AccessMedicine - Print Print Close Window Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright ©2006 The McGraw-Hill Companies. All rights reserved. Current Medical Dx & Tx > Infectious Diseases: General Problems > Infectious Diseases: Introduction Most infections are confined to specific organ systems, and many of the important infectious disease pathogens are discussed in chapters dealing with the relevant anatomic areas. This chapter discusses some important general problems related to infectious diseases. Fever of Unknown Origin (FUO) Essentials of Diagnosis ● Illness of at least 3 weeks duration. ● Fever over 38.3 °C on several occasions. ● Diagnosis has not been made after three outpatient visits or 3 days of hospitalization. General Considerations The intervals specified in the criteria for the diagnosis of FUO are arbitrary ones intended to exclude patients with protracted but self-limited viral illnesses and to allow time for the usual radiographic, serologic, and cultural studies to be performed. Because of costs of hospitalization and the availability of most screening tests on an outpatient basis, the original criterion requiring 1 week of hospitalization has been modified to accept patients in whom a diagnosis has not been made after three outpatient visits or 3 days of hospitalization. Several additional categories of FUO have been added: (1) Nosocomial FUO refers to the hospitalized patient with fever of 38.3 °C or higher on several occasions, due to a process not present or incubating at the time of admission, in whom initial cultures are negative and the diagnosis remains unknown after 3 days of investigation (see Nosocomial Infections, below). (2) Neutropenic FUO includes patients with fever of 38.3 °C or higher on several occasions with less than 500 neutrophils per microliter in whom initial cultures are negative and the diagnosis remains uncertain after 3 days (see Common Symptoms and Infections in the Immunocompromised Patient, below). (3) HIV-associated FUO pertains to HIV-positive patients with fever of 38.3 °C or higher who have been febrile for 4 weeks or more as an outpatient or 3 days as an inpatient, in whom the diagnosis remains uncertain after 3 days of investigation with at least 2 days for cultures to incubate (see Infectious Diseases: HIV). Although not usually considered separately, FUO in solid organ transplant recipients is a common scenario with a unique differential diagnosis and is discussed below. For a general discussion of fever, see the section on fever and hyperthermia in Common Symptoms. Common Causes Most cases represent unusual manifestations of common diseases and not rare or exotic diseases—eg, tuberculosis, endocarditis, gallbladder disease, and HIV (primary infection or opportunistic infection) are more common causes of FUO than Whipple's disease or familial Mediterranean fever. Age of Patient In adults, infections (25–40% of cases) and cancer (25–40% of cases) account for the majority of FUOs. In children, infections are the most common cause of FUO (30–50% of cases) and cancer a rare cause (5–10% of cases). file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (1 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print Autoimmune disorders occur with equal frequency in adults and children (10–20% of cases), but the diseases differ. Juvenile rheumatoid arthritis is particularly common in children, whereas systemic lupus erythematosus, Wegener's granulomatosis, and polyarteritis nodosa are more common in adults. Adult Still's disease, giant cell arteritis, and polymyalgia rheumatica occur exclusively in adults. In the elderly (over 65 years of age), multisystem immune- mediated diseases such as temporal arteritis, polymyalgia rheumatica, sarcoidosis, rheumatoid arthritis, and Wegener's granulomatosis account for 25–30% of all FUOs. Duration of Fever The cause of FUO changes dramatically in patients who have been febrile for 6 months or longer. Infection, cancer, and autoimmune disorders combined account for only 20% of FUOs in these patients. Instead, other entities such as granulomatous diseases (granulomatous hepatitis, Crohn's disease, ulcerative colitis) and factitious fever become important causes. One-fourth of patients who say they have been febrile for 6 months or longer actually have no true fever or underlying disease. Instead, the usual normal circadian variation in temperature (temperature 0.5–1 °C higher in the afternoon than in the morning) is interpreted as abnormal. Patients with episodic or recurrent fever (ie, those who meet the criteria for FUO but have fever-free periods of 2 weeks or longer) are similar to those with prolonged fever. Infection, malignancy, and autoimmune disorders account for only 20–25% of such fevers, whereas various miscellaneous diseases (Crohn's disease, familial Mediterranean fever, allergic alveolitis) account for another 25%. Approximately 50% remain undiagnosed but have a benign course with eventual resolution of symptoms. Immunologic Status In the neutropenic patient, fungal infections and occult bacterial infection are important causes of FUO. In the patient taking immunosuppressive medications (particularly organ transplant patients), cytomegalovirus (CMV) infections are a frequent cause of fever, as are fungal infections, nocardiosis, Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia, and mycobacterial infections. Classification of Causes of FUO Most patients with FUO will fit into one of five categories. Infection Both systemic and localized infections can cause FUO. Tuberculosis and endocarditis are the most common systemic infections, but mycoses, viral diseases (particularly infection with Epstein-Barr virus and CMV), toxoplasmosis, brucellosis, Q fever, cat-scratch disease, salmonellosis, malaria, and many other less common infections have been implicated. Primary infection with HIV or opportunistic infections associated with the AIDS—particularly mycobacterial infections—can also present as FUO. The most common form of localized infection causing FUO is an occult abscess. Liver, spleen, kidney, brain, and bone are organs in which abscess may be difficult to find. A collection of pus may form in the peritoneal cavity or in the subdiaphragmatic, subhepatic, paracolic, or other areas. Cholangitis, osteomyelitis, urinary tract infection, dental abscess, or paranasal sinusitis may cause prolonged fever. Neoplasms Many cancers can present as FUO. The most common are lymphoma (both Hodgkin's and non-Hodgkin's) and leukemia. Other diseases of lymph nodes, such as angioimmunoblastic lymphoma and Castleman's disease, can also cause FUO. Primary and metastatic tumors of the liver are frequently associated with fever, as are renal cell carcinomas. Atrial myxoma is an often forgotten neoplasm that can result in fever. Chronic lymphocytic leukemia and multiple myeloma are rarely associated with fever, and the presence of fever in patients with these diseases should prompt a search for infection. Autoimmune disorders Still's disease, systemic lupus erythematosus, cryoglobulinemia, and polyarteritis nodosa are the most common file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (2 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print autoimmune causes of FUO. Giant cell arteritis and polymyalgia rheumatica are seen almost exclusively in patients over 50 years of age and are nearly always associated with an elevated erythrocyte sedimentation rate (> 40 mm/h). Miscellaneous causes Many other conditions have been associated with FUO but less commonly than the foregoing types of illness. Examples include thyroiditis, sarcoidosis, Whipple's disease, familial Mediterranean fever, recurrent pulmonary emboli, alcoholic hepatitis, drug fever, and factitious fever. Undiagnosed FUO Despite extensive evaluation, the diagnosis remains elusive in 10–15% of patients. Of these patients, the fever abates spontaneously in about 75% and the clinician never knows the cause; in the remainder, more classic manifestations of the underlying disease appear over time. Clinical Findings Because the evaluation of a patient with FUO is costly and time-consuming, it is imperative to first document the presence of fever. This is done by observing the patient while the temperature is being taken to ascertain that fever is not factitious (self-induced). Associated findings that accompany fever include tachycardia, chills, and piloerection. A thorough history—including family, occupational, social (sexual practices, use of injection drugs), dietary (unpasteurized products, raw meat), exposures (animals, chemicals), and travel—may give clues to the diagnosis. Repeated physical examination may reveal subtle, evanescent clinical findings essential to diagnosis. Laboratory Tests In addition to routine laboratory studies, blood cultures should always be obtained, preferably when the patient has not taken antibiotics for several days, and should be held by the laboratory for 2 weeks to detect slow-growing organisms. Cultures on special media are requested if Legionella, Bartonella, or nutritionally deficient streptococci are considered possible pathogens. "Screening tests" with immunologic or microbiologic serologies ("febrile agglutinins") are of low yield and should not be done. Specific serologic tests are helpful if the history or physical examination suggests a specific diagnosis. A single elevated titer rarely allows one to make a diagnosis of infection; instead, one must demonstrate a fourfold rise or fall in titer to confirm a specific infectious cause. Because infection is the most common cause of FUO, other body fluids are usually cultured, ie, urine, sputum, stool, cerebrospinal fluid, and morning gastric aspirates (if one suspects tuberculosis). Direct examination of blood smears may establish a diagnosis of malaria or relapsing fever (Borrelia). Imaging All patients with FUO should have a chest radiograph. Studies such as sinus films, upper gastrointestinal series with small bowel follow-through, barium enema, proctosigmoidoscopy, and evaluation of gallbladder function are reserved for patients who have symptoms, signs, or a history that suggest disease in these body regions. CT scan of the abdomen and pelvis is also frequently performed and is particularly useful for looking at the liver, spleen, and retroperitoneum. When