|Year : 2021 | Volume
| Issue : 2 | Page : 175-178
Chronic non-healing lower-extremity ulcer in a 55-year-old male
Aarthi Rajkumar1, Jesse Dion2
1 Department of Internal Medicine, Canton Medical Education Foundation, Canton; Department of Internal Medicine, North East Ohio Medical University, Rootstown, Ohio, USA
2 Department of Internal Medicine, Canton Medical Education Foundation, Canton, USA
|Date of Submission||05-Jun-2020|
|Date of Decision||30-Jun-2020|
|Date of Acceptance||23-Jan-2021|
|Date of Web Publication||04-Jun-2021|
Dr. Aarthi Rajkumar
Canton Medical Education Foundation, 2600, 6th Street SW, Canton 44710, Ohio
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Rajkumar A, Dion J. Chronic non-healing lower-extremity ulcer in a 55-year-old male. J Med Evid 2021;2:175-8
| Medicine|| |
A 55-year-old male presented to the hospital for the first time for painful ulcers in his right lower extremity. He showed himself in the emergency department where he underwent local wound debridement and was discharged with a 7-day course of Bactrim and Keflex and was asked to follow-up with his primary care doctor and wound clinic.
Six months after this, he presented again to another hospital with wounds in the same spot. This time, he was admitted on account of purulence and malodorous discharge and concern for ongoing cellulitis and deeper soft-tissue involvement. During that admission, he underwent imaging studies which did not show any necrotising fasciitis or underlying osteomyelitis. He was treated with broad-spectrum antimicrobials including vancomycin and piperacillin–tazobactam. Wound and plastic surgical services were consulted, and vascular studies were planned to investigate his lower-extremity wounds; however, the patient left the hospital against medical advice on day 3 of his hospital stay.
This time, he again presented with multiple painful non-healing ulcers in his right leg of 2-month duration. He stated that he had used over the counter topical antibiotics and also treated himself with oral antibiotics that were prescribed to him last year for similar problems.
On physical examination, the patient was cachectic with poor hygiene. Vitals signs were normal. Cardiorespiratory and abdominal examination showed no abnormalities. A stage III, 7 cm × 6 cm ulcer was seen on his right anterior tibia, [Figure 1]a with two smaller ulcers each measuring around 2 cm × 2 cm close by. The larger ulcer was covered with yellow–brown slough and the margins were necrotic with erythematous borders. The smaller ulcers were shallow and had irregular borders with an erythematous base covered with minimal purulence and adjacent skin showed cellulitis. Additional skin lesions were noted on the right forearm [Figure 1]b left axilla [Figure 1]c and left ear [Figure 1]d which had appeared in the past week and were also described as painful and non-itchy. Pedal pulses were intact and there was no evidence of venous stasis.
|Figure 1: Non-healing wound on right lower extremity (a), retiform lesion on right upper arm (b), lesions on left axilla (c) and left ear lobe (d)|
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Laboratory investigation showed a white blood cell count of 3400 cells/mm3 with an absolute neutrophil count of 1300 cells/mm3. Aminoaspartate transferase was 179 U/l and amino alanine transferase was 252 U/l, the rest of the metabolic panel and complete blood count was normal.
Medical history was significant for untreated hepatitis C and family history of diabetes. The patient was also a chronic smoker and smoked about a pack of cigarettes a day for more than 30 years. He was a truck driver by profession and had multiple sexual partners. He also admitted to intravenous drug use as a teenager but has not used any intravenous drugs since. He did admit to using crack cocaine occasionally.
Initial cultures from the wound had Gram-positive cocci in clusters and so he was covered with vancomycin and piperacillin–tazobactam. X-ray of the right tibia was done and additional testing was sent out in light of his medical history. Arterial and venous Doppler studies were also done.
X-ray of the right tibia showed no periosteal reaction or signs of acute osteomyelitis. Arterial Doppler studies showed normal ankle-brachial index (ABI) and there was no evidence of venous insufficiency.
