Article on how contagious various respiratory infections actually are (NEJM 2003;348(13):1256)
clostridium makes toxin which lyses wbcs so no polys will be seen on the gram stain
Guidelines for Interpretation of Positive Blood Cultures
Some clinical and laboratory tools can aid physicians and microbiologists in deciding whether a blood isolate is a
pathogen or a contaminant. Obviously, the presence of predisposing factors and a consistent clinical presentation
can help clinicians interpret test results. The identity of the microorganism also provides important information
Table), and a predictive model has confirmed this.(16) Microorganisms that always or nearly always (greater than
or equal to 90%) represent true infection when isolated from blood cultures include S. aureus, S. pyogenes, S.
agalactiae, S. pneumoniae, E. coli and other members of the family Enterobacteriaceae, P. aeruginosa, B. fragilis
group, and Candida species. In contrast, coagulase-negative staphylococci (CoNS), Corynebacterium species,
Bacillus species other than anthracis, and P. acnes usually represent contamination. Isolation of the latter
microorganisms, mostly commonly with CoNS but also with corynebacteria (as in the case presented here), may
confuse clinicians. Corynebacterium species are part of the normal human skin flora, so they typically do not cause
true invasive disease. But Corynebacterium can cause clinically significant infections in the presence of medical
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devices such as joint prostheses, catheters, ports, vascular grafts, prosthetic heart valves, pacemakers, and AICDs
(as in this case).
The number of blood culture sets that grow a particular microorganism, especially when measured as a function of
the total number of blood cultures obtained, has proved to be a very useful aid in interpreting the clinical
significance of positive blood cultures (
Figure).(2,17,18) In true endovascular (within the blood vessels) infections
and other blood stream infections (BSIs), either all or most of the blood cultures obtained at the time of diagnosis
will be positive, whereas when a blood culture is contaminated, usually only one of several blood culture sets will
be positive. As the
Figure illustrates and this statement implies, this diagnostic maxim has no utility if only a single
blood culture is obtained. The value of multiple cultures largely flows from probability considerations: Most
institutions have contamination rates in the range of 3% per blood culture drawn. It follows, then, that the
probability of recovering the same microorganism in 2 culture sets from a patient, and of that organism being a
contaminant, is less than 1 in 1000 (0.03 x 0.03 = 0.0009). The clinician can be quite confident, then, that 2 out of
2 blood cultures positive with the same pathogen, even one that is commonly a contaminant, represents real
disease, assuming that the 2 blood cultures were obtained from separate venipunctures or catheter draws.
We cannot eliminate blood culture contamination entirely, but it is possible for institutions to reduce contamination
rates. One step is to use more efficacious antiseptic preparations. Povidone iodine preparations (iodophors) require
1.5 to 2 minutes of contact time to produce maximum antiseptic effect, whereas iodine tincture and chlorhexidine
gluconate only require 30 seconds.(
5,19) Many HCWs who obtain blood cultures are in a hurry, do not understand
the importance of antiseptic contact time, and are unlikely to wait up to 2 minutes before obtaining blood for
culture. Although the evidence-base has limitations,(
20) the Clinical and Laboratory Standards Institute, a
consensus organization that publishes guidelines based on best available data, recommends tincture of iodine,
chlorine peroxide, and chlorhexidine gluconate over povidone-iodine and further states that iodine tincture and
chlorhexidine gluconate are probably equivalent.(
11) Malani and colleagues (20) identified a possible benefit
related to the use of commercially marketed prepackaged skin antiseptic kits. However, available data are limited,
and I believe that no firm recommendations regarding these prepackaged kits can be made at this time.
Hospitals may also be able to reduce blood culture contamination rates by utilizing trained phlebotomists or blood
culture teams to obtain blood for culture rather than using random nursing personnel, nondegree nursing
assistants, medical students, and resident physicians to obtain these specimens.(
phlebotomists and blood culture teams can be better trained and focused on correct antiseptic technique.
Additionally, their individual contamination rates can be monitored as part of an institution’s performance
Because approximately half of all positive blood cultures in most institutions represent contamination, laboratories
should develop policies and procedures to limit the evaluation of likely contaminants.(
1,5,22) For example, if only
a single blood culture grows a coagulase-negative staphylococcus, Bacillus spp., Corynebacterium spp.,
Propionibacterium spp., viridans group streptococcus, Micrococcus spp., or Aerococcus spp., the likelihood of
contamination is high, and full identification of the microorganism as well as susceptibility testing should not be
done unless there is direct communication between the physician caring for the patient and the laboratory
Regarding the case history presented herein, a few issues are worth emphasizing. Microorganisms that are most
often contaminants can, in the right clinical setting, be clinically significant pathogens. The initial management of
this patientdeeming the initial positive blood cultures to be significantwas reasonable in my judgment. When
both the imaging studies and repeat blood cultures prior to antibiotics were negative, treatment was stopped and
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4 of 7 1/25/2008 5:46 PM
the patient was observed. However, 1 month later, the patient again had 2 of 2 blood cultures positive for
Corynebacterium spp. No action was taken by the covering physician, even though the probability of contamination
was less than 1 in 1000. I believe that this represented an interpretation error. Apparently, the PCP was not made
aware of this event (a communication error), and no medical intervention occurred, leading to delayed diagnosis
and treatment of the patient. Fortunately, the patient suffered no permanent harm, but patient morbidity and cost
to the health care system could have been prevented had these errors not occurred.
