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Next are neurologic manifestations and about 70,000 people are hospitalized each year in the United States with enterovirus, aseptic meningitis. So the leading cause of aseptic meningitis is enteroviruses.About 7,000 cases of encephalitis occur with enteroviruses each year. There are occasional cases of poliomyelitis-like illness and paralysis due to other enteroviruses in addition to polios 1, 2 and 3. Guillain-Barre syndrome, cerebellar ataxia, and occasionally neurologic sequelae. Some of these children will have CAT-scans looking like they have had strokes. Other manifestations; acute hemorrhagic conjunctivitis. First of all, conjunctivitis is a mild manifestation of many different enteroviruses. But a specific disease, acute hemorrhagic conjunctivitis with big-time conjunctivitis lasting for over a week occurs in outbreaks. Most of these original outbreaks were in tropical or semi-tropical countries and island communities, but they have been seen in areas more recently in the United States. These outbreaks have been due to coxsackie A-24 and most of the time to enterovirus 70. These are particularly severe, and also associated with this are a fair number of cases of neurologic disease of Guillain-Barre or a transverse myelitis-type illness. Pericarditis and myocarditis are due predominantly to coxsackie B viruses and there are changes. There are cycles of these, of new viruses in the population. Back in the 1950’s myocarditis in newborns was fairly common. This was acute, fulminant, myocarditis with considerable damage. But if they recovered, they recovered totally. In the present era with heart transplants and the diagnosis of cardiomyopathy there is a bit of confusion relating to myocarditis. There are studies, animal studies, which produced a more chronic cardiomyopathy-type picture. But these are different from what you see in children. The reason I bring this up is that there were attempts to treat the patients with this with steroids and anti-thymocyte globulin and things like that. But children should not be treated with that. They probably should get IVIG and they should get the antiviral proconerol on a compassionate plea basis.
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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.

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. In children they are less likely to have chest pain or the chest pain can’t be differentiated from abdominal pain and it appears like an acute abdomen. This can come and go and really confuse people and surgeons, and certainly cardiologists.
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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 compared to Rotavirus for example, or Norwalk virus, are not a major cause of either diarrhea disease or nausea and vomiting. It’s funny that you have diarrhea and constipation here but after a day or two, roughly 30% of children with EcHO-9 have constipation. More importantly is abdominal pain relating to pleurodynia but also situations that look like appendicitis but aren’t, but you can also have appendicitis just due to enterovirus infections. You can have peritonitis, mesenteric adenitis. Of causes of intussusception this has become popular because of the association with Rotavirus vaccine. But both enteroviruses in the summertime are probably the most common known cause of intussusception and adenoviruses at other times of the year.

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.

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. But then many of these, for example coxsackie A, produced a flaccid paralysis in mice, but many of them like coxsackie A-9 grows very well in tissue culture. So later on they were just called enteroviruses, of which there are 68-71; 72 was hepatitis A but that’s been removed from the enterovirus category. The enteroviruses are spread person-to-person. There is no animal reservoir but they can be spread by flies. Flies don’t get infected but they will pick up enteroviruses from sewage and things like that.
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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. Following this there is a minor viremia which multiple organs get seeded and congenital infection starts here. You get multiple infections and then you get major viremia, which is associated with symptoms. For example polio, there has always been a theory that didn’t get a hit now but gets a hit with secondary viremia. I’m not sure that that’s true but frequently you see … but I think it’s more immunologic. Then the infection clears by itself relatively rapidly and there is no persistent infection except for what I showed you with coxsackie A-16 and exanthem.
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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. Roughly a three-day period where the child may not be exactly with it, and may vomit once or have one loose stool, but just has fever. In your handout I’ve given you some frequencies of various things, which I’m not going to talk about, but they are in the handout. Enteroviruses, except for coxsackie A-21, rarely cause the common cold which we talked about. But pharyngitis is a major manifestation of most enteroviruses and can’t be differentiated from streptococcal disease clinically. Herpangina we talked about. This is a form of herpangina which was described and really hasn’t been noticed since. Stomatitis; I showed you pictures of that with hand-foot-and-mouth disease. Parotitis today, with the control of mumps, that enterovirus is a leading cause of parotitis in children except for children with exposure to mice. Bronchitis, bronchiolitis, pneumonia, are generally picked up in serologic surveys and are not particularly important.

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. This was demonstrated by a great general practitioner in England by the name of Hope Simpson many many years ago. What’s important about this is that these are children who have respiratory symptoms and frequently have been put on antibiotics for otitis and therefore they will have this rash for one or two days after they were put on amoxicillin online pharmacy, in particular. I think the important thing is that you don’t want to automatically label these children as penicillin allergic. Wait a day or two because these rashes don’t last. The rash will go away and you’ve continued your antibiotic and you haven’t labeled then penicillin-allergic.
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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 is only part of it. Find out exposure. Classic exanthems have a high clinical expression rate, so they should have had a history. For example, measles. There should be a case discernible. Varicella the same. Season; classic exanthems in the winter and spring, enteroviruses in the summer. Incubation period; short with enteroviruses, long with classics. Age; today most cases of rubella and measles will be seen in adults. Hopefully in a few years that will be true of varicella as well, because children should be being vaccinated. Relation of rash to fever and roseola. Adenopathy for rubella type distribution and other laboratory tests. I didn’t say much about them but workup, when it’s appropriate, for viruses, Mycoplasma, Epstein-Barr virus, infectious mono can have rash. So in general, a general workup rather than just looking at the rash.
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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. The peripheral distribution is distinct and occasionally they will go away and then come back. So you will have recurring lesions and sometimes they’ll be chronic with immune defects and sometimes with no apparent immune defects. Chronic reoccurring lesions. This is a classic case of the lesions on the heel of this child and also the buttock. The buttock lesions are usually just maculopapular and not vesicles. This is the tongue of this child’s aunt, which looks like aphthous stomatitis and this is the grandmother of that child with typical lesions on the hands. This is just to show the size of the lesions. The other day I showed you Herpes simplex lesions on the soft palate, and this is almost a 2 cm lesion in the mouth of this particular child.
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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. The illness is not seasonal but there have been occasional outbreaks. It has been associated with many different viruses, but recently, relatively recently, herpes virus 6 has been found to be the major cause of this but it’s not the only cause. The Japanese papers on this, the way they did their studies, it was destined to prove this was the cause. So the actual fact is there are multiple etiologies. It seems that this complex of fever and then fever dropping and rash occurring is a host phenomenon relating to multiple different virus antigens, of which the most important is probably herpesvirus 6.
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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.