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Common Dermatological Causes of Nail Abnormalities & Suspected Onychomycosis: Diagnostic Steps and Treatment Options

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PART A: COMMON DERMATOLOGICAL CAUSES OF NAIL ABNORMALITIES

1. Fungal Infections (Onychomycosis / Tinea Unguium)

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2. Psoriasis

Key point: In toenails, psoriasis may be clinically indistinguishable from onychomycosis — mycological confirmation is mandatory before initiating systemic antifungals. (Dermatology 2-Volume Set 5e; Andrews' Diseases of the Skin)

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3. Lichen Planus

• Trachyonychia (rough, sandpapered nails), pterygium unguis (dorsal — pathognomonic), longitudinal ridging, onycholysis, twenty-nail dystrophy.
• May involve the oral mucosa, helping differentiation.

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4. Alopecia Areata

• Geometric, regular, fine pitting (unlike the irregular pits of psoriasis), trachyonychia, Beau's lines, onychomadesis, red spotted lunula.

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5. Eczema / Contact Dermatitis

• Transverse ridging, Beau's lines, onycholysis, subungual hyperkeratosis.
• Involvement of the adjacent proximal nailfold (perionychia) is characteristic.

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6. Darier Disease (Keratosis Follicularis)

• Characteristic alternating red-and-white longitudinal streaks, subungual hyperkeratosis with V-shaped nicking at the free margin.

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7. Paronychia

• Acute paronychia: Staphylococcus aureus most common — painful, fluctuant swelling around the nailfold.
• Chronic paronychia: Candida colonisation + barrier disruption (wet work); cuticle loss, proximal/lateral nailfold swelling, Beau's lines, greenish discolouration if secondary Pseudomonas is present.

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8. Other Causes (Brief Mention)

• Trauma: Subungual haematoma (longitudinal dark streaks, fringed distal edge on dermoscopy), onychomadesis.
• Tinea Pedis with Nail Extension: Concurrent skin scaling on soles helps identify.
• Scabies (Crusted/Norwegian): Subungual debris and hyperkeratosis mimicking onychomycosis; generalised hyperkeratosis elsewhere.
• Langerhans Cell Histiocytosis: Subungual debris and haemorrhage as a systemic marker.

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PART B: DIAGNOSTIC STEPS & TREATMENT OPTIONS FOR SUSPECTED ONYCHOMYCOSIS

INTRODUCTION

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STEP 1: CLINICAL ASSESSMENT

A. History

• Duration, progression, nail(s) affected, family history, occupation (wet work, communal showers).
• Comorbidities: diabetes mellitus, HIV/immunosuppression, peripheral vascular disease (risk factors for PSO and total dystrophic onychomycosis).
• Drug history (systemic steroids, immunosuppressants).
• Concomitant tinea pedis / tinea manuum.

B. Clinical Subtypes to Identify

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STEP 2: INVESTIGATIONS (Diagnostic Workup)

1. Sample Collection

• Best sample: Subungual debris and nail clippings from the most proximal diseased area; avoid surface scrapings only.
• Drilling technique yields higher specimen density than curettage.
• For WSO: Scrape the white plaque directly from the nail surface.

2. Direct Microscopy with KOH Preparation

• Thin shavings/curettings placed in 10–20% KOH (± dimethylsulfoxide for faster clearing); ± calcofluor white for fluorescence enhancement.
• Demonstrates hyphae, pseudohyphae, or spores.
• Sensitivity: 40–80%; rapid (office-based); does not identify genus/species.

3. Fungal Culture (Gold Standard for Speciation)

• Sabouraud dextrose agar (with chloramphenicol) ± dermatophyte test medium (DTM).
• Important: For NDMs, use medium without cycloheximide (Mycosel agar inhibits NDMs).
• Sensitivity: 30–70%; takes 2–6 weeks.
• Identifies genus and species — essential for choosing appropriate antifungal.
• Combined KOH + culture sensitivity: 80–85%.

4. Histopathology with PAS Stain

• Nail clippings processed with Periodic Acid-Schiff (PAS) stain.
• Sensitivity: 41–93% (consistently higher than KOH or culture in multiple studies).
• Results available within 24 hours.
• Does not speciate the organism.
• Preferred when rapid confirmation is needed before initiating therapy.

5. Polymerase Chain Reaction (PCR)

• Emerging modality; highest sensitivity and specificity, enables speciation.
• Detects DNA of dermatophytes, NDMs, and Candida from nail specimens.
• Particularly useful when culture and KOH are negative but clinical suspicion is high.
• Cost and availability currently limit routine use.

