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Hesham Waly, MD, FACC University of Mansoura College of Medicine
Normal body temperature is maintained, despite environmental variations, because the hypothalamic thermo-regulatory center balances the excess heat production (derived from metabolic activity in muscle and the liver) WITH heat dissipation from the skin and lungs.
The mean oral temperature is 36.8° ± 0.4°C, with low levels at 6 A.M. and higher levels at 6 P.M. Normal diurnal temperature variation is 0.5–1 °C. The normal rectal or vaginal temperature is 0.5 °C > oral temperature, and the axillary temperature is correspondingly lower.
Fever: A.M. temperature: >37.2°C OR P.M.
Pathophysiology Fever: elevation of body temperature > normal daily variation and occurs in conjunction with an increase in the hypothalamic set point i.e. 37°C (normothermic) 39°C (febrile) Hyperpyrexia: fever >41.5°C, resulting from severe infection or CNS hge Hypothalamic fever: elevated temperature caused by abnormal hypothalamic fxn (trauma, hge, tumor, or intrinsic hypothalamic malfunction).
Pyrogenic cytokines (IL-1,6, TNF, IFN) and microbial toxins (Hypothalamic set point (mediated by PGE2 and cAMP (+) Neurons in vasomotor center (+) Peripheral VC and increased metabolic activity (Decrease heat loss peripherally (person feels cold Shivering“ heat production“
FEVER Decreased pyrogens / antipyretic use reset hypothalamic set point VD & sweating (heat loss)
– Microbial products – Microbial toxins
lipopolysaccahride endotoxin of G-negative bacteria Staph aureus enterotoxin GAS and GBS
– Whole microorganisms
Endogenous pyrogens / pyrogenic cytokines
– – – IL-1, IL-6, TNF, ciliary neurotropic factor (CNTF), IFN-α Produced by monocytes, neutrophils, and lymphocytes Production can be induced by infection, trauma, inflammation, and tissue necrosis
Hyperthermia is uncontrolled increase in
body temperature > body's ability to lose heat. In contrast to fever
– The setting of the hypothalamic thermoregulatory center is unchanged – Not mediated by cytokines
Endogenous heat production OR exogenous heat exposure are two mechanisms by which hyperthermia can result in dangerously high internal temperatures.
Heatstroke – Exertional: Exercise in higher-than-normal heat and/or humidity – Nonexertional: occurs in very young or elderly, particularly during heat waves. Anticholinergics, including antihistamines; antiparkinsonian drugs; diuretics; phenothiazines Malignant Hyperthermia: – Rare and fatal, DUE TO inherited abnormality of skeletalmuscle SR that causes rapid increase in intracellular Ca in response to inhalational anesthetics or succinylcholine. – Hyperthermia, muscle rigidity, rhabdomyolysis, acidosis, and CV instability.
Neuroleptic Malignant Syndrome: – Rare and fatal, DUE TO idiosyncratic reaction to major tranquilizers, particularly haloperidol and fluphenazine. – Hyperthermia, "lead-pipe" muscle rigidity, extrapyramidal side effects and autonomic dysregulation. Serotonin Syndrome: Resembles neuroleptic malignant syndrome BUT – Occurs within hrs of ingestion of agents that increase levels of serotonin in the CNS, including serotonin reuptake inhibitors, MAOIs, TCA – Distinguished by the presence of diarrhea, tremor, and myoclonus rather than the "lead-pipe" rigidity
– Amphetamines, cocaine, phencyclidine (PCP), methylene-dioxy-meth-amphetamine (MDMA; "ecstasy"), lysergic acid diethylamide (LSD), salicylates, lithium, anticholinergics, sympathomimetics
– Thyrotoxicosis, pheochromocytoma
– Cerebral hge, status epilepticus, hypothalamic injury www.MansFans.com
When to suggest hyperthermia
High core temperature in patient with Appropriate history (environmental heat exposure or treatment with anticholinergic or neuroleptic drugs, TCA, succinylcholine, or halothane) ALONG WITH Appropriate clinical findings (dry skin, hallucinations, delirium, pupil dilation, muscle rigidity, and/or elevated levels of CPK).
