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Fever of Unknown Origin Fever of Unknown Origin Initial testing for classic FUO should address any focal signs and symptoms and additionally includes complete blood count with differential, electrolyte levels, kidney and liver chemistries lntroduction (hepatitis serologr if results are abnormal), lactate dehydroge- Diagnostic advances have revealed a spectrum of diseases nase level, urinalysis or microscopy and urine culture, erythro- causing fever of unknown origin (FUO), with origins more cyte sedimentation rate, C-reactive protein, antinuclear rapidly identifiable for many cases. FUO falls into one of four antibodies, rheumatoid factor, HIV testing, cytomegalovirus categories: classic, health care-associated, neutropenic, and polymerase chain reaction testing, blood cultures (three sets, HIV associated (Table 34). each set obtained at least several hours apart), tuberculosis test- ing, and chest radiography (or chest CT). Q-fever serologz Causes should be considered if risk factors exist. In adults, FUO is usually attributed to one of several dozen If initial tests do not suggest a cause, abdominal or pelvic causes. Common causes of FUO include infections, neoplasm CT may be considered to evaluate for intra-abdominal abscess

Fever of Unknown Origin Initial testing for classic FUO should address any focal signs and symptoms and additionally includes complete blood count with differential, electrolyte levels, kidney and liver chemistries lntroduction (hepatitis serologr if results are abnormal), lactate dehydroge- Diagnostic advances have revealed a spectrum of diseases nase level, urinalysis or microscopy and urine culture, erythro- causing fever of unknown origin (FUO), with origins more cyte sedimentation rate, C-reactive protein, antinuclear rapidly identifiable for many cases. FUO falls into one of four antibodies, rheumatoid factor, HIV testing, cytomegalovirus categories: classic, health care-associated, neutropenic, and polymerase chain reaction testing, blood cultures (three sets, HIV associated (Table 34). each set obtained at least several hours apart), tuberculosis test- ing, and chest radiography (or chest CT). Q-fever serologz Causes should be considered if risk factors exist. In adults, FUO is usually attributed to one of several dozen If initial tests do not suggest a cause, abdominal or pelvic causes. Common causes of FUO include infections, neoplasm CT may be considered to evaluate for intra-abdominal abscess or malignancy, rheumatologic or inflammatory disorders, and or lymphoproliferative disorders. Liver,lymph node, and tem- miscellaneous causes (see Table 34). poral artery biopsies have a diagnostic yield of about 35%, particularly when performed when infection is unlikely. Posterior cervical, supraclavicular, infraclavicular, epitroch- Evaluation lear, hilar, mediastinal, and mesenteric lymph node biopsies Many FUO occurrences are atypical presentations of com- are more likely to provide a diagnosis than that of other lymph mon diseases. A careful history and physical examination nodes. Bone marrow biopsy can be helpful when leukopenia should be performed and repeated intermittently during or thrombocytopenia is present. The utility of nuclear imaging the evaluation period. The history should include proce- (PET scan, leukocyte scan) is limited. dures, surgeries, presence of foreign bodies or implants, A definitive diagnosis is lacking in up to half of patients immunosuppression, travel, animal and other exposures after extensive evaluation. FUO lasting more than 1 year is (including hobbies), dietary habits, and medications unlikely to be caused by infection or malignancy. Undiagnosed (including over-the-counter medications). The degree and FUO is generally associated with a benign long-term course, pattern of fever is nonspecific and nondiagnostic in most particularly when fever is not associated with weight loss or instances. other signs of under$ing serious disease.

