Short-Term and Long-Term Health Risks of Nuclear-Power-Plant Accidents

John P. Christodouleas, M.D., M.P.H., Robert D. Forrest, C.H.P., Christopher G. Ainsley, Ph.D., Zelig Tochner, M.D., Stephen M. Hahn, M.D., and Eli Glatstein, M.D. N Engl J Med 2011; 364:2334-2341June 16, 2011DOI: 10.1056/NEJMra1103676 Share: Article References Citing Articles (19) Letters On March 11, 2011, a 9.0-magnitude earthquake struck the east coast of Japan. The total number of people who died in the earthquake and the tsunami that it generated is still being assessed, but the official estimation already exceeds 14,000.1 The natural disaster also caused substantial damage to the Fukushima Daiichi nuclear power plant, the consequences of which are still unclear. The purpose of this review is to put the emergency at the Japanese power plant, even as it is evolving, into the context of the extensive literature on nuclear-reactor accidents by analyzing the mechanisms and major short-term and long-term health risks of radiation exposure. In addition, we briefly discuss the accidents at Three Mile Island in Pennsylvania in 1979 and at Chernobyl in Ukraine in 1986 because they illustrate the broad range of potential outcomes.

Mechanisms of Exposure Reactor Accidents and the Release of Radioactive Materials

In a nuclear power plant, the fuel, an isotope of either uranium or plutonium, undergoes fission to produce the energy that is used to heat water and turn steam-driven turbine generators. In addition to the release of energy, the split fuel creates radioactive fission products. In the event of an accident, the primary concern is that the support structure (core) containing the fuel and the fission products may become damaged and allow radioactive elements to escape into the environment. One mechanism by which this can happen is failure of the core cooling system. In such a circumstance, the reactor core and even the fuel itself can partially or completely melt. Elevated temperatures and pressures can result in explosions within the reactor, dispersing radioactive material. In most plants, the potential effects of a cooling-system failure are minimized by surrounding the reactor core with a steel-walled vessel, which in turn is surrounded by an airtight, steelreinforced concrete containment structure that is designed to contain the radioactive

material indefinitely (Figure 1Figure 1 Key Components of a Nuclear Power Plant.). Of note, the explosions that have been seen in reactor accidents are not the same as those seen after the detonation of a nuclear weapon, since the latter requires highly enriched uranium or plutonium isotopes in concentrations and configurations that are not present in power plants. In the partial meltdown at Three Mile Island, the plant's containment structure fulfilled its purpose, and a minimal amount of radiation was released.2 However, there was no such containment structure in place at the Chernobyl reactor the explosions and the subsequent fire sent a giant plume of radioactive material into the atmosphere. Although the Three Mile Island accident has not yet led to identifiable health effects,3-5 the Chernobyl accident resulted in 28 deaths related to radiation exposure in the year after the accident.6,7 The long-term effects of the Chernobyl accident are still being characterized, as we discuss in more detail below. The situation at Fukushima, though still in daily flux, will probably end up ranking between these two historical accidents in terms of radiation releases and health consequences.

Types of Radiation Exposure

Human radiation exposure as a result of reactor accidents is generally characterized in three ways: total or partial body exposure as a result of close proximity to a radiation source, external contamination, and internal contamination. All three types can affect a given person in a radiation accident. Total or partial body exposure occurs when an external source irradiates the body either superficially to the skin or deeply into internal organs, with the depth depending on the type and energy of the radiation involved. For example, beta radiation travels only a short distance in tissue, depending on its energy, and can be a significant source of dose to skin. High-energy gamma radiation, however, can penetrate deeply. In previous reactor accidents, only plant workers and emergency personnel who were involved in the aftermath had substantial total or partial body exposure. Persons who have had total or partial body exposure but no contamination are not radioactive and therefore cannot expose their caregivers to radiation. External contamination occurs when the fission products settle on human beings, thereby exposing skin or internal organs. Populations living near a reactor accident may be advised to remain indoors for a period to minimize the risk of external contamination. Internal contamination occurs when fission products are ingested or inhaled or enter the body through open wounds. This is the primary mechanism through which large populations around a reactor accident can be exposed to radiation. After Chernobyl, approximately 5 million people in the region may have had excess radiation exposure, primarily through internal contamination.7

Reactor accidents can release a variety of radioisotopes into the environment. Table

1Table 1 Estimated Releases of Isotopes during the Chernobyl Accident. lists the radioisotopes that were released during the Chernobyl accident.8 The health threat from each radioisotope depends on an assortment of factors. Radioisotopes with a very short half-life (e.g., 67 hours for molybdenum-99) or a very long half-life (e.g., 24,400 years for plutonium-239), those that are gaseous (e.g., xenon-133), and those that are not released in substantial quantities (e.g., plutonium-238) do not cause substantial internal or external contamination in reactor accidents. In contrast, iodine-131 can be an important source of morbidity because of its prevalence in reactor discharges and its tendency to settle on the ground. When iodine-131 is released, it can be inhaled or consumed after it enters the food chain, primarily through contaminated fruits, vegetables, milk, and groundwater. Once it enters the body, iodine-131 rapidly accumulates in the thyroid gland, where it can be a source of substantial doses of beta radiation. The release of radioactive water into the sea at the Fukushima plant has resulted in an additional route whereby the food chain may be affected, through contaminated seafood. Although the radioactivity in seawater close to the plant may be transiently higher than usual by several orders of magnitude, it diffuses rapidly with distance and decays over time, according to half-life, both before and after ingestion by marine life.

Clinical Consequences of Radiation Exposure Type of Radiation and Dose Rates

At a molecular level, the primary consequence of radiation exposure is DNA damage. This damage will be fully repaired or innocuous or will result in dysfunction, carcinogenesis, or cell death. The clinical effect of radiation exposure will depend on numerous variables, including the type of exposure (total or partial body exposure vs. internal or external contamination), the type of tissue exposed (tissue that is sensitive to radiation vs. tissue that is insensitive), the type of radiation (e.g., gamma vs. beta), the depth of penetration of radiation in the body (low vs. high energy), the total absorbed dose, and the period over which the dose is absorbed (dose rate). The type of radiation and the dose rates that are involved in a reactor accident would typically be very different from those seen in the detonation of a nuclear bomb, which is why the biologic consequences of these events may differ substantially. The literature on radiation refers to dose in terms of both gray (Gy), the unit of measurement for the absorbed dose, and sievert (Sv), the unit of measurement for the effective dose, which is the absorbed dose multiplied by factors accounting for the biologic effect of different types of radiation and the radiation sensitivities of different tissues. For high-energy gamma radiation and whole-body exposures, 1 Gy equals 1 Sv.

Table 2Table 2 Effective Doses of Radiation, According to Source of Exposure. shows estimated effective doses received during common medical and nonmedical activities and how these doses relate to those received by the populations around Three Mile Island and Chernobyl.9-15 Radiation exposure can potentially result in short-term and long-term effects in every organ system in the body. Comprehensive reviews of the literature on radiation exposure have been produced by the International Atomic Energy Agency and the World Health Organization.7,15 In this review, we focus on the two potential outcomes of radiation exposure that have garnered much of the media attention in the wake of the ongoing crisis in Fukushima: acute radiation sickness and increased long-term cancer risks.

Acute Radiation Sickness and Its Treatment

When most or all of the human body is exposed to a single dose of more than 1 Gy of radiation, acute radiation sickness can occur. Much of our understanding of acute radiation sickness is based on the clinical experience of more than 800 patients who have been described in national and international registries of radiation accidents that have been predominantly medical in source.16 Acute radiation sickness has not been seen in the general population in association with a nuclear-reactor accident. All 134 patients with confirmed acute radiation sickness at Chernobyl were either plant workers or members of the emergency response team.6 No confirmed diagnoses of acute radiation sickness were noted in workers or in the general population at Three Mile Island.17 Much of the short-term morbidity and mortality associated with a high total or near-total body dose is due to hematologic, gastrointestinal, or cutaneous sequelae. In the Chernobyl accident, all 134 patients with acute radiation sickness had bone marrow depression, 19 had widespread radiation dermatitis, and 15 had severe gastrointestinal complications.18 Hematologic and gastrointestinal complications are common because bone marrow and intestinal epithelium are especially radiosensitive as a result of their high intrinsic replication rate. Cutaneous toxic effects are common because external lowenergy gamma radiation and beta radiation are chiefly absorbed in the skin. In Chernobyl, estimated skin doses in some patients were 10 to 30 times the bone marrow doses.18 If total body doses are extremely high (>20 Gy), severe acute neurovascular compromise can occur. At Chernobyl, the highest absorbed dose in a worker was 16 Gy.19 Acute radiation sickness can be categorized into three phases: prodrome, latency, and

