Critical Care Medicine

Infections in Neutropenic Patient

Fever in the neutropenic ICU patient

Synonym

febrile neutropenia

Related conditions

Empiric antibacterial and antifungal therapy

1. Description of the problem

What every clinician needs to know

Fever during chemotherapy-induced neutropenia must be rapidly evaluated and treated.

Other signs and symptoms of infection may be absent in the neutropenic host.

Failure to start appropriated empiric antibiotics is associated with an unacceptably high morbidity and mortality

Guidelines and algorithms have been developed for optimal management.

Clinical features

Definitions

Fever: temperature of 38.3 C (101F) or more x 1, or sustained temperature greater than 38C (100.4F) for more than 1 hour.

Neutropenia: an absolute neutrophil count of fewer than 500 ( or fewer than 1,000 and expected to decline).

Absolute Neutrophil Count (ANC)= the total number of neutrophils + band forms, e.g.: WBC = 1,000 and 10% neutrophils. 5% bands. ANC = 1000 X 0.15=150.

Risk stratification

High risk for infection

Risk increases with depth and duration of neutropenia. Patients who have received allogeneic stem cell transplants or induction chemotherapy for acute leukemia are at higher risk for infection than patients receiving consolidation chemotherapy or autologous stem cell transplant. Important comorbidities: hypotension, pneumonia, abdominal pain, and neurologic changes.

Lower risk for infection

short expected neutropenia duration 7 days or less; no comorbidities

2. Emergency Management

The neutropenic patient with fever is at high risk for mortality from infection acutely. It is considered a medical emergency to institute prompt empiric broad spectrum antibiotics (see treatment)

Clinical evaluation

Localizing signs and symptoms of infection may be absent in the neutropenic host.

Careful complete physical exam should include:

  • Meticulous skin exam looking for lesions that could be a clue to disseminated infection.

  • Examination of all intravenous catheters for evidence of exit site or tunnel infection.

  • Oral examination looking for mucositis, ulcers due to herpes simplex reactivation, palate lesions that could indicate an angioinvasive fungal process eroding into the mouth from the sinuses.

  • Evaluation for sinus tenderness.

  • Evaluation for any new pulmonary, cardiac or abdominal findings.

  • Inspection of the perirectal area (most experts recommend deferring rectal exam in the neutropenic host).

The above should be repeated at least daily, and with any change in clinical status.

3. Diagnosis

Laboratory tests

  • CBC with differential to determine ANC.

  • Electrolytes with BUN and creatinine.

  • Hepatic transaminases and bilirubin.

  • Consider lactate.

  • At least two sets of blood cultures: simultaneously from central catheter (if 2 lumens send set from each) and from peripheral vein.

  • Cultures of any suspicious sites: sputum, urine, wounds, etc.

  • CXR if any signs or symptoms. If abnormal, consider CT chest.

  • Sinus CT if signs/symptoms of sinusitis.

  • Consideration for biopsy of any suspicious skin lesions.

  • C.difficile is a frequent complication and should be looked for in patients with diarrhea.

Diagnosis of catheter related bloodstream infection

Blood cultures should be drawn from the catheter and from a peripheral vein.A catheter-related bloodstream infection is suggested by cultures drawn through the catheter that become positive more than 120 minutes before peripherally drawn cultures, and by repeated isolation of the same organism over time.

Clinical presentation of invasive aspergillosis

1. Pulmonary aspergillosis

Symptoms:

  • Fever despite broad spectrum antibiotics (may be the only symptom).

  • New cough.

  • Pleuritic chest pain.

  • Shortness of breath.

  • Hemoptysis (can mimic pulmonary embolus or pulmonary infarction).

Signs:

  • Pleural friction rub.

  • Focal rhonchi on pulmonary examination.

Chest CT findings

Halo sign: an early and fairly specific finding in invasive aspergillosis: a dense, nodular infiltrate surrounded by a "halo" of ground glass opacification. (Figure 1).

Figure 1.

Halo sign: invasive aspergillosis

Air-crescent sign: a later CT finding with an area of infarcted lung separating from the rest of the lung parenchyma with a surrounding crescent of air. (Figure 2).

Figure 2.

