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Lung Infiltrates in Patients with Febrile Neutropenia

Date of document January 2012

1Definition and Basic Information

Febrile neutropenia with lung infiltrates is one of most common complications after intensive chemotherapy. The guideline was developed by the Infectious Disease Working Party AGIHO of the DGHO for these patients [1]. This guideline does not refer to patients undergoing allogenic hematopoietic stem cell transplantation. These patients are subject to a separate guideline.

Categories are based on the evaluation of study results and the recommendations developed by the Infectious Diseases Society of America, ISDA, see Table 1.

Table 1: Categories of Evidence  

Category, grade
Strength of Recommendation

Definition

A

Good evidence to support a recommendation for use

B

Moderate evidence to support a recommendation for use

C

Poor evidence to support a recommendation for use

D

Moderate evidence to support a recommendation against use

E

Good evidence to support a recommendation against use

Quality of Evidence

Definition

I

Evidence from ≥1 properly randomized, controlled trial

II

Evidence from ≥1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferable from >1 centre); from multiple time series; or from dramatic results of uncontrolled experiments

III

Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports from expert committees

2Epidemiology

Lung infiltrates (LIs) emerge in 15-28% of patients with profound neutropenia following intensive chemotherapy. As compared with other types of infections, treatment of LIs in neutropenic patients is more difficult and costly. These infiltrates may have numerous different causes including multi-resistant bacteria, filamentous fungi, Pneumocystis jiroveci und viruses. Differential diagnosis includes alveolar bleeding, infiltration by the underlying malignancy, cryptogenic organising pneumonia, immune reconstitution syndrome and lesions caused by chemotherapy or radiation.

Clinical trials, microbiological and histological results along with autopsy studies indicate that the majority of LIs in febrile neutropenic patients is caused by filamentous fungi. Clinical outcome of proven invasive aspergilliosis in neutropenic patients is poor, so that early pre-emptive antifungal treatment should be used in febrile patiens with prolonged severe neutropenia and LIs not typical for non-fungal origin and a with CT scan not typical for pneumocystis pneumonia (B-II).

3Diagnostics

The algorithm for rational diagnostics is depicted in Figure 1.

Figure 1: Algorithm for Clinical Management in Patients with Febrile Neutropenia and Lung Infiltrates 
1 CT – Computer Tomography;2  BAL - Bronchoalveolar Lavage;3  LI – Lung Infiltrate;4  invasive Diagnostics: e.g. open lung biopsy or fine needle biopsy; dotted lines indicate exceptions from recommended procedure

3.1Imaging

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.

3.2Bronchoscopy

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.

Table 2: Processing of Bronchoalveolar Lavage (BAL) Material (B-III). – Recommended Program 

Methods

Notes

Cytospin preparations

Distinction between intracellular from extracellular pathogens and identifying infiltration by underlying malignancy

Gram stain

Giemsa / May - Grünwald - Giemsa stain

Assessment of macrophages, ciliated epithelium, leukocytes)

Calcofluor-white or equivalent

Assessment of fungi and Pneumocystis jiroveci

Direct immunfluorescence test for Pneumocystis jiroveci

Confirmatory

Direct immunofluorescence for Legionella spp.

Ziehl-Neelsen / Auramin stain

Aspergillus – Antigen

Galactomannan Sandwich ELISA

Quantitative cultures

Dilutions of 10-2 to 10-4;
Culture media: blood, McConkey / Endo, Levinthal / Blood (bacterial culture), Legionella - BCYE α or equivalent (Legionella spp.), Löwenstein-Jensen or equivalent (mycobacteria), Sabouraud / Kimmig or equivalent (fungal culture)

Table 3: Processing of Bronchoalveolar Lavage (BAL) Material (B-III)– Optional Program  

Method

Note

Enrichment culture

Brain-Heart Infusion, dextrose broth

Direct immunofluorescence test for Chlamydia pneumoniae

Culture for Chlamydia pneumoniae

Legionella PCR

Shell vial technique and PCR for influenza, parainfluenza and adenovirus

Culturing or antigen detection of Herpes simplex and Varicella zoster virus

Cytomegalovirus early antigen; rapid culture

CMV antibody

ELISA, IgG/IgM

HSV antibody (ELISA, IgG/IgM)

ELISA, IgG/IgM

VZV antibody (ELISA, IgG/IgM/IgA)

ELISA, IgG/IgM/IgA

Respiratory syncytial virus (PCR, ELISA)

PCR, ELISA

Panfungal/Aspergillus PCR

Peripheral blood cultures 1 h after bronchoscopy

Diagnosis of transient bacteremia

Throat swab

Assessment of oral flora in comparison with BAL

Pneumocystis jiroveci PCR

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.

4Therapy

4.1Pre-emptive Antimicrobial Therapy

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.

Figure 2: Pre-emptive Antimicrobial Therapy 
1 ASCT – autologous Stem Cell Transplantation

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).

4.2Targeted Antimicrobial Therapy

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).

