1000-2000 5 ьшò

body surface area (BSA)

SJS: <10% BSA; SJS-TEN overlap: 10–30% BSA; TEN: >30% BSA

–Unlike erythema multiforme, strong association with preceding drug exposure as opposed to infection except in children where infection is more common (e.g., mycoplasma)

–Onset is 1 to 3 weeks after starting offending agent: flat atypical two-zone target lesions and erythematous macules that are truncal and generalized with mucosal involvement

–May develop confluent areas of bullae, erosions, and necrosis; significant risk for infection and sepsis

–SJS: 5–15% mortality; TEN: 30% mortality (5,6)

Lichenoid eruptions

–Flat-topped, violaceous, pruritic papules on extensor surfaces and involving oral mucosa

–Reticular pattern: Lesions heal with hyperpigmentation.

–Chronic lesions persist for weeks/months after the drug discontinued (2).

Photosensitivity reaction

–Phototoxic reactions: occur within 24 hours of light exposure with exaggerated sunburn reaction; usually confined to sun-exposed areas

–Photoallergic reactions: caused by UVAexposure; more pruritic than painful; can involve non–sun-exposed areas

Hypersensitivity vasculitis

–Petechiae/palpable purpura and/or maculopapular rash concentrated on lower extremities and dependent areas

–Biopsy shows neutrophils around an arteriole or venule.

–Possible renal, joint, and CNS involvement with fever, myalgias, arthritis, and abdominal pain (2)

Sweet syndrome

–Fever, neutrophilia, tender edematous violaceous papules, plaques, or nodules, with or without pustules/vesicles that spontaneously resolve

–May have oral ulcers or ocular manifestations, such as conjunctivitis

–Classically seen in young women after a mild respiratory illness or GI infection, but 7–56% associated with malignancy and pregnancy

Serum sickness–like reaction

–Fever, nonspecific cutaneous eruption with possible bullous lesions, arthralgias

–Onset 7 to 14 days

Exfoliative dermatitis/erythroderma

– Generalized erythema with exfoliation and/or fine desquamation >90% of

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body surface

–Difficult to distinguish between drug, primary cutaneous lymphoma, or inflammatory etiology

–Lymphadenopathy, hepatosplenomegaly, leukocytosis, eosinophilia, or anemia may be present.

–Increased risk of secondary infection and insensible fluid and temperature loss with hemodynamic instability

DIFFERENTIALDIAGNOSIS

Viral exanthem: Presence of fever, lymphocytosis, and other systemic findings may help in narrowing differential.

Primary dermatosis: Correlation of drug withdrawal to rash resolution may clarify diagnosis; skin biopsy is helpful.

Bacterial infection: Cultures of pustules may distinguish primary infection from AGEPand acneiform eruptions.

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Aminimum number of tests are useful in evaluating for internal organ involvement. CBC with differential; significant eosinophilia may be seen in DRESS and other drug-induced allergic reactions. LFT, urinalysis, and serum creatinine; chest x-ray if suspected vasculitis

Diagnostic Procedures/Other

Special tests depend on suspected mechanism:

–Type I: skin/intradermal testing, radioallergosorbent test (RAST)

–Type II: direct/indirect Coombs test

–Type III: ESR, C-reactive protein, ANA, antihistone antibody, tissue biopsy for immunofluorescence studies

–Type IV: patch testing, lymphocyte proliferation assay (investigational)

–Anaphylaxis/nonimmunologic mast and basophil cell reaction: serum tryptase levels

Cultures useful in excluding infectious etiology; skin biopsy is nonspecific but useful in characterizing an eruption and excluding primary skin pathologies.

Develop a timeline documenting the onset and duration of all drugs, dosages, and onset of cutaneous eruption (1)[A].