the CT scan is abnormal, the findings often lead to a specific diagnosis. A normal CT scan is not quite as useful; more invasive procedures such as biopsy or exploratory laparotomy may be needed. The role of MRI in the investigation of FUO has not been evaluated. In general, however, MRI is better than CT for detecting lesions of the nervous system and is useful in diagnosing various vasculitides. Ultrasound is sensitive for detecting lesions of the kidney, pancreas, and biliary tree. Echocardiography should be used if one is considering endocarditis or atrial myxoma. Transesophageal echocardiography is more sensitive than surface echocardiography for detecting valvular lesions, but even a negative transesophageal study does not exclude endocarditis (10% false-negative rate). The usefulness of radionuclide studies in diagnosing FUO is variable. Theoretically, a gallium or positron- emission (PET) scan would be more helpful than an indium-labeled white blood cell scan, because gallium and file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (3 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print fluorodeoxy-glucose may be useful for detecting infection, inflammation, and neoplasm whereas the indium scan is useful only for detecting infection. Indium-labeled immunoglobulin may prove to be useful in detecting infection and neoplasm and can be used in the neutropenic patient. It is not sensitive for lesions of the liver, kidney, and heart because of high background activity. In general, radionuclide scans are plagued by high rates of false-positive and false-negative results that are not useful when used as screening tests and, if done at all, are limited to those patients whose history or examination suggests local inflammation or infection. Biopsy Invasive procedures are often required for diagnosis. Any abnormal finding should be aggressively evaluated: Headache calls for lumbar puncture (see Figure: illustration) to rule out meningitis; skin from a rash should be biopsied to look for cutaneous manifestations of collagen vascular disease or infection; and enlarged lymph nodes should be aspirated or biopsied and examined for cytologic features to rule out neoplasm and sent for culture. Bone marrow aspiration with biopsy is a relatively low-yield procedure (except in HIV-positive patients, in whom mycobacterial infection is a common cause of FUO), but the risk is low and the procedure should be done if other less invasive tests have not yielded a diagnosis. Liver biopsy will yield a specific diagnosis in 10–15% of patients with FUO and should be considered in any patient with abnormal liver function tests even if the liver is normal in size. The role of exploratory laparotomy is debatable since the advent of CT scanning and MRI. Laparotomy or laparoscopy should be considered when the patient continues to deteriorate and the diagnosis is elusive despite extensive evaluation. Prepackaged disposable sterile tray for lumbar puncture. (Reproduced, with permission, from Chesnutt MS et al: Office & Bedside Procedures. Originally published by Appleton & Lange. Copyright © 1992 by The McGraw- Hill Companies, Inc.) Treatment Therapeutic trials are indicated if a diagnosis is strongly suspected—eg, it is reasonable to give antituberculous drugs if tuberculosis is suspected, or tetracycline if brucellosis is suspected. However, if there is no clinical response in several weeks, it is imperative to stop therapy and reevaluate the patient. In the seriously ill or rapidly deteriorating file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (4 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print patient, empiric therapy is often given. Antituberculosis medications (particularly in the elderly or foreign-born) and broad-spectrum antibiotics are reasonable in this setting. Empiric administration of corticosteroids should be discouraged; they can suppress fever if given in high enough doses, but they can also exacerbate many infections, and infection remains a leading cause of FUO. Crispin JC et al: Adult-onset Still disease as the cause of fever of unknown origin. Medicine (Baltimore) 2005;84:331. [PMID: 16267408] Knockaert DC et al: Fever of unknown origin in adults: 40 years on. J Intern Med 2003;253:263. [PMID: 12603493] Mourad O et al: A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med 2003;163:545. [PMID: 12622601] Ozaras R et al: Is laparotomy necessary in the diagnosis of fever of unknown origin? Acta Chir Belg 2005;105:89. [PMID: 15790210] Tal S et al: Fever of unknown origin in the elderly. J Intern Med 2002;242:295. [PMID: 12366602] Vanderschueren S et al: From prolonged febrile illness to fever of unknown origin. Arch Intern Med 2003;163:1033. [PMID: 12742800] Woolery WA et al: Fever of unknown origin: keys to determining the etiology in older patients. Geriatrics 2004;59:41. [PMID: 15508555] Infections in the Immunocompromised Patient Essentials of Diagnosis ● Fever and other symptoms may be blunted because of immunosuppression; early diagnosis may be difficult. ● A contaminating organism in an immunocompetent individual may be a pathogen in an immunocompromised one. ● The interval since