Medicine II Infectious Diseases BGD 1 Subsection B1 1

E.M. –42 years old, female, single –Filipino, Roman Catholic –San Pablo City, Laguna –Date of admission: 11/18/09 –Informant: patient –Reliability: 85% E.M. –42 years old, female, single –Filipino, Roman Catholic –San Pablo City, Laguna –Date of admission: 11/18/09 –Informant: patient –Reliability: 85% 2

Chief Complaint: non-healing ulcer on the left leg 3

4 History of Present Illness Pain, swelling over the area of the right Achilles tendon Consult: San Pablo Medical Center Ancillary: X-ray of the right leg – normal Management: unrecalled patch medications which provided relief of the pain, but persistence of the swelling

5 History of Present Illness persistence of the swelling Consult to a “manghihilot” Massage therapy was done undocumented fever temporarily relieved by intake of Paracetamol 500mg tab History of Present Illness

persistence of the swelling and fever Confined at San Pablo Medical Center Assessment: abscess of the right foot Patient was given unrecalled antibiotics. Discharged with cast applied over the right leg 6 History of Present Illness

After 7 days, patient noted heaviness of the right leg with pus dripping from the cast Consult - Removal of the cast Multiple ulcers on the right leg Wound debridement was done. Increase depth of the ulcer, skin graft from right thigh was harvested and was place over the area Wound had good coaptation and was completely healed 7 History of Present Illness

patient noted appearance of the same lesions over the of the wound Consult: Philippine General Hospital Biopsy: TB of the skin Medications: Anti-TB for 6 months After the therapy, the wound was noted to be completely healed. 3 1/2 years PTA 8 History of Present Illness

patient noted recurrence Consult: RITM Assessment: TB of the skin Advised transfer to another hospital San Pablo Medical Center Above the knee amputation of the right leg with skin graft from the left thigh was done. 2 1/2 years PTA 9 History of Present Illness

10 History of Present Illness New ulcer was noted on the medial aspect and dorsum of the left leg and right forearm Advised cleansing with bleach Healing of the wound with granulation tissue. 2 years PTA History of Present Illness

11 History of Present Illness Painful nodules on the anterior aspect of the left leg  erythematous patch  several moist ulcers over the dorsum and medial aspect of the left leg Cleanse with bleach and would heal with granulation tissue. Consult: PGH Ancillary: Venous duplex scan was requested – normal results Assessment: not disclosed. 1 1/2 months PTA History of Present Illness

12 History of Present Illness Recurrence of several painful nodules grade 8/10 on the anterior leg  erythematous patch  ulcers that coalesce with necrotic tissues and oozing with blood eventually affecting the posterior aspect of the left leg. self-medicated with Tramadol, Biogesic and Diclofenac which provided temporary relief of the pain 18 days PTA History of Present Illness

13 History of Present Illness rapid increase in size of the wound increase in the severity of the pain now grade 10/10 ADMISSIONADMISSION 3 days PTA History of Present Illness

14 Review of Systems General: (-) weight loss (-) fever, (-) excessive sweating, (-) weakness, (-) easy fatigability, (-) insomnia Skin: (-) itchiness, no photosensitivity, (-) hair changes Eyes: (-) blurring of vision, (-) itchiness, (-) pain Ear: (-) deafness, (-) discharge, (-) tinnitus Nose: (-) epistaxis, (-) colds, (-) discharge Throat: (-) soreness, (-) tonsillitis Mouth: (-) sores, (-) fissures, (-) bleeding gums Neck: (-) stiffness, (-) limitation of movement, (-) masses Vascular: (-) intermittent claudication

15 Pulmonary: (-)dyspnea, (-) no cough, (-) hemoptysis Cardiac: (-) chest pains,(-) palpitations, (-) PND, Gastrointestinal: (-) diarrhea, (-) constipation (-) change in bowel movements Genitourinary: (-) frequency, (-) flank pain, (-) gross hematuria Muscular: (-) joint swelling, (-) bone pains Endocrine: (-) nocturia, (-) polydipsia, (-) polyphagia, (-) polyuria (-) paresthesia, (-) heat-cold intolerance Hematopoetic: (-) abnormal bleeding (-) easy bruisibility Neurologic: (-) seizures Psychiatric: (-) anxiety, (-) depression, (-) interpersonal relationship difficulties Review of Systems

