Successful Treatment of Fournier’s Gangrene in Child with Relapsed Acute Lymphoblastic Leukemia: Case Report and Review of the Literature

Introduction

Acute lymphoblastic leukemia (ALL) is the most common type of the pediatric neoplasm characterized by clonal proliferation of B-cell or T-cell progenitors.¹ Neutropenia associated with anticancer treatment may contribute to high-mortality infections, especially those caused by multidrug-resistant (MDR) pathogens.² Bacterial infections indicate the highest mortality rate in onco-hematological patients (68%), followed by fungal (20%) and viral (12%) infections.^3,4 Pseudomonas aeruginosa (PsA) is a Gram-negative pathogen in the ESKAPE group of highly virulent and antibiotic-resistant pathogens. As their MDR rate increases, they can evade commonly used antibiotics and become the major cause of life-threatening infections in immunocompromised patients.^5,6

Fournier’s gangrene (FG) is a rare, rapid, progressively necrotizing, and potentially fatal perineum inflammation developed as an infectious complication of chemotherapy or neoplasm itself in cancer patients.⁷ It is classified as type 1 necrotizing fasciitis of polymicrobial etiology.⁸ The underlying cause is a mixed oxygen-anaerobic bacterial flora with different bacterial species.⁹ Mortality rates related to the Fournier’s gangrene vary from 4% to 88%, usually range from 20% to 40%.¹⁰ Despite its rarity, the disease is well-known from an unfavorable prognosis, but its course depends mostly on the timing. It is known that the latency of the first dose of antibiotics is a main risk factor of serious complications in neutropenic fever treated in an ICU. Treatment delay is usually accompanied by a high lethality (reaching 90%), not only because of the septic shock but also associated complications.¹¹

Here, we present a case of Fournier’s gangrene disease in a child with relapsed ALL during intensive chemotherapy.

Case Report

Twenty-seven months after the primary diagnosis of common preB-ALL, the 4-year-old girl was diagnosed with an isolated CNS (central nervous system) relapse of leukemia and started therapy according to the IntReALL SR 2010 protocol (Table 1). Two days after the 4^th course of intensive chemotherapy, the CRP (C-reactive protein) level suddenly elevated and other inflammation parameters were increasing, including white blood cells rising from neutropenic to the level of 3.76 × 10⁹/L. The empirical antibacterial treatment of piperacillin-tazobactam was administered and within the next few days inflammation parameters decreased, just to increase again a week later. Then, subsequent antibiotic therapy, including meropenem and linezolid was administered. One day later fever appeared (39°C), and the patient’s condition started deteriorating rapidly. She experienced increasing respiratory failure with such symptoms as tachypnoea shallow breathing with a great respiratory effort and oxygen saturation below 90%, circulatory failure (tachycardia, decreased left ventricular contractility and positive fluid balance despite administered diuretics). Moreover, the liver was enlarged and laboratory findings indicated abnormalities in the coagulation panel. Capillary blood gas analysis conjointly with lactate blood level depicted lactic acidosis. Immediately, metronidazole and micafungin were added. Nevertheless, fever persisted and skin lesions with traits of Fournier’s gangrene appeared in the left groin. It was swollen and painful. The bacteriological blood cultures and wound swab confirmed Klebsiella pneumoniae carbapenemase (KPC)-producing PsA, which the girl had not hosted earlier. Despite the antibacterial treatment, the patient developed multiple-organ dysfunction syndrome (MODS) and was transferred to the pediatric intensive care unit, where additionally to intensive antimicrobial treatment, mechanical ventilation and hemodiafiltration were administered. After the final microbiological result, due to resistance of PsA to meropenem, antibacterial therapy was replaced with ceftazidime-avibactam. The targeted antibiotic therapy lasted for 33 days. Due to concurrent probable invasive pulmonary aspergillosis, empirical antifungal treatment of micafungin was replaced by preemptive therapy with voriconazole. The wound was surgically debrided and treated with vacuum-assisted closure (VAC) (Figure 1). After clinical and hematological recovery, the girl continued anticancer treatment held due to the infection for 4 weeks. Unfortunately, in another episode of neutropenia, the subsequent wound on the girl’s neck appeared after wearing a necklace. Microbiological wound swab confirmed KPC-producing PsA, but this time resistant to both meropenem and also ceftazidime-avibactam. Luckily, PsA strain was sensitive to ceftolozane-tazobactam, which was administered subsequently, and the generalized infection did not occur. Due to the fact of constant immunosuppression and further therapy in front of the patient, anti-PsA vaccine was applied successfully. Neither PsA colonization nor infection has been observed since then. After CAR-T cell-based consolidation of ALL relapse treatment, the patient has been in complete remission for 13 months.

Table 1 Chemotherapy Regimen with Drug Names and Doses

Figure 1 The evolution of skin lesions with features of Fournier’s gangrene (photos are used with parental informed consent). Day 1: The appearance of skin lesions with traits of FG in the patient’s left groin. Day 2: Skin lesions with traits of FG the following day. Day 15: Skin lesions with traits of FG after 2 weeks (15 days) of conservative treatment. Day 18: Skin lesions with traits of FG after 18 days of conservative treatment. Day 32: Surgical debridement of the wound and implementation of vacuum-assisted closure (VAC). Day 42: Surgical debridement of the wound and reimplementation of VAC. Day 46: VAC removal and stitches placement.

