mRNA
vaccines 39. IgA nephropathy is a complex immune
disorder with IgA deposition in the mesangial layer. In these cases, the
development of IgA nephropathy could be speculated due to an elevated
response of immune cells in the germinal center, leading to massive
antibody production and increased production of pathogenic IgA similar
to immunization with influenza vaccine. The cases had gross hematuria.
Urine analysis, Kidney ultrasound, evaluation of immunoglobulin A
levels, and kidney biopsy were suggestive for IgA nephropathy in the
mentioned cases. Losartan and methylprednisolone were prescribed in
these cases. 40-42 showed proteinuria.
Thyroiditis
Subacute thyroiditis, also known as De Quervain’s thyroiditis, has been
another rare adverse event with an immunological source following the
Covid-19 vaccination 43-47. It is a self-limited
thyroid inflammation for weeks to months which commonly happens
following a viral upper respiratory tract infection48,49. This post-vaccine effect has been presented
with new-onset thyroid dysfunction in recently vaccinated individuals
and appears to be of female predominance. The relationship between
subacute thyroiditis and the type of Covid-19 vaccine is unclear as it
has occurred following various vaccine platforms, including Sinovac,
AstraZeneca, Bharat, Moderna, Pfizer. This phenomenon was previously
reported following H1N1, seasonal influenza, and hepatitis B vaccines50-53. Vaccines’ adjuvants are supposed to be
responsible for these reactions by stimulating immunogenic
cross-reactivity, causing autoimmune/inflammatory syndrome induced by
adjuvants (ASIA syndrome) 47,54. After vaccination,
subacute thyroiditis can develop due to ASIA syndrome, including
Covid-19 vaccines 54. The development of ASIA syndrome
could be attributed to the molecular mimicry, polyclonal activation of B
cells, and immunological imbalance of the host 47. In
addition to ASIA syndrome, the interaction between SARS-CoV-2 spike
protein with angiotensin-converting enzyme 2 (ACE2) receptor, which is
wildly expressed on thyroid cells, is another mechanism associated with
thyroiditis induction in vector-based vaccines such as AstraZeneca44. Clinical manifestations associated with
thyroiditis include pharyngitis, moderate fever, diffuse myalgia, and
cervical pain that radiates to the jaw and ears. Subacute thyroiditis is
often associated with negative anti-thyroglobulin and anti-thyroid
peroxidase antibodies 49.
In the mentioned cases, suppressed thyroid-stimulating hormone (TSH)
levels accompanied by elevated triiodothyronine (T3) and thyroxine (T4),
increased levels of inflammatory markers (ESR, CRP), ultrasound
findings, negative thyroid antibodies helped in diagnosing subacute
thyroiditis. Methylprednisolone, propranolol, and ibuprofen were
prescribed in these cases47,49,55. In this relation,
cases of Grave’s disease have also been reported following receiving the
SARS-CoV-2 vaccine with elevated anti-thyroid antibodies56.
Dermal filler reaction
Hyaluronic acid (HA) is a natural polysaccharide that has been widely
utilized in cosmetics 57. Reaction to HA fillers is
rare and typically self-limited. So far, triggers such as infections
(e.g., flu-like illnesses) and vaccination (e.g., influenza vaccine)
have been reported to exhibit filler reactions. Furthermore, several
cases have been identified following anti-SARS-CoV-2 mRNA vaccines
recently. Two cases with dermal fillers had developed swelling in lips
and face in the third phase of the Moderna vaccine trial.58 There are two possible explanations for its
pathophysiology. The first assumption is that the action of nonactive
components in vaccines cross-reacting with filler’s molecules and
provokes an immune response. 59 The second hypothesis
supports the alleviation of ACE2 conversion by mRNA vaccines, leading to
pro-inflammatory ACE2 in the skin and inflammation. Reactions are type
four hypersensitivity or delayed immune reactions mediated by T
lymphocytes. 59 Patients generally present with
flu-like symptoms and swelling of filler region days after vaccination.
Tenderness, swelling, erythema, and nodules can be seen in the
examination. 59 Since most of the lesions have been
resolved spontaneously, observation and follow-up is the first approach.
However, in case of not improving nodules with pain, tenderness, or
erythema, intervention is necessary. 59 Antibiotics
including tetracycline and macrolides should be administered for 3-5
days. If the nodule is non-inflammatory, hyaluronidase with or without
intralesional steroids can be utilized to resolve it.59 Moreover, drainage of the nodule should be
considered if the mass fluctuates. Interestingly, in some trials, low
doses of ACE inhibitors have been used for 3-5 days which showed a
significant effect in resolving the reactions. 59
Renal complications
Kidneys can be widely affected by SARS-CoV-2 due to the high expression
of ACE2, which is expressed more in proximal convoluted tubules (PCT).
Therefore, the most common type of injury following Covid-19 infection
is tubular injury. Other reported clinical pictures include nephrotic
syndrome and glomerular injury (e.g., minimal change disease)60,61. Several case reports of acute kidney injuries
in patients with or without prior renal pathology following vaccination62-64. The pathophysiology of SARS-CoV-2 related renal
injury is presumed to be multifactorial through direct (i.e., virus or
vaccine components) or indirect (i.e., immune-mediated like cytokine
storm or hyperactivity of T cells) effects 65. After
vaccination conducted by clinical symptoms, suspension to kidney injury
encompass oliguria or anuria, edema or anasarca, hypertension, and
dyspnea due to pleural effusion 60. Laboratory data
confirming the diagnosis include a variety of renal-associated factors’
impairment due to underlying pathology. For instance, minimal change
disease exhibits proteinuria, normal to increased creatinine, and
podocyte injury in lite microscopy assay 63. Acute
tubular necrosis can be presented with increased creatinine and urea
nitrogen, proteinuria, hypoalbuminemia, biopsy findings of diffuse PCT
injury, lymphocyte infiltration, and cell necrosis60,61.
