Successful Treatment of Refractory Candidal Granuloma by Itraconazole and Terbinafine in Combination with Hyperthermia and Cryotherapy

In recent years, the incidence of Candida infection has increased in immunocompromised patients [1]. Although C. albicans remains the leading pathogenic agent of clinical primary or secondary infections, infections caused by non-Candida albicans, especially C. tropical, are also increasing [2, 3]. C. tropicalis mainly causes superficial infections and candidemia [4]. Candidal granuloma is an extremely rare manifestation of C. tropicalis infection. Herein, we report a case of refractory candidal granuloma successfully treated in combination with antifungal therapy, hyperthermia and cryotherapy. Informed written consent was obtained for the patient to publish the article and their images.

A 57-year-old Chinese man with a known history of hypertension and stroke presented to our department for multiple plaques on his waist, right thigh and face in May 2019. Multiple verrucous plaques had been developing gradually on his waist and right thigh for 8 years without any apparent reason. He did not seek treatment for his lesions until 18 months ago; two continuously expanding plaques developed on his face with severe pruritus (Fig. 1a1, b1). He had been diagnosed with a subcutaneous fungal infection and treated with oral terbinafine 250 mg/day and topical povidone-iodine for 5 months. However, the lesions did not improve. Hence, the therapeutic regimen was replaced by oral itraconazole 200 mg/day for another 11 months. Lesions on the waist and right thigh partially improved but not those on the face.

Physical examination revealed two well-defined, regularly shaped, erythematous plaques with hyperkeratotic crusts, measuring 5 × 5 cm and 10 × 10 cm, on his cheeks. The superficial lymph nodes, liver and spleen were normal to palpation. Chest auscultation was clear. Serum electrolytes, liver, renal function, antinuclear antibodies, and rheumatoid factors were within the normal range. HIV, syphilis, tuberculosis and tumor test results were negative. Blood tests indicated decreased lymphocyte counts (CD3, 481 cells/μl, normal range: 941–2226 cells/μl; CD4, 295 cells/μl, normal range: 471–1220 cells/μl; CD8, 164 cells/μl, normal range: 303–1003 cells/μl). Dermoscopic manifestation (JEDA, Nanjing, China) of the verrucous granuloma revealed telangiectasia, yellow proliferative scales tightly adhering to the skin and the blackish-red dot sign on an erythematous base (Fig. 1c1).

Although microscopic examination and fungal culture of the crusts were all negative, the pathologic findings provided evidence for definitive clinical diagnosis. A skin biopsy exhibited parakeratosis, pseudoepitheliomatous hyperplasia in the epidermis and dense neutrophilic and multinucleated giant cells in the dermis (HE) (Fig. 2a). Abundant short hyphae and yeasts in the stratum corneum (PAS and GMS) were also observed (Fig. 2b, c).

Molecular verification was subsequently performed to identify the fungal elements, and genomic DNA was extracted from paraffin-embedded tissue by the phenol-chloroform extracting method. The amplification of the ITS (internal transcribed spacer) rDNA region was performed through PCR using primers pair ITS1 and ITS4 in a 25-µl reaction system containing 12.5 μl Taq polymerase (TaKaRa, Japan), 6.5 μl ddH₂O, 2 μl of each primer (10 µM) and 2 μl rDNA. Amplification was performed as follows: 95 °C for 4 min, followed by 35 cycles consisting of 94 °C for 45 s, 52 °C for 15 s, and 72 °C for 2 min, with a delay at 72 °C for 10 min. PCR products were sent to The Beijing Genomics Institute (Beijing, China) for direct sequencing. Compared with the GenBank database, our sequence displayed 100% similarity with Candida tropicalis. Then, we identified the fungi as Candida tropicalis and submitted the sequence to GenBank under accession no. MN171542.

Finally, the diagnosis of candidal granuloma caused by Candida tropicalis was confirmed based on clinical manifestation, molecular investigation and histopathologic examinations. The patient was treated with oral terbinafine 250 mg/day, itraconazole 200 mg/day and topical application of naftifine-ketoconazole cream. To achieve the desired effect, topical application of naftifine-ketoconazole cream followed by covering with an electric warmer band for hyperthermia (2 h at a time, twice daily, maintaining the temperature at approximately 45 °C) and liquid nitrogen cryotherapy (one session every 2 weeks) were applied. Cryotherapy using repeated freeze-thaw cycles was applied directly to the verrucous granuloma lesion with a cotton swab. Liver and kidney function examinations every 2 weeks were within the normal limit. The patient achieved a complete response within 4 months of follow-up (Fig. 1a2–a4, b2–b4). The blackish-red dots gradually disappeared during the treatment (Fig. 1c1–c4). The therapeutic course is summarized as Fig. 3.

