Differential diagnosis based on the severity of fever (Table 42.1)

Although considerable overlap may exist, differential diagnosis can be approached based on four categories (infectious, non‐infectious, mostly infectious, and mostly non‐infectious). Incidence and prevalence of causes in each subgroup may vary based on existing risk factors and local ICU, hospital, and geographic patterns.

Differential diagnosis based on type of leukocytosis (Table 42.2)

Differential diagnosis of sources of fever with WBC count of >30 000/μL

• Pulmonary infections including empyema.
  
• Clostridium difficile colitis.
  
• Urinary tract infections.
  
• Vascular infections.
  
• Abscess.

Emergent causes of early postoperative fever (<48 hours)

• Myonecrosis (surgical wound infection).
  
• Pulmonary embolism.
  
• Alcohol withdrawal.
  
• Bowel leak.
  
• Adrenal insufficiency.
  
• Malignant hyperthermia.

History and physical examination

• Vital signs.
  
• Vascular access, indwelling catheters, tubes.
  
• Skin – examine for rash, skin breakdown.
  
• Examine the surgical incision at least once daily for erythema, purulence, or tenderness.
  
• Examination of lungs, heart, abdomen.
  
• Examination of back and sacral area.
  
• Central nervous system examination including motor tone, nuchal rigidity.
  
• Observe appearance of urine, sputum, diarrhea.
  
• Muscle tenderness.

Common and important infectious causes of fever in the ICU

• Intravascular devices: a typical case would be abrupt onset of fever in a patient with a central venous catheter (non‐tunneled or tunneled and >2 calendar days old) with signs of sepsis but no localized signs at the device site, and no evidence of other nosocomial infections. Difficulty drawing or infusing through the catheter with peripheral blood cultures yielding organisms such as staphylococci, Corynebacterium jeikeium, Bacillus species, atypical mycobacteria, Candida, or Malassezia species strongly suggests infection of an intravascular device. A patient on hemodialysis via indwelling catheters may manifest signs of sepsis only when the catheter is used during dialysis.
  
• Ventilator‐associated events/pneumonia: ventilator‐associated events (VAEs) include a ventilator‐associated condition (VAC), an infection‐related ventilator‐associated complication (IVAC), and ventilator‐associated pneumonia (VAP), as defined by the Centers for Disease Control and Prevention (CDC). Each of these conditions requires deterioration in oxygen requirement after a period of stability. For more detailed information, refer to Chapter 44.
  
  
  
  • An increase of FiO₂ requirement of ≥20% or PEEP of ≥3 cmH₂O for a sustained period of ≥2 days is a VAC. The etiology could be infectious or non‐infectious (e.g. pulmonary edema, atelectasis).
    
  • VAC in the setting of fever/hypothermia or WBC count >12 000 or <4000/μL and when a new antibiotic is added for a minimum of 4 days, is defined as an IVAC.
    
  • IVAC with additional evidence of infection, such as purulent secretions or positive respiratory cultures (irrespective of chest film findings), may represent probable or possible VAP.
  
  
• C. difficile: risk factors for the development of C. difficile infection include advanced age, critical illness, use of antibiotics and enteral tube feedings, and history of gastrointestinal surgery. Diarrhea (≥3 loose stools/24 hours) or ileus (postoperative patients tend to manifest as ileus rather than diarrhea) in such patients should be investigated for C. difficile. Elevated lactic acid with a daily up‐trending WBC may be the only initial laboratory manifestations. WBC of >15 000/μL, serum albumin <3 g/dL, and/or a serum creatinine level ≥1.5 times the premorbid value are usually considered markers of severe disease and are more likely to be associated with ileus, pseudomembranous colitis, and toxic megacolon – a surgical emergency. The NAP1 strain is also a predictor of severe disease, poor outcome, and death.
  
• Urinary catheter‐associated bacteriuria or candiduria: although counts of >10³ cfu/mL represent true bacteriuria or candiduria in catheterized patients, there are no concrete data to show that higher counts are more likely to represent symptomatic infection than lower ones. In ICU patients, it usually represents colonization, and rarely causes fever or secondary bloodstream infection. Exceptions may apply to those with urinary tract obstruction, those with recent urologic procedure/surgery, or neutropenic patients. Catheter‐associated urinary tract infection (CAUTI) may be caused by multiresistant nosocomial Gram‐negative bacilli other than Escherichia coli, Enterococcus species, and yeasts.
  
