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InternalMed_Harrison. on the face and extremities, while varicella lesions are most prominent on the trunk. Herpes simplex virus infection (Chap. 216) is characterized by hallmark grouped vesicles on an erythematous base. Primary herpes infection is accompanied by fever and toxicity, while recurrent disease is milder. Rickettsialpox (Chap. 211) is often documented in urban settings and is characterized by vesicles followed by pustules. It can be distinguished from varicella by an eschar at the site of the mouse-mite bite and the papule/plaque base of each vesicle. Acute generalized eruptive pustulosis should be considered in individuals who are acutely febrile and are taking new medications, especially anticonvulsant or antimicrobial agents (Chap. 74). Disseminated Vibrio vulnificus infection (Chap. 193) or ecthyma gangrenosum due to Pseudomonas aeruginosa (Chap. 189) should be considered in immunosuppressed individuals with sepsis and hemorrhagic bullae.


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InternalMed_Harrison. Individuals with classic urticaria (“hives”) usually have a hypersensitivity reaction without associated fever. In the presence of fever, urticaria-like eruptions are most often due to urticarial vasculitis (Chap. 385). Unlike individual lesions of classic urticaria, which last up to 24 h, these lesions may last 3–5 days. Etiologies include serum sickness (often induced by drugs such as penicillins, sulfas, salicylates, or barbiturates), connective-tissue disease (e.g., systemic lupus erythematosus or Sjren’s syndrome), and infection (e.g., with hepatitis B virus, enteroviruses, or parasites). Malignancy, especially lymphoma, may be associated with fever and chronic urticaria (Chap. 72).


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InternalMed_Harrison. In immunocompromised hosts, nodular lesions often represent disseminated infection. Patients with disseminated candidiasis (often due to Candida tropicalis) may have a triad of fever, myalgias, and eruptive nodules (Chap. 240). Disseminated cryptococcosis lesions (Chap. 239) may resemble molluscum contagiosum (Chap. 220e). Necrosis of nodules should raise the suspicion of aspergillosis (Chap. 241) or mucormycosis (Chap. 242). Erythema nodosum presents with exquisitely tender nodules on the lower extremities. Sweet syndrome (Chap. 72) should be considered in individuals with multiple nodules and plaques, often so edematous that they give the appearance of vesicles or bullae. Sweet syndrome may occur in individuals with infection, inflammatory bowel disease, or malignancy and can also be induced by drugs.


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InternalMed_Harrison. Acute meningococcemia (Chap. 180) classically presents in children as a petechial eruption, but initial lesions may appear as blanch-able macules or urticaria. Rocky Mountain spotted fever should be considered in the differential diagnosis of acute meningococcemia. Echovirus infection (Chap. 228) may mimic acute meningococcemia; patients should be treated as if they have bacterial sepsis because prompt differentiation of these conditions may be impossible. Large ecchymotic areas of purpura fulminans (Chaps. 180 and 325) reflect severe underlying disseminated intravascular coagulation, which may be due to infectious or noninfectious causes. The lesions of chronic meningococcemia (Chap. 180) may have a variety of morphologies, including petechial. Purpuric nodules may develop on the legs and resemble erythema nodosum but lack its exquisite tenderness. Lesions of disseminated gonococcemia (Chap. 181) are distinctive, sparse, countable hemorrhagic pustules, usually located near joints.


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InternalMed_Harrison. and resemble erythema nodosum but lack its exquisite tenderness. Lesions of disseminated gonococcemia (Chap. 181) are distinctive, sparse, countable hemorrhagic pustules, usually located near joints. The lesions of chronic meningococcemia and those of gonococcemia may be indistinguishable in terms of appearance and distribution. Viral hemorrhagic fever (Chaps. 233 and 234) should be considered in patients with an appropriate travel history and a petechial rash. Thrombotic thrombocytopenic purpura (Chaps. 72, 129, and 140) and hemolytic-uremic syndrome (Chaps. 140, 186, and 191) are closely related and are noninfectious causes of fever and petechiae. Cutaneous small-vessel vasculitis (leukocytoclastic vasculitis) typically manifests as palpable purpura and has a wide variety of causes (Chap. 72).


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InternalMed_Harrison. The presence of an ulcer or eschar in the setting of a more widespread eruption can provide an important diagnostic clue. For example, the presence of an eschar may suggest the diagnosis of scrub typhus or rickettsialpox (Chap. 211) in the appropriate setting. In other illnesses (e.g., anthrax) (Chap. 261e), an ulcer or eschar may be the only skin manifestation. ChaPter 26 Fever of Unknown Origin Atlas of Rashes Associated with Fever Kenneth M. Kaye, Elaine T. Kaye Given the extremely broad differential diagnosis, the presentation of a patient with fever and rash often poses a thorny diagnostic challenge 25e for even the most astute and experienced clinician. Rapid narrowing of the differential by prompt recognition of a rash’s key features can result in appropriate and sometimes life-saving therapy. This atlas presents high-quality images of a variety of rashes that have an infectious etiology and are commonly associated with fever.


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InternalMed_Harrison. CHAPTER 25e Atlas of Rashes Associated with Fever Figure 25e-2 Koplik’s spots, which manifest as white or bluish lesions with an erythematous halo on the buccal mucosa, usually occur in the first 2 days of measles symptoms and may briefly overlap the measles exanthem. The presence of the erythematous halo (arrow indicates one example) differentiates Koplik’s spots from Fordyce’s spots (ectopic sebaceous glands), which occur in the mouths of healthy individuals. (Courtesy of the Centers for Disease Control and Prevention.) Figure 25e-3 In measles, discrete erythematous lesions become confluent on the face and neck over 2–3 days as the rash spreads downward to the trunk and arms, where lesions remain discrete. (Reprinted from K Wolff, RA Johnson: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)


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InternalMed_Harrison. (Reprinted from K Wolff, RA Johnson: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) Figure 25e-1 A. Erythema leading to “slapped cheeks” appearance in erythema infectiosum (fifth disease) caused by parvovirus B19. B. Lacy reticular rash of erythema infectiosum. (Panel A reprinted from K Wolff, RA Johnson: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) PART 2 Cardinal Manifestations and Presentation of Diseases Figure 25e-4 In rubella, an erythematous exanthem spreads from the hairline downward and clears as it spreads. (Courtesy of Stephen E. Gellis, MD; with permission.)


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InternalMed_Harrison. Figure 25e-4 In rubella, an erythematous exanthem spreads from the hairline downward and clears as it spreads. (Courtesy of Stephen E. Gellis, MD; with permission.) Figure 25e-7 This exanthematous, drug-induced eruption con-sists of brightly erythematous macules and papules, some of which are confluent, distributed symmetrically on the trunk and extremities. Ampicillin caused this rash. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) Figure 25e-5 Exanthem subitum (roseola) occurs most commonly in young children. A diffuse maculopapular exanthem follows resolu-tion of fever. (Courtesy of Stephen E. Gellis, MD; with permission.) Figure 25e-6 Erythematous macules and papules are apparent on the trunk and arm of this patient with primary HIV infection. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)


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InternalMed_Harrison. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) Figure 25e-8 Erythema migrans is the early cutaneous manifestation of Lyme disease and is characterized by erythematous annular patches, often with a central erythematous focus at the tick-bite site. (Reprinted from RP Usatine et al: Color Atlas of Family Medicine, 2nd ed. New York, McGraw-Hill, 2013. Courtesy of Thomas Corson, MD.) Figure 25e-9 Rose spots are evident as erythematous macules on the trunk of this patient with typhoid fever. (Courtesy of the Centers for Disease Control and Prevention.) Figure 25e-10 Systemic lupus erythematosus showing prominent malar erythema and minimal scaling. Involvement of other sun-exposed sites is also common. (Reprinted from K Wolff, RA Johnson: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.)


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InternalMed_Harrison. Figure 25e-11 Subacute lupus erythematosus on the upper chest, with brightly erythematous and slightly edematous coalescent pap-ules and plaques. (Reprinted from K Wolff, RA Johnson: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) Figure 25e-12 Chronic discoid lupus erythematosus. Violaceous, hyperpigmented, atrophic plaques, often with evidence of follicular plugging (which may result in scarring), are characteristic of this cuta-neous form of lupus. (Reprinted from K Wolff, RA Johnson, AP Saavedra: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 7th ed. New York, McGraw-Hill, 2013.) Figure 25e-13 The rash of Still’s disease typically exhibits evanes-cent, erythematous papules that appear at the height of fever on the trunk and proximal extremities. (Courtesy of Stephen E. Gellis, MD; with permission.) CHAPTER 25e Atlas of Rashes Associated with Fever


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InternalMed_Harrison. CHAPTER 25e Atlas of Rashes Associated with Fever Figure 25e-14 Impetigo is a superficial group A streptococcal or Staphylococcus aureus infection consisting of honey-colored crusts and erythematous weeping erosions. (Reprinted from K Wolff, RA Johnson: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) PART 2 Cardinal Manifestations and Presentation of Diseases Figure 25e-15 Erysipelas is a group A streptococcal infection of the superficial dermis and consists of well-demarcated, erythematous, edematous, warm plaques. (Reprinted from K Wolff, RA Johnson, AP Saavedra: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 7th ed. New York, McGraw-Hill, 2013.) Figure 25e-16 Top: Petechial lesions of Rocky Mountain spotted fever on the lower legs and soles of a young, otherwise healthy patient. Bottom: Close-up of lesions from the same patient. (Courtesy of Lindsey Baden, MD; with permission.)


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InternalMed_Harrison. Figure 25e-17 Primary syphilis with firm, nontender chancres. (Courtesy of M. Rein and the Centers for Disease Control and Prevention.) Figure 25e-19 Secondary syphilis commonly affects the palms and soles with scaling, firm, red-brown papules. Figure 25e-18 Secondary syphilis, demonstrating the papulosqua-mous truncal eruption. Figure 25e-21 Mucous patches on the tongue of a patient with secondary syphilis. (Courtesy of Ron Roddy; with permission.) Figure 25e-22 Petechial lesions in a patient with atypical measles. (Courtesy of Stephen E. Gellis, MD; with permission.) CHAPTER 25e Atlas of Rashes Associated with Fever Figure 25e-20 Condylomata lata are moist, somewhat verrucous intertriginous plaques seen in secondary syphilis.


