Cystic fibrosis

Vignette says a 5 year old male child presents to the pediatric clinic by his parents due to recurrent pulmonary infections and failure to thrive; His mother reports that he has had several episodes of pulmonary infections requiring hospitalizations in the past; He also had a history of meconium ileus (intestinal obstruction) shortly after birth, which was treated with surgery; The mother states that the child has difficulty gaining weight, despite having a healthy appetite; On examination, he appears thin with digital clubbing and barrel shaped chest; Lung auscultation reveals bilateral crackles and wheezing; Sputum culture shows staphylococcus aureus; Chest x-ray shows mild hyperinflation; Sweat chloride test shows elevated chloride levels (i.e. > 60 mmol/L on two occasions after administration of pilocarpine); Genetic testing shows mutation in CFTR gene; Diagnosis?

Diagnosis is Cystic fibrosis.

Pathophysiology:- Mutation of CFTR gene on chromosome 7 (ΔF 508; deletion of phenylalanine) which codes for CFTR protein; CFTR gene encodes an cAMP-activated chloride channel that secretes chloride in lungs & GI tract and reabsorbs chloride in sweat glands that results in:-

1. Decreased chloride secretion and consequently increased sodium (via epithelial Na+ channels (ENaC)) and water resorption, causes abnormally thick mucus secretions into lungs and gastrointestinal tract.

2. Increased chloride secretion in sweat glands.

Clinical Features:-

1. GI features include meconium ileus (failure to pass stool in the first 24 hours after birth) in infants with abdominal distention; Pancreatic insufficiency with steatorrhea and vitamin A, D, E, and K malabsorption; Recurrent pancreatitis; Diabetes mellitus; Weight loss; Distal intestinal obstruction; Biliary cirrhosis; Failure to thrive.

2. Pulmonary features include recurrent respiratory infections (e.g. S aureus [infancy and early childhood], P aeruginosa [adulthood], allergic bronchopulmonary aspergillosis [ABPA]), chronic bronchitis and bronchiectasis), productive cough, dyspnea, chest pain, chronic sinusitis, nasal polyps, nail clubbing.

3. Infertility in males (due to congenital bilateral absence of vas deferens).

4. Heat exhaustion.

Diagnosis:-

1. Elevated sweat chloride test (i.e. > 60 mmol/L on two occasions after administration of pilocarpine).

2. Increased immunoreactive trypsinogen (newborn screening) due to clogging of the pancreatic duct.

3. CXR shows bronchiectasis (reticulonodular pattern on chest x-ray), Pneumothorax, Scarring, Atelectasis, Hyperinflation.

4. Sputum cultures often grow Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae.

5. Genetic testing shows mutation in CFTR gene.

6. Spirometry (i.e. pulmonary function test).

Management:-

1. Chest physiotherapy.

2. Antibiotics for infections.

3. Inhaled bronchodilators (e.g. albuterol, salbutamol).

4. Aerosolized dornase alfa (DNase) (mucolytics, breaks down the massive amounts of DNA in respiratory mucus that clogs up the airways); Inhaled hypertonic saline also facilitates mucus clearance; Aerosolized N-acetyl cysteine (mucolytics, breaks disulfide bonds).

5. Pneumococcal and influenza vaccinations. 

6. Pancreatic enzyme replacement therapy for pancreatic insufficiency; Fat soluble vitamins supplemention (e.g. A, D, E and K).

7. Combination of lumacaftor or tezacaftor (corrects misfolded proteins and facilitates their transport to cell surface) with ivacaftor (opens chloride channels which improves chloride transport).

