Patient with

Dr Förhécz Zsolt Dehydration fever

Crimean-Congo hemorrhagic fever Febrile convulsions

Fever of unknown origin (FUO) Jaccoud's dissociated fever Lassa fever Jamshedpur fever Metal fume fever ‘Q’ fever Rat bite fever Rheumatic fever Sennetsu fever

Tsutsugamushi fever Valley fever Yellow fever West Nile fever INTRODUCTION

• FEVER(Pyrexia) Is an elevation of body temperature above the normal circadian range (daily variation) as a result of a change in the thermoregulatory center located in the anterior hypothalamus and pre-optic area (i.e. an increase in the hypothalamic set point of 37 C) due to , metabolic derangements or increased cell destruction. • Hyperthermia is a state of elevated core temperature that rises rapidly above 40°C, secondary to failure of thermoregulatio, that occurs when a body produces or absorbs more heat than it dissipates. • Hyperpyrexia — Hyperpyrexia is the term for an extraordinarily high fever (>41.5°C), which can be observed in patients with severe but most commonly occurs in patients with central nervous system (CNS) hemorrhages. Hyperthermia 1.

• In contradistinction to fever, the setting of the thermoregulatory center during hyperthermia remains unchanged at normothermic levels, while body temperature increases in an uncontrolled fashion and overrides the ability to lose heat. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures. It can be rapidly fatal, and its treatment differs from that of fever. • The underlying cause must be removed. Antipyretics do not reduce the elevated temperature. Rapid reduction of body temperature by physical means. Fluids. CAUSES: – Hypohydration is a major cause of hyperthermia. – Overinsulating clothing can result in elevated core temperature – Who work or exercise in hot environments –heat stroke syndromes – Hyperthyroidism Hyperthermia 2.

• Neuroleptic malignant syndrome (butyrophenones(haloperidol) or phenothiazines(promethazine,chlorpromazine) are reported to be at greatest risk, dopaminergic (levodopa), antiemetic (metoclopramide), lithium. • Serotonin syndrome (SSRI) • Anesthetic agents (such as halothane) or the paralytic agent succinylcholine. • Anticholinergics • Drugs that decouple oxidative phosphorylation may also cause hyperthermia. From this group of drugs the most well known is 2,4-Dinitrophenol. • Stimulant drugs, including amphetamines and cocaine, and hallucinogenic drugs, including PCP(Angel dust), LSD, and MDMA (Ectasy) PYROGENS — The term pyrogen is used to describe any substance that causes fever. Pyrogens are either exogenous or endogenous. Endogenous pyrogens belong to the class of biologically active proteins called cytokines.

• Exogenous pyrogens- mainly microbes or their products, such as toxins – lipopolysaccharide endotoxin produced by all gram-negative bacteria – Endotoxins belong to a classification of microbial products termed Toll-like receptor (TLR) ligands. – The toxic shock syndrome toxin (TSST-1) is associated with strains of Staphylococcus aureus – exotoxins from group A Streptococcus act both as direct toxins but also serve as "superantigens"

• Pyrogenic cytokines -Pyrogenic cytokines are specific cytokines produced upon activation of TLR that cause fever – IL-1, TNF, and IL-6, and each or all three cytokines trigger the hypothalamus to raise the set-point to febrile levels

MECHANISMS OF ANTIPYRETIC AGENTS — • The synthesis of prostaglandin E2 (PGE2) depends upon the constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic acid released from the cell membrane, and this release is the rate- limiting step in the synthesis of PGE2. • Inhibitors of cyclooxygenases (either COX-1 or COX-2) are potent antipyretics – Aspirin – Nonsteroidal antiinflammatory agents (NSAIDs), such as naproxen or ibuprofen, are excellent antipyretics – Acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and does not display noteworthy antiinflammatory activity; however, acetaminophen is oxidized in the brain by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity. – Corticosteroids are also effective antipyretics, which act at two levels. • Similar to the cyclooxygenase inhibitors, corticosteroids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2. • Corticosteroids block the transcription of the mRNA for the pyrogenic cytokines.