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InternalMed_Harrison. CHAPTER 25e Atlas of Rashes Associated with Fever Figure 25e-20 Condylomata lata are moist, somewhat verrucous intertriginous plaques seen in secondary syphilis. Figure 25e-25 Erythema multiforme is characterized by erythematous plaques with a target or iris morphology, sometimes with a vesicle in the center. It usually represents a hypersensitivity reaction to infections (especially herpes simplex virus or Mycoplasma pneumoniae) or drugs. (Reprinted from K Wolff, RA Johnson: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) Figure 25e-23 Tender vesicles and erosions in the mouth of a patient with hand-foot-and-mouth disease. (Courtesy of Stephen E. Gellis, MD; with permission.) PART 2 Cardinal Manifestations and Presentation of Diseases Figure 25e-24 Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. (Courtesy of Lindsey Baden, MD; with permission.)


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InternalMed_Harrison. Figure 25e-24 Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. (Courtesy of Lindsey Baden, MD; with permission.) Figure 25e-26 Scarlet fever exanthem. Finely punctuated ery-thema has become confluent (scarlatiniform); accentuation of linear erythema in body folds (Pastia’s lines) is seen here. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) Figure 25e-28 Diffuse erythema and scaling are present in this patient with psoriasis and the exfoliative erythroderma syndrome. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) Figure 25e-27 Erythema progressing to bullae with result-ing sloughing of the entire thickness of the epidermis occurs in toxic epidermal necrolysis. This reaction was due to a sulfonamide.


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InternalMed_Harrison. Figure 25e-27 Erythema progressing to bullae with result-ing sloughing of the entire thickness of the epidermis occurs in toxic epidermal necrolysis. This reaction was due to a sulfonamide. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.) Figure 25e-29 This infant with staphylococcal scalded skin syn-drome demonstrates generalized desquamation. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) CHAPTER 25e Atlas of Rashes Associated with Fever Figure 25e-30 Fissuring of the lips and an erythematous exan-them are evident in this patient with Kawasaki disease. (Courtesy of Stephen E. Gellis, MD; with permission.) PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Figure 25e-31 Numerous varicella lesions at various stages of evolution: vesicles on an erythematous base and umbilicated vesicles, which then develop into crusting lesions. (Courtesy of the Centers for Disease Control and Prevention.) Figure 25e-33 Herpes zoster is seen in this patient taking predni-sone. Grouped vesicles and crusted lesions are seen in the T2 derma-tome on the back and arm (A) and on the right side of the chest (B). (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.)


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InternalMed_Harrison. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) Figure 25e-32 Lesions of disseminated zoster at different stages of evolution, including pustules and crusting, similar to varicella. Note nongrouping of lesions, in contrast to herpes simplex or zos-ter. (Reprinted from K Wolff, RA Johnson, AP Saavedra: Color Atlas and Synopsis of Clinical Dermatology, 7th ed. New York, McGraw-Hill, 2013.) 25e-9 CHAPTER 25e Atlas of Rashes Associated with Fever Figure 25e-35 Ecthyma gangrenosum in a neutropenic patient with Pseudomonas aeruginosa bacteremia. Figure 25e-36 Urticaria showing characteristic discrete and confluent, edematous, erythematous papules and plaques. (Reprinted from K Wolff, RA Johnson, AP Saavedra: Color Atlas and Synopsis of Clinical Dermatology, 7th ed. New York, McGraw-Hill, 2013.)


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InternalMed_Harrison. Figure 25e-34 Top: Eschar at the site of the mite bite in a patient with rickettsialpox. Middle: Papulovesicular lesions on the trunk of the same patient. Bottom: Close-up of lesions from the same patient. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002.) Figure 25e-37 Disseminated cryptococcal infection. A liver transplant recipient developed six cutaneous lesions similar to the one shown. Biopsy and serum antigen testing demonstrated Cryptococcus. Important features of the lesion include a benign-appearing fleshy papule with central umbilication resembling molluscum contagiosum. (Courtesy of Lindsey Baden, MD; with permission.) Figure 25e-38 Disseminated candidiasis. Tender, erythematous, nodular lesions developed in a neutropenic patient with leukemia who was undergoing induction chemotherapy. (Courtesy of Lindsey Baden, MD; with permission.)


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InternalMed_Harrison. Figure 25e-40 Erythema nodosum is a panniculitis characterized by tender, deep-seated nodules and plaques usually located on the lower extremities. (Courtesy of Robert Swerlick, MD; with permission.) PART 2 Cardinal Manifestations and Presentation of Diseases Figure 25e-39 Disseminated Aspergillus infection. Multiple necrotic lesions developed in this neutropenic patient undergoing hematopoietic stem cell transplantation. The lesion in the photograph is on the inner thigh and is several centimeters in diameter. Biopsy demonstrated infarction caused by Aspergillus fumigatus. (Courtesy of Lindsey Baden, MD; with permission.) Figure 25e-41 Sweet syndrome is an erythematous indurated plaque with a pseudovesicular border. (Courtesy of Robert Swerlick, MD; with permission.) Figure 25e-42 Fulminant meningococcemia with extensive angu-lar purpuric patches. (Courtesy of Stephen E. Gellis, MD; with permission.)


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InternalMed_Harrison. Figure 25e-42 Fulminant meningococcemia with extensive angu-lar purpuric patches. (Courtesy of Stephen E. Gellis, MD; with permission.) Figure 25e-43 Erythematous papular lesions are seen on the leg of this patient with chronic meningococcemia (arrow indicates a lesion). Figure 25e-45 Palpable purpuric papules on the lower leg are seen in this patient with cutaneous small-vessel hypersensitivity vasculitis. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) CHAPTER 25e Atlas of Rashes Associated with Fever Figure 25e-44 Disseminated gonococcemia in the skin is seen as hemorrhagic papules and pustules with purpuric centers in a centrifu-gal distribution. (Courtesy of Daniel M. Musher, MD; with permission.) Figure 25e-46 The thumb of a patient with a necrotic ulcer of tula-remia. (Courtesy of the Centers for Disease Control and Prevention.)


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InternalMed_Harrison. Figure 25e-46 The thumb of a patient with a necrotic ulcer of tula-remia. (Courtesy of the Centers for Disease Control and Prevention.) Figure 25e-47 This 50-year-old man developed high fever and massive inguinal lymphadenopathy after a small ulcer healed on his foot. Tularemia was diagnosed. (Courtesy of Lindsey Baden, MD; with permission.) PART 2 Cardinal Manifestations and Presentation of Diseases Figure 25e-48 This painful trypanosomal chancre developed at the site of a tsetse fly bite on the dorsum of the foot. Trypanosoma brucei was diagnosed from an aspirate of the ulcer. (Courtesy of Edward T. Ryan, MD. N Engl J Med 346:2069, 2002; with permission.)


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InternalMed_Harrison. Figure 25e-49 Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/ DIHS). This patient developed a progressive eruption exhibiting early desquamation after taking phenobarbital. There was also associated lymphadenopathy and hepatomegaly. (Courtesy of Peter Lio, MD; with permission.) Figure 25e-50 Many small, nonfollicular pustules are seen against a background of erythema in this patient with acute generalized erup-tive pustulosis (AGEP). The rash began in body folds and progressed to cover the trunk and face. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) CHAPTER 25e Atlas of Rashes Associated with Fever


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InternalMed_Harrison. CHAPTER 25e Atlas of Rashes Associated with Fever Figure 25e-51 Smallpox is shown with many pustules on the face, becoming confluent (A), and on the trunk (B). Pustules are all in the same stage of development. C. Crusting, healing lesions are noted on the trunk, arms, and hands. (Reprinted from K Wolff, RA Johnson: Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, McGraw-Hill, 2009.) CHAPTER 26 Fever of Unknown Origin fever of unknown origin Chantal P. Bleeker-Rovers, Jos W. M. van der Meer DEFINITION Clinicians commonly refer to any febrile illness without an initially obvious etiology as fever of unknown origin (FUO). Most febrile ill-nesses either resolve before a diagnosis can be made or develop distin-26 guishing characteristics that lead to a diagnosis. The term FUO should be reserved for prolonged febrile illnesses without an established etiology despite intensive evaluation and diagnostic testing. This chapter focuses on classic FUO in the adult patient.


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InternalMed_Harrison. FUO was originally defined by Petersdorf and Beeson in 1961 as an illness of >3 weeks’ duration with fever of ≥38.3°C (101°F) on two occasions and an uncertain diagnosis despite 1 week of inpatient evaluation. Nowadays, most patients with FUO are hospitalized if their clinical condition requires it, but not for diagnostic purposes only; thus the in-hospital evaluation requirement has been eliminated from the definition. The definition of FUO has been further modified by the exclusion of immunocompromised patients, whose workup requires an entirely different diagnostic and therapeutic approach. For the optimal comparison of patients with FUO in different geographic areas, it has been proposed that the quantitative criterion (diagnosis uncertain after 1 week of evaluation) be changed to a qualitative criterion that requires the performance of a specific list of investigations. Accordingly, FUO is now defined as: 1. Fever >38.3°C (101°F) on at least two occasions 2.


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InternalMed_Harrison. Fever >38.3°C (101°F) on at least two occasions 2. Illness duration of ≥3 weeks 3. 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST). The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread Percentage of Cases Due to Indicated Cause


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InternalMed_Harrison. The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread Percentage of Cases Due to Indicated Cause PART 2 Cardinal Manifestations and Presentation of Diseases use of antibiotics, and the availability of new diagnostic techniques. The proportion of cases caused by intraabdominal abscesses and tumors, for example, has decreased because of earlier detection by CT and ultrasound. In addition, infective endocarditis is a less frequent cause because blood culture and echocardiographic techniques have improved. Conversely, some diagnoses, such as acute HIV infection, were unknown four decades ago. Table 26-1 summarizes the findings of several large studies on


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InternalMed_Harrison. FUO conducted over the past 20 years. In general, infection accounts for about 20–25% of cases of FUO in Western countries; next in frequency are neoplasms and noninfectious inflammatory diseases (NIIDs), the latter including “collagen or rheumatic diseases,” vasculitis syndromes, and granulomatous disorders. In geographic areas outside the West, infections are a much more common cause of FUO (43% vs 22%), while the proportions of cases due to NIIDs and neoplasms are similar. Up to 50% of cases caused by infections in patients with FUO outside Western nations are due to tuberculosis, which is a less common cause in the United States and Western Europe. The number of FUO patients diagnosed with NIIDs probably will not decrease in the near future, as fever may precede more typical manifestations or serologic evidence by months in these diseases. Moreover, many NIIDs can be diagnosed only after prolonged observation and exclusion of other diseases.


