Actinomycetoma Leg Ulcers in North India

Introduction. Actinomycetoma is a chronic subcutaneous infection caused by aerobic branching actinomycetes. Its clinical features are firm tumefaction of the affected site and the presence of abscesses, nodules, and sinuses that drain a seropurulent exudate containing filamenting granules. Cutaneous actinomycetoma has traditionally been deemed uncommon in the northern part of India, but recent studies have refuted this long-held notion. Thus, clinicians have to be more vigilant when they come across patients with long-standing cutaneous lesions with typical mycetomic features, as early diagnosis and treatment hold the key to a cure. Materials and Methods. This prospective study was carried out from June 2009 to December 2012 and comprises 13 cases of chronic nonhealing ulcers of the lower limb subsequently diagnosed as mycetoma. Socioetiological aspects, prevalence, early diagnosis, and treatment modalities of this condition are described in the study along with a simple, yet inclusive, scoring system to evaluate the post-treatment results. Results. Ten out of 13 cases with clinical suspicion of actinomycetoma were diagnosed with the condition. A majority of these diagnosed patients were middle aged and belonged to lower socioeconomic status. There was no sexual preponderance. Early treatment in the form of modified Welsh regime (amikacin + cotrimoxazole + rifampicin) was started and showed acceptable results. Post-treatment outcomes were measured on the basis of a new scoring system (Masoodi’s score) devised by the authors. Two patients had a score of > 7 (good), 5 patients had a score of 4-6 (fair), and 3 patients had a score of ≤ 3 (poor). Conclusion. Correct identification of the infective aetiological agent is imperative to direct therapy against actinomycetoma. Treatment success depends on an early diagnosis and instigation of treatment. Efficacy of chemotherapy, if started after an early diagnosis in the form of modified Welsh regime, produces acceptable results in the form of clinical and physical remission or cure. The functional and cosmetic parameters do not respond as well to treatment and the authors propose a new scoring system that takes into account the post-treatment results in totality.

  Mycetoma is a chronic granulomatous disease of the skin and subcutaneous tissues, which sometimes involves the muscles and neighboring bones. It is characterized by the triad of tumefaction, abscess formation, and fistulae. Mycetomas are divided into 2 categories depending on the infectious agent: fungi cause eumycetomas, while aerobic Actinomyces cause actinomycetomas.¹

  The discharging grains that characterize this disease represent aggregates of fungal hyphae or bacterial filaments. Agents of the genera Nocardia, Actinomadura, Streptomyces, and Nocardiopsis produce actinomycetomas. Nocardia is the most common agent, particularly in North America. Eumycetomas are caused by a large number of fungi, but Madurella mycetomatis is of particular significance, as it is the most prevalent causative agent in regions of India and Africa.²

  Nocardia brasiliencis, a saprophyte, was first discovered in a soil sample in Mexico in 1955.³ These saprophytes get implanted in the body after trauma, followed by chronic granulomatous infection. The fungal variant of this disease is highly prevalent in India, especially in southern parts of the country. Mycetoma due to Nocardia is rare in Asian settings and only a few studies are available on the prevalence of this disease in India.^4,5

  This prospective case study was carried out in a northern Indian hospital serving a primarily rural population. The intention of this study is to highlight the incidence, clinical presentations, and post-treatment outcomes in patients experiencing a cutaneous bacterial mycetoma of the lower limb. The sample consists of 13 patients with chronic, nonhealing, lower limb ulcers diagnosed as mycetoma on the basis of clinical features and substantiated by laboratory/histopathological examination. Responses to treatment, complications, and additional modalities of treatment are also briefly mentioned.

  As actinomycetoma has traditionally been deemed uncommon in northern India,⁶ it may escape the clinical acumen of the treating physician. This can lead to inappropriate and prolonged treatment of such lesions with no improvement of the wound condition. An additional monetary burden is imposed upon the already impoverished patients who usually bear the brunt of this disease, as shown in the current study. Hence, this paper challenges the notion of rarity associated with this disease in northern India and demands vigilance and high degree of suspicion amongst treating physicians when evaluating such patients.

