The viruses

Noroviruses are single-stranded RNA viruses and belong to the family Caliciviridae. There are three genogroups of noroviruses. New variants emerge every few years.

Epidemiology

Route of spread

Noroviruses most frequently spread by the ingestion or inhalation of vomit. Patients frequently have no prior warning that they are about to vomit, which results in environmental contamination.

Noroviruses are also transmitted by contaminated food (e.g. bivalve molluscs, such as cockles and oysters, contaminated by human sewage in sea water). Symptomatic food handlers can also contaminate food, resulting in outbreaks.

Prevalence

Norovirus infection is common and 90% of adults have been infected at some time in their lives. Immunity lasts for less than a year, and reinfection can occur with the same or different strains.

Incubation period

24–48 hours after contact with a contaminated environment or eating contaminated food.

Infectious period

From onset of symptoms to 48 hours after symptoms stop.

At-risk groups

All ages.

Clinical

Symptoms

Noroviruses are associated with diarrhoea and vomiting (especially projectile vomiting).

Outbreaks

Noroviruses cause large outbreaks in hospitals, cruise ships and in the community, especially in schools and nursing homes. Outbreaks occur more frequently in the winter (winter vomiting disease), but when new variants emerge outbreaks in the summer occur.

Chlamydia are obligate intracellular Gram-negative bacteria. They have a dimorphic growth cycle of elementary bodies (EB), which are electron-dense infectious structures and reticulate bodies (RB), which are non-infectious, intracellular forms. Elementary bodies attach to the cell to initiate cell infection. Once inside the cells they differentiate into RBs; RBs divide by binary fission and subsequently differentiate back to EBs to be released from the cell to initiate further infection.

Chlamydia belong to the family Chlamydiaceae, which has two genera:

1. Chlamydia – which has one species C. trachomatis. C. trachomatis is further subdivided into serovars.

1. Serovars A, B, Ba and C cause trachoma (a tropical eye infection).

2. Serovars D–K cause genital infection.

3. Lymphogranuloma venereum (LGV) 1, 2, 3 cause genital infection with inguinal lymphadenopathy in the tropics.

1. Chlamydophila – species in the genus are:

1. Ch. psittaci – natural infection in birds, both psittacine (parrots, budgerigars etc.) and other birds (e.g. pigeons). Human infection is acquired as a zoonosis from birds.

2. Ch. pneumoniae – is a human pathogen.

3. Ch. abortus – primarily infects sheep and causes abortion in pregnant ewes (hence the name), human infection is accidental from sheep.

4. Ch. caviae – causes infection in guinea pigs, but does not cause human infection.

Epidemiology

Both chlamydia and chlamydophila are prevalent worldwide. Trachoma is a disease of underdeveloped and developing countries, and the most important cause of blindness in these parts.

The viruses

Human papilloma viruses (HPV) and polyoma viruses are DNA viruses and belong to the family Papovaviridae. There are over a hundred known genotypes of HPV, some of which are oncogenic.

The envelope proteins E6 and E7 are transforming proteins and associated with initiating cancer by the oncogenic HPV genotypes.

Papilloma viruses

Epidemiology

Route of spread

• Sexual: the main route of spread for genital warts is sexual, and therefore it is a sexually transmitted infection.

• Vertical: laryngeal papilloma or warts in children are usually due to transmission to the baby at the time of delivery if the mother has genital warts.

• Direct contact with infected material: usually introduced through abraded skin (e.g. sharing towels, swimming pools, walking barefoot). Common skin warts are normally transmitted by this route.

Prevalence

Infection is prevalent worldwide. Human papilloma viruses 1–4 cause skin lesions, HPV 4 typically causes plantar warts and HPV 1 papillomatous lesions on fingers and trunks. Human papilloma viruses 6 and 11 are associated with genital warts and cause respiratory papilloma in children. Human papilloma viruses 16, 18 and other higher numbered genotypes also cause genital infection, which is directly linked to cervical cancer.

Most of the HPV prevalence figures are around genital infection. Human papilloma virus infection is the commonest sexually transmitted infection, and 25–40% of women between the ages of 15–25 years have evidence of HPV infection. There are an estimated 400 million cases of genital HPV infection worldwide. It is estimated that 250000 women die of cervical cancer each year with 500000 new diagnoses each year, 80% of which occur in the developing world.

The virus

Cytomegalovirus is a double-stranded DNA virus and member of the Herpesviridae family of viruses.

Epidemiology

Route of spread

Cytomegalovirus is transmitted via saliva and sexual contact, or from infected donated blood and organs.

Prevalence

Cytomegalovirus infection occurs worldwide and the prevalence of infection varies considerably. In the UK a rule of thumb is that the percentage of the community with CMV infection is equivalent to the age (e.g. approximately 20% of 20-year-olds will have had CMV infection). Prevalence tends to be higher in lower socio-economic groups, people born outside Western Europe, inner city areas and in communities living in overcrowded conditions.