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InternalMed_Harrison. In the West, the percentage of undiagnosed cases of FUO has increased in more recent studies. An important factor contributing to the seemingly high diagnostic failure rate is that a diagnosis is more often being established before 3 weeks have elapsed, given that patients with fever tend to seek medical advice earlier and better diagnostic techniques, such as CT and MRI, are widely available; therefore, only the cases that are more difficult to diagnose continue to meet the criteria for FUO. Furthermore, most patients who have FUO without a diagnosis currently do well, and thus a less aggressive diagnostic approach may be used in clinically stable patients once diseases with immediate therapeutic or prognostic consequences have been ruled out to a reasonable extent. This factor may be especially relevant to patients with recurrent fever who are asymptomatic in between febrile episodes. In patients with recurrent fever (defined as repeated episodes of fever interspersed with


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InternalMed_Harrison. may be especially relevant to patients with recurrent fever who are asymptomatic in between febrile episodes. In patients with recurrent fever (defined as repeated episodes of fever interspersed with fever-free intervals of at least 2 weeks and apparent remission of the underlying disease), the chance of attaining an etiologic diagnosis is <50%.


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InternalMed_Harrison. The differential diagnosis for FUO is extensive, but it is important to remember that FUO is far more often caused by an atypical presentation of a rather common disease than by a very rare disease. Table 26-2 presents an overview of possible causes of FUO. An atypical presentation of endocarditis, diverticulitis, vertebral osteomyelitis, and extra-pulmonary tuberculosis are the more common infectious disease diagnoses. Q fever and Whipple’s disease are quite rare but should always be kept in mind as a cause of FUO since the presenting symptoms


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InternalMed_Harrison. Bacterial, nonspecific Abdominal abscess, adnexitis, apical granuloma, appendicitis, cholangitis, cholecystitis, diverticulitis, endocarditis, endometritis, epidural abscess, infected vascular catheter, infected joint prosthesis, infected vascular prosthesis, infectious arthritis, infective myonecrosis, intracranial abscess, liver abscess, lung abscess, malakoplakia, mastoiditis, mediastinitis, mycotic aneurysm, osteomyelitis, pelvic inflammatory disease, prostatitis, pyelonephritis, pylephlebitis, renal abscess, septic phlebitis, sinusitis, spondylodiscitis, xanthogranulomatous urinary tract infection


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InternalMed_Harrison. Bacterial, specific Actinomycosis, atypical mycobacterial infection, bartonellosis, brucellosis, Campylobacter infection, Chlamydia pneumoniae infection, chronic meningococcemia, ehrlichiosis, gonococcemia, legionellosis, leptospirosis, listeriosis, louse-borne relapsing fever (Borrelia recurrentis), Lyme disease, melioidosis (Pseudomonas pseudomallei), Mycoplasma infection, nocardiosis, psittacosis, Q fever (Coxiella burnetii), rickettsiosis, Spirillum minor infection, Streptobacillus moniliformis infection, syphilis, tick-borne relapsing fever (Borrelia duttonii), tuberculosis, tularemia, typhoid fever and other salmonelloses, Whipple’s disease (Tropheryma whipplei), yersiniosis Fungal Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, Malassezia furfur infection, paracoccidioidomycosis, Pneumocystis jirovecii pneumonia, sporotrichosis, zygomycosis


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InternalMed_Harrison. Parasitic Amebiasis, babesiosis, echinococcosis, fascioliasis, malaria, schistosomiasis, strongyloidiasis, toxocariasis, toxoplasmosis, trichinellosis, trypanosomiasis, visceral leishmaniasis Viral Colorado tick fever, coxsackievirus infection, cytomegalovirus infection, dengue, Epstein-Barr virus infection, hantavirus infection, hepatitis (A, B, C, D, E), herpes simplex, HIV infection, human herpesvirus 6 infection, parvovirus infection, West Nile virus infection Systemic rheumatic and autoimmune Ankylosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet’s diseases disease, cryoglobulinemia, dermatomyositis, Felty syndrome, gout, mixed connective-tissue disease, polymyositis, pseudogout, reactive arthritis, relapsing polychondritis, rheumatic fever, rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus, Vogt-Koyanagi-Harada syndrome


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InternalMed_Harrison. Vasculitis Allergic vasculitis, Churg-Strauss syndrome, giant cell vasculitis/polymyalgia rheumatica, granulomatosis with polyangiitis, hypersensitivity vasculitis, Kawasaki’s disease, polyarteritis nodosa, Takayasu arteritis, urticarial vasculitis Granulomatous diseases Idiopathic granulomatous hepatitis, sarcoidosis


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InternalMed_Harrison. Granulomatous diseases Idiopathic granulomatous hepatitis, sarcoidosis Autoinflammatory syndromes Adult-onset Still’s disease, Blau syndrome, CAPSb (cryopyrin-associated periodic syndromes), Crohn’s disease, DIRA (deficiency of the interleukin 1 receptor antagonist), familial Mediterranean fever, hemophagocytic syndrome, hyper-IgD syndrome (HIDS, also known as mevalonate kinase deficiency), juvenile idiopathic arthritis, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis), recurrent idiopathic pericarditis, SAPHO (synovitis, acne, pustulosis, hyperostosis, osteomyelitis), Schnitzler’s syndrome, TRAPS (tumor necrosis factor receptor–associated periodic syndrome) CHAPTER 26 Fever of Unknown Origin


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InternalMed_Harrison. CHAPTER 26 Fever of Unknown Origin Hematologic malignancies Amyloidosis, angioimmunoblastic lymphoma, Castleman’s disease, Hodgkin’s disease, hypereosinophilic syndrome, leukemia, lymphomatoid granulomatosis, malignant histiocytosis, multiple myeloma, myelodysplastic syndrome, myelofibrosis, non-Hodgkin’s lymphoma, plasmacytoma, systemic mastocytosis, vaso-occlusive crisis in sickle cell disease Solid tumors Most solid tumors and metastases can cause fever. Those most commonly causing FUO are breast, colon, hepatocellular, lung, pancreatic, and renal cell carcinomas. Benign tumors Angiomyolipoma, cavernous hemangioma of the liver, craniopharyngioma, necrosis of dermoid tumor in Gardner’s syndrome


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InternalMed_Harrison. ADEM (acute disseminated encephalomyelitis), adrenal insufficiency, aneurysms, anomalous thoracic duct, aortic dissection, aortic-enteral fistula, aseptic meningitis (Mollaret’s syndrome), atrial myxoma, brewer’s yeast ingestion, Caroli disease, cholesterol emboli, cirrhosis, complex partial status epilepticus, cyclic neutropenia, drug fever, Erdheim-Chester disease, extrinsic allergic alveolitis, Fabry’s disease, factitious disease, fire-eater’s lung, fraudulent fever, Gaucher’s disease, Hamman-Rich syndrome (acute interstitial pneumonia), Hashimoto’s encephalopathy, hematoma, hypersensitivity pneumonitis, hypertriglyceridemia, hypothalamic hypopituitarism, idiopathic normal-pressure hydrocephalus, inflammatory pseudotumor, Kikuchi’s disease, linear IgA dermatosis, mesenteric fibromatosis, metal fume fever, milk protein allergy, myotonic dystrophy, nonbacterial osteitis, organic dust toxic syndrome, panniculitis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal


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InternalMed_Harrison. metal fume fever, milk protein allergy, myotonic dystrophy, nonbacterial osteitis, organic dust toxic syndrome, panniculitis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), polymer fume fever, post–cardiac injury syndrome, primary biliary cirrhosis, primary hyperparathyroidism, pulmonary embolism, pyoderma gangrenosum, retroperitoneal fibrosis, Rosai-Dorfman disease, sclerosing mesenteritis, silicone embolization, subacute thyroiditis (de Quervain’s), Sweet syndrome (acute febrile neutrophilic dermatosis), thrombosis, tubulointerstitial nephritis and uveitis syndrome (TINU), ulcerative colitis


InternalMed_Harrison

InternalMed_Harrison. Central Brain tumor, cerebrovascular accident, encephalitis, hypothalamic dysfunction Peripheral Anhidrotic ectodermal dysplasia, exercise-induced hyperthermia, hyperthyroidism, pheochromocytoma aThis table includes all causes of FUO that have been described in the literature. bCAPS includes chronic infantile neurologic cutaneous and articular syndrome (CINCA, also known as neonatal-onset multisystem inflammatory disease, or NOMID), familial cold autoinflammatory syndrome (FCAS), and Muckle-Wells syndrome.


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InternalMed_Harrison. can be nonspecific. Serologic testing for Q fever, which results from to consideration of infectious diseases such as malaria, leishmaniasis, exposure to animals or animal products, should be performed when histoplasmosis, or coccidioidomycosis. Fever with signs of endocardithe patient lives in a rural area or has a history of heart valve disease, tis and negative blood culture results poses a special problem. Culture-an aortic aneurysm, or a vascular prosthesis. In patients with unex-negative endocarditis may be due to difficult-to-culture bacteria such plained symptoms localized to the central nervous system (CNS), gas-as nutritionally variant bacteria, HACEK organisms (Haemophilus trointestinal tract, or joints, polymerase chain reaction (PCR) testing parainfluenzae, H. paraphrophilus, Aggregatibacter species [actinofor Tropheryma whipplei should be performed. Travel to or (former) mycetemcomitans, aphrophilus], Cardiobacterium species [hominis, residence in tropical countries or


InternalMed_Harrison

InternalMed_Harrison. Aggregatibacter species [actinofor Tropheryma whipplei should be performed. Travel to or (former) mycetemcomitans, aphrophilus], Cardiobacterium species [hominis, residence in tropical countries or the American Southwest should lead valvarum], Eikenella corrodens, and Kingella kingae; discussed below), 138 Coxiella burnetii (as indicated above), T. whipplei, and Bartonella species. Marantic endocarditis is a sterile thrombotic disease that occurs as a paraneoplastic phenomenon, especially with adenocarcinomas. Sterile endocarditis is also seen in the context of systemic lupus erythematosus and antiphospholipid syndrome. Of the NIIDs, large-vessel vasculitis, polymyalgia rheumatica, sarcoidosis, familial Mediterranean fever, and adult-onset Still’s disease are rather common diagnoses in patients with FUO. The hereditary autoinflammatory syndromes are very rare and usually present in young patients. Schnitzler’s syndrome, which can present at any age, is uncommon but can often be


InternalMed_Harrison

InternalMed_Harrison. in patients with FUO. The hereditary autoinflammatory syndromes are very rare and usually present in young patients. Schnitzler’s syndrome, which can present at any age, is uncommon but can often be diagnosed easily in a patient with FUO who presents with urticaria, bone pain, and monoclonal gammopathy. Although most tumors can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among the neoplasms. Sometimes the fever even precedes lymphadenopathy detectable by physical examination. Apart from drug-induced fever and exercise-induced hyperthermia, none of the miscellaneous causes of fever is found very frequently in patients with FUO. Virtually all drugs can cause fever, even that commencing after long-term use. Drug-induced fever, including DRESS (drug reaction with eosinophilia and systemic symptoms; Fig. 25e-49), is often accompanied by eosinophilia and also by lymphadenopathy, which can be extensive. More common causes of drug-induced fever are


InternalMed_Harrison

InternalMed_Harrison. reaction with eosinophilia and systemic symptoms; Fig. 25e-49), is often accompanied by eosinophilia and also by lymphadenopathy, which can be extensive. More common causes of drug-induced fever are allopurinol, carbamazepine, lamotrigine, phenytoin, sulfasalazine, furosemide, antimicrobial drugs (especially sulfonamides, minocycline, vancomycin, β-lactam antibiotics, and isoniazid), some cardiovascular drugs (e.g., quinidine), and some antiretroviral drugs (e.g., nevirapine). Exercise-induced hyperthermia (Chap. 479e) is characterized by an elevated body temperature that is associated with moderate to strenuous exercise lasting from half an hour up to several hours without an increase in CRP level or ESR; typically these patients sweat during the temperature elevation. Factitious fever (fever artificially induced by the patient—for example, by IV injection of contaminated water) should be considered in all patients but is more common among young women in health care professions. In


InternalMed_Harrison

InternalMed_Harrison. (fever artificially induced by the patient—for example, by IV injection of contaminated water) should be considered in all patients but is more common among young women in health care professions. In fraudulent fever, the patient is normothermic but manipulates the thermometer. Simultaneous measurements at different body sites (rectum, ear, mouth) should rapidly identify this diagnosis. Another clue to fraudulent fever is a dissociation between pulse rate and temperature. Previous studies of FUO have shown that a diagnosis is more likely in elderly patients than in younger age groups. In many cases, FUO in the elderly results from an atypical manifestation of a common disease, among which giant cell arteritis and polymyalgia rheumatica are most frequently involved. Tuberculosis is the most common infectious disease associated with FUO in elderly patients, occurring much more often than in younger patients. As many of these diseases are treatable, it is well worth pursuing the cause of


InternalMed_Harrison

InternalMed_Harrison. common infectious disease associated with FUO in elderly patients, occurring much more often than in younger patients. As many of these diseases are treatable, it is well worth pursuing the cause of fever in elderly patients.


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InternalMed_Harrison. APPROACH TO THE PATIENT: fever of unknown origin PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. Figure 26-1 shows a structured approach to patients presenting with FUO. The most important step in the diagnostic workup is the search for potentially diagnostic clues (PDCs) through complete and repeated history-taking and physical examination and the obligatory investigations listed above. PDCs are defined as all localizing signs, symptoms, and abnormalities potentially pointing toward a diagnosis. Although PDCs are often misleading, only with their help can a concise list of probable diagnoses be made. The history should include information about the fever pattern (continuous or recurrent) and duration, previous medical history, present and recent drug use, family history, sexual history, country of origin, recent and remote travel, unusual environmental exposures associated with travel or hobbies, and animal contacts. A complete physical examination should be performed, with special attention to the eyes, lymph nodes, temporal arteries, liver, spleen, sites of previous surgery,


InternalMed_Harrison

InternalMed_Harrison. or hobbies, and animal contacts. A complete physical examination should be performed, with special attention to the eyes, lymph nodes, temporal arteries, liver, spleen, sites of previous surgery, entire skin surface, and mucous membranes. Before further diagnostic tests are initiated, antibiotic and glucocorticoid treatment, which can mask many diseases, should be stopped. For example, blood and other cultures are not reliable when samples are obtained during antibiotic treatment, and the size of enlarged lymph nodes usually decreases during glucocorticoid treatment, regardless of the cause of the lymphadenopathy. Despite the high number of false-positive ultrasounds and the relatively low sensitivity of chest x-rays, the performance of these simple, low-cost diagnostic tests remains obligatory in all patients with FUO in order to separate cases that are caused by easily diagnosed diseases from those that are not. Abdominal ultrasound is preferred to abdominal CT as an obligatory test


InternalMed_Harrison

InternalMed_Harrison. in all patients with FUO in order to separate cases that are caused by easily diagnosed diseases from those that are not. Abdominal ultrasound is preferred to abdominal CT as an obligatory test because of relatively low cost, lack of radiation burden, and absence of side effects.


InternalMed_Harrison

InternalMed_Harrison. Only rarely do biochemical tests (beyond the obligatory tests needed to classify a patient’s fever as FUO) lead directly to a definitive diagnosis in the absence of PDCs. The diagnostic yield of immunologic serology other than that included in the obligatory tests is relatively low. These tests more often yield false-positive rather than true-positive results and are of little use without PDCs pointing to specific immunologic disorders. Given the absence of specific symptoms in many patients and the relatively low cost of the test, investigation of cryoglobulins appears to be a valuable screening test in patients with FUO.


InternalMed_Harrison

InternalMed_Harrison. Multiple blood samples should be cultured in the laboratory long enough to ensure ample growth time for any fastidious organisms, such as HACEK organisms. It is critical to inform the laboratory of the intent to test for unusual organisms. Specialized media should be used when the history suggests uncommon microorganisms, such as Histoplasma or Legionella. Performing more than three blood cultures or more than one urine culture is useless in patients with FUO in the absence of PDCs (e.g., a high level of clinical suspicion of endocarditis). Repeating blood or urine cultures is useful only when previously cultured samples were collected during antibiotic treatment or within 1 week after its discontinuation. FUO with headache should prompt microbiologic examination of cerebrospinal fluid (CSF) for organisms including herpes simplex virus (HSV; especially HSV-2), Cryptococcus neoformans, and Mycobacterium tuberculosis. In CNS tuberculosis, the CSF typically has elevated protein and


InternalMed_Harrison

InternalMed_Harrison. (CSF) for organisms including herpes simplex virus (HSV; especially HSV-2), Cryptococcus neoformans, and Mycobacterium tuberculosis. In CNS tuberculosis, the CSF typically has elevated protein and lowered glucose concentrations, with a mononuclear pleocytosis. CSF protein levels range from 100 to 500 mg/dL in most patients, the CSF glucose concentration is <45 mg/dL in 80% of cases, and the usual CSF cell count is between 100 and 500 cells/μL.


InternalMed_Harrison

InternalMed_Harrison. Microbiologic serology should not be included in the diagnostic workup in patients without PDCs for specific infections. A TST is included in the obligatory investigations, but it may yield false-negative results in patients with miliary tuberculosis, malnutrition, or immunosuppression. Although the interferon γ release assay is less influenced by prior vaccination with bacille Calmette-Guérin or by infection with nontuberculous mycobacteria, its sensitivity is similar to that of the TST; a negative TST or interferon γ release assay therefore does not exclude a diagnosis of tuberculosis. Miliary tuberculosis is especially difficult to diagnose. Granulomatous disease in liver or bone marrow biopsy samples, for example, should always lead to a (re)consideration of this diagnosis. If miliary tuberculosis is suspected, liver biopsy for acid-fast smear, culture, and PCR probably still has the highest diagnostic yield; however, biopsies of bone marrow, lymph nodes, or other involved organs


InternalMed_Harrison

InternalMed_Harrison. tuberculosis is suspected, liver biopsy for acid-fast smear, culture, and PCR probably still has the highest diagnostic yield; however, biopsies of bone marrow, lymph nodes, or other involved organs also can be considered.


InternalMed_Harrison

InternalMed_Harrison. The diagnostic yield of echocardiography, sinus radiography, radiologic or endoscopic evaluation of the gastrointestinal tract, and bronchoscopy is very low in the absence of PDCs. Therefore, these tests should not be used as screening procedures. After identification of all PDCs retrieved from the history, physical examination, and obligatory tests, a limited list of the most probable diagnoses should be made. Since most investigations are helpful only for patients who have PDCs for the diagnoses sought, further diagnostic procedures should be limited to specific investigations aimed at confirming or excluding diseases on this list. In FUO, the Fever ˜38.3° C (101° F) and illness lasting ˜3 weeks and no known immunocompromised state History and physical examination Stop antibiotic treatment and glucocorticoids Obligatory investigations:


InternalMed_Harrison

InternalMed_Harrison. Fever ˜38.3° C (101° F) and illness lasting ˜3 weeks and no known immunocompromised state History and physical examination Stop antibiotic treatment and glucocorticoids Obligatory investigations: ESR and CRP, hemoglobin, platelet count, leukocyte count and differential, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH, creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n=3), urine culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test


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InternalMed_Harrison. Stable condition: Follow-up for new PDCs Consider NSAID Deterioration: Further diagnostic tests Consider therapeutic trial PDCs present PDCs absent or misleading Exclude manipulation with thermometer Stop or replace medication to exclude drug fever Guided diagnostic tests DIAGNOSIS Cryoglobulin and funduscopy NO DIAGNOSIS FDG-PET/CT (or labeled leukocyte scintigraphy or gallium scan) Scintigraphy abnormal Scintigraphy normal Confirmation of abnormality (e.g., biopsy, culture) Repeat history and physical examination Perform PDC-driven invasive testing DIAGNOSIS NO DIAGNOSIS DIAGNOSIS NO DIAGNOSIS Chest and abdominal CT Temporal artery biopsy (˜55 years) DIAGNOSIS NO DIAGNOSIS CHAPTER 26 Fever of Unknown Origin


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 26 Fever of Unknown Origin FIguRE 26-1 Structured approach to patients with FUO. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography combined with low-dose computed tomography; LDH, lactate dehydrogenase; PDCs, potentially diagnostic clues (all localizing signs, symptoms, and abnormalities potentially pointing toward a diagnosis); NSAID, nonsteroidal anti-inflammatory drug.