  This prospective study was carried out at the Departments of Surgery and Plastic Surgery, Jawaharlal Nehru Medical College, Aligarh Muslim University, Uttar Pradesh, Aligarh, India, from June 2009 to December 2012, and included 13 cases of chronic nonhealing ulcers of the lower limb which showed no sign of improvement after routine treatment in the form of antibiotics and regular dressing changes. A lower limb wound was defined as any wound occurring on the leg below the knee joint, including the foot and digits. A wound was deemed chronic when it had been present for at least 6 weeks. The inclusion criteria were presence of a chronic lower limb wound that was unresponsive to treatment; clinical suspicion of mycetoma including tumefaction, discharging sinuses, and abscess formation; and presence of grains in all cases, whether on the surface or inside the abscesses or tissue. Wound location was observed and classified into upper third, middle third, and lower third, including feet. There were no exclusion criteria.

  Categorization of the lesion into eumycotic or actinomycotic was based upon the findings on the microscopic features of the crushed grains, with actinomycotic versions showing of 0.5 cm- to 1 cm-wide filaments and an intense neutrophilic tissue reaction surrounding the grains. Histopathological diagnosis was done only in cases where grains were not seen on the surface and included identification of the various morphological parameters such as grain size, grain morphology (ie, compact/disorganized, macro/micro filaments), staining qualities, presence or absence of Splendore-Hoeppli phenomenon around grains, and intensity of tissue reaction. Splendore-Hoeppli phenomenon is the deposition of amorphous, eosinophilic, and hyaline material around pathogenic organisms, seen in some fungal and parasitic diseases as the result of a local antigen-antibody reaction.

  Identification of the Nocardia species was done by culture, and results were obtained retrospectively up to 4 weeks after commencement of chemotherapy in the form of the modified Welsh regime. To avoid the logistical intricacies of temperature regulation and transport guidelines, the patient and the surgeon went to the microbiology lab and specimens for culture and histopathology were taken under the supervision of the microbiologist. Three patients in whom the offending agent turned out be a fungus were excluded from the study.

  After establishing a diagnosis of actinomycetic mycetoma, wound management, wherever deemed appropriate, was started in the form of daily cleaning and dressings. Actinomycetoma is usually treated with the modified Welsh regime which involves treatment with a combination of amikacin sulphate and cotrimoxazole, administered in cycles consisting of amikacin sulfate 15 mg/kg twice daily for 3 weeks, cotrimoxazole (trimethoprime/sulfomethoxazole) in a dose of 7 mg/kg and 35 mg/kg twice daily for 5 weeks, and oral Rifampicin (10mg/kg/day). Cycles are repeated until a cure is reached, with the average length of treatment being 1 year (Table 1). In the current study, chemotherapy and the modified Welsh regime, in combination with rifampicin, was started for all patients.⁷ Surgery was indicated in 3 cases of limited and localized disease in patients with bony involvement. The rationale of surgery was reduction in the size of the lesion and excision of affected bone to aid the medical therapy.

  Patients were followed for as long as possible and evaluated for improvement of the lesion. A new scoring system, formulated by the authors and explained in detail in this paper, comprises various physical, clinical, and histopathological elements of the disease to evaluate post-treatment results. According to the authors’ assessment, this scoring system is convenient and provides a comprehensive coverage of all aspects of post-chemotherapy results.

  From June 2009 to December 2012, a total of 13 patients presented at the authors’ clinic with complaints of nonhealing wounds of the leg and were suspected of having mycetoma on the basis of clinical presentation in the form of tumefaction, abscess formation, and fistulae.

