Two years into the global vaccination campaign, important questions about COVID-19 vaccines and autoimmune disorders have arisen. A growing number of reports have documented associations between vaccination and autoimmunity, and research is needed to elucidate the nature of these linkages as well as the mechanisms and causal directions (i.e., whether persons with no history of autoimmune disorders may experience them upon vaccination or persons with autoimmune disorders may experience exacerbation or new adverse events, autoimmune or not, post-vaccination). This scoping review will follow Arksey and O'Malley's framework, which is enhanced by Levac et al.'s team-based approach, to address the relationship between COVID-19 vaccinations and autoimmune disorders. Moreover, it will explore the evidence informing the consensus of care concerning COVID-19 vaccinations in people experiencing these disorders. Data from refereed articles and preprints will be synthesized through a thematic analysis. A subgroup analysis will compare the findings according to the previous existence of autoimmune disorders, presence of co-morbidities, vaccine type, and other potentially relevant factors. COVID-19 has triggered the largest vaccination campaign in history. Drug safety is critical to properly assess the balance of risks and benefits of any medical intervention. Our investigation should yield information useful to assist in clinical decision-making, policy development, and ethical medical practices.
Citation: Claudia Chaufan, Laurie Manwell, Camila Heredia, Jennifer McDonald. COVID-19 vaccines and autoimmune disorders: A scoping review protocol[J]. AIMS Medical Science, 2023, 10(4): 318-328. doi: 10.3934/medsci.2023025
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Two years into the global vaccination campaign, important questions about COVID-19 vaccines and autoimmune disorders have arisen. A growing number of reports have documented associations between vaccination and autoimmunity, and research is needed to elucidate the nature of these linkages as well as the mechanisms and causal directions (i.e., whether persons with no history of autoimmune disorders may experience them upon vaccination or persons with autoimmune disorders may experience exacerbation or new adverse events, autoimmune or not, post-vaccination). This scoping review will follow Arksey and O'Malley's framework, which is enhanced by Levac et al.'s team-based approach, to address the relationship between COVID-19 vaccinations and autoimmune disorders. Moreover, it will explore the evidence informing the consensus of care concerning COVID-19 vaccinations in people experiencing these disorders. Data from refereed articles and preprints will be synthesized through a thematic analysis. A subgroup analysis will compare the findings according to the previous existence of autoimmune disorders, presence of co-morbidities, vaccine type, and other potentially relevant factors. COVID-19 has triggered the largest vaccination campaign in history. Drug safety is critical to properly assess the balance of risks and benefits of any medical intervention. Our investigation should yield information useful to assist in clinical decision-making, policy development, and ethical medical practices.
The main purpose of this note is to provide an alternative construction of nonnegative and nonradially symmetric initial data for some Keller–Segel-type models which will enforce finite or infinite blowup. Consider the following functional:
F(u,v):=∫Ω(ulogu−uv+12|∇v|2+12v2)dx, |
where Ω⊂R2 is a bounded domain with C2 boundary ∂Ω and a pair of nonnegative smooth functions (u,v). The main result of this note is stated as follows.
Theorem 1.1. For any M>0 and Λ∈(4π,∞) there exists a pair of nonnegative functions (u0,v0)∈(C∞(¯Ω))2 satisfying
{‖u0‖L1(Ω)=Λ,F(u0,v0)<−M. |
The above functional F(u,v) appears in the study of the minimal Keller–Segel system:
{ut=Δu−∇⋅(u∇v)x∈Ω,t>0,vt=Δv−v+ux∈Ω,t>0,∂νu=∂νv=0x∈∂Ω,t>0,u(x,0)=u0(x),v(x,0)=v0(x),x∈Ω, | (1.1) |
and also one of the following chemotaxis model featuring a signal-dependent motility function of the negative exponential type:
{ut=Δ(e−vu)x∈Ω,t>0,vt=Δv−v+ux∈Ω,t>0,∂νu=∂νv=0x∈∂Ω,t>0,u(x,0)=u0(x),v(x,0)=v0(x),x∈Ω. | (1.2) |
Classical positive solutions of (1.1) satisfy the following energy-dissipation identity ([4,9]):
ddtF(u,v)(t)+∫Ωu|∇logu−∇v|2dx+‖vt‖2L2(Ω)=0, |
while for the classical solutions to (1.2), there holds ([2]):
ddtF(u,v)(t)+∫Ωue−v|∇logu−∇v|2dx+‖vt‖2L2(Ω)=0. |
In both cases, the above energy identities will immediately give rise to the a priori upper bound for F(u,v)(t). On the other hand, for any given initial data of small total mass such that ‖u0‖L1(Ω)<4π, one could derive a lower bound for the energy functional and then the classical solutions of both systems (1.1) and (1.2) exist globally in time and remain bounded uniformly in the two-dimensional setting (see [2,4,7,9]). For large data, unbounded solutions of the above problems could be constructed based on observations of the variational structure of the stationary problem and by taking an advantage of the subtle connection between its associated functional with the energy F. In [5] the authors introduced a transformation problem of the original system (1.1) with the unknowns being the cell density and the relative signal concentration. Then they constructed unbounded solutions for the transformed problem, which in turn implied blowup of the original one.
