AFRICAN HAEMORRHAGIC FEVER

African haemorrhagic fever is an acute onset fever, characterized by papular rash (1.65), proteinuria, pancreatitis, hepatitis and haemorrhage. It is caused by infection with either Marburg or Ebola viruses. Marburg disease was originally found in people in contact with green monkeys (Cercopithecus aethiops) which were obtained from Uganda. Subsequently there was evidence of transmission by needles and directly from person to person. Both viruses cause acute disseminated intravascular coagulation (DIC, see p. 464), and profound haemorrhage is the usual cause of death. There is no specific treatment, but the patients require intensive circulatory support and control of the DIC with heparin; they may benefit from plasma containing virusspecific antibodies. Extensive precautions are needed to prevent the spread of infection.
Haemorrhagic fever occurs widely throughout the world. Other causes include dengue (see p. 22), yellow fever (see p. 21), bunyavirus and hantavirus infections. All are potentially fatal conditions.

1.65 African haemorrhagic fever is often accompanied by a widespread papular rash, though this nonspecific sign may progress to more serious petechiae and haemorrhage.

1.66 Erythema infectiosum. This boy's erythematous rash appeared 24 hours after the onset of a mild fever and sore throat. Note the 'slapped cheek' appearance of the face.

ERYTHEMA INFECTIOSUM

This acute self-limiting disease, also known as fifth disease or slapped cheek disease, is caused by human parvovirus B19. It occurs in outbreaks, most often in spring and summer. Any age may be affected but it is most common in children, in whom the usual presentation is a mild febrile illness followed by marked erythema of the cheeks and the appearance of a pink maculopapular rash (1.66). The rash may become confluent and is most marked on the limbs; as it fades, it takes on a lacelike appearance. The rash may come and go over about 2-3 weeks. Adenopathy, arthralgia and arthritis are common especially in adults infected with the virus. Joints most involved are wrists and knees. The arthritis may, if prolonged, be mistaken for other forms of rheumatism. Transient marrow depression may occur during the course of the illness. In patients with congenital haemolytic anaemia, an aplastic crisis may be induced (see p. 434).
The diagnosis can be confirmed by finding a specific IgM antibody in the serum.
As the disease is self-limiting, children require no therapy. Analgesics and anti-inflammatory drugs may be needed for relief of joint pain in adults. If there is an aplastic crisis, blood transfusion is indicated. No vaccine is available for this disease.

HERPES SIMPLEX

The causal agents of herpes simplex are herpes simplex virus types I and II. Type 11 is associated with sexually transmitted genital infection, whereas most other infections are caused by type I. Following the primary infection, the virus remains latent in the tissues and may re-emerge at a later stage to produce local lesions.
Primary infection with type I virus usually occurs in childhood and takes the form of acute gingivostomatitis with multiple painful, shallow ulcers on the tongue, buccal mucosa and lips (1.4, 1.67). In genital herpes, ulcers are on the vulva, vagina, cervix or penis (1.68). In both instances, the primary lesions are self-limiting and clear in about 10 days. The local eruption may be accompanied by fever and malaise and, in the case of children, refusal to eat or drink. Other sites of primary infection are the fingers (herpetic whitlow) and the cornea (dendritic ulcer, 1.69). Herpes simplex encephalitis is a rare but very serious presentation (see p. 494). In the neonate, disseminated herpes simplex is a life-threatening illness. Patients with eczema may present with widespread lesions on the eczematous areas (eczema herpeticum, 2.26).
Reactivation of latent herpes simplex usually occurs in sites related to the primary infection (1.70). In the immunocompromised patient, reactivation of virus may cause very severe local lesions (1.31), with generalized viraemia and encephalitis.
Genital herpes has reached epidemic proportions and differs from other sexually transmitted diseases because of the likelihood of spontaneous recurrence. It is extremely contagious, being spread by secretions to partners and to the fetus. There is a causal relationship between genital herpes, cervical cell metaplasia and cervical carcinoma. Herpes simplex virus II is the most common infecting agent in young women. The primary lesions appear within a day or so of exposure and are thin-walled vesicles which are painful. In women there is usually a vaginal discharge followed by tender lymphadenopathy with generalized fever. In men the lesions are found on the glans, foreskin and penile shaft (1.78). In addition, lesions may be found in the perineum and perianal regions of homosexual men (1.37).
Recurrence of genital herpes is common and may be precipitated by local trauma, menstruation, pregnancy, stress, depression, intercurrent illness or immunosuppression. The recurrence tends to be more localized and not as severe as the first attack. Patients often recognize the prodrome of recurrence with local itching and tingling.
The virus can be cultured from vesical fluid or from swabs from genital or mouth ulcers. Viral particles can also be identified under the electron microscope. Rising antibody titres may be found in primary herpes simplex.
Most primary lesions are self-limiting and specific therapy is not usually required. If applied very early, acyclovir cream may abort the development of `cold sores'. Acyclovir is the treatment of choice for primary genital herpes and for recurrence (patients can start treatment at the first prodromal sign of recurrence). Intravenous acyclovir should be used to treat herpes encephalitis and severe infections in the immunocompromised host and in the neonate. An ophthalmological opinion should be sought when there is involvement of the eye.