Blood culture contamination is common, constituting up to half of all positive blood cultures at some
The identity of the organism isolated can help in determining if the culture is contaminated, as some
organisms rarely cause BSIs.
The number of blood cultures that yield a particular organism can help predict true infections. For example,
if 2 sets of blood cultures obtained by separate venipunctures in the same time frame are positive with the
same organism, the probability of contamination is less than 1 in 1000.
Institutions can reduce blood culture contamination by using the most effective antiseptic agents and
utilizing dedicated personal to draw blood cultures.
Melvin P. Weinstein, MD
Professor of Medicine and Pathology
Robert Wood Johnson Medical School
University of Medicine and Dentistry of New Jersey
Richter SS, Beekmann SE, Croco JL, et al. Minimizing the workup of blood culture contaminants: implementation
and evaluation of a laboratory-based algorithm. J Clin Microbiol. 2002;40:2437-2444.
[go to PubMed]
Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a
prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and
fungemia in adults. Clin Infect Dis. 1997;24:584-602.
[go to PubMed]
Bates DW, Goldman L, Lee TH. Contaminant blood cultures and resource utilization. The true consequences of
false-positive results. JAMA. 1991;265:365-369.
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Rupp ME, Archer GL. Coagulase-negative staphylococci: pathogens associated with medical progress. Clin Infect
[go to PubMed]
Weinstein MP. Blood culture contamination: persisting problems and partial progress. J Clin Microbiol.
[go to PubMed]
Weinbaum FI, Lavie S, Danek M, Sixsmith D, Heinrich GF, Mills SS. Doing it right the first time: quality
improvement and the contaminant blood culture. J Clin Microbiol. 1997;35:563-565.
[go to PubMed]
Surdulescu S, Utamsingh D, Shekar R. Phlebotomy teams reduce blood-culture contamination rate and save
money. Clin Perform Qual Health Care. 1998;6:60-62.
[go to PubMed]
Little JR, Murray PR, Traynor PS, Spitznagel E. A randomized trial of povidone-iodine compared with iodine
tincture for venipuncture site disinfection: effects on rates of blood culture contamination. Am J Med.
[go to PubMed]
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Mimoz O, Karim A, Mercat A, et al. Chlorhexidine compared with povidone-iodine as skin preparation before
blood culture: a randomized controlled trial. Ann Intern Med. 1999;131:834-837.
[go to PubMed]
Strand CL, Wajsbort RR, Sturmann K. Effect of iodophor vs. iodine tincture skin preparation on blood culture
contamination rate. JAMA. 1993;269:1004-1006.
[go to PubMed]
Wilson ML, Mitchell M, Morris AJ, et al. Principles and Procedures for Blood Cultures; Approved Guideline.
Wayne, PA: Clinical and Laboratory Standards Institute; 2007. ISBN: 1562386417.
Bryant JK, Strand CL. Reliability of blood cultures collected from intravascular catheter versus venipuncture.
Am J Clin Pathol. 1987;88:113-116.
[go to PubMed]
DesJardin JA, Falagas MA, Ruthazer R, et al. Clinical utility of blood cultures drawn from indwelling central
venous catheters in hospitalized patients with cancer. Ann Intern Med. 1999;131:641-647.
[go to PubMed]
Everts RJ, Vinson EN, Adholla PO, Reller LB. Contamination of catheter-drawn blood cultures. J Clin Microbiol.
[go to PubMed]
Spitalnic SJ, Woolard RH, Mermel LA. The significance of changing needles when inoculating blood cultures: a
meta-analysis. Clin Infect Dis. 1995;21:1003-1006.
[go to PubMed]
Bates DW, Lee TH. Rapid classification of positive blood cultures. Prospective validation of a multivariate
algorithm. JAMA. 1992;267:1962-1966.
[go to PubMed]
MacGregor RR, Beaty HN. Evaluation of positive blood cultures. Guidelines for early differentiation of
contaminated from valid positive cultures. Arch Intern Med. 1972;130:84-87.
[go to PubMed]
Weinstein MP, Reller LB, Murphy JR, Lichtenstein KA. The clinical significance of positive blood cultures: a
comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and epidemiologic
observations. Rev Infect Dis. 1983;5:35-53.
[go to PubMed]
King TC, Price PB. An evaluation of iodophors as skin antiseptics. Surg Gynecol Obstet. 1963;116:361-365. [go
Malani A, Trimble K, Parekh V, Chenoweth C, Kaufman S, Saint S. Review of clinical trials of skin antiseptic
agents used to reduce blood culture contamination. Infect Control Hosp Epidemiol. 2007;28:892-895.
Schifman RB, Pindur A. The effect of skin disinfection materials on reducing blood culture contamination. Am J
Clin Pathol. 1993;99:536-538.
[go to PubMed]
Baron EJ, ed. Cumitech 1C: Blood Cultures IV. Washington, DC: ASM Press; 2005.
