Diagnosis of fever of unknown origin

LOUIS REZNICK, D.O. Glendale, New York

nosis. Most FUO is not caused by rare disease, but Fever of unknown origin is often rather by an atypical presentation of a common an atypical manifestation of a disease. In the United States, tuberculosis is the common disease, consequently most common infectious cause. Fever is caused representing a diagnostic challenge mostly by two factors: (1) release of endogenous to the clinician. The systematic leukocytic pyrogen and body-cell prostaglandins; approach to diagnosis is best. To be and (2) hypothalamic dysfunction. Pyrogen and considered in the etiology are prostaglandins are released in response to six main infection, neoplasm, connective causes. The first is infection, which may be bacter- tissue disease, drugs, tissue ial, rickettsial, viral, mycoplasmal, fungal, or necrosis, and blood in body cavities. parasitic. Fungus and parasites are more common in a compromised host. The second cause is neo- plasm. Fever in cancer patients is often caused by infection resulting from impaired immunity or obstruction; otherwise, cancer stimulates release of pyrogen and prostaglandins through tissue ne- Fever of unknown origin (FUO) is one of the most crosis and hemorrhage. The third cause is connec- challenging diagnostic problems in medicine. tive tissue disease (CTD). The most common of Diagnosis is best accomplished by a systematic ap- these are juvenile rheumatoid arthritis (JRA ), proach, which is the focus of this paper. which may occur in adults, and systemic lupus Three criteria define FUO. One criterion is fever. erythematosus (SLE). The fourth cause is drugs. It must be greater than 101 F. on several occasions. The offending agent may be an over-the-counter This rules out habitual hyperthermia in which medication, an anesthetic agent, or an immuniza- there is a temperature of one degree above normal tion. The fifth cause is tissue necrosis such as oc- for unknown reasons, but no disease is present. It curs in myocardial infarction, pulmonary infarc- also rules out the normal diurnal temperature var- tion, or peripheral gangrene. The sixth cause is iation; depending on environmental temperature blood in body cavities (hemothorax, hemoperitone- and activity of people, the temperature normally urn, or retroperitoneal hematoma). reaches 100.2 F. in the late afternoon. Hypothalamic dysfunction is the second mecha- The second is unknown origin. Most fevers can be nism of fever production and is caused by intracra- diagnosed by history and physical, complete blood nial abnormalities such as tumor, infection, and count, urinalysis, venereal disease reaction level hemorrhage. Hypothalamic dysfunction, along (VDRL), SMA-12 survey, EKG, posteroanterior with drug-induced fever, tissue necrosis, and blood and lateral chest x-ray, antistreptolysin 0 titer in body cavities comprise 10 to 15 percent of cases of (ASOT), (Monospot test, and intermediate purified FUO.3 protein derivative skin test (PPD). In FUO, after these diagnostic elements are evaluated, there is Diagnosis still unknown origin. Thus, this criterion rules out After a careful and detailed history and physical diseases that are easily diagnosed by these tests. examination, the first step is to stop all drugs un- The third characteristic is ongoing. The fever less they are absolutely essential to survival. They lasts for 10 days or more, 2 thus ruling out self- may be the cause of fever or complicate its diag- limited infections. If treatment is started, the fever nosis by masking signs and symptoms or may pro- does not respond or returns when treatment ends. duce side effects mistaken for the signs and This rules out uncomplicated disease for which the symptoms of the illness producing the fever. treatment would have worked, and it also excludes Always ask the patient if he is or was taking drugs. self-limited infections. Pinning down a diagnosis of drug-induced fever can The etiology of FUO is shown in Table 1. save the patient from unnecessary hospitalization Although 5 to 10 percent of FUO cases go un- and diagnostic tests. Ask about drug addiction and diagnosed, they usually have a favorable prog- examine the patient for needle marks, since self-

Diagnosis of fever of unknown origin 714/107 TABLE L ETIOLOGY OF FEVER OF UNKNOWN ORIGIN. system. SBE is suggested by recurrences of bacte- remia after treatment, petechiae, neurologic signs Percent and symptoms secondary to septic emboli, and Endogenous pyrogen and prostaglandins echocardiography showing vegetations on heart Infection 40 Neoplasm 20 valves and premature closure of heart valves. Be- Connective tissue disease 20 cause blood culture yield depends on the amount of Drugs blood taken, a 10 cc. sample taken every hour (x 3) Tissue necrosis 15 Blood in body cavities for two days is recommended.5 There are two situa- Hypothalamic dysfunction tions where this amount of blood cannot be spared. Undiagnosed 5 One is pediatric patients. In children, 2cc. may be taken and a check for anemia and leukopenia must be done before more blood for culture is taken. The second situation is anemia and/or leukopenia in administered injections carry a high risk of fatal adults, which limits the amount of blood that may staphylococcal endocarditis. Anesthesia for dental be taken to 20 cc. 4 A repeat complete blood count or surgical procedures as well as over-the-counter (CBC) must be done before more blood can be medications are often overlooked causes of FUO. drawn, and if the leukocyte count falls to 4,000/cu. Finally, do not overlook occupational exposure to mm., transfusion becomes necessary. 4 Anemia re- chemicals as a possible cause. quires blood transfusion before blood for cultures can be considered; however, stains of thick periph- The second step is to control the fever by aspirin, eral blood smears and buffy coat smears can be sponge baths, adequate hydration, and thermal done. blanket (only if necessary) to prevent complica- Because tuberculosis is the most common infec- tions of high fever such as convulsions, delirium, tious cause of FUO, and the intermediate PPD skin and congestive heart failure secondary to the in- tests may give false-negative results because of creased metabolic demands of the illness. impaired or delayed host immune response, tuber- The third step is to obtain specimens for culture culosis should be suspected if there is unresolved and thick peripheral blood smears for Wrights, pneumonia, persistent cough, history of contact, Grams, and Giemsa stains. Blood is the most im- hemoptysis, weight loss, fatigue, night sweats, portant specimen, since it may be the only one that lymphadenopathy, lymphoma, leukemia, silicosis, will identify the causative organisms, as in sub- lung cancer, diabetes, and in post-gastrectomy pa- acute bacterial endocarditis (SBE). Because blood tients, immunosuppressed patients, and patients is a sterile body fluid, organisms identified usually who have been treated with cortisone. 6 To explore are not confused with contaminants or a natural this possibility to the maximum, culture for the flora. An early start on cultures is important be- tubercle bacillus with acid-fast stain on a first- cause some organisms, such as bacteroides and voided morning urine sample; on gastric washings; meningococci, may take 2 weeks to grow. Because on bronchoscopic washings; on sputum; and on antibiotics interfere with bacterial culturing, they pleural effusion, joint effusion, ascitic fluid, and should be discontinued or postponed until pericardial effusion. Sometimes the cerebral spinal specimens for culture are obtained. Blood should be fluid (CSF) is the only specimen that will yield cultured under both anaerobic and aerobic condi- identification of the tubercle bacillus in a patient tions and accompanied by thick peripheral blood with FUO. smears which can give a quicker diagnosis. Periph- If the pelvic examination reveals evidence of in- eral blood smears should have a Grams stain for fection, then vaginal cultures should be done and identification of bacteria, Wrights stain for identi- Thayer Martin media should be inoculated for fication of Borrelia (a spirochete), and Giemsa stain gonococcus culture. An extra Pap smear slide of the for identification of filaria, leishmania, trypanoso- cervix should be taken for Giemsa stain to identify miasis, malaria, rickettsia, and cytomegalovirus CMV. (CMV). The buffy coat, a leukocytic cream layer of Stool culture is helpful in identifying infectious anticoagulated blood, gives a high yield in identify- colitis secondary to salmonella, shigella, bacte- ing organisms in the blood. 4 Hopefully, the blood rioides and others, and for ova and parasites. cultures will yield bacteremia indicating that an Sterile body fluids should be cultured if there is organ or system of organs is infected and the infect- evidence of local infection. CSF should be taken in ing organism has invaded the blood stream. The children with FUO and in adults if the clinical organ systems most commonly causing bacteremia status worsens before diagnosis is established or if are genitourinary, respiratory, and central nervous neurologic signs and symptoms exist. A low glucose

