Chronic Ulcers and Malnutrition in an African Patient

Abstract

An 11-year-old female with a congenitally malformed left hand, sickle-cell trait, asthma, and history of appendicitis was transferred from Zambia for evaluation and treatment of widespread suppurative and ulcerative skin lesions that typically appeared following trauma to her skin. The ulcers first presented 3 years earlier but had markedly worsened in the 9 months prior to transfer, spreading circumferentially on her extremities and abdomen at the site of an appendectomy. They were painful and did not resolve with multiple courses of intravenous (IV) antibiotics and close management by a Pediatric Infectious Disease specialist working for a non-governmental organization (NGO) in her home country. The child had participated annually in health screenings at the NGO and previously had been average weight-for-age. The NGO arranged for international transfer to our pediatric academic medical center. Upon presentation she was severely malnourished with lesions covering approximately 35% of her body. Initial workup found leukocytosis of 21 × 10³ cells/μL (79% neutrophils), hemoglobin 6.1g/dL, and MCV 66 fl. Iron studies showed iron 18μg/dL, ferritin 55ng/mL, total iron binding capacity 222μg/dL, and transferrin saturation 8%. Inflammatory markers were elevated, CRP 20.1mg/dL, ESR 131mm/hr. A chest CT demonstrated bilateral pulmonary nodules, the largest in her left upper lobe measuring 2.4 × 2.0 × 1.9 cm. Our panel of experts reviews the evaluation and treatment of this patient with extensive suppurative and ulcerative skin lesions, severe malnutrition, hematological abnormalities and pulmonary nodules and the factors considered in offering charity care to international patients.

Table of Contents summary:

A previously healthy 11-year-old girl from southern Africa presents with widespread suppurative and ulcerative skin lesions that appear following trauma to her skin.

Case Presentation

Timothy Singer, MD, MS, Global Child Health Resident, Moderator

An 11-year-old female from Zambia was transferred to our institution for evaluation and treatment of ulcerative skin lesions. The lesions waxed and waned for about three years but became widespread and refractory to multiple interventions over the prior 9 months. Starting at age 6, the patient had attended enrichment programs and health screenings at a local non-governmental organization (NGO). According to NGO records, she was historically healthy. As her disease progressed, the NGO’s medical director, who is a Pediatric Infectious Disease specialist, managed her care. When her clinical course proved refractory to available treatments, the NGO arranged transfer through our International and Destination Medicine program.

The NGO provided a detailed medical history. The patient was born prematurely (reportedly 32 weeks) with a congenitally malformed left hand without several digits. An initial delay in developmental milestones resolved by age 5. Her other chronic diagnoses include sickle-cell trait and mild intermittent asthma.

At 8-years-old several “bug bites” on her extremities became coin-shaped ulcers which eventually self-resolved. At 10-years-old an abrasion superficial to her left tibia ulcerated and spread circumferentially around her calf. Historic records show that as her disease progressed, she had onset of failure to thrive. At age 6 she had weighed 19 kilograms, just below the 50th percentile on the World Health Organization weight-for-age growth chart. By age 8, her weight was virtually unchanged, and she had fallen to the 5th percentile. And, upon arrival at our institution, she weighed 20.5 kilograms. At 120 cm in length, her body mass index measured 13.7kg/m², nearly 3 standard deviations below the median for her age, placing her on the borderline of severe malnourishment.

Six months prior to her transfer, she underwent an urgent appendectomy for suspected appendicitis. Afterwards, her surgical incision ulcerated and the lesion spread across her right lower quadrant (RLQ). Post-operatively she remained admitted at the teaching hospital in the capital city. There, she was treated for severe malnutrition, underwent available infectious and immune work-up and received multiple courses of IV antibiotics. A wound biopsy was negative for bacterial growth; histopathology was not available. Immunoglobulins were within normal limits. As her hospital course prolonged, she developed ulcerations at sites where intravenous catheters had been inserted and she did not regain weight. At this point, the NGO contacted our institution.

Brittany Walters, what are the criteria for accepting international patients at our institution?