16 (+) Blood transfusion, number of units unrecalled when the patient underwent above the knee amputation (2007) (-) Hypertension (-) allergies (-) asthma (-) thyroid diseases (-) DM (-) skin disease Past Medical History

17 nulligravid OB History

18 M- 13 years old I days D- 3 days A-2 ppd moderately soaked S- dysmenorrhea Day 1 Menstrual History

19 the patient denies any sexual contact Sexual History

20 Non-smoker Non-alcoholic beverage drinker No diet preferences Personal & Social History

21 (+) CVD mother, died at 76 years old (+) sibling MI (-) skin disease (-) DM (-) asthma (-) allergies (-) thyroid diseases (-) autoimmune disorders Family History

22 Physical Examination Physical Examination Conscious, coherent, ill-looking, wheel chair borne not in cardiorespiratory distress BP: 120/80mmHg on both upper extremities and left lower extremity, PR 100 bpm, full, regular, RR 20 cpm, regular, T=37.0°C Wt 120lbs (54.54 kg) Ht 5’2 (157.48cm) BMI 22

23 (+) well defined ulcer on the entire left leg with purplish irregular border topped with bleeding necrotic tissue with slightly violaceous plaque topped with multiple punch out ulcer some with crusts on the right forearm, dorsum and medial aspect of left foot and right AKA stump, (+) scars over the right and left thigh.

24 Pale palpebral conjunctiva, anicteric sclera Moist buccal mucosa, no oral ulcers, anicteric frenulum lingua. Neck is not rigid, thyroid gland is not enlarged, no palpable cervical lymph nodes Symmetrical chest expansion, no retractions, resonant on percussion, no crackles, clear breath sounds unimpaired vocal and tactile fremitii Physical Examination Physical Examination

25 Adynamic precordium, AB at 5 th LICS AAL, s1>s2 at the apex, s1<s2 at the base, no heaves, no lifts, no thrills, no murmurs Flabby abdomen, normoactive bowel sounds, liver span 9cm MCL, tympanitic on percussion, soft, no mass, no tenderness, no murphy’s sign Pulses full and equal, no cyanosis, no edema Physical Examination Physical Examination

Neurologic Examination Conscious, coherent, oriented to three spheres, GCS 15 Cranial Nerves: – pupils 2-3mm ERTL –(+) corneal reflex –(+) ROR, clear disc margins, no visual field cuts –EOM full and equal –V1V2V3 intact –no ptosis –can smile, can raise eye brows, can puff cheeks –gross hearing intact –uvula midline on phonation –(+) gag reflex –can shrug shoulders –turns head side to side against resistance tongue midline on protrusion Motor: MMT 5/5 on the LLE and UE Sensory: no sensory deficits DTR’s: +2 on LLE, and UE. No Babinski No nuchal rigidity 26

SALIENT FEATURES Subjective Nulligravid Non-healing rapidly progressing ulcer on the left foot Not known diabetic (-) polyuria, polyphagia, nocturia, no weight loss Non-smoker (-) changes in bowel movement (-) joint pains, (-) morning stiffness (+) above the knee amputation right lower extremity Nulligravid Non-healing rapidly progressing ulcer on the left foot Not known diabetic (-) polyuria, polyphagia, nocturia, no weight loss Non-smoker (-) changes in bowel movement (-) joint pains, (-) morning stiffness (+) above the knee amputation right lower extremity Objective 42 y/o, Female BP 120/80mmHg on both upper extremities and left extremity, PR 100 bpm, full, regular, RR 20 cpm, regular, T=37.0°C Warm dry skin, (+) well defined ulcer on the entire left leg with purplish irregular border topped with bleeding necrotic tissue with slightly violaceous plaque topped with multiple punch out ulcer some with crusts on the right forearm, dorsum and medial aspect of left foot and right AKA stump, (+) scars over the right and left thigh. Pale palpebral conjunctiva, Pulses full and equal, no cyanosis, no edema 42 y/o, Female BP 120/80mmHg on both upper extremities and left extremity, PR 100 bpm, full, regular, RR 20 cpm, regular, T=37.0°C Warm dry skin, (+) well defined ulcer on the entire left leg with purplish irregular border topped with bleeding necrotic tissue with slightly violaceous plaque topped with multiple punch out ulcer some with crusts on the right forearm, dorsum and medial aspect of left foot and right AKA stump, (+) scars over the right and left thigh. Pale palpebral conjunctiva, Pulses full and equal, no cyanosis, no edema 27

