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New Treatments for Exanthems

Measles and smallpox were present 2,000 years ago and what I call newer exanthems are older than most of you in the room, but when the virus discovery period with the use of tissue culture occurred in the 1950’s a lot of new syndromes and viral infections were discovered fifths disease, erythema infectiosum, hand foot mouth disease. The other thing that has happened because of immunizations, the classic exanthems have changed. You rarely see measles and rubella. So what I’ll do now is just quickly go through the classic exanthems.

So first is scarlet fever. This has a short incubation period and illness starts with fever, vomiting, sore throat. Rash appears 12-48 hours later. The enanthem is streptococcal pharyngitis. The rash appears as red "sandpaper" which is the best description. There are lines and creases.

Next classic is measles. Measles has a relatively long incubation period compared to newer viral exanthems. So about nine days to the first symptoms, and they are fever, cough, coryza, conjunctivitis. About 11 days are complex spots and then rash occurs about day 13. The rash is erythematous, maculopapular, goes to confluence, starts centrally and spreads peripherally, lasts about seven days and there is considerable fever with measles. These are Koplik spots.

Okay, next is rubella. This is a long incubation period disease which, for children, is 17 days from exposure to onset of rash. Now with adults you have considerable prodrome, which goes unrecognized in children. Adults will tell you they have pain on lateral gaze, and they will have headache and sometimes photophobia. Also lymphadenopathy, subauricular and posterior.

The next is varicella and this also is a long incubation period disease, with about 16 days to the onset of rash. Now you’ll see in textbooks about a 1-2 day prodrome but I really don’t think there is much of a prodrome. Usually the first lesion is rash but it’s frequently overlooked because it’s only one or two lesions. So the patients are contagious when they have rash.

Now a change of pace, from classic exanthems. The first group I want to talk about are four illnesses that have some similarities with scarlet fever. The first of these are illness due to exfoliative toxin-producing staphylococci and there are four manifestations; bullosa impetigo, Ritter’s disease, scalded-skin syndrome and staphylococcal scarlatiniform eruption. These staph are predominantly group II. They are not particularly prevalent today but there are large cycles, so they will be back. The staph are not particularly invasive, so these diseases without treatment run their course, even though you should treat them. This is bullosa impetigo. The important thing.

Erythema infectiosum and this is caused by parvovirus B19. It has a case-to-case interval of 6-14 days. The important thing is that after exposure about a week later you are contagious, but generally asymptomatic or have a mild fever. Then a week after that the rash occurs and at that time the patient is no longer contagious. The rash starts on the face with a "slapped cheek" appearance. The original rash starts centrally, spreads peripherally, is not very diagnostic.

Now I want to switch over and talk a bit about enteroviruses, and I’m going to say more at the end about enteroviruses. But a lot of clinical manifestations can occur with enterovirus infections. This is … almost 40 years ago I occupied my time studying these things so everybody yawns when I try to make a big deal out of this. So I’m just going to go through and give you some major manifestations of what you should be aware of. Then we’ll come back and talk specifically about enterovirus epidemiology. I’m going to talk about EcHO-9 coxsackie A-9 and coxsackie A-16 as examples. EcHO virus 9 was the first of the enteroviruses.

Now coxsackie A-9; the reason I’m showing this is that this can cause rashes, maculopapular and petechial rashes, but it can also have vesicular and urticarial lesions. These frequently get misdiagnosed as contact dermatitis or poison ivy and bug bites. So this is a child who happens to have coxsackie A-9, has lesions that were quite pruritic and they look like papular urticaria. They look like bug bites. Urticaria around a central vesicular lesion. This is another enterovirus that looks like bug bites on this child, and this child as well. Also urticaria, large urticaria. This occurs in outbreaks that the first thing a lot of people think of are foods, but if you have this with fever it’s likely a viral infection, and it can be several different viruses.

The last of these is hand-foot-and-mouth syndrome, and this is the most distinctive enanthem/exanthem complex. The main etiology is coxsackie A-16 but this has been seen with other enteroviruses but in outbreak circumstances it has mainly been A-16. Or when it’s described to other viruses, they don’t usually have the complete syndrome. Most recently in Hong Kong and Taiwan they had an outbreak with enterovirus 71 and they described cases of hand-foot-and-mouth. The lesions most common on hands and then the feet and buttocks.

