Meningitis

Meningitis occurs when there is inflammation of the meninges covering the brain. This can be confirmed by finding inflammatory cells in the cerebrospinal fluid (CSF). Viral infections are the most common cause of meningitis, and most are self-resolving. Bacterial meningitis may have severe consequences. Other causes of non-infectious meningitis include malignancy and autoimmune diseases.

Bacterial meningitis

Over 80% of patients with bacterial meningitis in the UK are younger than 16 years old. Bacterial meningitis remains a serious infection in children, with a 5–10% mortality. Over 10% of survivors are left with long-term neurological impairment.

Pathophysiology

Bacterial infection of the meninges usually follows bacteraemia. Much of the damage caused by meningeal infection results from the host response to infection and not from the organism itself. The release of inflammatory mediators and activated leucocytes, together with endothelial damage, leads to cerebral oedema, raised intracranial pressure and decreased cerebral blood flow. The inflammatory response below the meninges causes a vasculopathy resulting in cerebral cortical infarction, and fibrin deposits may block the resorption of CSF by the arachnoid villi, resulting in hydrocephalus.

Organisms

The organisms which commonly cause bacterial meningitis vary according to the child’s age (Table 14.1).

Table 14.1

Organisms causing bacterial meningitis according to age

Neonatal–3 months	Group B streptococcus
	E. coli and other coliforms
	Listeria monocytogenes
1 month–6 years	Neisseria meningitidis
	Streptococcus pneumoniae
	Haemophilus influenzae
>6 years	Neisseria meningitidis
	Streptococcus pneumoniae

Presentation

The clinical features are listed in Figure 14.4. The early signs and symptoms of meningitis are non-specific, especially in infants and young children. Only children old enough to talk are likely to describe the classical meningitis symptoms of headache, neck stiffness and photophobia. But neck stiffness may also be seen in some children with tonsillitis and cervical lymphadenopathy. As children with meningitis may also be septicaemic, signs of shock, such as tachycardia, tachypnoea, prolonged capillary refill time, and hypotension, should be sought. Purpura in a febrile child of any age should be assumed to be due to meningococcal sepsis, even if the child does not appear unduly ill at the time; meningitis may or may not be present.

Investigations

The essential investigations are listed in Figure 14.4. A lumbar puncture is performed to obtain CSF to confirm the diagnosis, identify the organism responsible, and its antibiotic sensitivity. If any of the contraindications listed in Figure 14.4 are present, a lumbar puncture should not be performed, as under these circumstances, the procedure carries a risk of coning of the cerebellum through the foramen magnum. In these circumstances, a lumbar puncture can be postponed until the child’s condition has stabilised. Even without a lumbar puncture, bacteriological diagnosis can be achieved in at least 50% of cases from the blood by culture or polymerase chain reaction (PCR), and rapid antigen screens can be performed on blood and urine samples. Throat swabs should also be obtained for bacterial and viral cultures. A serological diagnosis can be made on convalescent serum 4–6 weeks after the presenting illness if necessary.

Management

It is imperative that there is no delay in the administration of antibiotics and supportive therapy in a child with meningitis. The choice of antibiotics will depend on the likely pathogen. A third-generation cephalosporin, e.g. cefotaxime or ceftriaxone, is the preferred choice to cover the most common bacterial causes. Although still rare in the UK, pneumococcal resistance to penicillin and cephalosporins is increasing rapidly in certain parts of the world. The length of the course of antibiotics given depends on the causative organism and clinical response. Beyond the neonatal period, dexamethasone administered with the antibiotics reduces the risk of long-term complications such as deafness.

Cerebral complications

These include:

• Hearing loss. Inflammatory damage to the cochlear hair cells may lead to deafness. All children who have had meningitis should have an audiological assessment promptly, as children who become deaf may benefit from hearing amplification or a cochlear implant.

• Local vasculitis. This may lead to cranial nerve palsies or other focal lesions.

• Local cerebral infarction. This may result in focal or multifocal seizures, which may subsequently lead to epilepsy.

• Subdural effusion. Particularly associated with Haemophilus influenzae and pneumococcal meningitis. This is confirmed by CT scan. Most resolve spontaneously but may require prolonged antibiotic treatment.

• Hydrocephalus. May result from impaired resorption of CSF (communicating hydrocephalus) or blockage of the ventricular outlets by fibrin (non-communicating hydrocephalus). A ventricular shunt may be required.

• Cerebral abscess. The child’s clinical condition deteriorates with the emergence of signs of a space-occupying lesion. The temperature will continue to fluctuate. It is confirmed on CT scan. Drainage of the abscess is required.