FACTITIOUS FEVER • This is defined as fever engineered by the patient by manipulating the thermometer and/or temperature chart apparently to obtain medical care. • uncommon and typically presents in young women with a medical and nursing background. • Examples include The dipping of thermometers into hot drinks to fake a fever. • The factitious disorder is usually medical but may relate to a psychiatric illness with reports of depressive illness. • CLUES TO THE DIAGNOSIS OF FACTITIOUS FEVER – A patient who looks well – Absence of temperature-related changes in pulse rate – Temperature > 41°C – Absence of sweating during the period of fever – Normal ESR and CRP despite high fever • Useful methods for the detection of factitious fever include 1) Supervised (observed) temperature measurement 2) Measuring the temperature of freshly voided urine TYPES OF FEVER- The pattern of temperature changes may occasionally hint at the diagnosis:

• Continuous/sustained fever: Temperature remains above normal throughout the day and does not fluctuate more than 1 °C in 24 hours, e.g. lobar pneumonia, typhoid fever, urinary tract infection,

• : The temperature elevation is present only for a certain period, later cycling back to normal (i.e. Normal temp. between fever episodes), e.g. pyaemia, or septicemia.

• Relapsing fever: temperature returns to normal for days before rising -Tertian fever (48 hour periodicity), typical of or

• : Temperature remains above normal throughout the day and fluctuates more than 1 °C in 24 hours , e.g., infective endocarditis.

• Pel-Ebstein fever : A specific kind of fever associated with Hodgkins lymphoma, being high for one week and low for the next week and so on. However, there is some debate as to whether this pattern truly exists. Presenting complaints of a patient with fever

• Feeling hot- A feeling of heat does not necessarily imply fever • Rigors. profound chills accompanied by chattering of the teeth and severe shivering, implies a rapid rise in body temperature. – Can be produced by : 1) brucellosis and malaria 2) with abscess 3) lymphoma • Excessive sweating. Night sweats are characteristic of , but sweating from any cause is usually worse at night. • Recurrent fever. Source is often a focus of bacterial infection such as cholecystitis or cholangitis or urinary tract infection especially associated with an obstruction or calculi. • Headache. Fever from any cause may provoke headache. Severe headache and photophobia, may suggests meningitis. • Delirium. Mental confusion during fever is well described and relatively more common in young children and in old age. • Muscle pain. Myalgia is characteristic of viral infections such as influenza, Malaria and brucellosis. Symptom analysis for fever

• Verify presence of fever- True or factitious fever • Duration- Acute or chronic • Mode of onset- Abrupt or gradual • Progression- Continuous or intermittent. If intermittent ask about frequency to determine the pattern. • Severity- how it affects daily work/physical activities. • Relieving and aggravating factors • Treatment received or/and outcome • Associated symptoms- Localizing symptoms may indicate the source of fever. • Respiratory tract symptoms: – 1) Sore throat, nasal discharge, sneezing-URTI – 2) Sinus pain and headache-suggests sinusitis – 3) cough, sputum, wheeze or breathlessness-suggests a LRTI • Genitourinary symptoms: – Frequency of micturition, dysuria, loin pain, and vaginal or urethral discharge- suggesting a) Urinary tract infection, b) Pelvic inflammatory disease and c) Sexually transmitted infection (STI) • Abdominal symptoms: – diarrhea, with or without blood, weight loss and abdominal pain -suggesting a) Gastroenteritis, b) Intra-abdominal sepsis, c) Inflammatory bowel disease, d) Malignancy • Skin rash: enquire about appearance and distribution as it may provide clues to the diagnosis- – 1) Macular- Measles,Rubella,toxoplasmosis – 2) Haemorrhagic- Meningococcal infections, viral haemorrhagic fever. – 3) Vesicular- Chickenpox, Shingles, herpes simplex – 4) Nodular- Erythema nodosum( TB and Leprosy) – 5) Erythematous- Drug rashes, Dengue fever – Joint symptoms: joint pain, swelling or limitation of movement is suggestive of active arthritis. – A) distribution : mono , oligo or poly arthritis – B) appearance : fleeting 1) infective arthritis- oligoarthritis 2) collagen vascular disease- fleeting 3) reactive arthritis

• Constitutional symptoms: – Weakness – Fatigue – Anorexia – Change of weight – Fever/chills – Lumps – Night sweats HISTORY-Past Medical /Surgical History

