Fever (Pyrexia) Notes PDF

(I) Fever (Pyrexia) (I) Fever (Pyrexia) Def.: abnormal elevation of body temperature due to resetting of hypothalamic thermostat. - A person with fever still regulates body temperature in response to...

(I) Fever (Pyrexia) (I) Fever (Pyrexia) Def.: abnormal elevation of body temperature due to resetting of hypothalamic thermostat. - A person with fever still regulates body temperature in response to heat or cold but at a higher set point. Causes: 1- Infections especially bacterial. 2- Physical trauma. 3- Stress. Pathophysiology of thermostat resetting: Chemical messengers called endogenous pyrogens (group of chemical mediators called interleukins as IL1) are released from macrophages in presence of infection circulate in blood reach the brain act on hypothalamic thermoreceptors reset thermostat at a new higher level i.e from 37 to 39 C by local synthesis of prostaglandins (PGE2) within the hypothalamus. N.B: IL1 also enhances resistance of host to infection & promote healing of damaged tissues. Stages of fever: 2 1 3 1  (I) Fever (Pyrexia) 3-Stage of 1-Stage of chills 2-Steady stage defervescence = lysis -blood temperature is -set point returned -resetting (raising) of Changes raised to be equal to the thermostat to new set point. to its normal value. set point. Set point 39 39 37 Bood 37 39 39 temperature i) heat gain mechanisms, ms. tone and shivering. - heat loss by: i-VD in Thermostat -shivering stops skin. ii-Sweating. ii) heat loss by V.C of cutaneous vessels. Sense cold warmth hot Skin Pale skin Red skin Flushed skin Benefits of fever: 1- Increase production of antibodies. 2- Prevent growth of microorganisms. 3- Prevent growth of tumors. (II) Hyperthermia Def.: increase in body temperature without change in the set point of hypothalamic thermostat. Causes: impairment of the hpothalamic thermostat by: 1- Excessive heat production (prolonged severe exercise) 2- Impaired heat loss (increase environmental humidity) 3- Excessive environmental heat. 2  (I) Fever (Pyrexia) Includes: a) Heat cramps -Slow painful skeletal muscle cramps & spasms. -Appear in most heavily used muscle. -Last for 1 - 3 min. Cause: salt depletion (due to replacement of fluid loss from heavy sweating by water alone) Body temperature normal or slightly elevated. b) Heat exhaustion Cause: over activity in hot environment marked increase in heat production increase body temperature stimulation of excessive heat loss mechanisms. State of collapse, in the form of fainting due to hypotension, that is caused by: 1- Depletion of plasma volume, 2 ry to sweating. 2- Extreme vasodilatation of skin blood vessels. Body temperature not elevated markedly (due to excessive sweating) c) Heat stroke -Represent a complete failure of heat regulating system increase body temperature more & more. -Extremely dangerous. 3  (I) Fever (Pyrexia) Causes: 1- Overactivity in hot humid environment. 2- End stage of prolonged untreated heat exhaustion dehydration impaired cerebral circulation. Characters: - Collapse -Convulsions - Failure to sweat - Prolonged unconsciousness Harmful Effects of High Temperature: a-Localn hemorrhages and parenchymatous degeneration of cells throughout the entire body especially in the brain. b-damage to the liver, kidneys, and other organs 🡢 organ failure 🡢 death.Treatment of heat exhaustion & stroke: 1- External cooling. 2- Fluid replacement. 3- Cessation of activity. Sun stroke - Due to direct exposure to sun rays. - May cause heat stroke. - Fatal if not treated. - Treatment as heat stroke. 4  (I) Fever (Pyrexia) Fevers DEFINITION: elevation of body temperature above average normal BODY TEMPERATURE Normal body temperature Abnormal body temperature Ranges from 36.5-37.2˚C 1. Decreased body temperature: - Axillary temperatures are unreliable (must a. Subnormal temperature: < 36.5˚C be verified by another method) b. Hypothermia: < 35˚C - Rectal temperatures parallel core temp (are typically 0.5-1˚C higher than oral temp) 2. Increased body temperature: Minor differences in temperatures exist due to genetics, sex, age and body size a. Fever (pyrexia): > 37.2˚C Diurnal range of 0.5˚C (lowest at - Typically due to reaction of the 6 AM and highest at 6 PM) body to infection Temperatures drop to 36.1˚C: - Rarely due to failure of the heat dissipating mechanisms unless the - During sleep temperature is high and prolonged - In cold weather b. Hyperpyrexia: > 41.5˚C Temperatures increase to 38.3- 38.9˚C: - In hot weather - During strenuous activity Pediatric temperatures may fluctuate, but generally parallel adult readings 5  (I) Fever (Pyrexia) CAUSES OF FEVER 1. Infections 2. Tissue trauma Crash injuries/bone fractures Myocardia or pulmonary infarction 3. Tissue destruction Phlebothrombosis Hemolytic anemia 4. Neoplastic diseases 5. Collagen diseases 6. Disturbance of heat Heat injury / sun stroke regulating center in the brain Cerebral hemorrhage Belladonna Barbiturates 7. Drugs Iodides Bromides Oxanmiquin 8. Hypersensitivity states Serum sickness SYMPTOMS AND SIGNS 1. Vague sense of warmth/flushing 2. Headache/myalgia 3. Malaise/anorexia/weight loss 4. Chills/rigors 5. Every 1°C increase over 37°C leads to: a.  O2 demand by 13% (problematic in adults with pre-existing cardiac or pulmonary insufficiency) b.  BMR by 8% c.  in heart rate by 10-15 beats/min → tachycardia 6. Extremes of age may manifest with: a. Febrile seizures in children b. Worsening of mental status in patients with dementia 6  (I) Fever (Pyrexia) Temperature/pulse dissociation occurs when the increase in heart rate does not accompany increased temperature Differential diagnosis temperature/pulse dissociation: 1. Infectious Salmonellosis Mycoplasma Tularemia causes Typhoid Pneumonia Dengue fever fever Meningitis with  Brucellosis intracranial pressure Legionellosis 2. Iatrogenic Drug fever causes Use of digitalis or beta blockers PATTERNS (TYPES) OF FEVER Characteristics Examples Pattern 1. Continuous or Fever continues for some time (days or a. Infections, e.g.: sustained fever weeks) without intermissions or marked Typhoid fever remissions (no more than 0.5-1C temperature difference between morning and Pneumonia evening) Meningitis Typhus b. CNS damage 2. Intermittent Fever that subsides completely once or more Benign 3ry malaria fever during the day Abscess Military TB Lymphoma Charcot's intermittent fever Fever usually accompanied by chills, right upper quadrant pain, and jaundice Due to recurrent biliary obstruction with secondary infection where a stone intermittently obstructs the common duct 3. Hectic fever A form of intermittent fever with a much Active TB wider temp range Amebic liver abscess Accompanied by facial flushing, sweating, Pyogenic abscess 7  (I) Fever (Pyrexia) rigors 4. Remittent Fever that abates every day but doesn't Septic conditions fever completely resolve, i.e. temperature shows Mycoplasma considerable variation between morning and pneumonia evening ( fluctuation more than 1C) but never returns to normal Rheumatic fever Rheumatoid arthritis SABE Falciparum malaria 5. Saddleback Biphasic remittent fever Dengue fever fever Continuous fever for a few days followed by remission then a second bout of fever associated with appearance of