1.67 Severe herpetic gingivostomatitis. This young child was acutely ill with a high fever and had multiple vesicular lesions on the tongue, lips and buccal mucosa. In adult patients, a more common manifestation of herpetic stomatitis is the cold sore; this is usually a reactivation of latent infection.

1.68 Primary genital herpes. Note the numerous lesions on the penis and the associated tissue reaction.

1.69 A primary herpetic dendritic ulcer, stained with fluorescein. Herpes simplex virus proliferates in the epithelial layer of the cornea. Urgent treatment with antiviral drops or ointment is indicated.

1.70 Recurrent herpes simplex on the cervix. The ulcers have recurred in a common primary site for genital infection. Other common sites include the external genitalia and the lips.

VARICELLA ZOSTER

Varicella zoster causes two distinct diseases - chickenpox (varicella) and shingles (herpes zoster).

Chickenpox

Chickenpox is a highly infectious disease caused by the Varicella zoster virus. It is usually mild in children but can be severe in adults and in immunocompromised patients. The incubation period is usually 14-15 days. In adults especially, there may be a short prodromal illness with fever, malaise, headache and occasionally a transient erythematous rash. The true rash is vesicular with a central distribution in the body (1.71). The spots are elliptical and come out in crops over a few days (1.72). Mucous membranes may also be affected (1.73). Scabs form rapidly and most have separated in 10-14 days. The most common complication, especially in children, is skin sepsis, usually due to superinfection with Staphylococcus aureus or Streptococcus pyogenes. Varicella pneumonia, which can be life-threatening, occurs mainly in adults who smoke and in the immunocompromised (1.74,10.73, 10.100). Other rare complications include encephalitis, cerebral ataxia and haemorrhagic chickenpox.
The diagnosis is usually made on clinical grounds but electron microscopy, viral culture and serology may be required in difficult cases.
No specific therapy is usually required. Children should be prevented, if possible, from scratching the spots. If the disease is severe, especially in the immunocompromised patient, the antiviral drug acyclovir may be used either parenterally or orally.
There is no active vaccine against Varicella zoster, though a live vaccine is in the late stages of development. Varicella zoster immune globulin may modify or prevent the disease if given within 1 week of contact. Acyclovir may also be given prophylactically to immunocompromised patients who have been exposed to the disease.

1.71 Chickenpox in a child, showing the predominantly central distribution of the rash (which used to be of great importance in differentiating chickenpox from the now-eradicated smallpox, in which the rash is predominantly peripheral).

1.72 Chickenpox can be a severe disease, especially in adult patients. After several days, the rash is pleomorphic, as the lesions emerge in crops at irregular intervals. The rash in this patient shows vesicles at different stages of development.

1.73 Vesicles on the palate in chickenpox often add to the discomfort of the disease. The vesicles rupture and ulcerate, but heal without scarring.

1.74 Chickenpox pneumonia affects mainly adults, and produces a severe illness with the characteristics of acute inflammatory pulmonary oedema. Chest X-ray shows widespread soft, nodular opacities throughout both lungs. The complication varies in severity from mild to lifethreatening.

