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Neutropenia and aspergillosis

Prophylaxis

Primary prophylaxis of invasive aspergillosis is problematic. Oral nystatin, amphotericin B, ketoconazole and fluconazole are completely ineffective. Some data suggesting efficacy of nasal or aerosolised amphotericin B ( Meunier-Carpentier et al, 1984; Meunier et al, 1987; Jeffrey et al 1991; Todeschini et al, 1993; Hartenstein et al, 1994) have been generated by and challenged recently by a large randomised study (Heinemann et al, 1997) and others (Jorgensen et al, 1989) and tolerance is often poor (Erjavec et al, 1997). Some data are consistent with a protective effect of intravenous amphotericin B (Rousey, 1991 ;Tollemar et al, 1993) but this is not a universal experience and large controlled studies are lacking. Itraconazole capsules appear to have some impact (Tricot et al, 1987; Thunnissen et al, 1991; Todeschini et al, 1993; Vreugdenhil et al, 1993) but no randomised studies have been done and serum concentrations were very low in some patients. Itraconazole solution does appear to have a protective effect (Morgenstern et al, 1997) but at the cost of gastrointestinal side effects (diarrhoea especially) and poor patient tolerance because of the flavour. Recent meta-analyses with itraconazole came to differing conclusions – probably because itraconazole capsules are ineffective in preventing invasive aspergillosis, whereas itraconazole solution is partially effective, but with any impact on mortality (Bow et al, 2002; Glasmacher et al, 2003). Thus no perfect prophylactic agent is currently available.

Monitoring for invasive aspergillosis

Invasive aspergillosis is relatively common in neutropenia. The incidence depends on duration and depth of neutropenia, other patient factors such as age, corticosteroid use, prior pulmonary disease etc, the levels of environmental contamination the criteria for diagnosis and how hard the diagnosis is sought. It is rare in patients with a duration of neutropenia of 10 days or less and common (up to 70%) in patients with neutropenia of 30 days duration or more (Gerson et al, 1984). The incidence of invasive aspergillosis is probably less in children, but it certainly occurs and carries the same poor prognosis if diagnosed late. This section overviews therapy in profoundly neutropenic patients such as those undergoing chemotherapy for leukaemia, aplastic anaemia and following bone marrow transplantation. Milder degrees of neutropenia and neutrophil dysfunction are dealt with in other sections.

The clinical features of IPA during neutropenia include non specific-chest pains, dry cough and hemoptysis including blood stained sputum. Fever is usual, but not present ~10-15% of patients, and may be low grade. Occasionally a culture of Aspergillus in the nasal secretions or in sputum is obtained. Also indicative of disease is a major biological inflammatory syndrome with a fibrinogen level higher than 6g/l (Caillot et al, 1997). An elevated C-reactive protein is not specific. Any of these features should prompt a thoracic CT scan to search for signs of IPA.

Monitoring for infection - CT scanning for IPA in neutropenic patients

The occurrence of a febrile episode (most often a new episode in patients receiving broad spectrum antibiotics) or the identification of a new chest X-ray infiltrate during prolonged neutropenia (most often >2 weeks) in patients with hematological malignancies should prompt immediate systematic evaluation for invasive aspergillosis (Caillot et al, 1997). In neutropenic patients, thoracic CT-scan is a major tool for the diagnosis of IPA. A high resolution seen is best using 10-mm-thick sections and additional 1-mm thin sections through any suspected fungal lesions. Two CT signs are clearly identified as indicators of IPA. The CT 'halo' sign is described as a mass-like infiltrate with a surrounding 'halo' of ground glass attenuation. The halo lesion was shown to correspond to a central fungal nodule surrounded by a rim of coagulative necrosis (Hruban et al,1987). This 'halo' sign is highly indicative of IPA and it occurs early (first 3-7 days) in the course of IPA during the neutropenic period (Kuhlman et al, 1985; Potente et al, 1989; Blum et al, 1994; Caillot et al, 1997;). Rarely the 'halo' sign occurs with Mucorales, Fusarium or Pseudallescheria infections or in Pseudomonas pneumonia (in which cases blood cultures are almost always positive). The 'air-crescent' sign is described as a form of pulmonary cavitation. It is a later sign that appears with bone marrow recovery (Potente et al, 1989; Mori et al, 1991; Blum et al, 1994;). The 'air-crescent' sign is not pathognomonic of aspergillosis but in the setting of patients with hematological malignancies and especially in leukemic patients, it is highly suggestive of filamentous fungal disease (Funada et al, 1984).