illness. Table 3Table 3 Signs and Symptoms of Acute Radiation Sickness in the Three Phases after Exposure. summarizes the constellation of hematologic, gastrointestinal, and neurologic symptoms, along with the time to onset and

dose dependence, associated with each of these phases. Cutaneous manifestations of acute radiation injury include mild erythema and pruritus with limited skin doses (3 to 15 Gy) and blistering and ulceration with very high skin doses (>15 Gy).6 The first step in the care of any patient who is exposed to radiation is to manage immediate life-threatening injuries, such as those from trauma or burns. The next step is to address external and internal radiation contamination, if any. Decontamination protocols are available from several sources.20,21 Once these issues have been addressed and acute radiation sickness is suspected, treatment is guided by the estimated total dose, which is determined on the basis of the initial clinical symptoms, lymphocyte depletion kinetics, and cytogenetic analyses, when available.22,23 Patients with modest whole-body doses (<2 Gy) may require only symptomatic support for nausea and vomiting. In patients with whole-body doses of more than 2 Gy, the treatment of the consequences of bone marrow depletion is paramount. Strategies include management of infections with antibiotics and antiviral and antifungal agents, the use of hematopoietic growth factors, and possibly bone marrow transplantation.20 The use of bone marrow transplantation is controversial, since outcomes after radiation accidents have been poor. After Chernobyl, only 2 of the 13 patients who underwent bone marrow transplantation survived long term. Among the 11 patients who died, complications from transplantation appeared to be the primary cause of death in 2 patients.24 Gastrointestinal radiation sequelae are managed with supportive care and possibly with the use of prophylactic probiotics.25 Cutaneous radiation injuries may evolve over the course of weeks. Treatment of such lesions involves minimizing acute and chronic inflammation with topical glucocorticoids while avoiding secondary infections. Several organizations have developed detailed treatment algorithms for acute radiation sickness that are publicly available.6,20,26,27

Increased Long-Term Cancer Risks

In the region around Chernobyl, more than 5 million people may have been exposed to excess radiation, mainly through contamination by iodine-131 and cesium isotopes.7 Although exposure to nuclear-reactor fallout does not cause acute illness, it may elevate long-term cancer risks. Studies of the Japanese atomic-bomb survivors showed clearly elevated rates of leukemia and solid cancers, even at relatively low total body doses.28,29 However, there are important differences between the type of radiation and dose rate associated with atomic-bomb exposure and those associated with a reactor accident. These differences may explain why studies evaluating leukemia30-36 and nonthyroid solid cancers37-40 have not shown consistently elevated risks in the regions around Chernobyl. Alternatively, small increases in the risks of leukemia and nonthyroid solid cancers may become more apparent with improved cancer registries or longer follow-up. In the population around Three Mile Island, there was a notable temporary increase in cancer diagnoses in the years immediately after the accident, but this increase may have been the result of intensified cancer screening in the area. Long-term follow-up has shown no increases in cancer mortality.4

However, there is strong evidence of an increased rate of secondary thyroid cancers among children who have ingested iodine-131. Careful studies of children living near the Chernobyl plant (which included estimates of the thyroid radiation dose) suggest that the risk of thyroid cancer increased by a factor of 2 to 5 per 1 Gy of thyroid dose.41-43 Although this relative increase in incidence is large, the baseline incidence of thyroid cancer in children is low (<1 case per 100,000 children). Factors that increase the carcinogenic effect of iodine-131 include a young age and iodine deficiency at the time of exposure. Among children in regions with endemic iodine deficiency, the risk of thyroid cancer per 1 Gy of thyroid dose was two to three times that among children in regions in which iodine intake was normal.44,45 Moreover, the risk of thyroid cancer among children who were given stable iodine after the Chernobyl accident was one third that among children who did not receive iodine.45 Studies of the effect of thyroid exposure to radiation in utero46,47 and in adulthood48-50 have been inconclusive. In accidents in which iodine-131 is released, persons in affected areas should attempt to minimize their consumption of locally grown produce and groundwater. However, since the half-life of iodine-131 is only 8 days, these local resources should not contain substantial amounts of iodine-131 after 2 to 3 months. On the advice of public health officials, area residents may take potassium iodide to block the uptake of iodine-131 in the thyroid. To be most effective, prophylactic administration of potassium iodide should occur before or within a few hours after iodine-131 exposure. The administration of the drug more than a day after exposure probably has limited effect, unless additional or continuing exposure is expected.51 Although potassium iodide can have toxic effects, the Polish experience with en masse administration of the drug after Chernobyl was reassuring. More than 10 million children and adolescents in Poland were given a single dose of prophylactic potassium iodide, with very limited morbidity.52 The Food and Drug Administration has issued guidelines for the administration of potassium iodide according to age and expected radiation exposure.53

Conclusions
Because nuclear-reactor accidents are very rare events, few medical practitioners have direct experience in treating patients who have been exposed to radiation or in the overall public health response. Organizations that could be involved in either activity because of their proximity to a power plant or their role in the health system must put detailed algorithmic response plans in place and practice them regularly. A critical component of the response, with respect to both treatment of individual patients and interaction with the community, is clear communication about exposure levels and corresponding risk, with an eye toward widespread public apprehension about acute radiation sickness and longterm cancer risks.

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A review of wide surgical excision of hidradenitis suppurativa

Ziyad Alharbi*, Jens Kauczok and Norbert Pallua

* Corresponding author: Ziyad Alharbi zalharbi@ukaachen.de

Equal contributors

Author Affiliations Department of Plastic and Hand Surgery-, Burn Unit, Medical Faculty, RWTH Aachen University, Aachen, Germany For all author emails, please log on. BMC Dermatology 2012, 12:9 doi:10.1186/1471-5945-12-9

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-5945/12/9

Received: 11 November 2011

Accepted: 26 June 2012 Published:26 June 2012

2012 Alharbi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Background

Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disorder that involves the infundibular terminal follicles in areas rich of apocrine glands. It can be associated with fistulating sinus, scarring and abscesses formation. Hidradenitis suppurativa is a challenging aspect and requires a proper treatment plan which may involve different specialties. We present herein the option of surgical treatment involving wide surgical excision and methods of reconstruction as well as the rate of recurrence. Furthermore, review of the literature regarding surgical treatment of hidradenitis suppurativa is provided.
Methods

A retrospective analysis reviewed 50 operative procedures for 32 patients in 5 anatomical sites. These anatomical sites have been divided to 23 sites involving the axilla, 17 sites involving the inguinal region and 8 sites involving the perianal/perineal area, 1 site involving the gluteal region and 1 site involving the trunk region.
Results

Twenty six patients (81, 25 %) showed no recurrence after surgery and the average time of hospital stay period was 5 days. Recurrence was observed only in 6 patients (18, 75 %).

Conclusion

Elimination of the acute inflammatory process should occur in advance, including the use of antibiotics and minor surgeries such as abscess drainage with proper irrigations. After stabilizing the acute phase, wide surgical excision is recommended. Herein, planning of surgical reconstruction should be initiated to achieve the best outcome and consequently decreasing the risk of recurrence and complications after surgery.
Keywords: Hidradenitis suppurativa; Acne inversa; Follicular diseases; Surgical reconstruction; Wide surgical excision

Background
Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disorder that involves the infundibular terminal follicles in areas rich of apocrine glands and associated with formation of abscesses and fistulating sinus [1-5]. The pathogenesis of the disease is not fully understood, although it was reported that HS is androgen dependent that can be associated with endocrine abnormalities [6]. Bacterial infection is considered as a secondary event in the pathogenesis. Furthermore, smoking and obesity are both known as risk factors and may increase the severity of the disease [1,6]. Clinical manifestations include painful nodules, abscesses, sinus tracts, and ropelike hypertrophic scars in the apocrine gland-bearing areas [7]. Consequently, the abscesses extend deeper into the subcutaneous tissue and then intercommunicating sinus tracts develop, resulting in irregular hypertrophic scars [8]. Hidradenitis suppurativa was initially classified by using Hurley's Staging System (Table 1) [9]. Table 1. Hurleys Staging System[10] Likewise, Sartorius et al. have suggested that the Hurley system is not enough to assess the efficacy of the treatment. Therefore, they described the Sartorius Staging System. Points are accumulated in each category to assess the treatment of HS in an accurate way [11]. The Sartorius Staging System [12] accumulates points according to:

