Category Archives: Infectious Diseases Tropical Medicine and Sexually Transmitted Diseases

Septicaemia

The term bacteraemia refers to the transient presence of organisms in the blood (generally without causing symptoms) as a result of local infection or penetrating injury. The term septicaemia, on the other hand, is usually reserved for when bacteria or fungi are actually multiplying in the blood, usually with the production of severe systemic symptoms such as fever and hypotension. Pyaemia describes the serious situation when, in a septicaemia, organisms and neutrophil polymorphs embolize to many sites in the body causing abscesses, notably in the lungs, liver and brain. Septicaemia has an extremely high mortality and demands immediate attention. Septic shock is discussed on p. 713.

CAUSES
The term primary septicaemia is used to describe the situation when the focus of infection is not apparent. Such patients are generally elderly, undernourished or suffering from chronic disease, particularly alcoholic cirrhosis and diabetes. The common sites of infection and infective agents responsible for secondary septicaemia are shown in Tables 1.3 and 1.4. Pneumococcus and Haemophilus influenzae are common causes of septicaemia in children, whereas in neonates Gram-negative rods and group B streptococci are the most likely aetiological agents. Neisseria gonorrhoeae is a common cause of septicaemia in young adults, but it is usually mild without serious effects intravenous drug abusers frequently suffer bacteraemia and septicaemia often caused by Staph. aureus, Pseudomonas and  erratia.

Septicaemia

Septicaemia

CLINICAL FEATURES

Fever, rigors and hypotension are the cardinal features of severe septicaemia. However, the illness may be preceded by less specific symptoms such as headache, lethargy, apprehension and subtle changes in conscious level. Other clinical features and their pathogenesis are shown in Table 1.5.

INVESTIGATION

Septicaemia is almost always treated initially on the basis of a clinical diagnosis after appropriate specimens have been sent to the laboratory. Probable origins of infection and likely pathogens must be sought on the basis of a careful history and examination. The type of infection

Septicaemia in hospitalized patien

Septicaemia in hospitalized patien

Special clinical features of septicaemia.

Special clinical features of septicaemia.

will clearly differ in hospitalized and otherwise previously healthy adults (see Tables 1.3 and 1.4). Body fluids or other specimens (blood, urine, CSF, tissue or abscess aspirates) should be submitted to full microbiological examination. Imaging investigations such as ultrasonography and CT scan may be required. Catheters or cannulae, which might be sources of infection, should be removed and sent for culture.

TREATMENT

Management of septic shock is discussed on p. 720. Antibiotic therapy should be commenced immediately. If the organism and its antibiotic sensitivities are unknown, a combination of drugs should be chosen to cover the likely pathogens. If there is an obvious site of skin sepsis, drugs such as flucloxacillin (1 g 6-hourly i.v.) plus benzylpenicillin (to cover f3-haemolytic streptococci) should be used. In severe sepsis with osteomyelitis or endocarditis, an aminoglycoside to cover Staph. aureus should be used. If bowel sepsis is suspected, then a broaderspectrum drug of the cephalosporin group (e.g. cefuroxime/cefotaxime/ceftazidime) would be advisable. In the absence of any helpful clinical guidelines, a combination of a penicillin drug that is active against Pseudomonas such as piperacillin (200-300 mg kg-l daily) with an aminoglycoside such as gentamicin (3-5 mg kg-l daily in divided doses every 8 hours) should be given. Metronidazole (1 g every 8 hours by rectum) is often added to provide additional cover against anaerobic organisms. Steroids should not be used for the treatment of septicaemia or septicaemic shock.

Pyrexia of Unknown Origin (PUO)

A major diagnostic problem is the patient who has a pyrexia, either intermittent or continuous, that lasts for 2 weeks or more and in whom routine investigations have failed to reveal a cause. Pl.l O may merely be an unusual presentation of a common disease.  formation box 1.1 shows some of the common causes of pua. Age is an important pointer, since cancer and the connective tissue diseases are more common in the elderly. Immunocompromised individuals are at particular risk of infectious disease and often present with a particularly unusual spectrum of infections (see p. 100).

An aggressive approach to the diagnosis of pua is justified since there is a good chance that determination of a specific diagnosis will influence management and result in curative treatment. It is always worth repeating the history and examination since new signs may have evolved since the patient’s initial admission to hospital. All drug therapy should be reassessed and, if possible, stopped.

