Fever without Localizing Signs and Symptoms - Non-infectious Causes of Fever (Table 2)

Table 2: Non-infectious Illnesses That May Present with Fever

Drug fever Malignancies: AML lymphoma hepatocellular carcinoma or metastasis to the liver renal cell carcinoma Collagen vascular diseases: vasculitis   temporal arteritis SLE Still’s disease Miscellaneous: rheumatic fever sarcoidosis inflammatory bowel disease thromboembolic disease thyroid disease gout

AML = acute myelogenous leukemia, SLE = systemic lupus erythematosus

Drug Fever

        Drug reactions can present with rash, fever, and/or eosinophilia, although all three symptoms occur in only a minority of cases. A previous history of drug allergy is present in less than 10% of the patients. The onset of a drug reaction occurs after an average of 7 days of drug use though drug reactions may occur as long as three weeks after initiation of the offending agent. No distinguishing fever pattern or temperature height helps to differentiate drug fever from other infectious or non-infectious causes of fever. Temperatures greater than 103^o (F) can occur along with shaking chills in over half of the patients. Relative bradycardia is uncommon. The rash, if it occurs, is a pruritic maculopapular erythema covering most of the body. It has been reported in less than 20% of patients with a drug reaction. Leukocytosis can be seen. Eosinophilia is reported in 22% of patients but is generally mild and does not correlate with the severity of the reaction. Once the implicated drug is discontinued, the fever almost always resolves within 24-36 hours. Agents that can cause drug fever are listed in Table 3. Sympathomimetic agents such as epinephrine, cocaine and amphetamines can cause temperature elevation. Large doses of anticholinergic agents such as atropine, trihexyphenidyl or benztropine mesylate may also cause fever. Amphotericin B and bleomycin can act as pyrogens causing fever during or shortly after administration. The Jarisch-Herxheimer reaction is a febrile reaction caused by the bacteriocidal effect of penicillin on Treponema pallidum during the treatment of syphilis. Chemotherapy-induced tumor cell lysis can result in febrile reactions. Malignant hyperthermia and neuroleptic malignant syndrome are other drug induced causes of fever. See Chapter 1. Acute hemolysis and fever can occur in the glucose-6-phosphate dehydrogenase deficient individual exposed to sulfonamides, antimalarials, nitrofurantoin, quinidine and chloramphenicol.

Table 3: Drugs That Can Cause Fever
Antimicrobial beta lactams: penicillins cephalosporins sulfonamides TMP-SMX amphotericin b tetracycline macrolides streptomycin vancomycin isoniazid para-aminosalicylic acid nitrofurantoin mebendazole	Cardiovascular quinidine procainamide hydralazine methyldopa nifedipine triamterene	Central nervous system carbamazepine phenytoin barbiturates chlorpromazine haloperidol thioridazine amphetamine
	Anti-inflammatory salicylates ibuprofen tolmetin
Anti-neoplastic bleomycin asparaginase daunorubicin procarbazine cytarabine streptozocin 6-mercaptopurine chlorambucil hydroxyurea	Miscellaneous allopurinol antihistamine iodide cimetidine levamisole metoclopramide clofibrate	folate prostaglandin e2 ritodrine interferon streptokinase propylthiouracil

 *bolded drugs are the most common causes of drug fever

 Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

Malignancy

        Fever may be a presenting symptom or part of a symptom complex in a patient presenting with malignancy. The most common malignancies that can cause fever include lymphoma, acute leukemia, hepatocellular carcinoma, renal cell carcinoma and various solid tumors with metastasis to the liver.

AML:    Fever is the presenting symptom in 10% of patients with acute myelogenous leukemia, although a portion of these will have associated neutropenic fever related infection that is actually causing the fever.

Lymphoma:    Malignant lymphoma, including Hodgkin’s Disease and Non-Hodgkin’s Lymphoma, is the most common cancer to cause fever. It is present in as many as 25-30% of patients with Hodgkin's disease and less than 20% in Non-Hodgkin’s lymphoma. The classic, but infrequent, Pel-Ebstein fever of Hodgkin’s disease is a pattern of relapsing episodes of evening fevers that last for 3 to 10 days alternating in cyclic fashion with afebrile periods.

Hepatocellular Carcinoma or Hepatoma:    Hepatocellular carcinoma or hepatoma generally occurs in the setting of underlying cirrhosis especially if caused by chronic hepatitis B or C virus infection. Hepatic metastasis from solid tumors such as from breast, lung, and gastrointestinal cancers can occasionally cause fever.

Renal Cell Carcinoma:    Renal cell carcinoma most often presents with hematuria or flank pain, although fever occurs in about 20% of patients. The persistently febrile patient with hematuria in whom a urinary track infection is not clearly the source should be suspected of having renal cell carcinoma. 

Collagen Vascular Disease

Vasculitis:    The vasculitis is a heterogeneous group of illnesses characterized by inflammation of the blood vessels. Vasculitis can exist as a primary disorder or as a secondary manifestation of infections (hepatitis B and C virus, Epstein-Barr virus, infective endocarditis), rheumatologic diseases (systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome), and certain malignancies (hairy cell leukemia). Table 4 summarizes the better defined primary vasculitic syndromes.

