A Case of Pulmonary Aspergillosis (with many teaching points)

A man in his 50s presented to our clinic for evaluation.  He is a former smoker.  Symptoms started 4 years prior with cough and hemoptysis.  He was found to have hilar lymphadenopathy with perihilar and upper lobe opacities.  He was given the diagnosis of sarcoidosis. After developing recurrent hemoptysis, imaging was repeated and showed what looked like an aspergilloma. Indeed, transbronchial biopsy demonstrated epithelioid granulomas and cultures grew Aspergillus fumigatus. 

When first seen by us, he endorsed fatigue, poor exercise capacity and chronic productive cough. He had hemoptysis almost on a daily basis ranging from blood-tinged sputum to clots.  He denied fevers.

We reviewed the imaging findings.  Prominent mediastinal and bilateral hilar lymphadenopathy was noted.  Conglomerate opacities with volume loss and architectural distortion was also seen.  Cavitary/cystic lesions were filled by nodular soft tissue admixed with gas.

Below you can see the CT images.  In the second image you can clearly see an aspergilloma within a cavitary lesion on the left.

The thinking was that the patient has underlying sarcoidosis with secondary fungal infection. I have been wondering whether he only has advanced aspergillosis (I will get back to that later).  

The Clinical Spectrum of Aspergillosis

Here is an overview of the different forms of pulmonary aspergillosis: Invasive pulmonary aspergillosis affects patients with severely impaired immune function (e.g.,  patients with neutropenia, hematopoietic stem cell or solid organ transplant). Chronic pulmonary aspergillosis typically affects  those with underlying lung disease without an overt immunocompromising condition. Allergic bronchopulmonary aspergillosis affects those with  allergic hypersensitivity (typically patients with asthma). I highly recommend reading a review article on the clinical spectrum of pulmonary aspergillosis authored by my colleagues Chris Kosmidis and David Denning.

So, who can be affected by chronic pulmonary aspergillosis? There is a long list of conditions: pulmonary tuberculosis (most common worldwide), nontuberculous mycobacterial infection, allergic bronchopulmonary aspergillosis, asthma treated with steroids, lung cancer, prior pneumothorax with bulla(e) formation, chronic obstructive pulmonary disease, fibrocavitary sarcoidosis,  rheumatoid arthritis with pulmonary nodules, ankylosing spondylitis, pneumoconiosis, silicosis and other rare conditions. 

As you can see, sarcoidosis is listed above. In a US cohort of patients with sarcoidosis, 2% had Aspergillus lung disease.  It is plausible that our patient had sarcoidosis which was complicated by aspergillosis. I note that he did not receive longterm glucocorticoid treatment which would have predisposed him to developing infection. One may argue that sarcoidosis causes a degree of immunosuppression, as it may affect lymphocyte counts. 

There is a pattern of slowly evolving aspergillosis with single or multiple lung cavities. These cavities may or may not be filled with mycetoma(s). The entity is called chronic cavitary pulmonary aspergillosis. In some patients with more rapid disease progression there is presence of nodules and consolidations with or without cavity. This is called subacute invasive aspergillosis or  chronic necrotizing pulmonary aspergillosis. In this patient, the consolidations may represent subacute invasive disease (if not related to sarcoidosis).

Antifungal Treatment

The patient was initially treated with voriconazole. He developed symptoms of peripheral neuropathy (pain and numbness in the distal lower extremities). It was not recognized that peripheral neuropathy was caused by voriconazole. His neuropathy became irreversible. Eventually, treatment was changed to isavuconazole and this led to mild pain improvement. 

Peripheral neuropathy is a well-recognized side effect of triazole use, most commonly occurring with itraconazole. I always discuss this with my patients receiving chronic therapy.  It has also been reported in association with voriconazole (and much less commonly with posaconazole or isavuconazole).  

Surgical Management

The patient was offered surgical management for his condition. Pulmonary function tests showed that he is eligible for bilateral upper lobectomy.  A staged approach was pursued.  Per my discussion with surgery, this was done to allow gradual healing.  

At first, the patient underwent left upper lobectomy. Histopathology demonstrated chronic granulomatous inflammation, cystic degeneration, and necrotic cavity. Below you can see images that we were able to retrieve using Digital Pathology. The Gomori methenamine silver (GMS) stain was used. Hyphal morphology is consistent with Aspergillus. 

 

The pathology report read as follows: "The extensive nature of the non-necrotizing granulomatous inflammation with associated fibrosis, as well as the distribution with an apparent lymphatic pattern, raise the possibility of background fibrotic sarcoidosis.The fungus has morphologic features consistent with Aspergillus, and is mainly present within the cavity without tissue invasion.  However, there are some areas of acute inflammation and necrosis associated with the cavity, and thus a semi-invasive infectious process cannot be excluded. Furthermore, the possibility that the background pulmonary non-necrotizing granulomatous inflammation is due to infection cannot be completely excluded, although it seems less likely based on overall morphologic features". So well thought-out!

Essentially, the pathologist believes that the patient has underlying fibrotic sarcoidosis but cannot exclude the possibility that the disease is merely caused by infection.

Azole Resistance

Operative cultures grew Aspergillus fumigatus. No surprise there. We continued isavuconazole. On postoperative follow-up, the surgical incision was healing well. However, the patient endorsed worsening hemoptysis (always a concerning symptom as it can be potentially life-threatening). 

Antifungal susceptibility testing showed resistance to two azole antifungals. Minimum inhibitory concentrations (MICs) in mcg/mL: Itraconazole 0.5, voriconazole 2, posaconazole 0.25 and isavuconazole 2. 

Is azole-resistant Aspergillus fumigatus present in the US? Apparently, it is! Prolonged mold-active azole exposure in a patient with mycetoma is the perfect setting for emergence of resistance. 

Acquisition of resistant strains from the environment has been reported in Western Europe (mainly in the Netherlands). It has been proposed that this is related to the use of fungicides in agriculture. Paul Verweij has extensively studied azole resistance in aspergillosis. Those interested should definitely review his work. At a national reference center for chronic pulmonary aspergillosis in the United Kingdom, we reported a rate of 16.7% of pan-azole resistance. Most of these patients had prolonged exposure to azole antifungals. Using high-volume sputum culture we were able to greatly enhance the detection of Aspergillus species and run antifungal susceptibility testing. This work was led by Malcolm Richardson.

Interestingly, resistance to voriconazole may be accompanied by resistance to isavuconazole. This has to do with the specific target and mechanism of drug action. As outlined above, the patient had prolonged exposure to both voriconazole and isavuconazole. We were left with posaconazole as the only treatment option (I would be very hesitant to use itraconazole in a patient with severe voriconazole-associated peripheral neuropathy). Novel antifungals with in vitro activity against Aspergillus include ibrexafungerp, olorofim and fosmanogepix. These are promising treatment options for azole-resistant strains. 

Closing the Case

The patient went for right upper lobectomy two months after the initial surgery. I believe that he is at risk for recurrent disease given his high fungal burden. Risk factors have not been clearly delineated. The risk of recurrence may be higher in the setting of  intraoperative fungal spillage or dense adhesions to the pleura. There may be genetic factors (Future research will show). We are continuing antifungal treatment for 12 months postoperatively and keeping an eye for emergence of posaconazole resistance.

By the way, do you know how Aspergillus got its name? The organism was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under the microscope, Micheli was reminded of the shape of the aspergillum that is used to sprinkle holy water.