Incubation period

3–6 weeks.

Infectious period

This varies for different groups of people. In immunocompetent people, the virus is present for a few weeks in saliva, blood and some other body fluids after primary infection. In immunocompromised people, the infectious period may be prolonged after primary infection. Also, when they experience reactivation of CMV, the infection may last for weeks or months.

Cytomegalovirus is a herpes virus, which becomes latent in humans once active infection has been resolved. The virus can reactivate to produce another infection later in life – this is much rarer in persons who are not immunocompromised.

At-risk groups

Cytomegalovirus can infect anyone who has saliva or sexual contact with an actively infected person, or who receives blood or organs from a CMV positive person.

Viral hepatitis is a clinical diagnosis and presents as a systemic infection primarily affecting the liver or as part of a general systemic infection. Hepatitis A, B, C, D and E viruses are all hepatotropic viruses and primarily cause hepatic infection, whereas Epstein–Barr virus (EBV), cytomegalovirus (CMV) and other viruses may cause hepatitis as part of a more generalized systemic infection. The differential diagnosis should also include non-viral causes such as leptospirosis.

Clinical

The clinical features of hepatitis include nausea, vomiting, lack of appetite and dark urine, and these may be accompanied by pain in the right upper quadrant. This is normally preceded by prodromal symptoms, which may include fever, arthralgia, myalgia, headache and rash. Clinically it is not possible to distinguish the etiological agent, although there may be clues in the epidemiology (Table 38.1). The majority of cases of acute viral hepatitis, especially in children, may be asymptomatic e.g. not accompanied by clinical jaundice. About 50% of adults with acute hepatitis A (HAV) and B (HBV) virus infections and 70% with acute hepatitis C (HCV) virus infection develop an asymptomatic infection. Diagnosis is only made by chance or due to investigations of non-specific symptoms or during follow up after known exposure. The main abnormal finding is elevated liver function tests (LFTs) with peak alanine aminotransferase (ALT) levels of >1000 U/L, especially in hepatitis A and B virus infections. Peak ALT levels tend to be lower in acute hepatitis C virus infection.

There are several viruses that can cause infections in or around the eye. These are best considered according to what symptoms they cause.

Conjunctivitis

Conjunctivitis is inflammation of the conjunctiva and is sometimes called ‘red eye’. Virus infections can cause these symptoms but it can also be caused by other conditions, e.g. allergies such as hay fever. Viral conjunctivitis is very infectious and can cause sizeable outbreaks. Although several viruses can cause these symptoms, adenoviruses and enteroviruses are the most likely causes.

Adenovirus conjunctivitis used to be called ‘shipyard eye’ because one of the earliest outbreaks of this condition occurred in a shipyard in the north of England. Occupational health staff inadvertently spread the infection between metal workers, who were attending to have pieces of metal removed from their eyes. The forceps used for this purpose were inadequately sterilized between patients, thus causing an outbreak.

Several enteroviruses (especially enterovirus 70 and coxsackie virus A24) can cause conjunctivitis. These viruses can cause extensive outbreaks and are very infectious. Enterovirus 70 used to be called ‘Apollo eye’ after a large outbreak in Africa, which it was alleged was a result of people staring at the sky to look at the Apollo spacecraft.

The viruses

Influenza A and B viruses are RNA viruses and belong to the family Myxoviridae. The RNA genome is split into eight segments, which allows the influenza A strains to exchange genetic information with each other giving rise to new strains all the time.

Both influenza A and B viruses have got two important surface proteins, namely haemagglutinin (H), which is responsible for attaching the virus to the cell surface, and neuraminidase (N). These two proteins are used in the nomenclature of strains (e.g. H2N3 and H5N1).

Epidemiology

Some influenza A strains infect other animals such as birds and pigs. Infections can spread from these animals to humans, sometimes causing an outbreak. We are most familiar with H5 (haemagglutinin type 5) and H7 (haemagglutinin type 7) strains transmitting from birds to humans. Usually, these infections are associated with single cases or clusters of cases in humans. There is always the fear that these avian viruses will mutate, becoming muchmore infectious to humans and causing a worldwide pandemic.

Influenza viruses are RNA viruses that mutate regularly (especially influenza Avirus). Viruses causing outbreaks one year are rarely the same as those causing outbreaks the following year. This is why the composition of influenza virus vaccines is different each year. This gradual change in RNA composition is called antigenic drift. It is thought that some new pandemics of influenza A arise because of antigenic shift, which usually occurs when two different strains of influenza A virus infect the same cell (especially in pigs, which can be infected with human strains).