4.3Respiratory Failure

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).

5References

  1. Maschmeyer G, Beinert T, Buchheidt D, Cornely OA, Einsele H, Heinz W, Heussel CP, Kahl C, Kiehl M, Lorenz J, Hof H, Mattiuzzi G. Diagnosis and antimicrobial therapy of pulmonary infiltrates in febrile neutropenic patients. 2008 updated guidelines of the Infectious Diseases Working Party of the German Society of Hematology and Oncology. Eur J Cancer 45:2462-72, 2009.

6Antimicrobial Drugs and Dose

Table 4: Betalactam Antibiotics (in alphabetical order) 

Drug

Daily Dose1

Application

Duration

Imipemem – Cilastatin

3 x 1 g oder
4 x 0,5 g

IV

until afebrile for at least 72 h

Meropenem

3 x 1 g

IV

until afebrile for at least 72 h

Piperacillin – Tazobactam

3 - 4 x 4,5 g

IV

until afebrile for at least 72 h

1 Dose for patients with normal renal function
Table 5: Antimycotics (in alphabetic order) 

Drug

Dose1

Application

Duration

Amphotericin, liposomal2

3 mg / kg

IV

until hematological recovery and resolution of clinical and radiological signs of infection

Voriconazole

Day 1: 2 x 6 mg / kg
From Day 2: 2 x 4 mg / kg

IV

until hematological recovery and resolution of clinical and radiological signs of infection

1 Dose for patients with normal renal function; 2 recommended in patients with pulmonary zygomycosis and in patients after treatment with voriconazole or posaconazole
Table 6: Antibiotics in Patients with Pneumocystis - Pneumonia 

Drug

Dose1

Application

Duration

Cotrimoxazole (Trimethoprim - Sulfamethoxazole)

3 - 4 x 30 - 40 mg/kg
or
3 - 4 x 2400 mg

IV

2 – 3 weeks and until hematological recovery and resolution of clinical and radiological signs of infection

Clindamycin plus Primaquine

3 - 4 x 600 mg plus
30 mg

IV
PO

2 – 3 weeks and until hematological recovery and resolution of clinical and radiological signs of infection

1 Dose for patients with normal renal function
Table 7: Antiviral Therapy in Patients with CMV Pneumonia 

Drug

Dose1

Application

Duration

Ganciclovir

2 x 5 mg / kg

IV

2 weeks and until hematological recovery and resolution of clinical and radiological signs of infection

1 Dose for patients with normal renal function;

8Authors’ Affiliations

Prof. Dr. med. Georg Maschmeyer
Klinikum Ernst von Bergmann
Zentrum für Innere Medizin
Klinik für Hämatologie, Onkologie
und Palliativmedizin
Charlottenstr. 72
14467 Potsdam
PD Dr. med. Thomas Beinert
Paracelsus-Kliniken
Klinik am See
Dehneweg 6
37581 Bad Gandersheim
Prof. Dr. med. Dieter Buchheidt
Klinikum Mannheim GmbH
Medizinische Fakultät Mannheim
III. Medizinische Klinik
Theodor-Kutzer-Ufer 1-3
68167 Mannheim
Prof. Dr. med. Oliver A. Cornely
Uniklinik Köln, Klinik I für Innere Med.
Zentrum für Klinische Studien
Infektiologie-Hämatologie-Onkologie
Kerpener Str. 62
50937 Köln
Prof. Dr. med. Hermann Einsele
Universitätsklinikum Würzburg
Medizinische Klinik und Poliklinik II
Oberdürrbacher Str. 6
97080 Würzburg
PD Dr. med. Werner Heinz
Kliniken Nordoberpfalz AG
Klinikum Weiden
Med. Klinik I
Söllnerstr.16
92637 Weiden
Prof. Dr. med. Claus Peter Heußel
Thoraxklinik am Universitätsklinikum Heidelberg
Abteilung für Diagnostische & Interventionelle Radiologie
Amalienstr. 5
69126 Heidelberg
Prof. Dr. med. Herbert Hof
Labor Dr. Limbach und Kollegen
Medizinisches Versorgungszentrum
Im Breitspiel 15
69126 Heidelberg
Prof. Dr. med. Christoph Kahl
Klinikum Magdeburg gGmbH
Klinik für Hämatologie, Onkologie und Palliativmedizin
Birkenallee 34
39130 Magdeburg
Prof. Dr. med. Michael Kiehl
Klinikum Frankfurt (Oder) GmbH
Medizinische Klinik I
Müllroser Chaussee 7
15236 Frankfurt (Oder)
Prof. Dr. med. Joachim Lorenz
Märkische Kliniken GmbH
Klinikum Lüdenscheid
Pneumologie und Internistische Intensivmedizin
Paulmannshöher Str. 14
58515 Lüdenscheid
Gloria Mattiuzzi
M.D. Anderson Cancer Center Houston
Department of Leukemia
Hematologic Malignancies
Supportive Care Program
Houston, Texas

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