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Diarrhoeal Diseases: Comprehensive Clinical Assessment, Rehydration, Diagnosis and Management Clinical Medicine Year 3 • acute, persistent and chronic diarrhoeal syndromes The first emergency is dehydration. Replace fluid and electrolytes immediately while investigating the cause. A stool result must never delay resuscitation in shock, severe dehydration, cholera or sepsis. Why diarrhoea is a clinical syndrome, not one diagnosis Diarrhoea can be caused by viruses, bacteria, protozoa, helminths, toxins, medicines, malabsorption, inflammation, endocrine disease or malignancy. The same patient may move from watery secretory diarrhoea to hypovolaemic shock, dysentery, haemolytic uraemic syndrome or severe malnutrition. Management starts with physiology—mental state, perfusion, urine and dehydration—then identifies the organism and the reason the illness persists. Learning outcomes Define acute, persistent and chronic diarrhoea and classify watery, inflammatory, fatty and osmotic patterns. Explain secretory, osmotic, invasive, malabsorptive and motility mechanisms. Assess dehydration and shock in adults, children, older people, pregnancy and severe malnutrition. Use Plan A, Plan B and Plan C rehydration principles and calculate ongoing losses. Recognise cholera, shigellosis, amoebiasis, enteric fever, C. difficile, giardiasis and HIV-associated diarrhoea. Choose stool, blood, electrolyte, imaging and endoscopic investigations appropriately. Use antibiotics, zinc, nutrition and infection-control measures selectively and safely. 1. Definition and classification Diarrhoea is passage of three or more loose or liquid stools in 24 hours, or more frequent stools than is normal for that person. In infants, stool frequency must be judged against the child’s usual pattern; breastfed infants normally pass soft stools. Classification Duration/appearance Main clinical question Acute diarrhoea Less than 14 days Is there dehydration, dysentery, cholera or sepsis? Persistent diarrhoea 14 days or more Is there malnutrition, HIV, parasite, post-infectious injury or inflammatory disease? Chronic diarrhoea More than four weeks Is there malabsorption, IBD, endocrine disease, malignancy or medication effect? Watery Large-volume liquid stool without visible blood Secretory toxin, virus, osmotic cause or cholera Dysentery Visible blood ± mucus, fever and tenesmus Invasive bacteria, amoebiasis, IBD or ischaemia Fatty/malabsorptive Bulky, greasy, foul, difficult-to-flush stool Giardia, pancreatic, bile or small-bowel disease 2. Causes 2.1 Infectious causes Viral: rotavirus, norovirus, adenovirus and other viruses—common in children and outbreaks. Invasive bacteria: Shigella, Campylobacter, non-typhoidal Salmonella, diarrhoeagenic E. coli, Yersinia and occasionally Vibrio. Secretory bacteria: toxigenic Vibrio cholerae, ETEC and other toxin-producing organisms. Protozoa: Entamoeba histolytica, Giardia duodenalis, Cryptosporidium, Cyclospora and Cystoisospora. Helminths and other infections: worms, HIV-associated infections, TB, CMV colitis and disseminated fungal disease. 2.2 Non-infectious causes Antibiotics and C. difficile, metformin, laxatives, magnesium, chemotherapy, inflammatory bowel disease, coeliac disease, lactose intolerance, pancreatic insufficiency, hyperthyroidism, adrenal disease, colorectal cancer, microscopic colitis, bile-acid diarrhoea, short bowel and functional disorders. 3. Pathophysiology 3.1 Secretory diarrhoea Enterotoxins activate chloride and bicarbonate secretion; water follows osmotically. Stool volume remains high even when the patient stops eating. Cholera produces massive secretory losses with bicarbonate and potassium depletion. 3.2 Osmotic diarrhoea Unabsorbed solute—lactose, poorly absorbed carbohydrates, magnesium or laxatives—retains water. Symptoms improve during fasting, although fasting is unsafe in children with acute infection. 3.3 Inflammatory/invasive diarrhoea Organisms invade mucosa or trigger cytotoxic injury, producing fever, abdominal pain, urgency, mucus, leukocytes and blood. Mucosal damage reduces absorption and can cause protein loss. 3.4 Malabsorptive diarrhoea Damage to villi or pancreatic/bile function causes bulky fatty stools, weight loss and deficiencies. Persistent infection can cause temporary lactose intolerance after mucosal injury. 3.5 The dehydration pathway Loss of water, sodium, chloride, bicarbonate and potassium reduces circulating volume. Tachycardia and thirst progress to poor perfusion, acute kidney injury, metabolic acidosis, hypoglycaemia, altered consciousness, shock and death. 4. History and examination 4.1 History Onset, frequency, volume, nocturnal symptoms, blood/mucus, tenesmus, pain and vomiting. Fever, thirst, urine amount, dizziness, fainting, confusion, seizures and weight change. Water source, sanitation, food, travel, outbreaks, sick contacts, raw milk/meat, antibiotics and healthcare exposure. HIV, pregnancy, malnutrition, diabetes, kidney/heart disease, immunosuppressants and previous bowel disease. Medication, laxative, metformin, chemotherapy and dietary history; relation to fasting or particular foods. 4.2 Examination Assess mental state, thirst, pulse, blood pressure, capillary refill, respiratory rate, temperature, oxygen saturation, mucous membranes, eyes, tears, skin pinch, peripheral temperature, abdominal tenderness/distension and bowel sounds. Record weight, urine output and stool losses. Examine for pallor, jaundice, oedema, oral thrush, perianal disease and signs of malnutrition. 5. Dehydration assessment Category Typical findings Action No dehydration Alert, drinks normally, moist mouth, normal eyes/skin, normal perfusion Plan A: extra fluids, nutrition, zinc for children, safety-net Some dehydration Restless/irritable, thirsty, sunken eyes, dry mouth, reduced tears, skin pinch slow Plan B: ORS under observation, reassess after four hours Severe dehydration/shock Lethargy/unconsciousness, unable to drink, very sunken eyes, weak pulse, cold extremities, very slow skin pinch, hypotension, oliguria Plan C: immediate IV/IO isotonic fluid, glucose/electrolytes, urgent monitoring Older people, obese patients, malnourished children and pregnant patients may not show classic skin-pinch or eye signs. Use perfusion, mental state, urine, weight change and response to fluids. 6. Rehydration plans Plan A: no dehydration Give extra safe fluid after each stool, continue breastfeeding and normal feeding, provide low-osmolarity ORS, and teach the caregiver the four rules: extra fluids, zinc for eligible children, continued feeding and when to return. Return urgently for persistent diarrhoea, increasing frequency/volume, repeated vomiting, increasing thirst, inability to drink/feed, fever, blood in stool, lethargy or worsening dehydration. Plan B: some dehydration Give ORS over approximately four hours according to the current IMNCI/WHO weight-band table, using frequent small sips and reassessing regularly. Replace ongoing stool losses, continue breastfeeding and restart normal feeds. If vomiting occurs, pause briefly and resume slowly; persistent vomiting or deteriorating mental state requires tube/IV management. Plan C: severe dehydration Start IV Ringer’s lactate or normal saline immediately. A commonly taught child protocol uses 100 mL/kg divided into 30 mL/kg then 70 mL/kg, with faster administration in older children; follow the current IMNCI table precisely for age. Give ORS by mouth or nasogastric tube as soon as the child can drink, reassess perfusion every 15–30 minutes initially and hourly thereafter, and treat hypoglycaemia, electrolyte disturbance and sepsis. If IV access is delayed: refer urgently, give ORS by mouth or nasogastric tube according to the current protocol if the airway is

