Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature review

ABSTRACT

Introduction

Pyoderma gangrenosum (PG) is the prototypical neutrophilic dermatosis, commonly associated with inflammatory bowel disease, with pulmonary involvement being the commonest extracutaneous manifestation. PG with tracheobronchial involvement may present as upper airway obstruction and can be life-threatening.

Areas covered

To evaluate the clinical characteristics and predictors of PG with pulmonary involvement, we reported a case of PG with tracheobronchial involvement in China, and performed a literature retrieval on PG with pulmonary involvement. Demographic data, clinical presentations, underlying diseases, radiological and histopathological findings, treatments, and clinical outcomes were collected and subjected to statistical analysis. Forty-seven cases (including ours) were identified. Diseases associated with PG with pulmonary involvement were similar. Clinical presentation of PG with pulmonary involvement was nonspecific, with cough and dyspnea being the most common clinical symptoms, and pulmonary infiltrates and cavitation being the most common radiological signs. Further univariate analysis suggested stridor and young age (p < 0.01) may be predictors of tracheobronchial involvement in PG.

Expert opinion

PG with tracheobronchial involvement can be life-threatening, with young age and stridor being possible predictors. Therefore, prompt airway assessment and management are required in younger patients with PG with pulmonary involvement presenting with stridor.

KEYWORDS:

• Life-threatening airway obstruction
• pyoderma gangrenosum
• tracheobronchial involvement

1. Introduction

Pyoderma gangrenosum (PG) belongs to a group of disorder called neutrophilic dermatoses, which is characterized by dermatological lesions with histology showing intense inflammatory infiltrates composed of mainly neutrophils [1]. The pathophysiology and etiology of this skin condition are not well understood [2]. The incidence of PG is estimated to be 3–10 cases per million population worldwide, with the peak incidence between 20 and 50 years old [3,4]. It is one of the common cutaneous manifestations of inflammatory bowel disease [5] and is also associated with a wide range of diseases including autoimmune disease such as rheumatoid arthritis [4,6], hematological malignancy, and rarely drugs such as cocaine and sunitinib (a tyrosine kinase inhibitor) [7,8].

Classic PG is characterized by the presence of pustules developing into burrowing ulcers with violaceous edges typically occurring over the shins [5]. However, extracutaneous manifestations are not uncommon, which can involve most of the organs in human, including the eye, brain, muscle, heart, gastrointestinal tract, kidney, and spleen, with pulmonary involvement being the most common manifestation [2,9]. Diagnosis of PG is mainly made through the PARACELSUS score, which includes three major criteria, four minor criteria and three additional criteria as there is no specific histological changes or pathognomonic tests for definitive diagnosis of this disease [10]. It would be more challenging in clinical setting if there is extracutaneous involvement of PG as it can mimic other diseases, especially opportunistic infections.

In this study, a case of PG with tracheobronchial involvement was reported. As our study demonstrated the severity of tracheobronchial disease, a review of current literature with statistical analysis was performed, so as to identify possible clinical characteristics that would predict such involvement in PG.

2. Case report

A 17-year-old boy was referred to our hospital as a result of fever for one week accompanied with nonproductive cough and wheezes for four days. He was previously diagnosed with inflammatory bowel disease 4 years before this admission. Prednisolone and mesalazine were started since then, and he was followed up regularly at the clinic with his disease under control. The patient was a nonsmoker, and he had no history of pulmonary tuberculosis or contact history with patients with tuberculosis.

On physical examination, he was found to have a high-grade fever, oral aphthous ulcers, wheezes and multiple painful ulcerative skin lesions on the face and all extremities with brownish exudates. Initial investigation revealed leukocytosis with thrombocytosis, and normal liver and renal function tests. C-reactive protein (CRP) was 153 mg/L, with procalcitonin 0.18 ng/ml (Cutoff for sepsis < 0.5 ng/mL). Serum IgA, IgG, IgM, C3 and C4 were all within the normal range. Septic workup including blood culture, nasopharyngeal swab for respiratory virus, and serum for Mycoplasma pneumoniae antibody were negative except numerous white blood cells were detected by Gram stain of the pus from the lower extremity wound and bacterial culture of the pus showed scanty growth of Streptococcus mitis, Rothia species, Actinomyces odotolyticus, and Staphylococcus lugdunensis. Herpes simplex virus DNA was not detected by polymerase chain reaction (PCR) from the pus swab. Serostatuses of human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and Treponema pallidum were all negative.

