Chapter 4 Infectious diseases, tropical medicine and sexually transmitted infections
‘Infection’ is defined as the process of foreign organisms invading and multiplying in or on a host. In practice, the term is usually reserved for situations in which this results in harm, rather than an infectious agent simply colonizing the host without ill effect. Infectious diseases remain the main cause of morbidity and mortality in man, particularly in developing areas where they are associated with poverty and overcrowding.
In the developed world increasing prosperity, universal immunization and antibiotics have reduced the prevalence of infectious disease. However, antibiotic-resistant strains of microorganisms and diseases such as human immunodeficiency virus (HIV) infection, variant Creutzfeldt–Jakob disease (vCJD), avian influenza and pandemic H1N1 influenza have emerged. There is increased global mobility, both enforced (as a result of war, civil unrest and natural disaster) and voluntary (for tourism and economic benefit). This has aided the spread of infectious disease and allowed previously localized pathogens such as dengue and West Nile virus to establish themselves across much wider territories. An increase in the movement of livestock and animals has enabled the spread of zoonotic diseases like monkeypox, while changes in farming and food-processing methods have contributed to an increase in the incidence of food- and water-borne diseases. Deteriorating social conditions in the inner city areas of our major conurbations have facilitated the resurgence of tuberculosis and other infections. Prisons and refugee camps, where large numbers of people are forced to live in close proximity, often in poor conditions, are providing a breeding ground for devastating epidemics of infectious disease. There are new concerns about the deliberate release of infectious agents such as smallpox or anthrax by terrorist groups or national governments.
In the developing world successes such as the eradication of smallpox have been balanced or outweighed by the new plagues. Infectious diseases cause nearly 25% of all human deaths (Table 4.1), rising to more than 50% in low income countries. Two billion people – one-third of the world’s population – are infected with tuberculosis (TB), up to 400 million people catch malaria every year and 200 million are infected with schistosomiasis. Some 500 million people are chronically infected with a hepatitis virus (either HBV or HCV) and 34 million people are living with HIV/AIDS, with 2.6 million new HIV infections in 2008 (65% in sub-Saharan Africa). Infections are often multiple and there is synergy both between different infections and between infection and other factors such as malnutrition. Many of the infectious diseases affecting developing countries are preventable or treatable, but continue to thrive owing to lack of money and political will.
|Disease||Estimated deaths (annual)|
Acute lower respiratory infection
The WHO has set eight Millennium Development Goals (MDGs), to be achieved by 2015: these include combating HIV/AIDS, malaria and other diseases. Currently, nine African and 29 non-African countries are on course to meet the malaria targets and the global incidence of TB is slowly falling. New HIV infections fell by 16% between 2000 and 2008 and antiretroviral treatment provision in low and middle income countries increased 10-fold between 2003 and 2008. A public/private partnership, the Global Fund, was established to combat AIDS, tuberculosis and malaria and has achieved much by providing the means for treatment for TB, insecticide-treated bed nets for malaria and antivirals for HIV. Several other funding streams (governmental, non-governmental and charitable) have also contributed to the fight against infection.
The impact of global warming on the spread of infection remains uncertain but may be significant. Both natural climatic events and the gradual global change in weather conditions can affect the spread and transmission of infectious diseases. Changes in temperature may directly influence the behaviour of insect vectors, while changes in rainfall may have an effect on water-borne disease. Climate change may also trigger population movement and migration, indirectly affecting infection transmission.
Prions are the most recently recognized and the simplest infectious agents, consisting of a single protein molecule. They contain no nucleic acid and therefore no genetic information: their ability to propagate within a host relies on inducing the conversion of endogenous prion protein PrPc into an abnormal protease-resistant isoform referred to as PrPSc.
Viruses contain both protein and nucleic acid and so carry the genetic information for their own reproduction. However, they lack the apparatus to replicate autonomously, relying instead on ‘hijacking’ the cellular machinery of the host. They are small (usually less than 250 nanometres (nm) in diameter) and each virus possesses only one species of nucleic acid (either RNA or DNA).
Bacteria are usually, though not always, larger than viruses. Unlike the latter they have both DNA and RNA, with the genome encoded by DNA. They are enclosed by a cell membrane and even bacteria which have adopted an intracellular existence remain enclosed within their own cell wall. Bacteria are capable of fully autonomous reproduction and the majority are not dependent on host cells.
