HIV and SJS/TEN
Enhanced expression of immune receptors may also be responsible for the
highly elevated incidence of SJS/TEN in HIV-infected patients. Indeed,
the mechanism underlying SJS has been found to be due to p-i, where
investigated [21, 23, 24]. HIV infection increases HLA expression,
and, although there are reduced T cells present, these circulating T
cells are highly activated. Thus, the opportunity for T cells to react
to drugs and stimulate p-i reactions is dramatically increased. This
could explain that the incidence of SJS/TEN (in response to various
drugs) is around 100-fold increased in HIV-infected compared to
non-infected individuals [25]. Some authors have proposed additional
factors such as HIV-induced depletion of immunoregulatory cells and
increased oxidative stress as favoring the development of DH [5,
51], but this remains controversial [50].
First DH, then virus release
In the above-mentioned examples, the viral infection primes the immune
system for enhanced reactivity to drugs and thus clearly precedes the
first manifestations of DH. However, there is an important exception to
this sequence of events. In DRESS, DH develops first, and viraemia of
endogenous herpes viruses (e.g. human herpes virus 6 (HHV6),
cytomegalovirus (CMV), Epstein-Barr virus (EBV)) is subsequently
detected. This viraemia can be detected already in the acute stage, but
most commonly it is found 3-6 weeks later [52-54]. That means the
viraemia develops, at least in the vast majority of cases,after cessation of the drugs which induce DRESS (Fig 3). Herpes
virus reactivation is a rather common event, and HHV6 is even included
in the Japanese definition of DRESS [54, 55]. Some of the herpes
viruses are regularly present simultaneously [56], and often the
viraemia remains asymptomatic. Severe complications as a result of this
viral reactivation appear to be rare and are described mainly during CMV
infections (colitis, myocarditis) [57, 58]. Whether the high
systemic cytokine levels (e.g., TNFα and G-CSF) in the acute phase of
DRESS play a role in CMV reactivation and related complications
[58], is doubtful, as CMV reactivation and these complications
usually appear much later [59].
An intense p-i stimulation, which involves the activation and expansion
of many (polyclonal) CD4+ and CD8+ T cells, underlies DRESS [9, 10,
60]. This stimulation develops over weeks and is mirrored by
lymphocytosis with many lymphoblasts in the peripheral blood (part of
DRESS definition). These p-i-activated T cells are cytotoxic and
infiltrate various tissues [61]. Additionally, DRESS is
characterized by a massive activation and expansion of eosinophils in
the peripheral blood and target organs.
The p-i stimulation affects both naïve and memory T cells and causes an
activation and expansion of various T cells (polyclonal, polyspecific,
cytotoxic) [9, 10]. Within this p-i activated T lymphocyte pool, are
also T cells that are specific for endogenous herpes viruses. Up to 10%
of all CD8+ T cells may be herpes virus-specific [62] and they
control viral replication, likely via local IFN-γ release
[63][64]. The p-i activation of these T cells may also have a
dramatic effect on their effector function. Virus-specific T cells
become cytotoxic due to the drug-induced p-i stimulation, and when they
encounter their target stimulus (i.e., HHV6, CMV, EBV) in the peripheral
tissue, these T cells kill the herpes-infected cells. In fact, an
increase in TNFα and IL-6 was observed before HHV6 reactivation in
DRESS, which was found to occur 3-4 weeks following the initial
diagnosis [65][66]. As a consequence, the endogenous
intracellular herpesviruses are released. The release of viral particles
results in blood viraemia, most often in the absence of actual viral
replication. In many cases, the viraemia remains asymptomatic.
Other authors have linked systemic cytokine storm, as detected in some
acute DRESS cases, to viral replication (as shown for TNFα and HHV6)
[67, 68], and, as in the case of CMV, serious, potentially fatal
complications. However, most viraemia is observed weeks after the
cytokine storm.
Beyond viral reactivations, the p-i-activation of T cells in DRESS may
also be linked to the occurrence of late autoimmune complications.
Instead of virus-specific T cells, the activation and subsequent
functional switch to a cytotoxic effector mode may happen in
autoreactive T cells [10].
Clinical impact and conclusion
Many factors influence the clinical manifestation of DH in the context
of viral infections. These can be virus-, drug- and/or patient-related.
Among the virus-related factors are the type and strain of the virus and
the length of infection. The drug itself, the dose, its ability to act
as a hapten, the patient’s underlying condition, antiviral/antidrug
immune response, and potential state of immunosuppression also
contribute in this setting. It is challenging, but important for a
better understanding of DHR in viral infections, to dissect the
respective contribution of these virus-, drug- and/or patient-related
factors.
The models proposed can be generalized to various virus infections, and
are not dependent on a specific type of virus: The analysis of the
timing of symptoms and therapy, as well as the careful monitoring of
virus load in SARS-CoV-2-infected patients, has emphasized that DH
manifestations are not linked to the presence of viruses, nor that
viraemia after DRESS is linked to the presence of a drug. They are due
to the virus- or drug-triggered immune stimulations, but are not
dependent on the presence of its elicitor (drug or virus). The
manifestations of DH can therefore occur after virus clearance – as
long as the state of immune activation persists. Vice versa, viral
release can occur in the absence of a drug, as illustrated in the late
complications of DRESS (Fig 3).
For the clinician, the following questions are important: