Infections Caused by Dimorphic Fungi
Epstein–Barr Virus Infection and Infectious Mononucleosis
Approach to the Patient with Fever of Unknown Origin
Hiv Infection and Aids
Approach to Infection in the Immunocompromised Host
Streptococcal Pharyngitis and Rheumatic Fever
Varicella-Zoster Virus Infection
DEFINITION, EPIDEMIOLOGY AND ETIOLOGY
Meningitis develops when the cerebrospinal fluid (CSF) in the subarachnoid space becomes infected, usually because of hematogenous spread. Community-acquired meningitis is particularly common among children, young adults, and the elderly. Among children and young adults, the most common pathogens are Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B, although the incidence of H. influenzae infection has decreased dramatically because of the wide use of vaccine. Elderly patients are infected most often by gram-negative bacilli, S. pneumoniae, and Listeria monocytogenes. Patients who have undergone splenectomy or who have sickle cell disease are particularly susccptible to S. pneumoniae and H. influenzae infection. Bacterial meningitis due to head trauma, craniotomy, CSF leak, or congenital defects such as spina bifida is most frequently caused by Staphylococcus aureus and S. pneumoniae and less frequently by Pseudomonas aeruginosa or other Enterobacteriaceae. Patients undergoing cancer chemotherapy and those with underlying immunodeficiency are prone to infection with a variety of pathogens, including L. monocytogenes, Enterobacteriaceae, mycobacteria, and fungi. An increasing proportion of cases are nosocomially acquired, and approximately one-third of such cases are caused by gram-negative bacteria other than H. influenzae.
The cardinal features are fever, headache, and nuchal rigidity. Other signs of cerebral dysfunction vary depending on the onset and clinical course of the illness. They include confusion, cranial nerve palsy, and seizures. In acute purulent meningitis caused by S. pneumoniae, N. meningitidis, and H. influenzae type B, progression from confusion and lethargy to coma can occur within 24 hours. Other common symptoms include weakness, anorexia, shaking chills, profuse sweats, photophobia, vomiting, and myalgia of the lower extremities. At examination, neck stiffness may be subtle or marked. Kernig’s and Brudzinski’s signs suggest meningeal inflammation. Cranial nerve palsy, principally of the third, fourth, sixth, and seventh nerves, occurs among 10% to 20% of patients. Focal neurologic findings such as hemiparesis, visual field defects, papilledema, and dysphasia suggest the coexistence of a brain abscess, subdural empyema, or septic thrombophlebitis.
DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC TESTS
The typical CSF profiles in bacterial and nonbacterial meningitis are shown in Table 431.3. Partially controlled bacterial meningitis typically is associated with lymphocytic predominance in the CSF. Patients with viral meningitis have polymorphonuclear pleocytosis in the CSF early in the course of disease. In bacterial meningitis, the yield of both Gram stain and culture is reduced by prior administration of antimicrobial agents. There are several techniques for the rapid detection of specific microbial antigens in the CSF. Blood culture results are positive in at least 50% of cases.
Table 431.4 lists choices for initial empiric antimicrobial therapy in various age groups. The final antibiotic selection should be guided by culture results and susceptibility data. Penicillin G remains the drug of choice for meningococcal meningitis. A third-generation cephalosporin such as ceftriaxone or cefotaxime is best for H. influenzae type B and penicillin-resistant S. pneumoniae, though vancomycin should be used if there is high-level penicillin resistance and an elevated minimum inhibitory concentration to third-generation cephalosporins. Newer quinolones such as trovafloxacin are effective against high-level penicillinresistant pneumococcal meningitis in experimental models, but clinical experience is limited. Meningitis caused by P. aeruginosa should be managed with the combination of an antipseudomonal b-lactam plus a fluoroquinolone or an aminoglycoside. Ampicillin or penicillin G plus an aminoglycoside should be used to control L. monocytogenes infection.
There is no consensus regarding the use of glucocorticoids as adjunctive therapy for acute bacterial meningitis among adults. It is also unclear whether therapy with monoclonal antibodies or other agents directed at blocking the effect of inflammatory cytokines in the CSF can prevent hearing loss, seizure disorders, or other chronic neurologic sequelae.
