Case Report: Primary Cutaneous Histoplasmosis in an Immunocompetent Patient After Cosmetic Injection of Platelet-Rich Plasma Treated with Trimethoprim-Sulfamethoxazole

Introduction

Histoplasmosis is a systemic mycosis caused by the dimorphic fungus Histoplasma, which can be found in soil that has a high concentration of bird or bat droppings. The fungus infiltrates the body through inhalation [1]. The conidia are engulfed by alveolar macrophages and transform into their yeast form, resulting in pulmonary infections. Hematogenous dissemination and disease severity are strongly influenced by the host immune response and the volume of the inoculum [1,2]. In immunocompetent individuals, cell-mediated adaptive immunity promotes macrophage activation and epithelioid granuloma formation to control infections [2]. This condition is diagnosed with clinical evaluation, imaging, and laboratory investigations, such as microscopic examination, culture, and serological testing. Treatment varies based on severity, with itraconazole or amphotericin B prescribed for mild or severe cases, respectively [3].

Histoplasmosis is considered a neglected disease worldwide; approximately 500,000 people are infected annually [4]. Latin America, including Venezuela, is recognized as an endemic region for histoplasmosis, largely due to the abundance of organic compounds such as bird and bat droppings [5]. Histoplasmosis presents in 3 distinct clinical forms: pulmonary histoplasmosis, disseminated histoplasmosis, and primary cutaneous histoplasmosis (PCH). The clinical manifestations of each form, including cutaneous presentations, are essential to consider when diagnosing patients from endemic areas such as Venezuela [6].

Histoplasma infection predominantly affects immunocompromised individuals, and is an AIDS-defining condition [7]. It is also linked to other forms of immunosuppression, such as malnutrition, cancer (notably Hodgkin’s lymphoma), tuberculosis, and the use of cytotoxic drugs [8]. Demographic and epidemiological factors play a key role in the prevalence and transmission of histoplasmosis [1].

The disease primarily affects those with occupational or environmental exposure to contaminated soil or droppings, including farmers, construction workers, and cave explorers [9]. However, in the last decade, more women and urban patients have been diagnosed with the disease, and the paradigm of a rural entity is changing [10,11]. In approximately 6–17% of immunosup-pressed patients, cutaneous histoplasmosis develops because of hematogenous or contiguous dissemination [12]. Disseminated histoplasmosis must be ruled out before diagnosing PCH [13].

PCH is an uncommon type of histoplasmosis in which the infection is limited to the skin, caused by direct exposure to Histoplasma. It manifests as skin lesions, nodules, or ulcers at the site of entry [14]. PCH occurs mostly in immunocompromised patients; however, a few cases have been recorded in immunocompetent patients [13,15].

Platelet-rich plasma (PRP) is usually indicated in different procedures including orthopedic treatments, cardiac surgery, plastic surgery, gynecology, urology, and more recently, in medical esthetics, especially to improve volume and skin texture [16,17].

Raina et al reported a case of an immunocompetent host in a non-endemic area; Batista et al presented a case of difficult-to-treat PCH in an immunocompetent patient; and Buitrago et al reported a case of an immunosuppressed patient with laboratory-acquired PCH [13,18,19].

This is the first report of PCH following cosmetic treatment with PRP. We describe herein a case of a 35-year-old immunocompetent Venezuelan woman who acquired PCH through cosmetic PRP treatment. The infection was histopathologically diagnosed, and successfully treated with trimethoprim-sulfamethoxazole (TMP/SMX).

Case Report

A 35-year-old female patient from Maracaibo, Zulia state, Venezuela, presented to a dermatology clinic 2 weeks after undergoing a cosmetic procedure, PRP injection, with nodule-like lesions at the application sites (face, neck, buttocks). Non-medical personnel performed the procedures in a covert clinic. The patient reported no improvement after following oral self-administration of an unidentified antibiotic, the name of which she could not remember. She denied any relevant personal, family, or disease history (diabetes, hypertension, or medication intake).

The patient was in good overall condition and afebrile on general physical examination. Vital signs were within normal limits. Dermatological examination revealed erythematous, indurated, nodule-like lesions and plaques in the areas of PRP application (Figure 1), some of which had developed central ulceration with purulent material discharge. The patient complained of mild general malaise 10 days before the appointment but denied any episode of fever.