8. Lung transplantation.

Celiac disease

Vignette says a 34 year old female presents to the gastroenterology clinic with the history of chronic diarrhea, bloating, intermittent abdominal pain and unintentional weight loss over the duration of 6 months; She describes her stool as loose, foul smelling and difficult to flush; She also reports fatigue and generalized weakness; She was previously diagnosed iron deficiency anemia and takes iron supplements; She notes a recent onset of pruritic rash with vesicles on her elbows and knees; On physical examination, her BMI is 21 kg/m2; CBC shows microcytic anemia; Iron studies show ↓ferritin, ↑TIBC, ↓serum iron, ↓% saturation; Serology shows positive anti-tTG, anti endomysial and anti deamidated gliadin antibodies; Small bowel biopsy shows villous atrophy, intra epithelial lymphocytes and crypts hyperplasia; D-xylose test shows decreased D-xylose absorption; Diagnosis?

Diagnosis is Celiac disease.

Celiac disease is an autoimmune condition characterized by immune-driven inflammation of the small intestine in response to the ingestion of gluten diet (i.e. Intolerance to gluten diet).

Presents with chronic diarrhea, bloating, abdominal discomfort, dermatitis herpetiformis (pruritic vesicular rash on extensor surfaces), weight loss, vitamin and mineral deficiencies in adults; Associated with HLA-DQ2, HLA-DQ8.

Diagnosis:-

1. CBC shows microcytic anemia (as celiac disease is associated with IDA).

2. Iron studies show ↓ferritin, ↑TIBC, ↓serum iron, ↓% saturation.

3. Serology shows anti-tTG, anti endomysial and anti deamidated gliadin antibodies.

4. Biopsy shows villous atrophy, intra epithelial lymphocytes and crypts hyperplasia.

5. Stool examination with sudan stain detects fat in stools.

6. The D-xylose test is abnormal.

Management:-

1. Gluten free diet; Avoid food containing wheat, barley and rye.

2. Supplementation of vitamins and minerals to address deficiencies.

2. Dapsone is used to treat dermatitis herpetiformis.

Multiple sclerosis

Vignette says a 32 year old female presents to the neurology clinic with intermittent episodes of limb weakness and sensory disturbances in her left leg over the past 18 months; She reports numbness and tingling in her left leg, along with mild weakness for 7 days and her symptoms are particularly worse in hot climate, and after exercise; Over the past few months, she also reports of blurry vision in her right eye, with pain on eye movements and also urinary incontinence; Vital signs are normal; Examination findings show:-
Motor:- Mild weakness with MRC grade of 4/5 in the left leg and 5/5 in the right leg.
Sensory:- Decreased sensation to light touch and vibration in the left leg.
Reflexes:- Hyperreflexia in the left leg with positive Babinski sign on the left leg.
Cranial nerves:- Decreased visual acuity in the right eye with positive relative afferent pupillary defect (RAPD) in the right eye. Fundoscopic examination is normal.
MRI of the brain and spinal cord shows multiple hyperintense lesions (i.e. demyelinating lesions) within the periventricular areas on T2/FLAIR images; CSF analysis shows IgG oligoclonal bands; Visual evoked potential shows delayed latency in the right eye; Diagnosis?

Diagnosis is Multiple sclerosis (i.e. relapsing remitting multiple sclerosis).

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system.

Types:-

1. Relapsing remitting type (MC type)

2. Primary progressive type

3. Secondary progressive type

Presents with fatigue, sensory deficits, motor weakness, autonomic disturbances, cranial nerve deficits, and visual disturbances (e.g. optic neuritis, INO); Higher prevalence in individuals residing in the northern part (due to vitamin D deficiency); Associated with Uhthoff's phenomenon (i.e. symptoms worse in heat), Lhermitte's sign (i.e. radicular pain in legs with neck flexion); Urinary incontinence (i.e. urge incontinence).

Optic neuritis is the first presenting symptom of multiple sclerosis; Presents with vision loss, pain with eye movements, RAPD or Marcus gunn pupil, color vision deficiency and Uhthoff’s phenomenon. Fundoscopy is normal in the acute phase but shows optic disc pallor in the chronic phase.