InternalMed_Harrison

InternalMed_Harrison. diagnostic pointers are numerous and diverse but may be missed drug is the cause. In patients without PDCs or with only misleading on initial examination, often being detected only by a very care-PDCs, funduscopy by an ophthalmologist may be useful in the early ful examination performed subsequently. In the absence of PDCs, stage of the diagnostic workup. When the first-stage diagnostic tests the history and physical examination should therefore be repeated do not lead to a diagnosis, scintigraphy should be performed, esperegularly. One of the first steps should be to rule out factitious or cially when the ESR or CRP level is elevated. fraudulent fever, particularly in patients without signs of inflammation in laboratory tests. All medications, including nonprescription Recurrent Fever In patients with recurrent fever, the diagnostic drugs and nutritional supplements, should be discontinued early in workup should consist of thorough history-taking, physical examithe evaluation to


InternalMed_Harrison

InternalMed_Harrison. In patients with recurrent fever, the diagnostic drugs and nutritional supplements, should be discontinued early in workup should consist of thorough history-taking, physical examithe evaluation to exclude drug fever. If fever persists beyond 72 h nation, and obligatory tests. The search for PDCs should be directed after discontinuation of the suspected drug, it is unlikely that this to clues matching known recurrent syndromes (Table 26-3). Patients


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Systemic rheumatic and autoimmune Ankylosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet’s diseases disease, cryoglobulinemia, gout, polymyositis, pseudogout, reactive arthritis, relapsing polychondritis, systemic lupus erythematosus Vasculitis Churg-Strauss syndrome, giant cell vasculitis/polymyalgia rheumatica, hypersensitivity vasculitis, polyarteritis nodosa, urticarial vasculitis Granulomatous diseases Idiopathic granulomatous hepatitis, sarcoidosis


InternalMed_Harrison

InternalMed_Harrison. Granulomatous diseases Idiopathic granulomatous hepatitis, sarcoidosis Autoinflammatory syndromes Adult-onset Still’s disease, Blau syndrome, CAPSb (cryopyrin-associated periodic syndrome), Crohn’s disease, DIRA (deficiency of the IL-1 receptor antagonist), familial Mediterranean fever, hemophagocytic syndrome, hyper-IgD syndrome (HIDS, also known as mevalonate kinase deficiency), juvenile idiopathic arthritis, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis), recurrent idiopathic pericarditis, SAPHO (synovitis, acne, pustulosis, hyperostosis, osteomyelitis), Schnitzler’s syndrome, TRAPS (tumor necrosis factor receptor–associated periodic syndrome) Angioimmunoblastic lymphoma, Castleman’s disease, colon carcinoma, craniopharyngioma, Hodgkin’s disease, non-Hodgkin lymphoma, malignant histiocytosis, mesothelioma


InternalMed_Harrison

InternalMed_Harrison. Angioimmunoblastic lymphoma, Castleman’s disease, colon carcinoma, craniopharyngioma, Hodgkin’s disease, non-Hodgkin lymphoma, malignant histiocytosis, mesothelioma Adrenal insufficiency, aortic-enteral fistula, aseptic meningitis (Mollaret’s syndrome), atrial myxoma, brewer’s yeast ingestion, cholesterol emboli, cyclic neutropenia, drug fever, extrinsic allergic alveolitis, Fabry’s disease, factitious disease, fraudulent fever, Gaucher’s disease, hypersensitivity pneumonitis, hypertriglyceridemia, hypothalamic hypopituitarism, inflammatory pseudotumor, metal fume fever, milk protein allergy, polymer fume fever, pulmonary embolism, sclerosing mesenteritis


InternalMed_Harrison

InternalMed_Harrison. Central Hypothalamic dysfunction Peripheral Anhidrotic ectodermal dysplasia, exercise-induced hyperthermia, pheochromocytoma aThis table includes all causes of recurrent fever that have been described in the literature. bCAPS includes chronic infantile neurologic cutaneous and articular syndrome (CINCA, also known as neonatal-onset multisystem inflammatory disease, or NOMID), familial cold autoinflammatory syndrome (FCAS), and Muckle-Wells syndrome.


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InternalMed_Harrison. should be asked to return during a febrile episode so that the history, physical examination, and laboratory tests can be repeated during a symptomatic phase. Further diagnostic tests, such as scintigraphic imaging (see below), should be performed only during a febrile episode because abnormalities may be absent between episodes. In patients with recurrent fever lasting >2 years, it is very unlikely that the fever is caused by infection or malignancy. Further diagnostic tests in that direction should be considered only when PDCs for infections, vasculitis syndromes, or malignancy are present or when the patient’s clinical condition is deteriorating.


InternalMed_Harrison

InternalMed_Harrison. Scintigraphy Scintigraphic imaging is a noninvasive method allowing delineation of foci in all parts of the body on the basis of functional changes in tissues. This procedure plays an important role in the diagnosis of patients with FUO in clinical practice. Conventional scintigraphic methods used in clinical practice are 67Ga-citrate scintigraphy and 111Inor 99mTc-labeled leukocyte scintigraphy. Focal infectious and inflammatory processes can also be detected by several radiologic techniques, such as CT, MRI, and ultrasound. However, because of the lack of substantial pathologic changes in the early phase, infectious and inflammatory foci cannot be detected at this time. Furthermore, distinguishing active infectious or inflammatory lesions from residual changes due to cured processes or surgery remains critical. Finally, CT and MRI routinely provide information only on part of the body, while scintigraphy readily allows whole-body imaging.


InternalMed_Harrison

InternalMed_Harrison. Fluorodeoxyglucose Positron Emission Tomography 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become an established imaging procedure in FUO. FDG accumulates in tissues with a high rate of glycolysis, which occurs not only in malignant cells but also in activated leukocytes, and thus permits the imaging of acute and chronic inflammatory processes. Normal uptake may obscure pathologic foci in the brain, heart, bowel, kidneys, and bladder. In patients with fever, bone marrow uptake is frequently increased in a nonspecific way due to cytokine activation, which upregulates glucose transporters in bone marrow cells. Compared with conventional scintigraphy, FDG-PET offers the advantages of higher resolution, greater sensitivity in chronic low-grade infections, and a high degree of accuracy in the central skeleton. Furthermore, vascular uptake of FDG is increased in patients with vasculitis. The mechanisms responsible for FDG uptake do not allow differentiation among


InternalMed_Harrison

InternalMed_Harrison. degree of accuracy in the central skeleton. Furthermore, vascular uptake of FDG is increased in patients with vasculitis. The mechanisms responsible for FDG uptake do not allow differentiation among infection, sterile inflammation, and malignancy. However, in patients with FUO, since all of these disorders are causes of FUO, FDG-PET can be used to guide additional diagnostic tests (e.g., targeted biopsies) that may yield the final diagnosis. Improved anatomic resolution by direct integration with CT (FDG-PET/CT) has further improved the accuracy of this modality.


InternalMed_Harrison

InternalMed_Harrison. Overall rates of helpfulness in final diagnosis of FUO are 40% for FDG-PET and 54% for FDG-PET/CT. In one study, FDG-PET was never helpful in diagnosing FUO in patients with a normal CRP level and a normal ESR. In two prospective studies in patients with FUO, FDG-PET was superior to 67Ga-citrate scintigraphy, with a similar or better diagnostic yield and results that were available within hours instead of days. In one study, the sensitivity of FDGPET was greater than that of 111In-granulocyte scintigraphy (86% vs 20%) in patients with FUO.


InternalMed_Harrison

InternalMed_Harrison. Although scintigraphic techniques do not directly provide a definitive diagnosis, they often identify the anatomic location of a particular ongoing metabolic process and, with the help of other techniques such as biopsy and culture, facilitate timely diagnosis and treatment. Pathologic FDG uptake is quickly eradicated by treatment with glucocorticoids in many diseases, including vasculitis and lymphoma; therefore, glucocorticoid use should be stopped or postponed until after FDG-PET is performed. Results reported in the literature and the advantages offered by FDG-PET indicate that conventional scintigraphic techniques should be replaced by FDG-PET/CT in the investigation of patients with FUO at institutions where this technique is available. FDG-PET/CT is a relatively expensive procedure whose availability is still limited compared with that of CT and conventional scintigraphy. Nevertheless, FDGPET/CT can be cost-effective in the FUO diagnostic workup if used at an early stage,


InternalMed_Harrison

InternalMed_Harrison. whose availability is still limited compared with that of CT and conventional scintigraphy. Nevertheless, FDGPET/CT can be cost-effective in the FUO diagnostic workup if used at an early stage, helping to establish an early diagnosis, reducing days of hospitalization for diagnostic purposes, and obviating unnecessary and unhelpful tests.


InternalMed_Harrison

InternalMed_Harrison. In some cases, more invasive tests are appropriate. Abnormalities found with scintigraphic techniques often need to be confirmed by pathology and/or culture of biopsy specimens. If lymphadenopathy is found, lymph node biopsy is necessary, even when the affected lymph nodes are hard to reach. In the case of skin lesions, skin biopsy should be undertaken. In one study, pulmonary wedge excision, histologic examination of an excised tonsil, and biopsy of the peritoneum were performed in light of PDCs or abnormal FDGPET results and yielded a diagnosis.


InternalMed_Harrison

InternalMed_Harrison. If no diagnosis is reached despite scintigraphic and PDC-driven histologic investigations or culture, second-stage screening diagnostic tests should be considered (Fig. 26-1). In three studies, the diagnostic yield of screening chest and abdominal CT in patients with FUO was ~20%. The specificity of chest CT was ~80%, but that of abdominal CT varied between 63% and 80%. Despite the relatively limited specificity of abdominal CT and the probably limited additional value of chest CT after normal FDG-PET, chest and abdominal CT may be used as screening procedures at a later stage of the diagnostic protocol because of their noninvasive nature and high sensitivity. Bone marrow aspiration is seldom useful in the absence of PDCs for bone marrow disorders. With addition of FDG-PET, which is very sensitive in detecting lymphoma, carcinoma, and osteomyelitis, the value of bone marrow biopsy as a screening procedure is probably further reduced. Several studies have shown a high prevalence of


InternalMed_Harrison

InternalMed_Harrison. sensitive in detecting lymphoma, carcinoma, and osteomyelitis, the value of bone marrow biopsy as a screening procedure is probably further reduced. Several studies have shown a high prevalence of giant cell arteritis among patients with FUO, with rates up to 17% among elderly patients. Giant cell arteritis often involves large arteries and in most cases can be diagnosed by FDG-PET. However, temporal artery biopsy is still recommended for patients ≥55 years of age in a later stage of the diagnostic protocol: FDG-PET will not be useful in vasculitis limited to the temporal arteries because of the small diameter of these vessels and the high levels of FDG uptake in the brain that overlies them. In the past, liver biopsies have often been performed as a screening procedure in patients with FUO. In each of two recent studies, liver biopsy as part of the later stage of a screening diagnostic protocol was helpful in only one patient. Moreover, abnormal liver tests are not predictive of a


InternalMed_Harrison

InternalMed_Harrison. FUO. In each of two recent studies, liver biopsy as part of the later stage of a screening diagnostic protocol was helpful in only one patient. Moreover, abnormal liver tests are not predictive of a diagnostic liver biopsy in FUO. Liver biopsy is an invasive procedure that carries the possibility of complications and even death. Therefore, it should not be used for screening purposes in patients with FUO except in those with PDCs for liver disease.


InternalMed_Harrison

InternalMed_Harrison. In patients with unexplained fever after all of the above procedures, the last step in the diagnostic workup—with only a marginal diagnostic yield—comes at an extraordinarily high cost in terms of both expense and discomfort for the patient. Repetition of a thorough history-taking and physical examination and review of laboratory results and imaging studies (including those from other hospitals) are recommended. Diagnostic delay often results from a failure to recognize PDCs in the available information. In these patients with persisting FUO, waiting for new PDCs to appear probably is better than ordering more screening investigations. Only when a patient’s condition deteriorates without providing new PDCs should a further diagnostic workup be performed.