Eukaryotes are the most sophisticated infectious organisms, displaying subcellular compartmentalization. Different cellular functions are restricted to specific organelles, e.g. photosynthesis takes place in the chloroplasts, DNA transcription in the nucleus and respiration in the mitochondria. Eukaryotic pathogens include unicellular protozoa, fungi (which can be unicellular or filamentous) and multicellular parasitic worms.
Each of us is colonized with huge numbers of microorganisms (1014 bacteria, plus viruses, fungi, protozoa and worms) with which we co-exist. The relationship with some of these organisms is symbiotic, in which both partners benefit, while others are commensals, living on the host without causing harm. Infection and illness may be due to these normally harmless commensals and symbiotes evading the body’s defences and penetrating into abnormal sites. Alternatively, disease may be caused by exposure to exogenous pathogenic organisms which are not part of our normal flora.
The symptoms and signs of infection are a result of the interaction between host and pathogen. In some cases, such as the early stages of influenza, symptoms are almost entirely due to killing of host cells by the invading organism. Usually, however, the harmful effects of infection are due to a combination of direct microbial pathogenicity and the body’s response to infection. In meningococcal septicaemia, for example, much of the tissue damage is caused by cytokines released in an attempt to fight the bacteria. The molecular mechanisms underlying host-pathogen interactions are discussed in more detail on page 78.
The endogenous skin and bowel commensals can cause disease in the host, either because they have been transferred to an inappropriate site (e.g. bowel coliforms causing urinary tract infection) or because host immunity has been attenuated (e.g. candidiasis in an immunocompromised host). Many infections are acquired from other people, who may be symptomatic themselves or be asymptomatic carriers. Some bacteria, like the meningococcus, are common transient commensals, but cause invasive disease in a small minority of those colonized. Infection with other organisms, such as the hepatitis B virus, can be followed in some cases by an asymptomatic but potentially infectious carrier state.
Zoonoses are infections that can be transmitted from wild or domestic animals to man. Infection can be acquired in a number of ways: direct contact with the animal, ingestion of meat or animal products, contact with animal urine or faeces, aerosol inhalation, via an arthropod vector or by inoculation of saliva in a bite wound. Many zoonoses can also be transmitted from person to person. Some zoonoses are listed in Table 4.2.
Most microorganisms do not have a vertebrate or arthropod host but are free-living in the environment. The vast majority of these environmental organisms are non-pathogenic, but a few can cause human disease (Table 4.3). Person-to-person transmission of these infections is rare. Some parasites may have a stage of their life cycle which is environmental (e.g. the free-living larval stage of Strongyloides stercoralis and the hookworms), even though the adult worm requires a vertebrate host. Other pathogens can survive for periods in water or soil and be transmitted from host to host via this route (see below): these should not be confused with true environmental organisms.
|Organism||Disease (most common presentations)|
Lung infection in cystic fibrosis
Legionnaires’ disease (pneumonia)
Mycobacteria other than tuberculosis (MOTT)
Local and disseminated infection
Meningitis, pulmonary infection
Mucormycosis (rhinocerebral, cutaneous)
The body’s own endogenous flora can cause infection if the organism gains access to an inappropriate area of the body. This can happen by simple mechanical transfer, e.g. colonic bacteria entering the female urinary tract. The nonspecific host defences may be breached, for example, by cutting or scratching the skin and allowing surface commensals to gain access to deeper tissues; this is frequently the aetiology of cellulitis. There may be more serious defects in host immunity owing to disease or chemotherapy, allowing normally harmless skin and bowel flora to produce invasive disease.
Many respiratory tract pathogens are spread from person to person by aerosol or droplet transmission. Secretions containing the infectious agent are coughed, sneezed or breathed out and are then inhaled by a new victim. Some enteric viral infections may also be spread by aerosols of faeces or vomit. Environmental pathogens such as Legionella pneumophila and zoonoses such as psittacosis, are also acquired by aerosol inhalation, while rabies virus may be inhaled in the dust from bat droppings.
Transmission of organisms by the faeco-oral route can occur by direct transfer (usually in small children), by contamination of clothing or household items (usually in institutions or conditions of poor hygiene) or most commonly via contaminated food or water. Human and animal faecal pathogens can get into the food supply at any stage. Raw sewage is used as fertilizer in many parts of the world, contaminating growing vegetables and fruit. Poor personal hygiene can result in contamination during production, packaging, preparation, or serving of foodstuffs. In the western world, the centralization of food supply and increased processing of food has allowed the potential for relatively minor episodes of contamination to cause widely disseminated outbreaks of food-borne infection.