EPIDEMIOLOGY AND PATHOGENESIS
Candida organisms are ubiquitous and are normal commensal organisms of humans and certain animals. Candida albicans is the most prominent of the eight species that infect humans with frequency. Most species exist in three forms—yeast (which may bud), hyphae, and pseudohyphae. Severe infections usually are iatrogenic. The two most important predisposing factors are neutropenia and exposure to broad-spectrum antibiotics. Candida organisms are the third most common pathogen in blood cultures of hospitalized patients.
Skin and mucous membranes: Intertrigo on the warm, moist areas of the skin occurs among obese and diabetic patients. Chronic mucocutaneous candidiasis is a long-standing, severe disease associated with lymphocyte-mediated immuno-deficiency. Thrush is manifest by white plaques in the oral cavity. It occurs among patients who have taken antibiotics or used inhaled steroids and among those who are severely debilitated or immunocompromised, such as patients with AIDS. Candidal esophagitis causes odynophagia and white plaques on the esophageal mucosa. It occurs frequently among patients receiving cytotoxic chemotherapy and among patients with AIDS.
Genitourinary system: Although Candida species are found in the urine of 8% of healthy men and 12% of healthy women, candiduria may signify cystitis, pyelonephiritis, papillary necrosis, or perinephric abscess. A common problem is prolonged colonization of the bladders of patients with indwelling Foley catheters.
Intravascular infection: About 2% of cases of endocarditis are caused by Candida organisms, and 50% of these are complications of cardiac surgery. The hallmarks of candidal endocarditis are large vegetations and occlusion of large vessels. Infection at sites of peripheral indwelling intravascular catheters is another common cause of persistent candidemia.
Disseminated Candidiasis: Widespread disseminated candidiasis occurs most frequently among patients with neutropenia and those experiencing prolonged, complicated postoperative courses of disease. Other predisposing factors include use of antibiotics, neutropenia, the presence of an indwelling intravascular catheter, and exposure to hyperalimentation fluid and steroids.
LABORATORY STUDIES AND DIAGNOSTIC TESTS
Intravascular infection is associated with positive results of blood cultures. Mucosal membrane infections can be diagnosed on the basis of the clinical appearance of the lesions and recovery of the organism from scrapings of the infected area. The diagnosis of candidal infection of deep organs requires biopsy evidence of the organism invading the tissue. There are no reliable serologic tests for invasive candidiasis.
Mucocutaneous infection is successfully controlled with azole antifungal agent such as fluconazole, itraconazole, and ketoconazole. For most patients, candiduria is self-limited, but some may need an amphotericin B bladder washout or treatment with oral fluconazole. All patients with candidemia should be treated with an antifungal agent. Removal of an infected intravenous catheter is necessary but not sufficient. Fluconazole has been demonstrated to be as effective as amphotericin B in the management of candidemia among patients with and without neutropenia. Until further studies are completed, therapy for life-threatening candidal infections is amphotericin B.
Cellulitis is a spreading acute infection of the skin and subcutaneous tissues characterized by erythema, warmth, swelling, and tenderness. It may be classified as mild and uncomplicated, severe, high risk, or necrotizing.
ETIOLOGY AND CLINICAL FEATURES
Most cases of cellulitis are mild and uncomplicated. They are caused by group A streptococci or Staphylococcus aureus. Diffuse erythema, swelling, and tenderness develop over 2 to 4 days. In an extremity, a red line along the course of lymphatic vessels indicates accompanying lymphangitis. Enlargement and tenderness of regional lymph nodes are common. Fever, malaise, and chills often are present.