Complementary tests such as a complete blood count, general biochemistry panel, HIV, venereal disease research laboratory (VDRL), and a chest X-ray were also requested. Additionally, a biopsy of the left buttock lesion with hematoxylin and eosin (H&E), and special stains such as Ziehl-Neelsen, Grocott, and Giemsa were performed to determine the presence of any microorganism. All tests were within normal values, featuring a “non-reactive” VDRL, a negative 4th generation HIV test, and a clear chest X-ray. These outcomes effectively ruled out the presence of immunosuppression and the extensive spread of systemic pathogens, including systemic histoplasmosis.

Based on the clinical history, atypical mycobacterial infection/ cutaneous mycobacteriosis was considered the main presumptive diagnosis, as this type of infection is common after the injection of contaminated mesotherapy. Empirical therapy was initiated with ciprofloxacin 500 mg twice daily, TMP/SMX 400/80 mg twice daily, and azithromycin 500 mg once a day for 1 month. After 1 month of treatment, the patient presented with complete clinical resolution of the lesions (Figure 2).

The pathology report revealed multiple intracytoplasmic inclusions of Histoplasma visible in HE-stained tissue sections (Figure 3), which confirmed the diagnosis of PCH. Ziehl-Neelsen stain ruled out the possibility of cutaneous mycobacteriosis (data not shown). Molecular techniques were unavailable, and limited resources prevented us from performing a culture.

The preferred antimycotic medication, itraconazole, was not accessible within the country. Nevertheless, in light of the patient’s favorable prior response to antibiotic therapy, TMP/SMX treatment was continued for a duration of 3 months. Upon the conclusion of medical intervention, the medical condition was entirely resolved.

Discussion

This case report demonstrates that immunocompetent patients may develop PCH following PRP-type cosmetic procedures, and that such infections can be effectively managed with atypical antibiotics like TMP/SMX.

Histoplasmosis is a systemic mycosis with global distribution and endemic areas [1]. The clinical spectrum varies, ranging from a severe multisystemic disease involving the bone marrow, liver, spleen, and lungs, to a slow infection involving the gastrointestinal tract, skin, adrenal glands, brain, meninges, and other extrapulmonary tissues [1]. There are 4 described species, some of them newly described: Histoplasma capsulatum sensu strictu, Histoplasma mississippiense, Histoplasma ohiense, and Histoplasma suramericanum [10]. In 90% of cases, infection is self-limited to the lungs after initial exposure to the fungus, while the remaining 10% develop disseminated or chronic disease [5,20].

Polymorphism in Histoplasma skin lesions makes diagnosis challenging and requires a high index of suspicion by healthcare personnel [20,21]. Most cases involve lesions caused by hematogenous dissemination or concurrent pulmonary infections that can be confused with other pathogens such as different forms of mycobacteria and other fungi such as Cryptococcus, Blastomyces, and Coccidioides, among others [22,23]. Cases of PCH are uncommon, particularly in immunocompetent patients; however, direct skin infection is possible, especially in immunocompromised patients. Because of this clinical polymorphism, it is one of the best mimics of various infectious and noninfectious diseases [7,12].

In Ecuador, there have been 2 prior documented cases of PCH in immunocompetent patients with underlying medical conditions. While these conditions do not necessarily result in a specific state of immunosuppression, they could potentially facilitate the development of the disease [24]. In these cases, as reported by Erazo et al, no highlights of the nutritional status of the patients were reported, and only 1 of them had a history of trauma in the area before diagnosis [24].

Honarpisheh et al and Negri et al independently reported PCH cases in immunocompromised individuals owing to medications or systemic disorders such as rheumatoid arthritis [12,25]. Manoj et al documented a case of disseminated PCH in a 60-year-old adult with no reported medical immunodeficiency, but positive smoking and alcoholic behaviors, in a 2012 study [16]. Raina et al described the first report of an immuno-competent patient who developed PCH 6 months after a motorcycle accident and was treated with amphotericin B [13].

