Week 2 - PUO, Arboviral and other Tropical infections Flashcards
What is fever?
• Pyrexia/fever = body temp increase by 1-4˚C. Protective - not fully known* (protective mechanism although mechanism not fully known).
Outline the pathophysiology of fever/inflammation.
• Inflammation is a defence mechanism with local and systemic effects and tissue injury. Also initiate healing process.
• Pyrogens (substances that induce fever) are important chemical mediators for inflammation and fever.
- Exogenous pyrogens: bacterial products, LPS (lipopolysaccharides).
- Endogenous pyrogens: IL-1, IL-6, TNF.
• Pathogenesis: pyrogens → increase cyclooxygenase → prostaglandins (PGE2) in hypothalamus → reset thermal clock → fever (pyrogens act by increasing cyclooxygenase levels and prostaglandin synthesis (particularly PGE2) in hypothalamus → reset thermal clock causing fever).
• During fever, there is peripheral vasoconstriction to conserve heat and central organ vasodilation → results in central core body temp increase.
- NSAIDs inhibit cyclooxgenase in hypothalamus → reduce systemic effects and local tissue injury without significantly affecting defence mechanism (inhibit the clinical features of pain and fever but do no significantly effect the defence mechanism). Routinely used unlike steroids, which totally block defence mechanism.
- Defective inflammation (e.g. diabetes mellitus) - increased infections, immunosuppression (defective inflammation → when there is abnormality of blood vessels e.g. diabetes → develop increased infections due to immunosuppression).
Identify the local and systemic effects of inflammation.
• Any damage to any tissue → releases chemical mediators e.g. TNF, IL-1, IL-6.
• Local inflammation:
- Apart from vascular changes, these chemical mediators are also released by WBCs → produce all the effects of what we see clinically - pain, fever, swelling (features of inflammation).
• Systemic protective effects:
- Act on the brain to produce fever through the mechanism of prostaglandins.
- Act on the liver to produce acute phase proteins e.g. CRP, SAA, fibrinogen.
- Stimulate the bone marrow to produce and release more WBCs.
• Systemic pathological effects (all the features of inflammation due to chemical mediators):
- TNF causes decreased cardiac output, shock in case of septicaemia.
- Thrombosis, vascular damage, increased permeability.
- Defective muscle metabolism due to insulin resistance (weakness, loss of weight).
• All the features of inflammation are mainly mediated by the 3 inflammatory mediators - TNF, IL-1, IL-6*
Define pyrexia of unknown origin (PUO/FUO) and identify the 4 types.
• ‘Lack of diagnosis of cause of fever’ (fever without any clinical diagnosis of cause → PUO).
- Classic PUO: >38.0˚C > 3 weeks.
- Nosocomial PUO (hospitalised patients): >38.3˚C, > 1 week of inpatient or > 3 days of investigations.
- Neutropenic PUO: >38.3˚C < 1x10^9 neutrophils (decreased neutrophils).
- HIV associated PUO: >38.3˚C > 4 week outpatient or > 3 days inpatient.
What are the causes of PUO?
- Infective - abscess, TB, viral infections, parasitic etc.
- Malignant - Hodgkins, Non-Hodgkins lymphoma, others (most common is lymphoma - lymphocytes release chemical mediators - endogenous pyrogens → produce more fever. Other malignancies can also be a cause but less common).
- Inflammatory (autoimmune disorders) - giant cell arteritis, SLE, rheumatic fever, ARF, sarcoidosis, rheumatoid arthritis (diagnosis very difficult).
- Undetermined: MI, PE, drugs, endocrine, hepatic, allergic, CVA etc.
- Unknown in around 19% of cases (even after many days of investigations, 19% of patients might not be diagnosed at all).
- Any tissue damage - but when the diagnosis is not made within these periods - cases labelled as PUO.
- Overall mortality of PUO is 30-40%, mainly attributable to malignancy in older patients.
- If no cause is found, the long-term mortality is low and the fever often settles spontaneously.
Outline the clinical approach to PUO.
- History:
• Is first important to confirm temperature.
• Look for signs usually accompanying fever (e.g. tachycardia, chills).
• Take a thorough history:
- Enquire about symptoms from all major systems.