Furthermore, hypodensity of renal parenchyma may have been seen in
computed tomography (CT) 65. Treatment consists of two
important approaches; firstly, kidney protection from further injury by
adjusting input and output fluids, excluding nephrotoxic drugs, and
monitoring creatinine level. Secondly, early immunosuppressive therapy
(non-selective or selective) or RRT due to patient condition65,66.
Dermatologic complications
Erythema multiforme
Erythema multiforme (EM), an inflammatory dermatologic disorder, is
mostly linked to infections (most commonly: herpes simplex andMycoplasma pneumoniae ), although various triggers, such as many
other infectious agents, immunizations, medications, and even various
diseases, have also been identified. Acral, targetoid papules,
consisting of three distinct concentric zones, are the hallmark lesions
of this disease. It is necessary to emphasize that vaccine-induced EM
has been known for a long time, with 984 cases reported to the Vaccine
Adverse Event Reporting System (VAERS) 67.
Furthermore, EM-like reactions both as typical acral lesions in younger
individuals and more widespread, atypical lesions in adults have already
been linked to SARS-CoV-2 infection. 68. The structure
codified in mRNA Covid-19 vaccines, SARS-CoV-2 spike protein, was shown
immunohistochemically in eccrine ducts epithelium and endothelial cells
in those individuals. EM is a rare adverse effect of many other
vaccines, and recent studies link this reaction to mRNA vaccines69. It has been suggested that a T-cell trigger by
viral antigen-positive cells containing the HSV-DNA polymerase gene
plays an important role in EM pathogenesis, and it causes viral gene
expression in the recruitment and skin 70. EM’s
clinical manifestations are diverse, and they can also manifest as
atypical palpable lesions with erythematous dusky bodies surrounded by a
paler halo. To rule out inflammatory, autoimmune, or malignant
disorders, swabs are performed for HSV-PCR, Tzanck smear, or other
serological tests. Direct and indirect immunofluorescence may be useful
in differentiating EM and distinguishing it from other lesions of
bullous vesicles. EM is managed with symptomatic treatments. The lesions
may heal in 3 to 6 weeks, but patients with severe EM may need to be
hospitalized for antiviral therapy, hydration, analgesics, and systemic
steroids 67,70.
Chilblains
Repeated exposure to cold air may cause inflammation in small blood
vessels, called chilblains, causing swelling, blistering, itching, and
red patches on hands and feet 71. The exact
pathophysiology remains unclear since the chilblain-like lesions due to
Covid-19 are common features with idiopathic and autoimmune-related
chilblains. Covid-19 has various clinical manifestations, including
pernio/chilblains-like lesions, a condition termed ”Covid-19 toes.”
However, after receiving the vaccines, this condition is associated with
Covid-19 72. These lesions have been reported
post-Pfizer and CoronaVac (inactivated vaccine) vaccinations73,74. These lesions could be extremely painful and
last for up to 150 days after vaccination 75,76. An
anticoagulant therapy (apixaban) and low-dose aspirin were prescribed
for the patient until circulating immune complexes were obtained after
14 days 75.
Hematologic complications
Disseminated intravascular coagulation
Disseminated intravascular coagulation) DIC) leads to extensive fibrin
deposition with the formation of extensive microvascular thrombosis77. During coagulation, coagulation factors decrease,
and platelets accumulate, thereby reducing clotting protein77. Infection by the SARS-CoV-2 increases the risk for
systematic multi-organ complications and venous, arterial
thromboembolism 77. CT scan demonstrated multiple
subacute intra-axial hemorrhages in atypical locations, such as the
right frontal and the temporal lobes. A successive CT angiography of the
chest added the findings of multiple contrast-filling defects with
multi-vessel involvement: at the level of the left interlobar artery, of
the right middle lobe segmental branches of the left upper lobe
segmental branches, and the right interlobar artery77. A plain old balloon angioplasty (POBA) of the
right coronary artery was conducted, with the restoration of distal flow
but with the persistence of extensive thrombosis of the vessel77. An abdomen CT angiography demonstrated filling
defects at the right supra-hepatic vein level and the left portal branch
level. Bilaterally, it was adrenal hemorrhage and blood in the pelvis77. An MRI on the same day demonstrated the presence
of an acute basilar thrombosis associated with the superior sagittal
sinus thrombosis. Alternative HIT-compatible anticoagulants prescribe in
case of acute thrombocytopenia/thrombosis 77.
Deep vein thrombosis and
pulmonary thromboembolism
Deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE) exist
on the spectrum of venous thromboembolic disease (VTE)78. DVT is known as the formation of blood clots
(thrombi) in the deep veins. It normally affects the deep leg veins
(e.g., the calf veins, popliteal vein, or femoral vein) or the deep
veins of the pelvis. DVT is a potentially dangerous condition, leading
to preventable morbidity and mortality 79. PE occurs
when a thrombus migrates from the venous circulation to the pulmonary
vasculature lodging in the pulmonary arterial system. The clinical
manifestation of acute PE ranges from incidentally discovered and
asymptomatic to massive PE, leading to death 78.