True sexually transmitted infections are those that are transmitted only through sexual activity, but there are many in which sexual transmission is one of the routes and others that even though not strictly transmitted via the sexual route may be transmitted through related sexual practices. It is important to remember that many of these patients may not perceive themselves at risk of a sexually transmitted infection, and therefore may present outside the genito-urinary medicine setting.

Clinical

Sexually transmitted viral infections can be divided into two groups:

• those that present with localized genital lesions or symptoms

• those that are systemic infections but may also be transmitted via sexual route or during related sexual activity.

This chapter will consider only those pathogens that cause local genital lesions; refer to the appropriate chapters in the book for those that have a systemic manifestation.

Vesicular or ulcerative genital lesions

Herpes simplex virus is the commonest cause, but occasionally varicella-zoster virus may also cause localized genital lesions, which may be clinically difficult to distinguish from herpes. Clinical examination may reveal a shingles-like distribution along a sensory nerve in a case of varicella-zoster virus infection. The distinction is important to make as a higher dose of aciclovir is required to treat varicella-zoster.

Acute syphilis may present as an ulcerative gummatous lesion.

There are several categories of immunocompromised patients. Different viruses cause different clinical symptoms in these patients as shown below. HIV positive/AIDS patients often have different symptoms from transplant recipients and need different treatment and prophylactic strategies.

Organ transplant recipients

See Table 43.1.

Cytomegalovirus (CMV)

Cytomegalovirus is the most important virus infection in transplant recipients. Infection acquired from the donor organ is usually most severe and can be fatal. Eighty per cent of CMV antibody negative patients who receive an organ from a CMV antibody positive donor will acquire primary CMV infection. The severity of their symptoms will depend on the amount and type of immunosuppressive treatment they are receiving. Lung and bowel transplants usually have more severe CMV disease than heart, liver or kidney recipients. Between 30% and 60% of CMV antibody positive organ recipients will experience CMV reactivation from one to three months after transplantation. Antiviral treatment for severe CMV disease is intravenous ganciclovir (or foscarnet or cidofivir if ganciclovir is contraindicated).

Herpes simplex virus (HSV)

Herpes simplex virus infection in transplant recipients is almost always a reactivation of latent infection, which occurs from a few weeks to a few months after transplantation. Symptoms can vary from a small cold sore, genital or skin lesion to extensive skin eruptions and, rarely, encephalitis. It can be treated with oral or intravenous aciclovir (depending on the severity of the symptoms).

The virus

Hepatitis E virus (HEV) is an RNA virus that resembles caliciviruses but as yet remains unclassified. There are at least four genotypes of the virus, genotypes 1 and 2 are limited to humans only, and genotype 3 and 4 have animals as their reservoir and therefore are zoonotic infections.

Epidemiology

Route of spread

Hepatitis E is spread by the faecal–oral route, mostly through drinking water and probably by eating contaminated food. Person-to-person spread may occur but is uncommon. Waterborne outbreaks occur commonly in countries where infection is endemic.

Prevalence

The infection was first reported from the Indian subcontinent and subsequently from other parts of Asia, the Middle East, Central and South America, Africa, Central Europe and Russia. People travelling to countries with high prevalence are therefore at risk of acquiring infection during their travel. Adult populations in endemic areas are generally susceptible and there is a high infection rate in epidemics.

Until recently cases reported from North America and Western Europe were travel related but recently many indigenous cases, including clusters of cases, have been reported indicating that hepatitis E infection is endemic. All the cases reported from the West have been due to genotype 3 of HEV, for which pigs are the main reservoir. The exact route of transmission is not clear and further studies are needed.

Very often it is difficult to make a clinical diagnosis of a specific viral infection, as many viruses have clinically similar presentation (e.g. hepatitis viruses,Chapter 38) and the same virus can have many different clinical presentations (e.g. enteroviruses, Chapter 5). It is therefore essential to seek specific laboratory diagnosis to enable correct management of the patient. This may be important from an epidemiological perspective as well. It has been shown that even experienced clinicians are not able to clinically diagnose cases of rubella or measles correctly. A specific diagnosis of a viral rash is important, not only to the clinical management of the patient, but essential for control of infection, outbreak control and the public health perspective of continuing to ensure the efficacy of vaccination programmes.

Antibodies are produced as a host response to viral infection. Immunoglobin A is produced at the local site of infection and provides local immunity, for example in the gut or respiratory tract. The generalized humoral immune response is mounted by B lymphocytes and the first antibody to appear is of the IgM class, which can be detected as early as a couple of days after an acute infection. Some of the B lymphocyte clones then switch over to producing IgG antibody, which appears from 7–15 days after onset of infection. Both classes of antibodies continue to rise in response to the infection, peaking at about 6 weeks post infection. Viral specific IgM then declines and is normally undetectable by about 3 months after infection.