Approach to patient with fever
– recent sick contacts – recent travel (especially overseas deployments or vacations in the preceding year) – environmental exposures associated with jobs or hobbies (such as ticks, mosquitoes, raw sewage, swimming in ground water, etc.) – animal exposure (including pets, birds, reptiles) – unusual dietary habits (such as eating raw seafood, undercooked meat, or unpasteurized milk) – high risk behavior (such as IV drug abuse or sexual behavior--always keep HIV seroconversion in mind) – detailed history of past surgeries (including prosthetic material placed) – hypersensitivities – family illnesses (CT diseases, malignancies, TB)
Understanding the Fever Pattern
The use of antipyretics can alter fever pattern, and they are used so often that "classic" fever patterns are rarely seen.
For example, the usual times of peak and trough temperatures may be reversed in typhoid fever and disseminated TB.
Sustained (Continuous) Fever
– – – Daily elevated temperature (>38 C) Fluctuation of elevated temperature < 0.3 C Examples: Drug Fever, Salmonella
– Daily elevated temperature (>38 C) – Returns to baseline but not to normal
– Intermittently elevated temperature (>38 C) – Return to baseline and to normal
Hectic Fever – Daily elevated temperature (>38 C) – Either remittent or intermittent pattern with wide temperature excursion >1.4 C. – Examples: Intermittent bacteremia (dental abscess, UTI), EBV , FMF, Crohn's Disease, Still's Disease (Juvenile RhA). Relapsing Fever – Malaria: Fever every 3rd or 4th day – Rat Bite Fever: Fever every 3-5 days – Borrelia species: Fever for days followed by 2-3 wks afebrile – Brucellosis: Fever for weeks followed by afebrile period that may be followed by relapse. – Hodgkin’s Disease (Pel-Ebstein Fever): Fever for 3-10 days followed by 3-10 days afebrile – Cyclic Neutropenia: Fever and neutropenia every 3 wks
Vital signs: Temperature-pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, and factitious fever. Skin, eyes, lymph nodes, nail beds, CV system, chest, abdomen, musculoskeletal system, and nervous system In women: do pelvic exam (possible PID)
CBC with special attention paid to the differential. – Neutrophilia and band forms (as well as toxic granulations and Dohle bodies): indicate bacterial infection, while Neutropenia: viral or parvovirus B19, typhoid, brucellosis, TB, histoplasmosis, infiltrative processes of the BM such as malignancy. – Lymphocytosis: viral, typhoid, brucellosis, TB, and atypical lymphocytes: EBV, CMV, HIV, dengue, rubella, measles, varicella, viral hepatitis – Monocytosis: typhoid, brucellosis, TB, or lymphoma. – Eosinophilia: parasitic infections, hypersensitivity drug reaction, or lymphoma. Blood Smear: malarial and babesial pathogens
Urinalysis with examination of the urinary sediment is indicated when symptoms suggest involvement of the GU system. Electrolytes, glucose, BUN, and creatinine should be checked as general measure of the patient’s condition. Liver function tests are also indicated if signs and symptoms point to hepatic involvement. Smears and cultures of specimens from throat, urethra, anus, cervix, or vagina should be obtained when symptoms or signs indicate involvement of those systems. Cultures of blood and urine are indicated whenever the illness is thought to be more than simple viral infection. CSF should be examined and cultured if there is severe headache, meningismus, change in mental status. If signs of increased ICT (focal neurologic deficit or papilledema) are present, CT of the head should be performed to R/O mass lesion before performing lumbar puncture.
Any abnormal fluid collection (pleural, peritoneal, or joint) should be examined and cultured. If fever is severe or prolonged → ESR or CRP as baseline. Non-specific to use for diagnostic purposes, but can be used to follow the patient’s progress. CXR should be considered standard in any patient with unclear diagnosis or if signs and symptoms point to the chest. X-rays of other areas, such as the abdomen or an extremity, may be indicated by the patient’s symptoms.
Repeated Examinations Are Very Important!