Computed tomography (CT) of thorax with contrast on admission showed multiple small scattered subpleural patchy infiltrates, and nodular mucosal lesions on the trachea, bronchi and right bronchioles (Figure 1(a)). Bronchoscopy revealed multiple nodular mucosal lesions extending from the trachea to bronchi (Figure 2(a)), with histological examination of tracheal lesion biopsy showing suppurative inflammation with squamous epithelial hyperplasia, but no definite granulomatous inflammation (Figure 2(b)). No suspicious organisms were identified by Ziehl-Neelsen stain, periodic acid Schiff stain, and Grocott methenamine stain of the biopsy tissue. Bacterial culture of broncho-alveolar lavage (BAL) fluid only showed scanty growth of Streptococcus mitis. Mycobacterium tuberculous DNA was not detected by PCR from BAL.

Figure 1. Comparative Computed Tomography of Thorax (a) on presentation and (b) after treatment. Note the presence and resolution of mucosal irregularity over the trachea before and after treatment.

Figure 2. (a) Bronchoscopy finding of our case with pyoderma gangrenosum with tracheobronchial involvement. Note the presence of multiple whitish nodular lesions over the trachea together with erythema over the mucosa to suggestive of marked inflammation over the tracheobronchial area. (b) Subsequent biopsy with histology showing suppurative inflammation with marked neutrophil infiltration together with squamous epithelial hyperplasia. No definite granulomatous inflammation was seen in the biopsy.

Empirical antibiotics for community acquired pneumonia, inhaled corticosteroids, bronchodilators together with oral thalidomide and mesalazine were given, but the patient developed further clinical deterioration with stridor, increasing inspiratory and expiratory wheezes, decreasing oxygen saturation, together with further progression of ulcerations on the nasal bridge and all extremities. The largest lesion was on the right shin with a diameter of 4 cm, and had a sharp edge, with circumferential edema and erythema (Figure 3).

Figure 3. Clinical photo of skin lesions on subsequent presentation. Presence of multiple burrowing ulcers with violaceous edges over right anterior shin, typical of pyoderma gangrenosum.

The patient was subsequently diagnosed to have PG with tracheobronchial involvement after consultation of the clinical microbiologist and rheumatologist 7 days later, according to two of the three major criteria including progressive course of disease and reddish-violaceous wound border, two of the four minor criteria including characteristically bizarre ulcer shape and extreme pain >4, and two of the three additional criteria including suppurative inflammation and systemic disease [10]. He was transferred to the Intensive Care Unit (ICU) for respiratory support in view of possible clinical deterioration to complete upper airway obstruction. Adalimumab (a tumor necrosis factor (TNF) antagonist) was started together with high-dose methylprednisolone, with subsequent defervescence and clinical improvement in both respiratory and dermatological condition. Parameters including white blood cell counts, erythrocyte sedimentation rate (ESR) and CRP were normalized after the above treatment. Reassessment CT Thorax two and half months later showed resolution of all mucosal lesions in the respiratory tract (Figure 1(b)). During the subsequent 12 months, there was no relapse in terms of respiratory symptoms or skin condition. The patient is currently followed up regularly at the Rheumatology clinic.

3. Method

3.1. Literature search

Literature review was performed using the search terms ‘pulmonary, lung, respiratory, bronchopulmonary, tracheobronchial or bronchial’ and ‘pyoderma gangrenosum’ in PubMed. Only articles in English were included in the review unless the abstract or available translation was sufficient to obtain clinical information for analysis. Patients with concurrent anti-neutrophil cytoplasmic antibodies (ANCA) positive vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis, and Churg-Strauss syndrome), pulmonary tuberculosis, invasive mold infection (e.g. Aspergillus and Fusarium), acute respiratory distress syndrome, sarcoidosis and pulmonary involvement secondary to inflammatory bowel disease such as chronic organizing pneumonia were excluded. Additional articles may be further included from the reference lists of the identified articles during the initial literature search.

We noticed a similar systemic review on pyoderma gangrenosum with pulmonary involvement was published in 2018 [11]. Our review followed the algorithm published and updated the review with new information in the past three years, at the same time analyzed the available data from the literature statistically to try to identify possible clinical predictors that allow us to alert to the possibility of tracheobronchial involvement.