Infection (40%)
Pyogenic abscess, e.g. liver
Tuberculosis
Urinary infection
Biliary infection
Subacute infective endocarditis
EBV infection
CMV infection
Q fever
Toxoplasmosis
Brucellosis
Cancer (30%)
Lymphomas
Leukaemia
Solid tumours, e.g.
Renal carcinoma
Hepatocellular carcinoma
Pancreatic carcinoma
Immunogenic (20%)
Drugs
Connective tissue and autoimmune diseases, e.g.
Rheumatoid disease
Systemic lupus erythematosus
Polyarteritis nodosa
Polymyalgia/cranial arteritis
Sarcoidosis
Factitious (1-5%)
Switching thermometers
Injection of pyrogenic material
Remain unknown (5-9%)

INVESTIGATION

First-line investigations such as a full blood count, blood culture, urinalysis, routine blood chemistry and chest Xray should be repeated.

Other investigations

CT AND ULTRASOUND SCANNING are particularly valuable in revealing primary and secondary neoplastic diseases and also for showing occult abscesses. MRI is occasionally useful.

ASPIRATION OR NEEDLE BIOPSY under imaging control provides a histological diagnosis.

LAPAROSCOPY may be required to confirm a gynaecological cause, e.g. pelvic inflammatory disease, multiple peritoneal metastases or
tuberculous peritonitis.

NEEDLE BIOPSY OF THE LIVER (histology and culture) may be required to confirm granulomatous hepatitis, tuberculosis or metastatic cancer.

SCANNING WITH 59GALLIUM, which is taken up by polymorphs, or indium-Ill or technetium-labelled leucocytes, can localize an abscess.

Diagnosis

HISTORY

Particular attention should be paid to the following:

1 Age of the patient
2 Foreign travel-remembering that certain diseases can exist both in the tropics and Europe, e.g. leishmaniasis, giardiasis
3 Immigrants-country of origin
4 Food and water-food poisoning is extremely common
5 Occupation, e.g.
(a) Sheep farmers-hydatid disease
(b) Sewer workers -leptospirosis
(c) Leather workers-anthrax

6 Domestic pets, e.g.
(a) Budgerigars-psittacosis
(b) Cats-toxoplasmosis
(c) Dogs- Toxocara canis infection, rabies

7 Sexual activity-hepatitis B, mixed enteric infections and HIV should be particularly considered in male homosexuals
8 Drug addiction-consider hepatitis Band C, HIV and pyogenic infections, e.g. staphylococcal
9 Tattooing-consider hepatitis B and C, HIV
10 Injections and transfusions-may act as a route of transmission for infections
11 Immunization history, e.g. BeG

CLINICAL EXAMINATION

A general examination should be performed with particular attention to skin rashes, lymphadenopathy and hepatosplenomegaly. In cases of sexually transmitted diseases the perineum, rectum and vagina should be inspected. The presence of a fever is helpful, but less emphasis is now placed on fever patterns because of improved laboratory diagnosis. High swinging fevers are characteristically seen with localized pus.

INVESTIGATION

Tests should be performed as appropriate. If the diagnosis is obvious, e.g. a measles rash is present, no tests are necessary. The list below gives examples of situations in which tests are useful.
1 Full blood count and film are usually performed and often give a guide to the type of infection, although the changes are not invariable:

(a) Polymorphonuclear leucocytosis- bacterial infections
(b) Neutropenia – viral infections, brucellosis, typhoid, overwhelming septicaemia
(c) Lymphocytosis-viral infections, whooping cough
(d) Atypical lymphocytes-infectious mononucleosis
(e) Eosinophilia-parasitic infections, helminths

The erythrocyte sedimentation rate (ESR) and Creactive protein are usually raised.

2 Liver biochemistry is often slightly abnormal In

Diagnosis

Diagnosis

infections but this is a non-specific sign. The serum transferases are also raised in hepatitis and other liver infections.

Urine analysis
4 Chest X-ray } These should also be performed, even in the absence of symptoms and signs

Further investigations specific diagnosis:
1 Blood culture.
2 Microscopic examination and culture of appropriate body fluids, e.g. urine, faeces, eSF, sputum.
3 Viruses can be identified in the above body fluids by:

(a) Electron microscopy.
(b) Tissue culture (cytomegalovirus).
(c) Immunological antigen capture techniques (rotavirus).

4 Immunodiagnosis-immunological techniques are now available for the identification of:

(a) Pathogen-specific antigens which can be detected in body fluids using polyvalent antisera or monoclonal antibodies .

(b) Specific serological responses to infection using immunodiffusion, complement fixation, indirect haemagglutination, indirect immunofluorescence or enzyme-linked immunosorbent assay (ELISA).