rash and terminating in lysis 6. Relapsing fever Febrile attacks that last for a few days, a. Infections, e.g.: separated by afebrile intervals of about the Brucellosis (undulant same length fever → wavy appearance of a long temp curve) Spirochete relapsing fever b. Diseases Hodgkin’s disease (Pel-Ebstein fever) 8  (I) Fever (Pyrexia) Other terminology associated with fever: 1. Essential fever: fever of unknown etiology 2. Fatigue (exhaustion) fever occurs following excessive and continued muscular exertion (may last up to several days) 3. Factitious fever: Self-induced, artificial fever Not associated with organic disease May be induced by ingestion or retention of hot fluids in the mouth immediately prior to temperature check Confirmed by rectal temperature checks 4. Malarial fever Characteristics Causative organism Usually due to double tertian malarial infection with: i. Two distinct groups of P. vivax that sporulate alternately every 48 hours 1. Quotidian fever Occurs daily ii. P. falciparum in combination with P. vivax iii. Infections by two distinct P. falciparum generations that mature on different days Recurs every 3rd day or every 2. Tertian fever 48h (day of paroxysm P. vivax considered day 1) 9  (I) Fever (Pyrexia) Recurs every 4th day or every 3. Quartan fever 72h (day of paroxysm P. malariae considered day 1) Paroxysms occurring every 48h with acute cerebral, renal 4. Malignant tertian or GIT manifestations due to fever (Falciparum P. falciparum clumping of infected red fever) blood cells → secondary capillary obstruction Double quotidian fever is not a malarial fever but is a daily two-spike fever seen in up to 50% of cases of gonococcal endocarditis Double quartan fever occurs on two successive days followed by one day without fever due to infection with two independent groups of quartan parasites CAUSES OF HYPERPYREXIA 1. Thyrotoxic crisis 2. Status epilepticus 3. Heat stroke 4. Encephalitis 5. Pontine hemorrhage CAUSES OF HYPOTHERMIA 1. Shock 2. Hypothyroidism 3. Pan-hypopituitarism 4. Starvation 5. Old age 10  Familial Mediterranean Fever FAMILIAL MEDITERRANEAN FEVER (PERIODIC FEVER) DEFINITION PROBABLE ETIOLOGY Clinical syndrome of probable 1. Inborn error of metabolism genetic origin, giving rise to 2. Autoimmune recurrent febrile episodes associated 3. Angioneurotic edema with peritonism, pleurisy, and arthropathy 4. Infective agent of unknown etiology Periodicity is the hallmark of the 5. Dietary allergy disease 6. Abnormal catecholamine metabolism Affected populations: 7. Endocrinal causes - Ethnicities such as Jews, Arabs, 8. Precipitating causes Armenians, and Turks Stress/anxiety Physical exercise - Children of consanguineous marriages Cold Menstruation CLINICAL PICTURE Recurrent acute attacks lasting 3-4 days occurring at intervals varying from days to weeks (even months) 1. Severe diffuse Pain simulates peritonitis → repeated laparotomies (diagnostic abdominal pain criteria) 2. Pleurisy Symmetrical non-destructive affection of large joints, more 3. Arthropathy commonly in sporadic Jews 4. Aura a. Erysipelas-like b. Henoch-Schonlein purpura 5. Dermatologic lesions lesion 11  Familial Mediterranean Fever c. Urticaria d. Vasculitis e. Bullous lesion a. Episcleritis b. Pharyngitis c. Acute orchitis 6. Less common symptoms d. Myocarditis e. Pericarditis Amyloidosis (amyloid A formation) more commonly in Jews and 7. Complications Turks (Arabs and Armenians are largely immune to this complication) DIAGNOSIS 1. Tel-Hashomer clinical criteria → diagnosis requires presence of 2 major or one major and 2 minor criteria Major criteria Minor criteria 1. Recurrent episodes of fever accompanied by 1. Recurrent episodes of fever peritonitis, synovitis, or pleuritis 2. Erysipelas-like erythema 2. AA type amyloidosis without predisposing 3. FMF history in 1st degree relatives disease 3. Improvement with colchicine treatment 2. Genetic testing for MEFV (Mediterranean fever) gene polymorphism is suggestive 3. Meta-araminol test: 10mg meta-araminol infusion → mild short febrile episode of FMF TREATMENT 1. Colchicine 0.5-1.5mg/d prevents attacks and the onset of amyloid nephropathy (unknown mechanism) 2. Biological treatment a. Anti-TNF agents, e.g. infliximab and etanercept, for patients unresponsive to colchicine b. IL-1 inhibitors, e.g. anakinra and canakinumab, for resistan 12  Temperature-Related Disorders TEMPERATURE-RELATED DISORDERS I. HEAT-RELATED DISORDERS Occur when generation or gain of heat by the body is faster than it can be lost RISK FACTORS 1. Medical conditions 2. Non-medical circumstances a. Obesity a. Exercising in hot environment b. Heart disease b. Lack of air conditioning or proper ventilation c. Skin disease (scleroderma, extensive burns) c. Lack of acclimatization to environmental changes (athletes) d. Endocrinal disorders (DM, hyperthyroidism, pheochromocytoma) d. Inappropriate clothing (occlusive, heavy, vapor-impermeable) e. Neurological disease (autonomic neuropathies, Parkinsonism, dystonias) e.  fluid intake f. Dehydration (vomiting, diarrhea) g. Fever **Extremes of age are particularly h. Drug intake susceptible to heat-related disorders − -blockers, anticholingergics a. Neonates → poorly developed thermoregulatory mechanisms − Sympathomimetics (-adrenergic b. Elderly patients agonists, cocaine, amphetamines) − Phenothiazines, tricyclic antidepressants, − Underlying illness lithium − Medication use − Diuretics, antihistamines −  thermoregulatory mechanisms − Antipyretics, ethanol 13  Temperature-Related Disorders SYMPTOMS 1. Heat fatigue Fatigue, headache, mental confusion Heavy sweating,  pulse rate, shallow breathing 2. Heat cramps Painful short-term muscle contractions mostly occurring in the extremities (usually legs) and abdomen when physical activity is done in a hot environment without proper muscle conditioning Exact cause is unknown but is related to dehydration  electrolyte loss Managed by resting in a cool environment + drinking plenty of fluids (preferably with electrolytes, e.g. sports drinks) 3. Heat exhaustion Often non-specific insidious onset of symptoms Headache, dizziness, irritability (no confusion) Fatigue, weakness, myalgia, muscle cramps Nausea, vomiting Sweating is present and skin is pale, moist, and clammy with possible piloerection Tachycardia Increased temperature not above 40C 4. Heat stroke (sun stroke): Rapid development of any/all symptoms of heat exhaustion with: a. Temperature 41C (initially may be normal or slightly elevated with pre-hospital cooling measures) 14  Temperature-Related Disorders b. Skin is red, hot, and dry and does not sweat c. Muscle cramps or flaccidity (unlike malignant hyperthermia or neuroleptic malignant syndrome where there is muscle rigidity) d. Organ system affection: Altered mental status (confusion, disorientation, bizarre behavior, hallucinations, delirium, coma) i.CNS dysfunction (80% of cases) Severe cases may demonstrate seizures, opisthotonos, decerebrate rigidity, cerebellar dysfunction, oculogyric crisis, and dilated pupils Tachycardia Tachyarrythmia not amendable to cardioversion ii.Hyperdynamic cardiovascular system  cardiac output  diastolic blood pressure  systemic vascular resistance Disseminated intravascular