Relapsing Fever: Complete Clinical Guide to Borrelia Infection Clinical Medicine Year 3 • louse-borne and tick-borne relapsing fever Clinical safety note: The first effective antibiotic dose can trigger a serious Jarisch–Herxheimer reaction. Monitor high-risk patients closely after treatment begins, especially those with hypotension, pregnancy, cardiac disease, high spirochaete burden or CNS involvement. Why the fever returns Relapsing fever is an acute infection caused by antigenically variable Borrelia spirochetes. A high-density bloodstream episode produces abrupt fever; antibodies clear one surface-antigen variant, but a new variant emerges and causes another episode. The patient may appear well between attacks, making the history of fever cycles crucial. Learning outcomes Distinguish louse-borne from tick-borne relapsing fever in organism, reservoir and transmission. Explain spirochaetaemia, antigenic variation and recurrent febrile episodes. Recognise haemorrhage, jaundice, myocarditis, shock, meningitis and pregnancy complications. Diagnose during fever using blood film, PCR or reference tests and distinguish malaria/sepsis. Start effective therapy, anticipate Jarisch–Herxheimer reaction and control vectors. 1. Organisms and epidemiological forms Feature Louse-borne relapsing fever Tick-borne relapsing fever Main organisms Borrelia recurrentis Several species; African examples include B. duttonii and B. crocidurae Vector Human body louse, Pediculus humanus corporis Soft ticks, especially Ornithodoros Reservoir Humans; louse-borne cycle is human-to-human Rodents and other animals maintain a zoonotic cycle Risk setting Overcrowding, displacement, homelessness, prisons, poor hygiene Rural/tick-infested sleeping areas, animal burrows and rodent exposure Public-health priority Delousing, hygiene, clothing/bedding and outbreak control Tick avoidance, rodent control, housing and environmental measures 2. Microbiology and transmission Borrelia are slender, actively motile spirochetes with loose coils and axial filaments. Louse-borne organisms infect lice; when an infested louse is crushed, organisms in its tissues contaminate abraded skin or mucosa. Tick-borne organisms are transmitted during the brief feeding of an infected soft tick. Unlike Lyme disease, this African relapsing-fever syndrome is often an acute high-spirochaete-burden illness. Transmission is favoured by poverty, overcrowding, poor access to bathing and laundry facilities, displacement, sleeping in rodent/tick habitats and lack of vector control. Ordinary casual contact without vector or contaminated blood exposure is not the usual route. 3. Pathogenesis and antigenic variation Inoculation through skin or mucosa is followed by rapid multiplication. High spirochaetaemia produces cytokine release, endothelial injury and the first fever. Neutralising antibodies clear the dominant surface-antigen variant, so fever falls. A new antigenic variant escapes the antibodies and multiplies, causing another febrile episode. Repeated cycles can produce three to five relapses; severe inflammation injures the myocardium, liver, brain and coagulation system. The rapid fall in organisms after antibiotics releases inflammatory products and can produce a Jarisch–Herxheimer reaction, sometimes more dangerous than the original fever. 4. Clinical presentation 4.1 Incubation and first attack Incubation is commonly 5–10 days. Fever begins abruptly, often 39–40°C, with rigors, severe headache, myalgia, arthralgia, nausea, vomiting, weakness and photophobia. Dry cough and abdominal discomfort may occur. 4.2 Physical signs Tachycardia, hypotension or a transient fall in blood pressure after rigors. Hepatomegaly, splenomegaly, jaundice and abdominal tenderness. Petechiae, epistaxis, gingival bleeding or subconjunctival haemorrhage. Confusion, meningism, cranial-nerve signs or seizures in CNS disease. Myocarditis, heart failure, arrhythmia or pulmonary oedema in severe infection. 4.3 The relapse After 3–7 days of fever, the temperature may fall with dramatic improvement. A symptom-free interval is followed by another abrupt fever when an antigenic variant emerges. Relapses may be milder or more severe and should not be mistaken for malaria treatment failure without testing. 4.4 Pregnancy and children Severe fever and spirochaetaemia may cause miscarriage, preterm birth, fetal infection or neonatal disease. Children may present with irritability, poor feeding, vomiting, seizures or shock. Use age/pregnancy-compatible treatment and refer severe cases. Danger signs: hypotension, altered consciousness, meningism, seizures, jaundice, bleeding, dyspnoea, pulmonary oedema, severe abdominal pain, oliguria, pregnancy with systemic illness or recurrent fever with shock. 5. History and examination Ask about Number, duration and spacing of fever attacks; rigors and recovery between episodes. Lice, overcrowding, homelessness, prison/displacement, infested bedding, rodents, ticks, rural sleeping and animal burrows. Bleeding, jaundice, headache, photophobia, confusion, weakness, chest pain, dyspnoea and reduced urine. Pregnancy, HIV, malaria treatment, antibiotics and contact with similar febrile patients. Examine Measure temperature repeatedly, pulse, blood pressure, respiratory rate, oxygen saturation, capillary refill, mental state, hydration and urine output. Look for lice/nits, petechiae, jaundice, hepatosplenomegaly and subconjunctival haemorrhage. Perform cardiac, respiratory and neurological examinations, including meningism and focal deficits. 6. Diagnosis 6.1 Blood during the fever Demonstration of spirochetes is most likely during a febrile episode, when organism density is high. Thick and thin blood films examined by experienced staff may show long, motile organisms; repeat films can be needed. PCR and reference laboratory methods improve confirmation. 6.2 Supporting tests FBC and platelets for anaemia, thrombocytopenia and severe disease. Glucose, electrolytes, urea/creatinine, liver tests, bilirubin and coagulation. Malaria testing, blood cultures and sepsis work-up according to local epidemiology. ECG/troponin/echo for myocarditis; chest imaging for pulmonary oedema; LP and neuroimaging for CNS signs after safety assessment. 6.3 Do not over-rely on serology Serological tests may support retrospective diagnosis but often cannot distinguish current from previous infection early enough to guide emergency care. A compatible febrile illness with exposure and spirochaetaemia deserves treatment even while confirmatory testing is pending. 7. Differential diagnosis Condition Why it resembles relapsing fever Useful distinction Malaria Rigors, fever cycles, splenomegaly, anaemia Repeated malaria tests, parasite morphology and exposure; co-infection possible Enteric fever Prolonged fever, abdominal symptoms Blood culture, bowel complications and exposure history Leptospirosis Fever, myalgia, jaundice, renal injury Water/animal urine exposure, conjunctival suffusion, renal pattern Rickettsial disease Fever, headache, vector exposure, rash Eschar/rash and serology/PCR where available Meningitis/sepsis Fever, confusion, hypotension Acute microbiology, CSF and source examination Viral haemorrhagic fever Fever, bleeding, shock Outbreak/travel history, isolation/public-health pathway and specific tests 8. Treatment Admit patients with severe disease, pregnancy, CNS signs, bleeding, hypotension, organ dysfunction or diagnostic uncertainty. Start a locally recommended effective antibiotic—options used in different protocols include doxycycline, penicillin-class therapy, ceftriaxone or another active agent—after considering pregnancy, age, CNS involvement and regional guidance. Do not delay life-saving therapy for a negative initial film. Uncomplicated adult disease Use the national recommended oral or parenteral antibiotic

