Double Atypical Co-Infection in Ecthyma Gangrenosum: A Peculiar Case Report

Abstract

Introduction Ecthyma gangrenosum (EG) is a rare cutaneous manifestation commonly associated with Pseudomonas aeruginosa infection in immunocompromised individuals. Additionally, different bacterial and fungal pathogens have also been identified. However, co-infection on EG lesions has never been reported before. Case report We present the case of a seven-year-old female Asian patient who initially was diagnosed with febrile neutropenia. Initially, on the sixth day of admission, dermatological status revealed multiple painless erythematous macules on the face and arms together with persistent fever followed by evolution to multiple black, deep-seated, and large central eschars and early identification of Pseudomonas aeruginosa in the blood culture. Further evaluation revealed the development of EG with XDR Acinetobacter baumannii and Aspergillus spp. isolated from the samples harvested intraoperatively. Conclusions Specific identification of etiological agents will serve its importance for early diagnosis, aggressive antibiotic treatment, and/or surgical intervention to improve the prognosis.

Introduction

Ecthyma gangrenosum (EG) is a rare cutaneous manifestation associated with Pseudomonas aeruginosa bacteremia [1,2]. This condition is usually observed in immunocompromised patients, particularly those with underlying (hematological) malignancy or neutropenia. Specific and dynamically changing skin lesions are suggestive for this condition and serve as a diagnostic hint. This manifestation requires prompt diagnosis and treatment. We report a case of an EG in a patient with relapsed acute lymphoblastic leukemia (ALL) aggravated by co-infection with extensively drug-resistant (XDR) Acinetobacter baumannii and Aspergillus spp.

Case report

A seven-year-old female was admitted to the emergency department of a secondary hospital with a chief complaint of fever and vomiting. The fever had developed three days ago with a reported highest temperature of 39.6 °C. The patient had been diagnosed with acute lymphoblastic leukemia (ALL) two years prior and had undergone chemotherapy per Indonesian Pediatric Society protocol. On initial admission, the patient appeared compos mentis while vital signs and general physical examinations were within normal limits. No abnormalities were found in the abdominal region. Laboratory blood tests revealed pancytopenia (hemoglobin level [8.80 (10.80–15.60) g/dL], leukopenia [460 (5000–10,000)/μL] and thrombocytopenia [58.000 (150,000–440,000)/μL]), neutropenia [absolute neutrophil count 101,2 (2500–6000) cells/μL] and slightly elevated liver enzymes [SGOT 34 (0–32) U/L] and SGPT [39 (0–33) U/L]. Renal function tests were within normal limits and polymerase chain reaction for SARS-CoV-2 was negative. A temporary working diagnosis of febrile neutropenia was established. Antibiotic treatment was initiated with intravenous ceftriaxone (1.5 g q24h). Furthermore, blood culture was performed for aerobic bacteria, but the growth of pathogenic bacteria was not found.

On the sixth day of admission, the patient developed persistent fever with multiple painless erythematous macules on the face and arms (Figure 1). Further laboratory examinations and evolution of the disease were performed as shown in the timeline (Figure 2). After further evaluation, a diagnosis of febrile neutropenia, pulmonary tuberculosis, P. aeruginosa bacteremia and systemic fungal infection was made. Based on the culture and antibiotic sensitivity result, the patient was started on meropenem (500 mg q8h), amikacin (125 mg q24h), micafungin (62.5 mg q24h) for 27 days. The patient was also initiated later on anti-tuberculosis medication [rifampicin (150 mg q24h), isoniazid (100 mg q24h), pyrazinamide (500 mg q24h), and ethambutol (500 mg q24h)]. Repeated blood culture revealed fungus and its elements with suspicion of Aspergillus spp. Nevertheless, the multiple erythematous macules progressed into purpura-like lesions, hemorrhagic pustules, and necrotic ulcers with a more generalized location involving the arms.