Now I’m going to move on to roseola. Roseola and phantom exanthem subitum is a classic pediatric exanthem and about somewhere between 10-30% of children have roseola. It usually will occur in the first two years of life and the illness is fever for 3-5 days. The fever usually falls rapidly and then you have the appearance of the rash. But a lot of physicians just call the first rash they see in a child roseola, which you shouldn’t do.

This is just an example of an outbreak of roseola that occurred in Rochester New York in 1974. This is the outbreak and from a number of these they isolated echovirus 16. So showing you that, at least in outbreak circumstances, enteroviruses may play a role.

Okay, next are winter exanthems and in the wintertime a lot of nondescript rashes, erythematous, maculopapular, discreet. Last one or two days. It turns out that with common respiratory viruses that we talked about - parainfluenza, RSV, rhinovirus and influenza viruses - all are associated with exanthem in 5-10% of the time.

Lastly are adenoviruses. Adenoviruses give a variety of rashes. Usually are more severe than enteroviruses but can look like roseola, can have a measles-like rash. Erythema multiforme and Stevens-Johnson syndrome.

How do you approach diagnosis of rashes? This is not the way, and I’ve already told you why, because you don’t want a situation like the obstetrician that exposed 240 pregnant women. This is another approach. But the way to approach it, and the dermatologists always kill me because they go and pronounce something, but really if you go through this and just looking at the rashes.

I want to switch over to the enteroviruses. Infections with enteroviruses are exceedingly common. Every summer literally every child has at least one enterovirus infection. These are usually quite trivial but the fact is that fevers in the summertime are invariably due to enteroviruses. Enteroviruses are not big viruses. They are small, 28 millimicrons in diameter. We now know that antibody to surface proteins is protective and so conceivably if new strains develop, vaccines like polio vaccines can be developed. Enteroviruses are polios 1,2,3. Coxsackie viruses group A, coxsackie group B and these were differentiated, and echoviruses, were differentiated on how they behaved in tissue culture or suckling mice.

The worldwide distribution; in temperate climates they occur in summer and fall. In the tropics they have caused disease throughout the whole year. This is the pathogenesis of infection. Infection is usually through the mouth, either oral or upper respiratory. Then local infection and then direct spread to tonsils and lymph nodes, Peyer’s patches and mesenteric lymph nodes.

There are a lot of clinical … every organ can be involved and I just want to go through some of this in the time remaining. The first thing is asymptomatic infection. Of course with polio we were aware that less than 5% - somewhere around 2% - of infections led to asymptomatic meningitis or paralytic polio. The majority were frequently called asymptomatic but it was better to say unrecognized because most of these had non-specific febrile illness. That is the major manifestation of enterovirus infections in the summertime.

And lastly is pleurodynia. This is an interesting disease historically and also interesting because the diagnosis doesn’t get made. It has names such as Bornholm disease because of the island where it was seen, and devils grip because it gives acute chest pain, excruciating chest pain, which lasts for a few minutes and then goes away and then comes back again. Many cases of adults who are thought to have heart attacks in actual fact have pleurodynia.

The next is gastrointestinal disease and since these are enteroviruses, when you discuss gastroenteritis somebody always says enterovirus. Yet a little bit of loose stool or nausea and vomiting is common. But as a cause of diarrhea without other manifestations, enteroviruses are actually quite rare. They have been statistically related with some outbreaks but by and large.

Hepatitis, severe hepatitis in neonates otherwise is not common. Other findings, pancreatitis and there is a tie with juvenile-onset diabetes and coxsackie B infections including isolation of the virus from the pancreas in fatal cases.

Next are neurologic manifestations and about 70,000 people are hospitalized each year in the United States with enterovirus, aseptic meningitis.

Orchitis; probably the leading cause of orchitis today are the enteroviruses, particularly coxsackie B. Other urinary tract findings; asymptomatic pyuria. You can get this with polio vaccine. So white cells in the urine, transitory, could be due to enterovirus infection. Myositis in mice; the coxsackie A viruses give myositis but this is extremely uncommon with children.

The last thing; enterovirus sepsis-like illness. Babies with a typical picture of bacterial sepsis, fever, poor feeding - or actually fever or hypothermia - distended abdomen, irritability, rash, lethargy, markedly elevated white count and the important thing is they have hepatitis, DIC and frequently a very bad outlook.