Candida spp. is an opportunistic pathogen, widely found in soil, water sources and wild bird droppings [5]. It can also be found in healthy human skin, the vagina, oral cavity and digestive tract, causing local or systemic infections with decreased body resistance or change in the local environment. The incidence of Candida infection has been increased drastically along with a more widespread pathogenic agent spectrum because of the use of broad-spectrum antibiotics, glucocorticoids, immunosuppressive agents and the extensive implementation of interventional diagnosis and treatment such as intravenous catheterization [1]. Studies have reported that C. albicans remains the leading pathogenic agent of clinical primary or secondary infections. Similarly, the number of infections caused by non-Candida albicans, especially C. glabrata and C. tropical, is also increasing [2‐4].

Candidal granuloma, first reported by Hauser and Rothman in 1950, is a rare type of cutaneous candidiasis. There are two clinical types of deep cutaneous candidiasis: Hauser-Rothman and Busse-Buschke [6]. The typical lesions are presented as inflammatory papules, nodules, blisters, pustules, abscesses and plaques covered with thick yellow-brown scabs [6]. The most commonly affected populations are infants and children with immunocytopenia or lymphocytopenia and adults with long-term use of immunosuppressants or glucocorticoids. C. albicans is reported as the main pathogen of candidal granuloma [1]. C. tropicalis mainly causes superficial and systemic infections, such as oral candidiasis, candida vaginitis, onychomycosis and candidemia [4]. Candidal granuloma is an extremely rare manifestation of C. tropicalis infection.

Systemic antifungal medication is the first-line therapy for candidal granuloma. However, the longer course of treatment, drug resistance and concerns about side effects may cause dissatisfaction in patients. Initially, the lesion was treated with oral terbinafine for 5 months as well as oral itraconazole for 11 months. Although the results of microscopy and fungal culture were negative, verrucous skin lesions slightly improved. Synergism of terbinafine with itraconazole is presumed to be due to the combined effects of the drugs on different stages of the ergosterol biosynthesis pathway. Considering the synergism effect observed in Candida and other strains such as Mucor irregularis, Malassezia and Cryptococcus [7‐10], we highly recommend treating the skin lesion with itraconazole and terbinafine. Furthermore, hyperthermia and liquid nitrogen cryotherapy also were suggested for a potentially better curative effect and shorter duration of treatment.

Hyperthermia and cryotherapy are extensively applied for the treatment of dermatologic infections [11]. Thermotherapy with its various formations is reported to be beneficial for bacterial and fungal infectious diseases, such as mycobacterial disorders, sporotrichosis and chromoblastomycosis [11, 12]. The application of ALA-PDT in the treatment of candidal infections has also been reported [13‐15]. In general, the use of an electric warmer band compared with ALA-PDT and in situ photoimmunotherapy is much cheaper and convenient. Similarly, cryotherapy is also applicable for infections because of an enhancement of immunocompetence and direct toxic effects on microbes. Liquid nitrogen cryotherapy is not only suitable for warts, but also deep cutaneous infections, such as chromoblastomycosis, cutaneous leishmaniasis and even candidal keratitis [11, 16]. There is limited experience with systemic itraconazole and terbinafine with the local application of hyperthermia and cryotherapy in the treatment of candidal granuloma.

Furthermore, the unique dermoscopic blackish-red dot sign observed in our case disappeared along with the effective antifungal therapy. Similar findings have been reported in cases of chromoblastomycosis, sporotrichosis and Talaromyces marneffei infections [12, 17‐20]. Those dots consisted of small hematic crusts, cellular debris and fungal structures [12]. This sign mainly represented the products of transepithelial elimination of the inflammatory response [21]. Therefore, we concluded that the blackish-red dot sign may be an indication for chronic infectious skin diseases, including candidal granuloma.

The newer combination therapy of itraconazole and terbinafine can be established for refractory candidal granuloma that failed to respond to antifungal monotherapy. For a better curative effect and shorter duration treatment, hyperthermia and cryotherapy can be regarded as cost-effective adjuvant therapy. Also, we presumed that the gradual resolution of the blackish-red dot sign could be a prominent marker to evaluate the efficacy of the treatment. However, further research is needed to confirm this phenomenon.