28 AssessmentAssessment

Differential Diagnosis 29

Cutaneous Tuberculosis

- extrapulmonary manifestation of TB - caused by: Mycobacterium Tuberculosis Mycobacterium Bovis - its development requires a degree of immunity impairment of the host Cutaneous Tuberculosis: Diagnosis and TreatmentAm J Clin Dermatol 2002; 3 (5): /02/ /$25.00/0

Cutaneous Tuberculosis Morphological Manifestations Granulomatous inflammation Variable necrosis Variable vasculitis Demonstration of M. tuberculosis via: 1. Culture 2.Staining 3.PCR Cutaneous Tuberculosis: Diagnosis and TreatmentAm J Clin Dermatol 2002; 3 (5): /02/ /$25.00/0

Cutaneous Tuberculosis Classification Tuberculous Chancre Tuberculosis Verrucosa Cutis Lupus Vulgaris Scrofuloderma Orificial Tuberculosis Miliary Tuberculosis Metastatic Tuberculosis Abscess Cutaneous Tuberculosis: Diagnosis and TreatmentAm J Clin Dermatol 2002; 3 (5): /02/ /$25.00/0

Cutaneous Tuberculosis Most plausible type for differential diagnosis based on course and features of the lesion: Tuberculous Chancre Lupus Vulgaris, ulcerative type Scrofuloderma Cutaneous Tuberculosis: Diagnosis and TreatmentAm J Clin Dermatol 2002; 3 (5): /02/ /$25.00/0

Cutaneous Tuberculosis Tuberculous Chancre Cutaneous Tuberculosis: Diagnosis and TreatmentAm J Clin Dermatol 2002; 3 (5): /02/ /$25.00/0

Cutaneous Tuberculosis Lupus Vulgaris Cutaneous Tuberculosis: Diagnosis and TreatmentAm J Clin Dermatol 2002; 3 (5): /02/ /$25.00/0

Cutaneous Tuberculosis Scrofuloderma Cutaneous Tuberculosis: Diagnosis and TreatmentAm J Clin Dermatol 2002; 3 (5): /02/ /$25.00/0

Cutaneous Tuberculosis But due to the presence of pain on the initiation and course of the lesion Tuberculous Chancre is ruled out. Further exclusion of Lupus Vulgaris ulcerative type and Scrofuloderma necessitates laboratory investigation.

Necrotizing fasciitis Rapidly spreading destructive disease of the fascia. Deep-seated infection of the subcutaneous tissue that progressively destroys fascia and fat but may spare the skin and muscle Usually attributable to Group A Streptococci Other etiologies: Mixed aerobe and anaerobe (Clostridium perfringens, Peptostreptococcus, Burkholderia and Bacteroides spp.) Risk factors: Surgeries, Diabetes, Peripheral vascular disease Harrison's Principles of Internal Medicine, 17th ed.

Necrotizing fasciitis 61-year-old Chinese man with a history of psoriasis and alcoholic liver cirrhosis sought treatment for left ankle swelling, erythema, and tenderness could not recall any antecedent trauma to the affected limb Febrile Progression to formation of blisters, extensive subcutaneous tissue and fascial necrosis, loss of resistance of the normally adherent superficial fascia to blunt dissection, and foul-smelling “dishwater” pus

Necrotizing fasciitis Culture: Burkholderia pseudomallei. (Endemic to Southeast Asia, Taiwan, China, Central and South America, and northern Australia) sporadic infections occur throughout the world Yi-Shi Wang, Chin-Ho Wong, and Asok Kurup. Cutaneous Melioidosis and Necrotizing Fasciitis Caused by Burkholderia pseudomallei. 2003