transplantation and the degree of immunosuppression can narrow the differential diagnosis. ● Empiric broad-spectrum antibiotics may be appropriate in high-risk patients whether or not symptoms are localized because of high infection-related morbidity and mortality. General Considerations Immunocompromised patients have one or more defects in their natural defense mechanisms that put them at an increased risk for infections. Not only is the risk of infection greater in these individuals, but once established it is often severe, rapidly progressive, and life-threatening. Organisms that are not usually pathogens in the immunocompetent person may cause life-threatening infection in the compromised patient (eg, Staphylococcus epidermidis, Corynebacterium jeikeium, Propionibacterium acnes, Bacillus species). Therefore, culture results must be interpreted with caution, and isolates should not be disregarded as merely contaminants. Although the type of immunodeficiency is associated with specific infectious disease syndromes, any pathogen can cause infection in any immunosuppressed patient at any time. Thus, a systematic evaluation is required to identify a specific organism. Impaired Humoral Immunity Defects in humoral immunity are often congenital, although hypogammaglobulinemia can occur in multiple myeloma, chronic lymphocytic leukemia, and in patients who have undergone splenectomy. Patients with ineffective humoral immunity lack opsonizing antibodies and are at particular risk for infection with encapsulated organisms, such as Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae. file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (5 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print Granulocytopenia (Neutropenia) Granulocytopenia is common following hematopoietic cell transplantation ("bone marrow transplantation") and among patients with solid tumors—as a result of myelosuppressive chemotherapy—and in acute leukemias. The risk of infection begins to increase when the absolute granulocyte count falls below 1000/mcL, with a dramatic increase in frequency and severity when the granulocyte count falls below 100/mcL. The infection risk is also increased when there is a rapid rate of decline of neutrophils and in those with a prolonged period of neutropenia. The granulocytopenic patient is particularly susceptible to infections with gram-negative enteric organisms, Pseudomonas, gram-positive cocci (particularly Staphylococcus aureus, S epidermidis, and viridans streptococci), Candida, Aspergillus, and other fungi that have recently emerged as pathogens such as Trichosporon, Scedosporium, Fusarium, and Pseudallescheria. The methods used for detection of deficiencies in the immune system can be found in Allergy & Immunology. Impaired Cellular Immunity Patients with cellular immune deficiency encompass a large and heterogeneous group, including patients with HIV infection (see Infectious Diseases: HIV); patients with lymphoreticular malignancies, such as Hodgkin's disease; and patients receiving immunosuppressive medications, such as corticosteroids, cyclosporine, tacrolimus, and other cytotoxic drugs. This latter group—those who are immunosuppressed as a result of medications—includes patients who have undergone transplantation, many patients receiving therapy for solid tumors, and patients receiving prolonged high-dose corticosteroid treatment (eg, for asthma, temporal arteritis, systemic lupus). Patients with cellular immune dysfunction are susceptible to infections by a large number of organisms, particularly ones that replicate intracellularly. Examples include bacteria, such as Listeria, Legionella, Salmonella, and Mycobacterium; viruses, such as herpes simplex, varicella, and CMV; fungi, such as Cryptococcus, Coccidioides, Histoplasma, and Pneumocystis; and protozoa, such as Toxoplasma. Hematopoietic Cell Transplant Recipients The length of time it takes for complications to occur in hematopoietic cell transplant recipients can be helpful in determining the etiologic agent. In the early (preengraftment) posttransplant period (day 1–21), almost all patients will become severely neutropenic for 7–21 days depending on whether growth factors are used and the source of stem cells. Patients are at risk for gram-positive (particularly catheter-related) and gram- negative bacterial infections as well as herpes simplex virus, respiratory syncytial virus, and candidal infections; mucositis is also a risk factor. In contrast to solid organ transplant recipients, the source of fever during this period cannot be found in 60–70% of hematopoietic cell transplant patients. Between 3 weeks and 3 months posttransplant, infections with CMV, adenovirus, Aspergillus, and Candida are most common. P jiroveci pneumonia can also be seen during this period, particularly in patients in whom graft-versus-host disease (GVHD) has developed and require immunosuppression. Patients continue to be at risk for infectious complications beyond 3 months following transplantation, particularly those who have received allogeneic transplantation and those who are taking immunosuppressive therapy for chronic GVHD. Varicella-zoster is