The current case involved a young patient whose immune system was not affected by immunosenescence, and who was a nonsmoker and non-alcohol drinker, eliminating the influence of 2 well-known conditions that affect the immunological response [26–28]. The clinical presentation of this immunocompetent patient did not suggest PCH as a diagnosis. Similarly, there was no evidence to suspect the presence of this fungus, since there were no previously reported cases of aesthetic procedures conducted with PRP contaminated with Histoplasma. In contrast, transcutaneous traumatic implantation of myco-bacteria and also of paracoccidioidomycosis, sporotrichosis, chromoblastomycosis, mycetoma, entomophthoramycosis, and lacaziosis have all been reported previously [29]. A comparable case of PCH resulting from traumatic implantation was documented by Buitrago et al; however, the patient in that case tested positive for HIV [19].

Under normal circumstances, PRP is nothing more than sterile autologous plasma with a high concentration of platelets and growth factors, and is safe for use in various medical specialties [30]. However, external contamination may occur if processing conditions are inadequate [21].

This pathogenic infection can be diagnosed via direct microscopy, staining, antigen-based immunological serology using ELISA, PCR, and visualization of fungal structures in tissue samples [31]. In our case, the diagnosis was confirmed through histological examination.

Amphotericin B and azoles, especially itraconazole, are the drugs of choice for histoplasmosis treatment [31–33]. Generally, amphotericin B is indicated in severe cases of acute infection, in patients with vomiting or diarrhea, central nervous system abnormalities, and in those receiving medicines that reduce itraconazole absorption (rifampicin, rifabutin, proton pump inhibitors, or phenytoin). To reduce the chances of recurrence, the remaining cases may be managed with oral itraconazole at a dosage of 400 mg/day for a minimum of 1 year. It is important to monitor the blood concentrations of the medication regularly, ensuring that they reach levels between 1 and 2 g/mL [5,32].

Due to a strong clinical suspicion, in our case, the initial treatment was directed towards atypical mycobacteria. Buitrago et al described a case of PCH resistant to amphotericin B [19]. In our case, when the pathology report diagnosed PCH, another treatment was not considered due to the patient’s positive response to TMP/SMX, the medication already prescribed to treat a hypothesized mycobacterial infection. In addition, the unavailability of the treatments of choice (itraconazole or amphotericin B) in the country, due to a complex humanitarian emergency [34,35], led to the decision to continue administration of TMP/SMX. TMP/SMX is known to have antifungal activity [36,37]. As its efficacy has been demonstrated both in vitro and in vivo, Histoplasma can be treated with this drug [38,39]; however, this treatment is not among the first pharmacological options for PCH. Given the paucity of research on TMP/SMX dose in these patients, and to avoid relapses, it was decided to continue treatment for another 2 months [40, with no relapses seen in the follow-up after 1 year.

While the exact size of the inoculum was unknown, it can be inferred that improper administration of PRP without adequate hygiene measures (such as potential reuse of blood collection tubes and contamination by fungal spores), carried out by unqualified personnel, was the factor that led to the infection. The patient’s immune system could not contain the infection on its own, perhaps because the inoculum size was high. This case suggests that performing aesthetic procedures or similar treatments under poor conditions can introduce Histoplasma, and therefore such procedures can be considered as risk factors for cutaneous histoplasmosis. Consideration of this diagnostic possibility is crucial, especially in hyperendemic areas such as Venezuela [30], since this condition is among the most important mimics of other diseases [8].

Ultimately, the patient’s immunocompetent status likely contributed to the swift improvement under the medication regimen, which, while not the first-choice treatment, proved effective. This approach could be further explored as a viable option for patients with similar clinical conditions or when ideal treatment is unavailable.

Conclusions

We report the first case of PCH following PRP administration, in an immunocompetent individual who was successfully treated with TMP/SMX. This case underscores the importance of considering histoplasmosis in endemic regions like Venezuela, particularly when conventional treatments fail, and highlights the need for strict hygiene measures during aesthetic procedures to prevent direct inoculation of Histoplasma. Resource-limited countries such as Venezuela may have limited access to first-line agents. Further research into TMP/SMX’s efficacy in managing histoplasmosis could benefit patients with similar clinical circumstances or limited treatment options.