1000-2000 5 ьшò

climates

Increased risk in whites versus nonwhites: 2- to 5-fold

Increased risk in Ashkenazi Jews: 3- to 5-fold

Prevalence

U.S. adults: 100 to 200 cases/100,000

ETIOLOGYAND PATHOPHYSIOLOGY

General: Clinical manifestations result from activation of inflammatory cells and subsequent tissue injury.

Mechanism of diarrhea: excess fluid secretion and impaired fluid absorption; bile salt malabsorption in inflamed ileum, with steatorrhea, bacterial overgrowth

Multifactorial: Genetics, environmental triggers, commensal microbial antigens, and immunologic abnormalities result in inflammation and tissue injury.

Genetics

15% of CD patients have a first-degree relative with inflammatory bowel disease (IBD); first-degree relative of an IBD patient has 3- to 30-fold increased risk of developing IBD by age 28 years; ~200 different genes associated with IBD

Mutations in susceptibility loci

–Ileal CD: IBD1 gene (chromosome 16)

–Early-onset CD (age ≤15 years): mutations in 5q31 to 33 (IBD5), 21q22, and 20q13

–Extraintestinal manifestations of CD: mutations in HLA-A2, HLA-DR1, HLA-DQw5

–Others: IL-10, IL-23 receptors; ATG16L1; IRGM

Associated genetic syndromes: Turner and Hermansky-Pudlak syndromes, glycogen storage disease type 1b

RISK FACTORS

Environmental factors

–Cigarette smoking doubles the risk of CD; tobacco cessation reduces flares and relapses.

–Dietary factors: higher incidence if diet high in refined sugars, animal fat, protein (meat, fish)

–Salmonella or Campylobacter increases risk of developing IBD.

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– Clostridium difficile infection may trigger flare and make treatment more difficult.

Immunologic abnormalities: an aggressive immune response against commensal enteric bacteria

–Tumor necrosis factor (TNF): upregulation of inflammatory Th1 cytokines

–Tissue inflammation may result from increased secretion of cytokines.

COMMONLYASSOCIATED CONDITIONS

Extraintestinal manifestations

–Arthritis (20%): seronegative, primarily involving large joints; axial arthritis or ankylosing spondylitis (AS) and sacroiliitis (SI)

–Skin disorders (10%): erythema nodosum, pyoderma gangrenosum, psoriasis

–Ocular disease (5%): uveitis, iritis, episcleritis

–Kidney stones: calcium oxalate stones (from steatorrhea and diarrhea) or uric acid stones (from dehydration and metabolic acidosis)

–Fat-soluble vitamin deficiency (A, D, E, K)

–Osteopenia and osteoporosis; hypocalcemia

–Hypercoagulability: venous thromboembolism prophylaxis essential in hospitalized patients

–Gallstones: cholesterol stones resulting from impaired bile acid reabsorption

–Primary sclerosing cholangitis (5%): more common in men with UC; asymptomatic, elevated alkaline phosphatase as marker

–Autoimmune hemolytic anemia

Conditions associated with increased disease activity

–Peripheral arthropathy (not SI and AS)

–Episcleritis (not uveitis)

–SI, AS, and uveitis are associated with HLA-B27.

–Oral aphthous ulcers and erythema nodosum

–Other complications: GI bleed, toxic megacolon, bowel perforation, peritonitis, malignancy, sclerosing cholangitis, rectovaginal fistula

DIAGNOSIS

HISTORY

Hallmarks: fatigue, fever, weight loss, prolonged diarrhea, perianal disease,

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crampy abdominal pain (+/− bleeding). Children may present with failure to thrive.

Factors exacerbating CD: concurrent infection, smoking, NSAIDs, and possibly stress

PHYSICALEXAM

Presentation varies with location of disease.