Test Interpretation

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Nonspecific histologic findings are superficial epidermal and dermal infiltrates composed variably of lymphocytes, neutrophils, and eosinophils. SJS/TEN: partial or full-thickness necrosis of the epidermis necrotic keratinocytes, vacuolization leading to subepidermal blister at basal membrane zone

TREATMENT

GENERALMEASURES

Monitor for signs of impending cardiovascular collapse: Anaphylactic reactions, DRESS, SJS/TEN, extensive bullous reactions, and generalized erythroderma may require inpatient treatment.

Do not rechallenge with drugs causing urticaria, bullae, angioedema, DRESS, anaphylaxis, or erythema multiforme.

MEDICATION

Immediate withdrawal of offending drug. Depending on the type of eruption, symptomatic treatment may be useful, but most require no additional therapy except cessation of offending agent.

Anaphylaxis or widespread urticaria: epinephrine 0.1 to 0.5 mg (1:1,000 [1 mg/mL] solution) IM in the mid-outer thigh every 5 to 15 min; prednisone may be given to prevent recurrence.

Acute urticaria (<6 weeks) and chronic urticaria (>6 weeks): 2nd-generation antihistamines (preferred, less sedating): cetirizine 10 to 20 mg daily, loratadine 10 to 20 mg daily, fexofenadine 180 mg daily, levocetirizine 5 to 10 mg daily. 1st-generation antihistamines: diphenhydramine 10 to 25 mg QHS, hydroxyzine 10 to 25 mg TID, doxepin 10 to 50 mg QHS H2 antagonists:

cimetidine 400 mg BID, ranitidine 150 mg BID

Anaphylaxis, severe urticaria: prednisone PO 1 mg/kg in tapering doses Erythema multiforme

–Treatment is generally supportive with management of suspected underlying infection.

–HSV-associated: prophylaxis with acyclovir 400 mg BID, valacyclovir 500 to 1,000 mg/day, or famciclovir 250 mg BID

–“Magic mouthwash” BID or TID is helpful for mucosal erosions. Consider ophthalmology consult for severe ocular involvement (4)[B].

SJS/TEN: Treatment is supportive. Consult with a dermatologist and

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ophthalmologist. Systemic corticosteroid use remains controversial. Consider

IVIG 2 to 3 g/kg for severe disease. In pediatric TEN patients, low-dose IVIG (0.05 to 0.10 g/kg/day) was effective; varied success rates reported with use of antitumor necrosis factor-α agents, cyclosporine, cyclophosphamide, and plasmapheresis (5)[C],(6)[A]

DRESS: prompt removal of offending drug and supportive measures; highpotency topical steroids for rash; systemic steroids with severe organ involvement; prednisone 0.5 to 2.0 mg/kg/day with prolonged taper 8 to 12 weeks (3)[B]

ONGOING CARE

FOLLOW-UPRECOMMENDATIONS

Patient Monitoring

For urticarial, bullous, DRESS, or erythema multiforme spectrum lesions, close follow-up is needed.

Patients with anaphylaxis/angioedema should be given EpiPens to be kept at home, work, and in the car for secondary prevention and a Med-Alert bracelet; label the patient’s medical record with the agent and reaction.

If the patient needs to take the inciting drug (e.g., antibiotic) in the future, induction of drug tolerance or graded challenge procedures may be necessary.

PROGNOSIS

Eruptions generally begin fading within days after removing offending agent. With morbilliform eruptions, eruption may spread distally even when agent is removed, resolving over time.

Anaphylaxis, angioedema, DRESS, SJS/TEN, and bullous reactions are potentially fatal.

COMPLICATIONS

Anaphylaxis, bone marrow suppression, hepatitis (dapsone, hydantoin), renal failure, and pulmonary and thyroid toxicity

REFERENCES

1.Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and

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Immunology, et al. Drug allergy: an updated practice parameter. Ann Allergy

Asthma Immunol. 2010;105(4):259–273.

2.Ahmed AM, Pritchard S, Reichenberg J. Areview of cutaneous drug eruptions. Clin Geriatr Med. 2013;29(2):527–545.

3.Chen YC, Chiu HC, Chu CY. Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases. Arch Dermatol. 2010;146(12):1373–1379.

4.Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45–53.

