An 11-year-old girl 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 after trauma to her skin. The ulcers first presented 3 years earlier but had markedly worsened in the 9 months before 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 antibiotics and close management by a pediatric infectious disease specialist working for a nongovernmental organization (NGO) in her home country. Per NGO records, she had previously been  average weight-for-age. On presentation after international transfer, she was severely malnourished, with lesions covering ∼35% of her body. In initial workup, leukocytosis of 21 × 103 cells per μL (79% neutrophils), hemoglobin of 6.1 g/dL, and mean corpuscular volume of 66 fL were found. Iron studies revealed an iron level of 18 μg/dL, ferritin level of 55 ng/mL, total iron binding capacity of 222 μg/dL, and transferrin saturation of 8%. Inflammatory markers were elevated, C-reactive protein was 20.1 mg/dL, and the erythrocyte sedimentation rate was 131 mm/h. A chest computed tomography scan revealed 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 and the factors considered in offering charity care to international patients.

An 11-year-old girl from Zambia was transferred to our institution for evaluation and treatment of ulcerative skin lesions. The lesions waxed and waned for ∼3 years but became widespread and refractory to multiple interventions over the previous 9 months. Starting at age 6, the patient had attended enrichment programs and health screenings at a local nongovernmental organization (NGO). According to the NGO’s 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 reveal that, as her disease progressed, she had an onset of failure to thrive. At age 6, she had weighed 19 kg, 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 fifth percentile, and, on arrival at our institution, she weighed 20.5 kg. At 120 cm in length, her BMI measured 13.7, nearly 3 SDs below the median for her age, placing her on the borderline of severe malnourishment.

Six months before her transfer, she underwent an urgent appendectomy for suspected appendicitis. Afterward, her surgical incision ulcerated, and the lesion spread across her right lower quadrant. Postoperatively, she remained admitted at the teaching hospital in the capital city. There, she was treated for severe malnutrition, underwent available infectious and immune workup, and received multiple courses of intravenous (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 IV 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?

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 whether 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 and lifelong conditions (eg, cerebral palsy), oncology care, and organ and stem cell transplant 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 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, after returning home, her care would be overseen.

On the night she arrived, the patient was in great distress, having endured 2 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 before illness.

On examination, she was afebrile and distressed because of pain. She had mild tachycardia (a heart rate of 100–130 beats per minute). Her hair was black, thin, and fine, without alopecia. Examination of her head, eyes, ears, nose, throat, heart, and lungs was otherwise unremarkable. Her abdominal examination revealed normal bowel sounds but was diffusely tender to palpation. Her extremities were wasted without edema. Suppurative ulcers with warmth and tenderness covered ∼35% of her body surface area (Fig 1). Ulcers were over her right lower quadrant abdominal wall, left arm from axilla to hand, entire right thigh, and left lower leg circumferentially. There were small (<2 cm 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. A, Left arm. B, Left shin. C, Right leg. D, abdomen.

FIGURE 1

Lesions on presentation. A, Left arm. B, Left shin. C, Right leg. D, abdomen.

Close modal

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

TABLE 1

Initial Laboratories

VariableResults on AdmissionReference Range
WBC count, 103 cells per μL 21.4 5–14.5 
Segmented neutrophils, % 79 33–76 
Lymphocytes, % 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 per 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 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, % 20–50 
VariableResults on AdmissionReference Range
WBC count, 103 cells per μL 21.4 5–14.5 
Segmented neutrophils, % 79 33–76 
Lymphocytes, % 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 per 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 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, % 20–50 

BUN, blood urea nitrogen; ESR, erythrocyte sedimentation rate; RBC, red blood cell; RDW, red blood cell distribution width; TIBC, total iron binding capacity; WBC, white blood cell.

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?

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 and 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 and 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 causes 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 tuberculosis is not known to be ulcerative.2  We considered Nocardia, Actinomyces, anthrax, yaws (caused by the spirochete bacterium Treponema pallidum), and parasitic infections, including leishmaniasis.37 

In addition to wound cultures and biopsy for histopathology, we requested a computed tomography (CT) scan 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 assessed the abdomen, liver, and spleen.