coagulation (DIC) → purpura Conjunctival hemorrhage iii.Coagulation disorders Bloody diarrhea Hemoptysis Hematuria Myocardial bleeding Intracranial hemorrhage Tachypnea Alkalosis iv.Respiratory symptoms Respiratory decompensation due to acute respiratory distress syndrome (ARDS) Hematuria v.Genitourinary symptoms Oliguria or anuria due to acute renal failure 15  Temperature-Related Disorders Symptom Heat exhaustion Heat stroke Skin Pale, cool, moist Flushed, hot, dry Nausea/vomiting Present Present Sweating Profuse Absent Core temperature  usually  39C   41C or more Headache, Throbbing fainting, dizziness, headache, dizziness, irritability agitation CNS Weakness Confusion, but no confusion hallucination, delirium, unconsciousness Seizures Rapid weak Rapid strong pulse pulse Tachycardia CVS Tachycardia Slight  BP at first then  LABORATORY INVESTIGATIONS (Heat stroke) 1. Hepatic transaminases Universally  (normal values exclude heat stroke) 2. CBC / PT / activated partial thromboplastin time / fibrinogen / DIC platelets 3. Creatinine / urea / electrolytes / acid-base disorders Acute renal failure 4. CK level  in rhabdomyolysis 5. Proteinuria, haematuria, myoglobinuria, or granular casts Acute renal failure or rhabdomyolysis 6. Urine specific gravity  (concentrated urine) Due to  use of glucose or hepatic 7. Hypoglycaemia damage leading to impaired gluconeogenesis To evaluate acid-base status, pulmonary 8. Arterial blood gases function, and tissue oxygenation 16  Temperature-Related Disorders **Chest X-ray and head CT-scan are useful in excluding other diagnoses TREATMENT Home care is appropriate for mild forms Heat stroke is a medical emergency of heat exhaustion 1. Remove patient from hot 1. Patient should lie down in a environment cool, shaded area with feet elevated (a fan 2. Administer intravenous fluids can be used to lower temp) to correct water deficit slowly (½ of 2. Give cool fluids, e.g. sports total water depletion replaced in the 1st drinks to replace lost salt but beverages 3-6h, the remainder over the next 6-9h) containing alcohol or caffeine should be 3. Supplemental oxygen and avoided (salty snacks can be given if assisted ventilation as indicated tolerated) 4. Initiate cooling measures 3. Loosen/remove clothing and apply cold compresses (do not use an a. Evaporative cooling alcohol rub) (preferred) **Ice water is effective in  body temp Safe, effective, easily but not recommended because peripheral accomplished, well-tolerated VC: Ideal goal →  patient’s core a. Leads to shunting of blood away temperature by 0.2°C/min from the periphery → less heat loss Undress the patient, spray with b. Limits cardiac and vital sign lukewarm water, and cool by large fans monitoring to maximise evaporative heat loss c. May result in hypothermic b. Apply ice packs to the overshoot patient’s neck, axillae and groin or cover the patient with a wet sheet c. Other modalities include ice water gastric, rectal, or peritoneal lavage, or cardiopulmonary bypass *No drugs can significantly  core temp in these patients 17  Temperature-Related Disorders II. COLD-RELATED DISORDERS Occur when the body loses heat faster than it can produce it, resulting in dangerously low body temperature (below 35C). RISK FACTORS 1. Hypothyroidism 2. Pan-Hypothyroidism 3. Shock 4. Stroke 5. Sepsis 6. Alcohol abuse 7. Starvation (anorexia nervosa) 8. Old age 9. Poor circulation and Raynaud’s disease (frostbite) A. HYPOTHERMIA Causes 1. Exposure to abnormally cold temperature 2. Immersion in cold water Signs and symptoms − Vary depending on the degree of hypothermia − Infants with hypothermia may feel cold when touched, with bright red skin and an unusual lack of energy. People with hypothermia may appear pale. − Divided into three stages of severity 18  Temperature-Related Disorders 1. Mild 2. Moderate 3. Severe Body temperature of Shivering stops Body temperature 32–35°C between 30–32°C 28°C Symptoms may be Mental status Continued  in blood vague changes: flow to the brain → Physiological responses − Amnesia unresponsiveness to preserve heat (due to − Confusion Continued  in BP, sympathetic − Slurred speech HR, and cardiac stimulation): − Continued decline in output − Shivering thinking ability Increased −  blood pressure Decreased reflexes susceptibility to −  heart rate Loss of fine motor abnormal heart −  respiratory rate skills rhythms − Contraction of blood Lethargy Congestion in lungs vessels (skin that is dry Enlarged and less  urine output (very and paler than usual) responsive pupils small amount) Tiredness Low blood pressure Loss of reflexes Mental confusion, Slow heart rate Failure of heart and decline in memory, Increased lung function (final judgment, and thinking susceptibility to outcome) ability abnormal heart Unclear speech rhythms Slow breathing rate  muscle tone Paradoxical  urine production due undressing, or to cold removal of clothes Liver dysfunction − Ocurs during Hyperglycemia due to: moderate and severe a.  glucose consumption hypothermia by cells − The person becomes b.  insulin secretion disoriented, c.  tissue sensitivity to confused, and insulin combative → may d.  glucose release from begin discarding the liver due to their clothing → sympathetic stimulation increases the rate of In people heat loss with alcoholic − May be due to: intoxication, hypoglycemia a. Cold-induced appears to be more malfunction of the common (hypoglycemia heat-regulating is also found in many center people with in hypothalamus hypothermia, as b. Loss of vasomotor hypothermia may be a tone → sudden surge result of hypoglycemia) of blood (and heat) to the extremities → person feels overheated 19  Temperature-Related Disorders Management Passive Involves the use of a person's own ability to Mild external generate heat by providing properly insulated rewarming dry clothing and moving to a warm environment Active Involves applying warming devices externally, Moderate external e.g. heating blanket or hot water bottles rewarming Involves the use of intravenous warmed fluids, irrigation of body cavities (the chest or abdomen) with warmed fluids, use of warm humidified inhaled air, or use of extracorporeal rewarming such as via a heart Active lung machine or extracorporeal membrane Severe internal rewarming oxygenation (ECMO) → maintains normal brain function in 50% Cardiopulmonary resuscitation (CPR): Should be continued with active rewarming even in absence of signs of life B. FROST BITE Injury caused by freezing of the skin and underlying tissues The underlying mechanism involves injury from ice crystals and blood clots in small blood vessels following thawing Signs and symptoms most common on the fingers, toes, nose, ears, cheeks, and chin according to stage of affection 20  Temperature-Related Disorders 1. Frostnip 2. Superficial frostbite 3. Deep (severe) frostbite − A mild form − Causes slight changes Progressive frostbite of frostbite in skin color affecting all layers of the skin and tissues − Continued − The skin may begin to below: cold exposure feel warm (sign of leads to serious skin a. Skin turns white/blue- numbness in involvement) gray the affected − Rewarming treatment b. Hard or waxy-looking area skin at this stage results in: − As skin c. Loss