3.2. Data extraction and assessment

Demographic data, initial clinical presentation, associated underlying diseases, radiological findings in CT/Chest X-ray, tissue biopsy results, treatment received together with clinical outcome were extracted from the available publications, and subjected to statistical analysis. Tracheal/bronchial involvement is defined as the presence of bronchoscopic findings of PG in the airway, biopsy showing neutrophilic infiltrates in the tracheobronchial mucosa or radiological finding of nodules in the airway. Categorical variables were analyzed by Fisher’s exact test, and continuous variables were analyzed by Mann Whitney U test using SPSS version 24.0. A p value of <0.05 was considered statistically significant.

4. Results

50 cases (from 47 literatures) of pyoderma gangrenosum with pulmonary involvement were identified from our literature review [12–58] (Table 1). After inclusion of our case, a total of 51 cases were included for statistical analysis.

Table 1. Summary of literature included in the systemic review

Reference (Author/ Year)	Sex/ Age	Underlying disease	Respiratory symptoms	Imaging findings	Histological features	Systemic involvement	Treatment	Patient outcome
Xu, 2019 [12]	M/32	N/A	Recurrent cough with hemoptysis	Multiple pulmonary nodules with internal cavitation	Inflammatory granulomatous disease	Spleen, skin	Prednisolone	Clinical improvement
Li, 2014 [13]	F/34	Ulcerative colitis	Nonproductive cough	Pleural based cavitary lesion in right lower lobe	Necrotizing inflammatory granulomas with neutrophilic infiltration	Skin	Prednisolone and mesalamine	Clinical improvement
Marchiori, 2014 [14]	M/74	Nil	Hemoptysis, cough with fever	Irregular cavitated opacity in the right lung	Diffuse neutrophilic infiltration without granuloma or angitis	Skin	Prednisolone	Clinical improvement
Brown, 2000 [15]	M/17	T cell (CD4) lymphopenia	Nonproductive cough, dyspnea and fever	Right upper lobe consolidation with central cavitation and abscess formation	Sterile neutrophilic infiltrates	Skin	Prednisolone	Clinical improvement
Sartini, 2016 [16]	F/30	Ulcerative colitis	Dyspnea	Round lesion in right lower lobe	Chronic inflammatory reactions without necrosis	Skin	Cyclosporine, azathioprine, operation, infliximab	Clinical improvement
Bostan, 2019 [17]	F/39	IgA monoclonal gammopathy	Cough, purulent expectoration	Parenchymal distortion, interlobular septal thickening, nodular opacities in both lungs	Not performed	Skin	Bortezomib, dexamethasone	Clinical improvement
Mercer, 2014 [18]	F/61	Myasthenia gravis	Dyspnea	Bilateral pulmonary parenchymal masses, with a crescentric cavitation	Necrotic pulmonary parenchyma with associated mixed inflammation and organizing granulation tissue	Skin	Corticosteroid, cyclosporine, intravenous immunoglobulin	Failed to response to treatment
Bittencourt Mde, 2014 [19]	M/17	Nil	Dyspnea, cough with hemoptysis, chest pain, fever	Cavitary pulmonary nodular lesions	Not performed	Skin	Prednisolone	Clinical improvement
Be, 2016 [20]	F/66	Rheumatoid Arthritis	Cough, Purulent sputum, left pleuritic chest pain	Multiple cavitary consolidations in both lungs	Not performed	Skin	Prednisolone	Clinical improvement
Kasuga, 1997 [21]	M/50	Nil	Cough, chest pain	Bilateral peripherally located multiple nodules lesions next to pleura	Chronic nonspecific inflammatory changes with neutrophil and lymphocyte infiltrates	Skin	Prednisolone	Clinical improvement
Krüger, 2001 [22]	F/45	Non-insulin–dependent diabetes mellitus	Cough, chest pain	Multiple pulmonary nodules with central necrosis	Inflammatory aseptic and necrosis process	Skin	Prednisolone	Clinical improvement
Allen, 2013 [23]	M/8	Nil	Nil	Two Pulmonary nodules	Chronic inflammation with no organism seen	Skin, spleen	Prednisolone, infliximab (subsequent adalimumab and cyclosporin)	Clinical improvement