Post-vaccination DVT and PTE have been reported in a few cases
worldwide. Duplex ultrasonography of the lower limbs demonstrated acute
DVT involving the superficial femoral, common femoral, popliteal,
anterior tibial, posterior tibial, and deep calf veins80. The patient underwent computed pulmonary
tomography angiography (CTPA) due to tachycardia, which demonstrated
saddle thrombus in the bifurcation of the pulmonary trunk and 40
extensive bilateral main pulmonary arteries emboli extending to both
lobar segmental and subsegmental branches 80.
Sporadic cases report viral vector vaccines injection, vaccine-induced
immune thrombotic thrombocytopenia (VITT), and cerebral venous sinus
thrombosis (CVST). Generally, CVST occurs in young adults, particularly
young women. In most cases, a risk factor is identified in patients81-84. With disease progression, focal neurological
deficits may develop due to seizure and venous infarction, more commonly
observed in patients with CVST than the other stroke subtypes. Full
recovery is achievable with timely disease diagnosis and treatment85. The SARS-CoV-2 infection has also been proved to
lead to CVST development in several studies 85,86.
SARS-CoV-2 VITT is a novel phenomenon occurring in post-viral vector
Covid-19 vaccines.
Contrary to the previous reports of post-vaccination thrombotic
thrombocytopenia, CVST is reported in these patients after the Covid-19
vaccination. Clinically, VITT mimics spontaneous autoimmune
heparin-induced thrombocytopenia (HIT). HIT occurs due to the complexion
of heparin with platelet factor 4 (PF4) platelet-activating IgG
antibodies. Next, the mentioned complex binds to the FcRγIIA receptors
in platelets, activates platelets, and forms platelet microparticles87. After that, microparticles start to form blood
clots inducing the prothrombotic cascade, leading to platelet depletion
and thrombocytopenia. Also, the reticuloendothelial system, especially
the spleen, aggregates thrombocytopenia through antibody-coated
platelets removal 87-90. Vaccine interaction with PF4
is considered a potential role in VITT pathogenesis.
This phenomenon may be attributed to the possible binding of
vaccine-free DNA to PF4, which may trigger the PF4-reactive
autoantibodies in the setting of VITT 91. 1) Moderate
to severe thrombocytopenia. Note that mild thrombocytopenia may be
observed in some cases, especially in the initial stages of VITT, 3)
Thrombosis often occurs in the CVST forms (patients may have a headache)
or splanchnic veins thrombosis (patients may have back or abdominal pain
(or both), in addition to nausea and vomiting). Less commonly, arterial
thrombosis may occur, and 4) ELISA confirm positive PF4 “HIT”
(heparin-induced thrombocytopenia) 92. Temporary
headaches are among the common side effect of vaccination, though
persistent headache, petechiae, blurred vision, easy bruising, or
bleeding suggests considering CVST after VITT 92.
Subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) were
observed in nearly half of the patients. Patients’ platelet count ranged
between 5,000-127,000/µL, and D-dimer and PF4 IgG Assay were positive in
most cases. Of 49 CVST patients, a minimum of 19 patients died (39%)
due to CVST and VITT complications 93. Heparin should
not be administered in suspected cases until ruled out VITT92. Close teamwork among hematologists, vascular
neurologists, and other relevant consultants is the cornerstone of CVST
and VITT-associated systemic thrombosis management 85.
Despite the limited data regarding treatment strategies, daily IVIG
administration (1 g/kg body weight) for two days is recommended
following sending PF4 antibodies 85. IVIG hinders
antibody-mediated platelet clearance; also, it may block FcRγIIa
receptors of platelets and thus lead to downregulation of platelet
activation 88.
Moreover, some experts have suggested administering high-dose
glucocorticoids, which enhance the platelet count within days88. On the other hand, plasmapheresis may be
considered a potential therapeutic approach since it may temporarily
remove pathologic antibodies and correct the coagulopathy94. Platelet transfusion is contraindicated since it
may lead to additional antibody-mediated platelet activation and
coagulopathy 94. Non-heparin anticoagulants, such as
direct thrombin inhibitors (bivalirudin, argatroban), indirect
(antithrombin-dependent) factor Xa inhibitors (fondaparinux,
danaparoid), and direct oral factor Xa inhibitors (rivaroxaban,
apixaban), at their therapeutic anticoagulant dosage may be considered91. In patients with severe thrombocytopenia (i.e.,
< 20,000/µL) or patients with reduced fibrinogen levels,
alteration of dosing strategy is mandatory 85.
Parenteral drugs with a short half-life are preferred in critically ill
patients 85,91. In patients with secondary ICH,
anticoagulation is obligatory in CVST for progressive thrombosis
prevention 85. In patients with full platelet count
recovery, with no other contraindications, it is recommended to use
vitamin K antagonists or direct oral anticoagulants for chronic/subacute
management 85.
Splanchnic vein thrombosis
Splanchnic vein thrombosis (SVT), including mesenteric, portal, splenic
vein thrombosis, and the Budd-Chiari syndrome, manifests venous
thromboembolism in an unusual site. Portal vein thrombosis and
Budd-Chiari syndrome are the most and the least common presentations of
SVT, respectively. In February 2021, a considerable number of VTE in
unusual sites (CVST and SVT) in combination with thrombocytopenia were
observed in individuals receiving the Covid-19 vaccine; which on March
15, 2021, in several countries, including Austria, Germany, the United
Kingdom, France, and Norway, prompted the temporary suspension of the
administration of such vaccination by the EMA 95,96.
Other cases of SVT have also been reported after the Covid-19
vaccination 91. All patients manifested concomitant
thrombocytopenia (median nadir of a platelet count of 20,000/µL; range
between 9,000-107,000/µL), and none of the patients
had previously received any form of heparin earlier than the onset of
symptoms. Diagnostic evaluation is usually affected by the lack of
specificity of clinical manifestations: the presence of one or more risk
factors in a patient with a high clinical suspicion could indicate—the
execution of diagnostic tests. Doppler ultrasonography is the first-line
diagnostic tool since its accurate and has wide availability.
Further assessments, such as magnetic resonance angiography and computed
tomography, should be executed in cases with suspected SVT-related
complications, suspected thrombosis of the mesenteric veins, or complete
information after Doppler ultrasonography 97. Symptom
onset started between 4–16 days post-vaccine administration. The same
treatment as VITT (mentioned earlier) was also suggested for SVT91.
Lymphadenitis
Besides the abundant reports of prominent lymphadenopathy, there have
been several cases of silent lymphadenopathy following Covid-19
vaccination in women undergoing imaging for breast cancer screening98-102. Lymph node enlargement has not conclusively
been the result of the Covid-19 vaccines. This phenomenon has previously
been reported following Bacillus Calmette-Guerin (BCG), smallpox, human
papillomavirus (HPV), H1N1 influenza A virus, and anthrax vaccines103-109. However, none of these vaccines have been
administered massively as SARS-CoV-2 vaccines, and clinical experience
suggests a notably higher incidence of lymphadenopathy following
Covid-19 vaccines than other vaccines. Lymphadenitis and lymphadenopathy
associated with Covid-19 vaccination usually occur within 4 weeks of
administration and have been reported in almost all body parts,
including axillary, pectoral, supraclavicular, cervical, inguinal, and
even intraparotid regions 102,110-112. The axillary
region seems to be the most common location for vaccine-associated lymph
node enlargement. However, the increasing rate of supraclavicular
lymphadenopathy following vaccination indicates that vaccines are
injected at a higher location than recommended 113.
This complication has been detected through ultrasound, PET/CT imaging,
or MRI in post-Covid-19 vaccinated individuals 98.
Nonetheless, we should not underestimate the significance of evaluation
for malignant causes of lymphadenopathy in vaccinated individuals since
vaccination is a well-known but uncommon cause of lymphadenopathy. Fine
needle aspiration is the best method for excluding cancer and metastasis114. Nevertheless, unnecessary biopsies of benign
reactive lymph nodes should be avoided 115. Therefore,
there should be a protocol for evaluation. Some authorities believe that
if lymphadenopathy appears within 6 weeks of vaccination in a patient
with no history of malignancy, the problem is ipsilateral to the vaccine
injection site. It is supposed to be vaccine-related; otherwise,
assessment for other causes, particularly neoplasms, should be done116,117. In individuals with pre-existing unilateral
cancer, vaccination should be given contralaterally if possible to avoid
misinterpretation 118.
Another interesting phenomenon following the Covid-19 vaccination has
been Kikuchi’s disease (KD), histiocytic necrotizing lymphadenitis,
presents with cervical lymphadenopathy or fever of unknown origin119. The etiology of this disease is not yet
determined; however, pathogens such as Epstein-Barr virus,
cytomegalovirus, varicella-zoster virus, human immunodeficiency virus,Yersinia enterocolitica , and Toxoplasma gondii , and
autoimmune disorders such as systemic lupus erythematosus (SLE),
antiphospholipid antibody syndrome, and scleroderma have been attributed
to this condition 120. There have been rare reports of
KD following human papillomavirus and influenza vaccines121,122. The diagnosis of this condition is confirmed
and differentiated from malignancies by histopathology and the presence
of necrosis without granulocytic cells.
Ocular complications
AAION and AZOOR
Various studies reported vaccine-induced ophthalmic events previously.
Arteritic anterior ischemic optic neuropathy (AAION) and bilateral acute
zonal occult outer retinopathy (AZOOR) are described as an abrupt
presentation of photopsia and scotomas due to the damage of external
retinal zones has been reported as an adverse event. The pathophysiology
for developing AZOOR and AAION could be ascribed to the cross-reaction
of neutralizing antibodies against SARS-CoV-2 spike protein or activated
helper T cells after vaccination that react with proteins and antigens
in large arteries, outer retinal layers, and retinal pigment epithelial
cells. Presentation of these ocular manifestations after the second dose
of a vaccine shot accompanied by high levels of ESR and CRP in both
cases strongly supports immune system overactivity patronaging this
assertion. Diagnosis of AAION was performed based on temporal artery
biopsy, macular optic coherence tomography (OCT), Fluorescein
angiography (FA), indocyanine green angiography (ICG), fixed and
multi-luminance electroretinography (ERG), multifocal ERG as well as
images of ganglion cell complex and retinal nerve fiber layer.
