Sandbox: HS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Differential diagnosis

Abbreviations: AP= Anteroposterior, CXR= Chest X-ray, CT= Computed tomography, ABG= Arterial blood gas, V/Q= Ventilation/perfusion scan , EKG= Electrocardiogram, COPD= Chronic obstructive pulmonary disease, BNP= Brain natriuretic peptide, DVT= Deep vein thrombosis, HRCT= High Resolution CT, IgE= Immunoglobulin E

Causes of cyanosis Disease Cyanosis Clinical manifestations/association Diagnosis Additional findings Symptoms Signs Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Respiratory Airway disorder Severe croup ✔ − ✔ ✔ − − − Audible stridor at rest Lymphocytosis AP Neck X ray for soft tissues: Steeple sign Lateral neck X ray: Distended hypopharynx during inspiration Croupy cough and stridor Intercostal, subcostal retractions Epiglottitis ✔ − ✔ ✔ − − − Stridor Leukocytosis with neutrophilia Blood cultures Throat culture in intubated patients Lateral neck X ray Thumbprint sign (swollen epiglottis) Laryngoscopy Sore Throat Dysphagia Odynophagia Muffled voice Drooling Foreign body aspiration ✔ − ✔ ✔ ✔ − − Decreased breath sounds Wheezing ABGs CXR Hyperinflation (children) Atelectasis (adults) Objects CT scan Foreign body Entrapment with edema or granulation tissue Bronchoscopy Complications: Inflammation Mediastinitis Local emphysema Atelectasis Cyanosis Bacterial tracheitis ✔ − ✔ ✔ ✔ − − Inspiratory stridor Blood cultures Gram stain Lateral neck X ray Confusing Steeple sign Irregular tracheal margin Laryngotracheo-bronchoscopy Brassy cough Retractions No drooling Hoarseness Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Parenchymal disorder Pneumonia − ✔ ✔ ✔ ✔ ✔ − Reduced breath sounds Rales, crackles, wheeze Pleural friction rub ABGs Leukocytosis Pancytopenia Hyponatremia CXR CT chest Bronchoscopy Sputum culture and gram stain Blood cultures Urine antigen Tachycardia Bradycardia (Legionella) CURB-65 Asthma (Late) − ✔ ✔ − ✔ ✔ in interstitial lung disease − End expiratory wheeze Absent wheeze and breath sounds in severe form ABG Eosinophilia IgE CXR to rule out other diagnosis complications like pneumonia, atelactasis HRCT Allergic bronchopulmonary aspergillosis Bronchiectasis Reversible obstructive disease Peak expiratory flow measurement is easy and very helpful GERD is a cause in case of refractory asthma. Triad of asthma, nasal polyps and rash is indicative of aspirin sensitivity. Cystic fibrosis ✔ − ✔ when infected ✔ ✔ − Wheeze or crackles Sputum stain and culture Sweat test Genetic test for CFTR (gene) CXR Hyperinflation Peribronchial thickening Nodules Bronchiectasis HRCT for detecting lung changes Sweat test Usually present since birth Recurrent pneumonia Recurrent wheezing Recurrent sinusitis Gastrointestinal manifestations Meconium ileus Pancreatic insufficiency COPD (Severe emphysema) ✔ − ✔ − ✔ − ✔ Reduced breath sounds Prolonged expiration Wheeze Inspiratory crackles Hematocrit ABG Sputum staining and culture Alpha 1-antitrypsin test CXR Elongated heart Flattening of diaphragms Prominent hilar vasculature HRCT Bullae HRCT Pulmonary hypertension Right heart failure Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Pulmonary vascular disorders Massive pulmonary embolism ✔ − ✔ ✔ ✔ − ✔ Reduced breath sounds Rales, crackles Loud P2 ABGs D-dimer EKG BNP CXR V/Q scan Spiral CT pulmonary angiogram Venous ultrasound for DVT Spiral CT pulmonary angiogram Tachycardia Shock Pulmonary hypertension can occur Pulmonary arterio-venous malformation − ✔ ✔ − ✔ ✔ − Pulmonary bruit CBC ABG CXR Round/oval mass lobulated well defined Connecting vessel in hilum Hemothorax Pulmonary angiography Contrast echocardiography Classic triad of dyspnea on exertion, cyanosis and clubbing Cerebral arteriovenous malformation Pregnancy can increase the size Chest wall disorders Flail chest − ✔ − − − Cardiovascular Pneumothorax ✔ − ✔ − ✔ − − Decreased breath sounds Wheezing Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Atrioventricular canal defect ✔ + ± + CBC EKG Pulse oximetry CXR (Cardiac enlargement, Increased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Ebstein anomaly ✔ + ± + CBC EKG Pulse oximetry CXR (Cardiac enlargement, decreased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Tetralogy of Fallot ✔ + ± + (systolic) CBC EKG Pulse oximetry