- Include general complaints (e.g. fever, weight loss, night sweats, headache, rash).
- Record all complaints even if they are not currently present.
- Previous illness including surgery and psychiatric problems are important.
- Discuss nutrition including consumption of dairy products.
- Immunisation status.
- Family history of illness (e.g. is anyone else in the family sick).
- Occupational history including exposure to chemicals/animals.
- History of travel and recreation (e.g. possible exposure to ticks/mosquitoes).
- Sexual history.
- Drug history (including OTC, prescription and illicit substances).
• Some associations to consider include:
- Fever and sweats (influenza-like illness).
- Rash (consider leptospirosis, Q fever, lyme disease).
- Cough or atypical pneumonia (consider Q fever, leptospirosis, orf, anthrax).
- Papular/pulstular lesions (consider orf, anthrax).
• Also consider possibility of patient ‘making up’ high fevers. - Physical Examination:
• Documentation of fever - measure fever more than once and in presence of another person.
• Physical examination should be repeated daily while the patient is in hospital, looking for:
- Rashes.
- Lymph node enlargement.
- Signs of arthritis.
- New/changing cardiac murmurs.
- Abdominal tenderness or rigidity.
- Fundoscopic changes and neurological deficits. - Investigations:
• Blood tests: FBC, ESR, U+Es, CRP, LFTs, Rh factor and TFT.
• Cultures: urine, sputum, stool, CSF and morning gastric aspirates (if suspect TB).
• Imaging: CXR, abdominal CT, echocardiogram (if suspect endocarditis), MRI, PET.
• Other:
- Lumbar puncture for headache.
- Skin biopsy for rash.
- Lymph aspiration or biopsy for lymphadenopathy.
- Bone marrow aspiration or biopsy in HIV positive patient.
- Serological tests for CT disorders (autoantibody, complement, Ig, cryoglobulins).
What are arboviral infections?
- Group of RNA viruses, zoonotic infections of wild animals (infections limited to wild animals).
- Spread by insects (arbo - mosquito most common) to man, no person to person spread.
- Increasing incidence, epidemics - global warming (increased incidence due to global warming causing an increase in insects).
- All notifiable diseases.
Identify the clinical features of common viruses.
- Polyarthralgia - RRV (most common), Barmah Forest.
- Fever and rash - Dengue (most common), RRV.
- Encephalitis - Murray Valley encephalitis.
- Febrile illness - Dengue, Murray Valley.
Identify different alphaviruses and flaviviruses.
Alphavirus:
• RRV.
• Barmah Forest.
• Chikungunya.
Flavivirus: • Dengue. • Murray Valley encephalitis. • Kunjin. • Japanese encephalitis. • West Nile encephalitis. • Kokobera.
- RRV and Dengue contribute to the majority of arboviral diseases followed by Barmah Forest and Kunjin etc.
- Almost all of these disorders can present with a febrile illness - RRV and Dengue are the two most important (more common).
- Bunyavirus (e.g. Colorado tick fever) not common in Australia - another group of arbovirus.
Describe arbovirus transmission in Australia.
- Transmitted to humans when we come in contact with mosquitoes or the wildlife (from animals through mosquitoes).
- Important part in the history would be the location in the tropical region or travel to the tropical region. Commonest in NQ, NT and all the Asia Pacific countries (tropical).
Outline Ross River fever:
- Epidemiology.
- Transmission.
- Incubation period.
- Clinical features.
- Diagnosis.
- Treatment.
Epidemiology:
• Australia’s most prevalent insect borne disorder.
• AKA endemic polyarthritis ~4000/year - long term joint pain/arthritis → have to consider RRV as one of the causes.
• First isolated from mosquitoes trapped beside Ross River near Townsville in 1959.
Transmission:
• Alphavirus transmitted by Culex/Aedes agypti mosquito.
• No person to person spread.
Incubation period:
• 3 day-3 week incubation (3-11 days commonest) - most incubation periods for arboviruses are 1 week.
Clinical features:
• Classic presentation - fever, fatigue, arthritis, rash.
• Red maculopapular rash after 1-10 days. No itching.