Anthrax: Complete Clinical Chapter on Cutaneous, Inhalational and Gastrointestinal Disease Clinical Medicine Year 3 • zoonosis, toxin-mediated sepsis and outbreak control Anthrax is a notifiable high-consequence infection. Isolate contaminated materials, notify public health/veterinary authorities, alert the laboratory before sending specimens and begin specialist-guided therapy when clinical suspicion is high. Do not incise, biopsy or surgically debride a classic eschar before expert review. Why anthrax must be recognised early Anthrax is caused by spore-forming Bacillus anthracis. Most human disease is cutaneous and may begin with a painless itchy papule, but inhalational, gastrointestinal, oropharyngeal and injectional disease can progress rapidly to oedema, bacteraemia, meningitis, shock and death. The patient’s occupation and recent contact with livestock, hides, wool, carcasses or contaminated soil may be more diagnostic than the first physical sign. Learning outcomes Describe the organism, spores, capsule, toxins, reservoirs and routes of exposure. Recognise the clinical sequence of cutaneous, inhalational, gastrointestinal/oropharyngeal and injectional anthrax. Distinguish anthrax from cellulitis, necrotising fasciitis, plague, tularemia and other eschars. Collect specimens safely and understand laboratory confirmation. Start urgent antimicrobial, antitoxin, supportive and exposure-management measures. Plan vaccination, post-exposure prophylaxis, livestock control and outbreak communication. 1. Causative organism and virulence B. anthracis is a large, gram-positive, non-motile, non-haemolytic, spore-forming bacillus. Vegetative bacilli multiply in nutrient-rich tissues and produce a poly-D-glutamic acid capsule that inhibits phagocytosis. Spores survive for years in soil, animal products and contaminated equipment. The tripartite toxin consists of: Protective antigen: binds host cells and permits entry of the other toxin components. Edema factor: an adenylate-cyclase activity that increases intracellular cAMP and produces marked oedema. Lethal factor: disrupts signalling pathways, macrophage function and vascular stability, contributing to shock and death. 2. Reservoir and transmission Herbivores acquire spores from contaminated soil, pasture, feed or carcasses. Humans are accidental hosts. The supplied teaching deck emphasises contact with cattle, sheep, goats, horses or pigs dying of disease; contaminated hair, wool, hides, drums, brushes, rugs, bone meal and soil; inhalation during hide/wool processing; ingestion of contaminated undercooked meat; and laboratory accidents. Ordinary person-to-person spread is not expected. Route Typical exposure Resulting form Cutaneous inoculation Handling carcass, hide, wool, meat, soil or infected animal tissue Cutaneous anthrax Inhalation Aerosolised spores in tanning, wool, bone processing or laboratory work Inhalational anthrax Ingestion Contaminated undercooked meat or animal products Oropharyngeal or gastrointestinal anthrax Injection Contaminated injected drugs Severe injectional soft-tissue/systemic anthrax 3. Pathogenesis Spores enter through skin, respiratory or gastrointestinal mucosa. Macrophages transport spores to regional lymph nodes, where germination produces encapsulated bacilli and toxins. Local oedema and necrosis are followed by lymphatic spread, bacteraemia and metastatic seeding. Inhalational disease causes haemorrhagic mediastinitis and pleural effusions; meningeal invasion causes haemorrhagic meningitis. Toxin-driven capillary leak and myocardial/vascular dysfunction lead to shock. 4. Incubation and clinical forms Incubation is commonly one to seven days, but inhalational spores may remain dormant longer and illness can appear weeks after exposure. Clinical disease has a short prodrome followed by local and systemic manifestations. 4.1 Cutaneous anthrax Usually begins as an itchy, painless papule on an exposed area. It progresses to vesicle, ulcer/malignant pustule and a depressed black eschar surrounded by non-pitting gelatinous oedema. Fever, malaise, headache, regional lymphadenopathy and lymphangitis may occur. Pain out of proportion, rapidly progressive necrosis or crepitus should raise concern for an alternative or coexisting necrotising infection. Many localised lesions heal over two to six weeks, but untreated disease can progress to bacteraemia, oedema of the face/neck, respiratory compromise, meningitis and death. Facial lesions are particularly dangerous because oedema can obstruct the airway. 4.2 Inhalational anthrax The first phase resembles influenza: fever, malaise, myalgia, fatigue, dry cough, chest discomfort, nausea or mild breathlessness. After a short improvement, the patient can abruptly deteriorate with severe dyspnoea, hypoxia, cyanosis, stridor, haemoptysis, shock, confusion, widened mediastinum and pleural effusions. The absence of productive cough does not reassure. 4.3 Oropharyngeal and gastrointestinal anthrax Oropharyngeal disease produces sore throat, dysphagia, neck oedema, cervical nodes and airway risk. Intestinal disease causes severe abdominal pain, fever, vomiting, bloody diarrhoea, ascites, bowel oedema, ileus, perforation and sepsis. It may be mistaken for surgical abdomen, cholera, dysentery or food poisoning. 4.4 Injectional anthrax Injection sites may show extensive painful oedema, necrosis, bullae and systemic toxicity without the classic eschar. It progresses rapidly and requires aggressive surgical/infectious-disease assessment. Anthrax red flags: painless black eschar with disproportionate oedema; unexplained widened mediastinum; severe fever after hide/wool exposure; bloody diarrhoea with animal-meat exposure; rapidly progressive injection-site necrosis; meningism or shock. 5. History and examination 5.1 Exposure questions Was there a sudden animal death, carcass opening, home slaughter, livestock outbreak or unexplained animal bleeding? Did the patient handle hide, wool, hair, bone meal, meat, placenta, carcass or contaminated soil? Was meat eaten raw/undercooked, or was a household member exposed? Does the patient work in farming, veterinary practice, abattoirs, leather/tanning, wool, laboratories or waste disposal? Any injection-drug exposure, travel or previous anthrax vaccination/prophylaxis? 5.2 Examination Assess airway, breathing and circulation first. Inspect all skin including hidden sites; describe lesion stage, pain, oedema, vesicles, eschar, lymphangitis and regional nodes. Examine oral cavity and neck, chest for hypoxia/pleural signs, abdomen for tenderness/ascites/peritonism, skin/soft tissue, mental state and neurological function. 6. Diagnosis 6.1 Clinical diagnosis In a compatible exposure, treatment should not wait for confirmation. Anthrax is confirmed by isolation of B. anthracis, detection by validated molecular/immunofluorescence methods or a significant antibody response in an appropriate case. Tell the laboratory in advance because handling cultures can generate dangerous aerosols. 6.2 Specimens Unopened vesicle fluid or swab from beneath the lesion edge, not an aggressively scraped eschar. Multiple blood cultures before antibiotics if this does not delay life-saving treatment. Pleural fluid, CSF, respiratory specimens or tissue only with specialist guidance and safe transport. Serum for paired antibody testing in selected cases. 6.3 Imaging and severity tests Chest radiograph/CT may show widened mediastinum, pleural effusions, hilar adenopathy or infiltrates. Ultrasound/CT evaluates abdominal disease and ascites. FBC, renal/liver profile, coagulation, lactate, glucose, blood gas, ECG and cultures stage sepsis and guide supportive care. 7. Differential diagnosis Anthrax presentation Important differential Clues favouring the alternative