A high titre of IgM specific to a pathogen (e.g. hepatitis A or B virus, cytomegalovirus) is diagnostic of a recent  infection. In infection a single raised IgG is unhelpful as this only indicates a previous rather than a current infection.

However, a rising titre can confirm the diagnosis (e.g. in brucellosis or Mycoplasma infection). These immunological techniques are particularly useful in the identification of pathogens that are difficult to culture by standard microbiological techniques or intracellular pathogens that require tissue culture.

S Tissue diagnosis-biopsy/aspiration with isolation of pathogen:

(a) Bone marrow/liver biopsy for generalized infections such as tuberculosis, leishmaniasis.
(b) Rarely, if the above technique is negative, splenic aspiration for leishmaniasis.
(c) Transbronchial biopsy for Pneumocystis carinii.

6 DNA/RNA-based techniques. Many genes encoding virulence factors and other specific proteins of pathogenic microorganisms have been cloned and sequenced. From this information DNA probes have been constructed and used for the detection of pathogen- specific DNA in body fluids or tissue. The use of amplification techniques like the polymerase chain reaction has increased the sensitivity of this approach which has already been introduced into practice.

7 Imaging procedures-ultrasound and CT scan (with needle aspiration) for abscesses in liver, lung, brain or abdomen.

Metabolic Consequences

Infection not only causes local damage but also has important generalized effects.

Fever
Body temperature is controlled by the thermoregulatory centre in the anterior hypothalamus in the floor of the third ventricle. This centre is sensitive to endogenouspyrogen (IL-1) which is released from a variety of cells involved in host defence, primarily blood monocytes and phagocytes, under the influence of microbial exogenous yrogens. IL-l is thought to act on the thermoregulatory centre by increasing prostaglandin synthesis.  The ntipyretic effect of salicylates is brought about, at least in part,
through its inhibitory effects on prostaglandin synthetase.

Fever

production is thought to have a positive effecton the course of nfection. However, for every 1°C risein temperature, there is a 13% increase in basal metabolicrate 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 nhibited in acute infections. This leads to an increasein skeletal muscle breakdown, releasing amino acids,which, via gluconeogenesis, are used to provide energy. In chronic infection there is time for adaptation and the body is able to utilize fat stores more effectively and thus weight loss is much slower.

Protein metabolism During acute infection three major changes occur in protein metabolism:

1 There is a diversion of synthesis away from somatic and circulating proteins such as albumin towards acute-phase proteins such as C-reactive protein, haptoglobin, aI-antitrypsin, caeruloplasmin and fibrinogen.

2 Protein synthesis is also directed towards immunoglobulin production and there is production of lymphocytes, neutrophils and other phagocytic cells.
3 There is a marked increase in nitrogen losses, which may reach 10-15 g per day.

Mineral metabolism and acid-base balance Mineral metabolism and acid-base balance are disturbed during acute infection. In general, sodium and water are retained, principally owing to the effects of increased levels of aldosterone and inappropriate secretion of antidiuretic hormone. During the convalescent period after a cute infection, a diuresis may occur. Acid-base balance disturbance is common, and includes respiratory alkalosis following tachypnoea related to fever, respiratory acidosis and hypoxaemia associated with pneumonia, and metabolic acidosis associated with septicaemia. In acute infection these changes are mild and resolve
promptly without specific intervention. However, in situations where infections are prolonged and resolution is slow, supportive care may be necessary, particularly with respect to managing nutritional deficits and electrolyte and acid-base disturbances.

Interaction between nutrition and infection

Undernutrition impairs host defence. Natural resistance to infection is lowered by alterations in the integrity of body surfaces, the reduced ability to repair epithelia, and the reduction in gastric acid production. In addition, immunological abnormalities are found:
MACROPHAGE FUNCTION. Tissue and circulating macrophage function is impaired.
T LYMPHOCYTE FUNCTION is depressed.
TOTAL LYMPHOCYTE COUNT is below 1 x 109 cells/litre, which is indicative of a relatively immunocompromised
host.
CELL-MEDIATED IMMUNITY is in a state of anergy, i.e. the body fails to respond to a recall antigen such as the Mantoux test.

ANTIBODY PRODUCTION is less sensitive to undernutrition, but in severe malnutrition depression in both circulating and secretory immunity are detectable. This is of importance clinically in that vaccination (e.g. against polio) may have to be more aggressive in malnutrition before protective immunity is achieved.