 Anatomic regions involved Number and types of lesions involved (abscesses, nodules, fistulas, scars, points for lesions of all regions involved) The distance between lesions, in particular the longest distance between two relevant lesions (i.e. nodules and fistulas in each region or size if only one lesion present) The presence of normal skin in between lesions It is indeed a challenging aspect and requires a proper treatment plan that may involve different specialties. Hidradenitis suppurativa is commonly misdiagnosed and sometimes even referred to many subspecialties [13]. In general, treatment includes the use of topical or systemic antibiotics, topical antiseptics and intralesional corticosteroids. Furthermore, systemic retinoids, antiandrogen therapy, immunotherapy (TNF alfa inhibitors) and oral immunosuppressive agents have also shown a positive effect on disease progression [10,12]. However, for most cases of advanced hidradenitis suppurativa, radical surgery can be the only curative treatment option [14]. It is also reported that early wide surgical excision is important and effective in order to prevent complications and the recurrence of hidradenitis suppurativa and to improve the quality of life [15]. This article focuses on the surgical treatment of hidradenitis suppurativa with special regard to the methods of reconstruction for resulted defects after wide surgical excision in the axilla, inguinal region, gluteal region, trunk, perineal and perianal area. The rate of recurrence will be also reviewed. Furthermore, a review of the literature regarding surgical treatment of hidradenitis suppurativa is provided.

Methods
This retrospective analysis reviewed 32 patients with chronic inflammatory moderate to severe hidradenitis suppurativa (Hurley grade II and III) treated in our hospital from 2003 to 2009 (Table 2). Follow up of all patients has been conducted in our out patient department (OPD) with

a mean period of 24months after surgery. 50 operative procedures were retrospectively reviewed in 5 anatomical sites, 23 sites involving the axilla, 17 sites involving the inguinal region and 8 sites involving the Perianal/perineal area, 1 site involving the gluteal region and 1 site involving the trunk region. The regional ethics committee advised that approval was not necessary for this retrospective analysis. However, all patients have provided written informed consent for the publication of their clinical details and any accompanying clinical images. Table 2. shows the recurrence rate with the type of surgical reconstruction in each site Twelve patients (37,5%) were males and 20 patients (62,5%) were females. The age at the time of presentation ranged from 17years to 51years (Table 3). Overall, 22 patients (68,75%) were obese. From this category, 5 patients (15,6%) had Body Mass Index (BMI) of more than 25 and 14 patients (43,75%) had BMI of more than 30. Two patients (6,2%) represented BMI of more than 35 and only one patient (3,1%) represented BMI of more than 40. The analysis also showed that 10 patients (31,25%) were smokers (5 males and 5 females). Table 3. Patients characteristics with Age, Body Mass Index, Smoking and Size of Defect The patients had chronic inflammatory hidradenitis suppurativa (Hurley grade II and III). Intravenous antibiotics were prescribed depending on wound tissue swab and laboratory results. Minor surgeries such as abscess drainage and irrigation were performed in order to irrigate the wounds. Further irrigation has been performed in the surgical ward prior to the surgical procedure. Wide surgical excisions were carried out for all patients with wide margin (i.e. 1cm) and deep margin including the skin, subcutaneous tissue till reaching fascia. Stool Management System (SMS) has been used to prevent contamination of the stool to the surrounded skin otherwise colostomy was conducted for selected patients with perianal or perineal lesions. Then, reconstruction techniques were conducted based on the site and the size of the defects including primary closure, skin grafting, local flaps as random pattern or pedicle pattern, regional flaps and the more invasive free (microvascular) tissue transfer in selected patients. The size of defects resulted after excision ranged from 16,5cm2 (5,5 x 3cm) to 735cm2 (35 x 21cm). At the time of surgery, all patients have been administrated with single dose intravenous antibiotics depending

on the previous swab results. One-stage operations: wide surgical excision and reconstruction of defect was performed for 26 patients (81,25%). Two-stages operations have been performed for 5 patients (15,63%) buy using the negative pressure therapy in one stage and the reconstructive art in the other stage. Only one patient has been operated in three stages (3,12%) which included the use of negative pressure therapy in one stage and other debridement with irrigation due to persistent pus secretions and then the reconstruction of defect in the third stage. For the axilla, rotation fasciocutaneous flap was performed in 7 sites (30,4%), and transposition fasciocutaneous flap including the Limberg flap was used in 9 sites (39,1%). Parascapular fasciocutaneous flap was selected in 5 patients (21,7%) and the thoracodorsal artery perforator (TDAP) flap was the option in 1 patient (4,3%). Anterolateral thigh perforator (ALTP) flap has been used in 1 patient (4,3%). For inguinal lesions, primary closure was used in 8 sites (47%) and 3 Split-thickness skin grafting techniques (17,75%) were performed. Rotation fasciocutaneous flap was used in 3 sites (17,75%) and transposition fasciocutaneous flap was carried out in 2 sites (11,8%). Only one patient (5,8%) was treated with abdominoplasty for reconstructing the defect involving the both inguinal areas and Mons pubis. Reconstruction of the perianal and the perineal regions included the using of transposition fasciocutaneous flap in 6 sites (75%) and Gracilis musculocutaneous flap was used in 2 patients (25%). Reconstruction of the trunk and gluteal region was carried out for only two patients by performing a split thickness skin graft for each site.

Results
Daily dressing has been performed in a sterile concept. Twenty eight Patients (87,5%) showed no complications after surgery. The average time of hospital stay period was 5days. Physiotherapy and post-operative rehabilitation were also started.

After follow up (mean follow up time is 24months), 26 Patients (81,25%) showed no recurrence. Recurrence rate (Tables 2 and 3) was observed in 6 patients (18,75%). The recurrence rate was seen in patients with Hurley grade III and 5 smokers out of 6 patients in this category (83,33%). Reconstruction of the axillary region included several techniques but primary closure and skin grafting were not performed based on expected complications such as contractures, excessive scarring. For those lesions in this area, rotation fasciocutaneous flap and transposition fasciocutaneous flap such as Limberg flap were performed successfully and showed good aesthetic as well as function results. Parascapular fasciocutaneous flap and even thoracodorsal artery perforator (TDAP) flap were selected for moderate to diffuse lesions. Massive lesions in the axillary region were reconstructed in 1 of our patients by the use of free (microvascular) tissue transfer in the form of anterolateral thigh perforator (ALTP) flap and showed good functional as well as aesthetic results (Figures 1, 2, 3, and 4).

Figure 1. Hidradenitis suppurativa (Hurley's Staging II) in the left axilla.

Figure 2. The resulted defect after wide surgical excision.

Figure 3. Adaptation of the ALTP flap after vascular anastomosis.

Figure 4. Post-operative photo demonstrates no healing abnormalities. Reconstruction of the inguinal region included primary closure for mild and moderate lesions. Likewise, split-thickness skin grafting was selected for large defects. Rotation fasciocutaneous flap and transposition fasciocutaneous flap were performed successfully and showed good aesthetic results. For bilateral inguinal lesions and involvement of Mons pubis, an abdominoplasty was performed for one patient and showed good outcome. For lesions located on the perianal and the perineal regions, several techniques have been carried out including the use of bilateral transposition flap (Figures 5, 6, 7, 8, and 9) or the using of Gracilis musculocutaneous flap for severe lesions. Both techniques required preservation of the vulva and the anal sphincter. For lesions located in the gluteal and the trunk area, skin grafting was used successfully.

Figure 5. Bilateral Hidradenitis suppurativa (Hurley's Staging III) in the perianal, perineal and mons pubis showing the left side.

Figure 6. Bilateral Hidradenitis suppurativa (Hurley's Staging III) in the perianal, perineal and mons pubis showing the right side.

Figure 7. The resulted defect after wide surgical excision.

Figure 8. Bilateral transposition flap used to cover large defects bilaterally.

Figure 9. The post-operative result of the bilateral trasposition flap.

Discussion
The literature on surgical treatment of hidradenitis suppurativa is huge and the review of this disease goes back to the 1950s [16-19]. Recently, many articles have been published regarding this point and some recent key references exist regarding surgical treatment of hidradenitis suppurativa [20,21]. Primary closure, healing by secondary intention and skin grafting are considered to be the most widely used procedures. Furthermore, several surgical techniques depending on secondary intention for minor or extensive disease are also described in the literature [21]. In fact, 18,75% recurrence rate can be considered high after extensive surgery procedures. On the other hand, this recurrence rate was strongly associated with the extent (Hurley grade) of disease. Herein, in very advanced cases with Hurley grade III, it can be very hard to radically remove all HS tissue even if very extensive surgery is applied and at least minor recurrence is expected and accepted. Sartorius score cannot, but Hurley classification with clinical margin evaluation can possibly give valuable information for proper treatment options. Excision and split skin grafting is a basic tool in the surgical treatment and the result of this procedure is often satisfactory [22-24]. Massive regional hidradenitis suppurativa can be successfully managed with wide surgical excision, VAC therapy, and skin grafting for better outcomes [25]. Furthermore, Negative-pressure dressings have been used as bolster for skin grafts in order to reconstruct such defects after wide surgical excision [26,27].