The timing of the CT evolution of IPA may be roughly described as a three weeks development (Caillot et al, 2001). A halo sign is present in the first week, allowing early diagnosis, while the second week is mainly shows non-specific CT aspects (air space consolidation) not helpful for diagnosis and the third week could be considered as a late confirmation of diagnosis with evidence of air-crescent sign in some patients. Therefore, to be useful for IPA diagnosis, the CT scan must be performed very early in the course of the disease.

Monitoring for infection - antigen detection

In neutropenic patients at risk of invasive fungal disease, twice weekly Aspergillus antigen testing using the Platelia Aspergillus (sandwich ELISA) test for galactomannan is helpful. Some patients with invasive aspergillosis do not have fever, or appear to respond partially to antibiotics. If a test is positive, it should be repeated the next day and other investigations for IPA (such as a CT scan of the thorax) should be performed. A high OD value (esp >2) is almost always indicative of invasive disease. Aspergillus antigen may also be positive in bronchoalveolar lavage fluid, cerebrospinal fluid (in cases of cerebral disease or meningitis), pericardial, sinus or peritoneal fluid. False positive tests occur frequently in urine and may be more frequent in blood in young children and after consumption of certain foods such as noodles. In the setting of neutropenic patients, the specificity of Platelia Aspergillus is high rising up to 85-90% (Caillot et al, 2001, Herbrecht et al, 2002). Nevertheless, its sensitivity is not as good, especially in probable or possible aspergillosis (Herbrecht et al, 2002).

Criteria for initiation of therapy

Standard criteria for the initiation of therapy for invasive aspergillosis in the neutropenic patient are shown below (Denning et al,1994). They are quite similar to the recent international consensus published in 2002 (Ascioglu et al, 2002).

1. Isolation of Aspergillus from any site including nose swab, blood, BAL etc.
2. New pulmonary infiltrates on chest X-ray.
3. Infiltrates on CT scan of chest showing characteristic features, e.g. halo or air crescent sign pleural-based sharply angulated lesion pleural-based lesion with pneumothorax
4. Persistent fevers (>7 days) with any localising clinical features, e.g. chest pain,dry cough, facial/sinus pain, epistaxis, hoarseness, new skin lesions consistent with aspergillosis(usually icthyma gangrenosum appearance)
5. Any sudden intracranial event including stroke or fit, with or without fever.
6. Positive result for Aspergillus antigen in serum or BAL.

Choice of Antifungal Agent

Up to 2000, amphotericin B was the first choice in the treatment of aspergillosis. A dose of 1-1.25mg/Kg daily of conventional amphotericin B was necessary for successful therapy of invasive aspergillosis in neutropenic patients. One of the lipid-associated amphotericin B preparations could be substituted for conventional amphotericin B if infusion-related or renal toxicity was a problem - using a dose of 4-5mg/Kg daily. Itraconazole (400mg/d) is effective in around 50-70% of neutropenic patients (Denning et al, 1994; Caillot et al, 1997) including in some patients who have failed 1mg/kg/d of amphotericin B. Likewise, Amphocil (White et al, 1997), Abelcet (Walsh et al, 1998) and AmBisome (Mills et al, 1994) also have salvaged patients failing conventional amphotericin B.

Currently, new drugs are available for the treatment of invasive aspergillosis. Voriconazole, a new triazole (iv and oral forms) seems to have good activity against Aspergillus spp. Its superiority to amphotericin B as first line therapy has been demonstrated in a large randomized study in the treatment of invasive aspergillosis (Herbrecht et al, 2002). In this study, better response and improvement of survival were achieved in the voriconazole group. For iv route, the daily dosage is 8 mg/kg/d divided in 2 infusions after a loading dose of 12 mg/kg the first day. For oral administration the daily dose is 200 mg b.i.d. At present time, voriconazole seems to be the drug of choice as first line therapy in the treatment of invasive aspergillosis in neutropenic patients. Patients on rifampicin or certain other enzyme inducing drugs should not be treated with voriconazole because it will be difficult to achieve adequate therapeutic concentrations, and certain other drugs are problematic.

Caspofungin, a new echinocandin (only available in iv form) has also a good efficacy in the treatment of aspergillosis (Maertens et al, 2002). Most often, caspofungin is used in refractory or intolerant patients with aspergillosis. In adult, the daily dose is 50 mg/d after a loading dose of 70 mg the first day.

If invasive aspergillosis is progressing despite antifungal agent an alternative regimen should be used: high dose of AmBisome (Walsh et al, 2001) or experimental therapy.