• Temporal arteritis, also known as cranial or giant cell arteritis, is a disease of the elderly characterized by headache, scalp tenderness, thickened tender or pulseless temporal artery, jaw claudication, fever, anemia, and markedly elevated ESR. However, it can often present subacutely with fever and nonspecific constitutional symptoms. The occurrence of temporal arteritis is closely associated with polymyalgia rheumatica. The ESR is usually > 50 in over 80% of cases.

Table 4: Vasculitis Syndromes
Syndrome	Population at risk	Symptoms	Organs involved	Laboratory assessment
Polyarteritis  nodosa	middle-aged men>women	fever, wt loss, rash, abdominal pain, arthralgia	kidneys, GI tract, skin, peripheral nerves	leukocytosis anemia, ↑ESR, p-ANCA, HbsAg, U/A
Churg-Strauss	middle-aged men>women	fever, wt loss, rash, asthma	lungs, skin, peripheral nerves	eosinophilia, p-ANCA, abnormal CXR
Wegener’s granulomatosis	male or female, adolescent to middle aged	fever, wt loss, nasal ulcers, cough, sinusitis, hemoptysis, arthralgia	upper and lower respiratory tracts, kidney	Leukocytosis, anemia, ↑ESR c-ANCA, U/A, abnormal CXR
Takayasu’s arteritis	young female, more common in Orient	fever, wt loss, arthralgia, loss of peripheral pulses, pain over vessels	aortic arch and branches	arteriography
Henoch Schönlein purpura	children and young adults	palpable purpura, arthralgia, abdominal pain, bloody stool	skin, kidneys, GI tract	U/A
Essential mixed cryoglobulinemia	middle aged women	purpuric lesions, ulcers, arthralgia, Raynaud’s phenomenon	kidney, skin	low C3, C4, CH50, U/A, HCV antibody

Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

ESR = erythrocyte sedimentation rate, ANCA = antinuclear cytoplasmic antibody, U/A = urinalysis, HbsAg = hepatitis B virus surface antigen, CXR = chest x-ray, GI = gastrointestinal, C = complement, HCV = hepatitis C virus

SLE:    Systemic lupus erythematosus is a multisystem disease characterized by a rash, arthritis, polyserositis, fever, oral or nasal ulcerations and fatigue. Most patients with fever caused by systemic lupus erythematosus show clinical evidence of active disease affecting multiple organ systems associated with leukopenia and high titers of antinuclear antibody.

Still's Disease:    Still’s disease is a disorder of unknown etiology characterized by seronegative polyarthritis, fever and rash. The illness has a bimodal age distribution. The first peak, termed “systemic-onset juvenile rheumatoid arthritis”, occurs in childhood. The second peak, labeled “adult-onset Still’s disease”, occurs in the third or fourth decade. The rash is evanescent, salmon-colored, macular or maculopapular, nonpruritic, and typically occurs over the neck, trunk and extensor aspects of extremities. There is often a leukocytosis and marked elevation of the erythrocyte sedimentation rate (ESR).       

Miscellaneous

        Rheumatic Fever:    Acute Rheumatic Fever is a sequela of Streptococcus pyogenes pharyngitis. The antecedent pharyngitis is asymptomatic in about half of the patients. All patients demonstrate serologic evidence of recent S. pyogenes infection. The latent period between pharyngitis and onset of acute rheumatic fever averages 18 days. Patients may present with carditis, polyarthritis, chorea, subcutaneous nodules and/or erythema marginatum. Fever is one of the minor Jones Criteria.

        Sarcoidosis:    Sarcoidosis is a chronic multisystemic disease of unknown etiology characterized by noncaseating granuloma formation primarily in the lungs and lymph nodes. It is more prevalent in women and African-Americans. It typically presents in persons 20-40 years of age with bilateral hilar lymphadenopathy, pulmonary infiltrates, and ocular and dermatological manifestations. Fever, if present, is usually seen in association with erythema nodosum, polyarthralgia and hilar lymphadenopathy.

        Inflammatory Bowel Disease:    Crohn’s Disease and ulcerative colitis are idiopathic inflammatory bowel diseases typically presenting with diarrhea and abdominal pain often associated with fever, fatigue, anorexia and weight loss. Some patients, particularly the elderly, may present with unexplained fever.

         Thromboembolic Disease:    Pulmonary embolism most often presents as the sudden onset of pleuritic chest pain, shortness of breath and hemoptysis. Fever may be associated with these symptoms and rarely be the presenting symptom. Deep venous thrombosis can occasionally cause fever in addition to the more usual symptoms of pain, swelling and erythema often suggestive of cellulitis.

        Thyroid Disease:    Hyperthyroidism can produce fever through excess thyroid hormone altering thermoregulation. Thyroiditis, an inflammatory disorder of the thyroid, can cause both cytokine release and thyroid hormone leakage from the injured gland to incite fever.

        Gout:    Gout is an acute inflammatory arthritis due to deposition of sodium urate crystals in the joints. The affected joint or joints are painful, swollen and erythematous and often are clinically indistinguishable from a septic arthritis. Fever may accompany the acute arthritis. In severe polyarticular attacks, high fevers and systemic toxicity are not unusual.