CXR (Boot shaped heart, decreased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Pulmonic stenosis ✔ + ± + (systolic) CBC EKG Pulse oximetry CXR (Cardiac enlargement, decreased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Total anomalous pulmonary venous connection ✔ + ± + (Systolic) CBC EKG Pulse oximetry CXR (normal heart size and venous congestion but in patients without obstruction have cardiomegaly and increased pulmonary blood flow.) Echocardiography MRI Cardiac catheterization Echocardiography Transposition of the great vessels ✔ + ± - CBC EKG Pulse oximetry CXR (Cardiac enlargement, increased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Truncus arteriosus ✔ + ± sys/±dias CBC EKG Pulse oximetry CXR (Cardiac enlargement, increased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Heart failure ✔ ✔ + + + + (S3) CBC Complete metabolic profile Cardiac enzymes BNP Thyroid profile Renal function tests EKG Exercise stress test ABG's Lipid profile CXR Increase in heart size compared to the old film. Pleural fluid Interstitial edema Echocardiography Angiography Cardiac MRI Nuclear imaging Echocardiography Endomyocardial biopsy can be used when a specific diagnosis is suspected that would influence therapy in heart failure patients. Valvular heart disease ✔ ✔ ± − + + CBC Complete metabolic profile Cardiac enzymes BNP Thyroid profile Renal function tests EKG CXR To assess pulomary congestion or other lung pathology. Echocardiography Doppler echocardiography Angiography To assess the need for concomitant coronary artery bypass surgery in elderly people. Echocardiography Myocardial infarction ✔ ✔ − + + + [[CBC [[Complete metabolic profile [[Cardiac enzymes BNP Thyroid profile Renal function tests EKG Lipid profile CXR Normal or may show signs of CHF Echocardiography Angiography Central Nervous system Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Methemoglobinemia ✔ + + + CBC Peripheral smear Complete metabolic profile Hemoglobin electrophoresis Serum nitrite levels Pulse oximetry ABG's Drug screen LDH CXR EKG Family history of methemoglobinemia or glucose-6-phosphate dehydrogenase (G6PD) deficiency is important to determine. Polycythemia ✔ + + CBC Raised all cell lines in primary and only raised erythrocytes in secondary polycythemia Pulse oximetry Erythropoietin levels (EPO) Ferritin levels ABG's Increased leukocyte alkaline phosphatase B12 levels JAK 2 mutation CXR EKG Tenderness in the sternum may indicate transformation to acute myeloid leukemia and should be properly investigated. Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Breath holding spells ✔ No confirmatory study CBC Serum ferritin Blood lead level video-EEG monitoring can be use in non diagnostic cases. Cyanotic breath-holding spells most commonly occur around 1 year of age with a range of six months to four years. Iron deficiency anemia is more prevalent in children with breath-holding spells.  Miscellaneous Shock ✔ + + (septic shock) + + (Cardiogenic shock) Complete metabolic profile CBC Cardiac enzymes ABG's Lactate BNP Renal function tests Coagulation studies and D-dimer level Echocardiography Chest radiography Angiography Smoke inhalation + + +  CBC Electrolytes BUN and CR, Lactate levels Toxicology screen CO-oximetry  CXR ECG Serial cardiac enzymes (in patients with chest pain)\ Pulmonary function testing Direct laryngoscopy and fiberoptic bronchoscopy CO toxicity should be suspected in any patient who presents following smoke inhalation unless co-oximetry shows normal carboxyhemoglobin. Cold exposure ✔ − − − − − − Fingerstick glucose (Hyperglycemia) Electrocardiogram (ECG) may show J wave, sinus bradycardia and prolongation of all ECG intervals. Serum electrolytes (including potassium and calcium) BUN and creatinine Serum hemoglobin, white blood cell, and platelet counts ( Raised HCT due to volume contraction) Coagulation profile acidosis) Creatine kinase (Rhabdomylosis) Arterial blood gas CXR Mild hypothermia: core temperature 32 to 35°C ; patient presents with confusion, tachycardia, and increased shivering. Moderate hypothermia: 28 to 32°C patient presents with lethargy, bradycardia and arrhythmia and decreased shivering. Severe hypothermia: below 28°C patient presents with coma, hypotension, arrhythmia, pulmonary edema, and rigidity.