Brucellosis: Complete Clinical Approach to a Zoonotic Intracellular Infection Clinical Medicine Year 3 • diagnosis, focal disease, treatment and One Health prevention Laboratory safety: Tell the laboratory when brucellosis is suspected. Brucella can be aerosolised during processing and is a recognised laboratory-acquired infection. Handle cultures using appropriate biosafety procedures and involve public-health/veterinary services. Why brucellosis is easy to miss Brucellosis may be an acute febrile illness, an undulating fever lasting months, or a focal infection of the spine, sacroiliac joint, testis, brain or heart. It often resembles malaria, tuberculosis, enteric fever, endocarditis or inflammatory rheumatologic disease. A precise animal, food and occupational history is often the diagnostic turning point. Learning outcomes Identify the medically important Brucella species, reservoirs, routes of transmission and occupational risks. Explain intracellular survival, reticuloendothelial dissemination and focal complications. Recognise acute, subacute, chronic, relapsing and localised disease. Select blood cultures, serology, PCR and site-specific specimens while protecting laboratory staff. Construct combination treatment plans for uncomplicated and focal disease, including pregnancy and children. Prevent infection through pasteurisation, protective equipment, animal control, safe abortion-material disposal and One Health collaboration. 1. Definition and causative species Brucellosis is a zoonotic infection caused by small, gram-negative, non-motile, non-spore-forming coccobacilli of the genus Brucella. The bacteria are facultative intracellular organisms that survive within macrophages and cause prolonged bacteraemia and granulomatous inflammation. Species Main animal reservoir Human exposure pattern B. melitensis Goats and sheep Unpasteurised dairy, small-ruminant births; often severe human disease B. abortus Cattle and buffalo Raw milk, abattoir and veterinary exposure B. suis Pigs and wild swine Hunters, butchers, pig farmers; abscesses and focal disease B. canis Dogs Breeders, kennel workers and contact with reproductive material Other species Marine mammals and wildlife Rare, occupational or travel-associated disease 2. Reservoirs and transmission 2.1 Food-borne transmission Unpasteurised milk, fresh cheese, yoghurt, ice cream and other dairy products can contain organisms. Meat is a less efficient route when thoroughly cooked, but handling raw meat or organs can inoculate broken skin. 2.2 Occupational and environmental exposure Farmers, herders, veterinarians, animal-health workers, abattoir staff, butchers, slaughterhouse cleaners, laboratory workers, hunters and people assisting animal births have the highest risk. Placenta, aborted fetuses, lochia, vaginal secretions, milk and contaminated bedding may contain large numbers of bacteria. Aerosols can be generated in slaughter, necropsy, laboratory culture or cleaning. 2.3 Person-to-person transmission Human transmission is uncommon, but has been reported through breastfeeding, sexual contact, blood transfusion, tissue transplantation and perinatal exposure. A patient with brucellosis does not usually require respiratory isolation, but standard precautions and safe handling of blood/secretions are essential. 3. Pathogenesis and immunology Brucella enters through the gastrointestinal tract, conjunctiva, respiratory tract or skin breaks. It is taken up by macrophages and uses intracellular trafficking and stress-response mechanisms to avoid killing. It travels to lymph nodes, liver, spleen, bone marrow and reproductive organs. Cell-mediated immunity forms granulomas and may suppress but not eradicate the organism. Bacteraemic phase: fever, chills, sweats, malaise and hepatosplenomegaly. Reticuloendothelial persistence: organisms survive in macrophages, producing prolonged or relapsing fever. Focal seeding: bacteria localise in osteoarticular tissues, testes, CNS, heart valves, liver, spleen and lungs. Relapse: incomplete therapy, inadequate tissue penetration, undrained abscess or an unrecognised focus permits recurrence. 4. Clinical forms 4.1 Acute brucellosis Sudden or gradual fever, chills, drenching sweats, severe fatigue, headache, anorexia, myalgia and arthralgia may follow exposure. The fever can rise and fall (“undulant fever”), but this classic pattern is not required. 4.2 Subacute and chronic disease Patients may complain of months of fatigue, insomnia, irritability, poor concentration, low back pain, depression, weight loss and intermittent fever. Chronic disease can be disabling even when inflammatory markers are modest. 4.3 Osteoarticular brucellosis Sacroiliitis, spondylitis, vertebral osteomyelitis, peripheral septic arthritis and bursitis are the commonest focal complications. Back pain, hip/buttock pain, restricted movement, night pain, radiculopathy or weakness warrants MRI or specialist imaging. A painful joint requires aspiration to distinguish Brucella, pyogenic infection, TB and crystal disease. 4.4 Genitourinary disease Epididymo-orchitis, testicular pain/swelling, prostatitis, infertility and pelvic inflammatory symptoms occur through direct or haematogenous seeding. Testicular torsion must be excluded urgently in acute scrotal pain. 4.5 Neurobrucellosis Headache, meningism, confusion, cranial-nerve palsy, hearing loss, seizures, focal deficits, myelitis or psychiatric change may occur. CSF often shows lymphocytic inflammation and raised protein, but results can be atypical. Treatment is longer and requires agents with CNS penetration. 4.6 Endocarditis Endocarditis is uncommon but accounts for a disproportionate number of deaths. Persistent bacteraemia, new murmur, heart failure, embolic stroke, splenic infarct or glomerulonephritis should prompt transthoracic and often transoesophageal echocardiography. 4.7 Hepatosplenic and pulmonary disease Hepatitis, cholestasis, splenomegaly, hepatic/splenic abscesses, pneumonia and pleural disease are less common but important in severe infection. 4.8 Pregnancy and neonatal disease Brucellosis in pregnancy has been associated with miscarriage, preterm birth, intrauterine infection and neonatal disease. Review unpasteurised dairy and animal-birth exposure, involve obstetrics and do not rely on a single negative test. Urgent referral: new murmur/heart failure, neurological signs, severe back pain or weakness, acute scrotum, septic arthritis, shock, jaundice, splenic tenderness or pregnancy with systemic illness. 5. History and examination 5.1 Essential questions Which animals are kept, slaughtered, hunted or handled? Are goats, sheep, cattle, pigs or dogs involved? Was there contact with abortions, placenta, blood, milk, birthing fluid, carcasses or animal vaccination? Does the patient drink raw milk, eat fresh cheese or handle unpasteurised dairy? What is the occupation of the patient and household members? Any similar illness? Travel to pastoral, livestock or known endemic areas; previous brucellosis; incomplete antibiotic courses. Back/joint pain, testicular symptoms, headache, hearing/vision changes, cardiac symptoms, weight loss and night sweats. 5.2 Examination Measure fever, pulse, blood pressure, weight and mental state. Examine lymph nodes, liver, spleen, spine, sacroiliac joints, peripheral joints, skin, testes, heart (murmur/heart failure), lungs and neurological function. Look for focal tenderness rather than waiting for obvious abscesses. 6. Diagnosis 6.1 Blood culture Collect adequate blood cultures before antibiotics and warn the laboratory. Cultures may be negative after treatment or in chronic disease and may require prolonged incubation. A negative culture does not exclude brucellosis when exposure