Our first impression came from photographs 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, because history revealed the hand deformity was congenital, whereas 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. Although 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 pretibial areas. Although extensive skin involvement has been reported, this is less common.9  Sarcoidosis, along with syphilis, is considered a great imitator 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 because ulcerations are uncommon and, if present, usually develop in preexisting 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 delineate histopathological findings. Although, in some rare cases, histopathological findings are so unique that a diagnosis can be made from a biopsy alone, more commonly, histopathological patterns help narrow the differential diagnosis by eliminating certain diagnoses and providing pathologic support for others.

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, 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.1517  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 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 extraintestinal 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 IVs placed in the United States, 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, mixed connective tissue disease, and ANCA vasculitis.

Bloodwork revealed 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 international normalized ratio of 1.2 and hepatic transaminases were within normal limits. Infectious assays were negative for viruses (HIV and 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 culture results were negative, and, using next generation sequencing of microbial cell-free DNA in the plasma, we did not detect microorganism DNA (Table 2).

TABLE 2

Further Studies

Results
Infectious disease  
 Viral HIV antibodies were nonreactive, and HIV-1 RNA PCR result was negative. Hepatic panel: HAV IgG positive, HAV IgM negative, HBcAb negative, and HBsAg negative results. 
 Bacterial Quantiferon result was negative. 
 Fungal Fungitell serum was <31, and Aspergillus galactomannan antigen were not detected. 
 Microbiology cultures Wound cultures were positive for Pseudomonas aeruginosa, Enterobacter cloacae, Eggerthella lenta, and Candida parapsilosis; aerobic, anaerobic, mycobacterial, and fungal blood culture results were negative; ova and parasite stool results were negative. 
 Next generation sequencing of microbial cell-free DNA No microorganisms were detected. 
Hematology  
 Peripheral smear Hypochromatic microcytic anemia consistent with iron deficiency anemia; toxic granulocytosis indicative of bacterial infection; no blasts, enlarged platelets, and no organisms. 
 Hemoglobin electrophoresis Sickle cell trait 
Rheumatology results ANA: positive; RF: negative; ANCA: negative; angiotensin converting enzyme: normal; APL panel (anti-B2: negative; anticardiolipin: negative; lupus anticoagulant: neg​ative). 
Immunology  
 Immunoglobulins  
  IgA 216 (66–295 mg/dL) 
  IgE 96 (0–200 IU/mL) 
  IgG 1200 (641–1353 mg/dL) 
  IgM 102 (40–80 mg/dL) 
 DHR testing Decreased neutrophil dihydrorhodamine fluorescence, suggesting significantly decreased NADPH oxidase activity. 
 Leukocyte adhesion deficiency panel Normal 
 Leukocyte phenotyping CD11b, CD15, and CD18 percentages are normal, and LAD is unlikely. 
 Lymphocyte proliferation assay Concanavalin A (low), Phytohemagglutinin (normal), Pokeweed Mitogen (low). 
 Lymphocyte phenotyping Lymphocytes are not within the normal limits for age, and she has a normal percent of T cells; however, she has low absolute numbers of CD4 and CD8 positive populations and an abnormal CD4 to CD8 ratio (would expect 2:1). B cells are present in normal percentage and number, with an appropriate memory B-cell population for age. NK cells are normal in percentage and number. 
Results
Infectious disease  
 Viral HIV antibodies were nonreactive, and HIV-1 RNA PCR result was negative. Hepatic panel: HAV IgG positive, HAV IgM negative, HBcAb negative, and HBsAg negative results. 
 Bacterial Quantiferon result was negative. 
 Fungal Fungitell serum was <31, and Aspergillus galactomannan antigen were not detected. 
 Microbiology cultures Wound cultures were positive for Pseudomonas aeruginosa, Enterobacter cloacae, Eggerthella lenta, and Candida parapsilosis; aerobic, anaerobic, mycobacterial, and fungal blood culture results were negative; ova and parasite stool results were negative. 
 Next generation sequencing of microbial cell-free DNA No microorganisms were detected. 
Hematology  
 Peripheral smear Hypochromatic microcytic anemia consistent with iron deficiency anemia; toxic granulocytosis indicative of bacterial infection; no blasts, enlarged platelets, and no organisms. 
 Hemoglobin electrophoresis Sickle cell trait 
Rheumatology results ANA: positive; RF: negative; ANCA: negative; angiotensin converting enzyme: normal; APL panel (anti-B2: negative; anticardiolipin: negative; lupus anticoagulant: neg​ative). 
Immunology  
 Immunoglobulins  
  IgA 216 (66–295 mg/dL) 
  IgE 96 (0–200 IU/mL) 
  IgG 1200 (641–1353 mg/dL) 
  IgM 102 (40–80 mg/dL) 
 DHR testing Decreased neutrophil dihydrorhodamine fluorescence, suggesting significantly decreased NADPH oxidase activity. 
 Leukocyte adhesion deficiency panel Normal 
 Leukocyte phenotyping CD11b, CD15, and CD18 percentages are normal, and LAD is unlikely. 
 Lymphocyte proliferation assay Concanavalin A (low), Phytohemagglutinin (normal), Pokeweed Mitogen (low). 
 Lymphocyte phenotyping Lymphocytes are not within the normal limits for age, and she has a normal percent of T cells; however, she has low absolute numbers of CD4 and CD8 positive populations and an abnormal CD4 to CD8 ratio (would expect 2:1). B cells are present in normal percentage and number, with an appropriate memory B-cell population for age. NK cells are normal in percentage and number. 