  There were 8 male and 5 female patients in this series, with a mean age of 38.1 (range 28-53 years). The follow-up period varied from 12 months to 28 months, with the most common reason for a shorter time period being that patients were lost to follow up. All lesions were single, contiguous lesions located in the lower limbs, with the lower-third of the leg, along with foot, the most common site of lesion (Table 1). Previous history of trauma was present in 6 out of the 13 cases. The age of the lesions varied from 5 months to 36 months with a mean of 14.5 months.

  Prasad classification is the most commonly used scale in India to measure the socioeconomic status in both rural and urban areas. It is based on the per capita monthly income and is computed as:

Per capita monthly income = Total monthly income of the family/Total members of family

  Most of the patients belonged to lower socioeconomic strata of the Indian society conforming to Prasad’s class 3 and 4.⁸ Confirmation of diagnosis, along with categorization into bacterial or fungal variants, was confirmed on the basis of microscopic analysis of grains stained with Gram and Ziehl–Neelsen techniques in 9 cases. Surface grains were not visible in 4 cases, and diagnosis was made with using histopathology for identification of the characteristic grains within the abscess cavity present in the dermis and/or subcutaneous tissue. Various morphological parameters such as grain size, grain morphology, and staining quality were carried out. Three out of the 13 cases were found to be suffering from eumycotic mycetoma and were excluded from further study since the lesions were fungal and not bacterial.

  Upon history taking, it was noted that all patients had only been treated with oral and topical antibiotics and had not undergone debridement or any other surgical procedure. The relevant characteristics of the patients are provided in Table 1.

  All patients were started on the modified Welsh regime. A gap of 2 weeks was given for amikacin in each cycle after 3 weeks of administration. Oral rifampicin (10 mg/kg/day) was added as a third drug. The cycle was repeated for up to 6 months, or stopped earlier if the results were found acceptable based on the scoring system devised by the authors. Two patients who developed intolerance against the modified Welsh regime were put on linezolid 600 mg twice daily for 6 months.⁹

  In terms of the outcome, all the patients were followed up for the maximum time possible, ranging from 12 months to 28 months. At the end of 6 months, which has been proven to be the minimum time requirement for the modified Welsh Regime to ameliorate the actinomycetomic lesion, patients were assessed on the basis of a simple scoring system that the authors devised and tentatively named Masoodi’s Score (Table 2). The authors propose 5 parameters including 1) skin appearance, 2) reduction in mass, 3) healing of sinuses, 4) biopsy result at 6 months, and 5) patients satisfaction with outcome. Each parameter received a grade ranging from good to worse. The scores were summed up and graded as follows: > 7 = good outcome; 4-6 = fair outcome; and ≤ 3 = poor outcome. In this study, 2 patients had a score of > 7 (good), 5 patients had a score between 4-6 (fair), and 3 patients had a score of ≤ 3 (poor) (Table 2).

  Cutaneous mycetoma is a disease characterized by a prolonged incubation period and slow clinical course; multiple causal agents add certain preconceived notions regarding its geographical distribution.¹⁰ These factors, along with the fact that individuals of lower socioeconomic status in the developing world are notorious for late consultation for their medical conditions, thereby making screening and early diagnosis scarce, result in the condition going undiagnosed in many cases.

  The agents of the bacterial variant of cutaneous mycetoma are more suited to regions with relatively higher rainfall, similar to the hotter and more humid southern parts of the Indian peninsula.^11,12 As such, having such a significant number of cases in the northern part of India where this study was carried out (Uttar Pradesh) despite the smaller population, is surprising. Not many studies are available on the incidence of mycetoma, especially the bacterial version, which causes chronic limb ulcers in northern India. The current study, as a seminal one on this topic, will hopefully increase awareness and remind doctors in northern India to keep this rare diagnosis in mind when treating patients with similar symptoms.

