Critical Care Medicine

Fever/Leukocytosis

Fever and Leukocytosis

Also known as: Fever: pyrexia, fever of unknown origin, pyrexia of unknown origin

Leukocytosis: elevated white blood cell count, granulocytosis, neutrophilia

Related Conditions: Fever: hyperthermia, post-operative fever, central fever

Leukocytosis: leukemoid reaction, bandemia, extreme leukocytosis

1. Description of the problem

What every clinician needs to know

Fever and leukocytosis are common findings in critically adult patients, both as presenting signs and symptoms on admission to an intensive care unit and as manifestations of one of the numerous complications that can evolve during the course of an intensive care unit stay. This discussion will focus on the assessment of new fever and/or leukocytosis in patients who present without these manifestations, and without an obvious explanation for these findings. However, the same considerations can be applied to patients admitted with fever and/or leukocytosis who have failed to respond to initial management and where the etiology of these findings remains in doubt.

Although fever and leukocytosis most often appear concurrently, each may present without the other. Some patient populations, such as the elderly and immunosuppressed patients, may have impaired febrile responses or even hypothermia rather than pyrexia as manifestations of some of the infectious and non-infectious processes discussed below. Severe or overwhelming infection can also present with hypothermia rather than fever. Fever is also not a useful marker in patients who are undergoing artificial body temperature manipulation such as those undergoing induced hypothermia protocols.

Patients with a variety of underlying acute and chronic illnesses may also not demonstrate the expected elevated leukocyte responses usually associated with infections and other inflammatory processes. Bone marrow dysfunction is a component of many chronic disease processes, and such patients may respond with left-shifted white blood cell counts with increase in bands and other immature forms without an elevation in total leukocyte count. Severe, overwhelming bacterial infections can also result in leukopenia with left-shifted cell counts, and leukopenia may be a specific hematologic manifestation of some atypical infections that might present as fever of unknown origin, such as vector-borne infections and viral processes.

The differential diagnosis of the possible explanations for new fever and leukocytosis in a critically ill patient is extremely broad, and the challenge for clinicians is to proceed with the evaluation in a timely but rational and cost-effective manner. Etiologies of fever can broadly be divided into infectious and non-infectious categories, and the likelihood of some of the processes in the differential diagnosis and the most appropriate sequence of studies in the workup may differ between general medical, post-surgical, neurologic and trauma patients in an intensive care unit.

New onset of fever and/or leukocytosis is an indication to initiate a careful clinical assessment of a patient. In some but not all instances, this may also be a trigger for additional laboratory and/or radiologic assessment as well as the possible initiation of empiric therapy, particularly antimicrobial therapy, pending results of the assessment. Decisions to initiate empiric therapy, especially for suspected nosocomial infections, will depend on the constellation of findings accompanying fever or leukocytosis as well as host-specific factors. New-onset hypothermia, defined as a temperature < 36.0 °C, in the absence of a clear explanation or environmental cause, should be considered equivalent to new onset of fever as an indication to initiate a clinical evaluation.

Definitions and methods for measurement of fever

Defining what exactly is a fever in critically ill patients is important, as this is the trigger for initiating further diagnostic evaluation for the cause of fever. A variety of definitions are used in the literature, and all have some limitations. The most commonly used definition is a core temperature of above 38.3 °C (101° F) either as a single value, as two consecutive readings, or sustained over an hour, in the absence of an obvious environmental cause. That temperature threshold may be lower in immunosuppressed or neutropenic patients and other patient cohorts who may not be able to manifest a febrile response. Since an elevated temperature should in fact be defined as a change above baseline core body temperature, elderly patients with lower basal body temperatures may in fact be febrile at temperatures of lower than 38.3 °C. Some studies of fever in the critically ill patient also include a category of "high fever" or "extreme fever" , usually defined as fever above 39.5 °C. There may be a higher association with both infection and mortality for patients with fevers in this range.

Some important patient groups who may fail to demonstrate a febrile response include those with end-stage liver or kidney disease and those on renal replacement therapy, patients with congestive heart failure, patients on ECMO, and patients with large burns or open abdomens. In these patients, even in the absence of fever, other unexplained clinical changes such as hypotension, tachycardia and tachypnea, new-onset rigors, and laboratory findings such as changes in white blood cell count or new lactic acidosis should trigger the need for clinical assessment and evaluation for infection as would a new fever.

The most accurate devices for measuring core temperature in critically ill patients are considered to be pulmonary artery thermistors, though this is not applicable in all patients. Other measuring devices that should closely reflect core temperatures include urinary catheter thermistors, esophageal probes and rectal probes. Oral probes and infrared ear thermometers are also acceptable, but correlate less well with true core body temperatures. Although core temperatures are considered the most useful indicator of body temperature, core temperatures may be lower than brain temperatures by as much as one to two degrees, and this difference may be important in patients with recent neurologic events.

Definition of Leukocytosis

Leukocytosis is generally defined as elevation of total WBC above 11,000 cells/μl. Usually this is due to an elevation of total neutrophils. This increase can be manifested as just an increase in mature neutrophils, or the white blood cell count can be "left shifted" with an increase in bands and other immature forms. Leukemoid reactions are defined as WBC counts over 50,000 cells/μl in the absence of leukemia or other primary hematologic disorders. Another term that is sometimes used to describe elevated WBC counts is "extreme leukocytosis," which is variously defined as total WBC counts of over 25,000 cells/μl or neutrophil counts, including mature and immature forms, of over 25,000 cells/μl. Leukocytosis is considered a trigger for evaluation for possible infection or other causes of the elevated white count, but the most appropriate evaluation of this has been less well studied than has elevation in temperature.