However, the use of flaps to prevent less favorable functional results was introduced at an early stage. A review of the Limberg flap for axillary hidradenitis was presented quite recently [28]. Local fasciocutaneous V-Y advancement flaps was reported for large defects following wide surgical excision of long-standing hidradenitis suppurativa of the axilla [29]. Other option is the double opposing V-Y perforator-based flaps which have been described for reconstruction of axillary defects following excision of hidradenitis suppurativa to recreate the axillary contour after wide surgical excision of the hair-bearing skin of the axilla [30]. More options exist like the use of a versatile transpositional flap for axillary hidradenitis suppurativa [31]. Some flaps may be indicated in particular cases such as the use of thoracodorsal artery perforator flap (TDAP) in axillary hidradentitis suppurativa [32,33]. Herein, lateral thoracic fasciocutaneous island flap was also used for treatment of recurrent hidradenitis axillaris suppurativa and other axillary skin defects [34]. The pedicled gracilis myocutaneous flap has been introduced as a surgical treatment of hidradenitis suppurativa of the groin and perineum [35]. It was even proposed that the medial thigh lift to be considered for immediate defect closure after radical excision of localised inguinal hidradenitis suppurativa provided that no perifocal signs of infection are present after debridement [36]. Furthermore, modified abdominoplasty was also reported as a functional reconstruction for recurrent hidradenitis suppurativa of the lower abdomen and groin [37]. The anterolateral thigh (ALT) flap has been reported for reconstruction of groin and vulval hidradenitis suppurativa [38]. Furthermore, the anterior Obturator Artery Perforator (aOAP) flap seems to be a save option for the reconstruction of perineal defects after wide surgical excision of hidradenitis suppurativa [39], although it was not introduced specifically for this disease. It should be noted that the use of colostomy is not an absolute indication for treating such defects in the perianal or perineal region. We believe that flaps in these areas are more susceptible to infections. Colostomy can be performed but should be preserved for selected patients with massive extensive defects. Some patients do not agree with colostomy and, thus the consent of this procedure does not apply in many cases. However, this does not interfere with the selected treatment plan.

For buttocks, more options have been stated in the literature such as the fasciocutaneous flaps in gluteal hidradenitis suppurativa [40]. Other options were also documented such as the extended split superior gluteus maximus musculocutaneous flap. This flap is easy to harvest and leaves aesthetically satisfactory results [41]. There is no doubt that this approach of treatment is mainly dependent on the size and the site of the defect. Despite the method of reconstruction, the hospitalization period can be reduced and, thus reducing the cost of treatment. This goal can be elusive and therefore radical excision and more advanced reconstruction techniques are performed in order to close defects in a permanent way. We found that wide surgical excision as well the direct closure technique showed better outcome and limited the cost of treatment and the hospitalization period as well as the recurrence rate. It is of great importance to determine the timing of wide surgical excision and the selected method of reconstruction. During the acute phase, surgical drainage, irrigation with the administration of antibiotics should only be the mainstay of the treatment. Our approach has not been conducted in this phase. It was important to obtain a non-infectious wound to perform this approach and not to expect septic complications. Then, planning of reconstruction should be initiated to achieve the best outcome and consequently decreasing the risk of recurrence and complications after surgery.

Conclusion
Treatment of hidradenitis suppurativa has wide modalities. However, surgical option can be the option of treatment especially for those severe cases being treated with conservative modalities. After eliminating the acute inflammatory phase, wide surgical excision is recommended and planning of reconstruction should be initiated to achieve the best outcome and consequently decreasing the risk of recurrence and complications after surgery. Our concept of treatment including reconstructive techniques decreased the time of hospital stay. It is cost effective and prevented skin contractures as well as excessive scarring and showed good functional and aesthetic results.

Competing interest
The authors have declared that no conflict of interest exists.

Authors contribution
ZA drafted the manuscript and participated in the analysis and interpretation of data. JK conceived the design and participated in the operations. NP participated in the operations as well as revised and edited the manuscript. All authors read and approved the final manuscript.

Acknowledgement
The authors would like to thank Mr. Werner Kriegel for the tremendous work in photo selection for the reviewed patients as well as the photo documentation for the selected patients during the hospitalization period and the follow up process.

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The treatment of melasma by silymarin cream

Tagreed Altaei

Correspondence: Tagreed Altaei tagreedaltaei@yahoo.com

Author Affiliations Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil City, Kurdistan, Iraq BMC Dermatology 2012, 12:18 doi:10.1186/1471-5945-12-18

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-5945/12/18

Received: 8 March 2012 Accepted: 28 September 2012 Published:2 October 2012

2012 Altaei; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Background

Melasma is an acquired increased pigmentation of the skin characterized by symmetrical and confluent grey-brown patches usually on the areas of the face exposed to the sun. Silymarin strongly prevents photocarcinogenesis, and significantly prevented melanin production. The objectives of this study were the assessment of safety and efficacy of topical Silymain (SM) cream in a double-blind placebo controlled study for treatment of melasma patients.

Methods

Experimentally on 24 Albino rabbits were randomly divided into 4 equal groups. [A] No treatment, [B] received placebo, [C] treated with SM cream (0.1), & [D] treated by SM (0.2), were applied topically before UV sun light exposure for 30 days, assessed clinically & tissue pathology. Clinically on 96 adults diagnosed with melasma randomized to three equal groups to receive one of the tested drugs applied twice daily for 4 weeks, evaluated by the response; lesion size, melasma area and severity index score, Physician global assessment, and subjective assessment.
Results

The Clinical and histopathology observations were reduced significantly in SM groups. Clinically; all patients showed significant excellent pigment improvement & lesion size reduction with SM treatments from the 1st week. All patients were fully satisfied 100%. No side effects were observed.
Conclusions

Silymarin showed tremendous improvement of melasma in a dose-dependent manner, and was effective in prevention of skin damage caused by U.V. sunlight. It is a safe new candidate effective treatment for melasma.
Trial registration

Australian New Zealand Clinical Trials Registry - ACTRN12612000602820

Keywords: Silymarin; Melasma; Sunlight

Background
Melasma is a common acquired pigmentary disorder that occurs usually in women (more than 90% of cases) of all racial and ethnic groups [1]. Melasma presents as brown to grey macules and patches, with serrated, irregular, and geographic borders [2]. The pigmented patches are

usually sharply demarcated [3] and symmetrical. Melasma has a predilection for sun-exposed areas. The etiology is not entirely elucidated; however, the ultraviolet sunlight exposure appears to be the most significant factor [4]. In those patients with epidermal type melasma, there are several treatments available. Topical agents include phenols, e.g., hydroquinone; retinoids, e.g., tretinoin; azelaic acid; kojic acid; and glycolic acid [1]. Silymarin, derived from the milk thistle plant Silybum marianum (L.) Gaertn] is a natural polyphenolic flavonoid. Its main component silybin (silibinin), is considered to be the most biologically active with potent antioxidant properties [5]. Cutaneous photoprotection mechanisms triggered by silymarin and silybin are numerous and mainly demonstrate mainly their ability to reduce and suppress harmful effects of solar UV radiation, such as UV-induced oxidative stress, inflammation, immune responses and DNA damage as well as induction of apoptosis [6]. Silymarin significantly prevented melanin production in a dose-dependent manner with an IC50 value (concentration producing 50% maximal inhibition) of 28.2 g/ml, without effects on cell viability [7]. Even in high doses, silymarin does not show any toxic effects and, in fact has no harmful effects on the embryo [8-10].

