Extensive eye-oral-bronchial mucosal nodules with eosinopgillia: a rare case report and literature review

Rare diseases are conditions that affect a small proportion of the population; the definition of rare disease varies from country to country due to the influence of region and population base. In the USA they are described as affecting fewer than 200,000 people (https://​rarediseases.​info.​nih.​gov), and in Europe as affecting fewer than one in 2000 (https://​www.​eurordis.​org/​about-rare-diseases). In China, the incidence rate is defined as less than one in 10,000 newborns and less than one in 500,000 people [1]. There are many kinds of rare diseases of respiratory system, which are easy to be missed and misdiagnosed in clinic. Current reports include: langerhans cell histiocytosis, eosinophilia, pulmonary alveolar proteinosis (PAP), lymphangioleyomiomatosis (LAM), bronchial amyloidosis, Wegener’s granuloma, Kartagener syndrome, bronchial mucosal tuberculosis, osteomalacia, etc. [2‐4]. We treated a patient with recurrent cough and expectoration, accompanying with multiple nodules in the oral mucosa and ophthalmic conjunctiva. Bronchoscopy, laryngoscopy and gastroduodenoscopy confirmed that widespread and dense nodules were distributed in the trachea, left and right bronchus, posterior pharyngeal wall and esophagus. In addition, the patient had congenital cleft palate and dextroversion of heart. Pathological and etiological examination were mainly characterized by inflammatory lesions with large numbers of neutrophils, lymphocytes, and varying degrees of eosinophils. The examination results also excluded specific pathogen infection, granulomatous disease, amyloidosis, calculosis, and neoplastic diseases. Treatment with a variety of antibiotics was invalid but tentative glucocorticoid therapy was beneficial. This patient may be a specific phenotype of eosinophilia or may be a novel multisystem disease with respiratory system as the primary symptom.

A 29-year-old non-smoking woman was referred to our department for repeated coughing and expectoration for more than 4 months and gradual appearance of eye and mouth nodules. At start in May 2019, the patient felt pain in her eyes with pustules developing around them. Later the patient began to experience pharyngeal itching, cough, expectoration, fatigue and occasional chest distress. There was no history of fever, night sweats, loss of appetite or weight, joint pains, rash, hair fall, oral ulcer, photophobia and decreased vision. She received intravenous antibiotics at local community hospital for a week but the curative effect was poor. On July 22, 2019, she was firstly admitted to Wuhan Union Hospital on suspicion of bronchial asthma. Physical examination revealed that both lungs had sporadic wheezing. Her ESR was 103 mm/H (normal range 0–20 mm/H) and IgE was 159.30 IU/ml (normal range 0–100 IU/ml). Pulmonary function examination showed severe mixed pulmonary ventilation dysfunction and bronchial dilation test (negative). Chest CT showed that the right upper lobe had minute nodules; the right lower lobe had proximal segmental lung insufficiency; the right paraspinal pleura was slightly thickened; the mediastinal lymph nodes were increased; and the wall of the esophagus was limited and slightly thickened. The patient was treated with piperacillin sulbactam sodium, loratadine and montelukast sodium. After a few days of symptom remission, her cough and expectoration aggravated again. On presentation to our institution on September 12, 2019, she had plentiful nodules on her eyelids and oral mucosa with uranoschisis in the upper jaw (Fig. 1).

Past medical history: in 2012, she underwent reduction surgery in Hubei provincial people’s hospital due to congenital dextrocardia. She denied any medical histories about tuberculosis, hepatitis, hypertension, diabetes and rheumatic immune diseases. The patient also had no history of allergies or blood transfusions. The patient declared no family history of any relevant conditions.