or malignancy, rheumatologic or inflammatory disorders, and or lymphoproliferative disorders. Liver,lymph node, and tem- miscellaneous causes (see Table 34). poral artery biopsies have a diagnostic yield of about 35%, particularly when performed when infection is unlikely. Posterior cervical, supraclavicular, infraclavicular, epitroch- Evaluation lear, hilar, mediastinal, and mesenteric lymph node biopsies Many FUO occurrences are atypical presentations of com- are more likely to provide a diagnosis than that of other lymph mon diseases. A careful history and physical examination nodes. Bone marrow biopsy can be helpful when leukopenia should be performed and repeated intermittently during or thrombocytopenia is present. The utility of nuclear imaging the evaluation period. The history should include proce- (PET scan, leukocyte scan) is limited. dures, surgeries, presence of foreign bodies or implants, A definitive diagnosis is lacking in up to half of patients immunosuppression, travel, animal and other exposures after extensive evaluation. FUO lasting more than 1 year is (including hobbies), dietary habits, and medications unlikely to be caused by infection or malignancy. Undiagnosed (including over-the-counter medications). The degree and FUO is generally associated with a benign long-term course, pattern of fever is nonspecific and nondiagnostic in most particularly when fever is not associated with weight loss or instances. other signs of under$ing serious disease. TABI-E 34. Categories and Common Causes of Fever of Unknown Origin Category Definition Common Causes Classic Temperature >38.3 "C (100.9 "F) for at least I nfection (endocard itis, tu bercu losis Iextrapulmonary/ 3 weeks with at least 1 week of in-hospital disseminatedl, abscess, endemic mycoses), neoplasm investigation" (leukemia, lymphoma, renal cell carcinoma, hepatocellular carci noma ), con nective tissue disease (ad u lt-onset Sti I I ar disease, polymyalgia rheumatica, vasculitis, systemic lupus Temperature >38.3 "C (100.9'F)for at least erythematosus, giant cell arteritis), endocrine disorder 3 weeks that remains undiagnosed after two ( hyperthyroid ism, su bacute thyroid itis), genetic (fami ial I

TABI-E 34. Categories and Common Causes of Fever of Unknown Origin Category Definition Common Causes Classic Temperature >38.3 "C (100.9 "F) for at least I nfection (endocard itis, tu bercu losis Iextrapulmonary/ 3 weeks with at least 1 week of in-hospital disseminatedl, abscess, endemic mycoses), neoplasm investigation" (leukemia, lymphoma, renal cell carcinoma, hepatocellular carci noma ), con nective tissue disease (ad u lt-onset Sti I I ar disease, polymyalgia rheumatica, vasculitis, systemic lupus Temperature >38.3 "C (100.9'F)for at least erythematosus, giant cell arteritis), endocrine disorder 3 weeks that remains undiagnosed after two ( hyperthyroid ism, su bacute thyroid itis), genetic (fami ial I visits in the ambulatory settingb or 3 days in the Mediterranean fever), or miscellaneous (drug fever, hospital factitious fever) Health care-associated Temperature >38.3 "C (1 00.9 oF) in patients Drug fevel septic thrombophlebitis, venous hospitalized >3 days (withoutfever or evidence thromboembolism, sinusitis in the settinq of a nasogastric of potential infection at the time of admission) tube, chronic sinusitis without n"rog.rlric tube, and negative evaluation for at least 3 days " postoperative abscess, Clostridioides difficile infection, device- or proced ure-related endocard itis Neutropenic Temperature >38.3 'C (100.9'F) and Bacterem ia, opportun istic fu ngal infections (aspergi llosis, neutrophil count <500/pL (0.5 x 1 Oell) for candidiasis; more common than bacteremia after 7 days), >3 days and negative evaluation after d ru g fever, venous th romboem bol ism, underlying 48 hours ma ig na ncy, a log raft rejection i n tra nspla nt; undiagnosed I I

visits in the ambulatory settingb or 3 days in the Mediterranean fever), or miscellaneous (drug fever, hospital factitious fever) Health care-associated Temperature >38.3 "C (1 00.9 oF) in patients Drug fevel septic thrombophlebitis, venous hospitalized >3 days (withoutfever or evidence thromboembolism, sinusitis in the settinq of a nasogastric of potential infection at the time of admission) tube, chronic sinusitis without n"rog.rlric tube, and negative evaluation for at least 3 days " postoperative abscess, Clostridioides difficile infection, device- or proced ure-related endocard itis Neutropenic Temperature >38.3 'C (100.9'F) and Bacterem ia, opportun istic fu ngal infections (aspergi llosis, neutrophil count <500/pL (0.5 x 1 Oell) for candidiasis; more common than bacteremia after 7 days), >3 days and negative evaluation after d ru g fever, venous th romboem bol ism, underlying 48 hours ma ig na ncy, a log raft rejection i n tra nspla nt; undiagnosed I I in 40"/"-600/" of cases HIV-associated Temperature >38.3 'C (1 00.9 'F)for >3 weeks Pri m a ry H lV i nfecti o n, o p po rtu n i sti c i nfecti o n s (outpatients) or >3 days (inpatients) in patients (cytomega lovi rus, cryptococcosis, tu bercu losis, atypica I

