Oesophageal and pulmonary invasive aspergillosis in a patient with multiple myeloma

Abstract

Invasive aspergillosis (IA) is a serious fungal infection that primarily affects patients with prolonged and profound neutropenia, and compromised cell-mediated immunity. Aspergillosis of the oesophagus and gastrointestinal tract is uncommon but seen in advanced cases of disseminated IA. However, it is difficult to diagnose antemortem due to the poor specificity of the symptoms and the absence of characteristic imaging findings. Therefore, the reported cases of gastrointestinal aspergillosis have been associated with high morbidity and mortality, and frequently diagnosed postmortem. Here we present a successful outcome in a patient with relapsed and refractory multiple myeloma who had presented with febrile neutropenia, cough and dysphagia, and was diagnosed with disseminated IA comprising of pulmonary and oesophageal involvement. This case highlights the need for a high index of suspicion and the importance of invasive procedures for histopathology and molecular diagnostics to ensure an early diagnosis and therapeutic intervention.

Background

Invasive aspergillosis (IA) is a life-threatening opportunistic infection of increasing incidence and importance in immunocompromised hosts. These include patients with prolonged neutropenia, high-dose and prolonged corticosteroid administration, allogeneic stem cell transplant recipients, solid organ transplant recipients or other conditions that can lead to chronically impaired cellular immune response.¹ Patients with multiple myeloma are not particularly at increased risk for invasive fungal infection early in the course of the disease; however, cumulative deficits in various arms of the immune system due to multiple lines of therapy for refractory or progressive disease may increase the risk for IA.²

Case presentation

A woman in her 60s with anxiety, peripheral neuropathy, and relapsed and refractory multiple myeloma who has previously undergone multiple lines of treatment (box 1) was presented with acute onset of fever associated with chills, and a 1-month history of left-sided pleuritic chest pain. She was on atovaquone 1.5 g once daily for anti-Pneumocystis prophylaxis and acyclovir 400 mg two times per day for Herpes simplex and Varicella zoster prophylaxis. Shortly after admission, she started having a productive cough with clear phlegm and shortness of breath. On evaluation, she was febrile (102.9°F) and in acute distress due to left-sided ribcage pain. Oxygen saturation on ambient air was normal. Respiratory system examination revealed crackles at lung bases. She had tenderness along the inferior aspect of the left scapula with intact skin exam.

Box 1. Multiple myeloma treatment history.

• Lenalidomide, bortezomib and dexamethasone

• Carfilzomib, pomalidomide and dexamethasone

• Autologous stem cell transplantation

• Pomalidomide

• Carfilzomib, pomalidomide and dexamethasone

• Daratumumab

• Talquetamab

• Chimeric antigen receptor T-cell therapy targeting B cell maturation antigen using fludarabine and cyclophosphamide lymphodepleting chemotherapy

• Bendamustine, bortezomib and dexamethasone

• Cevostamab

• Bortezomib, dexamethasone, cyclophosphamide, etoposide and cisplatin

Investigations

Laboratory studies revealed pancytopenia. White blood cell count was 0.2x10⁹/L, haemoglobin 74 g/L and platelet count 6x10⁹/L. The patient had chronic severe neutropenia and lymphocytopenia with an absolute neutrophil count below 500/µL and an absolute lymphocyte count below 1000/µL for the last 6 months prior to presentation. Serum creatinine was 0.5 mg/dL. CT of the chest showed multifocal dense pulmonary consolidations (figure 1A). Diagnostic bronchoscopy was performed showing normal tracheobronchial anatomy. Bronchoalveolar lavage and serum Aspergillus galactomannan antigen were positive, with an index of 3.05 and 2.18, respectively. No other infectious aetiology was identified.

Figure 1.

(A) Coronal chest CT reconstruction (lung window) showing a large lingular consolidation as well as a right upper and middle lobe focal consolidation. (B) Repeat chest CT 3 months later shows near complete resolution of pulmonary consolidations.