Brittany Walters, BSN, RN, CCM, International Patient Services

Whether a patient comes to us independently, as with this patient, or via an arrangement with their embassy, each case is reviewed extensively for the medical history and family social support. We consider whether the patient’s disease truly cannot be cared for in their home country, and that it is treatable. We try to anticipate the length of hospitalization and follow up. From the beginning, we look for who in the patient’s country will manage their care when they return. Of important note, at our institution patients with chronic, lifelong conditions (e.g. cerebral palsy), oncology care, organ and stem cell transplantation, are normally excluded. Finally, as a teaching institution we consider whether trainees will be able to be involved in patient care.

After we determine that we believe we can help the child, we ask the family to complete an application and to demonstrate that they will have support locally while their child receives treatment. This includes housing, food, transportation, supplies and some medications that would not be covered under our charity program. This patient had strong local support and we were in close contact with the NGO and their medical director, trusting that upon return home, her care would be overseen.

Dr. Singer

On the night she arrived, the patient was in great distress, having endured two days of commercial airline travel. Our first measures were comfort and pain control.

In gathering further history, she had experienced months of fatigue, waxing and waning fevers, intermittent night sweats, occasional emesis, and frequent loose stools. She denied shortness of breath or wheezing. She was not on long-term medications. Immunizations were up to date. Family medical and social histories were unremarkable. She had grown up in a middle-class family for her country in the capital city. Her mother, father and brother were all healthy. She had been in the age-appropriate grade level prior to illness.

On exam, she was afebrile and distressed due to pain. She had mild tachycardia (heart rate 100–130 bpm). Her hair was black, thin and fine without alopecia. Exam of her head, eyes, ears, nose, throat, heart and lungs were otherwise unremarkable. Her abdominal exam revealed normal bowel sounds but was diffusely tender to palpation. Her extremities were wasted without edema. Suppurative ulcers with warmth and tenderness covered approximately 35% of her body surface area. (Figure 1) Ulcers were over her RLQ abdominal wall, left arm from axilla to hand, entire right thigh and left lower leg circumferentially. There were small (<2cm diameter) ulcers over her left neck and scalp. On the dorsal side of her left hand, extensor tendons were exposed.

Figure 1:

Lesions on presentation

Initial laboratory studies showed leukocytosis of 21.4 × 10³/uL (79% neutrophils), hemoglobin 6.1g/dL, hematocrit 21%, and mean corpuscular volume of 66 fl. Iron studies were notable for iron 18μg/dL (55–150μg/dL), ferritin 55ng/mL (10–70ng/mL), total iron binding capacity 222μg/dL (250–400μg/dL), and transferrin saturation 8% (15–39%). Inflammatory markers were elevated, C-reactive protein (CRP) 20.1mg/dL, erythrocyte sedimentation rate (ESR) 131mm/hr. Renal function was normal. She was negative for HIV. (Table 1)

Table 1:

Initial labs

Variable	Results on admission	Reference Range
WBC count, 103 cells/μL	21.4	5–14.5
Segmented neutrophils, %	79	33–76
Lymphocytes, %	7	15–61
Hemoglobin, g/dL	6.1	11.5–15.5
Hematocrit, %	21	35–45
Mean corpuscular volume, fl	65.8	76–90
RDW, %	20.3	11.5–14
Platelet count, 103 cells/μL	471	150–450
ESR, mm/h	131	0–20
CRP, mg/dL	20.1	<1
Sodium, mmol/L	134	136–145
Potassium, mmol/L	4.4	3.5–5.5
Chloride, mmol/L	98	95–105
Carbon Dioxide, mmol/L	29	20–30
BUN, mg/dL	3	2–23
Creatinine, mg/dL	0.27	0.5–0.8
Glucose, mg/dL	101	70–100
Serum iron, μg/dL	18	60–170
Ferritin	55	7–140
TIBC, μg/dL	222	250–450
Transferrin saturation, %	8	20–50

• WBC, white blood cell; RBC, red blood cell; RDW, Red blood cell distribution width; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; BUN, blood urea nitrogen; TIBC, total iron binding capacity

She was admitted to the Pediatric Hospital Medicine service and initial consults were to the Infectious Disease, Dermatology, and Rheumatology services.