• Sinusitis: nasotracheal intubation is the major risk factor for sinusitis, with a prevalence of up to 33% after 7 days of nasotracheal intubation. Most patients have fever without localized signs and symptoms.
  
• Postoperative fever (beyond 48 hours after surgery): 25% of postoperative patients experience fever. Most fevers that develop after the first 48 hours of surgery should not be considered as benign (see later for benign postoperative fever). When evaluating postoperative fever, a helpful mnemonic is the ’four Ws‘: wind – pulmonary causes (pneumonia, aspiration, pulmonary embolism); water – UTI; wound – surgical site infection; what did we do? – iatrogenic causes (drug fever, transfusion reactions, intravascular device‐related infection). Fever with signs of sepsis in patients beyond the first two postoperative days should trigger evaluation for anastomotic leak, bowel ischemia, and abscess.
  
• Acalculous cholecystitis: this most often occurs in critically ill patients and can be precipitated by a prolonged enteral fasting state, such as those on total parental nutrition. Other risk factors include trauma, surgery, burns, HIV infection, heart failure, and severe sepsis with multiple organ failure. Fever, leukocytosis, and vague abdominal discomfort may be the only clinical signs. The pathogenesis primarily involves bile stasis due to increased lithogenicity predisposing to gallbladder wall ischemia, necrosis, and resultant systemic inflammatory response. Secondary infection with E. coli, Klebsiella, Enterococcus species, and Bacteroides can occur. Diagnosis of acalculous cholecystitis is based on clinical suspicion plus imaging (ultrasound or CT scan). Treatment is usually with percutaneous cholecystostomy and antibiotics coverage.
  
• Necrotizing skin and soft tissue infections: this includes necrotizing fasciitis, myonecrosis, and gangrenous cellulitis. Causative organisms are usually group A β‐hemolytic Streptococcus for necrotizing fasciitis, and anaerobes (Clostridium perfringens) in gangrenous cellulitis and myonecrosis. Polymicrobial infections are probably more common in each case. Typically, in necrotizing fasciitis the precipitating event is local trauma or severe muscle strain. On the other hand, myonecrosis usually results from either deep traumatic or surgical inoculation, or from hematogenous spread from an internal infectious focus in patient with underlying malignancy, neutrophil dysfunction, or bowel ischemia.
  
  
  
  • Irrespective of the precipitating event, the result is necrotizing soft tissue infection spreading along fascial planes and ultimately the overlying skin. Physical findings may be initially minimal (soft tissue edema and erythema) in the presence of severe pain and fever. Loss of pain is an ominous sign (ischemic peripheral neuropathy). The mortality rate is high without surgical intervention.
  
  
• Surgical site infections: apart from myonecrosis surgical site wound infections are generally rare in the first 3 days after surgery. Erythema, purulence, or wound tenderness are usually present. At‐risk patients include those with diabetes, who are obese, or who had considerable contamination of the incision site during an emergent and prolonged procedure without prophylactic antibiotics (24 hours prior to surgery).
  
• Central nervous system infection: CNS infection as the cause of fever should be especially considered in those with intracranial devices. For example, an external ventricular drain carries a 10% risk of infection during the first 10 days. For more detailed information, refer to Chapter 47.

Common and important non‐infectious causes of fever in the ICU

• Benign postoperative fever (within the first 48 hours after surgery): most fevers in the first two postoperative days are caused by the tissue injury and release of inflammatory cytokines. The temperature curve is generally highest on the first postoperative day and trends downwards toward normal by the fourth postoperative day. Careful history of the pre‐surgical and intraoperative periods, and the physical examination, will prompt additional studies if needed.
  
• Acute pancreatitis: this is typically accompanied by abdominal pain, tenderness, distension, nausea and vomiting. Abdominal pain improves by leaning forward. Risks include alcoholism, gallstones, and hypertriglyceridemia (>500 mg/dL). There is no evidence to support empiric antibiotic coverage.
  
• Pneumonitis: such as in cases of aspiration pneumonia.
  
• Mesenteric ischemia: fever with severe abdominal pain with distention and tenderness (typically periumbilical pain is usually out of proportion to the physical exam findings), lactic acidosis, with or without hematochezia and ileus, in at‐risk patients (those with severe atherosclerotic vascular disease of aorta) should raise suspicion of gut ischemia.
  