Shingles

Shingles is caused by reactivation of latent varicella virus in sensory root ganglia in patients previously infected with chickenpox. Reactivation is common in the elderly and in immunocompromised patients (1.38). The skin eruption, which is always unilateral, appears along the line of one or two dermatomes (1.75). The lesions are vesicular on an erythematous base. In ophthalmic herpes (1.76), especially if the nasociliary branch of the nerve is affected, there may be corneal ulceration (as in herpes simplex, 1.69) and iridocyclitis. Ophthalmic herpes zoster is a medical emergency: corneal scarring (1.77) and other serious complications may occur. Dissemination of virus in the blood stream may result in the appearance of scattered chickenpox lesions elsewhere on the body. Viraemia may be overwhelming in immunocompromised patients. Pain may precede the skin rash, and postherpetic neuralgia can be prolonged and severe, especially in the elderly. The most common complications are bacterial superinfection of the skin lesions and postherpetic neuralgia. Occasionally there may be motor nerve involvement, as in the Ramsay Hunt syndrome when seventh nerve paresis occurs (1.78). Meningoencephalitis is a more serious but rarer complication. Acyclovir given orally within 72 hours, or in severe cases intravenously, along with local applications of acyclovir skin cream may hasten healing and reduce viral shedding, but there is little evidence that acyclovir prevents or reduces postherpetic neuralgia. Analgesics are almost always required for pain control. If there is involvement of the eye, acyclovir should be given and an ophthalmological opinion should be sought.

1.75 Herpes zoster affecting the L2 dermatome. The rash shows the characteristic 'band' distribution, starting from the midline, where some vesicles can be seen.

1.76 Ophthalmic herpes. The vesicular skin eruptions are in the distribution of the ophthalmic division of the fifth cranial nerve. Serious opthalmic complications are a real threat, especially when the tip of the nose is affected (this indicates involvement of the nasociliary nerve, which also supplies the cornea).

1.77 Corneal scarring is a late complication of ophthalmic herpes, resulting from corneal anaesthesia. In this patient a protective lateral tarsorrhaphy has been carried out.

1.78 Ramsay Hunt syndrome (geniculate zoster). The patient has a right seventh nerve paresis. Full recovery occurs in about 50% of cases.

CYTOMEGALOVIRUS

Like other herpesviruses, cytomegalovirus remains latent in the body after primary infection and may only reactivate if the patient is stressed or becomes immunocompromised. The virus may be transmitted by respiratory secretions, sexually, by blood transfusion or by organ transplantation. Maternal infection spreads transplacentally or perinatally to the fetus.
Most cytomegalovirus infections in the immunocompetent are subclinical, but there may be a glandular fever-like syndrome with fever, generalized lymphadenopathy, abnormal liver function tests and atypical mononuclear cells in the blood. Primary infection or reactivation of latent infection in the immunocompromised patient may cause serious illness with pneumonia (1.79), chorioretinitis (1.36), gastroenteritis, involvement of the CNS, haemolytic anaemia and thrombocytopenia. Intrauterine infection may cause fetal death. Severe neonatal cytomegalovirus infection causes jaundice, hepatosplenomegaly (1.80), purpura, neurological damage and chorioretinitis. The infected infant may, however, appear normal at birth, and develop symptoms later.
The finding of specific IgM in serum is diagnostic of acute infection. Isolation of virus from urine or sputum may simply indicate prolonged excretion after past infection.
Cytomegalovirus inclusion bodies in biopsy specimens from the lung or gastrointestinal tract are diagnostic, so biopsy provides definitive diagnosis in the immunocompromised patient.
Most acquired infections are self-limiting but severe disease, especially in the immunocompromised, should be treated with intravenous ganciclovir or phosphonoformate. Treatment may have to be prolonged; relapses are common unless maintenance therapy is continued on a long-term basis.

1.79 Cytomegalovirus (CMV) pneumonia is often known as CMV pneumonitis, as the infection is generalized, and consolidation may not be seen on X-ray. CMV is second only to Pneumocystis as a cause of pulmonary disease in patients with HIV infection, and it is also seen in other immunocompromised patients, including those on anticancer therapy, systemic steroids, and drugs such as azathioprine and cyclophosphamide used to prevent organ transplant rejection. CMV pneumonia cannot be diagnosed on clinical grounds or X-ray appearances alone.

1.80 Congenital cytomegalovirus infection. This infant has massive splenomegaly, hepatomegaly and a purpuric rash. A similar picture may be caused by a number of prenatal virus infections.

1.91 Infectious mononucleosis. Numerous petechial haemorrhages are seen in the hard palate. In many patients there is also a tonsillitis, indistinguishable from that seen in acute streptococcal pharyngitis (1.3).