in 40"/"-600/" of cases HIV-associated Temperature >38.3 'C (1 00.9 'F)for >3 weeks Pri m a ry H lV i nfecti o n, o p po rtu n i sti c i nfecti o n s (outpatients) or >3 days (inpatients) in patients (cytomega lovi rus, cryptococcosis, tu bercu losis, atypica I with confirmed HIV infection mycobacte ria, toxo plasm osis, Pn e u m ocysti s j i rove ci i pneumonia), lymphoma, immune reconstitution inflammatory syndrome "Original definition of fever of unknown origin. bAmbulatory setting is the preferred venue for evaluation and treatment. 54

lmmunodeficiency Syndromes t( EY PO t 1{TS Diagnosis allows directed therapy, targeted immunization, and o Fever of unknown origin is categorized as classic, health optimized empiric treatment of secondary infections. care-associated, neutropenic, and HlV-associated. . In patients with fever of unknown origin, a careful his- Primary I m mu nodeficiencies tory and physical examination should be performed, Selective lgA Deficiency including past procedures or surgeries, presence of for- Selective IgA deficiency (SIgAD) is the most common primary eign bodies or implants, immunosuppression, travel, ani- antibody deficiency, although most patients remain asympto- mal or other exposures, dietary habits, and medications. matic. IgA provides mucosal immunity; therefore, patients . A definitive diagnosis is lacking in up to half of patients with SIgAD are susceptible to infections of the respiratory tract with fever of unknown origin after extensive evalua- and, less frequently, gastrointestinal tract. Sinopulmonary tion, but duration of more than l year is unlikely to be infections are the most common presenting manifestation, caused by infection or malignancy. particularly with encapsulated bacteria (see Table 35). Anti-lgA IgE antibodies can rarely cause anaphylaxis to blood products; however, transfusions can be given with close

t( EY PO t 1{TS Diagnosis allows directed therapy, targeted immunization, and o Fever of unknown origin is categorized as classic, health optimized empiric treatment of secondary infections. care-associated, neutropenic, and HlV-associated. . In patients with fever of unknown origin, a careful his- Primary I m mu nodeficiencies tory and physical examination should be performed, Selective lgA Deficiency including past procedures or surgeries, presence of for- Selective IgA deficiency (SIgAD) is the most common primary eign bodies or implants, immunosuppression, travel, ani- antibody deficiency, although most patients remain asympto- mal or other exposures, dietary habits, and medications. matic. IgA provides mucosal immunity; therefore, patients . A definitive diagnosis is lacking in up to half of patients with SIgAD are susceptible to infections of the respiratory tract with fever of unknown origin after extensive evalua- and, less frequently, gastrointestinal tract. Sinopulmonary tion, but duration of more than l year is unlikely to be infections are the most common presenting manifestation, caused by infection or malignancy. particularly with encapsulated bacteria (see Table 35). Anti-lgA IgE antibodies can rarely cause anaphylaxis to blood products; however, transfusions can be given with close lmmunodeficiency monitoring. XEY POI lII Syndromes o Patients with selective IgA deficiency may be asympto- lntroduction matic, present with sinopulmonary or gastrointestinal tract infections, or rarely experience anaphylaxis to Primary immunodeficiency disorders often present during blood products. childhood, but milder heritable forms may not manifest until adulthood. Primary immunodeficiency should be considered when patients have frequent infections or infections with Common Variable I mmu nodeficiency unusual organisms. The specific microbiologr is often a clue to Common variable immunodeficiency (CVID) is a heterogene- which arm of the immune system is affected (Table 35). ous syndrome associated with decreased quantitative