715/108 July 1980/Journal of AGA/vol. 79/no. 11 and a cell count greater than 5 indicate meningitis. Previous febrile diseases are worth investigating The CSF should have Grams stain, acid-fast stain, since recurrences are common in urinary tract in- and India ink preparation, and it should be cul- fection, biliary fever, hepatitis, tuberculosis, acute tured for bacteria, tuberculosis, and fungus and rheumatic fever, diverticulitis, and malaria. Also, then tested for cryptococcus latex agglutination recent exposure to tuberculosis and hepatitis de- titer. Pleural effusion, pericardial effusion, ascites, mands ruling out these contagious diseases. and synovial effusion, should be cultured for A history of extrinsic allergies demands investi- bacteria and tuberculosis and examined cytologi- gation of sinuses. Often, chronic bacterial sinusitis cally. As the synovial fluid clots, some should be is asymptomatic except for fever. Also, a history of put into a tube containing an anticoagulant. asthma demands investigation of periarteritis nodosa which causes wheezing. Complete history and physical A history of travel establishes the possibility of An incomplete history and physical examination is geographic diseases such as malaria from South- probably the most common reason for failing to east Asia; leishmania from East Africa and Egypt; diagnose FUO. There is no substitute for a detailed melioidosis from Indochina; San Joachim Valley and carefully taken history. This must be repeated fever ( coccidioidomycosis) from Southwest U.S. to support diagnostic hypotheses and to elicit new (California, Nevada, Utah, Arizona, New Mexico, helpful signs and symptoms. A tailored history is and Texas8), or Mississippi Valley fever (histo- provided here for diagnostic tips. plasmosis). Melioidosis is caused by a gram-nega- Since fever is easily measurable, what diagnostic tive bacillus (Bacillus pseudomallei) possibly spread help can we get from the fever itself? First, the by the rat flea and the Aedes aegypti mosquito; the magnitude of fever may be helpful. Temperatures reservoir of infection is guinea pigs and rabbits. above 105 F. suggest intracranial pathologic condi- Occupation is an important factor, especially if tion, factitious fever, malaria, pancreatitis, thyroid there is contact with animals. Farmers, veterinari- crises, urinary tract infection secondary to gram- ans, and meat packers commonly get brucellosis negative bacilli, and acute yellow atrophy of liver (undulant Malta fever). Glanders, a disease of secondary to viral hepatitis or alcoholism. Second, horses, is caused by a gram-negative bacillus ( Acti- relapsing Murchison-Pel-Ebstein fever consists of nobacillus mallei), and is similar to meliodosis. repeated episodes of 3 to 10 days of fever, with no Farmers and veterinarians are susceptible to this fever for about 1 week between episodes. This sug- infection. Introduction of the organism through the gests biliary fever, Hodgkins disease, Borrelia skin results in pustular eruptions and systemic (relapsing fever), and familial Mediterranean fever infection. Inhalation of organisms results in (FMF). Borrelia are long spirochetes (corkscrew- pneumonitis and granuloma formation throughout shaped bacteria) carried by ticks and lice. They the body. Grams stain of thick peripheral blood can be identified by Wrights or Giemsa stain of smears is helpful in diagnosis of glanders and thick peripheral blood smears and grow quickly in meliodosis.9 Finally, sick parrots and parakeets Noguchis ascetic culture medium. 3 Third, fever can spread psittacosis to man. The etiologic or- that resolves on weekends, holidays and vacations, ganism is Chlamydia which is classified as a suggests occupational exposure to chemicals. bacteria. The illness causes severe prostration. The Fourth, range of fever variation is helpful. A meta- complement fixation titer for psittacosis is helpful bolic fever is defined by a nonspiking narrow range in diagnosis. of elevated temperature without chills. This fever Joint pains and stiffness or swelling suggests a is typical of Hodgkins disease, hypernephroma, CTD, as well as JRA, lymphoma, bronchogenic car- pheochromocytoma, neuroblastoma, multiple cinoma, and abdominal tumors and abscesses. myeloma, and chronic lymphocytic leukemia. Old age and debility suggest a search for stones Fifth, duration of fever may be helpful. One that and tumors causing obstruction and infection, has been steady for months suggests hepatitis, tuberculosis, and infected bedsores. CMV, and bacterial infections.4 Urinary frequency requires urinalysis, urine cul- A family history of fever can help establish a ture and sensitivity, culture for tubercle bacillus, diagnosis of FMF. This is an autosomal recessive colony count, Grams and acid-fast stain. inherited illness prevalent among Jews, Arabs, Frequency of bowel movement requires stool ex- Italians, and Armenians. Signs and symptoms in- amination for ova and parasites, stool culture and clude abdominal pains from peritonitis, chest pains sensitivity, and x-rays of the gastrointestinal tract. from pleuritis, shoulder and joint pains, a WBC 15,000/cu. mm., and an elevated sedimentation Physical examination rate. Colchicine relieves signs and symptoms. The following is a physical examination to demon-