EPSTEIN-BARR VIRUS INFECTIONS

Infectious mononucleus
The Epstein-Barr virus (EBV) is the causal agent of infectious mononucleosis. Primary infection with EBV is often subclinical, especially in young children. Older children and young adults usually present with symptoms of glandular fever.
In the most common form of the disease, there is enlargement of glands both in the anterior and posterior triangles of the neck, and usually in the axillae and groins. The fauces and palate become inflamed and oedematous. There may be palatal haemorrhages and a whitish or yellow pseudomembrane appears on the tonsils (1.81). There is usually marked nasopharyngitis and often puffiness of the face.
In the more generalized form of the disease, throat involvement is less marked. Presenting features are fever, generalized adenitis, splenomegaly and occasionally jaundice. There may also be a pink, maculopapular rash on the trunk and limbs (1.82). A rash is more often seen in patients who have been given ampicillin or related drugs (1.83).
Complications of infectious mononucleosis include myocarditis, autoimmune haemolytic anaemia, thrombocytopenia and meningo-encephalitis. Splenic rupture is a rare complication which is usually associated with trauma. Postviral fatigue syndrome may follow EBV infection.
The diagnosis is aided by the identification of atypical mononuclear cells in peripheral blood (1.84). The Paul-Bunnell test for heterophil antibodies usually becomes positive in the second or third week of the illness. In children under about 7 years, the Paul-Bunnell test is rarely positive, and diagnosis should be confirmed by EBV serology.
Treatment is symptomatic. Antibiotics are not indicated and ampicillin and related drugs should not be prescribed because of the high incidence of allergic reactions. Steroid therapy may be indicated if there is respiratory obstruction or autoimmune manifestations.

1.82 Rash in infectious mononucleosis may be the result of the infection itself, as here. The maculopapular rash usually emerges during the second week of illness, and it is often indistinguishable from that of rubella (1.49).

1.83 Rashes in infectious mononucleosis are most commonly caused by the administration of ampicillin or related penicillin compounds (these are often administered early in the disease on the presumption that the patient has bacterial pharyngitis). Ampicillin rashes occur more commonly in patients with infectious mononucleosis than in other patients, so the appearance of this kind of rash in a patient with typical symptoms points strongly to the diagnosis of infectious mononucleosis.

1.84 Blood film in infectious mononucleosis showing two atypical mononuclear cells. There is a wide variation in cell size and shape and mitotic activity is greatly enhanced, but the cellular structure is not fundamentally deranged.

Burkitt's lymphoma and nasopharyngeal carcinoma

EBV has been implicated in the aetiology of Burkitt's lymphoma, a transmissible neoplastic tumour particularly involving the head and neck (1.85) that is found in tropical Africa. The disease has a similar range of distribution to malaria, and it is thought that the virus may be transmitted via mosquitoes.
EBV has also been implicated in some nasopharyngeal carcinomas, and it may play a role in the genesis of hairy leucoplakia (1.30) and in other premalignant and malignant disease.

ROSEOLA (SIXTH DISEASE)

Roseola infantum is a common, benign exanthematous disease of young children. After a rapid onset high fever, which lasts for a few days and then resolves, a generalized rubelliform rash appears (1.86). There may be cervical node enlargement and febrile convulsions may complicate the acute stage. The rash fades after 24-48 hours, and the patient usually makes a complete and uncomplicated recovery.
The disease is caused by herpes 6 virus (and the disease is also known as sixth disease).

ORF

Orf (contagious pustular dermatitis) is a paravaccinia virus infection of sheep and goats, which causes an eruption on the animals' lips. It is sometimes contracted by those who woik with these animals, and in humans it usually causes a single papule on the skin of the hand, which develops from a flat vesicle to a haemorrhagic bulla. Occasionally, more than one papule may occur (1.87). The lesions are usually self-limiting, but may ulcerate and may act as a trigger for the onset of erythema mul-' tiforme (see p. 94). Regional lymph node enlargement is common. Milker's nodules are similar lesions, caused by cowpox virus and seen in farm workers dealing with cattle. Other differential diagnoses include anthrax, vaccinial infection and infection with Erysipelothrix rhusiopathiae.

1.85 Burkitt's lymphoma, apparently originating in the maxilla and causing gross facial swelling in an African child.

1.86 Roseola infantum. An erythematous macular or rubelliform rash appears. It is often particularly prominent on the buttocks and fades within 2 days. If the child has been treated with an antibiotic for the fever, the rash may be mistaken for drug sensitivity.

1.87 Orf. 3-7 days after inoculation from an infected sheep or goat, one or more firm, painless, dark papules may appear on the finger or hand. These develop into pustules, but the condition is self-limiting, usually clearing within 4-8 weeks.
 

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