Causes of cyanosis Cyanosis Clinical manifestations/association Diagnosis Additional findings Symptoms Signs Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Respiratory Airway disorder Severe croup ✔ − ✔ ✔ − − − Audible stridor at rest Lymphocytosis AP Neck X ray for soft tissues: Steeple sign Lateral neck X ray: Distended hypopharynx during inspiration Clinical diagnosis Croupy cough and stridor Intercostal, subcostal retractions Epiglottitis ✔ − ✔ ✔ − − − Stridor Leukocytosis with neutrophilia Blood cultures Throat culture in intubated patients Lateral neck X ray Thumbprint sign (swollen epiglottis) Laryngoscopy Sore Throat Dysphagia Odynophagia Muffled voice Drooling Coma ✔ Seizures ✔ Head trauma ✔ Breath holding spells ✔ Miscellaneous Shock ✔ Smoke inhalation ✔ + + + Cold exposure ✔ − − − − − − − CBC Fingerstick glucose (Hyperglycemia) EKG- J wave Sinus bradycardia Prolongation of all ECG intervals. Serum electrolytes -K+ and calcium BUN and creatinine PT, PTT S. lactate ABG Mild hypothermia: core temperature 32 to 35°C ; Confusion Tachycardia Increased shivering. Moderate hypothermia: 28 to 32°C Lethargy Bradycardia Arrhythmia Decreased shivering. Severe hypothermia: <28°C Coma Hypotension Arrhythmia Pulmonary edema Rigidity Drugs† − − − − −

Differential diagnosis

Abbreviations: AP= Anteroposterior, CXR= Chest X-ray, CT= Computed tomography, ABG= Arterial blood gas, V/Q= Ventilation/perfusion scan , EKG= Electrocardiogram, COPD= Chronic obstructive pulmonary disease, BNP= Brain natriuretic peptide, DVT= Deep vein thrombosis, HRCT= High Resolution CT, IgE= Immunoglobulin E

Causes of cyanosis Disease Cyanosis Clinical manifestations/association Diagnosis Additional findings Symptoms Signs Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Respiratory Airway disorder Severe croup ✔ − ✔ ✔ − − − Audible stridor at rest Lymphocytosis AP Neck X ray for soft tissues: Steeple sign Lateral neck X ray: Distended hypopharynx during inspiration Croupy cough and stridor Intercostal, subcostal retractions Epiglottitis ✔ − ✔ ✔ − − − Stridor Leukocytosis with neutrophilia Blood cultures Throat culture in intubated patients Lateral neck X ray Thumbprint sign (swollen epiglottis) Laryngoscopy Sore Throat Dysphagia Odynophagia Muffled voice Drooling Foreign body aspiration ✔ − ✔ ✔ ✔ − − Decreased breath sounds Wheezing ABGs CXR Hyperinflation (children) Atelectasis (adults) Objects CT scan Foreign body Entrapment with edema or granulation tissue Bronchoscopy Complications: Inflammation Mediastinitis Local emphysema Atelectasis Cyanosis Bacterial tracheitis ✔ − ✔ ✔ ✔ − − Inspiratory stridor Blood cultures Gram stain Lateral neck X ray Confusing Steeple sign Irregular tracheal margin Laryngotracheo-bronchoscopy Brassy cough Retractions No drooling Hoarseness Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Parenchymal disorder Pneumonia − ✔ ✔ ✔ ✔ ✔ − Reduced breath sounds Rales, crackles, wheeze Pleural friction rub ABGs Leukocytosis Pancytopenia Hyponatremia CXR CT chest Bronchoscopy Sputum culture and gram stain Blood cultures Urine antigen Tachycardia Bradycardia (Legionella) CURB-65 Asthma (Late) − ✔ ✔ − ✔ ✔ in interstitial lung disease − End expiratory wheeze Absent wheeze and breath sounds in severe form ABG Eosinophilia IgE CXR to rule out other diagnosis complications like pneumonia, atelactasis HRCT Allergic bronchopulmonary aspergillosis Bronchiectasis Reversible obstructive disease Peak expiratory flow measurement is easy and very helpful GERD is a cause in case of refractory asthma. Triad of asthma, nasal polyps and rash is indicative of aspirin sensitivity. Cystic fibrosis ✔ − ✔ when infected ✔ ✔ − Wheeze or crackles Sputum stain and culture Sweat test Genetic