Key management points

1) Assess patient for hemodynamic instability and other potentially immediate life-threatening events accompanying fever and leukocytosis. Unstable patients need to be stabilized while concurrently being evaluated to identify processes requiring urgent intervention. The differential diagnosis of causes of new fever and leukocytosis is extremely broad, but there are some acute processes that would require life-saving interventions such as surgery or other invasive procedures. Some examples would be acute hemorrhage, acute intestinal ischemia or perforation, or an acute pulmonary embolus or infarct.

2) Assess the patient for evidence suggesting a severe new infection, such as findings of SIRS or septic shock in association with new fever that would mandate early initiation of empiric antibiotic therapy and other supportive measures.

3) Initiate evaluation for the specific cause of fever and/or leukocytosis. The minimal evaluation would include a clinical assessment of the patient that includes a physical examination and review of pertinent history and medications as well as record of any recent transfusion of blood products. The evaluation may also include microbiologic and other laboratory studies and imaging studies, but the evaluation should be individualized to the specifics of each individual patient.

The physical examination should pay careful attention to all vascular access devices and other indwelling devices and should include assessment of all surgical wounds. The skin should be carefully examined for evidence of new rashes.

Initial laboratory assessment may include blood cultures, chest radiographs, examination of pulmonary secretions, stool studies, particularly testing for Clostridium difficile infection, microscopic urinalysis and urine culture, liver function studies and lipase. Testing may also include biomarkers such as serum procalcitonin. Additional bedside studies may include echocardiograms, Doppler studies of the limbs to assess for deep venous thromboses, and bedside ultrasound. Need for non-bedside imaging studies such as CAT scans and MRIs must be balanced against the risk of sending unstable patients out of the intensive care unit.

4) Specific interventions to decrease fever

Hyperthermia syndromes should be managed with either specific or non-specific fever-lowering interventions. This requires the accurate identification of hyperthermia syndromes, including malignant hyperthermia, neuroleptic malignant syndrome, heatstroke, and endocrine processes, based on history and presentation, and use of specific antidotes when indicated. Antipyretic agents are generally not beneficial for these syndromes.

Interventions to decrease fever with antipyretic agents and cooling measures may be indicated in patients with acute neurologic injury or patients with unstable cardiac status. Use of temperature-lowering interventions is more controversial in neurologically stable febrile intensive care unit patients and should not necessarily be routinely employed. There may be differences in benefits of temperature-lowering interventions between medical, surgical, and post-trauma intensive care unit patients.

2. Emergency Management

1) Assess for hemodynamic and/or respiratory instability associated with onset of fever and leukocytosis and stabilize patient.

2) Assess for acute/emergent non-infectious processes that may present with fever and leukocytosis and require specific emergent management. Some are listed below; specific management of these is addressed in other chapters.

Acute hemorrhage or hematoma at any site

Acute ischemia or infarction of any organ or limb

Acute pulmonary embolus

Acute central nervous system events

Other acute surgical emergencies (eg, intestinal perforation and other acute abdominal emergencies)

3) Evaluate for evidence of SIRS/septic shock and initiate specific management.

Obtain blood and other appropriate cultures.

Initiate empiric antibiotics targeted at the suspected site(s) of infection.

Empiric therapy should be modified based on available culture data, risk of infection with multi-drug-resistant organisms, allergies, and other host-specific factors related to risk for unusual or opportunistic pathogens and drug-related toxicities..

Antibiotics should be administered within an hour of determination of need.

Address clinically obvious sources of infection -- for example, removal of obviously infected lines, surgical or interventional drainage of abscesses, surgical management of necrotizing skin and soft tissue infections.

Assess specifically for risks for disseminated candidiasis and for Clostridium difficile colitis and need to include treatment for these as components of initial empiric antimicrobial regimens.

4) Assess for risks for or other evidence of hyperthermia syndromes and initiate specific therapy if indicated.

Non-specific cooling measures: fans, ice packs, sponges, cooling fluids, cooling blankets, hypothermia devices

Discontinuation of medications potentially implicated

Specific antidotes/therapies for:

Malignant hyperthermia

Neuroleptic malignant syndrome

Thyrotoxicosis

Pheochromocytoma

Adrenal crisis

5) Initiate cooling measures, which may include antipyretics for patients at higher risk for complications from elevated temperatures, including:

Patients with acute neurologic events, including subarachnoid hemorrhage, acute stroke, and post-cardiac arrest

Patients with cardiac instability at risk for cardiac complications from effects of pyrexia

Consider risks and benefits of lowering of fever in other patient populations.

Antipyretic agents

Acetaminophen

Enteral or rectal: 1000 mg every 6 to 8 hours or 325 to 650 mg every 4 hours, maximum 4000 mg per day

Intravenous: 650 mg every 4 hours or 1000 mg every 6 hours, maximum 4000 mg per day

Use lower doses in patients with significant liver disease.

Ibuprofen

Enteral 200 to 400 mg every 4 to 6 hours

Intravenous: 400 mg every 6 hours or 100-200 mg every 4 to 6 hours

Other non-steroidal anti-inflammatory agents have also been used.

Treatment of malignant hyperthermia

Dantrolene: 1 mg/kg by IV push, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached.