Diagnosis of fever of unknown origin 716/109 strate diagnostic tips: present in SBE, SLE, and leukemia. First, ruling out factitious fever avoids unneces- Examination of the throat requires careful ob- sary and prolonged hospitalization. Factitious servation. Abscessed teeth can often be indicated fever is artificially created fever which occurs in by large cavities, tenderness of teeth and gums, and emotionally or neurologically upset patients. It is erythema of adjacent gum tissue. Gum hyperplasia more common among medical and paramedical suggests leukemia or Dilantin-induced fever. Pal- personnel who have experience in inducing fever. ate petechiae points to streptococcus infection, in- This may be accomplished by ingestion of fectious mononucleosis, or enterovirus. Ulcers are medicines, shaking the thermometer, injecting indicative of adenovirus, Vincents angina, or any materials under the skin, heating the thermome- other infecting agent. Vincents angina is an infec- ter, sipping hot liquids prior to oral temperature tion that is caused simultaneously by two organ- taking, or rubbing the buttocks together during isms—Borrelia, which is a spirochete, and a fusi- rectal temperature taking. To uncover this process, form bacillus.° It often causes pseudomembranes search the patients bedside and remove any in the tonsillar region. Buccal spots most common- medicines or injectables to the nursing station for ly are indicative of mycoplasma or adenovirus. safekeeping. Observe the patient during the tem- The neck should be examined for stiffness, which perature taking, use rectal temperature, and after when combined with FUO, demands a spinal tap; temperature is recorded, ask the patient for a lymphadenopathy, which indicates local or sys- specimen of urine. Take the temperature of the temic infection when painful and lymphoma when urine by using an electronic thermometer to painless; and thyroid tenderness, which suggests minimize heat loss. The urine should be within 2.7 thyroiditis. C. of the rectal temperature. If the patient is un- All lymph nodes should be examined. Gen- aware that the urine will be used for temperature eralized lymphadenopathy may result from any comparison, then the rectal temperature will be type of systemic infection, lymphoma, CTD, sar- greater than 2.7 C. above the urine temperature, coidosis, amyloidosis or serum sickness.° Serum demonstrating factitious fever. 4 Also, in factitious sickness is secondary to administration of drugs or fever, the pulse is not rapid and there is no weight blood and causes a pruritic rash; edema of face, loss or night sweats. A slow pulse with high fever eyelids, and glottis; and swollen, painful joints. also is found in typhoid and influenza. The heart should be auscultated for new mur- Sinuses should be palpated and transillumi- murs or a change in the sound of a previous mur- nated. If abnormality is suspected or if the patient mur, suggesting SBE. A pericardial friction rub has a history of allergies or headaches, then sinus and decreased heart sounds are evidence of x-rays with Waters view should be ordered. Pain pericarditis. A to-and-fro crunching sound (Ham- of acute sinusitis is intensified on bending forward, mans sign) is evidence of mediastinal emphysema coughing, sneezing, and blowing the nose. Chronic from a ruptured bronchus or visceral or parietal sinusitis is often asymptomatic except for the pres- pleura sometimes caused by severe coughing whgn ence of fever.° asthma or emphysema is complicated by a pulmo- Examination of the eye often is enlightening. nary infection; chest x-ray is diagnostic. This also is Conjunctivitis may be caused by allergy to drugs or caused by a ruptured esophagus or an infecting extrinsic allergens; viruses such as adenovirus and organism that forms gas such as Clostridium per- infectious mononucleosis; bacterial upper respira- fringens. tory infections such as pneumococcus, /3-hemolytic The lungs should be auscultated for abnormal streptococcus, and Haemophilus influenzae; CTD sounds and transmission of sound (pectoriloquy). such as systemic lupus erythematosus, perarteritis Assymetric pectoriloquy suggests unilateral nodosa and brucellosis. 1° Chorioretinitis is caused pneumonia, pleural effusion, pneumothorax, or by toxoplasmosis, tuberculosis, syphilis, and CMV hemothorax. Pleural effusion should be tapped for as a source of FUO." Iritis, especially with lacrimal culture and sensitivity, tuberculosis culture, gland involvement, is suggestive of sarcoidosis or Grams stain, acid-fast stain, and for cytologic CTD. Episcleritis is accompanied by pain and ten- study. derness of the eye and results in dilated blood ves- The abdomen must be examined for focal tender- sels just below the conjunctiva which appear ness, which suggests an abscess. A subdiaphrag- thicker and more purplish than in conjunctivitis matic abscess usually occurs after surgery. The and suggests rheumatoid arthritis or tuberculo- diaphragm is high and fixed, a pleural reaction is sis. 1° Cytoid bodies indicate SLE. Finally, Roth often present on chest x-ray, and shoulders are Spots, which are linear or somewhat boat-shaped painful. A liver abscess is often accompanied by a retinal hemorrhagic spots with white centers, are high, fixed diaphragm, a liver friction rub, and an