Turning to our specialists, what were your initial differentials, respectively?

Saki Ikeda, MD, Pediatric Infectious Diseases

On her first day in the hospital we spoke with the NGO medical director to review the disease course and antimicrobial history, which included trimethoprim/sulfamethoxazole, ceftriaxone, cefepime, meropenem, linezolid and vancomycin. Although she was HIV negative, we suspected she may have a primary immunodeficiency given the extent of her infections. With this in mind, we listed a differential of ulcer-causing pathogens, endemic infections to the region, and considered underlying autoimmune, malignant, and malnutrition-related etiologies. Regardless of the primary process, none of the providers had seen lesions as extensive as hers, which necessitated that we be open to atypical presentations.

On the top of our infectious differential were mycobacterial infections such as Mycobacterium ulcerans, which cause Buruli ulcers.¹ However, these are more typical in West Africa and Central Africa versus Southern Africa and lesions are usually single or less numerous than seen here. We tested for Mycobacterium tuberculosis, although cutaneous TB is not known to be ulcerative.² We considered Nocardia, Actinomyces, anthrax and yaws, caused by the spirochete bacterium Treponema palladum, and parasitic infections including leishmaniasis.^3,4,5,6,7

In addition to wound cultures and biopsy for histopathology, we requested a CT of the head, neck, chest, abdomen, and pelvis to determine the extent of internal disease. We looked for pulmonary nodules which could be associated with systemic infections including bacterial, mycobacterial or fungal infections, and to assess the abdomen, liver and spleen.

Audrey Chan, MD, Pediatric Dermatology

Our first impression came from photos sent by our resident. Without the benefit of a full history, it was hypothesized that her hand could represent the so-called “mitten deformity” characteristic of recessive dystrophic epidermolysis bullosa (RDEB). RDEB is an inherited skin fragility disorder leading to numerous erosions and ulcerations on the skin.⁸ However, as history revealed the hand deformity was congenital, while the skin ulcerations were of relatively recent onset, RDEB became unlikely.

After evaluating the patient, our primary concern was to rule-out infection given the suppurative ulcerations. We also considered numerous rheumatologic and auto-inflammatory disorders which can present with ulcerative lesions including pyoderma gangrenosum (PG) or sarcoidosis. While suppuration and ulceration are classically seen in PG, PG is a diagnosis of exclusion. PG more commonly affects adults and adolescents, with ulcers classically located on the pre-tibial areas. While extensive skin involvement has been reported, this is less common.⁹ Sarcoidosis along with syphilis are considered the great imitators of other diseases in dermatology. Thus, a rare presentation of ulcerative sarcoidosis was considered.¹⁰

Less likely diagnostic considerations were cutaneous malignancies and vasculitides. Cutaneous malignancies are unusual in children, especially in the absence of an underlying genetic disorder or photosensitivity disorder, such as xeroderma pigmentosum.¹¹ Even in these settings, this extensive skin involvement would be rare. Cutaneous lymphoma was also thought to be unlikely, as ulcerations are uncommon and, if present, usually develop in pre-existing plaques or nodules.¹² She lacked the more classic findings of vasculitis such as palpable purpura, or livedoid change in association with the ulcerations, although rarely PG-like ulcerations have been reported in granulomatosis with polyangiitis.¹³ The effect of the child’s malnutrition on wound healing confounded the clinical presentation.¹⁴

Skin biopsies for anatomic pathology and tissue cultures are critical to help eliminate infection as a possible etiology and to delineate histopathological findings. While in some rare cases, histopathological findings are so unique that diagnosis can be made from biopsy alone, more commonly, histopathological patterns help narrow the differential diagnosis by eliminating certain diagnoses and providing pathological support for others.

Monica Bray, MD, Pediatric Rheumatology

After considering our classic disease phenotypes, her pattern of inflammation did not clearly fit into a particular rheumatologic diagnosis. Extremely rare presentations of rheumatic disease remained on our differential but were diagnoses of exclusion, as mentioned by Dr. Chan.