6. Dermoscopy (Onychoscopy)

• Non-invasive, in-office adjunct.
• DLSO: Jagged proximal edge with spikes pattern; aurora borealis pattern.
• WSO: White transverse diffuse streaks.
• Useful for targeted biopsy guidance and differentiating from psoriasis (salmon-patch pattern).

7. Additional Workup

• Fasting blood glucose / HbA1c (screen for diabetes).
• HIV serology if PSO or widespread disease (all 20 nails).
• CBC, LFTs, renal function — baseline before initiating systemic therapy.

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STEP 3: DIFFERENTIAL DIAGNOSIS (to exclude before treating)

"Confirmatory tests to identify the fungus are mandatory — clinical diagnosis alone is insufficient." — Andrews' Diseases of the Skin

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STEP 4: TREATMENT OPTIONS

A. Topical Antifungals (for mild/superficial/limited disease)

• Topical agents are less effective than systemic but have fewer side effects; suitable when <50% nail involvement, no lunula involvement.

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B. Systemic Antifungals (First-Line for Moderate-Severe Disease)

• Children (terbinafine dosing): >40 kg: 250 mg/day; 20–40 kg: 125 mg/day; <20 kg: 62.5 mg/day
• Candida onychomycosis: Itraconazole preferred (pulse × 4 weeks minimum for fingernails, 12 weeks for toenails); fluconazole equally effective.
• NDM onychomycosis (Aspergillus, Fusarium): Itraconazole or voriconazole; oral griseofulvin is ineffective.
• HIV/PSO: Initiate HAART; terbinafine or itraconazole.

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C. Adjunctive & Newer Modalities

• Nd:YAG Laser (1064 nm): 50–60% cure after multiple sessions; no systemic side effects; expensive, not widely available.
• Dermatophytoma debridement: Yellow streaks within nail (fungal masses) may reduce efficacy — unroofing + curettage of dermatophytoma prior to systemic treatment improves outcomes.
• Nail avulsion: Chemical (40% urea) or surgical; used as adjunct in total dystrophic onychomycosis.

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D. Monitoring During Systemic Therapy

• LFTs at baseline for terbinafine and itraconazole; repeat if >12 weeks or symptomatic hepatotoxicity.
• Drug interactions: Itraconazole inhibits CYP3A4 — avoid warfarin, statins, cisapride, H2-blockers.
• Cure criteria: Clinical cure (normal nail) + mycological cure (negative KOH + culture); assess at 3 months post-completion.

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E. Prevention of Recurrence

• Treat concomitant tinea pedis aggressively.
• Keep feet dry; breathable footwear; avoid communal showers barefoot.
• Treat affected family members.
• Recurrence rates: Lower with itraconazole than terbinafine monotherapy; combined therapy does not further reduce recurrence.

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SUMMARY TABLE

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• Fitzpatrick's Dermatology (9th ed.), Vol. 1–2, Chapter 160
• Andrews' Diseases of the Skin: Clinical Dermatology (13th ed.), Chapter 15
• Dermatology 2-Volume Set, 5th ed. (Elsevier), Chapter 71
• PubMed PMID 39295115 (Gupta AK, 2025 — Pediatric dermatophyte onychomycosis: systematic review); PMID 39962858 (Onychomycosis in psoriasis: meta-analysis, 2025)

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Diagnostic Approach and Management of Severe Cutaneous Adverse Drug Reactions: SJS/TEN and DRESS

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INTRODUCTION

1. Stevens-Johnson Syndrome (SJS) — <10% body surface area (BSA) epidermal detachment
2. SJS/TEN overlap — 10–30% BSA
3. Toxic Epidermal Necrolysis (TEN) — >30% BSA
4. DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) — also known as Drug-Induced Hypersensitivity Syndrome (DIHS)

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PART I: STEVENS-JOHNSON SYNDROME (SJS) AND TOXIC EPIDERMAL NECROLYSIS (TEN)

A. DEFINITION & CLASSIFICATION

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B. CAUSATIVE DRUGS (High-Risk)

• Allopurinol — most frequent cause worldwide
• Aromatic anticonvulsants: Carbamazepine, Phenytoin, Phenobarbital
• Lamotrigine (especially co-administered with valproic acid)
• Sulfonamide antibiotics (sulfamethoxazole, sulfadiazine)
• NSAIDs — piroxicam, diclofenac
• Aminopenicillins, Cephalosporins, Quinolones
• NNRTIs — nevirapine, efavirenz
• Immune checkpoint inhibitors — ipilimumab, nivolumab

Onset: 7–21 days from first exposure; as early as 48 hours on re-exposure.