common, and Aspergillus and CMV infections are increasingly seen in this period as well. Solid Organ Transplant Recipients The length of time it takes for infection to occur following solid organ transplantation can also be helpful in determining the infectious origin. Immediate postoperative infections often involve the transplanted organ. Following lung transplantation, pneumonia and mediastinitis are particularly common; following liver transplantation, intra-abdominal abscess, cholangitis, and peritonitis may be seen; after renal transplantation, urinary tract infections, perinephric abscesses, and infected lymphoceles can occur. file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (6 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print Most infections that occur in the first 2–4 weeks posttransplant are related to the operative procedure and to hospitalization itself (wound infection, intravenous catheter infection, urinary tract infection from a Foley catheter) or are related to the transplanted organ. Infections that occur between the first and sixth months are often related to immunosuppression. During this period, reactivation of viruses occurs, and herpes simplex, varicella-zoster, and CMV infections are quite common. Opportunistic infections with fungi (eg, Candida, Aspergillus, Cryptococcus, Pneumocystis), Listeria monocytogenes, Nocardia, and Toxoplasma are also common. After 6 months, if immunosuppression has been reduced to maintenance levels, infections that are found in any population occur. Patients with poorly functioning allografts who receive long-term immunosuppression therapy continue to be at risk for opportunistic infections. Other Immunocompromised States A large group of patients who are not specifically immunodeficient are at increased risk for infection because of debilitating injury (eg, burns or severe trauma), invasive procedures (eg, hyperalimentation lines, Foley catheters, dialysis catheters), central nervous system dysfunction (which predisposes patients to aspiration pneumonia and decubitus ulcers), obstructing lesions (eg, pneumonia due to an obstructed bronchus, pyelonephritis due to nephrolithiasis, cholangitis secondary to cholelithiasis), and use of broad- spectrum antibiotics. Patients with diabetes mellitus have alterations in cellular immunity that make them disproportionately susceptible to some diseases (eg, mucormycosis, emphysematous pyelonephritis, and foot infections). Clinical Findings Laboratory Findings Routine evaluation includes complete blood count with differential, chest radiograph, and blood cultures; urine and sputum cultures should be obtained if indicated clinically or radiographically. Any focal complaints (localized pain, headache, rash) should prompt imaging and cultures appropriate to the site. Patients who remain febrile without an obvious source should be evaluated for viral infection (CMV blood cultures or antigen test), abscesses (which usually occur near previous operative sites), candidiasis involving the liver or spleen, or aspergillosis. Serologic evaluation may be helpful if toxoplasmosis, aspergillosis (detected by galactomannan level in serum), or an endemic fungal infection (coccidioidomycosis, histoplasmosis) is a possible cause. Special Diagnostic Procedures Special diagnostic procedures should also be considered. The cause of pulmonary infiltrates can be easily determined with simple techniques in some situations—eg, induced sputum yields a diagnosis of Pneumocystis pneumonia in 50–80% of AIDS patients with this infection. In other situations, more invasive procedures may be required (bronchoalveolar lavage, transbronchial biopsy, or even open lung biopsy). Other investigations such as skin, liver, or bone marrow biopsy may be helpful in establishing a diagnosis. Differential Diagnosis Transplant rejection, organ ischemia and necrosis, thrombophlebitis, and lymphoma (posttransplant lymphoproliferative disease) may all present as fever and must be considered in the differential diagnosis. Prevention There is great interest in preventing infection with prophylactic antimicrobial regimens but no uniformity of opinion about optimal drugs or dosage regimens. Hand washing is the simplest and most effective means of decreasing nosocomial infections in all patients, especially the compromised patient. Invasive devices such file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (7 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print as central and peripheral lines and Foley catheters are a potential source of infection. Some centers use laminar airflow isolation or high-efficiency particulate air (HEPA) filtering in hematopoietic cell transplant patients during the neutropenic phase. Pneumocystis & Herpes Simplex Infections Trimethoprim-sulfamethoxazole (TMP-SMZ), one double-strength tablet orally three times a week, one double-strength tablet twice daily on weekends, or one single-strength tablet daily for 3–6 months, is frequently used to prevent Pneumocystis infections in transplant patients. It may also decrease the incidence of bacterial pneumonia, urinary tract infections, Nocardia infections, and toxoplasmosis. In