Complications and Pitfalls of Childhood Exanthems

What happens after the rash in each of the six?

The six classic childhood exanthems are told apart less by the rash than by what follows it. Two of them can kill or disable: measles and scarlet fever. Measles brings pneumonia and a late neurological disease. Scarlet fever brings immune-mediated damage to the heart and kidneys, appearing weeks after the sore throat.

The other four are usually benign, and each has one situation in which it is not. That situation depends on who is infected: a pregnant woman, a person who depends on fast red cell production, an infant whose fever climbs quickly, an adult or a newborn.

Why does the timing of a complication point to its cause?

If the cost of the disease is what separates the six, then when that cost appears is the first clue to why. Complications are easier to remember by timing, and timing points to mechanism.

• Damage during the acute illness comes from the pathogen or from the immune response to it. The organism is present, or the response is active, so the injury arrives with the illness.
• Damage weeks or years later comes from an immune response that has outlived the infection. That is why it appears when the organism is gone.

Measles shows both kinds of timing.

What does measles do, early and late?

During the illness, measles complications are otitis media (middle-ear infection), diarrhoea, pneumonia and encephalitis. In Measles the virus travels in immune cells and damages the immune system, so the infections of the ear, gut and lung follow. The rates are:

• Otitis media: about 1 in 10 children.
• Diarrhoea: fewer than 1 in 10.
• Pneumonia: as many as 1 in 20 children. It may be viral, bacterial or mixed, and it is the commonest cause of death in young children.
• Encephalitis: about 1 in 1,000. It may leave deafness or intellectual disability.

The late complication is subacute sclerosing panencephalitis (SSPE), a progressive, fatal brain disease that appears 7-10 years after measles. It is the persistent virus after a long silent interval. Its risk is about 1 in 1,367 when measles occurred before age 5, and about 1 in 609 when it occurred before 12 months. So the younger the child at primary measles, the higher the risk of the late neurological complication.

Infancy matters for a second reason. It is the age at which measles vaccine cannot yet be relied on because of maternal antibody, and it is the age at which primary measles carries the greatest risk.

What does scarlet fever do, early and late?

Scarlet fever also divides by mechanism, and the timing differs accordingly. The rash itself is an immune reaction to a circulating streptococcal toxin, not an infection of the skin (Scarlet Fever).

The suppurative (pus-forming) complications result from spread of the infection itself. They are:

• cervical lymphadenitis, peritonsillar abscess, retropharyngeal abscess and otitis media;
• invasive group A streptococcal disease with sepsis, cellulitis, pneumonia, septic arthritis or osteomyelitis.

The immune-mediated complications appear weeks after the acute illness. They are caused by the immune response rather than by bacteria in the affected organ. The immune response needs time to build and is directed at the patient’s own tissue, which is why the delay exists.

Acute rheumatic fever is the dominant cause of acquired valvular heart disease in populations with limited antibiotic access. The valve is the lasting damage, which is why prevention carries weight. Its manifestations are the heart, joint, brain and skin involvement of one immune response: carditis (heart inflammation), arthritis, chorea (involuntary jerky movements), erythema marginatum and subcutaneous nodules. It typically appears about 1-5 weeks after the preceding streptococcal pharyngitis or skin infection.

Post-streptococcal glomerulonephritis is the kidney counterpart. It presents as a nephritic picture with haematuria (blood in urine) and hypertension. It appears about 10 days after pharyngitis, and up to 3 weeks after a skin infection.

PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) describes a neuropsychiatric presentation after streptococcal infection. Its evidence base is weaker than for rheumatic fever and post-streptococcal glomerulonephritis, and the literature remains confused about it.

Acute rheumatic fever and post-streptococcal glomerulonephritis both rest on molecular mimicry. Streptococcal antigens resemble proteins of the human heart and kidney, so the antibody response also recognises the patient’s own tissue. This is thought to explain how an infection of the throat or skin ends in heart and kidney disease.

Prevention differs between the two. Treating pharyngitis with a full 10-day antibiotic course prevents acute rheumatic fever. Treatment started within about 10 days of symptom onset still prevents it; later treatment does not. For post-streptococcal glomerulonephritis, prevention by antibiotics is not established, and it can follow whether or not the pharyngitis was treated. The two diseases share a mechanism but not a prevention rule, so the timing and the mechanism of each have to be learned separately.

When is each of the other four not benign?

The other four are usually benign, and each has one situation in which it is not.

Rubella and who is not immune

Rubella is the mildest of the six. Its importance lies almost entirely in who is not immune rather than in what it does to the child (Rubella).

Joint symptoms are rare in children and in adult men, but frequent in adult women, up to 70% in reported series. They usually begin around the time the rash appears and last up to about a month.

The consequential rubella problem is infection in pregnancy and the resulting congenital rubella syndrome, which belongs to the topic of congenital and maternal infections.