Table. Microorganisms Isolated from Blood Categorized According to Clinical Significance.
(Go to table citation in commentary)
Microorganism (No. of Isolates) No. (%) of Isolates per Indicated Category True Pathogen Contaminent Unknown Staphylococcus aureus (204) 178 (87.2) 13 (6.4) 13 (6.4) Coagulase-negative staphylococcus (703) 87 (12.4) 575 (81.9) 41 (5.8) Streptococcus pneumoniae (34) 34 (100) 0 0 Viridans streptococci (71) 27 (38.0) 35 (49.3) 9 (12.7) Other streptococci (31) 21 (67.7) 6 (19.4) 4 (12.9) Enterococcus spp. (93) 65 (69.9) 15 (16.1) 13 (14.0) Corynebacterium spp. (53) 1 (1.9) 51 (96.2) 1 (1.9) Bacillus spp. (12) 1 (8.3) 11 (91.7) 0 Escherichia coli (143) 142 (99.3) 0 1 (0.7) Klebsiella pneumoniae (65) 65 (100) 0 0 Other enteric gram-negative bacteria (108) 104 (96.3) 1 (0.9) 3 (2.8) Pseudomonas aeruginosa (55) 53 (96.4) 1 (1.8) 1 (1.8) Propionibacterium acnes (48) 0 48 (100) 0 Other Gram-positive anaerobes including Clostridium spp. (35) 19 (54.3) 15 (42.8) 1 (2.9) Bacteroides fragilis group (18) 16 (88.9) 0 2 (11.1) Other Gram-negative anaerobes (5) 2 (40) 2 (40) 1 (20) Candida spp. (60) 56 (93.3) 0 4 (6.7) Cryptococcus neoformans(8) 8 (100) 0 0 (Adapted with permission. Original table © 1997 by the University of Chicago. [Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24:584-602.])
(Go to figure citation in commentary)
Probably a myth that cultures must be collected at the time of actual fever spike (J. Clin. Microbiol. April 2008 vol. 46 no. 4 1381-1385)
Alcohol based washes are at least as effective as handwashing. Friction not important, just full coverage of all surfaces. Rub until it disappears. Fantastic review (Mayo Clin Proc 2004;79:109)
Intracranial, Sinusitis, Dental, Lungs, Endocarditis, Sub-Phrenic Abcess, Cholecystitis, Diverticulitis, Bladder, Prostatitis, Infected Prosthesis, Pressure Ulcers, Osteomyelitis, Appendicitis, Gallbladder
The combination of ongoing fever, nonspecific symptoms, and the presence of petechiae should at least raise the consideration of SBE.
Safe, though fairly useless
External cooling in fever (as opposed to hyperthermia) not helpful, and probably counterproductive due to cold pressor response. (Arch Intern Med 160, Feb 2000)
In the elderly, oral and tympanic miss fevers that rectal temps do not (J Emerg Med 2002;22(2):153-7)
West J Emerg Med 2011;12(4):505
- Largely arbitrary
- As an indicator of infection the lower the temperature defined as abnormal the higher the sensitivity but the lower the specificity
- As a general rule consider the possibility of infection in all ICU patients with temperature ³ 38.3° . NB. Infection without fever is not uncommon.
History and examination
- localizing complaints- ask the patient if possible. If not, look at notes.
- allergy to drugs
- duration of vascular cannulation
- sputum, wound drainage
- abdominal pain or tenderness
- skin: rash, vasculitis (ie palpable purpura)
- tender or inflammed IV site, ± purulence
- wound dressings should be taken down after 24 hours.
- legs for DVT, gout
- head and neck: fundi for candida, oral herpetic lesions. Think of sinusitis.
- lungs: auscultation may not be that useful, but a decrease in oxygenation, and CXR infiltrates may be more sensitive indicators of pneumonia, but not more specific.
- cardiac: may have a friction rub associated with Dresslers syndrome, or a murmur associated with endocarditis.
- abdominal findings may be unremarkable in the elderly and those who are sedated/unconscious.
- examination of the genitalia may reveal unsuspected epididymitis, prostatitis, prostatic abscess or perirectal abscess.
- urinalysis and culture and 2-3 sets of blood cultures
- sputum and gram stain
- except in neurosurgical patients , meningitis is an uncommon nosocomial infection
- joint fluid needs to be sampled if relevant. Look for crystals and gram stain and culture.
- ± ultrasound or CT or radionuclide studies
- in many cases the work-up will point towards a likely source and therefore the need or otherwise for antibiotics
- in the acutely ill patient it may be necessary to change, broaden, or stop antibiotics.
- negative cultures in a febrile patient who is clinically deteriorating may be a clue to fungal infection in high risk patient
Sites of infection
- The most common sites of infection in ICU patients are intravascular lines, chest, abdomen, wounds and urinary tract
- Other sites that need to considered include CNS and sinuses
See “Intravascular lines and infection”
See “Chest infection”
- Many febrile ICU patients have small pleural effusions. It is not necessary to perform a diagnostic tap in all these patients.
