|Year : 2021 | Volume
| Issue : 2 | Page : 100-106
Exanthema in pediatric dermatology - A confusing galaxy of myriad diseases
Department of Pediatric Dermatology, Foundation IRCCS Ca'Granda “Ospedale Maggiore Policlinico”; Deptartment of Pathophysiology and Transplantation, University of Milan, Milan, Italy
|Date of Submission||16-Sep-2020|
|Date of Decision||17-Sep-2020|
|Date of Acceptance||18-Sep-2020|
|Date of Web Publication||31-Mar-2021|
Dermatologic Clinic, Via Pace, 9, 20122 Milan
Source of Support: None, Conflict of Interest: None
In the medical literature, exanthem is the name given to a widespread rash that is usually accompanied by systemic symptoms such as fever, malaise, and headache. The combination of these factors, for example, the mobility of human populations, the onset of new diseases such as COVID and the continuous availability of new drugs, make today the interpretation of the exanthems more and more difficult. In this article, we will revise briefly the conceptual problems that, during many years, have contributed to hinder its comprehension. At the end, two tables will help physicians to orientate in this field.
Keywords: COVID, exanthem, mobility of human populations, new diseases, new drugs, rash
|How to cite this article:|
Gelmetti C. Exanthema in pediatric dermatology - A confusing galaxy of myriad diseases. Indian J Paediatr Dermatol 2021;22:100-6
|How to cite this URL:|
Gelmetti C. Exanthema in pediatric dermatology - A confusing galaxy of myriad diseases. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Jun 23];22:100-6. Available from: https://www.ijpd.in/text.asp?2021/22/2/100/312816
| Introduction|| |
Exanthems are one of the most striking presentations in pediatric dermatology practice. The combination of three factors - the mobility of human populations, the onset of new disease such as COVID, and the continuous availability of new drugs, makes the interpretation of the exanthems more and more difficult. In this review we will not give the updated list of the known exanthems (at present, more than 100!) nor we will propose the latest diagnostic guideline, but we will revise briefly the conceptual problems that, during many years, have contributed to confuse our mind. At the end, I will propose two simple tables that can help the clinicians to approach the exanthems and to understand the complex algorithms that are published in the contemporaneous literature.
Exanthem (pl. =exanthems or exanthemata) is a word that comes from the Greek which means: “a breaking out like a flower blossom” ([Late Latin: “exanthema”; from Greek = burst forth: ex-, = from- + ανθein, =to blossom (from ανθos = flower)]). In the medical literature, this word is the name given to a widespread rash that is usually accompanied by systemic symptoms such as fever, malaise, and headache. This definition is not very specific, so the terms “rash” and “eruption” are often used as synonyms. Today, there is still a lot of confusion concerning this chapter of medicine, even in the medical community. While in 2011, “an 'exanthem' is defined as a skin eruption occurring as a symptom of a general disease, usually an infectious process,“ in 2010, an Internet slide show entitled “Common rashes not to miss” included many diseases such as tinea capitis, tinea corporis, molluscum contagiosum, and intertrigo that do not represent a symptom of a general disease, and do not have an eruptive onset as the word “exanthem” implicates. Exanthems are usually of an infectious etiology such as viruses, bacteria, or parasites, and represents either a reaction to a toxin produced by the microorganism or an immune response to the same. Today, we know that exanthems may also be due to a drug or a combination of a microbe with a drug.
The word “exanthems” has been used since from the Hippocratic age and, in a sense, marks the beginning of the dermatology because the ancient physicians did not recognize external diseases (=skin diseases) as “true” diseases except the exanthems that were interpreted as a tentative of the body to expel a noxious substance. Indeed and paradoxically, these disease have been considered for centuries as the proof that the Hippocratic theory of “humors” was the right one….so that dermatologic diseases did not exist “per se,” but they were just a sign of internal disequilibrium! The ancient physicians were obviously aware of the broad variety of cutaneous lesions provoked by external causes such as wounds, burns.etc., but all cutaneous lesions of this type were classified as accidental and for this reason, not a sign of the imbalance of the four “humors,” i.e., the Hippocratic theory that dominated the Western medicine for almost 2000 years.