lmmunodeficiency monitoring. XEY POI lII Syndromes o Patients with selective IgA deficiency may be asympto- lntroduction matic, present with sinopulmonary or gastrointestinal tract infections, or rarely experience anaphylaxis to Primary immunodeficiency disorders often present during blood products. childhood, but milder heritable forms may not manifest until adulthood. Primary immunodeficiency should be considered when patients have frequent infections or infections with Common Variable I mmu nodeficiency unusual organisms. The specific microbiologr is often a clue to Common variable immunodeficiency (CVID) is a heterogene- which arm of the immune system is affected (Table 35). ous syndrome associated with decreased quantitative TABLE 35. Properties of Selected Primary lmmunodeficiency Disorders Common lnfections and Diagnostic Testing Treatment Pathogens Selective lgA deficiency Si nopu I mona ry i nfections: lgA level <7 mg/dL(0.07 g/L)with Vaccination against S. pneumoniae Streptococc u s p ne u m o n i a e normal lgG and lgM levels Live vaccines are contraindicated H ae m o ph i u s i nfl u e nzae I

TABLE 35. Properties of Selected Primary lmmunodeficiency Disorders Common lnfections and Diagnostic Testing Treatment Pathogens Selective lgA deficiency Si nopu I mona ry i nfections: lgA level <7 mg/dL(0.07 g/L)with Vaccination against S. pneumoniae Streptococc u s p ne u m o n i a e normal lgG and lgM levels Live vaccines are contraindicated H ae m o ph i u s i nfl u e nzae I Diarrhea/malabsorption : Giardia lamblia Common variable Sinopul monary i nfections: lgG level and either lgA or lgM <2 lmmune globulin replacement immunodeficiency S. pneumoniae standard deviations below the therapy H. influenzae mean PLUS impaired humoral lmmunization with inactivated Mycoplasma pneumoniae response to vaccination. Genetic vaccines testing may be used when Respiratory viruses antibody testing is nondiagnostic. Prophylactic antibiotics are not Diarrhea: routinely indicated Norovirus Campylobacter G.lamblia Urethritis: Mycoplasma Ureaplasma Complement deficiency Early components (C2-C4): Decreased level of total hemolytic Same as CVID for C2-C4 Similarto CVID complement (CHso) com plement deficiency ( may receive live vaccine) Late components (C5-C9): Low or undetectable level of CH56 Recurrent infections with or alternative pathway (AHso) Quadrivalent meningococca I

Diarrhea/malabsorption : Giardia lamblia Common variable Sinopul monary i nfections: lgG level and either lgA or lgM <2 lmmune globulin replacement immunodeficiency S. pneumoniae standard deviations below the therapy H. influenzae mean PLUS impaired humoral lmmunization with inactivated Mycoplasma pneumoniae response to vaccination. Genetic vaccines testing may be used when Respiratory viruses antibody testing is nondiagnostic. Prophylactic antibiotics are not Diarrhea: routinely indicated Norovirus Campylobacter G.lamblia Urethritis: Mycoplasma Ureaplasma Complement deficiency Early components (C2-C4): Decreased level of total hemolytic Same as CVID for C2-C4 Similarto CVID complement (CHso) com plement deficiency ( may receive live vaccine) Late components (C5-C9): Low or undetectable level of CH56 Recurrent infections with or alternative pathway (AHso) Quadrivalent meningococca I Neisseria gonorrhoeae or (factor B, factor D, or properdin) conjugate and serogroup B Neisseria me ningitidis meningococcal vaccines for C5-C9 complement deficiency or properdin deficiency

Neisseria gonorrhoeae or (factor B, factor D, or properdin) conjugate and serogroup B Neisseria me ningitidis meningococcal vaccines for C5-C9 complement deficiency or properdin deficiency CVID = common variable immunodeficiency 55