General: signs of sepsis/disease activity (fever, tachycardia, hypotension) or wasting/malnutrition

Abdominal: focal or diffuse tenderness, distension, rebound/guarding; rectal bleeding

Perianal: fistulae, fissures

Skin: erythema nodosum; psoriasis

DIFFERENTIALDIAGNOSIS

Acute, severe abdominal pain: perforated viscus, pancreatitis, appendicitis, diverticulitis, bowel obstruction, kidney stones, ovarian torsion

Chronic diarrhea with crampy pain (colitis like): UC, radiation colitis, infection, drugs, ischemia, microscopic colitis, IBD, celiac disease, malignancy (lymphoma, carcinoma), carcinoid

Wasting illness: malabsorption, malignancy

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

CBC, serum chemistries, LFTs, erythrocyte sedimentation rate, C-reactive protein, serum iron, vitamin B12, vitamin D-25 OH, stool calprotectin

If diarrhea, stool specimen for routine culture, fecal leukocytes, C. difficile, and ova and parasites

With severe flares, KUB to rule out toxic megacolon

Colonoscopy with ileoscopy provides the greatest diagnostic sensitivity and specificity for colonic disease and distal small bowel disease.

Small bowel: Sensitivity of CT or magnetic resonance enterography (MRE) better than small bowel follows through. MRE has no radiation exposure (important in younger patients). Capsule endoscopy allows small bowel visualization but no biopsy (1)[A].

–Signs of small bowel disease: narrowed lumen with nodularity and/or string sign; cobblestone appearance, fistula and abscess formation, bowel loop

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separation (transmural inflammation)

Gastroduodenal: upper GI endoscopy

– Signs of gastroduodenal disease: antral narrowing and segmental stricturing; inflammatory mucosa

Perirectal complications: combination of endoscopic ultrasound (EUS) or MRI with exam under anesthesia

Contraindications to endoscopy: perforated viscus, recent myocardial infarction, severe diverticulitis, toxic megacolon, or inability to undergo bowel preparation

In most cases, unprepared limited sigmoidoscopy allows adequate visualization to assess severity, extent, and aspirate stool for C. difficile, obtain biopsies to assess histologic severity, and exclude other disorders (e.g., cytomegalovirus).

Follow-Up Tests & Special Considerations

Evidence of complications

Stricture: obstructive signs—nausea, vomiting, pain, weight loss, diarrhea, or inability to pass gas/feces

Abscess/phlegmon: localized abdominal peritonitis with fever and abdominal pain; diffuse peritonitis suggests perforation or abscess rupture (may be masked by steroids, opiates).

Fistula:

–Enteroenteric: asymptomatic or a palpable, commonly indolent abdominal mass

–Enterovesical: pneumaturia, recurrent UTI

–Retroperitoneal: psoas abscess, ureteral obstruction

–Enterovaginal: vaginal passage of gas or feces; clear, nonfeculent drainage from ileal fistula (may be misdiagnosed as primary vaginal infection)

Diagnostic Procedures/Other

How to distinguish CD from UC

CD: small bowel disease, rectal sparing; skip lesions; granulomas, perianal disease, and/or fistulae; no gross bleeding: RLQ pain is common.

– Anti–Saccharomyces cerevisiae antibody (ASCA), Cbir-1, OmpC, I2 (70% sensitive)

UC: diffuse, continuous involving the rectum; loss of vascularity, friable tissue; perinuclear antineutrophil cytoplasmic antibody (pANCA); LLQ pain; typically only affects colon; rectal bleeding common

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ALERT

CD can mimic UC with continuous bowel involvement; 10–15% of cases are difficult to differentiate.

TREATMENT

Disease severity: Crohn Disease Activity Index (CDAI)

–Asymptomatic: spontaneous, after medical/surgical intervention, or while on steroids (CDAI <150)

–Mild to moderate CD: ambulatory patients able to tolerate PO intake without dehydration, obstruction, or >10% weight loss; no abdominal tenderness, toxicity, or mass (CDAI 150 to 220)

–Moderate to severe CD: patients who have failed initial treatment or who continue to have mild symptoms such as fever, weight loss, and abdominal pain (CDAI 220 to 450)

–Severe: persistent symptoms despite therapy with glucocorticoids and/or biologics or fulminant disease (peritonitis, cachexia, intestinal obstruction, abscess) (CDAI >450)

–Step-up approach: Begin treatment with milder therapy (5-ASA, antibiotics) followed by more aggressive agents (steroids, immunomodulators, anti-TNF agents) as needed.

