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VOL.11 NO.3 MARCH 2006
MedicalEditorial
Bulletin
Viral Exanthems - Why are They Good
Choices for Research by Family Physicians?
Dr. Antonio AT Chuh
MD(HK) FRCP(Irel) FHKCFP FHKAM(Fam Med)
Family physician in private practice, Part-time Associate Professor,
Department of Community and Family Medicine, The Chinese University of Hong Kong
Honorary Clinical Assistant Professor, Family Medicine Unit, Department of Medicine, The University of Hong Kong
Dr. Antonio AT Chuh
Abstract
Family physicians are well placed to study viral
exanthems because they see patients at an early stage of
the eruption, and can obtain early virological evidence.
Several exanthems are under-reported and underinvestigated in China and in Asia. Such provides good
opportunities for clinical research. Epidemiological data
are less biased in primary care than in secondary care
settings. Family physicians are also interested in the entire
illness instead of the disease only, and can thus evaluate
impacts of management in a comprehensive and
evidence-based manner.
Contrary to common belief, several exanthems of multiple
or unknown viral aetiologies such as Gianotti-Crosti
syndrome and pityriasis rosea are common conditions.
These rashes might appear to be uncommon merely
because of under-diagnosis and under-reporting.
Background
Viral exanthems are skin eruptions occurring as
symptoms of acute viral diseases.1 Exanthem comes from
the Greek word exanthema, meaning breaking out, and
anthos, denoting blossoming flowers. We shall discuss in
this article why viral exanthems matter much to family
physicians, and why family physicians are well placed to
investigate them. We shall also describe future challenges
in researching viral exanthems.
Viral exanthems matter much to
family physicians
The major viral exanthems are listed in Table 1. Viral
exanthems are important for family physicians because
most patients with such exanthems initially consult family
physicians instead of specialists. Early accurate diagnosis
removes the need for unnecessary investigations and
treatments. Adequate symptomatic relief can be given by
family physicians. Patients and parents can be advised on
the likely course of the disease, and symptoms and signs
of common and rare complications.
Early measures can also be taken by the family physician
on isolation if necessary to prevent an epidemic. On the
other hand, if isolation is unnecessary or not warranted,
patients, parents, and school or kindergarten teachers may
be reassured. Family physicians should also be aware that
several exanthems are notifiable.
Family physicians are well placed to
investigate viral exanthems
1. Early virological evidence
Family physicians see patients with exanthems at an early
stage of the eruption. Early virological evidence is thus
available. By the time these patients are referred to
secondary care specialists such as dermatologists or
paediatricians, viral DNA and mRNA transcripts will not
be detectable in the tissue samples such as the plasma for
many viruses, and virus loads will be low. Moreover,
parallel serological investigation of acute and convalescent
sera would not be possible. The analysis of results from
the convalescent serum alone is of limited value in
documenting acute infections.
Owing to such early presentation, we have been able to
investigate for human herpesvirus (HHV)-6 and -7 DNA
in the plasma and peripheral blood mononuclear cells,
virus subtyping, HHV-6 virus load, HHV-6 U91 mRNA
transcripts in peripheral blood mononuclear cells, and
HHV-6 and -7 serology in acute and convalescent blood
specimens of children with Gianotti-Crosti syndrome.2
We have been fortunate to be the first investigators
confirming that primary infection of HHV-6B is a cause of
Gianotti-Crosti syndrome (papular acrodermatitis of
childhood).2
Owing to such early presentation, we have also been able
to provide convincing evidence that patients with
pityriasis rosea in Hong Kong do not exhibit evidence of
primary infection or reactivation of HHV-7 and -6.3 We
also reported that pityriasis rosea is not caused by
infections by cytomegalovirus, Epstein-Barr virus,
parvovirus, 4 Chlamydia pneumoniae, C. trachomatis,
Legionella longbeachae, L. micdadei, L. pneumophila and
Mycoplasma pneumoniae.5 Our studies on the roles of other
viruses are in progress.6
2. Rarity of reports in China and in Asia
Several exanthems are relatively under-reported and
under-investigated for Chinese and Asian patients. This
provides good opportunities for clinical research. Owing
to such under-reporting, we have been fortunate to be able
to report the first series of Chinese children with GianottiCrosti syndrome.7, 8
Another example is asymmetric periflexural exanthem.
This exanthem is also known as unilateral laterothoracic
exanthem, and has been reported in France,9, 10 Italy,11, 12
Germany,13 Spain,14 Hungary,15 United Kingdom,16 USA,17
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Medical Bulletin
and Canada.18 It is likely to be endemic in parts of Europe
(Taieb - personal communication). To our best knowledge,
the occurrence of this exanthem in Asia has not been
reported in indexed journals. We reported the first patient
with asymmetric periflexural exanthem in Asia.19, 20 We
shall also report the first patients with a novel variant of
asymmetric periflexural exanthem in the world, which we
term unilateral mediothoracic exanthem.21
demonstrated that the effects on the quality of life are
independent of rash severity in adult patients with
pityriasis rosea.33 The implication of this finding is that
active intervention might be unnecessary even for some
patients with diffuse eruptions. We also documented
that effects on the quality of life are minimal for children
with pityriasis rosea,34 and that active treatment is
unnecessary for most children with this exanthem.
3. Epidemiology data - least biased in primary care
5. Exanthems of multiple or unknown viral
aetiologies are common conditions
Epidemiological data from primary care setting are the
best proxy measure of community-based diagnoses such
as viral exanthems. Such data from secondary care
specialists might be biased due to selective referral and
inevitable delay in the consultation.