Similarly, OCT, fixed and ERG, multifocal ERG, FA, ICG, and fundus
autofluorescence (FAF) were applied to diagnose AZOOR. Corticosteroid
pulse, oral prednisolone followed by Tocilizumab was administrated in
the case of AAION. AZOOR was also treated with an intravitreal implant
of dexamethasone 123.
Acute macular neuro-retinopathy
Acute macular neuro-retinopathy (AMNR) is a rare condition with the
sudden presentation of one or more paracentral scotomas causing either
temporary or permanent visual impairment. The pathophysiology underlying
AMNR development has not been identified yet 124;
however, a few cases of AMNR have been reported following the first shot
of the Covid-19 vaccination. Diagnostic evaluations including
ophthalmoscopy, OCT, swept-source optical OCT, and microperimetry were
all suggestive for AMNR in these patients. The use of oral
contraceptives is associated with AMNR development which further
supports Covid-19 vaccine-induced AMNR as one of the cases was consuming
OCP 125,126.
Paracentral acute middle maculopathy
Paracentral acute middle maculopathy (PAMM) is described as the presence
of a hyper-reflective band at the level of the inner nuclear layer
visualized in OCT, which indicates infarction of the inner nuclear
layer. Impaired perfusion of the retinal capillary system can be
associated with several causes, including occlusion of the central
retinal vein, retinal artery occlusion, and the non-proliferative
diabetic form of diabetic retinopathy causing inner nuclear layer
infarction127. PAMN has been reported, followed by the
Sinopharm vaccine. The mentioned case developed uncontrollable
hypertension 20 minutes after the vaccine shot, accompanied by the
simultaneous development of left eye inferior scotoma and headache.
Visual acuity was decreased on admission. OCT angiography and fundus
examination were all indicative of PAMM128.
Central serous retinopathy/chorioretinopathy
Central serous retinopathy (CSR), a common ocular disease, is described
as retinal pigment epithelium (RPE) decompensation, leading to the
detachment of either neurosensory retina or serous pigment epithelium.
Symptoms of CSR include blurred vision, metamorphopsia, micropsia,
dyschromatopsia, or even asymptomatic. Although CRS’s pathophysiology
has not been completely understood, increased permeability and thickness
of choroid due to ischemia, inflammation, or hydrostatic forces have
been proposed as the possible mechanism 129. mRNA
vaccines induced CSR have been postulated to develop due to the presence
of polyethylene glycol used in vaccine formulation, causing anaphylaxis,
choroid vessel thickening, and neovascularization. Possible release of
endogenous cortisol triggered by mRNA vaccines is also hypothesized to
be associated with CSR development after vaccination as high cortisol
levels in serum are associated with CSR. Another probable mechanism for
post-vaccination CSR is extracellular RNA presence which induces
increased endothelial cell permeability and thrombus formation, which is
also compatible with lobular ischemia seen in CSR. CSR has been
previously reported, followed by smallpox, yellow fever, influenza, and
anthrax vaccine. CSR development followed by Pfizer vaccine was reported
69 hours after the injection. OCT, OCT angiography, and FA were all
suggestive for CSR. Spironolactone 50 mg daily was prescribed, and the
patient became asymptomatic with normal visual tests after three
months130.
Bilateral Retinal Detachment
Retinal detachment is an emergency medical condition that requires
prompt treatment, leading to permanent blindness. There are three types
of retinal detachments, including tractional and exudative, which are
non-rhegmatogenous, and rhegmatogenous retinal detachment (RRD), which
is the most common point-of-care ultrasound (POCUS) of the eye was
suggestive for non-posterior vitreous detachment that is a form of RRD
which round holes that are associated with local thinning or atrophy of
retina including lattice degeneration. The patient then undergoes
bilateral vitrectomies 131.
Uveitis
Uveitis is a threatening, inflammatory eye disorder considered an
ophthalmic emergency. Uveitis develops mostly due to autoimmune
reactions, ocular trauma, infection, or it may be
isolated132. Uveitis development following vaccination
can present with a wide range of ocular manifestations such as redness
of the eye, blurred vision, floaters, and sensitivity to the light.
Conjunctival hyperemia and eye pain can also be the clinical
manifestations associated with vaccine-associated uveitis132. Vaccine-associated uveitis has been previously
reported following almost all the vaccines currently employed, such as
hepatitis B vaccine, the commonest vaccine-related uveitis, human
papillomavirus, and influenza vaccine133. The
pathophysiology underlying the development of vaccine-associated uveitis
could be attributed to autoimmune mechanisms caused by the vaccine. The
possible mechanisms involved in this autoimmunity includes molecular
mimicry due to the resemblance of uveal self-peptides and vaccine
peptides, cytokine production, new antigen induction, surface antigen
modification, B cell polyclonal activation, and adjuvants induced
inflammatory destruction134.
Most cases of vaccine-associated uveitis are anterior, transient, not
severe, and respond to topical steroids promptly; However, there have
been reports of posterior uveitis and pan-uveitis, including
Vogt-Koyanagi-Harada (VKH) and acute posterior multifocal placoid
pigment epitheliopathy (AMPPE) in severe cases following vaccination.
Previous studies showed conjunctival hyperemia, photophobia, decreased
visual acuity, and eye pain. Laboratory data, including WBC count, CRP,
and ESR levels, were normal with negative ANA and rheumatoid factor
(RF). Slit-lamp examination and OCT results were suggestive for uveitis.