Kitagawa, 2008 [24]	F/82	Nil	Cough	Large mass located at the right upper lobe	Chronic inflammation with epithelioid hyperplasia	Skin	Prednisolone, cyclosporine	Clinical improvement
Gade, 2015 [25]	M/61	Nil	Nil	Cavitating pulmonary lesions	Chronic granulomatous inflammation	Skin	Prednisolone, cyclosporine, methotrexate, infliximab	Clinical improvement
Gade, 2015 [25]	F/52	Nil	Shortness of breath, chest pain, productive cough	Several pulmonary lesions with one cavitating in the upper right lung with mediastinal lymph nodes	Chronic inflammation with no evidence of necrotic material or signs of vasculitis	Skin	Prednisolone, dapsone, methotrexate, infliximab	Clinical improvement
Chahine, 2007 [26]	F/33	Nil	Dyspnea, fever	Multiple pulmonary nodules, some with cavitation and mediastinal lymphadenopathy	Necrotic lesions and infiltration with neutrophils and monocyte, no vasculitis or granulomatous inflammation	Skin	Prednisolone	Clinical improvement
Chahine, 2007 [26]	M/31	AML	Constitutional symptoms	Numberous bronchiolar micronodules and moderate cystic lesions	Interstitial fibrosis, lipophagic granuloma and alveolitis with neutrophilic infiltrate	Skin	Prednisolone	Succumbed due to underlying AML 3 years later
Contreras-Verduzco, 2018 [27]	M/15	Nil	Cough	Pleural fibrosis, non cavitated nodules	Not performed	Skin, Eye	Prednisolone, dapsone and thalidomide	Clinical improvement
Sakta, 2016 [28]	M/19	Nil	Cough, shortness of breath, productive sputum	Multifocal bilateral peripheral areas of consolidation, cavitatory nodules and bilateral pleural effusions	Multifocal necrotizing organizing pneumonia with abscess formation, overlying pleuritis and vascular injury. Central neutrophilic abscess with cavitation surrounded by fibrinous exudate and hemorrhage, no granuloma seen.	Nil	Prednisolone	Clinical improvement
Matsumudra, 2010 [29]	F/57	MDS	Cough, wheezes	Nodular lesion in the right upper lobe	Not performed	Skin, gallbladder, liver, bone	Prednisolone	Clinical improvement
Scherlinger, 2017 [30]	M/57	MDS	Cough, dyspnea, fever	Bilateral alveolar opacites	Not performed	Skin	Prednisolone, infliximab	Clinical improvement
Wang, 1999 [31]	F/27	Nil	Cough, fever, shortness of breath	Shadows over right upper lung with right pleural effusion	Infiltration with neutrophils, monocytes. No vasculitic or granulomatous features seen	Skin	Prednisolone, cyclophosphamide	Clinical improvement
Vignon-Pennamen, 1989 [32]	F/60	IgA monoclonal gammopathy	Fever, constitutional symptoms	Roundish homogenous opacity of 7 cm in left lung, with cavity, left pleural effusion	No granuloma and tumor seen	Skin	Prednisolone	Clinical improvement
Fukuhara, 1998 [33]	F/75	Rheumatoid arthritis	Nil	Pleural effusion, well defined smooth walled lesions with fluid and air in bilateral lower lobes, suggestive of abscesses	Not performed	Skin	Dapsone	Clinical improvement
Maritsi, 2015 [34]	F/14 m	Nil	Nil	Consolidations with internal areas of cavitation, surrounding ground-glass changes and lymphadenopathy	Not performed	Skin	Steroid and IVIG	Clinical improvement
Kanoh, 2009 [35]	M/54	MDS	Dyspnea on exertion	Airspace consolidation in the right lower lung, thickening of the interlobular septa with ground glass opacities in the middle lobe	Actively inflamed granulation tissue with infiltration by numerous neutrophils and lymphoplasma cells with necrosis. No vasculitis or granulomas were apparent.	Skin	Steroid	Clinical improvement
Lebbé, 1992 [36]	F/58	Nil	Nil	Excavated lesion with irregular thick walls in the right middle lobe of the lung	Intra-alveolar neutrophilic infiltrate, suppurative exudate with interstitial pneumonitis and mild fibrosis	Skin, Eye	Prednisolone	Clinical improvement
Mlika, 2002 [37]	M/67	Lymphoid leukemia	N/A	N/A	Neutrophil	Skin	Steroid	Clinical improvement
Mlika, 2002 [37]	M/45	Hidradenitis suppurativa	N/A	N/A	Neutrophil	Skin	Not mentioned	Fatal