Necrotizing fasciitis (Group A Streptococci) A. Definite case 1. Necrosis of soft tissues with involvement of the fascia PLUS 2. Serious systemic disease, including one or more of the following: a) Death b) Shock (systolic blood pressure <90 mm of Hg). c) Disseminated intravascular coagulopathy

Necrotizing fasciitis d) Failure of organ systems a. respiratory failure b. liver failure c. renal failure 3. Isolation of group A Streptococcus from a normally sterile body site

Necrotizing fasciitis B. Suspected case and serologic confirmation of group A streptococcal infection by a 4- fold rise against: a) streptolysin O b) DNase B and histologic confirmation: Gram-positive cocci in a necrotic soft tissue infection

Usual Clinical Course 24 hours of the initial lesion— mild erythema, swelling, heat Next 24 to 48 hours-the erythema changed from red to purple and then to blue, and blisters and bullae, which contained clear yellow fluid Days 4 and 5- the purple areas became gangrenous. Day 7 to day 10- the line of demarcation became sharply defined, and the dead skin began to separate at the margins or breaks in the center, revealing an extensive necrosis of the subcutaneous tissue.

Necrotizing fasciitis More severe cases: the process advanced rapidly until several large areas of skin became gangrenous, and the intoxication rendered the patient dull, unresponsive, mentally cloudy, or even delirious. Streptococcal Toxic-Shock Syndrome:Spectrum of Disease, Pathogenesis, and New Concepts in Treatment Dennis L. Stevens, Ph.D., M.D. Emerging infectious Diseases Vol.1 No.3 July-Sept 1995

Necrotizing Fasciitis Necrosis of tissue and fascia Rapidly Progressive course Shock, DIC, Organ system Failure Isolation of causative agent in the site

Pyoderma gangrenosum

Pyoderma Gangrenosum poorly understood In 50 to 70% of the patients, PG is associated with underlying systemic diseases such as inflammatory bowel disease, myeloproliferative disorders, hematological or malignancies 49

Primary or Secondary? 50

SYSTEMIC LUPUS ERYTHEMATOSUS

Table Diagnostic Criteria for Systemic Lupus Erythematosus Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis (nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion) Serositis (pleuritis or pericarditis) Renal disorder (proteinuria >0.5 g/d or > or = 3+, or cellular casts) Neurologic disorder (seizures or psychosis without other causes) Hematologic disorder (hemolytic anemia or leukopenia (<4000/µL) or lymphopenia (<1500/µL) or thrombocytopenia (<100,000/µL) in the absence of offending drugs) Immunologic disorder (Anti-dsDNA, anti-Sm, and/or anti-phospholipid) Antinuclear antibodies *If > or = 4 of these criteria are present at any time in a patient’s history, the diagnosis is likely to be SLE. Specificity is ~95%; sensitivity is ~ 75%. NOTE: Our patient did not have any of the above mentioned signs and symptoms; therefore, not fulfilling the diagnostic criteria for SLE. Braunwald et al, Harrison’s Principles of Internal Medicine, 17 th Ed., p. 2077

Cutaneous Manifestations of Lupus Erythematosus A. Acute B. Subacute C. Chronic Braunwald et al, Harrison’s Principles of Internal Medicine, 17 th Ed., pp

Acute Cutaneous LE characterized by erythema of the nose and malar eminences in a “butterfly” distribution erythema is often sudden in onset, accompanied by edema and fine scale, and correlated with systemic involvement There may be widespread involvement of the face as well as erythema and scaling of the extensor surfaces of the extremities and upper chest. *Skin biopsy of acute lesions may show sparse dermal infiltrate of mononuclear cells and dermal edema. There may be cellular infiltrates around blood vessels and hair follicles are notable (hydropic degeneration of basal cells of the epidermis). Braunwald et al, Harrison’s Principles of Internal Medicine, 17 th Ed., pp

Subacute cutaneous lupus erythematosus (SCLE) Characterized by a widespread photosensitive, nonscarring eruption may present as a papulosquamous eruption that resembles psoriasis or annular lesions that resemble those seen in erythema multiforme. The papulosquamous form are discrete erythematous papules that arise on the back, chest, shoulders, extensor surfaces of the arms, and the dorsum of the hands; lesions are uncommon on the face, flexor surfaces of the arms, and below the waist. Braunwald et al, Harrison’s Principles of Internal Medicine, 17 th Ed., pp

