Short title: Viral infections and drug hypersensitivity
Werner J. Pichler 1 & Marie-Charlotte Brüggen2, 3, 4
1 ADR-AC GmbH, Holligenstr 91, 3008 Bern
2 Allergy Unit, Department of Dermatology, University
Hospital Zürich
3 Faculty of Medicine, University Zürich
4 Christine Kühne – Center for Allergy Research and
Education (CK-CARE)
ORCID IDs: Werner Pichler: 0000-0002-8117-359X Marie-Charlotte Brüggen: 0000-0003-3215-3370
Corresponding author: Werner J Pichler, MD ADR-AC GmbH Holligenstr 91 CH 3008 Bern Switzerland e-mail:
werner.pichler@adr-ac.ch
Acknowledgments: the authors thank Daniel Yerly and Oliver
Hausmann for inspiring discussions and Katja Martin as well as Clara
Clemens for help in preparing the figures and text.
Abstract:
Virus infections and T cell-mediated drug hypersensitivity reactions
(DHR) can influence each other. In most instances, systemic virus
infections appear first. They may prime the reactivity to drugs intwo ways: First, by virus-induced second signals: certain
drugs like β-lactam antibiotics are haptens and covalently bind to
various soluble and tissue proteins, thereby forming novel antigens.
Under homeostatic conditions, these neo-antigens do not induce an immune
reaction, probably because co-stimulation is missing. During a virus
infection, the hapten-modified peptides are presented in an
immune-stimulatory environment with co-stimulation. A drug-specific
immune reaction may develop and manifest as exanthema. Second, by
increased pharmacological interactions with immune receptors (p-i) :
drugs tend to bind to proteins and may even bind to immune receptors. In
the absence of viral infections, this low affine binding may be
insufficient to elicit T cell activation. During a viral infection
immune receptors are more abundantly expressed and allow more
interactions to occur. This increases the overall avidity of p-i
reactions and may even be sufficient for T cell activation and symptoms.
There is a situation, where the virus-DHR sequence of events is
inversed: in drug reaction with eosinophilia and systemic symptoms
(DRESS), a severe DHR can precede reactivation and viremia of various
herpes viruses. One could explain this phenomenon by the massive p-i
mediated immune stimulation during acute DRESS, which coincidentally
acvitates many herpes virus-specific T cells. Through p-i stimulation,
they develop a cytotoxic activity with killing of herpes
peptide-expressing cells and release of herpes viruses. These concepts
could explain the often transient nature of DHR occurring during viral
infections and the often asymptomatic herpes-virus viraemia after DRESS.
Keywords: exanthems, virus infection, drug hypersensitivity,
hapten, p-i concept, DRESS, herpes virus, viraemia, SARS-Cov2
Abbreviations: antigen-presenting cell: APC; drug
hypersensitivity reactions: DHR; p-i: pharmacological interactions with
immune recepto; human leukocyte antigens: HLA; T cell receptor: TCR;
maculopapular exanthema: MPE, Stevens-Johnson syndrome and toxic
epidermal necrolysis: SJS/TEN; drug reaction with eosinophilia and
systemic symptoms: DRESS; Epstein-Barr virus: EBV; human herpes virus 6:
HHV6; cytomegalovirus: CMV;
Introduction
Viral infections are common and can cause a multitude of symptoms. The
most frequently observed are respiratory , fever, and exanthems. Due to
the similarities between the symptoms presented during the early stages
of viral and bacterial infections (e.g., fever and tonsillitis) and/or
because a bacterial superinfection is considered, many patients with
viral infections are treated with antibiotics and antipyretics. Shortly
after these drugs were used in practice, a high incidence of exanthems
was observed, which was later attributed to viral infection. Such
connections between viral infections and drug hypersensitivity (DH) were
particularly apparent in young children experiencing their first
encounter with various respiratory viruses, and in adult patients with
Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV)
infections [1-5].
While the clinical manifestation of the interplay between viral
infections and DH has been widely acknowledged for many years, an
explanation for this increased incidence is missing. Indeed, the topic
is complex due to virus diversity, the number of causative drugs, and
the varied clinical manifestations involved.
The mechanisms underlying DH have been explored intensively in the last
25 years. A substantial fraction of DHR involves the adaptive immune
system (IgE, T cells), and drug-reactive T cells and antibodies have
been identified. Regarding T cell stimulations, two predominant
mechanisms have been elaboratedussed; the hapten and p-i concepts.
Some beta-lactams are haptens, which means that they bind by covalent
bonds to proteins, and thus form a new and stable antigen [6]. But
mostly they do not elicit immune reactions, presumably because no
co-stimulation (second signal) is provided by the drug itself [7].