–Top-down approach: early management with immunomodulators and/or anti-TNF agents before patients receive steroids, become steroid dependent, or require surgery

GENERALMEASURES

Oral lesions: triamcinolone acetonide in benzocaine and carboxymethyl cellulose or topical sucralfate for aphthous ulcers, cheilitis, and/or granulomatous sialadenitis

Gastroduodenal CD: no clinical trials; slow-release mesalamine may be beneficial. Case reports show success of anti-TNF therapies; symptomatic relief possible from proton pump inhibitors, H2-receptor blockers, and/or

sucralfate

Ileitis: Supplemental fat-soluble vitamins, iron, B12, folate, and calcium may

be necessary.

Treatment toxicity: pancreatitis, bone marrow toxicity, lymphoma, nonmelanoma skin cancer, infections (TB, histoplasmosis, others),

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malignancy

MEDICATION

First Line

Asymptomatic patients: observation Mild CD

–5-Aminosalicylates have minimal role in CD management; used for colonic CD without deep ulcerations or fibrostenosing disease

–Antibiotics are controversial. Controlled trials have not consistently demonstrated efficacy.

–Glucocorticoid therapy: controlled ileal release budesonide (9 mg/day for 8 to 16 weeks and then discontinued over 2- to 4-week taper) for distal ileum and/or right colon involvement (2)[A]

–Adjunctive therapy: antidiarrheals (loperamide); bile acid-binding resin (cholestyramine 4 to 12 g/day); probiotics (either alone or in combination may reduce inflammation/symptoms in acute CD)

–Induction/maintenance: 5-ASAis not recommended (2)[C]. Controlled ileal release budesonide, 9 mg/day, is effective for maintenance for up to 6

months.

Moderate to severe CD

–Induction: prednisone 40 to 60 mg/day or controlled-release budesonide (for isolated, moderate ileitis) or anti-TNF agents as initial induction agent or for lack of response to corticosteroid or immunomodulator (2)[A]

–Maintenance: no role for mesalamine. If steroids required for induction, use immunomodulator (2)[B] or biologic (anti-TNF agent) (2)[B] for maintenance.

–Except for budesonide, do not use steroids for maintenance (1)[A].

Severe disease: immunomodulators, anti-TNF agents ± steroids

–Azathioprine or 6-mercaptopurine: thiopurine methyltransferase (TPMT) and LFTs prior to initiation. Check CBC/LFTs q2–3mo.

–Methotrexate: effective for steroid-dependent and steroid-refractory CD Folic acid 1 mg/day; follow LFTs.

–Anti-TNF: active disease, fistulae, steroid sparing, extraintestinal disease; infliximab, adalimumab, certolizumab pegol

Check for evidence of TB and HBV infection prior to initiation of antiTNF therapy.

Avoid live vaccines.

Monitoring: Consider antidrug antibody levels to assess for

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immunogenicity. Serum concentrations of anti-TNF agents may also correlate with disease activity.

Combination therapy

–Azathioprine + infliximab is more effective than either alone if no previous treatment with either.

–Rare complication: hepatosplenic T-cell lymphoma (fatal, mostly seen in

young males)

Antiadhesion molecules: prevent inflammatory cells from entering GI tract

–Vedolizumab: gut-specific, can be used in anti-TNF failures or anti-TNF naive patients as induction and maintenance; given IV, no risk of progressive multifocal leukoencephalopathy (PML)

–Natalizumab: non–gut-specific, PMLrisk (1/1,000); can minimize risk by testing for John Cunningham (JC) virus antibody; however, can avoid risk

of PMLnow with vedolizumab

Anti–IL-12 and anti–IL-23 monoclonal antibody: ustekinumab: recently approved for CD

Therapeutic drug monitoring: Optimize biologics to avoid side effects. Measure trough levels of drug, and if drug not present, assess for antibody to the drug. If low or absent drug level and no antibodies, increase dose or frequency. If no drugs and high antibody levels, switch agents. If drug present and no antibodies, switch treatment if active disease (3)[C].