ANA, antinuclear antibody; APL, antiphospholipid antibody; DHR, dihydrorhodamine test; HAV, hepatitis A virus; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; IgA, immunoglobulin A; IgE, immunoglobulin E; IgG, immunoglobulin G; IgM, immunoglobulin M; LAD, leukocyte adhesion deficiency; NADPH, nicotinamide adenine dinucleotide phosphate; NK, natural killer; PCR, polymerase chain reaction; RF, rheumatoid factor.

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 revealed systemic inflammation but was not specific, including negative for SLE, with no autoantibodies specific to double stranded DNA, Smith, phospholipids, ANCA, proteinase 3, and myeloperoxidase.

The CT chest scan revealed multiple pulmonary nodules bilaterally, the largest measuring 2.4 × 2 × 1.9 cm in the left upper lobe. Axillary, lower neck, mediastinal, and peri-aortic lymphadenopathy was also observed (Fig 2). Notably, neither miliary pattern, nor pulmonary parenchymal, hilar, or mediastinal calcifications were found. The CT neck scan revealed irregularly shaped, subcutaneous loculations along the bilateral neck base. Altogether, infectious rather than malignant etiologies were suspected, including nontuberculosis bacterial, fungal, and protozoan. CT abdomen and pelvis scans revealed trace fluid and suspicion for pelvic calcifications versus surgical material deep to the patient’s appendectomy incision.

FIGURE 2

CT chest scan, revealing multiple bilateral nodules, the largest in the left upper lobe (2.4 × 2 × 1.9 cm). A, Axial. B, Coronal.

FIGURE 2

CT chest scan, revealing multiple bilateral nodules, the largest in the left upper lobe (2.4 × 2 × 1.9 cm). A, Axial. B, Coronal.

Close modal

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

Pulmonary nodules are often seen in the nongenetic form of juvenile sarcoidosis, similar to the adult phenotype.19  This form can be characterized by fatigue, weight loss, fever, respiratory symptoms, lymphadenopathy, and 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 on adult patients with sarcoidosis of ulcerating lesions and PG, but these lesions were more limited instead of widespread.23  Because of 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.

Biopsies were taken of the skin ulcerations and, in the third week of hospitalization, from the largest pulmonary nodule and the gastrointestinal tract.

Dr Fuller, can you interpret the biopsy results please?

Skin biopsies revealed nonspecific, predominantly neutrophilic inflammation, including neutrophilic abscesses, panniculitis, and skin ulceration, with abundant neutrophils as well as areas of lymphohistiocytic aggregates (Fig 3). The areas of intact epidermis revealed epidermal hyperplasia. No microorganisms were seen on stains for bacteria (including acid-fast bacilli) or fungus. Additionally, immunofluorescence stain results were negative. Because of 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 PG. 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 (hematoxylin and eosin stain; original magnification ×100).

FIGURE 3

Skin biopsy, with ulceration and abundant neutrophilic inflammation (hematoxylin and eosin stain; original magnification ×100).

