A 49 year old female with acute hypoxic respiratory failure and tracheal debris

Case Report: Final Diagnosis:
Aspergillus tracheobronchitis in the setting of influenza A infection
 
Brief history of the Present Illness:
This is a 49-year-old female with a history of Ehlers-Danlos, Chiari malformation, hypertension, and recurrent nephrolithiasis who was admitted on January 27, 202 as a transfer from an outside hospital for management of acute hypoxic respiratory failure. One week prior to admission, she developed decreased appetite and flu-like symptoms. She presented to her primary care provider’s office, where rapid flu test was negative. She subsequently developed fevers, chills, malaise, fatigue, and decreased appetite. Symptoms worsened, and the day prior to admission, she developed productive cough. On the morning of admission, she awoke with labored breathing and confusion. Per family members, she was not speaking coherently and seemed to be confused about where she was. No appreciable stridor. Review of systems was significant for a 38 pound weight loss in the past three months. No nausea, vomiting, diarrhea.
 
Emergency Medical Services (EMS) was called, and patient was transported initially to an outside hospital. There, CT chest showed multifocal pneumonia and a possible subglottic mass. Given progressive hypoxemia, she was transferred to our facility for a higher level of care.
 
Past Medical History:
Ehlers Danlos
Hypertension
Nephrolithiasis
Anxiety
Chiari I malformation
 
Allergies are reported to amoxicillin (swelling), cefaclor (swelling), cephalexin (swelling), erythromycin (not specified), and sulfonamide antibiotics (not specified).
 
Key Medications:
No immunosuppressing medications.
 
Epidemiological history:
She is a current 0.5 pack-per-day smoker, and has been smoking for 30 years. No alcohol use, and no history of illicit drug use. Further history not obtainable given worsening respiratory status necessitating BiPAP.
 
Physical Exam:
The patient’s vitals were as follows: temperature of 96.8F (36C), pulse of 129 beats per minute, blood pressure of 171/141 mmHg, respiratory rate of 32 breaths per minute, and oxygen saturation of 95% on BiPAP with a fraction of inspired oxygen (FiO2) of 40%, inspiratory positive airway pressure (IPAP) 10 cmH₂O, expiratory positive airway pressure (EPAP) 5 cmH₂O. She is awake and alert, but is ill-appearing and very anxious. She has a weak voice but is still able to speak in full sentences. Head and neck exam was notable for dry mucous membranes and clear oropharynx without obvious mass. Cardiovascular exam was notable for tachycardia without appreciable murmur. Respiratory exam was notable for tachypnea despite being placed on BiPAP. Anterior lung sounds were coarse with diffuse expiratory wheezing. There was no accessory muscle use. The remainder of her physical exam was unremarkable.
 
Laboratory Studies:
Complete blood count was notable for white blood cells 4.3 x10(3)/mcL (ref range 3.9-10.7 x10(3)/mcL) with absolute neutrophil diff of 3.80 x10(3)/mcL (ref range 1.60-8.10 x10(3)/mcL) but an absolute lymphocyte diff of only 0.37 x10(3)/mcL (ref range 1.10-3.50 x10(3)/mcL). Platelet count was 111 x10(3)/mcL (ref range 135-371 x10(3)/mcL).
 
Comprehensive metabolic panel was significant for sodium level 135 mmol/L (ref range 136-145 mmol/L), potassium level 3.2 mmol/L (ref range 3.3-4.8 mmol/L), chloride level 115 mmol/L (ref range 98-107 mmol/L), carbon dioxide level 10 mmol/L (ref range 22-29 mmol/L), glucose level 129 mg/dL (ref range 70-99 mg/dL). The calculated anion gap was 10.
 
HIV antigen/antibody testing was non-reactive.
 
PCR respiratory pathogen panel was positive for Influenza A H1N1-2009.
 
Imaging Studies:
A chest radiograph revealed patchy airspace opacities involving the right upper, right middle, and bilateral lung bases, without pleural effusion or pneumothorax.
 
A CT angiography of the chest showed patchy bilateral collections of airspace and groundglass opacities; extensive airway debris, likely mucous in the upper trachea; and partially calcified right mediastinal lymph nodes (Figures 1-2).
 
Clinical Course Prior to Diagnosis (if relevant): Note Figures if appropriate.
Following admission to the Medical Intensive Care Unit (MICU), the patient continued to require BiPAP for respiratory support. Her labs were notable for non-anion gap metabolic acidosis, and chest imaging confirmed bilateral pneumonia. Given her multiple reported allergies to penicillins and cephalosporins, she was started on IV vancomycin and IV levofloxacin for empiric treatment of post-influenza bacterial pneumonia. Given the severity of her illness, oseltamavir (Tamiflu) was started as well for Influenza A infection. The possible subglottic mass was thought to be a mucous plug, and the patient was given humidified air and initiated on aggressive pulmonary toilet to assist in clearing secretions.
 
Differential Diagnosis:

1. Streptococcus pneumoniae


2. Staphylococcus aureus


3. Pseudomonas aeruginosa


4. Streptococcus pyogenes


5. Haemophilus influenzae


6. Aspergillus fumigatus

 
 
 
Diagnostic Procedures and

Results:
Otolaryngology was consulted on hospital day 2 given CT findings of possible subglottic mass, and performed flexible fiberoptic endoscopic exam. Examination of the nasopharynx was normal. Examination of the oropharynx revealed widely patent airway without obstructive mucous plugs, with no masses or lesions are visualized in the subglottis upon limited view (exam was limited to the anterior 60-70% of the subglottis).  
 