At Hippocrates' time (IV century BCE), the microorganisms were only in the mind of some philosophers and the first theory of contagion was formally illustrated only 2000 years after, during the Renaissance mainly by Girolamo Fracastoro, the great scientist who invented the name of Syphilis. The first attempt to classify the exanthems into a modern system was made by Rhazes (Abū Bakr Muhammad ibn Zakariyyā alRāĪ(854–925 CE) is better known by his Latinized name Rhazes or Rasis.) the great Persian scientist and an important figure in the history of medicine. One of his books (Al-Judari wa al-Hasbah) was translated more than a dozen times into Latin and other European languages. The Latin translation (“De Variolis et Morbillis”) is, of course the most important because all the medical literature has been written in Latin until the age of contemporaneous dermatology (i.e., around 1850) [Figure 1]. However, the English version as “About smallpox and measles” does not translate correctly the idea of the old masters. At first, one could think that “De Variolis et Morbillis” is the first book describing smallpox and measles as distinct diseases, but the correct translation means: “About various blistering (skin) disorders and about minor (skin) diseases,” not only because “variolis” and “morbillis” are, in Latin, the ablative plural of the words, and therefore they cannot indicate a single disease, but also because the true meaning of these words at that time was clear for all physicians [Box 1].
|Figure 1: Two books treating «De Variolis et Morbillis ” in 17th and in 18th centuries. Modified from: Gelmetti C. dermatology and venereology in Italy. R. Cortina, Milan, 2019|
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To understand this question, it is sufficient to read the 1763 treatise (Nosologia Methodica) written by the French physician Francois Bossier de Sauvages. This text is considered the first modern classification of human diseases. De Sauvages, following the example of his friend, the Swedish naturalist Carl von Linné (1707–1778), established a classification system that listed ten major classes of diseases, which were divided into numerous orders, 295 genera, and 2400 species (individual diseases). In his book the chapter of variola (a word that, in Latin means simply or most probably: various [diseases]) includes a dozen of different diseases, all characterized by the presence of vesicles, more or less transparent, more or less pustular, more or less dark. Not surprisingly, together with the true variola (=smallpox) in all his forms, more or less aggressive and necrotic, we also find the classic varicella (=chickenpox).
In the following centuries, the effort of the physicians was directed toward the identification of a given exanthem with one given cause; in other words, to establish a biunivocal relationship between a given exanthem and its cause, i.e., measles (morbillus) is caused by morbillivirus; scarlet fever is caused by Streptococcus pyogenes and so on. This idea flourished in the 19th century during the glorious time of the birth of microbiology but today, unfortunately, it appears ingenuous.
Moreover, we have to consider that the cause of some exanthems may change with time and consequently also its related skin symptoms. Dermatologists and pediatricians knew well that Enterovirus A71 and coxsackievirus (CV) A16 were the most frequent serotypes involved in hand, foot, and mouth disease (HFMD) outbreaks. The recent detection of atypical forms of HFMD characterized by desquamation of the palms and soles and onychomadesis, is now explained by the detection of CV-A6 in those cases. Hence, given the fact that microbes (especially viruses and bacteria) can mutate frequently, this possibility must be always considered. As far it concerns the field of pharmacology, the continue introduction of new molecules complicates our task, just consider the new chapter of biologic drugs that carry new hopes but also new side effects, including skin rashes.
At present, it is difficult to understand why all these diseases that included measles and variola were considered, as a whole, minor diseases. However, we have to keep in mind that, in the late Middle Age and in Renaissance, the epidemics of plague (the black death) and syphilis were so common, deadly and violent, to obscure all the other diseases. Indeed, variola was named “smallpox” because the “great pox” was syphilis! Accordingly, in France, variola was named “petite vérole” (=small variola) because, again, the “grande vérole” (=big variola) was syphilis!
In the 18th and especially in the 19th centuries, after the birth of modern microbiology, the attempts to describe more rationally the diseases, arrived to the pivotal point of the list of the six “classical” exanthems that were numbered according to their chronologic description [Box 2].