Ulcerative cutaneous features can be presenting features of systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), sarcoidosis and systemic vasculitis, including Takayasu arteritis, polyarteritis nodosa, and antineutrophil cytoplasmic antibody associated (ANCA). Most of these conditions typically cause cumulative internal damage if left untreated. Thus we agreed that CT imaging was necessary.^15,16,17 She did not have examination findings consistent with the monogenic form of pediatric sarcoidosis, Blau syndrome, which often causes severe granulomatous arthritis and uveitis.¹⁸ Children can present with an acquired form of sarcoidosis similar to the adult phenotype; typical cutaneous manifestations include erythema nodosum and nodules of granulomatous inflammation.¹⁹ We also considered the rare, monogenic, autosomal dominant auto-inflammatory disorder “PAPA”, which stands for “pyogenic arthritis, PG and acne”. The absence of severe acne and pyogenic arthritis made this less likely.²⁰ Cutaneous inflammation including erythema nodosum and PG may also be extra-intestinal manifestations of inflammatory bowel disease (IBD).²¹

Especially interesting was the pattern of the lesions appearing after skin trauma, which was suspicious for a pathologic process called “pathergy”. Pathergy is defined as cutaneous hyperreactivity to minimal trauma, which can vary from an indurated papule to formation of a new disease lesion depending on the underlying diagnosis.²² Pathergy indicates a dysregulated inflammatory response. She had not yet demonstrated this response to IV’s placed in the US which had typically preceded the onset of her lesions while in Zambia. For initial studies, we recommended to trend inflammatory markers in response to correction of nutritional deficiencies, antibiotics and wound care. We also recommended serologies for SLE, MCTD and ANCA vasculitis.

Dr. Singer

Bloodwork showed iron deficiency anemia likely due to malnutrition and hemoglobin electrophoresis confirmed sickle-cell trait. Electrolytes, including calcium, were not deranged. In addition, her prealbumin and albumin were low, 4.6 mg/dL and 2.8 g/dL, respectively. Her INR of 1.2 and hepatic transaminases were within normal limits. Infectious assays were negative for viruses (HIV, Hepatitis panel), as well as M. tuberculosis (Quantiferon Gold) and fungal antigens. Wound cultures of lesions grew Pseudomonas aeruginosa, Enterobacter cloacae, Eggerthella lenta and Candida paraspilosis, all of which were considered superficial infections. Stool ova and parasite as well as blood cultures were negative. And, next generation sequencing of microbial cell-free DNA in the plasma did not detect microorganism DNA. (Table 2)

Table 2:

Further studies

Infectious Disease

Viral	HIV Ab non-reactive, HIV1 RNA PCR negative Hepatic panel: HAV IgG positive. HAV IgM negative, HBcAb negative, HBsAg negative
Bacterial	Quantiferon negative
Fungal	Fungitell serum <31, Aspergillus Galactomannan Antigen not detected​
Microbiology cultures	Wound cultures positive for Pseudomonas aeruginosa, Enterobacter cloacae, Eggerthella lenta and Candida parapsilosis; Aerobic/Anaerobic/Mycobacterial/Fungal Blood Cultures - negative; Ova & Parasite stool – negative
Next generation sequencing of microbial cell-free DNA	No micro-organisms detected

Hematology

Peripheral Smear	Hypochromatic microcytic anemia consistent with iron deficiency anemia; toxic granulocytosis indicative of bacterial infection; no blasts, platelets are enlarged, no organisms
Hemoglobin Electrophoresis	sickle-cell trait

Rheumatology

ANA -positive​, RF negative, ANCA negative, Angiotensin Converting Enzyme - normal; APL Panel: Anti-B2: negative, Anti-cardiolipin – negative,Lupus Anticoagulant - neg​ative