Subacute cutaneous lupus erythematosus (SCLE) Skin biopsy reveals a dense mononuclear cell infiltrate around hair follicles and blood vessels in the superficial dermis, combined with hydropic degeneration of basal cells in the epidermis. Braunwald et al, Harrison’s Principles of Internal Medicine, 17 th Ed., pp

Discoid lupus erythematosus (DLE) is characterized by discrete lesions, most often on the face, scalp, or external ears. The lesions are erythematous papules or plaques with a thick, adherent scale that occludes hair follicles (follicular plugging). When the scale is removed, its underside will show small excrescences that correlate with the openings of hair follicles and is termed a “carpet tack” appearance. Biopsy of DLE lesions shows hyperkeratosis, follicular plugging, and atrophy of the epidermis; hydropic degeneration of basal keratinocytes; and a mononuclear cell infiltrate adjacent to epidermal, adnexal, and microvascular basement membranes. Braunwald et al, Harrison’s Principles of Internal Medicine, 17 th Ed., pp

Antiphospholipid syndrome

Antiphospholipid antibodies syndrome a condition that can cause clotting within your arteries or veins and various other problems, some life-threatening immune system mistakenly produces antibodies to certain proteins in your blood that normally attack body invaders, such as viruses and bacteria antiphospholipid- syndrome/DS00921

Criteria The diagnosis of APS is made in case of a clinical event (vascular thrombosis or pregnancy event) and repeated positive tests of aPL performed 12 weeks apart (repeat aPL testing is necessary due to the naturally occurring presence of transient low levels of aPL following infections). The Updated Sapporo APS Classification Criteria (1998, published in 1999) are commonly used for APS diagnosis.Based on these criteria, APS diagnosis requires: a) Vascular Thrombosis (blood clots) in any organ or tissue or Pregnancy Event (one or more miscarriages after 10th week of gestation, three or more miscarriages before 10th week of gestation, or one or more premature births before 34th week of gestation due to eclampsia) and b) Persistently (6 weeks apart) Positive aPL (lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies, or moderate-to-high titer β 2 -glycoprotein-I antibodies). The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement, Definite CAPS diagnosis requires: a) Vascular Thrombosis in three or more organs or tissues and b) Development of manifestations simultaneously or in less than a week 'and c) Evidence of small vessel thrombosis in at least one organ or tissue and d) Laboratory confirmation of the presence of aPL. Some serological tests for syphilis may be positive in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive) although the more specific tests for syphilis that use recombinant antigens will be negative. * the patient did not have any of the above mentioned, therefore she did not fulfill the criteria for the diagnosis of APS

Antiphospholipid syndromeprimary no other autoimmune disorder infectionmedication genetic predisposition secondary w/lupus or other autoimmune disorder SLE syndrome/DS00921/DSECTION=causes

the diagnosis has to be established by clinical features as histologic alterations are unspecific and characteristic serologic or hematologic markers do not exist about 40% of patients with SLE have high levels of antiphospholipid antibodies such as lupus anticoagulant (LA) and cardiolipin antibodies about half of these patients develop a secondary antiphospholipid syndrome skin manifestations such as ulcers with antiphospholipid syndrome are a well known and typical epiphenomenon

Crohn’s disease

IDIOPATHIC INFLAMMATORY BOWEL DISEASE -The illnesses in this category, which include Crohn’s disease and chronic ulcerative colitis, are among the most common organic causes of chronic diarrhea in adults and range in severity from mild to fulminant and life-threatening. They may be associated with uveitis, polyarthralgias, cholestatic liver disease (primary sclerosing cholangitis), and various skin lesions (erythema nodosum, pyoderma gangrenosum)

There are many complications that can occur with Inflammatory Bowel Disease (IBD) including arthritis, liver disease, nutritional disorders, anemia, and skin disorders. Skin disorders are a fairly common problem, and may affect up to 25 percent of people who suffer from IBD. One type of skin disorder that may occur in IBD is pyoderma gangrenosum.