of all sensation of Appearance of warms, pain cold (numbness) mottled skin surface and tingling may be felt Stinging d. Pain or discomfort in affected area − Frostnip Burning doesn't cause e. Joints or muscles Swelling dysfunction permanent skin damage Appearance of fluid- f. Large blisters form 24- filled blister within 48 hours after 12-36 hours rewarming − Long-term g. The tissue turns black complications include: and hard as it dies a. Pain and numbness Complications include: b.  cold sensitivity a. Frostbite arthritis c.  risk of developing b. Damage to growth plate frostbite again (growth problems in children) c. Gangrene d. Autoamputation Management 1. Assessment and management of hypothermia other life-threatening complications of cold exposure. − Before treating frostbite, the core temperature should be raised above 35 °C. − Oral or intravenous (IV)fluids should be given. − Other considerations for standard hospital management include: 21  Temperature-Related Disorders a. Wound care: o Blisters can be drained by needle aspiration, unless hemorrhagic. o Aloe vera gel can be applied before breathable, protective dressings or bandages. b. Antibiotics in case of trauma, skin infection (cellulitis), or severe injury c. Tetanus toxoid should be administered according to local guidelines (uncomplicated frostbite wounds are not known to encourage tetanus) d. Pain control during painful rewarming process with NSAIDs or opioids 2. Rewarming − Rewarmed in the hospital with a warm bath with povidone or chlorhexidine antiseptic. − Active rewarming seeks to warm the injured tissue as quickly as possible without burning (the faster tissue is thawed the less tissue damage occurs). − Rewarming can be very painful, so pain management is important. 3. Medications − Tissue plasminogen activator (TPA) with heparin given to people with potential for large amputations and who present within 24 hours of injury if not contraindicated − Iloprost (vasodilator) may prevent blood vessel blockage if administered within 48 hours. 4. Surgery − Debridement or amputation of necrotic tissue is usually delayed unless there is gangrene or systemic infection (sepsis). 22  Emerging and re-emerging infections EMERGING AND RE-EMERGING INFECTIONS Emerging infections: Infectious diseases that have newly appeared in a population or have existed but are rapidly increasing in incidence or geographic range. Re-emerging infections: The reappearance of a previously known infection after a period of disappearance or decline in incidence. AVIAN (BIRD) FLU MICROBIOLOGY EPIDEMIOLOGY Of the three types of influenza First isolated from a goose in viruses (A, B, and C), influenza A China in 1996. virus is a zoonotic infection with a Human infections first reported natural reservoir almost entirely in in 1997 in Hong Kong. birds. Since 2003, more than 700 Avian influenza viruses are human cases have been normally found in both wild birds reported to the WHO. (swans) and domesticated birds Viruses are easily transmissible (chickens, turkeys). among birds but rarely cause Avian influenza typically refers to infections in people (infection influenza A virus. in birds is fatal). Most well-known HPAI (highly Affects humans or other pathogenic avian influenza) strain animals that come in contact is H5N1. with a carrier. 23  Emerging and re-emerging infections TRANSMISSION SYMPTOMS COMPLICATIONS 1. Direct or indirect Incubation Hypoxemia (dyspnea) contact with infected period (3-7 Pneumonia live or dead poultry. days) Acute respiratory 2. Contact with avian High grade distress influenza A virus- fever >38C Respiratory failure contaminated Cough / sore environments. Multiple organ throat dysfunction 3. Human-to-human Runny / blocked transmission occurs Secondary bacterial and nose ONLY with fungal infections mutations. Sneezing Malaise Headache Tiredness Limb or joint pain Diarrhea / vomiting, abdominal pain / chest pain / bleeding from nose and gum 24  Emerging and re-emerging infections DIAGNOSIS Sample 1. Nasopharyngeal aspirate / wash 2. Oropharyngeal / throat swab Tests 1. Rapid influenza Detect viral antigens (less accurate than diagnostic tests (RIDTs) other tests) 2. Rapid molecular assays More accurate than RIDTs 3. Reverse transcription polymerase chain reaction (RT-PCR) 4. Viral culture 5. Immunofluorescence assays TREATMENT PROPHYLAXIS 1. Hospitalization and isolation 1. Early detection and management 2. General and supportive 2. Containment of transmission treatment: 3. If human-to-human transmission Monitor vital signs occurs: Maintain hydration, electrolytes, a. Social distancing and avoidance of and nutrition social gatherings Paracetamol for fever b. Closure of schools and other institutions 25  Emerging and re-emerging infections 3. Oseltamivir (Tamiflu) 75 mg c. Restriction of travel and trading if twice daily for 5 days a large geographical area is 4. Zanamivir (Relenza) involved SWINE FLU MICROBIOLOGY EPIDEMIOLOGY Swine flu is caused by H1N1 H1N1 is one of several influenza influenza virus that infects the virus strains that can cause respiratory tract of pigs. seasonal flu. H1N1 appears to be mostly due 2009 swine flu pandemic from to a combination of human June 2009 to August 2010, is the influenza, swine and avian third recent flu pandemic viruses further combined with a involving the H1N1 virus: Eurasian pig flu virus, leading to a. The first was the 1918– the term "swine flu" 1920 Spanish flu pandemic b. The second was the 1977 Russian flu MODE OF TRANSMISSION 1. Direct droplet transmission from cough or sneeze of an infected person. 2. Indirectly through surfaces contaminated from an infected case. 3. Improper handling and cooking of pork products from swine infected with H1N1 virus. 26  Emerging and re-emerging infections CLINICAL PICTURE SYMPTOMS COMPLICATIONS 1. Symptoms are the same as 1. Pneumonia seasonal flu 2. Respiratory failure (death) 2. Fever, chills, fatigue 3. Secondary bacterial infection 3. Cough, sore throat, runny nose (children) 4. Body aches, headache / 4. Neuronmuscular complications 5. Diarrhea, vomiting (more in (rare) children) 5. Cardiovascular complications (rare) DIAGNOSIS Respiratory specimens should be collected within 4-5 days of illness (children may shed virus for 10 days or longer) Identification as a swine flu influenza A. TREATMENT PROPHYLAXIS 1. Hospitalization and isolation 1. Early detection and management 2. General and supportive treatment: 2. Containment of transmission a. Monitor vital signs 3. Vaccine (FDA approved) for: b. Maintain hydration, electrolytes, and a. Health care workers / pediatric care nutrition givers c. Paracetamol for fever b. Pregnant women 3. Oseltamivir (Tamiflu) 75 mg twice c. Schools (staff, students) daily for 5 days d. Under age 65 with risk factors 4. Zanamivir (Relenza) (pregnancy, immunocompromise) 27  Emerging and re-emerging infections ZIKA FEVER Zika virus MICROBIOLOGY TRAMSMISSION Zika virus is a member of 1. Spread by daytime- virus family flaviviridae active Aedes aegypti mosquitoes 2. Sexual contact 3. Blood transfusion 4. Vertical (mother-to-child) transmission EPIDEMIOLOGY Since the 1950s, it occured sporadically from Africa to Asia. From 2007 to 2016, the virus spread eastward, across the Pacific Ocean to the Americas, leading to the 2015–2016 Zika virus epidemic. CLINICAL PICTURE SIGNS AND SYMPTOMS COMPLICATIONS Incubation period 3-14 days 1. Infection during pregnancy: Typically asymptomatic a. Pregnancy complications such as fetal loss, stillbirth, and preterm birth Mild symptoms usually last 2-7 days: b. Microcephaly and other congenital 1. Low fever abnormalities in the developing fetus 2. Maculopapular rash and newborn. 