TREATMENT OF FEVER
The objectives in treating fever are: FIRST to reduce the elevated hypothalamic set point and SECOND to facilitate heat loss. Oral aspirin and NSAIDs In hyperpyrexia: cooling blankets
Physical cooling with sponging, fans, cooling blankets, and even ice baths should be initiated immediately in conjunction with the administration of IV fluids IV Dantrolene is 1-2.5 mg/kg / 6 hr for 24-48hr, until PO dantrolene can be administered
Fever of Unknown Origin
In 1961, Petersdorf and Beeson defined a fever of unknown origin (FUO) as the following:
Temperature > 38.3°C on several occasions, > 3 weeks' duration of illness, and Failure to reach a diagnosis despite 1 week of inpatient investigation.
FUOs are caused by: Infections (30-40%) Neoplasms (20-30%) Collagen vascular diseases (10-20%) Miscellaneous diseases (15-20%). 5-15% of FUO cases defy diagnosis, despite exhaustive studies
In children, infections are the most frequent cause of FUOs; While, neoplasms and CT disorders are more frequent in the elderly. In patients with FUOs lasting > 1 year, infections and neoplasms decline in frequency, and granulomatous diseases become the most frequent etiology. Patients with undiagnosed FUOs (5-15%) generally have benign long-term course, especially when the fever is not accompanied by substantial weight loss or other signs of serious underlying disease. In patients > 50 yrs, > 30% of FUO cases are related to CT disorders and vasculitic disorders. Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are the 2 principal CT etiologies, and they account for 50% of the cases.
Bacterial diseases – Consider abscesses, which usually are located intraabdominally, even in the absence of localizing symptoms. – TB usually is considered in the FUO differential diagnosis. – UTIs are rare causes of FUO because urinalysis is an easily performed routine test. – Endocarditis. Failure to diagnose it may be due to the absence of a murmur or the failure of blood cultures to yield the organism. – Hepatobiliary infections, cholangitis can occur without local signs and with only mildly elevated or normal liver function tests. – Osteomyelitis usually causes localized pain or discomfort, at least intermittently.
– Brucellosis is very important. Consider this disease in patients with persistent fever and a history of contact with cattle, swine, goats, and sheep or in patients who consume raw milk products. – Systemic infections due to Salmonella species, Neisseria meningitidis, or Neisseria gonorrhoeae as causes of FUO. Cutaneous changes may be the only sign other than fever in neisserial infections. Cultures and serologic tests establish the diagnosis of these infections. – The most important spirochete is Borrelia recurrentis, which is transmitted by ticks and is responsible for causing relapsing fever. Viral diseases – HIV: Prolonged febrile episodes are frequent in patients with advanced HIV infection. 75% of the cases are infectious in nature, about 20-25% are due to lymphomas, and small fraction (0-5%) is due to HIV itself. – CMV and EBV can cause prolonged febrile illnesses with constitutional symptoms and no prominent organ manifestations, particularly in the elderly.
Fungi: Immunosuppression, the use of broad-spectrum antibiotics, the presence of intravascular devices, and TPN all predispose people to disseminated fungal infections, and Candida albicans is the main organism. Parasites: Consider toxoplasmosis in patients who are febrile with LN enlargement; Rising antibody titers and IgM antibodies confirm the diagnosis. If the physician is unaware of history of recent travel to endemic area and if the fever pattern is nonsynchronized, malaria can be missed as a cause of fever. Rickettsia: Chronic infections with Coxiella burnetii, chronic Q fever, or Q fever endocarditis are identified in patients with FUO. Signs of hepatic involvement are frequent, and the infection is transmitted from cattle and sheep. Perform serologic tests in suspected cases. Chlamydia: Consider Chlamydia psittaci, the cause of psittacosis, in patient with FUO who has history of contact with birds.. Serology is essential for the diagnosis of chlamydial infections.