Outcome and follow-up

Patient was initially diagnosed with probable invasive pulmonary aspergillosis per the European Organisation for the Research and Treatment of Cancer and the Mycosis Study Group criteria.³ Antifungal therapy was started consisting of intravenous isavuconazole 372 mg every 8 hours for six doses followed by 372 mg daily and micafungin 100 mg intravenous daily. Isavuconazole was used instead of voriconazole given its safer drug profile and favourable pharmacokinetics, and micafungin was added for synergism. Fever subsided 2 days after treatment initiation and there was an improvement in cough and shortness of breath. However, soon thereafter she reported a postprandial heartburn associated with a sensation of food getting stuck behind her sternum. An upper endoscopy was performed that revealed a clean-based ulcer in the distal oesophagus (figure 2A). The remaining segments of the oesophagus and stomach were normal. Endoscopic biopsies showed an ulceration with invasive hyphae, morphologically suggestive of Aspergillus spp (figures 3 and 4).

Figure 2.

(A) Upper endoscopy showing a clean-based ulcer in the distal oesophagus. (B) Repeat upper endoscopy performed 6 weeks later shows an irregular Z-line with resolution of distal oesophageal ulcer.

Figure 3.

H&E stained oesophageal biopsy (×200 magnification) showing septated hyphae with acute-angle-branching suggestive of Aspergillus spp.

Figure 4.

Gomori methenamine-silver (GMS) stain (×400 magnification) highlighting fungal hyphae.

On resolution of symptoms that included dysphagia, she was discharged home with oral isavuconazole and intravenous micafungin. She developed an adverse drug reaction to antifungal agents, characterised by pulsatile tinnitus, particularly after completion of micafungin infusion. She also experienced nausea, dizziness and shortness of breath shortly after initiation of chemotherapy with selinexor, carfilzomib and dexamethasone, and while on isavuconazole. In light of these symptoms, she was switched to oral voriconazole 400 mg two times per day for day 1 followed by 200 mg two times per day with good tolerability. A voriconazole trough level collected 7 days after start date was subtherapeutic at 0.3 µg/mL (goal plasma level: 2–5 µg/mL) thus the dose was eventually increased by 50% to 200 mg three times per day achieving a therapeutic level of 2.9 µg/mL.

Repeat upper endoscopy performed 6 weeks after antifungal treatment initiation showed an irregular Z-line with resolution of distal oesophageal ulcer (figure 2B). Endoscopic biopsies were negative for fungal organisms. A CT chest done 12 weeks after initiation of treatment showed near complete resolution of pulmonary infiltrates (figure 1B). She was continued on voriconazole as secondary antifungal prophylaxis thereafter because of initiation of chemotherapy with selinexor, carfilzomib and dexamethasone.

Discussion

Invasive pulmonary aspergillosis (IPA) is the most common form of IA, whereas aspergillosis of the gastrointestinal (GI) tract is rather uncommon but reported in advanced cases of IA. The oesophagus is the most common site of infection in the GI tract, followed by the colon and small intestine while isolated gut aspergillosis is rarely seen.⁴ Disease mainly occurs from haematogenous spread, which was suspected in this case. The digestive tract has been suggested as a potential portal of entry in the setting of mucositis where the integrity of the gut lining is compromised.^{5 6} IPA may be complicated by contiguous spread to the oesophagus but this has been only anecdotally reported.⁷

In a retrospective series of 21 haematology patients with biopsy-proven GI IA, which included two cases with oesophageal involvement, the most common symptoms recorded were fever (67%), abdominal pain (81%), diarrhoea (47%), GI bleeding (33%) and intestinal occlusion (29%). These symptoms, which were non-specific, led to an endoscopic evaluation and ultimately diagnosis in only six patients (29%). GI IA was established by laparotomy in almost half of the patients (47%) whereas in five patients (24%) the diagnosis was made postmortem.⁸