3. Conjunctivitis 2. Guillain-Barré syndrome 4. Muscle and joint pain 3. Neuropathy 5. Malaise 4. Myelitis 6. Headache 28  Emerging and re-emerging infections DIAGNOSIS 1. Molecular testing a. RT-PCR for ZIKV RNA for presence of the b. Immunoassay for viral proteins virus c. Virus isolation for live virus Not recommended since antibodies against Zika: 2. Serological testing − Persist for years for presence of − Cross-react with other similar viruses, antibodies including dengue (ELISA) A positive lab result often cannot definitively tell you if you have a current or past infection or whether it is a Zika or dengue infection TREATMENT PREVENTION 1. No specific treatment for Zika virus 1. Mosquito control infection 2. Containment of transmission 2. Fluids to prevent dehydration. 3. No available vaccine 3. Paracetamol for joint pain and fever 29  Emerging and re-emerging infections SEVERE ACUTE RESPIRATORY SYNDROME (SARS) DEFINITION EPIDEMIOLOGY Severe acute respiratory First known cases occurred in syndrome (SARS) is a viral November 2002 respiratory illness of zoonotic Caused the 2002–2004 SARS origin caused by SARS- outbreak associated coronavirus No cases of SARS-CoV-1 have been (SARS-CoV). reported worldwide since 2004 TRANSMISSION SYMPTOMS COMPLICATIONS 1. Direct droplet 1. Fever, chills 1. Dry cough transmission from 2. Fatigue 2. Pneumonia cough or sneeze of an 3. Headache 3. Dyspnea infected person. 4. Sore throat 4. Hypoxia (fatal) 2. Indirectly through surfaces contaminated 5. Muscle pain 5. Secondary bacterial from an infected case. 6. Diarrhea (10- infections 20% of patients) 6. Multi-organ failure (GI, liver, kidney) 30  Emerging and re-emerging infections DIAGNOSIS 1. CT chest Indicative for atypical pneumonia or acute respiratory distress syndrome 2. ELISA, For SARS-CoV-specific antibodies immunuflourescence 3. PCR For virus identification TREATMENT PREVENTION 1. Hospital admission (isolation, close observation) 1. Early detection and 2. Treatment is supportive: management a. Ventilator to deliver oxygen (assist breathing) 2. Containment of transmission b. Antibiotics (for pneumonia and secondary bacterial infections) 3. No available vaccine c. High dose steroids (reduce swelling in lungs) d. Antiviral e.g. ribavirin is ineffective 31  Emerging and re-emerging infections MIDDLE EAST RESPIRATORY SYNDROME (MERS) DEFINITION EPIDEMIOLOGY Viral respiratory infection caused The first case was identified in by Middle East respiratory June 2012 in Jeddah, Saudi syndrome coronavirus (MERS- Arabia CoV) belonging to the genus Larger outbreaks have occurred betacoronavirus which is distinct in: from SARS coronavirus and − South Korea in 2015 common-cold coronavirus − Saudi Arabia in 2018 TRANSMISSION SYMPTOMS Humans are typically infected Range from asymptomatic from camels, either during direct disease to contact or indirectly. severe pneumonia leading to ARDS. Human-to-human spread typically requires close contact with an infected Complications include: person (healthcare or household − Kidney failure setting), so risk to global population is − DIC considered low − Pericarditis No evidence of transmission from asymptomatic cases 32  Emerging and re-emerging infections DIAGNOSIS 1. RT-PCR testing of blood and respiratory samples 2.  white blood cell count, especially  lymphocytes TREATMENT and PREVENTION same as SARS. COVID – 19 EPIDEMIOLOGY TRANSMISSION Novel coronavirus causing a cluster of 1. Inhalation of very small fine pneumonia cases was first identified in droplets and aerosol particles that Wuhan, China, at the end of 2019 → contain infectious virus rapidly spread → epidemic throughout 2. Deposition of virus carried in China → global pandemic. exhaled droplets and particles In February 2020, the World Health onto exposed mucous membranes Organization named the disease COVID-19 (such as being coughed on). (coronavirus disease 2019) caused by 3. Touching mucous membranes severe acute respiratory syndrome with hands soiled by exhaled coronavirus 2 (SARS-CoV-2). respiratory fluids containing virus or from touching inanimate Globally, over 500 million confirmed surfaces contaminated with virus. cases of COVID-19 have been reported. Reported cases underestimate the overall burden of COVID-19 (only a fraction of acute infections was diagnosed and reported). VIROLOGY Enveloped positive-stranded RNA virus In the same subgenus as the severe acute respiratory syndrome (SARS) virus SARS-CoV-2 evolves over time, but most mutations have no impact on viral function. 33  Emerging and re-emerging infections VARIANTS 1. Alpha Became the globally dominant variant until emergence of the Delta variant Approximately 50-75% more transmissible than previously circulating strains 2. Beta Identified in several countries but did not become a globally dominant variant 3. Gamma Identified in several countries but did not become globally dominant Mutations in this variant raised concern about increased transmissibility and an impact on immunity. 4. Delta Had since been the most prevalent variant worldwide until emergence of the Omicron variant. Compared with the Alpha variant, the Delta variant was: - More transmissible - Associated with a higher risk of severe disease and hospitalization Vaccine effectiveness may be slightly less effective against symptomatic Delta infection but remains high against severe disease and hospitalization. 5. Omicron May escape humoral immunity Associated with a higher risk of reinfection in individuals previously infected with a different strain. Risk of severe disease with Omicron infection is lower than with other variants. CLINICAL PICTURE 2. Asymptomatic infections Well documented About 33% of people with SARS-CoV-2 infection never develop symptoms. 