Treatment of serotonin syndrome

Intravenous benzodiazepines, titrate dose to effect

Enteral cyproheptadine: initial dose 12 mg, then 2 mg every 2 hours until symptoms improve

Sublingual olanzapine 10 mg

Intramuscular chlorpromazine (50 to 100 mg) are options

Treatment of neuroleptic malignant syndrome

Enteral bromocriptine 2.5 mg every 8 hours, and increasing every 24 hours by 2.5 mg per dose until a response is seen, maximum dose 60 mg

Dantrolene is also used; see dosing above.

Antimicrobial agents

Dosages for antimicrobial agents for treatment of specific infections in the ICU and for empiric therapy of sepsis syndromes and septic shock are specifically addressed in other chapters.

3. Diagnosis

Establishing the diagnosis

The initial evaluation of new-onset fever and/or leukocytosis in the critically ill patient begins with a careful physical examination and review of the pertinent history, recent interventions and procedures, medications, and other patient-specific risk factors. The differential diagnosis of fever in critically ill patients differs from the more general evaluation of unexplained fever (FUO) in other patient populations as it focuses more on complications and adverse events related to their hospitalization, such as nosocomial infections.

However, there is overlap between the general FUO work-up and the evaluation of fever in critically ill patients, especially if these patients are admitted with fever that does not resolve or if the episode of fever is prolonged. The differential diagnosis and urgent management strategies for unexplained fever will also vary in critically patients with additional specific risk factors such as neutropenia, post transplantation, and advanced HIV infection.

Approximately half of episodes of fever in the ICU are due to infection, and much of the initial evaluation and testing is based on assessment for the most common nosocomial infections, including intravascular device-associated infections, catheter-associated urinary tract infections, and nosocomial pneumonia, and post-surgical related infections in surgical and neurosurgical patients. In hemodynamically stable patients without additional risks for mortality from infection, such as neutropenia, the work-up can be performed in a staged, sequential manner, with need for additional or more aggressive studies based on results of initial testing.

In more unstable patients, it may be necessary to expedite the evaluation while concurrently initiating empiric interventions such as antimicrobial therapy. In ICUs with very low rates of nosocomial infection such as ventilator-associated pneumonia and central line-associated bacteremia, the proportion of non-infectious fevers may be higher than in other units with more nosocomial infections.

Although the magnitude and pattern of a patient's fever might provide some suggestions as to possible infectious and non-infectious diagnoses, particularly extremely elevated temperatures, such patterns are not specific enough to either rule in or rule out infection in critically ill patients. Similarly, elevations in white blood count and even extreme elevations are not specific for infection.

Table I.

Most Common Non-Infectious Etiologies of Fever or Hyperthermia in the Critically Ill Patient (Some etiologies can fit into several categories)
General Category Common Specific Etiologies of Fever
Medication and Drug Related Drug Fever: Common classes include beta-lactams and other antimicrobials, anti-epileptic agents, anti-arrhythmic agents and antihypertensives
Malignant hyperthermia
Serotonin syndromes
Neuroleptic malignant syndrome
Alcohol and other drug withdrawal syndromes
Adverse reaction to illicit drugs
Hematologic Transfusion reactions
Acute hemorrhage
Hematomas (superficial or deep)
Thrombotic thrombocytopenic purpura
Other platelet-related thrombotic disorders (eg, heparin-induced thrombocytopenia)
Venous Thrombosis Pulmonary embolism/ infarct
Deep venous thrombosis
Endocrine Processes Thyrotoxicosis
Pheochromocytoma
Adrenal crisis
Intraabdominal Processes Acalculous cholecystitis
Pancreatitis
Mesenteric ischemia
Neoplastic Causes Leukemia, lymphoma and lymphoproliferative disorders
Solid tumors: liver including metastases, brain, renal, sarcomas, other
Para-neoplastic syndromes
Tumor lysis syndromes
Rheumatologic and Immunologic Causes Systemic lupus erythematosus and related
Vasculitis syndromes
Acute gout
Adult Still's disease
Ischemia and Infarction Myocardial infarction
Stroke
Acute limb ischemia
Pulmonary Syndromes Fibroproliferative phase of ARDS
Chemical aspiration
Bronchiolitis obliterans and organizing pneumonia (BOOP)
Fat emboli syndrome
Neurologic Syndromes Subarachnoid hemorrhage
Traumatic brain injury
Spinal cord injury
Cardiac arrest
Other Specific Processes Organ rejection in transplant patients
Immune reconstitution/inflammatory syndrome in HIV disease
Pericarditis

General diagnostic approach

The diagnostic work-up always begins with the chart review and physical examination. Exams can be difficult in critically ill patients on intensive support, but the exams should include assessment of all vascular and other indwelling devices, all surgical sites, and examination of the skin for evidence of rashes. If wounds cannot be directly examined, communicate with the surgeons who are assessing these. Some potential occult sites of infection often missed on routine examination include otitis media, dental abscesses, sinusitis, necrotic tunneled decubiti, perirectal abscesses, and gynecologic infections, including retained tampons.

Communicate with nurses and review nursing assessments for observations such as new-onset diarrhea, new skin findings, or issues with intravascular catheters. Review medication lists. Review transfusion history and correlation with fever for diagnosis of possible transfusion-associated fever.