Transmissible spongiform encephalopathies (TSE) are a group of agents that give rise to spongiform degeneration in the brain. These agents do not possess any nucleic acid (DNA or RNA) and are very resistant to inactivation. They consist of only a glycoprotein core and the term prion or prion protein (PrP) has been coined to describe them. They infect both humans and animals, and have recently been shown to cross the species barrier, e.g. vCJD crossed into humans from cattle. See Table 31.1.

Epidemiology

The first agent to be described was scrapie. Scrapie has been known to cause infection in sheep in the UK for more than a hundred years. In the late 1980s and 1990s there was an outbreak of a bovine form of scrapie, namely bovine spongiform encephalopathy (BSE), which had previously not been described. This led to destruction of thousands of cattle in the UK and a public health crisis in the confidence of beef for human consumption.

Creutzfeldt–Jakob disease (CJD) is the human form of prion disease, and has been known to occur throughout the world since 1920. Kuru is the name given to the infection that was limited to only parts of Papua New Guinea. In the 1990s, a new form of CJD was described for the first time in the UK as a result of BSE transmission; this was named as variant CJD (vCJD) to distinguish it from the already existing CJD.

Human prion disease can be acquired through either an inherited or an infectious route.

Sending the correct specimens

It is important to establish which are the best specimens to send to the laboratory. Chapters in this book suggest which specimens are suitable for the diagnosis of different virus infections and clinical syndromes, but the reader is also advised to check with the local laboratory's user manual as not all assays are offered by all laboratories. It is important to consider when in the patient's clinical course specimens should be sent. There are a few simple rules of thumb.

• Virus antibody is usually not present in serum reliably until about 10 days after the onset of symptoms.

• For those viruses where specific IgM is not tested for, an acute sample taken as soon as possible after the onset of symptoms and a second specimen taken 10 days after the onset of symptoms allows for the detection of a specific antibody rise.

• Viruses causing maculopapular rashes (e.g. measles virus) usually produce specific IgM antibody within a few days of the onset of the rash.

• When diagnosing acute hepatitis, HBs Ag will be present at the onset of symptoms of HBV infection, but HAV IgM is not detectable until at least 5 days after the onset of symptoms.

• In general, if you are sending specimens for virus culture, send them in virus transport medium. Do not send dry swabs for virus investigations – they will almost always be discarded.

• In general, EDTA blood specimens are preferred for molecular diagnosis – but as with all test requests, check your local guidelines relating to which specimens to send when.

Molecular techniques are those that use the principles of molecular biology to detect viral genomes (RNA or DNA). The use of these techniques has been commonplace in virology and has led to the discovery of new viruses, the study of viral resistance, designing of new antiviral drugs and vaccines.

Many are in use in routine diagnostic laboratories to aid viral diagnosis. Those that are in current and common use are described.

DNA or RNA hybridization

A complementary RNA or DNA probe is used to bind to the DNA or RNA viral genome. The DNA–RNA hybrid can then be detected using a labelled monoclonal antibody. This technique can be used on tissue samples, in which case it is called in situ hybridization, or the viral genome can first be transferred on to a blotting paper (dot blot hybridization).

To obtain a positive reaction, high numbers of copies of viral DNA or RNA are required; therefore the technique is relatively insensitive and has been largely superseded by nucleic acid amplification techniques (NAATs).

Polymerase chain reaction (PCR)

This was the first NAAT to be described. It is a technique by which a single copy of DNA or RNA can be amplified more than a million times. To detect RNA viruses, RNA has to be first transcribed to complementary DNA by means of an enzyme called reverse transcriptase; this type of PCR is referred to as reverse transcription PCR (RT PCR).

The virus

Hepatitis A virus is a single-stranded RNA virus, which belongs to the genus Hepatovirus in the family Picornaviridae.

Epidemiology

Route of spread

Hepatitis A is spread by the faecal–oral route, through eating and drinking contaminated food and water, and person-to-person spread. Waterborne outbreaks have been described in countries where infection is endemic. Outbreaks have also occurred in intravenous drug users (IVDU) as a result of injecting substances reconstituted in contaminated water, and through oro–anal sex. Rarely it may be transmitted through blood transfusion through a viraemic donor.

Prevalence

In developed countries, because of good hygiene, the majority of adults have not acquired the infection, as compared to the developing countries where >90% of infection occurs in childhood. People travelling to countries with a high prevalence are therefore at risk of acquiring infection during their travel and this is the major risk factor for acquisition of infection in developed countries, most commonly by eating uncooked food e.g. salad washed in contaminated water. Shellfish grown in contaminated water are another source of hepatitis A infection, as they concentrate the virus. In Europe the prevalence of antibody in adults varies from 10–50%. People from lower socio-economic groups are more likely to have had infection.