Prophylaxis

Prophylactic treatment with rifampicin to eradicate nasopharyngeal carriage is given to all household contacts for meningococcal meningitis and Haemophilus influenzae infection. It is not required for the patient if given a third-generation cephalosporin, as this will eradicate nasopharyngeal carriage. Household contacts of patients who have had group C meningococcal meningitis should be vaccinated with the meningococcal group C vaccine.

Partially treated bacterial meningitis

Children are frequently given oral antibiotics for a nonspecific febrile illness. If they have early meningitis, this partial treatment with antibiotics may cause diagnostic problems. CSF examination shows a markedly raised number of white cells, but cultures are usually negative. Rapid antigen screens and PCR are helpful in these circumstances. Where the diagnosis is suspected clinically, a full course of antibiotics should be given.

Encephalitis/encephalopathy

Whereas in meningitis there is inflammation of the meninges, in encephalitis there is inflammation of the brain substance, although the meninges are often also affected. Encephalitis may be caused by:

In encephalopathy from a non-infectious cause, such as a metabolic abnormality, the clinical features may be similar to an infectious encephalitis.

The clinical features and investigation of encephalitis are described in Figure 14.4. Most children present with fever, altered consciousness and often seizures. Initially, it may not be possible to clinically differentiate encephalitis from meningitis, and treatment for both should be started. The underlying causative organism is only detected in 50% of cases. In the UK, the most frequent causes of encephalitis are enteroviruses, respiratory viruses and herpesviruses (e.g. herpes simplex virus, varicella and HHV6). Worldwide, microorganisms causing encephalitis include Mycoplasma, Borrelia burgdorferi (Lyme disease), Bartonella henselae (cat scratch disease), rickettsial infections (e.g. Rocky Mountain spotted fever) and the arboviruses.

Herpes simplex virus (HSV) is a rare cause of childhood encephalitis but it may have devastating long-term consequences. All children with encephalitis should therefore be treated initially with high-dose intravenous aciclovir, since this is a very safe treatment. Most affected children do not have outward signs of herpes infection, such as cold sores, gingivostomatitis or skin lesions. The PCR of the CSF may be positive for HSV. As HSV encephalitis is a destructive infection, the EEG and CT/MRI scan may show focal changes, particularly within the temporal lobes (Fig. 14.5). These tests may be normal initially and need to be repeated after a few days if the child is not improving. Later confirmation of the diagnosis may be made from HSV antibody production in the CSF. Proven cases of HSV encephalitis or cases where there is a high index of suspicion should be treated with intravenous aciclovir for 3 weeks, as relapses may occur after shorter courses. Untreated, the mortality rate from HSV encephalitis is over 70% and survivors usually have severe neurological sequelae.

Toxic shock syndrome

Toxin-producing Staphylococcus aureus and group A streptococci can cause this syndrome, which is characterised by:

The toxin can be released from infection at any site, including small abrasions or burns, which may look minor. The toxin acts as a superantigen and, in addition to the features above, causes organ dysfunction, including:

• Mucositis (Fig. 14.6): conjunctivae, oral mucosa, genital mucosa

• Gastrointestinal: vomiting/diarrhoea

• Renal impairment

• Liver impairment

• Clotting abnormalities and thrombocytopenia

• Central nervous system: altered consciousness.

Intensive care support is required to manage the shock. Areas of infection should be surgically debrided. Antibiotics often include a third-generation cephalosporin (such as ceftriaxone) together with clindamycin, which acts on the bacterial ribosome to switch off toxin production. Intravenous immunoglobulin may be given to neutralise circulating toxin. About 1–2 weeks after the onset of the illness, there is desquamation of the palms, soles, fingers and toes.

PVL-producing Staphylococcus aureus causes recurrent skin and soft tissue infections, but can also cause necrotising fasciitis and a necrotising haemorrhagic pneumonia following an influenza-like illness; they carry a high mortality. PVL-producing Staphylococcus aureus produces a toxin called Panton-Valentine leukocidin (PVL) which has emerged in the UK and other countries. PVL is produced by fewer than 2% of Staphylococcus aureus strains (both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA)). In children, the procoagulant state frequently results in venous thrombosis.

Necrotising fasciitis/cellulitis

This is a severe subcutaneous infection, often involving tissue planes from the skin down to fascia and muscle. The area involved may enlarge rapidly, leaving poorly perfused necrotic areas of tissue, usually at the centre. There is severe pain and systemic illness, which may require intensive care. The invading organism may be Staphylococcus aureus or a group A streptococcus, with or without another synergistic anaerobic organism. Intravenous antibiotic therapy alone is not sufficient to treat this condition. Without surgical intervention and debridement of necrotic tissue, the infection will continue to spread. Clinical suspicion of necrotising fasciitis warrants urgent surgical consultation and intervention. Intravenous immunoglobulin (IVIG) may also be given.

