Tracheobronchial ulcers caused by Aspergillus infection is a potential cause of retrosternal pain: A case report and literature review

Abstract

Retrosternal pain is a common symptom encountered in clinical practice. Although it is most frequently attributed to cardiac or esophageal disease, it is rarely considered an airway-related condition. Herein, we report the case of a patient who presented with fever, cough, retrosternal pain, dyspnea, and nausea accompanied by vomiting. The retrosternal pain was persistent and nonradiating and was aggravated by coughing. Based on the combination of retrosternal pain, fever, and dyspnea, viral myocarditis was strongly suspected. However, bronchoscopy performed after hospital admission revealed diffuse tracheobronchial ulcerations, and the patient was ultimately diagnosed with tracheobronchial ulcers and invasive pulmonary aspergillosis caused by Aspergillus infection. Following effective anti-Aspergillus treatment, the patient’s retrosternal pain gradually improved, suggesting that the pain was attributable to tracheobronchial ulceration. This case is rare and highlights the potential for diagnostic misinterpretation. We present this case to raise awareness of airway-related causes of retrosternal pain and to improve diagnostic accuracy.

Introduction

Retrosternal pain is a common symptom encountered in clinical diagnosis and treatment. In most cases, it is attributed to cardiac conditions such as coronary artery atherosclerotic heart disease and ischemic cardiomyopathy.^1,2 However, the causes of retrosternal pain are not limited to cardiac conditions. ³ An often overlooked etiology is Aspergillus infection, which can result in tracheobronchial ulcers and subsequently cause retrosternal pain. In immunocompromised individuals, Aspergillus can cause invasive infections, including tracheobronchial ulcers.^4,5 These ulcers can present with symptoms such as cough, hemoptysis, and dyspnea. Inflammatory irritation at the lesion site may trigger retrosternal pain. ⁶ This pain can closely mimic the retrosternal pain associated with cardiac disease, potentially leading to misdiagnosis. However, the management of tracheobronchial ulcers caused by Aspergillus differs substantially from that of cardiac conditions, highlighting the critical importance of accurate diagnosis.

Case report

Basic information

The patient was an approximately 40-year-old unemployed woman with a height of 163 cm and a weight of 65 kg. She had a 10-year history of rheumatoid arthritis and had been receiving oral baricitinib therapy for 1 year (2 mg once daily), which was continued at the time of presentation. Additionally, she had a 1-year history of hypertension, with a maximum recorded blood pressure of 160/110 mmHg, and was receiving treatment with amlodipine besylate tablets. One day after exposure to cold in late March 2023, the patient developed a sore throat and fever, with a maximum recorded temperature of 39.7°C. She then gradually developed a cough productive of yellowish-red, tenacious sputum, accompanied by retrosternal pain. The chest pain was persistent, nonradiating, and nontracting, and the pain was aggravated by coughing, with a visual analog scale (VAS) score of 6. The pain was mildly associated with respiration. She also experienced shortness of breath upon exertion, nausea, vomiting, and poor appetite. On the fifth day of illness, she presented to Baotou City Central Hospital, located at 61 Ring Road, Donghe District, Baotou, Inner Mongolia, China, for diagnosis and treatment. Chest computed tomography (CT) performed at that time did not reveal any abnormalities (Figure 1(a)). Electrocardiography (ECG) showed sinus tachycardia, left atrial enlargement, T-wave inversion, and myocardial ischemia. Blood laboratory tests were also conducted (Table 1). Based on the history of flu-like symptoms, retrosternal pain, fever, shortness of breath, nausea, and vomiting, the emergency department physician considered viral myocarditis and influenza to be the most likely diagnoses. Accordingly, the patient was treated with oseltamivir (75 mg, twice daily) administered orally for 2 days; however, her symptoms did not improve significantly. She continued to experience persistent fever, with worsening cough and shortness of breath, and the chest pain remained obvious. On the eighth day of illness, a repeat chest CT revealed multiple exudative lesions and partial consolidation in both lungs (Figure 1(b)). She was subsequently admitted to the Department of Respiratory and Critical Care Medicine for further diagnosis and treatment because of pneumonitis.

Figure 1.

Temporal evolution of chest CT findings in the patient following the onset of symptoms. CT: computed tomography.

Table 1.

Patient’s blood test results.