The patient underwent multiple surgical necrotomy/debridement procedures and extremity wound culture revealed XDR A. baumannii with sensitivity towards sulperazone (cefoperazone/sulbactam). A histopathological examination of the lower extremities revealed necrotic tissues with chronic inflammatory process. A histopathological examination of the nasal cavities revealed necrotic area and debris with acute-chronic inflammatory cells and colonies of fungal elements (hyphae and mycelium) indicative of aspergillosis (Figure 3). EG diagnosis was established as well as the following antibiotic sulperazone (750 mg q12h for seven days) and weekly outpatient necrotomy/debridement; her general condition gradually improved.

Discussion

To our knowledge, this is the first reported EG case complicated with XDR A. baumannii and Aspergillus spp. identified from the wound culture and nasal cavities, respectively. EG is a specific life-threatening skin lesion usually accompanied by P. aeruginosa infection [1]. Two pathogenic processes of EG have been identified, namely bacteremia and nonbacteremia types [3]. In our case, initial P. aeruginosa bacteremia suggested an association with EG formation. However, the disease progressed despite tailored antibiotic and antifungal therapies, revealing another etiological agent of a fungal origin in the blood and nasal cavities cultures and XDR A. baumannii in the wound culture. These findings alarmed the prolonged use of antibiotics as a risk factor for developing fungi and A. baumannii, especially in an immunocompromised state as shown by previous research [4]. Additionally, the administration of meropenem must also be prescribed with caution as it increases the risk of emerging drug-resistant pathogens, as in this case XDR A. baumannii [5].

A wide spectrum of diseases, such as malignancy, specific infectious diseases, connective tissue disorders, diabetes, AIDS, and other immunocompromising pathologies are common for patients with EG, regardless of the etiological agent. EG may affect people of all ages, although it is most common among immunocompromised patients (58.62–86.66%), particularly in disorders with aberrant neutrophil function or in patients with granulocytopenia. Leukemia, lymphoma, other malignant diseases, severe burns, or organ transplant are the most common causes of immunocompromised states [6]. In our case, the patient was diagnosed with EG and relapsed ALL, undergoing the induction phase of chemotherapy. This is supported by a recent study in Tennessee by Inaba et al. who reported that skin infection is frequently found in induction and between week ten and reinduction II of childhood ALL [7].

In a review article of EG by Vaiman et al. in 2015, P. aeruginosa was detected in 123 (73.65%) of the 167 reported EG cases recently evaluated, with other bacterial etiologies detected in 29 cases (17.35%) and fungal cases (9%), among which Streptococcus, Aeromonas hydrophila, Staphylococcus aureus, Serratia marcescens, Pseudomonas maltophilia, Citrobacter freundii, E. coli, Candida albicans, Aspergillus, and Mucor species [6,8,9]. P. aeruginosa is an opportunistic bacterium (usually seen in a hospitalized patient, and conditions such as neutropenia, hematologic malignancy, CD4+ lymphocyte count <50 cells/mm³) that seldom causes disease in immunocompetent subjects [6]. In this report, we will focus on A. baumannii as one of the confirmed agents complicating in this case.

Acinetobacter baumannii is an opportunistic glucose-oxidizing, non-motile, non-fastidious, catalase-positive, oxidative-negative, aerobic Gram-negative coccobacillus [10,11]. A. baumannii belongs to the Moraxellaceae family that cause infections in the respiratory tract, urinary tract, and wounds, with a possibility leading to developing septicemia. A. baumannii has several virulence factors identified, i.e., porins, capsular polysaccharides and lipopolysaccharides (LPS), phospholipase, outer membrane vesicles (OMVs), metal acquisition system, protein secretion systems, penicillin-binding protein 7/8 (PBP7/8) and β-lactamase PER-1, and others (CipA, Tuf, RecA, SurA1, GigABCD, UspA, GacS and PaaE, Pili, OmpR/EnvZ, FhaBC, AbeD) contributing to its proposed role in pathogenesis. For instance, porins (OmpA, Omp 33-36, Imp22, CarO, OprD-like) play a significant role in adherence and invasion, induction of apoptosis, serum resistance, biofilm formation, and persistence. Capsular polysaccharides are proposed to be involved in growth in serum, survival in tissue infection, and biofilm formation, while LPS are proposed to be involved in serum resistance, survival in tissue infection, and evasion of the host immune response [10].