Methods
Formulation of tested drugs

Silymarin (SM), App-Chem-Bio; China prepared in cream base of different concentrations [11]. Placebo is a cream base free from active constituent.
Experimental study

Twenty-four healthy New Zealand rabbits Albino rabbits (weight: 1500500 g each), were individually housed in suspended cages, for 1 week before the experiment. The ethics committee, before the experiment, has approved the experimental protocol. They were kept in the same environmental and nutritional conditions (temperature 252C, relative humidity 40%-60%, and 12 hours in light and 12 hours in darkness cycles) in the animal house of the college of medicine. At the beginning of the study, animals were randomly divided into 4 equal groups (n=6); group

[A] did not receive any treatment, [B] received placebo, [C] treated with SM (0.1 mg/ml.kg-1) cream, and [D] treated by SM cream (0.2 mg/ml.kg-1). 3 cm2 of Albino rabbits' back were shaved. Then after 48 hours, the tested drugs were applied topically by cotton pad stick on the shaved area of all groups daily, 30 minutes before each UV sun light exposure. The rabbits were exposed to UV sunlight (11+ extreme) for 3 hours during each day of June (temperature 432C) for 30 days. All animals were painlessly killed by chloroform and samples were taken from the shaved area for tissue pathology study, the samples were put in formalin buffer 10%.
Histopathological examination

All samples were cut into small blocks. These blocks of tissues were then routinely processed. These paraffin blocks were sectioned into 5 m thick and stained with hematoxylin & eosin. The stained tissues were examined for histopathological alterations. The histopathology departments' staffs were blinded to the tested drugs.
Clinical study

This is a double blind, randomized clinical study on patients with melasma attending the outpatient clinic of the Dermatology department of Medical City Hospital. The protocol was reviewed and approved by the ethic committee (University of Baghdad, College of Dentistry), and each participant signed a written informed consent. The inclusion criteria were adults with melasma without any topical, systemic, laser, and surgical treatment on face during the previous months. While the exclusion criteria were pregnant and nursing women, patients with history of hypersensitivity to some of the components of the formulas of the study, and coexistence of associate diseases and other pigmentation diseases, and concomitant use of other skin care products or systemic treatments. A history was taken from each patient, regarding age, gender, occupation, time of onset, history of pregnancy, contraceptive pills, and sun exposure. Patients were randomized in a double-blind manner to receive one treatment of the tested drugs; Group I (G I) SM (7 mg/ml) cream, Group II (G II) SM (14 mg/ml) cream, or Group III (G III) placebo, applied topically to the affected areas, twice daily for 4 weeks, also advised to avoid sun exposure and to use topical sunscreen with sun protection factor (SPF) of 15+ during the entire

period of treatment and thereafter. The patients were seen regularly every week for one month for assessment; the response to treatment was rated by the size of lesions. Skin pigment evaluation by melasma area and severity index (MASI), physician global assessment (PGA); assessment of overall treatment of disease activity, used a scale from 0 to 10, by an independent observer blinded to the treated groups, and record the presence of any side effect. The Subjective assessment depending on recording improvement in patient satisfaction measures during the time course, and graded as follows: Grade 0 =not satisfied, Grade 1 =moderately or partially satisfied, Grade 2 =greatly but not fully satisfied, Grade 3 =fully or completely satisfied.
Statistical analysis

In order to analyze the data, Chi-square test, Student t-test and X2 were used, P value of less than 0.05 was considered significant, data showed as mean SD (SPSS 18).

Results
Experimental study results

Some clinical features such as skin scaling, skin irregularity, erythema, skin hyperpigmentation, and edema were evaluated. The clinical observations are as follows: Group A (G A), without treatments, dermal scaling, skin irregularity, erythema & hyperpigmentation, and edema were observed at the highest level (100%). Group B (G B); received placebo, dermal scaling, skin irregularity, erythema & hyperpigmentation, and edema were observed at the level (90%). Group C (G C); treated with SM (0.1) cream, no clinical features were observed. Group D (G D); treated with SM (0.2) cream, no clinical features were observed. The significance between groups was; G A vs. B, C, & D groups; p=0.0001, G B vs. C, & D groups; p=0.0003, and G C vs. D; p>0.05, as showed in (Figure 1).

Figure 1. Percentage of clinical observations for animal groups after exposure to UV-sun light, level of significance [G A vs. B, C, & D groups; p=0.0001, G B vs. C, & D groups; p=0.0003, and G C vs. D; p>0.05].
Histopathology results

Epidermal hyperpigmentation, epidermal hyperkeratosis, lymphocyte infiltration into epidermis, squamous cell proliferation, edema and dermal thickness increase, infiltration of lymphocytes; plasma cells, and eosinophils into dermis were noticed in all cases of G A (100%), in G B were (58%, 50.2%, 3%, 45%, 60.2%, 60.2%) respectively. While in G C, & G D all the microscopic observations were not seen. The level of significance was; G A vs. B, C, & D groups; p=0.0002, G B vs. C, & D groups; p=0.0001, and G C vs. D; p>0.05, as showed in (Figure 2).

Figure 2. Histopathological observations in animals' skin after exposure to UV-sun light, level of significance [G A vs. B, C, & D groups; p=0.0002, G B vs. C, & D groups; p=0.0001, and G C vs. D; p>0.05]. Group A [G A] did not receive any treatment, group B [G B] received placebo, group C [G C] treated with SM cream (0.1 mg/ml.kg-1), & group D [G D] treated by SM (0.2 mg/ml.kg-1).
Clinical study results

Ninety-six melasma patients were enrolled in this study, female {F} 80 (83.3%) and male {M} 16 (16.66%), the ratio of sex distribution {F: M} within the groups were [G I (26:6), G II (27:5), and G III (27:5)]. The patients' age ranged from 28 to 55 years (median, 41 years). The duration of melasma varied from 2 to 6 years (median 4 years). Family history of melasma was found in 46 (47.916%) patients. The most frequent precipitating factors were the sun exposure (90%), and pregnancy (10%). The response to treatment was evaluated as per the size of the lesion at the end of each week till 4 weeks. G I & G II showed significant reduction in size of the lesion at the end of 1st week compared to G III, complete clearing of the lesion was shown in G II after 3 weeks of treatment, while G I in the fourth week, (Figure 3).

Figure 3. The response size of lesion (%) at baseline and after treatment with tested drugs in melasma patients, level of significance (p=0.002). G=group. The average MASI score of G I before treatment was 17.1 3.12. After treatment it changed into 12.32.3, 6.62.4, 0.21.72, & 0 at the end of 1st, 2nd, 3rd, & 4th week respectively. For G II before treatment was 16.52.8. After treatment it changed into 10.41.2, 3.51.4, 0, & 0 at the end of 1st, 2nd, 3rd, & 4th weeks respectively, and was statistically significant (P =0.0001). In G III there were no significant changes, as showed in Table 1. The PGA rated the G I improvement as excellent in 5 patients, good in 21, moderate in 2, and mild in 1 at the end of 1st week, excellent in 17 patients, good in 14, & moderate in 1at the end of 2nd week, while at the end of 3rd week; excellent in 28, good in 4 patients. While the G II improvement was excellent in 8 patients, good in 19, moderate in 5 at the end of 1st week, excellent in 20 patients, good in 12 at the end of 2nd week; and at the end of 3rd week were excellent in 29, good in 3 patients. Data showed statistical significance for SM treatments compared to placebo, (P = 0.002), (Figure 4).

Figure 4. Physicians Global Assessment (PGA) of G I (SM 7 mg/ml) & G II (SM 14 mg/ml) in treated melasma patients at the end of each week of study, (p=0.002). G=group.

Figure 5. Melasma patient (left side) treated with Silymarin. View at onset (A), five days later (B) with an excellent improvement, and ten days later (C) with disappearance of melasma pigment. Patients' satisfaction was recorded as 100% were highly & completely satisfied (Figure 5). During the period of treatment, no local or systemic adverse effects were recorded. Table 1. Changes in MASI scores of tested drugs in melasma patients

Discussion
Skin exposure to solar UV radiation induces a number of skin disorders, including erythema, edema, sunburn cell formation, hyperplasia, immune suppression, DNA damage, photoaging, melanogenesis and skin cancers. It is well documented that UV irradiation, both its UVB (290 320 nm) and UVA (320400 nm) component, induces the generation of reactive oxygen species (ROS), which create the oxidative stress in skin cells and play an important role in the initiation, promotion and progression of skin aging and carcinogenesis. Thus, the use of antioxidants, namely naturally occurring herbal compounds, is receiving considerable interest to protect skin from adverse biological effects of solar UV radiation [6]. In the SKH-1 hairless mice silymarin inhibited UVB induced skin edema, formation of sunburn and apoptotic cells, prevented UVBinduced infiltration of inflammatory leukocytes, and significantly reduced the activity of myeloperoxidase, a marker of tissue infiltration [12,13]. Cellular antioxidant status plays a crucial role in modulating the effects of unrepaired DNA lesions and cellular sensitivity to the DNA damaging effects of solar UV radiation [14]. Benefits have been observed from both systemic and topical administration. Significant inhibition of UVB-induced sunburn, apoptotic cell formation, and edema has been associated with topical application of silymarin [12]. The present study agrees with the previous studies that the experimental study showed no clinical or histopathological features in Silymarin treated groups (both concentrations) compared to placebo and none treated groups after exposure to UV sunlight. Also, it may be one of the mechanisms of action of Silymarin in the treatment of pigmented lesion. The body possesses endogenous defense mechanisms, such as antioxidative enzymes (superoxide dismutase, catalase, glutathione peroxidase) and nonenzymatic antioxidative molecules (vitamin E, vitamin C, glutathione, ubiquinone), protecting it from free radicals by reducing and neutralizing them [15]. Some can be inhibited by ultraviolet (UV) light [16]. It has been reported that UVA decreases intracellular glutathione status and subsequently increases UVA sensitivity of keratinocytes. The DNA-damaging effect of UVA can be reduced by improving the regulation of intracellular antioxidant status by suitable antioxidants [17].