Orbital cellulitis is a rare complication of sinusitis and carries a risk of blindness, brain abscess, and meningitis. Erysipelas usually follows a streptococcal sore throat and usually affects the young and the elderly. The infection involves the dermis and the lymphatic vessels and manifests as pain and bright-red peau d’orange lesions with advancing red borders that are sharply demarcated from normal skin. Erysipeloid is a form of cellulitis that occurs among workers who handle fish, meat, and poultry. It is caused by the gram-positive bacillus Erysipelothrix rhusiopathiae. About 1 week after a minor injury to the hand, a violaceous painful area appears. As the central area clears, the lesion spreads outward with distinct raised borders. Animal and human bites of the hands are potentially dangerous because of tissue damage and secondary infection. Pasteurella multocida often infects dog and cat bites, and Eikenella corrodens often is implicated in human bites. Deep infections such as tenosynovitis are particularly common after human bites. Necrotizing cellulitis is a serious gangrenous soft-tissue infection often associated with the presence of anaerobic bacteria, tissue toxins, and bacterial synergy. It should be suspected when a patient has edema out of proportion to erythema, skin vesicles, crepitus on palpation or air in the tissues on a radiograph, local anesthesia, or patchy gangrene of the skin.
Most cases of cellulitis can be managed simply on an outpatient basis. Severe, complicated, or high-risk infections necessitate aggressive inpatient antibiotic therapy and often surgery. Patients with necrotizing infections must be treated surgically. Uncomplicated mild cellulitis, commonly caused by Streptococcus pyogenes or S. aureus, responds well to oral cloxacillin or cephalexin (500 mg every 6 hours for 7 to 10 days). For patients allergic to penicillin, erythromycin (500 mg every 6 hours for 7 to 10 days) is an alternative. Local therapy includes cleansing the area and resting the extremity. In severe cellulitis, treatment should start with intravenous cloxacillin (1 g every 6 hours). Intravenous vancomycin (500 mg every 8 hours if renal function is normal) and teicoplanin (1 g daily) are alternatives for patients allergic to penicillin. An aminoglycoside may be added when the clinical setting suggests that gram-negative bacilli may play a role (e.g., perianal cellulitis, neutropenia, glucocorticoid therapy, and diabetes mellitus), although monotherapy with second- or third-generation cephalosporins is an alternative in these situations.
Erysipelas usually responds to intravenous penicillin G (1 million units every 6 hours). Orbital cellulitis is managed with broad-spectrum antibiotics. Computed tomographic evidence of an abscess or intracranial involvement and failure to respond to antibiotics within 48 hours are indications for prompt exploration and decompression of the orbit. Erysipeloid responds to amoxicillin–clavulanate or erythromycin. Animal and human bites necessitate therapy with oral amoxicilin-clavulanate and local debridement.
INFECTIONS CAUSED BY DIMORPHIC FUNGI
The dimorphic fungi are soil-growing organisms that exist in a mycelian form in the environment but grow as yeast at body temperature. Infections caused by these fungi include histoplasmosis, coccidioidomycosis, blastomycosis, and sporotrichosis. The clinical manifestations depend on the immune status of the host; normal hosts may have minimal symptoms, but those with immunocompromise may develop overwhelming, disseminated infection.
EPIDEMIOLOGY, CLINICAL FEATURES, AND DIAGNOSIS
Histoplasmosis: Histoplasma capsulatum is the etiologic agent of histoplasmosis, a disease endemic to the Ohio River and Mississippi River valleys. The organism is found in soil contaminated with droppings from fowl. The clinical manifestations depend on underlying host defense, intensity of exposure, and previous immunity. The acute self-limited illness is characterized by flulike symptoms of fever, chills, headache, myalgia, anorexia, nonproductive cough, and chest pain. A chest radiograph may show enlarged hilar and mediastinal lymph nodes with patchy infiltrates. After heavy inoculation, more extensive pulmonary disease may develop. Inflammatory complications such as arthritis and erythema nodosum occur among about 10% of patients with symptomatic infection. Dissemination is most likely among patients with advanced AIDS, organ transplant recipients, and patients receiving steroids or chemotherapy. The manifestations include fever, weight loss, gastrointestinal lesions, skin lesions, oropharyngeal ulceration, adrenal insufficiency, meningitis, endocarditis, hepatomegaly, lymphadenopathy, and pancytopenia from bone marrow involvement. The diagnosis is established by means of culture, histopathologic examination, or serologic testing. Skin tests are not useful because most persons in endemic zones have reactive skin tests, and cross reactions with other fungi are common.