717110 July 1960/Journal of A0A/vol. 79Mo. 11 elevated bilirubin and/or alkaline phosphatase Laboratory tests level. A chronic appendiceal abscess usually gives Laboratory tests should be ordered to follow up pain, local tenderness, and gastrointestinal signs clues obtained from the history and physical exam- and symptoms, Hepatosplenomegaly points to ination, which is more productive than blindly or- lymphoma, myeloid metaplasia, leukemia, or sys- dering tests. temic infection such as typhoid, infectious mono- A CBC can give direction in diagnosis. An in- nucleosis, CMV, and others. Naval discharge and/ creased leukocyte count plus a shift to the left gives or lump should make one suspicious of abdominal weight to a diagnosis of a bacterial infection. or pelvic malignancy. A hard abdomen with re- Always repeat the CBC in a few days since the bound tenderness suggests peritonitis. picture may change to a leukopenia plus a relative Rectal examination must not be overlooked since lymphocytosis which points to malaria, Malta fever perirectal abscess and prostatitis are common (brucellosis), influenza, tuberculosis, typhoid, causes of FUO. Likewise, pelvic examination may hepatitis, and rickettsial infections. Eosinophilia be the only clue for pelvic inflammatory disease or should be supported by a total eosinophil count. pelvic malignancy. Increased eosinophils suggests a search for drug Muscles, bones, and joints should be checked for allergy, parasites, gastroenteritis, periarteritis tenderness, stiffness, or swelling, indicating the nodosa, and pulmonary infiltration syndrome plus presence of CTD, trichinosis, osteomyelitis, or sep- eosinophilia (PIE)) as a cause of FUO. 3 The causes tic arthritis. are divided into intrinsic (systemic) and extrinsic The skin is the largest organ in the body and a causes. Intrinsic causes consist of periarteritis strong barrier of defense against infection. nodosa, sarcoidosis, histiocytosis X, and LOfflers Cutaneous lesions of unknown origin should be pneumonia. Periarteritis nodosa is a CTD causing biopsied and Grams stain used. When stained, ec- necrotizing arteritis; it also affects veins, nerves, thyma gangrenosum will demonstrate pseudomo- and muscles. It is characterized by pleuritic chest nas organisms. Vesicular fluid should be prepared pains, rash, erythema nodosum, wheezing, livedo with Giemsa stain and sent to a virology labora- reticularis, numbness in legs, and frequent infec- tory for tissue culture. tions. Laboratory confirmation consists of skin A rash may indicate drug-induced fever and biopsy stained with hematoxylin, microscopic CTD. A rash accompanies by hepatosplenomegaly hematuria, anemia, elevated sedimentation rate, suggests infectious mononucleosis, lymphoma, and and leukocytosis. Wegeners granulomatosis is a typhoid. A high fever in a 6-month to 2-year-old varient of periarteritis nodosa in which the sinus child with no other signs and symptoms suggests cavities are invaded by the disease. 1° Sarcoidosis roseola; this can be confirmed by observation when causes hilar adenopathy on chest x-ray that is out a rash appears and the fever simultaneously disap- of proportion to mild signs and symptoms or none at pears. A rash that comes and goes with no other all. Liver biopsy is often diagnostic as is scalene signs and symptoms except low-grade fever is evi- and mediastinoscopy directed lymph node biopsy. dence of fifth disease. On chest x-ray histiocytosis X presents a hon- Livedo reticularis is a net-like bluish red skin eycomb appearance because of a granulomatous pattern, which is suggestive of CTD, syphilis, process sparing the lower lung fields. Infiltration of tuberculosis, and neoplasm as a cause of FUO, as bone, liver, spleen, lymph nodes, and skin may well as disseminated intravascular coagulation occur. The usual signs and symptoms are exer- and dysproteinemia, which usually are not accom- tional dyspnea and recurrent spontaneous pneumo- panied by fever. thorax. Diagnosis can be made by sputum cytology, Erythema nodosum are large, round, red patches; if histiocytic-laden macrophages ae identified; if their central part is elevated, hard, and painful. not, tissue biopsy is necessary. In LOfflers pneu- Their presence warrants a work-up for drug-in- monia the PIE syndrome exists without these other duced fever such as oral contraceptives (the most causes; the patient has mild signs and symptoms or common cause of erythema nodosum today); strep- none at all, and pulmonary infiltrate disappears toccus infection; tuberculosis; sarcoidosis; viral in- completely within a few days or weeks. fections such as infectious mononucleosis; fungus Extrinsic causes are Aspergillus niger, which is infections such as histoplasmosis and coccidioido- diagnosed by culture on Sabarouds medium and mycosis; inflammatory bowel disease; and periar- the precipitin antibody titer for Aspergillus; Filar- teritis nodosa.3 ia, which is diagnosed by Giemsa stain of thick pe- A petechial rash suggests SBE, rickettsia, strep- ripheral blood smear and Filaria complement fixa- tococcal infection, infectious mononucleosis, viral tion titer; tuberculosis; histoplasmosis; coccidioido- infections, or meningococcal infections. mycosis; brucellosis; parasites; and drug allergy.1°

Diagnosis of fever of unknown origin 718/111 Urinalysis is often informative. The specimen treatment is indicated except in certain situations with the highest yield of information is a first- where isoniazid prophylaxis is recommended. 5 A voided morning specimen. Hematuria dictates a negative PPD with old calcified granulomas on work-up for genitourinary tract tumor with urine chest x-ray suggests histoplasmosis or coc- cytology, intravenous pyelogram, and cystoscopy. cidioidomycosis. Diagnosis of these diseases can be Urinalysis should be accompanied by colony count, made quickly by histoplasmin complement fixation culture, sensitivity, and Grams stain, which may titer followed by coccidioidin skin test. If a identify the causative organism. If none is found serologic test is positive, acute infection can only be and if genitourinary tract infection is suspected demonstrated by a rise in titer in a 48-hour repeat because of signs and symptoms or pyuria, then spe- and fall in titer on resolution of infection. cial cultures should be obtained for tuberculosis A sedimentation rate is not a highly specific test; and acid-fast stain. Protein in the urine without however, when elevated, it is indicative of acute erythrocytes accompanied by hemoglobinemia inflammation such as rheumatoid arthritis, tem- should make one suspicious of clostridial infec- poral arteritis, SLE, and other CTD, such as tions. tuberculosis, syphilis, gonorrhea, abscesses, A VDRL should be ordered routinely in work-up peritonitis, but not unruptured appendicitis or of FUO. A positive result should be followed by a chronic appendiceal abscess; and tissue destruction fluorescent treponema antibody test. If that is such as coronary thrombosis and malignancy. Very negative, we have a biologic false positive (BFP) high sedimentation rates accompany anemia, test for syphilis. This can result from certain hypercholesterolemia, and hyperglobulinemia viruses such as infectious mononucleosis and some from multiple myeloma or macroglobulinemia of bacterial infections. These acute BFPs convert to Waldenstriim and, therefore, may have little to do negative when the infection resolves. Chronic with the FUO. When the sedimentation rate is BFPs that remain positive are most commonly normal with FUO, one should suspect chronic ap- from CTD, malaria, tuberculosis, and spirochetes pendiceal abscess, scleroderma, which often does such as Borrelia." not elevate the sedimentation rate, and factitious The SMA-12 survey is helpful in localizing dis- fever; active tuberculosis and osteomyelitis may be ease in the liver, kidney, muscle, heart muscle, and eliminated as possible causes.s bone. Skin tests and serology offer a quick diagnostic The ECG is important for diagnosis of pericar- screen. They help to diagnose fungal and parasitic ditis. This is suggested by low-voltage, ST eleva- infections and thus are helpful in the compromised tion, and non-specific abnormalities such as ST-T host and in patients whose condition does not per- segment changes and ectopic beats. mit invasive procedures. Interpretation and se- The chest x-ray should be checked for infiltrate quence of these tests are important. A skin test for a and hilar adenopathy. Infiltrate suggests pneumo- particular disease should be preceded by the nia; tuberculosis, or tumor; hilar adenopathy points serologic test for that disease, except the coc- to sarcoidosis, tuberculosis, mononucleosis, and cidioidin skin test. This test does not cause antibod- lymphoma as the cause of the fever. An enlarged ies to coccidioidin but may induce histoplasmosis heart demands a cardiac scan to rule out peri- antibodies; therefore, histoplasmin complement fix- cardial effusion. ation titer should precede the coccidioidin skin Antistreptolysin 0 titer and Monospot tests are test. quick helpful tests to identify /3-hemolytic strep- Febrile agglutinin titers (Widal test) is espe- tococcal infection and infectious mononucleosis, re- cially called for when leukopenia plus relative spectively. lymphocytosis exist, when a rapid pulse does not A PPD must be done on all patients with FUO accompany the fever, when rose spots appear on the since tuberculosis is the most common infectious chest of a patient with FUO, and when hepato- cause and may be extrapulmonary. A reaction 15 splenomegaly is present. The presence of brucello- mm. is presumptive evidence of active tuberculosis; sis, salmonella, and rickettsia are suggested by 5 to 10 mm. suggests exposure to tuberculosis but titers of 1:100, 1:80, and 1:320, respectively. Rick- no active disease or disease with atypical mycobac- ettsia is suggested by the 0x19 antigen and causes teria. A positive skin test and negative chest x-ray epidemic typhus spread by body lice, endemic ty- should be evaluated by a sedimentation rate, phus spread by rat fleas, and Rocky Mountain sputum for acid-fast stain, tubercle bacillus cul- spotted fever spread by dog and wood ticks. An 0x19 ture, and clinical evaluation of pulmonary signs titer of 1:80 is usually caused by proteus infections and symptoms. If none exist and cultures are nega- or old resolved rickettsial infections. Borrelia is tive and sedimentation rate is normal, then no indicated by the Ox-K antigen.

