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Infectious diseases 13
Table 2.1 Diseases notifiable to local authority proper officers
under the Health Protection (Notification) Regulations 2010
Acute encephalitis
Acute infective hepatitis
Acute meningitis
Acute poliomyelitis
Anthrax
Botulinism
Brucellosis
Cholera
COVID-19**
Diphtheria
Ebola
Enteric fever – paratyphoid/typhoid
Food poisoning
Haemolytic uraemic syndrome (HUS)
Infectious bloody diarrhoea
Invasive group A
streptococcal disease
Legionnaires’ disease
Leprosy
*MERS, Middle East respiratory syndrome.
**COVID-19 is the notifiable disease caused by the notifiable causative agent
SARS-CoV-2.
Malaria
Measles
Meningococcal septicaemia
MERS*
Mumps
Plague
Rabies
Rubella
Scarlet fever
Severe acute respiratory syndrome
(SARS)
Smallpox
Tetanus
Tuberculosis
Typhus fever
Viral haemorrhagic fever
Viral hepatitis
Whooping cough
Yellow fever
Zika
• Radionuclide scanning. After injection of indium- or technetium-labelled
white cells (previously harvested from the patient) radionuclide scanning
may help to localize infection. It is most effective when the peripheral
white cell count (WCC) is raised, and is of particular value in localizing
occult abscesses.
• Microbiological investigations
• Microscopy and culture of blood, urine, cerebrospinal fluid (CSF) and
faeces should be performed as clinically indicated.
• Immunodiagnostic tests. These detect either a viral/bacterial antigen
using a polyvalent antiserum, a monoclonal antibody or the serological
response to infection.
• Nucleic acid detection. Nucleic acid probes can be used to detect
pathogen-specific nucleic acids in body fluids or tissue. The utility of
14 Infectious diseases
this approach has been enhanced by amplification techniques such as
the polymerase chain reaction (PCR), which increases the amount of
target DNA/RNA in the sample to be tested.
Septicaemia
• Bacteraemia refers to the transient presence of organisms in the blood
(generally without causing symptoms) as a result of local infection or
penetrating injury.
• Septicaemia is reserved for the clinical picture that results from the
systemic inflammatory response to infection.
Inflammation is normally intended to be a local and contained response
to infection. Activated polymorphonuclear leucocytes, macrophages and
lymphocytes release inflammatory mediators, including tumour necrosis
factor (TNF), interleukin-1 (IL-1), platelet-activating factor, IL-6, IL-8, interferon
and eicosanoids. In some cases, mediator release exceeds the boundaries of
the local environment, leading to a generalized response that affects normal
tissues. Clinical features include fever, tachycardia, an increase in respiratory
rate and hypotension. Septicaemia has a high mortality without treatment,
and demands immediate attention. The pathogenesis and management of
septic shock are discussed on pages 558 and 560.
Pyrexia of unknown origin
Pyrexia (or fever) of unknown origin (PUO) is defined as ‘a documented fever
persisting for >2 weeks, with no clear diagnosis despite intelligent and
intensive investigation’. Occult infection remains the most common cause
in adults (Table 2.2).
Investigations
A detailed history and examination is essential. The examination should
be repeated on a regular basis in case new clinical signs appear. First-line
investigations are usually repeated as the results may have changed since
the tests were first performed:
• FBC, including a differential WCC and blood film
• ESR and CRP
• U&Es, LFTs and blood glucose
• Blood cultures – a minimum of three sets from different sites at different
times
• Microscopy and culture of urine, sputum and faeces
• HIV testing (with appropriate consent)
• Chest X-ray.