Water-borne faeco-oral spread is usually the result of inadequate access to clean water and safe sewage disposal and is common throughout the developing world. Worldwide, 1.1 billion people have no access to clean water and 2.6 billion do not have basic sanitation.
Many tropical infections, including malaria, are spread from person to person or from animal to person by an arthropod vector. Vector-borne diseases are also found in temperate climates, but are relatively uncommon. In most cases part of the parasite life cycle takes place within the body of the arthropod and each parasite species requires a specific vector. Simple mechanical transfer of infective organisms from one host to another can occur, but is rare. Some vector-borne diseases are shown in Table 4.4.
Wuchereria bancrofti, Brugia malayi
West Nile fever
Louse-borne relapsing fever
Typhus (spotted fever group)
Tick-borne relapsing fever
Congo-Crimean haemorrhagic fever
Organisms can be passed on directly in a number of ways. Sexually transmitted infections are dealt with on page 160. Skin infections such as ringworm, and ectoparasites such as scabies and head lice, can be spread by simple skin-to-skin contact. Other organisms are passed on by blood- (or occasionally other body fluid) to-blood transmission. Blood-to-blood transmission can occur during sexual contact, from mother to infant either transplacentally or in the peripartum, between intravenous drug users sharing any part of their injecting equipment, when infected medical or other (e.g. tattoo needles) equipment is reused, if contaminated blood or blood products are transfused, or in any sporting or accidental contact when blood is spilled. Ingestion of infected breast milk is another route of person-to-person spread for some infections (e.g. HIV).
Infection can occur when pathogenic organisms breach the normal mechanical defences by direct inoculation. Some of the circumstances in which this can occur are covered under endogenous infection and blood-to-blood transmission above. Some environmental organisms may be inoculated by accident: this is a common mode of transmission of tetanus and certain fungal infections. Rabies virus may be inoculated by the bite of an infected animal.
Although many food-related zoonotic infections are due to contamination of food with animal faeces (and are thus, strictly speaking, faeco-oral), several diseases are transmitted directly in animal products. These include some strains of Salmonella (eggs, chicken meat), brucellosis (unpasteurized milk) E. coli and the prion diseases kuru and vCJD (neural tissue).
Infection control measures. Poor infection control practice in hospitals and other healthcare environments can cause the transfer of infection from person to person. This may be air-borne, via fomites or a direct contact route. It is essential that all healthcare workers wash or clean their hands before and after patient contact and whenever necessary they should wear gloves, aprons and other protective equipment. This is particularly necessary when performing invasive procedures, or manipulating indwelling devices such as cannulae.
Eradication of reservoir. In a few diseases, for which man is the only natural reservoir of infection, it may be possible to eliminate disease by an intensive programme of case finding, treatment and immunization. This has been achieved in the case of smallpox. If there is an animal or environmental reservoir, complete eradication is unlikely, but local control methods may decrease the risk of human infection (e.g. killing of rodents to control plague, leptospirosis and other diseases).
In recent years, the burden of morbidity, mortality and cost attributed to healthcare-associated infection has been highlighted in many developed countries. Although data from low income countries are lacking the impact of HCAI is likely to be even greater. Clostridium difficile, Staphylococcus aureus (especially MRSA), vancomycin-resistant enterococci and multiresistant Gram-negative organisms are all strongly associated with healthcare contact and are an increasing problem in hospitals worldwide. In the UK, the Department of Health estimates the risk of acquiring HCAI in a healthcare facility to be 6–10%, with HCAIs costing the NHS up to £1 billion per year. The response to HCAIs needs to be multifaceted. High standards of basic infection control (isolation, barrier precautions, hand hygiene and cleaning) need to be combined with decreased use of invasive devices such as vascular cannulae and urinary catheters, with better insertion and care standards when these are used. Antibiotic stewardship, with reduced overall usage and restriction of broad-spectrum agents, is essential to minimize antimicrobial resistance. There are already data to suggest that reduction in the use of cephalosporins has reduced the incidence of C. difficile. Often a combination of different methods can be used together to reduce a particular risk (e.g. ventilator-associated pneumonia): the so-called ‘care bundle’ approach.
Common source where there is a single source of infection but over a period of time, e.g. a symptomatic carrier of infection working with food preparation. Many people will be exposed over a long period of time.
