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The 2016 Sepsis-3 consensus shifted the diagnostic emphasis from systemic inflammation to life-threatening organ dysfunction arising from a dysregulated response to infection. Fever, tachycardia and leucocytosis are insufficiently specific to distinguish uncomplicated infection from sepsis when considered alone. Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Operationally, this means an acute rise of two or more points in the Sequential Organ Failure Assessment score. Septic shock is the subset in which, despite adequate fluid resuscitation, vasopressors are required to maintain a mean arterial pressure of 65 mmHg or above and the serum lactate exceeds 2 mmol/L. At the bedside, the quick SOFA screen flags a systolic pressure of 100 mmHg or below, a respiratory rate of 22 or more, and altered mentation. Two of these three should prompt escalation.

The haemodynamic signature of septic shock follows directly from its molecular chain. Pathogen-associated molecular patterns, together with damage-associated patterns from injured cells, are recognised by toll-like receptors, of which TLR4 binds endotoxin. Recognition activates NF-κB, and macrophages and endothelium release TNF-α, IL-1β and IL-6 in a cytokine storm. These cytokines induce nitric oxide synthase, while complement C5a and platelet-activating factor amplify the injury. The result is generalised vasodilatation, capillary leak and third-space loss. Cardiac output is consequently normal or high, systemic vascular resistance collapses, and the patient presents with warm peripheries and a bounding pulse despite hypotension. Lactate accumulates because perfusion, not oxygen content, has failed.

The Surviving Sepsis Campaign condenses the first hour into a bundle whose order carries its logic. Lactate is measured first because it reflects perfusion. Blood cultures are drawn before antibiotics, since a single dose can sterilise them. Broad-spectrum antibiotics follow within one hour for probable sepsis or shock, because each hour of delay increases mortality. For hypotension or a lactate of 4 mmol/L or above, 30 mL/kg of balanced crystalloid is given rapidly to restore preload. If pressure remains low after fluid, vasopressors are titrated to a mean arterial pressure of at least 65 mmHg.

Noradrenaline is the first-line vasopressor. Vasopressin is added when the noradrenaline dose climbs, and intravenous hydrocortisone is considered when the requirement persists. Sodium bicarbonate is not a treatment for hypoperfusion-induced lactic acidosis. The 2021 guideline reserves it for severe acidaemia with a pH of 7.2 or below in the setting of acute kidney injury.

Source determines the organism, and the organism determines the drug. In cirrhosis, a failing gut barrier allows enteric bacteria to translocate into ascites, so spontaneous bacterial peritonitis is dominated by Gram-negative bacilli such as Escherichia coli and Klebsiella. An ascitic neutrophil count of 250 cells per cubic millimetre or more is diagnostic, and cefotaxime is the empirical choice. Albumin at 1.5 g/kg on day one and 1 g/kg on day three reduces renal failure and mortality. Cellulitis, by contrast, is diagnosed clinically, because tissue culture is positive in only 20 to 30 per cent of cases.

All patients with suspected sepsis have lactate measured and cultures drawn before antibiotics, which must start within one hour.
Is the mean arterial pressure still below 65 mmHg after 30 mL/kg of crystalloid? Then noradrenaline is the first-line vasopressor.
On Sepsis-3 criteria, septic shock means vasopressor dependence plus a lactate above 2 mmol/L, not a count of inflammatory signs.
Lumen to peritoneum, enteric Gram-negative bacilli cause spontaneous bacterial peritonitis, diagnosed at 250 neutrophils and treated with cefotaxime.

Human immunodeficiency virus exploits cells central to adaptive immunity, converting their molecular machinery into a means of viral replication. Entry begins when the envelope glycoprotein gp120 binds the CD4 receptor. A conformational change then exposes the co-receptor binding site. Macrophage-tropic strains use CCR5, whereas T-cell-tropic strains use CXCR4, and gp41 drives fusion of the viral and cellular membranes. Reverse transcriptase copies the RNA genome into DNA, and integrase inserts it into the host chromosome as a provirus. People homozygous for the CCR5 delta-32 deletion resist R5 strains, and maraviroc mimics that deletion pharmacologically. Years of chronic viraemia follow, during which billions of virions are produced daily and CD4 cells are progressively depleted.

