Assessing Mailuoning injection in wound healing and thrombophlebitis management: A rat model study.

Thrombophlebitis is the inflammatory condition characterized by obstruction of one or more vessels, commonly in the legs, due to the formation of blood clots. It has been reported that traditional Chinese medicine, including Mailuoning injection, is advantageous for treating inflammatory and blood disorders. This research assessed the therapeutic efficacy of Mailuoning injection in the treatment of thrombophlebitis in rodents, as well as investigated its impact on fibrinolysis, inflammation, and coagulation. An experimental setup for thrombophlebitis was established in rodents via modified ligation technique. Five groups comprised the animals: sham operation group, model group, and three Mailuoning treatment groups (low, medium, and high dosages). The pain response, edema, coagulation parameters (PT, APTT, TT, FIB), serum inflammatory markers (IL-6, TNF-α, CRP), and expression levels of endothelial markers (ICAM-1, VCAM-1, NF-κB) were evaluated. Blood flow and vascular function were further assessed by measuring hemorheological parameters and the concentrations of TXB2, ET, and 6-k-PGF1α. In contrast to the sham group, model group demonstrated statistically significant increases in endothelial expression levels, coagulation latencies, and inflammatory markers (p < 0.05). The administration of mailing, specifically at high and medium dosages, resulted in a substantial reduction in inflammatory markers, enhancement of coagulation parameters, suppression of ICAM-1 and VCAM-1 expression, and restoration of hemorheological measurements to baseline (p < 0.05). Significantly higher concentrations of 6-k-PGF1α and lower levels of TXB2 and ET were observed in high-dose group, suggesting that pro- and anti-thrombotic factors were restored to equilibrium. Utilization of Mailuoning injection in rat model of thrombophlebitis exhibited significant therapeutic impact. This effect was manifested through pain alleviation, diminished inflammation, enhanced blood viscosity and facilitation of fibrinolysis. The study indicated that Mailuoning injection may serve as a viable therapeutic option for thrombophlebitis, potentially aiding in the improvement of wound healing by virtue of its anti-inflammatory and blood flow-enhancing characteristics.

Septic Pulmonary Embolism: A Contemporary Profile.

Septic pulmonary embolism (SPE) is a rare clinical entity that is distinct from the classic and more common non-septic thrombotic pulmonary embolism. SPE should be suspected in patients with a systemic acute inflammatory reaction or sepsis who develop signs and symptoms of pulmonary involvement. The diagnosis of SPE depends on the specific radiologic finding of multiple, peripheral, nodular, possibly cavitated lesions. SPE should prompt an immediate search for the primary source of infection; typically, right-sided infective endocarditis, cardiac implantable electronic devices, and septic thrombophlebitis as a complication of bone, skin, and soft tissue infection including Lemierre's syndrome, indwelling catheters, or direct inoculation via injection drug use. Invasive treatment of the infection source may be necessary; in thrombophlebitis, the efficacy and safety of anticoagulation remain undefined. Blood cultures may be negative, particularly among patients with recent antibiotic exposure, and broad-spectrum antimicrobial therapy should be considered. The in-hospital mortality of SPE ranges up to 20% in published case series. While trends in the incidence of SPE are unknown, the opioid epidemic, the growing use of cardiac implantable electronic devices worldwide, and the reported increase in cases of septic thrombophlebitis may be leading to an escalation in SPE cases. We provide a contemporary profile of SPE and propose a clinical management algorithm in patients with suspected or confirmed SPE.

Acute septic thrombophlebitis of the lower extremities due to foreign body injury and infection: a case report.

BACKGROUND: Septic thrombophlebitis (STP) of the lower extremities caused by foreign bodies is rare in the clinic, and the symptoms are serious. If the correct treatment is not implemented as soon as possible, the patient may progress to sepsis. CASE PRESENTATION: We report the case of a 51-year-old normally healthy male who developed fever 3 days after field work. When he was weeding with a lawn mower in the field, a metal foreign body from the grass flew into his left lower abdomen, resulting in an eschar on his left lower abdomen. He was diagnosed with scrub typhus but did not respond well to anti-infective treatment. After a detailed inquiry of his medical history and an auxiliary examination, the diagnosis was confirmed as STP of the left lower limb caused by a foreign body. After surgery, anticoagulation and anti-infection treatment, the infection and thrombosis were controlled, and the patient was cured and discharged. CONCLUSIONS: STP caused by foreign bodies is rare. Early detection of the aetiology of sepsis and early adoption of the correct measures can effectively block the progression of the disease and reduce the patient's pain. Clinicians should identify the source of sepsis through a medical history and clinical examination.