• Start by asking the patient if they have any medical problems • IHD/DM/Asthma/HT/RHD, TB/Jaundice/Fits e.g. if diabetic- mention time of diagnosis/current medication/clinic check up • Past surgical/operation history - E.g. time/place/ what type of operation. • Note any blood transfusion / blood grouping. • H/O dental extractions/circumcision & any excessive bleeding during these procedures. • Any minor operations or procedures including endoscopies, dental interventions, biopsies. • History of trauma/accidents- E.g. time/place/ and what type of accident • History of tattoo, piercing • Clinicians should note disorders or factors that predispose to infection, – such as immunocompromise (eg, due to disorders such as HIV infection, cancer, diabetes, or use of immunosuppressants), structural heart disorders, urinary tract abnormalities,operations, and insertion of devices (eg, IV lines, pacemakers, joint prostheses). HISTORY • Drug and allergy History-dosage, timing &how long. • Drug fever is uncommon and therefore easily missed-The culprits include : penicillin and cephalosporin sulphonamide anti tuberculous agents anticonvulsants particularly phenytoin • Vitamins/Traditional /Herbal medicine & alternative medicine such as acupuncture. • Blood transfusion. • Immunization against Hepatitis A &B, Typhoid fever. • Malaria prophylaxis • Family History – Any familial disease/running in families e.g. breast cancer, IHD, DM, Asthma, Arthritis – Infections running in families as TB, Leprosy. Cholera, typhoid in case of epidemics. Personal and Social History • Smoking history - amount, duration & type- strong risk factor for IHD • Alcohol history - amount, duration & type-Unhealthy alcohol use is associated with cardiomyopathy, CVA, liver cirrhosis, alcoholic hepatitis, hepatocellular carcinoma. • Occupation, social & education background, family social support& financial situation, Social class • Home conditions-Water supply, Sanitation status in his home & surrounding, Geographic area of living, fresh-water swimming. • Animals / birds in his/her house- exposure to birds (psittacosis) or animals (toxoplasmosis, brucellosis, leptospirosis) • Consumption of unpasteurized milk or milk products (tuberculosis, brucellosis and Q fever). • Sexual History- Unprotected exposure to sexual partner with STI, HIV • Illicit drug usage- injections and sharing of needles (HIV, hepatitis B &C, infective endocarditis), site of injection (e.g Femoral vein-septic arthritis, ilio-psoas abscess) Travel HistoryTravel to an area known to be endemic for certain disease • Name of the area, duration of stay • Onset of illness- (incubation period) – 1 –10 Days- Malaria, Dengue, Salmonella – 10 –21Days-Malaria,Typhoid,Brucella,HepatitisA – Weeks-Months- Amoebiasis, HIV, Hepatitis • Vital questions-(Always ask about foreign travel). – a) Where have you been? …Endemic area or not ? – b) What have you done? – c) How long were you there? – d) Did you have insect bites or contact with animals? – e) Did you take precautions/prophylaxis against malaria? • If the patient has been in an endemic area The most common diagnoses :Malaria, Typhoid fever, Viral hepatitis, Dengue fever Malaria must be excluded whatever the presenting symptoms Vital signs – Schock DD, SEPSIS!!!

CAUSE of relativ bradycardia • Infectious Causes • Intracellular organisms – Gram-negative bacteria :Salmonella typhi, Francisella tularensis, Brucella spp., Coxiella burnetii (Q fever), Leptospira interrogans, Legionella pneumophila, Mycoplasma pneumoniae – Tick-borne organisms Rickettsia spp., Orientia tsutsugamushi (scrub typhus), Babesia spp., – Other Corynebacterium diphtheriae, Plasmodium spp. (malaria) • Viruses/viral infections Yellow fever virus, Dengue virus, Viral hemorrhagic feversa, Viral myocarditis • Noninfectious Causes – Drug fever, Beta blocker use, Central nervous system lesions, Malignant lymphoma, Factitious fever Diagnostic tests • All of these tests should be viewed as adjuncts to the history and physical examination—not a replacement for them. The selection of initial tests should be based directly on the patient’s history and physical exam findings • White Blood Cell (WBCare often associated with infection,) – – though many viral infections are associated with leukopenia. – bacteria are associated with an increase in polymorphonuclear neutrophils, often with elevated levels of earlier developmental forms such as bands; – viruses are associated with an increase in lymphocytes; – and certain parasites are associated with an increase in eosinophils Causes of an Extremely Elevated Erythrocyte Inflammatory Markers Sedimentati on Rate (>100 mm/h) • The erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) level are indirect and direct measures of the acute- phase response, respectively, that can be used to assess a patient’s general level of inflammation • ESR changes relatively slowly, and its measurement more often than weekly usually is not useful; in contrast, CRP concentrations change rapidly, and daily measurements can be useful in the appropriate context. • Although these markers are sensitive indicators of inflammation, neither is very specific. Cultures

• The mainstays of infectious disease diagnosis include the culture of infected tissue (e.g., surgical specimens) or fluid (e.g., blood, urine, sputum, purulence from a wound). • Samples can be sent for culture of bacteria (aerobic or anaerobic), fungi, or vir • Ideally, specimens are collected before the administration of antimicrobial therapy uses.

