Nontuberculous Mycobacterial Infection Predisposing to Chronic Cavitary Pulmonary Aspergillosis

Aspergillus is a large group of spore-forming fungi in the phylum Ascomycota. Aspergillus infections more frequently occur in individuals with pre-existing lung conditions such as cystic fibrosis and asthma and immunosuppressed individuals, and less frequently in the immunocompetent population. Pulmonary aspergillosis can be subdivided into three categories: allergic bronchopulmonary aspergillosis, chronic pulmonary aspergillosis, and invasive pulmonary aspergillosis. We present a rare case of a 57-year-old male with a previously known diagnosis of pancreatic adenocarcinoma on chemotherapy who was found to have a co-infection of the respiratory tract by Aspergillus flavus and Mycobacterium avium intracellulare.


Introduction
Chronic pulmonary aspergillosis (CPA) comprises several different disease manifestations of chronic aspergillosis: simple aspergillomas, Aspergillus nodules, chronic cavitary pulmonary aspergillosis (CCPA), and chronic fibrosing pulmonary aspergillosis. CCPA, in particular, is characterized by one or more pulmonary cavities with or without aspergillomas, symptoms present for at least three months, and a positive Aspergillus immunoglobulin G (IgG) serology.
Mycobacterial infections are also capable of causing various pulmonary manifestations, particularly in immunosuppressed individuals. Both Aspergillus and Mycobacterium are opportunistic pathogens that can cause severe pulmonary disease, but co-infection of the respiratory tract with both pathogens is rarely reported in the literature [1]. It is estimated that up to 3 million people are affected by CPA worldwide [2]. Here, we present a rare case of a 57-year-old male with a previously known diagnosis of pancreatic adenocarcinoma on chemotherapy who was found to have co-infection of the respiratory tract by Aspergillus flavus and Mycobacterium avium intracellulare.

Case Presentation
A 57-year-old male with a past medical history pertinent for hyperlipidemia, pancreatic adenocarcinoma diagnosed six months prior and on chemotherapy, as well as recurrent bouts of pancreatitis presented to our institution due to shortness of breath, fever, chills, and epigastric abdominal pain radiating to his back and associated with nonbloody emesis that had been present for five days prior to arrival. Physical examination revealed a cachectic and frail man, with epigastric abdominal tenderness and voluntary guarding. Vital signs revealed a blood pressure of 102/63 mmHg, heart rate of 62 beats per minute, temperature of 36.9°C, oxygen saturation of 99% at room air, and a respiratory rate of 16 breaths per minute. Initial laboratory studies revealed an elevated lipase of 1671 U/L (10-140 U/L) and leukocytosis of 17.1 × 10 3 /uL (4.0-10.5 × 10 3 /uL) with a 75% neutrophilic predominance. A chest radiograph revealed a large right-sided apical cavitary lesion measuring up to 6 cm ( Figure 1). 1 2 3 4 4

FIGURE 1: Chest radiograph demonstrating a right-sided apical cavitary lesion (yellow arrow) and a chemotherapy port (blue arrow).
A computed tomography (CT) scan of the chest with intravenous (IV) contrast was obtained to further characterize the findings evident on the chest radiograph which revealed a cavitary lesion with internal dependent debris and air-fluid level in the right upper lobe apical and anterior segment measuring 5.7 × 5.7 × 5.8 cm (Figure 2). The patient was started on aggressive IV fluid hydration with Ringer's Lactate for the treatment of pancreatitis as well as IV piperacillin-tazobactam to cover for the possibility of bacterial cavitary pneumonia.
Bronchoscopy with bronchoalveolar lavage (BAL) was performed and fungal culture grew A. flavus with fungal smear revealing septate hyphae branching at 45-degree angles. A. flavus titers were elevated at 1:4, for which a diagnosis of CCPA was made. HIV testing was negative. Antifungal therapy with voriconazole 200 mg PO BID was initiated. Piperacillin-tazobactam was discontinued as the BAL cultures were negative for bacteria. BAL acid-fast bacilli culture grew M. avium intracellulare and the patient was started on ethambutol 800 mg PO QD, azithromycin 500 mg PO BID, and amikacin 250 mg IV BID.
The patient clinically improved with decreased oxygen requirement and down-trending white blood cell counts and was discharged from the hospital on voriconazole, ethambutol, azithromycin, and IV amikacin.
The patient returned to the emergency department at our institution with shortness of breath less than a week after being discharged. At this time, he had an oxygen saturation of 92% at room air, which improved to 97% with a 3 L nasal cannula. A chest radiograph showed evidence of a new right-sided spontaneous pneumothorax (Figure 3), which was also demonstrated on CT chest with IV contrast (Figure 4).

PICC: peripherally inserted central catheter
Daily chest radiographs were obtained to monitor the status of the pneumothorax. It continued to enlarge secondary to subsequent malpositioning of the chest tube. At this time, interventional radiology was consulted. A pigtail catheter was placed and the malpositioned chest tube was removed ( Figure 6).

PICC: peripherally inserted central catheter
Following pigtail catheter placement, the pneumothorax resolved within a week, and the catheter was removed without complications. A repeat chest radiograph demonstrated the resolution of the pneumothorax. The patient's oxygen saturation improved to 98% on room air.
Amikacin was changed from IV administration to the inhaled formulation to avoid nephrotoxicity on discharge. The patient was additionally sent home with voriconazole, azithromycin, and ethambutol. He was instructed to continue with close follow-up at our Infectious Disease Clinic.

Discussion
Co-infection in the respiratory tract between Aspergillus and Mycobacteria, particularly, nontuberculous mycobacteria (NTM) is a rare phenomenon, and its clinical significance has not been adequately defined and needs further research to help guide clinicians make clinical decisions when co-infection arises, as in our patient. Patients with NTM lung infection who also have CPA need to be identified by clinicians as they have worse clinical outcomes than those with NTM lung disease alone [3,4]. The majority of the patients with a mycobacterial infection who also have or later develop CPA typically have A. fumigatus or other Aspergillus species rather than A. flavus like in our patient [5][6][7][8]. Although A. flavus has not been traditionally mentioned as part of the diagnostic workup for CPA, our patient presenting with CPA secondary to A. flavus suggests there may be a benefit in including A. flavus serology in the diagnostic workup of CPA, even in areas where it is not typically endemic [9].

Conclusions
Although rare, CPA has been reported before in patients with NTM lung disease; recognizing this is extremely important for clinicians due to higher mortality in patients with NTM lung disease who are coinfected with CPA. A. flavus serology should be included in the diagnostic workup of patients with CPA due to its clinical significance, as demonstrated by our patient having CPA secondary to A. flavus.