As anyone can understand today, this list has only a limited interest for many reasons, e.g., indeed, this list has just a historical value mixing viral and bacterial exanthems and represents only the chronological registration of the different diseases, not taking into account their origin. Not enough, the 4th disease, that was described more than a century ago, is something not identified (in the past, the so-called Filatow–Duke disease was described as a minor form of scarlet fever). Misidentification can be logically attributed to failure in the critical abilities of the medical community at the time. Quite surprisingly, varicella (chickenpox) in not included in this list! Even the name of some exanthems was a matter of uncertainty. Until a few years ago, on the WEB site of the CDC you could read: “It was not until 1814 that (Rubella) was first described as a separate disease in the German medical literature, hence the common name “German measles.” However, at the same time, in the WEB site of the famous Mayo Clinic, the interpretation of the name was totally different: “The name German Measles has nothing to do with Germany. It comes from the Latin germanus, meaning “similar,” since rubella and measles share many symptoms!”
| The Phenotype of a Given Exanthem is not a Reliable Diagnostic Clue|| |
After the description of the “classic” six exanthems (indeed, just five), it became clear that the exanthematic diseases were much more numerous. Hence, physicians tried to approach the problem under a semeiologic perspective, i.e., classifying the phenotype of the elementary lesion: morbilliform, scarlatiniform, and roseoliform rash. However, this approach has a lot of limitations because some exanthems can be classified either as morbilliform or scarlatiniform depending on severity of the eruption and on the evaluation of the physician: for instance, asymmetrical periflexural exanthem of childhood has been described as rubeoliforrm or scarlatiniform or eczematiform. Another, different, approach was the attempt to reach a diagnosis following the dynamic topography of the lesions, e.g., the onset of the lesions in the 1st day of the rash and the topography of the lesions in the 3rd day of the exanthem [Figure 2]. This attempt is also commendable, but, in practice, has a lot of limitation, i.e., an expert physician should observe the exanthem since its beginning but, in the vast majority of cases, the patient sees a physician after a few days and his memory is frequently inaccurate. A more complex attempt is represented by the diagrams published more than once in the classic texts that has been (and still remains) a reference. These diagrams try to correlate the onset and the course of the exanthem with other signs and symptoms such as fever and adenopathy [Figure 3]. This is also an intelligent approach, but it does not take into account the individual variability induced, for instance, by previous vaccinations that can modify the natural course of the disease (e.g., measles, mumps, rubella vaccination). Finally, the vast majority of the new exanthems has an atypical phenotype. Hence, all these three diagnostic approaches can surely be useful but are always not fully reliable. In the 21st century, the medical literature has offered many algorithms that should permit a solid diagnosis; they are, of course, all commendable attempts, but none of these algorithms has become an universal standard (too long, too complex, too generic or a mixture of those).
|Figure 2: Krugman's pictograms showing the dynamic topography of some exanthems (modified)|
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|Figure 3: Graph demonstrating the characteristics of exanthema subitum|
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| The Etiopathogenesis of the Exanthems is Elusive in Most Cases|| |
Exanthems can be caused by an infection or by a drug or by a toxic substance. In the first case, many viruses (e.g., Morbillivirus, Epstein–Barr virus [EBV], cytomegalovirus [CMV], HIV, varicella zoster virus, rubellavirus, parvovirus B19, human herpesvirus 6 [HHV6], Dengue flavivirus, Zika, SARS-CoV-2, etc.) are known to be able to provoke a rash. On the other hand, bacteria (e.g., Staphylococcus aureus, Streptococcus pyogenes, Meningococcus) and parasites can also cause exanthematous eruptions. In addition, exanthems may be due to a drug, as (in a decreasing order of frequency) amoxicillin, ampicillin, trimethoprim sulfamethoxazole, semisynthetic penicillin and penicillin, blood, cephalosporins, quinidine, gentamicin, mercurial diuretics, and heparin. In addition, the so-called (also called: Baboon syndrome) symmetrical drug-related intertriginous and flexural exanthema, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis can be caused by drugs. Unfortunately, albeit more rarely, exanthems can also be caused by a toxic substance as it is the case of mercury that can trigger either Feer disease (also called: acrodynia or Pink