Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ierx20 Expert Review of Respiratory Medicine ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierx20 Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature review Fanfan Xing, Kelvin Hei-Yeung Chiu, Jin Yang, Haiyan Ye, Lijun Zhang, Chenjing Liu & Kwok-Yung Yuen To cite this article: Fanfan Xing, Kelvin Hei-Yeung Chiu, Jin Yang, Haiyan Ye, Lijun Zhang, Chenjing Liu & Kwok-Yung Yuen (2022) Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature review, Expert Review of Respiratory Medicine, 16:2, 149-159, DOI: 10.1080/17476348.2022.2027756 To link to this article: https://doi.org/10.1080/17476348.2022.2027756 © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 24 Jan 2022. Submit your article to this journal Article views: 1234 View related articles View Crossmark data Citing articles: 1 View citing articles
Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature review
Feb 13, 2023
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
Welcome message from author
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.
Transcript
Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature reviewFull Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ierx20
Expert Review of Respiratory Medicine
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierx20
Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature review
Fanfan Xing, Kelvin Hei-Yeung Chiu, Jin Yang, Haiyan Ye, Lijun Zhang, Chenjing Liu & Kwok-Yung Yuen
To cite this article: Fanfan Xing, Kelvin Hei-Yeung Chiu, Jin Yang, Haiyan Ye, Lijun Zhang, Chenjing Liu & Kwok-Yung Yuen (2022) Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature review, Expert Review of Respiratory Medicine, 16:2, 149-159, DOI: 10.1080/17476348.2022.2027756
To link to this article: https://doi.org/10.1080/17476348.2022.2027756
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Published online: 24 Jan 2022.
Submit your article to this journal Article views: 1234
View related articles View Crossmark data
Citing articles: 1 View citing articles
aDepartment of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; bDepartment of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China; cDepartment of Rheumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; dDepartment of Pediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; eState Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China; fCarol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China; gThe Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
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 involve- ment, 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 asso- ciated 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.
ARTICLE HISTORY Received 30 January 2021 Accepted 7 January 2022
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 der- matological lesions with histology showing intense inflamma- tory 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 devel- oping into burrowing ulcers with violaceous edges typically occur- ring 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 cri- teria, 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 tracheo- bronchial disease, a review of current literature with statistical analysis was performed, so as to identify possible clinical char- acteristics 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
CONTACT Kwok-Yung Yuen [email protected] State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
EXPERT REVIEW OF RESPIRATORY MEDICINE 2022, VOL. 16, NO. 2, 149–159 https://doi.org/10.1080/17476348.2022.2027756
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
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 ulcera- tive skin lesions on the face and all extremities with brownish exudates. Initial investigation revealed leukocytosis with thrombo- cytosis, and normal liver and renal function tests. C-reactive pro- tein (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, naso- pharyngeal 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 admis- sion 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 show- ing suppurative inflammation with squamous epithelial hyperpla- sia, but no definite granulomatous inflammation (Figure 2(b)). No suspicious organisms were identified by Ziehl-Neelsen stain, peri- odic 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.
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, increas- ing 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).
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 respira- tory support in view of possible clinical deterioration to com- plete upper airway obstruction. Adalimumab (a tumor necrosis factor (TNF) antagonist) was started together with high-dose methylprednisolone, with subsequent defervescence and clin- ical improvement in both respiratory and dermatological con- dition. 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.
Article highlights
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, immunosuppres- sants, 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.
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.
150 F. XING ET AL.
3. Method
3.1. Literature search
Literature review was performed using the search terms ‘pul- monary, lung, respiratory, bronchopulmonary, tracheobron- chial 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, inva- sive 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 gang- renosum 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 pre- dictors that allow us to alert to the possibility of tracheo- bronchial 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 clin- ical 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.
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.
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.
EXPERT REVIEW OF RESPIRATORY MEDICINE 151
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EXPERT REVIEW OF RESPIRATORY MEDICINE 155
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 disor- ders (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 com- mon, 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 dis- orders, 1 patient in our review had underlying hidradenitis suppurativa [36], which was previously thought to be asso- ciated 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 involve- ment 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), constitu- tional 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 pul- monary infiltrates (84.8%, 39/46), followed by cavitary lesions (39.1%, 18/46), pleural effusion (13.0%, 6/46), and consolida- tion (10.9%, 5/46). Other radiological findings included inter- stitial lung disease and interstitial pneumonia. Only 27 patients (52.9%, 27/51) received bronchoscopy or open/radi- ological 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 iso- lated 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 tra- cheobronchial 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 inflamma- tion [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 pneumo- nia [59], especially when PG is associated with diseases that are immunocompromising due to either the disease itself (hematological disorder) or the treatment received (inflamma- tory 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 find- ings 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 tubercu- losis infection is prevalent in South East Asia and well known to cause pulmonary cavitation [60]. As patients with inflam- matory 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