On examination, cell counts of white blood (12.12×10^9/L, normal range 3.5–9.5×10^9/L), neutrophils (8.27×10^9/L, normal range 1.8–6.3×10^9/L) and eosinophil (1.27×10^9/L, normal range 0.02–0.52×10^9/L) increased. Additionally, the ESR (34 mm/H, normal range 0-20 mm/H), hs-CRP (8.1 mg/L, normal range 0-1 mg/L) and IgE (178.8 IU/ml, normal range 0–100 IU/ml) also increased. Other laboratory workup including liver and renal functions, anti-cardiolipid antibody, antinuclear antibody, antistreptococcal O titers, rheumatoid factors, thyroid function, HIV antibody quantification did not reveal any abnormalities. No obvious abnormality was found in abdominal viscera and vascular ultrasound, cardiac function and electrocardiogram. There was no significant change in chest CT compared with the last CT (Fig. 2). To explore the etiology, we performed bronchoscopy to collect alveolar lavage fluid and biopsy. Fiberbronchoscopy showed that a large number of small bulges were densely distributed in the whole trachea, carina and bronchi, covered with more white viscous secretions. The surface of these bulges was smooth. Blood vessels were abundant and easy to bleed. The openings of the right middle lobe, the right lower lobe and the left upper lobe bronchial were markedly narrowed (Fig. 3). The smear and culture of bronchial lavage fluid didn’t show any evidence of bacteria, fungi, or tuberculosis. Next generation sequencing (NGS) technology only found a low copy number of haemophilus parainfluenzae (191) and rothia aeria (163). Laryngoscopy and gastroduodenoscopy showed that abundant yellow-white tuberculous uplifts were widely distributed in the posterior pharynx wall and inferior segmental esophagus (Fig. 3).

Biopsy specimens of bronchial nodules showed that part of the respiratory epithelium was squamous metaplasia with granulation tissue proliferating below, with numerous neutrophils and eosinophils infiltrating. No caseous necrosis, granulomatous lesions and tumor were observed in the sections. Immunohistochemical hinted that acid fast staining (−), congo red staining (−), CD34 (+), S-100 (−), CD1a (−), Langerin (−) (Fig. 4). Biopsy specimens of oral nodules showed a large amount of histiocytosis (some were foam cells) and neutrophil infiltration (the formation of a small abscess), with a small amount of eosinophils and lymphocytes infiltration in the subepithelial and salivary gland tissues without any caseous necrosis, obvious granulomatous lesions and neoplastic lesions (Fig. 5). Immunohistochemical showed that CD163(+), CD68(+), CD45-LCA(+), S-100(+), CD35(+), SMA(−), desmin(−), HMB45(−), Melan-A(−), Cathepsin K(−), SOX10(−), CD21(−), CD23(−), Langerin(−), mutated Braf (V600E)(−), Eber(−), CyclinD1(+), Ki67(+) (Fig. 5). Similarly, biopsy specimens of esophageal nodules only found numerous neutrophils and eosinophilic granulocyte infiltration (Fig. 5). Bone marrow examination showed no abnormality and rearrangement of FlP1L1/PDGFR gene which was associated with the negative result of primary hypereosinophilic syndrome (HES). These findings did not point specifically to a particular disease but were very similar to eosinophilia. She may be a specific phenotype of eosinophilia or may be a novel multisystem disease with respiratory system as the primary symptom, so we tried several treatment plans.

At first, the patient was treated with anti-infection (cefoperazone), anti-allergy (montelukast), anti-tussive (methoxyphenamine) and expectorant (ambroxol). However, these treatments showed few benefit after a month. In consideration of the extensiveness of the lesions, surgical resection was unfeasible. Thus, we tentatively gave her glucocorticoid (dexamethasone) 20 mg q.d, somac (pantoprazole) 40 mg q.d, caltrate D 300 mg q.d and arranged close follow-up. A month later, the symptoms of cough, expectoration, oral and eye mucosa nodules disappeared. The number of nodules on tracheal and bronchial mucosa also significantly reduced (Fig. 6).

In general, we found a strange disease in which patients presented recurrent cough and sputum, chest tightness, accompanied with extensive nodules of eye-mouth-bronchial mucosa. The biopsy specimen mainly showed inflammatory lesions (concluding a large number of neutrophils, moderate eosinophils and a small number of lymphocytes) and some granulation tissue proliferating, without caseoid necrosis and granuloma. Additionally, glucocorticoid rather than antibiotics was effective. Although it is not known whether this is related to the patient’s multisystem mucosal lesions, the patient also had a congenital dextrocardia and palatoschisis.

Mucosal nodules are visible as rounded, elliptic, or irregular hyperplasia initiated by tumour, infection, autoimmunity, trauma or foreign matter [5]. Many noninfectious diseases, such as eosinophilia, amyloidosis, sarcoidosis, Wegener’s granuloma, langerhans cell histiocytosis, foreign bodies ect., are associated with the formation of mucosal nodules, especially significant bronchial lesions [4, 6‐8]. Here we introduce the differential diagnoses and literature review of several rare bronchial diseases.