• Drug‐related fever: fever due to drugs can present a diagnostic challenge since any drug can cause fever, which may manifest simply as fever alone or a life‐threatening hypersensitivity reaction. There is nothing characteristic about drug fevers – it may occur days after administration and may take days to abate after discontinuation of the medication. Counter to general perception, rash occurs in only a small fraction of cases and eosinophilia is even rarer. The diagnosis of drug‐induced fever is usually established on the basis of history, examination findings, and clinical course (temporal relationship of the fever to starting and stopping the drug).
  
  
  
  • Drugs can cause fever/hyperthermia via various mechanisms that may involve a single drug effect and/or a pharmacodynamic/pharmacokinetic interaction with other agents.
    
  • Common examples are listed where appropriate:
    
    
    
    • By altering thermoregulation – drugs such as butyrophenones (haloperidol), phenothiazines (prochlorperazine), antihistamines, and antiparkinson drugs.
      
    • Hypersensitivity – drugs such as antimicrobials (β‐lactam drugs), anticonvulsants (phenytoin), antiarrhythmics (quinidine, procainamide), and antihypertensives (methyldopa).
      
    • Malignant hyperthermia – pathophysiology involves acute build‐up of calcium in skeletal muscles in genetically susceptible patients resulting in muscular rigidity (often starts in chest wall and extremities), sympathetic nervous system overdrive, altered mental status, hypercapnia, and multiorgan failure. Succinylcholine and inhalation anesthetics (halothane) are the common precipitating agents. Although mostly seen during induction, presentation could be delayed for up to 10 hours.
  
  
• Neuroleptic malignant syndrome: pathophysiology involves central dopamine D2 receptor blockade leading to elevated temperature, muscular rigidity, altered mental status, and autonomic dysfunction usually within 4–14 days of either starting or increasing the dose of the offending agent(s). Multiorgan failure can occur in severe cases. Butyrophenones (haloperidol), antiemetic medication (prochlorperazine, metoclopramide), and withdrawal of antiparkinson medication are the common precipitating agents/factors in the ICU. Beside supportive care, management includes stopping thermogenesis with dantroline, and repleting dopamine with dopamine agonists (bromocriptine, amantadine).
  
• Serotonin syndrome: pathophysiology involves increased CNS serotonergic activity that leads to elevated temperature, altered mental status, neuromuscular hyperactivity (clonus, tremor, or hypertonia), and autonomic dysfunction, usually within 24 hours of either starting or increasing the dose of an offending agent(s). Therefore any medication with serotomimetic or serotonergic properties when used alone or in combination can precipitate serotonin syndrome. Examples include: antidepressants (selective serotonin reuptake inhibitors (SSRIs), serotonin‐norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs)), antibiotics (linezolid), opioid analgesics (fentanyl), and even antiemetics (metachlopramide, ondansetron).
  
• Substance abuse: synthetic cannabinoids (e.g. synthetic marijuana, K2, Spice), synthetic cathinones (bath salts), amphetamine, cocaine, LSD, and MDMA.
  
• Drug withdrawal: fever can occur with severe alcohol withdrawal but usually is not associated with opioid or benzodiazepine withdrawal.
  
• Febrile transfusion reactions: a fever elevation of >1.1°C (>2°F) during transfusion needs to be assessed and evaluated carefully. If transfusion reaction is suspected, assume it to be hemolytic until proven otherwise (via laboratory investigations).
  
• Febrile non‐hemolytic transfusion reaction: although the overall incidence has decreased, this remains the most common transfusion reaction, occurring during or up to 4 hours after red blood cell (RBC) or platelet transfusion. Pathophysiology involves either preformed donor cytokines or recipient anti‐HLA antibody‐mediated donor WBC destruction.
  
  
  
  • Transfusion‐related acute lung injury (TRALI): this rare transfusion reaction is the leading cause of transfusion‐related deaths in the USA. Clinically, it presents as acute respiratory distress occurring within 6 hours of transfusion. Lack of pre‐existing acute lung injury and other risk factors for pulmonary edema are two additional diagnostic criteria. Fever, chills, and transient hypertension followed by shock is the typical course. Pathophysiology is not well understood. Platelet and plasma rather than RBS transfusions are most often associated with TRALI.
    
  • Acute hemolytic transfusion reaction: intravascular hemolysis due to ABO incompatibility presents as chills, fever, back/flank pain, hemoglobinuria, bleeding, disseminated intravascular coagulation, and even multiorgan failure.
    