In this note we would rather to construct an unbounded solution to the original system (1.1) or (1.2) in a more direct way. To this aim, let us sketch the main idea of the construction of an unbounded solution following [11] (see also [5]). First, the corresponding stationary solutions (us,vs) to (1.1) or (1.2) satisfy the following problem:
{vs−Δvs=Λ∫Ωevsdxevsin Ω,us=Λ∫Ωevsdxevsin Ω,∂vs∂ν=0on ∂Ω, | (1.3) |
for some Λ>0. Denote
S(Λ):={(us,vs)∈C2(¯Ω):(us,vs) is a solution to (1.3) } |
for Λ>0. By [5,Lemma 3.5] and [10,Theorem 1], for Λ∉4πN there exists some C>0 such that
sup{‖(us,vs)‖L∞(Ω):(us,vs)∈S(Λ)}≤C |
and
F∗(Λ):=inf{F(us,vs):(us,vs)∈S(Λ)}≥−C. |
On the other hand, let (u,v) be the classical positive solution to (1.1) or (1.2) in Ω×(0,∞). If the solution is uniform-in-time bounded, by the compactness method (cf. [13,Lemma 3.1]), there exist a sequence of time {tk}⊂(0,∞) and a solution (us,vs) to (1.3) with Λ=‖u0‖L1(Ω) such that limk→∞tk=∞ and that
limk→∞(u(tk),v(tk))=(us,vs)inC2(¯Ω), |
as well as
F(us,vs)≤F(u0,v0). |
Thus taking account of the above discussion, for a pair of nonnegative functions (u0,v0) satisfying
{‖u0‖L1(Ω)=Λ∉4πN,F(u0,v0)<F∗(Λ), | (1.4) |
the corresponding solution must be unbounded or blow up in finite time.
Recently in [2], we constructed nonnegative initial data satisfying (1.4) when Λ∈(8π,∞) in the radially symmetric case, which differs from those given in [5]. However, it was left open whether our idea for a construction of adequate initial data can be extended to the nonradial symmetric case if Λ∈(4π,8π). Theorem 1.1 of the present work gives an affirmative answer to this question and as a consequence, we have an alternative proof of the following corollaries ([5]).
Corollary 1.2. For any Λ∈(4π,∞)∖4πN there exists a nonnegative initial datum (u0,v0) satisfying (1.4) such that the corresponding classical solution of (1.1) satisfies either:
● exists globally in time and lim supt→∞(‖u(t)‖L∞(Ω)+‖v(t)‖L∞(Ω))=∞;
● blows up in finite time.
Remark 1.3. Finite time blowup solutions of the corresponding parabolic-elliptic system are constructed if Λ>4π in [8].
As to the system (1.2), global existence of classical solutions with any nonnegative initial data was guaranteed in [2], which excluded the possibility of finite-time blowup. Hence, we arrive at the following:
Corollary 1.4. For any Λ∈(4π,∞)∖4πN there exists a nonnegative initial datum (u0,v0) satisfying (1.4) such that the corresponding global classical solution of (1.2) blows up at time infinity.
In previous works [3,6,12,13], nonnegative initial data with large negative energy were constructed in several modified situations, e.g., the higher dimensional setting, the nonlinear diffusion case, the nonlinear sensitivity case and the indirect signal case. In those works, the initial datum has a concentration at an interior point of Ω. Similarly, in our precedent work [2], we constructed an initial datum which concentrates at the origin based on certain perturbation of the rescaled explicit solutions to the elliptic system
{−ΔV=Ux∈R2,eV=Ux∈R2,∫R2U=8π, |
provided that the total mass Λ>8π. However, without the radially symmetric requirement and when 4π<Λ<8π, we need to construct an initial datum that concentrates at a boundary point. To this aim, some cut-off and folding-up techniques are introduced. Besides, a lemma of analysis (Lemma 2.2) plays a crucial role in estimating the value of each individual integral in the energy functional and in order to get vanishing estimations of the error terms, the radius of the cut-off function used in our case needs to depend on the rescaled parameter as well, which in contrast was fixed in the radially symmetric case in [2].