719/112 July 1980/Journal of AOA/vol. 79/no. 11 Other helpful serologic tests are cryptococcus value after appropriate x-rays. No radiation is in- latex agglutination, which can also be performed volved and a sonogram often will localize tumors, directly on cerebrospinal fluid; aspergillus pre- abscesses, and intra-abdominal lymph nodes." cipitin titer; psittacosis complement fixation titer; Echocardiography is necessary when SBE is sus- mycoplasma complement fixation titer; filaria pected to demonstrate vegetation on heart valves complement fixation titer; CMV complement fixa- or early closure of heart valve. Also, gray scale tion titer; Sabin-Feldman dye test for toxoplas- ultrasonography is a safe screening procedure for mosis; and many others. Again, diagnosis by serol- evaluating the brain in infants up to 16 months of ogy should show a rise in titer on 48-hour repeat age. test and a fall when disease resolves. Nuclear medicine scans do expose the patient to A fluorescent antinuclear antibody test is a more radiation; however, they can localize tumor useful screen for CTD. If positive, it should be ac- and infection not seen on x-rays. A brain scan can companied by an LE preparation to check for SLE, demonstrate intracranial tumor, infection, and a latex fixation titer to test for rheumatoid ar- bleeding not seen on x-ray. A renal scan can dem- thritis, and an extractable nuclear antigen (ENA) onstrate renal artery stenosis and renal tumors not test. If it is positive, there is CTD and probably seen on x-ray. A liver scan can demonstrate 2 cm. lupus. The test is then repeated after the patients lesions that are not palpable. A spleen scan can serum has been treated with RNAase which digests differentiate an enlarged spleen from a stomach ribonucleoprotein. If the test is no longer positive, tumor. A cardiac scan can differentiate pericardial then anti-RNP antibodies were present indicating effusion from cardiac enlargement. A combined liv- mixed CTD. If the test is still positive, then anti- er and lung scan can demonstrate subphrenic ab- DNA antibodies are present and systemic lupus scess. A Gallium 67 scan is effective in localizing erythematosus is likely.6 obscure tumors and abscesses, since Gallium is at- Finally, when tumor is suspected, there are tracted to leukocytes and tumor cells. serum tests associated with various types of cancer. CAT scans have potential that is still being ex- Carcinoembryonic antigen is evidence of possible plored. They are more versatile than ultrasound colon and rectal cancer, alpha fetal globulin is evi- and can evaluate not only the abdomen, but the dence of possible hepatoma and embryonal car- thorax and intracranial contents. This procedure cinoma of the ovary, and acid phosphatase, when does expose the patient to more radiation. CAT elevated, suggests advanced prostatic cancer. Pros- scanning at present is the best method of ruling out tatic acid phosphate levels by radioimmunoassay brain abscess in FUO. Also, CAT scans may replace is helpful in picking up early prostatic cancer. On- lymphangiography and inferior venocavography cofetal antigen tests may become available in the for staging and preoperative evaluation of lym- near future. Serum glucagon levels are available phoma. for early detection of possible pancreatic cancer. Biopsy X-rays, sonography, scans, and CAT scans Biopsy is often necessary to make a diagnosis. Dis- X-rays can evaluate localized signs and symptoms, eased tissue is excised for culture and histology but they do not always show enough detail to pick studies. If patients condition permits, any diseased up a pathologic condition, and so additional x-ray tissue should be biopsied. This includes lymph techniques are helpful. If a chest x-ray does not nodes, tender muscle, tender temporal artery, ab- show suspected infiltrate, then order a Bucky chest normal skin, liver, bone marrow, and abnormal x-ray with posteroanterior and apical lordotic breast tissue. Consultation with a pathologist views. should be obtained prior to biopsy to have available If an intravenous pyelogram is ordered for FUO the necessary materials to put anticipated work-up, it should always include a lateral view. specimens in for culture of aerobes, anaerobes, fun- This view shows retroperitoneal disease such as gus, and tuberculosis and for histologic studies. lymphoma, kidney tumor or abscess which is not Liver and bone marrow core biopsies should be shown on anteroposterior views. accompanied by cultures; these tissues are fre- A barium enema x-ray and upper gastrointesti- quently invaded in systemic infections as well as nal tract x-ray which fail to visualize the terminal neoplasms, granulomatous disease, and sar- ileum in a FUO work-up should be followed by a coidosis. small bowel study. The terminal ileum is often Directed biopsy is performed through a directing invaded by tuberculosis, regional enteritis, lym- scope such as a bronchoscope, mediastinoscope, col- phoma, Whipples disease, and chronic appendiceal onoscope, gastroscope, and peritoneoscope. abscess. Peritoneoscopy gives visualization of the intra- Ultrasound study of the abdomen is of much abdominal cavity with a potential for directed