The second mechanism postulates a non-covalent (pharmacological,
off-target) binding to immune receptors like human leukocyte antigen
(HLA) or T cell receptors (TCR) [7, 8]. This binding to crucial
components of the cellular immune system, can result in an unorthodox,
sometimes severe immune stimulation in the absence of co-stimulation
(pharmacological interaction with immune receptors, p-i concept). This
concept has been summarized in previous review articlesemphasizing the
similarity to an allo-and partly superantigen stimulation[9-11].
Here we try to incorporate these two concepts of drug-induced T cell
stimulation to explain the association between viral infections and T
cell-mediated DHR. We highlight that DHRs during viral infections are
driven by co-stimulation of T cells, or simply by the increased
expression of TCR/HLA on T cells. We believe, these concepts explain the
transient nature and low reproducibility of most drug-induced exanthems
originally appearing in the context of (transient) virus infections.
Exanthems in DH
The typical manifestations of virus-related DHR are so-called
“rashes”. These are macular or maculopapular exanthems (MPE), some
have vesicles. They are often mild in nature, and transient. However,
some virus-linked DHRs which affect a large proportion of the body
surface area, can last much longer, are more maculopapular, and can be
associated with signs of liver involvement (transient elevation of
ALAT/ASAT) [12, 13].
Systemic MPE itself represents a rather strong immune stimulation [14,
15]. Patients display an expansion of activated lymphocytes in
peripheral blood, upregulation of HLA class II expression on CD8+
lymphocytes, expression of CD25 and CD69 on CD4+ cells, and increased
concentrations of IFN-γ, TNFα, IL-5, IL-6, etc in the serum [16].
Histological analysis of MPE reveals CD4+, and, to a lesser extent, CD8+
T cells infiltrating the dermis and epidermis [17, 18]. This
response has been demonstrated to be, in part, drug-specific [19].
Notably, in MPE, both the infiltrating CD8+ and CD4+ T cells are
cytotoxic [17, 18, 20]. The target of this cytotoxic reaction are
activated keratinocytes expressing HLA class II- and adhesion molecules
(e.g. ICAM) [17, 18].
The extent of CD8+ cell infiltration seems to be variable [14, 15].
In most drug-induced MPE, CD4+ T cells predominate in the skin and CD8+
T cells predominate in the circulation. Milder exanthems are mediated by
cytotoxic CD4+ T cells, while the more extensive and maculopapular forms
are due to both CD4+ and CD8+ cell-mediated cytotoxicity. Bullous forms
appear to be mediated mainly by CD8+ T cells [21]. A concomitant
virus infection may also boost the CD8+ T cell involvement in the
tissue. The recently described MPE during COVID-19 displayed massive
polyclonal T cell activation in the circulation and a rather high
percentage of infiltrating CD8+ T cells (CD8:CD4 ratio of 3:1) into the
cutis/epidermis [22]. A similar but more severe response was also
observed in some exanthemas following beta-lactam use during EBV
infection [12]. The most powerful example of how a concomitant virus
infection can impact DHR is seen during HIV infections. The incidence of
SJS/TEN, which is a predominantly CD8+/NK cell-mediated reaction [21,
23, 24], is about 100-fold increased in HIV patients compared to
non-infected individuals [25].
In normal MPE without virus involvement, around 50% of patients present
with substantial eosinophilia [26, 27]. In contrast, eosinophilia is
an unusual finding in viral exanthemas [27]. Indeed, some
drug-specific T cells from patients with MPE excrete high amounts of
IL-5, which may explain the typical eosinophilia in various forms of DHR
[28][22].
Why some viral infections exacerbate DHR more frequently than other
microorganisms is currently unknown. A partial explanation may lay in
the similarly complex immune responses stimulated by viruses and drugs.
They can provide soluble and cell-bound antigens, engage in peptide
presentation via HLA class I and II and manipulate various components of
the cellular immune system. This similarity is also reflected by the
similar clinical and histological appearance of virus- or drug-induced
exanthemas. Some drug-induced exanthemas are so similar to viral
exanthems, that they were named accordingly (morbilliform or
rubeola-like exanthems). Similar exanthems are also seen in
graft-versus-host disease, where eosinophilia is also observed [29].
There are clinical similarities between virus, allo-allele and
drug-induced exanthems and, as discussed previously, there may also be
mechanistic similarities [9].
Viral infections enhance T cell hypersensitivity to drugs
A clue to better understanding the interplay between virus infection and
DH lies in the two different ways, by which drugs can stimulate T cells.
First by forming a new antigen (hapten -protein
complex)[6] and second by the p-i mechanism, which
results in an unorthodox, mostly cytotoxic T-cell stimulation [8,
9].