34  Emerging and re-emerging infections 3. Symptomatic infections Simplified case definition: a. Mild No pneumonia or hypoxia b. Moderate Pneumonia without hypoxia c. Severe Pneumonia with hypoxia responding to oxygen therapy Pneumonia with hypoxia not responding to oxygen therapy d. Critically ill and/or organ dysfunction Risk factors for severe illness - Age ≥65 1. Demographic - Male sex factors - Black, Hispanic, and Southern Asian ethnicities - Obesity (BMI>40) - Pregnancy 2. Pre-existing - Uncontrolled Comorbidities conditions - Active Malignancy - On Chemotherapy Immunosuppressive Drug - Unvaccinated or not fully vaccinated - Persistent fever > 38 - Heart Rate ≥ 110 3. Clinical features - Respiratory Rate ≥ 25/min - Saturated oxygen (Sa02) 1 mcg/mL) -  prothrombin time -  troponin -  creatine phosphokinase Detection of viral RNA in the blood has been associated with severe disease, including organ 5. Viral factors damage (lung, heart, kidney), coagulopathy, and mortality 6. Genetic factors 35  Emerging and re-emerging infections Clinical manifestations - Incubation period: ▪ 14 days for COVID-19 (most cases occur about 4-5 days after exposure) ▪ Slightly shorter for Omicron variant (symptoms appear at around 3 days) - Clinical course may progress rapidly in some patients. Initial presentation Complications No specific symptoms or signs can reliably 1. Respiratory failure due to distinguish COVID-19 acute respiratory distress syndrome (ARDS) can 1. Fever, cough, myalgias, headache (most manifest shortly after onset common) of dyspnea 2. Sore throat, and smell/taste abnormalities 2. Cardiac and 3. Dyspnea developing about one week after cardiovascular onset of initial symptoms is highly complications suggestive of COVID 3. Thromboembolic 4. Mild upper respiratory symptoms (nasal complications congestion, sneezing) more common with 4. Neurologic complications, Delta and Omicron variants such as encephalopathy 5. Pneumonia 5. Inflammatory - Most frequent serious manifestation complications due to - Characterized by fever, cough, dyspnea, and massive inflammatory bilateral infiltrates on chest imaging response (leading to death) manifested by: 6. GIT findings (nausea and diarrhea) may present a. Persistent fevers 7. Dermatologic findings: b. Elevated inflammatory markers (D-dimer, ferritin) a. Maculopapular/morbilliform, urticarial, and vesicular eruptions c. Elevated proinflammatory cytokines b. Transient livedo reticularis 6. Chronic Fatigue Syndrome 8. Other findings a. Conjunctivitis b. Delirium, especially in older adults with underlying neurocognitive impairment 36  Emerging and re-emerging infections DIAGNOSIS 1. History of contact with diagnosed COVID-19 case. 2. Findings suggestive of COVID-19: a. Clinical manifestations b. Laboratory findings i. Lymphopenia ii.  aminotransaminase levels iii.  lactate dehydrogenase levels iv.  inflammatory markers (e.g. ferritin, C-reactive protein, ESR) v. Abnormalities in coagulation test vi.  D-dimer levels (denotes critical infection and mortality) c. Radiological findings, e.g. consolidation and ground-glass opacities, with bilateral, peripheral, and lower lung zone distributions 3. Viral testing a. NAATs (e.g. PCR) b. Antigen tests Laboratory tests to detect viral Rapid tests (results in 15-30 minutes) genetic material (detectable for up Less reliable than NAATs, especially in to 90 days) people without symptoms The most reliable tests for people Single, negative antigen test result does with or without symptoms (false not rule out infection (should be repeated positive result if subject had tested after 48 hours apart = called serial testing) positive in last 90 days) Follow-up NAAT to confirm antigen test result 37  Emerging and re-emerging infections TREATMENT A. GENERAL MANAGEMENT 1. Close monitoring of all patients with: a. Symptomatic COVID-19 b. Risk factors for progression of disease 2. Antiviral drugs Timing of antiviral drug administration is critical a. Before day 12 (stage of viral load) → antiviral drugs are essential b. After day 12 (stage of hyper-immune state): -  role of antiviral drugs -  role of anti-inflammatory immunomodulators Potential antiviral drugs under evaluation for the treatment of COVID-19: a. Molnupiravir 800 mg (4 x 200mg capsules) twice/day for 5 days (used within 7 days of onset of symptoms) b. Favipiravir 1600 2x/day on the first day then 600 mg 2x/day for 4 days c. Remdesivir 200 mg IV on day 1 then 100 mg IV daily for 5 to 10 days in high-risk populations (indicated in failure or no response to oral therapy) d. Nirmatrelvir 300mg with ritonavir 100mg (Paxlovid) orally 2x/day for 5 days (if available) 3. Monoclonal antibodies in mild and moderate cases with any risk of progression 4. Antibiotics Indications - Rapid development of consolidation pattern - Development of lobar consolidation - Leucocytosis with absolute neutrophilia - Reappearance of fever after febrile days 38  Emerging and re-emerging infections -  CRP with improved other markers, e.g. ferritin (procalcitonin is highly specific) Drugs a. Low-risk inpatients: i. Combination therapy: ß-lactam (ceftriaxone or cefotaxime) plus either a macrolide (azithromycin or clarithromycin) or doxycycline ii. Monotherapy: Fluoroquinolone (levofloxacin or moxifloxacin) b. High-risk inpatients: ß -lactam plus a macrolide or fluoroquinolone 5. Therapeutic anticoagulants or antiplatelet if indicated 6. Pregnancy: Remdesivir (compassionate use approval) Monoclonal antibodies used if there is any other risk factor 39  Emerging and re-emerging infections B. MANAGEMENT ACCORDING TO SEVERITY 1. Mild case No Check for risk pneumonia Present Absent Treatme + patient nt age 65 Antiviral therapy: Monoclonal a. Molnupiravir 800 mg antibodies in a. Strict home (4 x 200mg capsules) mild cases isolation twice/day for 5 days with any risk b. Symptomati b. Favipiravir 1600 twice factor for c treatment daily in the first day then (paracetamol is 600 mg twice daily for 4 the preferred days antipyretic) c. Nirmatrelvir 300mg  Supportive measures 40  Emerging and re-emerging infections 2. Moderate case = patient with pneumonia without hypoxia a. Antiviral i.Molnupiravir 800 mg (4 x 200mg capsules) twice/day for 5 days (used within 7 days of onset of symptoms) ii.Nirmatrelvir 300mg with ritonavir 100mg (Paxlovid) orally 2x/day for 5 days (if available) iii.Remdesivir 200 mg IV on day 1 then 100 mg IV daily for 5 to 10 days in high-risk populations (indicated in failure or no response to oral therapy) b. Anti- Dexamethasone (6mg or its oral equivalent) if inflammatory, e.g. steroids patient has: Severe dyspnea Respiratory rate 24 CT scan shows rapid deterioration c. Monoclonal In moderate cases with any risk factor for antibodies progression to severe disease d. Anticoagulants i.Prophylactic anticoagulant (parenteral heparin or enoxaparin 0.5mg/kg/day) (only for hospitalized patients) ii.Therapeutic anticoagulant only indicated for specific reasons 3. Severe case Characterized by any of the following criteria: - Respiratory rate  30 - Saturated oxygen (SaO2)  92 at room air - PaO2/FiO2 ratio  300 (PaO2/FiO2 = partial pressure of arterial blood to fractional inspired oxygen) - Chest radiography showing  50% lesions or progressive lesions within 24-48 hours 41  Emerging and re-emerging infections Requires hospitalization a. Antiviral Remdesivir 200 mg IV on day 1 then 100 mg IV daily for 5 to 10 days b. Anti- i.Steroids (methyl prednisolone 1mg/kg/day) inflammatory ii.Anti-interleukin-6 (anti-IL-6) Drugs (not used together due to risk of immunosuppression) - Tocilizumab 4-8mg/kg/day for 2 doses 12 hours apart - Sarilumab 400mg single dose - Baricitinib (started with remdesivir) 4mg once daily for 14 days or hospital discharge Contraindications - Bacterial infection - Absolute neutrophil count (ANC)  500 cells/mm3 - Platelets  50,000 cells/mm3 - ALT  5x upper limit of normal (ULN) c. Anticoagulants Therapeutic anticoagulant (parenteral heparin or enoxaparin 1mg/kg/day) 4. Critically ill patients Characterized by any of the following criteria: - Respiratory rate  30 - Saturated oxygen (SaO2)  92 at room air - PaO2/FiO2 ratio  200 despite oxygen therapy - Additional organ dysfunction 42  Emerging and re-emerging infections