- A diagnostic tap is indicated if the effusion is big enough to allow safe aspiration and there is one of:
- a suspicion of TB
- possible contamination of pleural space by surgery, trauma or fistula
- adjacent pulmonary infiltration on CXR
“See intra-abdominal infections”
“See intra-abdominal infections”
Common site of nosocomial infection
For operations in which a body cavity is entered wound is divided into superficial and deep components. The terms superficial and deep refer to the relationship to the layer of fascial closure
- superficial infection: purulent drainage from incision or drain located above fascia
- deep: purulent drainage from deep compartment but not from organ-space or spontaneous dehiscence of wound
- ASA score of 3 or greater
- Contaminated or dirty operation. Contaminated = major break in asepsis, gross spill of GI contents, entry into hollow organ containing infected contents. Dirty = acute purulent inflammation found, traumatic wounds requiring surgical repair, faeces or devitalized tissue in field of operation
- Long procedure time. Definition of long procedure time depends on procedure that was performed.
- In clean surgical procedures in which the GI, gynaecological and respiratory tracts have not been entered the usual organism is S. aureus
- In all other situations polymicrobial mixed aerobic-anaerobic infection with organisms found in the normal flora of the surgically resected organ is common
- Examine wound for erythema, purulence or tenderness
- If infection is suspected wound should be opened
- Gram stain and cultures should be performed on any expressed pus or material obtained from deep within wound site
- Bacteriuria is common but is often not clinically significant
- If colony count is <104 cfu/ml or pyuria is absent in a non-neutropaenic patient with an indwelling catheter then it is unlikely that fever is due to urinary tract infection
- Likely organisms: gram negative bacilli, Strep. faecalis, yeasts
Central nervous system
See “Meningitis“, “Brain abscess“, “Subdural empyema”
- CNS infection rarely causes encephalopathy in absence of detectable focal abnormalities. However difficulty of carrying out a detailed neurological examination in ICU patients means that CNS infection must always be considered in febrile ICU patients.
- Imaging and culture of CSF are central to the investigation of possible CNS infection. CT prior to LP is required in patients with focal neurological findings suggesting disease above foramen magnum. If bacterial meningitis is suspected and LP is delayed empirical antibiotic therapy should be started after blood cultures are taken.
- Patients with suspected brain abscesses should not undergo LP because the bacteriological yield from CSF analysis in this setting is too low to justify the risk of herniation. Aspiration of the suspected abscess is the investigation of choice.
- Basic tests to be performed on CSF include cell counts, glucose and protein concentration, gram stain and bacterial cultures. Additional tests such as testing for cryptococcal antigen, stains and culture for fungi, acid-fast smears and cultures and PCR for bacteria and HSV may be indicated in certain settings.
- NB The upper limit of normal for protein concentration in CSF varies according to the site from which is was obtained: – ventricular fluid: 0.2 g/l cisternal fluid: 2.5 g/l lumbar fluid: 0.4 g/l
- Most common risk factor for sinusitis in ICU is obstruction of ostia draining sinuses by nasogastric or nasotracheal tube
- Relatively uncommon to document sinusitis as cause of fever with much certainty so investigation for sinusitis should only be undertaken after more likely causes have been excluded.
Infection is usually due to organisms that colonize the pharynx of critically ill patients. Gram negative bacilli constitute 60% of isolates. P. aeruoginosa is most common. S. aureus is most common gram positive. Fungi make up 5-10% of isolates
- Presence of two major criteria or one major and two minor criteria for >7 days suggests the presence of acute bacterial sinusitis. Major criteria are cough and purulent nasal discharge while minor criteria are: periorbital oedema, headache, facial pain, tooth ache, earache, sore throat, foul breath, wheezing or fever.
- In ICU patients many of these clinical features are difficult to elicit. Purulent nasal discharge is present in only 25% of ICU patients with proven sinusitis
- plain radiographs, ultrasonograms, CT scans, and MRI scans can be obtained to diagnose acute sinusitis.
- air fluid levels are sensitive for detecting sinusitis, but are not very specific.
- in practice need a CT scan to improve the diagnostic yield
- ultrasound is useful only as a screening tool as not very specific
- definitive diagnosis by sampling is mandatory and provides the optimal means for tailoring antibiotic therapy.
- disadvantages are that sampling is invasive and that samples are susceptible to contamination with normal nasal flora if rigorous technique is not used
- If clinical findings suggest sinusitis CT should be performed
- If findings are consistent then should do a puncture. Gram stain the puncture and culture for aerobic and anaerobic organisms as well as fungi to determine the causative pathogens
– the only common enteric cause of fever in the ICU is Clostridium difficile which should be suspected in any patient with fever and diarrhoea who has received antibiotics or chemotherapy within 3 weeks of the onset of the diarrhoea
Evaluation for other pathogens:
– those with risk factors ie
- HIV (salmonella, microsporidium, CMV, or perhaps MAIS.)
- Recent travel (E.coli, ova, parasites and cyclospora, E. histolytica, and S. stercoralis)
Suggested workup and treatment:
- Day 1: send one stool sample for C. difficile
- If the first sample is negative, send an additional sample
- If severe disease is present and rapid tests for C. difficile are negative or cant be performed, then consider performing flexible sigmoidoscopy
- If severe illness is present, consider empirical therapy, with metronidazole, while awaiting results of tests. Empirical therapy is generally not recommended if two samples are negative when a reliable assay has been used.