Assess for patient-specific risk factors that would help target the initial work-up or would require consideration of additional diagnoses not generally considered in the general evaluation of the febrile ICU patient. Some of these are listed in Table II. Common but more difficult to diagnose infections in critically ill patients include disseminated candidiasis. Specific risks for this should be assessed that would justify initiation of pre-emptive antifungal therapy.

The tempo of the work-up and need to initiate empiric therapy including antimicrobial therapy should be dictated by patient stability and patient-specific risks for poorer outcome with untreated infection. In most studies, infectious etiologies are found only half of the time, and inappropriate/unnecessary antibiotic use results in increasing antibiotic resistance, antibiotic toxicities, and increased risk for C. difficile infection.

Always attempt to obtain microbiologic specimens prior to initiation or change in antimicrobial regimens. Lack of response to empiric antimicrobial therapy should prompt further work-up for non-infectious etiologies and be an indication to discontinue ineffective therapies. Antibiotics, especially beta-lactams, are common causes of drug fever.

The diagnostic work-up should be cost-effective and evidence-based, where evidence exists, or guided by best practices. The lists of potential testing that can be ordered is enormous. Guidelines and rationale for specific testing have been assessed and are discussed in the 2008 Critical Care Medicine and Infectious Diseases Society of America guidelines for evaluation of fever in critically ill patients. Studies should be ordered only if they will directly affect patient management. Additional considerations for ordering tests should include stability of the patient and need to transport him or her out of the critical care unit, other risks of the testing, and radiation exposures.

Table II.

Considerations in the Evaluation of Fever in Specific Patient Populations
Patient-Specific Factor Additional Specific Diagnostic ConsiderationsUnique Therapeutic Considerations General Medical ICU Patient See Text See TextPost Surgical Patient
Postoperative fever: typically 1st 48 hrs post surgery and often non-infectious, less likely 4 or more days post-surgery
Surgical site-specific complications including infection, hematoma, and mechanical complications
Most wound infections do not present in the first 2 days
Anesthesia-related malignant hyperthermia
Higher risk for thrombophlebitis, deep venous thrombosis and pulmonary embolus
Assess for risk of malignant hyperthermia
Post Trauma Patient
Early fever (day 1 to 2) not associated with increased infection or morbidity
Presence of low temperatures day 1-2 correlates with both infection and increased mortality, as well as positive blood cultures
Late fever (day 4 or later) correlates more strongly with infection
Adverse outcome found after aggressive treatment of fever in one randomized controlled trial in trauma patients Neurologic and Brain Injury Patient
Higher rates of fever (up to 70%)
Higher rates of unexplained fever, including "central" fever
Highest association of fever with poor outcome and mortality
Strongest evidence for use of cooling modalities, especially early Neutropenic Patient
Higher risk of death from untreated bacterial and fungal infections
Clinical site-specific manifestations of infection may be absent due to lack of neutrophils
Consider chemotherapy-related febrile reactions
Early empiric therapy for bacterial and fungal infections
Use of leukocyte colony-stimulating factors
Post Myocardial Infarction and Cardiothoracic Surgery PatientRisk for Dressler's syndrome (pericarditis)
Consider fever-lowering modalities for cardiac benefit
Anti-inflammatory treatment for pericarditis if indicated
Advanced HIV-infected Patient
Risk for opportunistic infections at low CD4 counts
Risk for Immune reconstitution inflammatory syndromes (IRIS) if recently started on antiretroviral therapy
Malignancies such as lymphoma and Kaposi's sarcoma
Corticosteroids for some IRIS syndromes
Role of initiating antiretroviral therapy in the ICU not clearly established
Post Organ or Bone Marrow Transplant Patient
Organ rejection syndromes
Graft vs. host disease
Opportunistic infections, including viral and fungal
Consider transplant type, time from transplant event, and immunosuppressive regimen in differential diagnosis
May include either increase in immunosuppressive medications if organ rejection, or decrease in immunosuppressive medications for specific infectionsRecent Immigrant/Returning TravelerHigher risk for imported infections such as tuberculosis, typhoid fever, malaria and otherConsider empiric therapy for severely ill patients with high risk of specific infectionsProlonged Outpatient FUO Prior to Admission
Work up as classical fever of unexplained origin
Differential diagnosis includes malignancy, connective tissue diseases, chronic infections such as tuberculosis and many other conditions

Diagnostic work-up of fever and/or leukocytosis in the critically ill patient

Microbiologic studies

Blood cultures: At least 2 sets of blood cultures should be drawn within 24 hours of the onset of new fever. If at all possible, blood cultures should be obtained prior to the initiation of antibiotics, or prior to change in therapy in patients already on antibiotics. Paired cultures provide much more useful information than single cultures. Cultures can be drawn concurrently from separate sites, but if evaluating for possible endocarditis or other endovascular infection it may be preferable for cultures to be separated over time. For patients with indwelling vascular catheters, obtain at least one culture from the catheter and one peripheral blood culture. If a patient has more than one access, it may be appropriate to draw cultures from all potentially infected lines.

Additional blood cultures do not need to be drawn on each subsequent day of fever. They should be repeated if there is clinical suspicion of ongoing or recurrent bacteremia or fungemia, other major change in clinical status, or if needed as follow-up to prior positive cultures to assess for resolution of bacteremia or fungemia. The yield of blood cultures in evaluation of new fever may vary with the patient population. In one large study in critically ill trauma patients, there was very poor correlation between presence of fever and leukocytosis and the recovery of pathogens in blood cultures.