Requires intensive care unit a. Antiviral Same as severe cases b. Anti- inflammatory c. Anticoagulants i. Prophylactic anticoagulant (parenteral heparin or enoxaparin 0.5mg/kg/day) ii. Therapeutic anticoagulant only indicated for specific reasons Use of therapeutic parenteral anticoagulant in severe cases and prophylactic parenteral anticoagulant in critically ill cases is due to the increased risk of bleeding. d. Breathing aids i. HFN (high-flow nasal oxygen therapy), NIV (non-invasive ventilation), or CPAP (continuous positive airway pressure) decreases mortality in patients who maintain good oxygen saturation but have high respiratory rate on oxygen therapy ii. Invasive mechanical ventilation if patient becomes distressed 43  Emerging and re-emerging infections PREVENTION 1. Containment of transmission 2. Vaccinations Company/developer Platform Pfizer/BioNTech mRNA Moderna mRNA Novavax Recombinant protein, adjuvanted Janssen/Johnson & Johnson Replication-incompetent adenovirus 26 vector 44  Human Immunodeficiency Virus (Hiv) HUMAN IMMUNODEFICIENCY VIRUS (HIV) MICROBIOLOGY Enveloped RNA virus belonging to the p32 integrase gp120 retrovirus family gp41 The HIV- 1 virion is composed of: p10 protease 1. Viral envelope made from host cell membrane inserted with HIV- 1 envelope proteins (e.g. p17 gp41 and gp120) and host proteins (e.g. MHC ssRNA p24 class II molecules) Reverse transcriptase (p64) MHC proteins 2. Matrix mainly of protein p17 3. Core containing: a. Viral RNA associated with protein p7 b. The enzymes reverse transcriptase, protease, and integrase c. The major structural proteins p6 and p24 TYPES AND SUBTYPES (Dual HIV- 1/2 infection can occur) HIV- 1 Accounts for most worldwide infections Primarily in West Africa Less readily transmissible than HIV- 1 HIV- 2 Associated with lower viral loads, higher CD4 counts, and slower disease progression Treatment is more complex (not susceptible to NNRTIs or fusion inhibitors) TRANSMISSION 1. Unprotected sexual intercourse 2. Mother-to-child 3. Needle sharing/needlestick injury 4. Recipients of infected blood/organ 45  Human Immunodeficiency Virus (Hiv) LIFE CYCLE 1. Binding HIV virus binds to receptors on the surface of CD4 cells. 2. Fusion HIV viral envelope fuses with the membrane of the CD4 cell using a glycoprotein called GP120, thereby allowing the viral contents to enter the cell, including reverse transcriptase, integrase, and other proteins. 3. Reverse HIV RNA is converted into DNA using the enzyme reverse transcriptase, allowing the transcription virus’ genetic material to enter the nucleus of the CD4 cell. 4. Integration HIV DNA integrates into host DNA using the enzyme integrase. 5. Replication HIV uses the host cell’s machinery to produce long chain HIV proteins which can be used to build more HIV as well as more of its own genetic material (RNA). 6. Assembly New HIV proteins and RNA move to the edge of the CD4 cell and become immature HIV (non-infectious form) 7. Budding Immature HIV is pushed out of the cell and modified by protease enzyme into mature and infectious HIV. IMMUNOLOGY/PATHOPHYSIOLOGY HIV viral load 1. Infected T-CD4 cells → reach lymph nodes and plasma → rapid  in HIV Viral ‘set point’ RNA levels + massive CD4 T- cell (predictive of depletion (especially GI compartment) time of AIDS → ACUTE INFECTION CD4 Tcell count 2. Rebound of CD8 cells +  of plasma HIV RNA levels → Sero-conversion ‘SEROCONVERSION’ symptoms Tim 3. After 6 months → stabilization of HIV Acute Loss of immune control RNA levels at ‘set point’ → variable infection period of time →  in HIV RNA levels +  CD4 T cells once again → consequent pathology ‘AIDS’ Rapid replication rate occurs due to viral escape mutations to evade host immune response. 46  Human Immunodeficiency Virus (Hiv) Monocyte/macrophage lineage: 1. Reservoir of infection 2. Involved in pathogenesis of HIV-associated CNS disease 3. Contribute to impaired host defenses against intracellular pathogens Immune dysregulation in HIV: 1. Serial depletion of CD4+ T-cell population 2. Loss of immune activation of other immune cells (B cells, natural killer cells, CD8+ T cells, macrophages) 47  Human Immunodeficiency Virus (Hiv) CLINICAL SYNDROMES Frequently asymptomatic A. Primary infection Possible brief flu-like illness, (acute HIV, seroconversion) ± rash and lymphadenopathy Asymptomatic phase (median B. Clinical latent infection duration 10 years) (chronic HIV, asymptomatic) May be persistent generalized lymphadenopathy CD4+ T 1. Laboratory CD4+ T cells < cells < 14% OR parameters cells/mm3 total lymphocytes 2. Viral CMV retinitis infection a. Pulmonary or extrapulmonary tuberculosis 3. Bacterial / b. Recurrent pneumonia mycobacterial c. Mycobacterium avium infection (disseminated or extrapulmonary) C. Symptomatic HIV (AIDS- d. Recurrent Salmonella defining clinical septicaemia conditions) a. Oesophageal/tracheal candidiasis 4. Fungal b. Extrapulmonary infection cryptococcosis c. Pneumocystis jirovecii pneumonia a. Kaposi sarcoma b. Invasive cervical cancer 5. Malignancy c. Burkitt lymphoma d. Primary CNS lymphoma 48  Human Immunodeficiency Virus (Hiv) HIV antibody ELISA (caution: 1. ELISA (conventional antibody ‘window period’ before antibody assays) appears) Detection of both HIV-1 and HIV-2 2. Fourth-generation assays antibodies + HIV p24 antigen (reduce window period) 3. Antibody Differentiation For confirmation and differentiation Immunoassay of positive tests For detection of virus in negative 4. Nucleic Acid Amplification test cases 5. Screening for other blood borne viruses (HBV, HCV), syphilis, other sexually In case of positive assays transmitted infections a. Weight loss (wasting syndrome) b. Fever, night sweats c. Rash d. Shingles (varicella zoster reactivation) e. Recurrent skin/nail infections f. Risk of drug side effects 6. Other HIV- g. Persistent associated cryptosporidium/isospora diarrhea symptoms and syndromes h. Bone marrow dysfunction: low platelets, anemia, neutropenia, eosinophilia i. Renal disease: HIV- associated nephropathy j. CNS disease: HIV-related encephalopathy; progressive multifocal leukoencephalopathy; HIV dementia, toxoplasmosis, psychosis, stroke, depression k. Cardiac disease: HIV- associated cardiomyopathy, ischemic heart disease 49  Human Immunodeficiency Virus (Hiv) HIV Testing Algorithm 4th Generation Immunoassay (detects both HIV-1 and HIV-2 antibodies with IgM and IgG antibodies and p24 antigen Positive Negative or inconclusive Repeat on same HIV-1/HIV-2 sample HIV-1 Nucleic Acid Antibody Amplification Differentiation Immunoassay Immunoassay Positive for Positive for Positive for Negative HIV-1 HIV-2 HIV-1 for HIV-1 Consider HIV-2 DNA testing DIAGNOSIS MANAGEMENT British HIV Association (BHIVA) recommendations Aim: To start antiretroviral therapy (ART) promptly in cases with confirmed acute or chronic infection, irrespective of CD4+ T-cell count to consistently suppress viral load, maintain high CD4 cell counts, prevent AIDS, prolong survival, and reduce risk of transmitting HIV to others. Drugs used: 1. NRTI = nucleos(t)ide reverse transcriptase inhibitor 2. PI = protease inhibitor 3. NNRTI = non-nucleos(t)ide reverse transcriptase inhibitor 4. INI = integrase inhibitor 50  