Additional laboratories include an HIV screen which was negative, hepatitis C was positive and viral load was pending. Syphilis was negative. Urine analysis did not show any proteinuria; however, urine toxicology screen was positive for cocaine. Cryoglobulin was elevated at 182 uG/mL, and antinuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA) and complement levels were normal. A punch biopsy of the lesion was done on hospital day number 6 and a diagnosis was made.
| Differential Diagnosis of Chronic Lower-Extremity Wound|| |
Chronic lower limb ulcer is a wound of the leg that has been present for over 6 weeks and has not healed after 3 months of appropriate treatment.
The patient is a 55-year-old male with 30 pack-year smoking history, untreated hepatitis C and cocaine use who presents with recurrent chronic non-healing lower-extremity ulcer.
There are several causes of chronic lower-extremity wounds with venous and arterial insufficiency constituting over 80% of all causes of non-healing ulcers. The rest include neuropathic, infections, vasculitis, malignancy and haematological disorders.
Chronic venous ulcers
Venous insufficiency is the most common cause of lower-leg ulcers worldwide. Risk factors for venous ulcers include old age, obesity, prior leg injuries, deep-venous thrombosis and phlebitis. The ulcers are usually located over the medial malleolus/medial aspect of the legs in the region between the calf and ankle. Venous valve incompetence leading to retrograde blood flow, stasis and venous hypertension is thought to contribute to microvascular damage, release of cytokines and inflammatory mediators which result in tissue hypoxia and injury perpetuating a vicious cycle causing non-healing ulcers. The ulcers are typically shallow with flat undermined edges and base covered with granulation tissue and moderate-to-heavy fibro purulent slough. The adjacent skin shows features of hyperaemia, chronic stasis, lymphedema with varicose veins and haemosiderin-laden pigments. Our patient lacked any features of chronic long-standing venous stasis, and hence, this diagnosis was excluded.
Arterial leg ulcers occur as a result of reduced arterial blood flow and subsequent tissue hypoperfusion leading to ulceration. Peripheral arterial disease (PAD) due to atherosclerosis, diabetes with microvascular or macrovascular disease and/or vasculitis could contribute to arterial insufficiency. In addition, vasoconstrictors like cocaine could also worsen limb perfusion. Arterial ulceration typically occurs over the toes, heels and bony prominences of the foot. The ulcer has a typical 'punched out' appearance with sharp well-demarcated edges and a pale, non-granulating and necrotic base. Pedal pulses are usually feeble; the limb appears cold with the absence of hair. The patient presented here has a long-standing history of tobacco use which can cause thromboangiitis obliterans/Berger's disease and also PAD, however, his arterial Doppler showed normal ABI which excludes this diagnosis. Cocaine use can lead to transient vasoconstriction but would not account for the degree of wounds he presented with.
These usually occur on the plantar aspect of feet in patients with diabetes, peripheral sensory neuropathy arising from infections like leprosy of from other systemic diseases such as amyloidosis or sarcoidosis. The location of ulcers in our patient makes this diagnosis less likely.
Cryoglobulinaemia can cause leucocytoclastic vasculitis (LCV). Systemic lupus erythematosus, rheumatoid arthritis and polyarteritis nodosa also have to be entertained. Cutaneous lesions in LCV classically present with tiny purpuric papules predominately on the lower extremities and other dependent areas. Sometimes, these lesions become indurated, necrotic and occasionally confluent and ecchymotic with adjacent cellulitis-associated oedema of the affected limb. Vesicles, pustules and urticarial papules are sometimes seen, but larger haemorrhagic bullae, subcutaneous nodules and livedo reticularis are less common and should raise suspicion of vasculitis involving medium-sized vessels. He did have increased cryoglobulin levels but other vasculitis work up was negative including ANA and ANCA. Skin lesions were also no very typical of those seen in cryoglobulinemic vasculitis.