On hospital day 3, the patient developed altered mental status, increasing tachypnea, and increasing work of breathing with tripoding. Labs were concerning for persistent acidemia without appropriate respiratory compensation. Given persistent combined respiratory and metabolic (non-anion gap) acidosis, hypoxemia, and encephalopathy, the decision was made to intubate the patient. Bronchoscopy was performed immediately following intubation. It was noted that “the large airways and carina were markedly abnormal. There were large, whitish, exudative, pseudomembranous-like lesions throughout the large airways, distorting the carina. Some of these lesions seemed somewhat friable and were suctioned. There were minimal secretions” (Figure 4). Bronchoalveolar lavage was unsuccessful due to thick pseudomembranes, but bronchial washing was sent for culture and cytology.
 
Gram stain revealed polys, gram positive cocci, and fungal elements. Cytopathology revealed acute-angle branching hyphae consistent with Aspergillus (Figure 5). Bacterial culture was finalized with methicillin-susceptible Staphylococcus aureus and light growth mold. Fungal culture from bronchial washing ultimately was finalized with Aspergillus fumigatus.

Treatment/Follow-up:
The patient was started on IV amphotericin, in addition to IV vancomycin, IV levofloxacin, and oseltamivir. Despite the addition of anti-fungal coverage and continued supportive respiratory care, she developed refractory hypotension requiring vasopressors and persistent refractory hypoxemia, requiring up to 100% fraction of inspired oxygen (FiO2). Peak and plateau pressures were also elevated and chest radiograph was concerning for developing acute respiratory distress syndrome. Despite deep sedation, adjustments to ventilator settings to maximize ventilation, and paralysis, there was no improvement in her respiratory acidosis or hypoxemia. Over the subsequent days, she developed oliguric renal failure requiring continuous renal replacement therapy as well as increasing vasopressor requirements. Overall, her prognosis was poor given the severity of her illness, shock, and multi-organ failure, and goals of care discussions were held with her family. Further escalation of care was determined to be futile, and a “do not resuscitate” order was placed. Shortly thereafter, the patient had a cardiac arrest and was pronounced dead on hospital day 7.
 
Brief Discussion of Differential/Major Teaching points of case:
Aspergillus tracheobronchitis is a rare form of invasive pulmonary aspergillosis which is characterized by isolated invasion of the tracheobronchial tree by Aspergillus spp. Infection can lead to thick mucous plugging, pseudomembrane formation and ulceration with transmural bronchial necrosis, which can rarely result in tracheal perforation [2, 3]. It primarily occurs in immunocompromised individuals, and risk factors include neutropenia, hematopoietic and solid-organ transplantation, prolonged corticosteroid use, malignancy and acquired immunodeficiency syndrome [2]. It can very rarely occur in immunocompetent or mildly immunocompromised individuals, such as those with diabetes, alcoholism, chronic liver disease, COPD, or influenza infection [2]. The incidence of Aspergillus tracheobronchitis is less than 7% out of pulmonary Aspergillosis cases [1]. Despite appropriate anti-fungal therapy, Aspergillus tracheobronchitis is fatal in 78% of cases overall, and the need for mechanical ventilation is a predictor of high mortality in these patients [3].
 
Pathogenesis is thought to be multifactorial, and includes viral disruption of the respiratory epithelium, including the tracheobronchial mucosa; disruption of ciliary clearance, further increasing the risk for colonizing Aspergillus to become invasive; impaired local immunity, including impaired local phagocytosis, reduction of NK functionality, and disruption of cytokine pathways; loss of normal respiratory flora; viral-induced T-helper cell changes; and lymphopenia [4].
 
Diagnosis can be challenging for multiple reasons. Oftentimes, the affected patients are healthy, with few co-morbidities and no history of immunosuppression. Symptoms are non-specific, and usually mimic presenting symptoms with bronchopneumonia, such as cough, exertional dyspnea, productive sputum, fevers, and night sweats [4]. Radiographic features are often non-specific [4].  The gold standard for diagnosis is the combination of histopathological examination of lung tissue, with findings of septate, acute branching hyphae invading lung tissue, and a culture positive for Aspergillus from the same site.
 
Final Diagnosis:
Aspergillus tracheobronchitis in the setting of influenza A infection
 
 

References:

1. Cho B, Oh Y, Kang E, Hong Y, Jeong H, Lee O, Change Y, Choe K, Lee K, An J. Aspergillus Tracheobronchitis in a Mild Immunocompromised Host. Tuberc Respir Dis (Seoul). 2014 Nov; 77 (5): 223-226. PubMed PMID: 25473411


2. Argüder E, Şentürk A, Hasanoğlu A, Hasanoğlu I, Kanbay A, Doğan H. Unique Case of Pseudomembranous Aspergillus Tracheobronchitis: Tracheal Perforation and Horner’s Syndrome. Mycopathologia. 2016 June; 181: 885-889. PubMed PMID: 27255521


3. Kousha M, Tadi R, Soubani O. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011 Sep; 20(121): 156-74. PubMed PMID: 21881144


4. Crum-Cianflone N. Invasive Aspergillosis Associated with Severe Influenza Infections. Open Forum Infect Dis. 2016 Sep; 3(3) :ofw171. PubMed PMID: 27704024