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C. PATHOGENESIS

• Impaired detoxification of reactive drug metabolites → neoantigenic drug-tissue complex.
• Three proposed mechanisms: (1) Hapten/pro-hapten concept (covalent binding); (2) p-i concept (direct pharmacologic interaction with MHC/TCR); (3) Altered self-peptide presentation.
• HLA associations (pharmacogenomics):
  • HLA-B*15:02 — Asians/East Indians + carbamazepine → SJS/TEN
  • HLA-B*58:01 — Han Chinese + allopurinol → SJS/TEN
  • HLA-A*31:01 — Europeans + carbamazepine
• Drug-reactive CD8+ cytotoxic T lymphocytes + granulysin (key mediator of keratinocyte apoptosis in TEN) drive epidermal cell death.

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D. DIAGNOSTIC APPROACH

1. Clinical Diagnosis

• High fever, malaise, sore throat, photophobia, burning eyes, painful skin.

• Begin as dusky/grey, ill-defined macules on the trunk and face.
• Progress to atypical target lesions (flat, without a raised middle zone — distinguishes from EM).
• Coalesce → flaccid bullae → epidermal detachment (sheets of "wet cigarette paper" appearance).
• Positive Nikolsky sign: Application of lateral pressure to lesional skin causes epidermal shearing.
• Asboe-Hansen sign: Pressure on an intact bulla causes lateral extension.

• Oral: hemorrhagic erosions, pseudomembranes.
• Ocular: conjunctival injection, erosions, photophobia.
• Genital: erosions, painful micturition.
• Respiratory tract: mucosal involvement may cause bronchial shedding.

2. Histopathology (Confirmatory)

• Early lesions: Scattered apoptotic keratinocytes in basal/suprabasal layers, vacuolar basal changes, minimal inflammation (correlates with dusky hue clinically).
• Late lesions: Full-thickness epidermal necrosis with subepidermal blistering, sparse perivascular lymphocytic infiltrate.
• Key distinction from SSSS: SSSS has a subcorneal split (granular layer); TEN has a subepidermal split with full-thickness necrosis.
• Direct immunofluorescence: Negative (excludes autoimmune bullous disease).

3. Investigations

4. Severity Scoring: SCORTEN

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E. MANAGEMENT OF SJS/TEN

Step 1: Immediate Actions

• Immediate withdrawal of culprit drug — reduces mortality risk by ~30% per day of early withdrawal; favour drugs with short half-lives.
• Emergency ICU/burn unit transfer for TEN (>30% BSA).
• Multidisciplinary team: Dermatology, Ophthalmology, ICU, Nutrition, Gynaecology/Urology.

Step 2: Supportive Care (Cornerstone of Management)

Step 3: Immunomodulatory Therapy (Adjunctive — Evidence Still Debated)

Key principle: Supportive care remains paramount. No single immunomodulatory therapy has robust RCT data.

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PART II: DRESS (DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS)

A. DEFINITION & EPIDEMIOLOGY

• A potentially fatal, delayed, multi-organ drug hypersensitivity syndrome.
• Incidence: 1 in 1,000–10,000 drug exposures.
• Synonyms: Drug-Induced Hypersensitivity Syndrome (DIHS), DIDMOHS.
• Mortality: 2–10% (mainly from hepatic failure).
• Onset: 2–8 weeks after starting the causative drug (significantly later than other drug reactions — a hallmark).

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B. CAUSATIVE DRUGS

• Aromatic anticonvulsants: Phenobarbital, Carbamazepine, Phenytoin, Lamotrigine, Oxcarbazepine
• Sulfonamides: Trimethoprim-sulfamethoxazole, Sulfasalazine
• Allopurinol, Dapsone, Minocycline, Vancomycin
• Antiretrovirals: Abacavir, Nevirapine
• Immune checkpoint inhibitors: Ipilimumab, Nivolumab, Durvalumab
• Targeted cancer therapies: Vemurafenib, Imatinib

Cross-reactivity exists between aromatic anticonvulsants (phenytoin, carbamazepine, phenobarbital) due to shared arene oxide metabolites.

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C. PATHOGENESIS

1. Defective detoxification: Genetic polymorphisms → accumulation of toxic drug metabolites → immune activation.
2. HLA associations: Drug-specific HLA alleles increase susceptibility (see Table 21.3).
3. T cell activation: IL-5 drives eosinophilia; drug-specific CD4+ and CD8+ T cells activated in skin and visceral organs.
4. Herpesvirus reactivation: HHV-6, HHV-7 (most common), EBV, CMV reactivation — occurs in ~76% of DRESS patients. HHV-6 reactivation is a hallmark feature and correlates with disease severity. Viral reactivation is thought to be triggered by the immune dysregulation induced by the offending drug.