Chronic infections caused by Mycobacterium tuberculosis or Mycobacterium leprae and also atypical mycobacterium infections caused by Mycobacterium ulcerans, Mycobacterium marinium, Mycobacterium fortuitum and Mycobacterium chelonei have to be considered. The patient does not reside in an area where M. tuberculosis is common; however, non-mycobacterium tuberculosis (NTB) infections can certainly cause non-healing recurrent ulcers. These organisms are known to be present ubiquitously in water sources and are transmitted via direct inoculation through skin barriers. They have widespread clinical manifestations and range from cellulitis to papular lesions to nodules abscesses and chronic ulcers. Diagnosis is usually by the demonstration of acid-fast bacilli in tissue biopsies.
Any chronic long-standing wound should raise concern for cutaneous malignancies such as squamous cell carcinoma and basal cell carcinoma. The appearance of malignant ulcers is characteristic and they usually have a heaped up margin or rolled over margin
Sickle cell disease with vaso-occlusive crisis can lead to chronic tissue hypoxia and skin break downs increasing susceptibility to chronic wounds and poor healing
This is an inflammatory, non-infectious, ulcerative skin disorder characterised by rapidly enlarging, painful lesions. It is known to be associated with a number of systemic diseases, inflammatory bowel disease – ulcerative colitis – being the most common one. Others include myeloproliferative diseases, chronic active hepatitis, rheumatoid arthritis and habitual cocaine use. Pyoderma gangrenosum usually starts innocuously at a site of injury, often at the site of a minor injury as a small pustule or a blood blister and then progresses rapidly into a wide painful ulcer with a characteristic purple undermined margin. It is usually a diagnosis of exclusion and biopsy often shows neutrophilic infiltration at ulcer edge.
| Pathology|| |
A punch biopsy was taken from the right lower-extremity wound. It showed skin and subcutaneous tissue and an area of ulceration with acute and chronic inflammation. There was severe dermal necrosis, vascular fibrin thrombi with karyorrhexis and subcutaneous fat necrosis [Figure 2]. Fungal and acid-fast stain did not show any organisms and direct immunofluorescence (DIF) testing was also negative
|Figure 2: Skin lesion showing microvascular fibrin thrombi and karyorrhexis suggesting leucocytoclastic vasculitis (H and E, ×400)|
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The above features represent a leucocytoclastic vasculitis. In a patient with increased cryoglobulins, this may represent cryoglobulinaemic vasculitis. Keeping in mind that the patient is a cocaine user, the possibility of levamisole-induced vasculitis is also to be considered. There have been increasing case reports of an ANCA-associated vasculitis in a patient who abuse cocaine. It would be worthwhile to check a levamisole level if possible, on this patient. Also knowing if he regularly uses cocaine would also help determine any association with regular cocaine use and the chronology of the wounds.
| Hospital Course|| |
After the biopsy results were obtained, the patient was asked about his cocaine use. He admitted to using it on a daily basis for the past year and a half. His last use was the day before this hospitalisation. Antibiotics were stopped and plastic surgery consult was sought. They recommended rigorous wound care with the application of sterile dressing soaked with Dakin solution, complete abstinence from cocaine and follow-up once wounds have healed for skin grafting. His hepatitis viral load also came back as 125,000 IU/L and he was noted to have genotype 1a. Ultrasound of the liver did not show an evidence of cirrhosis and he was also given a referral to follow-up with gastroenterology to start treatment for hepatitis C.
He was discharged from the hospital with instructions to follow up with wound care and plastic surgery and strictly asked not to use cocaine. A follow-up phone call with the patient 1-month post-hospital discharge for an update on his condition confirmed that he has been following up at the wound clinic, had not used cocaine since discharge and is noticing significant improvement of his lesions. During his most recent follow-up at wound care clinic, his right leg wound was noticeably smaller. wounds from the rest of his body resolved. He was also to be started on ledipasvir/sofosbuvir (Harvoni) for hepatitis C infection.