With such unreferred data, we have been able to
demonstrate significant temporal case clustering in
pityriasis rosea. 22 Temporal clustering is a well
established method in investigating the infectious origin
of a condition, and has been applied in Kawasaki
disease23 and childhood leukaemia.24 There has been
previous report on temporal clustering in pityriasis
rosea.25 However, the statistical method previously used
was based on a fixed scanning window. As
epidemiology variables such as incubation period and
infectious period of pityriasis rosea are unknown,
adopting a fixed scanning window might not be the most
appropriate. Collaborating with statisticians from
France, we applied a novel regression analysis model
with bootstrapped simulations. 26 Our method is
independent of cluster size, can detect multiple clusters,
and has been validated by application on other data sets.
The demonstration of significant temporal clustering
provided indirect evidence substantiating an infectious
aetiology for pityriasis rosea. We subsequently validated
our findings by collaborating with researchers from the
US, France, Kuwait and Turkey, performing regression
analysis on 1379 patients with pityriasis rosea in three
geographic locations around the world.27 Further work
by our group on spatial-temporal clustering in GianottiCrosti syndrome28 and other exanthems are in progress.
4. Family physicians care for the person, not only
the disease
While some specialists might concentrate their efforts on
the disease, family physicians have a heart for the patient
and the illness as well. We are concerned about the
impacts of exanthems on the quality life of patients, and
whether schooling and work of patients are affected. We
are therefore disheartened to find that major treatment
trials on pityriasis rosea, for example, do not include
quality of life as one of the outcome measures.29-32 Even
pruritus, the major symptom in pityriasis rosea, was not
investigated in some of the studies. 29, 30 These
investigators only measured how the rash severity and
extensiveness were modified by medications. Many of
the patients could have no or little pruritus, and the face
and distal aspects of extremities are uncommonly
affected in this exanthem. These patients might not
warrant active intervention in the first place.
Recognising this gap in knowledge, we investigated and
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VOL.11 NO.3 MARCH 2006
Family physicians should concentrate their already
limited research efforts and resources on common
conditions. Contrary to common belief, there exists
epidemiological evidence from primary care setting that
several exanthems of multiple or unknown viral
aetiologies including Gianotti-Crosti syndrome35 and
pityriasis rosea36, 37 are in fact common conditions. The
incidence of asymmetric periflexural exanthem is
unknown. However, emerging data substantiate that it is
endemic in European countries (Taieb - personal
communication). These eruptions might appear to be
uncommon merely because of under-diagnosis and
under-reporting. It is known, for example, that primary
care physicians significantly underdiagnose pityriasis
rosea.38
A pertinent analogy here is erythema infectiosum. In the
1960s and 1970s, this was assumed to be an uncommon
disease entity,39 and many physicians had not even heard
of the disease. 39 It is now known that erythema
infectiosum is likely to be the commonest viral rash in
school children in developed countries,40 and that the
previously assumed low incidence of erythema
infectiosum is likely to be due to under-diagnosis only.41
Discussion and future challenges for
research
Viral exanthems serve as good models for which family
physicians can collaborate with international and
multidisciplinary investigators. We have good support
and pleasurable collaboration with other family
physicians, dermatologists, paediatricians, virologists,
pathologists, epidemiologists, statisticians, quality of
life investigators, linguists, systemic review experts and
consumer reviewers (patients with the exanthem).
Our present network embraces investigators from
Columbia, France, Hong Kong, India, Kuwait,
Philippines, Romania, Switzerland, Turkey, United
Kingdom and USA. We are amazed that several
overseas investigators are in private practice, with
honorary academic posts in prestigious universities and
institutions. They are every bit as eager to contribute to
research as their full-time academic colleagues, but for
reasons other than promotions up the academic ladder.
We hope to open up new horizons and opportunities
for research with the aims of not only producing high
quality publications but also exerting direct impact on
the quality of management to patients.
There lies many future challenges in research. The
aetiologies of many exanthems have not been elucidated
VOL.11 NO.3 MARCH 2006
and further search for the roles of other viruses might
shed light on the management strategies.42 The roles of
atopy and hyperimmunoglobulinaemia E states in viral
exanthems,43 and conversely, the role of early viral
infections in atopic states44 warrant further investigations.
Further studies should be performed to establish the
validity and reliability of diagnostic criteria for several
exanthems.45-47 The treatment of the exanthems are at
present largely empirical. Clinical trials and systematic
reviews48 would rationalise patient management.
There lies rough water ahead, and we are acutely aware of
our limitations such as constraints in time and resources.
We also lack the clinical expertise possessed by our
specialist colleagues. Dedication, commitment and
perseverance might overcome some, but not all, of our
hindrances. The rest will have to depend on support from
specialist colleagues and the development of a sustainable
infrastructure in family medicine research deliberated in
the Editorial of this issue.
MedicalEditorial
Bulletin
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Acknowledgements
30.
An article based on part of this manuscript was selected
in the 14th Congress of the European Academy of
Dermatology and Venereology, 2005, London, as "One
of the Most Worth Reading Papers in Medical
Dermatology of the Year".
31.
Part of this manuscript was presented in the Joint
Research Meeting of Family Medicine Units of The
Chinese University of Hong Kong and The University
of Hong Kong, 2005.
33.
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Table 1 Viral exanthems
Multiple or unknown viral aetiology
Known viral aetiology
Gianotti-Crosti syndrome
Roseola infantum
Pityriasis rosea
Erythema infectiosum
Papular purpuric gloves and
Chickenpox
socks syndrome
Enterovirus
Asymmetric periflexural
Infectious mononucleosis
exanthem
Rubella
Eruptive pseudoangiomatosis
Measles
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