syndrome, Bilderbeck, Selter, Swift or Swift–Feer disease) or Baboon syndrome. Finally, exanthems may also be caused by the combination of a virus with a drug, as it is the case of EBV and amoxicillin or ampicillin. In most of the cases, the pathogenesis of the exanthems is not understood even though the causative agent is well known. The mechanisms can be either a reaction to a toxin produced by the organism, damage to the skin by the organism, or an immune response. Pathogenesis is quite clear only in a few cases as in herpetic infections, in which the virus can be found in the lesion leading to cell degeneration and death. In many other cases, pathogenesis can only be suspected: in measles, an antigen-antibody mechanism is supposed because the rash starts when antibodies are appearing. In many other cases, pathogenesis can only be suspected. Some authors claim that the cause of an exanthem can be identified in 70% of cases, but in real life, this percentage can be much lower. The present availability of most sophisticated techniques in major research centers will probably change the present landscape, but it is not for tomorrow. Only very recently, it has been possible to demonstrate the SARS-CoV-2 virus in the wall of dermal vessel underneath chilblain-like lesions in otherwise asymptomatic patients (paper in publication). The fact that many patients with an exanthem have taken one or more drugs, makes often impossible to distinguish between a form induced by microorganisms or a form induced by a drug. More, drugs can provoke almost every type of exanthem including the three major patterns, i.e., morbilliform, scarlatiniform, and roseoliform rashes.
All the exanthems, including the so-called minimal diseases, should be carefully considered, taking into account the possible extracutaneous morbidities and the possible consequences among the relatives.
Viral exanthems are mostly associated with self-limited diseases. However, in some cases, diagnosis of an exanthem may be crucial to patients and their contacts. This is especially true in immunocompromised patients and in undernourished population. In general, it can be said that in adults, primary infection results in more severe constitutional symptoms compared with children.
However, there are a lot of exceptions, and we will illustrate here just some examples.
In measles, complications can occur in the very young and in the malnourished. Encephalitis is not exceptional and is unpredictable. Fortunately, death and brain damage occur only in a small minority. Thrombocytopenia and resultant purpura may occur. Bacterial superinfections, including otitis media or pneumonia, can also be observed.
In rubella, splenomegaly and arthritis may occur, more commonly in adults. Arthritis involves both small and large joints with or without swelling. Encephalitis occurs rarely and is usually mild. Thrombocytopenia, epistaxis, gastrointestinal hemorrhage, and hematuria may occur and usually resolves within 1 month. Congenital rubella syndrome cases are now rare in developed countries but still present in many regions of the world.
In exanthema subitum, HHV-6 has been associated with seizures and in some cases, it is unclear whether these symptoms are secondary to fever or to the HHV-6 infection itself. There are also rare reports of hepatitis, pneumonitis, neuropathy, meningoencephalitis, thrombocytopenia, intussusception, and encephalopathy. Even though many patients with central nervous system involvement have a normal recovery, neurologic sequelae have been reported
In parvovirus B19 infection, severe consequences may occur in the immunocompromised, in the fetus, and in patients with hemoglobinopathies.
In hand-foot-mouth disease, most cases resolve without complications, but first-trimester infection may lead to spontaneous abortion or intrauterine growth retardation. Other complications, albeit rare, have been reported including myocarditis, meningoencephalitis, pulmonary edema, and even death.
In Kawasaki disease, most scary effect is on the heart where it can cause fatal coronary artery aneurysms. Without treatment, mortality may approach 1%, usually within 6 weeks of onset.
Even Pityriasis Rosea of Gibert, a rash that is still considered among the mildest disease could be considered a possible life-threatening condition for the fetus.
After this list, three conclusions can be drawn:
- It does not exist an exanthem that can be considered without danger; surely, nonfebrile exanthems are usually harmless, while febrile exanthems are sually more severe
- The danger can be minimal or absent in the patient affected by the given exanthem, but it can be very serious for the community or for the offspring as it is the case for rubella,,, parvovirus B19,, Zika, and SARS-CoV-2,,,,,,
- The microbe (virus or bacteria) responsible of the given exanthem can provoke many problems and even death without the exanthem; in this case, we are facing the disease without a visible sign of its presence [Figure 3].