Diagnosis:-

1. MRI of the brain and spinal cord shows multiple hyperintense lesions (i.e. demyelinating lesions) within the periventricular, juxtacortical and infratentorial areas on T2/FLAIR images i.e. multiple sclerotic plaques (demyelinating lesions) within the periventricular, juxtacortical and infratentorial areas.

2. CSF analysis shows IgG oligoclonal bands.

3. Visual evoked potential tests.

Management:-

1. Acute attacks are managed with high dose corticosteroids (e.g. IV methylprednisolone).

2. Disease-modifying therapies are the mainstay of treatment of relapsing-remitting MS;

Disease modifying drugs are:-

a. Interferon-beta

b. Fingolimod

c. Natalizumab (associated with progressive multifocal leukoencephalopathy due to JC virus reactivation)

d. Glatiramer

e. Rituximab

3. Symptomatic measures are gabapentin for neuropathic pain, baclofen for spasticity, oxybutynin (muscarinic cholinergic antagonist) for urge incontinence, SSRIs for major depression disorder and modafinil for fatigue.

4. Supportive measures are exercise, avoid excessive heat, smoking cessation, and vitamin D supplementation.

Legionella pneumonia

Vignette says a 65 year old male with a history of chronic obstructive pulmonary disease presents to the pulmonology clinic with chief complaints of fever, cough and shortness of breath over the past few days; He also reports of fatigue, malaise, myalgias, headache and diarrhea over the past few days; He had recently completed his cruise ship travel prior to the appearance of above mentioned complaints; Vital signs show blood pressure of 110/70 mm of Hg, pulse rate of 58 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 101.2 F; CBC shows leukocytosis, RFT shows hyponatremia and LFT shows elevated AST & ALT; Urinary legionella antigen test is positive; Chest x-ray shows diffuse infiltrates; Diagnosis?

Diagnosis is Legionella pneumonia.

Presents with fever, cough, shortness of breath, myalgias, headache, and diarrhea; Classically acquired via aerosols.

Risk factors include older age, smoking, chronic lung disease and immunocompromised states.

Etiologies:-
1. Recent travel (e.g. hotels, cruise ships).
2. Exposure to contaminated water sources (air conditioning, hot tubs and fountains).

Diagnosis:-
1. Urine antigen test for the detection of Legionella antigen.
2. Sputum culture with BCYE agar shows Legionella growth.
3. CBC shows leukocytosis, RFT shows hyponatremia and LFT shows elevated AST & ALT.
4. Chest x-ray shows unilateral or bilateral patchy or diffuse infiltrates.

Management:-
1. Outpatient management is azithromycin or respiratory fluoroquinolone (i.e. levofloxacin).
2. Inpatient management is ceftriaxone and azithromycin.

Pseudomembranous colitis

Vignette says a 55 year old female presents to the emergency department with chief complaints of abdominal cramping, watery diarrhea, and a low-grade fever for the past 5 days; She was recently diagnosed with cystitis and was treated with ciprofloxacin; She denies any recent travel or known exposures to contaminated food or water; Abdominal examination is soft, mild tenderness on palpation and hyperactive bowel sounds on auscultation; Vital signs show blood pressure of 120/80 mm of Hg, pulse rate of 108 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 100.2 F; CBC shows WBC count of 12,000 cells/mm3; PCR test for Clostridium difficile toxin A and B are positive; Diagnosis?

Diagnosis is Pseudomembranous colitis.

Pseudomembranous colitis is caused by Clostridium difficile; often secondary to antibiotic use, especially clindamycin, ampicillin/amoxicillin, cephalosporin, fluoroquinolones; These antibiotics alter the normal intestinal flora favoring the growth of the clostridium difficile.

Clostridium difficile produces toxins A and B that damages the enterocytes; Toxin A (enterotoxin) damages the brush border whereas Toxin B (cytotoxin) damages the cytoskeleton.