Fifth disease and red cell production

Parvovirus B19 infects the red cell precursors of the bone marrow and halts red cell production (erythropoiesis). Its complications therefore depend on how much each person relies on continuous red cell production. The joint symptoms come from the immune response instead, and the rash is the immune phase that follows the infectious one (Fifth Disease).

The household situation shows why this matters. A pregnant woman whose child develops parvovirus B19 infection is at risk of exposure during the child’s febrile viraemic phase, which is when no one yet knows the diagnosis. By the time the slapped cheek rash appears, the child is no longer infectious, and the mother’s exposure window has usually passed.

Roseola and febrile seizures

The complication of roseola comes from its fever: febrile seizures (Roseola Infantum). They occur in roughly 10-15% of children with primary HHV-6B infection, the human herpesvirus 6 variant behind most cases of roseola, and mostly in the 6-18 month age band.

The seizures are usually simple: generalised, brief, without focal features or persistent neurological findings. They reflect how an immature brain reacts to a fever that climbs quickly, rather than spread of the virus into the central nervous system.

A child who looks well after a brief generalised seizure, and whose fever has a recognisable source, needs no lumbar puncture and no empirical antibiotics. A child who stays drowsy, has focal signs, or has a prolonged or repeated seizure is a different problem. In that case meningitis and encephalitis take priority, and the rash should not be taken as the explanation.

Varicella and who is infected

Varicella complications depend on who is infected (Varicella). The commonest one can affect any child who scratches, whereas the most serious fall on adults, immunocompromised patients, newborns and fetuses.

• Secondary bacterial infection is the commonest complication and can affect any child, through scratching, which opens the skin to bacteria. Suspect it if fever persists beyond day 3 of the rash.
• Pneumonia occurs in adults and immunocompromised patients, with high mortality in adults.
• Cerebellar ataxia (unsteady, uncoordinated movement) occurs in young children. It is post-infectious and usually self-limited.
• Encephalitis is rare, and may be direct viral or post-infectious.
• Neonatal varicella follows maternal infection from 5 days before to 2 days after delivery, and the newborn is exposed without maternal antibody. Roughly 20-50% of exposed newborns are affected, and the mortality is concentrated in babies whose rash starts at 5-12 days of life.
• Congenital varicella syndrome follows maternal infection before 20 weeks. It occurs in roughly 2% of such pregnancies, with high mortality in affected infants.

How do an infectious and an allergic exanthem differ?

Those are the infectious causes. An exanthem may also be allergic, and an allergic eruption can look like one of the six while requiring opposite management. Both are widespread, repetitive eruptions, and many drugs and infections provoke such a rash. An allergic eruption is an immune reaction to a drug or allergen, so it settles when the trigger is withdrawn, whereas a viral exanthem runs the course of the infection.

Two pointers carry most of the weight: involvement of the palms and soles, and the absence of an orderly cranio-caudal (head-to-foot) march. The other half of the assessment is a careful history of drug exposure in the preceding days, because that is how a trigger that is still being given is caught. Where the trigger continues to be given, a drug eruption can progress to erythroderma (redness of almost the whole skin) with desquamation. So the exposure history is not a formality.

Why are corticosteroids a hazard in a viral exanthem?

The commonest consequence of mistaking one rash for the other is a treatment that is right for the allergy and wrong for the infection. Systemic corticosteroids are not used to treat viral exanthems. They suppress the immune response that clears the virus, which is why a viral illness can get worse. In varicella, corticosteroids are a recognised risk factor for severe disease. A child with a viral exanthem who is given corticosteroids for a presumed allergic rash may do worse rather than better.

Which errors recur across the six?

Corticosteroids for a viral exanthem are one of a small set of errors that recur across the six diseases. In each, a reasonable action is taken for the wrong child or at the wrong point in the illness.

• Treating the viral prodrome (early illness before the rash) with antibiotics. An early maculopapular rash with fever and pharyngitis is often viral, and a viral rash does not respond to antibiotics. The reverse error, failing to recognise streptococcal pharyngitis in a school-age child, is the more consequential one.
• Missing scarlet fever because the tongue finding is subtle. The cost is acute rheumatic fever, which is preventable within the treatment window and irreversible afterwards.
• Giving aciclovir to a healthy child with varicella, or withholding it from a child in a risk group. The aciclovir decision is risk-stratified, not universal.
• Not isolating a child with measles for the full contagious period. Measles spreads for days before the rash, and through air that remains infectious for up to 2 hours, so a waiting room can be a transmission site.
• Failing to connect fifth disease to a pregnant household contact. The exposure happened during the febrile phase, so the assessment belongs there rather than after the rash.
• Investigating roseola and fifth disease as if they were undiagnosed fevers. In both the diagnosis is clinical. By the time the rash is visible, the child needs no tests, no antibiotics and no isolation, because the rash comes with or after the end of the infectious and febrile phase.

If each of these mistakes is a sensible action at the wrong moment, what should a clinician settle first when a febrile child with a rash is in front of them: the cause, the stage of the illness, or who is at risk?