Pylephlebitis: An uncommon complication of sigmoid diverticulitis.

Pylephlebitis is defined as a septic thrombophlebitis of the portal vein, usually secondary to infection in regions contiguous to or drained by the portal system. Although extremely uncommon in the modern era, pylephlebitis still carries an appreciable risk of severe morbidity and mortality, if unrecognized and left untreated. Herein we report the case of severe pylephlebitis in a patient with acute sigmoid diverticulitis. Although highly elusive, prompt diagnosis is crucial to ensure appropriate management and limit associated morbidity.

Safety and Tolerability of 23.4% Hypertonic Saline Administered Over 2 to 5 Minutes for the Treatment of Cerebral Herniation and Intracranial Pressure Elevation.

BACKGROUND: Hyperosmolar therapy is the cornerstone of medical management of sustained elevated intracranial pressure from cerebral edema. Acute intracranial hypertension and herniation is a medical emergency that requires rapid treatment and stabilization to prevent secondary brain injury or death. Intravenous hypertonic sodium chloride (NaCl) 23.4% is an effective treatment modality commonly used in this setting. Because of its high osmolarity, use has historically been limited primarily to central venous line administration as an intermittent infusion due to concerns about thrombophlebitis, injection site pain, and tissue necrosis or injury with extravasation. The objective of this analysis was to prospectively evaluate the safety of administration of 23.4% NaCl as a rapid intravenous push over 2-5 min. METHODS: A prospective analysis of patients admitted between April 2021 and December 2021 who received 23.4% NaCl intravenous push over 2-5 min in a central or peripheral line was performed. Safety end points included incidence of new onset hypotension [defined as systolic blood pressure (SBP) < 90 mm Hg or SBP decrease of at least 20 mm Hg], bradycardia (defined as heart rate < 50 beats per minute), and infusion site reactions documented within 1 h of administration. For secondary safety outcomes, highest and lowest SBP and lowest heart rates documented within 1 h before 23.4% NaCl administration were compared with values collected within 1 h post administration and evaluated by mixed-design analysis of variance test with adjustment for peripheral versus central line administration. RESULTS: We identified 32 patients who received 79 administrations of 23.4% NaCl through a central line or peripheral line during the study period. An SBP decrease of at least 20 mm Hg was observed in 13% of patients, an SBP < 90 mm Hg occurred in 16% of patients, and bradycardia occurred in 3% of patients who received 23.4% NaCl. Injection site pain was reported by one patient without documented thrombophlebitis, cellulitis, or tissue damage. Pain was not reported during two subsequent administrations in the same patient. There was no documented occurrence of soft tissue injury or necrosis in any patient. Compared with baseline vital signs before 23.4% NaCl administration, no difference in vital signs post administration was observed. CONCLUSIONS: Central and peripheral administration of 23.4% NaCl over 2-5 min was well tolerated, and incidence of hypotension, bradycardia, or infusion site-related adverse events was rare.

Odontogenic Lemierre's syndrome with septic superior ophthalmic vein and cavernous sinus thrombophlebitis complicated by blindness and ophthalmoplegia.

Lemierre's syndrome is a triad consisting of oropharyngeal infection, internal jugular vein thrombophlebitis, and systemic embolisation typically involving lung and brain. Orbital involvement in this life-threatening condition is rare but potentially blinding and may be an indicator of intracranial involvement. We describe a case of odontogenic Lemierre's syndrome complicated by extensive orbital and intracranial septic venous thrombosis, with optic and cranial neuropathy resulting in monocular blindness and ophthalmoplegia. A multidisciplinary approach with abscess drainage, antibiotic and antithrombotic therapy, and close radiological monitoring was critical for preserving contralateral vision and neurological function.

PROMETHAZINE-INDUCED THROMBOPHLEBITIS IN A NIGERIAN MAN: A CASE REPORT.