Presents with fever, abdominal cramping, watery diarrhea, leukocytosis and toxic megacolon.

Diagnosis:- 

1. PCR or antigen detection of one or both toxins in stool; Clostridium difficile produces toxins A and B that damages the enterocytes.

Treatment:-

1. Stop the offending drugs.

2. Supportive measures like intravenous fluids and probiotics.

3. Antibiotics (e.g. oral vancomycin or fidaxomicin).

4. Fecal microbiota transplant in refractory cases. 

5. Monitor for complications such as toxic megacolon, perforation.

Figure:- Antibiotic Associated Diarrhea

Liddle syndrome

Vignettes says a 16 year old male presents to the cardiology clinic with persistent high blood pressure noted during a school health check-up; He has no significant past medical history and no family history of hypertension; He reports occasional muscle cramps and weakness; Vital signs show blood pressure of 160/100 mm of Hg, pulse rate of 78 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 97.9 F; Laboratory studies show serum sodium of 135mEq/L, serum potassium of 2.8 mEq/L, low plasma aldosterone, low plasma renin activity; Genetic testing reveals a mutation in the β-subunit of the epithelial sodium channel (ENaC); USG (A+P) is normal; Diagnosis?

Diagnosis is Liddle syndrome. 

Liddle syndrome is an autosomal dominant disorder due to mutation of epithelial Na+ channels (i.e. ENaC); causes increased absorption of sodium in collecting tubules (due to increased activity of ENaC).

Pathogenesis:- Normally, ENaC are degraded by ubiquitin proteasome pathway; Nedd4-2 (i.e. ubiquitin-protein ligase) binds with ENaC and facilitates its degradation. ENaC is activated by aldosterone via the RAAS pathway (i.e. Aldosterone activates serum and glucocorticoid-regulated kinase (SGK)-1; SGK-1 phosphorylates and inactivates Nedd4-2 that cannot bind with ENaC preventing its degradation). However, in Liddle syndrome mutated epithelial Na+ channels cannot bind with Nedd4-2 preventing its degradation and causing its increased activation.

Presents with hypertension, hypokalemia, and metabolic alkalosis; Laboratory parameters show low plasma aldosterone and low renin activity.

Management:- Epithelial Na+ channel blockers i.e. ENaC blockers (e.g. Amiloride); Amiloride also is useful for lithium-induced nephrogenic diabetes insipidus as it blocks Li+ transport into collecting tubule cells. 

Iron deficiency anemia (IDA)

Vignette says a 35 year old woman presents to her primary care physician with a history of fatigue and generalized weakness over the past 6 months; She also complains of shortness of breath with mild physical exertion; Over the last few weeks, she has also developed cravings for ice and eats ice frequently; She is vegetarian by diet; Additionally, she has been experiencing rectal bleeding for the past several months and describes blood being present on the toilet paper after bowel movements and also on the surface of the stool; She denies any pain during bowel movements but has occasional anal itching and discomfort; She has a history of chronic constipation and has been straining during bowel movements for years; Per rectal examination (PRE) shows external hemorrhoids with mild rectal tenderness; Examination shows pallor in the skin and conjunctiva; There are no signs of lymphadenopathy or hepatosplenomegaly; CBC shows low hemoglobin and low MCV; Iron studies show ↓ferritin, ↑TIBC, ↓serum iron, ↓% saturation; Diagnosis?

Diagnosis is Iron deficiency anemia (IDA).

Iron deficiency anemia is defined as hemoglobin below two standard deviations of the mean for the age and gender of the patient.

Pathogenesis:- ↓iron →↓heme →↓hemoglobin → microcytic anemia

Etiologies are insufficient iron intake, decreased absorption, increased requirement or blood

loss.

Presents with features of anemia (i.e. pallor, fatigue, SOB, palpitations), koilonychia, and

pica; Associated with Plummer vinson triad (i.e. IDA, esophageal webs and dysphagia,

glossitis).