Disseminated candidiasis is an important consideration in febrile patients on broad-spectrum antimicrobial therapy. Most candida species will grow well in routine bacterial blood culture bottles; thus, fungal blood cultures are rarely indicated. However, candida may grow more slowly in blood cultures compared to aerobic bacterial pathogens.

Vascular catheter tip cultures: Semi-quantitative catheter tip cultures are a reliable tool for the diagnosis of catheter-related infection, especially if correlated with concurrent blood cultures, but this necessitates removal of the catheter. All vascular catheter sites should be examined, and if the site is erythematous or purulent, then the catheter should be removed and the tip cultured. If a short-term catheter is strongly suspected of being the site of infection, the catheter should be removed and the tip cultured.

It is not necessary to remove all short-term catheters as part of an initial fever evaluation, though this should be considered in patients with septic shock with no other identified source. Paired peripheral and line blood cultures and time to positivity are useful to define a catheter infection. Decisions to remove long-term catheters are more complex, but these should be removed if there is evidence of tunnel infection, embolic phenomena or vascular complications.

Respiratory cultures: Respiratory cultures are part of the evaluation for febrile critically ill patients suspected of having nosocomial or ventilator-associated pneumonia. Cultures should be obtained prior to initiation or change of antimicrobial therapy. However, microbiologic specimens from the respiratory tract should only be obtained in patients with other evidence suggesting pneumonia. The diagnosis of pneumonia relies on clinical and radiographic evidence with use of microbiologic data to guide therapy. Positive cultures without evidence of pneumonia may lead to unnecessary and inappropriate antimicrobial therapy.

Specimens can be obtained by expectorated sputum, induced sputum, or trached secretions or by alveolar lavage techniques. When available, quantitative cultures may be more useful than routine cultures. Specimens should be transported promptly to the laboratory to maximize yield. In immunosuppressed patients additional respiratory specimens such as fungal and mycobacterial cultures, viral diagnostics, and cytologic specimens for diagnosis of Pneumocystis jiroveci may be indicated. Molecular diagnostic studies such as PCR for viral pathogens should be more rapid and more sensitive than culture.

Urine cultures: Pyuria and bacteriuria are common findings in critically ill patients with indwelling catheters, but are much less commonly the cause of infection in the intensive care unit, especially in the first several days after catheter insertion. Urine studies, including microscopic analysis and culture with susceptibility testing, should be performed in all patients with fever and/or leukocytosis who are at higher risk for urinary tract infection or complications from bacteriuria, such as pregnant patients, neutropenic patients, those with recent urologic instrumentation and other urologic abnormalities.

Urine studies are also appropriate in those with symptoms referable to the urinary tract or those with otherwise unexplained severe sepsis or septic shock. Specimens should be collected from sampling port and not the drainage bag of indwelling catheters, and patients with multiple urinary devices such as Foley catheters and nephrostomy tubes should have separate samples from each site. Colony counts of > 103cfu per ml correlate with true bacteriuria rather than contamination, but do not help determine whether the bacteriuria is clinically significant. The magnitude of the bacterial count and presence or absence of pyuria lack specificity for the diagnosis of symptomatic catheter-associated UTI.

Stool studies: The major gastrointestinal pathogen causing new fever and leukocytosis in critically ill patients is C. difficile. Evaluation for bacterial pathogens, intestinal parasites, and viruses may be appropriate in patients newly presenting to the hospital and ICU with diarrhea or other gastrointestinal complaints, and may be important considerations in specific hospitalized populations such as immunosuppressed patients, HIV-infected individuals, and returning travelers.

C. difficile colitis usually presents with diarrhea in addition to fever and leukocytosis, but may present occasionally with ileus or toxic megacolon and rarely as leukocytosis without diarrhea. Culture for C. difficile is rarely performed. Diagnosis relies either on a combination of antigen testing and EIA toxin assays or use of nucleic acid-based tests. EIA toxin assays alone are specific but not sensitive enough to exclude the diagnosis.

Other microbiologic specimens: Cultures of other clinically infected sites or suspected sites should be obtained as necessary. CSF specimens for cell count and culture should be obtained in febrile post neurosurgical or head trauma patients or in other febrile patients where suspicion of bacterial meningitis is high. Pleural fluid cultures should be obtained in febrile patients with increasing effusions, and ascitic fluid should be tapped if present for diagnosis of peritonitis.

Cultures from purulent drainage from operative surgical sites should be obtained as part of the evaluation of surgical site infections, but care must be taken to distinguish surface colonizing organisms from true pathogens. Non-infected-appearing surgical wounds should not be cultured. In patients with fever and radiographic evidence of sinusitis on CAT scan, sinus aspirates obtained either by puncture or endoscopic aspiration should be sent for bacterial and fungal culture.

Other diagnostic studies for less commonly seen specific infections that may present as unexplained fever are listed in Table III.

Table III.