Diagnosis depends on knowing what each assay can and cannot see. The fourth-generation antigen and antibody immunoassay is highly sensitive but not confirmatory, so a reactive result requires a differentiation assay or Western blot before notification. In acute infection, antibody and even p24 antigen may be absent for the first weeks. Only HIV RNA reliably detects this window, and it should be requested whenever a compatible illness follows a recent exposure.

The CD4 count is a clock, and each threshold uncovers a different pathogen. Below 200 cells per microlitre, Pneumocystis pneumonia appears, prevented and treated with co-trimoxazole. Below 100, Toxoplasma encephalitis and cryptococcal meningitis emerge. Below 50, cytomegalovirus retinitis and disseminated Mycobacterium avium complex follow. Tuberculosis, candidiasis, zoster and Kaposi sarcoma can occur at any count. A CD4 count below 200 defines AIDS by itself. Non-Hodgkin lymphoma, Kaposi sarcoma and invasive cervical cancer are AIDS-defining, whereas Hodgkin lymphoma, although more frequent, is not.

Antiretroviral therapy should start as soon as possible after diagnosis, regardless of CD4 count. Current Australian guidance prefers an integrase inhibitor such as bictegravir combined with emtricitabine and tenofovir alafenamide. Sustained suppression restores CD4 cells and eliminates sexual transmission. The PARTNER studies recorded no linked transmissions from partners with an undetectable viral load, the basis of undetectable equals untransmittable. Without treatment, vertical transmission occurs in about 25 to 30 per cent of pregnancies. With suppressive therapy it falls below one per cent.

Tuberculosis co-infection demands sequencing. Tuberculosis treatment starts first, and antiretroviral therapy follows within two weeks when the CD4 count is below 50. At higher counts it may be started within eight weeks, but tuberculous meningitis is the exception. There, therapy is deferred for four to eight weeks because intracranial immune reconstitution raises mortality. Rifampicin, a potent CYP3A4 inducer, renders boosted protease inhibitors sub-therapeutic. Rifabutin, or an alternative regimen, is substituted.

All reactive HIV screening tests require a confirmatory assay, and acute infection is detected by HIV RNA rather than antibody.
Is the CD4 count below 200? Then Pneumocystis prophylaxis with co-trimoxazole begins, and below 100 the same drug covers Toxoplasma.
On treatment, an undetectable viral load sustained for six months means the virus cannot be transmitted sexually.
Lucid rule for tuberculosis: start antiretrovirals within two weeks when the CD4 count is below 50, but wait four to eight weeks in meningitis.

The classical hypersensitivity framework organises immune-mediated injury by the effector involved, the target recognised and the mechanism through which damage occurs. The Gell and Coombs framework yields four answers. Type I is immediate and IgE-mediated, acting through mast cells within minutes. Type II is antibody directed at cell-surface antigens, either destroying the cell through complement or antibody-dependent cytotoxicity, or altering receptor function. Graves disease and myasthenia gravis belong here, not to Type I or III. Type III is deposition of immune complexes, recruiting complement and neutrophils over days, as in serum sickness and lupus. Type IV alone is antibody-independent. T cells and macrophages produce contact dermatitis, the tuberculin response and graft rejection at 48 to 72 hours.

Type I hypersensitivity is a two-act play. In the sensitisation phase, dendritic cells present the allergen to naive CD4 cells in an IL-4-rich environment, which drives differentiation towards Th2. IL-4 instructs B cells to switch class to IgE. That IgE occupies the high-affinity receptor FcεRI on mast cells and basophils and waits. On re-exposure the allergen cross-links adjacent IgE molecules and triggers degranulation. Preformed histamine and tryptase are released at once, while leukotrienes C4 and D4 and prostaglandins are synthesised within minutes. Smooth muscle contracts, vessels dilate and leak, and mucus pours. Four to eight hours later, IL-5 recruits eosinophils for the late-phase response. The immediate and late phases are therefore one mechanism in two tempos, not two types.