Immunology

Immunoglobulins
IgA	216 (66–295 mg/dL)
IgE	96 (0–200 IU/mL)
IgG	1,200 (641–1,353 mg/dL)
IgM	102 (40–80 mg/dL)
DHR testing	Decreased neutrophil dihydrorhodamine fluorescence suggesting a significantly decreased NADPH oxidase activity
Leukocyte adhesion deficiency panel:	Normal
Leukocyte Phenotyping	CD11b, CD15 and CD18 percentages are normal and LAD unlikely
Lymphocyte Proliferation Assay	Concanavalin A (low), Phytohemagglutinin (normal), Pokeweed Mitogen (low)
Lymphocyte Phenotyping	Lymphocytes not within normal limits for age and she has normal percent of T cells however low absolute numbers of CD4 and CD8 positive populations and abnormal CD4:8 ratio (would expect 2:1). B cells are present in normal percentage and number with appropriate memory B cell population for age. NK cells are normal in percentage and number.

• HIV, human immunodeficiency virus; PCR, polymerase chain reaction; HAV, hepatitis A virus; HBcAb, hepatitis B core antibody; ANA, antinuclear antibodies; RF, rheumatoid factor; ANCA, anti-neutrophil cytoplasmic antibody, APL, antiphospholipid antibody; Ig, immunoglobulin; DHR, dihydrorhodamine test, NADPH, Nicotinamide adenine dinucleotide phosphate; NK, natural killer; LAD, leukocyte adhesion deficiency

Immunologic studies found normal levels of immunoglobulins, decreased neutrophil activity on an oxidative burst assay and abnormal T-cell proliferation. We conferred with the Allergy and Immunology service who interpreted these abnormalities to be secondary to malnutrition rather than primary immunodeficiency.¹⁴ Rheumatologic workup showed systemic inflammation but was not specific, including negative for SLE, with no specific autoantibodies to dsDNA, Sm, phospholipids, ANCA, proteinase 3 and myeloperoxidase.

The CT chest revealed multiple pulmonary nodules bilaterally, the largest measured 2.4 × 2 × 1.9 cm in the left upper lobe. Axillary, lower neck, mediastinal, and peri-aortic lymphadenopathy was also observed. (Figure 2) Notably, no miliary pattern, nor pulmonary parenchymal, hilar or mediastinal calcifications were found. The CT neck found irregularly shaped, subcutaneous loculations along the bilateral neck base. Altogether, infectious rather than malignant etiologies were suspected including non-tuberculosis bacterial, fungal, and protozoan. CT abdomen and pelvis showed trace fluid and suspicion for pelvic calcifications versus surgical material deep to the patient’s appendectomy incision.

Figure 2:

CT Chest, multiple bilateral nodules, largest in left upper lobe upper lobe 2.4 × 2 × 1.9 cm

Dr. Bray, how did the CT findings influence the rheumatologic differential?

Dr. Bray

Pulmonary nodules are often seen in the non-genetic form of juvenile sarcoidosis, similar to the adult phenotype.¹⁹ This form can be characterized by fatigue, weight loss, fever, respiratory symptoms, lymphadenopathy, skin and ocular manifestations.¹⁹ The most common dermatologic manifestations of “adult-type” sarcoidosis are erythema nodosum and granulomatous skin nodules.¹⁹ However there are case reports in adult patients with sarcoidosis of ulcerating lesions and PG, but these lesions were more limited versus widespread.²³ Due to the severity and extent of her skin lesions, we remained concerned about an infectious cause of the lung nodules, which could not be distinguished from sarcoidosis without a biopsy.

Dr. Singer

Biopsies were taken of the skin ulcerations, and in the 3^rd week of hospitalization, from the largest pulmonary nodule and the GI tract.

Dr. Fuller, can you interpret the biopsy results please?