Enteric Fever (Typhoid and Paratyphoid): Complete Clinical Diagnosis and Management Clinical Medicine Year 3 • systemic Salmonella infection, complications and prevention Clinical safety note: Use current Uganda Clinical Guidelines, the local antibiogram and culture susceptibility results when selecting antibiotics. Resistance patterns change; the antibiotic examples below are teaching principles and must not replace a current prescription protocol. Why enteric fever deserves more than a “typhoid” summary Enteric fever is a bloodstream and reticuloendothelial infection caused by human-adapted Salmonella. It can begin as an apparently mild prolonged fever, then produce intestinal ulceration, gastrointestinal haemorrhage, ileal perforation, encephalopathy, myocarditis, hepatitis, shock or chronic gallbladder carriage. The clinical pattern is modified by early antibiotics, malnutrition, HIV, age and antimicrobial resistance. The doctor’s task is to combine a careful exposure history, repeated examination, appropriate cultures, malaria and sepsis assessment, early fluids, resistance-aware antimicrobial treatment and surveillance for complications—especially after the first week of illness. Learning outcomes Define typhoid and paratyphoid fever and distinguish enteric fever from acute gastroenteritis. Describe Salmonella antigens, reservoirs, faecal–oral transmission and the pathogenesis of bacteraemia. Explain the clinical evolution through incubation, week one, week two, week three, relapse and carrier state. Take a relevant history and identify dehydration, sepsis, intestinal bleeding, perforation and encephalopathy. Interpret blood/stool/urine culture, susceptibility, full blood count, imaging and the limitations of Widal testing. Manage uncomplicated, severe, resistant, paediatric and pregnancy-associated disease and arrange surgical review when needed. Prevent outbreaks through water, sanitation, food safety, vaccination, case notification and carrier control. 1. Definition and terminology Enteric fever is a systemic febrile illness caused by Salmonella enterica serovar Typhi (typhoid fever) or serovars Paratyphi A, B or C (paratyphoid fever). It is different from non-typhoidal Salmonella gastroenteritis, which usually causes acute diarrhoea after contaminated food and does not follow the same prolonged bacteraemic course. Typhoid means disease caused by S. Typhi; paratyphoid is caused by S. Paratyphi. Clinically they overlap, and laboratory identification is needed to distinguish them. Humans are the major reservoir for both. 2. Organism and microbiology Salmonella enterica is a motile, facultative anaerobic, gram-negative bacillus in the Enterobacterales. Important surface structures include: O (somatic) antigen: part of the lipopolysaccharide cell wall; contributes to endotoxin activity and serological reactions. H (flagellar) antigen: associated with motility and antibody responses. Vi capsular antigen: particularly associated with S. Typhi, helping evade phagocytosis and complement. The Vi antigen is also the basis of typhoid conjugate vaccines. Intracellular survival: organisms can persist in macrophages and the gallbladder, allowing relapse and chronic carriage. Antimicrobial resistance may involve multidrug resistance, reduced fluoroquinolone susceptibility, extended-spectrum beta-lactamase production and extensively drug-resistant strains. Therefore, a historical “typhoid drug” is not automatically an appropriate modern treatment. 3. Epidemiology and transmission The supplied teaching deck emphasises contaminated water and food, houseflies, overcrowding, poor personal hygiene, poverty, inadequate sanitation and open defecation. Enteric fever spreads by the faecal–oral route when organisms from an infected person or carrier reach another person’s food or water. Risk setting/exposure Why risk rises Questions to ask Unsafe water Human sewage contaminates wells, springs, taps or storage containers Source, boiling/chlorination, recent water interruption Street/uncooked food Food handled after cooking or washed with contaminated water Raw vegetables, ice, milk, shellfish, vendors Household case Shared toilets, hands, food and towels Anyone with prolonged fever/diarrhoea or recent treatment? Institutional outbreak Schools, barracks, prisons, hospitals and crowded settlements amplify exposure Other students/workers affected? Chronic carrier Gallbladder colonisation causes intermittent stool shedding Food-handler occupation, recurrent family clusters Travel and resistance Imported strains may have different resistance patterns Recent travel, treatment abroad or previous antibiotics 4. Pathogenesis: why fever becomes systemic 4.1 Ingestion and intestinal invasion After ingestion, organisms must survive gastric acid. They reach the terminal ileum, attach to M cells over Peyer patches and cross the intestinal epithelium. Macrophages ingest them, but the bacteria survive and replicate inside the mononuclear phagocyte system. 4.2 Lymphatic and primary bacteraemia Organisms pass through mesenteric lymphatics to regional nodes and then the bloodstream. The early bacteraemia may be clinically silent and blood cultures can be negative. The liver, spleen, bone marrow and gallbladder become important sites of intracellular multiplication. 4.3 Secondary bacteraemia and clinical illness After replication in reticuloendothelial organs, organisms re-enter the bloodstream in larger numbers. Endotoxin and inflammatory mediators produce sustained fever, malaise, relative bradycardia in some patients and organ dysfunction. Organisms return to the intestine through bile, where Peyer patches become swollen, necrotic and ulcerated. 4.4 The ileal ulcer Longitudinal ulcers in the terminal ileum can erode vessels and cause haemorrhage. Full-thickness necrosis can perforate the bowel, releasing intestinal contents and causing peritonitis, sepsis and shock. The risk rises in untreated or late-presenting disease, often during the second or third week. 4.5 Relapse and carrier state Relapse may occur after apparent recovery, usually within weeks, and is often shorter and milder. Persistent organisms in the gallbladder—especially with gallstones—can lead to chronic carriage and faecal shedding without symptoms. 5. Incubation and clinical evolution Incubation is commonly 6–30 days but varies with inoculum, gastric acidity, immunity and previous vaccination. Antibiotics can blur the classical sequence. Week one: insidious onset Gradually increasing fever, malaise, headache, anorexia, dry cough and vague abdominal discomfort. Weakness, myalgia, sore throat or constipation may precede diarrhoea. The “step-ladder” fever pattern is a teaching classic, not a requirement. Week two: established systemic disease Persistent high fever, toxic appearance, coated tongue with a relatively clean tip, abdominal tenderness, diarrhoea or constipation. Relative bradycardia can occur but is neither sensitive nor specific. Hepatosplenomegaly and faint salmon-coloured rose spots on the trunk may appear; absence does not exclude disease. Apathy, confusion, delirium or a “typhoid state” suggests encephalopathy and severe illness. Week three: complications Untreated patients may develop intestinal bleeding, perforation, peritonitis, encephalopathy, myocarditis, hepatitis, pneumonia, renal injury, shock or disseminated intravascular coagulation. Recovery, relapse and prolonged fatigue Fever and systemic symptoms may abate over two to four weeks after effective therapy, but lethargy, weight loss and reduced concentration can persist. Relapse resembles the original illness but is commonly shorter. Persistent fever must trigger a search for resistance, a complication