Pathogen-Specific Testing • Numerous pathogen-specific tests (e.g., serology, antigen testing, PCR testing) Analysis of Cerebrospinal Fluid (CSF

• Assessment of CSF is critical for patients with suspected meningitis or encephalitis.

• An opening pressure should always be recorded, and fluid should routinely be sent for cell counts, Gram’s stain and culture, and determination of glucose and protein levels. A CSF Gram’s stain typically requires >105 bacteria/mL for reliable positivity; its specificity approaches 100%

• PCR analysis of CSF is increasingly being used for the diagnosis of bacterial (e.g., N. meningitidis, S. pneumoniae, mycobacteria) and viral (e.g., herpes simplex virus, enterovirus) infections; Radiology

• Imaging provides an important adjunct to the physical examination, allowing evaluation for lymphadenopathy in regions that are not externally accessible (e.g., mediastinum, intraabdominal sites), assessment of internal organs for evidence of infection, and facilitation of image-guided percutaneous sampling of deep spaces. – X-ray, CT, MRI, ultrasound, nuclear medicine, use of contra TREATMENT • Physicians often must balance the need for empirical antibiotic treatment with the patient’s clinical condition. • When clinically feasible, it is best to obtain relevant samples (e.g., blood, CSF, tissue, purulent exudate) for culture prior to the administration of antibiotics, as antibiotic treatment often makes subsequent diagnosis more difficult. • Although a general maxim for antibiotic treatment is to use a regimen with as narrow a spectrum as possible, empirical regimens are necessarily somewhat broad, given that a specific diagnosis has not yet been made. • These regimens should be narrowed as appropriate once a specific diagnosis is made WHEN TO OBTAIN AN INFECTIOUS DISEASE CONSULT?

• Multiple studies have demonstrated that an infectious disease consult is associated with positive outcomes for patients with various diseases. • Specific situations that might prompt a consult include – (1) difficult-to diagnose patients with presumed infections, – (2) patients who are not responding to treatment as expected, – (3) patients with a complicated medical history (e.g., organ transplant recipients, patients immunosuppressed due to autoimmune or inflammatory conditions), and – (4) patients with “exotic” diseases (i.e., diseases that are not typically seen within the region). Fever of unknown origin (FUO)

• is defined as fever higher than 38.3ºC on several occasions lasting for at least three (some use two) weeks without an established etiology despite intensive evaluation and diagnostic testing. • Three general categories of illness account for the majority of "classic" FUO cases and have been consistent through the decades. These categories are: – Infections (25 to 50%) – Connective tissue disorders (10 to 20%) – Neoplasms (5 to 35%) – Miscellaneous (15 to 25%) • The most important aspects of the evaluation of a patient with FUO are: – to take a careful history, – perform a detailed physical examination, – and to reassess the patient frequently. FUO is currently classified into 4 distinct categories

• Classic FUO: Fever for > 3 wk with no identified cause after 3 days of hospital evaluation or ≥ 3 outpatient visits • Health care–associated FUO: Fever in hospitalized patients receiving acute care and with no infection present or incubating at admission if the diagnosis remains uncertain after 3 days of appropriate evaluation • Immune-deficient FUO: Fever in patients with immunodeficiencies if the diagnosis remains uncertain after 3 days of appropriate evaluation, including negative cultures after 48 h • HIV-related FUO: Fever for > 3 wk in outpatients with confirmed HIV infection or > 3 days in inpatients with confirmed HIV infection if the diagnosis remains uncertain after appropriate evaluatio

• Infections are the most common cause of FUO.

• In patients with HIV infection, opportunistic infections (eg, TB; infection by atypical mycobacteria, disseminated fungi, or cytomegalovirus) should be sought.

• Common connective tissue disorders include SLE, RA, giant cell arteritis, vasculitis, and juvenile RA of adults (adult Still disease).

• The most common neoplastic causes are lymphoma, leukemia, renal cell carcinoma, hepatocellular carcinoma, and metastatic carcinomas. However, the incidence of neoplastic causes of FUO has been decreasing, probably because they are being detected by ultrasonography and CT, which are now widely used during initial evaluation.

