Acute invasive aspergillosis may occur in patients with prolonged severe neutropenia, as a complication of immunosuppressive treatment in allogeneic hematologic or solid organ transplantation, or in prolonged treatment with high doses of corticosteroids. However, this infection may arise unexpectedly in different circumstances and be misdiagnosed in vivo, as it is diagnosed only by necropsy in up to 40% of the cases [1]. There are anecdotal reports of this complication in patients with AL amyloidosis and heart plus stem cell transplantation, in AA amyloidosis with chronic lung disease, recurrent infections and steroid treatment, or AIDS. Nevertheless, there are no references regarding invasive aspergillosis in end stage renal disease except for patients with kidney allograft. Herein we report a unique patient with recent diagnosis of multiple myeloma, congestive heart failure and end stage renal disease, who died after an acute respiratory failure shortly after starting chemotherapy, showing unexpected findings at necropsy. In a review of the literature (Medline by Ovid and PubMed) with keywords: aspergillosis, myeloma, amyloidosis and advanced renal failure, we have not found any similar case.

A 58 year old male was admitted because of persistent back pain, which started a few months before, and more recent asthenia, legs edema, and progressive dyspnea. On clinical examination the patient appeared in acute distress with mucocutaneous pallor, generalized weakness, and tachypnea at 22 breaths per minute, with basal oxygen saturation at 91%, blood pressure at 100/60 Hg mm and arrhythmic pulse at 64 beats per minute.Neck venous distension and hypoventilation with crackles in lung bases were noted, without murmurs in heart auscultation or palpable liver or spleen. Lower limb peripheral edema was noted. Blood tests showed severe normocytic anemia (hemoglobin:6.8 g/dl), mild leukocytosis (12000/microliter;76% neutrophils), normal platelets count, high serum urea (381 mg/dl) and creatinine (20 mg/dl), hyperuricemia (10.5 mg /dl), hyperphosphatemia (8.6 mg /dl), hyperpotassemia (7 meq/L), hypertransaminasemia (GPT:529 U/L), raised alkaline phosphatase (297 U/L) and LDH (772 U/L), metabolic acidosis with low bicarbonate (9 meq /L) and pH (7.1), and hypoalbuminemia (3.2 g/dl). Beta2-microglobuline was raised at 58 mg/L, and a serum monoclonal component of κ chains (with a κ / λ ratio of 320/2.8 mg/dl) and urine Bence-Jones κ proteinuria (1.4 g/24 hours) were detected.Electrocardiogram showed an atrial fibrillation with wide QRS and QS pattern in III and aVF leads.Cardiomegaly, hilar congestion, bilateral pleural effusion and an extrapleural mass in left hemithorax were observed in chest radiography. Enlarged suprahepatic veins and signs of renal cortical atrophy were found in abdominal ultrasound.

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Figure 1. Rib plasmocytoma.

The patient was started on hemodialysis and blood transfusion (two units of packed red blood cells) with improvement of anasarca, heart failure and liver function tests. Echocardiogram showed septal wall thickness of 0.9 cm and left ventricular ejection fraction of 55%. Radiological survey and computed tomography showed an extrapleural mass (figure 1) and lytic lesions in the fourth lumbar vertebra and right iliac bone. Rib tumor biopsy was diagnostic of k light chain plasmacytoma, and iliac crest aspiration and biopsy showed a 58% infiltration of k light chain plasma cells.

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Figure 2. Lung aspergillosis.

K light chain multiple myeloma, III B Durie-Salmon, 3 International Staging System score, was diagnosed and darbopoetin along with vincristine-adriamycin-dexamethasone combination started, without any clinical or analytical improvement after the first dose. A pacemaker was implanted because of symptomatic atrioventricular blockade alternating with supraventricular tachycardia. Chemotherapy schedule was switched to bortezomib-dexamethasone, although the first cycle was terminated due to clinical worsening with adynamic ileus and increasing dyspnea without fever. Chest radiograph showed bilateral alveolar infiltrates.A suspected bronchoaspiration pneumonia was empirically treated with piperacillin-tazobactam. Nevertheless, the patient continued to worsen and deceased, 50 days after admission. Neutrophil count had been sustainedly over 1400/microliter.The accumulated dose of dexamethasone had been three cycles of four days with a daily 40 mg dose in the first cycle of chemotherapy and two cycles of two days with a daily 20 mg dose in association with bortezomib in the second.