Anaphylaxis is that mechanism expressed systemically, and its treatment has a single first line. Adrenaline at 0.01 mg/kg, to a maximum of 0.5 mg of the 1:1000 solution, is injected intramuscularly into the anterolateral thigh and repeated every five minutes if needed. Alpha-1 stimulation restores vascular tone, beta-1 supports the heart, beta-2 relaxes bronchi, and mast cell release is suppressed. The patient lies flat, because standing can precipitate cardiovascular collapse. Oxygen and 20 mL/kg of crystalloid follow for hypotension. Antihistamines relieve only itch, corticosteroids have no proven role, and intravenous bolus adrenaline is reserved for cardiac arrest. Serum tryptase within one to two hours, compared with a baseline sample, confirms mast cell degranulation.

Not every swelling is histamine. Chronic spontaneous urticaria itches, wheals and responds to second-generation antihistamines, escalated to four times the licensed dose and then omalizumab. Hereditary angioedema, by contrast, is painless, non-itchy and unresponsive to antihistamines, because deficient C1 inhibitor allows bradykinin to accumulate. A low C4 level screens for it, and treatment is C1 inhibitor concentrate or icatibant.

Allergic diseases are rising as environments become cleaner. The hygiene hypothesis proposes that reduced microbial exposure in infancy leaves Th1 immunity underdeveloped and tilts the balance towards Th2. Prolonged antibiotic use therefore increases, rather than reduces, the risk of asthma. House dust mite remains the most important inhaled allergen, and it is visible under an ordinary light microscope.

All patients with anaphylaxis receive intramuscular adrenaline 0.5 mg into the thigh first, lying flat, with antihistamines and steroids as adjuncts only.
Is the swelling painless, non-itchy and unresponsive to antihistamines? Then suspect bradykinin-mediated hereditary angioedema and check C4.
On re-exposure, allergen cross-links IgE on FcεRI, releasing histamine immediately and recruiting eosinophils through IL-5 hours later.
Lucid rule for classification: Graves disease and myasthenia are Type II receptor diseases, and only Type IV is independent of antibody.

Although primary immunodeficiencies are diverse, the pattern and timing of infection can help identify the affected component of immune defence. The pattern of infection is the fingerprint of the missing arm. Two clues, the pathogen and the age of onset, solve most cases. Antibody deficiency presents after six months, once maternal IgG has waned, with encapsulated bacteria such as pneumococcus and Haemophilus, enteroviruses and Giardia. T-cell deficiency presents early and severely with viruses, Candida, Pneumocystis and intracellular organisms, and live vaccines may be lethal. Phagocyte defects produce abscesses and granulomas from catalase-positive organisms, because the pathogen destroys the hydrogen peroxide the cell fails to make. Deficiency of complement components C5 to C9 leaves Neisseria unkilled, causing recurrent meningococcal disease.

Severe combined immunodeficiency is the emergency of this field. The commonest form is X-linked, caused by mutation of the common gamma chain shared by the receptors for interleukins 2, 4, 7, 9, 15 and 21. Loss of IL-7 signalling abolishes T cells and loss of IL-15 signalling abolishes NK cells, so the phenotype is T-negative, B-positive, NK-negative. Adenosine deaminase deficiency instead accumulates toxic deoxyadenosine triphosphate and destroys T, B and NK cells alike. In either form a total lymphocyte count below 2.5 × 10⁹/L in an infant is a red flag. Live vaccines, including rotavirus and BCG, are absolutely contraindicated, and haematopoietic stem cell transplantation before infection sets in offers the best survival. Newborn screening for T-cell receptor excision circles now detects most cases before the first pneumonia.