Testing Considerations for Less Common Microbial Pathogens that May not be detected on Routine Bacterial Cultures
Pathogen Class Specific Agent Testing methodologies
Fungal Pathogens Candida Should grow on routine blood culturesYield from other specimens may be higher on fungal mediaAdjunctive Testing: 1-3 beta-glucan assay
Aspergillosis Fungal stains and fungal mediaAdjunctive testing: serum galactomannan or 1-3 beta-glucan assay
Zygomycetes (Mucormycosis) Fungal stains and fungal culture media
Cryptococcus Routine and fungal culture mediaCSF India ink stainSerum and CSF cryptococcal antigen
Histoplasmosis Fungal stain and cultureFungal blood culturesUrine histoplasmosis antigen
Pneumocystis jiroveci Direct and antibody labeled stains of cytologic specimens
Mycobacteria M. tuberculosis Acid Fast Stains and cultureNAAT on sputum
Atypical mycobacteria Acid fast stains and culture
Other Atypical Bacterial Pathogens Legionella Urine Legionella antigenCulture (slow)NAAT on respiratory specimens
Nocardia Gram and modified acid fast stainGrows on bacterial and fungal culture media
Rickettsia, Ehrlichia and Anaplasma species including Rocky Mountain spotted fever (RMSF) SerologyImmunohistochemical stains for RMSFNAAT for Ehrlichia and Anaplasmosis in blood
Spirochetal Diseases Syphilis Rapid plasma reagin (RPR) and specific treponemal tests
Lyme SerologyNAAT for meningitis
Viral Diseases Herpes viruses; HSV and VZV (varicella zoster) Tzanck prepViral cultureNAAT especially for CSF but also for skin lesions
Cytomegalovirus Immunopathologic staining of biopsy specimensViral cultureNucleic acid amplification tests, especially for blood
Epstein-Barr virus Heterophile antibodySerologyNAAT on blood and CSF
Influenza A/B including novel H1N1 Rapid antigen testsViral cultureNAAT of nasal and respiratory secretions
Human immunodeficency virus Antibody testing with Western blot confirmationAcute seroconversion illness: serum antigen or NAAT on serum
Human herpes virus 6 and 7 Viral cultureNAAT of serum
Adenovirus Viral cultureNAAT of respiratory specimens
West Nile virus Viral cultureSerologyNAAT of serum and CSF
Dengue Serology
Parasitic Diseases Malaria Peripheral blood smearsRapid blood antigen tests
Babesiosis Peripheral blood smearsSerologyNAAT
Strongyloidiasis Stool, gastric aspirate or lung aspirate wet mounts
Toxoplasmosis Serum antibodyImmunohistopathologic stains of biopsy material
Bacterial Diseases Clostridium difficile Stool toxinA/B assaysAntigen testing for glutaraldehyde antigenNAAT for toxin gene

Other laboratory studies

These studies may be indicated based on the initial assessment of the patient and diagnoses under consideration.

Liver enzymes and pancreatic enzyme studies are indicated as part of the assessment of those patients with abdominal pain or distention or other abdominal findings, and in patients post abdominal or biliary procedures. However, abdominal examinations may be of limited value in sedated patients, in the elderly, and in immunosuppressed patients, and a benign exam cannot exclude the possibility of significant abdominal pathology. Abnormalities in liver enzymes are common in critically ill patients and can be found with a wide variety of focal and systemic processes, including shock liver from hypotension and SIRS, but in the appropriate clinical circumstances may also be clues to biliary tract infections, acalculous cholecystitis, acute viral infections and some adverse drug reactions that may be causes of unexplained fever.

Thyroid studies and adrenal studies may be indicated in febrile patients with clinical manifestations of hyperthyroidism or adrenal crisis. Specific testing for catecholamines is indicated for diagnosis of pheochromocytoma.

Measurements of creatine kinase may provide clues as to inflammatory muscle processes.

Inflammatory markers and other specific rheumatologic serologies may be indicated in febrile patients with a history of known immune diseases and those with more prolonged fever and multi-system illnesses where the differential diagnosis includes inflammatory diseases such as lupus, adult Still's, temporal arteritis and systemic vasculitis. Generally there are other clues besides fever and leukocytosis for these diagnoses, and these are more commonly causes of unexplained fever on admission to the critical care unit than as fevers arising during the ICU stay.

Other biomarkers

Serum procalcitonin levels have been used to distinguish bacterial infection from other causes of fever in patients admitted to ICUs and has been extensively studied in over 10 randomized controlled trials as a guide to determining need for continuing or discontinuing antibiotics in critically ill patients. Although sensitivity of the testing may vary and there are still many trials ongoing, serum procalcitonin levels may be used as an adjunctive test for making decisions on empiric therapy in febrile critically ill patients.

Endotoxin detection assays using a kinetic luminometric assay in one multicenter ICU study had good negative predictive value for excluding gram-negative infection.

C-reactive protein levels are elevated with a wide variety of processes that cause inflammation and are not specific for infection or sepsis. However, low C-reactive protein values can be helpful in ruling out severe infections. C-reactive protein levels must be interpreted in clinical context.

Radiographic studies

Nosocomial pneumonia is a common cause of fever and leukocytosis in ICU patients, especially mechanically ventilated patients, and is an early diagnostic consideration in most febrile patients. The evaluation for pneumonia includes clinical examination and assessment of respiratory status and secretions, chest radiograph, and respiratory cultures. Portable radiographs with patients in an erect sitting position are generally adequate as an initial study.

The chest radiograph lacks both sensitivity and specificity for the diagnosis of pneumonia. Of all the abnormalities studied, unilateral air bronchograms have the highest predictive value for diagnosis of pneumonia, but even these have low specificity. Negative radiographs also do not exclude the diagnosis of pneumonia as well as other significant pulmonary infections such as empyema and lung abscess. CAT scans have much higher sensitivity, but require transport of critically ill patients out of the unit. CAT scans should be obtained for evaluation of immunocompromised patients due to much higher sensitivity for detection of findings of opportunistic infections.