patients allergic to TMP- SMZ, aerosolized pentamidine is used in a dosage of 300 mg once a month, as is dapsone, 50 mg orally daily or 100 mg three times weekly. (Glucose-6-phosphate dehydrogenase (G6PD) levels should be determined before therapy when the latter is instituted.) Acyclovir prevents herpes simplex infections in bone marrow and solid organ transplant recipients and is given to seropositive patients who are not receiving acyclovir or ganciclovir for CMV prophylaxis. The usual dose is 200 mg orally three times daily for 4 weeks (hematopoietic cell transplants) to 12 weeks (other solid organ transplants). CMV Prevention of CMV is more difficult, and no uniformly accepted approach has been adopted. Prevention strategies often depend on the serologic status of the donor and recipient and the organ transplanted, which determines the level of immunosuppression after transplant. In solid organ transplants (liver, kidney, heart, lung), the greatest risk of developing CMV disease is in seronegative patients who receive organs from seropositive donors. These high-risk patients usually receive ganciclovir, 2.5–5 mg/kg intravenously twice daily, during hospitalization (usually about 10 days) and then are given oral valganciclovir, 900 mg twice daily, or oral ganciclovir, 1 g three times daily, for 3 months; of note, oral ganciclovir is not absorbed as well as oral valganciclovir. Other solid organ transplant recipients (seropositive recipients) are at lower risk for developing CMV disease and usually receive intravenous ganciclovir while in the hospital followed by either high- dose oral acyclovir at a dosage of 800 mg four times daily or oral ganciclovir for 3 months. Ganciclovir, valganciclovir, and acyclovir prevent herpes virus reactivation. Because immunosuppression is increased during periods of rejection, patients treated for rejection usually receive intravenous ganciclovir during rejection therapy. Recipients of hematopoietic cell transplants are more severely immunosuppressed than recipients of solid organ transplants, are at greater risk for developing serious CMV infection, and thus usually receive more aggressive prophylaxis. Two approaches have been used: universal prophylaxis or preemptive therapy. In the former, all high-risk patients (seropositive patients who receive allogeneic transplants) receive 5 mg/kg of intravenous ganciclovir every 12 hours for a week, followed by oral valganciclovir, 900 mg twice daily, or oral ganciclovir (which is not absorbed as well as valganciclovir), 1 g three times daily to day 100. This method is costly and associated with significant toxicity and is therefore being used less frequently. Alternatively, patients can be monitored without specific therapy and have blood sampled weekly for the presence of CMV. If CMV is detected by an antigenemia assay, preemptive therapy with ganciclovir is given (5 mg/kg intravenously twice daily for 7–14 days, followed by oral valganciclovir, 900 mg twice daily for a minimum of 3 weeks or until day 100, whichever is longer). This approach is effective but does miss a small number of patients in whom CMV disease subsequently develops. Other preventive strategies include use of CMV-negative or leukocyte-depleted blood products for CMV-seronegative recipients. Other Organisms Routine decontamination of the gastrointestinal tract to prevent bacteremia in the neutropenic patient is file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (8 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print not recommended. Prophylactic administration of antibiotics in the afebrile, asymptomatic neutropenic patient is controversial, although many centers have adopted this strategy. Rates of bacteremia are decreased, but overall mortality is not affected and emergence of resistant organisms is a common problem. Use of intravenous immunoglobulin is reserved for the small number of patients with severe hypogammaglobulinemia following bone marrow transplantation and should not be routinely administered to all transplant patients. Prophylaxis with antifungal agents to prevent invasive mold (primarily Aspergillus) and yeast (primarily Candida) infections is routinely used, but the optimal agent, dose, and duration have not been standardized. Moderate-dose (0.5 mg/kg/d) and low-dose (0.1–0.25 mg/kg/d) amphotericin B, lipid- based preparations of amphotericin B, aerosolized amphotericin B, and itraconazole (capsules and solution) have all been used with varying success in the neutropenic patient. Because voriconazole appears to be more effective than amphotericin for documented Aspergillus infections, one approach to prophylaxis is to use oral fluconazole (400 mg/d) for patients at low risk for developing fungal infections (those who receive autologous bone marrow transplants) and oral voriconazole (200 mg twice daily) for those at high risk (allogeneic transplants) at least until engraftment (usually 30 days). In solid organ transplant recipients, the risk of invasive fungal infection varies considerably (1–2% in liver, pancreas, and kidney transplants and 6–8% in heart and lung transplants). Whether universal prophylaxis or observation with