Diagnosis:-

1. CBC shows low hemoglobin, microcytic and hypochromic RBCs with ↑red cell distribution

width and MCV < 80.

2. Iron profiling shows ↓ferritin, ↑TIBC, ↓serum iron, ↓% saturation. ↑Soluble transferrin

receptor (STFR) is elevated in IDA as in IDA there is an increased number of transferrin

receptors as they try to acquire more iron to compensate for deficiency.

3. ↑ Free erythrocyte protoporphyrin.

4. Mentzer index >13 suggests IDA; Mentzer index is MCV/RBC (million/uL).

Management:-

1. Iron supplementation (e.g. oral, intravenous); oral iron (e.g. Ferrous sulfate) is given along

with vitamin C to facilitate iron absorption; Reticulocytes are the first of improvement in iron

deficiency anemia.

2. Treat the underlying cause.

Kawasaki disease

Vignette says a 5 year old female child presents to the emergency department with history of high grade fever and red eyes for 6 days; Examination shows red, cracked tongue, red lips, and a faint maculopapular rash initially on the trunk that has now spread to her limbs; Her palms and soles are red and swollen, and she has enlarged bilateral cervical lymph nodes; Laboratory studies show elevated inflammatory markers (i.e. elevated CRP and ESR); Echocardiography shows coronary artery aneurysms; Diagnosis?

Diagnosis is Kawasaki disease. 

Kawasaki disease (aka mucocutaneous lymph node syndrome) is an acute, self-limited medium vessel vasculitis of an unknown etiology commonly affecting children.

Fever for at least 5 days with any 4 out of the 5 “CRASH” features.
Conjunctivitis
Rash (polymorphous, non vesicular on trunk and extremities)
Adenopathy (i.e. bilateral non-suppurative cervical lymphadenopathy)
Strawberry tongue
Hands/Feet edema and erythema 

Diagnosis:-
1. CBC shows leukocytosis.
2. Inflammatory markers (e.g. CRP, ESR) are elevated.
3. Echocardiography shows coronary artery aneurysms.

Treatment:- Aspirin + IVIG is the mainstay of treatment and should be initiated within the first 10 days of fever onset; IVIG is given at 2 g/kg in a single infusion and high dose aspirin is given at 80–100 mg/kg/day during the acute phase of the disease; The dose is gradually reduced to 3–5 mg/kg/day when the patient has been afebrile for over 48-72 hours.

Complication:- Coronary artery aneurysms and Myocardial infarction.

Atrial fibrillation

Vignette says a 55 year old female presents to the emergency department with a sudden onset of palpitations that started 30 minutes ago; She describes the sensation as her "heart racing" and feels lightheaded and dizziness but denies chest pain, shortness of breath or syncope; She states that she had similar episodes in the past that resolved spontaneously; She has a history of coronary artery disease; Vital signs show pulse rate of 180 beats/min, blood pressure of 110/70 mm of Hg, respiratory rate of 16 breaths/min, oxygen saturation of 96% in RA and temperature of 98.2 F; Laboratory studies show CBC, serum electrolytes, BMP, TSH and HbA1C within normal limits; ECG shows absent P waves, irregularly irregular rhythm (i.e. irregular R-R interval) and narrow QRS complexes; Transesophageal echocardiography shows thrombus in the left atrium; Diagnosis?

Diagnosis is Atrial fibrillation. 

Atrial fibrillation

Types:- 
1. Paroxysmal AFib:- Episodes of AFib shorter than 7 days, either self terminated or cardioverted (usually self terminated within 48 hours, often triggered in pulmonary veins). 

2. Persistent AFib:- Episodes of AFib longer than 7 days, either self terminated or cardioverted. 
3. Long standing persistent AFib:- AFib lasting more than 1 year and rhythm control strategy is being adopted. 
4. Permanent AFib:- Episodes of AFib where no more rhythm strategy is adopted (i.e. as the rhythm is unresponsive). 