Pneumococcal infections

Streptococcus pneumoniae is often carried in the nasopharynx of healthy children. Asymptomatic carriage is particularly prevalent among young children and may be responsible for the transmission of pneumococcal disease to other individuals by respiratory droplets. The organism may cause pharyngitis, otitis media, conjunctivitis, sinusitis as well as ‘invasive’ disease (pneumonia, bacterial sepsis and meningitis). Invasive disease, which carries a high burden of morbidity and mortality, mainly occurs in young infants as their immune system responds poorly to encapsulated pathogens such as pneumococcus. With the inclusion of the 13-valent pneumococcal vaccine into the standard immunisation schedule in the UK, the incidence of invasive disease has declined. Children at increased risk, e.g. from hyposplenism, should also be given daily prophylactic penicillin to prevent infection by strains not covered by the vaccine.

Haemophilus infection

H. influenzae type b was an important cause of systemic illness in children, including otitis media, pneumonia, epiglottitis, cellulitis, osteomyelitis and septic arthritis and was the second most common cause of meningitis in the UK. Immunisation has been highly effective and it now rarely causes systemic disease.

Staphylococcal and group A streptococcal infections

Staphylococcal and streptococcal infections are usually caused by direct invasion of the organisms. They may also cause disease by releasing toxins which act as superantigens. Whereas conventional antigens stimulate only a small subset of T cells which have a specific receptor, superantigens bind to a part of the T-cell receptor which is shared by many T cells and therefore stimulates massive T-cell proliferation and cytokine release. Other diseases following staphylococcal and streptococcal infections are immune-mediated.

Impetigo

This is a localised, highly contagious, staphylococcal and/or streptococcal skin infection, most common in infants and young children. It is more common where there is pre-existing skin disease, e.g. atopic eczema. Lesions are usually on the face, neck and hands and begin as erythematous macules which may become vesicular/pustular or even bullous (Fig. 14.9). Rupture of the vesicles with exudation of fluid leads to the characteristic confluent honey-coloured crusted lesions. Infection is readily spread to adjacent areas and other parts of the body by autoinoculation of the infected exudate. Topical antibiotics (e.g. mupirocin) are sometimes effective for mild cases. Narrow-spectrum systemic antibiotics (e.g. flucloxacillin) are needed for more severe infections, although more broad-spectrum antibiotics such as co-amoxiclav or cefaclor have simpler oral administration regimens, taste better and therefore have better adherence. Affected children should not go to nursery or school until the lesions are dry. Nasal carriage is an important source of infection which can be eradicated with a nasal cream containing mupirocin or chlorhexidine and neomycin.

Periorbital cellulitis

In periorbital cellulitis there is fever with erythema, tenderness and oedema of the eyelid (Fig. 14.10). It is almost always unilateral. In young, unimmunised children it may also be caused by Haemophilus influenzae type b which may also be accompanied by infection at other sites, e.g. meningitis. It may follow local trauma to the skin. In older children, it may spread from a paranasal sinus infection or dental abscess. Periorbital cellulitis should be treated promptly with intravenous antibiotics to prevent posterior spread of the infection to become an orbital cellulitis. In orbital cellulitis, there is proptosis, painful or limited ocular movement and reduced visual acuity. It may be complicated by abscess formation, meningitis or cavernous sinus thrombosis. Where orbital cellulitis is suspected, a CT scan should be performed to assess the posterior spread of infection and a lumbar puncture may be required to exclude meningitis.

Scalded skin syndrome

This is caused by an exfoliative staphylococcal toxin which causes separation of the epidermal skin through the granular cell layers. It affects infants and young children, who develop fever and malaise and may have a purulent, crusting, localised infection around the eyes, nose and mouth with subsequent widespread erythema and tenderness of the skin. Areas of epidermis separate on gentle pressure (Nikolsky sign), leaving denuded areas of skin (Fig. 14.11), which subsequently dry and heal without scarring. Management is with an intravenous anti-staphylococcal antibiotic, analgesia and monitoring of fluid balance.

Summary

Staphylococcal and streptococcal infections

• Symptoms are caused by direct invasion of bacteria or by release of toxins

• Impetigo is highly contagious

• Periorbital cellulitis should be treated aggressively to prevent spread to the orbit or brain

• Scalded skin syndrome is rare but serious.

The human herpesviruses

There are currently eight known human herpesviruses: herpes simplex virus 1 and 2 (HSV1 and HSV2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and human herpesviruses 6, 7 and 8 (HHV 6–8). HHV8 is associated with Kaposi sarcoma in HIV-coinfected individuals. The other herpesviruses will be discussed in this section, in order of their prevalence.