preemptive therapy is the best approach has not been determined. Although fluconazole is effective in preventing yeast infections, emergence of resistant strains of Candida krusei, other Candida species, and molds (Fusarium, Aspergillus, Mucor) has raised concerns about its routine use as a prophylactic agent. Treatment General Measures Because infections in the immunocompromised patient can be rapidly progressive and life-threatening, diagnostic procedures must be done promptly, and empiric therapy is usually instituted before a specific pathogenic organism has been isolated. Reduction or discontinuation of immunosuppressive medication may jeopardize the viability of the transplanted organ, but in life-threatening infections, it is necessary as an adjunct to effective antimicrobial therapy. Hematopoietic growth factors (granulocyte and granulocyte-macrophage colony-stimulating factors) stimulate proliferation of bone marrow stem cells, resulting in an increase in peripheral leukocytes. These agents shorten the period of neutropenia and have been associated with fewer infections. Use of growth factors in patients with prolonged neutropenia (> 7 days) is an effective means of reversing immunosuppression. Specific Measures Antimicrobial drug therapy is rationally based on culture results (see Infectious Disease: Antimicrobial Therapy). Therapy should be specific for isolated pathogens, and bactericidal agents should be used. Combinations of antimicrobials are often required to provide synergy, to prevent resistance, or to serve as broad- spectrum coverage of multiple pathogens (since infections in these patients are often polymicrobial). Empiric therapy is often instituted at the earliest sign of infection in the immunosuppressed patient because prompt therapy favorably affects outcome. The antibiotic or combination of antibiotics used depends on the type of immunocompromise and the site of infection. For example, in the febrile neutropenic patient, the primary concern is bacterial and fungal infections. In this patient population, an algorithmic approach to therapy is often used, with initial treatment directed at gram-positive and gram-negative organisms. If the patient does not file:///C|/Documents%20and%20Settings/Adminis nfectious%20Diseases%20General%20Problems.htm (9 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print respond, broader-spectrum antibiotics and antifungal drugs are added. Although a number of different agents can be used, choices should be based on local microbiologic trends. One example would be to initiate therapy with a fluoroquinolone active against gram-positive organisms (such as levofloxacin, gatifloxacin, or moxifloxacin) when the absolute neutrophil count falls below 500/mcL. If fever develops, cultures are obtained, and vancomycin, 10–15 mg/kg intravenously every 12 hours, is given to cover methicillin-resistant S aureus, S epidermidis, and enterococcus. If fever continues after 48–72 hours, antifungal coverage can be increased by changing to either caspofungin, 50 mg daily intravenously, or voriconazole, 200 mg intravenously or orally twice daily (if the patient was receiving fluconazole prophylaxis); broader-spectrum antibiotics can be added sequentially. For example, to better cover Acinetobacter, Citrobacter, and Pseudomonas, the fluoroquinolone may be switched to cefepime, 2 g every 8 hours intravenously; with continued fever, imipenem, 500 mg intravenously every 6 hours (or meropenem, 1 g intravenously every 8 hours), with or without tobramycin, 1.8 mg/kg intravenously every 8 hours, may be used in place of cefepime. If fevers persist, TMP-SMZ at 10 mg/kg/d (of trimethoprim) intravenously in three divided doses can be added to cover Stenotrophomonas. Regardless of whether the patient becomes afebrile, therapy is continued until resolution of neutropenia. Failure to continue antibiotics through the period of neutropenia is associated with a high incidence of relapse that can be associated with septic shock. Patients with fever and neutropenia who are at low risk for developing complications (neutropenia expected to persist for less than 10 days, no comorbid complications requiring hospitalization, and cancer adequately treated) can be treated with oral antibiotic regimens, such as ciprofloxacin, 750 mg every 12 hours, plus amoxicillin- clavulanic acid, 500 mg every 8 hours. In the organ transplant patient with interstitial infiltrates, the main concern is infection with Pneumocystis or Legionella species, so that empiric treatment with a macrolide and TMP-SMZ would be reasonable. If the patient does not respond to empiric treatment, a decision must be made to add more antimicrobial agents or perform invasive procedures (see above) to make a specific diagnosis. By making a specific diagnosis, therapy can be specific and polypharmacy with multiple potentially toxic agents can be avoided. Bucaneve G et al: Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med 2005;353:977. [PMID: 16148283] Kalil AC et al: Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med 2005;143:870. [PMID: 16365468] Rubin RH: The direct and indirect effects of infection in liver transplantation: pathogenesis, impact, and clinical management. Curr Clin Top Infect Dis 2002;22:125. [PMID: 12520651] Viscoli C et al: Treatment of febrile neutropenia: what is new? Curr Opin Infect Dis 2002;15:377. [PMID: 12130933] Walsh TJ et al: Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004;351:1391. [PMID: 15459300] file:///C|/Documents%20and%20Settings/Admini fectious%20Diseases%20General%20Problems.htm (10 of 54) [14/12/2006 8:12:28 μμ] [...]