Maren Y. Fuller, MD, Pediatric Pathology

Skin biopsies showed non-specific, predominantly neutrophilic inflammation, including neutrophilic abscesses, panniculitis, skin ulceration with abundant neutrophils as well as areas of lymphohistiocytic aggregates. (Figure 3) The areas of intact epidermis showed epidermal hyperplasia. No microorganisms were seen on stains for bacteria (including acid-fast bacilli) or fungus. Additionally, immunofluorescence stains were negative. Due to the case complexity, it was shared at a local dermatopathology consensus conference. In light of her full clinical picture and negative results of multiple microbiology studies, the consensus opinion was the diagnosis of pyoderma gangrenosum. As noted previously, PG is a diagnosis of exclusion, and histology alone cannot be used to make the diagnosis. Recently, an international group of experts published their consensus opinion of diagnostic criteria of ulcerative PG, although further clinical validation is necessary.²⁴

Figure 3:

Skin biopsy with ulceration and abundant neutrophilic inflammation (H&E stain, 100x magnification)

Biopsy of the left upper lobe lung lesion showed non-specific inflammatory findings without evidence of infection, vasculitis, or granulomatous disease. Endoscopic upper and lower GI biopsies were near-normal, showing only mild chronic esophagitis and gastritis but without evidence of IBD.

Dr. Singer

Returning to the consulting specialists, with the diagnosis of PG, what did you consider in making her treatment plan?

Dr. Ikeda

The wound cultures most likely represented colonization and not primary causes of her lesions. For patients with chronic wounds, we aim to avoid long courses of systemic antibiotics to limit the risk of resistance. Initially, in order to calm her systemic inflammation, we treated the Pseudomonas and Enterobacter with 2 weeks of IV meropenem based on susceptibilities. We also treated Candida. Once her wounds were improved, we changed her antibiotic to a prophylaxis regimen with oral levofloxacin and fluconazole while she received immunosuppressive therapy. Later, we transitioned to topical silver gels which, although not an antibiotic per se, have antimicrobial properties.²⁵

Dr. Chan

First-line dermatologic treatment for PG is systemic steroids, which were started, but we always plan for a steroid-sparing agent. Here, we began with cyclosporine, which was favored because its onset of action is days to weeks compared with months of other steroid-sparing agents including methotrexate, mycophenolate mofetil, and tumor necrosis factor (TNF)-alpha inhibitors.²⁶ Cyclosporine was a bridge therapy while we worked with the Rheumatologists, who used a cytokine panel to determine a more targeted agent.

Dr. Bray

The patient met criteria for PG, but without a clear underlying etiology – termed idiopathic PG.²⁴ For an uncertain etiology of systemic inflammation, we prefer a short acting agent that can be quickly adjusted if the response is inadequate. The persistent, extreme elevation of CRP and neutrophilia were concerning for an inappropriate activation of her interleukin-1 (IL-1) pathway, a potent activator of neutrophils.²⁷ While these markers are commonly elevated in infections, especially bacterial, the lack of response to antibiotics was concerning for a dysregulation of this pathway. In autoinflammation, or inappropriate activation of the innate immune system, trends of markers are more important than absolute values. There are case reports of efficacy of anakinra, a recombinant human IL-1 receptor antagonist, in PG, and CRP is a useful biomarker for monitoring clinical response.²⁸ Thus, in addition to the medium daily dose of steroids, we started anakinra since it was originally designed for sepsis and likely is less risk in patients with concurrent infections.²⁹ However, anakinra is typically given subcutaneously daily. Thus, to avoid pathergy, we administered anakinra intravenously. Her laboratory markers and severe pain improved significantly within two days of therapy initiation.

Dr. Singer

Over weeks her wounds responded excellently, aided by three times weekly dressing changes under sedation by the wound care specialists. With intensive nutrition support, she steadily gained weight.

The patient was discharged from the hospital after 102 days. She and her mother lived with a host family locally which allowed for outpatient monitoring and preparation for her return to her home country. While living locally, she attended 5^th grade regular classes. Her wounds continued to improve. (Figure 4)

Figure 4:

Lesions 4 months post-discharge

Dr. Bray, how do you choose which medications to use given the long-term plan for her to return to her home country?

Dr. Bray

We were grateful to have time to monitor her after discharge in order to confirm the medication regimen that would both control her disease and be available in her home country. Prior to discharge, we switched her to TNF-alpha inhibitors due to the availability of more affordable “biosimilars” in this category.³⁰ Ideally, the biologic agent would be discontinued prior to returning home but we planned for the possibility that she would require cytokine blockade long-term. We also treated with cyclosporine and dapsone, non-biologic agents, which are available in her home country. Our hope is to use these agents along with a TNF-alpha inhibitor, if necessary.

