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Q1: What do the computed tomograms show?
Computed tomography of the thorax (fig 1, see p 733) showed multiple nodules of varying sizes in the lung parenchyma. There is also a mass measuring 3 × 4 cm at the apical segment of the right lower lobe with adjacent consolidation. These findings were not seen in the chest radiograph that was performed one day earlier. However repeat radiography that was done one week after the computed tomography of the thorax showed a cavitating mass at the apex of the right lower lobe and two nodules measuring 1–2 cm at the right middle and left lingular lobes. Computed tomography of the abdomen (fig 2, see p 733) revealed numerous small non-enhancing lesions in the spleen.
Box 1: Stratification of episodes and definitions of invasive aspergillosis1
Positive tissue biopsy with typical filamentous fungi + positive culture for aspergillus species from the same site, or
Positive culture for aspergillus from an otherwise sterile body fluid (not including brochoalveolar lavage fluid).
Positive brochoalveolar lavage test for aspergillus (direct examination and/or culture) + suggestive thoracic computed tomography (halo or air crescent signs)*.
In patients without positive culture or cytology:
Computed tomography evidence of invasive infection of the nasal passage, sinuses, or central nervous system in high risk patients.
Typical clinical signs and symptoms (for example, pleuritic chest pain) in the presence of characteristic features on computed tomography of the thorax.
In persistently neutropenic patients with negative cultures for bacteria and without evidence of viral illness (with or without pulmonary infiltrates):
Fever not responding to five days of adequate broad spectrum antimicrobials.
Relapsing after initial defervescence.
- Highly probable of invasive pulmonary aspergillosis
Q2: What is the most likely cause of the persistent fever in this patient and how would you confirm the diagnosis?
The clinical and radiological findings were strongly suggestive of deep seated fungal infection. Although pulmonary tuberculosis can present as cavitating lesions, nodules are an unusual presentation. Tuberculous granuloma of the spleen and liver may produce similar radiological appearances but it is less likely with persistent fever that is not responsive to broad spectrum antibacterial agents in a profoundly neutropenic patient. Opportunistic infection of the liver and spleen due to Pneumocystis carinii,Candida albicans, and aspergillus can produce a similar radiological appearance. P carinii infection is less likely as the patient was given co-trimoxazole prophylaxis and the lung changes are not suggestive of this condition. In the present case, Aspergillus fumigatus was identified in the splenic aspirate. Aspergillus antigen was also detected in the serum samples using latex particle agglutination test. Stratification of definitions of invasive aspergillosis is summarised in box 1.1
Persistent fever in a neutropenic host suggests an occult fungal infection.
Aspergillus pneumonia is the most common fungal pulmonary infection in immunosuppressed patients.
Invasive aspergillosis can be suggested by the clinical picture in an appropriate setting.
In leukaemic patients who have been neutropenic for more than seven days and remain febrile despite broad spectrum antibacterial therapy, any nodular infiltrate is highly suggestive of invasive aspergillosis.
Blood culture and plain chest radiograph are insensitive means of making a diagnosis of invasive aspergillosis.
In neutropenic patients, thoracic computed tomography is a major tool for the diagnosis of invasive pulmonary aspergillosis.
The successful management of invasive aspergillosis depends on earlier initiation of antifungal therapy (within 96 hours of onset).
Computed tomograms allow earlier diagnosis of invasive aspergillosis and thereby could improve the prognosis dramatically among febrile neutropenic patients.
Q3: What is the treatment for this condition?
Amphotericin B is the standard treatment for invasive aspergillosis but has limited success.2 There are numerous regimens for the administration of this drug but in neutropenic patients, it is important to give the full dose from the outset. High dose must be used (at least 1.0 mg/kg/day of conventional amphotericin B). The optimum duration of treatment has not been established, but amphotericin B should be continued at least until the neutrophil count is >0.5 × 109/l. Thereafter treatment should be continued until symptoms resolve and radiological (on radiography and computed tomography) abnormalities disappear. Consolidation therapy with itraconozole is often appropriate, often for long periods. Relapse occurs even after months of treatment if patients remain immunocompromised. If renal dysfunction is likely to be a major problem or the fungal infection progresses despite treatment with an adequate dose of conventional amphotericin B, then one of the lipid associated preparations of amphotericin B or itraconazole is appropriate.3 Our patient received amphotericin B, resulting in resolution of the symptoms two weeks later. The lesions in the lung and liver cleared while residual nodules were noted in the spleen after a total of 1.3 g of conventional amphotericin B. The patient declined further inpatient treatment and was discharged with itraconazole 400 mg/day and currently awaiting allogeneic stem cell transplantation.
Invasive aspergillosis is an increasingly recognised condition in immunocompromised hosts. Patients with prolonged and severe neutropenia after chemotherapy for haemato-oncological disorders and steroid treated allogeneic bone marrow transplant recipients are particularly at risk. Its prognosis remains poor in leukaemic patients, despite amphotericin B treatment. The crude mortality rate of invasive aspergillosis approaches 100% and results at least partly from difficulties in obtaining a reliable diagnosis at an early stage of the disease.4 Improvement of prognosis needs early recognition of invasive aspergillosis and effective antifungal treatment. Confirmation of such infection by clinical and laboratory examination can be extremely difficult. Definite proof of invasive aspergillosis implies the demonstration of hyphal invasion in tissue specimens with a positive culture for species from the same specimen.5 Cultures may require days or weeks to grow, while the histopathological examination of tissue specimens obtained by invasive procedures is often precluded by profound cytopenia. Consequently, in daily clinical practice, physicians combine clinical, radiological, and/or microbiological criteria to define the level of probability of invasive aspergillosis. However, these criteria either lack sensitivity and specificity or depend largely on a high fungal burden.6 The detection of circulating fungal antigens had been advocated as a promising indirect diagnostic method to overcome these drawbacks. Serial determination of serum galactomannan (a major aspergillus exoantigen released during invasive disease) at a lower threshold should allow earlier diagnosis of invasive aspergillosis.1 7 Caillotet al analysed the course of invasive pulmonary aspergillosis in 37 patients with haematological malignancy and demonstrated that systematic computed tomography allows earlier diagnosis of invasive pulmonary aspergillosis and thereby improves overall survival among these patients.8 The computed tomography features that were identified as indicators of invasive pulmonary aspergillosis included angiotropic nodular parenchymal lesions (>0.5 cm), the halo sign, air crescent sign, and wedge shaped, pleural based infiltrates. The computed tomography halo sign is described as a mass-like infiltrate with a surrounding halo of ground glass attenuation and it occurs early in the course of invasive pulmonary aspergillosis. The air crescent sign is a cavitating pulmonary lesion. We have demonstrated in this case that computed tomograms are useful for making an early diagnosis of invasive aspergillosis and it had significantly influenced the outcome of the treatment. Performance of high resolution pulmonary computed tomography as early as possible is warranted in neutropenic patients presenting with non-resolving fever even if the chest radiograph is normal.
Invasive aspergillosis in the lungs, spleen, and liver.
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