CT Chest: Air crescent sign (invasive aspergillosis)

Other CT findings

  • Nodular or mass-like infiltrates.

  • Peripheral, wedge-shaped infiltrates.

2. Invasive sinusitis

Symptoms:

  • Early symptoms may be subtle.

  • Rhinorrhea.

  • Post-nasal drip.

  • Sinus pain/pressure.

Signs:

  • Periorbital edema/erythema.

  • Sinus tenderness.

  • Facial swelling over sinuses.

  • Palate lesions (indicating erosion from the sinus into the mouth) - often dusky or necrotic appearing.

Signs and symptoms concerning for invasion into the orbital apex:

  • Pain on moving the eye.

  • Increase in lacrimation.

  • CN Vi and/or III nerve palsies.

  • Decreased visual acuity.

  • Proptosis.

3. Disseminated mold infection: skin findings

Fusarium disseminated to the skin (clues to disseminated fungal infection are necrotic center, duskiness, central bullous changes. (Figure 3)

Figure 3.

Dusky embolic skin lesion-disseminated fusarium

Erosion of invasive aspergillus from sinus to skin. (Figure 4)

Figure 4.

Necrotic skin lesion eroding from sinuses: aspergillosis

When to think about rhinocerebral or pulmonary mucormycosis (Rhizopus, Mucor and others)

  • Agents of mucormycosis are resistant to voriconazole - clinical signs and symptoms of invasive mold that occur in patients receiving voriconazole should raise the suspicion for mucormycosis.

  • Rapid progression with necrosis through tissue plans.

Evaluation for invasive fungal infection

  • Patients with neutropenic fever and pulmonary complaints: early Chest CT may pick up halo sign and other findings specific for invasive fungal infection.

  • Sinus CT in patients with neutropenic fever and sinus complaints.

  • Sinus/nasal endoscopy in patients with sinus symptoms and/or CT findings of sinusitis. A biopsy should be performed in any areas that appear devitalized, dusky or are insensate.

  • The role of serial galactomannan (aspergillus antigen) and beta-D-glucan serodiagnostic testing has not been completely defined, but appears promising.

  • Attempt should be made to make a microbiologic diagnosis since different organisms have different antifungal susceptibility.

  • The yield of bronchoscopic lavage without biopsy is low (< 50%).

  • Finding of aspergillus in the sputum in a neutropenic host should arouse a high degree of suspicion for invasive disease.

Clinical presentation of invasive candidiasis

  • Blood cultures may be negative in up to half of patients with candidemia.

  • Disseminated infection is more common in neutropenic patients once candida is in the blood.

  • The chance of dissemination increases with the duration of candidemia.

  • There can be microabscesses in any organ (liver/spleen most typical).

Multiple small pulmonary nodules due to candida in a patient with hematogenous disseminated candidiasis

  • Clinical presentation includes: fever alone, skin lesions (pink papules, macules, pustules or necrotic lesions), visual changes to candida retinitis.

  • Patients with disseminated hematogenous candidiasis (hepatosplenic) often present with fever at the time of neutrophil recovery in conjunction with rising liver associated tests (particularly alkaline phosphatase) and right upper quadrant pain/tenderness. Are often negative and the diagnosis is suggested by CT abdomen and confirmed by liver biopsy.

Disseminated, hematogenous (hepatosplenic) candidiasis with hypodensities in liver. (Figure 5)

Figure 5.

Lesions in the liver due to disseminated candida

Viral infections in the neutropenic host

Commonly seen viral infections

  • Herpes simplex virus-- reactivation of oral lesions, often with mucous membrane involvement . May look like mucositis from chemotherapy.

  • Respiratory viruses : influenza, parainfluenza, respiratory syncytial virus and adenovirus. Can cause lower respiratory infections in neutropenic hosts and disseminated infection in stem cell transplant recipients.

Patchy nodular appearance of respiratory syncytial virus (RSV) pneumonia in a neutropenic stem cell transplant recipient (Figure 6)

Figure 6.

CT chest: respiratory syncytial virus

  • CMV- mainly seen in hematopoietic stem cell transplant recipients where it can cause pneumonitis, esophagitis, gastritis, colitis, hepatitis or retinitis.