Silymarin shows strong free radical-scavenging activity that is severalfold greater than that of vitamin E [18]. It inhibits lipid peroxidation and provides significant protection against UVBinduced depletion of catalase activity. Therefore, silymarin can effectively terminate the harmful biochemical reactions by scavenging free radicals and ROS, and by strengthening the cellular antioxidant status [19]. This may be the other mechanism of action of Silymarin in the treatment of melasma. Silymarin inhibited l-DOPA oxidation activity of tyrosinase, the rate-limiting melanogenic enzyme, in cell based-systems, but it did not directly affect cell-free tyrosinase activity. Furthermore, Western blot analysis indicated that silymarin decreased the expression of tyrosinase protein [7]. This explains the exact main mechanism of action of silymarin in the treatment of melasma. This study showed a significant reduction of pigment, melasma lesion in a short period of time. Silymarin has the efficacy to treat melasma in a dose dependent manner. It is safe. No side effect was observed. All patients were fully and completely satisfied from the first week of treatment with Silymarin. The author suggests studying other pharmaceutical preparations of Silymarin like gel or paint and other dosing intervals in the treatment of melasma.

Competing interests
The author declares that there are no competing interests.

Authors contributions
TA, designed and made the whole work of this original study. The author read and approved the final manuscript.

Acknowlegments

The author would like to thanks all patients enrolled in this study, Professor D. Nazar Talabani, PhD Oral medicine and histopathology, College of Dentistry; Professor D. Makram M. Al-Waiz MD, DDS, PhD, Dermatology & Venereology; D Sami y. Guirges, College of Medicine; and the other staff, for their kind assistance.

References
1. Rendon M, Berneburg M, et al.: Treatment of melasma. J Am Acad Dermato 2006, 154(5 Suppl):S272-S281. 2. Wolff K, Johnson RA, et al.: Fitzpatricks Color Atlas and Synopsis of Clinical Dermatology. Toronto: McGraw-Hill; 2005. PubMed Abstract | Publisher Full Text 3. James WD, Berger TG, et al.: Andrews Diseases of the Skin Clinical Dermatology. Tenth edition. Toronto: Saunders Elsevier; 2006. PubMed Abstract | Publisher Full Text 4. Hern R, Andez-Barrera B, Torres-Alvarez , et al.: Solar elastosis and presence of mast cells as key features in the pathogenesis of melasma. Clin Exp Dermatol 2008, 33(3):305-308. PubMed Abstract | Publisher Full Text 5. Morazzoni P, Bombardelli E: Silybum marianum (Carduus marianus). Fitoterapia 1995, 64:3-42. 6. Vladimir K, Daniela W: Silybin and silymarin new effects and applications. Biomed Papers 2005, 149(1):29-41. Publisher Full Text 7. Choo S-J, Ryoo , et al.: Silymarin inhibits melanin synthesis in melanocyte cells. J Pharm Pharmacol 2009, 61:663-667. PubMed Abstract | Publisher Full Text 8. Hahn VG, Lehmann HD, et al.: Pharmacology and toxicology of silymarin, the antihepatotoxic agent of Silybum marianum (L.) Gaertn. Arzneimittelforschung 1968, 18:698-704. PubMed Abstract 9. Mereish KA, Bunner DL, et al.: Protection against microcystin-LR-induced hepatotoxicity by Silymarin: biochemistry, histopathology, and lethality. Pharm Res 1991, 8:273-277. PubMed Abstract | Publisher Full Text 10. Wagner VH, Diesel P, et al.: Chemistry and analysis of silymarin from Silybum marianum Gaertn.

Arzneimittelforschung 1974, 24:466-471. PubMed Abstract 11. Winfield AJ, Richards RME: Routes of administration and dosage forms. 3rd edition. Churchill Livingstone: 213; 2004:213-214. [Pharmaceutical practice] 12. Katiyar SK, Korman NJ, et al.: Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 1997, 89:556-566. PubMed Abstract | Publisher Full Text 13. Katiyar SK: Treatment of silymarin, a plant flavonoid, prevents ultraviolet lightinduced immune suppression and oxidative stress in mouse skin. Int J Oncol 2002, 21:1213-1222. PubMed Abstract | Publisher Full Text 14. Kastan MB, Zhan Q, et al.: A mammalian cell cycle checkpoint pathway. Cell 1992, 71:587-597. PubMed Abstract | Publisher Full Text 15. Shindo Y, Witt E, Han D, et al.: Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin. J Invest Dermatol 1994, 102(1):122-124. PubMed Abstract | Publisher Full Text 16. Fuchs J, Huflejt ME, et al.: Impairment of enzymic and nonenzymic antioxidants in skin by UVB irradiation. J Invest Dermatol 1989, 93(6):769-773. PubMed Abstract | Publisher Full Text 17. Applegate LA, Lautier D, et al.: Endogenous glutathione levels modulate the frequency of both spontaneous and long wavelength ultraviolet induced mutation in human cells. Carcinogenesis 1992, 13:1557-1560. PubMed Abstract | Publisher Full Text 18. Valenzuela A, Guerra R, et al.: Antioxidant properties of the flavonoids silybin and (+)-cyanidanol-3: comparison with butylated hydroxyanisole and butylated hydroxytoluene. Planta Med 1986, 5:438-440. 19. Rana P, Singh , Rajesh agarwal : Flavonoid Antioxidant Silymarin and Skin Cancer. Antioxid Redox Signal 2002, 4(4):655-663. PubMed Abstract | Publisher Full Text

Male Circumcision for the Prevention of HSV-2 and HPV Infections and Syphilis
Aaron A.R. Tobian, M.D., Ph.D., David Serwadda, M.Med., M.P.H., Thomas C. Quinn, M.D., M.Sc., Godfrey Kigozi, M.B., Ch.B., M.P.H., Patti E. Gravitt, Ph.D., Oliver Laeyendecker, M.S., M.B.A., Blake Charvat, M.Sc., Victor Ssempijja, B.Stat., Melissa Riedesel, M.P.H., Amy E. Oliver, B.A., Rebecca G. Nowak, M.P.H., Lawrence H. Moulton, Ph.D., Michael Z. Chen, M.Sc., Steven J. Reynolds, M.D., M.P.H., Maria J. Wawer, M.D., M.H.Sc., and Ronald H. Gray, M.D., M.Sc. N Engl J Med 2009; 360:1298-1309March 26, 2009DOI: 10.1056/NEJMoa0802556 Share: Abstract Article References Citing Articles (118) Letters Herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis are common sexually transmitted infections. HSV-2 infection and syphilis are two of the main causes of genital ulceration1-3 and have been associated with an increased risk of human immunodeficiency virus (HIV) infection in observational studies.1,2,4 The prevalence of HPV is significantly increased in developing nations.5 HPV infection can cause genital warts, and high-risk HPV genotypes are associated with penile and anal cancer, as well as with cervical cancer in female partners.5,6 Three randomized trials and multiple observational studies showed that male circumcision significantly decreased the incidence of HIV infection in male subjects.7-9 The rate of self-reported genital ulcer disease was decreased among circumcised men in a trial conducted in Rakai, Uganda, which suggested that male circumcision might reduce the incidence and prevalence of ulcerative sexually transmitted infections.7 However, previous findings with regard to the effects of male circumcision on the incidence of HSV-2 infection and syphilis have been more equivocal. Two observational studies suggested that male circumcision significantly decreased the incidence of HSV-2 infection,10,11 whereas other studies showed no association.12-15 Similarly, two observational studies showed that male circumcision decreased the incidence of syphilis,16,17 whereas other studies showed no association.15,18 According to a metaanalysis of circumcision studies, among male subjects who had been circumcised, the odds ratio for HSV-2 infection was 0.88 (95% confidence interval [CI], 0.77 to 1.01), and the odds ratio for syphilis was 0.67 (95% CI, 0.54 to 0.83), as compared with those who had not been circumcised.19 Although most observational studies have suggested that male circumcision decreases the incidence of penile HPV infection,20,21 some studies have shown no effect.22,23

Many of the observational studies evaluating male circumcision and sexually transmitted infections had limited statistical power, were vulnerable to confounding by sexual practices correlated with a high risk of transmission, and evaluated the status of circumcision solely on the basis of self-report. Thus, the potential efficacy of male circumcision for the prevention of sexually transmitted infections can be determined only in randomized trials. We used data from randomized, controlled trials of male circumcision for the prevention of HIV infection in Rakai, Uganda, to assess the efficacy of male circumcision for the prevention of HSV-2 and HPV infections and syphilis in adolescent boys and men.