The most recent example of this possibility is the present pandemic of SARS-CoV-2 in which the cutaneous signs of the infection are absent in most cases.,,,,,, Moreover, it should be considered the same phenotype (e.g., PPGSS = Papular purpuric gloves and socks syndrome, G-C syndrome = Gianotti–Crosti syndrome; etc.) can be cause by different biologic agents. Not enough, it is now established that the same biologic agent (e.g., Parvovirus B19) can give origin to different diseases (e.g., 5th disease or PPGSS) [Figure 4]. Therefore, the old idea connecting a definite exanthematic disease with a single cause, cannot anymore considered valid.
|Figure 4: Biunivocal relationship between phenotypes and their causes, does not exists|
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Most drug-induced maculopapular exanthems are mild and will recede with withdrawal of the offending agent. However, these cutaneous reactions can represent the early manifestation of rare, severe drug-induced cutaneous reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, which result in epidermal detachment and have high rates of morbidity and mortality. Therefore, withdrawal of the offending treatment is imperative in patients with maculopapular exanthem where drug involvement is suspected, particularly when fever or flu-like symptoms are also present or where there is mucosal involvement. The presence of pruritus should be a characteristic of drug-induced exanthem, but it is not a prerequisite as it is shown, for instance, by Baboon syndrome. This acute rash, that is almost asymptomatic, has been connected in the past with some drugs or toxic substance such as mercury, iodinated radio contrast media, hydroxyzine, penicillin, and itraconazole, can also be triggered by infectious such as EBV and CMV.
To make the story even more complex, consider the possibility of a systemic allergic contact dermatitis as it has been the case of an acute generalized pruritic rash in a toddler in which biologic or pharmacologic triggers could not be demonstrated. At the end of the investigations, the cause was found: it was a metal coin (nickel) involuntary swallowed.!
Mancini wrote: “Viral exanthems in children can present a diagnostic challenge for even the most seasoned of clinicians.” He is surely right, but I am more pessimistic and I would say: “Exanthems, in general, are a diagnostic challenge for even the most seasoned of clinicians.”
| Conclusion|| |
The take-home messages are the following:
Exanthems are extremely common, but their cutaneous expression can be nonspecific and the number of potential agents is large and continuously increasing, so specific etiologic diagnoses can be difficult, if not impossible.
Cutaneous signs of exanthems can be typical or mild or very mild, but they do not always represent the severity of internal disorders; for instance, COVID is frequently a deadly disease but its cutaneous counterpart, when exists, is a specific and mild. In other words, the severity of dermatologic manifestations is not predictive of the severity of systemic manifestations.
Exanthems can be mild diseases for the patient we are visiting, but they can be severe or very severe for family/community members or for a fetus.
[Figure 5] and [Figure 6] can help to orientate physicians: their advantage is that are simple; their disadvantage is that they are not totally reliable.
|Figure 6: Checklist for differential diagnosis of biotic exanthems versus drugs exanthems|
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There is a need for a better definition of this medical terms; “exanthem” is still a vague, imprecise word whose meaning is not so much different from Hippocrates' time but my suggestion is as follows:
Exanthem is the visible counterpart of a disease that can be provoked by a myriad of different causes (microbiologic, drugs, etc.). Keeping in mind the original meaning of the word, exanthems should qualify only those visible widespread disorders characterized by a rapid onset, regardless of their origin and regardless of their association with systemic symptoms.
All other visible diseases characterized by a slow, hesitant, onset, and chronic course should not be called in this way.
Unfortunately, it does not exist an exanthem the diagnosis of which can be surely done on the mere basis of clinical signs and symptoms; the only notable exception could be herpes zoster whose linear pattern and unilateral distribution cannot be missed. However, herpes zoster follows almost always (We know that herpes zoster affecting two dermatomes are also possible; albeit rare, but still possible, are the cases in which the zoster affects two symmetrical dermatoses or is diffuse [varicelliform zoster]. But all these examples concern a minimal percentage of all the cases of herpes zoster that is not typically a widespread rash.) One single dermatome and for this reason is not a widespread rash and cannot be consequently considered an exanthem following my definition.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]