156 F. XING ET AL.
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 presenta- tion and young age were associated with tracheobronchial involvement, and the finding is compatible with previous evidence of stridor indicating a high likelihood of involve- ment 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 asso- ciated underlying disease and immunomodulation by the use of systemic corticosteroids and immunosuppressants, including steroid-sparing agent such as azathioprine, cyclos- porine, 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…
Expert Review of Respiratory Medicine
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierx20
Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature review
Fanfan Xing, Kelvin Hei-Yeung Chiu, Jin Yang, Haiyan Ye, Lijun Zhang, Chenjing Liu & Kwok-Yung Yuen
To cite this article: Fanfan Xing, Kelvin Hei-Yeung Chiu, Jin Yang, Haiyan Ye, Lijun Zhang, Chenjing Liu & Kwok-Yung Yuen (2022) Pyoderma gangrenosum with pulmonary involvement: a pulmonary special report and literature review, Expert Review of Respiratory Medicine, 16:2, 149-159, DOI: 10.1080/17476348.2022.2027756
To link to this article: https://doi.org/10.1080/17476348.2022.2027756
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Published online: 24 Jan 2022.
Submit your article to this journal Article views: 1234
View related articles View Crossmark data
Citing articles: 1 View citing articles
aDepartment of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; bDepartment of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China; cDepartment of Rheumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; dDepartment of Pediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; eState Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China; fCarol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China; gThe Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
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 involve- ment, 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 asso- ciated 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.
ARTICLE HISTORY Received 30 January 2021 Accepted 7 January 2022
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 der- matological lesions with histology showing intense inflamma- tory 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 devel- oping into burrowing ulcers with violaceous edges typically occur- ring 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 cri- teria, 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 tracheo- bronchial disease, a review of current literature with statistical analysis was performed, so as to identify possible clinical char- acteristics 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
CONTACT Kwok-Yung Yuen [email protected] State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
EXPERT REVIEW OF RESPIRATORY MEDICINE 2022, VOL. 16, NO. 2, 149–159 https://doi.org/10.1080/17476348.2022.2027756
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
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 ulcera- tive skin lesions on the face and all extremities with brownish exudates. Initial investigation revealed leukocytosis with thrombo- cytosis, and normal liver and renal function tests. C-reactive pro- tein (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, naso- pharyngeal 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 admis- sion 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 show- ing suppurative inflammation with squamous epithelial hyperpla- sia, but no definite granulomatous inflammation (Figure 2(b)). No suspicious organisms were identified by Ziehl-Neelsen stain, peri- odic 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.
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, increas- ing 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).
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 respira- tory support in view of possible clinical deterioration to com- plete upper airway obstruction. Adalimumab (a tumor necrosis factor (TNF) antagonist) was started together with high-dose methylprednisolone, with subsequent defervescence and clin- ical improvement in both respiratory and dermatological con- dition. 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.
Article highlights
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, immunosuppres- sants, 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.
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.
150 F. XING ET AL.
3. Method
3.1. Literature search
Literature review was performed using the search terms ‘pul- monary, lung, respiratory, bronchopulmonary, tracheobron- chial 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, inva- sive 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 gang- renosum 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 pre- dictors that allow us to alert to the possibility of tracheo- bronchial 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 clin- ical 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.
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.
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.
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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 disor- ders (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 com- mon, 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 dis- orders, 1 patient in our review had underlying hidradenitis suppurativa [36], which was previously thought to be asso- ciated 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 involve- ment 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), constitu- tional 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 pul- monary infiltrates (84.8%, 39/46), followed by cavitary lesions (39.1%, 18/46), pleural effusion (13.0%, 6/46), and consolida- tion (10.9%, 5/46). Other radiological findings included inter- stitial lung disease and interstitial pneumonia. Only 27 patients (52.9%, 27/51) received bronchoscopy or open/radi- ological 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 iso- lated 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 tra- cheobronchial 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 inflamma- tion [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 pneumo- nia [59], especially when PG is associated with diseases that are immunocompromising due to either the disease itself (hematological disorder) or the treatment received (inflamma- tory 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 find- ings 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 tubercu- losis infection is prevalent in South East Asia and well known to cause pulmonary cavitation [60]. As patients with inflam- matory 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
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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 presenta- tion and young age were associated with tracheobronchial involvement, and the finding is compatible with previous evidence of stridor indicating a high likelihood of involve- ment 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 asso- ciated underlying disease and immunomodulation by the use of systemic corticosteroids and immunosuppressants, including steroid-sparing agent such as azathioprine, cyclos- porine, 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…
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