Dexamethasone eye drops six times a day and atropine 1% (cycloplegic
agent) twice daily was prescribed for patient 143. Several diffuse
scleral hyperemia lesions were observed on slit photos. Scleritis
resolved one week after prescribing topical steroids for the
patient128. Pan uveitis-associated Covid-19 vaccine
has also been reported with substantial vision loss, ocular pain, and
light sensitivity. Fluorescein angiography, OCT imaging, and B-scan were
used to diagnose OCT and B-scan showing choroidal thickening. Oral
prednisolone (50 mg/kg) and Difluprednate eye drop were prescribed for
patient 133.
Vogt-Koyanagi-Harada syndrome is a rare granulomatous inflammatory
disorder that targets pigmented structures, including the inner ear,
eye, meninges, hair, and skin. The disease causes non-necrotizing
panuveitis and exudative retinal detachment. The pathophysiology
underlying VKH has been mediated by Th1 lymphocytes against melanocyte
antigenic components. A case of VHK has been reported 4 days, followed
by the Covid-19 vaccine with bilateral acute vision loss. Slit photo,
OCT, and Fundus examination helped diagnose VKH. Oral systemic
prednisolone (1.5 mg/kg) was prescribed for the patient daily135.
Gastrointestinal complications
Autoimmune hepatitis
Autoimmune hepatitis is characterized by inflammatory liver disease,
which can be triggered by various factors such as viruses, bacteria,
drugs, and some substances in genetically predisposed patients. Acute
autoimmune hepatitis has been reported to develop, followed by
hepatotropic viruses, such as hepatitis A, B, and C viruses, and
non-hepatotropic viruses, including Epstein-Barr virus (EBV)136. Recently infection with SARS-CoV-2 has been
associated with autoimmune hepatitis development. Furthermore,
autoimmune hepatitis happened following Covid-19 mRNA vaccines137,138. As autoimmune conditions leading to tissue
destruction following severe SARS-CoV-2 infection have been reported, it
could be similarly stated that molecular mimicry is responsible for the
development of autoimmune hepatitis in these cases137. The cases were negative for viral hepatitis
(hepatitis A, B, C, and E, cytomegalovirus, EBV, herpes simplex virus,
and HIV). Laboratory data showed elevated bilirubin, albumin, and liver
enzymes, suggestive of hepatocellular injury. Double-stranded DNA
antibodies (dsDNA) and antinuclear antibodies (ANA) were positive in
these cases with elevated IgG levels. There was no evidence of biliary
lithiasis or dilation. Histopathological evaluations were also
compatible with autoimmune hepatitis, showing portal inflammation,
interface hepatitis, rosette formation, and eosinophils, which increase
the possibility for drug-induced autoimmune hepatitis in mentioned
cases. Budesonide or prednisolone 20 mg daily can be administrated to
treat Covid-19 vaccine induced autoimmune hepatitis.
Cardiovascular complications
Myocardial infarction
Myocardial infarction (MI) is a term used for an event of a heart attack
due to the formation of plaques in the arteries’ interior walls,
resulting in reduced blood flow to the heart and injuring heart muscles
because of lack of oxygen supply 139. MI is a rare
complication of the post-Covid-19 vaccine, but it is a major problem,
and it can be a life-threatening adverse event. There are some potential
explanations of myocardial infarction after the Covid-19 vaccine. First,
prothrombotic immune thrombocytopenia induced by the vaccine has
similarities to heparin-induced thrombocytopenia leading to thrombotic
manifestation. Second, Covid-19 vaccines increase demand of the heart as
a contributing factor, then causes a demand-supply mismatch. Third, this
can result from Kounis syndrome, defined as an acute coronary syndrome
caused by an allergic reaction or a strong immune reaction to various
substances, including excipients, drugs, or other substances. MI
clinical manifestations include chest pain which travels from left arm
to neck, shortness of breath, sweating, nausea, vomiting, abnormal heart
beating, anxiety, fatigue, weakness, stress,
depression140,141. Paraclinic findings would be
Non-ST-elevation and ST-elevation with or without T segment inversion
and even reciprocal changes in ECG, abnormal motion of the wall in
echocardiography, high-level biomarkers such as Creatine-Kinase-MB
isoform and Cardiac Troponin (the biomarker of choice), cardiac troponin
I is the gold standard of MI diagnosis, and angiography to localized
blot clots formation in coronary vessels142. The aim
of myocardial infarction management is thrombolysis and reperfusion of
the myocardium, although a variety of drugs such as anti-platelets
(aspirin), heparin, anti-anginal (β-blockers, and nitrates) might also
be considered. Percutaneous coronary intervention (PCI) is for
reperfusion of the myocardium. If there is no emergency percutaneous
coronary intervention facility, thrombolytic therapy with 1.5 million
IU/h intravenous streptokinases can be
administered140.
Myocarditis and pericarditis
Pericarditis is inflammation of the pericardium, a two-thin-layer
sac-like structure that surrounds the heart, and also myocarditis is
inflammation of the myocardium (heart muscle). This inflammation can
result from an immune response to an infection or other
substances143. Viral infections, such as adenovirus,
coxsackievirus, herpes virus, influenza, and even SARS-CoV-2, are the
most common cause of myocarditis and pericarditis144.
Previously, myocarditis and pericarditis have been reported after
smallpox vaccination and less after Other live viral vaccines (including
measles-mumps-rubella, varicella, oral polio, or yellow fever vaccine).
Recently myocarditis and pericarditis have been reported due to Covid-19
vaccination, especially mRNA vaccines145.