Crohn’s disease Lab abnormalities: elevated ESR and CRP In more severe cases: hypoalbuminemia, anemia, and leukocytosis Endoscopic feature: rectal sparing, aphthous ulceration, fistulas, and skip lesions, continuous disease, “Cobblestoning, granuloma on biopsy Clinical: gross blood in stool, mucus, systemic symptoms, pain, abdominal mass, significant perineal disease, fistulas, small- intestine obstruction, colonic obstruction, response to antibiotics, recurrence after surgery, ANCA-positive, ASCA-positive Radiographic: small bowel significantly abnormal, abnormal terminal ileum, segmental colitis, asymmetric colitis, stricture *the patient did not have any of the signs and symptoms mentioned above and therefore does not have Crohn’s disease

Primary Pyoderma gangrenosum

Diagnosis Criteria Abela C.B., et.al. Pyoderma gangrenosum. British Journal of Oral and Maxillofacial Surgery. SW17 0QT, UK. Department of Plastic and Reconstructive Surgery, St George’s Hospital, Blackshaw Road, Tooting, London SW17 0QT, UK. 3 November 2005 ? ? ? Patient still awaiting biopsy results

Pyoderma gangrenosum Inflammatory condition of skin characterized histologically by necrosis, ulceration and vasculitis years old- most commonly affected lesions most commonly found on the lower extremities and trunk Its character is non infectious No identifiable infective pathogen, unknown cause Abela C.B., et.al. Pyoderma gangrenosum. British Journal of Oral and Maxillofacial Surgery. SW17 0QT, UK. Department of Plastic and Reconstructive Surgery, St George’s Hospital, Blackshaw Road, Tooting, London SW17 0QT, UK. 3 November 2005 Pyoderma gangrenosum: a review. A. Neil Crowson, Martin C. Mihm Jr., and Cynthia Magro, pp 98

Pyoderma gangrenosum: Classification and management. Frank C. Powell, FRCPI, W. P. Daniel Su, MD, Harold O. Perry, MD. Dublin, Ireland, and Rochester, Minnesota *Mainly involves lower extremities

Pathophysiology Involves dysregulation of immune system there may be a neutrophil dysfunction causing metabolic oscillation and abnormal transit of neutrophils Altered eosinophil chemotaxis may be involved Pyoderma gangrenosum: a challenge to the rheumatologist. Luciano Ferreira Coelho, Francine Guilherme Correia, Fernanda Assis Ottoni, Flávia Patrícia Sena Teixeira Santos, Luciana Baptista Pereira, Cristina Costa Duarte Lanna

CrowsonAN,Magro C, MihmMCJr.Py odermagangrenosum: a review. JCutan Pathol 2003; 30: 97^107.#BlackwellMunksgaard Pathophysiology Direct immunofluorescence testing supports a vasculopathy as playing a role in lesional propagation in some patients by virtue of perivascular deposition of immunoreactants, mainly IgM, C3 and fibrin ; ;

nodes or painful sterile pustules occur central ulceration develops Are deep and reach dermis and the subcutaneous tissue classic ulcer is extensive, with infiltrated borders, erythematous-violaceous, undermined, with necrotic background and granulation tissue NB:  Ulcers may be single or multiple, are more frequent in lower limbs and may be found in any other part of the body.  Almost 30% of the patients present previous trauma caused by a wound(pathergy).  Polypoid or bullous forms may rarely occur. Pyoderma gangrenosum: a challenge to the rheumatologist. Luciano Ferreira Coelho, Francine Guilherme Correia, Fernanda Assis Ottoni, Flávia Patrícia Sena Teixeira Santos, Luciana Baptista Pereira, Cristina Costa Duarte Lanna Picture taken from medscape.com

Histopathology Skin biopsies of all forms of PG show a central zone of necrotizing suppurative inflammation. ;

Histopathology “Sweet-like” vascular reaction defined by perivascular and intramural lymphocytic infiltrates with a peripheral neutrophilic component, usually without concomitant fibrinoid necrosis. ;