– Lymphomas: Hodgkin and non-Hodgkin lymphomas frequently cause fever, night sweats, and weight loss. The diagnosis can be delayed if the tumor is difficult to detect (eg, when the disease is confined to the retroperitoneal lymph nodes). – Leukemias: Acute leukemias are another important neoplastic group that can cause FUO. In preleukemic states, the peripheral blood smear and BM aspirate may not reveal the correct diagnosis; therefore, perform BM biopsy. – Solid tumors:
Among solid tumors, renal cell carcinoma most commonly is associated with FUO, with fever being the only presenting symptom in 10% of cases. Hematuria may be absent in 40% of cases, whereas anemia and a highly elevated ESR frequently occur. Other solid tumors: Solid tumors such as adenocarcinomas of the breast, liver, colon, or pancreas and liver metastases from any primary site may present with fever.
Collagen vascular and autoimmune diseases: These can present as FUO if the fever precedes other more specific manifestations (eg, arthritis, pneumonitis, renal involvement).
– SLE ,nowadays, it is readily diagnosed in most cases by the
demonstration of ANA.
– Systemic-onset JRA is a cause of FUO that often is difficult to
diagnose. High-spiking fevers, non-pruritic rashes, arthralgias and myalgias, pharyngitis, and lymphadenopathy typically are present.
– Consider other collagen vascular diseases (ie, PAN, RhA, and mixed CT diseases) because of their potential for nonspecific presentations. RF can be difficult to diagnose because it is rare in the developed world .
– Other vasculitides that cause FUO GCA: Classic symptoms include temporal headache, jaw claudication, fever, visual disturbances ,weight loss, anorexia, fatigue, and cough. PMR: This is characterized by symmetrical pain and stiffness involving the lumbar spine and large proximal muscles, most notably the neck, shoulders, hips, and thighs. Symptoms usually are worse in the morning. Constitutional symptoms (eg, fever, malaise, depression, weight loss) also are observed. PAN: ranks a distant third as a cause of FUO.
Granulomatous diseases – Sarcoidosis: Given its multiorgan involvement, it rarely manifests with fever and malaise without evidence of LN and pulmonary involvement. Erythema nodosum occasionally is present, and the finding of noncaseous granulomas in the liver should raise concern. – Regional enteritis: Crohn disease is the most common GI cause of FUO. Diarrhea and other abdominal complaints are common. Diagnose by endoscopy and biopsy. – Hepatic granuloma: TB, syphilis, brucellosis, sarcoidosis, Crohn disease, Hodgkin disease. Endocrine – Hyperthyroidism – Adrenal insufficiency. Consider it in patients with nausea, vomiting, weight loss, skin hyperpigmentation, hypotension, hyponatremia, and hyperkalemia.
Miscellaneous causes – Peripheral PE and occult thrombophlebitis can cause FUO. – Factitious fever is responsible for as many as 10% of FUO cases. Rapid changes of body temperature without associated shivering or sweating, large differences between rectal and oral temperature, and discrepancies between fever, pulse rate, or general appearance typically are observed in patients who manipulate or exchange their thermometers, the most common cause of factitious fever. – Drug fever: The most common are beta-lactam antibiotics, procainamide, isoniazid, alpha-methyldopa, quinidine, and diphenylhydantoin. When suspecting drug fever, discontinue the implicated drug. If the drug, in fact, was responsible for the fever, stopping the drug generally leads to defervescence within 2 days. – Inherited diseases: FMF most often is found, but not exclusively, in patients of Mediterranean descent. Recurrent febrile episodes at varying intervals are associated with pleural, abdominal, or joint pain due to polyserositis. This is a diagnosis of exclusion.
Diagnostic approach to adults with FUO – Inquire about symptoms from all major organ systems, including a detailed history of general complaints (eg, fever, weight loss, night sweats, headaches, rashes). – Record all complaints, even if they disappeared before the exam. Previous illnesses are important, including surgeries and psychiatric illnesses. – Provide a detailed evaluation including the following: Family history Immunization status Occupational history Travel history Nutrition (including consumption of dairy products) Drug history (over-the-counter medications, prescription medications, illicit substances) Sexual history Recreational habits Animal contacts (including exposure to ticks and other vectors)
Definitive documentation of fever and exclusion of factitious fever are essential early steps in the physical exam. – Measure the fever more than once. – Electronic thermometers facilitate the rapid and unequivocal documentation of fever. The pattern of fever (continuous, remittent, intermittent) usually is of little help in the evaluation. – In general, correlation between fever patterns and specific diseases is weak. Notable exception is malaria. – Other diseases (eg, brucellosis, borreliosis, Hodgkin disease) tend to cause recurrent episodes of fever. Repeat physical exam daily while the patient is hospitalized. Pay special attention to rashes, new or changing cardiac murmurs, signs of arthritis, abdominal tenderness or rigidity, LN enlargement, funduscopic changes, and neurologic deficits.