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InternalMed_Harrison. Empirical therapeutic trials with antibiotics, glucocorticoids, or antituberculous agents should be avoided in FUO except when a patient’s condition is rapidly deteriorating after the aforementioned diagnostic tests have failed to provide a definite diagnosis. Antibiotic or antituberculous therapy may irrevocably diminish the ability to culture fastidious bacteria or mycobacteria. However, hemodynamic instability or neutropenia is a good indication for empirical antibiotic therapy. If the TST is positive or if granulomatous disease is present with anergy and sarcoidosis seems unlikely, a therapeutic trial for tuberculosis should be started. Especially in miliary tuberculosis, it may be very difficult to obtain a rapid diagnosis. If the fever does not respond after 6 weeks of empirical antituberculous treatment, another diagnosis should be considered. COLCHICINE, NONSTEROIDAL ANTI-INFLAMMATORY DRugS, AND gLuCOCORTICOIDS


InternalMed_Harrison

InternalMed_Harrison. Colchicine is highly effective in preventing attacks of familial Mediterranean fever but is not always effective once an attack is well under way. When familial Mediterranean fever is suspected, the response to colchicine is not a completely reliable diagnostic tool in the acute phase, but with colchicine treatment most patients show remarkable improvements in the frequency and severity of subsequent febrile episodes within weeks to months. If the fever persists and the source remains elusive after completion of the later-stage investigations, supportive treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful. The response of adult-onset Still’s disease to NSAIDs is dramatic in some cases. The effects of glucocorticoids on giant cell arteritis and polymyalgia rheumatica are equally impressive. Early empirical trials with glucocorticoids, however, decrease the chances of reaching a diagnosis for which more specific and sometimes life-saving treatment might be more


InternalMed_Harrison

InternalMed_Harrison. are equally impressive. Early empirical trials with glucocorticoids, however, decrease the chances of reaching a diagnosis for which more specific and sometimes life-saving treatment might be more appropriate, such as malignant lymphoma. The ability of NSAIDs and glucocorticoids to mask fever while permitting the spread of infection or lymphoma dictates that their use should be avoided unless infectious diseases and malignant lymphoma have been largely ruled out and inflammatory disease is probable and is likely to be debilitating or threatening.


InternalMed_Harrison

InternalMed_Harrison. Interleukin (IL) 1 is a key cytokine in local and systemic inflammation and the febrile response. The availability of specific IL-1-targeting agents has revealed a pathologic role of IL-1-mediated inflammation in a growing list of diseases. Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks the activity of both IL-1α and IL-1β. Anakinra is extremely effective in the treatment of many autoinflammatory syndromes, such as familial Mediterranean fever, cryopyrin-associated periodic syndrome, tumor necrosis factor receptor–associated periodic syndrome, hyper-IgD syndrome, and Schnitzler’s syndrome. There is a growing list of other chronic inflammatory disorders in which the reduction of IL-1 activity can be highly effective. A therapeutic trial with anakinra can be considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests. Although most chronic inflammatory conditions without a known basis can be controlled


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InternalMed_Harrison. with anakinra can be considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests. Although most chronic inflammatory conditions without a known basis can be controlled with glucocorticoids, monotherapy with IL-1 blockade can provide improved control without the metabolic, immunologic, and gastrointestinal side effects of glucocorticoid administration.


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 26 Fever of Unknown Origin 142 PROgNOSIS FUO-related mortality rates have continuously declined over recent decades. The majority of fevers are caused by treatable diseases, and the risk of death related to FUO is, of course, dependent on the underlying disease. In a study by our group (Table 26-1), none of 37 FUO patients without a diagnosis died during a follow-up period of at least 6 months; 4 of 36 patients with a diagnosis died during follow-up due to infection (n = 1) or malignancy (n = 3). Other studies have also shown that malignancy accounts for most FUO-related deaths. NonHodgkin’s lymphoma carries a disproportionately high death toll. In nonmalignant FUO, fatality rates are very low. The good outcome in patients without a diagnosis confirms that potentially lethal occult diseases are very unusual and that empirical therapy with antibiotics, antituberculous agents, or glucocorticoids is rarely required in stable patients. In less affluent regions, infectious diseases


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InternalMed_Harrison. diseases are very unusual and that empirical therapy with antibiotics, antituberculous agents, or glucocorticoids is rarely required in stable patients. In less affluent regions, infectious diseases are still a major cause of FUO, and outcomes may be different.


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InternalMed_Harrison. Cardinal Manifestations and Presentation of Diseases Syncope is a transient, self-limited loss of consciousness due to acute global impairment of cerebral blood flow. The onset is rapid, duration brief, and recovery spontaneous and complete. Other causes of transient loss of consciousness need to be distinguished from syncope; these include seizures, vertebrobasilar ischemia, hypoxemia, and hypoglycemia. A syncopal prodrome (presyncope) is common, although loss of consciousness may occur without any warning symptoms. Typical presyncopal symptoms include dizziness, lightheadedness or faintness, weakness, fatigue, and visual and auditory disturbances. The causes of syncope can be divided into three general categories: (1) neurally mediated syncope (also called reflex or vasovagal syncope), (2) orthostatic hypotension, and (3) cardiac syncope.


InternalMed_Harrison

InternalMed_Harrison. Neurally mediated syncope comprises a heterogeneous group of functional disorders that are characterized by a transient change in the reflexes responsible for maintaining cardiovascular homeostasis. Episodic vasodilation (or loss of vasoconstrictor tone) and bradycardia occur in varying combinations, resulting in temporary failure of blood pressure control. In contrast, in patients with orthostatic hypotension due to autonomic failure, these cardiovascular homeostatic reflexes are chronically impaired. Cardiac syncope may be due to arrhythmias or structural cardiac diseases that cause a decrease in cardiac output. The clinical features, underlying pathophysiologic mechanisms, therapeutic interventions, and prognoses differ markedly among these three causes.


InternalMed_Harrison

InternalMed_Harrison. Syncope is a common presenting problem, accounting for approximately 3% of all emergency room visits and 1% of all hospital admissions. The annual cost for syncope-related hospitalization in the United States is ~$2.4 billion. Syncope has a lifetime cumulative incidence of up to 35% in the general population. The peak incidence in the young occurs between ages 10 and 30 years, with a median peak around 15 years. Neurally mediated syncope is the etiology in the vast majority of these cases. In elderly adults, there is a sharp rise in the incidence of syncope after 70 years.


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InternalMed_Harrison. In population-based studies, neurally mediated syncope is the most common cause of syncope. The incidence is slightly higher in females than males. In young subjects, there is often a family history in first-degree relatives. Cardiovascular disease due to structural disease or arrhythmias is the next most common cause in most series, particularly in emergency room settings and in older patients. Orthostatic hypotension also increases in prevalence with age because of the reduced baroreflex responsiveness, decreased cardiac compliance, and attenuation of the vestibulosympathetic reflex associated with aging. In the elderly, orthostatic hypotension is substantially more common in institutionalized (54–68%) than community-dwelling (6%) individuals, an observation most likely explained by the greater prevalence of HigH-RiSK fEATuRES inDiCATing HoSPiTALizATion oR inTEnSivE EvALuATion of SynCoPE


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InternalMed_Harrison. HigH-RiSK fEATuRES inDiCATing HoSPiTALizATion oR inTEnSivE EvALuATion of SynCoPE Chest pain suggesting coronary ischemia Features of congestive heart failure Moderate or severe valvular disease Moderate or severe structural cardiac disease Electrocardiographic features of ischemia History of ventricular arrhythmias Prolonged QT interval (>500 ms) Repetitive sinoatrial block or sinus pauses Persistent sinus bradycardia Bior trifascicular block or intraventricular conduction delay with QRS duration≥120 ms Atrial fibrillation Nonsustained ventricular tachycardia Family history of sudden death Preexcitation syndromes Brugada pattern on ECG Palpitations at time of syncope Syncope at rest or during exercise predisposing neurologic disorders, physiologic impairment, and vasoactive medication use among institutionalized patients.


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InternalMed_Harrison. The prognosis after a single syncopal event for all age groups is generally benign. In particular, syncope of noncardiac and unexplained origin in younger individuals has an excellent prognosis; life expectancy is unaffected. By contrast, syncope due to a cardiac cause, either structural heart disease or primary arrhythmic disease, is associated with an increased risk of sudden cardiac death and mortality from other causes. Similarly, mortality rate is increased in individuals with syncope due to orthostatic hypotension related to age and the associated comorbid conditions (Table 27-1).


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InternalMed_Harrison. The upright posture imposes a unique physiologic stress upon humans; most, although not all, syncopal episodes occur from a standing position. Standing results in pooling of 500–1000 mL of blood in the lower extremities and splanchnic circulation. There is a decrease in venous return to the heart and reduced ventricular filling that result in diminished cardiac output and blood pressure. These hemodynamic changes provoke a compensatory reflex response, initiated by the baroreceptors in the carotid sinus and aortic arch, resulting in increased sympathetic outflow and decreased vagal nerve activity (Fig. 27-1). The reflex increases peripheral resistance, venous return to the heart, and cardiac output and thus limits the fall in blood pressure. If this response fails, as is the case chronically in orthostatic hypotension and transiently in neurally mediated syncope, cerebral hypoperfusion occurs.


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InternalMed_Harrison. Syncope is a consequence of global cerebral hypoperfusion and thus represents a failure of cerebral blood flow autoregulatory mechanisms.


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InternalMed_Harrison. FIguRE 27-1 The baroreflex. A decrease in arterial pressure unloads the baroreceptors—the terminals of afferent fibers of the glossopharyngeal and vagus nerves—that are situated in the carotid sinus and aortic arch. This leads to a reduction in the afferent impulses that are relayed from these mechanoreceptors through the glossopharyngeal and vagus nerves to the nucleus of the tractus solitarius (NTS) in the dorsomedial medulla. The reduced baroreceptor afferent activity produces a decrease in vagal nerve input to the sinus node that is mediated via connections of the NTS to the nucleus ambiguus (NA). There is an increase in sympathetic efferent activity that is mediated by the NTS projections to the caudal ventrolateral medulla (CVLM) (an excitatory pathway) and from there to the rostral ventrolateral medulla (RVLM) (an inhibitory pathway). The activation of RVLM presympathetic neurons in response to hypotension is thus predominantly due to disinhibition. In response to a sustained


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InternalMed_Harrison. ventrolateral medulla (RVLM) (an inhibitory pathway). The activation of RVLM presympathetic neurons in response to hypotension is thus predominantly due to disinhibition. In response to a sustained fall in blood pressure, vasopressin release is mediated by projections from the A1 noradrenergic cell group in the ventrolateral medulla. This projection activates vasopressin-synthesizing neurons in the magnocellular portion of the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus. Blue denotes sympathetic neurons, and green denotes parasympathetic neurons. (From R Freeman: N Engl J Med 358:615, 2008.)