Methods Study Design and Subjects

We conducted two parallel but independent trials of male circumcision for the prevention of HIV infection and other sexually transmitted infections in Rakai, Uganda, as described previously.7,24 In the first trial (Rakai-1, which was funded by the National Institutes of Health), we enrolled 4996 HIV-negative, uncircumcised boys and men between the ages of 15 and 49 years who accepted voluntary HIV counseling and testing and agreed to learn their HIV results. The second trial (Rakai-2, which was funded by the Bill and Melinda Gates Foundation) had as its primary goal the assessment of the safety of male circumcision and its effects on sexually transmitted infections in HIV-infected men and their partners. However, the latter trial also included 595 HIV-negative subjects, of whom 155 (26.1%) declined to learn their HIV results and 440 (73.9%) agreed to learn their HIV results but were included in the study to provide blinding of subjects' HIV status so as to prevent potential stigmatization of HIV-infected subjects who were participating in the trial. The two trials, which were conducted concurrently, had identical protocols. At each visit, all subjects were offered free HIV counseling and testing, health education, and condoms. All subjects who were found to be HIV-positive were referred to an HIV treatment program funded by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR). All subjects provided written informed consent. Both the Rakai-1 and Rakai-2 trials were approved by four institutional review boards: the Science and Ethics Committee of the Uganda Virus Research Institute (Entebbe, Uganda), the HIV subcommittee of the National Council for Science and Technology (Kampala, Uganda), the Committee for Human Research at Johns Hopkins University's Bloomberg School of Public Health (Baltimore, MD), and the Western Institutional Review Board (Olympia, WA). The Rakai-1 trial was overseen by the data and safety monitoring board for vaccine safety and prevention of the National Institutes of Health and by a separate board for Rakai-2. We performed physical examinations and conducted interviews to ascertain sociodemographic characteristics and rates of sexual practices at baseline and at 6, 12, and 24 months. Additional details on the study design, specimen testing, and analyses are

presented in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Virus and Syphilis Detection

HSV-2 testing was performed with the use of an enzyme-linked immunosorbent assay (ELISA) (Kalon Biological). On the basis of previous evaluation of test performance in Ugandan serum samples, subjects who had positive tests for HSV-2 had an opticaldensity index value of 1.5 or more,25 and all seroconversions that were detected by ELISA were confirmed by Western blot (Euroimmun). HIV status was determined with the use of two separate ELISAs and confirmed by HIV-1 Western blot analysis, as described previously.7 HPV genotyping was performed with the use of the HPV Linear Array (Roche Diagnostics), as described previously.26,27 HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 were considered the primary high-risk (carcinogenic) genotypes.28,29 (We included HPV genotype 66 [HPV-66] in our definition of carcinogenic HPV genotypes after its reclassification, in 2005.29) For the primary analyses of HPV prevalence, we excluded subjects who were HPV-negative and had no detectable beta-globin in the sample, since the presence of cellular material could not be demonstrated. Active Treponema pallidum infection was determined by means of a positive rapid plasma reagin test (Becton Dickinson) or a toluidine red unheated serum test (TRUST) (New Horizons Diagnostics) and was confirmed by a positive T. pallidum particle agglutination assay (Serodia TP-PA kit, Fujirebio).

Statistical Analysis
For end points for HSV-2 infection and syphilis, we performed time-to-event analyses, using the protocol-specified KaplanMeier method, with the end point defined as the time to the detection of HSV-2 or syphilis seropositivity, with censoring of data at the last visit. In the primary intention-to-treat analysis, we performed an adjustment for baseline characteristics using a Cox proportional-hazards model for the time to detection of HSV2 or syphilis seropositivity. In secondary analyses, adjustments were also made for the trial (Rakai-1 or Rakai-2), changes in sexual practices (number of sexual partners, condom use, and alcohol use with sexual intercourse), and symptoms of sexually transmitted infections (genital ulcers, urethral discharge, and dysuria) during follow-up as time-varying covariates. In addition, we conducted an as-treated analysis in which crossover subjects (i.e., subjects in the intervention group who did not undergo surgery and those in the control group who underwent surgery elsewhere) were classified according to their actual circumcision status. We used Poisson regression to estimate incidence-rate ratios, risk ratios for prevalence, and 95% confidence intervals. Additional details regarding subgroup analyses of the incidence of HSV-2 infection according to covariates and HPV analysis are available in

the Supplementary Appendix. The rates of sexual practices and symptoms of sexually transmitted infections were tabulated at each follow-up visit, and differences between the two study groups were assessed with the use of chi-square tests. All reported P values are two-sided and have not been adjusted for multiple testing.

Results Subjects
Subjects were enrolled in the Rakai-1 trial from September 2003 through September 2005 and in the Raiki-2 trial from February 2004 through December 2006. Of the 6396 subjects who were initially screened in both the Rakai-1 and Rakai-2 trials, 3003 were excluded from the analyses reported here because of preexisting positive or indeterminate

HSV-2 or HIV-1 status (Figure 1Figure 1 Enrollment and Outcomes in the Evaluation of Herpes Simplex Virus Type 2 (HSV-2) Infection.). For the analysis to determine HSV-2 seroconversion, we evaluated 3393 HIV-negative, HSV-2negative, uncircumcised subjects between the ages of 15 and 49 years; of these subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision in 24 months (control group). The retention rates at 24 months were 81.9% (1370 of 1673 subjects) in the intervention group and 82.0% (1395 of 1701) subjects in the control group. For the HSV-2 study population, baseline sociodemographic characteristics and rates of sexual practices and symptoms of sexually transmitted infections were similar in the two

study groups (Table 1Table 1 Baseline Characteristics, Sexual Practices, and Symptoms of Sexually Transmitted Infections in the Evaluation of Herpes Simplex Virus Type 2 (HSV-2) Infection.). Subjects who were enrolled in the Rakai-2 trial had higher sexual-risk profiles at enrollment than subjects in the Rakai-1 trial because the Rakai-2 trial permitted enrollment of subjects who declined to learn their HIV status, whereas the Rakai-1 trial required receipt of HIV results. The Rakai-2 subjects were significantly older than those in the Rakai-1 trial, were more likely to be currently or previously married, had had a higher number of sexual partners in the previous year, and had had a higher rate of alcohol use with sex in the previous 6 months.