lmmunodeficiency Synd romes immunoglobulin levels and impaired humoral response to Abnormalities in the Complement System antigens. The humoral response can be tested by measuring Infections and other antigenic stimuli trigger an inflamma- specific antibody production before and after immunization tory reaction through the classical, alternative, or lectin path- with tetanus and pneumococcal polysaccharide vaccines. way of the complement cascade system. The result is forma- Diagnosis is usually delayed until adolescence or adulthood, tion of the membrane attack complex, which adheres to although a history of recurrent infection throughout child microbial pathogens to facilitate immune detection and hood may often be elicited. destruction. C\rlD increases risk of upper and lower respiratory tract infec- Complement deficiencies can be divided into deficien- tions caused by encapsulated bacteria, Mycoplasmo species, and cies in early or activating components (C2, C3, C4) and late respiratory viruses. Gastrointestinal infections typically present or terminal components (CS-C9). Early component defi- with acute diarrhea caused by common enteropathogenic viruses ciency, especially C4, is associated with increased rates of or bacteria. Chronic diarrhea with malabsorption suggests giardia- systemic lupus erythematosus and increased risk of infec- sis or chronic norovirus infection, an increasingly recognized path- tion with encapsulated organisms. Patients with early com- ogen in this population. Additionally, patients with CVID are at plement deficiency present similarly to patients with CVID, increased risk of autoimmune disease, inflammatory bowel dis- with recurrent sinopulmonary infections. Terminal comple- ease, granulomatous disease (noncaseating granulomas in the ment protein defects lead to an inability to form the mem- lymphoid or solid organs), bronchiectasis, and malignanry. brane attack complex and typically present with recurrent Pooled immune globulin replacement therapy is per- infections of Neisserio species, particularly meningococcal formed through intravenous infusions or subcutaneous injec- meningitis. lf. meningitidis infection in this population tions. Passive replacement is associated with lower rates of tends to be less severe than in immunocompetent persons, infections and hospitalizations. Immunization is only partially perhaps owing to uncommon serogroups. A personal or effective because of impaired vaccination response; live vac- family history of recurrent l{eisserio infections is an indica- cines should be avoided. Prophylactic antibiotics are not typi- tion to test the total hemolytic complement (CHro) level cally indicated because they can predispose patients to because any defect in the classical complement pathway will infection with more resistant organisms. result in a low total level. XEY POIilTS I(EY POI ilTS o Patients with common variable immunodeficiency can . Early component complement deficiency is associated experience recurrent infections and are at increased with an increased rate of systemic lupus erythematosus risk of noninfectious complications, including autoim- and risk of infection with encapsulated organisms; mune disease, inflammatory bowel disease, granuloma- terminal complement defects can result in recurrent tous disease, bronchiectasis, and malignancy. Neisserio infections. . Live vaccines should be avoided in persons with com- o Any defect in the classical complement pathway will mon variable immunodefi ciency. result in low total hemolytic complement (CHro) level.