Stool cultures for other enteric pathogens are rarely indicated and should be done only if appropriate.
– fever is common is the first 48 hours postoperatively
– mostly non-infectious in origin
– after 96 hours likely to represent infection
- UTI common due to the use of catheters
- Wound infection: can develop 1-3 days after surgery
- Suppurative phlebitis
- Catheter related infection
- Aggressive chest physiotherapy
- Urine should be cultured if febrile for >72 hours
- Surgical wounds should be examined daily-culture only if looks infected or suspect
- Maintain a high level of suspicion for DVT, etc
Non-infectious causes of fever in the ICU
- drugs and drug withdrawal
- malignant hyperpyrexia, neuroleptic malignant syndrome
- blood products
- rapid killing of organisms eg Jarisch-Herxheimer reaction
- tumour lysis syndrome
- -cytokine related fever has occurred in association with infusion of IL-2, granulocyte-macrophage colony stimulating factor, and on occasion, G-CSF during the treatment of certain malignancy.
- deep vein thrombosis, pulmonary infarction
- myocardial infarction
- chronic/acute pancreatitis
- endocrine causes
- fat emboli
- organ transplant rejection
O’Grady, N.P., Barie, P.S., Bartlett, J.G., Bleck, T., Garvey, G., Jacobi, J., Linden, P., Maki, D.G., Nam, M., Pasculle, W., Pasquale, M.D., Tribett, D.L., and Masur, H. Practice guidelines for evaluating new fever in critically ill adult patients. Clinical Infectious Diseases 26:1042-1059, 1998
Approach to the Adult Patient with Fever of Unknown Origin
ALAN R. ROTH, D.O., and GINA M. BASELLO, D.O., Jamaica Hospital Medical Center, Mount Sinai School of Medicine Family Practice Residency Program, Jamaica, New York
Fever of unknown origin (FUO) in adults is defined as a temperature higher than 38.3°C (100.9°F) that lasts for more than three weeks with no obvious source despite appropriate investigation. The four categories of potential etiology of FUO are classic, nosocomial, immune deficient, and human immunodeficiency virusrelated. The four subgroups of the differential diagnosis of FUO are infections, malignancies, autoimmune conditions, and miscellaneous. A thorough history, physical examination, and standard laboratory testing remain the basis of the initial evaluation of the patient with FUO. Newer diagnostic modalities, including updated serology, viral cultures, computed tomography, and magnetic resonance imaging, have important roles in the assessment of these patients. (Am Fam Physician 2003;68:2223-8. Copyright© 2003 American Academy of Family Physicians.)
A PDF version of this document is available. Download PDF now (6 pages /83 KB). More information on using PDF files. See page 2113 for definitions of strength-of-evidence levels.
Adult patients frequently present to the physician’s office with a fever (temperature higher than 38.3°C [100.9°F]).1 Most febrile conditions are readily diagnosed on the basis of presenting symptoms and a problem-focused physical examination. Occasionally, simple testing such as a complete blood count or urine culture is required to make a definitive diagnosis. Viral illnesses (e.g., upper respiratory infections) account for most of these self-limiting cases and usually resolve within two weeks.2 When fever persists, a more extensive diagnostic investigation should be conducted. Although some persistent fevers are manifestations of serious illnesses, most can be readily diagnosed and treated.
Definitions and Classifications
The definition of fever of unknown origin (FUO), as based on a case series of 100 patients,3 calls for a temperature higher than 38.3°C on several occasions; a fever lasting more than three weeks; and a failure to reach a diagnosis despite one week of inpatient investigation. This strict definition prevents common and self-limiting medical conditions from being included as FUO. Some experts have argued for a more comprehensive definition of FUO that takes into account medical advances and changes in disease states, such as the emergence of human immunodeficiency virus (HIV) infection and an increasing number of patients with neutropenia. Others contend that altering the definition would not benefit the evaluation and care of patients with FUO.4
The four categories of potential etiology of FUO are centered on patient subtype–classic, nosocomial, immune deficient, and HIV-associated. Each group has a unique differential diagnosis based on characteristics and vulnerabilities and, therefore, a different process of evaluation (Table 1).5
TABLE 1 Classification of Fever of Unknown Origin (FUO)
Category of FUO
Classic Temperature >38.3°C (100.9°F) Duration of >3 weeks Evaluation of at least 3 outpatient visits or 3 days in hospital Infection, malignancy, collagen vascular disease Nosocomial Temperature >38.3°C Patient hospitalized >=24 hours but no fever or incubating on admission Evaluation of at least 3 days Clostridium difficile enterocolitis, drug-induced, pulmonary embolism, septic thrombophlebitis, sinusitis Immune deficient (neutropenic) Temperature >38.3°C Neutrophil count <=500 per mm3 Evaluation of at least 3 days Opportunistic bacterial infections, aspergillosis, candidiasis, herpes virus HIV-associated Temperature >38.3°C Duration of >4 weeks for outpatients, >3 days for inpatients HIV infection confirmed Cytomegalovirus, Mycobacterium avium-intracellulare complex, Pneumocystis carinii pneumonia, drug-induced, Kaposi’s sarcoma, lymphoma
HIV = human immunodeficiency virus.Adapted with permission from Durack DT, Street AC. Fever of unknown origin–reexamined and redefined. Curr Clin Top Infect Dis 1991;11:37
The classic category includes patients who meet the original criteria of FUO, with a new emphasis on the ambulatory evaluation of these previously healthy patients.6 The revised criteria require an evaluation of at least three days in the hospital, three outpatient visits, or one week of logical and intensive outpatient testing without clarification of the fever’s cause.5 The most common causes of classic FUO are infection, malignancy, and collagen vascular disease.