Second-line investigations are performed in conditions that remain
undiagnosed and when repeat physical examination is unhelpful:
Infectious diseases 15
Table 2.2 Causes of pyrexia of unknown origin
Infection (20%–40%) Pyogenic abscess, e.g. liver, pelvic, subphrenic,
Malignant disease
(10%–30%)
Vasculitides (15%–20%) Adult Still’s disease
Miscellaneous
(10%–25%)
Undiagnosed (5%–25%)
epidural
Tuberculosis
Infective endocarditis
Toxoplasmosis
Viruses: Epstein–Barr, cytomegalovirus
Primary HIV infection
Brucellosis
Lyme disease
Whipple’s disease
Lymphoma
Leukaemia
Renal cell carcinoma
Hepatocellular carcinoma
Rheumatoid arthritis
Systemic lupus erythematosus
Granulomatosis with polyangiitis
Giant cell arteritis
Polymyalgia rheumatica
Drug fevers
Thyrotoxicosis
Inflammatory bowel disease
Sarcoidosis
Granulomatous hepatitis, e.g. tuberculosis,
sarcoidosis
Factitious fever (switching thermometers, injection
of pyogenic material)
Familial Mediterranean fever
• Abdominal imaging with ultrasound, CT or MRI to detect occult
abscesses and malignancy
• Echocardiography for infective endocarditis
• Biopsy of liver and bone marrow occasionally; temporal artery biopsy
(p.305) should be considered in the elderly.
16 Infectious diseases
Management
The treatment is of the underlying cause, demonstrating the importance of
the exhaustive investigations listed above to find the cause. Blind antibiotic
therapy should not be given unless the patient is very unwell. In a few
patients, no diagnosis is reached after thorough investigation and in most of
these the fever will resolve on follow-up.
COMMON VIRAL INFECTIONS
Viral infections that are confined to a single organ (or system) are discussed
in the relevant chapter, e.g. the common cold caused by one of the rhinoviruses is discussed in Chapter 11 on respiratory diseases (page 499).
Measles
Measles is caused by infection with an RNA paramyxovirus. With the introduction of aggressive immunization policies, the incidence fell in the West
(when immunization schedules were adhered to), but it remains common
in developing countries, where it is associated with a high morbidity and
mortality. One attack confers lifelong immunity. It is spread by droplet
infection and the period of infectivity is from 4 days before and up to 4
days after the onset of the rash (after which the infected person can return
to work or school).
nd
Clinical features
The incubation period is 7–18 days. Two distinct phases of the disease can
be recognized.
The pre-eruptive and catarrhal stage is characterized by fever, cough,
rhinorrhoea, conjunctivitis and pathognomonic Koplik’s spots in the mouth
(small, grey, irregular lesions on an erythematous base, commonly on the
inside of the cheek).
The eruptive or exanthematous stage is characterized by the presence
of a maculopapular rash, which starts on the face and spreads to involve
the whole body. The rash becomes confluent and blotchy. It fades in about
a week.
Complications
These are uncommon in the healthy child but carry a high mortality in
the malnourished or those with other diseases. Complications include
gastroenteritis, pneumonia, otitis media, encephalitis and myocarditis.
Rarely, persistence of the virus with reactivation pre-puberty results in
subacute sclerosing panencephalitis with progressive mental deterioration
and death.
Common Viral Infections 17
Management
The diagnosis is usually clinical but acute infection can be confirmed by
saliva or serum testing for measles-specific immunoglobulin (Ig)M. Treatment
is symptomatic. Measles vaccine is given to children of 13 months (9 months
in developing countries) to prevent infection. In some countries, including
the UK, it is given in combination with mumps and rubella vaccines (MMR).
For some patient groups who have been exposed to the virus, human normal immunoglobulin or the MMR vaccine can be used as post-exposure
prophylaxis.
nd
Mumps
Mumps is also caused by infection with a paramyxovirus, spread by droplets.
The incubation period averages 18 days.
Clinical features
It is primarily an infection of school-aged children and young adults. There
is fever, headache and malaise, followed by painful parotid gland swelling.
Less common features are orchitis, meningitis, pancreatitis, oophoritis, myocarditis and hepatitis. Sensorineural deafness is a recognized complication.