Cases of some infectious diseases should be notified to the public health authorities so that they are aware of cases and outbreaks. Diseases that are notifiable in England and Wales are listed in Table 4.5.
Man constantly interacts with the world of microorganisms from birth to death. The majority cause no harm and some play a role in the normal functioning of the mouth, vagina and intestinal tract. However many microorganisms have the potential to produce disease. This may result from inoculation into damaged tissues, tissue invasion, a variety of virulence factors, or toxin production.
Microorganisms are often highly specific with respect to the organ or tissue they infect (Fig. 4.1). For example, a number of viruses are hepatotropic, such as those responsible for hepatitis A, B, C and E and yellow fever. This predilection for specific sites in the body relates partly to the presence of appropriate receptors on different cell types and partly to the immediate environment in which the organism finds itself; e.g. anaerobic organisms colonize the anaerobic colon, whereas aerobic organisms are generally found in the mouth, pharynx and proximal intestinal tract. Other organisms that show selectivity include:
Even within a species of bacterium such as E. coli, there are clear differences between strains with regard to their ability to cause gastrointestinal disease (see p. 110), which in turn differ from uropathogenic E. coli responsible for urinary tract infection.
Within an organ a pathogen may show selectivity for a particular cell type. In the intestine, for example, rotavirus predominantly invades and destroys intestinal epithelial cells on the upper portion of the villus, whereas reovirus selectively enters the body through the specialized epithelial cells, known as M cells that cover the Peyer’s patches (see p. 262).
Figure 4.2 summarizes some of the steps that occur during the pathogenesis of infection. In addition, pathogens have developed a variety of mechanisms to evade host defences. For example, some pathogens produce toxins directed at phagocytes: Staphylococcus aureus (α-toxin), Streptococcus pyogenes (streptolysin) and Clostridium perfringens (α-toxin), while others such as Salmonella spp. and Listeria monocytogenes can survive within macrophages. Several pathogens possess a capsule that protects against complement activation (e.g. Strep. pneumoniae). Antigenic variation is an additional mechanism for evading host defences that is recognized in viruses (antigenic shift and drift in influenza), bacteria (flagella of salmonella and gonococcal pili) and protozoa (surface glycoprotein changes in Trypanosoma).
Many bacteria attach to the epithelial substratum by specific organelles called pili (or fimbriae) that contain a surface lectin(s) – a protein or glycoprotein that recognizes specific sugar residues on the host cell. This family of molecules is known as adhesins (see p. 23). Following attachment, some bacteria, such as species of coagulase-negative staphylococci, produce an extracellular slime layer and recruit additional bacteria, which cluster together to form a biofilm. These biofilms can be difficult to eradicate and are a frequent cause of medical device-associated infections which affect prosthetic joints and heart valves as well as indwelling catheters. Many viruses and protozoa (e.g. Plasmodium spp., Entamoeba histolytica) attach to specific epithelial target-cell receptors. Other parasites such as hookworm have specific attachment organs (buccal plates) that firmly grip the intestinal epithelium.
Exotoxins have many diverse activities including inhibition of protein synthesis (diphtheria toxin), neurotoxicity (Clostridium tetani and C. botulinum) and enterotoxicity, which results in intestinal secretion of water and electrolytes (E. coli, Vibrio cholerae). Colonization and secretion in many classical diarrhoeal diseases is the result of virulence-associated genes which encode protein secretion systems (Fig. 4.3).
Endotoxin is a lipopolysaccharide (LPS) in the cell wall of Gram-negative bacteria. It is responsible for many of the features of septic shock (see p. 881), namely hypotension, fever, intravascular coagulation and, at high doses, death. The effects of endotoxin are mediated predominantly by release of tumour necrosis factor.
Figure 4.3 Protein secretion pathways for Gram-negative bacteria. These specialized pathways are necessary for virulence. Types I and II facilitate protein (toxin) secretion into the extracellular space (Type I). Type II does this in two stages. Types III and IV pathways secrete toxins as well as inject toxins directly into the host cells via multiprotein complexes across the bacterial cell envelope and host cell membrane. Type V is a minor variation of Type II. Type VI pathway is unclear but is involved in cytotoxicity.
(Reproduced with permission from Yarh TL. A critical new pathway for toxin secretion? New England Journal of Medicine 2006; 355:1171–1172.