Tuberculosis (TB): A Complete Clinical Guide to Pathogenesis, Diagnosis, Treatment and Prevention Clinical Medicine Year 3 • Uganda-focused, student-doctor teaching chapter Clinical safety note: This chapter is for learning and clinical reasoning. Anti-tuberculosis regimens, doses, HIV timing, preventive therapy and drug-resistant TB combinations must be checked against the current Uganda Clinical Guidelines, Uganda National TB and Leprosy Programme (NTLP) protocols, the patient’s weight, susceptibility result, pregnancy status, organ function and drug-interaction profile. Why tuberculosis deserves a full chapter Tuberculosis is not only a respiratory illness. It is a dynamic interaction between an inhaled organism, the host immune response, social conditions and the health system. A patient may have contagious cavitary pulmonary disease, a small lymph-node lesion, tuberculous meningitis, spinal cord compression, disseminated miliary disease or post-TB lung damage. The same patient may also have HIV, diabetes, malnutrition, pregnancy, renal disease or previous treatment that changes the presentation and the safest regimen. The essential clinical job is therefore broader than “give six months of tablets.” The clinician must find infectious cases early, collect the right specimen before antibiotics when possible, interpret a negative test in context, identify rifampicin resistance, assess HIV and comorbidities, start the correct regimen, support adherence, monitor toxicity, screen contacts and document the treatment outcome. Learning outcomes Define TB disease, latent TB infection, pulmonary TB, extrapulmonary TB and drug-resistant TB. Describe the microbiology of Mycobacterium tuberculosis, its transmission and its survival within macrophages. Explain the formation of the Ghon focus, primary complex, granuloma, caseation, cavitation, latency and reactivation. Recognise the clinical features of pulmonary, pleural, lymph-node, CNS, spinal, abdominal, genitourinary, pericardial, miliary and congenital/childhood TB. Take a complete TB history and perform a focused examination, including red-flag assessment. Select sputum, extrapulmonary and childhood specimens; interpret molecular tests, smear, culture, chest imaging, LF-LAM, TST/IGRA and susceptibility testing. Construct a safe management plan for drug-susceptible TB, TB/HIV, children, pregnancy, TB meningitis/pericarditis and drug-resistant TB. Recognise adverse effects, treatment failure, relapse, complications, post-TB lung disease and infection-control needs. Plan contact investigation, TB preventive treatment, vaccination, adherence support and public-health follow-up. 1. Definition and important distinctions Tuberculosis disease is illness caused by active multiplication of organisms in a person’s tissues, with symptoms, signs, microbiological evidence, imaging abnormalities or a combination of these. It can affect any organ. Latent TB infection (LTBI) means viable bacilli are contained by the immune system without clinical disease. The person has no symptoms caused by TB and does not ordinarily transmit infection, but can develop disease later if immune control weakens. Infectious TB usually refers to untreated pulmonary or laryngeal disease in which bacilli are aerosolised. Most isolated extrapulmonary disease is not transmitted person-to-person, although pulmonary involvement must be excluded. TB/HIV co-infection means both infections are present. HIV changes the probability of progression, the radiological pattern, the frequency of extrapulmonary disease, the interpretation of tests and the timing/choice of antiretroviral therapy. 2. Causative organism and microbiology 2.1 The tubercle bacillus Mycobacterium tuberculosis is a slender, aerobic, non-motile, non-spore-forming bacillus. Its lipid-rich mycolic-acid cell wall makes it “acid-fast”: once stained, it resists decolourisation by acid-alcohol. The organism grows slowly, prefers oxygen-rich tissues and can survive for years in a dormant state inside granulomas. Acid-fastness: useful for smear microscopy, but a smear shows acid-fast bacilli and cannot by itself prove that every bacillus is M. tuberculosis. Slow growth: explains why culture and some susceptibility tests take longer than molecular tests. Intracellular survival: prevents easy killing by macrophages and permits persistence in a low-metabolic state. Lipid cell wall: contributes to resistance to environmental stress and affects drug penetration. Complex rather than single species: M. tuberculosis complex includes M. bovis and related organisms; this matters for zoonotic exposure and pyrazinamide susceptibility. 2.2 Why the organism is difficult to eradicate Within one patient, bacilli may occupy different biological environments: rapidly multiplying organisms in cavities, slowly multiplying organisms in acidic necrotic tissue and dormant bacilli within granulomas. Combination therapy is required so that resistant mutants are suppressed and organisms in different compartments are treated. Poor adherence, inadequate absorption, drug interactions or an incorrect regimen can select drug resistance. 3. Epidemiology and determinants of disease The linked Uganda teaching resource describes TB as a continuing public-health emergency and highlights the current national strategy’s emphasis on rapid molecular diagnosis, shorter regimens, decentralised care and digital adherence monitoring. It identifies a high burden of TB/HIV co-infection, childhood TB and drug-resistant TB. WHO updates burden estimates annually, so students should use the latest report rather than memorising an old global number. Read the Uganda TB teaching resource. Determinant How it increases risk Clinical implication HIV infection Loss of CD4-mediated containment; rapid progression and disseminated disease Test every presumptive/diagnosed patient; look for extrapulmonary TB and opportunistic illness Young children Immature immunity and inability to expectorate sputum Household contact tracing, stool/gastric aspirate and clinical diagnosis may be needed Diabetes Impaired cellular immunity and altered pharmacokinetics Screen, optimise glucose and monitor treatment response Undernutrition Weakens immune responses and worsens drug toxicity Nutrition assessment, supplementation and weight-band dose review Silicosis/mining Damaged macrophage function and high occupational exposure Ask about mining/quarry work and screen actively Prisons, slums, refugee settlements Crowding, poor ventilation and delayed diagnosis Active case finding, ventilation, rapid isolation and contact investigation Smoking and alcohol Impaired mucociliary clearance, immunity and adherence Brief intervention and adherence support Immunosuppressive treatment Loss of granuloma integrity Screen before biologics/high-dose steroids and investigate new symptoms urgently Previous TB therapy Raises probability of acquired resistance or relapse Obtain old records and perform rapid resistance testing 4. Transmission and infection-control reasoning 4.1 How transmission occurs When a person with infectious pulmonary or laryngeal TB coughs, speaks, sings or undergoes an aerosol-generating procedure, tiny droplet nuclei containing bacilli remain suspended in air. Transmission is more likely indoors, in crowded rooms, in poor ventilation and after prolonged exposure. A brief outdoor encounter is generally much less risky than sharing a poorly ventilated sleeping room. Infection is not normally acquired from handshakes, sharing plates or touching intact skin. However, respiratory secretions and contaminated tissues still require standard infection-control precautions.