Diagnostic Approach

Pyoderma gangrenosum is a diagnosis of exclusion. Misdiagnosis of pyoderma gangrenosum can result in substantial complications in patients who have other causes of severe cutaneous ulceration. No laboratory finding is diagnostic of paraderma gangrenosum. Weenig R.H. et al. Skin ulcers misdiagnosed as pyoderma gangrenosum N Engl J Med, Vol. 347, No. 18;

Skin Biopsy Aim: to rule out diagnoses that mimic pyoderma gangrenosum Protocol: Elliptical incisional biopsy preferable to punch biopsy; include inflamed border and ulcer edge at a depth that includes subcutaneous fat Specimen from inflamed border — routine histology (hematoxylin-and-eosin staining) and special staining (Gram’s, methenamine silver, and Fite) to detect microorganisms Specimen from edge of ulcer — culture in appropriate culture media (to detect bacteria, fungi, and atypical myobacteria) Weenig R.H. et al. Skin ulcers misdiagnosed as pyoderma gangrenosum N Engl J Med, Vol. 347, No. 18;

Skin Biopsy Early- stage lesionsLate-stage lesionsAdvancing, inflamed border lesions dermal neutrophilic abscess. epidermal necrosis and ulceration, superficial dermal edema, and a dense, mixed dermal infiltrate that may extend to the panniculus. dense perivascular lymphocytic inflammation, which may at times be associated with vascular destruction. Weenig R.H. et al. Skin ulcers misdiagnosed as pyoderma gangrenosum N Engl J Med, Vol. 347, No. 18; None of these histologic features is pathognomonic.

Abela C.B., et.al. Pyoderma gangrenosum. British Journal of Oral and Maxillofacial Surgery. SW17 0QT, UK. Department of Plastic and Reconstructive Surgery, St George’s Hospital, Blackshaw Road, Tooting, London SW17 0QT, UK. 3 November 2005

Direct Immunofluorescence may be the result of a hypersensitive reaction of the immune system due to an altered, exaggerated and uncontrolled inflammatory response to specific and non-specific stimuli, leading to a neutrophilic vasculitis characterised by perivascular deposition of immunoreactants, mainly immunoglobulin M (IgM), C3 and fibrin Carlesimo M et al, A case of pyoderma gangrenosum successfully treated with intravenous immune globulin

Treatment

Tx: Pyoderma gangrenosum Medical Surgery

Surgical intervention in PG Ulcer excision, skin grafting Not supported by literatures because of recurrence or even worsening of PG

Medical Intervention of PG Local therapy –Topical treatment Corticosteroid ointments tacrolimus ointments intralesional injections Systematic therapy

Systematic / Disseminated PG Corticosteroid / Cyclosporin –First line of treatment –Rapid response, stabilization of disease within 24hrs

Cyclosporin immunosuppressant drug Inhibits activation of transcription of interleukin 2, lymphokine production and interleukin release and, therefore, leads to a reduced function of effector T-cells

Corticosteroid Anti-inflammatory Immunosuppresant can be use in pulsed doses

Systematic / Disseminated PG MedicationRecommended dosage Corticosteroids0.5-1 mg methylprednisolone/kg/d Corticosteroids (pulsed-dose)1 g methylprednisolone/d for 1-5 days Cyclosporine5 mg cyclosporine/kg/d Corticosteroids and cyclosporine0.3-1 mg prednisolone/kg/d; 5 mg cyclosporine/kg/d

Complication Corticosteroid –Long term therapy may result to iatrogenic Cushing’s syndrome –Predispose patient to infection of wounds Cyclosporin –Nephrotoxicity, hypertension, tremor, increased risk of malignancy

Systematic / Disseminated PG mycophenolate mofetil; tacrolimus; thalidomide; infliximab –Alternative drugs Systemic antibiotics –Inhibits secondary bacterial infections

Systematic / Disseminated PG Plasma Exchange –consists of the removal of large volumes of the patient' s plasma and replacing it with exogenous plasma or plasma substitutes Action: removes from the circulation any pathogenic material decrease T lymphocytes (indirect action) normalize abnormal T4/T8 ratio (indirect)

Potential complications include: a.vasovagal reactions b.hypovolemia or fluid c.overload, d.electrolyte abnormalities e.infection of indwelling lines, f.bleeding tendency caused by depletion of platelets or clotting factors, In Px given plasma as replacement fluid: a.allergic reactions b.transfusion-related infections (hepatitis, HIV) c.difficulty in gaining vascular access, d.lesions can develop at venipuncture sites.