COMPLEMENT LEVELS fall rapidly in severe acute malnutrition and remain low during long periods of established. suboptimal nutritional status. Complement

Metabolic consequences

Metabolic consequences

levels have been used as a biochemical marker of nutritional status.

Host defence and susceptibility

Principles and Basic Mechanisms

Specificity

Some infectious agents are strictly species selective. Amoebiasis, for example, only naturally affects humans. Even within a species, relative resistance is apparent, such as the decreased susceptibility of Duffy blood group negative individuals to Plasmodium vivax malaria.

Microorganisms are also highly specific with respect to the organ or tissue that they infect. This predilection for specific sites in the body relates partly to the milieu exterieur, i.e. the immediate environment in which the organism finds itself; for example, anaerobic organisms colonize the highly anaerobic colon, whereas aerobic organisms are generally found in the mouth, pharynx and
proximal intestinal tract. Other organisms that clearly show selectivity are:

• Streptococcus pneumoniae (respiratory tract)
• Escherichia coli (urinary and alimentary tract)

Even within a species of bacterium such as E. coli; different strains will show selectivity towards a particular organ, e.g. the enterotoxigenic E. coli causes acute diarrhoeal disease, whereas the uropathogenic E. coli is responsible for urinary tract infection.

Even 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.

Epithelial attachment

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. Such is the specificity of this attachment mechanism that it limits enterotoxigenic E. coli infection, for example, to certain species.

Some viruses and protozoa (Plasmodium, Entamoeba histolytica) also interact with their target -cell surface membrane by a similar mechanism. Other parasites such as hookworm have specific attachment organelles (buccal plates) that firmly grip the intestinal epithelium.

Multiplication and colonization

These follow epithelial attachment. Pathogens may then either remain within the lumen of the organ that they have colonized or may invade the tissues.

Invasion
Invasion may result in:

1 An intracellular location for the pathogen (e.g. viruses,

Principles and Basic Mechanisms

Principles and Basic Mechanisms

Toxoplasma, Leishmania, Plasmodium)
2 An extracellular location for the pathogen (e.g. mycobacteria,
staphylococci and Entamoeba histolytica)
3 Invasion directly into the blood or lymph circulation (e.g. schistosome larvae, trypanosomes, Leishmania and Plasmodium) Once the pathogen is firmly established in its target tissue, a series of events follow that usually culminates in damage
to the host.

Tissue dysfunction or damage

The mechanism by which microorganisms produce disease has been the subject of intensive investigation and a number of well-defined mechanisms have now been described.

EXOTOXINS AND ENDOTOXINS. Microorganisms may secrete exotoxins. These have many diverse activities, including inhibition of protein synthesis (diphtheriatoxin), neurotoxicity (Clostridium perfringens, C. tetaniand C. botulinum) and enterotoxicity, which results inintestinal secretion of water and electrolytes (E. coli, v. cbolerae).Endotoxin is a lipopolysaccharide (LPS) in the cell wall of Gram-negative bacteria. It is responsible for many of the features of shock, namely hypotension, fever, intravascular coagulation and, at high doses, death.

TUMOUR NECROSIS FACTOR (TN F). This is released from a variety of phagocytic cells (macrophages/ monocytes) and non-phagocytic cells (lymphocytes, natural killer cells) in response to infections and inflammatory stimuli (Table 1.2). TNF itself then stimulates the release of a cascade of other mediators involved in inflammation and tissue remodelling, e.g. interleukin (IL-l and IL-6), prostaglandins, leukotrienes, corticotrophin. TNF is therefore responsible for many of the effects of an infection

Bacterial endotoxin (LPS)
Toxic shock syndrome toxin-l (TSST-l)
Mycobacterial cord factor (see p. 36)
Virus
Complement component CSa
Interleukin-l (tt-t)
Fungal and protozoal antigens
LPS, lipopolysaccharide.

TISSUE INVASION. Staphylococcus aureus has tissueinvasive qualities, e.g. abscess formation and bacteraemia, as well as producing toxins causing diarrhoea and a toxin responsible for a widespread erythema (staphylococcal scalded skin syndrome). Similarly, some pathogenic E. coli can produce tissue invasion without production of a specific toxin.

SECONDARY IMMUNOLOGICAL PHENOMENA. All organisms can initiate secondary immunological mechanisms, e.g. complement activation, immune complex formation and antibody-mediated cytolysis of cells.

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.