  • Delayed hemolytic transfusion reactions: hemolysis occurring at least 24 hours but less than 28 days after transfusion. Antibody is formed (either primarily or from an anamnestic response) to non‐ABO red cell antigen leading to extravascular hemolysis. Presentation is usually asymptomatic hemolytic anemia, but fever can occur. A peripheral blood smear usually shows spherocytes and a Coombs test is positive.
    
  • Transfusion‐transmitted infection: this is extremely rare. Platelet contamination with Gram‐positive cocci is the commonest followed by red cells contaminated with Gram‐negative rods (Yersinia enterocolitica is the most reported historically). Signs and symptoms will mimic sepsis.

Less common non‐infectious causes of fever in the ICU

• Status epilepticus.
  
• Pulmonary embolism.
  
• Gout: the knee is the commonest site. Keep a high index of suspicion in those with a prior history of gout.
  
• Stroke.
  
• Myocardial infarction (MI).
  
• Thyroid storm.
  
• Transplant rejection.
  
• Tumor lysis syndrome: typically in the setting of lymphomas with a high tumor burden.
  
• Dressler’s syndrome (pericardial injury syndrome): pericarditis with or without a pericardial effusion typically 7 days post MI constitutes post‐cardiac injury syndrome.

Questionable causes of fever in the ICU

• Atelectasis.
  
• Deep venous thrombosis.

List of diagnostic tests

• Routine blood tests: to start with, each patient should have a baseline comprehensive metabolic panel (including liver function tests), complete blood count with differential and basic coagulation profile. In addition, thyroid function tests, disseminated intravascular coagulation profile, and serum cortisol if deemed necessary. Such a battery of basic investigations is cost effective and almost always helps in narrowing the differential diagnosis.
  
• Blood cultures: paired aerobic and anaerobic blood cultures (at least one culture set from a peripheral vein), are collected in a sterile manner prior to the initiation of antibiotics. Skin preparation should be performed utilizing chlorhexidine. Quantitative catheter tip cultures have been utilized for diagnosis of CLABSI, using growth of >15 cfu as positive. A positive catheter tip culture itself, however, is not sufficient for diagnosis. Blood cultures should be drawn only if there is clinical suspicion of continuing or recurrent bacteremia or fungemia or for test of cure 48–96 hours after initiation of appropriate therapy for bacteremia/fungemia. Immunocompromised patients may warrant culture of blood for unusual pathogens.
  
• Respiratory specimen: for Gram stain and culture if suspecting a lower respiratory tract infection. Respiratory specimens can be obtained via expectoration, induction, tracheal aspiration, or bronchoalveolar lavage (BAL). Bronchoscopy should be performed for diagnosis of Pneumocystis jirovecii, Aspergillus and other filamentous fungi, Nocardia, Legionella, and Mycobacterium species. Not all organisms that are recovered from respiratory secretions are pathogenic. Enterococci, viridans streptococci, coagulase‐negative staphylococci, and Candida species are unlikely to be respiratory pathogens. Isolation of cytomegalovirus (CMV) is common from BAL of HIV patients (especially those with Pneumocystis pneumonia) and has even been associated with poorer prognosis, but CMV in itself is usually a bystander rather than a pathogen in such cases. See Chapter 46 for further information on pneumonia.
  
• Pleural fluid: many febrile patients in an ICU have small amounts of pleural fluid and it is not necessary to perform a diagnostic thoracentesis in every febrile patient. However, patients with a significant parapneumonic effusion should undergo thoracentesis if fluid is accessible.
  
• Stool: if suspecting C. difficile, polymerase chain reaction (PCR) assays are rapid and very sensitive methods to confirm the presence of C. difficile toxin. Unless the patient was admitted with diarrhea, is infected with HIV, or is a part of an outbreak evaluation, stool for bacterial cultures or ova and parasite examination is usually not required.
  
• Urine for urinalysis and culture: this should be done in all patients who present with an indwelling urinary catheter with a suspected UTI. Routine monitoring or ‘surveillance’ cultures of urine contribute little to management of a febrile patient. Of note, in contrast to community‐acquired UTI, rapid dipstick tests alone are unreliable to detect CAUTI. The rapid dipstick test relies upon leukocyte esterase (corresponds to pyuria) and nitrites (corresponds to Enterobacteriaceae), both of which may not be present in CAUTI due to Enterococcus species, Candida species, and coagulase‐positive Staphylococcus species.
  
• Wound culture: if suspecting surgical site (wound) infection, the wound should be opened, drained, and then cultured. Superficial cultures are of limited value.
  