Additionally, in the review by Vaiman et al. in 2015, out of the 123 EG cases with P. aeruginosa as the etiological agent, 72 cases (58.5% of Pseudomonas cases or 43.1% of all cases) had bacteremia/sepsis/septicemia, while 51 cases had reported the absence of septicemia (41.5% of Pseudomonas cases). Fungal flora may also be identified from the blood culture of patients with EG and the lesions [9]. These findings were in line with our case where the patient was immunocompromised followed by P. aeruginosa bacteremia complicated by XDR A. baumannii and fungal etiological agent identified from the lesions. P. aeruginosa and A. baumannii have a close relation in antibiotic resistance, where exopolysaccharide-producing strains of Acinetobacter spp. have been shown to increase the pathogenicity of other Gram-negative bacteria in a polymicrobial infection. Chemical signals released by co-infective agents may trigger biofilm development by increasing A. baumannii autoinducer synthase synthesis or vice versa [12].

The pathophysiological basis of EG of other causative organisms is less defined. For P. aeruginosa, the primary driving factor appears to be the presence of numerous viable organisms at the point of involvement. Pseudomonas invasion and elastase dissolve the elastic lamina of blood arteries (media and adventitia of small veins and arteries), allowing the bacilli to enter and invade the subcutaneous tissues. The further proliferation of the organism in the adjacent tissue in conjunction with exotoxin A and proteases results in ulcerative lesions characterized by hemorrhage encircled by a rim of reactive erythema [1,13].

Diagnosis of EG requires detailed history taking, physical examination, and laboratory examination for optimal and precise diagnosis. Clinical manifestation of the lesion primarily comprises maculopapular lesions rapidly evolving into necrotizing ulcers involving the buttocks and/or lower extremities (65.8%) and various parts of the body, including the face (34.2%) [6,9].

The face and the entire head and neck region are affected much more frequently than is commonly thought in EG, as in our case. Surprisingly, case reports about EG involving the nasal cavity were also reported. Nevertheless, due to the rarity of the case, further studies are required to clarify the clinical picture. Laboratory examinations constituted of blood cultures and skin biopsy. A skin biopsy should be sent for tissue culture for further microbiological investigations, i.e., bacterial, fungal, yeasts, and mycobacterial examinations. Any isolated organisms should be subjected to sensitivity tests [9].

EG and its differential diagnoses such as: “warfarin-induced skin necrosis, cocaine-induced skin necrosis, calciphylaxis, septic emboli, loxoscelism, diabetic microangiopathy, disseminated intravascular coagulation, paraneoplastic extensive necrotizing vasculitis, pyoderma gangrenosum, livedoid vasculopathy, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cutaneous necrotizing vasculitis as a manifestation of familial Mediterranean fever, and necrosis secondary to the use of vasoactive drugs”, should be distinguished and considered before establishing the diagnosis [9].

The principle of EG management comprises three stages: 1) administration of empiric antibiotic therapy, 2) therapy based on the established etiological agent (prescription of aggressive antibiotic or antifungal treatment), and due to the necrotizing soft-tissue lesions 3) surgical excision. No uniformity in the results of antimicrobial agents was reported. Surgical excision varies from mild plastic surgery to aggressive surgical debridement and skin grafting. Nonetheless, a surgical procedure was required in 76.6% (128 out of 167 cases) with a similar approach between Pseudomonas and non-Pseudomonas cases. Standard wound care incorporated wet to dry dressing changes [9]. The management in our case followed these three stages principle and yielded a successful outcome. Our case report highlighted the need for immediate lesion culture with blood culture in conjunction with antibiotic sensitivity to rapidly identify the etiological agent and proper antibiotic prescription to avoid co-infection.

Conclusions

Ecthyma gangrenosum is a rare, life-threatening lesion generally caused by P. aeruginosa. In patients with a history of malignancy and immunocompromised state, rapidly progressive maculopapular lesions involving the buttocks and/or lower extremities should be considered carefully as EG. Ruling out of possible differential diagnoses should be considered before establishing the diagnosis of EG. Specific management of EG required a multidisciplinary approach and modalities comprising empiric antibiotic therapy, specific therapy based on microbiological investigations, and surgical procedures. Lastly, prudent antibiotic prescription should consistently be implemented to avoid drug-resistant organisms.