Coccidioidomycosis: Coccidioidomycosis is caused by Coccidioides immitis, a soil organism endemic to the southwestern United States, Mexico, and South America. Infection is asymptomatic for 60% of infected persons and is indicated by a positive skin test result. For the remaining 40%, a self-limited, flulike illness develops 1 to 3 weeks after exposure. It is characterized by a dry cough, pleuritic chest pain, myalgia, arthralgia, fever, sweats, anorexia, and weakness. Immune complex complications can include an erythematous macular rash, erythema multiforme, and erythema nodosum. Acute infection usually resolves without therapy. Approximately 5% of persons with the infection have pulmonary residua, which include nodules and cavities. Chronic progressive pulmonary infection is characterized, particularly among immunocompromised patients, by the development of extensive thin-walled cavities that may be complicated by cavity rupture, bronchopleural fistula, and empyema. Extrapulmonary disease develops in 1 in 200 patients and typically involves the skin and soft tissues, bones, and meninges. The diagnosis can be established by means of identification of spherules in histopathologic specimens or by means of culture. Serologic tests can be performed, although skin tests are of limited utility.
Blastomycosis: Most cases of blastomycosis, which is caused by Blastomyces dermatitidis, occur in the midwestern and southeastern United States and the Canadian provinces of Ontario, Quebec, and Alberta. About 50% of infected persons have symptoms such as fever, chills, cough, myalgia, and arthralgia. A chest radiograph may show lobar or segmental consolidation, although a nodular pattern may be seen with chronic infection. The acute pulmonary symptoms usually resolve, but patients may have progressive pulmonary disease or disseminated infection. The skin is the most frequent site of dissemination; the verrucous or ulcerative lesions may be mistaken for squamous cell carcinoma. Other extrapulmonary sites include subcutaneous tissue, bones, the genitourinary tract (prostate and epididymis), and the central nervous system. The diagnosis is established by means of demonstration the organism on wet preparations or histopathologic study. The organism can be cultured, but the presence of the mycelian form before conversion to a yeast does not confirm the diagnosis. Serologic studies are less reliable.
Sporotrichosis: Sporotrichosis is caused by the soil fungus Sporothrix schenckii, usually by means of direct inoculation from contaminated soil or plants, especially thorny plants such as roses. After an incubation period of 1 to 10 weeks, reddish-purple, nodular, cutaneous lesions appear that follow the lymphatic vessels and frequently ulcerate. Direct spread to bone or joints sometimes occurs. Pulmonary infection and disseminated infection are uncommon.
Guidelines for selection of an antifungal agent are given in Table 336.1. In general, amphotericin B is preferred as initial treatment of profoundly ill patients. Side effects include fever, chills, and hypotension during initiation of therapy; malaise; anemia; azotemia, renal tubular acidosis; hypokalemia; and hypomagnesemia. Lipid-associated formulations cause less nephrotoxicty but are very expensive. They are most appropriate for patients who are intolerant of therapy with standard amphotericin B. The azoles (ketoconazole, itraconazole, and fluconazole) are used as primary treatment of less acutely ill patients and as long-term therapy after a brief course of amphotericin B. All have oral formulations and have a potential for pharmacokinetic interaction with many other agents. The chief side effect is hepatotoxicity.
DEFINITIONS AND PATHOGENESIS
Infective endocarditis (IE) is microbial invasion of the endocardium, usually involving valvular surfaces. Disruption of the endocardial surface exposes collagen and promotes adherence of platelets and fibrin. IE occurs when circulating microorganisms colonize the injured endocardial surface. Bacteria invade the blood through local barriers, such as skin and mucous membranes, or are directly inoculated into capillaries and venules, as in dental surgery.
EPIDEMIOLOGY AND MICROBIOLOGY
The epidemiologic pattern of IE is a function of the frequency of bloodstream invasion by pathogens and the prevalence of predisposing endocardial disease. The mean age of patients with IE has increased and is now about 55 years. Risk factors include valvular heart disease (including mitral valve prolapse), intravenous drug abuse (IVDA), and use of intravascular or intracardiac devices.