Batalla, 2011 [38]	F/34	Nil	N/A	N/A	N/A	Skin	Not available	Not available
Bhat, 2007 [39]	F/37	Psoriasis, ulcerative colitis	Nonproductive cough, wheezes, dyspnea	Collapse left upper lobe	mild to moderate chronic nonspecific inflammation	Skin	Steroid	Clinical improvement
Merke, 1996 [40]	M/9 m	Nil	Stridor	(Tracheitis, therefore CT not performed)	Polymorphonuclear cells	Skin	Steroid, dapsone	Clinical improvement
Deregnaucourt, 2013 [41]	M/17	Ulcerative colitis	Fever	Bilateral excavated nodules	Not performed	Skin	Infliximab	Clinical improvement
Field, 2008 [42]	F/52	Ulcerative colitis	Fever, cough, hemoptysis	Homogenous shadowing in the right upper lobe of the lung	Multifocal neutrophilic micro abscess with granulomatous inflammation, multinucleated giant cells	Skin	Surgery	Clinical improvement
Rajan, 2009 [43]	F/4 m	Nil	Stridor	Small, peripheral wedge-shaped opacities	Not performed	Skin	Steroid, cyclosporin, dapsone, infliximab	Clinical improvement
Watanabe, 2016 [44]	M/60	Nil	Desaturation (dyspnea)	Ground-glass opacity and infiltrative shadows around bilateral hilar regions, thickening of interlobular septa, and bilateral pleural effusions	Not performed	Skin	Steroid	Clinical improvement
Poiraud, 2010 [45]	M/60	CMML	Fever, odynophagia, constitutional symptoms	Interstitial lung disease	Not performed	Skin, joint, mesentery	Steroid	Clinical improvement
Mirkamali, 2007 [46]	M/57	Nil	Not available	Left middle lobe cavitary lesion with fluid level	Not performed	Skin	Immunosuppressive	Clinical improvement
Takeuchi, 2003 [47]	F/5	Nil	Barking cough, biphasic stridor and remittent fever	Bronchoscopy revealed flared ulcerative lesions throughout the trachea (No CT performed)	Not performed due to laryngeal spasm	Skin	Steroid	Clinical improvement
Sasaki, 2003 [48]	F/64	Nil	Shortness of breath	Interstitial pneumonia	N/A	Skin	Steroid, cyclosporin A	Clinical improvement
Grattan, 1998 [49]	F/28	Nil	Nil	Cystic changes in right lower zone	Not done	Skin	Prednisolone	Clinical improvement
Liu, 2008 [50]	M/65	IgA monoclonal gammopathy	Hemoptysis	Multiple nodules in the pulmonary, some with cavitation	Not performed, refused by patient	Skin	Prednisolone, dapsone	Clinical improvement
Vignon-Pennamen, 1991 [51]	M/38	Nil	Fever, chest pain, cough	Pulmonary infiltrates	N/A	Skin	Steroid	Not mentioned
Peters, 1998 [52]	F/48	MDS	Fever, chest pain	Pulmonary infiltrates in the right lower and middle lobe with a pleural effusion, without cavitary lesion	Not performed	Skin	Steroid, chemotherapy	Died during treatment
Shands, 1987 [53]	F/48	Nil	Fever	Pulmonary infiltrates	N/A	Skin	Steroid	N/A
Urano, 1995 [54]	F/37	Nil	Fever, constitutional symptoms	Pulmonary infiltrates	N/A	Skin	Steroid	Clinical improvement
Kędzierska, 2020 [55]	F/51	Vitiligo, Hashimoto’s disease	Fever, cough	Widespread inflammatory infiltrates with or without central necrosis. Ground glass opacity with pulmonary fibrosis	Not performed	Skin, Spleen, Mesorectal area	Steroid, IVIg, cyclosporin A, cyclophosphamide, methotrexate, mycophenolate mofetil, azathioprine, dapsone, etanercept, Adalimumab, Infliximab	Clinical improvement
Gallou, 2021 [56]	M/66	IgA monoclonal gammopathy	Dyspnea	Cavitary mass lesion	N/A	Skin	Steroid, Tofactinib	Clinical improvement
Hooton, 2021 [57]	F/51	Plasma cell dyscrasia	Sputum production	N/A	Bronchocentric granulomatous inflammation and fibrosis	Skin	Steroid, cyclosporin	Clinical improvement
Arai, 2021 [58]	M/62	Nil	Chest pain	Pulmonary nodule	Epithelioid granuloma with pyogenic inflammation	Spleen	Steroid	Clinical improvement
Our Case	M/17	Inflammatory bowel disease	Fever, cough, stridor	Multiple small scattered subpleural patchy infiltrates, and nodular mucosal lesions on the trachea, bronchi and right bronchioles	Suppurative inflammation with squamous epithelial hyperplasia, but no definite granulomatous inflammation	Skin	Steroid, Adalimumab	Clinical improvement