| Discussion of Pathology|| |
Levamisole is a veterinary deworming agent which has been linked to rising cases of vasculitis among cocaine users. It was initially introduced to treat helminthic infections in humans, and because of its immunomodulatory effects, it was used for many conditions including rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis and even as an adjunct therapy for cancer. However, adverse reactions were noted including reports of skin rash in patients receiving levamisole for colon cancer and rheumatoid arthritis and biopsy of these lesions showed leucocytoclastic vasculitis. Other adverse reactions such as agranulocytosis, thrombocytopenia and arthritis were also reported. Due to these side effects and availability of alternative medications, levamisole was withdrawn from human use in 1999 and since then has been restricted solely to veterinary medicine. After levamisole was banned from human use, it started to be utilised as a cutting agent in cocaine as it was indistinguishable from cocaine and also provided an additional rush prolonging the effect of cocaine. Effects similar to the ones observed with therapeutic use of levamisole started to emerge and a review of published studies shows several documented reports of levamisole-induced vasculitis (LIV). Despite the widespread use of cocaine that is adulterated with levamisole, this condition remains underdiagnosed. It is important for clinicians to consider LIV in cases of non-healing ulcers, especially among those with a history of cocaine use.
LIV is characterised by a reticular purpura predominantly involving the face, ears and nose, arthralgia, agranulocytosis and cutaneous necrosis. The underlying pathology is thought to be related to a drug-induced vasculitis. Most cases of LIV are associated with production of autoantibodies such as pANCA, ANA and lupus anticoagulant. It is believed that levamisole may interact with a collection of deoxyribonucleic acid, histones and neutrophil granules called neutrophil extracellular traps (NETs) increasing the antigenicity of NETs and thereby provoking an exaggerated immune response. There have also been case reports of LIV without any underlying autoantibodies and the mechanism of vasculitis in these instances remains elusive. Agranulocytosis occurs from electrophilic reactive metabolites of levamisole which act as a hapten and generates immune reaction causing leucopenia. Individuals with HLA B27 genotype are particularly susceptible to this complication. Bacterial superinfection is common due to an immunosuppressed state from leucopenia as well as poor wound care.
Testing for levamisole levels is not routinely recommended due to the extremely short half-life of the drug, although gas chromatographic techniques can detect levels up to 48 h in various human tissues. Skin biopsy characteristically shows leucocytoclastic vasculitis with the presence of microvascular fibrin thrombi. Immune complex deposits and fibrin may also be noted on DIF.
| Discussion of Treatment|| |
The treatment of chronic non-healing ulcers requires a multimodal approach. A thorough history especially occupation, smoking, illicit drug use, past and current medical details of relevant diseases including diabetes, autoimmune and connective tissue disorders, inflammatory bowel disease, PAD, past history of varicose veins and deep-vein thrombosis is very crucial. A detailed examination with specific attention to location, size, ulcer margin, base and any associated skin conditions is important. In long-standing non-ulcers, it is always prudent to obtain a skin biopsy to look for any occult malignancies or vasculitis.
Once underlying aetiology is determined, the focus should be on clearing any superficial infection, treating underlying precipitating factors and adherence to diligent skin and wound care. Smoking cessation and abstinence from drugs is also the key.
Wound care and plastic surgery should be involved early to assist with ongoing care and plan for skin grafting at appropriate time.
| Case Conclusion|| |
For a few weeks after diagnosis was made, the patient diligently followed up with a specialist and started treatment with Harvoni and attained a sustained virologic remission. Skin grafting was planned; however, he was lost to follow-up. He once again presented after 8 months with similar wounds and admitted to cocaine use again. This time, he was treated with antibiotics and after a minimal improvement, he left the hospital again.
Final diagnosis: Levamisole-induced vasculitis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
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Jacob RS, Silva CY, Powers JG, Schieke SM, Mendese G, Burlingame RW, et al
. Levamisole-induced vasculopathy: A report of 2 cases and a novel histopathologic finding. Am J Dermatopathol 2012;34:208-13.
[Figure 1], [Figure 2]