These findings suggest that GI IA remains undiagnosed and underestimated, particularly in patients with haematological malignancy where abdominal symptoms could be attributed to conditions such as neutropenic colitis, mucositis or graft-versus-host disease. For instance, in a postmortem case series of patients with haematological malignancy and IA, GI IA was seen in a third of cases and neither were clinically suspected nor diagnosed antemortem though half of the patients had some symptoms, including upper abdominal pain and massive melena.⁹ Aspergillus galactomannan antigenaemia unexplained by pulmonary lesions should also raise suspicion for GI IA in the presence of abdominal symptomatology.

In our case, the presence of dysphagia prompted an endoscopic evaluation that established an accurate and timely diagnosis of oesophageal IA which otherwise would have been missed. Endoscopic examination typically demonstrates focal areas of ulceration of variable depth and abscess formation. Histopathological sections show hyphal infiltration of the digestive tract wall, arteritis and thrombus formation within intramural vessels.¹⁰

Aspergillosis of the oesophagus and GI tract is managed with antifungal therapy and, in some cases, surgical intervention in attempts to prevent complications of haemorrhage, perforation, obstruction or infarction. The Infectious Diseases Society of America guidelines recommend the use of voriconazole as primary antifungal agent for IA, while isavuconazole and amphotericin B are considered alternative therapies.¹ However, in a recent randomised controlled trial isavuconazole has demonstrated similar efficacy compared with voriconazole for the treatment of IA.¹¹ As a result, international guidelines now recommend isavuconazole, as well as voriconazole, as standard treatment for IA in patients with underlying haematological malignancies.^{1 12 13} In our patient, treatment with isavuconazole was initiated after the patient met criteria for probable IPA because of the more favourable pharmacokinetic and tolerability profile, and fewer drug-drug interactions than voriconazole. Micafungin was added because of the in vitro and clinical data suggesting that administration of an echinocandin in combination with triazole may improve outcomes in immunocompromised patients with IA.¹⁴ The patient developed a suspected micafungin-induced ototoxicity which mechanism is unclear as there are currently no reports of this phenomenon in the literature. Isavuconazole therapy was also complicated by non-specific adverse effects that coincided with the restart of chemotherapy. Cytochrome P450 3A4 inhibition by isavuconazole leading to increased dexamethasone concentrations may have contributed to these non-specific adverse effects; however, similar reactions are also expected with voriconazole making drug interactions a less likely cause of these adverse events.^{11 15} Although drug-related adverse events in clinical trials were more common in patients receiving voriconazole than isavuconazole, voriconazole was better tolerated in this particular case. In patients with IPA, the treatment should be continued for a minimum of 12 weeks or until radiological resolution, whichever occurs later.1 12 13 16 The optimal duration of antifungal therapy in oesophageal IA has not been determined because of the paucity of data.¹

The few well documented cases of GI IA have been associated with high morbidity and mortality as the diagnosis is rarely made antemortem. In published case series, the overall mortality of GI IA was between 47% and 60%.^{4 8} In our patient, a high index of suspicion combined with histopathology and molecular diagnostic techniques were important to establish an accurate diagnosis and prompt treatment which positively impact the patient’s survival.

Patient’s perspective.

I was very scared when the tests confirmed the diagnosis of a fungal infection in my body. I started feeling better a week after the antifungal treatment was started, and I am happy to say that I survived this infection.

Learning points.

• Aspergillosis of the oesophagus and gastrointestinal tract is difficult to diagnose, and it carries a high mortality.

• Digestive tract involvement should be considered in patients with invasive pulmonary aspergillosis who develop dysphagia, abdominal pain, bloody diarrhoea or melena.

• Prompt endoscopic evaluation and tissue biopsy is the key to establish the diagnosis of invasive aspergillosis.

Ethics statements

Patient consent for publication

Consent obtained directly from the patient(s).