Abbreviations: N/A: Not applicable (information not provided by the initial research article); AML, acute myelocytic leukemia; MDS, myelodysplastic syndrome; IVIG, intravenous immunoglobulin; CMML, chronic myelomonocytic leukemia

The majority of the patients were female, accounting for 27 out of 51 patients (52.9%) in our review, with age ranging from 4 months to 82 years old (median age 48 years old). The extracutaneous PG was associated with hematological disorders (23.5%, 12/51), inflammatory bowel disease (11.8%, 6/51) and autoimmune disease (9.8%, 5/51). Within hematological disorders, myelodysplastic syndrome (33.3%, 4/12) and IgA monoclonal gammopathy (33.3%, 4/12) were the most common, followed by myeloid leukemia (16.7%, 2/12), lymphoid leukemia (8.3%, 1/12), and plasma cell dyscrasia (8.3%, 1/12). Besides the above three major categories of associated disorders, 1 patient in our review had underlying hidradenitis suppurativa [36], which was previously thought to be associated with PG. Another patient was also found to have T cell lymphopenia [15], whereas the association with PG was less certain.

Initial clinical presentation of PG with pulmonary involvement was usually nonspecific. Cough (43.1%, 22/51) was the most common symptom, followed by dyspnea (27.5%, 14/51), chest pain (15.7%, 8/51), hemoptysis (9.8%, 5/51), constitutional symptoms (9.8%, 5/51), and stridor (7.8%, 4/51).

Concerning further investigation among the 51 patients included in this review, 46 patients (90.2%) received a CT of the thorax for further delineation of underlying pulmonary pathology. The most common radiological findings were pulmonary infiltrates (84.8%, 39/46), followed by cavitary lesions (39.1%, 18/46), pleural effusion (13.0%, 6/46), and consolidation (10.9%, 5/46). Other radiological findings included interstitial lung disease and interstitial pneumonia. Only 27 patients (52.9%, 27/51) received bronchoscopy or open/radiological guided lung biopsy for further confirmation of the diagnosis as well as exclusion of other similar etiologies. Neutrophil infiltration or inflammation (85.2%, 23/27) was a common finding in the histopathology of the respiratory specimen, with 2 patients (11.1%, 3/27) showing pulmonary fibrosis and 5 patients (22.2%, 6/27) showing granulomatous inflammation, and with negative bacterial and fungal staining excluding the possibility of opportunistic infection in these patients.

Majority of patients (96.1%, 49/51) also had co-existing dermatological involvement, except two patients with isolated respiratory involvement [28,58]. Other organ involved included the spleen (7.8%, 4/51), eye (3.9%, 2/51) and bone (3.9%, 2/51). Tracheobronchial involved of PG was present in 11 patients, and more than one third (36.4%, 4/11) of these patients presented with stridor on presentation. Further univariate analysis suggested that stridor (p < 0.01, by Fisher’s exact test) and young age (p < 0.01, by Mann Whitney U test) might be the predictors of tracheobronchial involvement, with the age range of patients without tracheobronchial involvement (14 months to 82 years old) higher than those with tracheobronchial involvement (4 months to 54 years old).