5.Mockenhaupt M. Stevens-Johnson syndrome and toxic epidermal necrolysis: clinical patterns, diagnostic considerations, etiology, and therapeutic management. Semin Cutan Med Surg. 2014;33(1):10–16.

6.Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR study. J Am Acad Dermatol. 2008;58(1):33–40.

CODES

ICD10

L27.1 Loc skin eruption due to drugs and meds taken internally

L50.0 Allergic urticaria

R21 Rash and other nonspecific skin eruption

CLINICALPEARLS

Virtually, any drug can cause a rash; antibiotics are the most common culprits that cause cutaneous drug reactions.

Focus on drug history with new suspicious skin eruptions.

Usually self-limited after withdrawal of offending agent

Symptoms such as tongue swelling/angioedema, skin necrosis, blisters, high fever, dyspnea, and mucous membrane erosions signify more severe drug reactions.

Useful resources: Drug Eruption Reference Manual by Jerome Litt; www.drugeruptiondata.com

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CYSTIC FIBROSIS

Fozia Akhtar Ali, MD Reethu K. Nayak, MD Deepika

Ram, MD

BASICS

DESCRIPTION

Cystic fibrosis (CF) is an autosomal recessive genetic mutation (CFTR gene) that most prominently affects the pulmonary and pancreatic systems.

The GI, endocrine, and reproductive systems as well as the liver, sinuses, and skin can all be involved.

Initially a pediatric disease, CF has become a chronic pediatric and adult medical condition as improvements in medical care have led to a dramatic increase in long-term survival resulting in adults living with the disease outnumbering children in 2014 (1)[A].

EPIDEMIOLOGY

CF is the most common lethal inherited disease in Caucasians and is found in every racial group.

Incidence

Number of infants born with CF in relation to the total number of live births in the United States

1 in 3,000 Caucasians

1 in 4,000 to 10,000 Latin Americans

1 in 15,000 to 20,000 African Americans

1 in 30,000 Asian Americans

Prevalence

30,000 patients with CF living in the United States

ETIOLOGYAND PATHOPHYSIOLOGY

Primary defect is abnormal function of an epithelial chloride channel protein encoded by the CFTR gene on chromosome band 7q31.2. Abnormal CFTR function leads to abnormally viscous secretions that alter organ function.

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The lungs: Obstruction, infection, and inflammation negatively affect lung growth, structure, and function.

–Decreased mucociliary clearance

–Infection is accompanied by an intense neutrophilic response.

–Degradation of supporting tissues causes bronchiectasis and eventual failure.

Genetics

CFTR gene (CF transmembrane conductance regulator). >1,500 mutations exist that can cause varying severity of phenotypic CF, all of which are recessively inherited. Most common is loss of the phenylalanine residue at 508th position (deltaF508), which accounts for 8.7% of affected alleles in the CF population in the United States. G551D mutation accounts for 4.3% of affected alleles.

RISK FACTORS

CF is a single-gene disorder. The severity of the phenotype can be affected by the specific CFTR mutation (most predictive of pancreatic disease), other modifier genes (CFTM1 for meconium ileus), gastroesophageal reflux disease (GERD), severe respiratory virus infection, and environmental factors such as tobacco smoke exposure.

Preconception counseling

–American Congress of Obstetricians and Gynecologists (ACOG) recommends preconception or early (1st/2nd trimester) genetic analysis for all North American couples planning a pregnancy, with appropriate counseling to identified carriers and genetic analysis of siblings of known CF patients.

–Universal newborn screening (NBS) has been integral in early diagnosis (64% of new CF diagnosis in 2014 were found by NBS). Patients diagnosed prior to onset of symptoms have better lung function and nutritional outcomes and should receive referral and early intervention services by an accredited regional CF center.

Pregnancy Considerations

Pulmonary disease may worsen during pregnancy.

CF may cause increased incidence of preterm delivery, IUGR, and cesarean section (2)[A].

Advances in fertility treatments now allow men with CF to father children (1) [A].