New/Investigational therapies:

– JAK kinase inhibitor and SMAD-7 inhibitor under investigation

COMPLICATIONS

Peritonitis: bowel rest and antibiotic therapy (7 to 10 days parenteral antibiotics, followed by 2- to 4-week course of PO ciprofloxacin and metronidazole); surgery as indicated

– Consider holding steroids which masks sepsis.

Abscess: antibiotics, percutaneous drainage, or surgery with resection of affected segments

Small bowel obstruction: IV hydration, nasogastric (NG) tube for decompression, total parenteral nutrition (TPN) for malnutrition, resolution typically in 24 to 48 hours; surgery for nonresponders

ONGOING CARE

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FOLLOW-UPRECOMMENDATIONS

Patient Monitoring

Vaccinations

Check titers; avoid live vaccines (MMR, varicella, zoster) in patients on immunosuppressive therapy (steroids, 6MP, AZA, MTX, or biologics).

Regardless of immunosuppression: HPV, influenza, pneumococcal, meningococcal, hepatitis A, B; Tdap

Cancer prevention

–Colonoscopy with targeted biopsies every 1 to 3 years after 8 to 10 years of CD with colonic involvement; consider chromoendoscopy if available (4) [C].

–Annual PAPsmears if immunocompromised

–Annual skin exam if immunocompromised

Bone health

–Calcium and vitamin D supplementation with each course of corticosteroids or if vitamin D deficient

–Bone density assessment if previous steroid use, maternal history of osteoporosis, malnourished, amenorrheic, postmenopausal

PATIENT EDUCATION

Crohn and Colitis Foundation: (800) 343-3637; www.ccf.org

REFERENCES

1.Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380(9853):1590– 1605.

2.Talley NJ, Abreu MT, Achkar JP, et al. An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol. 2011;106(Suppl 1):S2–S26.

3.Vande Casteele N, Feagan BG, Gils A, et al. Therapeutic drug monitoring in inflammatory bowel disease: current state and future perspectives. Curr Gastroenterol Rep. 2014;16(4):378.

4.Laine L, Kaltenbach T, Barkun A, et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastroenterology. 2015;148(3):639.e28–651.e28.

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CODES

ICD10

K50.919 Crohn’s disease, unspecified, with unspecified complications

K50.00 Crohn’s disease of small intestine without complications K50.10 Crohn’s disease of large intestine without complications

CLINICALPEARLS

Cigarette smoking doubles the risk of CD; tobacco cessation reduces flares and need for surgery.

MRE allows assessment of luminal and extraluminal CD without radiation exposure.

Assess for TB and HBV infection prior to initiating anti-TNF therapy.

Test for C. difficile infection when evaluating diarrhea in all CD patients.

Hospitalized CD patients require deep vein thrombosis prophylaxis.

Top-down therapy favored for moderate to severe CD

Anti-TNF therapy effective in delaying or preventing postoperative recurrence in CD

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CROUP (LARYNGOTRACHEOBRONCHITIS)

Ryan Paul B. Urbi, MD Olga L. Nunez, MD Mark T. Nadeau, MD, MBA

BASICS

DESCRIPTION

Croup is a subacute viral illness characterized by upper airway symptoms such as seal-like barking cough, inspiratory stridor, and fever. “Croup” is used to refer to viral laryngotracheitis or laryngotracheobronchitis (LTB). It is sometimes used for LTB with pneumonitis, bacterial tracheitis, or spasmodic croup.

Most common cause of upper airway obstruction or stridor in children Spasmodic croup: noninfectious form with sudden resolution

–No fever or radiographic changes

–Initially treated as croup

–Usually self-limiting and resolves with mist therapy at home

–Often recurs on same night or in 2 to 3 nights

System(s) affected: respiratory

Synonym(s): infectious croup; viral croup

EPIDEMIOLOGY

Predominant age

–Common among children 6 months to 3 years

–Most common during the 2nd year of life

–Rare among those <3 months and >6 years

Predominant sex: male > female (1.5:1)

Timing

–Possible during any time of year but is most common in autumn and winter (with parainfluenza 1 and respiratory syncytial virus [RSV])

Incidence

Six cases per year per 100 children <6 years old 1.5–6% of cases require hospitalization.

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