Diagnosis of fever of unknown origin 720/115 biopsy of diseased tissue and liver biopsy. The en- bophlebitis, colchicine for FMF, emetine for doscopist and pathologist should collaborate prior amebiasis, and isonizaid plus ethambutol for to procedure to prepare necessary materials for tuberculosis. Rifampin and streptomycin are ef- contemplated specimens. Liver biopsy should be fective antibiotics for many organisms and, there- obtained even if the liver is normal, as it has a high fore, are not good agents for a therapeutic trial. diagnostic yield. Closed biopsy does not involve exploratory Pediatric considerations surgery and may be done by needle biopsy such as Management of pediatric patients with FUO de- in the breast and liver. Open biopsy involves explo- serves special attention because diagnostic and ratory surgery such as laparotomy. It is indicated therapeutic considerations are somewhat different. only if there is evidence of intra-abdominal disease First, the common causes of FUO in children are: such as organosplenomegaly; palpable mass; suspi- (1) juvenile rheumatoid arthritis; (2) granulomat- cious x-rays, scans, CAT scans, and sonogram; or ous disease of intestines (regional enteritis); (3) persistent abnormal laboratory tests such as acute bacterial infection, especially meningitis, alkaline phosphatase that is twice the normal urinary tract infections, tuberculosis, pneumonia, value, indicating stone or tumor obstructing com- and otitis media; (4) neuroblastoma; (5) cytomeg- mon bile duct. alovirus; (6) leukemia; (7) immunizations; and (8) If there is no evidence of progressive organ im- self-limited virus infections. pairment and the patients general condition is Second, during the first 3 months of life, any stable, observation is certainly reasonable; how- degree of fever must be taken seriously, since ex- ever, if progressive organ impairment is demon- tensive disease can exist without any signs and strated from laboratory tests and the patients gen- symptoms. From 3 months to 3 years of age, signs eral condition is deteriorating, then exploratory and symptoms are often hard to elicit. 20 Beyond 3 laparotomy or peritoneoscopy may be the only way years, signs and symptoms are reliable, but a tem- a diagnosis can be established in time to be of value perature of 100.4 F. rather than 101 F. is signifi- before treatment must be started. Internal cant. medicine evaluation may be necessary for deter- Third, always consider meningitis. It is common mining which procedure to do, the type of anes- in children and signs and symptoms often are ab- thesia, and whether the patient can tolerate a liver sent. Convulsions or worsening of the patients biopsy and possible definitive surgery when the condition demands lumbar puncture.17 pathologic condition is revealed.° Fourth, dont forget immunizations as a cause of FUO. Fever may occur 7 to 10 days after immuniza- Therapy tion. Ideally, therapy for any illness should be specific Fifth, children often pick up self-limited virus for that illness. Unfortunately, sometimes FUO infections characterized by high fevers. In such in- remains undiagnosed after an exhaustive work-up; stances, children often show a specific response to then, exploratory laparotomy or peritoneoscopy aspirin. The fever falls dramatically 1 hour after should be considered for diagnosis. If the patients aspirin is given at a dose of 1 grain per year of age. condition does not permit this or if the patient re- If temperature falls to 98.6 F. or less, it is pre- fuses or indications are not present and patient can sumptive evidence of an acute self-limited infection no longer be observed because the condition is dete- and observation is indicated. Often a sibling also riorating, then treatment without definitive diag- will be ill from the same infection. nosis should be contemplated. There are four prin- Sixth, 50 percent of FUO in children resolve ciples in a therapeutic trial. First, make the best spontaneously, thus making laparotomy and diagnostic guess. Second, try to get specimens for therapeutic trials unnecessary. Occasionally, lapa- culture, cytology, histology, and laboratory tests rotomy is needed if the abdomen is rigid, suggest- to support the diagnosis. Third, choose an agent ing peritonitis.17 specific for the diagnosis. Last, record the patients Seventh, blood cultures must be limited to 2 cc. response to treatment.8 per day. A CBC should be done to check for anemia The principle of using an agent specific for the and neutropenia prior to taking more blood for cul- diagnosis is that if the diagnosis is wrong, then the ture; however, a small amount of blood can usually patients condition will not respond and we know be spared for peripheral blood smears that can be the diagnostic guess was wrong; and if the diagnos- stained by Wrights, Giemsa, or Grams stain. tic guess was correct, then the treatment will dra- Eighth, growth failure is helpful diagnostically matically improve the patients condition, as aspi- in children. It occurs in JRA, granulomatous dis- rin for acute rheumatic fever, heparin for throm- ease of the intestines, and CMV.

721/116 July 1980/Journal of AOA/vol. 79/no. 11 TABLE 2. SYSTEMATIC APPROACH TO DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN. Diagnostic items Diagnostic considerations A. Stop all drugs unless absolutely necessary If fever stops—drug-induced fever B. Control fever 1 grain ASA/per year of age-1 hour later,—afebrile, self-lim- ited viral infection C. Peripheral smears and cultures 1. Thick peripheral blood smears Grams stain Brucella, typhoid, leptospira, glanders, melioidosis Wrights stain Borrelia Giemsa stain Borrelia, filaria, Trypanosoma, leishmania, rickettsia, malaria, cytomegalovirus (CMV) 2. Blood cultures Gram-positive and gram-negative bacteria Aerobic and anaerobic bacteria (Borrelia, bacteroides) organ or systemic bacterial infection, subacute bacterial endocarditis, pneumonia, meningitis, urinary tract infection Noguchis ascetic culture medium Borrelia 3. Urine—Colony count, Grams stain Urinary tract infection Acid-fast stain, T.B. culture Renal Tuberculosis (TB) 4. Stool—Culture and sensitivity Salmonella, shigella, bacteroides Ova and parasites Parasites 5. If sore throat is present, throat swab Pharyngitis, Haemophilus influenzae, Diplococcus pneumo- niae, Staphylococcus aureus, beta-hemolytic streptococcus 6. If tuberculosis is suspect, gastric washings TB 7. Sputum, C and S and Grams stain Bronchitis, pneumonia T.B. culture and acid-fast stain TB Cytology Bronchogenic carcinoma 8. Sterile body fluids (a) Spinal tap—Grams stain Bacterial meningitis Acid-fast stain Tuberculous meningitis India Ink Cryptococcus Latex Agglutination Cryptococcus neoformans Giemsa stain Parasites, fungus ; CMV Sabarouds medium Fungus (b) Pleural effusion Pleurisy, TB, lung carcinoma, empyema (c) Pericardial effusion Pericarditis—viral, TB; Bacterial, connective tissue disease (CTD); lymphoma (d) Ascites Carcinoma—pancreatic, liver, ovarian, mesothelioma; and TB (e) Synovial effusion Juvenile rheumatoid arthritis (JRA), septic arthritis, CTD, acute rheumatic fever D. History and Physical 1. Drugs Drug-induced fever, staphylococcal endocarditis 2. Temperature (a) greater than 105 F. Intracranial pathology, factitious fever, malaria, pancreatitis, thyroid crisis, UTI with gram-negative bacilli, acute yellow atrophy of liver (b) Pel-Ebstein fever Biliary, Borrelia, familial Mediterranean fever (FMF), Hodg- kins disease, malaria (c) Metabolic fever Multiple myeloma, chronic lymphocytic leukemia (CLL), Hodg- kins disease, hypernephroma, pheochromocytoma, neuro- blastoma (d) Duration greater than 1 month Hepatitis, CMV, bacterial infection, TB 3. Family history of febrile illness FMF 4. Previous febrile illnesses TB, hepatitis, acute rheumatic fever, malaria, biliary fever, diverticulitis 5. Occupation Brucellosis, occupational chemical exposure, glanders, psit- tacosis 6. Travel Malaria, coccidiomycosis, meliodosis, histoplasmosis, leish- mania 7. Allergies Sinusitis, periarteritis nodosa 8. Recent exposure to illness TB, hepatitis 9. Joints—pain, stiffness, swelling CTD, lymphoma, bronchogenic, abdominal abscess, tumors 10. Old age and debility TB, infected bed sores, stones and tumors causing obstruction and infection 11. Frequency of stool Parasites, chronic appendiceal abscess, regional enteritis, ul- cerative colitis and infectious colitis 12. Urine frequency UTI, renal TB, genitourinary tract tumor Physical 1. Observe during rectal temperature and follow by Factitious fever vs. real fever urine temperature 2. Bradycardia Factitious fever, typhoid, viral 3. Abscence of night sweats and weight loss Factitious fever 4. Sinuses Palpate and transilluminate Sinusitis, Wegeners granulomatosis continued on page 723/121