Nosocomial FUO is defined as fever occurring on several occasions in a patient who has been hospitalized for at least 24 hours and has not manifested an obvious source of infection that could have been present before admission. A minimum of three days of evaluation without establishing the cause of fever is required to make this diagnosis.5 Conditions causing nosocomial FUO include septic thrombophlebitis, pulmonary embolism, Clostridium difficile enterocolitis, and drug-induced fever. In patients with nasogastric or nasotracheal tubes, sinusitis also may be a cause.7,8
Immune-deficient FUO, also known as neutropenic FUO, is defined as recurrent fever in a patient whose neutrophil count is 500 per mm3 or less and who has been assessed for three days without establishing an etiology for the fever.5 In most of these cases, the fever is caused by opportunistic bacterial infections. These patients are usually treated with broad-spectrum antibiotics to cover the most likely pathogens. Occult infections caused by fungi, such as hepatosplenic candidiasis and aspergillosis, must be considered.9 Less commonly, herpes simplex virus may be the inciting organism, but this infection tends to present with characteristic skin findings.
HIV-associated FUO is defined as recurrent fevers over a four-week period in an outpatient or for three days in a hospitalized patient with HIV infection.5 Although acute HIV infection remains an important cause of classic FUO, the virus also makes patients susceptible to opportunistic infections. The differential diagnosis of FUO in patients who are HIV positive includes infectious etiologies such as Mycobacterium avium-intracellulare complex, Pneumocystis carinii pneumonia, and cytomegalovirus. Geographic considerations are especially important in determining the etiology of FUO in patients with HIV. For example, a patient with HIV who lives in the southwest United States is more susceptible to coccidioidomycosis. In patients with HIV infection, noninfectious causes of FUO are less common and include lymphomas, Kaposi’s sarcoma, and drug-induced fever.9,10
The differential diagnosis of FUO generally is broken into four major subgroups: infections, malignancies, autoimmune conditions, and miscellaneous (Table 2). Several factors may limit the applicability of research literature on FUO to everyday medical practice. These factors include the geographic location of cases, the type of institution reporting results (e.g., community hospital, university hospital, ambulatory clinic), and the specific subpopulations of patients with FUO who were studied. Despite these limiting factors, infection remains the most common cause of FUO in study reports.3,11,12
TABLE 2Common Etiologies of Fever of Unknown Origin
Infections Tuberculosis (especially extrapulmonary) Abdominal abscesses Pelvic abscesses Dental abscesses Endocarditis Osteomyelitis Sinusitis Cytomegalovirus Epstein-Barr virus Human immunodeficiency virus Lyme disease Prostatitis Sinusitis
Malignancies Chronic leukemia Lymphoma Metastatic cancers Renal cell carcinoma Colon carcinoma Hepatoma Myelodysplastic syndromes Pancreatic carcinoma Sarcomas
Autoimmune conditions Adult Still’s disease Polymyalgia rheumatica Temporal arteritis Rheumatoid arthritis Rheumatoid fever Inflammatory bowel disease Reiter’s syndrome Systemic lupus erythematosus Vasculitides
Miscellaneous Drug-induced fever Complications from cirrhosis Factitious fever Hepatitis (alcoholic, granulomatous, or lupoid) Deep venous thrombosis Sarcoidosis
Of the many infectious diseases that are associated with FUO, tuberculosis (especially in extrapulmonary sites) and abdominal or pelvic abscesses are the most common.13 Intra-abdominal abscesses are associated with perforated hollow viscera (as occurs in appendicitis), diverticulitis, malignancy, and trauma. Other common infections that should be considered as the source of FUO include subacute bacterial endocarditis, sinusitis, osteomyelitis, and dental abscess.11,13 As the duration of fever increases, the likelihood of an infectious etiology decreases. Malignancy and factitious fever are more common diagnostic considerations in patients with prolonged FUO.14
Because of a substantial increase in the elderly population, as well as advances in the diagnosis and treatment of diseases common in this population, malignancy has become a common etiologic consideration in elderly patients. Malignancies that sometimes are difficult to diagnose, such as chronic leukemias, lymphomas, renal cell carcinomas, and metastatic cancers, often are found in patients with FUO.12
Rheumatoid arthritis and rheumatic fever are inflammatory diseases that used to be commonly associated with FUO, but with advances in serologic testing, these conditions usually are diagnosed more promptly. At this time, adult Still’s disease and temporal arteritis have become the most common autoimmune sources of FUO because they remain difficult to diagnose even with the help of laboratory testing.