DCM 3101 • LWA 1 • Sub-topic 1.2 Factors influencing disease transmission and control Transmission is the movement of an infectious agent from a reservoir or source to a susceptible host. Control means reducing incidence, prevalence, complications and transmission; elimination and eradication are more ambitious endpoints. A clinician controls disease at the bedside and through the health system by identifying the active link in the transmission cycle. Learning outcomes Explain the epidemiological triad of agent, host and environment. Identify predisposing factors that increase acquisition or severe disease. Distinguish contact, droplet, airborne, food-borne, water-borne, blood-borne, sexual, vertical and vector transmission. Apply the chain of infection to a patient, household and health-care outbreak. Select primary, secondary and tertiary control measures and evaluate their limitations. 1. The epidemiological triad Disease patterns emerge from interaction among the agent, the host and the environment. A wet climate may increase mosquito habitat; human drainage may reduce stagnant water; altitude and temperature may alter agent survival or vector development. When the interaction remains relatively stable, disease may be endemic. When one component changes, transmission can increase or collapse. Component Factors Clinical and public-health question Agent Infective dose, survival, virulence, invasiveness, toxin production, antigenic change and antimicrobial resistance. How much exposure is required, how long does it survive, and can treatment reduce shedding? Host Age, sex, pregnancy, immunity, vaccination, nutrition, genetics, comorbidities, behaviour and access to care. Who is susceptible, who is infectious, and who needs prophylaxis or priority protection? Environment Climate, season, housing, crowding, sanitation, water, food, vectors, occupation, travel, conflict and health-care systems. What conditions allow persistence and which environmental change would interrupt transmission? 2. Predisposing factors Factor How it increases transmission or disease Examples Poor environmental sanitation Allows faecal contamination, vectors and unsafe waste disposal. Polluted water, open defecation, blocked drains, poor air quality. Poor personal hygiene Increases hand, fomite, food and contact transmission. Infrequent handwashing, unsafe food handling, shared personal items. Crowding and displacement Increases close contact, reduces isolation and disrupts health services. Refugee settlements, prisons, dormitories, mass gatherings. Substance use and risky behaviour May damage immunity, increase exposure or reduce adherence to prevention. Smoking, harmful alcohol use, unsafe injections, unprotected sex. Low vaccination and limited health access Leaves susceptible hosts and delays diagnosis, treatment and contact tracing. Missed immunisation, transport barriers, medicine stock-outs. Climate and geography Changes vector density, water safety, agent survival and population movement. Floods, drought, warm humid climates, forests and stagnant water. Host vulnerability Weakens barriers or immune responses. Infancy, old age, pregnancy, malnutrition, diabetes, HIV and immunosuppression. Socio-economic conditions Shape housing, nutrition, occupation, sanitation and ability to seek care. Poverty, overcrowded housing, hazardous work and food insecurity. 3. Modes of transmission Mode How it occurs Control examples Direct contact Infectious blood, body substances, skin or mucosa contact another person or animal directly. Gloves when indicated, wound covering, condoms, hand hygiene and safe sharps. Indirect contact Hands, surfaces, utensils, linen, phones, keyboards, taps or instruments pass organisms. Cleaning, disinfection, sterilisation, equipment separation and hand hygiene. Droplet Larger respiratory particles from cough, sneeze, talk or splash reach nearby mucosa. Source control, masks, distance, ventilation and respiratory etiquette. Airborne Small aerosols or droplet nuclei remain suspended and are inhaled over distance or time. Ventilation, respirators, appropriate isolation and reduced crowding. Food-borne Consumption of contaminated or inadequately cooked food. Safe preparation, temperature control, hand hygiene and inspection. Water-borne Consumption or use of contaminated water. Safe water, chlorination, protected wells, sanitation and outbreak response. Vector-borne A mosquito, tick, tsetse fly or other vector carries the agent biologically or mechanically. Bed nets, repellents, indoor spraying, drainage, protective clothing and case treatment. Blood-borne and sexual Blood, semen, vaginal fluid or other infectious material enters tissue or mucosa. Condoms, testing, safe injections, screened blood, PrEP/PEP where indicated. Vertical Mother-to-child transmission during pregnancy, delivery or breastfeeding. Antenatal testing, maternal treatment, safe delivery and infant prophylaxis. 4. The disease-transmission cycle The cycle links pathogen, reservoir, portal of exit, mode of transmission, portal of entry and susceptible host. A respiratory pathogen may leave through the nose, travel in droplets, enter another person’s airway and establish infection. A diarrhoeal pathogen may leave in stool, contaminate water or food, enter through the mouth and multiply in the intestine. The same principle guides both clinical precautions and community control. Break the link Agent: effective treatment, sterilisation and disinfection. Reservoir: diagnose, treat, isolate, clean the environment and manage animal sources. Portal of exit: masks, cough etiquette, wound covering, safe toilets and sharps safety. Transmission: hand hygiene, PPE, ventilation, food and water safety, vector control. Portal of entry: vaccination, barrier methods, aseptic technique and protective equipment. Susceptible host: vaccination, prophylaxis, nutrition, chronic-disease control and early care. 5. Airborne and droplet transmission in practice Droplets can deposit on the eyes, nose or mouth after sneezing, coughing, talking or splashes. Airborne aerosols remain suspended longer and may be inhaled in poorly ventilated spaces. The distinction is not merely a label: it determines room ventilation, distance, mask or respirator selection, patient placement and duration of precautions. Influenza, mumps, rubella and meningococcal disease illustrate droplet risk; tuberculosis and measles require airborne thinking. 6. Contact transmission and fomites Direct contact occurs when infectious material reaches another person through skin, mucosa, wounds or sexual contact. Indirect contact occurs through inanimate objects such as phones, keyboards, taps, linen, utensils or poorly processed instruments. Health-care workers can become a bridge between patients; hand hygiene at the correct moments and cleaning of shared equipment are high-value interventions. 7. Control and prevention Level Purpose Examples Primary prevention Prevent exposure or initial infection. Vaccination, safe water, sanitation, condoms, vector control, ventilation, nutrition and hand hygiene. Secondary prevention Detect early disease and interrupt further spread. Screening, testing, contact tracing, isolation, notification, prophylaxis and prompt treatment. Tertiary prevention Reduce complications, disability, relapse and onward transmission from chronic disease. Rehabilitation, adherence support, chronic infection care and prevention of organ damage. Control programme Reduce incidence, prevalence or impact to a planned level. Surveillance, case management, vaccination campaigns and quality improvement. Elimination Reduce transmission to zero in a defined geographic