Gene-to-syndrome pairs recur. X-linked agammaglobulinaemia is a BTK defect arresting B cells at the pre-B stage. Hyper-IgM syndrome is a defect of CD40 ligand, CD40 or AID, preventing class switching. Wiskott–Aldrich syndrome is a WASp cytoskeletal defect, not an NF-κB defect, producing eczema, small platelets and infection. DiGeorge syndrome is a 22q11.2 deletion with thymic and parathyroid hypoplasia. Chronic granulomatous disease is NADPH oxidase deficiency, confirmed by an abnormal dihydrorhodamine test.

Vaccination is the same logic reversed: a safe antigen trains a chosen arm. Live attenuated vaccines replicate, inducing strong, durable cellular and humoral immunity, but they are forbidden in pregnancy and significant immunodeficiency. Inactivated, toxoid and subunit vaccines cannot replicate and are safe, but they stimulate mainly antibody and need adjuvants and boosters. Route matters as well. Oral vaccines generate secretory IgA at the mucosa, whereas injected vaccines generate systemic IgG.

The conjugate vaccine is the most examinable idea. Plain capsular polysaccharide is a T-independent antigen, so infants below two years make no memory and no booster response to it. Coupling the polysaccharide to a protein carrier converts it into a T-dependent antigen. B cells present carrier peptides to follicular helper T cells, receive CD40–CD40L help, and switch to high-affinity IgG with memory. The T cell recognises the carrier, not the sugar, yet the protective antibody targets the sugar. This is why conjugate pneumococcal, Hib and meningococcal vaccines protect infants, while the plain polysaccharide vaccine waits until age two.

All infants with early Candida, chronic diarrhoea, pneumonia and a lymphocyte count below 2.5 × 10⁹/L are investigated urgently for severe combined immunodeficiency.
Is the child possibly T-cell deficient? Then no live vaccine, especially rotavirus or BCG, until immunology has excluded the diagnosis.
On the common gamma chain, X-linked SCID is T-negative, B-positive, NK-negative, whereas adenosine deaminase deficiency removes all three.
Lucid rule for conjugate vaccines: the protein carrier recruits T-cell help, so infants make memory IgG against a polysaccharide they could not otherwise remember.

Effective treatment alone does not ensure control of tuberculosis, HIV or viral hepatitis; outcomes also depend on diagnosis, access, continuity of care and support for sustained treatment. Tuberculosis tests whether treatment is completed, HIV tests whether the fearful will come forward, and hepatitis tests whether a vaccine and a short course can rewrite a generation's cancer risk.

Treatment failure in tuberculosis is usually a failure of duration rather than potency. Two months of isoniazid, rifampicin, pyrazinamide and ethambutol are followed by four months of isoniazid and rifampicin. However, symptoms often settle within three or four weeks, and patients who stop at that point leave behind the bacilli that were hardest to kill. Multidrug-resistant tuberculosis is thus selected by interrupted therapy, not created by an unusual host. Directly observed therapy exists for precisely this reason, because it transfers responsibility for completion from the patient to the health system.

Latent infection is the second battlefield. A person with latent tuberculosis is not ill, is not infectious, has a normal chest radiograph and a negative sputum culture. Yet roughly one in ten will develop active disease during their lifetime, and far more will do so if immunity fails. Treating latency therefore defuses a future source of transmission rather than curing a present disease. The interferon-gamma release assay uses ESAT-6 and CFP-10, antigens encoded in the RD1 region deleted from BCG. Consequently, prior vaccination causes false-positive tuberculin skin tests but leaves the assay unaffected. Shorter regimens such as twelve weekly doses of isoniazid and rifapentine raise completion.

HIV control is limited less by pharmacology than by fear, since undiagnosed people neither take treatment nor protect their partners. Anonymous testing lowers the psychological threshold, and sustained viral suppression means the virus is not transmitted sexually. Pre-exposure prophylaxis protects the uninfected, but it must never be started before infection is excluded. A partial regimen given during the acute window selects resistant virus, and early infection is detected only by RNA or p24 antigen. Post-exposure prophylaxis must begin within seventy-two hours and continue for four weeks.