Introduction: Promethazine is a phenothiazine derivative that possesses antihistamine, anti-dopaminergic and anticholinergic properties. It is commonly used to treat motion sickness, allergic conditions, nausea and vomiting, in addition to its use as a sedative. Promethazine has vesicant properties and is highly caustic to the intima of blood vessels and surrounding tissues. Intravenous administration may result in thrombophlebitis, unintentional intra-arterial administration, perivascular extravasation and tissue necrosis. To the best of our knowledge there is no previous published report of promethazine-induced thrombophlebitis from sub- Saharan Africa. Case Report: A 29-year-old Nigerian male was admitted at our hospital on account of malaria with acute gastroenteritis. Due to persistent vomiting, he was administered 25 mg of promethazine injection via a size 22G intravenous cannula which was inserted the previous day on the anteromedial aspect of his right forearm and maintained with continuous intravenous crystalloid infusion. Upon administration of promethazine, he experienced intense burning and erythema. The cannula was removed immediately, another cannula was inserted on the contralateral arm, and promethazine was replaced with ondansetron. Subsequently, he developed a tender, subcutaneous cord-like swelling extending from the middle-third of the anteromedial aspect of his right forearm, corresponding with the site of previous venous cannulation. Ultrasonography revealed a hypoechoic, non-compressible basilic vein, with no flow on colour Doppler interrogation, in keeping with superficial thrombophlebitis. He was treated with a topical anti-inflammatory agent, and the pain and redness subsided after four weeks. Conclusion: The preferred parenteral route of administration of promethazine is deep intramuscular injection. Recommendations to prevent promethazine-induced thrombophlebitis include: use of large and patent veins, use of lower doses, drug dilution and slow administration, use of alternative therapies, and patient education. Promethazine-induced tissue injury is under-reported in this part of the world. Creating awareness through this case report would help reduce the morbidity following promethazine administration.

[Iliopsoas muscle hematoma after anticoagulant therapy for pyogenic thrombophlebitis that spilled over from ascending colon diverticulitis:a case report].

A 79-year-old male patient presented to our hospital with chief complaints of fever, abdominal pain, and jaundice. Laboratory data revealed marked hepatobiliary enzyme and inflammatory marker elevations, and computed tomography revealed ascending colon diverticulitis, thrombophlebitis, portal vein thrombus, and intrahepatic cholangitis. Blood culture revealed the presence of Prevotella sp. The patient was treated with anticoagulant therapy in addition to antimicrobial therapy;however, activated partial thromboplastin time prolongation remained insufficient. Antithrombin therapy was combined with the current therapy because antithrombin levels were low, which resulted in iliopsoas muscle hematoma. The hematoma resolved conservatively after discontinuing anticoagulation, and the patient was discharged after 19 days of hospitalization with improved cholangitis and diverticulitis. The portal vein thrombus remained after discharge;however, anticoagulation therapy was not restarted due to adverse events. This case was presented because of its difficult treatment.

Infected deep vein thrombophlebitis in people who inject drugs: missed opportunities and potential for alternative antimicrobial approaches.

Infected deep vein thrombophlebitis (i-DVT) in people who inject drugs (PWID) is a clinically challenging but poorly characterised disease. We undertook a retrospective observational study of 70 PWID presenting acutely with i-DVT to improve the clinical and microbiological characterisation of this disease. i-DVT was frequently associated with bacteraemia (59.1% patients with blood cultures obtained), groin abscesses (in 34.3%; of which 54.2% required surgical drainage), and septic pulmonary emboli (38.6%) requiring anticoagulation. Network analysis identified a cluster of patients presenting with respiratory symptoms but lacking typical DVT symptoms, more likely to have septic pulmonary emboli. A microbiologic diagnosis was frequently achieved (70%). Causative pathogens were predominantly gram-positive (S. aureus and streptococci, especially anginosus group), whereas gram-negative pathogens were identified very infrequently (in 6.1% of microbiological diagnoses). This suggests routine empiric therapy against gram-negative bacteria, though commonly administered, is not required. High rates of clinical cure (88.6%) were observed despite the complex nature of infections and independently of the highly variable intravenous and total antimicrobial durations received. There exists a rationale to devise pragmatic approaches to implement novel individualised treatment plans utilising oral antimicrobial therapy for i-DVT. Despite frequent healthcare interactions, opportunities to address HCV treatment and opioid substitution therapy were frequently missed during these acute admissions.

Postpartum septic pelvic thrombophlebitis and ovarian vein thrombosis after caesarean section: a rare case report.