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InternalMed_Harrison. Myogenic factors, local metabolites, and to a lesser extent autonomic neurovascular control are responsible for the autoregulation of cerebral blood flow (Chap. 330). The latency of the autoregulatory response is 5–10 s. Typically cerebral blood flow ranges from 50 to 60 mL/min per 100 g brain tissue and remains relatively constant over perfusion pressures ranging from 50 to 150 mmHg. Cessation of blood flow for 6–8 s will result in loss of consciousness, while impairment of consciousness ensues when blood flow decreases to 25 mL/min per 100 g brain tissue.


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InternalMed_Harrison. From the clinical standpoint, a fall in systemic systolic blood pressure to ~50 mmHg or lower will result in syncope. A decrease in cardiac output and/or systemic vascular resistance—the determinants of blood pressure—thus underlies the pathophysiology of syncope. Common causes of impaired cardiac output include decreased effective circulating blood volume; increased thoracic pressure; massive pulmonary embolus; cardiac bradyand tachyarrhythmias; valvular heart disease; and myocardial dysfunction. Systemic vascular resistance may be decreased by central and peripheral autonomic nervous system diseases, sympatholytic medications, and transiently during neurally mediated syncope. Increased cerebral vascular resistance, most frequently due to hypocarbia induced by hyperventilation, may also contribute to the pathophysiology of syncope.


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InternalMed_Harrison. Two patterns of electroencephalographic (EEG) changes occur in syncopal subjects. The first is a “slow-flat-slow” pattern (Fig. 27-2) in which normal background activity is replaced with high-amplitude slow delta waves. This is followed by sudden flattening of the EEG—a cessation or attenuation of cortical activity—followed by the return of slow waves, and then normal activity. A second pattern, the “slow pattern,” is characterized by increasing and decreasing slow wave activity only. The EEG flattening that occurs in the slow-flat-slow pattern is a marker of more severe cerebral hypoperfusion. Despite the presence of myoclonic movements and other motor activity during some syncopal events, EEG seizure discharges are not detected.


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InternalMed_Harrison. Neurally mediated (reflex; vasovagal) syncope is the final pathway of a complex central and peripheral nervous system reflex arc. There is a sudden, transient change in autonomic efferent activity with increased parasympathetic outflow, plus sympathoinhibition (the vasodepressor response), resulting in bradycardia, vasodilation, and/or reduced vasoconstrictor tone. The resulting fall in systemic blood pressure can then reduce cerebral blood flow to below the compensatory limits of autoregulation (Fig. 27-3). In order to elicit neutrally mediated syncope, a functioning autonomic nervous system is necessary, in contrast to syncope resulting from autonomic failure (discussed below).


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InternalMed_Harrison. FIguRE 27-2 The electroencephalogram (EEG) in vasovagal syncope. A 1-min segment of a tilt-table test with typical vasovagal syncope demonstrating the “slow-flat-slow” EEG pattern. Finger beat-to-beat blood pressure, electrocardiogram (ECG), and selected EEG channels are shown. EEG slowing starts when systolic blood pressure drops to ~50 mmHg; heart rate is then approximately 45 beats/min (bpm). Asystole occurred, lasting about 8 s. The EEG flattens for a similar period, but with a delay. A transient loss of consciousness, lasting 14 s, was observed. There were muscle jerks just before and just after the flat period of the EEG. (Figure reproduced with permission from W Wieling et al: Brain 132:2630, 2009.)


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InternalMed_Harrison. Multiple triggers of the afferent limb of the reflex arc can result network within the medulla that integrates the neural impulses and in neutrally mediated syncope. In some situations, these can mediates the vasodepressor-bradycardic response. be clearly defined, e.g., the carotid sinus, the gastrointestinal tract, or the bladder. Often, however, the trigger is less easily recognized Classification of Neurally Mediated Syncope Neurally mediated syncope and the cause is multifactorial. Under these circumstances, it is likely may be subdivided based on the afferent pathway and provocathat different afferent pathways converge on the central autonomic tive trigger. Vasovagal syncope (the common faint) is provoked by intense emotion, pain, and/or orthostatic stress, whereas the situational reflex 120 syncopes have specific localized stimuli125 that provoke the reflex vasodilation and 100 bradycardia that leads to syncope. The


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases 60 most of these situational reflex syncopes. The afferent trigger may originate in the pulmonary system, gastrointestinal system, urogenital system, heart, and carotid artery (Table 27-2). Hyperventilation leading to hypocarbia and cerebral vaso constriction, and raised intrathoracic pressure that impairs venous return to the 80 heart, play a central role in many of the situational reflex syncopes. The afferent pathway of the reflex arc differs among 40 these disorders, but the efferent response FIguRE 27-3 A. The paroxysmal hypotensive-bradycardic response that is characteristic of neurally mediated syncope. Noninvasive beat-to-beat blood pressure and heart rate are shown over 5 min (from 60 to 360 s) of an upright tilt on a tilt table. B. The same tracing expanded to show 80 s of the episode (from 80 to 200 s). BP, blood pressure; bpm, beats per minute; HR, heart rate.


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InternalMed_Harrison. via the vagus and sympathetic pathways is similar. Alternately, neurally mediated syncope may be subdivided based on the predominant efferent pathway. Vasodepressor syncope describes syncope predominantly due to efferent, sympathetic, vasoconstrictor failure; cardioinhibitory syncope describes syncope predominantly associated with bradycardia or asystole due CAuSES of SynCoPE A. Neurally Mediated Syncope


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InternalMed_Harrison. CAuSES of SynCoPE A. Neurally Mediated Syncope Vasovagal syncope Provoked fear, pain, anxiety, intense emotion, sight of blood, unpleasant sights and odors, orthostatic stress Situational reflex syncope Pulmonary Cough syncope, wind instrument player’s syncope, weightlifter’s syncope, “mess trick”a and “fainting lark,”b sneeze syncope, airway instrumentation Urogenital Postmicturition syncope, urogenital tract instrumentation, prostatic massage Gastrointestinal Swallow syncope, glossopharyngeal neuralgia, esophageal stimulation, gastrointestinal tract instrumentation, rectal examination, defecation syncope Cardiac Bezold-Jarisch reflex, cardiac outflow obstruction Carotid sinus Carotid sinus sensitivity, carotid sinus massage Ocular Ocular pressure, ocular examination, ocular surgery B. Orthostatic Hypotension


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InternalMed_Harrison. B. Orthostatic Hypotension Primary autonomic failure due to idiopathic central and peripheral neurodegenerative diseases—the “synucleinopathies” Lewy body diseases Parkinson’s disease Lewy body dementia Pure autonomic failure Multiple system atrophy (the Shy-Drager syndrome) Secondary autonomic failure due to autonomic peripheral neuropathies Diabetes C. Cardiac Syncope aHyperventilation for ~1 minute, followed by sudden chest compression. bHyperventilation (~20 breaths) in a squatting position, rapid rise to standing, then Valsalva. to increased vagal outflow; and mixed syncope describes syncope in 145 which there are both vagal and sympathetic reflex changes.


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InternalMed_Harrison. Features of Neurally Mediated Syncope In addition to symptoms of orthostatic intolerance such as dizziness, lightheadedness, and fatigue, premonitory features of autonomic activation may be present in patients with neurally mediated syncope. These include diaphoresis, pallor, palpitations, nausea, hyperventilation, and yawning. During the syncopal event, proximal and distal myoclonus (typically arrhythmic and multifocal) may occur, raising the possibility of epilepsy. The eyes typically remain open and usually deviate upward. Pupils are usually dilated. Roving eye movements may occur. Grunting, moaning, snorting, and stertorous breathing may be present. Urinary incontinence may occur. Fecal incontinence is very rare. Postictal confusion is also rare, although visual and auditory hallucinations and near death and out-of-body experiences are sometimes reported.


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InternalMed_Harrison. Although some predisposing factors and provocative stimuli are well established (for example, motionless upright posture, warm ambient temperature, intravascular volume depletion, alcohol ingestion, hypoxemia, anemia, pain, the sight of blood, venipuncture, and intense emotion), the underlying basis for the widely different thresholds for syncope among individuals exposed to the same provocative stimulus is not known. A genetic basis for neurally mediated syncope may exist; several studies have reported an increased incidence of syncope in first-degree relatives of fainters, but no gene or genetic marker has been identified, and environmental, social, and cultural factors have not been excluded by these studies.


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InternalMed_Harrison. Reassurance, avoidance of provocative stimuli, and plasma volume expansion with fluid and salt are the cornerstones of the management of neurally mediated syncope. Isometric counterpressure maneuvers of the limbs (leg crossing or handgrip and arm tensing) may raise blood pressure by increasing central blood volume and cardiac output. By maintaining pressure in the autoregulatory zone, these maneuvers avoid or delay the onset of syncope. Randomized controlled trials support this intervention.


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InternalMed_Harrison. Fludrocortisone, vasoconstricting agents, and betaadrenoreceptor antagonists are widely used by experts to treat refractory patients, although there is no consistent evidence from randomized controlled trials for any pharmacotherapy to treat neurally mediated syncope. Because vasodilation is the dominant pathophysiologic syncopal mechanism in most patients, use of a cardiac pacemaker is rarely beneficial. Possible exceptions are older patients (>40 years) in whom syncope is associated with asystole or severe bradycardia and patients with prominent cardioinhibition due to carotid sinus syndrome. In these patients, dual-chamber pacing may be helpful.


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InternalMed_Harrison. Orthostatic hypotension, defined as a reduction in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of standing or head-up tilt on a tilt table, is a manifestation of sympathetic vasoconstrictor (autonomic) failure (Fig. 27-4). In many (but not all) cases, there is no compensatory increase in heart rate despite hypotension; with partial autonomic failure, heart rate may increase to some degree but is insufficient to maintain cardiac output. A variant of orthostatic hypotension is “delayed” orthostatic hypotension, which occurs beyond 3 min of standing; this may reflect a mild or early form of sympathetic adrenergic dysfunction. In some cases, orthostatic hypotension occurs within 15 s of standing (so-called “initial” orthostatic hypotension), a finding that may reflect a transient mismatch between cardiac output and peripheral vascular resistance and does not represent autonomic failure.