For this reason, FDA attached a caution about the risk of
myopericarditis to the information sheet of mRNA anti-SARS-CoV-2
vaccines146. Immunopathological mechanisms of Covid-19
vaccination can be theoretical risks of myocarditis and pericarditis of
post-Covid-19 vaccination147. Potential hypothesized
mechanisms include 1) very high antibody generation response, similar to
the multisystem inflammatory syndrome in children (MIS-C) associated
with SARS-CoV-2 infection, 2) anti-idiotype cross-reactive
antibody-mediated cytokine expression induction in the myocardium, 3)
non-specific innate inflammatory response or a molecular mimicry
mechanism between the viral spike protein and an unknown cardiac
protein, and 4) immunogen potential of RNA itself in vaccine and
adjuvant effect production by cytokine activation of pre-existing
autoreactive immune cells 146.
Although it was difficult to separate myocarditis from pericarditis from
the published cases, the most common signs and symptoms are not
effort-related chest pain but positional and worsened by deep breathing,
which may be followed by fever, and less common are dyspnea, cough, and
headache. Furthermore, symptoms onset occurred between 1-7 days after
vaccination146,147. Diagnosis is based on medical
history and physical examination, echocardiography, ECG findings, blood
test. Cardiac MRI and biopsy are confirmation diagnostic evaluations,
but these are not available in most centers. Therefore, abnormal Lab
findings, including troponin, brain natriuretic peptide, erythrocyte
sedimentation rate, C-reactive protein, and cardiac antibodies when
coupled with a concerning clinical presentation and ECG, can be used to
make a presumptive diagnosis148. The most common
changes in a post-Covid-19 vaccination patient’s ECG are diffuse ST
elevation and ST depression without reciprocal changes,
T-inversion, sinus tachycardia associated with non-specific ST/T-wave
changes. Trans-thoracic echocardiography (TTE) and CMR are used to
diagnose effusion and pericardial thickening143,148.
Due to inflammation and high troponin, CRP may become high because of
muscle damage resulting from myocarditis146.
First step evaluation should be ECG and laboratory tests such as CBC,
electrolytes, renal and liver function test, CRP and troponin level, and
SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR)
test. Notice that normal ECG presentation and Normal troponin level do
not rule out isolated pericarditis. Cardiac MRI should be performed if
the clinical findings are highly probable and the cardiac troponin level
is elevated 145. There is not enough evidence to
support anti-inflammatory drug prescription for all patients post
Covid-19 vaccination myocarditis or pericarditis. Generally, based on
the evidence we have, pain management and NSAIDs with or without
colchicine can be used for mild or moderate. Also, in severe cases, IVIG
and corticosteroids might be considered. In unstable hemodynamic
patients, inotrope drug and cardiogenic shock management might be
required 145,146,148
Neurologic complications
Guillain-Barré syndrome
Guillain-Barré syndrome (GBS) is a rare acute severe acquired
immune-mediated inflammatory polyradiculoneuropathy that affects
peripheral nerves149. The exact pathophysiology is not
fully understood, but it often occurs after a recent
infection150. Campylobacter jejuni , CMV, HEV,
Epstein–Barr virus, influenza, mycoplasma pneumoniae, and Zika virus
are the most common infection associated with GBS 151.
also, recently, GBS after the Covid-19 infection has been reported, but
on the other hand, we have some cases of GBS-related post-Covid-19
vaccination.151,152 Since the Covid-19 vaccines cause
immunization against SARS-CoV-2 infection spike proteins, which bind to
gangliosides and glycoproteins on cell surfaces, the causal connection
could be the cross-reaction between antibodies is produced by Covid-19
vaccines and GBS153. Progressive, ascending,
symmetrical flaccid paralysis of the limbs, simultaneously with hypo or
areflexia, is the typical clinical pattern of the GBS154 and even may include cranial nerve and respiratory
muscle involvement. However, based on some reports about GBS-related
post-Covid-19 vaccination, we have, it seems bifacial weakness may be
the characteristic clinical manifestation of GBS-related post-Covid-19
vaccination155. The diagnosis as GBS diagnostic
criteria is mainly based on history and physical
examination, Electromyography and nerve conduction velocity
(EMG/NCV) studies, and cerebrospinal fluid analysis as a confirmation
diagnostic test. GBS treatment would be intravenous
immunoglobulin IVIg (0.4 g/kg/day for 5 days) and plasma exchange150,151,154.
Stroke
An ischemic stroke could happen because of coagulopathy, blood clot
formation, and thrombosis in the vasculature that carries blood to the
brain156. However, stroke and cerebral accidents are
coagulopathy- and thrombosis-related complications of the Covid-19. Some
evidence of coagulopathy and cerebral vascular accident after the
Covid-19 vaccination has recently been reported157.
The definite underlying mechanism is unknown. It may mimic
heparin-induced thrombocytopenia with existing anti-PF4 but in the
absence of heparin, also known as VITT 89. Clinical
manifestation based on which vessel is affected would vary, but sudden
unilateral weakness or numbness in the face or arm and legs, speech
difficulty, hearing or sight loss in one or both eyes, dizziness, and
confusion are the most common signs and symptoms. Platelet
count < 100,000/µL with
a high D-dimer level and an inappropriately low fibrinogen level would
be typical laboratory findings 89.