BACKGROUND: Septic pelvic thrombophlebitis (SPT) is a well-recognized but rare puerperal complication that has two types: ovarian vein thrombophlebitis (OVT) and deep septic pelvic thrombophlebitis (DSPT). The present case report describes the clinical and imaging findings of a female patient diagnosed with right ovarian vein infectious thrombophlebitis after caesarean section (C-section). CASE PRESENTATION: A 35-year-old G3P2 female who presented with a foetal vein Galen malformation at 41 weeks of gestation underwent C-section. The patient had high fever after C-section, and anti-inflammatory treatment was not effective within 1 week. An abdominal wall incision haematoma was found, and a second surgery for the removal of the abdominal wall haematoma was performed. The patient was ultimately diagnosed with abdominal incision haematoma and right ovarian vein infectious thrombophlebitis after C-section. We used imipenem and tigecycline to strengthen the anti-inflammatory effects, simultaneously administrating low-molecular-weight heparin and warfarin as anticoagulant therapy. On the 30th day after C-section, the right ovarian vein thrombus disappeared. CONCLUSION: This case illustrates the need to consider the potential relationship between abdominal incision haematoma and ovarian vein thrombophlebitis. Despite advances in the management of venous thromboembolism globally, more data on epidemiology in terms of first incidence, prevalence, recurrence and risk factors, management of bleeding complications, and increased awareness in Asian populations are necessary.

Phlegmasia Cerulea Dolens in the Upper Extremity: A Case Report and Literature Review.

Phlegmasia cerulea dolens (PCD) is a rare condition characterized by deep venous thrombosis with gangrene. It can result in critically severe edema that affects the blood supply to the limbs. PCD generally occurs in the lower rather than upper extremity. We herein present a case report of upper extremity PCD and discuss thrombophilia secondary to low protein S activity as the main cause. Catheter-directed thrombolysis via the occluded end of the artery may be one of the best treatment methods for PCD.

Lemierre's Syndrome: Case Presentation of a Rare and Possibly Life-Threatening Condition.

Lemierre's syndrome is, presently, a very rare condition, but a life-threatening one. The syndrome was first described in 1936 by Andre Lemierre and comprises an oropharyngeal infection (most commonly associated with anaerobic bacteria Fusobacterium necrophorum), internal jugular vein thrombophlebitis and, possibly, secondary septic metastasis (common sites are lungs or brain). We describe such a rare case diagnosed at our Infectious Diseases Department in September 2019.

DEEP SEPTIC PELVIC THROMBOPHLEBITIS - A LIFE-THREATENING CONDITION IN POSTPARTUM PERIOD.

Deep septic pelvic thrombophlebitis is a rare but potentially devastating complication in the puerperium. Early diagnosis and aggressive treatment of this postpartum complication is essential. We report a case of a 23-year-old multipara, who presented with persistent high fever and abdominal pain two days after delivery. Diagnosis of deep septic pelvic thrombophlebitis was suspected and confirmed by using contrast-enhanced computerized tomography. Upon admission in the intensive care unit, she developed shortness of breath together with hypoxemia, which was attributed to septic pulmonary emboli. Streptococcus pyogenes group A was cultured from cervical swab. Treatment consisted of broad spectrum antibiotic therapy and low molecular weight heparin. She was dismissed for home care symptom-free fourteen days after delivery and referred to hematologist to diagnose the possible causes of thrombophilia.

Management and outcomes of pediatric septic thrombophlebitis: a case series.

Septic thrombophlebitis is a potentially life-threatening condition. Pediatric hematologists are often consulted to provide recommendations regarding anticoagulation management. We conducted a ten-year retrospective, single-center study of hospitalized pediatric patients who were treated for septic thrombophlebitis. Our primary outcome was resolution of thrombophlebitis. Twenty-eight patients were included in the study. Eighty-nine percent of patients received both antibiotic and anticoagulation therapy. The median durations of intravenous and total antibiotic therapy were 47.5 days (range 14-120) and 65 days (range 14-281), respectively, and median duration of anticoagulation therapy was 92 days (range 41-268). Resolution of thrombosis defined by magnetic resonance imaging, computed tomography, or ultrasound imaging was documented in 16 of 28 (57%) patients. Despite the high rate of persistent thrombosis, there was a low risk of relapse of infection in cases where antibiotic and/or anticoagulation was discontinued prior to complete resolution of the thrombus. Further research is needed to determine if duration of antibiotic and/or anticoagulation treatment can be shortened.

Pulmonary embolism caused by postpartum ovarian vein thrombophlebitis after vaginal delivery: Case report and brief review of the literature.