Other radiographic studies are generally not part of the initial evaluation of all febrile patients but may become important for specific patients or as subsequent testing where the cause of fever or leukocytosis remains in doubt. Abdominal films may show evidence of abdominal perforation or obstruction as well as evidence of megacolon in patients with C. difficile infection, but CAT scans provide much more information for the assessment of abscesses, pancreatitis, colitis and post-operative infectious and non-infectious abdominal processes contributing to fever.

Plain sinus films may show evidence of sinusitis, but CAT scans are more sensitive. Radiographic findings of sinusitis are non-specific and should be supplemented with more specific diagnostic modalities such as nasal endoscopy. Head imaging with CAT scans and MRIs may be indicated with fever and evolving neurologic processes, especially patients with subarachnoid hemorrhage or post-neurosurgery.

Additional invasive diagnostic radiographic studies such as arteriograms may be indicated for the evaluation of specific complications in individual patients but are not part of the general diagnostic work-up.

Other imaging studies

Ultrasound studies have an advantage over CAT scans in that they can be performed at the bedside. Abdominal ultrasound may be useful for assessment of liver and biliary tree, including acalculous cholecystitis, and chest ultrasound may help localize large pleural effusions that require diagnostic or therapeutic thoracentesis. Doppler studies can be used to look for evidence of superficial and deep venous thromboses and complications associated with indwelling central venous catheters. Suspected infected superficial fluid collections such as abscess and infected hematomas can in many instances be localized by ultrasound.

Transthoracic and transesophageal echocardiography (TEE) may be indicated for evaluation of fever and leukocytosis to assess for pericardial complications as well as for assessment of valves in patients with positive blood cultures and suspicion of endovascular infection. TEE is more sensitive for the diagnosis of native and especially prosthetic valve endocarditis.

Additional Diagnostic Testing for Less Common Microbial Pathogens

Additional diagnostic testing for less common microbial pathogens

Routine bacterial cultures may be insufficient to identify some of the less common pathogens encountered during the evaluation of fever in critically ill patients. Some of these tests are listed in Table III.

Pathophysiology

Elevated body temperatures in the critically ill patient can be divided broadly into three categories: hyperthermia syndromes, infectious fevers, and non-infectious fevers. All involve alterations in thermoregulatory homeostasis, but the mechanisms responsible for the hyperthermia syndromes differ from those of infectious and most other non-infectious causes of fever.

In the hyperthermia syndromes, elevated body temperatures result from thermoregulatory failure. This occurs either from environmental exposure to heat, such as in heatstroke, or by production of heat beyond the ability of the body to dissipate it. Unlike what occurs during infectious fevers and other fevers that are a manifestation of the febrile response, there is no resetting of the temperature set points in the thermoregulatory centers of the anterior hypothalamus. The hyperthermia syndromes include heatstroke, malignant hyperthermia, neuroleptic malignant syndrome, other drug-related syndromes such as serotonin syndromes and adverse reactions to illegal drugs, and a variety of endocrine syndromes, especially thyrotoxicosis and pheochromocytoma. These are characterized by very high measured core temperatures, and are usually identified at initial presentation from appropriate exposure history and medication review.

Fever as a manifestation of infectious processes as well as other inflammatory conditions is mediated by the febrile response. Current theories of fever and temperature regulation attribute the febrile response to an elevation of the central thermoregulatory set point of the thermoregulatory center, located in the anterior hypothalamus. Exogenous pyrogens such as gram-negative LPS and a wide variety of other bacterial and viral components initiate the febrile response through the binding of these pyrogens to Toll-like receptors, resulting in the stimulation of signal transduction in macrophages and other immune cells and the synthesis and release of cytokines such as interleukin-1, tumor necrosis factor and many others.

There are also a variety of endogenous pyrogens that stimulate cytokine release from macrophages and other effector cells. Some of these mediators act directly and others indirectly in temperature-sensing regions adjacent to the preoptic areas of the hypothalamus. Both exogenous and endogenous pyrogens result in the increased synthesis of prostaglandins, especially PGE2. PGE2 is considered to be the central mediator of fever at the level of the thalamus. Areas of the hypothalamus surrounding the preoptic area appear to be critical in thermogenesis through the activation of thermogenesis in brown adipose tissue.

Fever as a clinical manifestation occurs when the increase in thermoregulatory set point results in an increase in core temperature. Neuronal sensory pathways from the periphery as well as in body core areas including the brain, spinal cord, and abdomen also provide neuronal input into the preoptic area of the hypothalamus. There are also negative regulators that prevent the set point from becoming overly elevated. The body uses a variety of heat-generation and -conservation mechanisms to elevate the core temperature to reach the new set point, and has a variety of heat-dissipation mechanisms to bring the core temperature down when the temperature is above the set point.

Most antipyretics, including acetaminophen and non-steroidal anti-inflammatory agents, work by inhibiting the cyclooxygenase enzyme that converts arachidonic acid to prostaglandins, thus working to lower the set point in the thermoregulatory center, in opposition to the stimuli that are contributing to elevation of the set point. These agents should not decrease the set point below normal physiologic values. These agents have little impact on hypothermia syndromes, where the set point is unaltered, and for treatment of hyperthermia syndromes. Cooling measures and specific antidotes such as dantrolene or bromocriptine are indicated.