With the available information, systemic corticosteroid (85.7%, 42/49) was the mainstay of treatment, with occasional use of other immunosuppressants (36.7%, 18/49) and even targeted therapy (20.4%, 10/49), such as TNF alpha blockers (Infliximab, Adalimumab), proteasome inhibitors (Bortezomib) and Janus kinase inhibitors (Tofacitinib). 91.8% of patients (45/49) recovered with the resolution of clinical symptoms, skin lesions or progress imaging after treatment, however, 4 patients (8.2%) unfortunately deteriorated due to either poor response to treatment or underlying disease.

5. Discussion

5.1. Implications

PG, as well as other conditions presenting with neutrophilic dermatoses, can be classified into neutrophilic disease, and almost every organ can be involved by neutrophilic inflammation [11]. Although pyoderma gangrenosum with pulmonary involvement is an unusual presentation of a rare disease, pulmonary involvement is the commonest extracutaneous manifestation of PG, with the age of patients and associated diseases (namely inflammatory bowel disease, hematological disorder together with autoimmune disease) similar to those reported in existing literature in classic PG [3,4].

However, the diagnosis of PG with pulmonary involvement is usually difficult. Firstly, the initial presenting symptoms of majority of the patients in our literature review were cough and dyspnea, which were nonspecific that clinicians might consider other more common differential diagnosis such as heart failure or pneumonia. Even if further imaging such as chest radiographs or CT of the thorax was ordered for these patients, the radiological findings could be so subtle that clinicians might not be aware of the possibility of PG with pulmonary involvement. Furthermore, patients may refuse invasive procedures such as bronchoscopy or open lung biopsy. It will be even more challenging as 4% of patients in our literature review presented with pyoderma gangrenosum with isolated pulmonary involvement. With the above reasons, although our literature search only yielded 51 cases, this number is likely an underestimation of the current situation.

In our case report, the treatment of PG with pulmonary involvement was delayed. One of the reasons is that the pulmonary radiological finding may mimic other pathology such as ANCA associated vasculitis, malignancy and pneumonia [59], especially when PG is associated with diseases that are immunocompromising due to either the disease itself (hematological disorder) or the treatment received (inflammatory bowel disease and autoimmune disease). In addition to that, treatment of PG requires the use of high dose steroids and immunosuppressants. With the common radiological findings of pulmonary cavitation in patients with PG, physicians will be reluctant to start treatment early while awaiting further investigation to rule out opportunistic infection. To further complicate the picture, in our locality, Mycobacterium tuberculosis infection is prevalent in South East Asia and well known to cause pulmonary cavitation [60]. As patients with inflammatory bowel disease and autoimmune disease may receive TNF alpha blockers and patients with hematological diseases may have persistent neutropenia, these will increase the risk of acquiring Mycobacterium tuberculosis [61].

Another important point demonstrated by our case report is that tracheobronchial involvement of PG could be life-threatening if the clinicians were not aware of this disease manifestation and treatment was not given promptly. In our case, the patient first presented to the hospital with normal oxygen saturation, however, as the treating clinician was not aware of the possibility of pulmonary involvement of PG, the patient was treated with multiple empirical antibiotics, which delayed the optimal treatment of the patient and caused the disease to further progress into upper airway obstruction. Our literature review demonstrated that stridor on presentation and young age were associated with tracheobronchial involvement, and the finding is compatible with previous evidence of stridor indicating a high likelihood of involvement of trachea [62], therefore in a patient with suspected PG with pulmonary involvement, prompt airway assessment and treatment should be given to patients in younger age group.

Management of PG comprises of identification of associated underlying disease and immunomodulation by the use of systemic corticosteroids and immunosuppressants, including steroid-sparing agent such as azathioprine, cyclosporine, thalidomide, and dapsone, together with targeted therapy such as TNF alpha blockers and proteasome inhibitors. To date, there is still no clinical guideline for the treatment for patients with PG with pulmonary involvement. As the number of cases is limited, it is difficult to comment on the difference in the efficacy of different treatment combination, but at least the majority of patients receiving immunosuppressant responded to treatment.

5.2. Limitations

One of the limitations of our study is that the literature involved in our review are all in English. There are several literature and case reports in other languages such as Japanese and French, which were not included in our review. In addition, the above statistical analysis was based on the limited information available in the publications, whereas information not included in the literature was not able to be included in the statistical analysis. Furthermore, information such as ethnicity was unfortunately not available in most literature for further analysis, therefore the difference between the presentation of this disease entity in different ethnicity is still unknown.