Hepatitis B is decided at birth, because the younger the age at infection, the higher the chance of chronic carriage. Around ninety per cent of infected infants become carriers as their tolerant immune systems accept the virus as self. A first vaccine dose within twenty-four hours, with immunoglobulin when the mother is infectious, interrupts transmission before tolerance forms. Universal infant vaccination lowered childhood carriage from about ten per cent to below one per cent and reduced childhood hepatocellular carcinoma. Hepatitis C has no vaccine, because its envelope proteins mutate too quickly, but direct-acting antivirals cure more than ninety-five per cent within eight to twelve weeks.

All resistance in tuberculosis is selected by interrupted therapy, so directly observed completion of six months is the core of control.
Is the contact BCG-vaccinated? Then use the interferon-gamma release assay, whose RD1 antigens are absent from BCG, and remember that latent infection is neither illness nor infectious.
On HIV, prophylaxis before exposure requires proof of a negative test, while prophylaxis after exposure must start within seventy-two hours and last four weeks.
Lucid rule for hepatitis: B is decided at birth by a vaccine dose within twenty-four hours, whereas C is cured by direct-acting antivirals in eight to twelve weeks.

Cerebrospinal fluid interpretation depends on the relationship between cellular composition, protein, glucose and the clinical presentation, rather than any isolated measurement. Low glucose means the pathogen consumes sugar, which is true of bacteria, mycobacteria and fungi, whereas normal glucose points to a virus. Protein rises in almost every meningitis, so it cannot discriminate on its own. The decisive pairing is the dominant cell type with the glucose ratio. Neutrophils with very low glucose and high pressure indicate bacterial meningitis. Lymphocytes with normal glucose indicate viral disease, while lymphocytes with low glucose and very high protein suggest tuberculosis or fungi.

The sequence of management matters as much as the diagnosis. Blood cultures are drawn first, antibiotics follow immediately, and dexamethasone is given before or with the first dose to limit inflammation from bacterial lysis. Imaging precedes lumbar puncture only when consciousness is reduced, deficits are focal or papilloedema is present. Even then, antibiotics are never delayed for the scan. Healthy adults receive vancomycin with a third-generation cephalosporin. However, neonates, adults over fifty, pregnant women and the immunocompromised also need ampicillin. Listeria is a gram-positive bacillus that cephalosporins cannot reach, and vancomycin or ciprofloxacin treat it poorly.

Two other central nervous system infections carry their own rules. Cryptococcal meningitis in advanced HIV is treated in three phases, not four weeks. Induction with amphotericin B and flucytosine lasts at least two weeks, consolidation with fluconazole eight weeks, and maintenance continues for a year or until the CD4 count recovers. Herpes simplex encephalitis burns the temporal lobe and is treated the moment it is suspected. Polymerase chain reaction is highly accurate, yet it may be falsely negative within seventy-two hours and often stays positive for days after aciclovir begins.

Hospital-acquired infection follows three axes: the device, the position of the patient and the resistant organism. Ventilator-associated pneumonia arises from supine aspiration, sedation and the tube itself, so the bed is raised to thirty degrees or more. Sucralfate does not raise gastric pH and therefore does not increase that risk. Alcohol hand rub fails on visibly soiled hands and after caring for patients with Clostridioides difficile, whose spores demand soap and water. Febrile neutropenia is treated with a single antipseudomonal beta-lactam, and vancomycin is reserved for line infection, skin infection or instability. MRSA resists every beta-lactam through the altered target PBP2a, and daptomycin cannot treat pneumonia because surfactant inactivates it.

Urinary infection is stratified by fever. Cystitis stays in the bladder, whereas pyelonephritis produces fever, loin tenderness and nausea. Escherichia coli causes most cases at both levels. Recurrent infection in infancy calls for ultrasound first and then a voiding cystourethrogram to find reflux. Spinal cord injury above the sacral centre produces a spastic bladder, while sacral or cauda equina damage produces a flaccid one. Interstitial cystitis is sterile and should never receive antibiotics.