Diagnosis of fever of unknown origin 722/117 TABLE 2. SYSTEMATIC APPROACH TO DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN continued, Diagnostic items Diagnostic considerations 5. Eye (a) conjunctivitis Allergy—drugs, eictrinsic Viruses—adenovirus, infectious mononucleosis CTD, brucellosis, bacterial UTI (b) chorioretinitis Toxoplasmosis, TB, syphilis, CMV (c) iritis Sarcoidosis, CTD (d) episcleritis Rheumatoid arthritis (RA), TB (e) cytoid bodies Systemic lupus erythematosus (SLE) 6. Throat (a) teeth Dental abscess (b) gum hyperplasia Leukemia, Dilantin-induced fever (c) palate petechia Streptococcus, infectious mononucleosis, enterovirus (d) ulcers Adenovirus, Vincents angina (e) pseudomembrane Vincents angina and diptheria (f) buccal spots Mycoplasma, adenovirus 7. Neck (a) stiffness RA, meningitis, viral infection (b) lymphadenopathy--painless Lymphoma painful Local or systemic infection (c) thyroid Thyroiditis, thyroid crisis 8, Generalized lymphadenopathy Systemic infection, lymphoma, leukemia, serum sickness. CTD. sarcoidosis 9. Heart murmur SBE friction rub and decreased sounds Pericarditis 10. Lungs, rhonchi, pectoriloquy TB, lung tumor, pneumonia 11. Abdomen (a) focal tenderness Abscess—subdiphragmatic, liver, chronic appendiceal (b) liver friction rub Liver abscess (c) hepatosplenomegaly Lymphoma, leukemia, myeloid metaplasia. systemic infection, infectious mononucleosis, typhoid, CMV (d) naval discharge or lump Abdominal or pelvic malignancy (e) rigidity and rebound Peritonitis, pancreatitis 12. Rectal Perirectal abscess, prostatitis 13. Pelvic exam Pelvic inflammatory disease !YID), pelvic malignancy Giemsa stain or cervical smear CMV 14. Muscles, bones and joints Trichinosis, osteomyelitis, septic arthritis, CTD 15. Skin (a) petechia SBE, rickettsia, viral, streptococcal, infectious mononucleosis, meningococcal (b) livedo reticularis CTD, syphilis, TB, neoplasm (c) erythema nodosum Drug induced—oral contraceptives, streptococcus, TB, sarcoido- sis, viruses—infectious mononucleosis, fungus—histoplas- mosis. coccidiomycosis, CTD, inflammatory bowel disease (d) Rash (1) hepatosplenomegaly Infectious mononucleosis. lymphoma, typhoid (2) no other s/s and evanescent Fifths disease (3) evanescent, looks run down, stops growing JRA (e) Sacral region Infected decubiti E. Laboratory tests to follow up clues from history and physical 1. CBC (a) Inc. WBC + shift to left Local or systemic bacterial infection (b) Dec. WBC + relative lymphocytosis Malaria, brucellosis, influenza, TB, typhoid, hepatitis, rickett- sia (c) Eosinophilia Drug allergy, parasites, gastroenteritis, periarteritis nodose. pulmonary infiltration syndrome (PIE 2. Urinanalysis—pyuria TB, UTI hematuria Genitourinary malignancy 3. VDRL + FTA Syphilis VDRL - FTA Acute Bacterial infection and infectious mononucleosis Chronic Borrelia, CTD, malaria, TB 4. SMA12 Liver, kidney, muscle, heart muscle, bone disease 5. EKG Pericarditis, endocarditis 6. Chest x-ray—infiltrate Pneumonia. TB, tumor. PIE syndrome hilar adenopathy Sarcoidosis, TB, infectious mononucleosis, lymphoma enlarged heart Pericarditis 7. ASOT Beta-hemolytic streptococcal infection 8. Monospot test Infectious mononucleosis. CMV. toxoplasmosis. listerrisis 9. Intermediate PPD TB, histoplasmosis, coccidiomycosis 10. Sedimentation rate increased CTD, infection, tissue destruction—malignancy and coronary thrombosis (b) normal Scleroderma, factitious fever, chronic appendiceal abscess, ap- pendicitis and not TB, nor osteomyelitis 11, Skin tests and serology (a) histoplasmin complement fixation titer Histoplasmosis (b) coccidiodin skin test Coocidiamycosis

Diagnosis of fever of unknown origin 728;121 TABLE 2 SYSTEMATIC APPROACH TO DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN. (continued) Diagnostic items Diagnostic considerations (c) Coccidiodes CF titer Coccidiomycosis (d) febrile agglutinins Brucellosis, typhoid, rickettsia, Borrelia, proteus (e) hepatitis-associated antigen Hepatitis, CMV (f) Sabin-Feldman dye test Toxoplasmosis (g) CMV, CF titer CMV (h) Cryptococcus latex agglutination titer Cryptococcus neoformans (i) Mycoplasma CF titer Mycoplasma (j) Filaria CF titer Filaria (k) Aspergillus precipitin titer Aspergillosis (1) Psittacosis CF titer Psittacosis 12. Other serologic tests Fluorescent antinuclear antibodies CTD ENA CTD, lupus erythematosus After treatment with RNAase ENA—negative Mixed CTD ENA—positive Lupus erythematosus CEA Colon and rectal cancer Alpha fetal globulin Hepatoma and embryonal carcinoma of ovary Prostatic acid phosphatase Late prostate carcinoma Radioimmunoassay Early prostate carcinoma Counterimmune electrophoresis Early prostate carcinoma Oncofetal antigen Pancreatic carcinoma F. Radiology (1) X-rays Pneumonia, TB, tumors, sarcoidosis, abscesses, regional enter- itis, Whipples disease, lymphoma (2) Sonogram Tumor, abscess, lymphoma (3) Scans Tumor, infection, abscess, hepatosplenomegaly, pericardial ef- fusion (4) CAT scan Lymphoma, tumor, abscess, hematoma G. Biopsy Histology Granulomatous disease, infection, neoplasm, CTD, temporal arteritis, histiocytosis X Culture Infectious organism Noguchis ascetic culture medium Borrelia Sabarouds Fungus TB culture TB Bacterial culture Bacteria Stains Hematoxylin Histiocytosis X, CTD, periarteritis nodosa Wrights Borrelia Giemsa Parasites, fungus, rickettsia, CMV Grams Bacteria India Ink Cryptococcus