Multisystem inflammatory diseases such as temporal arteritis and polymyalgia rheumatica have emerged as the autoimmune conditions most frequently associated with FUO in patients older than 65 years.15 Elderly patients who present with symptoms consistent with temporal arteritis associated with an elevation of the erythrocyte sedimentation rate should be referred for temporal artery biopsy.16
TABLE 3Agents Commonly Associated with Drug-Induced Fever
Allopurinol (Zyloprim) Captopril (Capoten) Cimetidine (Tagamet) Clofibrate (Atromid-S) Erythromycin Heparin Hydralazine (Apresoline) Hydrochlorothiazide (Esidrix) Isoniazid Meperidine (Demerol) Methyldopa (Aldomet) Nifedipine (Procardia) Nitrofurantoin (Furadantin) Penicillin Phenytoin (Dilantin) Procainamide (Pronestyl) Quinidine
Complications from cirrhosis and hepatitis (alcoholic, granulomatous, or lupoid) are also potential causes of FUO.12,13 Deep venous thrombosis, although a rare cause of FUO, must be considered in relevant patients, and venous Doppler studies should be obtained.17 Factitious fever has been associated with patients who have some medical training or experience and a fever persisting longer than six months.18 Failure to reach a definitive diagnosis in patients presenting with FUO is not uncommon; 20 percent of cases remain undiagnosed. Even if an extensive investigation does not identify a cause for FUO, these patients generally have a favorable outcome.19
Evaluation of the Patient with FUO
The initial approach to the patient presenting with fever should include a comprehensive history, physical examination, and appropriate laboratory testing. As the underlying process develops, the history and physical assessment should be repeated. The first step should be to confirm a history of fever and document the fever pattern. Classic fever patterns such as intermittent, relapsing sustained, and temperature-pulse disparity may prove to be useful but rarely are diagnostic.20
In taking a history from a patient with FUO, particular attention should be given to recent travel, exposure to pets and other animals, the work environment, and recent contact with persons exhibiting similar symptoms. In patients returning from areas where tuberculosis and malaria are common, the index of suspicion for these diseases should be elevated. In patients who have had contact with pets or other animals, diseases common to animal handlers must be suspected.
The family history should be carefully scrutinized for hereditary causes of fever, such as familial Mediterranean fever. The medical history also must be examined for conditions such as lymphoma, rheumatic fever, or a previous abdominal disorder (e.g., inflammatory bowel disease), the reactivation of which might account for the fever. Finally, drug-induced fever must be considered in patients who are taking medications.19
Diagnostic clues often are not readily apparent on physical examination; repeated examination may be essential. Careful attention to the skin, mucous membranes, and lymphatic system, as well as abdominal palpation for masses or organomegaly, is important. The physician’s choice of imaging should be guided by findings from a thorough history and physical examination21 (e.g., a cardiac murmur in the presence of negative blood cultures should be investigated with a transthoracic echocardiogram or, if needed, transesophageal echocardiogram) rather than strictly following the stepwise approach outlined in Figure 1. Also, Duke’s clinical criteria include two major and six minor criteria that help determine the likelihood of endocarditis.22 [Evidence level A, validated clinical decision tool] A cost-effective individualized approach is essential to the evaluation of these patients, and without a thoughtful and focused investigation, inappropriate tests might be performed.
Diagnosis of Fever of Unknown Origin FIGURE 1. Algorithm for the diagnosis of fever of unknown origin. (CBC = complete blood count; LFT = liver function test; ESR = erythrocyte sedimentation rate; PPD = purified protein derivative; CT = computed tomography; AFB = acid-fast bacilli; HIV = human immunodeficiency virus; CMV = cytomegalovirus; EBV = Epstein-Barr virus; ASO = antistreptolysin-O antibodies; ANA = antinuclear antibody; TTE = transthoracic echocardiography; TEE = transesophageal echocardiography; MRI = magnetic resonance imaging)
The preliminary evaluation helps in the formulation of a differential diagnosis and guides further studies that are more invasive or expensive. These preliminary investigations should include a complete blood count, liver function test, erythrocyte sedimentation rate, urinalysis, and basic cultures. Simple clues found during initial testing often will guide the clinician toward one of the major subgroups of FUO. The decision to obtain further diagnostic studies should be based on abnormalities found in the initial laboratory work-up and not represent a haphazard use of costly or invasive modalities.
TABLE 4Diagnostic Imaging in Patients with FUO
Chest radiograph Tuberculosis, malignancy, Pneumocystis carinii pneumonia CT of abdomen or pelvis with contrast agent Abscess, malignancy Gallium 67 scan Infection, malignancy Indium-labeled leukocytes Occult septicemia Technetium Tc 99m Acute infection and inflammation of bones and soft tissue MRI of brain Malignancy, autoimmune conditions PET scan Malignancy, inflammation Transthoracic or transesophageal echocardiography Bacterial endocarditis Venous Doppler study Venous thrombosis FUO = fever of unknown origin; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography.
Skin testing for tuberculosis with purified protein derivative (PPD) is an inexpensive screening tool that should be used in all patients with FUO who do not have a known positive PPD reaction. However, a positive PPD reaction alone does not prove the presence of active tuberculosis. A chest radiograph also should be obtained in all patients to screen for possible infection, collagen vascular disease, or malignancy. If this initial assessment does not disclose the source of fever, more specific investigatory techniques, such as serology, sonography, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine scanning should be conducted, based on clinical suspicion.