A straightforward calculation leads us to the following lemma.
Lemma 2.1. For any λ≥1 and r∈(0,1), the functions
uλ(x):=8λ2(1+λ2|x|2)2,vλ(x):=2log1+λ21+λ2|x|2+log8for all x∈R2, |
satisfy
∫R2uλdx=8π,uλ(x)≤8λ2,vλ(x)>log8>0in Br(0):={x∈R2||x|<r}. |
Since ∂Ω is C2 class, for any boundary point P∈∂Ω there exist some R′=R′P∈(0,1) and some C2 function γP:R→R such that
Ω∩BR′(0)={(x1,x2)∈BR′(0)|x2>γP(x1)} |
(cf. [1,Appendix C.1]). Moreover since Ω is a bounded domain, we can find some point P0=(P1,P2)∈∂Ω satisfying that there exists R∈(0,R′) such that
(γP0)′′(x1)≥0for all |P1−x1|<R. | (2.1) |
By translation, we may assume P0=(0,0). Hereafter we fix the above R∈(0,1) and γ=γP0. In this setting, we have the following lemma:
Lemma 2.2. Let f:R2→R be a radially symmetric, nonnegative and continuous function. For any r∈(0,R) it follows that
12∫Br(0)f(x)dx−K(R)(supx∈Br(0)f(x))⋅r3≤∫Br(0)∩Ωf(x)dx≤12∫Br(0)f(x)dx, |
where
K(R):=max|ξ|≤Rγ′′(ξ)>0. | (2.2) |
Proof. We first note that for any r∈(0,R),
Ω∩Br(0)={(x1,x2)∈Br(0)|x2>γ(x1)}. |
Since γ(0)=0 and the assumption (2.1), it follows by Taylor's theorem that for all x1∈(−R,R) we have
γ′(0)x1≤γ(x1)≤γ′(0)x1+12K(R)⋅x21, |
where K(R):=max|ξ|≤Rγ′′(ξ)>0. Thus we can deduce that
A+ε⊂(Ω∩Br(0))⊂A, |
where
A+ε:={(x1,x2)∈Br(0)|x2>γ′(0)x1+12K(R)⋅r2},A:={(x1,x2)∈Br(0)|x2>γ′(0)x1}. |
By denoting
B+ε:={(x1,x2)∈Br(0)|γ′(0)x1+12K(R)⋅r2≥x2>γ′(0)x1}, |
we confirm that
A+ε=A∖B+ε. |
Since the radial symmetry of f implies
∫Af(x)dx=12∫Br(0)f(x)dx, |
we have
12∫Br(0)f(x)dx−∫B+εf(x)dx≤∫Ω∩Br(0)f(x)dx≤12∫Br(0)f(x)dx. |
Since
|B+ε|≤12K(R)r2⋅2r=K(R)r3, |
we have that
12∫Br(0)f(x)dx−(supx∈Br(0)f(x))⋅K(R)⋅r3≤∫Ω∩Br(0)f(x)dx≤12∫Br(0)f(x)dx, |
which concludes the proof.
For any 0<η1<η2 we can construct a radially symmetric function ϕη2,η1∈C∞(R2) satisfying
ϕη2,η1(B(0,η1))={1}, 0≤ϕη2,η1≤1, ϕη2,η1(R2∖B(0,η2))={0}, x⋅∇ϕη2,η1(x)≤0. |
For any λ>max{1,(4R)65}, we fix
r:=λ−56,r1:=r2, |
and then 0<r1<r<min{1,R4}. Noting that
f(λ):=1−11+(λr1)2=1−44+λ13↗1 as λ→∞, |
and by the increasing property of f, we can find λ∗>max{1,(4R)65} such that
4π⋅f(λ∗)−8K(R)λ−12∗>2π, |
where K(R) is defined in (2.2). Here we confirm that for any λ>λ∗,
4π⋅f(λ)−8K(R)λ−12>2π. |
Now we define the pair
(u0,v0):=(auλϕr,r1χΩ,avλϕR2,R4χΩ) |
with some a>0. Here we remark that u0 and v0 are nonnegative functions belonging to C∞(¯Ω).