Surgery should also be considered (see below). However, the severity of invasive aspergillosis in neutropenic means that combinations of certain antifungal agents in patients who do not respond to first line therapy. No study has compared single agent to combinations of antifungal agents have been done in invasive aspergillosis. Nevertheless, the complementary mechanism of action of caspofungin suggests that its combination with voriconazole or lipid derived of amphotericin B (as AmBisome or Abelcet) could be effective. Actually, only case reports about the use of combination of antifungal agents are available.

Surgery for invasive pulmonary aspergillosis

There are 3 indications for surgical resection of a pulmonary aspergillary lesion:

1. Prevention of massive hemoptysis when IPA threatens the integrity of pulmonary artery (emergency procedure).
2. Surgical reduction of a remaining Aspergillus mass before a new myeloablative treatment (especially before bone marrow transplantation)
3. Open lung tissue biopsy to confirm the diagnosis.

In immunocompromised patients with IPA and especially in neutropenic patients, massive hemoptysis directly causes death in 10-15% of patients in this setting (Pagano et al, 1995). The angiotropism of Aspergillus could explain the mechanism of hemoptysis although the precise mechanism is not clear. During the neutropenic period following chemotherapy, Aspergillus hyphae colonize the bronchi and invade small arteries and cause a local infarction (Przyjemski & Mattii, 1980). When marrow recovery occurs, the granulocyte count increases and proteolytic enzymes are released from leukocytes at the site of the aspergillary infection. This can cause local destruction of lung tissue (Weiss, 1989). In the setting of invasive pulmonary aspergillosis located near a pulmonary artery (or its dividing branches) this may cause a massive hemoptysis by arterial perforation. So the recovery of granulocyte count is a critical and dangerous period for the patient (Albeda et al, 1985). In the situation where IPA threatens the integrity of the pulmonary artery it is likely that a preventive surgical resection of the fungal lesion reduces the risk of death related to arterial perforation (Bernard et al,1997, Yeghen et al, 2000, Caillot et al 2001). The need for surgical intervention in these cases is best judged on observation of repeated contrast-enhanced CT scans. If a lesion is progressing and is in immediate proximity to a major pulmonary vessel, emergency surgery should be done before marrow recovery, due to potential deleterious effects of marrow recovery. Despite persistent neutropenia, perioperative complications are uncommon if the resection is limited to a lobectomy (Caillot et al, 1997 and 2001; Bernard et al, 1997, Yeghen et al, 2000)).

The surgical reduction of a remaining Aspergillus mass before further myeloablative treatment (including bone marrow transplantation) should be considered as an additional means of treatment (Wong et al, 1992; Moreau, et al, 1993). In these cases, surgery is performed after the recovery of neutropenia. In this setting, surgery can be either a lobectomy or a segmentectomy or a wedge resection, depending of the localisation of the aspergillosis lesion. 

Finally, the surgery is useful to make a diagnosis in patients with a pulmonary peripheral nodule. In this case the resection of an aspergillary nodule is done under thoracoscopy if possible (Bernard et al, 1997). Patients with pulmonary zygomycosis have a much lower mortality if treated surgically (Tedder et al, 1994) and as the diagnosis is not always clear, this way diagnostic approach may also be therapeutic.

Secondary prophylaxis

Secondary prophylaxis is indicated in those with persistent Aspergillosis who require further cytotoxic chemotherapy or bone marrow transplantation (Robertson & Larson, 1988; Martino et al, 1997, Offner et al, 1998). Typically amphotericin B (1mg/Kg daily) is used starting with the administration of cytotoxic chemotherapy (Karp et al, 1988). Secondary prophylaxis is particularly indicated for patients with Aspergillus sinusitis as these patients have a 50% relapse rate. Surgery may also be appropriate (Schathenberg et al, 1988; Martino, 1997; Offner et al, 1998)

Outcome

Patients whose leukaemia has relapsed also respond less well (Ribrag et al, 1993) as do those with bilateral pulmonary involvement (Caillot et al, 1997). A late diagnosis however is the most significant poor prognostic factor (von Eiff et al, 1995).

Prepared by:
Dr Denis Caillot, MD
Hopital Le Bocage
10, boulevard Marechal de Lattre de Tassigny
21000 Dijon
France

David W. Denning FRCP FRCPath FIDSA FMedSci
Professor of Medicine and Medical Mycology
Director, National Aspergillosis Centre
Education and Research Centre
University Hospital of South Manchester (Wythenshawe Hospital)
Southmoor Road
Manchester M23 9LT UK