Abdominal sonography, pelvic sonography, or CT scanning should be performed early in the diagnostic process to rule out such common causes of FUO as intra-abdominal abscess or malignancy, depending on the primary evaluation.17 This testing, including directed biopsies, has greatly reduced the need for more invasive operative studies.23
MRI should be reserved for clarifying conditions found through the use of other techniques or when the diagnosis remains obscure. The use of radionucleotide scanning, such as gallium 67, technetium Tc 99m, or indium-labeled leukocytes, is warranted for detecting inflammatory conditions and neoplastic lesions that often are underdiagnosed by CT scans; however, these tests tend not to detect collagen vascular disease and other miscellaneous conditions24 (Table 4).
Endoscopic procedures may be helpful in the diagnosis of disorders such as inflammatory bowel disease and sarcoidosis. The newest diagnostic technique in the evaluation of the patient with FUO is positron emission tomography (PET). This modality appears to have a very high negative predictive value in ruling out inflammatory causes of fever. However, because of its limited availability it is too early to determine if PET scans will prove to be a useful diagnostic tool in the evaluation of these patients.25,26
More invasive testing, such as lumbar puncture or biopsy of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation. When the definitive diagnosis remains elusive and the complexity of the case increases, an infectious disease, rheumatology, or oncology consultation may be helpful.
The authors indicate that they do not have any conflicts of interests. Sources of funding: none reported.
ALAN R. ROTH, D.O., is chairman and program director of the Jamaica Hospital Medical Center, Mount Sinai School of Medicine Family Practice Residency Program, Jamaica, N.Y. He is also associate professor of community and preventive medicine at Mount Sinai School of Medicine. Dr. Roth received his medical degree from the New York College of Osteopathic Medicine, Old Westbury, N.Y., and completed a family medicine residency at the Jamaica Hospital Medical Center.
GINA M. BASELLO, D.O., is assistant director of the Jamaica Hospital Medical Center, Mount Sinai School of Medicine Family Practice Residency Program, and clinical instructor of community and preventive medicine at the Mount Sinai School of Medicine. She received her medical degree from the New York College of Osteopathic Medicine and completed a family medicine residency at Jamaica Hospital Medical Center.
Address correspondence to Alan R. Roth, D.O., Jamaica Hospital Medical Center, Family Practice Residency Program, 89-06 135th Street, Suite 3C, Jamaica, NY 11418 (e-mail: email@example.com) Reprints are not available from the authors.
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- Hughes WT, Armstrong D, Bodey GP, Feld R, Mandell GL, Meyers JD, et al. From the Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 1990;161:381-96.
- Armstrong WS, Katz JT, Kazanjian PH. Human immunodeficiency virusassociated fever of unknown origin: a study of 70 patients in the United States and review. Clin Infect Dis 1999;28:341-5.
- De Kleijn EM, Vandenbroucke JP, van der Meer JW. Fever of unknown origin (FUO). I. A prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group. Medicine [Baltimore] 1997;76:392-400.
- Knockaert DC, Vanneste LJ, Bobbaers HJ. Recurrent or episodic fever of unknown origin. Review of 45 cases and survey of the literature. Medicine [Baltimore] 1993;72:184-96.
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- Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc 1993;41:1187-92.
- Epperly TD, Moore KE, Harrover JD. Polymyalgia rheumatica and temporal arteritis. Am Fam Physician 2000;62:789-96.
- Mourad O, Palda V, Detsky A. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med 2003; 163:545-51.
- Mackowiak P, Durack D. Fever of unknown origin. In: Mandell GL, Douglas RG, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000:623-31.
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- Kupferwasser LI, Darius H, Muller AM, Martin C, Mohr-Kahaly S, Erbel R, et al. Diagnosis of culture-negative endocarditis: the role of the Duke criteria and the impact of transesophageal echocardiography. Am Heart J 2001;142:146-52.
- Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med 1994;96:200-9.
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- Suga K, Nakagi K, Kuramitsu T, Itou K, Tanaka N, Uchisato H, et al. The role of gallium-67 imaging in the detection of foci in recent cases of fever of unknown origin. Ann Nucl Med 1991;5:35-40.
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Guidelines for fever workup from ACCM 2008 (Crit Care Med 2008;36:1330)
MRSA colonization doesn’t predict that the infection is caused by MRSA (Crit Care Med 2010;38:1991)
Screening for resistant gram-negative microorganisms to guide empiric therapy of subsequent infection. Intensive Care Med (2008) ;34(12):21692175.
J. Clin. Microbiol. April 2008 vol. 46 no. 4 1381-1385
only appropriate for gram negative bacteremia. 1 dose will do you
a) Aminoglycosides have very good bacteriocidal activity and IF THE IS GM NEG BACTERAEMIA – they are a often the best choice
b) Used as second agent for gm neg cover (double gm neg etc) initially (“hit hard up front”)
c) One large dose is NOT nephrotoxic
d) Aminoglyocisdes don’t penetrate lung well at all, so really… unless there is bacteraemia – limited benefit.