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Figure 3. Coronary vessel thrombus with aspergillus (inset).

Necropsy was performed. Macroscopic examination showed bilateral bronchopneumonia with large areas of necrosis, cardiomegaly with whitish lesions in the pericardium, left atrium and ventricle, hepatosplenomegaly and costal and left iliac bone tumors. Microscopic examination yielded septate, radiated, branching with 45-degree angle hyphae within pneumonic infiltrates, invading parenchymatous vessels, concordant with aspergillus sp. (figure 2). These hyphae were also found in myocardium, endocardium, and pericardium abscessified areas. Coronary arteries occlussion by neutrophils and hyphae was observed in myocardium (figure 3).

An amorphous eosinophylic material was detected in vascular walls and among muscle fibers, as well as in hepatic and splenic vessels. In kidneys the eosinophylic deposit was distributed around tubules and vascular walls sparing glomeruli (figure 4). Immunohistochemistry of this material was positive for κ chains and P amyloid component. It was concluded that the cause of dead was an invasive acute lung and heart aspergillosis in the setting of multiple myeloma with AL amyloidosis and multifactorial renal failure.

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Figure 4. Kidney amyloidosis.

Multiple aspergillus species are present in our environment and inhalation of infectious conidia is considered frequent. First defense line against fungi proliferation resides in pulmonary macrophages, while polymorfonuclear leucocytes and cellular immunity prevent invasive disease [2].This explains why invasive aspergillosis is generally observed in patients with prolonged severe neutropenia, as in the period of hematological recovery after allogeneic transplantation, prolonged treatment with high doses of corticosteroids, or prolonged immunosuppression in solid organ transplantation. In multiple myeloma patients acute invasive aspergillosis has been observed in the setting of allogeneic stem cell transplantationand, also in AL amyloidosis after heart allograft and autologous stem cell transplantation [3]. While prolonged corticosteroid therapy, often in a background of chronic lung disease, has been associated with invasive aspergillosis [4], in our patient dexamethasone dose was not high (the usual in initial treatment of myeloma) and of short duration. There was not either an environmental exposure with possible inhalation of high levels of aspergillus conidia in our patient. In addition, necropsy observations and experimental studies suggest that invasive aspergillosis in the setting of prolonged neutropenia is characterized by remarkable angioinvasivity, severe necrosis and high burden of fungi, while that associated with high doses of steroids is associated with a more prominent inflammatory component and a lower load of microorganisms [5], unlike the microscopic findings observed in our patient. Notably, in this case, with absent risk factors and such an atypical presentation, diagnosis of acute invasive aspergillosis was totally unexpected.

Different causes of death were reasonably ruled out. Diagnosis of cardiac AL amyloidosis was suspected in vivo because of diastolic heart failure and electrocardiographic record with alternating slow and fast arrhythmias. Initial volume overload responded to hemodialysis, so the final outcome was not attributable to heart amyloidosis. Regarding the type of renal failure, in this case, as in a low proportion of AL amyloidosis, peritubular and vessel wall involvement with amyloid deposit sparing glomeruli was observed, with isolated k light chain proteinuria. These findings are in contrast with the usual preferentially glomerular involvement with prominent proteinuria typical of AL amyloidosis [6]. Accordingly, in our case the size of the kidneys was decreased, unlike typical AL amyloidosis. As for the episode of abdominal distention with adynamic ileus, both amyloid autonomic neuropathy and bortezomib treatment may have been involved. Neither renal nor abdominal involvement were critical on the patient's condition, and were undoubtedly unrelated to the early fatal outcome. Conversely, severe cardiac involvement by aspergillus invasive infection explains the rapid deteriorationand death despite supporting therapy.

This case illustrates the need for awareness of this severe life threatening infectious complication, which may occur even in the absence of typical risk factors, as it did in our patient. A high degree of suspicion of acute invasive aspergillosis, even beyond its usual clinical setting, may prompt appropiate diagnostic procedures and early specific treatment, and thus improve survival. Fungal infections need to be ruled out in cases of severe worsening unexplained disease in patients with haematological and multiorganicl diseases, even in cases without significant immunosuppressive treatment.

All authors have seen and approved the manuscript and contributed significantly to the work. The manuscript has not been previously published nor is being considered for publication elsewhere.

Conflict of interest: Authors declare no conflict of interest