4. Specific Treatment

Empiric antibiotic therapy

Empiric antibiotic therapy should be instituted immediately in all febrile neutropenic patients. The following antibiotics have been demonstrated to be effective as single agents in this setting in large clinical trials:

  • cefepime

  • meropenem

  • imipenem-cilastatin

  • pipercillin-tazobactam

Choices between these antibiotics should be driven by knowledge of the local pathogens in your particular ICU environment.

Alternatives for patients allergic to beta-lactams

Every attempt should be made to clarify the patient's allergy history, as beta-lactam antibiotics (penicillins, cephalosporins or carbapenems) are the drugs of choice in this setting, and other options such as flouroquinolones offer inadequate coverage of several Gram negative organisms (such as Pseudomonas aeruginosa) in many ICUs.

Many patients will be able to tolerate one of the beta-lactams. For example, if a patient has a history of a delayed hypersensitivity reaction (e.g. rash) to penicillin, cefepime or meropenem, a beta-lactam might be a reasonable choice.

Beta-lactams should be avoided in patients with history of immediate hypersensitivity (hives or bronchospasm or laryngeal edema).

Non-beta-lactam options:

  • ciprofloxacin plus clindamycin

  • aztreonam plus vancomycin

Note that patients receiving flouroquinolone prophylaxis at the time of neutropenic fever should not receive empiric therapy with a fluoroquinolone.

Additional considerations

  • If resistance is suspected or patient is hemodynamically unstable, consider the addition of an aminoglycoside (gentamicin, amikacin, tobramycin) or vancomycin. These are not otherwise routinely recommended.

  • If a skin or soft tissue infection or catheter site infection, or worsening pneumonia, consider the addition of vancomycin.

  • There are no firm recommendations regarding additional empiric therapy for patients known to be colonized with resistant organisms (e.g adding linezolid or daptomycin for patients colonized with VRE), but consideration should be given, particularly in hemodynamically unstable patients.

  • Consideration for anaerobic coverage in patients with significant mucositis or neutropenic enterocolitis/typhlitis.

Catheter-related bloodstream infections: when to pull the catheter

Strongly recommend removal of catheter for the following:

  • S. aureus (MRSA or MSSA).

  • Pseudomonas aeruginosa.

  • Fungi.

  • Mycobacteria.

  • S. maltophilia.

  • Infection with other organisms associated with:

  • -septic physiology.

  • -failure to clear bloodstream after 3 days.

  • Tunnel infection.

  • Port pocket infection.

When should the empiric antibiotics be modified?

Antibiotics should be tailored to the infections identified (although with ongoing fever, broad spectrum coverage with one of the standard agents is recommended). A change in antibiotics is not warranted in a stable patient who remains febrile with no new findings or culture data.

If vancomycin was started empirically (e.g. for a hemodynamically unstable patient) and cultures do not reveal evidence of a Gram positive infection within 48 hours, vancomycin can be stopped.

Patients who become hemodynamically unstable should have the antibiotics broadened. In general, switching to a broader agent is preferable to adding an aminoglycoside. For example, if a patient becomes unstable on Cefepime in an ICU known to have extended-spectrum beta-lactamase producing organisms (ESBL), a switch to meropenem might be reasonable.

Some Gram negative organisms are resistant to all beta-lactam antibiotics (e.g. KPCs) and may warrant treatment or empiric therapy with alternative agents such as colistin or tigecycline (consultation with an infectious disease expert is recommended).

When should empiric antifungal therapy be initiated?

  • The duration of neutropenia is the risk factor for invasive fungal infection, not the duration of fever.

  • Empiric antifungal therapy should be started in patients who are febrile after 4-7 days of empiric antibacterial therapy. Patients who have had more than 7 days of neutropenia and who have recurrent fever after initial defervescence on empiric antibiotics should be started on empiric antifungal therapy (i.e. should not wait an additional 4-7 days).

  • Therapy should be directed at yeasts, such as Candida species, and mold, particularly Aspergillus species.

Useful antifungal agents

  • Amphotericin B.

  • Lipid preparation of amphotericin.

  • Intraconazole.

  • Voriconazole-- does not cover agents of mucormycosis.

  • Caspofungin, micafungin, anidulafungin- do not cover agents of mucormycosis.