She came here with a severe, long-standing disease that has required aggressive treatment. At times her disease has been difficult to control. We continue to monitor her and are hopeful that she is nearing being ready to return home. We look forward to advising her local physicians once she is back in her home country.

Summary

Here we report the presentation, evaluation, and treatment of an 11-year-old African patient with uniquely extensive pyoderma gangrenosum. PG is a diagnosis of exclusion, thus a broad differential was first considered and ruled-out before ultimately depending on the input of a city-wide conference of dermatopathologists to confirm the diagnosis.

As Maverakis and colleagues concluded in their 2017 Delphi-method consensus meeting, diagnosis of PG is made by confirmation of neutrophilic-infiltrate on histology, the “major” criteria, and at least 4 of 8 “minor” criteria: “(1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or ‘wrinkled paper’ scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s).”²⁴ Currently, 4 of 8 minor criteria have a sensitivity and specificity of 86% and 90%, respectively for PG, though further clinical validation is needed.²⁴ Our patient met the major criteria on histology as well as absence of infectious etiology, positive history of pathergy, presentation with multiple ulcerations in typical locations (e.g. pre-tibial), and demonstrated a therapeutic response. Yet, the etiology of her disease remains unclear, thus a working diagnosis of idiopathic PG. In a systematic review of 170 pediatric patients with pyoderma gangrenosum, 77/170 (58%) patients were found to have idiopathic disease.⁹ However, the number of idiopathic cases is likely over-represented, as PG may present months to years before the underlying etiology manifests, highlighting the importance of long-term monitoring of pediatric patients with PG. For example, as noted above, PG can occur as part of PAPA or as an extraintestinal manifestation of IBD. Pediatric and adult studies have estimated a similar prevalence of PG in patients with IBD, approximately 0.3% and 0.5–5% respectively.^31,32 Conversely, the exact comorbidity of IBD in children with PG is unknown, though a recently published retrospective case series by Schoch and colleagues looking at 13 children (<18 years) with PG found that seven (54%) had concurrent Crohn’s Disease.³³A comparison of the clinical characteristics and images of the PG lesions from the patients in the series emphasizes the unique extensiveness of our patient’s disease at presentation. Our patient was also unique in presenting with pulmonary nodules which are a rare extracutaneous manifestation of pyoderma gangrenosum.³⁴

The ultimate plan for our patient is for her to return home on cyclosporine, dapsone and a subcutaneous biosimilar that blocks TNF-alpha, if necessary. However, at times her disease has been difficult to control and has necessitated additional rounds of steroids. Currently, one year after presentation, she remains in the United States while her medications are adjusted to ensure disease control. This has presented the care team and the patient’s family with a challenging dilemma: when is it safe for her to go home? And, how to manage flares of her disease remotely? This challenge, however, is in-part alleviated by the strong working relationship that has developed with the NGO who first referred her to our institution. She will be followed closely, and our specialists will conduct telemedicine visits.

Our patient’s history and disease course illustrate both the possibilities and long-term responsibilities of conducting an international patient program. Her recovered health is the result of profound resilience by the patient and her loved ones as well as teamwork spanning continents. To accept the care of such a patient requires careful consideration of how this essential teamwork will be carried forward sustainably. Given the refractory course of her disease, it is anticipated that she may have complications in the future. Accordingly, she remains our patient, and we remain her physicians, even after she returns home.

Abbreviations:

CRP

C-reactive protein

ESR

erythrocyte sedimentation rate

IBD

inflammatory bowel disease

IL-1

interleukin-1

MCTD

mixed connective tissue disease

NGO

non-governmental organization

PG

pyoderma gangrenosum

PAPA

pyogenic arthritis-pyoderma gangrenosum and acne

RDEB

recessive dystrophic epidermolysis bullosa

RLQ

right lower quadrant

SLE

systemic lupus erythematosus

TNF-alpha

tumor necrosis factor-alpha