DCM 3101 • LWA 1 • Sub-topic 1.2 Principles of infectious disease Infection is the establishment of a foreign organism in or on a host. It may remain as colonisation, progress to tissue injury and clinical disease, or become an opportunistic or endogenous infection when host defences are impaired. The clinical student must understand the organism, the host response and the transmission context together. Learning outcomes Classify infectious agents and relate their biology to clinical disease. Explain normal flora, colonisation resistance and endogenous infection. Describe the six links in the chain of infection. Explain pathogenicity, virulence factors, toxins, invasion, biofilm and intracellular survival. Relate innate and adaptive responses to fever, inflammation, organ dysfunction and recovery. 1. Infection is an interaction, not only the presence of an organism Colonisation may occur without overt tissue injury. Infectious disease occurs when the interaction between pathogen and host produces damage and clinical illness. Communicable disease is transmitted between hosts; endogenous disease arises from organisms already colonising the patient. Opportunistic infection occurs when natural defence is compromised by HIV, malnutrition, malignancy, immunosuppressive medicine, invasive devices or other conditions. 2. Groups of infectious agents Agent Key biology Clinical principle Prions Abnormally folded proteins without nucleic acid; induce abnormal folding of normal host protein. Cause transmissible spongiform encephalopathies and are not treated like bacteria or viruses. Viruses Contain DNA or RNA in a capsid, sometimes with a lipid envelope; depend on host cells for replication. Enveloped viruses are generally less environmentally stable; non-enveloped viruses often survive better on surfaces. Bacteria Prokaryotes that can synthesise proteins and nucleic acids; Gram-positive and Gram-negative cell walls differ. Capsules, plasmids, flagella, spores and endotoxin influence disease and treatment. Fungi Eukaryotes occurring as yeasts, moulds or dimorphic forms; membranes contain ergosterol and walls contain chitin or glucan. Superficial, systemic and opportunistic disease differ in host risk and therapy. Protozoa Unicellular eukaryotes, often with complex life cycles or vectors. Travel, water, food, vector and immune status guide diagnosis. Helminths Multicellular parasites including nematodes, trematodes and cestodes. Clinical disease reflects tissue migration, adult burden, eggs and host immune response. 3. Koch’s postulates and their limits Classical postulates linked a microorganism to a disease by finding it in cases, isolating it, reproducing disease in a susceptible host and recovering it again. They remain historically important but do not apply fully to organisms that cannot be cultured, agents that require specific host cells, members of normal flora or diseases with multiple causes. Modern evidence also uses molecular detection, serology, epidemiology and experimental models. 4. Normal human flora and colonisation resistance Humans carry large communities of resident and transient microorganisms. Resident flora survive and replicate at a body site; transient flora remain briefly. Normal flora can be mutualistic, commensal or parasitic depending on the interaction. They contribute vitamins, occupy attachment sites, lower local pH, produce bacteriocins and stimulate protective antibodies. Antibiotics, surgery, immune suppression and barrier damage can cause overgrowth, translocation or cross-infection. Endogenous disease Normal flora cause illness when they overgrow at their usual site, move into a normally sterile site, or are transferred to another susceptible person. Examples include vaginal thrush after antibiotics, urinary infection from enteric flora, dental caries and device-associated infection. 5. Pathogenicity, infectivity and virulence Pathogenicity is the capacity to cause disease; infectivity is the capacity to establish infection; virulence is the degree of harm. Primary pathogens can cause disease in healthy hosts; opportunistic pathogens generally require impaired defence. Virulence factors include adhesins, capsules, motility, invasins, enzymes, toxins, antigenic variation, immune evasion and mechanisms that acquire nutrients. Plasmids, bacteriophages, mutation, recombination and horizontal gene transfer can change pathogenicity and antimicrobial resistance. 6. How pathogens establish disease Adherence: adhesins bind host receptors and determine tissue tropism. Colonisation: the organism survives local pH, oxygen, nutrients, mucus, flow and competing flora. Invasion: organisms cross epithelium, enter tissue or exploit wounds, devices and injections. Multiplication and dissemination: pathogens spread through contiguous tissue, lymph, blood, nerves or vectors. Tissue injury: direct cytotoxicity, nutrient theft, obstruction, invasion, toxins or immune-mediated damage. Persistence: latency, intracellular survival, biofilm and antigenic change permit chronic or recurrent disease. 7. Toxins and microbial injury Endotoxin is chiefly a component of Gram-negative outer membrane lipopolysaccharide released during bacterial damage or lysis and causes broad inflammatory effects. Exotoxins are proteins released by living bacteria and often produce specific effects on target cells. Toxin-mediated disease may be severe even when the organism is no longer present at the site of injury. 8. Intracellular pathogens and biofilm Viruses replicate inside cells. Some bacteria, parasites and fungi survive within macrophages or other cells after phagocytosis. Biofilms are communities embedded in an extracellular matrix on teeth, prostheses, catheters and other surfaces; organisms in biofilms communicate, exchange genes and become less accessible to immune cells and antimicrobials. Device removal or source control may therefore be as important as drug choice. 9. Host defence Defence Examples Clinical importance Physical and chemical barriers Skin, mucosa, mucus, cilia, cough, gastric acid, bile, urine flow Breaks, burns, catheters, obstruction and aspiration increase risk. Normal flora Competition, pH change, bacteriocins and immune priming Antibiotics can remove colonisation resistance. Innate immunity Neutrophils, macrophages, complement, NK cells, pattern receptors and cytokines Fast response; excessive activation can injure tissue. Adaptive immunity Antibodies, B cells, T cells, memory and cellular cytotoxicity Specific protection; impaired cellular or humoral immunity changes pathogens. 10. Host response can help and harm Clinical manifestations reflect both microbial virulence and the host response. Cytokines and antimicrobial factors help contain infection but may damage tissue. Excess inflammation can cause fever, hypotension, capillary leak, thrombosis, acute lung injury and organ dysfunction. Immune reconstitution inflammatory syndrome illustrates how recovery of immune function can paradoxically worsen inflammation against a persisting pathogen. 11. Fever and systemic inflammation Microbial and endogenous pyrogens stimulate monocytes and macrophages to release cytokines such as IL-1, TNF and IL-6. These alter hypothalamic thermoregulation through prostaglandin E2. Rigors occur when the body attempts to raise its core temperature. Fever should be interpreted with age, immune status, antipyretic use, perfusion and organ function; absence of fever