• Symptoms - fever, arthritis (pain in wrists, knees, ankles, joints in hands and feet), rash, muscle pains, fatigue (debilitating), headaches, lymph node enlargement (swelling). Symptoms can last years.
• Ross River disease - when there is no fever (fever is not present in all cases).
Diagnosis:
• 4 fold increases in serum antibody levels confirms diagnosis - IgG and IgM.
Treatment:
• There is no treatment or cure for Ross River fever - people take all types of alternative medicine because there is no specific treatment (no anti-viral).
• Self limited 4-7 months (recover fully after 4-7 months but some patients go on for years).
Outline Dengue fever:
- Epidemiology.
- Characteristics.
- Transmission.
- Incubation period.
- Clinical features.
- Complications.
Epidemiology:
• Break bone fever, Dinga ~ evil spirit, increasing - global warming (increased insects).
• Children affected more commonly.
Characteristics:
• Flavivirus.
• 4 serotypes DEN 1-4. Weak cross protection among serotypes - reinfection causes very severe form of dengue. First time is mild.
Transmission:
• Vector - Aedes aegypti (white band) feeds during day - white banded mosquito that feeds during day unlike other mosquitoes (night).
Incubation period:
• Incubation period: 4-7 days (3-14 days).
Clinical features:
• Fever, myalgia, abdominal pain, headache, arthralgia and serositis.
• Marked muscle and joint pains (break bone fever) - characteristic.
• Fever 5-7 days biphasic. Saddleback fever curve - initially high fever, comes down and then rises again.
• Infective period: 3-5 days/during fever. Needs 8-12 days maturation in mosquito to infect other person (transmitted person to person via mosquito).
• Asymptomatic self-limited → death due to shock (ranges from initial attack - mild asymptomatic to severe - death due to shock).
• 2 clinical forms - febrile form flu-like or classic Dengue fever - flu-like fever or with joint pain etc.
Complications:
• Immune complications - DHF and DSS in re-infection (immune complications occur in some cases particularly after re-infection - dengue haemorrhagic fever and dengue shock syndrome - high fatality).
Explain the pathophysiology of Dengue fever.
Viral non structural protein (NS) release proteases, cause inflammation and block IFN response. • Inflammatory rush. • Cytokine and activate T cells. • Endothelial damage. • Plasma leakage. • Platelet activation. • Thrombocytopenia. • Serositis. • Hepatitis. • Shock.
- Dengue virus causes severe activation of inflammation → stimulates macrophages, T lymphocytes and causes release of cytokines.
- Particularly NS proteins in the virus that cause all of the inflammatory responses.
- Also directly release proteases → causes endothelial damage, leakage of plasma.
- Blood becomes thick because of loss of fluid (severe hydration).
- Loss of protein, particularly albumin resulting in hypoalbuminaemia.
- Platelet activation leads to thrombocytopenia due to endothelial damage.
- Patients develop serositis - pleural/peritoneal inflammation causing accumulation of fluid - ascites.
- Shock - severe due to dehydration.
Outline Dengue haemorrhagic fever (DHF).
4 criteria for DHF:
- Fever or recent history of acute fever.
- Haemorrhagic manifestations.
- Low platelet count (<100 x 10^9/L).
- Objective evidence of ‘leaky capillaries’ (increased permeability):
- Elevated haematocrit (<20% - due to loss of fluid).
- Ascites, pleural and other effusions.
- Low albumin.
4 grades of DHF:
• Grade 1 - fever and non-specific symptoms.
• Grade 2 - spontaneous bleeding.
• Grade 3 - circulatory failure.
• Grade 4 - profound shock - Dengue shock syndrome (DSS).
- Grade 1 and 2 - slight haemorrhage.
- Grade 3 and 4 - severe haemorrhage.
- Usually follows the first phase of just fever → then manifests with haemorrhage → low platelet count because of endothelial damage. Patient presents with severe bleeding.
What are the initial warning signals and alarm signals of DHF?
3 to 6 days after onset of fever, joint pain, rash.
Initial warning signals:
• Disappearance of fever.
• Drop in platelets.
• Increase in haematocrit.
Alarm signals: • Shock. • Prolonged vomiting. • Fever to hypothermia. • Change in level of consciousness.