The hallmark of the herpesviruses is that, after primary infection, latency is established and there is long-term persistence of the virus within the host, usually in a dormant state. After certain stimuli, reactivation of infection may occur.

Herpes simplex infections

Herpes simplex virus (HSV) usually enters the body through the mucous membranes or skin, and the site of the primary infection may be associated with intense local mucosal damage. HSV1 is usually associated with lip and skin lesions, and HSV2 with genital lesions, but both viruses can cause both types of disease. The wide variety of clinical manifestations are described below. Treatment is with aciclovir, a viral DNA polymerase inhibitor, which may be used to treat severe symptomatic skin, ophthalmic, cerebral and systemic infections.

Asymptomatic

Herpes simplex infections are very common and are mostly asymptomatic.

Gingivostomatitis

This is the most common form of primary HSV illness in children. It usually occurs from 10 months to 3 years of age. There are vesicular lesions on the lips, gums and anterior surfaces of the tongue and hard palate, which often progress to extensive, painful ulceration with bleeding (Fig. 14.12). There is a high fever and the child is very miserable. The illness may persist for up to 2 weeks. Eating and drinking are painful, which may lead to dehydration. Management is symptomatic, but severe disease may necessitate intravenous fluids and aciclovir.

Skin manifestations

Mucocutaneous junctions and damaged skin are particularly prone to infection. ‘Cold sores’ are recurrent HSV1 lesions on the gingival (lip) margin.

Eczema herpeticum – In this serious condition, widespread vesicular lesions develop on eczematous skin (Fig. 14.13). This may be complicated by secondary bacterial infection, which may result in septicaemia.

Herpetic whitlows – These are painful, erythematous, oedematous white pustules on the site of broken skin on the fingers. Spread is by auto-inoculation from gingivostomatitis and infected adults kissing their children’s fingers. In sexually active adolescents, HSV2 may be the cause.

Eye disease

Eye disease may cause a blepharitis or conjunctivitis. It may extend to involve the cornea, producing dendritic ulceration. This can lead to corneal scarring and ultimately loss of vision. Any child with herpetic lesions near or involving the eye requires ophthalmic investigation of the cornea by slit lamp examination.

Central nervous system infection

Neonatal infection (see Ch. 10) – The infection may be focal, affecting the skin or eyes or encephalitis or may be widely disseminated. Its morbidity and mortality are high.

Infection in the immunocompromised host – Infection may be severe. Cutaneous lesions may spread to involve adjacent sites, e.g. oesophagitis and proctitis. Pneumonia and disseminated infections involving multiple organs are serious complications.

Summary

Herpes simplex virus infections

• Most are asymptomatic

• Gingivostomatitis – may necessitate intravenous fluids and aciclovir

• Skin manifestations – mucocutaneous junctions, e.g. lips and damaged skin

• Eczema herpeticum – may result in secondary bacterial infection and septicaemia

• Herpetic whitlows – painful pustules on the fingers

• Eye disease – blepharitis, conjunctivitis, corneal ulceration and scarring

• CNS – aseptic meningitis, encephalitis

• Pneumonia and disseminated infection in the immunocompromised.

Chickenpox (primary varicella zoster infection)

Clinical features

These are shown in Figure 14.14.

There are a number of rare but serious complications that can occur in previously healthy children:

• Secondary bacterial infection with staphylococci, group A streptococcal, or other organisms. May lead to further complications such as toxic shock syndrome or necrotising fasciitis. Secondary bacterial infection should be considered where there is onset of a new fever or persistent high fever after the first few days.

• Encephalitis. This may be generalised, usually occurring early during the illness. In contrast to the encephalitis caused by HSV, the prognosis is good. Most characteristic is a VZV-associated cerebellitis. This usually occurs about a week after the onset of rash. The child is ataxic with cerebellar signs. It usually resolves within a month.

• Purpura fulminans. This is the consequence of vasculitis in the skin and subcutaneous tissues. It is best known in relation to meningococcal disease and can lead to loss of large areas of skin by necrosis. It may rarely occur after VZV infection due to production of antiviral antibodies which cross-react and inactivate the coagulation factor protein S. There is subsequent dysregulation of fibrinolysis and an increased risk of clotting, most often manifest in the skin.

In the immunocompromised, primary varicella infection may result in severe progressive disseminated disease, which has a mortality of up to 20%. The vesicular eruptions persist and may become haemorrhagic. The disease in the neonatal period is described in Chapter 10.