Lab Studies: – CBC count and microscopic examination – Anemia suggests serious underlying disease. – NOT miss leukemias in aleukemic or preleukemic cases. – Lymphocytosis with atypical cells suggests herpesvirus. – Leukocytosis suggests occult bacterial infection. – Direct exam of peripheral blood smear to diagnose malaria and spirochetal diseases. – Urinalysis: – Exclude UTIs and malignant tumors of the urinary tract; however, not all of them consistently are associated with pathologic findings in the urine. – Serum chemistry – At least one liver function test is usually abnormal, with an underlying disease originating in the liver or a disease that causes nonspecific alterations of the liver (eg, granulomatous hepatitis).
Cultures – Blood cultures are essential in the evaluation. – Routinely culture the patients' urine. – Cultures of sputum and stool may be helpful in the presence of signs or symptoms suggestive of pulmonary or GI disease, respectively. – Obtain cultures of tissues and liquids that are sampled during workup. These tissues and fluids include CSF, pleural or peritoneal fluid, and fluid from the liver, bone marrow, and lymph nodes. Serologies – Serologies are most helpful if paired samples show significant, usually 4-fold, increase of antibodies specific to infectious microorganism. Other tests – Frequently check ANA titers, rheumatologic factor, thyroxine level, and ESR because they are helpful in diagnosing selected condition (SLE, RhA, thyroiditis, hyperthyroidism, GCA, PMR).
Imaging Studies: – Routinely CXR. – Routine abdominal US, even in the absence of signs of an intraabdominal process. – CT scans If US studies fail to help reveal the diagnosis, obtain CT scans of the abdomen in all patients with
– symptoms suggesting intraabdominal process, – suspected retroperitoneal tumors or infections, – abnormal liver function tests.
IV pyelography may be more sensitive than the CT scan in detecting processes involving the descending urinary tract, but the CT scan is preferred for most other processes of the retroperitoneal space. – MRI can be very useful in cases where osteomyelitis is suspected.
Other Tests: – Endoscopic examination Endoscopic exam of the upper and lower GI tract, including retrograde cholangiography when searching for Crohn disease, Whipple disease, biliary tract disease, and GI tumors. Occasionally, complementing endoscopic studies with barium enemas or upper GI series is necessary. – Radionucleotide studies V/Q scan to document PE. Obtain pulmonary angiography when suspecting PE. Tc bone scan for diagnosis osteomyelitis. Gallium citrate or granulocytes labeled with indium In 111 scan for diagnosis of occult abscesses. – ECHO: This technique is highly sensitive in diagnosing endocarditis.
The final diagnosis is obtained during direct biopsy examination of involved tissue.
– Biopsies are easily performed in enlarged accessible lymph nodes, other peripheral tissues, and bone marrow. – The decision to biopsy is more difficult if it necessitates exploratory surgical procedure (eg, laparotomy). This rarely is indicated (eg, when imaging techniques are nondiagnostic and an intraabdominal source is suspected). www.MansFans.com
Medical Care: Direct treatment toward the underlying cause. Surgical Care: Because of a better understanding of the etiologies and careful diagnostic approaches, patients with FUO rarely need surgical treatment.
Further Inpatient Care:
– 5-15% of patients remain undiagnosed, even after extensive evaluations. These patients usually have benign long-term course, especially in the absence of substantial weight loss or other signs of serious underlying disease. – No evidence supports prolonged hospitalization in patients who are clinically stable and whose workup is unrevealing.
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