Lemma 2.3. Let Λ∈(4π,∞). For λ>λ∗ there exists
a=a(λ)∈(Λ4π,Λ2π) | (2.3) |
such that
∫Ωu0dx=Λ. | (2.4) |
Proof. Firstly by changing variables, we see that
∫B(0,ℓ)uλdx=8∫B(0,λℓ)dy(1+|y|2)2=8π∫(λℓ)20dτ(1+τ)2=8π⋅(1−11+(λℓ)2) for ℓ>0, | (2.5) |
and that
8π⋅(1−11+(λr1)2)<∫Br(0)uλϕr,r1dx<8π⋅(1−11+(λr)2). |
Here in light of the radial symmetry of uλϕr,r1, we can invoke Lemma 2.2 to have
4π⋅(1−11+(λr1)2)−K(R)8λ2r3<∫Ωuλϕr,r1χΩdx<4π⋅(1−11+(λr)2), |
where we used
maxx∈Br(0)uλϕr,r1(x)=8λ2and∫Ωuλϕr,r1χΩdx=∫Br(0)∩Ωuλϕr,r1dx. |
By the choice of r>0, we have
4π⋅f(λ)−8K(R)λ−12<∫Ωuλϕr,r1χΩdx. |
Therefore for any λ>λ∗ we find some a=a(λ) satisfying
Λ4π<a<Λ2π |
and (2.4). We conclude the proof.
Lemma 2.4. There exists C>0 such that for all λ>λ∗,
∫Ωu0logu0dx≤8πalogλ+C, | (2.6) |
where a=a(λ) is defined in Lemma 2.3.
Proof. Since slogs≤tlogt+1e for s≤t and u0≤auλχBr(0)∩Ω, it follows
∫Ωu0logu0dx≤∫Ω(auλχBr(0)∩Ω)log(auλχBr(0)∩Ω)dx+|Ω|e≤a∫ΩuλχBr(0)∩Ωloguλdx+(aloga+e−1)∫Ωuλdx+|Ω|e. |
Since loguλ≤log(8λ2)=2logλ+log8 and ∫Ωuλ≤8π, we have
∫Ωu0logu0dx≤2alogλ∫ΩuλχBr(0)∩Ωdx+8π(alog8+aloga+e−1)+|Ω|e. |
By Lemma 2.2 we obtain
∫ΩuλχBr(0)∩Ω≤12∫Br(0)uλ≤12∫R2uλ=4π. |
Therefore
∫Ωu0logu0dx≤8πalogλ+C, |
where we remark that the constant C is independent of a and λ in view of (2.3). We conclude the proof.
Lemma 2.5. There exists C>0 such that for all λ>λ∗,
∫Ωu0v0dx≥16πa2logλ−64πa2logλ4+λ13−K(R)λ−12(2log(1+λ2)+log8)−C, | (2.7) |
where a=a(λ) is defined in Lemma 2.3.
Proof. Using vλ>0 in B(0,r), u0=0 on B(0,r)c and r1<R4, we see that
∫Ωu0v0dx≥a2∫B(0,r1)uλvλχBr1(0)∩Ωdx. |
Since uλvλ is radially symmetric and
maxx∈Br1(0)uλvλ(x)=8λ2(2log(1+λ2)+log8), |
we apply Lemma 2.2 and recall r1=2−1λ−56 to deduce that
∫Ωu0v0dx≥12a2∫B(0,r1)uλvλdx−K(R)8λ2(2log(1+λ2)+log8)⋅r31=12a2∫B(0,r1)uλvλdx−K(R)λ−12(2log(1+λ2)+log8). |
Since
vλ(x)>2log1+λ21+λ2|x|2 for x∈B(0,r1), |
we have that
12a2∫B(0,r1)uλvλdx≥12a2∫B(0,r1)uλ⋅2log1+λ21+λ2|x|2dx>2a2logλ∫B(0,r1)uλdx−a2∫B(0,r1)uλlog(1+λ2|x|2)dx. |
By (2.5), it follows
2a2logλ∫B(0,r1)uλdx≥2a2logλ⋅8π(1−11+(λr1)2)=16πa2logλ−64πa2logλ4+λ13. |
On the other hand, by (2.3) and direct calculations we see
a2∫B(0,r1)uλlog(1+λ2|x|2)dx=8a2∫B(0,r1)λ2log(1+λ2|x|2)(1+λ2|x|2)2dx=16πa2∫λr10slog(1+s2)(1+s2)2ds<8πa2∫∞0log(1+ξ)(1+ξ)2dξ<∞. |
Combining above estimates, we obtain that
∫Ωu0v0dx≥16πa2logλ−64πa2logλ4+λ13−K(R)λ−12(2log(1+λ2)+log8)−C |
for λ>λ∗ with some positive constant C, which is independent of a and λ due to (2.3).