Item	Fifth day	Eighth day	10th day	14th day	16th day	20th day	48th day
CRP (0–8 mg/L)	54	242	124	50.30	10.7	4.65	–
Procalcitonin (<0.1 ng/mL)	0.1	2.75	0.44	0.1	–	–	–
White blood cells (3.5–9.5 × 109/L)	4.54	10.5	10.30	10.48	7.19	–	7.18
Neutrophils (1.8–6.3 × 109/L)	3.32	9.19	7.92	7.44	4.84	–	3.41
Lymphocytes (1.1–3.2 × 109/L)	0.89	0.68	1.78	2.46	1.74	–	3.10
Monocytes (0.1–0.6 × 109/L)	0.33	0.62	0.59	0.54	0.59	–	0.55
Eosinophils (0.02–0.52 × 109/L)	0.00	0.01	0.01	0.03	0.01	–	0.09
Platelets (125–350 × 109/L)	179	161	277	316	390	–	314
Hemoglobin (130–175 g/L)	136	124	131	136	119	–	147
Total bilirubin (≤26 μmol/L)	14.2	27.9	–	15.2	–	–	–
Direct bilirubin (0.0–6.8 μmol/L)	3.4	14.6	–	7.2	–	–	–
Alanine aminotransferase (ALT) (7–45 U/L)	35	20	–	8	–	–	–
Aspartate aminotransferase (AST) (15–45 U/L)	50	27	–	15	–	–	–
Total protein (65–85 g/L)	–	–	58.5	62.7	–	–	77
Albumin (65–85 g/L)	–	–	35.4	39.2	–	–	51.47
PaO2/FiO2	267	238	252	296	326	367	393

CRP: C-reactive protein; PaO₂/FiO₂: ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen.

On physical examination at admission, the patient had a body temperature of 38.0°C, pulse rate of 102 beats/min, respiratory rate of 36 breaths/min, blood pressure of 115/81 mmHg, and blood oxygen saturation of 90%. She appeared acutely ill, was lethargic with slow reactions, and exhibited cyanosis of the lips. No tenderness was detected on the chest wall. Breath sounds were coarse in both lungs, with a few moist rales and scattered wheezing. The heart rate was 102 beats/min with an irregular rhythm.

Course of diagnosis and treatment

Upon admission, blood cultures and influenza nucleic acid testing (pharyngeal swab) were performed. Electronic bronchoscopy (Figure 2(f)) revealed diffuse ulcers in the trachea and bronchi, with the bronchi of the right superior lobe, left lingula, and left inferior lobe completely blocked by yellow, viscous sputum. Sputum samples were collected for bacterial and fungal cultures. After clearing the sputum, a saline lavage sample was obtained from the basal segment of the left inferior lobe, and the fluid was sent for bacterial culture, fungal culture, and quantitative metagenomic next-generation sequencing (Q-mNGS). Initial empirical anti-infective treatment was started with tigecycline (50 mg, intravenous (IV) drip, q12h). On the ninth day of illness (early April), the influenza nucleic acid test returned positive for influenza A virus, and baloxavir marboxil tablets (40 mg) were subsequently initiated orally. After 48 h, the patient’s body temperature returned to normal and her dyspnea improved significantly. Pulse oxygen saturation was 98% with oxygen inhalation via a nasal cannula at 3 L/min. Procalcitonin and C-reactive protein decreased significantly compared with previous measurements, and the lymphocyte count in the blood routine test returned to normal. However, the patient’s retrosternal pain and cough showed no signs of relief. The 48-h efficacy assessment was recorded as “partial response.” On the 10th day of illness, results of second-generation Q-mNGS revealed Staphylococcus aureus, Aspergillus fumigatus, and influenza A virus. The serum galactomannan (GM) assay was positive. Given the patient’s use of an immunosuppressant (baricitinib), history of viral infection, and current Aspergillus fumigatus infection, antifungal therapy was initiated with voriconazole (loading dose: 360 mg, q12h, intravenous infusion (ivgtt); maintenance dose: 240 mg, q12h, ivgtt).

Figure 2.

Progression of tracheal lesions observed via bronchoscopy in the patient following symptom onset.

On the 11th day of illness, the sputum bacterial culture revealed methicillin-susceptible Staphylococcus aureus, which was β-lactamase positive, with an amoxicillin–clavulanate minimum inhibitory concentration (MIC) of ≤0.5. Based on the drug susceptibility test, tigecycline was discontinued and replaced with amoxicillin–clavulanate potassium (1.2 g, intravenous (IV) drip, q6h). On the 14th day of illness (mid-April), the sputum fungal culture showed growth of Aspergillus fumigatus, with a voriconazole MIC of ≤0.5; therefore, voriconazole was continued for antifungal therapy. On the 15th day of illness (14 April), the patient’s cough and retrosternal pain were mildly alleviated. Repeat electronic bronchoscopy (Figure 2(g)) revealed improvement of the tracheobronchial ulcers and a reduced amount of phlegm in the right superior lobe, left lingula, and left inferior lobe. On the 16th day of illness (mid-April), follow-up chest CT (Figure 1(c)) showed that the extent of exudative lesions in both lungs had decreased and multiple cysts had formed in both lungs. Considering the formation of new cysts, nebulized amphotericin B (5 mg in 250 mL sterile water for injection) and bronchoscope-guided segmental lavage of the affected lung segments were added. On the 20th day of illness, retrosternal pain was completely alleviated, cough was markedly improved, and follow-up bronchoscopy (Figure 2(h)) showed significant healing of the tracheobronchial ulcers and a marked reduction in sputum.