6. Conclusion

In summary, pulmonary involvement is the most common extracutaneous presentation of PG, and it may mimic other disease entities such as opportunistic infection in terms of clinical presentations and radiological findings, especially in immunocompromising conditions that PG typically associates. Tracheobronchial involvement can present as upper airway obstruction and may be life-threatening. Young patients and stridor on presentation may suggest a higher likelihood of involvement of trachea/bronchus and require prompt airway assessment and management.

7. Expert opinion

Pyoderma gangrenosum with pulmonary involvement is an unusual presentation of a rare disease. The nonspecific nature of initial presenting symptoms, radiological findings together with requirement of invasive procedures such as bronchoscopy and lung biopsy are the challenges of making the correct diagnosis. It is paramount for clinicians to be aware of the possibility of pulmonary involvement of pyoderma gangrenosum in younger population, as a delay in diagnosis without prompt treatment may result in life-threatening consequences. We believe that early involvement of dermatologists in patients presented with pyoderma gangrenosum-like lesions may shorten the time from clinical presentation to arriving at the correct diagnosis. In order to guide non-dermatologists in diagnosing PG, useful and novel diagnostic algorithms should be designed and introduced in order to strengthen the awareness of clinicians on this clinical entity. Although currently such diagnostic algorithms are not yet available, scoring system approach based on underlying disease, age and extend of rash involvement may be helpful for clinicians in evaluation of the likelihood of the pulmonary involvement is due to pyoderma gangrenosum or not. Furthermore, PG with pulmonary involvement is still an entity that requires further investigation and study, as its relationship with other demographic factors such as ethnicity is not yet well understood.

To date, there is no practical guidelines for the optimal treatment of PG with pulmonary involvement, and the approach is mainly derived from small uncontrolled studies, clinical experience and expert opinion. From our case and literature review, systemic corticosteroids, the first-line therapy of PG with extensive or rapidly progressing disease, were prescribed for the patients as the mainstay of treatment. Steroid sparing agents such as cyclosporin can be an alternative regimen if patients are unable to tolerate systemic glucocorticoid therapy. Other second-line agents such as mycophenolate mofetil, azathioprine, and methotrexate may be beneficial and have also been reported in the literature. With the advance in development of biologics, such as TNF alpha blockers, targeted therapeutic agents specifically targeting certain pathway are useful in reduction of the dosage and adverse effect of corticosteroids. However, due to the limited cases in the literature, it is difficult to ascertain the best treatment regimens for patients with PG with pulmonary involvement. Therefore, further researches such as case control study or randomized-controlled trial are necessary to determine the optimal treatment for this group of patients.

In addition to that, it should be emphasized that upper airway obstruction is a life-threatening complication of pyoderma gangrenosum, therefore early clinical suspicious of pyoderma gangrenosum, prompt initiation of appropriate treatment together with close monitoring of patient in intensive care unit are paramount to the clinical outcome of the patient.

Article highlights

• Pulmonary involvement is an extracutaneous manifestation of pyoderma gangrenosum.

• Diagnosis of pyoderma gangrenosum with pulmonary involvement is difficult for non-dermatologists due to the nonspecific symptoms, subtle radiological finding, and requirement of invasive procedures.

• Delayed diagnosis of tracheobronchial involvement in pyoderma gangrenosum may be life-threatening.

• Treatment for patients with pyoderma gangrenosum with pulmonary involvement comprises of systemic corticosteroids, immunosuppressants, and targeted therapeutic agents.

• Majority of patients with pyoderma gangrenosum with pulmonary involvement responded to the current combination therapy, but further researches are required for determination of optimal therapy for this condition.

Ethics approval and consent to participate

Written informed consent was obtained from the patient included in the study.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We are grateful to the staff at the Department of Clinical Microbiology and Infection Control, the Department of Pathology, The University of Hong Kong-Shenzhen Hospital, and Department of Microbiology, The University of Hong Kong for facilitation of the study.

Additional information

Funding

This study was partly funded by the High Level-Hospital Program of Health Commission of Guangdong Province and the Sanming Project of Medicine in Shenzhen (No. SZSM201911014). The sponsors had no role in the design and conduct of the study, in the collection, analysis and interpretation of data, or in the preparation, review or approval of the manuscript.