Management
Diagnosis is usually clinical. Acute infection can be confirmed by PCR
analysis of buccal mucosa or demonstration of specific IgM. Treatment is
symptomatic. The disease is prevented by administration of a live attenuated
mumps virus vaccine (as MMR, see above). Children can return to school 5
days after the onset of the swelling.
nd
Rubella
Rubella (‘German measles’) is caused by an RNA virus and has a peak age
of incidence of 15 years. The incubation period is 14–21 days. During the
prodrome the patient complains of malaise, fever and lymphadenopathy
(suboccipital, post-auricular, posterior cervical nodes). A pinkish macular
rash appears on the face and trunk after about 7 days and lasts for up to
3 days. Maternal infection during pregnancy may affect the fetus, particularly
if infection is acquired in the first trimester.
Diagnosis
The diagnosis may be suspected clinically and a definitive diagnosis is made
by demonstrating a rising serum IgG titre in paired samples taken 2 weeks
apart, or by the detection of rubella-specific IgM.
18 Infectious diseases
Management
Treatment is symptomatic. Complications are uncommon but include
arthralgia, encephalitis and thrombocytopenia. Prevention is with a live
vaccine (see Measles). Children can return to school 4 days after the onset
of the rash.
Herpes viruses
Herpes simplex virus (HSV)
The hallmark of all herpes virus infections is the ability of the viruses to
establish latent infections that persist for the life of the individual. Two types
of herpes simplex virus (HSV) have been identified:
• HSV-1 is the major cause of herpetic stomatitis, herpes labialis (‘cold
sore’), keratoconjunctivitis and encephalitis. The portal of entry is usually
via the mouth or, occasionally, the skin. The primary infection may go
unnoticed or produce an inflammatory reaction. Approximately 70% of
the population are infected with HSV-1 and recurrent infections occur
in one-third of individuals. Complications include transfer to the eye
(dendritic ulceration, keratitis), acute encephalitis, nail-bed infections
(herpetic whitlow) and erythema multiforme.
• HSV-2 is transmitted sexually and causes genital herpes, with painful
genital ulceration, fever and lymphadenopathy. Anorectal infection may
occur in male homosexuals. There may be systemic infection in the
immunocompromised host, and in severe cases death may result from
hepatitis and encephalitis.
These divisions are not rigid, because HSV-1 can also give rise to genital
herpes.
Recurrent HSV infection occurs when the virus lies dormant in ganglion
cells and is reactivated by trauma, febrile illnesses and ultraviolet irradiation.
This leads to recurrent labialis (‘cold sores’) or recurrent genital herpes.
HSV-2 is also associated with recurrent ‘aseptic’ meningitis.
Investigations
The diagnosis is often clinical. A firm diagnosis is made by detection of
virus from the lesions usually by HSV DNA detection by PCR. Herpes simplex
encephalitis is discussed on page 748.
Management
Oral aciclovir, famciclovir and valaciclovir for 5 days are useful if started while
lesions are still forming; after this time there is little clinical benefit. Longterm suppressive therapy for 6–12 months reduces the frequency of attacks
in recurrent genital herpes. Topical antiviral preparations are available but are
less effective in the treatment of anogenital lesions.
Common Viral Infections 19
Varicella zoster virus
Varicella (chickenpox)
Primary infection with this virus causes chickenpox, which may produce a
mild childhood illness, although this can be severe in adults and immunocompromised patients. Chickenpox is rarely contracted twice by the same
individual.
Clinical features. After an incubation period of 14–21 days there
is a brief prodromal period of fever, headache and malaise. The rash,
predominantly on the face, scalp and trunk, begins as macules and develops
into papules and vesicles, which heal with crusting. Complications include
pneumonia (more common in adults, particularly smokers) and central
nervous system involvement, presenting as acute truncal cerebellar ataxia
(occurring in about 1 in 1000 cases). Individuals are considered infective
for 2 days before the appearance of the vesicles until the lesions crust over.
Infectious virus is spread from the throat and from fresh skin lesions by
airborne transmission or direct contact.
Investigations. The diagnosis is usually clinical but is confirmed by
detection of viral DNA in vesicular fluid by PCR, electron microscopy or
immunofluorescence.