 Watch for the child with chickenpox whose fever initially settles, but then recurs a few days later – it is likely to be due to secondary bacterial infection.

Treatment and prevention

Oral aciclovir has minimal benefit and is not recommended in the UK. Immunocompromised children should be treated with intravenous aciclovir initially. Oral valaciclovir can be substituted if organ dissemination has not occurred. Valaciclovir can be considered for adolescents and adults unlucky enough to develop primary VZV infection, as it is more severe when contracted beyond childhood. Human varicella zoster immunoglobulin (VZIG) is recommended for high-risk immunosuppressed individuals with deficient T-lymphocyte function following contact with chickenpox. Protection from infection with zoster immunoglobulin is not absolute, and depends on how soon after contact with chickenpox it is given.

 Beware of admitting a chickenpox contact to a clinical area with immunocompromised children, in whom it can disseminate and be fatal.

Shingles (herpes zoster)

Shingles is uncommon in children. It is caused by reactivation of latent varicella-zoster virus (VZV), causing a vesicular eruption in the dermatomal distribution of sensory nerves (shingles). It occurs most commonly in the thoracic region, although any dermatome can be affected (Fig. 14.15). Children, unlike adults, rarely suffer neuralgic pain with shingles. Shingles in childhood is more common in those who had primary infection in the first year of life. Recurrent or multidermatomal shingles is strongly associated with underlying immune suppression, e.g. HIV infection. In the immunocompromised, reactivated infection can also disseminate to cause severe disease.

 Recurrent or multidermatomal shingles suggests a T-cell immune defect.

Summary

Chickenpox

• Clinical features – fever and itchy, vesicular rash which crops for up to 7 days

• Complications – secondary bacterial infection, encephalitis; disseminated disease in the immunocompromised

• Human varicella zoster immunoglobulin (VZIG) – if immunosuppressed and in contact with chickenpox or if maternal chickenpox shortly before or after delivery

• Treatment is symptomatic; i.v. aciclovir for severe chickenpox or the immunocompromised.

Epstein–Barr virus: infectious mononucleosis (glandular fever)

Epstein–Barr virus (EBV) is the major cause of the infectious mononucleosis syndrome, but it is also involved in the pathogenesis of Burkitt lymphoma, lymphoproliferative disease in immunocompromised hosts and nasopharyngeal carcinoma. The virus has a particular tropism for B lymphocytes and epithelial cells of the pharynx. Transmission usually occurs by oral contact and the majority of infections are subclinical.

Older children, and occasionally young children, may develop a syndrome with:

Other features include:

Diagnosis is supported by:

Symptoms may persist for 1–3 months but ultimately resolve. They are caused by the host immune response to the infection, rather than the virus itself.

Treatment is symptomatic. When the airway is severely compromised, corticosteroids may be considered. In 5% of infected individuals, group A streptococcus is grown from the tonsils. This may be treated with penicillin. Ampicillin or amoxicillin may cause a florid maculopapular rash in children infected with EBV and should be avoided.

Cytomegalovirus

Cytomegalovirus (CMV) is usually transmitted via saliva, genital secretions or breast milk, and more rarely via blood products, organ transplants and transplacentally. The virus causes mild or subclinical infection in normal hosts. In developed countries, about half of the adult population show serological evidence of past infection. In developing countries, most children have been infected by 2 years of age, often via breast milk. In the immunocompromised and the fetus, CMV is an important pathogen.

As with EBV, CMV may cause a mononucleosis syndrome. Pharyngitis and lymphadenopathy are not usually as prominent as in EBV infections. Patients may have atypical lymphocytes on the blood film but are heterophile antibody-negative. Maternal CMV infection may result in congenital infection (see Ch. 9), which may be present at birth or develop when older. In the immunocompromised host, CMV can cause retinitis, pneumonitis, bone marrow failure, encephalitis, hepatitis, colitis and oesophagitis. It is a very important pathogen following organ transplantation. Organ recipients are closely monitored for evidence of CMV activation by sensitive tests such as blood polymerase chain reaction (PCR). Interventions used to reduce the risk of transmission of CMV disease are CMV-negative blood for transfusions and anti-CMV drug prophylaxis; also, if possible, CMV-positive organs are not transplanted into CMV-negative recipients.

CMV disease may be treated with ganciclovir or foscarnet, but both have serious side-effects.