Streptococci are the most commonly reported cause of native valve endocarditis (NVE), Streptococcus viridans species predominating (about 35% of all cases). About 80% of patients have underlying cardiac disease and are infected when the bacteria, which are normal oral flora, gain access to the bloodstream. Enterococcal IE accounts for about 10% of all cases. About 40% of patients have no known underlying heart disease. Older men undergoing urologic procedures, women undergoing gynecologic procedures, and parenteral drug users are at particular risk. Streptococcus bovis IE is associated with bowel lesions, including colon cancer. Staphylococci cause 25% of cases of NVE; 90% are caused by Staphylococcus aureus. No prior valve abnormality is recognized in one-third of these patients. Aerobic gram-negative bacteria cause 5% to 10% of cases; risk factors include IVDA and the presence of prosthetic valves. For another 5% to 10% of patients with presumed IE, no etiologic microorganism is isolated from the blood, most commonly because of prior antibiotic use. Coagulase-negative staphylococci are the most common cause of prosthetic valve endocarditis (PVE).
History: There may be known underlying heart disease and a preceding bacteremic event such as dental work, IVDA, or instrumentation of the gastrointestinal or genitourinary tracts. Fever is present in more than 90% of cases. Most patients with subacute IE have nonspecific symptoms such as malaise, arthralgia, myalgia, and fatigue. Symptoms of congestive heart failure are present among about 50% of those with NVE. Emboli to the lungs or abdominal organs can cause chest or abdominal pain.
Physical examination: Most patients with left-sided valvular disease have murmurs at some point but may not initially. Classic peripheral signs include petechiae, Roth’s spots (oval retinal hemorrhages), splenomegaly, clubbing, Osler’s nodes (painful, purple to red nodules on the pads of the fingers or toes), linear splinter hemorrhages beneath the fingernails or toenails, and red, macular Janeway lesions on the palms or soles.
Special situations: IE associated with IVDA most commonly involves S. aureus infection of the tricuspid valve. Such patients typically have an acute onset of fever, pleuritic chest pain, dyspnea, and cough. A murmur of tricuspid regurgitation usually is heard. The initial chest radiograph is abnormal in most cases and may show nodular opacities, abscesses with cavitation, patchy pneumonitis, or pleural effusions. Gram-negative infections are frequent. Infection with Pseudomonas aeruginosa is associated with high mortality.
Prosthetic valve IE occurs among about 2% of patients after valve replacement, one-third of these cases occurring within 2 months of surgery. Infection by staphylococci (both S. aureus and coagulase-negative species) is the most common cause, but gram-negative bacilli and fungi are more common than in NVE. Patients come to medical attention in much the same manner as those with NVE, although a higher frequency of a new or changed murmur reflects a higher rate of local suppurative complications, such as valve ring abscess.
LABORATORY STUDIES AND DIAGNOSTIC TESTS
The blood culture is the most important laboratory test. Bacteremia is typically low grade and constant. One of the first two sets yields the etiologic bacteria in 90% of cases. At least three sets should be obtained within the first 24 hours for patients with suspected IE. Nonspecific laboratory abnormalities include anemia and an elevated erythrocyte sedimentation rate. Leukocytosis is unusual in subacute IE but is more likely in acute IE caused by staphylococci, pneumococci, or gonococci. Hematuria, proteinuria, and detectable rheumatoid factor are present in about one-half of cases. Echocardiography is the most useful imaging study. Transthoracic echocardiography reveals vegetations in about 50% to 60% of patients. Transesophageal echocardiography is more accurate and has a sensitivity approaching 90%. Echocardiography is useful for defining the severity of valvular destruction, detecting complications such as abscess or aortic mycotic aneurysm, and assessing the hemodynamic effects of IE. The Duke criteria for IE are listed in Table 270.2.
Cardiac: Valvular dysfunction, usually insufficiency, is the most important complication. Extension of a paravalvular abscess in the conduction system may cause varying degrees of atrioventricular block and bundle branch block. This is most common in aortic valve IE. Pericarditis is especially frequent with staphylococcal disease. Heart failure is the most common cause of death. Valvular dysfunction is the usual basis, but embolic myocardial infarction, myocarditis, and conduction disturbances can contribute.