Epidemiology

The prevalence of infectious diseases varies markedly throughout the world and depends on climatic conditions, sanitation, the quality of the water supply, and to some extent the specific disease resistance of the indigenous population at risk. The continuance of infectious diseases in a human population requires:\

• Reservoirs of infection
• Effective modes of transmission

Reservoirs

HUMAN RESERVOIRS are necessary for the agents of those diseases that (under natural conditions) exclusively afflict humans. Specific examples of such diseases are hepatitis A and B, cholera and shigellosis. Many sites in the body act as permanent reservoirs for microorganisms:

• Skin, e.g. Staphylococcus epidermidis
• Nasopharynx, e.g. meningococci
• Intestinal tract, e.g. Giardia, Entamoeba histolyticaboth can continue to colonize after clinical recovery

Viruses may remain in the body for many months or years, notable examples being hepatitis B virus and the neurotropic herpesviruses.

Helminths may remain in the circulation (e.g. schistosomes in the portal vein) or lymphatic system (e.g. filarial worms) for many years, the former constantly producing millions of ova, a high proportion of which are deposited back into the environment.

ANIMAL RESERVOIRS of human disease are also important both in the developed and developing worlds. The following are common examples of zoonoses (infections that can be transmitted from animals, except arthropods, to man):

• From battery-farmed chickens-Salmonella or Campylobacter jejuni infection
• From domestic cats- Toxoplasma gondii infection
• From domestic and wild animals – Giardia infection
• From cattle-Cryptosporidium parvum infection

Diseases that rely on arthropods for their transmission include malaria, yellow fever, Dengue fever and rickettsial infections.

ENVIRONMENT RESERVOIRS may also act as a temporary lodging place for some bacteria, viruses and parasites.
Water contaminated with enteropathogens is a constant cause of concern in the tropics; water may also be a reservoir of hepatitis A virus. Cysts of some protozoa, notably Giardia, may remain viable despite apparently effective water-purification procedures.

Soil is also a source of the agents of human disease, particularly spore-forming bacteria such as Clostridium spp. and Bacillus anthracis, whose spores can remain viable under suitable climatic conditions for many months.

Transmission 

AIRBORNE SPREAD. Some viruses, bacteria and bacterial spores can be carried directly by the wind. Some are generally spread by droplets in the air, e.g. influenza viruses, and other microorganisms such as Legionella are spread by aerosol, characteristically from air-conditioning units.

SPREAD BY DIRECT CONTACT. This includes:

• Person-to-person spread, e.g. skin infections (impetigo, ringworm and scabies) and sexually transmitted diseases
• Faecal-oral spread, particularly amongst children in residential institutions, e.g. shigellosis, giardiasis and hepatitis A
• Inoculation of infection, e.g. transfusion of blood or blood products containing hepatitis B, C or HIV or by contaminated needles (drug abusers, medical and paramedical personnel)
• Insect bites, e.g. mosquitoes (leishmaniasis), ticks (babesiosis)
disease)
• Entry through the skin, which occurs with the larval forms of some helminths that can survive in soil or water, e.g. Schistosoma, Strongyloides and hookworm (malaria), sandfly and bugs (Chagas’
SPREAD BY FOOD AND WATER. Contaminated food and water is the usual mode of transmission of enteropathogens. Some bacteria, such as Shigella, require as few as 102 organisms to initiate infection, whereas others like Vibrio cholerae require approximately 108 organisms.

Cysts of parasites such as Giardia and Entamoeba histolytica can survive in water for many months and are relatively resistant to water-treatment procedures. Swimming pools are also recognized to be a source of these parasites.

SPREAD BY FOMITES. Transmission of infection can occur between persons via an inanimate object, e.g. bed linen, books.

Global Impact

Infectious diseases are the commonest afflictions of humans and are a major source of morbidity and mortality in both developed and developing countries. Table 1.1 shows estimated morbidity and mortality figures for the common infectious diseases. Increase in world travel in the past 30-40 years has brought Westerners into contact with a number of diseases unusual in the West, such as malaria and schistosomiasis.

New infective agents continue to be identified including Helicobacter pylori, the new hepatitis viruses C and E, the agent of Whipple’s disease, Tropheryma whippeii, and new diarrhoea-producing enteropathogens such as Cyclospora cayatenensis. Human immunodeficiency virus (HIV) infection continues to increase. There is an increasing problem of infections in the immunosuppressed, not only in those with HIV but also in organ transplant recipients and those receiving anticancer chemotherapy.

The control of infectious diseases worldwide has been vastly improved by the use of effective vaccines and antimicrobial agents. Technological advances in molecular

Table 1.1 League table of infectious diseases worldwide.

Table 1.1 League table of infectious diseases worldwide.

biology have also improved diagnosis, treatment and the development of new vaccines.