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DIAGNOSIS

HISTORY

Suspect with failure to thrive, steatorrhea, and recurrent respiratory problems.

–Chronic/recurrent respiratory symptoms, including airway obstruction and infections

–Persistent infiltrates on chest x-rays (CXRs)

–Hypochloremic metabolic acidosis

Hx during neonatal period

–Meconium ileus (20%) (generally considered pathognomonic for CF)

–Prolonged jaundice

Hx during infancy

–Failure to thrive

–Chronic diarrhea

–Anasarca/hypoproteinemia

–Pseudotumor cerebri (vitamin Adeficiency)

–Hemolytic anemia (vitamin E deficiency)

Hx during childhood

–Recurrent endobronchial infection

–Bronchiectasis

–Chronic pansinusitis

–Steatorrhea

–Poor growth

–Distal intestinal obstruction syndrome (DIOS)

–Allergic bronchopulmonary aspergillosis (ABPA)

Hx for adolescence and adulthood (7% diagnosed >18 years old) (3)[A]

–Recurrent endobronchial infection

–Bronchiectasis

–ABPA

–Chronic sinusitis

–Hemoptysis

–Pancreatitis

–Portal hypertension

–Azoospermia

–Delayed puberty

PHYSICALEXAM

Respiratory

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–Rhonchi and/or crackles

–Hyperresonance on percussion

–Nasal polyps

GI: hepatosplenomegaly when cirrhosis present

Other: digital clubbing, growth retardation, and pubertal delay

COMMONLYASSOCIATED CONDITIONS

CF-related diabetes (CFRD)

–May present as steady decline in weight, lung function, or increased frequency of exacerbation

–Leading comorbid complication (20.7%)

–Result of progressive insulin deficiency

–Early screening and treatment may improve reduced survival found in CFRD.

Upper respiratory

–Rhinosinusitis is seen in up to 100% of patients with CF.

–Nasal polyps are seen in up to 86% of patients.

The GI tract

–Pancreatic exocrine insufficiency (85–90%)

–Malabsorption of fat, protein, and fat-soluble vitamins (A, D, E, and K)

–Hepatobiliary disease (12.6%)

–Focal biliary cirrhosis

–Cholelithiasis

–Meconium ileus at birth (10–15%)

–DIOS: intestinal blockage that typically occurs in older children and adults (5.3%) (1)[A]

–GERD (32.7%) (1)[A]

Endocrine

–Bone mineral disease (16.6%) (1)[A]

–Joint disease (3.0%) (1)[A]

–Hypogonadism

–Frequent low testosterone levels in men

–Menstrual irregularities are common.

Reproductive organs

– Congenital bilateral absence of the vas deferens: obstructive azoospermia in 98% of males

Depression (12.8%) (1)[A]

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DIFFERENTIALDIAGNOSIS

Immunologic

– Severe combined immunodeficiency

Pulmonary

–Difficult-to-manage asthma

–COPD

–Recurrent pneumonia

–Chronic/recurrent sinusitis

–Primary ciliary dyskinesia

Gastrointestinal

–Celiac disease

–Protein-losing enteropathy

–Pancreatitis of unknown etiology

–Shwachman-Diamond syndrome

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

NBS tests blood levels of immunoreactive trypsin (IRT) (1)[A].

Patients must have clinical symptoms of CF involving at least one organ system.

Sweat test (gold standard)

–Sweat chloride

>60 mmol/L(on 2 occasions) is (+) for CF.

<40 mmol/Lis normal.

–CFTR mutation analysis

–Limited panel testing: Allele-specific polymerase chain reaction (PCR) identifies >90% of mutations; finite chance of false-negative finding. Fullsequence testing is more costly and time-consuming.

–Nasal potential difference (when sweat test and DNAtesting inconclusive)

–CXR

Follow-Up Tests & Special Considerations

To further investigate the presence of CF-related complications, these tests are generally ordered:

Sputum culture (common CF organisms)

Pulmonary function tests (PFTs) 72-hour fecal fat, stool elastase

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