Human herpesvirus 6 (HHV6) and HHV7

Human herpesvirus 6 (HHV6) and HHV7 are closely related and have similar presentations, although HHV6 is more prevalent. Most children are infected with HHV6 or HHV7 by the age of 2 years, usually from the oral secretions of a family member. They classically cause exanthem subitum (also known as roseola infantum), characterised by a high fever with malaise lasting a few days, followed by a generalised macular rash, which appears as the fever wanes. Many children have a febrile illness without rash, and many have a subclinical infection. Exanthem subitum is frequently clinically misdiagnosed as measles or rubella; these infections are rare in the UK and if suspected should be confirmed serologically. Another frequent occurrence in primary HHV6 infection is that infants seen by a doctor during the febrile stage are prescribed antibiotics, and when the rash appears, it is erroneously attributed to an ‘allergic’ reaction to the drug. Primary HHV6/HHV7 infections are a common cause of febrile convulsions. Rarely, they may cause aseptic meningitis, encephalitis, hepatitis, or an infectious mononucleosis-like syndrome.

Parvovirus B19

Parvovirus B19 causes erythema infectiosum or fifth disease (so-named because it was the fifth disease to be described of a group of illnesses with similar rashes), also called slapped-cheek syndrome. Infections can occur at any time of the year, although outbreaks are most common during the spring months. Transmission is via respiratory secretions from viraemic patients, by vertical transmission from mother to fetus and by transfusion of contaminated blood products. Parvovirus B19 infects the erythroblastoid red cell precursors in the bone marrow.

Parvovirus causes a range of clinical syndromes:

Enteroviruses

Human enteroviruses, of which there are many (including the coxsackie viruses, echoviruses and polioviruses), are a common cause of childhood infection. Transmission is primarily by the faecal–oral route. Following replication in the pharynx and gut, the virus spreads to infect other organs. Infections occur most commonly in the summer and autumn. Over 90% of infections are asymptomatic or cause a non-specific febrile illness, sometimes with a rash usually over the trunk that is blanching or consists of fine petechiae. A history of loose stools or some vomiting, or a contact history, would be supportive. The child is not usually systemically unwell, but if the rash is non-blanching, admission for observation and 48 h of parenteral antibiotics (such as ceftriaxone) is indicated. It is better to treat a number of enteroviral infections than to send home a child with meningococcal disease, only to have them return moribund 12 h later.

Other characteristic clinical syndromes exist and are listed below. (For polioviruses, see the Immunisation section, below.)

Clinical features

These are shown in Figure 14.16. There are a number of serious complications which can occur in previously healthy children:

In developing countries, where malnutrition and vitamin A deficiency lead to impaired cell-mediated immunity, measles often follows a protracted course with severe complications. Impaired cellular immune responses such as in HIV infection may result in a modified or absent rash, with an increased risk of dissemination, including giant-cell pneumonia or encephalitis.

Treatment

Treatment for measles is symptomatic. Children who are admitted to hospital should be isolated. In immunocompromised patients, the antiviral drug ribavirin may be used. Vitamin A, which may modulate the immune response, should be given in developing countries.

Prevention

Prevention by immunisation is the most successful strategy for reducing the morbidity and mortality of measles.

Mumps

Mumps occurs worldwide, but its incidence has declined dramatically because of the mumps component of the MMR vaccine. Following the decrease in the uptake of the MMR immunisation in the late 1990s, there has been a rise in unimmunised children and unvaccinated young adults. Mumps usually occurs in the winter and spring months. It is spread by droplet infection to the respiratory tract where the virus replicates within epithelial cells. The virus gains access to the parotid glands before further dissemination to other tissues.

Rubella (German measles)

Rubella is generally a mild disease in childhood. It occurs in winter and spring. It is an important infection, as it can cause severe damage to the fetus (see Ch. 9). The incubation period is 15–20 days. It is spread by the respiratory route, frequently from a known contact. The prodrome is usually mild with a low-grade fever or none at all. The maculopapular rash is often the first sign of infection, appearing initially on the face and then spreading centrifugally to cover the whole body. It fades in 3–5 days. Unlike in adults, the rash is not itchy. Lymphadenopathy, particularly the suboccipital and postauricular nodes, is prominent. Complications are rare in childhood but include arthritis, encephalitis, thrombocytopenia and myocarditis. Clinical differentiation from other viral infections is unreliable. The diagnosis should be confirmed serologically if there is any risk of exposure of a non-immune pregnant woman. There is no effective antiviral treatment. Prevention therefore lies in immunisation.

Kawasaki disease

Kawasaki disease (KD) is a systemic vasculitis. Although uncommon, it is an important diagnosis to make because aneurysms of the coronary arteries are a potentially devastating complication. Prompt treatment reduces their incidence.