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InternalMed_Harrison. Characteristic symptoms of orthostatic hypotension include lightheadedness, dizziness, and presyncope (near-faintness) occurring in response to sudden postural change. However, symptoms may be 75 74 and inflammatory neuropathies (Chaps. 459 and 460). Less frequently, orthostatic hypotension is associated with the 72 peripheral neuropathies that accompany vitamin B12 deficiency, neurotoxic exposure, HIV and other infections, and 70 porphyria. Patients with autonomic failure and the elderly are susceptible to falls in blood pressure associated with meals. 200 180 The magnitude of the blood pressure fall is exacerbated by large meals, meals high 150 in carbohydrate, and alcohol intake. The PART 2 Cardinal Manifestations and Presentation of Diseases mechanism of postprandial syncope is not fully elucidated.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases mechanism of postprandial syncope is not fully elucidated. Orthostatic hypotension is often iatrogenic. Drugs from several classes may lower peripheral resistance (e.g., alphaadrenoreceptor antagonists used to treat hypertension and prostatic hypertrophy; antihypertensive agents of several classes; 60 120180 240 300 360 180190 200210 220 nitrates and other vasodilators; tricyclic A Time (sec) Time (sec) agents and phenothiazines). Iatrogenic


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InternalMed_Harrison. B volume depletion due to diuresis and FIguRE 27-4 A. The gradual fall in blood pressure without a compensatory heart rate increase volume depletion due to medical causes that is characteristic of orthostatic hypotension due to autonomic failure. Blood pressure and heart (hemorrhage, vomiting, diarrhea, or rate are shown over 5 min (from 60 to 360 s) of an upright tilt on a tilt table. B. The same tracing decreased fluid intake) may also result in expanded to show 40 s of the episode (from 180 to 220 s). BP, blood pressure; bpm, beats per decreased effective circulatory volume, minute; HR, heart rate.


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InternalMed_Harrison. absent or nonspecific, such as generalized weakness, fatigue, cognitive slowing, leg buckling, or headache. Visual blurring may occur, likely due to retinal or occipital lobe ischemia. Neck pain, typically in the suboccipital, posterior cervical, and shoulder region (the “coat-hanger headache”), most likely due to neck muscle ischemia, may be the only symptom. Patients may report orthostatic dyspnea (thought to reflect ventilation-perfusion mismatch due to inadequate perfusion of ventilated lung apices) or angina (attributed to impaired myocardial perfusion even with normal coronary arteries). Symptoms may be exacerbated by exertion, prolonged standing, increased ambient temperature, or meals. Syncope is usually preceded by warning symptoms, but may occur suddenly, suggesting the possibility of a seizure or cardiac cause.


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InternalMed_Harrison. Supine hypertension is common in patients with orthostatic hypotension due to autonomic failure, affecting over 50% of patients in some series. Orthostatic hypotension may present after initiation of therapy for hypertension, and supine hypertension may follow treatment of orthostatic hypotension. However, in other cases, the association of the two conditions is unrelated to therapy; it may in part be explained by baroreflex dysfunction in the presence of residual sympathetic outflow, particularly in patients with central autonomic degeneration. Causes of Neurogenic Orthostatic Hypotension Causes of neurogenic orthostatic hypotension include central and peripheral autonomic nervous system dysfunction (Chap. 454). Autonomic dysfunction of other organ systems (including the bladder, bowels, sexual organs, and sudomotor system) of varying severity frequently accompanies orthostatic hypotension in these disorders (Table 27-2).


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InternalMed_Harrison. The primary autonomic degenerative disorders are multiple system atrophy (the Shy-Drager syndrome; Chap. 454), Parkinson’s disease (Chap. 449), dementia with Lewy bodies (Chap. 448), and pure autonomic failure (Chap. 454). These are often grouped together as “synucleinopathies” due to the presence of alpha-synuclein, a small protein that precipitates predominantly in the cytoplasm of neurons in the Lewy body disorders (Parkinson’s disease, dementia with Lewy bodies, and pure autonomic failure) and in the glia in multiple system atrophy. Peripheral autonomic dysfunction may also accompany small-fiber peripheral neuropathies such as those seen in diabetes, amyloid, immune-mediated neuropathies, hereditary sensory and autonomic neuropathies (HSAN; particularly HSAN type III, familial dysautonomia), orthostatic hypotension, and syncope.


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InternalMed_Harrison. The first step is to remove reversible causes—usually vasoactive medications (Table 454-6). Next, nonpharmacologic interventions should be introduced. These interventions include patient education regarding staged moves from supine to upright; warnings about the hypotensive effects of large meals; instructions about the isometric counterpressure maneuvers that increase intravascular pressure (see above); and raising the head of the bed to reduce supine hypertension. Intravascular volume should be expanded by increasing dietary fluid and salt. If these nonpharmacologic measures fail, pharmacologic intervention with fludrocortisone acetate and vasoconstricting agents such as midodrine, L-dihydroxyphenylserine, and pseudoephedrine should be introduced. Some patients with intractable symptoms require additional therapy with supplementary agents that include pyridostigmine, yohimbine, desmopressin acetate (DDAVP), and erythropoietin (Chap. 454).


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InternalMed_Harrison. Cardiac (or cardiovascular) syncope is caused by arrhythmias and structural heart disease. These may occur in combination because structural disease renders the heart more vulnerable to abnormal electrical activity. Arrhythmias Bradyarrhythmias that cause syncope include those due to severe sinus node dysfunction (e.g., sinus arrest or sinoatrial block) and atrioventricular (AV) block (e.g., Mobitz type II, high-grade, and complete AV block). The bradyarrhythmias due to sinus node dysfunction are often associated with an atrial tachyarrhythmia, a disorder known as the tachycardia-bradycardia syndrome. A prolonged pause following the termination of a tachycardic episode is a frequent cause of syncope in patients with the tachycardia-bradycardia syndrome. Medications of several classes may also cause bradyarrhythmias of sufficient severity to cause syncope. Syncope due to bradycardia or asystole is referred to as a Stokes-Adams attack.


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InternalMed_Harrison. Ventricular tachyarrhythmias frequently cause syncope. The likelihood of syncope with ventricular tachycardia is in part dependent on the ventricular rate; rates below 200 beats/min are less likely to cause syncope. The compromised hemodynamic function during ventricular tachycardia is caused by ineffective ventricular contraction, reduced diastolic filling due to abbreviated filling periods, loss of AV synchrony, and concurrent myocardial ischemia.


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InternalMed_Harrison. Several disorders associated with cardiac electrophysiologic instability and arrhythmogenesis are due to mutations in ion channel subunit genes. These include the long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. The long QT syndrome is a genetically heterogeneous disorder associated with prolonged cardiac repolarization and a predisposition to ventricular arrhythmias. Syncope and sudden death in patients with long QT syndrome result from a unique polymorphic ventricular tachycardia called torsades des pointes that degenerates into ventricular fibrillation. The long QT syndrome has been linked to genes encoding K+ channel α-subunits, K+ channel β-subunits, voltage-gated Na+ channel, and a scaffolding protein, ankyrin B (ANK2). Brugada syndrome is characterized by idiopathic ventricular fibrillation in association with right ventricular electrocardiogram (ECG) abnormalities without structural heart disease. This disorder is also genetically


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InternalMed_Harrison. is characterized by idiopathic ventricular fibrillation in association with right ventricular electrocardiogram (ECG) abnormalities without structural heart disease. This disorder is also genetically heterogeneous, although it is most frequently linked to mutations in the Na+ channel α-subunit, SCN5A. Catecholaminergic polymorphic tachycardia is an inherited, genetically heterogeneous disorder associated with exerciseor stress-induced ventricular arrhythmias, syncope, or sudden death. Acquired QT interval prolongation, most commonly due to drugs, may also result in ventricular arrhythmias and syncope. These disorders are discussed in detail in Chap. 277.


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InternalMed_Harrison. Structural Disease Structural heart disease (e.g., valvular disease, myocardial ischemia, hypertrophic and other cardiomyopathies, cardiac masses such as atrial myxoma, and pericardial effusions) may lead to syncope by compromising cardiac output. Structural disease may also contribute to other pathophysiologic mechanisms of syncope. For example, cardiac structural disease may predispose to arrhythmogenesis; aggressive treatment of cardiac failure with diuretics and/or vasodilators may lead to orthostatic hypotension; and inappropriate reflex vasodilation may occur with structural disorders such as aortic stenosis and hypertrophic cardiomyopathy, possibly provoked by increased ventricular contractility.


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InternalMed_Harrison. Treatment of cardiac disease depends on the underlying disorder. Therapies for arrhythmias include cardiac pacing for sinus node disease and AV block, and ablation, antiarrhythmic drugs, and cardioverter-defibrillators for atrial and ventricular tachyarrhythmias. These disorders are best managed by physicians with specialized skills in this area. APPROACH TO THE PATIENT: Syncope is easily diagnosed when the characteristic features are present; however, several disorders with transient real or apparent loss of consciousness may create diagnostic confusion.


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InternalMed_Harrison. Syncope is easily diagnosed when the characteristic features are present; however, several disorders with transient real or apparent loss of consciousness may create diagnostic confusion. Generalized and partial seizures may be confused with syncope; however, there are a number of differentiating features. Whereas tonic-clonic movements are the hallmark of a generalized seizure, myoclonic and other movements also may occur in up to 90% of syncopal episodes. Myoclonic jerks associated with syncope may be multifocal or generalized. They are typically arrhythmic and of short duration (<30 s). Mild flexor and extensor posturing also may occur. Partial or partial-complex seizures with secondary generalization are usually preceded by an aura, commonly an unpleasant smell; fear; anxiety; abdominal discomfort; or other visceral sensations. These phenomena should be differentiated from the premonitory features of syncope.


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InternalMed_Harrison. Autonomic manifestations of seizures (autonomic epilepsy) may provide a more difficult diagnostic challenge. Autonomic seizures have cardiovascular, gastrointestinal, pulmonary, urogenital, pupillary, and cutaneous manifestations that are similar to the premonitory features of syncope. Furthermore, the cardiovascular manifestations of autonomic epilepsy include clinically significant tachycardias and bradycardias that may be of sufficient magnitude to cause loss of consciousness. The presence of accompanying non-autonomic auras may help differentiate these episodes from syncope.


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InternalMed_Harrison. Loss of consciousness associated with a seizure usually lasts longer than 5 min and is associated with prolonged postictal drowsiness and disorientation, whereas reorientation occurs almost immediately after a syncopal event. Muscle aches may occur after both syncope and seizures, although they tend to last longer and be more severe following a seizure. Seizures, unlike syncope, are rarely provoked by emotions or pain. Incontinence of urine may occur with both seizures and syncope; however, fecal incontinence occurs very rarely with syncope.