Presents with palpitations, SOB, syncope, and features of underlying conditions (e.g. stroke, sepsis, thyrotoxicosis). 

Causes:- 
1. Ischemic heart disease 
2. HTN 
3. Thyrotoxicosis 
4. Mitral stenosis or mitral regurgitation 
5. Alcohol 
6. OSA 

Diagnosis:- 
1. ECG shows absent P waves, irregularly irregular rhythm (i.e. irregular R-R interval), narrow QRS complex and tachycardia. 
2. Echocardiography (TEE or TTE) is done prior to cardioversion to prevent embolic stroke. 
3. Cardiac Monitor
4. EPS

Management:- 
1. Rate control:- Beta blockers (e.g. metoprolol, carvedilol, atenolol), non-dihydropyridine CCBs (e.g. verapamil, diltiazem) and Digoxin (in patients with CHF).
2. Rhythm control:- Pharmacological cardioversion (e.g. ibutilide, amiodarone, flecainide) or electrical cardioversion (DC 200J biphasic); It helps to return to sinus rhythm; Immediate cardioversion is deployed if the AFib has been present for less than 48 hours or the patient are hemodynamically unstable whereas delayed cardioversion is deployed if the AFib has been present for more than 48 hours and the patient are hemodynamically stable. 

What are the options for cardioversion for new-onset atrial fibrillation or atrial fibrillation of uncertain duration? 
· TEE prior to cardioversion while on effective anticoagulation with at least 4 weeks of therapeutic anticoagulation to follow (continue indefinitely if suggested by stroke risk).
· Alternatively, may therapeutically anticoagulate for at least 3 weeks prior to cardioversion and continue for at least 4 weeks afterwards, in lieu of TEE.

3. Anticoagulation:- Warfarin, DOACs (e.g. apixaban, rivaroxaban); CHA2DS2VASc is a clinical tool for prescribing anticoagulants in patients with nonvalvular atrial fibrillation; Congestive heart failure (1), Hypertension (1), Age ≥75 years (2), Diabetes (1), Stroke/TIA (2), Vascular disease e.g. previous myocardial infarction or peripheral arterial disease (1), Age 65-74 years (1), Sex category female (1). In non-valvular AFib, warfarin or Novel oral anticoagulants (NOACs) is indicated when CHA2DS2-VASc score ≥2 in men and ≥3 in women and should be considered CHA2DS2-VASc score >1 and >2 in men and women respectively. In valvular AFib, warfarin should be considered and targeted INR should be 2-3. 

4. Percutaneous ablation of pulmonary veins (i.e. pulmonary vein isolation) is first line for symptomatic paroxysmal atrial fibrillation. Catheter ablation for atrial fibrillation in patients with heart failure was associated with a significantly lower rate of a composite end point of death from any cause or hospitalization for worsening heart failure than was medical therapy (i.e. CASTLE-HTx TRIAL).

5. Percutaneous left atrial appendage occlusion (if patients are contraindicated for long term anticoagulation therapy) i.e. Watchman, Watchman-FLX and Amlet devices. Percutaneous left atrial appendage occlusion is recommended in AF patients with a risk of stroke who have contraindications to long term anticoagulation. For high bleeding risk (HAS-BLED is greater than or equal to 3 if DOAC contraindicated.

6. Surgical ablation in patients with concomitant plan for cardiac surgery (e.g.maze procedure).
HAS-BLED score monitors a patient’s risk of major bleeding whilst on anticoagulation (i.e. Bleeding risk associated with anticoagulation); H - Hypertension, A - Abnormal renal and liver function, S - Stroke, B - Bleeding, L - Labile INRs (whilst on warfarin), E - Elderly, D - Drugs or alcohol; HAS-BLED score ≥ 3 (indicates high risk of bleeding).

Figure:- Management Guidelines of Atrial Fibrillation