Noncardiac: Emboli, which occur among about one-third of patients, may be bland (uninfected) or septic and are most common with S. aureus and fungal IE. In left-sided IE, the spleen, kidney, brain, and heart are most commonly affected. Mycotic aneurysms complicate 15% to 25% of cases; they occur most frequently in the central nervous system and abdominal aorta. The main risk is rupture with bleeding, sometimes months to years after the infection has resolved. Renal failure from immune-complex glomerulonephritis occurs among 10% of patients.
Antibiotics: Therapy must include bactericidal drugs given parenterally for a prolonged time (2 to 6 weeks, depending on the clinical circumstances). Antimicrobial therapy should be started without delay in the following four situations: when the clinical diagnosis seems certain, although blood culture results are not yet available; when the diagnosis seems likely and the patient is seriously ill; when antimicrobial therapy for another condition is necessary; and when the patient may have IE, and blood culture results are positive. Empiric therapy must include agents likely to be effective against enterococci. Antistaphylococcal agents should be considered in the treatment of patients with PVE; those with a rapidly progressive illness that suggests acute IE; those with aortic valve involvement but without prior valvular abnormality; those with IVDA; those with a previously infected intravenous catheter; and those undergoing long-term hemodialysis. Once the infecting pathogen is identified, a more specific antibiotic regimen is administered.
Surgery: Indications include severe or refractory heart failure, valvular obstruction, fungal endocarditis, ineffective antimicrobial therapy, and instability of a prosthetic valve. Relative indications in NVE include nonstreptococcal IE, recurrent IE, intracardiac extension of infection, the presence of two or more emboli, and echocardiographic detection of vegetations or mitral valve preclosure. Relative indications in PVE include early infection, nonstreptococcal late PVE, and periprosthetic leak. Tricuspid valve IE is generally well tolerated hemodynamically; persistent infection with resistant bacteria or fungi is the most common surgical indication.
Although the use of prophylactic antibiotics to prevent IE is recommended in certain situations, no randomized, controlled trials addressing this issue have been performed, and most cases if IE do not occur in association with an invasive procedure. The risk of bacteremia is highest for some dental and oral procedures, intermediate for urologic procedures, and lowest for most gastrointestinal procedures (with the exception of esophageal dilation and variceal sclerotherapy), including those that involve biopsy. According to the American Heart Association, high-risk cardiac conditions include the presence of prosthetic valves, prior IE, complex cyanotic congenital defects, and the presence of surgically constructed systemic-pulmonary shunts. Rheumatic heart disease and mitral valve prolapse with valvular regurgitation are classified as moderate risk. Antibiotic selection is directed against S. viridans for dental, oral, respiratory, and esophageal procedures (2 g amoxicillin before the procedure is the preferred antibiotic) and against enterococci for other gastrointestinal and urologic procedures (amoxicillin or ampicillin with or without gentamicin, depending on risk).
EPSTEIN–BARR VIRUS INFECTION AND INFECTIOUS MONONUCLEOSIS
Epstein–Barr virus (EBV) is a DNA human herpesvirus associated with infectious mononucleosis (IM) and a number of malignant diseases, such as Hodgkin’s disease, Burkitt’s lymphoma in Africa, and nasopharyngeal carcinoma in China. It is also the causative agent of hairy leukoplakia of the tongue among immunocompromised patients.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
EBV occurs worldwide and spreads from person to person by close contact and exchange of oral secretions. IM typically occurs in adolescence and the early third decade of life. The incubation period is 4 to 6 weeks. The virus infects lymphocytes and the oropharyngeal epithelium. Like other herpesviruses, EBV causes infections with three phases—primary, latent, and reactivated. Reactivation is associated with the malignant conditions.