Male Circumcision and HSV-2 Acquisition

At 24 months in the intention-to-treat population, HSV-2 infection was detected in 114 subjects in the intervention group and in 153 subjects in the control group (Figure

2Figure 2 KaplanMeier Estimates of the Probability of Detection of Herpes Simplex Virus Type 2 (HSV-2) Infection at 24 Months.). The cumulative probability of HSV-2 infection during the 24-month period was lower in the intervention group (7.8%) than in the control group (10.3%) with an unadjusted hazard ratio of 0.75 (95% CI, 0.60 to 0.94; P=0.02). After adjustment for enrollment characteristics and rates of sexual practices and symptoms of sexually transmitted infections, the hazard ratio was 0.72 (95% CI, 0.56 to 0.92; P=0.008). After adjustment for time-varying covariates during follow-up, the hazard ratio was 0.77 (95% CI, 0.62 to 0.97; P=0.03). In the astreated analysis, the unadjusted hazard ratio for detection of infection was 0.73 (95% CI, 0.59 to 0.93; P=0.01); after adjustment for baseline characteristics, the hazard ratio was 0.72 (95% CI, 0.59 to 0.91; P=0.009). In separate analyses of data from the Rakai-1 and Rakai-2 trials, male circumcision reduced the incidence of HSV-2 infection in both trials. In the Rakai-1 trial, the cumulative probability of HSV-2 infection at 24 months in the intention-to-treat population was lower in the intervention group (7.7%) than in the control group (9.9%), with an unadjusted hazard ratio of 0.77 (95% CI, 0.59 to 0.99). In the Rakai-2 trial, the cumulative probability of HSV-2 infection was 8.6% in the intervention group and 14.0% in the control group (unadjusted hazard ratio, 0.59; 95% CI, 0.27 to 1.27). There was no significant difference in efficacy between the Rakai-1 trial and the Rakai-2 trial (P=0.52 for interaction). The cumulative rates of HSV-2 seroconversion per 100 person-years, sexual practices, and symptoms of sexually transmitted infections are shown in Figure 3Figure 3

Incidence of Herpes Simplex Virus Type 2 (HSV-2) Infection and Incidence-Rate Ratios, According to Sociodemographic and Clinical Characteristics.. Overall, the incidence of HSV-2 infection was lower among circumcised subjects, and there were no significant differences in the hazard ratios in subgroup analyses. Subjects who reported symptoms of sexually transmitted infections had a higher incidence of HSV-2 infection than asymptomatic subjects. At 24 months, the cumulative prevalence rates of self-reported symptoms of genital ulcer disease were higher among subjects with HSV-2 seroconversion (10.3%) than among subjects without seroconversion (2.7%) (relative risk, 3.78; 95% CI, 2.87 to 4.98; P<0.001).

For the HSV-2 study population, rates of sexual practices that were stratified according to

circumcision status are shown in Table 2Table 2 Rates of Sexual Risk Behavior in the Evaluation of Herpes Simplex Virus Type 2 (HSV-2) Infection.. At 6 months, reported condom use was higher in the intervention group than in the control group (P<0.001), but no significant differences between the two study groups were observed thereafter. There were no significant between-group differences in the reported number of sexual partners, but nonmarital sexual relationships were more frequently reported by subjects in the intervention group than in the control group, and these differences were significant at 12 and 24 months (P=0.04 and P=0.03, respectively). At all follow-up intervals, rates of reported alcohol use with sexual intercourse were higher in the control group than in the intervention group, differences that were significant at 6, 12, and 24 months. Reported transactional sexual intercourse (which was defined as the exchange of sex for money or gifts) was infrequent, and rates did not differ significantly between the two study groups. Genital ulcer disease was more frequent in the control group than in the intervention group at 6 months (P<0.001), 12 months (P<0.001), and 24 months (P=0.02). However, there were no significant differences between the two groups in reported genital discharge or dysuria.

Male Circumcision and Acquisition of Syphilis

To determine the efficacy of circumcision in preventing syphilis, subjects who tested negative for HIV and T. pallidum infections at baseline were evaluated for active T. pallidum infection during follow-up. Enrollment characteristics were similar in the two study groups. At 24 months, syphilis was detected in 50 of 2083 subjects (2.4%) in the intervention group, as compared with 45 of 2143 subjects (2.1%) in the control group (hazard ratio, 1.14; 95% CI, 0.77 to 1.75; P=0.50). Adjustment for enrollment characteristics and rates of sexual practices and symptoms of sexually transmitted infections did not significantly affect these estimates of circumcision efficacy (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P=0.44).

Male Circumcision and Prevalence of HPV

Overall, baseline sociodemographic characteristics and rates of sexual practices and symptoms of sexually transmitted infections were similar in the two study groups for subjects in the HPV substudy population (see the table in the Supplementary Appendix). At enrollment, the prevalence of high-risk HPV genotypes was 38.1% in the intervention group and 37.1% in the control group (P=0.79). In the primary intention-to-treat analyses at 24 months, high-risk HPV genotypes were detected in 42 of 233 subjects in the intervention group (18.0%), as compared with 80 of 287 subjects in the control group (27.9%), with an unadjusted risk ratio of 0.65 (95% CI,

0.45 to 0.94; P=0.01) (Table 3Table 3 Male Circumcision and the Prevalence of Human Papillomavirus (HPV) Infection.). Adjustment for enrollment characteristics and rates of sexual practices and symptoms of sexually transmitted infections did not significantly affect this estimate (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P=0.009). When the analysis was confined to subjects who had beta-globin positive samples at the 24-month visit, high-risk HPV genotypes were detected in 32 of 215 subjects (14.9%) in the intervention group, as compared with 69 of 260 subjects (26.5%) in the control group (risk ratio, 0.56; 95% CI, 0.37 to 0.85; P=0.007). At 24 months, multiple high-risk HPV genotypes were detected in 10 of 233 subjects (4.3%) in the intervention group and in 35 of 287 subjects (12.2%) in the control group (risk ratio, 0.35; 95% CI, 0.17 to 0.71; P=0.004). The prevalence of nonhigh-risk HPV genotypes at the 24-month visit was also lower in the intervention group (26.2%) than in the control group (39.4%) (risk ratio, 0.66; 95% CI, 0.49 to 0.91; P=0.01).

Discussion
In our study, the circumcision of adolescent boys and men in a rural Ugandan population significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection during 24 months of follow-up but did not affect the incidence of syphilis. The efficacies of circumcision for the prevention of HSV-2 incidence and HPV prevalence were 25% and 35%, respectively. Adjustment resulted in a modest increase in efficacy to 28% for HSV-2 infection but did not change efficacy for HPV infection. These findings are compatible with those of observational studies, in which reduced rates of HSV-2 and HPV infections were associated with circumcision,10,11,19-21 and with the results of one clinical trial, which showed that circumcision decreased the risk of HPV infection.30,31 These findings, in conjunction with those of previous trials, indicate that circumcision should now be accepted as an efficacious intervention for reducing heterosexually acquired infections with HSV-2, HPV, and HIV in adolescent boys and men. However, it must be emphasized that protection was only partial, and it is critical to promote the practice of safe sex. The biologic mechanisms for the reduction in rates of HSV-2 and HPV infections by means of circumcision may involve anatomical factors, cellular factors, or both. The retraction of the foreskin over the shaft during intercourse exposes the inner preputial mucosa to vaginal and cervical fluids7,19,32 and can also result in microtears during intercourse, particularly in the frenulum.7,19,32 The moist subpreputial cavity may provide a favorable environment for the survival of HSV-2 and HPV and consequent epithelial infection.7,19,33 Both HSV-2 and HPV replicate in epithelial cells of the epidermis and dermis,34 and the inner mucosa of the foreskin is lightly keratinized, which may facilitate the access of HSV-2 and HPV to underlying epithelial cells in

uncircumcised adolescent boys and men. After circumcision and keratinization of the surgical scar, the risk of such epithelial infection is probably reduced. In observational studies,2,35 genital HSV-2 infection has been associated with an increased risk of HIV acquisition. In our trial, we found that male circumcision reduced the rate of symptomatic genital ulcerative disease.7 Since genital ulcerative disease and HSV-2 infection are both thought to be cofactors in HIV acquisition,2,36,37 male circumcision may provide protection against HIV acquisition by reducing the risk of HSV-2 infection and its associated genital ulcers. However, the possibility of confounding because of sexual practices correlated with a high risk of transmission cannot be excluded. Two trials of HSV-2 suppression in HSV-2positive, HIV-negative subjects did not show protection against HIV acquisition,38,39 which suggests that more research is required on the acquisition of HSV-2 and HIV infections. With respect to the use of circumcision to prevent HPV infection, our study was limited, since it was confined to a subgroup of subjects who were observed both at enrollment and at 24 months. In both the intervention and control groups, these subjects may represent a self-selected population of compliant subjects who could be at lower risk for HPV infection than the general population; this factor could result in an underestimation of the efficacy of male circumcision. Also, since samples were evaluated only at 24 months, we were limited in our ability to determine whether the reduced HPV prevalence after circumcision was due to a reduced rate of HPV acquisition, an increased rate of HPV clearance, or both. Nevertheless, these findings, in conjunction with data from observational studies20,21 and one trial in South Africa,31 demonstrate the efficacy of circumcision in decreasing the prevalence of HPV in adolescent boys and men. Male circumcision has now been shown to decrease the rates of HIV, HSV-2, and HPV infections in men and of trichomoniasis and bacterial vaginosis in their female partners.79,40 Circumcision also reduces symptomatic ulceration in HIV-negative men and women and HIV-positive men.7,24,40 Thus, male circumcision reduces the risk of several sexually transmitted infections in both sexes, and these benefits should guide public health policies for neonatal, adolescent, and adult male circumcision programs.