Staphylococcus aureus presents an excellent example of the repertoire of microbial virulence. The clinical expression of disease varies according to site, invasion and toxin production and is summarized in Table 4.6. Furthermore, host susceptibility to infection may be linked to genetic or acquired defects in host immunity that may complicate intercurrent infection, injury, ageing and metabolic disturbances (Table 4.7).
The natural host defences to infection are those of an intact surface epithelium with local production of secretions, antimicrobial enzymes (e.g. lysozyme in the eye) and in the stomach, gastric acidity. The mucociliary escalator of the large airways is unique to the lung.
Antibody and cell-mediated immune mechanisms play a vital role in combating infection. All organisms can initiate secondary immunological mechanisms, such as complement activation, immune complex formation and antibody-mediated cytolysis of cells. The immunological response to infection is described in Chapter 3.
Body temperature is controlled by the thermoregulatory centre in the anterior hypothalamus in the floor of the third ventricle. Body temperature is maintained at 36.8°C in health, with a diurnal variation of ±0.5°C. Gram-negative bacteria contain lipopolysaccharide (LPS) and peptidoglycan, which is also a component of Gram-positive bacterial cell walls. Toll-like receptors (TLR, see p. 55) on monocytes and dendritic cells recognize these lipopolysaccharides and generate signals leading to formation of inflammatory cytokines, e.g. IL-1, -6, -12, TNF-α and many others. These cytokines act on the thermoregulatory centre by increasing prostaglandin (PGE2) synthesis. The antipyretic effect of salicylates is brought about, at least in part, through its inhibitory effects on prostaglandin synthase.
Fever production has a positive effect on the course of infection. However, for every 1°C rise in temperature, there is a 13% increase in resting metabolic rate and oxygen consumption. Fever therefore, leads to increased energy requirements at a time when anorexia leads to decreased food intake. The normal compensatory mechanisms in starvation (e.g. mobilization of fat stores) are inhibited in acute infections. This leads to an increase in skeletal muscle breakdown, releasing amino acids, which, via gluconeogenesis, are used to provide energy.
The inflammatory response is a fundamental biological response to a variety of stimuli including microorganisms or their products, such as endotoxin which acts on monocytes and macrophages. Non-phagocytic cells (lymphocytes, natural killer cells) are also involved. The release of cytokines, notably TNF-α, IL-1, IL-6 and interferon-γ, leads to the release of a cascade of other mediators involved in inflammation and tissue remodelling, such as interleukins, prostaglandins, leukotrienes and corticotropin. TNF is therefore responsible for many of the effects of an infection.
The biological behaviour of the pathogen and the consequent host response are responsible for the clinical expression of disease that often allows clinical recognition. The incubation period following exposure can be helpful (e.g. chickenpox 14–21 days). The site and distribution of a rash may be diagnostic (e.g. shingles), while symptoms of cough, sputum and pleuritic pain point to lobar pneumonia. Fever and meningismus characterize classical meningitis. Infection may remain localized or become disseminated and give rise to the sepsis syndrome and disturbances of protein metabolism and acid–base balance (see Ch. 16). Many infections are self-limiting and immune and non-immune host defence mechanisms will eventually clear the pathogens. This is generally followed by tissue repair, which may result in complete resolution or leave residual damage.
Infectious diseases can affect any organ or system and can cause a wide variety of symptoms and signs. Fever is often regarded as the cardinal feature of infection, but not all febrile illnesses are infections and not all infectious diseases present with a fever. History-taking and examination should aim to identify the site(s) of infection and also the likely causative organism(s).
Sexual activity: as well as the traditional sexually transmitted diseases, HIV, hepatitis B and occasionally other blood-borne infections can be transmitted sexually. Some enteric infections are more common among men who have sex with men.
Intravenous drug use: as well as blood-borne viruses, drug injectors are susceptible to a variety of bacterial and fungal infections due to inoculation. Other needle exposures, such as tattooing and body piercing and receipt of blood products (especially outside the UK), are also risk factors for blood-borne viruses.
A thorough examination covering all systems is required. Skin rashes and lymphadenopathy are common features of infectious diseases and the ears, eyes, mouth and throat should also be inspected. Infections commonly associated with a rash are listed in Box 4.1. Rectal, vaginal and penile examination is required in sexually transmitted infections. The fever pattern may occasionally be helpful, e.g. the tertian fever of falciparum malaria, but too much weight should not be placed on the pattern or degree.
Infections commonly associated with a rash