JRA presents as fever without chills, which often One out of every 700 births are damaged by CMV precedes joint signs and symptoms by months. At from microcephaly, hearing loss, mental retarda- least two joints must be involved with swelling or tion, growth retardation, and Downs syndrome. limited range of motion plus heat, pain, or tender- Other signs and symptoms include jaundice, ness for 6 weeks or more. The child appears run thrombocytopenia, hepatosplenomegaly, chronic down and stops growing before joint signs and interstitial pneumonia, and chorioretinitis. 27 This symptoms start. 2 Other features include a macu- illness is characterized by latency, and it can be lar evanescent rash, subcutaneous nodules, tor- reactivated later in life. The disease is transmitted ticollis, hip subluxation, overgrowth of affected ex- by saliva, respiratory secretions, and is sexually tremities, splenomegaly, lymphadenopathy, and transmitted between semen and cervical mucus. increased sedimentation rate. Any woman who has ever been infected can reinfect Neuroblastoma is diagnosed by intravenous her baby in utero. Management of CMV consists of pyelography with a lateral view, sonogram of the isolating the infant, symptomatic and supportive abdomen, and renal scan. treatment, and, if the condition worsens, transfer Finally, a discussion of CMV is in order to com- factor and adenine arabinoside or cytosine plete pediatric considerations of FUO. This viral arabinoside.22 illness affects in utero 1 percent of all infants born. Diagnosis in the newborn or infant should be

724/122 July 198041ournal d A0A/vol. 79/no. 11 suspected by FUO by itself. Giemsa stain of periph- 4. Eichenwald, H.F., et al.: Probing probable causes of FUO. Patient Care (Roundtable) 11:18-52, 15 Feb 77; Pursuing elusive FUO in the eral blood smears or urine sediment and cerebros- hospital 11:78-98, 1 Mar 77 pinal fluid is often diagnostic. This stain demon- 5. Medsger, TA., Jr.: Mixed connective tissue disease. Medical Chal- strates multinucleated giant cells with intranu- lenge 10:31-7, Jan 78 6. Farer, L.S.: All about T.B.—What the practicing physician must know clear inclusion bodies. Also, serum should be and can do about tuberculosis. Clin Notes Respir Dis 16:3-14, 1978 tested for CMV complement fixation titer. And, 7. Wolff, S.M.: Familial Mediterranean fever (Familial paroxysmal polyperositis. In Harrisons principles and practice of internal medicine. finally, a urine and blood specimen should be Ed. 6. McGraw-Hill Book Company, New York, 1970, p. 1076 placed on ice cubes to keep at 0 to 4 C. and sent to 8. Lindquist, J.R.: Coccioidomycosis. Six-year experience in an endemic the public health department for culture on tissues. area. Todays Clinician 2:39, Mar 78 9. Smith, D.T., Conant, N.F., and Overman, J.R.: Actinobacillus mallei Results take 2 to 3 weeks. and glanders. Melioidosis and actinobacillosis. Ed. 13. In Microbiology, CMV in adults and older children usually has edited by Zinsser. Appleton-Century-Crofts, New York, 1964, p. 563 three presentations. It can be asymptomatic; it can 10. Diamond, S.: Headache. Almost never sinusitis. Consultant 16:123-9, Nov 76; Sussman, W.: A guide to common eye problems, part 2, cause hepatitis with negative hepatitis associated conjunctivitis, iritis and episcleritis. Consultant 16:93-7, Nov 76 antigen test; and it can cause infectious 11. Nover, A.: The ocular fundus VII. Diseases of the choroid. Lea mononucleosis triad with a negative Monospot test Febiger, Philadelphia, 1966, p. 133 12. Brainerd, H., Margen, S., and Chatton, M.J.: Miscellaneous and negative Paul-Bunnell heterophil test. Infecti- spirochetal diseases relapsing fever. In Current diagnosis and treatment. ous mononucleosis triad consists of pharyngitis, Lange Medical Publications, Los Altos, California, 1968, p. 813 13. De Gowin, E.L., and De Gowin, R.L.: Bedside diagnostic examination. posterior cervical lymphadenopathy, and lym- The lymphatic system. Ed. 3. Macmillan Publishing Co., New York, p. 454 phocytosis. The differential count contains greater 14. Ravel, L.: Tests for syphilis. In Clinical Laboratory Medicine. Year than 50 percent lymphocytes and more than 20 Book Medical Publishers, Inc., Chicago, 1969, p. 341 15. Palmer, D.L.: Infectious diseases. What skin tests can tell you. Con- percent of these are atypical. The infectious sultant 14:91-5, May 74 mononucleosis triad is also found in toxoplasmosis 16. Reece, R.M.: Erythema nodosum. Amer Fam Phys 13:99-102, Mar 76 and listeriosis. 17. Gleckman, R.: Diagnostics. Fever of unknown origin—the value of abdominal exploration. Postgrad Med 62:191-2, Jul 77 18. Jawetz, E.: Antibiotics. Four steps to correct antimicrobial drug Summary choice. Consultant 17:42-8, Aug. 77 To summarize, FUO is a most challenging diagnos- 20. Froad, L.: Evaluation of fever, questions and answers. Infectious tic problem. The systematic approach used for Diseases. 15 Mar 71 21. Athreya, B.H.: Juvenile rheumatoid arthritis—practical pointers for diagnosis of FUO can be applied to solve other early diagnosis and therapy. Modern Medicine 46:45-53, 30 Mar 78 diagnostic problems such as tumor diagnosis. Table 22. Plotkin, S.A.: Childhood disease. The invisible epidemic, 2 gives a list of diagnostic items that should be cytomegalovirus. Consultant 17:47-8, Sep 77 checked to establish a diagnosis. Accepted for publication in August 1978. Updating, as neces- sary, has been done by the author. 1. Cross, A.S.: What to do when the patients fever has no obvious cause. Modern Medicine 46:62.70, 15 Apr 78 Dr. Reznick, who is board certified in family practice, is in 2. American College of Physicians/American Society of Internal private practice in Glendale, New York. He is on the attending Medicine: Fever of undetermined origin. In H-ICDA/792.2, ICDA-8/788.6, staff of Interboro General Hospital (Brooklyn), Terrace Heights Jun 76 Hospital (Hollis, New York), and The Osteopathic Hospital and 3. Harvey, AM., et al, eds.: The problems of fever of obscure origin. In Clinic of New York, Inc. (Flushing). The principles and practice of medicine. Ed. 18. Appleton-Century- Crofts, New York, 1972, pp. 1069-84 Dr. Reznick, 6451 Central Avenue, Glendale, New York 11227.

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