  • Posaconazole.

  • There is no definitive best choice.

  • Fluconazole does not cover Aspergillus and other molds, and is a choice for patients at low risk (i.e. short duration of neutropenia).

Antifungal therapeutic drug monitoring

Therapeutic drug levels should be measured periodically for voriconazole and posaconazole

Drug interactions

There is a long list of drug interactions and side effects for most antifungal agents, and all concomitant drugs should be reviewed carefully.

How long should antifungal therapy be continued?

Empiric antifungal therapy is usually continued until the ANC is 500 or more. If there is clinical suspicion or evidence for invasive fungal infection, length of treatment should be per treatment guidelines for specific infections

5. Disease monitoring, follow-up and disposition

NA

Pathophysiology

Neutrophils are an important part of host defense against bacteria and fungi.

Neutropenic patients frequently have additional risk factors for infection:

  • Mucositis can result in bacterial translocation of bacteria from the mouth or other areas of the GI tract to the bloodstream.

  • Indwelling catheters - a frequent source of bloodstream infection with bacteria or candida.

  • Broad spectrum antibiotics may increase risk for invasive candida and C. diffiicile colitis.

In addition to Gram negative bacterial infections, many other organisms can be associated with septic physiology in the neutropenic host, including viridans streptococci, corynebacteremia, clostridial species, capnocytophagia species and candida species.

Most common causes of bloodstream infections

Gram positive bacteria (Gram positive is more common than Gram negative):

Coagulase negative staphylococci

Other Gram positive organisms:

  • S.aureus - including MRSA.

  • Eenterococci - including VRE.

  • Viridans streptococci.

  • S. pneumoniae.

  • Corynebacteria.

  • Bacillus species.

  • Anerobes: Clostridium septicum, C.tertium and others.

Gram negative bacteria:

  • Ppseudomonas.

  • E. coli.

  • Klebsiella.

  • Acinetobacter.

  • Enterobacter.

  • S. maltophilia.

  • Anerobes: Bacteroides species.

Candida species

Mold infections

As the duration of neutropenia increases, the risk for invasive mold infections increase, and include:

Invasive aspergillus:

  • See most often after at least 2 weeks of profound neutropenia

  • Other factors may increase risk as well: Stem cell transplant, corticosteroids, graft versus host disease, etc.

  • Usually pulmonary or sinus involvement, as organism is inhaled

  • Have a high degree of suspicion for invasive disease if Aspergillus is found in sputum sample

Epidemiology

Fever is very common during neutropenia. It is seen in more than 80% of patients who are neutropenic from chemotherapy for a hematologic malignancy, whereas documented infection occurs in only 20-30%. In addition, 10-25% of patients will have bloodstream infections.

Prognosis

NA

Special considerations for nursing and allied health professionals.

Prevention of infection

Handwashing is the key preventative measure. Gowns, gloves and masks are not recommended unless circumstances otherwise dictate (e.g. masks for patients with known or suspected respiratory virus infections, gowns and gloves for MRSA or VRE, etc.). Hematopoeitic stem cell transplant (HSCT) patients should be in HEPA filtered rooms, and should avoid exposure to plants and flowers.

What's the evidence?

"Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patient with Cancer: 2010 Update by the Infectious Diseases Society of America". Clinical Infectious Disease. vol. 52. 2011. pp. e56-93.

(Guidelines for the treatment of infections in neutropenic hosts.)

Sipsas, NV, Bodey, GP, Kontoyiannis, DP. "Perspectives for the management of febrile neutropenic patients with cancer in the 21st century". Cancer. vol. 103. 2005. pp. 1103.

(Management of the neutropenic patient with fever.)

Marr, KA, Patterson, T, Denning, D. "Aspergillosis, pathogenesis, clinical manifestations, and therapy". Infect Dis Clin North Am. vol. 16. 2002. pp. 875.

(DIagnosis and treatment of aspergillosis.)

Viscoli, C, Varnier, O, Machetti, M. "Infections in patients with febrile neutropenia, epidemiology, microbiology, and risk stratification". Clin Infect Dis. vol. 40. 2005. pp. S240.

(Types of infections and risk factors in patients with neutropenic fever.)
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