Management. Healthy children require no treatment. Anyone over the
age of 16 years should be considered for antiviral therapy with aciclovir
(if they present within 48 hours) because they are more at risk of severe
disease. Women in pregnancy are prone to severe chickenpox and, in
addition, there is a risk of intrauterine infection with structural damage to
the fetus. Therefore susceptible pregnant women exposed to the varicella
zoster virus should receive prophylaxis with zoster-immune immunoglobulin
(ZIG), and treatment with aciclovir if they develop chickenpox. The risk to the
fetus depends on the stage of pregnancy. Immunocompromised patients are
treated in a similar manner. A live vaccine is available for non-immune health
workers and some other specific patient groups.
Herpes zoster (shingles)
After the primary infection, the varicella virus remains dormant in dorsal
root ganglia and/or cranial nerve ganglia until reactivation causes herpes
zoster or shingles. A person with shingles (particularly if the rash is weeping) could cause chickenpox in a non-immune person after close contact
and touch.
Clinical features. Pain and tingling in a dermatomal distribution precede
the rash by a few days. The rash consists of papules and vesicles in the same
dermatome. The most common sites are the lower thoracic dermatomes and
the ophthalmic division of the trigeminal nerve.
Management. Treatment is with oral aciclovir, valaciclovir or famciclovir
given as early as possible. The main complication is post-herpetic neuralgia
(PHN), which can be severe and last for years. This can be treated with
20 Infectious diseases
amitriptyline, duloxetine, gabapentin, pregabalin or topical agents such as
capsaicin cream. The development of PHN is reduced by prompt treatment
with an antiviral agent such as aciclovir. Both recombinant and live
attenuated vaccines have been shown to reduce shingles-related morbidity
and PHN. Vaccination is recommended for all adults over the age of 70years.
Epstein–Barr virus infection
Acute Epstein–Barr virus (EBV), also referred to as infectious mononucleosis
or glandular fever, predominantly affects young adults. EBV is transmitted in
saliva and by aerosol. EBV is also the major aetiological agent responsible
for Burkitt’s lymphoma, nasopharyngeal carcinoma and post-transplant
lymphoproliferative disorders. In patients with HIV it is associated with nonHodgkin’s lymphoma and oral hairy leucoplakia.
Clinical features
Many cases of acute EBV infection are subclinical. If clinical symptoms
are present they include fever, headache, sore throat and a transient
macular rash (more common following administration of amoxicillin given
inappropriately for a sore throat). There may be palatal petechiae, cervical
lymphadenopathy, splenomegaly and hepatitis. Rare complications include
splenic rupture, myocarditis and meningitis. Cytomegalovirus (CMV), toxoplasmosis and acute HIV infection produce a similar illness.
Investigations
Atypical lymphocytes (activated CD8-positive T lymphocytes) on a peripheral blood film strongly suggest EBV infection. In association with a
compatible clinical syndrome, detection of heterophile antibodies to sheep
red blood cells (the Paul–Bunnell reaction) or horse red blood cells (the
Monospot test) is diagnostic. However, false negatives may occur in the
early stages of infection. False-positive results can occur in leukaemias,
lymphoma, systemic lupus erythematosus (SLE) and HIV infection. If the
diagnosis is in question, then measurement of EBV-specific antibodies
may be necessary. IgM and IgG antibodies against the viral capsid antigen
(VCA) are present in acute illness because of the long incubation period.
IgG to EBV nuclear antigen (EBNA) appears 6–12 weeks post infection;
therefore, a positive EBV VCA IgM and negative EBNA IgG is indicative of
acute infection. PCR can be used for EBV DNA quantification in peripheral
blood but is most useful in the assessment of lymphoproliferative disease
in the post-transplant setting.
Management
Most cases require only symptomatic treatment. Corticosteroids are considered if there is neurological involvement (encephalitis, meningitis), when
tonsillar enlargement causes airway obstruction or if there is severe aplastic
anaemia.
Bacterial Infections 21
BACTERIAL INFECTIONS
Most bacterial infections are discussed under the relevant system, e.g.
meningitis in Chapter 17, cellulitis in Chapter 18 and pneumonia in Chapter 11.