Kawasaki disease mainly affects children of 6 months to 4 years old, with a peak at the end of the first year. The disease is more common in children of Japanese and, to a lesser extent, Afro-Caribbean ethnicity, than in Caucasians. Young infants tend to be more severely affected than older children and are more likely to have ‘incomplete’ cases, in which not all the cardinal features are present. Although the specific cause is unknown, it is likely to be the result of immune hyperreactivity to a variety of triggers in a genetically susceptible host (a polymorphism in the ITPKC gene, a negative regulator of T-cell activation on chromosome 19 is strongly associated with susceptibility to the disease).

There is no diagnostic test; instead, the diagnosis is made on clinical findings (Fig. 14.17). In addition to the classic features, affected children are strikingly irritable, have a high fever that is difficult to control, and may also have inflammation of their BCG vaccination site. They have high inflammatory markers (C-reactive protein, ESR, white cell count), with a platelet count that rises typically in the second week of the illness. The coronary arteries are affected in about one-third of affected children within the first 6 weeks of the illness. This can lead to aneurysms which are best visualised on echocardiography (see Case History 14.2). Subsequent narrowing of the vessels from scar formation can result in myocardial ischaemia and sudden death. Mortality is 1–2%.

Prompt treatment with intravenous immunoglobulin (IVIG) given within the first 10 days has been shown to lower the risk of coronary artery aneurysms. Aspirin is used to reduce the risk of thrombosis. It is given at a high anti-inflammatory dose until the fever subsides and inflammatory markers return to normal, and continued at a low antiplatelet dose until echocardiography at 6 weeks reveals the presence or absence of aneurysms. When the platelet count is very high, antiplatelet aggregation agents may also be used to reduce the risk of coronary thrombosis. Children with giant coronary artery aneurysms may require long-term warfarin therapy and close follow-up. Children suspected of having the disease but who do not have all the clinical features should still be considered for treatment. Sometimes, fever recurs despite treatment and these children are given a second dose of IVIG. Persistent inflammation and fever may require treatment with infliximab (a monoclonal antibody against TNF-α), steroids or ciclosporin.

Case History

14.2 Kawasaki disease

This 2-year-old boy developed a high fever of 2 days’ duration. Examination showed a miserable child with mild conjunctivitis, a rash and cervical lymphadenopathy. A viral infection was diagnosed and his mother was reassured. When he presented to hospital 3 days later, he was noted to have cracked red lips (Fig. 14.18a). He was admitted and a full septic screen, including a lumbar puncture, was performed and antibiotics started. The following day, he was still febrile and irritable; his C-reactive protein (CRP) had risen to 135, and ESR (erythrocyte sedimentation rate) to 125. Kawasaki disease was suspected and he was treated with intravenous immunoglobulin and high-dose oral aspirin. His clinical condition improved and he became afebrile the following morning. An echocardiogram at this stage showed no aneurysms of the coronary arteries, which are the most serious complication associated with delayed diagnosis and treatment. On the fifteenth day of the illness there was peeling of the fingers and toes (Fig. 14.18b).

Prevention and contact tracing

BCG immunisation has been shown to be helpful in preventing or modifying TB in the UK. However, its usefulness worldwide in preventing the disease is controversial. In the UK, BCG is recommended at birth for high-risk groups (communities with a relatively high prevalence of TB; i.e. Asian or African origin or TB in a family member in the previous 5 years or if the local area has a high prevalence rate). The UK programme of routine BCG for all tuberculin-negative children between 10 and 14 years has been discontinued. BCG should not be given to HIV-positive or other immunosuppressed children due to the potential risk of dissemination.

As most children are infected from a household contact, it is essential to screen other family members for the disease. Children who are exposed to smear-positive individuals (where organisms are visualised on sputum) should be assessed for evidence of asymptomatic infection. Mantoux-negative children over 5 years should receive BCG immunisation. Some clinicians suggest that those who are Mantoux-negative and <5 years old should receive chemoprophylaxis (e.g. rifampicin and isoniazid for 3 months). If at the end of this time they remain Mantoux-negative they should also receive BCG immunisation. Again, the aim of treatment is to decrease the risk of reactivation of TB infection later in life.

Reduction of vertical transmission

Mothers who are most likely to transmit HIV to their infants are those with a high HIV viral load and more advanced disease. Where mothers breast-feed, 25–40% of infants become infected with HIV and it is known that avoidance of breast-feeding reduces the rate of transmission. In developed countries, perinatal transmission of HIV has been reduced to <1% by using a combination of interventions:

This effective combination of interventions is not available to all women globally. Avoidance of breast-feeding is not safe in many parts of the world, where use of formula-feeding increases the risk of gastroenteritis and malnutrition. It may be safer for babies in this environment to breast-feed, and antiretroviral drugs may be given to the breast-feeding baby or mother to reduce the ongoing risk of mother-to-child transmission through this route.