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D. CLINICAL FEATURES

Skin:

• Starts as morbilliform eruption → becomes edematous, sometimes erythrodermic (>70% BSA).
• Facial oedema — hallmark feature.
• Vesicles, follicular pustules (~20%), purpuric lesions, EM-like lesions in severe cases.
• Mucosal involvement: mild or absent (unlike SJS/TEN).

Systemic:

• Fever (>38°C) in 85%; begins before or with cutaneous eruption.
• Lymphadenopathy (>30%): Reactive lymphadenopathy — bilateral, cervical commonest.
• Hepatitis (~80%): Liver injury is the most common and most dangerous visceral manifestation.
• Renal: Interstitial nephritis.
• Cardiac: Myocarditis, eosinophilic pericarditis.
• Pulmonary: Interstitial pneumonitis.
• Thyroid: Autoimmune thyroiditis (may present weeks to months after drug withdrawal).
• Neurological: Eosinophilic brain infiltration (rare).
• Haematological: Eosinophilia, atypical lymphocytosis; may evolve to Haemophagocytic Lymphohistiocytosis (HLH).

Visceral involvement may persist or develop new organ dysfunction weeks to months after drug withdrawal — including during corticosteroid taper. This distinguishes DRESS from all other SCARs.

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E. DIAGNOSTIC CRITERIA

1. RegiSCAR Scoring System (European)

• Score ≥5 = definite DRESS; 3–4 = probable DRESS.

2. J-SCAR (Japanese) Diagnostic Criteria

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F. INVESTIGATIONS FOR DRESS

Basic Screening (Acute Phase — Repeat Twice Weekly):

• CBC with differential + peripheral smear (atypical lymphocytes, eosinophils)
• BUN, creatinine, urinalysis + spot urine protein:creatinine ratio
• LFTs, CK, lipase, CRP
• TSH, free T4 (baseline; repeat at 3 months, 1 year, 2 years for thyroid autoimmunity)
• Fasting glucose (before initiating corticosteroids)

Additional Testing:

• ECG + troponin T + echocardiogram (cardiac involvement)
• Quantitative PCR for HHV-6, HHV-7, EBV, CMV
• ANA, blood cultures (exclusion criteria in RegiSCAR)
• Wright stain of urine for eosinophilia (before corticosteroids)
• If HLH suspected: Ferritin, triglycerides, LDH, bone marrow examination

Skin Biopsy:

• Variable patterns: eczematous, interface dermatitis, AGEP-like, EM-like.
• Dermal infiltrate often contains eosinophils — characteristic.
• Epidermal necrosis is absent (unlike SJS/TEN) or minimal.

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G. MANAGEMENT OF DRESS

Step 1: Drug Withdrawal

• Immediate cessation of culprit drug — mandatory; however, clinical symptoms may not resolve promptly.
• Avoid all cross-reactive compounds (especially aromatic anticonvulsants).
• Replace with structurally unrelated alternatives.

Step 2: Organ-Based Supportive Care

• Fluid management, antipyretics (avoid NSAIDs), antihistamines for pruritus.
• Monitor LFTs, renal function, thyroid function serially.
• Ophthalmology review; nephrology/hepatology consult as needed.

Step 3: Immunosuppressive Therapy

DRESS Severity Score ≥4 (Mizukawa scoring) → associated with later CMV disease; consider early anti-CMV therapy.

Step 4: Long-term Follow-up

• Minimum 1 year of longitudinal evaluation.
• Serial thyroid function (autoimmune thyroiditis may develop months later).
• Cardiac surveillance (eosinophilic myocarditis).
• Patient education: Written documentation of culprit drug; medical alert bracelet.
• Genetic testing (HLA-B*15:02 prior to carbamazepine in Asians, as now recommended by the FDA).

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COMPARISON TABLE: SJS/TEN vs DRESS

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SUMMARY

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• Dermatology 2-Volume Set, 5th ed. (Elsevier) — Chapters 20 & 21
• Fitzpatrick's Dermatology 9th ed. — Drug Hypersensitivity
• Bastuji-Garin S et al. Arch Dermatol 1993 (SJS/TEN classification)
• PubMed PMID 38878166 (Outcome measures in epidermal necrolysis, Sys Rev 2024); PMID 38063272 (Wound care in TEN, Meta-analysis 2024)