On the 23rd day (late April), the patient was discharged after showing improvement and was instructed to continue oral amoxicillin–clavulanate potassium for an additional week along with voriconazole tablets (200 mg, q12h, orally). On 48th day (mid-May), a follow-up chest CT (Figure 1(d)) was performed at the outpatient clinic, which showed significant absorption of exudates in both lungs and multiple areas of bronchiectasis. Bronchoscopy (Figure 3) was repeated, which revealed healed tracheobronchial ulcers; however, smooth-surfaced polyps were visible in the lower trachea and at the carina. Biopsies were obtained, and the pathology report showed granulation tissue. On the 90th day (late June), follow-up chest CT (Figure 1(e)) demonstrated significant improvement of bronchiectasis and residual exudates in both lungs, and voriconazole therapy was discontinued.

Figure 3.

Bronchoscopy on the 90th day of illness; follow-up bronchoscopy after discharge showing that the tracheobronchial ulcers had healed.

Discussion

Invasive pulmonary aspergillosis (IPA), also known as secondary pulmonary aspergillosis, frequently occurs in patients with chronic lung diseases and severe underlying medical conditions. It is particularly prevalent among individuals with compromised immune systems, especially those receiving high-dose corticosteroids or immunosuppressants.^7–9 Recent respiratory viral diseases, including severe acute respiratory syndrome (SARS), avian influenza, H1N1 influenza, and coronavirus disease 2019 (COVID-19), have been shown to significantly increase the incidence of pulmonary aspergillosis.^10–14 Diffuse tracheobronchial mucosal ulceration often follows a viral infection, resulting in a secondary Aspergillus infection.^5,15–17 Influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the two main viruses associated with the development of IPA. ¹³ In patients with influenza and invasive Aspergillus tracheobronchitis, 89% test positive for serum GM, ⁵ whereas 65% of patients with influenza-associated pulmonary aspergillosis (IAPA) show a positive serum GM result. These findings suggest that angioinvasive growth occurs early in the disease process. ⁵

Although we have treated many patients with pulmonary aspergillosis, with and without immune deficiencies, we have not previously encountered a case in which Aspergillus infection presented with retrosternal pain. Therefore, an extensive review of the literature was conducted to explore the potential underlying mechanisms. Influenza virus initially compromises the tracheal mucosal barrier by damaging epithelial cells and cilia and suppresses local immunity by impairing macrophage and neutrophil function as well as the T-cell response,^18–20 thereby creating favorable conditions for Aspergillus colonization. The colonized fungus secretes proteases and toxins that further degrade and invade the damaged tissue. Fungal hyphae exhibit strong penetrating capacity and have a tendency to invade blood vessels.^21,22 Simultaneously, neutrophils recruited during the host antifungal response release large amounts of inflammatory mediators and reactive oxygen species, resulting in severe tissue injury.^23,24 This triple assault, viral-induced damage, direct fungal invasion, and excessive host inflammatory response, synergistically leads to necrosis and sloughing of deep tracheal tissue, ultimately resulting in ulcer formation, often accompanied by necrosis and bleeding. ⁸ Ulceration exposes the richly supplied sensory nerve endings in the submucosa, subjecting them to direct chemical irritation by fungal toxins and inflammatory mediators such as bradykinin and prostaglandins as well as mechanical irritation from airflow, particularly during severe coughing, when violent expansion, contraction, and vibration of the airway wall occur. ²⁵ Concurrently, inflammatory mediators markedly sensitize the nerve endings, lowering their pain threshold and causing the pain to intensify and persist.^26,27 The trachea is innervated by the vagus nerve, and pain originating from this region is often referred to the retrosternal area, resulting in retrosternal pain. ²⁸ This pain is closely associated with respiration and coughing movements. At present, the precise mechanism underlying retrosternal pain associated with Aspergillus infection remains unclear, and further studies are required to establish a definitive explanation.

The patient’s long-term use of baricitinib for rheumatoid arthritis represents a critical factor. As a Janus kinase 1 (JAK1)/2 inhibitor, baricitinib broadly interferes with the cytokine signaling pathways and cellular functions essential for innate immunity, specifically neutrophils and macrophages, and adaptive immunity, including Th1 and Th17 cells, which are necessary to effectively combat Aspergillus infection.^29–32 This profound immunosuppression, compounded by the patient’s underlying diseases and recent viral infection, significantly increases the risk of invasive Aspergillus infection. The alleviation of retrosternal pain in this patient was closely associated with the extent of tracheal ulcer healing observed during bronchoscopy. In the early phase of the disease, retrosternal pain was persistent and exacerbated by coughing, suggesting a strong association between the pain and tracheal ulceration caused by Aspergillus infection.

Conclusion

This case highlights that in patients presenting with fever and cough accompanied by retrosternal pain, especially those with underlying immunocompromised status, infectious mucosal ulceration of the trachea and bronchi should be considered in the differential diagnosis.

The reporting of this study conforms to the Case Report (CARE) guidelines. ³³