Close modal

A biopsy of the left upper lobe lung lesion revealed nonspecific inflammatory findings without evidence of infection, vasculitis, or granulomatous disease. Endoscopic upper and lower gastrointestinal biopsies were near-normal, revealing only mild chronic esophagitis and gastritis but were without evidence of IBD.

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

The wound cultures most likely represented colonization and were 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, to calm her systemic inflammation, we treated the Pseudomonas and Enterobacter with 2 weeks of IV meropenem on the basis of susceptibilities. We also treated for 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 

The first-line dermatologic treatment of 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 like other steroid-sparing agents, including methotrexate, mycophenolate mofetil, and tumor necrosis factor (TNF)-α inhibitors.26  Cyclosporine was a bridge therapy while we worked with the rheumatologists, who used a cytokine panel to determine a more targeted agent.

The patient met the 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 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 interleukin-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 because 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 2 days of therapy initiation.

Over weeks, her wounds responded excellently, aided by dressing changes 3 times weekly 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 fifth grade regular classes. Her wounds continued to improve (Fig 4).

FIGURE 4

Lesions 4 months postdischarge. A, Right thigh. B, Left calf. C, Left arm.

FIGURE 4

Lesions 4 months postdischarge. A, Right thigh. B, Left calf. C, Left arm.

Close modal

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

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

Here, we report the presentation, evaluation, and treatment of an 11-year-old African patient with uniquely extensive PG. 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 et al24  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 IBD 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). Currently, 4 of 8 minor criteria have a sensitivity and specificity of 86% and 90%, respectively, for PG, although further clinical validation is needed.24  Our patient met the major criteria on histology as well as the absence of infectious etiology, positive history of pathergy, and presentation with multiple ulcerations in typical locations (eg pretibial) and demonstrated a therapeutic response. Yet, the etiology of her disease remains unclear, thus, we favored a working diagnosis of idiopathic PG. In a systematic review of 170 pediatric patients with PG, 77 of 170 (58%) patients were found to have idiopathic disease.9  However, the number of idiopathic cases is likely over-represented because 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 pyogenic arthritis, PG, and acne or as an extraintestinal manifestation of IBD. Pediatric and adult studies have estimated a similar prevalence of PG in patients with IBD, ∼0.3% and 0.5% to 5%, respectively.31,32  Conversely, the exact comorbidity of IBD in children with PG is unknown, although in a recently published retrospective case series, Schoch et al,33  looking at 13 children (<18 years) with PG, found that 7 (54%) had concurrent Crohn’s disease. A 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 PG.34 

The ultimate plan for our patient is for her to return home on cyclosporine, dapsone, and a subcutaneous biosimilar that blocks TNF-α, 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 patient’s family with a challenging dilemma: when is it safe for her to go home, and how can flares of her disease be managed remotely? This challenge, however, is, in part, alleviated by the strong working relationship that has developed with the NGO that first referred her to our institution. She will be managed 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.

We thank Dr Michael Bradford Guffey, MD, Robyn Petty, Claire Callaway, and the tremendously caring staff and friends of Family Legacy. We thank the patient’s many providers, including Armando Correa, MD, (International and Destination Medicine), Julie Lowe (Wound Care Nursing), Dr Krista Preisberga, MD, and Dr Julia Shelburne, MD, (Pediatric Hospital Medicine), Dr Marietta De Guzman, MD, (Rheumatology), Dr Claire Bocchini, MD, and Dr C. Mary Healy, MD (Infectious Disease), Dr John Hicks, MD, and Dr Hao Wu, MD (Pathology).

Written consent was provided by the patient’s family and primary caretaker to publish this article.

Dr Singer initiated this collaborative project, conceptualized, recruited, and interviewed all subspecialists, and drafted and edited the manuscript; Dr Falco initiated this collaborative project, conceptualized the initial manuscript, supervised the recruitment of subspecialists, and reviewed and revised the entire manuscript; Drs Bray, Chan, Ikeda, Fuller and Ms Walters contributed to the writing and revision of the manuscript in their respective fields and the revision of the entire manuscript; all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Dr Bray was supported by T32 training program HL139425 from the National Institutes of Health National Heart Lung and Blood Institute.