Lyme disease
Lyme disease is a multisystem inflammatory disease caused by the spirochaete Borrelia burgdorferi and occasionally other Borrelia species. Infection
is spread from deer and other wild mammals by Ixodes ticks. It is widespread
in Europe and North America and present in some parts of Asia. It is most
likely to occur in rural wooded areas in the spring and summer months.
Clinical features
• Early localized infection. The first stage, occurring usually within 1 month of
infection, is characterized by erythema migrans (EM) at the site of the tick
bite and, in some cases, constitutional symptoms. EM is pathognomonic of
Lyme disease and characterized by an erythematous rash expanding over
several days with central clearing (‘bull’s eye’ appearance).
• Early disseminated infection. The second stage follows weeks to
months later and there may be no apparent history of previous EM.
Neurological manifestations include meningoencephalitis and cranial
or polyneuropathies. Cardiac manifestations include myocarditis or
conduction defects.
• Late Lyme. This stage often presents months to years after primary
infection. Most commonly there is arthritis affecting the large joints,
in particular the knee. There may also be a subtle encephalopathy
or polyneuropathy. Acrodermatitis chronica atrophicans is a skin
manifestation seen particularly in Europe.
Patients may develop persistent non-specific symptoms following
treatment but there is no objective evidence that this is due to persistent
infection with Borrelia.
Investigations
In endemic areas, EM is pathognomonic and no further investigation is
required prior to treatment.
Serology is used to confirm early disseminated or late disease. IgM
antibodies are detectable in the first month and IgG antibodies are invariably
present late in the disease. Sensitive antibody detection tests are available
but false-positive results occur and an initial positive test should always be
followed by a confirmatory immunoblot assay.
Management
Amoxicillin or doxycycline given early in the course of the disease shortens
the duration of the illness in approximately 50% of patients. In arthritis,
22 Infectious diseases
treatment is extended to 1 month. Intravenous ceftriaxone is used for neurological or cardiac involvement. To prevent infection in tick-infested areas,
repellents and protective clothing should be worn and ticks removed
promptly from the site of a bite.
Leptospirosis
This zoonosis is caused by a Gram-negative organism, Leptospira interrogans,
which is excreted in animal urine and enters the host through a skin abrasion
or intact mucous membranes. Individuals who work with animals, take part in
water sports or have occupational exposure which bring them into close contact with rodents (e.g. freshwater swimming, sewage workers) are most at risk.
nd
Clinical features
Most cases are mild; however, some are severe and life threatening.
Following an incubation period of about 10 days the initial leptospiraemic
phase is characterized by fever, headache, malaise, myalgia and conjunctival
suffusion (redness of the conjunctiva resembling conjunctivitis but without
involving inflammatory exudates). The ‘immune phase’ follows, which is
most commonly manifested by meningism. A small proportion of cases go
on to develop hepatic and renal failure, haemolytic anaemia and circulatory
collapse (Weil’s disease). Rhabdomyolysis, myocarditis, acute respiratory
distress syndrome (ARDS) and pulmonary haemorrhage are also seen.
Investigations
Serology is most often used to confirm the diagnosis but in patients with
appropriate environmental exposure, a clinical diagnosis is made and
empirical treatment should not be delayed. Blood or CSF culture can identify
the organisms in the first week of the disease, but culture requires special
media and may take several weeks. The organism may be detected in the
urine during the second week. Specific IgM antibodies start to appear from
the end of the first week and the diagnosis is often made retrospectively
with a microscopic agglutination test (MAT) showing a fourfold rise. There
is typically a leucocytosis and, in severe infection, thrombocytopenia and an
elevated creatine phosphokinase.
Management
Oral doxycycline is given for mild disease and intravenous penicillin or ceftriaxone for more severe disease. The complications of the disease may require
renal replacement therapy or ventilatory support.
Rickettsia
Rickettsiae are small, intracellular bacteria that are spread to humans by
arthropod vectors, including body lice, fleas, hard ticks and larval mites.