Lemma 2.6. For any ε1>0 there exists C(ε1)>0 such that for all λ>λ∗,
12∫Ω(v20+|∇v0|2)dx≤8π(1+ε1)a2logλ+C(ε1), | (2.8) |
where a=a(λ) is defined in Lemma 2.3.
Proof. Since
1+λ21+λ2|x|2≤1+λ2λ2|x|2≤(2|x|)2for λ>1, |
we see that for λ>1
|vλ(x)|≤4log2|x|+log8 in B1(0). |
Hence it follows from straightforward calculations that there is a positive constant C satisfying
∫Ωv20dx≤a2∫B1(0)(4log2|x|+log8)2dx≤C, | (2.9) |
where the constant C is independent of a and λ due to (2.3).
Moreover by Young's inequality, for any ε1>0 there exists C′(ε1)>0 such that
|∇v0|2=a2|ϕR2,R4∇vλ+∇ϕR2,R4vλ|2χBR2(0)∩Ω≤a2(1+ε1)ϕ2R2,R4|∇vλ|2χBR2(0)∩Ω+C′(ε1)a2|∇ϕR2,R4|2v2λχBR2(0)∩Ω. |
Since by (2.9) we have some C>0 such that
a2∫Ω|∇ϕR2,R4|2v2λχBR2(0)∩Ωdx≤C |
and by the direct calculations, we have
|∇vλ(x)|=4λ2|x|1+λ2|x|2, |
and then we infer that
∫Ω|∇v0|2dx≤a2(1+ε1)∫Ωϕ2R2,R4|∇vλ|2χBR2(0)∩Ωdx+C′(ε1)a2∫Ω|∇ϕR2,R4|2v2λdx≤16a2(1+ε1)∫BR2(0)∩Ωλ4|x|2(1+λ2|x|2)2dx+C′′(ε1) |
with some C′′(ε1)>0. Since λ4|x|2(1+λ2|x|2)2 is radially symmetric, we can invoke Lemma 2.2 to see
∫Ω|∇v0|2dx≤8a2(1+ε1)∫BR2(0)λ4|x|2(1+λ2|x|2)2dx+C′′(ε1), |
thus
12∫Ω|∇v0|2dx≤4a2(1+ε1)∫B1(0)λ4|x|2(1+λ2|x|2)2dx+C′′(ε1)2. |
On the other hand,
∫B1(0)λ4|x|2(1+λ2|x|2)2dx=π∫λ20τ(1+τ)2dτ≤π∫λ2011+τdτ=πlog(1+λ2). |
Since λ>1, it follows
log(1+λ2)≤log(2λ2)=2logλ+log2. |
Hence
12∫Ω|∇v0|2dx≤4πa2(1+ε1)⋅(2logλ+log2)+C′′(ε1)2. |
Therefore we conclude
12∫Ω|∇v0|2dx≤8πa2(1+ε1)logλ+C(ε1), |
where the constant C(ε1) is independent of a and λ due to (2.3).
Proof of Theorem 1.1. For any Λ∈(4π,∞), we have Λ/4π>1. In view of (2.3), we can fix ε1>0 independently of λ such that (1−ε1)a−1>(1−ε1)Λ4π−1>0, where a=a(λ) is defined in Lemma 2.3. Then it follows that
a((1−ε1)a−1)>Λ4π((1−ε1)Λ4π−1)>0,for all λ>λ∗. | (2.10) |
Collecting (2.6), (2.7) and (2.8), we infer that there exists some C>0 such that
F(u0,v0)≤I1⋅logλ+I2+C, |
where
I1:=8πa−16πa2+8πa2(1+ε1)=−8πa((1−ε1)a−1),I2:=64πa2logλ4+λ13+K(R)λ−12(2log(1+λ2)+log8). |
Here (2.10) implies I1<0 for all λ>λ∗. On the other hand, we note
limλ→∞I2=0. |
Based on the above discussion, for Λ∈(4π,∞) and M>0, we can choose some λ>λ∗ such that
F(u0,v0)<−M. |
We conclude the proof.
The authors thank the anonymous referee's careful reading and useful suggestions. K. Fujie is supported by Japan Society for the Promotion of Science (Grant-in-Aid for Early-Career Scientists; No. 19K14576). J. Jiang is supported by Hubei Provincial Natural Science Foundation under the grant No. 2020CFB602.
The authors declare no conflict of interest.
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