Therefore, this is a rare but life-threatening adverse event that needs
critical and rapid management. This phenomenon should be considered in
patients with focal neurological deficits or other serious neurological
disorders, with platelet counts under 100,000/µL up to one month after
the Covid-19 vaccination. First step evaluation includes brain CT scan
with additional venography and lab test like CBC, Retic counts,
peripheral blood smear, PT, aPTT, fibrinogen, D-dimer test,
antiphospholipid LDH level, paroxysmal nocturnal screening, and
ADAMTS-13 should be done for suspected cases. Also, serum samples for
anti-PF4 antibodies should be sent immediately89.
Since diagnosis and management of these critical and challenging
situations will need close collaboration, hematologist and neurologist
consultation is another main part of the better management and should be
prepared. It should be noticed that for VITT management, heparin drugs
in all forms (unfractionated heparin, or low-molecular-weight heparin,
e.g., enoxaparin) and platelets transfusion because of exacerbation are
all avoided89. Nevertheless, you can use non-heparin
agents like direct oral anticoagulants (DOACs, fondaparinux, danaparoid,
or argatroban) depending on the clinical picture for anticoagulation.
Also, IVIG administration is recommended (1 g/kg, which can be given in
divided doses over two days)89,158.
Bell’s palsy
Acute onset peripheral mononeuropathy can cause paresis or paralysis of
the facial nerve (seventh cranial nerve, IV) and is also known as Bell’s
palsy. Bell’s palsy is the most common sudden onset mononeuropathy and
has a very potent predilection for women159. Diabetes,
obesity, hypertension, pregnancy and upper respiratory tract infection
could be risk factors of the condition160. Although
the exact pathophysiology is unknown, this phenomenon could result from
cranial nerve VII inflammation and edema caused by viral
infections160. The relationship between the intranasal
influenza vaccine and Bell’s palsy was shown in
2004160. However, we had reports about bell’s
palsy-related SARS-CoV-2 infection161, but even some
reports about bell’s palsy occurring after the Covid-19 vaccination have
been addressed recently162. The mechanism of bell’s
palsy-related Covid-19 -the vaccine is under investigation, but there is
some potential explanation hypothesis. First, the mRNA vaccines are
associated with interferon type 1 and can cause transient lymphopenia
about 1-3 days after administration, on the other hand, Cluster of
differentiation (CD) 3 and 4 are down in the acute phase of bell’s
palsy. Second, Alpha interferon which is a type of interferon 1 can
cause tolerance disruption of myelin sheath
antigen163. Therefore SARS-CoV-2 vaccination should be
considered as an additional reason for Bell’s palsy besides other causes
like idiopathic and viruses163. The diagnosis is based
on clinical presentation and no additional test. Although Bell’s palsy
will be cured spontaneously in many cases, a high-dose
corticosteroid as a routine dosage based on guidelines would be
helpful, and in severe cases, antiviral agents such as valacyclovir or
acyclovir might be effective to enhance outcome159.
Transverse myelitis
Transverse myelitis (TM) is a rare, acquired focal neurological disorder
resulting from an inflammatory condition that affects the spinal cord
without any compression. Demyelinating disorders such as multiple
sclerosis, neuromyelitis optica (NMO), infections, and vaccines are the
most common causes164. Although post-vaccination
transverse myelitis is uncommon, some studies TM-related vaccines after
diphtheria, Tetanus, pertussis, measles, mumps, rubella, HBV, seasonal
influenza, oral polio vaccine administration have been reported.
Recently, transverse myelitis following Covid-19 vaccination has been
reported 165. The definitive mechanism of this
condition is not obvious. Some supposals can justify this phenomenon,
but molecular mimicry is the most common mechanism because of the
similarity between microbial pathogen antigens and
self-antigens166. Clinical manifestations vary based
on the place of involvement, but transverse myelitis is described by the
sudden onset of acute or sub-acute bilateral sensory-motor and autonomic
dysfunction with a clearly defined sensory level166.
Most patients present with legs and arms weakness, pain, tingling,
burning sensation, sensory alteration, bladder dysfunction, urinary
retention, defecation disturbance, paraplegia, hyperactive
reflexes164,166. In general, the first step in
transverse myelitis diagnosis is history and physical examination. The
next step would be ruling out the compressive etiologies by
gadolinium-enhanced MRI and after structural abnormality investigation,
cerebrospinal fluid (CSF) analysis for inflammation and define
demyelinating extension.
Further workup may be performed to investigate other possible causes
like infections or vitamin B12 deficiency167.
Currently, we do not have specified guidelines for the treatment of TM
following Covid-19 vaccination164, but treatment would
be the administration of steroids (1 g intravenous methylprednisolone
daily for 3-5 days). Plasmapheresis therapy can be used if the patient’s
symptoms do not improve165,168,169.
Conclusion
There have been abundant reports of adverse events following Covid-19
vaccines, though many of which are self-limited and non-serious.
Nevertheless, some of the rare adverse events are reported to be
life-threatening (Table 1). Therefore, it is vital to monitor at-risk
vaccinated people for such adverse events, and if necessary, appropriate
diagnostic modalities and therapeutic options should be utilized to
minimize such catastrophic events. Also, as the incidence of such rare
adverse events is significantly lower after administering Covid-19
vaccines than the disease itself, the benefits of vaccination outweigh
its risks for all genders and age groups. Hence, all stakeholders,
medical professionals, and governments should encourage people to
receive the Covid-19 vaccine.