     
  • ANCA

    antineutrophil cytoplasmic antibody associated

  •  
  • CRP

    C-reactive protein

  •  
  • CT

    computed tomography

  •  
  • IBD

    inflammatory bowel disease

  •  
  • IV

    intravenous

  •  
  • NGO

    nongovernmental organization

  •  
  • PG

    pyoderma gangrenosum

  •  
  • RDEB

    recessive dystrophic epidermolysis bullosa

  •  
  • SLE

    systemic lupus erythematosus

  •  
  • TNF

    tumor necrosis factor

1
Guarner
J
.
Buruli ulcer: review of a neglected skin mycobacterial disease
.
J Clin Microbiol
.
2018
;
56
(
4
):
e01507
-
17
2
van Zyl
L
,
du Plessis
J
,
Viljoen
J
.
Cutaneous tuberculosis overview and current treatment regimens
.
Tuberculosis (Edinb)
.
2015
;
95
(
6
):
629
638
3
Stefano
PC
,
Noriega
AL
,
Kobrin
AL
, et al
.
Primary cutaneous nocardiosis in immunocompetent children
.
Eur J Dermatol
.
2006
;
16
(
4
):
406
408
4
Valour
F
,
Sénéchal
A
,
Dupieux
C
, et al
.
Actinomycosis: etiology, clinical features, diagnosis, treatment, and management
.
Infect Drug Resist
.
2014
;
7
:
183
197
5
Bradley
JS
,
Peacock
G
,
Krug
SE
, et al
;
AAP Committee on Infectious Diseases and Disaster Preparedness Advisory Council
.
Pediatric anthrax clinical management
.
Pediatrics
.
2014
;
133
(
5
).
6
Marks
M
,
Lebari
D
,
Solomon
AW
,
Higgins
SP
.
Yaws
.
Int J STD AIDS
.
2015
;
26
(
10
):
696
703
7
Ash
MM
,
Phillips
CM
.
Parasitic diseases with cutaneous manifestations
.
N C Med J
.
2016
;
77
(
5
):
350
354
8
Bruckner-Tuderman
L
.
Dystrophic epidermolysis bullosa: pathogenesis and clinical features
.
Dermatol Clin
.
2010
;
28
(
1
):
107
114
9
Kechichian
E
,
Haber
R
,
Mourad
N
,
El Khoury
R
,
Jabbour
S
,
Tomb
R
.
Pediatric pyoderma gangrenosum: a systematic review and update
.
Int J Dermatol
.
2017
;
56
(
5
):
486
495
10
Karadağ
AS
,
Chen
W
.
Great imitators in dermatology: part I
.
Clin Dermatol
.
2019
;
37
(
3
):
173
174
11
Ventéjou
S
,
Bagny
K
,
Waldmeyer
J
,
Cartault
F
,
Machet
L
,
Osdoit
S
.
Skin cancers in patients of skin phototype V or VI with xeroderma pigmentosum type C (XP-C): a retrospective study
.
Ann Dermatol Venereol
.
2019
;
146
(
3
):
192
203
12
Kempf
W
,
Kazakov
DV
,
Belousova
IE
,
Mitteldorf
C
,
Kerl
K
.
Paediatric cutaneous lymphomas: a review and comparison with adult counterparts
.
J Eur Acad Dermatol Venereol
.
2015
;
29
(
9
):
1696
1709
13
Jorgaqi
E
,
Fida
M
,
Janushaj
E
,
Mala
R
,
Vasili
E
.
A rare case of granulomatous Wegener with multiple pyoderma gangrenosum-like ulcers
.
Dermatol Ther (Heidelb)
.
2020
;
33
(
2
):
e13255
14
Lekwuttikarn
R
,
Teng
JMC
.
Cutaneous manifestations of nutritional deficiency
.
Curr Opin Pediatr
.
2018
;
30
(
4
):
505
513
15
Levy
DM
,
Kamphuis
S
.
Systemic lupus erythematosus in children and adolescents
.
Pediatr Clin North Am
.
2012
;
59
(
2
):
345
364
16
Sahin
S
,
Hopurcuoglu
D
,
Bektas
S
, et al
.
Childhood-onset Takayasu arteritis: a 15-year experience from a tertiary referral center
.
Int J Rheum Dis
.
2019
;
22
(
1
):
132
139
17
Jariwala
MP
,
Laxer
RM
.
Primary vasculitis in childhood: GPA and MPA in childhood
.
Front Pediatr
.
2018
;
6