Epidemiology

Fever is a very common finding in critically ill patients, but few studies have carefully evaluated the epidemiology of fever in this population. The results of the few published studies are heavily influenced by the type of ICU and patient mix. In several studies in general ICUs using similar definitions of fever, incidence of fever ranged from 28% to 70%, and in many cases fever was present on admission.

In the largest study, by Laupland of over 20,000 critically ill patients from four ICUs over 6 years, the cumulative incidence of fever at any time during ICU stay was 44%, including 27% of patients who did not have fever at the time of ICU admission. The incidence of fever was highest in trauma patients and those with a neurologic diagnoses, lower for medical and general surgical patients and lowest for cardiac patients. This study identified high fever (> 39.5 °C) in 8% of patients.

In most studies, an infectious etiology for fever was identified approximately half the time. Using the more rigorous criteria of culture-confirmed infection with positive cultures within 2 days of onset of fever, Laupland found microbiologically defined infection in 31% of episodes of fever. The non-infectious etiologies of fever were quite diverse in these studies, and differed between medical, surgical, neurosurgical and trauma patients. Many patients were still febrile by the time of discharge from the ICU.

In all of the published studies, fever was associated with increased mortality, often as much as two- to three-fold higher mortality, but many of these studies failed to adjust for other potential confounders. In the Laupland study, medical patients who acquired high fever in the ICU had OR of death of 1.91.

There is only limited information on the epidemiology of leukocytosis in critically ill patients. Though the incidence of leukocytosis and leukopenia is reported for a number of specific diagnoses for which patients present to the ICU, such as sepsis and pneumonia, there is little information on the incidence of new elevations in WBC while in an ICU. In one study of post-surgical patients, leukocytosis but not fever correlated with the presence of postoperative infection. The magnitude of the leukocyte elevation does not predict the presence of an infection.

In one study of 100 patients without leukemia or other hematologic malignancies, only 48% of extreme elevations in leukocyte count were attributable to infection. Infectious diagnoses included pneumonia and empyema, urinary tract infections, Clostridium difficile infection, and abscesses, but also many other infectious diagnoses. Most common non-infectious causes of extreme leukocytosis included metastatic cancers and other tumors and acute hemorrhage, but also a wide variety of other processes.

What's the evidence?

O’Grady, NP, Barie, PS, Bartlett, JG, Bleck, T, Carroll, K, Kalil, AC. "Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America". Crit Care Med. vol. 36. 2008. pp. 1330-49.

(Evidence-based guideline for the prudent and cost-effective evaluation of a new fever in an ICU patient from an expert panel of Critical Care and Infectious Diseases specialists.)

Laupland, KB. "Fever in the critically ill medical patient". Crit Care Med. vol. 37. 2009. pp. S273-8.

(A good overview of the pathogenesis and management of fever in the ICU patient.)

Laupland, KB, Shapori, R, Kirkpatrick, AW, Ross, T, Gregson, DB, Stelfox, HT. "Occurrence and outcome of fever in critically ill adults". Crit Care Med. vol. 36. 2008. pp. 1531-5.

(Largest study of the epidemiology of fever in 28,000 patients admitted to four intensive care units, including occurrence and associations of fever with infection and mortality.)

Mermel, LA, Allon, M, Bouza, E, Craven, DE, Flynn, P, O'Grady, NP. "Clinical practice guidelines for the management of intravascular catheter infection: 2009 update by the Infectious Diseases Society of America". Clin Infect Dis. vol. 49. 2009. pp. 1-45.

(Recently updated evidence-based guidelines for the evaluation of suspected infection of short- and long-term intravascular catheters, including recommendations for assessment of fever in patients with intravascular catheters.)

Claridge, JA, Golob, JF, Fadlalla, AM, Malangoni, MA, Blatnick, J, Yowler, C. "Fever and leukocytosis in critically ill trauma patients: It is not the blood". Am Surg. vol. 75. 2009. pp. 405-10.

(One of several studies in critically ill trauma patients demonstrating poor correlation of fever and leukocytosis with microbiologic recovery of pathogens.)

Reinhart, K, Meisner, M. "Biomarkers in the critically ill patient: Calcitonin". Crit Care Clin. vol. 27. 2011. pp. 253-63.

(Well-written review and summary of the literature for the use of serum procalcitonin in critically ill patients.)

Greer, DM, Funk, SE, Reaven, NL, Ouzounelli, M, Uman, G. "Impact of fever on outcome of patients with stroke and neurologic injury: a comprehensive meta-analysis". Stroke. vol. 39. 2008. pp. 3029-35.

(This recent meta-analysis addresses the impact of fever across the continuum of neurologically injured patients and provides the rationale for interventions to decrease temperature in this population.)

Schulman, CI, Namias, N, Doherty, J, Manning, RJ, Li, P, Elhaddad, A. "The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study". Surg Infect. vol. 6. 2005. pp. 369-75.

(A well-done randomized controlled trial of anti-pyretic therapy in a cohort of critically ill trauma patients, excluding neurosurgical patients. Patients were randomized to an aggressive strategy of treatment of fever above 38.5 with antipyretics, or a permissive strategy of cooling only for fever above 39.5. Mortality was significantly higher in the aggressive therapy arm.)

Mackowiak, PA, LeMaistre, CF. "Drug fever: A critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature". Ann Intern Med. vol. 106. 1987. pp. 728-33.

(An old but classic reference on presentation of drug fevers.)
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