Discussion

Hematologic patients belong to a high-risk group for bacterial infections, to which they are particularly predisposed due to complex immune deficiencies resulting from their underlying disease and treatment.^12,13 The following factors qualified our patient to the highest group of infectious complications, including Fournier’s gangrene, ie relapse of ALL, neutropenia, recently applied steroid and chemotherapy.^12–14

Fournier’s gangrene belongs to necrotizing fasciitis associated with a high mortality rate, involving both skin and subcutaneous tissue on the external genitalia and in the perianal region.⁷ Moreover, the frequency is higher in adults, including 10–40 times higher in males.¹¹ However, despite its usual infrequency in children, this has been also reported as one of the potential consequences of treatment in pediatric onco-hematological population.¹⁵ Immunosuppression, including this phenomenon arising from hematological malignancies, such as treated relapsed leukemia in our patient, is a recognized risk factor for necrotizing fasciitis.^16,17 However, the diagnosis and therapy of Fournier’s gangrene still remain challenging and troublesome.

The etiological factor of a Fournier’s gangrene is a mixed oxygen-anaerobic bacterial flora,⁹ mostly the physiological flora of the urogenital or anorectal region, such as enteric rods (Escherichia coli, Klebsiella spp., Proteus spp)., Gram-positive cocci (staphylococci, streptococci, enterococci) and obligate anaerobic bacteria (Clostridium spp., Bacteroides spp., Fusobacterium),⁸ and in rare cases fungi, including Candida spp. or molds.^18,19 However, the cultures of patients with concurrent Fournier’s gangrene and hematological malignancies usually contain Gram-negative bacteria, such as PsA and Escherichia coli. Moreover, in patients with onco-hematological diseases monomicrobial PsA infection is more common than in the general population of Fournier’s gangrene patients.⁷

The causative microflora is often polymicrobial (aerobic and anaerobic); hence, drugs of choice for Fournier’s gangrene treatment are III–IV generation cephalosporins with antibiotics of the group of nitroimidazole, fluoroquinolones, aminoglycosides. Carbapenems should be introduced within the complex antibacterial therapy, providing the refractory forms.¹¹ In our patient due to rapidly deteriorating general condition, the de-escalation regimen of antibiotic therapy was chosen in the management of Fournier’s gangrene.^12,14 Unfortunately, the presence of KPC-PsA, the MDR strain predisposed by multiple previous antibiotic treatments, prolonged hospitalization, immunosuppression, underlying disease and damage to the mucosal barrier, led to the development of septic shock.^12,20,21 An appropriate combination of antimicrobial drugs, especially in combination with ceftazidime-avibactam recommended for MDR PsA infection, followed by V generation cephalosporin + beta-lactamase inhibitor, ie ceftolozane-tazobactam, consolidated with subsequent administration of an anti-PsA vaccine enabled therapeutic success and continuation of anticancer treatment without recurrence of invasive PsA infection.^21–23

A significantly relevant issue to consider in the treatment of Fournier’s gangrene is an emergency surgical intervention concomitant with antibacterial therapy. It is known that the most effective way to complement systemic treatment of Fournier’s gangrene is using negative pressure wound therapy with VAC.²⁴ It accelerates healing of difficult wounds by accelerating granulation of the wound bed. It is also an effective method of wound debridement, cutting off the fasciitis process.^25,26 This may provide significant treatment benefits, leading to improved clinical outcomes and patient quality of life, as well as shorter hospital stays, less analgesic use, faster wound closure, reduced markers of sepsis, fewer operations and postoperative dressing changes.^27–30 Interestingly, lower percentages of surgical treatments in immunocompromised patients have been reported by some authors compared with non-immunocompromised patients. Albasanz-Puig A. et al observed that only 62.5% of hematological patients underwent surgical treatment of necrotizing fasciitis, compared with 100% of non-hematological patients.¹⁶ The hypothesised reason could be the fear of increased intraoperative bleeding associated with severe pancytopenia, eventually leading to high intraoperative mortality.¹⁶ Fortunately, results from the literature review depict that most hematological patients affected by Fournier’s gangrene undergo surgical debridement with long-term benefits.⁷

Conclusions

The presented case is an example of a patient with Fournier’s gangrene, which developed due to the burden of intensive oncological treatment of a childhood ALL relapse, especially after chemotherapy followed by the neutropenic phase. Results from the presented case and review of the literature have relevant clinical implications. High index of suspicion followed by early diagnosis, target antimicrobial therapy, and early surgery are the key factors of successful Fournier’s gangrene management. Fournier’s gangrene is well-known for its aggressiveness, especially in onco-hematological patients, but surprisingly a high recovery rate in pediatric patients has been reported. Therefore, Gram-negative bacteria, mainly PsA, must be included in the spectrum of antibiotics administered in these group of patients.