... fluid examination as the first step toward etiologic diagnosis (Table 3 0–1 and Figure: illustration) Table 3 0–1 Typical cerebrospinal fluid findings in various central nervous system diseases Diagnosis Cells/mcL Glucose (mg/dL) Protein (mg/ Opening dL) Pressure Normal 0–5 lymphocytes 4 5–8 51 1 5–4 5 7 0–1 80 mm H2O Purulent meningitis (bacterial)2 20 0–2 0,000 Low (< 45) High (> 50) Markedly elevated community-acquired... lasts 4–8 days food handlers Noroviruses and diarrhea that by infected stool common in adults), fever, myalgias, abdominal cramps Lasts 1 2–6 0 hours Supportive care PCR = polymerase chain reaction Treatment Treatment usually consists of replacement of fluids and electrolytes and, very rarely, management of hypovolemic shock and respiratory compromise In mild diarrhea, increasing ingestion of juices and. .. and fried rice consumption is associated with B cereus toxin Prominent features of some of these causes of diarrhea are listed in Table 3 0–3 Table 3 0–3 Acute bacterial diarrheas and "food poisoning." Organism Incubation Period Vomiting Diarrhea Fever Associated Foods Diagnosis Clinical Features and Treatment Staphylococcus 1–8 hours +++ ± ± Staphylococci Clinical Food Abrupt onset, grow in meats, and. .. cereus (diarrheal ± +++ – Toxin in meats, Clinical Food Abdominal stews, and and stool can cramps, watery gravy be tested for diarrhea, and toxin toxin) 1 0–1 6 hours nausea lasting 2 4–4 8 hours Supportive care file:///C|/Documents%2 0and% 20Settings/Admini fectious%20Diseases%20General%20Problems.htm (26 of 54) [14/12/2006 8:12:28 μμ] AccessMedicine - Print Clostridium 8–1 6 hours ± +++ – Clostridia grow Stools... diarrhea, meat and enterotoxin or abdominal poultry dishes perfringens cultured cramps, nausea; and produce vomiting an enterotoxin occasionally Recovery usual without treatment in 2 4– 48 hours Supportive care; antibiotics not needed Clostridium 1 2–7 2 hours ± – – Stool, serum, Diplopia, in anaerobic and food can dysphagia, acidic be tested for dysphonia, environment toxin Stool respiratory eg, canned and food... study and culture of the cerebrospinal fluid, and a chest film The fluid must be examined for cell count, glucose, and protein, and a smear stained for bacteria (and acidfast organisms when appropriate) and cultured for pyogenic organisms and for mycobacteria and fungi when indicated Latex agglutination tests can detect antigens of encapsulated organisms (S pneumoniae, H influenzae, N meningitidis, and. .. Food Abrupt onset, grow in meats, and stool can intense nausea dairy, and be tested for and vomiting for bakery (preformed toxin) toxin up to 24 hours, products and recovery in 2 4– produce 48 hours enterotoxin Supportive care ± – Acute onset, and stool can severe nausea be tested for and vomiting diarrhea +++ Clinical Food rice causes 1–8 hours (preformed toxin) Reheated fried vomiting or Bacillus cereus... Trichomonas vaginalis, 15%; and bacterial vaginosis, 34%), and the risk of acquiring infection as a result of the assault is significant but is often lower than the preexisting rate (N gonorrhoeae, 6–1 2%; C trachomatis, 4–1 7%; T vaginalis, 12%; syphilis, 0. 5–3 %; and bacterial vaginosis, 19%) Victims should be evaluated within 24 hours after the assault, and cultures for N gonorrhoeae and C trachomatis should... aged 2–2 3 months and for certain children aged 2 4–5 9 months Pneumococcal polysaccharide vaccine (PPV) is recommended in addition to PCV for certain high-risk groups See MMWR 2000;49(No RR-9): 1–3 7 9 Hepatitis A vaccine Hepatitis A vaccine is recommended for children and adolescents in selected states and regions, and for certain high-risk groups Consult local public health authority Children and adolescents... pneumoniae, H influenzae, N meningitidis, M tuberculosis, B burgdorferi, and Tropheryma whippelii) and viruses (herpes simplex, varicella-zoster, CMV, Epstein-Barr virus, and enteroviruses) in patients with meningitis The greatest experience is with PCR for herpes simplex and varicella-zoster, and the tests are very sensitive (> 95%) and specific Tests to detect the other organisms may not be any more . infections (2 5–4 0% of cases) and cancer (2 5–4 0% of cases) account for the majority of FUOs. In children, infections are the most common cause of FUO (3 0–5 0% of cases) and cancer a rare cause ( 5–1 0% of. risk is low and the procedure should be done if other less invasive tests have not yielded a diagnosis. Liver biopsy will yield a specific diagnosis in 1 0–1 5% of patients with FUO and should. a diagnosis. Differential Diagnosis Transplant rejection, organ ischemia and necrosis, thrombophlebitis, and lymphoma (posttransplant lymphoproliferative disease) may all present as fever and