All low-glucose cerebrospinal fluid means bacteria, mycobacteria or fungi, whereas viral meningitis keeps glucose normal.
Is the patient a neonate, over fifty, pregnant or immunocompromised? Then add ampicillin for Listeria, which cephalosporins never cover.
On suspicion of bacterial meningitis, take blood cultures, give dexamethasone with the first antibiotic dose, and never delay treatment for imaging or lumbar puncture.
Lumbar puncture in suspected herpes encephalitis may be falsely negative within seventy-two hours, so aciclovir starts on suspicion and continues until the diagnosis is excluded.

Antimicrobial resistance emerges and spreads through genetic variation, gene transfer and selection, rather than a purposeful response by individual organisms. Every large bacterial population contains a few organisms carrying resistance genes, which grow slowly under that burden. A broad-spectrum antibiotic clears their susceptible neighbours and empties the niche, so the resistant few inherit the whole space. Hospitals breed resistant organisms because three conditions coincide: the highest antibiotic density, the weakest hosts and the most invasive devices. Reducing unnecessary selection pressure and interrupting transmission are therefore central to control, alongside effective diagnostics, appropriate treatment and the development of new therapies.

Carbapenem-resistant Acinetobacter baumannii illustrates the mechanism. It stacks an OXA-type carbapenemase, loss of outer membrane porins and active efflux pumps, so it usually resists almost every other class as well. Moreover, it tolerates dryness and survives for weeks on bed rails, keyboards and ventilator screens. Environmental cleaning and contact precautions therefore matter as much as any antibiotic. MRSA resists through an altered target, PBP2a encoded by mecA, so beta-lactamase inhibitors achieve nothing. Community strains carry Panton-Valentine leukocidin and cause abscesses and necrotising pneumonia in the young. Among carbapenem-resistant Enterobacterales, KPC is a serine enzyme, whereas NDM, IMP and VIM are zinc-dependent metallo-beta-lactamases that clavulanate cannot inhibit.

Antimicrobial stewardship asks four questions: the right drug, the right dose, de-escalation and duration. Prospective audit with feedback and pre-authorisation are its principal tools. Healthcare-associated infection follows one structure, a device, a duration and a host. Central line, catheter and ventilator each bypass a natural barrier, and organisms ascending them lay down a biofilm. Within that film metabolism slows, antibiotics penetrate poorly and immune cells cannot enter, so the cure is removal rather than escalation. Every bundle ends with daily assessment of necessity, and each infection is defined after more than two days of device exposure.

Central line insertion demands hand hygiene, maximal sterile barriers, chlorhexidine skin preparation and avoidance of the femoral site, with hub disinfection thereafter. Urinary catheters are inserted only for clear indications, drained in a closed system kept below the bladder and never on the floor. Ventilated patients are nursed at thirty to forty-five degrees with daily sedation interruption, chlorhexidine mouth care and subglottic drainage. Surgical prophylaxis is given within sixty minutes before incision, hair is clipped rather than shaved, and glucose and temperature are controlled.

Hand hygiene has five moments arranged by causation. Before touching a patient and before an aseptic procedure protect the patient. After body fluid exposure, after touching the patient and after touching the surroundings protect the next patient and the worker. Alcohol rub fails on soiled hands and after Clostridioides difficile. Isolation is layered on standard precautions. Contact applies to MRSA, Acinetobacter and difficile, and droplet with surgical masks to influenza, pertussis and meningococcus. Airborne isolation with negative pressure and N95 respirators is reserved for tuberculosis, measles and varicella. The 2003 SARS epidemic taught that isolation must separate rather than aggregate, leaving behind fever screening, patient flow design and the TOCC history.

All carbapenem-resistant Acinetobacter is selected by prior carbapenems and spreads on dry surfaces, so cleaning and contact precautions equal any antibiotic.
Is the pathogen measles, varicella or tuberculosis? Then airborne isolation with negative pressure and N95 is required, whereas meningococcus needs only droplet precautions.
On any device, a biofilm defeats antibiotics, so every bundle ends with daily assessment and prompt removal.
Lumen-dwelling Enterobacterales with NDM carry a zinc metallo-beta-lactamase that clavulanate cannot inhibit, while MRSA resists through the altered target PBP2a.