Lung Infiltrates in Patients with Febrile Neutropenia

Patients with fever of unknown origin (FUO) or documented infections other than lung infiltrates not responding to antimicrobial therapy during the first 72-96 h should be subjected to repeated clinical, imaging and microbiological examination (B-II). Thoracic CT should be done within 24 h (B-II). A higher rate of pathological findings is obtained by the use of high-resolution or thin-section multi-slice technique (B-II).

In patients with pathologic findings on chest radiographs additional thoracic CT scan is recommended for a more detailed imaging of the lung infiltrates.

In patients with LIs, a fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) of the affected region is recommended (B-III). The maximum period between sampling and start of laboratory work-up should be less than 4 h. Samples should be transported under cooling conditions (+4^°C) (A-III). The recommended program for microbiological work-up is shown in Tables 2 and 3.

Microbiological findings from neutropenic patients must be interpreted critically with respect to their etiological significance.

Etiologically significant are:

• Pneumocystis jiroveci, Gram-negative aerobic pathogens, pneumococci, Mycobacterium tuberculosis or Aspergillus spp. or Aspergillus-Galactomannan or zygomyzetes obtained from BAL or sputum samples; positive rapid culture for CMV or detection of CMV ”immediate early antigen”

• Isolation of pneumococci, alpha-haematolytic streptococci or Gram-negative aerobic pathogens from blood culture

• Any detection of pathogens in biopsy material.

• Positive Legionella or pneumococcal antigen in urine

• Positive Aspergillus-Galactomannan in blood samples

Etiologically insignificant for lung infiltrates are

• Isolation of enterococci from blood culture, smears, sputum or BAL

• Coagulase-negative staphylocci or Corynebacterium spp. obtained from any material

• Isolation from Candida spp. from swabs, saliva, sputum or tracheal aspirates

• Findings from surveillance cultures, feces and urine cultures.

Note: Detection of these pathogens may indicate other infections.

Pre-emptive therapy is defined as the administration of antimicrobial agents on the basis of clinical, imaging and/or laboratory findings indicative of a particular infection in patients at risk for, but without proof of this infection.

In patients with acute leukemia or other aggressive hematological malignancies and severe neutropenia lasting for more than 10 days and LIs, initial antimicrobial therapy should consist of an anti-pseudomonal beta-lactam antibacterial agent plus voriconazole (6 mg/kg every 12 h on day 1, followed by 4 mg/kg every 12 Stunden) or liposomal amphotericin B (3 mg/kg daily) (B-II), see Figure 2. Recommendations on dosage are summarized in the Addendium Antimicrobial Therapy, see Tables 4, 5, 6 and 7.

Liposomal amphotericin B is preferred in patients in whom a pulmonary zygomycosis is considered and in those patients who have recently been treated with voriconazole or posaconazole (B-III). The antimycotic therapy should be continued until hematopoetic recovery and regression of clinical and radiological signs of infection (B-III).

Empirical administration of antiviral drugs, glycopeptides or macrolide antibiotics without a target pathogen isolated from clinically significant samples is not recommended (D-II).

Patients after autologous stem cell transplantation (ASCT) have a very low risk of fungal pneumonia. Therefore, pre-emptive antifungal therapy should be restricted to individual patients with febrile neutropenia and lung infiltrates (B-II). In patients with LIs of unknown origin after CD34-selected ASCT, bronchoscopy with BAL should be considered to eventually diagnose CMV infection (B-III). In case of a positive rapid culture or detection of ‘immediate early antigen’, pre-emptive ganciclovir treatment is indicated (B-III).

Voriconazole or liposomal amphotericin B is the agent of choice for primary treatment of invasive pulmonary aspergillosis, whereas for zygomycosis, liposomal amphotericin B is recommended. Antifungal therapy should be continued after patient discharge (B-III). In patients with progressive LIs and worsening gas exchange, failure of antifungal treatment should only be considered after other causes such as second infection, immune reconstituion or too short duration of treatment have been ruled out (B-II).

Patients with proven Pneumocystis jiroveci (PcP) pneumonia should be treated primarily with trimethoprim-sulfamethoxazole (cotrimoxazole) at a daily dosage of TMP 15-20mg/kg plus SMX 75-100 mg/kg, divided into 3-4 doses (A-II). In non-responders to at least 14 d of treatment, a second infection should be discussed. In case of confirmed resistance or TMP/SMX intolerance, second-line therapy with clindamycin plus primaquine is an alternative (C-III).

Non-invasive CPAP with mask is recommended in patients with progressive respiratory failure (B-II). The value of glucocorticoids in this setting is unclear. Neutropenic cancer patients with respiratory failure caused by LIs may have a favorable outcome under intensive care, including mechanical ventilation. Therefore, it is not justified to withhold intensive care from cancer patients with respiratory failure caused by lung infiltrates only with respect to their underlying malignancy (A-II).