immunoglobulin levels and impaired humoral response to Abnormalities in the Complement System antigens. The humoral response can be tested by measuring Infections and other antigenic stimuli trigger an inflamma- specific antibody production before and after immunization tory reaction through the classical, alternative, or lectin path- with tetanus and pneumococcal polysaccharide vaccines. way of the complement cascade system. The result is forma- Diagnosis is usually delayed until adolescence or adulthood, tion of the membrane attack complex, which adheres to although a history of recurrent infection throughout child microbial pathogens to facilitate immune detection and hood may often be elicited. destruction. C\rlD increases risk of upper and lower respiratory tract infec- Complement deficiencies can be divided into deficien- tions caused by encapsulated bacteria, Mycoplasmo species, and cies in early or activating components (C2, C3, C4) and late respiratory viruses. Gastrointestinal infections typically present or terminal components (CS-C9). Early component defi- with acute diarrhea caused by common enteropathogenic viruses ciency, especially C4, is associated with increased rates of or bacteria. Chronic diarrhea with malabsorption suggests giardia- systemic lupus erythematosus and increased risk of infec- sis or chronic norovirus infection, an increasingly recognized path- tion with encapsulated organisms. Patients with early com- ogen in this population. Additionally, patients with CVID are at plement deficiency present similarly to patients with CVID, increased risk of autoimmune disease, inflammatory bowel dis- with recurrent sinopulmonary infections. Terminal comple- ease, granulomatous disease (noncaseating granulomas in the ment protein defects lead to an inability to form the mem- lymphoid or solid organs), bronchiectasis, and malignanry. brane attack complex and typically present with recurrent Pooled immune globulin replacement therapy is per- infections of Neisserio species, particularly meningococcal formed through intravenous infusions or subcutaneous injec- meningitis. lf. meningitidis infection in this population tions. Passive replacement is associated with lower rates of tends to be less severe than in immunocompetent persons, infections and hospitalizations. Immunization is only partially perhaps owing to uncommon serogroups. A personal or effective because of impaired vaccination response; live vac- family history of recurrent l{eisserio infections is an indica- cines should be avoided. Prophylactic antibiotics are not typi- tion to test the total hemolytic complement (CHro) level cally indicated because they can predispose patients to because any defect in the classical complement pathway will infection with more resistant organisms. result in a low total level. XEY POIilTS I(EY POI ilTS o Patients with common variable immunodeficiency can . Early component complement deficiency is associated experience recurrent infections and are at increased with an increased rate of systemic lupus erythematosus risk of noninfectious complications, including autoim- and risk of infection with encapsulated organisms; mune disease, inflammatory bowel disease, granuloma- terminal complement defects can result in recurrent tous disease, bronchiectasis, and malignancy. Neisserio infections. . Live vaccines should be avoided in persons with com- o Any defect in the classical complement pathway will mon variable immunodefi ciency. result in low total hemolytic complement (CHro) level. TABLE 36. Select Medications Causing Secondary lmmunodeficiency Disorders and Preventive Measures" Medication lndication Pathogens Prevention or Management Tumor necrosis lnflammatory bowel Mycobacterial, fungal Screen for hepatitis B and C viruses before factor-cr disease, inflammatory (H i stop I a s m a, Co cci d i oi d e s), initiation; screen for tuberculosis before initiation inhibitors arthritis, psoriasis reactivation of hepatitis B and if a tuberculosis exposure occurs Natalizumab Multiple sclerosis, JC virus Screen for seropositivity at baseline, with repeat Crohn disease testing and brain MRI based on serostatus Eculizumabb Hemolytic uremic Neisseria meni ngitid is lmmunization with quadrivalent and serogroup B syndrome, paroxysmal meni ngococcal vaccines 2 weeks before i nitiation, nocturnal prophylactic penicil lin hemoglobinuria Rituximab B-cell malignancies, JC virus, reactivation of chronic Screen for hepatitis B with treatment of antigen- autoimmune diseases hepatitis B, cytomega lovi rus positive patients and consideration of treatmentfor previously infected a ntigen-negative patients Glucocorticoids Multiple uses Hepatitis B, herpes zoster, Pneumocystis prophylaxis for patients with >1 month Stro n gyl oi des ( reactivatio n ); of glucocorticoid use at dose equivalent to >20 mg Pn eu m o cysti s j i roveci i of prednisone "MKSAP 19 Rheumatology includes further information on some medications mentioned in this table. bTerminal complement inhibitor, conferring up to a 2O0O-fold increased risk of meningococcal disease.

TABLE 36. Select Medications Causing Secondary lmmunodeficiency Disorders and Preventive Measures" Medication lndication Pathogens Prevention or Management Tumor necrosis lnflammatory bowel Mycobacterial, fungal Screen for hepatitis B and C viruses before factor-cr disease, inflammatory (H i stop I a s m a, Co cci d i oi d e s), initiation; screen for tuberculosis before initiation inhibitors arthritis, psoriasis reactivation of hepatitis B and if a tuberculosis exposure occurs Natalizumab Multiple sclerosis, JC virus Screen for seropositivity at baseline, with repeat Crohn disease testing and brain MRI based on serostatus Eculizumabb Hemolytic uremic Neisseria meni ngitid is lmmunization with quadrivalent and serogroup B syndrome, paroxysmal meni ngococcal vaccines 2 weeks before i nitiation, nocturnal prophylactic penicil lin hemoglobinuria Rituximab B-cell malignancies, JC virus, reactivation of chronic Screen for hepatitis B with treatment of antigen- autoimmune diseases hepatitis B, cytomega lovi rus positive patients and consideration of treatmentfor previously infected a ntigen-negative patients Glucocorticoids Multiple uses Hepatitis B, herpes zoster, Pneumocystis prophylaxis for patients with >1 month Stro n gyl oi des ( reactivatio n ); of glucocorticoid use at dose equivalent to >20 mg Pn eu m o cysti s j i roveci i of prednisone "MKSAP 19 Rheumatology includes further information on some medications mentioned in this table. bTerminal complement inhibitor, conferring up to a 2O0O-fold increased risk of meningococcal disease. 56