• Lactic acid: it is recommended that serum lactate be drawn if infection is suspected in order to assess the severity of sepsis. Serum lactate levels should not be used as a sole resuscitation endpoint. Rather, lactate should be used as one of the hemodynamic parameters, in addition to urine output and organ perfusion examination. Irrespective of the primary cause of lactic acidosis, if levels continue to rise (or not improve) despite adequate therapy, one may consider bowel or limb ischemia as a possible cause. Patients with baseline thiamine deficiency may exhibit delayed clearing of lactic acid.
  
• Procalcitonin: emerging data suggest it is a potentially useful biomarker for generalized bacterial infection with a good negative predictive value. Downtrending levels may help in guiding the duration of antibiotic therapy. The reference value in adults is ≤0.15 ng/mL and an elevated level (>2 ng/mL) is usually associated with severe bacterial infections. However, levels may not rise with localized infections (such as osteomyelitis or abscess). Furthermore, patients with major burns, severe trauma, acute multiorgan failure, or major abdominal or cardiothoracic surgery can also have elevated levels. Viral infections and chronic inflammatory states are associated with normal levels. Therefore, procalcitonin is not a definitive biomarker, but rather can be used in the clinical context.
  
• Antigen testing:
  
  
  
  • Urinary antigen for Legionella pneumophila type 1 and Streptococcus pneumoniae.
    
  • Blood antigen for CMV, histoplasmosis, and cryptococcosis.
    
  • Serum or body fluid PCR for CMV, varicella‐zoster virus, human herpes virus 6, and adenovirus.
    
  • Cerebrospinal fluid (CSF) molecular testing in those with suspected encephalitis. Panel should include adenovirus, enterovirus, herpes simplex virus (HSV) 1 and 2, varicella‐zoster virus, CMV, Epstein–Barr virus, and human herpesvirus 6. From June through November, in the USA, the panel should also include West Nile virus, St. Louis encephalitis, Eastern equine encephalitis, Cache Valley, and California serogroup viruses. When sending CSF for PCR viral studies, the sample should be withdrawn from the least bloody tube because blood is an inhibitor of PCR reaction (false negative results). Of note, PCR can be falsely negative within the first 72 hours of onset of HSV encephalitis. A repeat CSF PCR in such cases will yield positive results.
    
  • Blood galactomannan and β‐D‐glucan for aspergillosis and Candida. The high negative predictive value makes these tests useful to exclude invasive fungal infection. Serial levels can be obtained to assess response to treatment.
  
  
• Lumbar puncture (LP): if altered consciousness is unexplained in the setting of fever, a diagnostic LP should be considered unless there is a contraindication. If new focal neurologic findings suggest disease above the foramen magnum, an imaging study should be performed prior to performing an LP. Opening pressure should always be measured. Routine LP results in meningoencephalitis/encephalitis and cases of early meningitis can be misleading and should never be used alone to refute a diagnosis.

List of imaging techniques

• CXR: although sensitivity and specificity is low for an AP portable CXR, among all radiographic signs unilateral air bronchograms have been shown to have the best predictive value for pneumonia.
  
• CT scan: CT chest is useful in immunocompromised patients with unrevealing CXR but suspected to have small nodular or cavitary pulmonary lesions. Abdominal CT is useful in those with suspected intra‐abdominal pathology (e.g. abscess, pyelonephritis, pancreatitis, vascular graft infection, intestinal obstruction and colitis).
  
• Ultrasound: perform a renal US if suspecting pyelonephritis or hydronephrosis, or a right upper quadrant US if suspecting acute cholecystitis, in which it has a sensitivity of 91% and a specificity of 79%. If US is equivocal, a HIDA scan can be utilized.
  
• Hepatobiliary iminodiacetic acid (HIDA) scan: in a normal (or negative) HIDA scan, the gallbladder is visualized (hence cystic duct is patent), whereas lack of gallbladder visualization (within 4 hours of IV contrast) constitutes a positive study and indicates the presence of cholecystitis or cystic duct obstruction. For acute calculus cholecystitis, HIDA is 97% sensitive and 90% specific, whereas it has both poor negative and positive predictive power in acalculous cholecystitis.
  
• WBC tagged scan: in those with an occult source of infection.
  
• Transthoracic echocardiogram (TTE): as part of initial evaluation for endocarditis.
  
• Transesophageal echocardiogram (TEE): for bacterial endocarditis.
  
• Electroencephalogram (EEG): for status epilepticus.