Human intravenous immune globulin (IVIG) Therapy human IVIG, 0.4 gm/kg per day, for 5 days effective in one patient with PGP after failure to respond to prednisone, dapsone, cyclosporine,and pulse methylprednisolone while therapy with cyclosporine and prednisone was continued. * When used at the higher doses, IVIG possesses immunosuppressive activity through poorly understood mechanisms.

Systematic / Disseminated PG Human intravenous immune globulin (IVIG) Therapy – human IVIG, 0.4 gm/kg per day, for 5 days – effective in one patient with PGP after failure to respond to prednisone, dapsone, cyclosporine,and pulse methylprednisolone while therapy with cyclosporine and prednisone was continued. * When used at the higher doses, IVIG possesses immunosuppressive

The principal disadvantages of this treatment a.high cost b.adverse effects (headache, chills, fever) c.potential for transmission of diseases with pooled sera.

Pseudomonas aeruginosa These bacteria show resistance to antibiotics A combination of two or more antibiotics is used to destroy the bacteria Antibiotic Selection takes into account local patterns of antimicrobial susceptibility

Combination therapy in most severe infections due to P. Aeruginosa, two antipseudomonal antibiotics to which the strain is sensitive should be administered together Benefits of this combined therapy: 1.Increased efficacy (more efficacious than monotherapy) 2.Achievement of additive or synergistic killing 3.Prevention of antibiotic resistance emergence Fauci et al. Harrison’s Principles of Internal Medicine

Antimicrobial agents active against Pseudomonas aeruginosa 1.aminoglycosides (gentamicin, amikacin, tobramycin) 2.quinolones (ciprofloxacin, levofloxacin, and moxifloxacin) 3.cephalosporins (ceftazidime, cefepime, cefoperazone, cefpirome, but not cefuroxime, ceftriaxone, cefotaxime) 4.ureidopenicillins and carboxypenicillins (piperacillin, ticarcillin: P. aeruginosa is intrinsically resistant to all other penicillins) 5.carbapenems (meropenem, imipenem, doripenem, but not ertapenem) 6.polymyxins (polymyxin B and colistin) 7.monobactams (aztreonam) Fauci et al. Harrison’s Principles of Internal Medicine

Duration of Antibiotic therapy depends on: 1.Type 2.Location 3.Severity of infection * In general: therapy lasts for weeks or even months rather than days Fauci et al. Harrison’s Principles of Internal Medicine

Antibiotic Resistance in P. aeruginosa is both: Intrinsic - as reflected by the relative paucity of antibiotics with inherent activity against wild type strains Acquired - as defined by high level resistance to agents that normally would be expected to exhibit antimicrobial activity Fauci et al. Harrison’s Principles of Internal Medicine

Increase in Antibiotic resistance Inadequate infection control procedures Increased severity of illness in hospitalized patients Expanding use of immunosuppressive therapies Growing antibiotic use Fauci et al. Harrison’s Principles of Internal Medicine

Therapy for RESISTANT P. aeruginosa infections Antimicrobial agents selected on basis of extended susceptibility testing Increased treatment duration Surgical drainage and removal of infected tissues Fauci et al. Harrison’s Principles of Internal Medicine

Follow-up and Monitoring Close, continuous follow-up. Monitor response to side effects of therapy.

Effect of long term steroid therapy Glaucoma and cataracts Fluid retention, edema in lower legs Increased blood pressure Weight gain, redistribution of body fat High blood sugar and worsening of diabetes Prednisone and other corticosteroids: Balance the risks and benefits

Effect of long term steroid therapy Increased risk of infections Osteoporosis and fractures Menstrual irregularities Suppressed adrenal gland hormone production Thin skin, easy bruisability Prednisone and other corticosteroids: Balance the risks and benefits

Follow up of patients on long term steroid therapy Vitamin D and calcium supplementation, and a baseline bone densitometry Antiresorptive therapy to prevent osteoporosis Fasting Blood Sugar Ophthalmologic exam

If no response to treatment, reconsider diagnosis. 109

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