:
226
18
Rosé
CD
,
Aróstegui
JI
,
Martin
TM
, et al
.
NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain
.
Arthritis Rheum
.
2009
;
60
(
6
):
1797
1803
19
Rosé
CD
,
Wouters
CH
. Pediatric Sarcoidosis. In:
Cassidy
J
,
Petty
R
,
Laxer
R
,
Lindsley
C
, eds.
Textbook of Pediatric Rheumatology
.
Philadelphia, PA
:
Elsevier
;
2011
20
Rigante
D
.
The broad-ranging panorama of systemic autoinflammatory disorders with specific focus on acute painful symptoms and hematologic manifestations in children
.
Mediterr J Hematol Infect Dis
.
2018
;
10
(
1
):
e2018067
21
Huang
BL
,
Chandra
S
,
Shih
DQ
.
Skin manifestations of inflammatory bowel disease
.
Front Physiol
.
2012
;
3
:
13
22
Gündüz
Ö
. Histopathological Evaluation of Behçet’s Disease and Identification of New Skin Lesions. In:
Patholog Res Int
, vol.
2012
.
2012
:
209316
23
Jun
L
,
Jia-Wei
L
,
Hong-Zhong
J
.
Ulcerative sarcoidosis
.
Int J Dermatol
.
2014
;
53
(
4
):
e315
e316
24
Maverakis
E
,
Ma
C
,
Shinkai
K
, et al
.
Diagnostic criteria of ulcerative pyoderma gangrenosum a Delphi consensus of international experts
.
JAMA Dermatol
.
2018
;
154
(
4
):
461
466
25
Politano
AD
,
Campbell
KT
,
Rosenberger
LH
,
Sawyer
RG
.
Use of silver in the prevention and treatment of infections: silver review
.
Surg Infect (Larchmt)
.
2013
;
14
(
1
):
8
20
26
Ahn
C
,
Negus
D
,
Huang
W
.
Pyoderma gangrenosum: a review of pathogenesis and treatment
.
Expert Rev Clin Immunol
.
2018
;
14
(
3
):
225
233
27
Dinarello
CA
.
Overview of the IL-1 family in innate inflammation and acquired immunity
.
Immunol Rev
.
2018
;
281
(
1
):
8
27
28
Beynon
C
,
Chin
MF
,
Hunasehally
P
, et al
.
Successful treatment of autoimmune disease-associated pyoderma gangrenosum with the IL-1 receptor antagonist anakinra: a case series of 3 patients
.
J Clin Rheumatol
.
2017
;
23
(
3
):
181
183
29
Opal
SM
,
Fisher
CJ
 Jr.
,
Dhainaut
JFA
, et al.;
The Interleukin-1 Receptor Antagonist Sepsis Investigator Group
.
Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial
.
Crit Care Med
.
1997
;
25
(
7
):
1115
1124
30
Yamauchi
P
,
Crowley
J
,
Kaur
P
,
Spelman
L
,
Warren
R
.
Biosimilars: what the dermatologist should know
.
J Eur Acad Dermatol Venereol
.
2018
;
32
(
7
):
1066
1074
31
Dotson
JL
,
Hyams
JS
,
Markowitz
J
, et al
.
Extraintestinal manifestations of pediatric inflammatory bowel disease and their relation to disease type and severity
.
J Pediatr Gastroenterol Nutr
.
2010
;
51
(
2
):
140
145
32
Monsén
U
,
Sorstad
J
,
Hellers
G
,
Johansson
C
.
Extracolonic diagnoses in ulcerative colitis: an epidemiological study
.
Am J Gastroenterol
.
1990
;
85
(
6
):
711
716
33
Schoch
JJ
,
Tolkachjov
SN
,
Cappel
JA
,
Gibson
LE
,
Davis
DMR
.
Pediatric pyoderma gangrenosum: a retrospective review of clinical features, etiologic associations, and treatment
.
Pediatr Dermatol
.
2017
;
34
(
1
):
39
45
34
Gade
M
,
Studstrup
F
,
Andersen
AK
,
Hilberg
O
,
Fogh
C
,
Bendstrup
E
.
Pulmonary manifestations of pyoderma gangrenosum: 2 cases and a review of the literature
.
Respir Med
.
2015
;
109
(
4
):
443
450

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.