• Important miscellaneous causes include drug reactions, deep venous thrombosis, recurrent pulmonary emboli, sarcoidosis, inflammatory bowel disease, and factitious fever.

• No cause of FUO is identified in about 10% of adults. Physical examination

• The skin is thoroughly inspected for focal erythema (suggesting a site of infection) and rash(eg, malar rash of SLE). Clinicians should also check for cutaneous findings of endocarditis, including painful erythematous subcutaneous nodules on the tips of digits (Osler nodes),nontender hemorrhagic macules on the palms or soles (Janeway lesions), petechiae, and splinter hemorrhages under the nails.

• The entire body (particularly over the spine, bones, joints, abdomen, and thyroid) is palpated for areas of tenderness, swelling, or organomegaly; digital rectal examination and pelvic examination are included. The teeth are percussed for tenderness (suggesting apical abscess).

• During palpation, any regional or systemic adenopathy is noted.

• The heart is auscultated for murmurs (suggesting bacterial endocarditis) and rubs (suggesting pericarditis due to a rheumatologic or infectious disorder). Red flags

• The following are of particular concern: • • Immunocompromise • • Heart murmur • • Presence of inserted devices (eg, IV lines, pacemakers, joint prostheses) • • Recent travel to endemic areas Minimum diagnostic evaluation:

• blood cultures • erythrocyte sedimentation rate or C-reactive protein, • serum lactate dehydrogenase, • HIV antibody test and viral load, • rheumatoid factor, heterophile antibody test, creatine phosphokinase, antinuclear antibodies, • tuberculin skin test or interferon-gamma release assay, • serum protein electrophoresis, • and computed tomography scan of abdomen and chest

Imaging tests are guided by symptoms and signs. • Typically, areas of discomfort should be imaged— – eg, in patients with back pain, MRI of the spine (to check for infection or tumor); – In patients with abdominal pain, CT of the abdomen. – However, CT of the chest, abdomen, and pelvis should be considered to check for adenopathy and occult abscesses even when patients do not have localizing symptoms or signs. • If blood cultures are positive or heart murmurs or peripheral signs suggest endocarditis, echocardiography is done. • In general, CT is useful for delineating abnormalities localized to the abdomen or chest. • MRI is more sensitive than CT for detecting most causes of FUO involving the CNS and should be done if a CNS cause is being considered. • Venous duplex imaging may be useful for identifying cases of deep venous thrombosis. • Radionuclide scanning with indium-111–labeled granulocytes may help localize some infectious or inflammatory processes. This technique has generally fallen out of favor because it is thought to contribute very little to diagnosis, but some reports suggest that it provides a higher diagnostic yield than CT. • PET may also be useful in detecting the focus of fever.

• Biopsy may be required if an abnormality is suspected in tissue that can be biopsied (eg, liver (possible miliary tuberculosis, granulomatous hepatitis, or other granulomatous diseases such as sarcoidosis), bone marrow, skin, pleura, lymph nodes (malignancy, especially lymphoma, or infections such as cat-scratch disease), intestine, muscle). Biopsy specimens should be • evaluated by histopathologic examination and cultured for bacteria, fungi, viruses, and mycobacteria or sent for molecular (PCR) diagnostic testing. • Muscle biopsy or skin biopsy of rashes may confirm vasculitis. • Bilateral temporal artery biopsy may confirm giant cell arteritis in elderly patients with unexplained ESR elevation. • Patients with FUO should not have empiric antibiotics started solely to treat fever. • A therapeutic trial of glucocorticoids for an inflammatory process should not replace relevant biopsies for steroid-responsive disease such as sarcoidosis, other granulomatous diseases, or vasculitis. • The rapid and marked decrease in temperature following a therapeutic trial of naproxen is said to distinguish the fever of malignancy, and especially lymphomas, from infectious causes. • Antipyretics improve patients' comfort, reducing headache, myalgias, arthralgias, and fatigue. In addition, they may also prevent delirium, particularly in older adults, and reduce exacerbations of chronic lung and heart disease. However, drugs with antipyretic effects may delay or obscure early symptoms and signs of specific diseases. Thus, we try to avoid prescribing acetaminophen, nonsteroidal antiinflammatory drugs, or glucocorticoids. The most important aspects of the evaluation of a patient with FUO are

• to take a careful history, • perform a detailed physical examination, • and to reassess the patient frequently.