Human Immunodeficiency Virus (Hiv) Recommended regimen: e.g. Atazanvir / e.g. Tenofovir + PI ritonavir / emtricitabine darunavir 2 NRTIs PLUS (BACKBONE e.g. Efavirenz / ONE OF OF OR NNRTI etravirine / EITHER THERAPY) nevirapine Abacavir + INI e.g. Raltegravir lamivudine 51  Meningitis and meningoencephalitis MENINGITIS AND MENINGOENCEPHALITIS 1. MENINGITIS: Inflammation of protective membranes (meninges) covering the brain and spinal cord. 2. ENCEPHALITIS: Inflammation of the brain parenchyma 3. MENINGOENCEPHALITIS: Inflammation of both the meninges and brain parenchyma Difference between meningitis and encephalitis: Characteristics Meningitis Encephalitis Definition Inflammation of the protective Acute inflammation of the membranes that cover the brain parenchyma brain and spinal cord (the meninges) Causative agent Bacteria, viruses, fungi Mostly viruses Commonest Streptococcus pneumoniae Herpes simplex virus -1 causes Neisseria meningitidis Japanese encephalitis Forms 1. Acute 1. Primary (virus directly invades the brain) 2. Chronic 2. Secondary or post- infectious (virus first infects another organ then enters the brain) Symptoms 1. Headache 2. Fever 1. Headache 3. Confusion 2. Neck stiffness 4. Drowsiness 3. Fever 5. Fatigue 4. Confusion 6. Seizures or convulsions 5. Altered consciousness 7. Tremors 6. Vomiting 8. Hallucinations 7. Intolerance to light (photophobia) or loud 9. Memory problems noises (phonophobia). 52  Meningitis and meningoencephalitis Diagnosis 1. Physical examination 1. Clinical presentation 2. CSF 2. CSF 3. CBC with differential count 3. Neuroimaging abnormalities 4. C-reactive protein 4. PCR 5. Blood for Gram stain and culture Rash May be present Absent Altered Mental No focal deficits or AMS Altered Mental Status Status Treatment Ampicillin plus an IV acyclovir in hospital for at aminoglycoside or a least ten days. cephalosporin (cefotaxime) ETIOLOGY OF MENINGITIS I-BACTERIAL MENINGITIS 1-Acute pyogenic ( septic ) meningitis: the CSF contains P.N.L o Meningococcal meningitis o Pneumococcal meningitis o Haemophilus influenzae o Staphylococcal meningitis o Listeria monocytogenes 2- Chronic bacterial meningitis: T.B. II-VIRAL MENINGITIS o Enteroviruses (coxsackie A, coxsackie B, echoviruses) o Herpesviruses, e.g. Ebstein-Barr virus, herpes simplex viruses, varicella- zoster virus (causes chickenpox and shingles) o HIV, West Nile fever virus & Lymphocytic choriomeningitis virus. 53  Meningitis and meningoencephalitis III-FUNGAL MENINGITIS: Cryptococcus neoformans : in immunocompromised patients NB: Encephalitis is caused by mostly viral agents Q: Aseptic meningitis: CSF test result is negative with routine bacterial cultures I. Infectious o Viral : the most common cause o TB & fungal infections o partially treated bacterial meningitis II. Non infectious o Drug-induced aseptic meningitis, e.g., ciprofloxacin, metronidazole, penicillin, NSAIDs, carbamazepine, vaccines against hepatitis B and mumps. o Autoimmune diseases e.g., SLE & Behçet syndrome o Subarachnoid hemorrhage 54  Meningitis (Bacterial Meningitis) MENINGITIS (BACTERIAL MENINGITIS) CAUSES 4. Meningococcal meningitis 5. Hemophilus influenzae 6. Streptococci 7. Tuberculosis 8. Staphylococcus aureus (rare) MENINGOCOCCAL MENINGITIS Neisseria meningitides MICROBIOLOGY Gram-negative intracellular diplococci; non-motile Characteristically ‘bean shaped’ PATHOPHYSIOLOGY Most species of Neisseria are harmless commensals → undergo uptake of new genetic material → become pathogenic species via: 1. Production of LPDS capsule 2. IgA protease 3. Pili expression 4. Secretion systems for toxins 5. Molecular mimicry → antigens similar to human antigens so as to evade antibodies 55  Meningitis (Bacterial Meningitis) CLASSIFICATION ≥ 13 serogroups identified, based on capsule; most common are: A Most epidemic meningitis, especially in Africa (‘meningitis belt’); end of dry season B Epidemics and outbreaks (major cause of sporadic disease in UK) C Local outbreaks, e.g. military, ships, universities (pre-vaccination) W135 Hajj outbreaks (Saudi Arabia) and outbreaks in meningitis belt X Rare Y Rare Z Disease only in immunocompromised TRANSMISSION RISK FACTORS Humans are the only known host Travel to high-risk areas Droplet spread, transmitted in Lack of vaccination crowded conditions Household contacts of cases Contact with infected Complement deficiencies nasopharyngeal secretion, blood, Immunocompromise: lupus, asplenia, CSF myeloma EPIDEMIOLOGY Commonly in Sub-Saharan Africa ‘meningitis belt’, mainly meningitis A +/- W135 Bimodal age distribution M > F Cases Winter > summer Age 0-3y 18-23y (end of dry season in Africa) 56  Meningitis (Bacterial Meningitis) CLINICAL SYNDROMES (incubation period 4-5 days) 1. Meningitis alone 2. Bacteremia/toxemia 3. Other (~15%) alone (~25%) presentations/complications Classic signs of Due to organism 1. Nervous meningitis in only endotoxins  Encephalitis ∼50%  Fever up to 39-40C  Hydrocephalus a. Meningeal irritation  Pulse initially slow then  Hemiplegia  Photophobia rapid  Palsy of 3rd, 4th, 6th, 7th cranial  Constant severe  Rash appears as nerves headache petechiea or purpura 2. Eyes associated with  Kernig’s sign positive vasculitis  Purulent conjunctivitis (extension of the knee while hip is fully Can be chronic  Iridocyclitis flexed → painful (associated with  Keratitis spasm of hamstring complement  Blindness (rare) muscle deficiencies) 3. Ears → deafness due to 8th  Brudzinski neck sign nerve affection or otitis media (+ve flexion of neck → flexion of hip and 4. Cardiac → endocarditis or knee) pericarditis  Brudzinski leg sign 5. Respiratory → pneumonia (+ve flexion of one leg 6. Abdominal → flexion of the other  Peritonitis leg)  Adrenal infarction b. Increased intracranial tension 7. Genitourinary tract (ICT) (infection)  Projectile vomiting  Nephritis/pyelitis 57  Meningitis (Bacterial Meningitis)  Headache and  Epididymitis/orchitis convulsions 8. Joint → arthritis of knee and  Bulging anterior shoulder fontanelle (infants) Poor prognostic signs: shock, rash, leukopenia, confusion Diffuse neurological involvement is typical 10–20% permanent sequelae, including deafness DIAGNOSIS 1. CSF examination: a. High-pressure CSF, turbid b. ↑ WCC, high protein (clots on standing), low glucose c. Gram stain 2. Blood picture → marked polymorphonuclear leukocytosis 3. Culture → transparent, non-hemolytic colonies (from blood/CSF/other samples) 4. Serotyping/subtyping/multilocus sequence typing 5. PCR (whole blood) 58  Meningitis (Bacterial Meningitis) MANAGEMENT 1. General → good nursing, antipyretics, analgesics 2. Intravenous antibiotics a. Cefotaxime/ceftriaxone (do not cross uninflamed meninges, but pass into CSF when infection present) b. Alternative: chloramphenicol  sulphadiazine or crystalline penicillin c. Sulphadiazine and crystalline penicillin (infection commonly resistant to sulphonamides, and resistance to penicillin increasing) 3. Corticosteroids → parenteral hydrocortisone in fulminant cases 59  Meningitis (Bacterial Meningitis) PREVENTION 1. Management of contacts 2. Population prevention Risk to contacts is highest in One monovalent conjugate vaccine first week but persists for ≥ 4 1. Meningitis B (menB) weeks