Puerperal ovarian vein thrombophlebitis is a rare pathology. We present the case of a 23-year-old female who presented with fever and cough that occurred after vaginal delivery and persisted after several courses of antibiotics between the 2nd and 20th day postpartum. CT pulmonary angiography revealed right subsegmental pulmonary embolism. An abdominal ultrasonographic examination led to the diagnosis of ovarian vein thrombosis. She was treated with warfarin for 2 weeks with a good response. Our case highlights the importance of prompt ultrasonographic diagnosis and clinical treatment of ovarian vein thrombosis to prevent morbidity and mortality.

Lemierre's Syndrome: An Atypical Presentation.

Septic thrombophlebitis is a rare diagnosis in this era of widespread antibiotic usage. The clinical diagnosis requires astute clinical suspicion and evaluation. We describe an asplenic 63-year-old woman who presented to the emergency department with a 24-hour history of a tender, swollen, right neck and upper chest wall. She denied any recent illnesses, but two years before, she was hospitalized and treated for Streptococcus pneumoniae meningitis and endocarditis. An enhanced computed tomography scan demonstrated inflammatory changes around a thrombosed right internal jugular vein, which extended to the brachiocephalic/superior vena cava junction. A retropharyngeal effusion was present, but no pulmonary or oropharyngeal abscess was identified. Lemierre's syndrome, although rare, must be recognized promptly to reduce morbidity and mortality associated with this condition.

Thrombolysis for Management of Phlegmasia Cerulea Dolens in the First Trimester of Pregnancy.

BACKGROUND: Pregnancy is a hypercoagulable state associated with a fivefold increase in the risk of venous thromboembolism. Thrombolysis is the preferred level of care for patients with acute iliofemoral deep vein thrombosis (DVT); however, most studies exclude pregnant patients, highlighting the lack of data regarding the efficacy and safety of thrombolytic therapy for mother and fetus. METHODS: We describe the successful use of thrombolytic therapy in conjunction with ultrasound to remove a large ileofemoral DVT in a first-trimester patient with phlegmasia cerulea dolens. The procedure was performed safely for both mother and fetus. RESULTS: No radiation or contrast dye was used, and intravascular ultrasound confirmed patency of the entirety of the venous system. She delivered a healthy term baby after the procedure and had no further sequalae. CONCLUSION: Thrombolysis with intravascular ultrasound may be considered in first-trimester pregnant patients with threatened limb due to DVT.

Septic superficial thrombophlebitis in Klippel-Trenaunay syndrome.

This is a rare case of a young patient with Klippel-Trenaunay syndrome that presented with extensive septic superficial thrombophlebitis of the lower extremity. Treatment included intravenous antibiotics based on cultures, anticoagulant therapy as well as surgical removal of thrombi.

A challenging case of carbapenemase-producing Klebsiella pneumoniae septic thrombophlebitis and right mural endocarditis successfully treated with ceftazidime/avibactam.

INTRODUCTION: The emergence of carbapenemase-producing Klebsiella pneumonia (KPC-Kp) has become a significant problem in terms of public health and clinical outcome in many hospitals in Southern Europe. Treatment options are usually limited and effective treatment of infections caused by these pathogens is a considerable challenge for clinicians. Ceftazidime-avibactam has been recently approved for the treatment of difficult-to-treat infections due to aerobic Gram-negative organisms in patients with limited treatment options. CASE REPORT: We reported the first case of KPC-Kp septic thrombophlebitis and right atrial endocarditis associated with metastatic lung abscesses successfully treated with a prolonged ceftazidime/avibactam plus ertapenem treatment course, suggesting that this combination therapy could be safe and effective for serious Gram-negative infections. Interestingly, we also observed an apparent discrepancy between clinical and microbiological courses: the patient became rapidly afebrile; hemodynamically stable and his procalcitonin levels showed a prompt decreasing trend. Nevertheless, blood cultures remained persistently positive for a prolonged period. CONCLUSION: In conclusion, ceftazidime-avibactam plus ertapenem was a safe and effective therapy of serious endovascular infection due to KPC-Kp. Moreover, in this setting, follow-up blood cultures might represent an irreplaceable tool to guide the therapy.

Treatment for superficial thrombophlebitis of the leg.

BACKGROUND: The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the third update of a review first published in 2007. OBJECTIVES: To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (March 2017), CENTRAL (2017, Issue 2), and trials registries (March 2017). We handsearched the reference lists of relevant papers and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included people with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in a superficial vein. DATA COLLECTION AND ANALYSIS: Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo-controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low-quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects. AUTHORS' CONCLUSIONS: Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.