Primary EBV infection causes about 90% of cases of IM. The onset is insidious, and acute pharyngltis often is the primary symptom. The classic findings are fever lasting up to 3 weeks or more, lymphadenopathy, splenomegaly, and florid atypical lymphocytosis, with malaise that may be slow to resolve. Coupled with a positive heterophil antibody reaction or Monospot test, these findings are sufficient for diagnosis in most cases. The diagnosis is made definite by the finding of EBV antibodies. Complications include acute hepatitis that usually is mild and transient, neurologic syndromes such as encephalitis, neuritis, transverse myelitis, and Guillain–Barré syndrome, and hematologic abnormalities such as agranulocytosis, aplastic anemia, and thrombocytopenia. These usually resolve without therapy. A rare complication is splenic rupture. Acute IM sometimes seems to lapse into a chronic phase that lasts as long as a year or more and is marked by persistent fatigue, low-grade fevers, malaise, and a labile emotional state. IM caused by cytomegalovirus mimics that caused by EBV, although sore throat and atypical lymphocytosis may not be as prominent.
For IM, the diagnosis is confirmed by finding antibodies to EBV viral capsid antigen (CVA) (both IgG and IgM in primary infection) and, ideally, EBV early antigen (EA-D) but not EBV nuclear antigen (EBNA) antibodies. Antibodies to EA-D are transient and indicate recent or reactivated infection, whereas antibodies to EBNA often cannot be detected in primary infection, and appear only months later. The characteristic pattern of past infection would be a moderate titer of IgG VCA antibodies and a low titer of EBNA antibodies, both persistent for life.
PROGNOSIS AND MANAGEMENT
Most cases are mild and resolve within 2 to 3 weeks. Treatment is supportive. Controlled trials of acyclovir for IM have disclosed marginal benefit, in part because many of the symptoms are caused by secondary immunopathologic processes unaffected by antiviral therapy. There is also no evidence that so-called chronic mononucleosis responds to antiviral drugs.
APPROACH TO THE PATIENT WITH FEVER OF UNKNOWN ORIGIN
Fever is a complex physiologic process characterized clinically by a body temperature higher than 37.7°C (100°F). The temperatures of the rectum, mouth, and tympanic membrane all can be used to estimate core temperature. On average, rectal readings exceed oral readings by 0.4°C (0.7°F) and exceed tympanic membrane readings by 0.8°C (1.4°F).
PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS
Fever is a process in which the thermoregulatory set point is altered by the action of various cytokines on the anterior hypothalamus. Hyperthermia, in contrast, is an increase in body temperature not mediated by such cytokines. Hyperthermia is not regulated, is not defended by physiologic mechanisms, and does not respond to standard antipyretic agents. Disorders associated with hyperthermia include malignant hyperthermia, neuroleptic malignant syndrome, pheochromocytoma, and thyrotoxicosis, all of which increase heat production, and dehydration and heatstroke, which decrease heat loss. Experiments with animals have shown that fever enhances survival during some infections. However, when fever is extreme, the beneficial effect is reversed, and febrile convulsions can occur.
Most fevers either resolve spontaneously or are diagnosed quickly, usually in association with an infection. Fevers that persist for 2 to 3 weeks and defy intensive diagnostic scrutiny (fevers of unknown origin) occur more often with common diseases that have unusual manifestations than they do with exotic disorders. The three most common causes of the syndrome are infection, malignant neoplasia, and connective tissue disorders (Table 266.4). Familial Mediterranean fever is a hereditary disorder characterized by recurrent episodes of unexplained fever, frequently accompanied by peritonitis, pleuritis, or monarticular arthritis. Long-term colchicine therapy reportedly decreases the incidence of attacks and complications. Many medications have been reported to cause drug fever. Quinidine, a-methyldopa, and penicillins have been implicated most frequently. The various medications differ in the average duration of therapy that precedes the fever. For antibiotics, the median time lag between initiation of therapy and the onset of drug fever is 6 days. The fever generally abates within 48 to 72 hours of discontinuation of the offending agent.
HISTORY AND PHYSICAL EXAMINATION
A detailed history and careful examination are crucial. Important historical features include occupation, recent travel, exposure to a pet, and food consumption. When performing the physical examination, one should not overlook the fundoscopic examination, the less prominent chains of lymph nodes, and the prostate, epididymis, and testicles.