  This study highlights the increasing prevalence of actinomycetoma in northern India, as shown by the incidence of this study vs other studies available in literature on this topic, which was previously thought to harbor the mycotic variant of mycetoma only. In this regard, the authors agree with the findings of Bakshi et al,¹³ who carried out their study in a northwestern part of India not far from the focus area of the current study: their study also shows that bacterial version of mycetoma is not as rare as previously thought in north India.

  Although some studies show a male preponderance to actinomycetoma^14,15 the current study found no preponderance to gender. The authors believe this may be because most females in rural India actively assist their families in farming and are as engaged in the work as their male counterparts, which leads to similar exposure to environmental conditions, and hence, equal risk to bacterial exposure. Also, the most common occupation in the study group was farming, which amplifies exposure of subjects to soil and the habitat of actinomycotic agents.¹⁶ Previous history of trauma was present in 4 out of 10 cases (40%), which again reinforces the association of environmental contact and subsequent infection.¹⁷ Interestingly, the authors did not encounter overwhelming prevalence of the much-publicized association of barefoot walking¹⁸ and mycetoma formation, as only 2 out of 10 patients gave history of any substantial barefoot walking. The majority of the patients (9 out of 10) were more than 30 years of age, which further establishes the notion of mycetoma as a disease of the third and fourth decade of life.¹⁹

  Mycetoma due to bacterial agents is usually more aggressive and less indolent in comparison to the mycotic varieties²⁰; this holds especially true for N. brascilences. In this study, the most consistent and suggestive clinical feature was the presence of multiple sinuses which were usually surrounded by a raised border or punched out. Underlying bone was involved in 3 cases and all of them were associated with N. brascilences.

  Demonstration of the organism from clinical specimens by Gram stain was the mainstay of diagnosis. Gram positive and acid-fast, thin, beaded, branching filaments are the characteristic appearance of the organism. Identification of the Nocardia species by culture is a tedious process. The organism grows slowly and may take up to 4 weeks for isolation from a clinical specimen.²⁰ Species classification could be done in 8 out of 10 cases, with 2 cases showing no growth on culture media. In all cases, the subclassification of the species was a retrospective exercise, and empirical treatment was started as soon as Nocardia was found in a specimen.

  A worthwhile finding of this study was that all the N. brascilences cases (n = 5) were associated with more distressing clinical features and a comparatively shorter history (in months) while the cases due to N. asteroides (n = 2) were associated with a more indolent course and a longer history (in years). S. somaliensis, which is very rarely found in the Indian subcontinent, was identified as a causative agent in 1 case.²¹

  Patients were put on the modified Welsh regime as soon as the tissue diagnosis revealed Nocardial presence, irrespective of the detection of species. The efficacy of the modified Welsh regime has been demonstrated in several studies.²² The only concern was the ototoxic and nephrotoxic potential of the aminoglycosides for which the patients underwent a weekly renal function test. Two of the patients had to be taken off the modified Welsh Regime, as one with a known case of Type 2 renal failure exhibited deranged renal functions, and another experienced a repeated adverse drug reaction to the regime (possibly cotrimoxazole). These 2 patients were put on linezolid 600 mg twice daily for 6 months.

  The post-treatment outcome has generally been a subjective exercise with most clinicians taking into account the general condition of the wound including some clinical or physical aspects. In the author’s opinion, the devised scoring system, Masoodi’s Score, is the first that incorporates all relevant parameters of the condition including clinical, physical, histopathological, as well as nonmedical patient-related aspects. This scoring scale can lead to a more accurate measurement of post-treatment outcomes as it involves objective, as well as subjective, aspects of the disease.

  Even so, these scores show that despite chemotherapy and surgery, the cosmetic results are not ideal and cutaneous signs suggestive of disease are evident even after remission. The patient seldom achieves his pre-mycetoma state (ie, smooth skin or normal appearance) and telltale signs of the disease persist more often than not. The lowest-scoring parameter in this study was skin appearance and patient satisfaction with treatment. This is partly because of the disfigured and variegated skin surface that mycetoma leaves behind even after cure is achieved. Patients need to be categorically educated about this aspect of the disease at the onset of treatment, and clinicians must explain in clear terms that there will be some form of disfigurement of the affected body part. Counseling will help manage patients’ expectations and lessen their apprehensions at the end of the treatment phase. The factor most amenable to treatment was the presence of discharging sinuses, as all patients were free from sinuses at the end of the treatment.