Rationale behind the immunisation programme

Diphtheria – infection causes local disease with membrane formation affecting the nose, pharynx or larynx or systemic disease with myocarditis and neurological manifestations. Immunisation has eradicated the disease in the UK (Fig. 14.26a).

Pertussis – clinical features described in Chapter 16. Huge decline in incidence with immunisation, but epidemics recur when immunisation rates fall (Fig. 14.26b).

Haemophilus influenzae type b – causes invasive disease in young children The number of reports of infection dropped dramatically after the introduction of Hib vaccination (Fig. 14.26c), but a gradual rise from 1988 occurred because protection was not maintained throughout childhood. This was managed with a Hib catch-up programme, and to prevent a further resurgence, a Hib booster dose has been introduced at 12 months of age.

Poliovirus infection – Although most infected children are asymptomatic or have a mild illness, some develop aseptic meningitis and <1% develop paralytic polio. Almost eradicated worldwide (Fig. 14.26d).

Meningococcal C – The marked fall in the number of reports in all age groups is shown in Figure 14.26e.

Pneumococcal vaccination – introduced into the immunisation programme in 2006. Prior to this, about 530 children under 2 years of age developed invasive pneumococcal disease in England and Wales each year. In 2010, a 13-valent conjugate vaccine (PCV, effective against 13 serotypes) was introduced, which protects against about 90% of disease-causing pneumococcal serotypes.

Human papillomavirus (HPV) vaccine – introduced in 2008. Provides protection against the two strains (HPV16 and 18) that cause 70% of cervical cancer. Three doses of vaccine are given over a 6-month period to all girls aged 12–13 years of age.

BCG immunisation – although the number of notifications of TB is rising, it remains uncommon and mainly confined to high-risk populations. BCG immunisation in the neonatal period is therefore targeted to those at increased risk. The main value of BCG is in prevention of disseminated disease (including meningitis) in younger children, hence the rationale for changing the timing of vaccination from early adolescence to the neonatal period.

Hepatitis B and varicella vaccination – included in the immunisation programme in the USA and many other countries. In the UK, hepatitis B immunisation is given to babies born to hepatitis B surface antigen positive (HBsAg) mothers at 0, 1, 2 and 12 months of age. Babies born to highly infectious e-antigen positive mothers (HBeAg positive) should additionally receive hepatitis B immunoglobulin at birth. Varicella vaccine is not routinely given in the UK, but may be given to the siblings of ‘at-risk’ children (e.g. those undergoing chemotherapy).

Developing countries – huge effort and funds are devoted to improving immunisation uptake and programmes. The Expanded Programme on Immunization of the WHO is tailored according to healthcare systems. The majority use measles vaccine rather than MMR, for cost–benefit reasons.

Complications and contraindications

Following vaccination, there may be swelling and discomfort at the injection site and a mild fever and malaise. Some vaccines, such as measles and rubella, may be followed by a mild form of the disease 7–10 days later. More serious reactions, including anaphylaxis, may occur but are very rare. Local guidelines about vaccination and its contraindications should be followed. Vaccination should be postponed if the child has an acute illness; however, a minor infection without fever or systemic upset is not a contraindication. Live vaccines should not be given to children with impaired immune responsiveness (except in children with HIV infection in whom MMR vaccine can be given).

The controversy regarding a possible association between MMR vaccination and autism and inflammatory bowel disease has been discredited by a large number of well-conducted studies. However, public confidence in the immunisation programme was damaged, and uptake rates dropped (Fig. 14.26f). The MMR vaccine is only contraindicated in children with proven non-HIV-related immunodeficiency and those who are allergic to neomycin or kanamycin, which may be present in small quantities in the vaccine. Children with a history of anaphylaxis to egg (the virus is grown in fibroblast cultures generated from chick embryos) should be immunised with MMR under medical supervision. There is a 10% vaccine failure rate from primary vaccination with MMR at 12–13 months of age, but the proportion of susceptible school-age children in the UK has been reduced by the introduction of a preschool booster of MMR. Detailed information on MMR and other vaccines is available at: http://www.dh.gov.uk/en/Publichealth/Immunisation; further information about contraindications to vaccination can be found in the Department of Health Green Book, at: http://www.dh.gov.uk/en/Publichealth/Immunisation/Greenbook.

Primary immune deficiencies

Many of the primary immunodeficiencies are inherited as X-linked or autosomal recessive disorders. There may be a family history of parental consanguinity and unexplained death, particularly in boys. Immune deficiency should be considered in children who present with Severe, Prolonged, Unusual or Recurrent (SPUR) infections (Box 14.3). The clinical presentation of the different primary immune deficiencies is shown in Figure 14.27.