test for CFTR (gene) CXR Hyperinflation Peribronchial thickening Nodules Bronchiectasis HRCT for detecting lung changes Sweat test Usually present since birth Recurrent pneumonia Recurrent wheezing Recurrent sinusitis Gastrointestinal manifestations Meconium ileus Pancreatic insufficiency COPD (Severe emphysema) ✔ − ✔ − ✔ − ✔ Reduced breath sounds Prolonged expiration Wheeze Inspiratory crackles Hematocrit ABG Sputum staining and culture Alpha 1-antitrypsin test CXR Elongated heart Flattening of diaphragms Prominent hilar vasculature HRCT Bullae HRCT Pulmonary hypertension Right heart failure Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Pulmonary vascular disorders Massive pulmonary embolism ✔ − ✔ ✔ ✔ − ✔ Reduced breath sounds Rales, crackles Loud P2 ABGs D-dimer EKG BNP CXR V/Q scan Spiral CT pulmonary angiogram Venous ultrasound for DVT Spiral CT pulmonary angiogram Tachycardia Shock Pulmonary hypertension can occur Pulmonary arterio-venous malformation − ✔ ✔ − ✔ ✔ − Pulmonary bruit CBC ABG CXR Round/oval mass lobulated well defined Connecting vessel in hilum Hemothorax Pulmonary angiography Contrast echocardiography Classic triad of dyspnea on exertion, cyanosis and clubbing Cerebral arteriovenous malformation Pregnancy can increase the size Chest wall disorders Flail chest − ✔ − − − Cardiovascular Pneumothorax ✔ − ✔ − ✔ − − Decreased breath sounds Wheezing Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Atrioventricular canal defect ✔ + ± + CBC EKG Pulse oximetry CXR (Cardiac enlargement, Increased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Ebstein anomaly ✔ + ± + CBC EKG Pulse oximetry CXR (Cardiac enlargement, decreased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Tetralogy of Fallot ✔ + ± + (systolic) CBC EKG Pulse oximetry CXR (Boot shaped heart, decreased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Pulmonic stenosis ✔ + ± + (systolic) CBC EKG Pulse oximetry CXR (Cardiac enlargement, decreased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Total anomalous pulmonary venous connection ✔ + ± + (Systolic) CBC EKG Pulse oximetry CXR (normal heart size and venous congestion but in patients without obstruction have cardiomegaly and increased pulmonary blood flow.) Echocardiography MRI Cardiac catheterization Echocardiography Transposition of the great vessels ✔ + ± - CBC EKG Pulse oximetry CXR (Cardiac enlargement, increased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Truncus arteriosus ✔ + ± sys/±dias CBC EKG Pulse oximetry CXR (Cardiac enlargement, increased pulmonary vascular markings) Echocardiography MRI Cardiac catheterization Echocardiography Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Heart failure ✔ ✔ + + + + (S3) CBC Complete metabolic profile Cardiac enzymes BNP Thyroid profile Renal function tests EKG Exercise stress test ABG's Lipid profile CXR Increase in heart size compared to the old film. Pleural fluid Interstitial edema Echocardiography Angiography Cardiac MRI Nuclear imaging Echocardiography Endomyocardial biopsy can be used when a specific diagnosis is suspected that would influence therapy in heart failure patients. Valvular heart disease ✔ ✔ ± − + + CBC Complete metabolic profile Cardiac enzymes BNP Thyroid profile Renal function tests EKG CXR To assess pulomary congestion or other lung pathology. Echocardiography Doppler echocardiography Angiography To assess the need for concomitant coronary artery bypass surgery in elderly people. Echocardiography Myocardial infarction ✔ ✔ − + + + [[CBC [[Complete metabolic profile [[Cardiac enzymes BNP Thyroid profile Renal function tests EKG Lipid profile CXR Normal or may show signs of CHF Echocardiography Angiography Central Nervous system Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Methemoglobinemia ✔ + + + CBC Peripheral smear Complete metabolic profile Hemoglobin electrophoresis Serum nitrite levels Pulse oximetry ABG's Drug screen LDH CXR EKG Family history of methemoglobinemia or glucose-6-phosphate dehydrogenase (G6PD) deficiency is important to determine. Polycythemia ✔ + + CBC Raised all cell lines in primary and only raised erythrocytes in secondary polycythemia Pulse oximetry Erythropoietin levels (EPO) Ferritin levels ABG's Increased leukocyte alkaline phosphatase B12 levels JAK 2 mutation CXR EKG Tenderness in the sternum may indicate transformation to acute myeloid leukemia and should be properly investigated. Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Breath holding spells ✔ No confirmatory study CBC Serum ferritin Blood lead level video-EEG monitoring can be use in non diagnostic cases. Cyanotic breath-holding spells most commonly occur around 1 year of age with a range of six months to four years. Iron deficiency anemia is more prevalent in children with breath-holding spells.  Miscellaneous Shock ✔ + + (septic shock) + + (Cardiogenic shock) Complete metabolic profile CBC Cardiac enzymes ABG's Lactate BNP Renal function tests Coagulation studies and D-dimer level Echocardiography Chest radiography Angiography Smoke inhalation + + +  CBC Electrolytes BUN and CR, Lactate levels Toxicology screen CO-oximetry  CXR ECG Serial cardiac enzymes (in patients with chest pain)\ Pulmonary function testing Direct laryngoscopy and fiberoptic bronchoscopy CO toxicity should be suspected in any patient who presents following smoke inhalation unless co-oximetry shows normal carboxyhemoglobin. Cold exposure ✔ − − − − − − Fingerstick glucose (Hyperglycemia) Electrocardiogram (ECG) may show J wave, sinus bradycardia and prolongation of all ECG intervals. Serum electrolytes (including potassium and calcium) BUN and creatinine Serum hemoglobin, white blood cell, and platelet counts ( Raised HCT due to volume contraction) Coagulation profile acidosis) Creatine kinase (Rhabdomylosis) Arterial blood gas CXR Mild hypothermia: core temperature 32 to 35°C ; patient presents with confusion, tachycardia, and increased shivering. Moderate hypothermia: 28 to 32°C patient presents with lethargy, bradycardia and arrhythmia and decreased shivering. Severe hypothermia: below 28°C patient presents with coma, hypotension, arrhythmia, pulmonary edema, and rigidity.

Causes of cyanosis Cyanosis Clinical manifestations/association Diagnosis Additional findings Symptoms Signs Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Respiratory Airway disorder Severe croup ✔ − ✔ ✔ − − − Audible stridor at rest Lymphocytosis AP Neck X ray for soft tissues: Steeple sign Lateral neck X ray: Distended hypopharynx during inspiration Clinical diagnosis Croupy cough and stridor Intercostal, subcostal retractions Epiglottitis ✔ − ✔ ✔ − − − Stridor Leukocytosis with neutrophilia Blood cultures Throat culture in intubated patients Lateral neck X ray Thumbprint sign (swollen epiglottis) Laryngoscopy Sore Throat Dysphagia Odynophagia Muffled voice Drooling Coma ✔ Seizures ✔ Head trauma ✔ Breath holding spells ✔ Miscellaneous Shock ✔ Smoke inhalation ✔ + + + Cold exposure ✔ − − − − − − − CBC Fingerstick glucose (Hyperglycemia) EKG- J wave Sinus bradycardia Prolongation of all ECG intervals. Serum electrolytes -K+ and calcium BUN and creatinine PT, PTT S. lactate ABG Mild hypothermia: core temperature 32 to 35°C ; Confusion Tachycardia Increased shivering. Moderate hypothermia: 28 to 32°C Lethargy Bradycardia Arrhythmia Decreased shivering. Severe hypothermia: <28°C Coma Hypotension Arrhythmia Pulmonary edema Rigidity Drugs† − − − − −