  There were mixed results in the reduction in mass, with 100% resolution in 3 patients, up to 60% reduction in 3 patients, 40%-60% reduction in 2 cases, and < 40% reduction in 2 cases. All values were based on the measurement of the circumference of the affected part of the lower limb.

  Similarly, histopathology from lesions at 6 months showed equivocal results with negative biopsies in 5 patients, inconclusive biopsies in 2 patients, and positive biopsies in 3 patients. The biopsy results seemed to be independent of the clinicophysical results, as all 3 patients with positive biopsy demonstrated cessation of sinuses, reduction in mass size, and better skin texture.

  Role of surgery. Three patients with bony involvement (2 cases of tibial and 1 case of calcaneal involvement) required concomitant wound and bone management through cleansing and dressing, which greatly accelerated and aided the effect of chemotherapy. One of the patients with debridement of calcaneum, despite achieving cure, had a residual defect over his heel (Figure 2a). The patient sought additional reconstructive cure and underwent a rotational flap cover to reconstruct the heel defect (Figure 2b). The postoperative recovery was uneventful and there was no recurrence of mycetoma in the reconstructed heel (Figure 2c).

  Another patient with severe disfigurement of her post-treatment leg underwent excision and coverage with split-thickness skin graft. The patient also recovered well and was satisfied with his post-grafting skin contour (Figure 3).

  Though the sample of patients who underwent additional surgical procedures is small, it highlights the definitive role of surgery in either supplementing the treatment phase by debridement and debulking, or in functional or cosmetic augmentation.²³

  The disease is easy to identify for a seasoned clinician once they are aware to be on the lookout for it and, even for the microbiologist, it is not difficult to substantiate the diagnosis. An early diagnosis can do wonders for patient outcomes, as prompt institution of chemotherapy in conjunction with surgery can provide satisfactory treatment results. When diagnosis is delayed, the morbidity caused by actinomycetoma is extensive, and in areas where it is endemic, local health care facilities and health education are usually insufficient and inadequate.

  When the patient is in the care of an astute and well-experienced clinician, actinomycetoma is an easily recognized disease in many tropical and subtropical regions. The most important factor is the treating clinician’s awareness and ability to keep this rare diagnosis in mind when encountering a patient with a chronic leg ulcer exhibiting the typical characteristics of actinomycetoma. There is a need to redefine certain preconceived geographical and aetiological attributes that have been ascribed to actinomycetoma over the years. Typically, the disease is characterized by late presentation, with patients often seeking medical advice years after the first lesions have developed.

  The clinical and socioeconomic impact of mycetoma has essentially remained unchanged over the past few decades. Correct identification of the infective aetiological agent is imperative to direct therapy. Treatment success depends on an early diagnosis and instigation of treatment when lesions are small. Efficacy of chemotherapy, if started after an early diagnosis in the form of a modified Welsh regime, produces acceptable results in the form of clinical and physical remission or cure. The functional and cosmetic parameters are less amenable to treatment, and the authors propose a new scoring system that takes into account the totality of post-treatment results. Surgical intervention plays a small but definitive role in the treatment and reconstructive phase of the disease.

The authors are from the Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.

Address correspondence to:
Zulqarnain Masoodi, MCh-(Std)
Department of Plastic, Burns and Reconstructive Surgery
Jawaharlal Nehru Medical College Aligarh Muslim University
Aligarh, Uttar Pradesh 202002
India
doctor_zmasoodi@yahoo.com

Disclosure: The authors disclose no financial or other conflicts of interest.